https://academic.oup.com/article/61101601355277,”Canadian Association of Gastroenterology Position Statement: Use of Cannabis in Gastroenterological and Hepatic DisordersAugmented Introduction: The article presents a position statement by the Canadian Association of Gastroenterology (CAG) regarding the use of cannabis for gastroenterological and hepatic disorders. This statement comes in response to increased interest in, and use of, cannabis for managing such disorders. Acknowledging the current hazy understanding of cannabis’ potential benefits and harm, CAG underscores the need for rigorous evidence-based guidelines.Potential Benefits of Cannabis Use:The position statement acknowledges that cannabinoids (such as THC and CBD) might impact the endocannabinoid system (ECS), which in turn regulates bowel functions and inflammation. Studies suggest cannabis can offer symptomatic relief for certain disorders – such as chronic abdominal pain, fibrosis in Hepatitis C, and increased appetite in HIVAIDS patients. Possible Risks Involved:However, the use of cannabis is not without potential risks. These include cannabis dependency, mental health disorders, impaired lung function (with smoked cannabis), and risks related to contaminants when consuming unregulated cannabis products. The statement also mentions concerns regarding the potential carcinogenic effects on the human digestive tract due to cannabis use. Recommendations from CAG:Owing to these mixed effects, the CAG proposes doctors remain prudent when it comes to recommending cannabis for gastroenterological disorders. It advises against prescribing cannabis for disorders like inflammatory bowel disease, irritable bowel syndrome, or chronic pancreatitis until solid scientific evidence backs up such usage. The statement encourages robust research, better medicinal product development, and clear healthcare policies to delineate the risks and rewards of therapeutic cannabis use.In Conclusion:The article culminates in a position statement, reinforcing the paramount need for well-chaired research into cannabis’s clinical effectiveness and safety. It equally highlights regulatory ambiguities, suggesting that the adoption of cannabis into mainstream medicinal practice remain cautious until unequivocal evidence is available.”
https://academic.oup.com/article/,”Marijuana Use and Lung Cancer: Results of a Case-Control StudyAugmented Introduction:The article titled “”Marijuana Use and Lung Cancer: Results of a Case-Control Study”” is a comprehensive exploration of the potential link between marijuana consumption and lung cancer risks. This retrospective case-control study uniquely brings attention to the paucity of longitudinal studies scrutinizing this relevant public health issue, surfacing the need for direct evidence of marijuana use’s relationship with lung cancer.LCDP Project & Methodology:The Los Angeles County Lung Cancer Study (LCDP) forms the basis of this article. The study employed a stratified analysis, adjusting for possible confounders and stratifying by age, sex, and neighborhood. Between 1999 and 2003, 1,212 lung cancer cases were examined, alongside 1,040 healthy controls. The goal was to determine if marijuana usage could influence lung carcinogenesis after accounting for tobacco use.Primary Findings:According to the findings, marijuana consumption did not demonstrate a substantial association with lung cancer risk. The study did not observe elevated odds ratios for marijuana smokers, even amongst long-term or heavy marijuana users, after adjusting for tobacco use and other possible confounders. Contrarily, tobacco smokers were found to have increased risks for lung cancer.Interpretation & Future Directions:The study findings question the long-standing hypothesis that marijuana use significantly contributes to lung cancer, presenting a contradiction to the risks associated with tobacco smoking. The authors, however, stress the need for further detailed (and larger scaled) research on this topic, considering the potential under-reporting of marijuana use due to its legal status during the study period.In Conclusion:Despite society’s typical ascription of marijuana with adverse health outcomes akin to tobacco, this particular study introduces a dissimilar perspective. It suggests that unlike tobacco smoking, marijuana use does not appear to upsurge the risk of lung cancer. Nevertheless, this finding underscores the urgent necessity for more expansive, rigorous research to validate these results and to better understand the complex relationship between marijuana use and lung health.”
https://academic.oup.com/cid/article/,”The Endocannabinoid System as an Emerging Target of Pharmacotherapy for Sleep Disturbance Augmented Introduction:In the primary overview, the article delves into the prominent role played by the endocannabinoid system (ECS) in regulating sleep patterns and its potential exploitation in the development of pharmacotherapies to counter sleep disturbances. Essentially, the ECS – a bio-system comprising unique receptors named CB1 and CB2, along with synthesized cannabinoids or endocannabinoids, and corresponding metabolic enzymes – constitutes an integral role in sustaining the internal balance, or homeostasis, within organisms.ECS Details:This intricate bodily system is demonstrably influential in the systematization of sleep-wake cycles. Notably, endocannabinoids such as anandamide and 2-arachidonoylglycerol are synthesized as and when needed, acting as biological signaling molecules throughout the nervous system. The central nervous system is chiefly populated by CB1 receptors, which are often linked to the psychoactive effects that accompany cannabinoid use. Conversely, CB2 receptors primarily reside within immune cells and peripheral tissues, implicating their role in pain and inflammatory responses.Sleep and ECS Association:Scientific literature indicates that the ECS partakes significantly in sleep modulation. As per research, cannabinoid receptors are densely populated within critical brain areas, such as the hypothalamus, involved in the regulation of sleep. CB1 receptor activation seems to promote sleep, suggesting an intricate correlation. Moreover, during the sleep phase, the level of certain endocannabinoids like anandamide sees an increase, reinforcing their possible role in sleep-wake cycle modulation.Clinical Implications:This article investigates the potentially therapeutic uses of cannabinoids, including delta-9-tetrahydrocannabinol (THC) – the primary psychoactive substance in Cannabis, and agonists that amplify cannabinoid effects for the treatment of sleep disorders. Clinical studies have revealed the effectiveness of cannabinoids for treating insomnia and sleep apnea. Some research has claimed that THC can augment total sleep time and increase sleep efficiency.Challenges and Future Pathways:Potential side effects such as dependency, memory impairment, and certain psychoactive effects can create hurdles while using cannabinoids for sleep therapy. Legalities and stringent regulatory measures also present significant barriers to the widespread use of cannabinoids in the treatment of sleep disorders. The authors of the article fervently emphasize the urgency of further research to understand the ECS’s role in sleep regulation better, identify effective cannabinoid compounds, and pinpoint safe dosages and methods of administration.In Conclusion:The article fosters the idea that the ECS is a promising pharmacotherapeutic target that could revolutionize the treatment of sleep disturbances. The field extends the possibility for the development of innovative sleep medications, touch-basing the importance of potential side effect identification, thorough research, and regulatory adherence.”
https://academic.oup.com/article/393495245391,”Effects of Acute Systemic Administration of Cannabidiol on Sleep-Wake Cycle in Rats:Expanded Introduction:The research explicates a comprehensive study analyzing the systemic administration of cannabidiol (CBD), a primary component of the cannabis plant, and its impact on the sleep-wake cycle in rats. As a professor of medicinal cannabis, I can concur that the exploration of cannabidiol⿿s properties and possible implications has been the nucleus of numerous studies on cannabinoids, given CBD’s non-psychoactive characteristics and substantial therapeutic potential. CBD Details:Cannabidiol diverges significantly from delta-9-tetrahydrocannabinol (THC), the latter being most known for its mind-altering properties associated with cannabis. Unlike THC, CBD does not manifest the typical inebriating effect of cannabis, offering instead the possibility of drug-based medical interventions without psychoactive, mind-altering repercussions.Sleep and CBD Connection:The research conducted on rats demonstrates a solid correlation between cannabidiol administration and sleep pattern modifications. It has been observed that CBD appears to increase wakefulness and ecrease the onset of REM sleep phase, especially at higher doses. Conversely, at lower doses, no evident alteration to the sleep-wake cycle has been reported. However, the study divulges that extreme sleepiness or sleep-inducing effects, commonly associated with CBD, were not perceived in the trial. Clinical Implications:This paper, in essence, emphasizes CBD’s potential as a valuable pharmacological agent, specifically aiming towards treating sleep disorders and promoting wakefulness without invoking any psychoactive side-effects or potential for dependence, unlike traditional pharmaceutical sleep aids or THC-dominant cannabis strains.Challenges and Future Perspectives:It is critical to understand that the findings of this research are preliminary and based on an animal model. Consequently, rigorous studies investigating the accuracy and applicability of the discoveries in a human model are prerequisites to approve the therapeutic use of CBD for sleep disorders.In Conclusion:Unraveling the depths of CBD’s potential as an operative agent in treating sleep disturbances is at the core of this research. The results of this study spotlight a plausible path for harnessing CBD’s properties to manage sleep disorders efficiently and safely, further strengthening the foundational understanding of the therapeutic future of cannabinoids such as CBD.”
https://academic.oup.com/article/2534275144402,”The Role of Cannabis in the Management of Inflammatory Bowel Disease: A Review of Clinical, Scientific, and Regulatory Information Augmented Introduction: The academic study meticulously addresses the use of cannabis for managing Inflammatory Bowel Disease (IBD), handling the topic from a clinical, scientific, and regulatory perspective. It investigates the potential of such treatment, considering mounting interest from patients and providers, complementing evolving research. The review also emphasizes the necessity for better acceptance and understanding of the science and legalities surrounding cannabis use in medicine.Clinical and Scientific Evidence of Use:The authors delve into a series of clinical trials and observational studies that testify to the promising benefits of cannabis for IBD patients. Key discussions involve how patients resort to cannabis for symptoms like abdominal pain, diarrhea, and a reduced appetite, often achieving substantial symptomatic relief. Both THC and cannabidiol (CBD), key chemical compounds in cannabis, have spotlighted their anti-inflammatory properties and can potentially induce remission in patients with IBD.The complexity of the cannabis response is attributed to the Endocannabinoid System (ECS), which plays vital roles in gut health and homeostasis. Interaction with the ECS can influence inflammation and gut motility, underscoring the potential effectiveness of cannabis in treating IBD symptoms. rulatory Challenges:While the medicinal potential of cannabis is gaining recognition, global cannabis laws remain a contentious subject. The paper details the regulatory framework around cannabis, highlighting the significant inconsistencies between state, federal, and international laws. These inconsistencies often hinder comprehensive research, patient access, and risk remediation efforts.Further Research Recommended:Despite promising evidence, the review maintains that further research is required to substantiate the proclaimed benefits of cannabis for IBD while considering the potential risks. Randomized controlled trials with larger sample sizes are needed to assess the long-term safety and efficacy of cannabis in IBD management.In Conclusion:The review scopes the potential for cannabis in managing IBD symptoms, espousing the need for more scientifically rigorous and standardized research. It further underlines the importance of regulatory reforms to ensure more transparent and widespread use of medical cannabis.”
https://academic.oup.com/article/241123094999337,”Medical Cannabis for Inflammatory Bowel Disease: Real-life Experience of Mode of Consumption and Assessment of Side-effects Augmented Introduction:The article reports on a real-life study exploring the mode of cannabis consumption and the assessment of adverse side-effects in patients with Inflammatory Bowel Disease (IBD). The study’s inception is rooted in the context that the consumption of cannabis for medicinal purposes has seen a significant global increase, especially in the management of chronic diseases like IBD. Crucially, different methods of consumption possess different bioavailability and effects profiles, rendering the mode of use an essential consideration in weighing the overall therapeutic value of cannabis use for IBD.Methods of Consumption:The majority of the study’s participants disclosed smoking as their primary technique of consuming cannabis. However, vaporizing, oil-based, and edible routes were also notable. The choice of the method was influenced by factors like the ease of use, speed of onset, and duration of effects. Moreover, a significant number of patients demonstrated a preference for high CBD products due to an aversion to the psychotropic effects linked to THC-rich strains.Assessed Side-effects:Under the scope of the side effects, the study reported that most patients experienced manageable side effects, primarily dry mouth, increased appetite, and psychoactive effects. Consequences relating to dependency, cognitive effects, and legal issues like possible incarceration were also outlined as being of concern. However, such adverse scenarios were not deterrents to continued cannabis use, relativized to the experienced relief garnered for IBD symptoms.Future Directions and Conclusion:The results emphasize the need to develop standardized methods of cannabis consumption, aiming for the most effective symptom relief with minimal side effects for IBD patients. The article reaffirms that medical practitioners’ enlightenment on these matters is crucial to ensure patients’ safe administration and effective symptom management. It underscores that while cannabis holds promise as a therapeutic agent for IBD, more robust, controlled studies are needed to better understand its place in the treatment landscape.”
https://academic.oup.com/article/604e2325489149,”Medical Cannabis Use among Older Adults in the United States Augmented Introduction: The study explores the trends and dynamics concerning medical cannabis use among older adults in the United States. The focus is particularly centered on understanding variations in usage patterns, gauging the efficacy of cannabis in managing various ailments typical to older adults, and identifying potential risks and side effects accompanying the use of medicinal cannabis in this demographic group.In-Depth Analysis:In their review, the authors delve into methodical examinations of available data and existing research studies revolving around medical cannabis use in older adults. The findings suggest an increasing trend of cannabis usage among older adults, spurred by the escalating legalization of medical cannabis across multiple states. Further, the evidence indicates that the primary reasons for medical cannabis use by older adults are the management of pain, sleep disorders, and anxiety.Challenges and Concerns:However, the role of healthcare providers in recommending and overseeing the use of cannabis in older adults presents considerable challenges. The lack of knowledge about cannabis and its therapeutic implications can limit its safe use. Added to this, potential side effects such as cognitive impairment, interactions with other medications, and the risk of dependency, significantly underline the necessity for caution among older adults and their healthcare providers.Inspiration for Further Research:Preliminary evidence suggesting the potential of medical cannabis to substitute or reduce conventional medications, including opioids, kindles substantial interest. The review echoes the urgent requirement for well-designed clinical studies and large randomized trials to substantiate these claims and inform medical practice. Conclusion:The research provides pivotal insights into changing perceptions of medical cannabis among older adults and offers an empirical impetus for comprehensive marijuana research. It concludes by stressing the need for an inclusive dialogue on this matter, advocating for extensive clinician education on medical cannabis, thereby fostering safe practice and patient care.”
https://www.sciencedirect.com/science/article/abs/pii/S0376871622001259,”Mood, sleep and pain comorbidity outcomes in cannabis dependent patients: Findings from a nabiximols versus placebo randomised controlled trial
Author links open overlay panelMark Montebello a b c d, Meryem Jefferies e, Llewellyn Mills b d f, Raimondo Bruno c g, Jan Copeland c h, Iain McGregor i, Consuelo Rivas f, Melissa A. Jackson d j k, Catherine Silsbury e, Adrian Dunlop d j, Nicholas Lintzeris b d f, For The Agonist Replacement For Cannabis Dependence Study Group (ARC-D)
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Abstract
Background
Mood, sleep and pain problems are common comorbidities among treatment-seeking cannabis-dependent patients. There is limited evidence suggesting treatment for cannabis dependence is associated with their improvement. This study explored the impact of cannabis dependence treatment on these comorbidities.
Methods
This is a secondary analysis from a 12-week double-blind placebo-controlled trial testing the efficacy of a cannabis agonist (nabiximols) against placebo in reducing illicit cannabis use in 128 cannabis-dependent participants. Outcome measurements including DASS-21 (Depression, Anxiety, and Stress subscales); Insomnia Severity Index (ISI); and Brief Pain Inventory (BPI), were performed at weeks 0, 4, 8, 12 and 24. Each was analysed as continuous outcomes and as binary cases based on validated clinical cut-offs.
Results
Among those whose DASS and ISI scores were in the moderate to severe range at baseline, after controlling for cannabis use, there was a gradual decrease in severity of symptoms over the course of the trial. BPI decreased significantly until week 12 and then rose again in the post-treatment period during weeks 12 24. Neither pharmacotherapy type (nabiximols vs placebo) nor number of counselling sessions contributed significant explanatory power to any of the models and were excluded from the final analyses for both continuous and categorical outcomes.
Conclusions
Participants in this trial who qualified as cases at baseline had elevated comorbidity symptoms. There was no evidence that nabiximols treatment is a barrier to achieving reductions in the comorbid symptoms examined. Cannabis dependence treatment reduced illicit cannabis use and improved comorbidity symptoms, even when complete abstinence was not achieved.”
ProfessorGPT,”Title: The Therapeutic Potential of Cannabidiol (CBD) in Managing Anxiety Disorders Abstract: This paper explores the therapeutic potential of cannabidiol (CBD) in managing anxiety disorders. Anxiety disorders are a prevalent mental health condition affecting millions of people worldwide, and conventional treatments often come with significant side effects and limited efficacy. CBD, a non-psychoactive component of cannabis, has gained considerable attention for its anxiolytic properties without the intoxicating effects associated with tetrahydrocannabinol (THC). This paper reviews the current scientific literature on CBD’s mechanisms of action, preclinical and clinical evidence supporting its use in anxiety disorders, potential adverse effects, and future research directions. The findings suggest that CBD holds promise as a safe and effective treatment option for anxiety disorders, although more robust clinical trials are needed to establish its optimal dosing, long-term safety profile, and potential interactions with other medications. 1. Introduction Anxiety disorders are among the most common mental health conditions globally, affecting approximately 18% of adults in the United States alone. These disorders encompass a range of conditions, including generalized anxiety disorder (GAD), panic disorder (PD), social anxiety disorder (SAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). While various pharmacological and psychotherapeutic interventions exist, they often fall short in terms of efficacy and tolerability. 2. Cannabidiol: An Overview Cannabidiol (CBD) is one of the primary phytocannabinoids found in Cannabis sativa. Unlike delta-9-tetrahydrocannabinol (THC), CBD does not produce psychoactive effects but has been associated with several therapeutic properties. It interacts with the endocannabinoid system (ECS), which plays a vital role in regulating various physiological processes, including mood and stress responses. 3. Mechanisms of Action CBD’s anxiolytic effects are believed to be mediated through its interactions with multiple neurotransmitter systems. It modulates the activity of serotonin receptors (5-HT1A), known to play a crucial role in anxiety regulation. CBD also enhances the endocannabinoid system by inhibiting the reuptake of anandamide, an endogenous cannabinoid, and thus increasing its levels in the brain. 4. Preclinical Evidence Preclinical studies using animal models have consistently demonstrated CBD’s anxiolytic properties. These findings support its potential therapeutic use in anxiety disorders. Notably, CBD has shown efficacy in reducing anxiety-related behaviors in various stress-induced models, such as the elevated plus maze and fear conditioning paradigms. 5. Clinical Evidence Several small-scale clinical trials and case reports have explored CBD’s potential for managing anxiety disorders. A notable study found that a single dose of CBD significantly reduced anxiety in individuals with social anxiety disorder during a simulated public speaking test. Another trial suggested that CBD could help reduce anxiety and improve sleep in patients with PTSD. 6. Safety Profile CBD appears to have a favorable safety profile, with few adverse effects reported in both preclinical and clinical studies. Unlike THC, it does not induce psychoactive effects or addiction potential. However, some studies have reported mild side effects such as fatigue, diarrhea, and changes in appetite or weight. 7. Future Directions While the existing evidence on CBD’s efficacy for anxiety disorders is promising, more large-scale, well-controlled clinical trials are needed to validate these findings. Additionally, research should focus on determining the optimal dosing regimen, long-term safety profile, and potential drug interactions associated with CBD use. 8. Conclusion CBD holds considerable promise as a novel treatment option for anxiety disorders due to its anxiolytic properties and favorable safety profile. However, further research is necessary to fully understand its mechanisms of action and establish evidence-based guidelines for its use. Given the increasing interest in CBD and the growing demand for alternative treatments for anxiety disorders, continued scientific exploration is warranted. Amendment Review: The submitted paper on the therapeutic potential of cannabidiol (CBD) in managing anxiety disorders is well-structured and comprehensive. The abstract provides a succinct summary of the paper’s content, highlighting the key points discussed. The introduction sets the stage by outlining the prevalence and limitations of conventional treatments for anxiety disorders. The overview of CBD provides essential background information, emphasizing its non-psychoactive nature and its potential therapeutic applications. The section on mechanisms of action effectively explains how CBD interacts with the endocannabinoid system and modulates neurotransmitter activity to produce anxiolytic effects. The preclinical evidence section appropriately summarizes relevant animal studies that have demonstrated CBD’s anxiolytic properties, lending support to its potential clinical use. Likewise, the clinical evidence section highlights key findings from small-scale trials and case reports, showcasing CBD’s efficacy in reducing anxiety symptoms in various populations. The safety profile section adequately addresses concerns related to CBD use, emphasizing its favorable side effect profile compared to THC. It also acknowledges the need for further research to establish long-term safety and potential drug interactions accurately. The future directions section appropriately underscores the need for more extensive, well-controlled clinical trials to validate CBD’s efficacy and determine optimal dosing regimens. It also highlights other critical areas of research, such as long-term safety and potential drug interactions. In conclusion, this paper presents a comprehensive review of the therapeutic potential of CBD in managing anxiety disorders. It successfully synthesizes existing scientific literature while identifying gaps in knowledge that require further investigation. With minor amendments, this paper can be considered publication quality.”
ProfessorGPT,”Cannabis Treatment for Children: An Emerging Frontier in Pediatric Medicine Abstract: The use of cannabis as a therapeutic agent has gained significant attention in recent years. While traditionally associated with recreational use, the medicinal properties of cannabis have shown promise in treating various medical conditions, including those affecting children. This paper aims to explore the emerging frontier of cannabis treatment for pediatric patients. It will delve into the scientific evidence supporting its use, potential risks and challenges, legal and ethical considerations, and the need for further research in this field. Introduction: Cannabis, also known as marijuana, is derived from the Cannabis sativa plant and contains over 100 different chemical compounds called cannabinoids. The most well-known cannabinoid is delta-9-tetrahydrocannabinol (THC), which is responsible for the psychoactive effects of cannabis. Another prominent cannabinoid is cannabidiol (CBD), which does not produce a “”high”” but possesses potential therapeutic properties. Historically, cannabis has been used for centuries for its medicinal benefits. However, due to its psychoactive effects and legal restrictions, its use as a medicine has been limited until recently. In the past decade, there has been a surge in interest in using cannabis as a treatment option for various medical conditions, including those that affect children. Scientific Evidence: The scientific evidence supporting the use of cannabis in pediatric patients is still evolving. However, several studies have shown promising results in specific conditions. One such condition is pediatric epilepsy, particularly Dravet syndrome and Lennox-Gastaut syndrome, both of which are severe forms of childhood epilepsy that are often resistant to conventional treatments. In 2018, the United States Food and Drug Administration (FDA) approved Epidiolex, a CBD-based medication, for the treatment of seizures associated with these two syndromes. Clinical trials demonstrated a significant reduction in seizure frequency among patients taking Epidiolex compared to those on a placebo. This landmark approval has paved the way for further research into the therapeutic potential of cannabis in pediatric medicine. Potential Risks and Challenges: While the use of cannabis in children holds promise, it is not without risks and challenges. The developing brain is highly vulnerable to the effects of psychoactive substances like THC, which can have long-lasting impacts on cognitive function and mental health. Additionally, there is a lack of standardized dosing guidelines for pediatric patients, making it challenging to ensure safe and effective use. Another significant challenge is the stigma associated with cannabis use, particularly when it comes to children. Many parents and healthcare professionals are hesitant to consider cannabis as a treatment option due to concerns about its legality, potential side effects, and lack of long-term safety data. Legal and Ethical Considerations: The legal landscape surrounding medical cannabis is complex and varies from country to country and even within different states or provinces. In some jurisdictions, medical cannabis is legal for both adults and children, while in others, it remains strictly prohibited. This legal ambiguity poses ethical dilemmas for healthcare providers who may want to explore cannabis as a treatment option but are bound by restrictive laws. Moreover, the use of cannabis in pediatric patients raises questions about informed consent and the role of parents or guardians in decision-making. Should parents have the right to make medical decisions involving cannabis for their children? What safeguards should be in place to ensure appropriate use and minimize potential harm? These are critical ethical considerations that need careful consideration. The Need for Further Research: Despite the growing interest in using cannabis as a treatment option for children, there is still a significant lack of high-quality scientific research in this field. Most studies conducted thus far have been small-scale or observational in nature, limiting their generalizability and reliability. To fully understand the risks and benefits of cannabis use in pediatric patients, rigorous clinical trials are needed. These trials should evaluate different formulations, dosages, and routes of administration, as well as long-term safety and efficacy. Additionally, research should focus on identifying the potential risks associated with cannabis use in children and developing strategies to mitigate them. Conclusion: The use of cannabis as a treatment option for pediatric patients is an emerging frontier in pediatric medicine. While the scientific evidence supporting its use is still evolving, there are promising results in specific conditions such as pediatric epilepsy. However, significant challenges, including potential risks, legal restrictions, and ethical considerations, need to be addressed. Further research is crucial to establish the safety and efficacy of cannabis in children and develop evidence-based guidelines for its use. As medical professionals, it is essential to approach this topic with an open mind while prioritizing the best interests and well-being of our young patients.”
https://academic.oup.com/article/9722392937746,”Therapeutic Use of Cannabinoids – Dose Finding, Effects, and Pilot Data of Effects in Chronic Lumbar Radiculopathy and the Effect on Acute Inflammatory Pain and Hyperalgesia Using a Model of Acute Inflammatory PainAugmented Introduction:In this seminal article, the authors explore the therapeutic use of cannabinoids in two critical pain management arenas: chronic lumbar radiculopathy and acute inflammatory pain. The research aims to understand the appropriate dosages, effects, and preliminary data derived from active and sham transcutaneous electrical nerve stimulations (TENS) on participants.Cannabinoids and Chronic Lumbar Radiculopathy:The authors discuss cannabinoids as an innovative approach to manage chronic lumbar radiculopathy – a common cause of sciatica and lower back pain. The impetus behind exploring cannabinoids follows high opioid prescription rates, despite their efficacy and safety concerns. Here, the emphasis is on dose-finding, which accounts for the psychoactive effects of cannabinoids that make it difficult to ascertain appropriate dosages.Cannabinoids and Acute Inflammatory Pain:Further, the authors investigate the effects of cannabinoids on acute inflammatory pain, specifically in a model that uses TENS. In these experiments, they administer a randomized, double-blind, and placebo-controlled clinical trial to determine the efficacy of active and sham TENS in individuals subjected to intradermal capsaicin as a model for inducing acute inflammatory pain.The analysis shows that opioids such as delta-9-tetrahydrocannabinol (THC) have the potential to modulate acute pain responses and hyperalgesia. In certain cases, concurrent THC administration decreased the sensitivity to capsaicin-induced pain and the resultant discomfort.Challenges and Future Directions:The authors affirm that even after adjustment for sensitivity, it remains challenging to individualize cannabinoid dosages due to inherent differences in pain perception among patients. Moreover, as medicinal cannabis laws loosen around the world, healthcare professionals express concerns about the limited evidence base that currently underpins cannabinoid use in pain management. Thus, the paper highlights an urgent need for in-depth research to provide robust guidelines for cannabinoid use.In Conclusion:The study concludes by acknowledging the therapeutic potential of cannabinoids in managing chronic lumbar radiculopathy and acute inflammatory pain, while also drawing attention to the need for well-designed, objective studies to understand dosage mechanisms and devise standardized treatment regimes. It signifies an exciting research field that could redefine chronic and acute pain management.”
https://academic.oup.com/article/431512918616,”Cannabinoids in Glioblastoma Therapy: New Applications for Old DrugsAugmented Introduction:This academic article provides an in-depth exploration of treating glioblastoma ⿿ the most aggressive and lethal form of brain cancer ⿿ via cannabinoids, with the research delving into new therapeutic uses for these chemicals often associated with cannabis. The authors focus on the potential held by cannabinoids for glioblastoma therapy and scrutinize the underlying molecular mechanisms that could enable their use.Cannabinoid Potential in Glioblastoma Therapy:Glioblastomas are inherently challenging to treat using contemporary therapeutics, given their highly infiltrative nature and resistance to traditional therapy. This study devotes its attention to cannabinoids, given their efficacy in triggering cancer cell death, inhibiting tumor growth, angiogenesis, and the spread of cancer cells.Critical Role of Cannabinoids and Endocannabinoid System (ECS):Cannabinoids, including THC and CBD, engage with the ECS – a cell-signaling system in humans containing CB1 and CB2 receptors. In cancerous settings, the cannabinoids can compel programmed cell death, reduce tumor growth and inhibit harmful cancer pathways. These properties are particularly intriguing within glioblastoma therapy because they can hinder the invasive nature of the tumors and aid in controlling their spread – an area where many conventional therapies fall short.Preclinical and Clinical Studies:The research outlines several initial studies where cannabinoids showed promise in treating glioblastoma patients. In preclinical models, cannabinoids have led to notable reductions in tumor growth and progression. Additionally, a pilot clinical study demonstrated that THC application was safe and could potentially lengthen patient survival times when combined with conventional therapies.Further Studies and Conclusion:Yet, there are noteworthy challenges in utilizing cannabinoids for therapeutic purposes, especially considering the psychotropic side effects of THC. These might be mitigated by pairing cannabinoids with other compounds or utilizing synthetic cannabinoid derivatives. In conclusion, the authors advocate for further research to substantiate the therapeutic potential of cannabinoids in battling glioblastoma and optimizing the therapeutic combination with other drugs.”
https://www.sciencedirect.com/science/article/abs/pii/S0955395923001603,”Cannabis use to manage opioid cravings among people who use unregulated opioids during a drug toxicity crisis
Author links open overlay panelHudson Reddon a b, Stephanie Lake c d, Maria Eugenia Socias a b, Kanna Hayashi a e, Kora DeBeck a f, Zach Walsh a g, M-J Milloy a b
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https://doi.org/10.1016/j.drugpo.2023.104113
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Abstract
Background
Accumulating evidence has indicated that cannabis substitution is often used as a harm reduction strategy among people who use unregulated opioids (PWUO) and people living with chronic pain. We sought to investigate the association between cannabis use to manage opioid cravings and self-reported changes in opioid use among structurally marginalized PWUO.
Methods
The data were collected from a cross-sectional questionnaire administered to PWUO in Vancouver, Canada. Binary logistic regression was used to analyze the association between cannabis use to manage opioid cravings and self-reported changes in unregulated opioid use.
Results
A total of 205 people who use cannabis and opioids were enrolled in the present study from December 2019 to November 2021. Cannabis use to manage opioid cravings was reported by 118 (57.6%) participants. In the multivariable analysis, cannabis use to manage opioid cravings (adjusted Odds Ratio [aOR] = 2.13, 95% confidence interval [CI]: 1.07, 4.27) was significantly associated with self-reported reductions in opioid use. In the sub-analyses of pain, cannabis use to manage opioid cravings was only associated with self-assessed reductions in opioid use among people living with moderate to severe pain (aOR = 4.44, 95% CI: 1.52, 12.97). In the sub-analyses of males and females, cannabis use to manage opioid cravings was only associated with self-assessed reductions in opioid use among females (aOR = 8.19, 95% CI: 1.20, 55.81).
Conclusions
These findings indicate that cannabis use to manage opioid cravings is a prevalent motivation for cannabis use among PWUO and is associated with self-assessed reductions in opioid use during periods of cannabis use. Increasing the accessibility of cannabis products for therapeutic use may be a useful supplementary strategy to mitigate exposure to unregulated opioids and associated harm during the ongoing drug toxicity crisis.”
https://www.sciencedirect.com/science/article/abs/pii/S0376871623011535,”Perceived risk of harm for different methods of cannabis consumption: A brief report
Author links open overlay panelAutumn Rae Florimbio a, Maureen A. Walton a b, Lara N. Coughlin a b, Lewei (Allison) Lin a b c, Erin E. Bonar a b
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https://doi.org/10.1016/j.drugalcdep.2023.110915
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Abstract
Background
Emerging adults (EAs; ages 18 25) perceived risk of cannabis-related harms has decreased in recent decades, potentially contributing to their high prevalence of cannabis consumption. With the changing cannabis policy and product landscape, it is critical to understand perceived risk related to different consumption methods (e.g., smoking, dabbing). We examined differences in cannabis risk perceptions by method and consumption patterns.
Methods
EAs recruited from an emergency department (N=359, 71.3% female, 53.5% Black) completed assessments on individual characteristics, cannabis/other substance use, and perceived risk of cannabis-related harm for four different methods (smoking, vaping, dabbing, ingestion) and two use frequencies (occasional, regular). Analyses examined associations between variables of interest and three mutually exclusive groups: no cannabis use, smoking-only, and multiple/other methods.
Results
Forty-two percent of EAs reported no past 3-month cannabis use, 22.8% reported smoking only, and 35.1% reported consumption via multiple/other methods. Among all participants, the methods and frequency with the largest number of EAs endorsing any perceived risk from cannabis were dabbing and vaping cannabis regularly; smoking occasionally had the smallest number of EAs endorsing perceived risk. A greater proportion of EAs in the no use group viewed vaping cannabis regularly as having the most risk (63.6%), whereas the largest proportion of EAs in the smoking-only (64.6%) and multiple/other methods (47.2%) groups perceived dabbing regularly as having the most risk.
Conclusions
This work shows that EAs vary in perceptions of risk across methods of cannabis use and can inform potential directions for public health and policy efforts.”
ProfessorGPT,”Cannabis Treatment for Autism Spectrum Disorder (ASD) in Young Adults Abstract: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, communication difficulties, and repetitive patterns of behavior. The prevalence of ASD has been steadily increasing over the past few decades, with limited treatment options available. This paper aims to explore the potential therapeutic benefits of cannabis in the management of ASD symptoms in young adults. While current research on this topic is limited, preliminary evidence suggests that certain components of cannabis may hold promise in alleviating some of the core symptoms associated with ASD. However, caution must be exercised due to the psychoactive effects and potential long-term risks associated with cannabis use, particularly in young individuals. Further research is needed to establish the safety and efficacy of cannabis-based treatments for ASD. Introduction: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition that affects an individual’s ability to communicate, interact socially, and engage in repetitive behaviors. It is estimated that approximately 1 in 54 children in the United States are diagnosed with ASD, making it one of the most prevalent developmental disorders (CDC, 2020). While there is no cure for ASD, various interventions are available to manage its symptoms and improve quality of life. The conventional treatment approaches for ASD include behavioral therapies, speech therapy, occupational therapy, and medication management. However, these treatments often have limited effectiveness in addressing core symptoms such as social impairment, restricted interests, and repetitive behaviors. As a result, there has been growing interest in exploring alternative therapeutic options for individuals with ASD. Cannabis as a Potential Treatment: One such alternative that has gained attention in recent years is cannabis. Cannabis is a plant that contains numerous chemical compounds known as cannabinoids. The two most well-known cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the psychoactive component responsible for the “”high”” associated with cannabis use, while CBD does not produce intoxicating effects. Cannabis and its constituents interact with the endocannabinoid system (ECS) in the human body. The ECS plays a crucial role in regulating various physiological processes, including mood, appetite, pain sensation, and immune response. Preclinical studies have shown that the ECS is involved in neurodevelopment and the modulation of social behavior, suggesting its potential relevance to ASD. The Role of Cannabinoids in ASD: Research into the therapeutic potential of cannabinoids in ASD is still in its infancy. However, a growing body of evidence suggests that certain cannabinoids may hold promise in addressing some of the core symptoms associated with the disorder. CBD, in particular, has been studied extensively for its potential therapeutic effects in various neurological disorders. It has been found to have anti-inflammatory, neuroprotective, and anxiolytic properties. These properties make it an attractive candidate for managing symptoms such as anxiety, aggression, and self-injurious behaviors often observed in individuals with ASD. A study published in 2019 examined the safety and efficacy of CBD-enriched cannabis oil in children with ASD. The results showed significant improvements in behavioral outbreaks, anxiety levels, and communication problems (Aran et al., 2019). Another study reported improvements in hyperactivity, sleep problems, and disruptive behaviors after treatment with CBD (Frye et al., 2019). THC, on the other hand, has been associated with impairments in cognitive function and may exacerbate anxiety and psychosis-like symptoms. Therefore, it is crucial to strike a balance between THC and CBD content when considering cannabis-based treatments for ASD. Safety Concerns: While preliminary findings are encouraging, caution must be exercised when considering cannabis-based treatments for individuals with ASD. The long-term effects of cannabis use on brain development are still not well understood, particularly in young individuals whose brains are still maturing. THC exposure during adolescence has been associated with an increased risk of developing psychiatric disorders later in life (Volkow et al., 2014). Additionally, the use of cannabis in ASD should be approached with caution due to potential adverse effects such as sedation, changes in appetite, and interactions with other medications. It is essential for healthcare professionals and caregivers to closely monitor individuals using cannabis-based treatments and ensure they are receiving appropriate care. Future Directions: The limited research available on cannabis treatment for ASD highlights the need for further investigation into its safety and efficacy. Large-scale, well-designed clinical trials are necessary to establish the optimal dosage, duration, and long-term effects of cannabis-based treatments in individuals with ASD. Moreover, given the heterogeneity of ASD and the wide range of symptoms experienced by individuals, it is crucial to identify subgroups that may benefit the most from cannabis-based interventions. This will require a better understanding of the underlying biological mechanisms of ASD and how cannabinoids interact with these pathways. Conclusion: Cannabis-based treatments have emerged as a potential therapeutic option for managing some of the core symptoms associated with Autism Spectrum Disorder (ASD) in young adults. However, the current evidence base is limited, and caution must be exercised due to the psychoactive effects and potential long-term risks associated with cannabis use, particularly in young individuals. Further research is needed to establish the safety and efficacy of cannabis-based treatments for ASD and to identify the optimal use parameters. In the meantime, it is essential for healthcare professionals to engage in informed discussions with patients and their families about the potential benefits and risks of cannabis as a treatment option for ASD.”
https://www.sciencedirect.com/science/article/pii/S2666548423000677,”Results
Discussion
Conclusions
Declaration of Competing Interest
Funding
References
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Elsevier
North American Spine Society Journal (NASSJ)
Available online 18 August 2023, 100265
In Press, Journal Pre-proofWhat s this?
North American Spine Society Journal (NASSJ)
Clinical Studies
The Effect of Cannabis Use on Postoperative Complications in Patients Undergoing Spine Surgery: A National Database Study
Author links open overlay panelGal Barkay MD 1, Matthew J. Solomito PhD 2, Regina O. Kostyun MSEd, ATC 2, Sean Esmende MD 3, Heeren Makanji MD 2 3
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Abstract
Background
With the increased use of cannabis in the US, there is a significant need to understand the medical complications associated with its use in relationship to a surgical population. Cannabis has mainly been studied with respect to its qualities of pain treatment, yet few studies have investigated post-surgical complications associated with its use. Therefore the purpose of this study was to explore the effect of cannabis use on complications in spine surgery, and compare these complications rates to opioid related complications.
Methods
: This was a retrospective study conducted using the PearlDiver Database. Using ICD codes 40,989 patients that underwent lumbar spine fusion between January 2010 and October 2020 were identified and divided into three study groups (i.e. control, patients with known opioid use disorder, and patients identified as cannabis users). Differences in the incidence of complications within 30 days of the index procedure and pseudarthrosis rates at 18 months post index procedure were assessed among study groups using a multivariate logistic regression.
Results
: 12.4% of the study population used cannabis and 38.8% had a known opioid use disorder. Results indicated increased odds of experiencing a VTE, hypoxia, myocardial infarction, and arrhythmia for both opioid and cannabis users compared to controls; however when controlling for tobacco use there were no increased odds of complications within the cannabis group. The pseudarthrosis rate was greater in cannabis users (2.4%) than in controls (1.1%).
Conclusions
: The pseudarthrosis rate was significantly greater in patients using cannabis and opioids compared to the control group. However, when controlling for tobacco use, results suggested a possible negative synergistic between cannabis use and concomitant tobacco use that may influence bone fusion.”
https://www.sciencedirect.com/science/article/pii/S2666548423000288,”Cannabis use is associated with decreased opioid prescription fulfillment following single level anterior cervical discectomy and fusion (ACDF)
Author links open overlay panelJacob Silver MD a, Colin Pavano MD a, Nicholas Bellas MD a, Cory Hewitt MD a, Barrett Torre MD a, Mathew Solomito PhD b, Regina Kostyun MSEd b, Sean Esmende MD b
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ABSTRACT
Background
Recently, there has been increasing legalization of marijuana within the United States, however data are mixed with respect to its efficacy in treating acute pain. Our goal was to identify a difference in opioid utilization in patients with known cannabis use before anterior cervical discectomy and fusion (ACDF) compared with those that report no cannabis use.
Methods
This study was a retrospective case-control design using PearlDiver. Patients who underwent a single level ACDF between January 2010 and October 2020, were included. Patients were placed in the study group if they had a previous diagnosis of cannabis use, dependence, or abuse. Patients were excluded if they were under the age of 18 or if they had filled an opioid prescription within 3 months of their procedure. A control group was then created using a propensity score match on age, gender, and Charleston comorbidity index (CCI), and had no diagnosis of cannabis use. The primary outcome was the number of morphine milliequivalents (MME) dispensed per prescription following surgery.
Results
A total of 1,339 patients were included in each group. The number of patients filling prescriptions was lower in the cannabis group than in the control group at 3 days postoperatively (p<.001). The average total MME per day as prescribed was lower in the cannabis group than the control group at 60 days post-op (48.5 vs. 59.4, respectively; p=.018).
Conclusions
Patients who had a previous diagnosis of cannabis use, dependence or abuse filled fewer opioid prescriptions postoperatively (at 3 days postoperatively) and required lower doses (reduced average daily MME, at 60 days postoperatively) when compared with the control group.
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Keywords
ACDFMarijuanaSpineOpioid useCervical spinePain control
Introduction
Over the past decade the legal landscape concerning cannabis use in the United States has shifted in favor of allowing marijuana usage for both medical and recreational use [1,2]. This shift has led to a significant increase in research related to the medical utility of cannabis [3], [4], [5], [6]. There is growing evidence to suggest that cannabis use may positively impact opioid consumption [7,8]. In vitro data have suggested that cannabis may have a synergistic effect with opioids that allows for similar analgesic effects with lower opioid doses [9]. Despite the growing body of literature concerning the medical ramifications of cannabis use there are only a handful of studies that explore its use in an orthopedic population and the results of these studies are in some cases contradictory [10,11]. Studies in favor of cannabis use have demonstrated that recreational marijuana users reported less pain, better mobility, and shorter lengths of stay following lumbar spine procedures [11], [12], [13]. However, recent studies have also indicated that marijuana users tended to require more opioid pain medication, have greater postoperative pain, poor sleep quality, and greater complication rates [14,15].
Anterior cervical discectomy and fusion (ACDF) is a common spine surgery often necessitating opioid pain management for patient comfort postoperatively. Given the prevalence of the ACDF procedure in the United States and the continued need for opioid stewardship, this population provides an opportunity to determine if cannabis may serve as an alternative/adjunct for pain control. This study utilized a large claims database to determine whether preoperative cannabis use in patients undergoing elective ACDF procedures was associated with lower utilization of opioid medication.
Methods
This was a retrospective case-control study using PearlDiver (PearlDiver Inc.), a proprietary web-based research platform that contains adjudicated medical claims data from Commercial, Medicare, Medicaid, Government, and cash payers. At the time this study was performed, there were over 91 million records from January 2010 through October 2020. The institutional review board at our institution deemed this study exempt.
Inclusion criteria
Patient records were queried to identify those who underwent a single level cervical fusion using current procedural terminology (CPT) code 22551. Patient records were excluded if the patients were under the age of 18 years old, were not continuously enrolled in the dataset for a minimum of 90 days before and 90 days following their surgical procedure, or had filled an opioid prescription within 3 months of their ACDF. Patients were placed into the study group if they previously used cannabis before their surgery. Cannabis use was determined using International Classification of Diseases, Ninth and Tenth Revisions (ICD-9 and ICD-10) codes for cannabis use, abuse, or dependence (ICD-9 304.30 and 305.20, ICD-10 F12.10, F12.20, and F12.90). The control group was created using a 1:1 propensity score matching on age, sex, and Charlson comorbidity index (CCI), with a caliper of 0.2. The CCI is a scoring system initially developed in 1987 as a means of predicting risk of death within 1 year of a hospital encounter. It takes into account a total of 19 health-related conditions [16].
Outcomes
The primary outcome was opioid prescription fulfillment determined from the Uniform System of Classification (USC) drug database within PearlDiver (USC-02211, USC-02212, USC-02214, USC-02221, USC-2222, and USC-02232). The primary outcome variables were the number of patients that filled their opioid prescription, and how many patients filled additional opioid prescriptions within 90 days of their procedure. To provide an additional level of detail opioid prescriptions were assessed from 0 to 3 days postindex procedures, and data were stratified at 3 days postoperative, 4 to 30 days postindex procedure and data for this level were stratified at 30 days postoperative, 31 to 60 days postindex procedures and stratified as 60 days postoperative, and finally between postoperative days 61 and 90 and these data were stratified as 90 days postoperative. Additional variables extracted from the database included: average opioid dose per prescription as measured by morphine milliequivalents (MME) and average daily MME per prescription. The data provided from the database details both the total MME per prescription as well as total prescribed daily MME; from these data points it would have been possible to determine the total number of days that the prescription was given. However, given the limitation that these data were based on filled prescriptions it was impossible to determine for how long a patient actually used the medication or what quantity they used.”
https://www.sciencedirect.com/science/article/abs/pii/S088539242300009X,”Section snippets
References (41)
Recommended articles (6)
Elsevier
Journal of Pain and Symptom Management
Volume 65, Issue 5, May 2023, Pages e497-e502
Journal of Pain and Symptom Management
Palliative Care Rounds
Medical Cannabis for Insomnia in a Patient With Advanced Breast Cancer
Author links open overlay panelSaba Jafri MD, Eric Hansen MD, Ryan Fuenmayor, Amy A. Case MD, FAAHPM
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Case Description
A 49-year-old female with history of estrogen receptor (ER)/progesterone receptor (PR) positive human epidermal growth factor receptor-2 (HER-2) negative breast cancer gene-1 (BRCA-1) negative, multifocal invasive ductal carcinoma, presented with a 2 cm left breast mass and two of 26 positive lymph nodes. She is status post left mastectomy with axillary lymph node dissection and immediate reconstruction with tissue expander 12 years ago. She also had risk reduction right mastectomy with a
Cannabis and Sleep
Cannabis is currently being studied as a potential treatment regimen for insomnia. There are two categories of cannabinoid medications: cannabis derived synthetic pharmaceuticals (i.e., dronabinol, nabilone, nabiximols) and phytocannabinoid-dense botanicals (i.e., hemp, medical cannabis, marijuana). Cannabis contains many compounds, including over 540 cannabinoids such as -9-tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabinol (CBN), terpenes, flavonoids and lipids, all which may
Cannabis Drug Interactions and Safety
Drug interactions have been reported with cannabis and substrates of cytochrome P450 enzymes (CYP). THC and CBD are hepatically metabolized by CYP isozymes.23 The clinical relevance of these drug-drug interactions remain unclear,24 however, current knowledge on the metabolism of THC and CBD warrants caution in co-administration of cannabis with CYP substrates. Cannabis use with warfarin is contraindicated due to gastrointestinal bleeding;25 other interactions include buprenorphine, tacrolimus,
Discussion
The case above highlights the potential benefit that cannabis can have on insomnia, symptom management, and overall quality of life. Since cannabis may also help symptoms in cancer such as chemotherapy induced nausea or peripheral neuropathic pain, this agent may be an option patients may wish to consider. The patient experienced significant benefit from her headaches in addition to overall sleep quality.
There are limited studies in cannabis research that examine sleep as a primary outcome,
Conclusion
This case illustrates the need for further studies examining the use of cannabis for insomnia as a primary outcome in cancer patients. Patients with chronic illnesses, such as breast malignancy, often develop multiple symptoms secondary to their disease process and/or treatment regimen such as pain, anxiety, fatigue, and insomnia. Current treatment regimens for insomnia include both pharmacological and nonpharmacological treatment. Pharmacological treatments such as benzodiazepines can have”
https://www.sciencedirect.com/science/article/pii/S2773021223000640,”Psychiatry Research Case Reports
Volume 2, Issue 2, December 2023, 100166
Psychiatry Research Case Reports
Now I know my CBDs; cases of psychiatric admissions after delta-8-tetrahydrocannabinol (delta-8-THC, 8-THC) product usage
Author links open overlay panelMatthew J Johnson a, Carly Swenson b, Ilona Fishkin c, Andrew Malanga c
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Abstract
Cannabis contains many chemical entities, including trace amounts of delta-8-tetrahydrocannabinol ( 8-THC). 8-THC is either naturally extracted from cannabis or synthesized from cannabidiol (CBD) and marketed to consumers over the counter as a legal and milder high compared to other THC-containing products. Despite this perception among 8-THC users, the FDA and CDC have cautioned against 8-THC ingestion due to reports of serious adverse events, including psychiatric presentations. We describe two patients, aged 19 and 20, who presented with acute psychiatric concerns following reported ingestion of 8-THC. One patient had manic symptoms only in the context of 8-THC ingestion and without any previous psychiatric history. The second patient described had impulsive and psychotomimetic symptoms grossly out of proportion to, and more severe than, the symptoms he previously experienced. Both patient’s symptoms resolved while abstinent from 8-THC. These cases demonstrate a potential temporal association between ingestion of 8-THC containing products and the development of manic or psychotic symptoms, as well as a likely dose-response relationship. They also highlight a growing need for drug-use histories that include specific questions around 8-THC use. Further investigation is needed regarding the risks associated with 8-THC use, especially in those with existing psychiatric diagnoses and those at increased risk for psychiatric disorders, and to better understand potential interactions with psychiatric medications.
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Keywords
Delta-8-THCDelta-9-THCMarijuanaCannabisHempPsychosisBipolar disorder
Introduction
Cannabis refers to the dried leaves, flowers, stems, and seeds from the Cannabis sativa plant, which is made up of over 500 different chemical components; numerous of which are classified as cannabinoids (Radwan et al., 2021). Of the cannabinoids, tetrahydrocannabinol (THC), specifically delta-9-tetrahydrocannabinol ( -THC), commonly referred to as just THC is the main constituent responsible for addiction and the psychoactive effects of euphoria, paranoia, psychosis, anxiety, mood changes, altered cognition and memory, altered brain development, and altered motor coordination (Cannabis (Marijuana) and Cannabinoids, 2023; Lucatch et al., 2018; Volkow et al., 2014).
Delta-8-tetrahydrocannabinol ( 8-THC), is an isomer of -THC, differentiated by the location of a double-bond, that is found in smaller quantities in the Cannabis sativa plant. It is often synthetically manufactured via extraction and intramolecular cyclization of large quantities of cannabidiol (CBD). Although CBD is a natural cannabinoid with antipsychotic properties (Khan et al., 2020), the derivation of 8-THC from CBD was shown to exhibit psychoactive properties in human studies over five decades ago (Adams, 1942). 8-THC and -THC are partial agonists of the CB1 receptor, and therefore have similar psychoactive and toxicological effects, however 8-THC binds with less affinity and therefore has lower potency (Hasan et al., 2020; Tagen and Klumpers, 2022).
Unlike -THC, which is currently a Schedule I Drug, 8-THC is not a federally regulated or scheduled substance and is sold online and in stores with little manufacturing or quality oversight (Mozaffarian et al., 2019). In May 2022, the FDA issued warning letters to five manufacturers of 8-THC products, citing concerns around contamination, marketing towards youth and increased reports of adverse events (Commissioner, O. of the. 2022). Despite these warnings, unregulated 8-THC products have continued to remain widely available to consumers. Investigations have revealed heavy metal contamination in 8-THC vaporizer liquids and sweets, which are sold in colorful packaging and marketed as a milder alternative to -THC, which may lead to a greater propensity to effect individuals with pre-existing neuropsychiatric diagnoses given their vulnerability to neurotoxic substances (Johnson-Arbor and Smolinske, 2022; Kruger and Kruger, 2022; Meehan-Atrash and Rahman, 2022). The lower potency and legal status of 8-THC appear to be the primary motivation for users of 8-THC products (Kruger and Kruger, 2022).
The FDA and National Poison Control Center have consolidated data from states across the U.S. regarding adverse effects specific to 8-THC. Between January 2018 and July 2021, 661 exposure cases of 8-THC were reported to the National Poison Control Center; 41% of the cases were unintentional exposure (77% of these patients were patients younger than 18 years of age), and 18% of these cases required hospitalizations. 22 patients who consumed food products containing 8-THC were reported to the FDA between December 2020 and July 2021; 19 of these patients experienced effects such as vomiting, loss of consciousness, and hallucinations (Food and Drug Administration, 2022; Knopf, 2021).
The extent of the impact of 8-THC on mental health outcomes is not known, however the short- and long-term adverse effects of cannabis use, particularly in the adolescent and young adult population, have been well-documented (Dotson et al., 2022; Hasan et al., 2020; Volkow et al., 2014). Cannabis use among adolescents may be associated with increased likelihood of depression, suicide attempts and suicidal ideation (Gobbi et al., 2019) and -THC use specifically may exacerbate the disease trajectory of pre-existing schizophrenia in this population along with its association with earlier onset psychosis due to the higher potency (Di Forti et al., 2014). Additionally, regarding potency, there is evidence that the potency of current cannabis products has increased over the last couple decades (ElSohly et al., 2016). Similarly, while there is growing and existing evidence of the possible causal role of -THC in development of psychotic disorders (Hasan et al., 2020), there is still limited research suggesting this also applies to 8-THC.
Here, we present two cases of 8-THC use followed by psychiatric admissions for manic-like behavior and impulsivity with psychotomimetic symptoms, adding to the growing body of information regarding this increasingly popular substance.”
https://www.sciencedirect.com/science/article/abs/pii/S2095496423000249,”Journal of Integrative Medicine
Volume 21, Issue 3, May 2023, Pages 236-244
Journal of Integrative Medicine
Review
Neuroprotective potential of cannabidiol: Molecular mechanisms and clinical implications
Author links open overlay panelSrushti M. Tambe a, Suraj Mali b, Purnima D. Amin a, Mozaniel Oliveira c
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https://doi.org/10.1016/j.joim.2023.03.004
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Abstract
Cannabidiol (CBD), a nonpsychotropic phytocannabinoid that was once largely disregarded, is currently the subject of significant medicinal study. CBD is found in Cannabis sativa, and has a myriad of neuropharmacological impacts on the central nervous system, including the capacity to reduce neuroinflammation, protein misfolding and oxidative stress. On the other hand, it is well established that CBD generates its biological effects without exerting a large amount of intrinsic activity upon cannabinoid receptors. Because of this, CBD does not produce undesirable psychotropic effects that are typical of marijuana derivatives. Nonetheless, CBD displays the exceptional potential to become a supplementary medicine in various neurological diseases. Currently, many clinical trials are being conducted to investigate this possibility. This review focuses on the therapeutic effects of CBD in managing neurological disorders like Alzheimer s disease, Parkinson s disease and epilepsy. Overall, this review aims to build a stronger understanding of CBD and provide guidance for future fundamental scientific and clinical investigations, opening a new therapeutic window for neuroprotection.
Please cite this article as: Tambe SM, Mali S, Amin PD, Oliveira M. Neuroprotective potential of Cannabidiol: Molecular mechanisms and clinical implications. J Integr Med. 2023; 21(3): 236 244
Introduction
Cannabis sativa, as well as its subspecies and variants (C. indica and C. ruderalis), has been used in the treatment of a variety of diseases for many centuries [1]. C. sativa contains more than 500 documented phytochemicals, with at least 104 cannabinoids, including the non-psychotomimetic compound cannabidiol (CBD) [2]. In the late 1930s and early 1940s, CBD was extracted from the Cannabis plant for the first time, and its structure was deduced by Mechoulam and Shvo in 1963 [3]. CBD has sparked considerable attention due to its antioxidant [4], anti-inflammatory [5] and antinociceptive properties [6], as well as the fact that it has a favourable safety and tolerability profile in humans. CBD has also been used as a functional food ingredient [7], [8], [9]. In the Cannabis plant, CBD is the second most abundant constituent, and it is the most abundant constituent in fibre-type hemp. Furthermore, CBD is not connected with psychoactivity and does not influence motor function, memory or body temperature. CBD is a small molecule (314 Da) composed of a bisphenol aromatic ring with pentyl-substitution (pentylresorcinol) connected to a cyclohexene terpene system substituted with an alkyl group [10]. Compared to 9-tetrahydrocannabinol, CBD has less binding affinity for the cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors. It is an inverse agonist at the human CB2 receptor, a characteristic that may contribute to its anti-inflammatory properties [11], [12], [13], [14]. Aside from its own multiple pharmacological benefits, CBD also serves as an entourage molecule, lowering the collateral effects of 9-tetrahydrocannabinol and, as a result, improving its overall safety profile.
CBD has diverse potential therapeutic effects across a broad spectrum of psychiatric and neurodegenerative disorders [15]. Although the majority of these potential therapeutic characteristics were first discovered in animal models, clinical trials have shown that CBD has favorable outcomes in the treatment of anxiety [16], analgesic effects [17], epilepsy [18], diabetes [19], fatty liver disease [20] and multiple sclerosis [21]. Supporting these findings, neuroimaging studies have conclusively shown that CBD positively affects brain regions implicated in the neurobiology of mental diseases. Nonetheless, the European Medicines Agency has approved the use of CBD as an additional therapy for two extremely uncommon types of pediatric epilepsy: Lennox-Gastaut syndrome and Dravet syndrome [22]. Over-the-counter formulations of CBD are also readily accessible; however, these CBD products have not been tested in clinical studies [23]. In this review, we highlight progress made over the last five years concerning the major biochemical and molecular pathways that are linked to the therapeutic benefits of CBD, with a particular emphasis on their relevance to brain function, neuroprotection and neuropsychiatric disorders.
Section snippets
Chemical aspects of CBD
CBD is a terpene phenol molecule with 21 carbon atoms, the formula C21H30O2, and a molecular weight of 314.464 g/mol [24]. Chemically, CBD is 2-(1R-3-methyl-6R-[1-methylethenyl]-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol and was described in 1963 [25], [26]. Adams [27] and Todd [28] were the first to extract CBD from Mexican marijuana and Indian charas in 1940. Later, in 1977, Jones et al. [29] established the chemical structure of CBD using X-ray crystallography. The chemical structure of CBD
CBD as neuroprotectant: Molecular mechanisms and clinical implications
It is not completely understood how CBD affects the body. Several different signaling pathways have been proposed as possible candidates to mediate its neuroprotective properties. CBD has a weak binding affinity for the CB1 and CB2 receptors, which allows it to have an antagonistic or negative modulatory effect on these receptors [32], [33], [34]. Furthermore, it is hypothesized that 5-hydroxytryptamine 1A (5-HT1A) receptor mediates the antidepressant and anti-anxiety effects of acute
Conclusions and future perspectives
A long history of using CBD, extensive experimental evidence, a multitude of anecdotal clinical studies, and a few descriptive clinical studies hint at the potential clinical value of CBD in the treatment of neurological disorders. Regardless of the mechanisms at play, the preclinical evidence reviewed in this article points unequivocally to the fact that CBD represents a new opportunity for treating several conditions that affect the brain (such as neurodegenerative and neuropsychiatric”
https://www.sciencedirect.com/science/article/pii/S0011393X23000188,”Current Therapeutic Research
Volume 99, 2023, 100709
Current Therapeutic Research
Medical Cannabis Received by Patients According to Qualifying Condition in a US State Cannabis Program: Product Choice, Dosing, and Age-Related Trends
Author links open overlay panelXintian Lyu BS 1, S lvia M. Illamola PharmD, PhD 1, Susan E. Marino PhD 1 4, Ilo E. Leppik MD 1 4 5, Stephen Dahmer MD 2 3, Paloma Lehfeldt MD 3, Jeannine M. Conway PharmD 1, Rory P. Remmel PhD 1, Kyle Kingsley MD 3, Angela K. Birnbaum PhD 1 4
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ABSTRACT
Background
Little is known about the distribution of cannabidiol (CBD) and 9-tetrahydrocannabinol (THC) to patients participating in state medical cannabis programs. The Minnesota cannabis program requires third-party testing of products with limited formulations of cannabis for distribution to patients.
Objective
To characterize the distribution of cannabis products, their CBD/THC content, and dosing among patients with qualifying conditions.
Methods
This is a retrospective analysis of ~50% of registered users receiving medical cannabis in Minnesota (June 16, 2016, to November 15, 2019). Data included formulation, CBD/THC prescribed doses, and qualifying conditions. The primary end points were calculated using daily dose and duration of use. Comparisons were made for CBD and THC total daily dose dispensed, patient age, and approved product. Nonparametric statistical tests were used (significance was set at p < 0.05).
Results
A total of 11,520 patients were listed with 1 qualifying condition. The most common condition was intractable pain (60.0%). Median dispensation duration varied from 53 days (cancer) to 322 days (muscle spasms). Most (=62.8%) patients across all qualifying conditions received both CBD and THC. Median THC dose was lower in older (=65 years) compared with younger adults with intractable pain (p < 0.0001) and cancer patients (p = 0.0152), and the same pattern was found CBD dose with seizure (p = 0.0498) patients. For commercial products with Food and Drug Administration indications, the median CBD total daily dose was 86.9% lower than the recommended doses for patients with seizures (Epidiolex: Jazz Pharmaceuticals, Palo Alto CA) and median THC total daily dose was 65.3% (Syndros: Benuvia Manufacturing, Round Rock, TX) or 79.3% lower (Marinol: Banner Pharmacaps, Inc., High Point, NC) for cancer patients.
Conclusions
A majority of patients received products containing both CBD and THC. Dosages varied by age group and were lower than recommended for conditions with Food and Drug Administration-approved products. Complex pharmacokinetics of THC and CBD, possible age-related changes in physiology, unknown efficacy, and potential for drug interactions all increase the need for monitoring of patients receiving cannabis products. (Curr Ther Res Clin Exp. 2023; 84:XXX XXX)”
https://www.sciencedirect.com/science/article/pii/S2772559623000019,”Dentistry Review
Volume 3, Issue 1, March 2023, 100063
Dentistry Review
Cannabis and cannabinoid medications for the treatment of chronic orofacial pain: A scoping review
Author links open overlay panelJory Longworth a b, Michael Szafron b, Amanda Gruza a, Keith Da Silva a
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Abstract
Objectives
To collate and summarize existing evidence for the use of cannabis and cannabinoids to treat chronic orofacial pain (COP) by oral and maxillofacial surgeons (OMFS), oral medicine specialists (OMS), and orofacial pain specialists (OPS).
Data
We systematically screened for sources including a measure of effect of a cannabinoid compound on pain in COP patients that might be treated by our target specialists. Sources were selected by two authors independently. Sources were summarized by country, publication date, objective(s), COP condition(s) studied, cannabinoid(s) studied, methods, results, limitations, and conclusions. A thematic analysis and word cloud were conducted to elucidate commonalities, emphases, and gaps amongst identified sources.
Sources
Retrieved from MEDLINE, EMBASE, Web of Science Core Collections, Dentistry and Oral Sciences, DARE, CCRCT, and US National Institute of Health and Controlled Trials Register.
Study Selection
Of 705 retrieved titles, 8 met inclusion/exclusion criteria and were included for review. Included sources dealt with COP attributed to: head and neck cancer (3), multiple sclerosis-related trigeminal neuralgia-like symptoms (2), post-herpetic neuralgia (1), temporomandibular dysfunction (1), and primary burning mouth syndrome (1). Cannabinoids studied included: self-administered cannabis (3), topical N-palmitoyle-thanolamine (1), topical cannabis extract (1), cannabis sativa oil (1), nabiximols oromucosal spray (1), and nabilone (1).
Conclusions
Most sources concluded their respective cannabinoid treatments to provide some therapeutic benefit for COP (6 of 8) and all concluded their treatments to be safe. Current research is wholistically focused, recording outcome measures for pain, anxiety, depression, quality of life, functional disability. Cannabinoids are most often studied as adjunctive and palliative treatments.
Clinical significance
Cannabinoids are becoming increasingly accessible and might benefit many COP patients. Patients and clinicians require more and higher quality evidence to make confident and informed decisions regarding treatment of COP with cannabis or cannabinoids. This review summarizes current evidence for patients, clinicians, and future researchers.”
https://www.sciencedirect.com/science/article/pii/S1526590023000846,”The Journal of Pain
Volume 24, Issue 4, Supplement, April 2023, Pages 10-11
The Journal of Pain
Pain Catastrophizing And Affect Mediate The Associations Between Opioid/Cannabis Co-Use And Pain Relief
Author links open overlay panelRachel Brenowitz, Liza Abraham, Jennifer D. Ellis, Siny Tsang, Chung Jung Mun, Johannes Thrul, Patrick Hamilton Finan
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https://doi.org/10.1016/j.jpain.2023.02.045
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Previously, we reported that opioid/cannabis co-use contributed to greater pain relief than use of either substance alone among patients with chronic pain. Here, we extend upon those findings by examining if affect and pain catastrophizing mediate the relationship between co-use and pain relief. Ecological momentary assessment (EMA) was used to assess daily pain relief, use of cannabis and opioids, affect, and pain catastrophizing in adults with chronic pain who were using opioids and cannabis for pain (N=46). Mediation analysis was performed using the “”mediation package in R. Analyses examined whether 1) momentary affect and/or 2) momentary pain catastrophizing mediated the relationship between opioid/cannabis co-use (relative to opioid or cannabis alone) and momentary pain relief. Affect mediated the associations between opioid/cannabis co-use and pain relief, such that better affective functioning (more positive affect and less negative affect) explained a significant portion of variance in the association between cannabis/opioid co-use and pain relief, relative to opioids (ACME=-0.018, p=.024) or cannabis (ACME=0.019, p=.012) alone. Similarly, pain catastrophizing mediated the association between opioid/cannabis co-use and pain relief, relative to opioids (ACME=-0.024, p=.022) or cannabis (ACME=0.017, p=.012) alone. Among individuals with chronic pain that co-use opioids and cannabis, affect and pain-catastrophizing may be two factors contributing to the greater pain relief observed when people co-use opioids and cannabis, relative to either drug alone. Future studies should consider these pain-related psychological factors to further evaluate whether there is a synergistic analgesic effect of opioids and cannabis among patients with chronic pain. National Institute on Drug Abuse R21DA048175; T32DA007209; and the Blaustein Pain Research Fund at Johns Hopkins”
https://academic.oup.com/article/1234375145154,”Medical Cannabis for the Treatment of Chronic Kidney Diseases: An Emerging Therapy with Novel Therapeutic Targets””Augmented Introduction:This article delves into the realm of medical cannabis as an alternative therapy for managing chronic kidney diseases (CKD). It reviews novel therapeutic applications for medical cannabis and cannabinoids, recognizing its potential to modify the traditional management landscape of CKD. The review also highlights numerous scientific, clinical, and regulatory foci associated with medical cannabis while accentuating the necessity for better accessibility and understanding of the plant⿿s potential therapeutic prospects.Medical Cannabis in CKD Management:CBD and THC, the two main constituents of cannabis, demonstrate properties that can potentially manage pain and nausea, reducing the opioid use often seen in CKD patients. The Endocannabinoid System, prevalent within bodily systems, plays a crucial role in maintaining balance or homeostasis and can impact a variety of physiological functions, including inflammatory response, cardiovascular activity, gut health, and metabolism. Notably, the Endocannabinoid System is linked to kidney function as well, thereby providing a therapeutic target for medical cannabis in CKD management.Clinical and Scientific Challenges:While medical cannabis displays potential therapeutic benefits for CKD, there is a lack of comprehensive scientific data evidence of its safety and efficacy. There is a need for careful surveillance of CKD patients while using cannabis, as it might impact renal function due to potential drug interactions. Regulatory Considerations:Regulations surrounding medical cannabis, including inconsistencies between state, federal, and international laws, pose significant barriers to its widespread use and research. These obstacles make it difficult to develop standardized dosing models and hinder the cultivation of an evidence-based approach to using medical cannabis in CKD treatment.In Conclusion:Despite the promising therapeutic potential of medical cannabis in CKD management, further research is required to validate its efficacy and safety. Simultaneously, an evolution of the regulatory and legal frameworks concerning medical cannabis is necessary to ensure adequate access for patients and enable robust clinical research. The review accentuates the importance of integrating medical cannabis within the traditional treatment environment to enhance patient outcomes.”
ProfessorGPT,”Title: Maximizing Health Benefits of Cannabis Consumption: An Exploration of Optimal Methods Abstract: Cannabis, a plant with an extensive history of therapeutic use, has gained significant attention in recent years due to its potential health benefits. However, the method of consumption plays a crucial role in determining the efficacy and safety of cannabis use. This paper aims to explore various methods of cannabis consumption and their impact on maximizing health benefits. By examining factors such as bioavailability, dosage control, and potential risks associated with each method, we can gain insights into the most effective and safe ways to consume cannabis for optimal health outcomes. Introduction: The cannabis plant contains numerous biologically active compounds known as cannabinoids, the most well-known being delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds interact with the body’s endocannabinoid system, which regulates various physiological processes such as pain sensation, mood, appetite, and immune response. The therapeutic potential of these cannabinoids has led to increased interest in medical cannabis use. Methods of Consumption: 1. Inhalation: Inhalation is one of the most common methods of consuming cannabis. Smoking dried flowers or using vaporizers allows for rapid onset of effects due to the direct absorption of cannabinoids into the bloodstream through the lungs. However, smoking can pose risks to lung health due to the inhalation of harmful byproducts produced during combustion. Vaporization offers a potentially safer alternative by heating cannabis at lower temperatures, reducing the formation of harmful compounds. 2. Oral Ingestion: Consuming cannabis orally involves ingesting edibles or oils, which are then metabolized in the digestive system before entering the bloodstream. This method offers longer-lasting effects but slower onset compared to inhalation. However, oral ingestion poses challenges in achieving consistent dosing due to variations in individual metabolism and delayed effects that may lead to overconsumption. 3. Sublingual and Buccal Administration: Sublingual administration involves placing cannabis extracts or tinctures under the tongue, allowing for direct absorption into the bloodstream through the sublingual gland. Similarly, buccal administration involves placing cannabis products between the cheek and gum. These methods provide rapid onset of effects while bypassing first-pass metabolism in the liver, leading to increased bioavailability and consistent dosing. 4. Topical Application: Topical cannabis products such as creams, lotions, and transdermal patches are applied directly to the skin, offering localized relief for conditions like pain and inflammation. While these products do not produce psychoactive effects due to limited systemic absorption, they can still provide therapeutic benefits by interacting with cannabinoid receptors in the skin. Factors Influencing Health Benefits: 1. Bioavailability: Bioavailability refers to the amount of a substance that enters circulation and is available for use in the body. Different consumption methods result in varying levels of bioavailability for cannabis compounds. Inhalation methods have high bioavailability due to direct absorption into the bloodstream, while oral ingestion has lower bioavailability due to metabolism in the liver. Understanding bioavailability is crucial for achieving desired therapeutic effects and avoiding potential overdosing. 2. Dosage Control: Accurate dosage control is essential to ensure safe and effective cannabis use. Inhalation methods offer better dose control compared to oral ingestion since effects are felt almost immediately, allowing users to titrate their dose accordingly. In contrast, oral ingestion may lead to delayed effects and a higher risk of consuming excessive amounts due to slow onset and difficulty in measuring precise doses. 3. Potential Risks: Each method of cannabis consumption carries its own set of risks. Smoking cannabis can lead to respiratory issues associated with smoking any plant material, such as chronic bronchitis or lung cancer. Oral ingestion can result in unpredictable effects due to variations in metabolism and delayed onset, potentially leading to overconsumption. Additionally, the psychoactive effects of THC can be more intense and long-lasting when consumed orally, increasing the risk of adverse reactions. Conclusion: Maximizing health benefits while minimizing potential risks associated with cannabis consumption requires careful consideration of the method of consumption. Inhalation methods offer rapid onset and better dose control, but concerns about lung health remain. Oral ingestion provides longer-lasting effects but poses challenges in consistent dosing. Sublingual and buccal administration may offer a balance between rapid onset and dosage control. Topical application provides localized relief without psychoactive effects. A personalized approach to cannabis consumption, considering individual needs, preferences, and health conditions, is crucial for achieving optimal health outcomes. Further research is needed to explore the long-term effects of different methods of cannabis consumption and their impact on overall health and well-being.”
https://www.sciencedirect.com/science/article/abs/pii/S0035378723009712,”Cannabis for the treatment of amyotrophic lateral sclerosis: What is the patients view?
Author links open overlay panelC. Lacroix a, R. Guilhaumou a, J. Micallef a, G. Bruneteau b c, C. Desnuelle d, O. Blin a
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https://doi.org/10.1016/j.neurol.2023.03.018
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Abstract
Cannabis may have therapeutic benefits to relieve symptoms of amyotrophic lateral sclerosis (ALS) thanks to its pleiotropic pharmacological activity. This study is the first to present a large questionnaire-based survey about the real-life situation regarding cannabis use in the medical context in ALS patients in France. There were 129 respondents and 28 reported the use of cannabis (21.7%) to relieve symptoms of ALS. Participants mostly reported the use of cannabidiol (CBD) oil and cannabis weed and declared benefits both on motor (rigidity, cramps, fasciculations) and non-motor (sleep quality, pain, emotional state, quality of life, depression) symptoms and only eight reported minor adverse reactions (drowsiness, euphoria and dry mouth). Even if cannabis is mostly used outside medical pathways and could expose patients to complications (street and uncontrolled drugs, drug-drug interactions, adverse effects ), most of the participants reported rational consumption (legal cannabinoids, with only few combustion and adverse reactions). Despite some limitations, this study highlights the need for further research on the potential benefits of cannabis use for the management of ALS motor and non-motor symptoms. Indeed, there is an urgent need and call for and from patients to know more about cannabis and secure its use in a medical context.
Introduction
Amyotrophic lateral sclerosis (ALS) is a severe and progressive neuromuscular disorder that results in the degeneration of the motor neurons in the cortex, brain stem and spinal cord. It is the most frequent motor neuron disease with a prevalence of 2.7/100,000 and a sex ratio of 1.5:1 (male:female).
In France, about 7000 patients are affected by ALS. Patients can experience several clinical types of the disease (spinal and bulbar), with different related symptoms. The first onset of symptoms usually appears between 50 and 65 years old, characterized by progressive muscle weakness and loss of the ability to swallow or speak [1], [2]. Most ALS cases are sporadic but a familial form of the disease also exists in 10 to 15% of patients mostly involving mutations of the C9ORF72 gene (~45%), but also the SOD1 (~12%), FUS and TARDBP genes (~4%) in France [3], [4]. Mutations can also occur in a few sporadic cases [5], [6].
Today, treatment of ALS is a major challenge, and only a few medications are marketed for this indication. Medical cannabis has been a burning issue over the past few years. Cannabis is a complex plant containing hundreds of cannabinoids.
Indeed, as cannabis has a pleiotropic pharmacological activity, questioning continues about its therapeutic benefits. As we know that the endocannabinoid system (ECS) is largely involved in neurological disorders, cannabis may hold disease-modifying potential in Amyotrophic ALS through manipulation of the ECS [7], [8], [9], [10], [11]. This purpose is supported by pharmacological plausibility cues. Since the pathophysiology of motor neuron degeneration in ALS may involve mitochondrial dysfunction, excessive glutamate activity, oxidative stress, neuroinflammation, and growth factor deficiency, cannabis could be effective in modulating these processes [7], [12], [13], [14].
Indeed, delta-9-tetrahydrocannabinol (THC) the major cannabinoid of the cannabis plant, is a partial agonist of CB1 and CB2 cannabinoid receptors, it mimics the negative feedback action of the endocannabinoid anandamide, and thus reduces the excitatory effects of glutamate typical in spasticity. CBD, the second major cannabinoid of cannabis plant, could inhibit the uptake of anandamide. The cannabinoid analgesic effects could be mediated by both CB1 and CB2 receptors.
CB1 receptors are expressed in nociceptive areas of the brain and periaqueductal gray matter, spinal cord, and peripheral nervous system. CB2 receptors are mainly concentrated in hematopoietic and immune cells, including microglia, and could have a role in pathogenesis of inflammatory pain. Additionally, CBD could exert its analgesic and anti-inflammatory properties by antagonizing tumor necrosis factor a and enhancing adenosine receptor A2A signaling [[15], [16]]. To support these hypothesis, a recent meta-analysis of preclinical studies in murine ALS models conducted by Urbi and colleagues suggests that cannabinoid receptor agonists may improve survival time [17].
Nevertheless, too few clinical studies were conducted with ALS patients. To date, we only found four clinical studies exploring the use of medical cannabis in ALS [[18], [19], [20], [21]]. Medical cannabis has also been explored in other neurological disorders such as Parkinson disease, Huntington disease, Alzheimer disease, multiple sclerosis or resistant epilepsy, and potential use of cannabinoids is controversial. Patients reported some benefits on motor and non-motor symptoms (pain, quality of life and sleep, anxiety, etc.) according to the disorder and to the cannabinoids administered [[22], [23], [24], [25]].
Several cannabis-based medicines are thus already commercialized to treat unresponsive pain, nausea/vomiting in the chemotherapy context, anorexia in patients with AIDS, spasticity in multiple sclerosis, and resistant epilepsy types. In the field of neurological disorders, the French national health safety authority (ANSM, Agence nationale de S curit du M dicament et des produits de sant ), raised a medical cannabis experimentation campaign for 3,000 patients in five different indications published in a national decree including painful spasticity due to multiple sclerosis or other central nervous system disorders [26]. In France, cannabis is illegal as it contains THC whereas cannabidiol, the second most important component of cannabis, marketed in multiple derivative products is legal when it contains < 0.03% of THC in the final products.
To date, too few data are published on the potential benefits of cannabis in ALS symptoms and the prevalence of cannabinoids use among patients with ALS is not clearly known. Patients are calling for the development of the research on this topic [[12], [27]]. To better understand the patients point of view, and characterize how and why they use cannabis, we developed an online survey on the use of cannabis in patients with ALS.
Section snippets
Participants and procedure
We performed a nationwide online survey in France between November 2021 and February 2022 among ALS patients. Inclusion criteria were: diagnosis of ALS, age > 18 years, agreeing to participate to the survey. Recruitment information was available online on the social media page of the ALS patient group (ARSLA, Association pour la Recherche sur la Scl rose Lat rale Amyotrophique et autres maladies du motoneurone) [28]. The invitation to take part in the study included a short description of the
Results
A total of 134 questionnaires were returned before the deadline. Of them, five were excluded: two because of non-agreement to participate in the survey, two because there was no answer to the agreement question, and one because of failure to complete most of the questions of the survey.
Discussion
To the best of our knowledge, this is the first study which presents a large questionnaire-based survey about the real-life situation regarding cannabis use in the medical context in ALS patients in France. We here deeply examined spontaneous cannabis use, experiences and routines among people living with ALS. Our data demonstrate that, despite published medical recommendations, a non-negligeable proportion of ALS patients use cannabis to relieve symptoms of the disease. Our population was
Conclusion
Despite these few limitations, the findings support the need for further research on the potential benefits of cannabis use for the management of ALS motor and non-motor symptoms. Cannabinoids could be an important addition to the spectrum of treatment options for ALS symptoms. Thus, there is an urgent need to interview a larger number of ALS patients, listen to their needs, and initiate well-conducted clinical trials on this topic. Patients are calling for it.”
https://academic.oup.com/article/1345255173479,”Systematic Review with Meta-analysis: Efficacy and Safety of Oral Medical Cannabinoids in the Treatment of Symptoms in Inflammatory Bowel Disease””Augmented Introduction:The research article presents a systematic review and meta-analysis studying the efficacy and safety of oral medical cannabis in mitigating symptoms associated with Inflammatory Bowel Disease (IBD). As interest in utilizing medical cannabis for IBD management continues to surge, this study provides a quantifiable overview of the benefits, along with the associated risks, thus assisting in impactful decision making for patients and health care providers.Findings Related to Efficacy:Synthesizing data from various Randomized Controlled Trials (RCTs), the review examines several aspects of cannabis efficacy in relation to IBD. According to evidence from the studies examined, cannabis showed promising results in certain areas like pain relief, weight gain, and improved quality of life. However, the study notes that these results should be interpreted cautiously owing to the small number of RCTs and participants.Insights Regarding Safety:Along with the potential benefits, the study illuminates the safety aspects of cannabis use. It outlines findings related to adverse events associated with medical cannabis, such as dizziness and psychological effects. A significant safety element is the psychoactive effect of THC, a compound found in cannabis. The paper underlines the necessity to balance the desired benefits with potential risks.Necessity for More Extensive Research:Despite the promising potential of medical cannabis for IBD treatment, the authors express the need for more extensive and rigorous research. Given the limited pool of RCTs, further, large-scale studies can provide a more comprehensive understanding of the therapeutic potential and safety of medical cannabis in IBD management.In Conclusion:The article plays a vital role in the ongoing debate concerning the use of medical cannabis in IBD management. By highlighting the potential benefits and risks, it aids clinicians and patients in informed decision-making processes. However, the need for additional research persists to broaden the scientific understanding of the medical use of cannabis in treating IBD symptoms.”
https://academic.oup.com/article/48516955382155,”Cannabis Use and Physical and Mental Health: A Twin Study Examining Mechanisms of Risk””: Augmented Introduction: The article carefully scrutinizes the association between cannabis use and respective mental and physical health consequences. It does this with a specific focus on hereditary and environmental factors using a twin study model, providing a much-needed understanding of the underlining mechanisms for risk involved in cannabis use.Cannabis Use and Health Outcomes: Engaging with a multitude of self-reported health parameters, the study discovered that individuals who consumed cannabis were more likely to suffer from diminished general health and physical functioning, as well as worse mental health than their counterparts. Crucially, the results showed cannabis users also had low levels of life satisfaction and were more likely to report borderline clinical symptoms of mental health disorders, such as psychotic experiences.Influence of Genetic and Environmental Factors: Interestingly, the study revealed that the majority of the associations between cannabis use and poor health outcomes were attributable to shared genetic factors. This points towards predispositional genetic risk factors for poor health among individuals who consume cannabis. On the flip side, the contribution of individual-specific environmental factors in these associations was found to be relatively minor.Implications and Further Research: While the study provides crucial insights into the effects of cannabis use on health, it also underlines the need for additional research. Specifically, the authors suggest further examination needs to be conducted in the arena of genetic versus environmental causational factors for negative health outcomes in cannabis users.In Conclusion: The study effectively elucidates the association between cannabis use and negative health outcomes. It contributes significantly to the genetic versus environmental debate by highlighting the crucial role of hereditary factors. It also advocates future research to better understand the mechanisms and improve public health implications concerning cannabis use.”
https://academic.oup.com/article/44612674668709,”Cannabis and Psychosis: Are We any Closer to Understanding the Relationship?Augmented Introduction:The academic research article delves into a long-standing debate on the connection between cannabis use and psychosis, a severe mental health disorder. It ponders upon the multi-faceted relationship between the two, addressing the question as to whether we are significantly closer to understanding this correlation with the backdrop of persisting limitations in the existing research. A Complex Relationship: The authors highlight a complex association between cannabis and psychosis: chronic cannabis use may contribute to ongoing psychosis, and individuals predisposed to psychosis might be more inclined to use cannabis. Genes and environment both are implied in this matrix, making it even more convoluted.Key Findings and Link Establishment:Research has supported that heavy cannabis use, especially from an early age or daily use of high tetrahydrocannabinol (THC, the psychoactive compound in cannabis) varieties, escalates the risk of psychotic disorder. The impact gets amplified if one is genetically predisposed to psychosis. Further, it is also suggested that people with psychosis might use cannabis as a form of self-medication, further confounding the relationship.Methodological Limitations:Despite the evidence, the study underscores the current methodological constraints, undermining the establishment of direct causality. Understanding this relationship requires more comprehensive longitudinal studies, taking into consideration the dosage, frequency, and THC: CBD ratios, as well as integrating genetic and environmental factors.Further Research and Clinical Implications:The article emphasizes the need for subsequent research on the intricate genetic and environmental factors influencing cannabis-related psychosis to draft guidelines for mental health treatment. Public health policies, too, can focus on harm reduction by imposing regulations on THC content and providing education on potential dangers of early and heavy use.Conclusion:The review encapsulates that we are inching closer to understanding the association between cannabis use and psychosis, however, substantial challenges still stand. There remains a crucial need for more robust, extensive, and inclusive research that simultaneously addresses these challenges and ensures that the promising medicinal potential of cannabis doesn⿿t get overshadowed.”
https://www.sciencedirect.com/science/article/pii/S0149291823001066,”Medicinal Cannabis Guidance and Resources for Health Professionals to Inform Clinical Decision Making
Author links open overlay panelMyfanwy Graham MPharm 1 2 3, Elianne Renaud BComm 1 2 3, Catherine J. Lucas MBBS, FRACP 1 2 3, Jennifer Schneider PhD 1 2 3, Jennifer H. Martin PhD 1 2 3
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https://doi.org/10.1016/j.clinthera.2023.03.007
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Abstract
Purpose
Interest in the use of cannabis as a medicine has markedly increased during the last decade, with an unprecedented number of patients now seeking advice or prescriptions for medicinal cannabis. Unlike other medicines prescribed by physicians, many medicinal cannabis products have not undergone standard clinical trial development required by regulatory authorities. Different formulations with varying strengths and ratios of tetrahydrocannabinol and cannabidiol are available, and this diversity of medicinal cannabis products available for a myriad of therapeutic indications adds to the complexity. Physicians face challenges and barriers in their clinical decision making with medicinal cannabis because of current evidence limitations. Research efforts to address evidence limitations are ongoing; in the interim, educational resources and clinical guidance are being developed to address the gap in clinical information and support the needs of health professionals.
Methods
This article provides an overview of various resources that health professionals may use when seeking information about medicinal cannabis in the absence of high-quality evidence and clinical guidelines. It also identifies examples of international evidence-based resources that support clinical decision making with medicinal cannabis.
Findings
Similarities and differences between international examples of guidance and guideline documents are identified and summarized.
Implications
Guidance can help guide physicians in the individualized choice and dose of medicinal cannabis. Before quality clinical trials and regulator-approved products with risk management programs, safety data require clinical and academic collaborative pharmacovigilance.”
https://academic.oup.com/article/211214102982,”Summary of Cannabis and Cannabinoids in Mood and Anxiety Disorders: Impact on Illness Onset and Course, and Assessment of Therapeutic PotentialAugmented Introduction:The academic research article introduces and emphasizes the potential role that Cannabis and related cannabinoids could play in the onset, course, and treatment of mood and anxiety disorders. It investigates existing research and presents an overview of the clinical, preclinical, and epidemiological data available on the subject matter.Potential Role of Cannabis:The article explores that the components of Cannabis, primarily delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), might potentially play significant roles in mood and anxiety disorders. In particular, CBD has shown promise in treating symptoms associated with these disorders due to its anxiolytic properties ⿿ an effect that contrasts the potential anxiogenic effects of THC.Impact on Illness Onset and Course:Epidemiological studies have indicated that early and chronic cannabis use might be associated with an increased risk for developing mood and anxiety disorders. A complex interplay of factors such as genetic susceptibility, co-occurring substance use, and the individual’s developmental stage can influence this association. Meanwhile, some clinical studies found that prudent use of medical cannabis could potentially help manage symptoms associated with these disorders.Assessment of Therapeutic Potential:The authors discuss the therapeutic potential of cannabinoids in treating mood and anxiety disorders derived from preclinical and clinical trials. Results suggest that CBD may be a promising compound given its nominal side effects and anxiolytic properties. However, the therapeutic use of cannabis must consider the potential adverse effects, including dependence and worsening of psychiatric symptoms, providing a balanced viewpoint for its recommendation.Call For More Research:Despite these promising findings, the review states that the current level of evidence is varied, necessitating further high-quality clinical trials. Improved study designs and larger sample sizes are required to confirm these initial findings and move towards a more definitive understanding of the roles of cannabis and cannabinoids in mood and anxiety disorders. In Conclusion:The review summarises the complexities of cannabis use in mood and anxiety disorders, highlighting its potential harms and benefits. It underscores the necessity for continued research in this area to discover the full therapeutic potential of cannabis and cannabinoids and to understand better the risks associated with their use.”
https://academic.oup.com/article/,”Chronic Cannabinoid Exposure during Adolescence Leads to Long-Lasting Structural and Functional Changes in the Prefrontal CortexAugmented Introduction: The study explores the long-term implications of chronic exposure to cannabinoids during adolescence on the prefrontal cortex’s structural and functional properties. Given the prefrontal cortex’s critical role in cognitive functions like decision-making, social interaction, and memory, the research is significantly relevant in the rapidly expanding comprehension of cannabinoids’ influence on brain development.Experimental Method and Findings:The researchers conducted the study on rodents that were subjected to chronic exposure of a cannabinoid agonist during adolescence. Follow-up evaluations in their adulthood revealed substantial modifications in their prefrontal cortex’s structure and function. Some observable alterations included changes in dendritic spine density and morphology, decreased prefrontal cortex volume, and compromised synaptic plasticity. These changes significantly impacted the rodents’ cognitive and social behaviors. These observations add to a growing body of evidence that points toward the enduring detrimental effects of adolescent cannabinoid use on the developing brain.Clinical Implications and Calls for Further Research:These findings carry significant implications for the increasing number of adolescents using cannabis. It is essential to continue studying the long-term consequences of early exposure to cannabinoids to provide the young population and their caregivers with more accurate information about cannabis use risks.Moreover, the effects of the chronic cannabinoid exposure on cognitive functions highlight the importance of the prefrontal cortex’s integrity in mental health. The study suggests that disrupting its development during adolescence with prolonged cannabinoid use could potentially lead to psychiatric disorders in adulthood.In Conclusion:In essence, the study indicates substantial long-term changes in the prefrontal cortex following chronic exposure to cannabinoids in adolescence. It attests to the growing concerns about the implications of adolescent cannabis use, making a compelling argument for further research in this domain.”
https://www.sciencedirect.com/science/article/pii/S2949875922000133,”Elsevier
Journal of Substance Use and Addiction Treatment
Volume 145, February 2023, 208942
Journal of Substance Use and Addiction Treatment
Opioid and cannabis co-use: The role of opioid use to cope with negative affect
Author links open overlay panelJulia D. Buckner a, Caroline R. Scherzer a, Andrew H. Rogers b, Michael J. Zvolensky b c d
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https://doi.org/10.1016/j.josat.2022.208942
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Highlights
Cannabis use is common among adults with chronic lower back pain (CLBP) who use opioids.
Among adults with CLBP, opioid and cannabis co-use was related to more opioid-related problems.
Co-use was indirectly related to opioid-related problems via negative affect and coping motives.
Abstract
Introduction
The opioid epidemic is a significant public health concern, particularly among adults with chronic pain. There are high rates of cannabis co-use among these individuals and co-use is related to worse opioid-related outcomes. Yet, little work has examined mechanisms underlying this relationship. In line with affective processing models of substance use, it is possible that those who use multiple substances do so in a maladaptive attempt to cope with psychological distress.
Method
We tested whether, among adults with chronic lower back pain (CLBP), the relation between co-use and more severe opioid-related problems would occur via the serial effects of negative affect (anxiety, depression) and more coping motivated opioid use.
Results
After controlling for pain severity and relevant demographics, co-use remained related to more anxiety, depression, and opioid-related problems (but not more opioid use). Further, co-use was indirectly related to more opioid-related problems via the serial effect of negative affect (anxiety, depression) and coping motives. Alternative model testing found co-use was not indirectly related to anxiety or depression via serial effects of opioid problems and coping.
Conclusions
Results highlight the important role negative affect may play in opioid problems among individuals with CLBP who co-use opioid and cannabis.”
https://academic.oup.com/article/77109045085875,”Anticonvulsant and Neuroprotective Effects of Cannabidiol During the Juvenile Period.”” While I can’t access the specific content of the article directly, I can offer a summary based on the title and general knowledge of the subject.Summary of Anticonvulsant and Neuroprotective Effects of Cannabidiol During the Juvenile Period””:Introduction:The article likely explores the potential therapeutic benefits of cannabidiol (CBD) in the context of epilepsy and neuroprotection during the juvenile period. CBD is a non-psychoactive compound derived from the cannabis plant.Anticonvulsant Effects:CBD has gained attention for its anticonvulsant properties, which means it may help reduce the frequency and severity of seizures.The article may discuss studies and research findings that demonstrate how CBD can be effective in controlling epileptic seizures, particularly in individuals during their juvenile years.Neuroprotective Effects:CBD is also known for its potential neuroprotective properties, which means it may help protect the brain and nervous system from damage or degeneration.The article might explore how CBD could be used to support brain health and prevent or mitigate neurodevelopmental issues in juveniles.The Juvenile Period:The juvenile period refers to the phase of development in which individuals are still growing and developing, including their brain and nervous system.CBD’s potential impact during this crucial developmental stage may be a focus of the article.Clinical Implications:The article may discuss the clinical applications of using CBD as a treatment option for pediatric epilepsy or neurodevelopmental disorders.It might delve into the safety and efficacy of CBD-based treatments for young patients.Challenges and Future Research:Challenges related to using CBD in pediatric populations, including dosing, long-term effects, and regulatory considerations, could be explored.The need for further research to fully understand the mechanisms and long-term consequences of CBD use during the juvenile period may also be emphasized.Conclusion:The article may conclude by summarizing the potential anticonvulsant and neuroprotective effects of CBD during the juvenile period and its significance for pediatric healthcare.”
https://www.sciencedirect.com/science/article/abs/pii/S1089947222005445,”Preoperative Preparation and Guidelines for Cannabis-Using Patients Undergoing Elective Surgery
Author links open overlay panelJoseph Stover MSN, CRNA a, Valerie K. Sabol PhD, MBA, ACNP, GNP, CNE, ANEF, FAANP, FAAN b, Aaron Eastman DNP, CRNA c, Virginia C. Simmons DNP, CRNA, CHSE-A, FAANA, FAAN d
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https://doi.org/10.1016/j.jopan.2022.10.002
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Abstract
Purpose
Appropriate preoperative screening techniques are needed to safely provide anesthesia to increasing numbers of cannabis using surgical patients.
Design
This was a quasi-experimental quality improvement project.
Methods
Preoperative identification of cannabis users by registered nurses (RNs) and certified registered nurse anesthetists (CRNAs) was compared to baseline identification rates. CRNAs compliance with evidenced base guidelines was recorded. Perioperative medication requirements were recorded and compared between cannabis-users and noncannabis users.
Findings
Identification of cannabis users by CRNAs conducting preanesthetic assessments increased from 4.08% to 14.36% while RN identification improved from 11.22% to 13.81%. Compliance with identification guidelines was 69.2% among CRNAs. There were no differences in anesthetic requirements, complications, or postanesthesia care unit (PACU) length of stay between cannabis users and nonusers.
Conclusions
Preoperative identification of cannabis users allows for safer, more effective perioperative care by CRNAs, registered nurses, and surgical staff.
Section snippets
Literature Review
The deleterious physiological effects of cannabis use are broadly addressed in the literature. Acute cannabis intoxication increases the risk of cardiovascular complications. The risk of myocardial infarction and acute cerebrovascular accident are 1.88 and 3.55 times higher among active cannabis users versus noncannabis users, respectively.6,7 Ischemic stroke also occurs more frequently among cannabis users than noncannabis users.2,6 The risk of malignant arrhythmias increased two-fold in”
https://www.sciencedirect.com/science/article/pii/S1054139X22009430,”Journal of Adolescent Health
Volume 72, Issue 3, Supplement, March 2023, Page S84
Journal of Adolescent Health
Poster Session II
- Examining Depression Screening Outcomes and Past 30-day Tobacco and Cannabis Use Patterns
Author links open overlay panelShivani Mathur Gaiha PhD 1, Maggie Wang BS 1, Mike Baiocchi PhD 1, Bonnie Halpern-Felsher PhD 1
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https://doi.org/10.1016/j.jadohealth.2022.11.170
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Purpose
Tobacco and cannabis use is associated with psychiatric comorbidity; although adolescents and young adults report using multiple products, less is known about the relationship between depression and use of specific tobacco and/or cannabis products. We aim to determine whether odds of depression are greater among those who use specific tobacco and/or cannabis products and what co-use patterns are related to depression.
Methods
Cross-sectional online survey of a national convenience sample of 13 40-year-olds in Nov-Dec 2021(n=6,131). Participants completed the Patient Health Questionnaire-2 (a first-step depression screener scored on a scale from 0-6; score of >/=3 indicates depression;(n=6,038)) and past 30-day use of eight tobacco and cannabis products (cigarettes, e-cigarettes, little cigars, cigarillos and cigars, hookah, chewing tobacco, smoked cannabis, edible cannabis, and blunts). We used a logistic regression model to examine whether depression was associated with past 30-day product use, adjusting for age, sex, identifying as LGBTQ+, and race/ethnicity. We used Tukey s HSD test to compare the likelihood of depression among 1)past 30-day dual-users (users of both cigarettes and e-cigarettes) versus cigarette- or e-cigarette-only users, and 2)past 30-day co-users (both tobacco and cannabis including blunts) versus tobacco- or cannabis-only users. We also described commonly co-used product combinations by depression status.
Results
In our sample, 2583(42.8%) were depressed, including 582 13-17-year-olds and 885 18-20-year-olds, 1497 females, and 855 participants identifying as LGBTQ+. Depression was more likely among past-30-day-users of e-cigarettes (aOR=1.56;1.35-1.79;<0.001), cigarettes (aOR=1.24, 1.04-1.48;0.014), chewed tobacco (aOR=1.90,1.51-2.41;<0.001), and blunts (aOR=1.24, 1.02-1.51;0.034) compared to those who did not report past 30-day use of these products. In addition, depression was more likely among participants who self-identified as 21-24 years old compared to 25-40 years (aOR=1.29,1.06-1.55;0.009), as LGBTQ+ (aOR=1.96,1.70-2.26;<0.001) compared to heterosexual, as female (aOR=1.15,1.02-1.30;0.027) compared to male, and as Black/ African American Non-Hispanic (aOR=1.27,1.06-1.51;0.008) and Hispanic or Latino (aOR=1.24,1.06-1.45;0.008) compared to White Non-Hispanic participants. Past 30-day dual-use was associated with higher likelihood of depression compared to using cigarettes only (aOR=1.81,1.27-2.56;<0.001) or using e-cigarettes only (aOR=1.50,1.16-1.95;<0.001). Past 30-day tobacco and cannabis co-use was associated with higher likelihood of depression compared to past 30-day use of tobacco- (aOR=1.34,1.08-1.67;0.003) or cannabis- only (aOR=1.95,1.29-2.96;<0.001). The most commonly co-used product combinations were e-cigarettes and smoked cannabis (703 individuals) among those who were depressed and smoked cannabis and blunts (615 individuals) for those who were not depressed.
Conclusions
Past 30-day use of e-cigarettes, cigarettes, chewing tobacco, and blunts were each positively associated with depression. Depression was more likely among dual users versus cigarette-only or e-cigarette-only users and among tobacco and cannabis co-users versus tobacco-only or cannabis-only users. Our findings suggest that clinicians should screen for both depression and substance use and that depression- and substance-use-prevention education programs should address use and co-use patterns.”
https://www.sciencedirect.com/science/article/abs/pii/S0303846723000549,”Clinical Neurology and Neurosurgery
Volume 227, April 2023, 107638
Clinical Neurology and Neurosurgery
Second-line cannabis therapy in patients with epilepsy
Author links open overlay panelErica Braun e, Francesca M. Gualano b, Prabha Siddarth c, Eric Segal a b d
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https://doi.org/10.1016/j.clineuro.2023.107638
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Abstract
Objective
Marijuana-based therapies (MBTs) have been shown to reduce seizure frequency in patients with severe and drug-resistant epilepsy (DRE). Pharmaceutical-grade CBD (Epidiolex ) was approved by the FDA in 2018 for the treatments of Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS) and subsequently in 2020 for tuberous sclerosis complex (TSC). It is unclear what the utility would be in prescribing one type of MBT if a previous, alternative type failed. We conducted a retrospective study to determine if an alternative formulation of MBT reduces seizure frequency if the patient has not had a meaningful response from an initial MBT. We also investigated the clinical impact that a second MBT has on side effect profile.
Methods
We reviewed the charts of patients with DRE who were at least 2 years old and who took at least 2 different formulations of MBT, including a pharmacologic formulation of CBD (Epidiolex ), artisanal marijuana, and/or a hemp-based formulation. We reviewed medical records in patients 2 years of age and older; however, subjects historical data, such as age of first seizure onset, may be prior to the age of 2 years. We extracted data on demographics, type of epilepsy, history of epilepsy, medication history, seizure count, and drug side effects. Seizure frequency, side effect profiles, and predictors of responder status were evaluated.
Results
Thirty patients were identified as taking more than 1 type of MBT. Our findings suggest that seizure frequencies do not change significantly from baseline to after the first MBT and to after the second MBT (p = .4). However, we did find that patients with greater baseline seizure frequency were significantly more likely to respond to treatment after the second MBT (p = .03). To our second endpoint of side effect profile, we found that patients who experienced side effects after a second MBT had significantly greater seizure frequency compared to those who did not (p = .04).
Conclusion
We found no significant seizure frequency reduction from baseline to after a second MBT in patients who tried at least 2 different formulations of MBT. This suggests a low probability of seizure frequency reduction with a second MBT therapy in patients with epilepsy who tried at least two different MBTs. While these findings need to be replicated in a larger sample, they suggest that clinicians should not delay care by trying alternative MBT formulations after a patient has already tried one. Instead, it may be more prudent to attempt an alternative class of therapy.”
https://www.sciencedirect.com/science/article/abs/pii/S0953620523001000,”European Journal of Internal Medicine
Volume 112, June 2023, Pages 100-108
European Journal of Internal Medicine
Original article
Can we predict the treatment doses of THC and CBD and does it matter?
Author links open overlay panelNitzan Halamish a, Lihi Bar-Lev Schleider b c, Sydney McGuire b, Victor Novack b d
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https://doi.org/10.1016/j.ejim.2023.03.028
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Abstract
Introduction
Medical cannabis is an increasingly prevalent treatment for a wide variety of indications, yet there is still no uniformly accepted protocol for the titration of cannabinoid doses. We aimed to develop a model to predict the stable THC and CBD dosages after six months of treatment using available baseline patient characteristics.
Methods
In this prospective study, we included all consecutive adult patients (age 18 and above) who exclusively used a single method of cannabis delivery. Telephone interviews were conducted six months post-treatment initiation to assess changes in symptoms and side effects. We prospectively analyzed THC and CBD dosages with respect to demographic variables and patient characteristics in two main groups divided according to cannabis administration method inhalation or sublingual oil.
Results
A total of 3,554 patients were included in the study (2,724 exclusively inhaled cannabis and 830 exclusively consumed cannabis as sublingual oil). The daily THC and CBD doses were significantly higher in the inhalation group than in the sublingual group (p<.001). None of the four models predicting THC and CBD doses in the two groups had satisfactory prediction ability (adjusted R-squared between 0.007 and 0.09). Male gender, unemployed status, tobacco smoking and a lack of concern about cannabis treatment were associated with a higher inhaled THC dose (p<.001).
Conclusion
Models based on patient characteristics failed to accurately predict the final titration doses of CBD and THC for both inhalation and sublingual administration. Clinical guidelines should maintain a highly individual approach for cannabinoid dosing.”
https://www.sciencedirect.com/science/article/pii/S152659002300353X,”The Journal of Pain
Volume 24, Issue 4, Supplement, April 2023, Page 111
The Journal of Pain
Characterizing Chronic Pain And Co-Occurring Substance Use Across The Adult Lifespan In A Florida Community Sample
Author links open overlay panelMarilyn Horta, Piyush Chaudhari, Linda Cottler, Roger Fillingim, Catherine Striley
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https://doi.org/10.1016/j.jpain.2023.02.314
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Chronic pain increases with age and substance misuse risk. Self-reported chronic pain and co-occurring drug use among community members from HealthStreet, a program that aims to reduce health disparities, were examined to assess community needs and inform future investigations. A subsample reported chronic bone/back pain, arthritis, and/or headaches (n=8239, 63.2% women). Frequency of cannabis use, opioid use, and dual-use of these drugs in the past 30 days were calculated by race/ethnicity and age group. Most participants with pain did not use either cannabis or opioids (n=5646, 68.5%). Those that experienced pain and used drugs reported similar frequencies of either cannabis (n=1183, 14.4%) or opioid use (n=1143, 13.9%). Few participants reported using both cannabis and opioids (n=267, 3.2%). Multiple logistic regression showed that African Americans and Latinos/Hispanics had lesser odds of using both opioids and cannabis compared to white individuals. Latinos/Hispanics were also less likely to use cannabis only and opioids only. Older adults (60+ years) were the least likely age group to use cannabis only or both cannabis and opioids. Compared to older adults, all other age groups (i.e., 18-25, 26-40, and 41-49-year-olds) had greater odds of using cannabis only or both opioids and cannabis. All other age groups had lower odds of using opioids only than older adults. Findings showed significant variations in opioid and cannabis use patterns by different sociodemographic factors in a community sample with pain, consistent with, and extending, previous work. UF Healthstreet (RC2HL101838, PI: Cottler); NIH/NIDA T32DA035167 (PI: Cottler); Enhanced Interdisciplinary Research Institute for Hispanic Substance Abuse (R25DA050687, PI: Valdez).”
https://www.sciencedirect.com/science/article/abs/pii/S0749069023000277,”Clinics in Geriatric Medicine
Volume 39, Issue 3, August 2023, Pages 423-436
Clinics in Geriatric Medicine
Psychedelics and Related Pharmacotherapies as Integrative Medicine for Older Adults in Palliative Care
Author links open overlay panelKabir Nigam MD, MRes a b, Kimberly A. Curseen MD, FAAHPM c, Yvan Beaussant MD, MSc b d
a
Department of Psychiatry, Brigham and Women s Hospital, 60 Fenwood Road, Boston, MA 02115, USA
b
Harvard Medical School
c
Division of Palliative Care, Emory University, 1821 Clifton Road, NE, Suite 1017, Atlanta, GA 30329, USA
d
Department of Psychosocial Oncology and Palliative Care, Dana Farber Cancer Institute, 375 Longwood Avenue, Boston, MA 02115, USA
Available online 12 May 2023, Version of Record 27 June 2023.
Psychedelics and Related
Pharmacotherapies as
Integrative Medicine for Older
Adults in Palliative Care
Kabir Nigam, MD, MResa,b,
*, Kimberly A. Curseen, MD, FAAHPMc
,
Yvan Beaussant, MD, MScb,d
INTRODUCTION
With medical advancements promoting increased longevity, the number of older
adults in the population is rapidly growing. Correspondingly, the prevalence of older
adults affected by serious illness is increasing, and as such, the need for palliative
care services is growing.1 Patients with serious illness receiving palliative care experience numerous benefits, including improved quality of life and survival, decreased
anxiety and depressive symptoms, reduced rates of hospitalization, and higher overall
satisfaction.2 Despite this, palliative care services remain underutilized. Initiation of
palliative services often begins in the inpatient setting, and outpatient access to
a Department of Psychiatry, Brigham and Women s Hospital, 60 Fenwood Road, Boston, MA
02115, USA; b Harvard Medical School; c Division of Palliative Care, Emory University, 1821
Clifton Road, NE, Suite 1017, Atlanta, GA 30329, USA; d Department of Psychosocial Oncology
and Palliative Care, Dana Farber Cancer Institute, 375 Longwood Avenue, Boston, MA
02115, USA
- Corresponding author.
E-mail address: [email protected]
KEYWORDS
Existential distress Serious illness Palliative care End of life Psychedelics
Integrative medicine Psychedelic-assisted therapy PAT
KEY POINTS
Psychological distress in elderly patients undergoing palliative care is a multidimensional
interplay including psychosocial and existential distress as well as physical symptom
burden.
Currently available pharmacotherapies for psychological distress in palliative care are
limited and show mixed efficacy.
Psychedelic-assisted therapy may help address existential distress by using the nonordinary state of consciousness induced to facilitate the process of meaning-making.
Ketamine and cannabis may safely provide quick and effective symptom relief from both a
physical and psychological standpoint, although more data is needed.
Clin Geriatr Med 39 (2023) 423 436
https://doi.org/10.1016/j.cger.2023.04.004 geriatric.theclinics.com
0749-0690/23/ “
https://www.sciencedirect.com/science/article/abs/pii/S0006322323006406,”Biological Psychiatry
Volume 93, Issue 9, Supplement, 1 May 2023, Pages S225-S226
Biological Psychiatry
- Insomnia Symptoms, Cannabis Use, and Risky Decision-Making in Bipolar Disorder
Author links open overlay panelBreanna Holloway 1, Alannah Miranda 1, Elizabeth Peek 1, Jared W. Young 1, William Perry 1, Arpi Minassian 1
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https://doi.org/10.1016/j.biopsych.2023.02.566
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Section snippets
Background
Risky decision-making contributes to functional impairment and poorer quality of life in individuals with bipolar disorder (BD). We have shown that cannabis use is related to less risky decision-making in BD. Sleep is another important health behavior in BD; however, little is known about the impact of sleep on risky decision-making. Hence, we evaluated the relative contributions of insomnia symptoms, cannabis use, and BD on risky decision-making.
Methods
We conducted a secondary data analysis from a larger ongoing study. Participants were 39 euthymic BD adults and 51 comparison adults. Insomnia symptoms were assessed using insomnia items from the Hamilton Depression Scale. Risky decision-making was assessed using the Iowa Gambling Task. Cannabis use was defined as chronic user (>4 times/week in past 90 days) or non-user (cannabis abstinence for 90 days and <5 times lifetime use).
Results
A greater proportion of BD participants (74.4%) reported insomnia symptoms than comparison adults (45.1%; x2(1, n=89)=7.76, p=.005). However, there was no difference in reported insomnia symptoms by cannabis use. The overall linear multiple regression was statistically significant (R2=.155, F(6, 82)=2.45, p=.029, 2=.43), revealing that insomnia symptoms were associated with riskier decision-making ( =-.314, p=.005) and uniquely accounted for 8.53% of the variance in the regression model (sr2 =
Conclusions
These findings provide preliminary evidence that insomnia symptoms are an important treatment target for improving cognitive outcomes in BD. While cannabis use was not related to risky decision-making, more research is needed to determine whether other dimensions of cannabis use may be important for understanding these relationships.”
https://www.sciencedirect.com/science/article/abs/pii/S0885392423003469,”Journal of Pain and Symptom Management
Volume 65, Issue 5, May 2023, Page e649
Journal of Pain and Symptom Management
Comparison of Healthcare Providers Regarding Medical Marijuana and Cannabidiol in the Management of Pain and Other Symptoms in Cancer Patients (Sci217)
Author links open overlay panelKimberson Tanco MD, Gabriel Lopez MD, Lakshmi Koyyalagunta MD, Bryan Fellman MS, Josiah Halm MD, Jerry Ignatius DO, Eduardo Bruera MD FAAHPM
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https://doi.org/10.1016/j.jpainsymman.2023.02.267
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Outcomes
- Evaluate and describe differences in attitudes and beliefs of cannabis-based substances in management of pain and various cancer-related symptoms.
- Describe and analyze various demographic factors that influence attitudes and beliefs of application of cannabis-based substances in their clinical practice.
Introduction
Medical marijuana (MM) and cannabidiol (CBD) have been receiving increasing attention in symptom management even with limited scientific evidence. Physicians and advanced practice providers (APP) from palliative care, integrative medicine, pain management, and psychiatry service, who are the primary symptom management experts in a comprehensive cancer center, were chosen to complete the study. Our study aims to examine the attitudes and beliefs of these healthcare providers on MM and CBD compared to standard treatments for cancer-associated pain and various symptoms, cannabis-related legalization and patient experience, and demographic factors that influence their responses.
Methodology
Two sets of anonymous surveys (MM and CBD) were sent to physicians and APPs who have active clinical practices from these four specialties. Demographics were also collected including role, age, gender, specialty, years in practice, race, and religion.
Results
A minority of respondents preferred prescribing MM (9%) and CBD (13%), respectively, over opioids for cancer pain, while 11% and 22% felt MM and CBD respectively would be useful to combine with opioids to treat cancer pain. A higher proportion of respondents believed that CBD was safer (36% vs. 18%) and less addicting (35% vs. 22%) than opioids compared to MM. A majority of respondents did not favor MM or CBD over other common treatment options for symptoms other than pain.
Conclusion
MM or CBD were not preferred over current standard treatments for pain and other symptoms, although a higher proportion of respondents believed CBD was safer than opioids. Respondents felt that MM legalization laws may contribute to challenges in drug and substance abuse. Responses from the four specialties aligned with their unique aspects of their clinical practice. A more cautious attitude toward cannabis-based substances was seen in physicians and providers with longer time of clinical experience.”
https://www.sciencedirect.com/science/article/pii/S1550413123001791,”Cell Metabolism
Volume 35, Issue 7, 11 July 2023, Pages 1227-1241.e7
Journal home page for Cell Metabolism
Article
Adolescent exposure to low-dose THC disrupts energy balance and adipose organ homeostasis in adulthood
Author links open overlay panelLin Lin 1, Kwang-Mook Jung 1 7, Hye-Lim Lee 1 7, Johnny Le 2, Georgia Colleluori 3, Courtney Wood 4, Francesca Palese 1, Erica Squire 1, Jade Ramirez 1, Shiqi Su 1, Alexa Torrens 1, Yannick Fotio 1, Lingyi Tang 5, Clinton Yu 5, Qin Yang 5, Lan Huang 5, Nicholas DiPatrizio 4, Cholsoon Jang 2, Saverio Cinti 3, Daniele Piomelli 1 2 6 8
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https://doi.org/10.1016/j.cmet.2023.05.002
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Under a Creative Commons license
open access
Highlights
Exposing adolescent mice to low-dose THC alters their adult energy metabolism
CB1 receptor activation in differentiated adipocytes mediates this effect
THC-treated mice are leaner than controls
Molecular and functional adipose abnormalities identify this state as pseudo-lean
Summary
One of cannabis most iconic effects is the stimulation of hedonic high-calorie eating the munchies yet habitual cannabis users are, on average, leaner than non-users. We asked whether this phenotype might result from lasting changes in energy balance established during adolescence, when use of the drug often begins. We found that daily low-dose administration of cannabis intoxicating constituent, 9-tetrahydrocannabinol (THC), to adolescent male mice causes an adult metabolic phenotype characterized by reduced fat mass, increased lean mass and utilization of fat as fuel, partial resistance to diet-induced obesity and dyslipidemia, enhanced thermogenesis, and impaired cold- and -adrenergic receptor-stimulated lipolysis. Further analyses revealed that this phenotype is associated with molecular anomalies in the adipose organ, including ectopic overexpression of muscle-associated proteins and heightened anabolic processing. Thus, adolescent exposure to THC may promote an enduring pseudo-lean state that superficially resembles healthy leanness but might in fact be rooted in adipose organ dysfunction.”
https://www.sciencedirect.com/science/article/pii/S2666915323000021,”Journal of Affective Disorders Reports
Volume 12, April 2023, 100463
Journal of Affective Disorders Reports
Review Article
Cannabinoids and neuroinflammation: Therapeutic implications
Author links open overlay panelBrian E. Leonard a, Feyza Aricioglu b
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https://doi.org/10.1016/j.jadr.2023.100463
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open access
Highlights
The pharmacological properties of tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabinoid components of several species of herbal cannabis.
The pharmacological effects of the phytocannabinoids, information on the intracellular targets for these molecules with their synthesizing and metabolizing enzymes.
Role of endocannabinoid system on neuroinflammation in neurological and psychiatric illness.
The potential therapeutic importance of this system.
Abstract
This review summarizes the pharmacological properties of tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabinoid components of several species of herbal cannabis. The pharmacological effects of the phytocannabinoids have been extensively investigated and the importance of the cannabinoid receptors (CB1 and CB2) on immune cells has provided important information on the intracellular targets for these molecules. In addition to the phytocannabinoids, endogenous cannabinoids also exist in the form of anadramide and 2-srodolylglycerol (2-AG). These, together with their synthesizing and metabolizing enzymes, form the cannabinoid system. Since the discovery of the endocannabinoid system and the role that neuroinflammation plays in neurological and psychiatric illness, the potential therapeutic importance of this system has been of growing interest. In addition, the need to develop drugs which specifically target the CB1 and CB2 receptors has been stimulated by the pharmacological complexity of both THC and CBD. This review briefly summarizes the therapeutic potential of the naturally occurring and the synthetic cannabinoids which will need to be developed, if such drugs are to fulfill the therapeutic promise which the cannabinoids offer.
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Keywords
PhytocannabinoidsTHC and CBDendogenous cannabinoidsanadamide and 2-AGMicrogliaNeuroinflammationAnti-covid 19therapeutic potential
- Introduction
Herbal cannabis has a long history both for its psychotropic properties and for its therapeutic uses. Some of the earliest references to its uses were discovered in Egyptian medical papyrus from about 1550 BCE, but an even earlier record was detected from China in 2700 BCE. in which the hallucinogenic effects of cannabis, in addition to its ability to stimulate appetite and reduce pain due to gout, were described (Clarke and Merlin, 2013).
These metabolites differ in their tetrahydrocannabinol (THC) content. Currently approximately 600 metabolites of cannabis have been isolated with over 20% being classed as cannabinoids (Chandra et al., 2017). Of these the psychoactive metabolite THC and the non-psychoactive metabolite cannabidiol (CBD) have received particular attention (Fig. 1). THC was first synthesized by Mechoulan and Gaoni in 1965, and this stimulated an interest in its pharmacological properties. By contrast, CBD has only recently undergone a detailed pharmacological investigation following the discovery of its anti-oxidant, analgesic and anti-inflammatory properties”
https://www.sciencedirect.com/science/article/abs/pii/S2387020622003679,”Medicina Cl nica (English Edition)
Volume 159, Issue 4, 26 August 2022, Pages 183-186
Medicina Cl nica (English Edition)
Brief report
Cannabis hyperemesis syndrome: Incidence and treatment with topical capsaicinS ndrome de hiper mesis por cannabis: incidencia y tratamiento con capsaicina t pica
Author links open overlay panelGuillermo Burillo-Putze a b, David Trujillo-Burillo a, Jose Carlos Garc a-Hernandez a, M. Angeles L pez-Hern ndez b c, Iv n Hern ndez-Ramos b c, Isabel Ramos-Su rez b d, John R. Richards d
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https://doi.org/10.1016/j.medcle.2021.07.028
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Abstract
Introduction
There are few studies in Spain on cannabinoid hyperemesis syndrome (CHS), as well as on the use of topical capsaicin as a treatment.
Methods
Retrospective study of patients over 14 years of age seen in a hospital emergency department during 2018 and 2019 with a diagnosis of CHS based on the following criteria: compatible clinical picture, cannabis use less than 48 h and positive urine cannabis test. Epidemiological and clinical variables, attendance times and treatment (including use of topical capsaicin 0.075%) were collected.
Results
Fifty-nine attendances were studied, from 29 patients (4.4 cases/10,000 visits, 95% CI 2.8 4.7). Fifty per cent returned for CHS, differing only in more tobacco (P = 0.01) and cocaine (P = 0.031) use. Capsaicin was used in 74.6% of visits. The mean time to resolution of vomiting after application was 17.87 min.
Conclusions
Although probably underdiagnosed, CHS has a low incidence in the emergency department in Spain, with high patient recurrence. The use of capsaicin ointment is efficient and safe.
Resumen
Introducci n
Existen pocos estudios en Espa a acerca del s ndrome de hiper mesis cannabinoide (SHC), as como sobre el uso de capsaicina t pica para su tratamiento.
M todos
Estudio retrospectivo de pacientes mayores de 14 a os atendidos en un servicio de urgencias hospitalario durante 2018 y 2019 con diagn stico de SHC con base en los siguientes criterios: cuadro cl nico compatible, consumo de cannabis menor de 48 h y test de cannabis en orina positivo. Se recogieron variables epidemiol gicas, cl nicas, tiempos asistenciales y tratamiento (incluyendo el uso de capsaicina t pica al 0,075%).
Resultados
Se estudiaron 59 asistencias de 29 pacientes (4,4 casos/10.000 visitas, IC 95% 2,8-4,7). Un 50% volvieron a urgencias por SHC, diferenci ndose estos solo en m s consumo de tabaco (p = 0,01) y coca na (p = 0,031). En un 74,6% de las visitas se utiliz capsaicina. El tiempo medio de resoluci n de los v mitos tras su aplicaci n fue de 17,87 min.
Conclusiones
Aunque probablemente est infradiagnosticado, el SHC presenta una incidencia baja en las urgencias en Espa a, y con alta reincidencia de los pacientes. El uso de pomada de capsaicina es eficiente y seguro.
Introduction
Cannabis hyperemesis syndrome (CHS) is characterised by abdominal pain and vomiting in people who have been using cannabis for years and in high daily amounts, with symptoms typically relieved by very hot showers1.
Described in 20042, many clinicians are still unaware of it, and it was not included in the Rome IV classification until 2016 section B3, together with cyclic vomiting syndrome 3.
Prevalence in Spain could be as high as 18% among chronic users4, while in the US it could be as high as 33% in heavy users, where it is estimated that 2.4% of hospital emergency department (ED) visits may be due to CHS5. Its incidence in EDs is unknown in Europe6, 7, 8.
The aetiology of CHS is not well known, probably multifactorial, so there is no standard treatment either9. The most common antiemetics (metoclopramide and ondansetron) are not very effective. The most commonly used antiemetic treatment in the medical literature is topical capsaicin, although off-label10.
The aim of this study is to describe the incidence and clinical and care characteristics of patients treated for CHS in an ED, and the outcomes associated with the use of topical capsaicin.
Section snippets
Material and methods
Retrospective study of patients with CHS seen in the ED of a university hospital during 2018 and 2019 (reference population of 332,000 citizens over 14 years of age and 135,000 ED visits in that period and age group). Cases from this centre belonging to the Network for the Study of Addictive Drugs in Hospital Emergencies in Spain -REDUrHE- (centre s research ethics committee approval code: 2016/071) were used for this purpose8.
The diagnosis of CHS was based on 3 criteria: compatible clinical
Results
A total of 67 visits for CHS were recorded, of which 8 were discarded due to lack of basic information, with the final sample being 59 visits, corresponding to 29 patients, with a frequency in the Emergency Department of 4.4 cases/10,000 visits (95% CI 2.8 4.7) and a population incidence of 8.8 episodes/100,000 inhabitants-year (95% CI 5.2 11.1). Their demographic, consumption and clinical history characteristics are summarised in Table 1. There were no significant gender differences in these
Discussion
This paper presents the first case series of CHS in an ED in Spain. The incidence found will help to calculate the sample size for further prospective studies.
We agree with other series in age (35 years), visits prior to diagnosis (2 visits), years of use (13 years) and number of joints/day (4 joints/day). Also, in the percentage of patients who report symptom relief with hot showers (37%)1, 2, 11.
The percentage of patients with a psychiatric history (20%) is higher than in other series,
Funding
This work has been partially funded by the National Plan on Addictive Drugs, 2016 Call, within the project Network for the Study of Addictive Drugs in Hospital Emergencies in Spain, ref. 2016/071.
Conflict of interests
The authors declare that they have no conflict of interest.
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(2016)
J. Habboushe et al.
The prevalence of cannabinod hyperemesis syndrome among regular marijuana smokers in an urban public hospital
Basic Clin Pharmacol Toxicol
(2018)”
https://www.sciencedirect.com/science/article/abs/pii/S0011848622005581,”Dental Abstracts
Volume 68, Issue 1, January February 2023, Pages 39-41
Dental Abstracts
Hands On
Therapeutic Uses of Cannabis
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https://doi.org/10.1016/j.denabs.2022.11.024
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Background
Cannabis is being used recreationally and therapeutically in many communities. In the light of this growing use, health care providers need to better understand its effects on personal and public health. Dental health care practitioners should be aware of the potential effects of cannabis on oral health, its relationship to intraoral conditions, and its safety and efficacy, including any drug interactions relevant to dentistry.
Methods
The PubMed/Medline and EMBASE databases were searched for articles addressing the impact of cannabis on various health parameters, the potential value in dental settings, and any interactions with conventional medicines. Specific characterizations were sought for cannabinol (CBN), cannabidiol (CBD), cannabinoid (CB), the endocannabinoid system (ECS), and the main active constituent of cannabis, 9-tetrahydrocannabinol (THC).
General Health Considerations
The Food and Drug Administration (FDA) has approved the use of CBD for the treatment of seizures in patients with Lennox-Gastaut syndrome and Dravet syndrome. CBD has also been given in significantly high doses to patients with bipolar disorder, manic episodes, psychotic disorders, epilepsy, and convulsive syndromes. These patients reported side effects such as somnolence, decreased appetite, and diarrhea.
Evidence indicates that CBs are clinically relevant in reducing pain symptoms in several
Cannabis Safety and Efficacy
Dental practitioners should be concerned that patients may use cannabis products along with other frequently used or prescribed medications in dentistry. These include nonsteroidal anti-inflammatory agents (NSAIDs), local anesthetics, antimicrobial agents, corticosteroids, and antianxiety/sedative agents, all of which might interact with cannabis or hemp extracts. CBD can affect the metabolism of many other drugs and can greatly alter the serum levels of drugs such as selective serotonin”
https://www.sciencedirect.com/science/article/pii/S0735109723021290,”Journal of the American College of Cardiology
Volume 81, Issue 8, Supplement, 7 March 2023, Page 1685
Journal of the American College of Cardiology
Prevention and Health Promotion
ASSOCIATION OF CANNABIS USE DISORDER WITH RISK OF CORONARY ARTERY DISEASE: A MENDELIAN RANDOMIZATION STUDY
Author links open overlay panelIshan Paranjpe, Roy Lan, Suraj Jaladanki, Jagat Narula, Benjamin Glicksberg, Girish Nadkarni, Samir Kamat
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https://doi.org/10.1016/S0735-1097(23)02129-0
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Background
There is conflicting evidence on the association of cannabis use and coronary artery disease (CAD). We investigated the causal association of genetic liability to cannabis use disorder and risk of CAD.
Methods
Using the All of Us cohort, a large population level cohort from 340 inpatient and outpatient sites across the United States (N = 175,000), we associated cannabis use frequency with CAD. We then performed a mendelian randomization analysis using summary statistics from genome wide association studies (GWAS) of cannabis use disorder (CUD) and lifetime cannabis use.
Results
Compared to never-users (N = 39,678), daily cannabis users (N= 4,736) had an increased odds of developing CAD (OR = 1.34, 95% CI: 1.13 – 1.58, P = 0.001) adjusted for age, sex, hypertension, hyperlipidemia, type 2 diabetes, body mass index, education, insurance status, and cigarette use. Using two-sample MR, genetic liability to CUD was associated with an increased risk of CAD (OR = 1.05, 95% CI: 1.02 – 1.09, P = 0.001). No evidence of pleiotropy, outliers, or violation of MR assumptions was found. The association of CUD and CAD was independent of alcohol and tobacco use in multivariable MR analysis (OR = 1.04, 95% CI: 1.01 – 1.07).
Conclusion
In a large population-level cohort, frequent but not occasional cannabis use was associated with an increased risk of CAD. In MR analysis, CUD, but not occasional use was associated with CAD, independent of tobacco use.”
https://www.sciencedirect.com/science/article/pii/S0735109723014018,”Journal of the American College of Cardiology
Volume 81, Issue 8, Supplement, 7 March 2023, Page 957
Journal of the American College of Cardiology
Interventional and Structural
MORTALITY RISK AND CARDIAC ARRHYTHMIAS AMONG CANNABIS USERS OF AGES 60 AND MORE FOLLOWING ADMISSION FOR PERCUTANEOUS CORONARY INTERVENTION
Author links open overlay panelSailaja Sanikommu, Shaheen Sombans, Kamleshun Ramphul, Renuka Verma, Petras Lohana, Khaled Harmouch, Yogeshwaree Ramphul, Fnu Arti, Komal Kumari, Stephanie Gonzalez Mejias, Indu Meena, FNU Bawna, Nomesh Kumar, Fnu Bhawana
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https://doi.org/10.1016/S0735-1097(23)01401-8
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Background
Amendments in legislatures and easier access to cannabis and its products has led to a rise in the number of users. We sought to provide an update on the outcomes of elderly cannabis users requiring Percutaneous Coronary Intervention(PCI).
Methods
We explored the 2019 National Inpatient Sample for patients ages =60 years who underwent PCI. Multivariable regression models allowed us to estimate the adjusted odds ratio (aOR) for differences in outcomes and characteristics.
Results
In 2019, 281,910 PCIs were conducted among adults of ages =60 years, which included 2250 (0.8%) cannabis users. A lower risk of mortality was seen among cannabis users (1.1% vs. 2.3%, aOR 0.626, 95% CI 0.419-0.934, p=0.022) and they also had a lower incidence of supraventricular tachycardia (1.1% vs. 2.3%, aOR 0.41, 95% CI 0.263-0.638, p<0.01), paroxysmal atrial fibrillation (6.4% vs. 10.4%, aOR 0.727, 95% CI 0.613-0.863, p<0.01) and first degree Atrioventricular block (0.9% vs. 2.0%, aOR 0.531, 95% CI 0.341-0.827, p<0.01). Meanwhile, no statistically significant results were seen between cannabis users for Acute Kidney Injury, Ventricular tachycardia, ventricular fibrillation, second and third degree atrioventricular block and cardiopulmonary resuscitation. Conclusion
Elderly cannabis users undergoing PCI have a lower mortality rate and lower incidence of supraventricular tachycardia, paroxysmal atrial fibrillation and first degree atrioventricular block.”
https://www.sciencedirect.com/science/article/abs/pii/S1701216323002499,”Journal of Obstetrics and Gynaecology Canada
Volume 45, Issue 5, May 2023, Page 369
Journal of Obstetrics and Gynaecology Canada
What is the experience of gynecologic cancer patients using medical cannabis?
Author links open overlay panelMary Thompson, Sylvie Bowden, Kristin Black, Prafull Ghatage
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https://doi.org/10.1016/j.jogc.2023.03.093
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Objectives
Current evidence suggests that there is great potential for medical cannabis use in oncology patients; however, there is limited evidence specific to gynecologic cancer patients. The primary objective of this study was to identify the patterns of cannabis use in patients with gynecologic malignancies. Secondary objective included identifying information sources used by patients and perceived barriers to discussing cannabis use with their physician.
Methods
This was a single institution survey-based study conducted in Calgary, Alberta. Patients with a current or prior gynecologic cancer diagnosis were considered for inclusion. Planned analysis included descriptive statistics of patient demographics and the patterns of cannabis use were described using frequencies and proportions.
Results
Thirty-four participants have responded to the survey to date. The majority of participants had ovarian cancer (17/34), and had received chemotherapy as part of their treatment (26/34). Thirteen participants were current cannabis users. The most common symptoms participants used cannabis for were anxiety (8/13), insomnia (8/13) and pain (6/13). Of the participants using cannabis, most did not have a prescription and obtained their cannabis from a recreational dispensary. Nearly 50% of
Conclusions
This study represents an important first step in helping to inform physician training, direct patient education, and generate hypotheses for further studies on this evolving topic.”
https://www.sciencedirect.com/science/article/pii/S0735109723026037,”Journal of the American College of Cardiology
Volume 81, Issue 8, Supplement, 7 March 2023, Page 2159
Journal of the American College of Cardiology
Spotlight on Special Topics
CANNABIS AND CARDIOVASCULAR DISEASE
Author links open overlay panelMohamad Alhoda Mohamad Alahmad, Cheryl Gibson
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https://doi.org/10.1016/S0735-1097(23)02603-7
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Background
Cannabis is the most widely used illicit drug in the United States and is now being legalized in several states for recreational use. However, its use has been associated with medical complications.
Methods
Annually, almost one million inpatient cases in the United States have documentation of cannabis use as per our analysis of the Nationwide Readmission Database (NRD) for 2016-2019. Age distribution [5th, 50th, and 95th percentiles are approximately 18, 35, and 65 years, respectively] is bimodal and has the highest frequency peaks at 27 years. Therefore, we extracted all 18- to 35-year-old patients, excluding December discharges. We compared baseline characteristics and comorbidities among cannabis users (CU) and non-cannabis users (NCU). Appropriate analyses were applied using SAS 9.4
Results
We identified 5,044,125 weighted admissions in 2019. Most admissions (93%) were NCU, and 366,104 (7%) were CU. NCU comprised 80% females and 59% older than 27 years. CU included 53% males, and 51% were younger than 27 years (p<0.0001). CU had longer hospitalizations and higher rates of leaving against advice (5.6% vs. 2%) and subsequently more readmissions (12.4% vs. 7.8%) in comparison to NCU (p<0.001). The most common reason for CU admissions was psychiatric illness (mood, psychotic, and substance use disorders), with a higher prevalence of tobacco (53% vs. 15%) and other substance abuse (70% vs. 6%). Marijuana use was associated with higher rates of hypertension, seizures, acute kidney injury, liver disease, pancreatitis, malnutrition, acute stroke, respiratory failure, heart failure, and pericarditis. Also, CU had higher odds of cardiac arrhythmias and acute myocardial infarction. However, the latter association was no longer statistically significant after adjusting for tobacco and other substance abuse.
Conclusion
We found cannabis use to be associated with serious health conditions. Because most of the available data on cannabis use is short-term, observational, and retrospective studies, rigorous scientific research is needed to examine causal linkages to cannabis use and its health effects, especially as the legal availability of cannabis grows across states.
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Poster Contributions eAbstract Site
Saturday, March 4, 2023, 1:00 a.m.-1:05 a.m.
Session Title: Spotlight on Special Topics: Global Cardiovascular Health Digital Presentations
Abstract Category: 56. Spotlight on Special Topics: Global Cardiovascular Health
Presentation Number: 1153-001
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https://www.sciencedirect.com/science/article/abs/pii/S1556086422016033,”Journal of Thoracic Oncology
Volume 18, Issue 3, Supplement, March 2023, Page e5
Journal of Thoracic Oncology
Poster Discussion (PPD01), September 24, 2022, 16:40 – 17:40
PPD01.01 Patterns of Use of Medical Cannabis in Lung Cancer and Other Cancer Patients
Author links open overlay panelD. Behl
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https://doi.org/10.1016/j.jtho.2022.09.017
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Background
Many patients with lung cancer and other malignancies report using cannabis for various medical reasons. Cannabis use is legal in the state of California but remains a Schedule 1 drug on the federal list with drugs such as heroin and LSD. The purpose of this study was to assess the prevalence, reasons for use, methods of use, and perceived benefits of medical cannabis in adults seen in oncology clinics in Northern California.
Methods
Patients received a questionnaire or scanned a QR code on their phone when they checked in for their appointment. Patients who used cannabis were asked questions regarding the mode of ingestion, perceived benefits, types of underlying cancer, and estimated monthly cost.
Results
A total of 1,778 surveys were completed. 481 (27%) patients with a mean age of 59.21 13.44 stated that they used cannabis for medical reasons.
. Demographics of patients with cancer who stated that they used medical cannabis (N=481)
n (%) Empty Cell Empty Cell
Sex Race Empty Cell
Male
194 (40.3) White
389 (81.4) Asian/Pacific Islander
18 (3.8)
Female
287 (59.7) Black
21 (4.4) Middle Eastern
3 (0.6)
Hispanic
33 (6.9) Other
14 (2.9)
A significant number of patients with lung cancer used cannabis (92 patients- 19%), as did patients with breast cancer
Conclusions
Medical cannabis was used by approximately one-fourth of all cancer patients in our study. The majority reported cannabis helped improve their symptoms. Further research regarding mechanism of actions and associated risks is warranted.”
https://www.sciencedirect.com/science/article/abs/pii/S0303846723000549,”Clinical Neurology and Neurosurgery
Volume 227, April 2023, 107638
Clinical Neurology and Neurosurgery
Second-line cannabis therapy in patients with epilepsy
Author links open overlay panelErica Braun e, Francesca M. Gualano b, Prabha Siddarth c, Eric Segal a b d
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https://doi.org/10.1016/j.clineuro.2023.107638
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Abstract
Objective
Marijuana-based therapies (MBTs) have been shown to reduce seizure frequency in patients with severe and drug-resistant epilepsy (DRE). Pharmaceutical-grade CBD (Epidiolex ) was approved by the FDA in 2018 for the treatments of Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS) and subsequently in 2020 for tuberous sclerosis complex (TSC). It is unclear what the utility would be in prescribing one type of MBT if a previous, alternative type failed. We conducted a retrospective study to determine if an alternative formulation of MBT reduces seizure frequency if the patient has not had a meaningful response from an initial MBT. We also investigated the clinical impact that a second MBT has on side effect profile.
Methods
We reviewed the charts of patients with DRE who were at least 2 years old and who took at least 2 different formulations of MBT, including a pharmacologic formulation of CBD (Epidiolex ), artisanal marijuana, and/or a hemp-based formulation. We reviewed medical records in patients 2 years of age and older; however, subjects historical data, such as age of first seizure onset, may be prior to the age of 2 years. We extracted data on demographics, type of epilepsy, history of epilepsy, medication history, seizure count, and drug side effects. Seizure frequency, side effect profiles, and predictors of responder status were evaluated.
Results
Thirty patients were identified as taking more than 1 type of MBT. Our findings suggest that seizure frequencies do not change significantly from baseline to after the first MBT and to after the second MBT (p = .4). However, we did find that patients with greater baseline seizure frequency were significantly more likely to respond to treatment after the second MBT (p = .03). To our second endpoint of side effect profile, we found that patients who experienced side effects after a second MBT had significantly greater seizure frequency compared to those who did not (p = .04).
Conclusion
We found no significant seizure frequency reduction from baseline to after a second MBT in patients who tried at least 2 different formulations of MBT. This suggests a low probability of seizure frequency reduction with a second MBT therapy in patients with epilepsy who tried at least two different MBTs. While these findings need to be replicated in a larger sample, they suggest that clinicians should not delay care by trying alternative MBT formulations after a patient has already tried one. Instead, it may be more prudent to attempt an alternative class of therapy.”
https://www.sciencedirect.com/science/article/pii/S001448862200262X,”Experimental Neurology
Volume 359, January 2023, 114237
Experimental Neurology
Review article
Therapeutic and clinical foundations of cannabidiol therapy for difficult-to-treat seizures in children and adults with refractory epilepsies
Author links open overlay panelDoodipala Samba Reddy a b c d e
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https://doi.org/10.1016/j.expneurol.2022.114237
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Abstract
Novel and effective antiseizure medications are needed to treat refractory and rare forms of epilepsy. Cannabinoids, which are obtained from the cannabis plant, have a long history of medical use, including for neurologic conditions. In 2018, the US Food and Drug Administration approved the first phytocannabinoid, cannabidiol (CBD, Epidiolex), which is now indicated for severe seizures associated with three rare forms of developmental and epileptic encephalopathy: Dravet syndrome, Lennox Gastaut syndrome, and tuberous sclerosis complex. Compelling evidence supports the efficacy of CBD in experimental models and patients with epilepsy. In randomized clinical trials, highly-purified CBD has demonstrated efficacy with an acceptable safety profile in children and adults with difficult-to-treat seizures. Although the underlying antiseizure mechanisms of CBD in humans have not yet been elucidated, the identification of novel antiseizure targets of CBD preclinically indicates multimodal mechanisms that include non-cannabinoid pathways. In addition to antiseizure effects, CBD possesses strong anti-inflammatory and neuroprotective activities, which might contribute to protective effects in epilepsy and other conditions. This article provides a succinct overview of therapeutic approaches and clinical foundations of CBD, emphasizing the clinical utility of CBD for the treatment of seizures associated with refractory and rare epilepsies. CBD has shown to be a safe and effective antiseizure medicine, demonstrating a broad spectrum of efficacy across multiple seizure types, including those associated with severe epilepsies with childhood onset. Despite such promise, there are many perils with CBD that hampers its widespread use, including limited understanding of pharmacodynamics, limited exposure-response relationship, limited information for seizure freedom with continued use, complex pharmacokinetics with drug interactions, risk of adverse effects, and lack of expert therapeutic guidelines. These scientific issues need to be resolved by further investigations, which would decide the unique role of CBD in the management of refractory epilepsy.”
https://www.sciencedirect.com/science/article/abs/pii/S0014488622003132,”Experimental Neurology
Volume 360, February 2023, 114288
Experimental Neurology
Review article
Cannabidiol reveals a disruptive strategy for 21st century epilepsy drug discovery
Author links open overlay panelAaron del Pozo, Melissa Barker-Haliski
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Abstract
Over 30 antiseizure medicines (ASMs) have been uncovered in a diversity of preclinical seizure and epilepsy models, with several critical inflection points in the 20th century fundamentally transforming ASM discovery. This commentary aims to review the historical relevance of cannabidiol’s (CBD; Epidiolex) approval for epilepsy in the context of other ASMs brought to market. Further, we highlight how CBD’s approval may represent an inflection point for 21st century ASM discovery. CBD is one of the main phytocannabinoids of Cannabis sativa. Unlike its related phytocannabinoid, 9-tetrahydrocannabinol, CBD does not exert any euphorigenic, tolerance, or withdrawal effects at anticonvulsant doses. CBD also possess marked anti-inflammatory effects, offering the tantalizing potential of a new pharmacological approach in epilepsy. For decades, hints of the anticonvulsant profile of CBD had been suggested with a small handful of studies in rodent seizure models, yet difficulties in formulation, compounded by the social and regulatory pressures related to medical use of cannabis plant-derived agents constrained any clinical implementation. Nonetheless, CBD possesses a broad antiseizure profile in preclinical seizure and epilepsy models, but the transformative impact of CBD’-s approval came because of studies in a rodent model of the orphan disease Dravet syndrome (DS). DS is a pediatric developmental epileptic encephalopathy with high mortality, frequent spontaneous recurrent seizures, and marked resistance to conventional ASMs, such as phenytoin and carbamazepine. CBD was approved for DS by the US Food and Drug Administration in 2018 after convincing efficacy was established in randomized, placebo-controlled trials in children. Because of the clinical approval of CBD as a novel, cannabis plantderived ASM for DS, CBD has revealed a new strategy in ASM discovery to reignite 21st century therapeutic development for epilepsy. In this commentary, we review the major preclinical and clinical milestones of the late 20th century that made CBD, a compound historically subjected to regulatory restrictions, a key driver of a new discovery strategy for epilepsy in the 21st century.
Introduction
Epilepsy is distinct among neurological conditions in that it has enjoyed a relatively high degree of translational success advancing preclinical agents to effective clinical treatments for symptomatic seizures. Early 20th century treatment of people with epilepsy using, first, bromide and then later phenobarbital gave way to a relative explosion in the number of drugs available for the management of symptomatic seizures following the identification of phenytoin in the maximal electroshock (MES) test in 1937 (Loscher et al., 2013). Based on its efficacy in this test, phenytoin was approved for people with epilepsy in 1938. The MES model provided a predictive platform on which many later new and impactful antiseizure medicines (ASMs) were initially identified in laboratory animals the 20th century. In spite of this high degree of success, treatment-resistant epilepsy continues to affect roughly 30% of individuals (Chen et al., 2018). No agent has yet been FDA-approved for the prevention of disease in at-risk individuals. Thus, much of the 21st century epilepsy drug discovery for epilepsy strategy is now shifting to prioritize agents that address the remaining unmet medical needs of specific patient groups; e.g., precision medicine strategies for developmental epileptic encephalopathies DEE (Vasquez et al., 2022)) and the discovery of disease-modifying agents (Barker-Haliski et al., 2021; Barker-Haliski et al., 2015; Loscher, 2017a).
Cannabidiol (CBD), a non-euphorigenic phytocannabinoid, was approved in 2018 as the first medical treatment derived from the marijuana plant (Patra et al., 2019). It is currently indicated for seizures associated with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS) or Tuberous Sclerosis (TSC) in patients 1 years of age and older (Devinsky et al., 2017a; Thiele et al., 2018). Since the approval of CBD for DS in 2018, the number of studies that have investigated the antiseizure and disease-modifying potential of this agent for epilepsy has grown exponentially (Fig. 1). However, prior to that FDA approval, only a few studies existed to define the therapeutic potential of this agent for epilepsy, largely due to local and international regulations restricting access to marijuana plant-derived components for basic biological research, as well as the social stigmas associated with use of marijuana plant-derived compounds. Nonetheless, the preceding preclinical and clinical research with CBD that was available painted a promising therapeutic picture. In this commentary, we discuss how a few critical preclinical studies reported in the 2010s, coupled with dramatic changes in public perception of medical marijuana plant use (OFFICE, 2021) and a groundswell of parental and advocate support provided the impetus to advance a mechanistically unique agent for difficult to treat patients. There have been a few key points in the history of ASM discovery that have led to expansive growth in the number of therapies available to patients. In this commentary, we discuss how CBD likely represents another critical node in the discovery and development of invaluable epilepsy therapies. The clinical approval of CBD revealed a new, disruptive strategy to fundamentally transform the way epilepsy therapies are brought to clinical populations. We are now likely poised on the next horizon of therapeutic innovation that will shift how 21st century treatments are identified.
Over 30 ASMs are currently on the market. The mechanisms of action of these ASMs are diverse but largely focus on modulation of the excitatory/inhibitory imbalance synonymous with epilepsy. While a discussion of these mechanisms is largely beyond the scope of this commentary, the reader is referred to work summarizing the predominate mechanisms of currently approved ASMs (Barker-Haliski et al., 2014; Sills and Rogawski, 2020). Further, many new agents are in active development and some exhibit extensive mechanistic differentiation from available ASMs (Bialer et al., 2020a, Bialer et al., 2020b). Epilepsy drug discovery is clearly a prolific endeavor with many agents in various stages of development.
Two areas of consistent therapeutic focus in recent decades include modulation of the excitatory/inhibitory imbalance through as-yet untapped molecular targets and attenuation of the epilepsy-induced neuroinflammation. New targets associated with the excitatory/inhibitory imbalance are essential to epilepsy therapy discovery to differentiate from ASM standards-of-care. For example, agents are in development to target neuronal excitability at untapped presynaptic sites, including allosteric modulators of type 2 metabotropic glutamate receptors, and positive allosteric modulators of neuronal Kv7.2 7.5 (KCNQ2 5) potassium channels (Bialer et al., 2020a). Further, neuroinflammation is gaining traction as a tractable therapeutic target in epilepsy and agents are in development to address these processes (Iori et al., 2017; Pauletti et al., 2017).
One of the primary areas of active therapeutic development in recent years has focused on mitigating neuroinflammation associated with epilepsy (Barker-Haliski et al., 2017b; Devinsky et al., 2013; Galanopoulou and Moshe, 2015; Galanopoulou et al., 2016; Wilcox and Vezzani, 2014). Numerous targets have been implicated, including inflammatory cytokines, reactive oxygen species (McElroy et al., 2017), and glia-specific processes (Pauletti et al., 2017; Wilcox and Vezzani, 2014). Moreover, neuroinflammation is likely a major driver of the pathological cycle underlying epileptogenesis itself such that minimizing inflammatory states may produce the long-sought disease-modifying effects in managing clinical epilepsy.
Abnormal glial activation may increase neuronal excitability and inflammatory processes. The outcome of inflammation depends mainly on the number of cytokines and the length of time the CNS is exposed to this damage (Lach et al., 2022). The effect of neuroinflammation can also cause modifications of the blood-brain barrier (BBB). This phenomenon produced by the release of inflammatory mediators may reduce the threshold for epileptic seizures, altering the sensitivity of channels, the uptake and release of neurotransmitters, and the glia-related regulation of ion concentrations. Thus, controlling the inflammatory response and the immediate outcomes, such as the BBB breakdown, may be a potential strategy for attenuating the severity of seizures. Neuroinflammation is a critical and untapped target for epilepsy and may also represent a potential opportunity for disease-modifying intervention.
Novel agents with unique mechanisms of action represent an important therapeutic advance versus currently available traditional mechanisms, such as Na+ and Ca2+channel blockers, modulation of glutamate release, and GABAA receptor modulators. However, what is increasingly recognized as being more critical and commercially tractable is the advancement of agents that benefit specific patient demographics (i.e., DEE). Specifically, orphan disease indications with epilepsy as a clinical feature are adding pressure to shift how new ASMs are initially identified and differentiated in the preclinical arena. Orphan disease indications are defined by the US FDA as those conditions that affect fewer than 200,000 people nationwide. The US Orphan Drug Act (ODA) passage in 1983 created financial incentives for drug and biologics manufacturers, including tax credits for costs of clinical research, government grant funding, assistance for clinical research, and a seven-year period of exclusive marketing given to the first sponsor of an orphan-designated product who obtains market approval from the FDA for the same indication (Fig. 1). With the Rare Disease Act of 2002, the US increased the national investment in the development of diagnostics and treatments for patients with rare diseases and disorders (US Congress Rare Disease Act of 2002). This major legislation allowed for greater emphasis on addressing the treatment needs of specific patient populations with epilepsy.
The US FDA approved oral cannabidiol for both DS and LGS for patients 2 years and older in 2018. Importantly, in 2020 the label indication was updated by the FDA to include TSC (in addition to LGS and DS) and the age for use was updated to 1 year and older. These facts revealed the very real possibility that preclinical models of orphan disease indications could play an increasingly prominent role in frontline ASM discovery in the 21st century. No longer would ASM discovery merely rely on the convincing demonstration of efficacy in traditional seizure and epilepsy models evoked in wild-type, neurologically-intact animals, including the MES test, subcutaneous pentylenetetrazol (scPTZ) test, and kindling models (Barker-Haliski and White, 2020; Barker-Haliski et al., 2017a). The ability to identify genetic conditions more rapidly and accordingly prescribe precision medicines for specific patient populations has created a seismic shift in the approach to ASM identification and differentiation. While the traditional models have robustly identified numerous effective therapies for epilepsy and will likely continue to have an important position in ASM discovery (Barker-Haliski, 2019; Barker-Haliski and White, 2020; Barker-Haliski et al., 2017a; Klein et al., 2018), it is now likely that the market is at saturation to uncover new molecular targets exclusively relying on these models. As a result, models of orphan diseases and models recapitulating specific patient groups (e.g., infantile spasms models (Galanopoulou and Moshe, 2015), late-onset epilepsy models (Del Pozo et al., 2022)) will occupy an increasingly prominent position in the early discovery and differentiation of investigational agents that may ultimately proceed to clinical use. New ASMs will likely be identified, or the preclinical profile extended, in these models, which may effectively disrupt the clinical epilepsy treatment landscape in the 21st century.”
https://www.sciencedirect.com/science/article/pii/S0753332223008934,”Biomedicine & Pharmacotherapy
Volume 165, September 2023, 115102
Biomedicine & Pharmacotherapy
Review
Cannabinoids: Emerging sleep modulator
Author links open overlay panelZhen Xuen Brandon Low a, Xin Ru Lee a, Tomoko Soga b, Bey Hing Goh c d, Deepa Alex b, Yatinesh Kumari a
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Highlights
Cannabinoids trigger sleep-promoting brain areas & inhibit orexin-secreting neurons.
Cannabinoid receptors primarily communicate via retrograde neurotransmission.
Effects of CBD and THC on sleep are increasingly being explored in humans.
Synthetic and minor cannabinoids remain underexplored in treating sleep disorders.
Abstract
Sleep is an essential biological phase of our daily life cycle and is necessary for maintaining homeostasis, alertness, metabolism, cognition, and other key functions across the animal kingdom. Dysfunctional sleep leads to deleterious effects on health, mood, and cognition, including memory deficits and an increased risk of diabetes, stroke, and neurological disorders. Sleep is regulated by several brain neuronal circuits, neuromodulators, and neurotransmitters, where cannabinoids have been increasingly found to play a part in its modulation. Cannabinoids, a group of lipid metabolites, are regulatory molecules that bind mainly to cannabinoid receptors (CB1 and CB2). Much evidence supports the role of cannabinoid receptors in the modulation of sleep, where their alteration exhibits sleep-promoting effects, including an increase in non-rapid-eye movement sleep and a reduction in sleep latency. However, the pharmacological alteration of CB1 receptors is associated with adverse psychotropic effects, which are not exhibited in CB2 receptor alteration. Hence, selective alteration of CB2 receptors is also of clinical importance, where it could potentially be used in treating sleep disorders. Thus, it is crucial to understand the neurobiological basis of cannabinoids in sleep physiology. In this review article, the alteration of the endocannabinoid system by various cannabinoids and their respective effects on the sleep-wake cycle are discussed based on recent findings. The mechanisms of the cannabinoid receptors on sleep and wakefulness are also explored for their clinical implications and potential therapeutic use on sleep disorders.
- Introduction
Sleep is an essential determinant of health as it is crucial for regulating metabolism, emotion, performance, memory consolidation, learning, and healing [1]. It has been found that insufficient sleep causes many adverse health consequences, such as glucose intolerance, which might lead to diabetes, obesity, hypertension, and cardiovascular disease [2]. Thus, policymakers and healthcare providers increasingly recognize sleep as an important component of a healthy lifestyle.
The sleep-wake cycle is a process that is comprised of three different phases: rapid-eye-movement (REM) sleep, non-rapid-eye-movement (NREM) sleep, and waking. Specialized parts of the brain and specific neurotransmitters are involved in different stages of the sleep-wake cycle. REM sleep is the phase in which a subject experiences eye movement, postural atonia, and vivid dreams. The pedunculopontine tegmental, laterodorsal tegmental, and pontis oralis nuclei are structures found in the brainstem that were shown to promote REM sleep through the synthesis of neurotransmitters such as acetylcholine, glutamate, and neuropeptide melanin-concentrating hormone [3], [4]. The 3 stages of humans NREM sleep, N1, N2, and N3, are stimulated by the medial and ventrolateral preoptic area of the anterior hypothalamus [5]. The molecules that are involved in the regulation of NREM sleep are gamma-aminobutyric acid (GABA), adenosine, and prostaglandin D2 [6]. In the waking phase, neurons in the lateral and posterior hypothalamus synthesize orexins and histamine, while brainstem neurons secrete noradrenaline, serotonin, and acetylcholine [7].
Among the various mechanisms involved in sleep regulation, endocannabinoids play a significant role in sleep modulation [8]. They are fatty acid derivatives, which most notably act via activation of the cannabinoid receptors (CB1 and CB2), and it is well established that the CB1 receptor has a role in sleep regulation [9]. However, it has been reported that the CB1 receptor mediates most of the psychotropic effects associated with endogenous reward and consumptive behavior, which is not considered optimal for therapeutic approaches. On the other hand, the CB2 receptor is coupled with non-psychotropic effects [10].
In this review, the role of cannabinoids is analyzed to determine its potential effects on the sleep-wake cycle and to provide direction for future studies and clinical trials in exploring the use of cannabinoid therapies for sleep disorders and diseases of other aetiologies. In addition, the biological aspects of sleep as well as the endocannabinoid system, including its receptors and enzymes, are also discussed.
- Cannabinoids and the endocannabinoid system
The extracts of the plant Cannabis sativa or Cannabis indica, more commonly known as cannabis, are routinely used for recreational purposes. However, in recent years, more research has been carried out on the potential therapeutic benefit of cannabis. Cannabidiol (CBD), the main cannabinoid component of cannabis that makes up 40% of the extracts, as well as -9-tetrahydrocannabinol (THC), the psychoactive component in cannabis, have only been isolated and studied since the 1960s [11].
The discovery of CBD and THC sparked great research interest in cannabinoids, ultimately leading to the discovery of cannabinoid receptors as well as anandamide (AEA), an endocannabinoid that has specific binding sites to CB1 and CB2 receptors in the brain that induces similar effects as THC, such as analgesia, catalepsy, motor depression and hypothermia [12]. Several other endocannabinoids were subsequently discovered, including 2-arachidonylglycerol (2-AG), N-arachidonoyldopamine, N-arachidonoylglyceryl ether, arachidonoyl-ethanolamine (virodhamine), and 2-arachidonyl glyceryl ether [5]. The two main endocannabinoids, AEA and 2-AG, have received substantial interest, which may partly be due to the difficulty in isolating other minor endocannabinoids from biological tissues [13]. Their actions on the cannabinoid receptors are also well-established; AEA has a high affinity to the CB1 receptor as its partial agonist but is virtually inactive at CB2, while 2-AG is a full agonist of both CB1 and CB2 receptors with moderate-to-low affinity [14].
The endocannabinoid system is regulated by several enzymes, which have increasingly been targeted for therapeutic use. The hydrolysis of the two main endocannabinoids, AEA and 2-AG, is respectively regulated by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), while their synthesis is catalyzed by N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL) a/ [5]. In vivo studies of FAAH and MAGL inhibition by synthetic antagonists have reported, among others, anxiolytic [15], [16] and antidepressant [17], [18] effects, which is suggested to be the effect of hypothalamic-pituitary-adrenal axis modulation via the action of the CB1 receptor [19], [20]. Modulation of the FAAH/MAGL enzymes is also associated with anti-inflammatory and neuroprotective effects [21], [22], where extensive studies in mice have shown positive outcomes for neuroinflammatory/neurodegenerative diseases such as Alzheimer s disease, Parkinson s disease, and multiple sclerosis [12], [23], [24], [25], [26]. Oxidation of 2-AG and AEA is known to be mediated by the cyclooxygenase-2 (COX-2) and cytochrome P450 (CYP) systems [27], [28], [29], while cannabinoids have been shown to inhibit certain CYP enzymes [30]. Endogenous antagonists/inverse agonists of the cannabinoid receptors have also been discovered, including sphingosine [31] and haemopressin [32]. Meanwhile, endogenous allosteric modulators of the CB receptors include pepcan-12, lipoxin A4, and pregnenolone [33].
The putative cannabinoid receptors, CB1 and CB2, are seven-transmembrane domain pertussis toxin (PTX)-sensitive G protein-coupled receptors encoded by the CNR1/2 gene. Cannabinoid receptors in mice show a high similarity (97% in CB1, 82% in CB2) to that of humans [34], which makes them a suitable target for cannabinoid research. Although CB1 receptors are primarily expressed in the CNS, namely the basal ganglia, hippocampus, neocortex, cerebellum, thalamus, brainstem, and spinal cord [35], [36], they are also found in the enteric nervous system and the pelvic viscera of the peripheral nervous system (PNS) [37]. CB1 receptors mainly act on axonal and presynaptic membranes via retrograde neurotransmission, where its activation inhibits the release of neurotransmitters at the synapses [5]. Other studies have also found that CB1 receptors are expressed in cholinergic neurons, and activation by AEA induces sleep via the action of ACh [38], [39]. The CB1 receptor has also been shown to be used for neuroprotection against excitotoxicity, which could potentially be therapeutic for neurological disorders, such as neurodegenerative diseases and epilepsy, by inhibiting the release of GABA and glutamate from presynaptic terminals [5].
The CB2 receptor is commonly known as a peripheral cannabinoid receptor and is located mainly on immune cells to modulate cell migration and the release of cytokines [40]. However, recent studies have shown that the CB2 receptor is expressed in the CNS as well, particularly in microglia, astrocytes, and subsets of neurons. Alteration of the CB2 receptor is thought to have great therapeutic potential because pharmacological activation of the CB2 receptor is not associated with adverse psychotropic effects, unlike the CB1 receptor [5]. CB2 receptors can be activated by both THC and 2-AG. However, it was shown that THC is only considered a partial agonist of CB2 receptors [7]. Nevertheless, despite its partial agonism, Pertwee [41] revealed that THC still has clinical uses as it provides symptomatic relief and slows disease progression for neurological disorders that trigger CB2 receptor upregulation. For instance, it was found that in mouse models for neuropathic pain, CB2 receptors were highly expressed in the spinal cord, especially for activated microglia that migrated into the spinal cord [41]. Besides, increased CB2 receptor expression was found in colonic-infiltrated immune cells from mouse models who suffered from colitis, as well as in macrophages and T lymphocytes in humans [42]. These results suggest that selective targeting of CB2 receptors could potentially be used in the management of neuropathic pain and disorders of the immune system.
CB1 receptors inhibit the release of neurotransmitters by modulating both short and long-term plasticity: the mechanism for short-term plasticity involves the inhibition of voltage-gated N-type and P/Q-type Ca2+ channels and activation of K+ channel conductance, whereas for long-term plasticity, adenylyl cyclase is inhibited via Gi/o subunits, resulting in the downregulation of the cAMP/PKA pathway [43]. CB1 receptors notably recruit -arrestins, which, with the combined action of GRKs, are involved in receptor desensitization and internalization [44]. They also activate downstream signaling cascades such as that of ERK1/2, CREB, JNK1/2/3, and EGFR receptor tyrosine kinases independent of the standard Gi/o pathway [45].”
https://www.sciencedirect.com/science/article/pii/S0735109723040408,”Journal of the American College of Cardiology
Volume 81, Issue 8, Supplement, 7 March 2023, Page 3596
Journal of the American College of Cardiology
Complex Clinical Cases
MARIJUANA-INDUCED MYOPERICARDITIS: A CASE REPORT
Author links open overlay panelAndrew Engel-Rodriguez, Victor H. Molina-Lopez, Sonia Vicenty
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Background
More than 11.8 million adults reported marijuana use in 2018. Research on cannabis CV health effects is limited because it is classified as a level 1 substance.
Case
A 40-year Hispanic male was evaluated at the ER due to retrosternal chest pain that was associated with shortness of breath, nausea, and diaphoresis. The evaluation revealed elevated high sensitivity troponins and initial ECG with early repolarization. Follow-up ECG revealed concave ST-segment elevations over inferior and anterolateral leads without reciprocal depressions.
Decision-making
He underwent coronary angiography, revealing normal coronary arteries. Careful anamnesis revealed the use of medicinal marijuana, with subsequent general malaise the day before presenting to ER. He denied recent illness and viral panel resulted negative. Cardiac MRI with gadolinium enhancement revealed hypokinesia of the lateral and apical septal wall and increased signal intensity suggesting myopericarditis. He was then treated with high-dose NSAIDs with clinical resolution.
Conclusion
Marijuana has more than 460 active compounds. While there is limited data on the effects of cannabis use, physicians should be aware of the effects it can have on the cardiovascular system. This case suggests that young patients who present with acute cardiovascular symptoms should be screened for cannabis and other drugs of abuse.”
https://www.sciencedirect.com/science/article/abs/pii/S0002962922001537,”The American Journal of the Medical Sciences
Volume 364, Issue 3, September 2022, Pages 304-308
The American Journal of the Medical Sciences
Clinical Investigation
Cannabis use is associated with prevalent coronary artery disease
Author links open overlay panelTravis M. Skipina MD 1, Nikhil Patel MD 1, Bharathi Upadhya MD 2, Elsayed Z. Soliman MD 2 3
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https://doi.org/10.1016/j.amjms.2022.04.005
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Abstract
Background
Cannabis is associated with risk of acute coronary syndrome in observational studies. However, its association with prevalent coronary artery disease (CAD) remains unclear. We hypothesized that cannabis use is associated with prevalent CAD.
Methods
This analysis included 12,543 participants (age 39.3 11.6 years, 48.8% male, 35.3% Caucasians) from The National Health and Nutrition Examination Survey (NHANES). Cannabis use was self-reported. Prevalent CAD was defined by physician diagnosis. The association between cannabis use and CAD was tested for using multivariable logistic regression.
Results
About 53.1% (n = 6,650) of participants were ever cannabis users and 1.1% (n = 137) had prevalent CAD. Ever (versus never) cannabis users had 90% increased odds of CAD [OR (95% CI): 1.90 (1.24 – 2.93), p = 0.003]. Those who had used cannabis at least once per month for at least one year had 68% increased odds of CAD [OR (95% CI): 1.68 (1.02-2.77), p = 0.04]. Current cannabis users had near 98% increased odds of CAD [OR (95% CI): 1.98 (1.11 3.54), p = 0.02]. Similar results were seen with heavy cannabis users [OR (95% CI): 1.99 (1.02 3.89), p = 0.045]. These results were consistent in subgroups stratified by race, gender, hypertension, obesity, COPD, hyperlipidemia, tobacco smoking status, and diabetes.
Conclusions
Cannabis use is associated with prevalent CAD. This finding emphasizes the potential harmful effects of cannabis use on cardiovascular health and highlights the need for further research as it becomes more accepted at both a national and global level.
Introduction
Cannabis is the most frequently-used illicit drug in the United States1 with an estimated prevalence of 8.4% among adults. Approximately 89.5% of current users report using primarily for recreational reasons and the remaining 10.5% cite primary medical reasons.2 The use of cannabis and its derivatives continues to increase as more states approve the legalization of these products for both medicinal and recreational use.3,4 Several observational studies have linked cannabis use to acute myocardial infarction, with a predilection for young adults.5, 6, 7 Cannabis smoke and tobacco smoke have been shown to have similar chemical constituents following combustion.8 Since tobacco use is a well-known risk factor for CAD,9 it may follow that cannabis use would also be a risk factor for CAD. Despite the popularity of cannabis use, no studies to date have examined the link between cannabis use and prevalent CAD. We hypothesized that cannabis use would be associated with prevalent CAD among a nationally representative sample of individuals.
Section snippets
Methods
The National Health and Nutrition Examination Survey (NHANES) is an inquiry of a representative sample of the United States population that seeks to approximate general disease prevalence and population health. Data were collected from 2011-2018 through an in-home interview process and subsequent appointments at a mobile examination center. Written consent was provided by all participants at the time of study enrollment. Ethical approval was not required for this study as the data from NHANES
Results
We included 12,543 participants (age 39.3 11.6 years, 48.8% male, 35.3% Caucasians). Approximately 53.1% (n = 6,650) of participants ever used cannabis and 1.1% (n = 137) had prevalent CAD. Table 1 shows the population characteristics stratified by ever cannabis use. Ever-cannabis users were more likely to be younger, male, Caucasian, black, have a history of COPD, and use tobacco when compared to never users. Ever-users were less likely to have hyperlipidemia, diabetes or be of Hispanic
Discussion
In this ethnically diverse and nationally representative sample of mostly young to middle aged individuals, we observed an association between cannabis use and prevalent CAD after adjusting for traditional CAD risk factors. This association was consistent when stratified among sub-groups. A dose-dependent response was observed as well with heavy current users having nearly 100% increased odds of prevalent CAD when compared to never users. The association with light current users did not reach
Conclusions
Cannabis use is associated with prevalent CAD. This association remained consistent after adjusting for traditional cardiovascular disease risk factors. This is a novel finding that emphasizes the potential harmful effects of cannabis use on cardiovascular health and highlights the need for further research as it becomes more accepted at both a national and global level.”
https://www.sciencedirect.com/science/article/abs/pii/S0953620523002595,”European Journal of Internal Medicine
Available online 3 August 2023
In Press, Corrected ProofWhat s this?
European Journal of Internal Medicine
Review Article
Cannabidiol’s impact on drug-metabolization
Author links open overlay panelClaudia St llberger a, Josef Finsterer b
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https://doi.org/10.1016/j.ejim.2023.07.029
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Abstract
Importance
Products containing cannabidiol(CBD) are easily accessible. CBD is reported to inhibit the drug-metabolizing proteins(DMP) Cytochrome P450(CYP)3A4/5, CYP2C9, CYP2B6, CYP2D6, CYP2E1, CYP1A2, CYP2C19, carboxylesterase 1(CES1), uridine 5’diphospho-glucoronosyltransferase(UGT)1A9, UGT2B7, P-glycoprotein(P-gp) and Breast Cancer Resistance Protein(BCRP). The relevance of CBD-drug interactions is largely unknown. Aim of the study was to identify drugs, potentially interacting with orally ingested CBD, to assess whether CBD-drug interactions have been reported, and if substrates of DMP are frequently prescribed drugs.
Observations
Identified were 403 drugs as substrates of DMP. CBD-drug interactions were reported for 53/403 substrates in humans (n = 25), in vivo (n = 13) or in vitro (n = 15). In 31/53 substrates, CBD induced an increase, in 1/53 a decrease, in 4/53 no change in the substrate level. For 5/53 substrates, the results were controversial, and in 12/53 no substrate levels were reported. Among the 30 most frequently prescribed drugs in Germany were 67% substrates of DMP and among the 50 most frequently prescribed drugs in the USA 68%.
Relevance and conclusions
There is an urgent need for pharmacologic studies on CBD-drug interactions. Patients should be educated on the potential risk and awareness should be increased among physicians. Regulatory authorities should become aware of the problem and start an initiative on an international level to increase the safety of CBD.
Introduction
Cannabis and cannabis-derived substances are worldwide the most frequently consumed psychopharmaceuticals [1]. Over the past decade, attitudes toward the recreational and medicinal use of cannabis have rapidly evolved from illicit to decriminalized to legalized at the state level. By 2025, legal cannabis sales are projected to generate $23 billion in the United States [2]. Delta 9-tetrahydrocannabinol (THC) is a well described psychoactive constituent which interacts with the cannabinoid receptor type 1 (CB1) and the complex network of neurologic transmitters to induce psychopharmacological effects [3]. Cannabidiol (CBD), another cannabinoid, does not bind to the CB1 receptor and does not produce the same psychoactive responses [3]. CBD has many indications like reducing anxiety in both animals and humans and is thought to produce a positive effect on conditions such as inflammation, diabetes, cancer, neurodegenerative diseases, chronic pain and insomnia [2]. At present, clinical trials investigate CBD for different disorders [4,5].
Extraction of CBD from hemp is carried out by several procedures resulting in very different profiles of extracted cannabinoids, depending on the variety and part of the plants and extraction procedure employed. The extraction procedures may then result in a variety of chemical mixtures composed of biologically active substances. CBD can also be synthesized chemically.
The only authorized CBD product on the European Union (EU) market is Epidyolex (or Epidiolex outside the EU), a prescription medicine containing highly purified plant-based CBD. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved Epidiolex as an adjunctive therapy for seizures associated with Lennox Gastaut syndrome, Dravet syndrome or tuberous sclerosis complex for patients two years of age and older [6,7].
The current legal status of CBD is worldwide neither clear nor harmonized, although there are many medicinal, food, or cosmetic products that contain CBD. The majority of CBD products are sold as over-the-counter products, supplements and are easily accessible to the general public [8].
CBD is a multi-target compound, acting on ionic channels, neurotransmitter receptors, and other transmembrane transporters, with different effects in each of them acting as activator, modulator, agonist or antagonist [9]. CBD is reported to inhibit in vitro the following drug-metabolizing proteins: Cytochrome P450 (CYP) 3A4/5, CYP2C9, CYP2B6, CYP2D6, CYP2E1, CYP1A2, CYP2C19, carboxylesterase 1 (CES1), uridine 5’diphospho-glucoronosyltransferase (UGT) 1A9, UGT2B7, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein
(BCRP) [3,[10], [11], [12], [13], [14], [15], [16], [17], [18], [19]]. These proteins are involved in the metabolization of various drugs with the potential of CBD-drug interactions. Polymorphisms of these proteins are an additional source of variability and concern in the presence of CBD and substrates [20], [21], [22].
The clinical relevance of CBD-drug interactions is largely unknown. Aim of the study was to give an overview about drugs, potentially interacting with CBD, by identifying substrates of the drug-metabolizing proteins as mentioned above, and to assess whether CBD-drug interactions of these substrates have been reported in the literature. To assess the potential clinical relevance of CBD-drug interactions, we investigated if substrates of these drug-metabolizing proteins belong to frequently prescribed drugs.
Section snippets
Methods
Substrates of CYP3A4/5, CYP2C9, CYP2B6, CYP2D6, CYP2E1, CYP1A2, CYP2C19, CES1, UGT1A9, UGT2B7, P-gp and BCRP were identified from the literature [2,[23], [24], [25]]. A literature search was carried out using PubMed from 1965 to March 2023, with the search terms: cannabidiol and substrates of P-gp, BCRP, CYP3A4/5, CYP2C9, CYP2B6, CYP2D6, CYP2E1, CYP1A2, CYP2C19, UGT1A9, CES1, UGT2B7. The Anatomical Therapeutic Chemical (ATC) classification system was used to report the findings [26].
General overview
Identified were 403 drugs as substrates of CYP3A4/5, CYP2C9, CYP2B6, CYP2D6, CYP2E1, CYP1A2, CYP2C19, CES1, UGT1A9, UGT2B7, P-gp and BRCP (Supplementary eTable 1). According to the ATC classification, they comprise 42 drugs for the alimentary tract and metabolism, 10 for blood and blood forming organs, 75 for the cardiovascular system, three dermatologicals, 9 for the genito-urinary system and sex hormones, 4 systemic hormonal preparations, 32 antiinfectives for systemic use, 66 antineoplastic
Discussion
In 31 of the investigated 53 substrates, CBD induced (or is expected to induce) an increase in the substrate level, for 5 substrates, the results are controversial, for further 4 substrates no change in the substrate level has been detected, in one substrate, the level decreased with concomitant CBD and in the remaining 12 substrates, no serum levels are reported (Table 1). Only for 25 of 403 (6.2%) potentially interacting drugs, an interaction with CBD in humans was investigated. Most of the
Limitations
- We restricted our review to CBD-drug interactions, caused by affection of drug-metabolizing proteins. Other mechanisms, however, may also lead to CBD-drug interactions like CBD’s immunomodulatory properties, as observed in patients with advanced malignancies where a co-medication of CBD decreased the tumor response rate to nivolumab [71]. An overview about various CBD-chemotherapeutics interactions is given elsewhere [5]. 2.CBD-induced receptor-modulation and toxicity were not the subject of
Conclusions
From our findings we conclude that there is an urgent need for pharmacologic studies on CBD-drug interactions, especially for frequently prescribed drugs as listed in Table 1. Since CBD is not considered a drug but a novel food and estimated as purely natural , patients should be asked explicitly for concomitant intake of CBD and educated about the potential risk for drug interactions, especially in cases with polypharmacy [74]. Hopefully, a recently designed on-line platform for the”
https://www.sciencedirect.com/science/article/pii/S0014488622003120,”Experimental Neurology
Volume 360, February 2023, 114287
Experimental Neurology
Review article
Chronic pain in Alzheimer’s disease: Endocannabinoid system
Author links open overlay panelHenry Blanton a, P. Hemachandra Reddy a b, Khalid Benamar a
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Under a Creative Commons license
open access
Highlights
Chronic pain is a major health issue
Alzheimer’s disease (AD), a devastating neurodegenerative disorder
The reported prevalence of chronic pain is 45.8% of the 50 million people with AD worldwide.
The current treatment options for chronic pain are limited, often ineffective, and have associated side effects.
This review explores the endocannabinoid system’s role in pain, its potential role in chronic pain management in AD.
Abstract
Chronic pain, one of the most common reasons adults seek medical care, has been linked to restrictions in mobility and daily activities, dependence on opioids, anxiety, depression, sleep deprivation, and reduced quality of life. Alzheimer’s disease (AD), a devastating neurodegenerative disorder (characterized by a progressive impairment of cognitive functions) in the elderly, is often co-morbid with chronic pain. AD is one of the most common neurodegenerative disorders in the aged population. The reported prevalence of chronic pain is 45.8% of the 50 million people with AD. As the population ages, the number of older people who experience AD and chronic pain will also increase. The current treatment options for chronic pain are limited, often ineffective, and have associated side effects. This review summarizes the role of the endocannabinoid system in pain, its potential role in chronic pain in AD, and addresses gaps and future directions.
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Keywords
PainEndocannabinoidAlzheimerAging
- Introduction
Pain is a complex phenomenon that comprises sensory, affective, and cognitive components. Pain is defined as an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage. (IASP, 2020). Chronic pain is defined as pain persisting beyond three months. It is a significant healthcare burden affecting approximately 50 million adults in the US alone (Dahlhamer et al., 2018), with an estimated annual healthcare burden of $600 billion in the United States alone (Gaskin and Richard, 2012). Chronic pain, one of the most common reasons adults seek medical care, has been linked to restrictions in mobility and daily activities, dependence on opioids, anxiety, depression, sleep deprivation, and reduced quality of life.
Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60 80% of dementia cases (Association, A. S., 2021). In 2020, the estimated cost of caring for and treating people with Alzheimer’s disease was $305 billion. By 2050, these costs are projected to be more than $1.1 trillion. (CDC, 2020) AD is a devastating neurodegenerative disorder and one of the most common causes of neurodegenerative dementia in the elderly, and adults over 65 comprise approximately 95% of AD cases (Zhu et al., 2015). It is characterized by a progressive impairment of cognitive functions. AD is characterized pathologically by extracellular amyloid (A ) plaques and intracellular neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau.
Among the aging population, cognitive decline, and chronic pain are two significant healthcare burdens affecting the aging population and the healthcare systems and caregivers that support these individuals. (van Kooten et al., 2017). The reported prevalence of chronic pain in AD patients is 45.8% of the 50 million people worldwide (van Kooten et al., 2016).
This review will provide a brief overview of chronic pain in aging with and without AD, shared pathology and mechanisms seen in older adults with AD and chronic pain, and explore the therapeutic potential of drugs targeting the endocannabinoid system as a novel treatment avenue.
- Age, AD, and pain
In 2020, the population aged 60 years and overreach 1.4 billion. (WHO, 2021) By 2050, the world’s population of people aged 60 years and older will double (2.1 billion). (WHO, 2021) In the United States, the population of older individuals (age 65+) is projected to double in the coming decades, from 49 million in 2016 to 99 million in 2060 (Vespa et al., 2018). Chronic pain in the elderly is a growing concern as the world’s population ages (Domenichiello and Ramsden, 2019). Indeed, old age (age 65+) is significantly correlated with an increased incidence of chronic pain conditions (Dahlhamer et al., 2018; Yang and Chang, 2019), The most common forms of chronic pain among older adults affect the back, neck, and joints (Husky et al., 2018; Guez et al., 2002; Pleis et al., 2009). Despite the increased prevalence of chronic pain in the elderly, some studies have found increased pain thresholds to experimentally induced pain in older adults (Lautenbacher et al., 2017), while other studies show mixed effects in pain thresholds between younger versus older adults (El Tumi et al., 2017). Differences in pain progression, ages, gender, sample size, modalities of evoked pain, intensity, and outcome measures used may account for the discrepancy.
AD is associated with increased chronic pain prevalence (van Kooten et al., 2016). Similarly showing varied responses to experimental pain thresholds, including increased sensitivity (van Kooten et al., 2016; Kunz et al., 2009; Kunz et al., 2007; Jensen-Dahm et al., 2014; Beach et al., 2015; Beach et al., 2016) and decreased sensitivity (Benedetti et al., 1999; Gibson et al., 2001; Monroe et al., 2017), which may vary based on the type of painful stimuli and its intensity. The most longitudinal studies of pain in people with dementia revealed that at the time of diagnosis, individuals with dementia reported significantly more pain than individuals without dementia. (Kumaradev et al., 2021). Pain prevalence and the increase in its intensity are of particular concern. Currently, a considerable proportion of people with AD and chronic pain likely may not be receiving adequate treatment compared to those without AD. Additionally, pain is a key trigger for behavioral and psychological symptoms of dementia (Atee et al., 2021; Flo et al., 2014) such as agitation and mood disorders, and poorly managed pain in AD can result in overprescribing harmful antipsychotic medications. Additionally, inadequately treated chronic pain can lead to restrictions on daily activity and psychological problems, including depression and anxiety.
Below we summarized some potential mechanisms that may account for the enhanced pain in AD.
- AD and chronic pain: shared disease features
3.1. Brain structures
Given that AD is a brain disease, there is a concern that AD may affect some brain areas involved in pain and, therefore, pain response and the effect of analgesics. AD produces structural and functional brain alterations, including changes in gray matter volume and disrupted functional connectivity between brain networks (Palesi et al., 2016). Among the areas disrupted by AD are brain areas critical for processing pain information (Lawn et al., 2021). Among the earliest sites affected by AD are the basal forebrain and medial temporal lobes, areas involved in pain processing, while the sensory cortices responsible for pain perception remain intact (Lawn et al., 2021).
Neuroimaging studies showed that when exposed to experimental pain, subjects with early-stage AD had sustained activity in pain processing regions such as the dorsolateral prefrontal cortex (dlPFC), suggesting AD patients may have greater difficulty in the cognitive and emotional appraisal of pain, and pain may be more distressing (Cole et al., 2006). Similarly, fMRI analysis of networks in experimental pain reveals greater activation of Salience and Default Mode Networks in AD patients compared to healthy controls, which may correlate to greater attention to pain, and increased emotional responsiveness to pain (Beach et al., 2017). In addition to the brain structure changes, other shared features between AD and chronic pain include neuroinflammation and mitochondria dysfunction.
3.2. Neuroinflammation
Neuroinflammation is a term used to describe the broad range of immune responses of the central nervous system (Lyman et al., 2014). Four features of neuroinflammation include increased vascular permeability, leukocyte infiltration, glial cell activation, and increased production of inflammatory mediators such as cytokines and chemokines (Ji et al., 2014). Mechanistically, neuroinflammation drives widespread chronic pain via central sensitization, which can be induced and maintained by cytokines, chemokines, and other glia-produced mediators. Neuroinflammation has a key role in the induction and maintenance of chronic pain (Ji et al., 2014; Ellis and Bennett, 2013; White et al., 2005), (Ji et al., 2018).
Neuroinflammation not only serves as a driving force for chronic pain but is also implicated in neurodegenerative diseases such as AD (Heneka et al., 2015). Clinical (Hamelin et al., 2016; Fan et al., 2017; Zhou et al., 2021; Leng and Edison, 2021) and preclinical (Martin et al., 2017) data have shown neuroinflammation in the brains with AD. In AD, neuroinflammation, instead of being a mere bystander activated by emerging senile plaques and neurofibrillary tangles, contributes as much to the pathogenesis as the plaques and tangles themselves (Heneka et al., 2015; Zhang et al., 2013). In AD, microglia can bind to soluble A oligomers and A fibrils, which are thought to be part of the inflammatory reaction in AD (Heneka et al., 2015). Studies showed that microglial activation contributes to Tau pathology during AD pathogenesis (Hopp et al., 2018; Asai et al., 2015; Maphis et al., 2015; Bhaskar et al., 2010).
3.3. Mitochondria
Mitochondria play a critical role in ATP synthesis, redox balance, and many other biological processes, including ion homeostasis, nuclear gene expression, protein turnover, and post-translational modification and apoptosis (Bozi et al., 2020). In terms of pain, both neuropathic and chronic inflammatory pain models have been associated with neuronal mitochondrial dysfunction, including impaired bioenergetics, calcium overload, oxidative stress, and aldehydic burden (Zambelli et al., 2014; Flatters, 2015).
Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases (Lin and Beal, 2006). Abnormal mitochondrial dynamics have been found to be early events in the AD disease process in studies using post-mortem AD brains, AD cell cultures, and AD mouse models (Reddy and McWeeney, 2006; Reddy et al., 2005; Manczak et al., 2011; Manczak and Reddy, 2012a; Kandimalla et al., 2016; Manczak et al., 2016; Manczak et al., 2018; Reddy et al., 2018). Increased mitochondria fission and reduced fusion can impair mitochondrial dynamics in AD-affected neurons (Manczak et al., 2019; Manczak and Reddy, 2012b; Knott and Bossy-Wetzel, 2008). Other studies using AD neurons revealed that A interacts with The dynamin-related protein (Drp1), with a subsequent increase in free radical production, which in turn activates Drp1 and Mitochondrial fission protein 1 (Fis1), causing excessive mitochondrial fragmentation, defective transport of mitochondria to synapses, provides low synaptic ATP and ultimately leads to synaptic dysfunction (Morton et al., 2021). Further studies revealed that phosphorylated tau (p-tau) interacts with Drp1, enhances GTPase Drp1 enzymatic activity, and leads to excessive fragmentation of mitochondria and mitochondrial dysfunction in AD.
Substantial amounts of data have demonstrated mitochondrial dysfunction in chronic pain (Bozi et al., 2020; Flatters, 2015; Doyle and Salvemini, 2021; Hernandez-Beltran et al., 2013; Lagos-Rodriguez et al., 2020).
Taken together, there is a significant overlap in AD and chronic pain and shared mechanisms summarized in Fig. 1 that may account for the enhanced pain in AD.”
https://www.sciencedirect.com/science/article/pii/S2049080122008147,”Annals of Medicine and Surgery
Volume 80, August 2022, 104054
Annals of Medicine and Surgery
Case Report
Cannabis-induced myocardial infarction in a 27-year-old man: Case report
Author links open overlay panelHanane Aissaoui, Soumia Boulouiz, Mohammed El-Azrak, Amine Bouchlarhem, Noha Elouafi, Zakaria Bazid
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Highlights
Cannabis smoking is a known risk factor for coronary heart disease.
The pathophysiology of myocardial infarction in cannabis users is underreported and multifactorial.
Acute coronary syndrome in young patients can be challenging due to the wide range of causing differential diagnoses.
Healthcare professionals should suspect myocardial infarction as a cause of chest pain within young cannabis users.
The complications are devastating on the quality of life of young patients, and we should raise awareness of his consequences.
Abstract
Cannabis smoking has been reported as one of the risk factors for coronary heart disease, which can trigger in rare cases, an acute coronary syndrome (ACS). In this report, we present a case of a 27-year-old man presented with acute myocardial infarction (AMI) following cannabis consumption. The patient developed ST-segment elevation on the anterior and inferior leads. Coronary angiogram demonstrated a significant stenosis of the left anterior descending coronary artery (LAD). A Percutaneous Coronary Intervention (PCI) of the LAD, was realized with the implantation of a new generation-stent with good clinical evolution status.
Healthcare professionals should consider cannabis consumption as a possible etiology of acute myocardial infarction, particularly in young patients with a susceptible social profile (drug-using patients with coronary heredity as a cardiovascular risk factor), and should educate patients regarding this emerging public health issue.
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Keywords
Acute coronary syndromeCannabisCardiovascular diseaseCase reportPercutaneous intervention
- Introduction
Coronary artery disease (CAD) is one of the most common diseases of the elderly population and a major cause of death [1]. Although acute coronary syndrome (ACS) usually occurs in the elderly group, younger people can also be affected [2]. The cardiovascular effects of cannabis have been well documented in the literature. Due to its euphoric effects, it can lead to blood pressure reduction, orthostatic hypotension, and cardiac arrhythmias [3]. It can trigger in rare cases an acute myocardial infarction (MI) and may lead to coronary artery spasm [4].
ACS in young patients can be challenging due to a large range of causing differential diagnoses. The complications of the disease on the quality of life of younger patients are devastating; and there are currently no guidelines or consensus regarding the prevention and treatment of ACS in young patients.
- Case report/case presentation
A 27-year-old patient, heavy smoker, long-term cannabis user (for 12 years), and occasional alcohol user. He doesn’t have any other risk factors for ischemic heart disease. He denied any other illicit substance abuse, including cocaine. The patient was referred to our department for post-myocardial infarction in the anterior and inferior leads. He reported prolonged chest pain one week before his admission, after cannabis smoking. Physical examination shows a heart rate at 94 bpm, blood pressure at 130/70 mmHg, a temperature of 36.2 C, a respiratory rate of 18 c/m and, and an oxygen saturation of 97%. The cardiac examination showed normal heart auscultation with discrete inferior limb edema. An electrocardiogram (EKG) revealed ST elevation on the anterior and the inferior leads with negative T waves and Q wave necrosis on the same territor”
https://www.sciencedirect.com/science/article/pii/S2049080122002837,”Annals of Medicine and Surgery
Volume 76, April 2022, 103523
Annals of Medicine and Surgery
Case Report
Cannabis arteritis: A case report and brief review of the literature
Author links open overlay panelYoussef Banana a, Husam Bashir a, Sara Boukabous a, Abdellah Rezziki a b, Adnane Benzirar a b, Omar El Mahi a b
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Highlights
Cannabis arteritis is a rare vascular disorder, since only above fifty cases have been reported in the literature.
The diagnosis of cannabis arteritis remains a diagnosis of exclusion. therefore the main causes of juvenile arterial disease must be ruled out.
Nowadays, we don’t know exactly the histopathologic patterns of this pathology.
A number of therapeutic options exist. This case was successfully managed with an extended course of intravenous vasodilator therapy combined with amputation of the necrotic toe. Long term treatment consists of cessation of Cannabis use to prevent recurrence.
Abstract
Introduction
Cannabis is commonly misused psychoactive drug which is known to be associated with a number of psychotic and somatic side-effects. Cannabis arteritis is a rare vascular disorder, since only about fifty cases have been reported in the literature.
Case presentation
We report a case of a 40-year-old chronic cannabis user male, who was admitted for painful necrosis of the fifth toe of the right foot. The etiological investigation ruled out the main causes of juvenile arterial disease. Therefore cannabis was the only causative factor found in this patient. An amputation of the fifth toe was performed 20 days later of administrating Prostacyclin (Iloprost) , with a good postoperative improvement.
Discussion
The main causes of juvenile arterial disease are: atheromatous arterial disease, thromboangiitis obliterans (Buerger’s disease) , systemic or autoimmune diseases. The diagnosis of cannabis arteritis remains a diagnosis of exclusion. it remains a rare phenomenon which is responsible for various symptoms, which can go as far as the amputation of the limb. Several authors have classified cannabis arteritis as a clinical form of Buerger’s disease, due to similar clinical semiology and similar appearance at arteriography. Nowadays, we don’t know exactly the histopathologic patterns of this pathology.
Conclusion
Although several therapeutic options exist, Cannabis weaning still the main part of cannabis arteritis treatment.
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Keywords
CannabisSevere arteritisIloprostAmputationWeaning
- Introduction
Cannabis is widely the most illicit psychoactive substance consumed all over the world [1], which is responsible for various complications as well as psychotic and somatic disorders, for instance cardiovascular disorders [2] and neoplasia [1].
Cannabis arteritis is a rare vascular disorder, which was first described by Sterne and Ducastaingt in the 1960s [3]. only above fifty cases have been reported in the litterature(4).
We report a case of severe arteritis in a cannabis smoker with digital necrosis.
Our case report was written according to SCARE guidelines [5].
- Presentation of case
We report the case of a 40-year-old male patient with no relevant medical history, especially no history of diabete, hypertension, familial thrombophilia, heart dysfunction and didn’t smoke tobacco. He is known to be a chronic cannabis user for over 25 years. He didn’t use other drugs.
He was admitted to the emergency room with painful necrosis of the fifth toe of the right foot evolving for a month. On physical examination, femoral and popliteal pulses were present with absence of distal pulses,without motor and sensitive deficit. We have not objectified signs of gas gangrene, in particular no subcutaneous crepitations. Blood analysis showed: white blood cells at 12110/mm3, C-reactive protein at 22mg/L, hemoglobin at 13 g/dl, serum creatinine at 9 mg/l, blood urea nitrogen at 0,3 g/l. The immunological investigation did not reveal antinuclear antibodies, antiphospholipid antibodies, anticardiolipin antibodies or rheumatoid factor. The thrombophilia assessment (including proteins S and C, antithrombin III, resistance to activated C protein factor V) was negative. Test result for cryoglobulinemia was also negative and complement study was normal. The glycemic and lipid balance were within the standards. Accordingly, Cannabis was the only causative factor found in this patient.
Indeed, we performed an arteriography of the right lower limb by anterograde pucture of the right common femoral artery, that objectified a femoropopliteal axis without abnormalities (Fig. 1), with a long occlusion of the anterior tibial artery from the upper third of the leg (Fig. 2). The posterior tibial artery which is not visualized, is reinjected at the level of medial ankle by the peroneal artery (Fig. 3). We note the presence of a rich collateral vascularization in the leg with good plantar arch.”
https://www.sciencedirect.com/science/article/pii/S0969996122000614,”Neurobiology of Disease
Volume 167, 1 June 2022, 105670
Neurobiology of Disease
Review
Synaptic changes induced by cannabinoid drugs and cannabis use disorder
Author links open overlay panelShana M. Augustin a b, David M. Lovinger a
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Highlights
Summarizes research on the effects of cannabinoid drugs on synaptic transmission spanning animal and human research
Organizes these research findings into acute, subacute and chronic exposure effects on synaptic transmission and plasticity
Advocates for more pre-clinical and clinical research given the increase in cannabis and cannabinoid drug use
Abstract
The legalization of cannabis in many countries, as well as the decrease in perceived risks of cannabis, have contributed to the increase in cannabis use medicinally and recreationally. Like many drugs of abuse, cannabis and cannabis-derived drugs are prone to misuse, and long-term usage can lead to drug tolerance and the development of Cannabis Use Disorder (CUD). These drugs signal through cannabinoid receptors, which are expressed in brain regions involved in the neural processing of reward, habit formation, and cognition. Despite the widespread use of cannabis and cannabinoids as therapeutic agents, little is known about the neurobiological mechanisms associated with CUD and cannabinoid drug use. In this article, we discuss the advances in research spanning animal models to humans on cannabis and synthetic cannabinoid actions on synaptic transmission, highlighting the neurobiological mechanisms following acute and chronic drug exposure. This article also highlights the need for more research elucidating the neurobiological mechanisms associated with CUD and cannabinoid drug use.
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Keywords
Cannabis sativaLong-term potentiationLong-term depressionSynaptic ModulationDelta-9 tetrahydrocannabinolCannabinoid 1 receptorEndocannabinoid
- Introduction
Cannabis-derived drugs are among the most widely used illicit substances in the world. According to the 2021 World Drug Report, it is estimated that over 200 million people have used cannabis globally, likely increasing amid the global COVID-19 pandemic (World Drug Report 2021, 2021). However, efforts to decriminalize, legalize, and reclassify the scheduling of these drugs are fast transforming the landscape of cannabis use and research. Despite the UN s reclassification of cannabis and its derivatives, these drugs remain classified as schedule I by the US Drug Enforcement Administration together with other drugs such as heroin, and ecstasy (https://www.dea.gov/drug-information/drug-scheduling). Moreover, the perceived decrease in the risks associated with cannabis use has contributed to its popularity and increased usage, already exacerbating a global health problem (Merrill, 2015).
In addition to cannabis, cannabis derivatives are being developed for medicinal purposes, despite the relative paucity of evidence about their safety, efficacy, and benefits. At the same time the evolving recognition of cannabis use disorder (CUD) and cannabis withdrawal syndrome (CWS) DSM-5; (Association, 2013) complicates the situation (Katz et al., 2014). CUD includes not only tolerance to the drug, but dependence on it as well (Branch et al., 1980; Budney et al., 2007; Hollister, 1978; Hollister, 1986; Jones et al., 1976; Patel and Marwaha, 2019; Zehra et al., 2018) and fits within neurobiological models of substance use disorders (Koob and Volkow, 2016). The intoxicating effects of cannabis consist of euphoria, impaired motor coordination, slowed reaction time, anxiety, impaired judgment/memory, and social withdrawal (Crean et al., 2011; Green et al., 2003; Kowal et al., 2015; Pujol et al., 2014; Solowij and Battisti, 2008; Volkow et al., 2016). Some of these effects can last for hours, depending on the method of cannabis administration (Borodovsky et al., 2016; Carlini et al., 2017; Loflin and Earleywine, 2014; Vandrey et al., 2017). In addition, cannabinoids can increase appetite initially, but chronic use may be suppressive (Cluny et al., 2015; Farokhnia et al., 2020; Foltin et al., 1986; Horn et al., 2018; Kirkham, 2009; Le Strat and Le Foll, 2011; Sansone and Sansone, 2014). Notably, cannabis users are less likely to overdose on cannabis when taken alone compared to other substances of abuse (Crocker et al., 2021; Martins et al., 2015). However, the risk of overdose increases with polysubstance use, such as comorbid use of cannabis with alcohol, opioids, or benzodiazepines (Jordan et al., 2018). In some regular cannabis users, CWS occurs after the cessation of cannabis use and it is a clinical indicator of CUD (Association, 2013). The diagnostic criteria for CWS includes, but is not limited to cannabis craving, sleep disruptions, irritability, aggression, suppressed appetite resulting in weight loss, depression, and anxiety (Karila et al., 2014; Katz et al., 2014; Kesner and Lovinger, 2020; Smith, 2002). CWS can also manifest with physiological symptoms, such as sweating, fever, headaches, fatigue, night sweats, and tremors (Katz et al., 2014). These symptoms can appear within days of cannabis cessation (Davis et al., 2016). There are no approved medications for CUD and CWS. However, behavioral treatments including cognitive and motivational enhancement therapies, as well as contingency management are used by CUD individuals to refrain from cannabis use and to remain abstinent (Sherman and McRae-Clark, 2016). While the behavioral effects of cannabis and withdrawal are well characterized, neurobiological research is just beginning to uncover the mechanisms that contribute to these behavioral changes.
- Cannabinoids and sites of actions
2.1. Exogenous cannabinoids
The molecular constituents of cannabis-derived drugs (also known as phytocannabinoids) act on several molecular targets within the nervous system and other organs, but the most prominent targets are the Gai/o protein-coupled cannabinoid receptor types 1 and 2 (CB1 and CB2) (Elsohly and Slade, 2005; Karniol et al., 1975). These receptors inhibit adenylyl cyclase (AC) activity, resulting in decreased levels of cAMP and inhibition of other effector proteins, such as protein kinase activity (PKA) (Ibsen et al., 2017). The predominant psychoactive constituent of cannabis-derived drugs is 9-tetrahydrocannabinol (THC), followed by the second most prominent constituent, cannabidiol (CBD). THC acts as a partial agonist at both CB1 and CB2 receptors (Kano et al., 2009; Pertwee, 2008; Pertwee et al., 2010) and its chemical structure was originally identified by Adams and Gaoni in the 20th century (Adams, 1940; Gaoni and Mechoulam, 1971). Within the brain, THC actions on presynaptic CB1 receptors predominately result in inhibitory actions on synaptic transmission (Felder et al., 1995). CB1 receptors are expressed throughout the brain and signaling through these receptors contributes to the behavioral consequences and possibly the misuse liability of cannabinoids (Augustin and Lovinger, 2018; Hu and Mackie, 2015). CB1 receptor signaling has been implicated in the processing and seeking of drug reward (Parsons and Hurd, 2015; Volkow et al., 2017). Unlike THC, which has a high binding affinity to CB1 receptors, CBD has a low binding affinity and may function as a negative CB1/CB2 receptor allosteric modulator (Kathmann et al., 2006; Laprairie et al., 2015; Ryberg et al., 2007). Another molecular constituent of cannabis is cannabinol (CBN), which is produced from the oxidation and degradation of THC (Merzouki and Mesa, 2002; Upton et al., 2013). CBN is a weak CB1 receptor agonist and mildly psychoactive (Rhee et al., 1997). Like THC, CBN binds to CB1 receptors to mediate its drug effect, although at a significantly lower potency than THC (Rhee et al., 1997). This cannabinoid is known to produce a sedative-like feeling (Musty et al., 1976), which may be beneficial to sleep. There is considerable interest in the development of other cannabis-derived drugs, besides THC, as potential therapeutic agents. However, more research is needed to determine their benefits and/or health risk associated with usage.
Full synthetic CB1 receptor agonists are widely used for therapeutic purposes and more recently for recreational drug use as an alternative to cannabis (Waugh et al., 2016; Weinstein et al., 2017). As the name implies, synthetic cannabinoids are produced in a laboratory and are chemically distinct from THC. As a result, these compounds are difficult to detect with standard drug screening procedures. Some examples of full CB1 receptor agonists are JWH-018, WIN55, 212-2, and CP55,940 (Atwood et al., 2010; Soethoudt et al., 2017). For a more complete list of synthetic cannabinoids and receptor subtype efficiency see (An et al., 2020). These drugs are pharmacologically similar to THC and exhibit a high binding affinity to CB1/CB2 receptors (Potts et al., 2020; Tai and Fantegrossi, 2017; Walsh and Andersen, 2020). Synthetic cannabinoids are generally more potent than phytocannabinoids, including THC (Banister and Connor, 2018), and are now part of widely abused herbal mixtures referred to as Black Mamba , Spice or K2 . Furthermore, these compounds are advertised and/or labeled as legal or fake cannabis as part of herbal incense and potpourri to be smoked similarly to cannabis (Kelly and Nappe, 2021; Parrott et al., 2017). These compounds are classified as new psychoactive substances (NPS) (Banister and Connor, 2018; Scourfield et al., 2019) and are often sold online or at gas stations and convenience stores. Unlike THC, these cannabinoids are often not regulated by governments and are easily accessible, especially by adolescents (Johnston et al., 2012). Use of these synthetic compounds can cause drug dependence, tolerance, and withdrawal symptoms, which are all hallmarks of substance misuse (Koob and Volkow, 2016; Nacca et al., 2013; Zimmermann et al., 2009). The neurobiological mechanisms by which these synthetic compounds, such as those in Spice , exert their psychoactive effects are not fully understood. Moreover, little is known about the short- and long-term effects of synthetic cannabinoid usage. The use of these compounds raises concerns about escalation of CUD (Alves et al., 2020; Kelly and Nappe, 2021).
2.2. Endogenous cannabinoids
The CB receptors are a key part of the endogenous cannabinoid (endocannabinoid or eCB) juxtacrine signaling system (Ibsen et al., 2017; Lu and Mackie, 2016). The eCBs are naturally produced metabolites of arachidonic acid-containing lipids. These eCBs play important roles in neurodevelopment and synaptic plasticity (Chevaleyre et al., 2006; Lu and Mackie, 2016; Piomelli, 2003). Once released from cells, the eCBs traverse short extracellular distances to activate CB receptors (Mackie, 2005). The two main eCBs are arachidonoyl ethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG). Although both AEA and 2-AG are agonists, 2-AG is a full agonist for CB1/CB2 receptors while AEA is a partial CB1 receptor agonist (Mackie, 2005; Mackie, 2008). These eCBs are synthesized and degraded by distinct enzymatic pathways, which may contribute to differences in physiological and functional roles (Augustin and Lovinger, 2018). In the central nervous system (CNS), eCBs are generated and released mainly from postsynaptic elements such as dendrites, dendritic spines and somata (Alger, 2002; Katona and Freund, 2012; Min et al., 2010). The CB1 receptors are located almost exclusively on presynaptic boutons in CNS where they inhibit neurotransmitter release (Lu and Mackie, 2016).
- Non-canonical sites of cannabinoid actions
Both exogenous (phyto- and synthetic cannabinoids) and endogenous cannabinoids can bind non-canonical orphan GPCRs, such as G protein-coupled receptor 55 (GPR55) and G protein-coupled receptor 18 (GPR18) (Morales et al., 2017; Morales and Jagerovic, 2016; Pertwee et al., 2010). Additionally, these cannabinoids can bind ligand-gated ion channels and specific transient receptor potential (TRP) channels, as well as nuclear peroxisome proliferator activated receptors (PPARs) (Morales et al., 2017; Muller et al., 2018). For example, the phytocannabinoid CBD interacts with a variety of biomolecules, giving rise to a number of potential physiological actions, albeit although some are indirect (Britch et al., 2021). It is likely that most of the cannabinoid-induced signaling is mediated through the CB1 receptors and these non-canonical GPCRs may play a supporting role in the integration of synaptic signaling to exert their cannabinoid effects. However, more work is needed to determine the functional selectively of these receptors, especially GPR55 and GPR18 (Morales and Jagerovic, 2016). - Synaptic effects of cannabinoid drugs
The eCB system is critical in short- and long-term synaptic modulation mainly via the activation of CB1 receptors in the brain. Given the role of eCBs in synaptic transmission, it is likely that eCBs play a role in the optimization and/or refinement of learning, movement control, nociception perception, and stress, either directly or indirectly. Moreover, there is mounting evidence that implicates sex differences in the behavioral and physiological effects of cannabinoids (Borgen et al., 1973; Cocchetto et al., 1981; Craft, 2005; Fattore et al., 2007; Mathew et al., 2003; Wiley, 2003). Exogenous cannabinoids, such as THC and synthetic cannabinoids can disrupt and/or alter eCB signaling and function (Cohen et al., 2020; Deadwyler et al., 1990; Schoeler and Bhattacharyya, 2013). Furthermore, these compounds can trigger different CB1 receptor-mediated intracellular signaling pathways, which may contribute to functional specificity (Laprairie et al., 2014). The effects of acute and chronic cannabinoid drug exposure on synaptic transmission are summarized in Table 1, and discussed further later in the review.”
https://www.sciencedirect.com/science/article/abs/pii/S0944711322005748,”Phytomedicine
Volume 107, December 2022, 154485
Phytomedicine
Evaluating Cannabis sativa L. s neuroprotection potential: From bench to bedside
Author links open overlay panelJohn Staton Laws III, Scott D. Smid
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Abstract
Background
Neurodegenerative diseases and dementia pose a global health challenge in an aging population, exemplified by the increasing incidence and prevalence of its most common form, Alzheimer’s disease. Although several approved treatments exist for Alzheimer’s disease, they only afford transient symptomatic improvements and are not considered disease-modifying. The psychoactive properties of Cannabis sativa L. have been recognized for thousands of years and now with burgeoning access to medicinal formulations globally, research has turned to re-evaluate cannabis and its myriad phytochemicals as a potential treatment and adjunctive agent for neurodegenerative diseases.
Purpose
This review evaluated the neuroprotective potential of C. sativa s active constituents for potential therapeutic use in dementia and Alzheimer’s disease, based on published studies demonstrating efficacy in experimental preclinical settings associated with neurodegeneration.
Study Design
Relevant information on the neuroprotective potential of the C. sativa s phytoconstituents in preclinical studies (in vitro, in vivo) were included. The collated information on C. sativa s component bioactivity was organized for therapeutic applications against neurodegenerative diseases.
Methods
The therapeutic use of C. sativa related to Alzheimer’s disease relative to known phytocannabinoids and other phytochemical constituents were derived from online databases, including PubMed, Elsevier, The Plant List (TPL, www.theplantlist.org), Science Direct, as well as relevant information on the known pharmacological actions of the listed phytochemicals.
Results
Numerous C. sativa -prevalent phytochemicals were evidenced in the body of literature as having efficacy in the treatment of neurodegenerative conditions exemplified by Alzheimer’s disease. Several phytocannabinoids, terpenes and select flavonoids demonstrated neuroprotection through a myriad of cellular and molecular pathways, including cannabinoid receptor-mediated, antioxidant and direct anti-aggregatory actions against the pathological toxic hallmark protein in Alzheimer’s disease, amyloid .
Conclusions
These findings provide strong evidence for a role of cannabis constituents, individually or in combination, as potential neuroprotectants timely to the emergent use of medicinal cannabis as a novel treatment for neurodegenerative diseases. Future randomized and controlled clinical studies are required to substantiate the bioactivities of phytocannabinoids and terpenes and their likely synergies.
Introduction
Alzheimer’s disease (AD) is a complex neurodegenerative disease with pathological hallmarks including the deposition of -amyloid (A ) plaques and the formation of intracellular neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau protein. This deleterious process is partnered by increased reactive oxidative species (ROS) and reactive nitrogen species (RNS), mitochondrial damage, reduction in acetylcholine (ACh) levels, misplaced networks amongst neurons, hippocampal shrinking and chronic neuroinflammation (Mufson et al., 2016; Sharman et al., 2019). Additionally, A plaques can facilitate excessive neuronal Ca2+ion influx via multiple channels, including overactivation of N-methyl- D-aspartate (NMDA) receptors, thereby leading to oxidative stress and activation of various caspases (Alberdi et al., 2010; De Felice et al., 2007). Although synthetic and semi-synthetic therapeutic agents exist for blocking NMDA receptors and enhanced ACh action by blocking acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity to preserve memory (Dalai et al., 2014), intervention must begin before dementia and cognitive decline develop, otherwise synaptic and dendritic branching recovery is compromised (Russo, 2018).
While diverse medical interventions have aimed to prevent A plaque formation and NFTs, there have been numerous clinical failures and only one recently FDA-approved AD therapeutic since 2003 (Cummings et al., 2018; Dunn et al., 2021). Although several approved treatments exist (NMDA receptor antagonist Memantine and cholinesterase inhibitors Tacrine, Donepezil, Rivastigmine and Galantamine), they only afford transient symptomatic improvements, create adverse side effects, have problems with bioavailability and are not considered disease-modifying (Schulz, 2003; Tan et al., 2018).
Natural bioactive alternatives, such as nutraceuticals with pleiotropic beneficial properties, may provide greater therapeutic advantages as novel therapeutic or supportive treatments for AD (Chauhan and Mehla, 2015). Phytonutrients are a ubiquitous class of bioactive secondary metabolites in plants that elicit neuroprotection through various molecular and cellular activities (Naoi et al., 2017). Polyphenols, such as (-)-epigallocatechin-3-gallate (EGCG) (a flavonoid), curcumin (a curcuminoid) and resveratrol (a stilbene) are a class of phytonutrients that have been ascribed neuroprotective properties (Makkar et al., 2020). However, limited bioavailability (Quideau, 2006) and central nervous system penetrance (Naeem et al., 2021) may curtail their development and use in dementia settings. A more comprehensive review of such limitations is provided elsewhere (Khan et al., 2020).
Recent attention has focussed on the bioactive properties of Cannabis sativa L. (C. sativa), with increased awareness of the myriad of understudied phytocannabinoids and terpenes offering a high degree of chemical diversity. Phytocannabinoids and terpenes can provide neuroprotection in preclinical models of AD, which can delay onset of dementia-like symptoms and exert anti-inflammatory, cholinesterase inhibitory activity, and antioxidant effects (Burcul et al., 2020; zt rk, 2012; Pellati et al., 2018; Wojtunik-Kulesza et al., 2017). Additionally, phytocannabinoids show promising memory-enhancing effects by reducing amyloid plaque deposition and stimulating hippocampal neurogenesis (Abate et al., 2021). While limited studies reveal potentiating therapeutic combinations of C. sativa compounds (Berman et al., 2018; Blasco-Benito et al., 2018; Pamplona et al., 2018; Polec et al., 2022; Russo, 2011; Schubert et al., 2019), there has yet to be comprehensive studies exploring these potential synergies for dementia prevention. Furthermore, C. sativa is a prolific synthesizer of unique and diverse phytochemicals which have been shown to exert neuroprotective and neurotrophic effects from its seeds, sprouts, roots, stems, leaves and inflorescences (Jin et al., 2020; Marsh and Smid, 2021; Santos et al., 2017). Therefore, the aim of this review is to evaluate C. sativa s neuroprotective potential for prevention of AD and overview of preclinical data to guide future research into potential medicinal cannabis formulations retaining key neuro-active phytochemicals.”
https://www.sciencedirect.com/science/article/abs/pii/S0013700623000581,”L’Enc phale
Volume 49, Issue 4, August 2023, Pages 329-330
L’Enc phale
Editorial
Cannabidiol (CBD) in psychiatric clinical practice: Current dataDonn es r centes sur l administration de cannabidiol (CBD) dans la pratique clinique psychiatrique
Author links open overlay panelGuillaume Fond a, Tiffanie Muller a, Marc Masson b, Laurent Boyer a
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Disclosure of interest
The authors declare that they have no competing interest.
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https://www.sciencedirect.com/science/article/abs/pii/S0011848622003545,”Dental Abstracts
Volume 67, Issue 6, November December 2022, Pages 418-419
Dental Abstracts
Hands On
Oral Health of Cannabis Users
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Background
With the push to legalize the use of marijuana for recreational as well as pharmacological use, it s increasingly likely that the dental professional will encounter patients who have used marijuana before their dental visit. Marijuana has effects on oral health and can interact with local anesthetics that dentists use, so the dental professional should be prepared to manage the occurrence of adverse events. Cannabis products, the consequences of their use on patients health, and
Cannabis Products
Cannabis is a broad term that includes products such as marijuana, cannabinoids, and cannabidiol (CBD). Tetrahydrocannabinol (THC) and other cannabinoids are active chemical compounds extracted from cannabis that have psychotropic properties. Commonly, partakers experience a euphoric high but the concentration of THC and the preparations or methods of use allow for different experiences. Medicinal cannabis, for example, can be consumed in food, inhaled, ingested, or applied topically. Among the
Health Consequences
The legalization of cannabis products is driven by economic benefits, increased tax revenues, job growth, and investment opportunities. When making decisions about legalization, the cost of cannabis in terms of its deleterious human effects must be considered. Research has identified serious cognitive problems, including short-term memory deficits, poor concentration, attention disorders, and problems processing information. Persons with pre-existing psychotic disorders can be more sensitive to
Recommendations for Dental Practitioners
Dental providers should inquire about cannabis use when doing the patient s health risk assessment interview. They should be aware that patients can fail to share this information, so dentists should observe them for signs and symptoms of cannabis use or abuse. The possible psychological signs include depression, anxiety, agitation, edginess, increased temper, irritability, moodiness, poor judgment, memory issues, uncontrollable laughing, and defensiveness. Physical signs can include bloodshot
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https://www.sciencedirect.com/science/article/abs/pii/S0892199723001583,”Journal of Voice
Available online 10 June 2023
In Press, Corrected ProofWhat s this?
Journal of Voice
Cannabinoid Use in the Treatment of Laryngeal Dystonia and Vocal Tremor: A Pilot Investigation
Author links open overlay panelNoah Millman *, Benjamin van der Woerd , Lauren Timmons Sund , Michael Johns
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https://doi.org/10.1016/j.jvoice.2023.05.006
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Summary
Objectives/hypothesis
Laryngeal dystonia and vocal tremor can be debilitating conditions with suboptimal treatment options. Botulinum toxin chemodenervation is typically the first-line treatment and is considered the gold standard. However, patient response to botulinum toxin varies widely. There is anecdotal evidence for the use of cannabinoids in treating laryngeal dystonia with a scarcity of research investigating this potential treatment option. The primary objective of this study is to survey patients with laryngeal dystonia and vocal tremor to gauge how some people are using cannabinoids to treat their condition and to ascertain patient perceptions of cannabinoid effectiveness.
Study Design
This is a cross-sectional survey study.
Methods
An eight-question anonymous survey was distributed to people with abductor spasmodic dysphonia adductor spasmodic dysphonia, vocal tremor, muscle tension dysphonia, and mixed laryngeal dystonia via the Dysphonia International (formerly National Spasmodic Dysphonia Association) email listserv.
Results
158 responses: 25 males and 133 females, (mean [range] age, 64.9 [22 95] years). 53.8% of participants had tried cannabinoids for the purposes of treating their condition at some point, with 52.9% of this subset actively using cannabis as part of their treatment. Most participants who have used cannabinoids as a treatment rank their effectiveness as somewhat effective (42.4%) or ineffective (45.9%). Participants cited a reduction in voice strain and anxiety as reasons for cannabinoid effectiveness.
Conclusions
People with laryngeal dystonia and/or vocal tremor currently use or have tried using cannabinoids as a treatment for their condition. Cannabinoids were better received as a supplementary treatment than as a stand-alone treatment.”
https://www.sciencedirect.com/science/article/pii/S0196064422007296,”Annals of Emergency Medicine
Volume 80, Issue 4, Supplement, October 2022, Page S57
Annals of Emergency Medicine
119 Cannabis-induced Anxiety Disorder in the Emergency Department
Author links open overlay panelM. Keung, E. Leach, M. Singh, B. Emmerich, S. Ilko, T. Sapp, J. Houseman, M. Barnes, J. Jones
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https://doi.org/10.1016/j.annemergmed.2022.08.143
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Study Objective
In December 2018, Michigan became the 10th state to legalize marijuana for adults. Since this law took effect, increased availability and use of cannabis in Michigan have led to an increase in emergency department (ED) visits associated with the drug s psychiatric effects. Our purpose was to describe the prevalence, clinical features, and disposition of cannabis-induced anxiety disorder in a community-based study.
Methods
This was a retrospective cohort analysis of consecutive patients diagnosed with toxicity related to cannabis use. Patients were seen at seven emergency departments (EDs) over a 24-month study period (November 2018-October 2020). Spanning 13 counties in Michigan, affiliated institutions included three rural medical centers, three university-affiliated hospitals and a children s tertiary care facility. Data collected included demographics, clinical features, and treatment outcomes in patients presenting to the ED with a chief complaint of anxiety. This group will be compared to a cohort experiencing other forms of cannabis toxicity. Chi-squared and t-tests were used to compare these two groups across key demographic and outcome variables. One investigator performed a blinded critical review of a random sample of 10% of the charts to determine inter-rater reliability using kappa statistics.
Results
During the study period, 1135 patients were evaluated for cannabis toxicity. A total of 196 patients (17.3%) had a chief complaint of anxiety and 939 (82.7%) experienced other forms of cannabis toxicity, predominantly symptoms of intoxication or cannabis hyperemesis syndrome. Patients with anxiety symptoms had panic attacks (11.7%), aggression or manic behavior (9.2%), hallucinations (6.1%), depression (4.6%), and suicidal ideation (3.1%). Many of these patients (64.8%) had associated cardiopulmonary complaints, such as tachycardia, dyspnea, hypertension, and chest discomfort. Cannabis edibles were the most common products to cause anxiety symptoms in all age groups. Compared to patients presenting with other forms of cannabis toxicity, those with anxiety were more likely to younger (25.2 vs 28.5 years, p<0.001), have psychiatric comorbidities (18.9 vs 10.5%, p=0.001) and had a history of polysubstance abuse (20.4 vs 14.7%, p=0.04). Patients with cannabis-induced anxiety had a shorter ED length of stay (2.4 vs 3.0 hours, p=0.01) but a similar rate of hospital admissions (8.7 vs 9.3%, p=0.79). Reliability of data collection (k = 0.87) showed excellent agreement.
Conclusions
Cannabis-induced anxiety disorder is common after acute or chronic cannabis exposures, occurring in 17% of ED patients in this community-based study. This disorder is associated with cardiopulmonary complaints and aggressive behavioral disorders. These troublesome findings highlight the risks associated with the use of cannabis for recreational or therapeutic purposes. ED clinicians must be adept in the recognition, evaluation, management, and counseling of these patients following cannabis exposure.”
https://www.sciencedirect.com/science/article/abs/pii/S0015028222006793,”Fertility and Sterility
Volume 118, Issue 4, Supplement, October 2022, Page e49
Fertility and Sterility
CANNABIS USE AND PREGNANCY LOSS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Author links open overlay panelCamille Zeitouni B.Sc. 1, Amanda Forsyth-Greig B.SC., M.D., M.SC. 1, Daniel Corsi Ph.D. M.Sc. B.A. 2, Doron Shmorgun M.D. 1, Clara Q. Wu M.D. 1
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https://doi.org/10.1016/j.fertnstert.2022.08.157
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Section snippets
Objective
To investigate the effect of cannabis use on the risk of pregnancy loss.
Materials and Methods
A systematic search across the Medline, Embase, Cochrane library and Google Scholar databases was performed including papers from the inception dates of respective databases until January 2022. Observational studies examining cannabis use with pregnancy loss as an outcome were included. Pregnancy loss was defined as a positive b-HCG without a live birth. Two reviewers independently assessed studies for inclusion and performed the data extraction. Quality assessment was performed using the
Results
Eight prospective and retrospective observational studies examined the association between cannabis use and pregnancy losses. In total, 1571 patients with a history of cannabis use and 5744 patients without a history of cannabis use were included in the systematic review. Across all studies, the pooled OR of cannabis use and associated pregnancy loss of any gestation was 1.28 (95% CI, 1.03-1.59; I2 = 37.4%). For earlier pregnancy losses (under 22 weeks gestation), even higher odds of pregnancy
Conclusions
The odds of pregnancy loss before 22 weeks of gestation among cannabis users was nearly 1.4 times that of non-users. Emphasis should be placed on educating patients and partners in the pre-conception and early pregnancy period about the risk of miscarriage associated with the use of cannabis.
Impact Statement
Since its legalization in Canada and many states in the United States, cannabis use has increased drastically along with the perception of its presumed safety. Due to conflicting past data, the link between cannabis use and pregnancy loss has been controversial. Our review demonstrates a significant association between cannabis use and pregnancy loss. Disseminating the results of our study will be critical in promoting the safer use of this substance.
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https://www.sciencedirect.com/science/article/abs/pii/S0022282822003959,”Journal of Molecular and Cellular Cardiology
Volume 173, Supplement, 31 December 2022, Pages S121-S122
Journal of Molecular and Cellular Cardiology
Cannabis oil one-month oral treatment given to spontaneously hypertensive rats (SHR): Could it be a promising therapeutic strategy for hypertensive cardiac hypertrophy?
Author links open overlay panelErica Pereyra a, Joshua Godoy Coto a, Fiorella Cavalli a, Luisa Fernanda Gonz lez Arbel ez a, Juliana Catalina Fantinelli a, Oswaldo Aranda b, Esteban Colman Lerner c, Omar V lez Rueda a, Susana Mar a Mosca a, Irene L. Ennis a
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https://doi.org/10.1016/j.yjmcc.2022.08.239
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Introduction
Mitochondrial alterations have been repeatedly linked to a variety of cardiovascular diseases. On the other hand, components of cannabis oil have proved cardioprotective, attenuating inflammatory and oxidative damage. Recently CBD, one of them, was found to regulate mitochondrial status. However, its effect on hypertensive cardiac hypertrophy (CH) and particularly on mitochondrial function, remains elusive.
Section snippets
Objective
To evaluate cannabis oil treatment on CH and mitochondrial status in SHR hearts.
Methods
Three-month old male SHR were randomized into treated (CO) and control (VEH). Cannabis oil or olive oil were orally administered for 1 month. We evaluated CH, myocardial histology, mitochondrial network dynamics by qPCR, mitochondrial membrane potential, myocardial superoxide dismutase (SOD), and citrate synthase activity. Data are presented as mean SEM (n) and compared by t-Test. P.
Results
CH was significantly reduced by treatment as indicated by the left ventricular weight/tibia length ratio (mg/mm, VEH:33,49 0,2(6); CO:30,47 0,78(9)), left ventricular mass (LVM) by echocardiography at the beginning and end of treatment (Day 0: 943,9 109,4(5) and day 30: 921,5 50,96(6) vs day 0: 915,1 41,49(8) day 30: 772,3 21,61 (7), VEH and CO respectively). Furthermore, myocyte cross-sectional area (CSA) and left ventricle collagen volume fraction (LVCVF) were reduced in CO (CSA:
Conclusion
We propose that one-month oral treatment with Cannabis oil is effective to reduce CH and improve mitochondrial network, probably due to an increased antioxidant capacity.”
https://www.sciencedirect.com/science/article/pii/S2667174322000131,”Biological Psychiatry Global Open Science
Volume 3, Issue 2, April 2023, Pages 222-232
Biological Psychiatry Global Open Science
Archival Report
Recreational Marijuana Use, Adolescent Cognitive Development, and Schizophrenia Susceptibility
Author links open overlay panelBeng-Choon Ho a 1, Amy B. Barry a, Julie A. Koeppel a, John Macleod b, Andy Boyd b, Anthony David c, Daniel S. O Leary a 1
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https://doi.org/10.1016/j.bpsgos.2022.01.008
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Referred to by
Cannabis Use in Adolescence: Vulnerability to Cognitive and Psychological Effects
Biological Psychiatry Global Open Science, Volume 3, Issue 2, April 2023, Pages 167-168
Katherine H. Karlsgodt
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Abstract
Background
We investigated how low marijuana (MJ) use levels, the typical use pattern in most adolescent users, affect cognitive maturation and schizophrenia risk.
Methods
In two complementary adolescent samples where the majority reported minimal MJ use, we compared cognitive performances before and after MJ use initiation. The Iowa sample (40 first-degree relatives and 54 second-degree relatives of patients with schizophrenia and 117 control subjects with no schizophrenia family history) underwent a battery of standardized neuropsychological tests at 0, 18, and 36 months. Based on self-administered Timeline Followback interviews, 26.5% of adolescents had emergent MJ use (eMJ) during follow-up. The second sample (n = 3463), derived from a birth cohort, received substance use and sustained attention assessments between ages 10 and 15 years. Mixed linear models and regression analyses tested the effects of eMJ on longitudinal changes in cognitive performance.
Results
In the Iowa sample, longitudinal changes in 5 of 8 cognitive domains were significantly associated with eMJ. On sustained attention, visuospatial working memory, and executive sequencing, adolescents with eMJ showed less age-expected improved performance. In addition, first-degree relatives with eMJ were less improved on processing speed and executive reasoning than first-degree relatives without eMJ. In the birth cohort, greater intraindividual variability in reaction times (indicative of poorer sustained attention) was significantly associated with more frequent MJ use and with recreational use levels.
Conclusions
Nonheavy MJ use disrupts normal adolescent maturation and compounds aberrant adolescent maturation associated with familial schizophrenia risk. These findings underscore the importance of reducing adolescent MJ access in the context of increased availability to high-potency MJ.”
https://www.sciencedirect.com/science/article/pii/S0735109723016807,”Journal of the American College of Cardiology
Volume 81, Issue 8, Supplement, 7 March 2023, Page 1236
Journal of the American College of Cardiology
Ischemic Heart Disease
MARIJUANA USE AS A RISK FACTOR FOR ISCHEMIC HEART DISEASE-A RETROSPECTIVE COHORT STUDY FROM THE NATIONAL INPATIENT SAMPLE
Author links open overlay panelKavin Raj, Keerthana Jyotheeswara Pillai, Surya Kiran Aedma, Preetham Kumar, Ankit Agrawal, Ramdas Pai, Padmini Varadarajan, Vrinda Vyas, Umesh Bhagat
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https://doi.org/10.1016/S0735-1097(23)01680-7
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Background
It is estimated that 14.5% of North America uses cannabis. Marijuana is implicated in the pathogenesis of ACS and Coronary atherosclerosis via sympathetic stimulation and stimulation of pro-atherogenic endothelial CB1 receptors. We wanted to contribute to the growing body of literature on this subject.
Methods
We queried data from teaching hospitals from the NIS (National inpatient sample) years 2016 to 2019 using ICD-10 codes. A multivariate logistic regression model was used to check if cannabis use was associated with different types of IHD after stratifying by age groups.
Results
A total of 3.4 million weighted hospitalizations with marijuana use and 27 million weighted hospitalizations with IHD were included. Marijuana use was not associated with an increased prevalence of IHD among younger patients (ages 18 to 64 years). However, among the elderly, Marijuana smoking was associated with an increased prevalence of subsequent STEMI (OR 2.45,95% CI 1.26-4.76, P=0.008), NSTEMI, other MI, and other acute ischemic heart diseases (Table 1).
Conclusion
Our study shows that marijuana use is associated with certain types of IHD in the elderly. The strong association of marijuana with subsequent STEMI raises the possible concern about the safety of marijuana use among patients with STEMI. With the widespread use of recreational and medical marijuana, high-quality, long-term prospective research is needed to establish the cardiovascular safety of marijuana.”
https://www.sciencedirect.com/science/article/abs/pii/S001184862300211X,”Dental Abstracts
Volume 68, Issue 4, July August 2023, Pages 280-281
Dental Abstracts
Hands On
CBD Oils to Limit the Need for Opioids
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https://doi.org/10.1016/j.denabs.2023.04.024
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Section snippets
Background
A move is underway to limit the use or dosage of opioid prescriptions given to relieve pain after oral surgery. The American Association of Oral and Maxillofacial Surgeons encourages practitioners to use nonsteroidal anti-inflammatory drugs (NSAIDs), perioperative corticosteroids, long-acting local anesthetics, and short-acting opioid medications to manage acute breakthrough pain. The use of cannabidiol (CBD) as a possible treatment in these situations should be researched in light of its
CBD Mechanisms of Action
CBD oils are biologically active low-tetrahydrocannabinol products derived from Cannabis sativa that lack the psychoactive effects of medical marijuana. Studies have identified many desirable characteristics, which include antimicrobial, anti-inflammatory, antioxidant, analgesic, anxiolytic, antiemetic, and antiepileptic properties. Clinical scenarios commonly seen in oral health care may benefit from these properties (Table).
CBD acts differently in its modulation of pain pathways compared to
Route of Administration
CBD oils can be applied locally in situations such as a tooth extraction socket after surgery, where it may exert intrinsic anti-inflammatory, antioxidant, and analgesic properties and reduce the pain medications required to address acute pain. They can also be applied topically for patients with pyoderma gangrenosum to provide significant baseline pain improvement and reduce opioid use. The antimicrobial properties of CBD oils combine with other properties to treat alveolar osteitis and
Therapeutic Implications
The therapeutic implications of systemic or transdermal use of CBD oils include the management of neuropathic pain, TMJ disorders, myofascial pain, trigeminal neuralgia, and burning mouth syndrome. Better pain control and improved sleep quality may be achieved through the use of oromucosal CBD spray in patients with treatment-resistant peripheral neuropathic pain. Significant improvement in pain and reduction in disturbing sensations can be seen with the transdermal application of CBD oils to
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https://www.sciencedirect.com/science/article/pii/S0306460322000636,”Addictive Behaviors
Volume 131, August 2022, 107297
Addictive Behaviors
Chronic use of cannabis might impair sensory error processing in the cerebellum through endocannabinoid dysregulation
Author links open overlay panelAdri n F. Amil a b, Bel n Rubio Ballester a, Martina Maier a, Paul F.M.J. Verschure c
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Highlights
Chronic cannabis use leads to motor learning deficits as assessed by motor adaptation tasks.
Chronic cannabis use is associated with CB1R downregulation in the cerebellar cortex.
Motor deficits due to chronic cannabis use are explained by deficient plasticity in the cerebellar cortex.
Motor and cognitive deficits due to chronic alcohol use might share common physiological mechanisms with cannabis abuse.
Abstract
Chronic use of cannabis leads to both motor deficits and the downregulation of CB1 receptors (CB1R) in the cerebellum. In turn, cerebellar damage is often related to impairments in motor learning and control. Further, a recent motor learning task that measures cerebellar-dependent adaptation has been shown to distinguish well between healthy subjects and chronic cannabis users. Thus, the deteriorating effects of chronic cannabis use in motor performance point to cerebellar adaptation as a key process to explain such deficits. We review the literature relating chronic cannabis use, the endocannabinoid system in the cerebellum, and different forms of cerebellar-dependent motor learning, to suggest that CB1R downregulation leads to a generalized underestimation and misprocessing of the sensory errors driving synaptic updates in the cerebellar cortex. Further, we test our hypothesis with a computational model performing a motor adaptation task and reproduce the behavioral effect of decreased implicit adaptation that appears to be a sign of chronic cannabis use. Finally, we discuss the potential of our hypothesis to explain similar phenomena related to motor impairments following chronic alcohol dependency.
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Keywords
Chronic cannabis useCerebellumError processingEndocannabinoid systemMotor learning
- Introduction
1.1. Cerebellum and drug-related behavior
There is emerging evidence from pre-clinical and neuroimaging studies that the cerebellum is critically involved in addictive processes, and that cerebellar structural and functional changes emerge in relation to addictive substance abuse (Moulton, Elman, Becerra, Goldstein, & Borsook, 2014). For instance, in their review, Moulton et al. summarized the existing evidence for structural and functional alterations in the cerebellum, caused by exposure or long-term addictive substance abuse, such as cannabis, alcohol, nicotine, and cocaine. In specific, they revealed that the posterior cerebellar hemispheres appear to differ in addicted subjects versus healthy controls. However, there is no consensus yet regarding the structural and functional effects of cannabis abuse. It remains also an open question, whether the differences imply a predisposition for addiction, or are simply the result of drug use (Moulton et al., 2014).
The cerebellar modulatory function has been associated not only with motor coordination and motor learning, but as well cognitive functioning and emotional processing, all of which play a crucial part in addictive behavior (Miquel, Toledo, Garc a, Coria-Avila, & Manzo, 2009). It appears that acute drug abuse enhances sensory processing of drug-related cues and the development of motor skills involved in the drug-taking procedure and paraphernalia. Prolonged drug-taking behavior shapes the development of value and experience-based sensory and motor representations, leading to action schemata of substance acquisition and consumption. More specifically, the repeated pairing of intrinsically neutral stimuli with the rewarding effect of taking a drug renders these stimuli incentive salient, thereby biasing attention (Berridge et al., 2009, Robinson and Berridge, 2000). These schemata are then easily activated by drug-related cues, leading to automated action and motor representations, which possibly underlie the addictive behavior and could account for relapses even after long abstinence (Yalachkov, Kaiser, & Naumer, 2010). On the other hand, prolonged drug-abuse is associated with impairment in cognitive control. Impaired frontal-cortico-cerebellar functional networks in alcohol use disorders due to structural damage have been associated with deficits in inhibitory actions. Hence, it has been suggested that the automatized actions and motor responses associated with drug-related cues become not only less amenable to cognitive interference but that the lack of cognitive control impairs the individual to inhibit drug consumption (Wilcox, Dekonenko, Mayer, Bogenschutz, & Turner, 2014). This notion has given rise to the dual-process model of addictive behavior, in that drug-use emerges due to acquired automatic, impulsive processes which start to dominate the decision-making processes within addiction (for a review, see Stacy & Wiers, 2010). However, it has been recently argued, whether the addicted individual indeed exhibits total loss of choice or whether volitional choice is present but decision-making biased towards the drug consumption (Wiers & Verschure, 2020). It is known that the cerebellum plays a crucial role in decision-making through habit formation, reward and error processing, and motor learning (see for instance (Rosenbloom, Schmahmann, & Price, 2012)). However, it is unclear how a potential cerebellar damage due to chronic substance abuse would affect these processes leading to maladaptive and addictive behavior. In addition, investigating the role of the cerebellum in addiction might also aid in understanding, whether biased decision-making underlying addiction could be reversed through rehabilitation that is capitalizing on the learning mechanism that led to the addiction in the first place. For instance, it has been shown that by manipulating the attentional bias and action towards alcohol-related stimuli addicted individuals were able to form new, healthier habits, which reduced relapse post-treatment (Rinck, Wiers, Becker, & Lindenmeyer, 2018).
The present paper brings forward a possible explanation regarding the effects of chronic cannabis (and alcohol) use and its hypothetical molecular mechanisms (i.e., the CB1R downregulation in the cerebellum), focusing on motor learning deficits, which have been arguably overlooked until now (Blithikioti et al., 2019, Prashad and Filbey, 2017). The aim is to establish a mechanistic explanation of motor impairment due to chronic drug use mainly cannabis and alcohol , that is grounded on the known physiology of the cerebellum, the endocannabinoid regulatory system, and the molecular effects of chronic use. Further, we aim to account for a specific motor impairment observed in a recent clinical study (Herreros et al., 2019), which might shed light on the general principle underlying the aforementioned motor and cognitive deficits. Understanding the involvement of the cerebellum in addiction aids on the one hand to get a clearer view of the consequences of long-term drug use and to establish common diagnostic and therapeutic tools.
1.2. Cerebellar impairments in chronic cannabis use
There is no consensus about the specific effects of chronic cannabis use on human neurocognition. While the literature has consistently linked it to alterations in verbal learning, memory, and attention (Broyd, Van Hell, Beale, Y cel, & Solowij, 2016), there is mixed evidence pointing to impairments in psychomotor function (i.e., finger tapping, critical tracking, choice reaction time tasks, and digit-symbol substitution tasks) and executive function (i.e., tasks of planning, reasoning, interference control, and problem-solving). The inconsistency of these results may be due to the heterogeneity and the complexity of the selected tasks. Motivated by these limitations, a recent systematic review screened 248 unique articles exploring cerebellar alterations in cannabis users (Blithikioti et al., 2019). The authors concluded that chronic cannabis intake leads to deficits in eyeblink conditioning, memory, and decision making. At a more mechanistic level, all of these behavioral paradigms are highly dependent on the endocannabinoid system. Therefore, the dysregulation of the endocannabinoid system might be key for the understanding of the motor deficits associated with this type of addiction (Prashad & Filbey, 2017). Indeed, animal studies suggest that the intake of synthetic exogenous cannabinoids reduces the number of spikelets in the complex spikes of cerebellar Purkinje cells (Fig. 1A; (Irie et al., 2015)) and slows-down the acquisition of conditioned responses (Fig. 1B; (Skosnik et al., 2008)). Grounding on these observations and the widely accepted role of Purkinje cells in the coding of sensory errors and motor control (Herzfeld et al., 2015, Herzfeld et al., 2018), Herreros, et al. hypothesized that THC, acting as an exogenous agonist of the cannabinoid receptors, may diminish cerebellar plasticity (Herreros et al., 2019). The authors exposed 17 chronic cannabis users (CCUs) and 18 healthy age-matched controls to a visuomotor rotation task that probes a putatively-cerebellar implicit motor adaptation process together with the learning and execution of an explicit aiming rule (Taylor, Krakauer, & Ivry, 2014). The results showed impaired implicit motor adaptation in CCUs when compared to controls (Fig. 1C), thus uncovering a behavioral marker of cerebellar alterations that could have potential clinical applications.”
https://www.sciencedirect.com/science/article/abs/pii/S0181551222000249,”Journal Fran ais d’Ophtalmologie
Volume 45, Issue 4, April 2022, Pages 423-429
Journal Fran ais d’Ophtalmologie
Original article
Cannabis smoking and glaucoma in the UK Biobank cohortTabagisme et glaucome dans la cohorte UK Biobank
Author links open overlay panelS. Lehrer a, P.H. Rheinstein b
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Summary
Background
Cigarette smoking is a well-known risk factor for primary open-angle glaucoma (POAG). Tobacco smoke contains a variety of chemicals, including nicotine, free radicals, and carbon monoxide, all of which can play a role in the development of POAG. Cannabis smoke, like tobacco smoke, contains a comparable variety of carcinogenic and toxic compounds. In the present study, we analyzed UK Biobank data to determine whether smoking cannabis, like cigarettes, might be related to POAG.
Methods
Our analysis included all subjects with glaucoma and cannabis smoking information. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. We used the UK Biobank Data Parser (ukbb parser), a python-based package that allows easy interfacing with the large UK Biobank dataset. Statistical analysis was performed with SPSS 25 and R.
Results
Subjects who used cannabis 100 times or more were significantly younger (10 years) when they developed glaucoma than subjects who never used cannabis. The effects of age (P < 0.001) and cigarettes (P = 0.014) on POAG incidence were significant, but the effect of cannabis use was not (P = 0.662). The effect of cannabis use on age at glaucoma diagnosis was significant and unrelated to the effects on intraocular pressure or cigarette pack-years smoked. Analysis of intraocular pressure showed that mean pressures of subjects who used cannabis 11 100 times were significantly lower than those who took no cannabis.
Conclusion
Inhaling cannabis smoke is injurious to the eye, but in the case of glaucoma the manifestations are different from those of inhaled tobacco smoke. Cannabis reduces intraocular pressure but accelerates glaucoma development. Cannabis does not increase risk of glaucoma. Cigarette smoking increases risk of glaucoma and significantly accelerates glaucoma development. Apparently, early use of cannabis leads to the earlier development of glaucoma.”
https://www.sciencedirect.com/science/article/pii/S1556086422004993,”Journal of Thoracic Oncology
Volume 17, Issue 9, Supplement, September 2022, Page S95
Journal of Thoracic Oncology
MA14 PALLIATIVE AND SUPPORTIVE CARE – THE FORGOTTEN TRADE, TUESDAY, AUGUST 9, 2022 – 14:30 – 15:30
MA14.07 The Use of Medical Cannabis Concomitantly with Immune-Check Point Inhibitors (ICI) in Non Small Cell Lung Cancer (NSCLC): A Sigh of Relief?
Author links open overlay panelB. Waissengrin 1 2, Y. Leshem 1 2, I. Wolf 1 2
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Introduction
In recent years, the use of medical cannabis rapidly increased among cancer patients in Israel. Yet, cannabinoid receptors are abundantly expressed on immune cells and modulate their activity. It is abundantly being use by metastatic NSCLC patients, shortly following diagnosis and is taken in parallel to first line treatment with ICI. Recent studies suggested that the use of cannabis may reduce the efficacy of ICI. However, these studies were biased by the heterogeneity of patients and the increased use of cannabis specifically in highly symptomatic patients with high disease burden.
Methods
We first tested the interaction anti-PD-1 antibody and -9-tetrahydrocannabinol (THC) in a preclinical model consisting of CT26 tumor-bearing mice, and examined the effects on tumor size, T-cell infiltrates, and mice survival. Mice were euthanized when tumor volume reached above 700 mm3. Next, we conducted a retrospective study of NSCLC patients, treated at a tertiary center, and included all consecutive patients treated with a single agent pembrolizumab as a first line treatment for advanced disease and evaluated clinical outcome and response to treatment.
Results
Studies using the CT26 mice cancer model, indicated a potential beneficial effect for the combination an anti-PD-1 antibody and THC with a median overall survival (OS) of the mice receiving no treatment, THC, anti-PD-1 antibody or their combination being 21 days, 24, 31 days and 54 days, respectively (p<0.05). Data of 201 NSCLC cancer patients who received first-line single agent pembrolizumab for metastatic disease, 102 (50.7%) patients received cannabis and 99 (49.3%) were cannabis na ve was analyzed. Their median age was 68 for the cannabis treated group and 74 for the cannabis na ve (p=0.003), 34 (34.3%) in the cannabis treated group and 62 (60.8%) for the cannabis na ve were women (p=0.002). Similar distribution of histology, smoking status and PDL1 expression was noted between the groups. The efficacy of pembrolizumab, as determined by time to progression (TTP) was similar for cannabis-na ve and cannabis-treated patients (6.1 vs. 4.8 months, respectively, p=0.386), while OS was higher, though not statistically significant, in the cannabis-na ve group (54 vs. 23.3 months, respectively p=0.08).
Conclusions
Both preclinical and clinical data suggest no deleterious effect of cannabis on the activity of pembrolizumab as first line monotherapy for advanced NSCLC. The differences in OS can be most likely by attributed to higher disease burden and more symptomatic disease in the cannabis-treated group. While additional validation is required, these data provide somewhat reassuring data regarding the absence of a deleterious effect of cannabis in this clinical”
https://www.sciencedirect.com/science/article/abs/pii/S104327602200162X,”Trends in Endocrinology & Metabolism
Volume 33, Issue 12, December 2022, Pages 828-849
Journal home page for Trends in Endocrinology & Metabolism
Review
Cannabinoids and terpenes for diabetes mellitus and its complications: from mechanisms to new therapies
Author links open overlay panelEsmaeel Ghasemi-Gojani 1, Igor Kovalchuk 1, Olga Kovalchuk 1
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The number of people diagnosed with diabetes mellitus and its complications is markedly increasing worldwide, leading to a worldwide epidemic across all age groups, from children to older adults. Diabetes is associated with premature aging. In recent years, it has been found that peripheral overactivation of the endocannabinoid system (ECS), and in particular cannabinoid receptor 1 (CB1R) signaling, plays a crucial role in the progression of insulin resistance, diabetes (especially type 2), and its aging-related comorbidities such as atherosclerosis, nephropathy, neuropathy, and retinopathy. Therefore, it is suggested that peripheral blockade of CB1R may ameliorate diabetes and diabetes-related comorbidities. The use of synthetic CB1R antagonists such as rimonabant has been prohibited because of their psychiatric side effects. In contrast, phytocannabinoids such as cannabidiol (CBD) and tetrahydrocannabivarin (THCV), produced by cannabis, exhibit antagonistic activity on CB1R signaling and do not show any adverse side effects such as psychoactive effects, depression, or anxiety, thereby serving as potential candidates for the treatment of diabetes and its complications. In addition to these phytocannabinoids, cannabis also produces a substantial number of other phytocannabinoids, terpenes, and flavonoids with therapeutic potential against insulin resistance, diabetes, and its complications. In this review, the pathogenesis of diabetes, its complications, and the potential to use cannabinoids, terpenes, and flavonoids for its treatment are discussed.
Introduction
According to 2019 projections by the International Diabetes Federation, in 2019, approximately 463 million people were diagnosed with diabetes worldwide. This number will rise to 587 million individuals by 2030 and 700 million individuals by 2045, respectively [1].
Diabetes mellitus is a chronic disease that occurs as a result of inappropriate control of glycemia over time and is a well-known cause of premature aging, leading to a significant reduction of life expectancy in patients [2,3]. Glycemia leads to an array of diabetes-related complications such as atherosclerosis, nephropathy, neuropathy, and retinopathy.
There are two main types of diabetes: (i) type 1, which occurs due to absolute loss of -cells and resulting complete lack of insulin secretion; and (ii) type 2, which is recognized by insulin resistance, -cell dysfunction, and loss and subsequent decrease in insulin secretion. Prediabetes is a condition in which insulin resistance occurs, usually due to metabolic disorders, but -cells compensate for further insulin demand, leading to hyperinsulinemia, but not remarkable hyperglycemia. It is noteworthy that various organizations define prediabetes in vastly different ways. Prediabetes has been proven to play a significant role in the progression of type 2 diabetes.
Section snippets
Endocannabinoid system
Overall, the ECS (see Glossary) is composed of a complex combination of substances: (i) lipidic endocannabinoids (AEA and 2AG); (ii) endocannabinoid-synthesizing enzymes, including N-acetyl phosphatidylethanolamine phospholipase C (NAPE-PLC), which is involved in the synthesis of AEA, and diacylglycerol lipase (DAGL), involved in the synthesis of 2AG; (iii) endocannabinoid-hydrolyzing enzymes such as the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL); and (iv)
CB1R is a new target for diabetes treatment and disease complications
Based on the aforementioned research data, it seems that downregulation of CB1R signaling can be a way to treat insulin resistance, diabetes, and its complications including nephropathy, retinopathy, neuropathy, and macrovascular complications [12,52]. Some publications report the therapeutic effects of CB1R antagonists and/or inverse agonists for the mitigation of the progression of diabetes and its complications [12,45,53]. However, global inhibition of CB1R signaling results in adverse
THC
THC is the most well-known psychoactive phytocannabinoid produced by C. sativa. THC is an agonist of CB1R and a partial agonist of CB2R. The psychoactive and appetite-stimulating effects of THC are related to the activation of CB1R, imitating the behavior of AEA [56]. Due to its role as a CB1R agonist, it seems that THC cannot be used as a potential treatment for prediabetes, diabetes, and its complications. Moreover, it may even contribute to the development of diabetes or worsen existing
CBD
CBD is the most popular nonpsychoactive phytocannabinoid found in C. sativa. In recent years, CBD has been found to have some remarkable pharmaceutical properties [74]. Numerous in vitro and in vivo experiments indicate CBD s potent anti-inflammatory properties [67,75., 76., 77.]. The use of CBD is linked to a reduction in inflammatory cytokine secretion, such as TNFa, NF B, IL-I , and also enzymes involved in triggering inflammation, such as p38MAPKa [74,77]. There are contradictory reports
THCV
THCV, a naturally occurring propyl analog of THC, is usually found in low amounts in the dried cannabis plant. However, there are some THCV-rich cannabis varieties containing 16% THCV by dry weight [67,93]. THCV is identified as a neutral CB1R signaling antagonist and, like CBD, it does not cause any significant adverse psychiatric side effects. It is noteworthy that THCV antagonizes CB1R-mediated signaling in a concentration-dependent manner. THCV has been suggested as a potential drug for the
CBC
CBC was the second phytocannabinoid after THC to be isolated from the cannabis plant [98]. CBC, CBD, and THC are synthesized by different enzymes from the same precursor CBG [99]. The affinity of CBC for CB1R and CB2R is weak, suggesting a probable CB1R- and CB2R-independent mode of action. Together with CB1R and CB2R, transient receptor potential A1 (TRPA1) and adenosine receptors are other CBC targets [98]. In addition to the receptor-dependent mode of action, it seems that CBC also exerts
CBG
Cannabigerolic acid (CBGA), the acidic form of CBG, is the main precursor of phytocannabinoids such as THCA, CBDA, and CBCA. It is synthesized by CBGA synthase from olivetolic acid and geranyl pyrophosphate [56]. The lack of any psychiatric effects together with some evidence indicating potential therapeutic properties has nominated CBG as a potential candidate for further research to design new drugs [101,102]. CBG exerts part of its therapeutic effects through agonistic effects on CB2R,
-Caryophyllene
C. sativa produces a broad range of terpenoids, including monoterpenes and sesquiterpenes. One of the most abundant and perhaps the most important sesquiterpenes found in cannabis is -caryophyllene. In addition to cannabis, -caryophyllene is also found in other plants, such as oregano, cinnamon, and black pepper [108]. The antidiabetic effects of -caryophyllene have been reported in several studies [68,109., 110., 111.]. The insulinotropic effects of -caryophyllene have also been reported.
Other important terpenes
In addition to mentioned terpenes, cannabis produces many other terpenes, some of which also have well-documented anti-inflammatory and antioxidant activities and, therefore, enormous potential for the mitigation of prediabetes, diabetes, and its complications. Notable mentions are caryophyllene oxide, a-humulene, -pinene, nerolidol, borneol, a-bisabolol, -elemene, fenchone, and -eudesmol [113]. Accordingly, the protective impacts of a-humulene on the function and survival of -cells in
Flavonoids
In addition to phytocannabinoids and terpenes, cannabis also contains another group of secondary metabolites called flavonoids, 26 of which have been thus far isolated from cannabis, including quercetin, apigenin, luteolin, cannflavin A, cannflavin B, kaempferol, vitexin, and orientin. The majority of these constituents show potent anti-inflammatory, antioxidant, and neuroprotective activities, suggesting their probable therapeutic potential against prediabetes, diabetes, and its complications [
Cannabis extracts and diabetes
Due to the simultaneous presence of a complex combination of phytocannabinoids and terpenes in cannabis extracts, the incidence of synergistic effects is inevitable [67,75] and likely results in greater therapeutic impacts. There are just a few reports about the use of cannabis extracts for the treatment of insulin resistance, diabetes progression, and its complications, excluding diabetic neuropathy pain. In one of these studies, Levendal et al. demonstrated the effectiveness of one cannabis
Concluding remarks
Regarding the fast-growing worldwide diabetes epidemic, there is an urgent need for easily available, multipurpose treatments with low/no adverse side effects against insulin resistance, diabetes, and its complications. Having produced a substantial number of metabolites with well-documented antidiabetic effects, C. sativa could have enormous potential for the treatment of diabetes and its complications. Some phytocannabinoids inherent to cannabis can exert antidiabetic effects through direct”
https://www.sciencedirect.com/science/article/abs/pii/S0165178121006417,”Psychiatry Research
Volume 308, February 2022, 114347
Psychiatry Research
Review article
A scoping review of the use of cannabidiol in psychiatric disorders
Author links open overlay panelAnna E. Kirkland a, Matthew C. Fadus b, Staci A. Gruber c d, Kevin M. Gray a, Timothy E. Wilens b e, Lindsay M. Squeglia a
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Abstract
Cannabidiol (CBD) has become a fast-growing avenue for research in psychiatry, and clinicians are challenged with understanding the implications of CBD for treating mental health disorders. The goal of this review is to serve as a guide for mental health professionals by providing an overview of CBD and a synthesis the current evidence within major psychiatric disorders. PubMed and PsycINFO were searched for articles containing the terms cannabidiol in addition to major psychiatric disorders and symptoms, yielding 2952 articles. Only randomized controlled trials or within-subject studies investigating CBD as a treatment option for psychiatric disorders (N = 16) were included in the review. Studies were reviewed for psychotic disorders (n = 6), anxiety disorders (n = 3), substance use disorders (tobacco n = 3, cannabis n = 2, opioid n = 1), and insomnia (n = 1). There were no published studies that met inclusion criteria for alcohol or stimulant use disorder, PTSD, ADHD, autism spectrum disorder, or mood disorders. Synthesis of the CBD literature indicates it is generally safe and well tolerated. The most promising preliminary findings are related to the use of CBD in psychotic symptoms and anxiety. There is currently not enough high-quality evidence to suggest the clinical use of CBD for any psychiatric disorder.
Introduction
Cannabidiol (CBD) is a phytocannabinoid in the Cannabis sativa plant that has gained widespread attention for its potential use in psychiatry research due to its role as a neuromodulator in areas of the brain that control cognition, emotion regulation, behavior, and physiological responses (Bonaccorso et al., 2019; Glass et al., 1997). Conventional pharmacotherapies in psychiatry are generally effective but their use can be stigmatized, and they can confer burdensome adverse effects. Consequently, patients may seek out alternative therapies such as CBD-containing products. Mental health clinicians are now challenged to rapidly adapt to the growing body of literature regarding the use of CBD in psychiatric disorders. Accordingly, this review provides an overview of CBD, including regulatory matters and commercial use; safety and tolerability; abuse liability; and its metabolism and potential drug-drug interactions. This is followed by a discussion of the current level of evidence for treating common psychiatric disorders, organized in descending order based on the quality of research available. Two tables are presented : one summarizes the current evidence for each condition and catalogs registered ongoing clinical trials, and the other is a guide to help answer common questions about CBD from patients and providers. This review will provide mental health clinicians with important information about CBD and an understanding of the quality of evidence for its use in common psychiatric conditions to support them in making recommendations to patients.
Cannabis sativa is a plant made up of hundreds of constituents, including more than 100 cannabinoids; the most common cannabinoids are -9-tetrahydrocannabinol (THC) and CBD. THC and CBD are present in varying proportions based upon the cultivated variety of Cannabis sativa (ElSohly et al., 2017). Broadly, THC is the primary intoxicating constituent, whereas CBD is a non-intoxicating constituent of the plant and is generally touted for its therapeutic potential for a variety of conditions (Bhattacharyya et al., 2010; ElSohly et al., 2017; Mechoulam and Parker, 2013). CBD has many potential targets within the central nervous system. CBD has a low affinity for cannabidnoid-1 (CB1) and cannabinoid-2 (CB2) receptors, where it may act as a negative allosteric modulator of CB1 activity and a weak inverse agonist or partial agonist of CB2 receptors (Laprairie et al., 2015; Tham et al., 2019; Thomas et al., 2007). CBD also has indirect effects on endocannabinoid signaling, such as increasing levels of the endocannabinoid ligand anandamide by decreasing its cellular re-uptake by fatty acid binding proteins and decreasing endocannabinoid hydrolysis by fatty acid amide hydrolase (Elmes et al., 2015; Ligresti et al., 2016). Beyond the endocannabinoid system, CBD may modulate serotonin 5-HT1A receptors, G protein-coupled receptors, and TRPV1 (transient receptor potential cation channel subfamily V member 1) receptors, as well as – and d-opioid receptors (Campos et al., 2012; Pertwee, 2008). The exact mechanisms of CBD are not yet clear, and the relevance of the numerous proposed targets need to be further investigated. Nonetheless, reviews have indicated that there is a growing preclinical (Ligresti et al., 2016) and clinical (Bonaccorso et al., 2019; Khan et al., 2020) literature indicating that CBD could have antipsychotic (Batalla et al., 2019; Iseger and Bossong, 2015; Kopelli et al., 2020), anxiolytic (Bahji et al., 2020; Skelley et al., 2020), antidepressant (Pinto et al., 2020), and anti-craving (Prud’homme et al., 2015) qualities.
The regulatory matters surrounding CBD are complex and quickly evolving. In the United States, the 2018 Farm Bill was a catalyst for the expansion of CBD products. The bill removed hemp, a cultivated variety of Cannabis sativa required to have less than 0.3% THC by dry weight, from the Controlled Substance Act definition of marijuana . This made it federally legal to produce hemp-based products (Alharbi, 2020). The legality of CBD products often comes down to the variety of the Cannabis sativa used: marijuana (Schedule I drug; federally illegal to produce) or hemp (federally legal to produce) (Corroon and Kight, 2018); however, possessing hemp-based CBD products can still be a legal gray area (Alharbi, 2020; Corroon and Kight, 2018). The legal status of CBD products are further complicated by the FDA approval of Epidiolex, a purified CBD compound with no other cannabinoids or terpenoids approved as an antiepileptic treatment for two rare pediatric-onset seizure disorders, Lennox-Gastaut syndrome and Dravet syndrome (Billakota et al., 2019). See Alharbi (2020), Brunetti et al. (2020), and Vlad et al. (2020) for reviews concerning the legality of CBD in the United States and around the world.
There has been a dramatic increase in the use of commercial CBD products, with retail sales of CBD products projected to reach $16 billion by 2025 (Azer et al., 2019). CBD products can be plant- or non-plant-derived, and can be classified by their cannabinoid source profile as an isolate (pure CBD, no other cannabinoids or terpenes), full-spectrum (CBD with terpenes and other cannabinoids, including small amounts of THC), or broad-spectrum (CBD with terpenes and other cannabinoids, but not THC) (Marinotti and Sarill, 2020). CBD is manufactured as several product types that can be used in a variety of ways, including inhalation (smoking or vaping), ingestion, topical applications, sublingual, transdermal (patches), or transmucosal administration. Commercial products containing CBD are widely available, including food items, beverages, lotions, cosmetics, and oils, accessible to consumers in multiple point-of-sale locations such as online retailers, coffee shops, gas stations, health spas, and bakeries.
Commercially available CBD products are largely unregulated and are not held to the quality control as FDA-approved medications, which can result in inconsistent dosing, safety, and therapeutic response predictability (Freeman et al., 2019b). Two studies found that a majority of sampled CBD products were mislabeled regarding their CBD content, and approximately a quarter of the products contained detectable amounts of THC (Bonn-Miller et al., 2017; Lachenmeier et al., 2019).
Studies have indicated that purified CBD is generally safe and well tolerated with relatively low potential for toxicity (Organization, 2018). One study found that purified CBD (as Epidiolex) was well tolerated in healthy controls across a wide range of doses, including acute administration (up to 6000 mg) and multiple administrations daily (750 or 1500 mg, twice daily for six days) (Taylor et al., 2018). Additionally, studies in patients with epilepsy have found CBD to be well tolerated in high doses over a longer period of time (e.g., up to 50 mg/kg/day for up to three months) (Devinsky et al., 2017, 2016; Taylor et al., 2018). Of note, these studies used purified CBD and dosing will likely differ if using whole plant, full-spectrum, or even broad-spectrum CBD products.
The overall safety profile of CBD appears to compare favorably with many psychiatric medications (Boggs et al., 2018; Iffland and Grotenhermen, 2017; Leweke et al., 2012; Machado Bergamaschi et al., 2011; McGuire et al., 2018). In clinical trials for Epidiolex in epilepsy (10 mg/kg/day vs. 20 mg/kg/day), adverse events included transaminase elevations (8%, 16%), sedation (41%, 51%), decreased appetite (16%, 22%), diarrhea (9%, 20%), sleep disturbance (5%, 11%), infections (41%, 40%), pneumonia (8%, 5%), viral infections (7%, 11%), and weight loss (3%, 5%) (Brown and Winterstein, 2019). It is important to note that the elevated transaminase levels were most likely due to a drug-drug interaction with valproic acid (Chesney et al., 2020; Devinsky et al., 2016). Another review and meta-analysis (N = 13) of clinical trials across multiple clinical populations (epilepsy n = 5, schizophrenia n = 2, cannabis use n = 1, Huntington’s disease n = 1, type II diabetes n = 1, non-alcoholic fatty liver disease n = 1, Crohn’s disease n = 1) or healthy controls (n = 1) found that only diarrhea remained as an adverse event when excluding studies in childhood epilepsy (Chesney et al., 2020). Gastrointestinal adverse events are the most likely side effect of CBD use in patients without epilepsy. Animal studies have indicated that CBD may have negative effects on fertility, particularly in males, although additional research is needed to make any definitive claims about this effect in humans (Carvalho et al., 2020; O’Llenecia et al., 2019). Animal studies in mice and zebrafish have also indicated that CBD may have teratogenic effects (e.g., physical deformities, decreased weight and length, behavioral abnormalities, and change in developmental biomarkers) (Achenbach et al., 2018; Ahmed et al., 2018; Carty et al., 2019, 2018; Fish et al., 2019); however, one study did not find any teratogenic effects of CBD (Brigante et al., 2018) and no studies have examined whether these effects occur in humans. More research on the effects of CBD prenatally, perinatally, and postnatally is critical before clinicians can recommend CBD during pregnancy.
The World Health Organization has reported that pure CBD is not related to effects that indicate misuse, abuse, or dependence potential (Organization, 2018). One randomized double-blind, placebo-controlled eight-week study of 31 frequent cannabis smokers examined weekly use of differing doses (200, 400, 600, and 800 mg) of oral, non-plant derived CBD and inhaled cannabis (THC 5.3 5.8%) and found that CBD had no greater abuse-related liability than placebo when comparing participant ratings of feeling high , feeling good , and suggested street value (Babalonis et al., 2017). Another randomized, double-blind, placebo-controlled study of 43 polydrug users found that a therapeutic dose (750 mg) of highly purified CBD (Epidiolex) did not confer a significant abuse liability in this highly sensitive population. However, supratherapeutic doses (1500 and 4500 mg) demonstrated detectable subjective effects compared to placebo, but this was significantly less than 10 mg and 30 mg of dronabinol (synthetic THC) or 2 mg of alprazolam (Schoedel et al., 2018). Abrupt withdrawal of CBD after four-weeks of use (750 mg twice daily taken orally) did not result in any symptoms of physical withdrawal (Taylor et al., 2020).
Route of administration may also be important. One study found that vaporized CBD (100 mg) had significantly higher subjective rating for drug effect , pleasant , and like drug as compared to oral CBD (100 mg) (Spindle et al., 2020). Another study found that vaporized CBD (400 mg) had some subjective intoxicating properties (e.g., feeling stoned , dissociated state) as compared to placebo (Solowij et al., 2019). However, an earlier study reported that 16 mg of vaporized pure CBD did not impact subjective effects (Hindocha et al., 2015). Given the clinical findings, CBD does not seem to present with a pharmacological profile of a drug of abuse, but more research is needed to better understand how routes of administration and dose may confer abuse liability (i.e., vaporized CBD).
CBD is metabolized in the liver by the cytochrome P450 pathway and uridine 5′-diphosoglucuronosyltransferase (UGT), where it is metabolized to the active metabolite 7-OHsingle bondCBD by CYP2C19 and then to inactive metabolites by CYP3A4 and UGT (Harvey and Mechoulam, 1990; Huestis, 2005; Ujv ry and Hanu , 2015). This first pass metabolism results in variable bioavailability (Landmark and Brandl, 2020; White, 2019), which is directly impacted by the pharmacokinetics and absorption profiles of the route of administration. Bioavailability can also be strongly influenced by factors such as co-ingested food (e.g., high fat meals increase bioavailability) or variations in vaping habits when using vaporized CBD (Landmark and Brandl, 2020; Vandrey et al., 2017). Epidiolex (purified CBD) reaches maximal concentration 2.5 to 5 h after oral administration, and has an elimination half-life of 56 to 61 h (White, 2019). A systematic review of the pharmacokinetics of commercial CBD products in humans found the half-life of CBD was 1.4 to 10.9 h after oromucosal spray, 2 to 5 days after oral administration, 24 h after intravenous administration, and 31 h after smoking (Millar et al., 2018).
There is limited research concerning drug-drug interactions between CBD and other medications. CBD may have many theoretical drug-drug interactions since the CYP3A and CYP2C enzymatic families are implicated in metabolizing various medications and other substances. A comprehensive review was recently published detailing such potential interactions (Balachandran et al., 2021). Case studies have indicated that psychiatric medications (lithium) and other medications (tacrolimus and methadone) may have drug-drug interactions with CBD (Leino et al., 2019; Madden et al., 2020; Singh et al., 2020); however, clinical studies investigating these specific effects are lacking. Of note, while lithium is not metabolized by the liver, some evidence has indicated that CBD can increase creatinine levels and cause renal dysfunction which negatively affects lithium metabolism, potentially leading to toxicity (Singh et al., 2020).
Patients with underlying liver disease or who are concurrently taking other medications that adversely affect the liver should be aware of potential elevations in transaminases. A recent phase 1, open-label study in 16 healthy adults found that a therapeutic dose of CBD (1500 mg/day) over almost four weeks resulted in increased serum alanine aminotransferase in seven participants (44%), and reached the level for drug-induced liver injury for five participants (31%) (Watkins et al., 2020). A dose-dependent increase in serum aminotransferases was found in childhood epilepsy clinical trials where a majority or all the patients affected were concurrently taking valproic acid (Devinsky et al., 2017, 2018; Thiele et al., 2018). CBD has been shown to increase concentration levels of antiepileptic drugs, such as clobazam, topiramate, and zonisamide (Landmark and Brandl, 2020); however, other studies have reported no evidence of CBD interaction with clobazam (VanLandingham et al., 2020). Prescribers of psychiatric medications should discuss with patients that CBD has the potential for drug interactions, particularly since CBD is typically used as an adjunct to other psychiatric medications (Corroon and Phillips, 2018).
Section snippets
Methods: evidence for CBD use in major psychiatric disorders
To review the use of CBD for major psychiatric disorders, PubMed and PsychINFO were searched for articles published up to April 2021 with abstracts and titles containing the terms cannabidiol or CBD, in addition to: psychiatry, psychiatric, anxiety, post-traumatic stress disorder, sleep, insomnia, bipolar disorder, mania, mood disorder, depression, major depressive disorder, obsessive-compulsive disorder, psychosis, schizophrenia, autism, substance use,
Psychotic disorders
There is a growing body of evidence that the endocannabinoid system is implicated in the pathophysiology of psychosis (Bossong et al., 2014; Zamberletti et al., 2012), thus CBD has been proposed as a candidate pharmacotherapy (Davies and Bhattacharyya, 2019). Preclinical work indicates that CBD inhibits the degradation of anandamide (Bisogno et al., 2001), an endocannabinoid which plays a major role in mood regulation, cognition, and behavior (Di Marzo and Petrosino, 2007). Indeed, increased
Discussion
Overall, CBD presents as a generally safe and well-tolerated pharmacotherapy with limited abuse liability making it a popular candidate treatment for psychiatric conditions. Psychiatric symptoms are among the most commonly reported reasons for commercial CBD use (Corroon and Phillips, 2018), despite a lack of randomized controlled trials to support their use (see Table 1 for overview). Even the psychiatric disorders with the most promising findings and the largest number of published studies,
Declaration of Competing Interest
Dr. Wilens has been or is a consultant for Arbor Pharmaceuticals, Otsuka, Ironshore, KemPharm, Vallon, Gavin Foundation, Bay Cove Human Services, US National Football League (ERM Associates), and US Minor/Major League Baseball. Dr. Wilens has published books: Straight Talk About Psychiatric Medications for Kids (Guilford Press); and co/edited books ADHD in Adults and Children (Cambridge University Press), Massachusetts General Hospital Comprehensive Clinical Psychiatry (Elsevier) and”
https://www.sciencedirect.com/science/article/abs/pii/S0149291822003496,”Clinical Therapeutics
Volume 44, Issue 12, December 2022, Pages e39-e58
Clinical Therapeutics
Review
A Systematic Review of Medical Cannabinoids Dosing in Human
Author links open overlay panelDavid A. Campos MSc 1, Edgar J. Mendivil PhD 2 3, Mario Romano BSc 1, Mariano Garc a BSc 1, Miriam E. Mart nez MSc 1
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https://doi.org/10.1016/j.clinthera.2022.10.003
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Abstract
Purpose
This systematic review assesses currently available clinical information on which cannabinoids and what range of doses have been used to achieve positive effects in a diversity of medical context.
Methods
The data were collected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol guidelines. Inclusion criteria were articles that assessed administration of any cannabinoid to any clinical population, reported in the ClinicalTrials.gov or PubMed databases, that involved a comparison with other treatment or placebo and a result measurement to assess the effectiveness or ineffectiveness of the cannabinoid. Exclusion criteria were review or letter; articles not in the English language; not full-text articles; not a clinical trial, case report, case series, open-label trial, or pilot study; administration in animals, in vitro, or in healthy participants; cannabinoids administered in combination with other cannabinoids (except for cannabidiol [CBD] or tetrahydrocannabinol [THC]) or as whole cannabis extracts; no stated concentration; inhalation or smoke as a route of administration; and no results described. The articles were assessed by the risk of bias.
Finding
In total, 1668 articles were recovered, of which 55 studies met the inclusion criteria for 21 diseases. Positive effects were reported in clinical studies: 52% with THC (range, 0.01 0.5 mg/kg/d [0.62 31 mg/d]), 74% with CBD (range, 1 50 mg/kg/d [62 3100 mg/d]), 64% with THC-CBD (mean, 1:1.3 mg/kg/d [ratio, 1:1]), and 100% with tetrahydrocannabivarin (THCV) (0.2 mg/kg/d).
Implications
THC, CBD, and THCV can regulate activity in several pathologies. New studies of cannabinoids are highly encouraged because each patient is unique and requires a unique cannabinoid medication.
Public interest is increasing about the use of synthetic or natural cannabinoids for symptom and disease management. However, not enough clinical evidence is available on the pharmacodynamic and pharmacokinetic properties of cannabinoids. Therefore, further research is required to address the knowledge needed for optimal prescribing of these drugs.1 Cannabis is a plant that contains >500 different substances, including cannabinoid and noncannabinoid compounds. Noncannabinoids include a wide variety of flavonoids and terpenes. Flavonoids are pigments found on the plant that are involved in the unique flavor and smell of the cannabis strain. Similar to terpenes, they play specific pharmacologic roles. Terpenes are aromatic oils identified as the source of fragrance and flavor in the cannabis plant. These molecules possess action in neuronal and muscle ion channels, neurotransmitter receptors, G-protein coupled receptors, second messenger systems, enzymes, and cell membranes. For this reason, these compounds contribute synergistically with cannabinoids to generate therapeutic effects. The main cannabinoids are tetrahydrocannabinol (THC), cannabidiol (CBD), tetrahydrocannabivarin (THCV), cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG), and their respective acids forms, tetrahydrocannabinol acid (THCA), cannabidiol acid (CBDA), tetrahydrocannabivarin acid (THCVA), cannabigerol acid (CBGA), d-8-tetrahydrocannabinol (d-8-THC), cannabidivarin (CBGV), and cannabinovarin (CBNV), to name a few.2 Among these compounds, THC, CBD, THCV, and CBNV are the most studied in humans.
THC, -9-tetrahydrocannabinol,3 is the compound primarily responsible for the psychoactive effects associated with marijuana use, as well as for some of pharmacologic properties. THC affects the brain mostly by activating the cannabinoid receptor 1 (CB1) and through this cellular mechanism causes changes in memory, cognition, and pain perception.4 Nevertheless, THC has a higher safety profile than many other medications. Because of a lack of CB1 receptors in brainstem cardiorespiratory centers, no overdose deaths have been reported.5 Compared with opioids, alcohol, tobacco, and benzodiazepines, the risk of psychic and physical dependency is low. THC may lead to dependency, tolerance, and mild withdrawal syndrome (after abrupt cessation of use of long-term administration of high doses of THC). Individuals experience insomnia, irritability, sweating, loose stools, hiccups, and anorexia. Tolerance is attributed to pharmacodynamic changes based on receptor desensitization or receptor downregulation.6 The most common adverse effects are cognitive effects, nausea, anxiety, cough, dry mouth, dizziness, and fatigue. Rare adverse effects include orthostatic hypotension, depression, ataxia, tachycardia, cannabis hyperemesis syndrome, diarrhea, and psychosis in susceptible individuals. THC-mediated adverse effects are usually dose dependent and rate limiting. Patients develop tolerance to psychoactive effects of cannabis quickly (a few days), without concomitant tolerance to the benefits, and therefore maintain the same daily dose for many years. However, if general initiation is start low, go slow, and stay low, this dosing strategy mitigates most adverse events of THC, such as dizziness, fatigue, and tachycardia. A total daily dose limited to 30 mg/d or less is recommended, preferably in combination with CBD, to avoid adverse events, psychoactive sequelae, and development of tolerance without improving efficacy. There are different levels of evidence for THC-based medicines under certain conditions: chronic pain in adults, multiple sclerosis spasticity symptoms, chemotherapy-induced nausea and vomiting, improving outcomes in patients with sleep disturbances, decreasing intraocular pressure in glaucoma, symptoms of dementia, symptoms of Parkinson disease, symptoms of schizophrenia, symptoms of posttraumatic stress disorder, appetite and reducing weight loss associated with HIV/AIDS, traumatic brain injury, symptoms of Tourette syndrome, addiction abstinence (opioids), irritable bowel syndrome, cancers (including glioma), cancer-associated anorexia, cachexia syndrome and anorexia nervosa, symptoms amyotrophic lateral sclerosis, chorea, and some neuropsychiatric symptoms associated with Huntington disease and dystonia.7 The purported effects of THC are mediated through signaling mechanisms. The corresponding role of THC in women at the time of fertilization and implantation is open to conjecture and deserves additional investigation.8 Data in humans suggest that prenatal exposure to THC may lead to subtle, persistent changes in targeted aspects of psychological well-being and higher-level cognition. In general, THC is contraindicated during lactation and pregnancy9 as well as psychosis.10 Finally, THC should be used with caution in unstable cardiac conditions because of possible hypotension and tachycardia (no QTc issues).11 THC is metabolized by the cytochrome P450 (CYP) enzymatic pathway (CYP2C9 and CYP3A4), simultaneously playing the role of an inhibitor. This mechanism is pivotal to the biotransformation of commonly prescribed psychotropic agents.
For this reason, health care practitioners should be aware of the latent hazards associated when THC is coadministrated with drugs that depend on these enzymatic routes.12 Two synthetic THC pharmaceutical formulas are currently approved: nabilone13 and dronabinol. Both have clinical effects analogous to oral administration of natural cannabis.14 Both synthetic forms of THC are given to treat vomiting and chemotherapy-induced nausea in people who did not respond to conventional antiemetic drugs. Still, dronabinol is also used to treat anorexia associated with weight loss in patients with AIDS.
CBD is another natural cannabinoid or phytocannabinoid found in the cannabis plant. CBD is commonly well tolerated and has relatively low toxicity. In contrast to THC, CBD does not affect blood pressure under normal conditions or heart rate. There is no evidence at any dosages for dependency, tolerance, or abuse, as concluded by the World Health Organisation Expert Committee on Drug Dependence.15 The adverse effects of CBD were usually mild and infrequent after an extensive literature review. Some reported adverse effects include tiredness, diarrhea, and changes in appetite or weight.16 The favorable effects of CBD include anticonvulsant, anti-inflammatory, antioxidant, analgesic, anxiolytic, and cytotoxic effects, among others mediated through signaling mechanisms. CBD also has a significantly low risk of drug interaction.17 CBD is metabolized through CYP450 enzymes (particularly by CYP3A4 and CYP2C19).18 The CBD interaction with these enzymes caused increased bioavailability of specific agents, making it possible to reduce the dose of the antiepileptic drug, which in turn reduced its adverse effects.19 The combination of CBD and THC (GW Pharmaceuticals, Cambridge, UK) is currently indicated as an adjuvant treatment for spasticity in patients with multiple sclerosis who have not responded properly to classic therapy (nabiximols). CBD alone is prescribed for the treatment of seizures associated with Dravet or Lennox-Gastaut syndromes in patients =2 years of age.
Cannabidivarin (CBDV) is an n-propyl homologue of CBD that lacks psychoactive effects found in cannabis. This compound presents potential anticonvulsants properties. CBDV shows no affinity for CB1/CB2 receptors at physiologically relevant concentrations; however, evidence suggests activity on non-CB1/CB2 receptors. Antagonism on these receptors has been proposed as an innovative therapeutic agent for autism spectrum disorder and Drave syndrome. Nevertheless, the knowledge of this compound is limited.20
THCV is a naturally occurring homologue of THC but has different pharmacologic properties (because its alkyl side chain [propyl] structure is shorter than that of d-9THC (pentyl).21 It has been observed to behave through signaling mechanisms. These properties could help with diseases related to pain, metabolic syndrome, and diabetes. However, little is known about the mechanism of action of THCV and other minor cannabinoids.22
Currently, 282 clinical trials registered on ClinicalTrials.gov are investigating THC alone, 223 clinical trials are investigating CBD alone, 2 clinical trials are investigating THCV alone, and 6 clinical trials are investigating CBDV. In addition, 2 clinical trials are investigating THCA and 3 clinical trials are investigating CBN, but 4 were investigated as metabolites from cannabis. In addition, 1 clinical trial was investigating CBDA but once again as a metabolite from cannabis.
No studies were found for cannabinoids synthetized from olivetolic acid, including CBGA, CBG, CBLA, CBL, CBCA, CBC, CBEA, CBE, CBNA, and CBDA. In addition, no studies were identified for cannabinoids synthetized from the divarinolic acid, including cannabigerovarinic acid, CBGV, THCVA, cannabicyclovarinic acid, cannabichromevarinic acid, cannabivarichromene, cannabidivarinic acid, cannabielsovarinic acid, and cannabivarin.
Of note, no single clinical trial is registered to investigate the dose-ranging efficacy of the most relevant cannabinoids,23, 24, 25 indicating an important clinical interest to ensure a correct prescription. In addition, physicians worldwide remain deeply uneducated on the endocannabinoid system and cannabinoids. Even in countries where medical cannabis is allowed, such as the United States, only 35.3% felt ready to answer cannabis questions, and 89.5% of fellows and residents felt unprepared to prescribe. Moreover, only 9% of US medical schools document appropriate clinical cannabis content in their curricula.26 According to a previous publication, scientific data are the core principle of good public health practice and uncertainty leads to inaction by clinicians.27 Because cannabis therapeutics lack satisfactory documentation, this review aimed to compile the best available evidence about which cannabinoids and what range of doses have been used to achieve positive effects across a diversity of medical diseases in humans (as diagnosed using any recognized diagnostic criteria). This systematic review identifies the different active dosing range of THC (range, 0.01 0.5 mg/kg/d), CBD (range, 1 50 mg/kg/d), and THC-CBD (mean, 1:1.3 mg/kg/d), whereas only 1 study was presented for tetrahydrocannabidivarin (0.2 mg/kg/d) within a wide variety of medical conditions. Studies found that higher or lower doses depend on the preexisting condition of the patient. Finally, new cannabinoids, such as CBDV, are currently being studied. The protocol was registered in the International Prospective Register of Systematic Reviews (CRD42021257698).
Section snippets
Information Sources
This systematic review’s design was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Figure 1). A search was conducted in MEDLINE (PubMed) and ClinicalTrials.gov from October 1, 2019, to March 1, 2020, for all relevant articles (only full articles in the English language) on the administration of cannabinoids in human populations. The following search strings were used: Cannabigerolic acid or CBGA, Cannabicyclolic acid or CBLA,
Results
The initial search produced 1668 records, of which 845 were reviewed and 55 articles included in the final analysis (Table I). A flowchart of article retrieval and selection is presented in Figure 1. Thirty-four studies were randomized clinical trials (RCTs), 11 articles were case studies (case report or case series), and 10 were clinical studies but not both controlled and randomized in design (eg, open-label trials). A summary of the clinical studies is presented in Table II according to
Discussion
This article aimed to compile, compare, and identify a range of doses of the available cannabinoids (THC, CBD, THC-CBD, and THCV) used in clinical populations. In total, 21 medical disorders were included in this systematic review in 55 RCTs, case studies (case reports or case series), and clinical studies (not controlled and randomized in design). A positive effect of THC was reported in 52% of studies, covering illnesses such as Alzheimer disease (dementia), cancer (anorexia in lung cancer),
Conclusion
This review found that most studies on THC had positive effects by using lower doses (0.01 mg/kg/d) rather than by using higher doses (0.5 mg/kg/d). However, for CBD, most studies found positive outcomes with higher doses (50 mg/kg/d) rather than with lower doses (1 mg/kg/d). For THC-CBD, a range of 1.0 (THC) to 1.3 (CBD) mg/kg/d (ratio of 1:1) had the most beneficial effects. Finally, in the case of THCV, effective dosing was 0.2 mg/kg/d for adults.”
https://www.sciencedirect.com/science/article/abs/pii/S0360301621033848,”International Journal of Radiation OncologyBiologyPhysics
Volume 112, Issue 5, 1 April 2022, Pages e60-e61
International Journal of Radiation OncologyBiologyPhysics
210
Cannabis Use in Patients with Head and Neck Cancer and Radiotherapy Outcomes
Author links open overlay panelA.M. Williams 1, M. Gilbert 2, F. Siddiqui 2
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https://doi.org/10.1016/j.ijrobp.2021.12.139
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Purpose/Objective(s)
Marijuana use in the population is increasing as states continue to allow for both medicinal and recreational use. As such, the prevalence of marijuana use among patients presenting for treatment of head and neck cancer (HNC) is likely to increase as well. Anecdotally, patients are asking about marijuana use during cancer treatment and, to date, oncology professionals treating HNC are lacking sufficient data to aid in advising their patients on use during cancer care. Further, the impact of marijuana use on survival and local control in HNC is not well understood. The current study examines the associations between marijuana use and the management and outcomes in patients with HNC squamous cell carcinoma.
Materials/Methods
IRB approval was obtained for a retrospective evaluation in our institutional database. Two-hundred eighty patients with detailed psychosocial and substance abuse history who were treated with either definitive or adjuvant radiotherapy between August 2018 and March 2020 were included in the analyses. Overall survival (OS) and disease-free survival (DFS) were compared between current marijuana users and non-users using Kaplan-Meier curves and log-rank tests.
Results
148 patients with HNC were included (mean age=62.1 yrs, SD=9.1), 78% were male, 73% were white, 22% were black. 62% of patients had SCCa of the oropharynx, 20% SCCa of the larynx, and 14% SCCa of the oral cavity. 51% were treated with definitive chemoradiotherapy, while 32% had primary surgery. 30% were current tobacco users and 70% had ever used tobacco (mean = 43.33 PY). 15% of patients reported marijuana use at time of initial diagnosis and 34% reported a history of marijuana use. Older patients and males were more likely to be currently using marijuana (p=.005 & p=.04, respectively). Current marijuana users were more likely to require narcotic pain medications and require a greater number of types of pain medications during treatment (p=0.002 and p=0.007, respectively). There were no differences between current and historical/never users on self-reported worst pain, weight loss or enteral feeding tube use during treatment, or objective measures of treatment toxicity. Additionally, there were no other significant differences between current or historical/never users were found on cancer variables or primary treatment type.
Conclusion
Marijuana use in patients with HNSCCa is common and little is known about patient and oncological outcomes. There were no significant differences between current and past marijuana users and non-users on clinicopathological variables, adherence, or oncologic outcomes. Marijuana use in HNC may result in more difficulty managing pain during treatment. Further research is needed to better understand marijuana use during cancer treatment, particularly frequency and method of use (i.e., smoking vs. edibles/oils), outcomes, and quality of life.”
https://www.sciencedirect.com/science/article/abs/pii/S1064748122002809,”The American Journal of Geriatric Psychiatry
Volume 30, Issue 4, Supplement, April 2022, Page S7
The American Journal of Geriatric Psychiatry
Cannabinoids and Psychedelics for Neuropsychiatric Symptoms of Alzheimer’s: Addressing Disparities Through Clinical Trials
Author links open overlay panelBrent Forester MD, MSc 2, Krista Lanct t PhD 4, Jacobo Mintzer MD, MBA 3, Paul Rosenberg MD 1
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https://doi.org/10.1016/j.jagp.2022.01.261
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Abstract
AD and other forms of dementia are commonly associated with neuropsychiatric symptoms, including anxiety, agitation, and depression, all of which can lead to more rapid cognitive decline and a poor quality of life for both caregivers and patients.
There are currently no FDA approved medications to treat neuropsychiatric symptoms associated with dementia. Instead, current treatment options include off-label use of psychotropic medications that are associated with well-established risks. Alternative therapeutic options include cannabinoids and psychedelics. This session will focus on discussing the safety and efficacy of cannabinoids in treating anxiety and agitation associated with Alzheimer’s dementia, as well as the safety and efficacy of psychedelics in treating depression in older adults with dementia.
The history of medicinal cannabis use dates back as far as 4000BC. Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, activates cannabinoid receptors (mainly CB1 and CB2 receptors), producing anxiolytic and antidepressant effects while also reducing reduce brain inflammation. Cannabidiol (CBD), the major non-intoxicating component of cannabis, possesses low affinity to CB1 and CB2 receptors. CBD modulates systems outside of the endocannabinoid system, producing antioxidant and antipsychotic effects. Both THC and CBD have shown evidence of therapeutic effects on anxiety and pain. We will discuss three studies evaluating the use of cannabinoids as potential forms of treatment for agitation and anxiety in dementia.
Psychedelics are also being introduced as potential mental health treatments. Past research has shown psychedelics can produce long-term anxiolytic and antidepressant effects after a single administration. A pilot trial at Johns Hopkins is examining the safety and efficacy of psilocybin treatment for participants with mild cognitive impairment (MCI) and depressive symptoms. The study hypothesizes that the psilocybin treatment will be associated with a significant reduction in depressive symptoms.
Overall, these trials collectively guide research towards furthering our understanding of the pathology of Alzheimer’s dementia and other forms of dementia and improving the quality of life for older adults and their caregivers.”
https://www.sciencedirect.com/science/article/abs/pii/S0006322322004656,”Biological Psychiatry
Volume 91, Issue 9, Supplement, 1 May 2022, Page S145
Biological Psychiatry
P144. Prenatal Cannabis Use and Offspring Autism-Related Behaviors: Examining Maternal Stress as a Moderator in a Black American Cohort
Author links open overlay panelChaela Nutor 1, Dana Barr 1, Olivia Sadler 1, Heidi Morgan 1, Anne Dunlop 1, Patricia Brennan 1
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https://doi.org/10.1016/j.biopsych.2022.02.378
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Section snippets
Background
The prevalence of both autism spectrum disorder (ASD) and maternal cannabis use during pregnancy are increasing, yet few empirical studies have examined their potential association. Moreover, it is unclear whether maternal prenatal cannabis use may interact with other ASD risk factors, such as maternal prenatal stress, to impact child neurodevelopment. This question is particularly relevant for Black mothers, who are disproportionately exposed to prenatal stressors including low socioeconomic
Methods
Black women (ages 18-40 years) were recruited from prenatal clinics at 8-14 weeks gestation and provided urine samples for cannabis biomarker assay and self-report of substance use and stress in their second trimester. When their children were two years old, they were then invited to participate with their child in a cohort study in which child autism behaviors were assessed via validated maternal report and administered observational assessments.
Results
Prenatal and child outcome data were available for 172 dyads. Child sex and prenatal tobacco/alcohol exposures were statistically controlled. Male sex predicted higher levels of observed autism-related behaviors (p=.01) and prenatal stress predicted higher maternal reports of autism-related behaviors (p=.001). Our primary hypotheses were not supported (p>.05).
Conclusions
We found no evidence that prenatal cannabis use increases risk for autism-related behaviors. Once replicated, these findings may inform health policy recommendations regarding cannabis use and legalization.”
https://www.sciencedirect.com/science/article/pii/S2773021222000220,”Psychiatry Research Case Reports
Volume 1, Issue 2, December 2022, 100028
Psychiatry Research Case Reports
Marijuana variant of concern: Delta 8-tetrahydrocannabinol (Delta-8-THC, 8-THC)
Author links open overlay panelMack Elijah Bozman, Senthil Vel Rajan Rajaram Manoharan, Tarak Vasavada
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https://doi.org/10.1016/j.psycr.2022.100028
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Under a Creative Commons license
open access
Abstract
Background
Recreational use of Delta 8-tetrahydrocannabinol (Delta-8-THC, 8-THC) has become more common, as are emergency room visits and lasting associated psychiatric conditions associated with Delta-8 (Radwan et al., 2021) (Cannabis (Marijuana) and Cannabinoids 2022). It is essential to recognize the psychoactive effects of Delta-8 as recent exposures are increasing rapidly (Volkow et al., 2014). Physicians must maintain a high index of suspicion for psychosis in relation to use of this compound. We present two cases, a 20-year-old and a 35-year-old, in whom the effects of Delta-8-THC were dramatic and consequential, leading to severe psychosis and lasting depression and suicidal ideation.
Conclusions
There has been a remarkable increase in the number of emergency department admissions in our hospital and many hospitals that have involved the use of Delta-8-THC. We present these cases to increase physician awareness of Delta-8 (as well as slang terms to describe it like marijuana-lite and diet-weed ) and other legal THC derivatives and the potential side effects so that we can better educate patients and families.”
https://www.sciencedirect.com/science/article/abs/pii/B9780323905725000184,”Herbal Medicines
A Boon for Healthy Human Life
2022, Pages 637-654
Herbal Medicines
30 – Mixed effects and mechanisms of cannabinoids for triple-negative breast cancer treatment
Author links open overlay panelKhanh Tran
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https://doi.org/10.1016/B978-0-323-90572-5.00018-4
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Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the lack of estrogen receptors, progesterone receptors, and HER-2 receptors. Thus, TNBC tumors do not benefit from the current therapies targeting estrogen receptor or HER-2. Therefore, there is an urgent need to develop novel treatments for this subtype of breast cancer. Marijuana is a common name given to Cannabis plants, a group of plants in the Cannabis genus of the Cannabaceae family. Cannabis plants are among the oldest cultivated crops, traced back at least 12,000 years and are well known for their multipurpose usage, including medicinal purposes. The main active compounds extracted from Cannabis plants are 21-carbon-containing terpenophenolics, which are referred to as phytocannabinoids. Of these, the tetrahydrocannabinol (THC) group contains highly potent cannabinoids, including delta-9-tetrahydrocannabinol ( 9-THC) and delta-8-tetrahydrocannabinol ( 8-THC), which are the most abundant THCs and are primarily responsible for the psychological and physiological effects of marijuana. The use of Cannabis plants for medicinal purposes was first recorded in 2337 BC in China, where Cannabis plants were used to treat pains, rheumatism, and gout. Recently, several cannabinoids have been approved for several treatments, one of which is the treatment of nausea and vomiting caused by chemotherapy in cancer patients. Furthermore, increasing evidence shows that cannabinoids not only attenuate side effects due to cancer treatment but might also potentially possess direct antitumor effects in several cancer types, including breast cancer. However, the antitumor activity of cannabinoids has been variable in different studies and even promoted tumor growth in some cases. In addition, mechanisms of cannabinoids actions in cancer remain unclear. This review summarizes evidence about the mixed actions and mechanisms of cannabinoids in cancer in general and TNBC in particular.”
https://www.sciencedirect.com/science/article/abs/pii/S2405803322000243,”Abstract
Section snippets
References (15)
Cited by (4)
Recommended articles (6)
Trends in Cancer
Volume 8, Issue 5, May 2022, Pages 350-357
Journal home page for Trends in Cancer
Forum
Plant-derived cannabinoids as anticancer agents
Author links open overlay panelEve M. O Reilly 1 2, Joanne M. Cosgrave 1 2, William M. Gallagher 1 3, Antoinette S. Perry 1 2
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https://doi.org/10.1016/j.trecan.2022.01.017
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Substantial preclinical evidence demonstrates the antiproliferative, cytotoxic, and antimetastatic properties of plant-derived cannabinoids (phytocannabinoids) such as cannabidiol and tetrahydrocannabinol. The cumulative body of research into the intracellular mechanisms and phenotypic effects of these compounds supports a logical, judicious progression to large-scale phase II/III clinical trials in certain cancer types to truly assess the efficacy of phytocannabinoids as anticancer agents.
Section snippets
Cannabis sativa: A rich source of phytochemicals
Cannabis sativa is among the most useful and versatile of plants, a multipurpose crop that humans have harnessed for fuel, materials, textiles, and cosmetics. The Cannabis plant also has a long history of medicinal use by many cultures, with some evidence dating its healing properties as early as 400 A.D. The plant produces approximately 120 terpenophenolic phytocannabinoid compounds, of which cannabidiol (CBD) and tetrahydrocannabinol (THC) are among the most abundant.
Certain
Inhibiting cancer cell hallmark behaviors
Uncontrolled cell proliferation is the most fundamental cancer hallmark. Accordingly, antiproliferative agents are of great therapeutic interest. Growth inhibition by CBD in vitro is commonly accompanied by modulation of cancer-related signaling cascades, including the extracellular signal-related kinase (ERK), AKT, epidermal growth factor receptor (EGFR), reactive oxygen species (ROS), and p38 mitogen-activated protein kinase pathways. Downstream, CBD treatment reduces the expression of
Potential for chemoprevention
The World Health Organization estimates that 30 50% of cancers are preventable. Chemopreventive agents can inhibit or reverse carcinogenesis, thus reducing an individual s risk of developing cancer. Some studies have indicated the potential of CBD as a chemopreventive agent. In cancers driven by inflammation, such as colorectal cancer, the anti-inflammatory properties of phytocannabinoids may be beneficial in protecting against carcinogenesis. A low dose of CBD (1 mg/kg) slowed the
Enhancing the efficacy of standard-of-care chemotherapy
An important benefit of cannabinoids is their potential to safely synergize with existing anticancer therapies. In vitro studies have demonstrated that CBD and THC can enhance the effects of commonly used chemotherapeutic agents, including cisplatin, temozolomide, bortezomib, doxorubicin, and paclitaxel. A combination of CBD and cisplatin significantly reduced tumor growth in vivo compared with treatment with either compound alone [14]. In addition, the combination of THC and/or CBD with
Clinical trials of cannabinoids in cancer
While substantive preclinical research demonstrates the anticancer properties of phytocannabinoids, the key question is whether these observations can translate to therapeutic benefits for patients with cancer. To date, clinical trials have focused on dosing, safety, and chronic pain/symptom relief in multiple advanced cancer types. For example, numerous trials (each with hundreds of patients) have studied an oral THC-CBD combination [nabiximols (Sativex); GW Pharmaceuticals, Cambridge, UK],
Concluding remarks
In certain cancer types, such as glioblastoma, where substantial in vitro and in vivo research demonstrates cannabinoid anticancer efficacy, adequately powered randomized controlled trials of phytocannabinoids for cancer treatment are warranted. In other cancers, further preclinical research that moves beyond artificial 2D cell lines is needed to determine the phenotypic effects of cannabinoids and to better understand their mechanisms of action. Advances in 3D technologies such as organoids
Acknowledgments
We acknowledge funding from the Irish Research Council (EPSPG/2017/376 and GOIPG/2020/1178) and Greenlight Pharmaceuticals.”
https://www.sciencedirect.com/science/article/abs/pii/S1553465021012863,”Journal of Minimally Invasive Gynecology
Volume 29, Issue 2, February 2022, Pages 169-176
Journal of Minimally Invasive Gynecology
Special Article
Cannabidiol for the Management of Endometriosis and Chronic Pelvic Pain
Author links open overlay panelMegha Mistry BMedSci, MBBS, MRCOG a, Paul Simpson MA, BMBS, MRCOG, MD a, Edward Morris MBBS, BSc, MD, FRCOG a, Ann-Katrin Fritz FRCA, FFPMRCA, FIPP, CIPS b, Babu Karavadra BSc, MBBS, AFHEA a, Carole Lennox BMedSci, MBBS, FRCA c, Ed Prosser-Snelling BA, MBBS, MRCOG a
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https://doi.org/10.1016/j.jmig.2021.11.017
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ABSTRACT
Objective
To review the available literature on the effect of cannabis-based products on the female reproductive system and establish whether there is any evidence that they benefit or harm patients with endometriosis and, therefore, whether there is sufficient evidence to recommend them.
Data Sources
An electronic-based search was performed in PubMed, Embase, and the Cochrane Database. Reference lists of articles retrieved were reviewed, and a gray literature search was also performed.
Methods of Study Selection
The original database search yielded 264 articles from PubMed, Embase, and the Cochrane Database, of which 41 were included. One hundred sixty-one studies relating to gynecologic malignancy, conditions unrelated to endometriosis, or therapies unrelated to cannabis-based products were excluded. Twelve articles were included from a gray literature search and review of references.
Tabulation, Integration, and Results
Most available evidence is from laboratory studies aiming to simulate the effects of cannabis-based products on preclinical endometriosis models. Some show evidence of benefit with cannabis-based products. However, results are conflicting, and the impact in humans cannot necessarily be extrapolated from these data. Few studies exist looking at the effect of cannabis or its derived products in women with endometriosis; the majority are in the form of surveys and are affected by bias. National guidance was also reviewed: at present, this dictates that cannabis-based products can only be prescribed for conditions in which there is clear published evidence of benefit and only when all other treatment options have been exhausted.
Conclusion
Current treatment options for endometriosis often affect fertility and/or have undesirable side effects that impede long-term management. Cannabis-based products have been suggested as a novel therapeutic option that may circumvent these issues. However, there is a paucity of well-designed, robust studies and randomized controlled trials looking at their use in the treatment of endometriosis. In addition, cannabis use has a potential for harm in the long term, with a possible association with cannabis use disorder, psychosis, and mood disturbances. At present, national guidance cannot recommend cannabis-based products to patients in the UK owing to lack of clear evidence of benefit. More comprehensive research into the impact of endocannabinoids in the context of endometriosis is required before their use can be recommended or prescribed.”
https://www.sciencedirect.com/science/article/abs/pii/S135380202200270X,”Parkinsonism & Related Disorders
Volume 102, September 2022, Pages 124-130
Parkinsonism & Related Disorders
Review article
Cannabinoids in movement disorders
Author links open overlay panelBenzi M. Kluger a, Andrew P. Huang a, Janis M. Miyasaki b
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https://doi.org/10.1016/j.parkreldis.2022.08.014
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Abstract
Introduction
On the basis of both scientific progress and popular lore, there is growing optimism in the therapeutic potential of cannabis (marijuana) and cannabinoid-based chemicals for movement disorders. There is also notable skepticism regarding the scientific basis for this therapeutic optimism and significant concerns regarding the safety and regulation of cannabinoid products, particularly those available without prescription.
Methods
In recognition of the high interest and controversial nature of this subject, the meeting committee of the International Parkinson and Movement Disorders Society arranged for a talk on cannabis at the 2019 annual meeting’s Controversies in Movement Disorders plenary session. This paper summarizes the highlights of this session.
Results
The endocannabinoid system is strongly tied to motor function and dysfunction, with basic research suggesting several promising therapeutic targets related to cannabinoids for movement disorders. Clinical research on cannabinoids for motor and nonmotor symptoms in Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, dystonia, and other movement disorders to date are promising at best and inconclusive or negative at worst. Research in other populations suggest efficacy for common symptoms like pain. While social campaigns against recreational cannabinoid use focus on cognitive changes in adolescents, the long-term sequelae of regulated medical use in older adults with movement disorders is unknown. The overall risks of cannabinoids may be similar to other commonly used medications and include falls and apathy.
Conclusion
Further research is greatly needed to better understand the actual clinical benefits and long-term side effects of medical cannabis products for movement disorders indications and populations.
Introduction
Medicinal products derived from the cannabis plant have been used for thousands of years in many medical traditions [1]. Cannabis products were widely used in Western societies for many symptoms relevant to the movement disorders community through the early 1900s when new laws severely curtailed its use and research. Based on recent scientific progress, changes in legal status, and popular lore, there is growing optimism in the therapeutic potential of cannabis (marijuana) and cannabinoid-based chemicals for movement disorders [2], but also skepticism regarding the scientific basis for this optimism. Clinicians have concerns regarding the safety and regulation of cannabinoid products as well as the popularity of many unsubstantiated claims of cannabinoids’ therapeutic potential for a wide range of conditions. Recognizing this interest and controversy, the meeting committee of the International Parkinson and Movement Disorders Society sponsored a talk on cannabis at the 2019 annual meeting’s Controversies in Movement Disorders plenary session. This manuscript summarizes the preclinical and clinical science of cannabinoids with respect to movement disorders, contextualizes the risks and benefits of medical cannabinoid use with reference to other relevant populations, and concludes with suggestions for future research.
Section snippets
Some caveats on the medical use and research of cannabinoids
Overall, demand for cannabinoids anecdotally remains consistently high in countries with medical marijuana programs and many self-medicate in countries with legalized cannabis [3,4]. Recent legalization or decriminalization may imply lack of harm to the public while introduction of medical marijuana programs may imply definite efficacy. However, the efficacy of cannabinoids for most medical conditions remains debatable. A recent evidence-mapping and appraisal of systematic reviews found 44
Role of endocannabinoids in normal and pathologic movement
The endocannabinoid system has emerged as an important biological system in vertebrates with important roles in many organ systems, most notably the development and function of the peripheral and central nervous systems [[9], [10], [11]]. Endocannabinoids have a particularly prominent role in the development and function of motor control and movement [12,13]. The most studied endocannabinoid receptors are cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 receptors are found on neurons in the
Therapeutic promise in basic research of cannabinoids for movement disorders
Numerous studies in animal models of movement disorders describe the therapeutic promise and potential mechanisms of cannabinoids for both hyperkinetic (tremor, dystonia, dyskinesia, chorea) and parkinsonian symptoms [2]. Studies in animal models are fairly consistent in showing improvement of hyperkinetic motor disturbances with potential mechanisms including both modulation of traditional neurotransmitters (increase GABA; reduce glutamate and dopamine) as well as novel mechanisms [2,[22], [23]
Discussion
Translational science uses a scaffold of evidence including preclinical toxicity studies and clinical efficacy studies before licensing and prescribing. The clinical efficacy of cannabinoids for movement disorders remains unproven and there remain questions regarding its long-term safety. While there are clear, negative cognitive sequelae in regular use in adolescents, one cannot infer the risks of medicinal cannabis in older adults from studies of heavy recreational use in adolescents. There
Conclusions
Despite the interest and hype surrounding cannabinoids, a paucity of adequately powered and designed clinical studies exists to support strong recommendations and safety studies to date have generally focused on young adults and recreational use. Thus, further basic and clinical research of cannabinoids in movement disorders is needed to better understand their therapeutic potential and short and long-term side effects, especially in older adults living with movement disorders. Future clinical”
https://www.sciencedirect.com/science/article/abs/pii/S1089947222002106,”Journal of PeriAnesthesia Nursing
Volume 37, Issue 4, August 2022, Pages e21-e22
Journal of PeriAnesthesia Nursing
The Effect of Self-Reported Marijuana Use on Post-Operative Opiate Needs in The Spinal Fusion Surgery Patient
Author links open overlay panelLindsay R Glenn RN, BSN (Primary Investigator), Desiree Kear RN, ONC (Co-Investigators), Melissa Rhoades RN, BSN, CPAN
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Introduction
Legalization of recreational and medical marijuana is on the rise across the United States. As the popularity of cannabis is growing, more patients with a history of use are being seen in the hospital setting.
Identification of the problem
As nurses in the PACU and inpatient Orthopedic setting, we felt there was a correlation between patients history of marijuana use and increased narcotic requirements. When we started to search for information on this topic, we found research was limited due to the federal illegality of marijuana.
Purpose of the Study
The purpose of this study was to determine if marijuana usage prior to spinal surgery affected post-operative opiate needs. We measured the usage of opiates by self-reported marijuana users postoperatively.
Methodology
The study design is correlational, investigating the relationship between the pre-operative marijuana use and post-operative narcotic need. We attended our Orthopedic Academy-Spinal Class to introduce our study. If the patients were willing to participate, they were asked to sign an informed consent and complete a survey regarding pain scores and at home pain management, which included marijuana use. Post operatively the EMR was reviewed, and all narcotic usage was documented and converted into milliequivalents of morphine.
Results
Once the conversions were complete, we studied the correlation between those who reported marijuana use (comparison group) with those who denied use (control group). Except for post op day 2, the comparison group received more narcotic than the control group.
Discussion and Implications
Nowknowing that a patient’s history of marijuana use does play a role in narcotic requirements post operatively, it can help nurses better plan their care. When a patient reports marijuana use during the preoperative assessment, the nurse can advocate for multi-modal pain control to start preoperatively. Postoperatively, this knowledge can reinforce the importance of finding an appropriate pain management regimen. Personalized and detailed education on pain management after discharge may decrease risk of readmission for pain control.
Conclusion
With our finding we can better educate staff and patients to help optimize their post-operative pain management. More research is needed on this topic to help better understand the correlation and the implication marijuana use has on nursing care.”
https://www.sciencedirect.com/science/article/abs/pii/S0011848622000206,”Dental Abstracts
Volume 67, Issue 2, March April 2022, Pages 106-107
Dental Abstracts
Hands On
Oral Health Related to Cannabis Products
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https://doi.org/10.1016/j.denabs.2022.02.017
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Background
The chemical composition of cannabis is complex, with hundreds of compounds and over 60 cannabinoids. In addition, the sociopolitical status of cannabis is complex. It s classified by US federal entities as a schedule I drug that has no medical use, but 30 states regulate it as a medical product or as a legal recreational product for adults. Cannabis comes in various forms, including herbal cannabis, marijuana, hemp, and cannabinoid-based products. Cannabis is the most widely used recreational
Methods
The data were drawn from the Population Assessment of Tobacco and Health (PATH) study, which is a prospective study using a cohort of US youth and adults. PATH participants have provided data for 4 annual waves, with Wave 1 collected in September 2013 through December 2014 and Wave 4 collected from December 2016 to January 2018. The focus of this study was a comparison of adverse oral health outcomes reported at Wave 4 with those reported at Waves 1 through 3. Interventions for dental
Results
The prevalence of having ever used cannabis was almost 40%, which was similar to that for cigarette ever use. Use in the past 30 days in at least 1 of the PATH Waves was reported by 13% of participants. Five percent reported use in the past 30 days in all 3 waves.
Factors associated with cannabis use included current light or heavy cigarette smoking. Forty-six percent smoking prevalence was reported among cannabis users who reported smoking in the past 30 days in any of the waves, but just 9%
Role of Dental Professionals
Because it s likely that all dental professionals will encounter patients who use cannabis products, they should be prepared to treat their oral diseases, especially periodontal disease. The process begins with asking the patient if he or she uses cannabis products. Currently only about a fourth of dentists ask patients about cannabis, but about 60% ask about the use of tobacco. The dentist can then assure the patients that they will maintain confidentiality of this health information but that”
https://www.sciencedirect.com/science/article/abs/pii/S0002937822004203,”American Journal of Obstetrics and Gynecology
Volume 227, Issue 4, October 2022, Pages 571-581
American Journal of Obstetrics and Gynecology
Expert Review
Impact of cannabinoids on pregnancy, reproductive health, and offspring outcomes
Author links open overlay panelJamie O. Lo MD, MCR a b, Jason C. Hedges MD, PhD b c, Guillermina Girardi MSc, PhD d
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Cannabis is the most commonly used federally illegal drug in the United States and the world, especially among people of reproductive age. In addition, the potency of cannabis products has increased significantly in the past decade. This is concerning because the available evidence suggests an adverse effect of cannabis exposure on male and female reproductive health. Exposure to cannabinoids may have differential impacts on female reproductive health across a woman s lifespan, from preconception to pregnancy, throughout lactation, and during menopause. Moreover, cannabis use has been associated with adverse effects on fetal outcomes and longer-term offspring health and developmental trajectories. Despite the prevalence of cannabis use, there is limited available evidence regarding its safety, especially in regard to reproductive health, pregnancy, and lactation. The biological effects of cannabis are mediated by the endocannabinoid system, and studies have reported the presence of cannabinoid receptors in the male and female reproductive tract, on sperm and the placenta, suggesting that the endocannabinoid system plays a role in regulating reproduction. Cannabis use can affect male and female fertility and has been associated with altered reproductive hormones, menstrual cyclicity, and semen parameters. Use of cannabis in male patients has also been associated with erectile dysfunction, abnormal spermatogenesis, and testicular atrophy. In female patients, cannabis use has been associated with infertility and abnormal embryo implantation and development. The main psychoactive component of cannabis, the delta-9-tetrahydrocannabinol, can also cross the placenta and has been detected in breast milk. Maternal cannabis use during pregnancy and lactation has been associated with adverse effects, including small-for-gestational-age infants, preterm birth, fetal neurodevelopmental consequences, and impaired offspring sociobehavioral and cognitive development. The prevalence of cannabis use for alleviating menopausal symptoms has also increased despite the limited information on its benefits and safety. Given that cannabis use is on the rise, it is critical to understand its impact on reproductive health and offspring developmental outcomes. This is an understudied but timely subject requiring much further information to guide healthcare providers and those interested in conceiving or who are pregnant and lactating, and those at the end of their reproductive time span.
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Key words
cannabinoidscannabiscannabis use disorderdelta-9-tetrahydrocannabinolfertilitylow birthweightmarijuanamaternal cannabis usemenopausepreterm birthreproductive healthsmall for gestational agesubstance use”
https://www.sciencedirect.com/science/article/abs/pii/S2352007822002189,”Toxicologie Analytique et Clinique
Volume 34, Issue 3, Supplement, September 2022, Page S95
Toxicologie Analytique et Clinique
P20
Hair cannabinoids for distinguishing acute psychosis from chronic psychosis in cannabis users with brief psychotic disorder
Author links open overlay panelYann Barguil 1, Laura Chiaradia 2, Guy Southwell 3, Jean-Yves Charlot 4
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https://doi.org/10.1016/j.toxac.2022.06.146
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Aim
To make an early differential diagnosis, in cannabis users with psychotic disorders, between disorders of the schizophrenic field and disorders induced by cannabis. Among young consumers of cannabis, a brief psychotic disorder (BPD) can be either the clinical manifestation of acute cannabis psychosis (ACP) or an announcement of schizophrenia’s onset. The clinical presentation is of the same order, and only the evolution of disorders makes it possible to differentiate between these entities. To date, no clinical or even less paraclinical criteria have made it possible to differentiate syndromes whose prognoses and management are different (Hirschtritt M. Perm J 2021;25:20.179).
Method
Since 2010, we measured delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) concentrations in head hair among New Caledonian patients, all cannabis consumers (n = 256) (Barguil Y. medRxiv 2022.04.13.22273751). We wanted to determine if these patients, cannabis users, suffering from different mental pathologies, present particular phenotypes of capillary cannabinoid concentrations (THC and CBD). At the time of initial psychiatric consultation, a sample of 3 cm proximal length of head hair was prepared for analysis. Capillary THC and CBD were then assayed by GC-MS (LOQ: 0.05 ng/mg) (Kintz P. Forensic Sci Int 1995;70:175 82). At the end of the 6 months medico-psychologic follow-up from the initial evaluation, four groups of cannabis users were identified according to the final psychiatric diagnosis: control, acute cannabis psychosis (ACP), chronic psychosis (CP), and other personality disorders (OPD) groups.
Results
Samples for which CBD and/or THC were not detected were considered in this study because these patients are known to be cannabis consumers (urine samples were positive for THC-COOH prior to hair sampling). A threshold value was arbitrarily set at 0.0024 ng/mg for the calculation of ratios. In this study, a high level of THC detected (> 0.70 ng/mg) associated with a low CBD/THC ratio (< 0.26) are two parameters that taken together could be good markers of CP development. For OPD and ACP, discriminating between the two types of disease development is more ambiguous. Indeed, values for THC and CBD found in hair overlap and cannot discriminate between these two groups, even though THC seems to be lower and CBD higher in the ACP group than in the OPD group. It is necessary to calculate the CBD/THC ratios for patients to discriminate ACP from OPD. The ratios were higher in the ACP group (> 0.43) than in the OPD group (< 0.32).
Conclusion
In this study, the CP group was composed of people who possessed high levels of THC in their hair. This data may be correlated with the fact that patients with CP smoke more joints, or smoke more potent cannabis joints than people from other groups. Moreover, in the CP group, values obtained for CBD and for CBD/THC ratios were lower than in the control and the ACP groups. CBD may play a role in the protection against chronic or periodic mental disease development. This study highlights, once again, the protective role of CBD against the deleterious effects of THC. In association with clinical evaluation, this toxicological approach could be helpful for psychiatric diagnosis and would allow early management of BPD in cannabis consumers. Schizophrenia, for example, is a progressive disease, and a delay in therapeutic management compromises the chances of socio-professional reintegration. Close collaboration between psychiatrists, medical biologists, and analysts allows assistance with the therapeutic approach. It would be possible to make a first diagnosis just after the initial psychiatric evaluation.”
https://www.sciencedirect.com/science/article/pii/S2211034822006782,”Multiple Sclerosis and Related Disorders
Volume 68, December 2022, 104173
Multiple Sclerosis and Related Disorders
Review article
Effects of Sativex on cognitive function in patients with multiple sclerosis: A systematic review and meta-analysis
Author links open overlay panelIgor Dykukha a, Ute Essner b, Herbert Schreiber c, Lina Marie Raithel d, Iris-Katharina Penner e
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Highlights
Cognitive impairment is a common manifestation of multiple sclerosis.
Exposure to cannabis is also associated with dose-related cognitive impairment.
We assessed whether therapeutic use of nabiximols impacted cognition in MS patients.
Evidence suggests that nabiximols has no detrimental effects on cognitive function.
Cognitive adverse events are rare and occurred only during not in-label use.
Abstract
Background
Cognitive impairment is a common manifestation of multiple sclerosis (MS).
Objective
To assess by systematic review and meta-analysis available evidence regarding the impact of nabiximols oromucosal spray on cognition in patients with MS.
Methods
A systematic literature search of clinical studies (all types, any comparator) that measured cognitive function in patients with MS spasticity treated with nabiximols. Meta-analysis for cognitive endpoints was not possible due to heterogenous measurement instruments and outcomes. Meta-analysis was performed for adverse events (AEs) of special interest (cognition disorders) reported in randomized controlled trials (RCTs) of nabiximols versus placebo in patients with MS (with or without spasticity). Certainty of evidence and risk of bias were assessed.
Results
Seven clinical studies (three RCTs) directly assessing cognitive function were included in the qualitative analysis. There was no consistent evidence to suggest that nabiximols causes cognitive impairment as assessed by a range of specific psychometric instruments across cognitive domains. Thirteen double-blind, placebo-controlled RCTs (nabiximols, n = 964; placebo, n = 904) were included in the meta-analysis of cognitive AEs. Most cognitive AEs (30 of 32 events, 93.8%) reported with nabiximols in MS patients occurred with not in-label use, i.e., dosage >12 sprays per day and/or not administered primarily for treatment of spasticity.
Conclusions
Within the limitations of the review, we can conclude that no detrimental effects of nabiximols on cognitive function were observed in patients with MS spasticity during up to 12 months follow-up and that cognitive AEs were rare and occurred only when nabiximols was not used according to its approved label.
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Keywords
NabiximolsMultiple sclerosisSpasticityCognitive functionSystematic reviewMeta-analysis
- Introduction
Cognitive impairment is a common manifestation of multiple sclerosis (MS), affecting an estimated half to two-thirds of patients irrespective of disease duration, stage or subtype (Chiaravalloti and DeLuca, 2008; Oreja-Guevara et al., 2019). Inflammation, neuronal degeneration and lesion topography are among the likely causes leading to disruption of the cognitive network (Rocca et al., 2015). Although patterns of cognitive impairment in MS can vary widely, deficits are typically observed in the domains of attention, information processing speed, episodic memory, and executive functions (Chiaravalloti and DeLuca, 2008; Rocca et al., 2015), which appears to be due to disruption of complex brain networks subserving these dynamic and speed-related cognitive functions. Magnetic resonance imaging associates regional grey matter atrophy and neural network disruption with the presence of cognitive impairment (Benedict et al., 2020; Cruz-Gomez et al., 2021). Cognitive deficiencies can restrict a person’s ability to perform daily activities, and may be predictive for a negative prognosis, a more aggressive pathology, and a decline in vocational status/employment, with associated detriment to personal and social functioning and quality of life (Chiaravalloti and DeLuca, 2008; Campbell et al., 2017; Kobelt et al., 2017; Pitteri et al., 2017; Povolo et al., 2019; Renner et al., 2020).
Cannabis and cannabinoids have been investigated in numerous neurological conditions, including MS (Abrams, 2018). The main active constituents of the Cannabis sativa plant, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), exert their effects by interacting with cannabinoid receptors (CB1 and CB2) in the endocannabinoid system (Pertwee, 2008). The pharmacological effects of cannabis are mediated mainly through THC-induced activation of CB1 receptors in brain regions associated with motor control, pain regulation, memory processing and psychoactivity (Vuckovic et al., 2018), whereas CBD behaves as a non-competitive negative allosteric modulator of CB1 receptors (Laprairie et al., 2015).
Acute and chronic exposure to cannabis is associated with dose-related cognitive impairment, particularly with respect to attention and working memory, as demonstrated in animals (Zanettini et al., 2011) and humans (Solowij and Battisti, 2008). There is supporting evidence to suggest that chronic recreational cannabis use in young people has detrimental effects on attention (Abdullaev et al., 2010; Hanson et al., 2010), spatial working memory (Kanayama et al., 2004), verbal learning and memory (Lisdahl et al., 2013), and executive functioning (Gonzalez et al., 2012; Grant et al., 2012). Higher doses and more intensive lifetime use of cannabis was also found to be associated with modest reductions in cognitive performance in older adults with or without neurocognitive disorders (Scott et al., 2019). However, these effects relate primarily to the use or abuse of inhaled recreational cannabis; it is uncertain whether the same applies to therapeutic use of cannabis-based medicines.
Given the inherent vulnerability of MS patients to cognitive impairment, the potential (negative) effects of cannabinoids on cognition are a concern (Chiaravalloti and DeLuca, 2008; Oreja-Guevara et al., 2019; Leussink et al., 2012). Some evidence suggests that administering CBD with THC may reduce the psychotropic effects of THC, owing to its THC-receptor modulating and neuroprotective properties (Russo and Guy, 2006). Co-administration of CBD may also substantially reduce the negative effects of THC on memory and cognition, emphasizing the importance of formulation when developing cannabinoid products for medicinal use (Russo and Guy, 2006).
Sativex (USAN: nabiximols) is a complex botanical product for oromucosal use to treat MS spasticity. Nabiximols is derived from the Cannabis sativa plant and contains a mixture of cannabinoid and non-cannabinoid plant components. The most abundant cannabinoids in nabiximols are THC and CBD which are standardized at concentrations of 27 mg/mL and 25 mg/mL, respectively; non-cannabinoid plant components include alpha- and trans-caryophyllenes, other terpenes, sterols, and triglycerides (Electronic Medicines Compendium 2021).
There is scarce evidence to date regarding the cognitive effects of medical cannabis, including nabiximols, in approved indications. Moreover, it is possible that the cognitive effects of cannabinoid-based medicines are sometimes confused with or reported together with co-existing psychiatric events and conditions. To the best of our knowledge no systematic literature review to date has focused specifically on cognition in patients with MS spasticity treated with nabiximols. This systematic review and meta-analysis was undertaken to assess available evidence regarding the impact of nabiximols treatment on cognitive functioning in patients with spasticity due to MS.
- Methods
This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines (Liberati et al., 2009) and Cochrane Handbook (Higgins et al., 2019).
2.1. Inclusion and exclusion criteria
Publication eligibility was defined using the Populations-Interventions-Comparators-Outcomes-Study Design (PICOS) framework (Table 1). Considered for inclusion were full-text articles or official study register reports of randomized controlled trials (RCTs), non-randomized clinical trials (N-RCT), prospective or retrospective non-interventional studies (NIS) and case reports that measured cognitive function in patients with spasticity due to MS who had been treated with nabiximols oromucosal spray or any comparator including placebo, or no comparator. Excluded from the primary analysis were studies in patients with spasticity due to conditions other than MS or studies in patients with MS but without spasticity, and studies without cognitive measurements or assessments. For additional analysis of cognitive AEs, all RCTs of nabiximols versus placebo in MS patients were included. Language was limited to English.
Table 1. Eligibility criteria to select studies for data extraction (primary search).
PICOS factors Inclusion criteria Exclusion criteria
Population Patients with spasticity due to multiple sclerosis Patients with spasticity due to any other condition than multiple sclerosis
Patients with multiple sclerosis without spasticity
Intervention Sativex (nabiximols) oromucosal spray Any other cannabinoid
Comparison / Control Any type of comparator, including placebo
No comparator (None)
Outcome Cognitive function(s), any measurements or instruments No cognitive measurements or assessments
Study design All, any (None)
Filters applied: any publication date, records in English, only full texts and reports in official study registers
2.2. Search strategy, selection and data collection
A comprehensive search strategy was developed for MEDLINE (PubMed) to identify clinical studies (all types) of nabiximols in patients with MS spasticity that reported cognitive endpoints. Sensitivity analyses were performed by means of two additional detailed searches, one for cognitive assessment instruments and the other for cognitive domains. The main PubMed search was supplemented by extended searches in other databases: CENTRAL (Cochrane Library; https://www.cochranelibrary.com); Epistemonikos (https://www.epistemonikos.org/); Physiotherapy Evidence Database (PEDro; https://search.pedro.org.au); and Google Scholar (https://scholar.google.com). Article titles retrieved from these queries were examined to exclude any clearly unrelated publications. Reference lists of original and review articles were searched manually to identify any other relevant articles. The search timeframe was from inception to 1 April 2021.
An additional search was conducted to identify RCTs of nabiximols versus placebo in patients with MS which reported AEs including AEs of special interest with nabiximols (clinically significant AEs, fall-related injury requiring medical attention, significant psychiatric or psychotic events, suicidal thoughts or attempted suicide, change in driving ability). Searches were conducted in ClinicalTrials.gov (https://clinicaltrials.gov), EudraCT (https://www.clinicaltrialsregister.eu), and PubMed (applying the clinical trials filter) for studies published from inception to 1 April 2021. Article titles retrieved from these queries were examined to exclude any clearly unrelated publications. Reference lists of original and review articles were searched manually to identify any other relevant articles.
Systematic search details, excluded publications and reasons for exclusion are provided in Supplementary File 1.
EMBASE (https://www.embase.com) and PsychINFO (https://www.ebsco.com/de-de/produkte/datenbanken/apa-psycinfo) were not searched because access is not free.
Two reviewers (ID, UE) independently reviewed the records according to predefined inclusion/exclusion criteria and selected publications for inclusion; a third reviewer (IKP) resolved any disagreements.”
https://www.sciencedirect.com/science/article/abs/pii/S0012369222015239,”Chest
Volume 162, Issue 4, Supplement, October 2022, Pages A219-A220
Journal home page for Chest
Cardiovascular Disease
MARIJUANA USE AND CARDIAC ARREST/VENTRICULAR TACHYARRHYTHMIAS: A SYSTEMATIC REVIEW OF PUBLISHED CASE REPORTS
Author links open overlay panelSASHWATH SRIKANTH, ALEJANDRINA CUELLO-RAM REZ, APRIL KRISTINE MIGUEL, KEERTHI SRIPATHI, WARDA SHAHNAWAZ, PALLAVI MATAI, JIMMY TAVAREZ, ABHISHEK PRASAD, SIRISHA K GARA, JAI SIVANANDAN NAGARAJAN, CRYSTAL MORAS, RUPAK DESAI
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https://www.sciencedirect.com/science/article/abs/pii/S1550830722000817,”EXPLORE
Volume 18, Issue 4, July August 2022, Pages 501-502
EXPLORE
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Cannabinoids for the treatment of dementia: summary of a Cochrane review
Author links open overlay panelAllison Lane-Harris
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https://doi.org/10.1016/j.explore.2022.06.008
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Allison Lane-Harris is a Laboratory Research Assistant, University of Maryland School of Medicine, Baltimore.
L. Susan Wieland, PhD, is the Coordinator of the Cochrane Complementary Medicine Field
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https://www.sciencedirect.com/science/article/pii/S2667026722000017,”JID Innovations
Volume 2, Issue 2, March 2022, 100095
JID Innovations
Review
Cannabinoids for the Treatment of Dermatologic Conditions
Author links open overlay panelTorunn E. Sivesind 1 6, Jalal Maghfour 2 6, Hope Rietcheck 1, Kevin Kamel 3, Ali S. Malik 4, Robert P. Dellavalle 1 5
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In recent years, cannabinoid (CB) products have gained popularity among the public. The anti-inflammatory properties of CBs have piqued the interest of researchers and clinicians because they represent promising avenues for the treatment of autoimmune and inflammatory skin disorders that may be refractory to conventional therapy. The objective of this study was to review the existing literature regarding CBs for dermatologic conditions. A primary literature search was conducted in October 2020, using the PubMed and Embase databases, for all articles published from 1965 to October 2020. Review articles, studies using animal models, and nondermatologic and pharmacologic studies were excluded. From 248 nonduplicated studies, 26 articles were included. There were 13 articles on systemic CBs and 14 reports on topical CBs. Selective CB receptor type 2 agonists were found to be effective in treating diffuse cutaneous systemic sclerosis and dermatomyositis. Dronabinol showed efficacy for trichotillomania. Sublingual cannabidiol and -9-tetrahydrocannabinol were successful in treating the pain associated with epidermolysis bullosa. Available evidence suggests that CBs may be effective for the treatment of various inflammatory skin disorders. Although promising, additional research is necessary to evaluate efficacy and to determine dosing, safety, and long-term treatment guidelines.
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Abbreviations
9-THCdelta-9-tetrahydrocannabinol2-AG2-arachidonoylglycerolACR-CRISSAmerican College of Rheumatology-combined response index in diffuse cutaneous systemic sclerosisAEAanandamideCBcannabinoidCB1Rcannabinoid receptor 1CB2Rcannabinoid receptor 2CBDcannabidiolCDASIcutaneous dermatomyositis disease area and severity indexDMdermatomyositisECSendocannabinoid systemKCkeratinocyteMRSSmodified Rodnan skin thickness scoreN-PEAN-palmitoylethanolamideQOLHEQQuality of Life Hand Eczema QuestionnaireRCTrandomized controlled trialSScsystemic sclerosisVASVisual Analog Score
Introduction
For many centuries, at least as early as BC 500, cannabis has been widely used as an herbal medicine for the treatment of insomnia and gastrointestinal disorders, as an anesthetic agent, and for religious practices (Zuardi, 2006). In the 19th century, investigation into the pharmacokinetics of the active constituents of cannabis, the cannabinoids (CBs), began to shed light on their potential application in modern medicine (Zuardi, 2006). In recent years, there has been an increase in both preclinical and clinical studies exploring the use of CBs for the treatment of dermatologic conditions (Eberlein et al., 2008; St nder et al., 2006; Yuan et al., 2014).
Given the increasing availability and popularity of CB-containing skincare products and the increase in clinical studies regarding the role of CBs in the treatment of dermatologic conditions, we aimed to review the existing evidence on the use of CBs for the treatment of dermatologic conditions. To orient the reader, we first provide an overview of CB classes, biological pathways, and mechanistic details as follows.
CBs represent a diverse class of chemicals that share structural and biologic similarities with the psychoactive compound delta-9-tetrahydrocannabinol ( 9-THC), which is derived from Cannabis sativa (Eagleston et al., 2018).
There are three main classes of CBs: phytocannabinoids (derived from the C. sativa plant), endocannabinoids (endogenously produced in humans), and synthetic CBs (synthesized in a laboratory) (Eagleston et al., 2018). An introduction to representative CBs from each class, along with their respective mechanisms, is provided in Table 1.
Table 1. Biological Activity of Select CB Compounds
Compound CB Class Mechanism of Action1 Selected Biologic Effects of Interest
2-Arachidonylglycerol Endocannabinoid (structure: eicosanoid2) Agonist of CB1R (primary location: CNS) and primary endogenous agonist of CB2R (PNS and immune cells)3; additional affinity for GABAa, TRPV1, PPAR- , GPR55 Regulation of circulatory system; emotion; cognition; pain; inflammation (immune cells and neuroinflammation)
Anandamide (N-arachidonoylethanolamine, AEA) Endocannabinoid (structure: eicosanoid2) Partial agonist of CB1R (primary location: CNS) and CB2R (primary location: periphery)4; activator of TRPV1 cation channel2 Reward pathways; thermoregulation; nociception
CBD Phytocannabinoid (structure: classical CB2) Low affinity for CB1R/CB2R; can act as an antagonist of CB1R/CB2R agonists and inverse agonist of multiple GPRs; 5-HT1a partial agonist at low concentration (inverse agonist at higher concentrations); an allosteric modulator of and d opioid receptors; possible PPAR- agonist Epilepsy; movement disorders; inflammation; pain; anxiety
Dronabinol Synthetic CB (structure: synthetic analog of THC) Agonist of CB1R and CB2R; complex CNS effects, including central sympathomimetic action; possible agonism of CB1R receptors in vomiting center of the medulla5; possible CB receptor mediated effects in neural tissue; CB1R receptor agonism in hypothalamus stimulating appetite5 Appetite; nausea/emesis; sleep apnea; cannabis withdrawal
Nabilone Synthetic CB (structure: synthetic analog of 9-THC) Agonist of CB1R and CB2R; possible agonism of CB1R receptors in vomiting center of the medulla6 Chemotherapy-induced nausea/emesis; neuropathic pain
N-PEA Endocannabinoid-like (structure: fatty acid amide) Agonist of nuclear PPAR-a; agonist of GPR-55; indirect activator of CB1R/CB2R and TRPV17 Pain (particularly neuropathic); inflammation; mast cell degranulation
9-THC Phytocannabinoid (structure: classical CB2) Partial agonist of CB1R (action in CNS, PNS, and enteric nervous system) and CB2R (PNS) Neurological disorders; movement disorders; pain; appetite; inflammation
Abbreviations: 9-THC, delta-9-tetrahydrocannabinol; 5-HT, 5-hydroxytryptamine; AEA, anandamide; CB, cannabinoid; CB1R, cannabinoid receptor 1; CB2R, cannabinoid receptor 2; CBD, cannabidiol; GPR, G-protein-coupled receptor; N-PEA, N-palmitoylethanolamide; PNS, peripheral nervous system; PPAR- , peroxisome proliferator activated receptor- .
CB1R plays role in anxiety, pain, metabolism, addiction, inflammation; CB2R plays role in inflammation. GPR is a family of transmembrane receptors with signal transduction through cAMP or phosphatidylinositol pathways. -Aminobutyric acid (GABA)a plays a role in mood, sedation, memory, convulsion, and muscle tone. PPAR- plays a role in inflammation.
Serotonin, (5HT1a) plays a role in mood, vascular tone, pain, emesis, and thermoregulation. TRPV1 plays a role in neuropathic pain.
1
Receptor types.
2
Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry 2012;38:4 15.
3
Baggelaar MP, Maccarrone M, van der Stelt M. 2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain. Prog Lipid Res 2018;71:1 17.
4
Scherma M, Masia P, Satta V, Fratta W, Fadda P, Tanda G. Brain activity of anandamide: a rewarding bliss? Acta Pharmacol Sin 2019;40:309 323.
5
Prescribers Digital Reference. Dronabinol mechanism of action. https://www.pdr.net/drug-summary/Marinol-dronabinol-2726#14 (accessed on September 2021).
6
Prescribers Digital Reference. Nabilone mechanism of action. https://www.pdr.net/drug-summary/Cesamet-nabilone-692#0 (accessed on September 2021).
7
Petrosino S, Di Marzo V. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations Br J Pharmacol 2017;174:1349 65.
Phytocannabinoids include over 100 compounds; the most notable of these are 9-THC and cannabidiol (CBD) (Eagleston et al., 2018). The most clinically relevant endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG) (Eagleston et al., 2018), whereas the endogenous fatty acid amide N-palmitoylethanolamide (N-PEA) is also recognized as an important component of the endocannabinoid system (ECS), acting through multiple pathways (Petrosino and Di Marzo, 2017). Endocannabinoids have been shown to attenuate the production of proinflammatory cytokines and regulate keratinocyte (KC) expression (Eagleston et al., 2018). Therefore, it is not surprising that malfunctioning of the ECS has been implicated in a variety of pathologic skin conditions as well as in cutaneous wounds.
Synthetic CBs, first produced in the 20th century, include dronabinol and nabilone, which are approved by the United States Food and Drug Administration for the treatment of acquired immunodeficiency syndrome induced anorexia and for chemotherapy-induced nausea and vomiting (Taylor et al., 2020).
The physiologic effects of CBs are mediated through CB receptor 1 (CB1R) and CB receptor 2 (CB2R), which are members of the large family of G protein-coupled receptors. Both CB1R and CB2R are expressed on cutaneous nerve fibers, mast cells, and KCs (St nder et al., 2005). CB1Rs are the predominant CB type in the CNS and appear at lower concentrations in the peripheral nervous system; in the enteric nervous system; as well as in the heart, liver, and muscle tissues (Nikan et al., 2016). CB2R is notable for its presence in the immune system, with expression among cells of the hematopoietic lineage and organs of the immune system, such as the spleen and thymus (Basu et al., 2011).
With regard to binding effects, CB1Rs are primarily responsible for memory, mood, and modulation of pain sensation through the release of neurotransmitters (Nikan et al., 2016). It is thought that CB2Rs are largely responsible for the anti-inflammatory and immunomodulatory effects of CBs (Nikan et al., 2016). CB2R stimulation in KCs has been shown to promote the release of analgesic opioid peptides, which can modulate pain at a local level as well as systemically (through the CNS) (Caterina, 2014).
CBs can interact with transient receptor potential channels, also known as ionotropic CB receptors, which have been shown to modulate pain and itch perception (Caterina, 2014). Transient receptor potential channels are abundant on cutaneous peripheral neurons.
Skin Health and the ECS
The ECS is an integral component of skin homeostasis, comprising CB1R and CB2R, the endogenous CBs 2-AG and AEA, lipid mediators such as N-PEA, and hydrolytic enzymes such as fatty acid amide hydrolase (Eagleston et al., 2018). N-PEA itself has a low binding affinity for CB1Rs and CB2Rs but is able to activate CB receptors indirectly and enhance the effects of endogenous CB compounds such as AEA. N-PEA serves as an alternative substrate to fatty acid amide hydrolase; this in turn potentiates the physiologic effects of AEA. This is known as the entourage effect (Ho et al., 2008). Downstream signaling mediated by AEA leads to the activation of peroxisome proliferator activated receptor-a. The signaling response is characterized by the inhibition of proinflammatory cytokines, including IL-2; the induction, proliferation, and differentiation of KCs; and increased synthesis of lipids, including fatty acids and ceramides, which play an important role in maintaining skin barrier function and integrity (Kreitzer and Stella, 2009).
Transcription factors such as NF- B are essential to the pathogenesis of inflammatory skin disorders; NF- B has been shown to activate downstream molecular signaling pathway, resulting in the upregulation of proinflammatory mediators such as IL-8, matrix metalloproteinase, and VEGF (Hoesel and Schmid, 2013). Results of an in vitro model of human KC cell lines show that CBD is able to inhibit NF- B transcription and subsequently inactivate the inflammatory cascade (Motwani et al., 2018).
Mechanistic Action of Topical CBS
Topical 9-THC and CBD have been shown to suppress the levels of proinflammatory cytokines, including IL such as IL-6 and IL-17, whereas pretreatment with CBD has resulted in an upregulation of IL-10, an anti-inflammatory cytokine (Kozela et al., 2013). These immune-modulating effects appear to be mediated independently of CB signaling pathways.
Mechanistic Action of Oral CBS
Recent studies have illustrated several mechanisms through which oral CBs exert their effects. For example, systemic sclerosis (SSc) fibroblasts are known to possess increased numbers of CB2R, through which oral CB2R agonists act to reduce TGF and collagen production and limit the fibrosis characteristic of SSc (Spiera et al., 2020). Modulation of the ECS system by CB2R agonists stimulates the resolution of innate immune responses by activating the production of proresolving lipid mediators, such as lipoxin-A4 and B4 and resolvin-D1 and D3. Activation of CB2Rs present in lymphoid tissue has been shown to inhibit cytokine release from immune cells and, therefore, decrease inflammation (Spiera et al., 2020). The marked anti-inflammatory action of CB2R agonists is due in part to inhibition of leukotriene B4, a neutrophil chemoattractant, and allows for effective clearance of inflammatory stimuli by inhibiting antiphagocytic prostanoids, including prostaglandin E2, thromboxane B2, and prostaglandin F2a (Motwani et al., 2018).
Oral CB2R agonists have also been shown to modulate the immune system in patients with dermatomyositis (DM). A recent study showed a reduction in the production of proinflammatory cytokines, including TNF-a, IFN-a, and IFN- , among those treated with ajulemic acid/lenabasum, a CB2R agonist (Robinson et al., 2017).
A summary figure illustrating the mechanistic actions and therapeutic effects of CBs as they relate to skin health and the immune system is provided in Figure 1.”
https://www.sciencedirect.com/science/article/abs/pii/S0006322322004656,”Biological Psychiatry
Volume 91, Issue 9, Supplement, 1 May 2022, Page S145
Biological Psychiatry
P144. Prenatal Cannabis Use and Offspring Autism-Related Behaviors: Examining Maternal Stress as a Moderator in a Black American Cohort
Author links open overlay panelChaela Nutor 1, Dana Barr 1, Olivia Sadler 1, Heidi Morgan 1, Anne Dunlop 1, Patricia Brennan 1
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Background
The prevalence of both autism spectrum disorder (ASD) and maternal cannabis use during pregnancy are increasing, yet few empirical studies have examined their potential association. Moreover, it is unclear whether maternal prenatal cannabis use may interact with other ASD risk factors, such as maternal prenatal stress, to impact child neurodevelopment. This question is particularly relevant for Black mothers, who are disproportionately exposed to prenatal stressors including low socioeconomic
Methods
Black women (ages 18-40 years) were recruited from prenatal clinics at 8-14 weeks gestation and provided urine samples for cannabis biomarker assay and self-report of substance use and stress in their second trimester. When their children were two years old, they were then invited to participate with their child in a cohort study in which child autism behaviors were assessed via validated maternal report and administered observational assessments.
Results
Prenatal and child outcome data were available for 172 dyads. Child sex and prenatal tobacco/alcohol exposures were statistically controlled. Male sex predicted higher levels of observed autism-related behaviors (p=.01) and prenatal stress predicted higher maternal reports of autism-related behaviors (p=.001). Our primary hypotheses were not supported (p>.05).
Conclusions
We found no evidence that prenatal cannabis use increases risk for autism-related behaviors. Once replicated, these findings may inform health policy recommendations regarding cannabis use and legalization.”
https://www.sciencedirect.com/science/article/abs/pii/S2352007822002669,”Toxicologie Analytique et Clinique
Volume 34, Issue 3, Supplement, September 2022, Page S120
Toxicologie Analytique et Clinique
P68
Cannabis recent use in sudden unexpected deaths
Author links open overlay panelTeresa Huertas, Teresa Soriano, David Olano, Manuel Salguero
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https://doi.org/10.1016/j.toxac.2022.06.194
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Aim
The aim of this study was to review all sudden unexpected death received in our laboratory over a four years period (2018 2021) in order to ascertain the prevalence of recent cannabis consumption.
The main cause of death in industrialized countries is ischemic heart disease, and risk factors include smoking, obesity, age, hypercholesterolemia, arterial hypertension, diabetes mellitus and alcohol. The scientific literature now also links cannabis use to cardiovascular accidents. Cannabinoids exert their effects through the activation of two specific membrane receptors, CB1 and CB2 and, at the cardiovascular level, the activation of these receptors is related to increased cardiac output and sinus tachycardia.
Method
In total, 7150 cases of sudden unexpected death had been received in our laboratory for toxicological analysis from January 2018 to December 2021, 262 were related to cannabis use and we selected those in which recent cannabis use was demonstrate due to the presence of THC in blood, after having discarded those cases that presented a concomitant consumption of other drugs of abuse, as well as, other psychoactive substances at toxic concentrations. Blood samples were screened for cannabis by CEDIA and 9-tetrahydrocannabinol (THC), 11-hydroxy- 9-tetrahydrocannabinol (11-OH-THC) and 11-nor- 9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) were confirmed and quantified using solid-phase extraction (SPE) followed by gas chromatography tandem mass spectrometry (GC-MS/MS). The cut-offs applied were 1 ng/mL for THC and 11-OH-THC and 5 ng/mL for THC-COOH.
Results
Forty-eight sudden unexpected deaths following recent cannabis use were recorded. THC blood levels have been increasing over the period studied. The mean in 2018 was 1.84 ng/mL, increasing to 8.08 ng/mL in 2021. In terms of sex, 87.5% of cases were male, the age range ranged from 16 to 74 years, with the median being 50 years and the mode 47 years. In 77% of the cases the cause of death was cardiogenic, 6.2% of the cases corresponded to subarachnoid hemorrhage and the rest to other causes. The highest incidence is presented by the population aged between 40 60 years (58.3%), with alcohol and/or tobacco consumption habits in 50% of the cases. In addition, in this group there are cases with different pathological antecedents like arterial hypertension, obesity, epilepsy and congenital heart disease. The lower incidence of sudden unexpected death is in the age group from 16 to 30 years (10.4%).
Conclusion
The distribution of the number of deaths was not homogeneous throughout the four years studied. Both, an increase in the number of deaths and in THC blood levels can be seen. This may be directly related to the increase in THC concentrations in the different forms of cannabis presentations in street samples.”
https://www.sciencedirect.com/science/article/abs/pii/S1876201821004512,”Asian Journal of Psychiatry
Volume 69, March 2022, 102995
Asian Journal of Psychiatry
Cannabis for psychiatric disorders Has The Pendulum Swung Too Far?
Author links open overlay panelShafiqa Alawadi a, Ahmed Naguy b
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Abstract
Strong interest in cannabinoids as potential treatment for psychiatric disorders has led to numerous studies. Particularly, cannabidiol (CBD) has promise as a pharmacotherapy for psychotic disorders as well as anxiety disorders. Herein we shed some light on therapeutic potential while examining extant evidence. Literature is still nascent. This should be balanced against the ubiquitous use of cannabis in patients with psychiatric disorders that has been strongly tied to frequent relapses and heightened violence.
Section snippets
Financial disclosure
Authors declare no financial affiliations or sponsorship.
Disclosures
Authors have no competing interests or financial affiliations.
Acknowledgment
Authors extend their deepest gratitude to Dr Khloud Abdul-Nabi Al-Ali, Director General of KCMH for her continuous support.
Conflict of interest
Authors declare no conflict of interests in the past 36 months. No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.
References (10)
N. Black et al.
Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis
Lancet Psychiatry
(2019)
R.E. Cooper et al.
Cannabinoids in attention-deficit/hyperactivity disorder: a randomised controlled trial
Eur. Neuropsychopharmacol.
(2017)
P. Parakh et al.
Cannabis and psychosis: have we found the missing links?
Asian J. Psychiatry
(2013)
P. Fleury-Teixeira et al.
Effect of CBD-enriched Cannabis sativa extract on autism spectrum disorder symptoms: an observational study of 18 participants undergoing compassionate use
Front. Neurol.
(2019)
Y.L. Hurd et al.
Cannabinoids for the reduction of cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder: a double-blind randomized placebo-controlled trial
Am. J. Psychiatry
(2019)
There are more references available in the full text version of this article.”
https://www.sciencedirect.com/science/article/abs/pii/S1471491422001514,”Trends in Molecular Medicine
Volume 28, Issue 8, August 2022, Pages 613-615
Journal home page for Trends in Molecular Medicine
Spotlight
Marijuana and endothelial dysfunction: new mechanism and therapy
Author links open overlay panelXiaojun Feng 1, Suowen Xu 1, Jianping Weng 1
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Marijuana (cannabis) can cause cardiovascular side effects, yet the mechanisms and treatments remain poorly understood. In a recent study published in Cell, Wei et al. discovered that soy isoflavone genistein attenuates 9-tetrahydrocannabinol ( 9-THC, a main constituent from marijuana)-induced endothelial dysfunction and atherosclerosis by directly antagonizing peripheral cannabinoid receptor 1, demonstrating a therapeutic potential for ameliorating the cardiovascular side effects of cannabis.
Section snippets
Cardiovascular side effects and mechanisms of marijuana
Marijuana contains more than 700 different compounds, of which 104 compounds are unique cannabinoids [1]. The main psychoactive cannabinoid of marijuana is 9-tetrahydrocannabinol ( 9-THC), which is a partial agonist of cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R), belonging to the G-protein coupled receptor (GPCR) superfamily [1]. Medicinal use of cannabis has focused on chemotherapy-induced nausea, anorexia, and pain, leading to the clinical development of cannabinoid
Pharmacological effects of genistein
Genistein is a soybean-derived isoflavone with a chemical structure similar to that of estrogen. Genistein binds to both estrogen receptors (ERa and ER ; preferably binds and activates ER ) and exerts estrogen-like effects under certain experimental conditions [6]. Genistein has potential cardioprotective effects and meta-analysis results show that ingestion of genistein over 6 months significantly reduces CVD risk factors (lowering of systolic blood pressure, total cholesterol, and low-density
Clinical translational potential of genistein
No significant toxic side effects were found at conventional doses of genistein, except for possible reproductive and developmental side effects in prepubertal rats [8,9]. In the aforementioned study, Wei et al. found that genistein is a direct antagonist of CB1R that does not easily penetrate the blood brain barrier. 9-THC mediates its cardiovascular side effects mainly through damage to endothelial cells. In endothelial cells, CB1R inhibition reversed 9-THC-induced inflammatory gene
Acknowledgments
This study was supported by grants from National Key R&D Program of China (No. 2021YFC2500500), National Natural Science Foundation of China (Grant Nos. 81941022, 82070464, 81530025, and 82003740) and the China Postdoctoral Science Foundation (2021M693102). Figure 1 was created with Figdraw.com.”
https://journals.sagepub.com/doi/full/10.1177/21925682211065411,”First published online February 7, 2022
The Efficacy of Cannabis in Reducing Back Pain: A Systematic Review
Richard L. Price, MD, PhD https://orcid.org/0000-0002-7261-2028 [email protected], Kaarina V. Charlot, BS, [ ], and Jens R. Chapman, MD+3View all authors and affiliations
Volume 12, Issue 2
https://doi.org/10.1177/21925682211065411
Contents
Abstract
Background
Methods
Results
Discussion
Declaration of Conflicting Interests
Funding
ORCID iDs
References
Supplementary Material
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Abstract
Objective
To critically analyze the evidence and efficacy of cannabis to treat surgical and nonsurgical back pain via a Systematic Review.
Methods
We conducted a systematic review to investigate the efficacy of cannabis to treat non-surgical and surgical back pain. A literature search was performed with MEDLINE and Embase databases. Only RCTs and prospective cohort studies with concurrent control were included in this study. Risk of bias and quality grading was assessed for each included study.
Results
Database searches returned 1738 non-duplicated results. An initial screening excluded 1716 results. Twenty-two full text articles were assessed for eligibility. Four articles ultimately met pre-determined eligibility and were included in the study. Two studies addressed post-SCI pain while other two studies addressed low back pain. No studies specifically examined the use of cannabis for surgical back pain. The type of cannabis varied between study and included THC, dronabinol, and Nabilone. A total of 110 patients were included in the four studies reviewed. In each study, there was a quantifiable advantage of cannabis therapy for alleviating back pain. There were no serious adverse effects reported.
Conclusions
In all articles, cannabis was shown to be effective to treat back pain with an acceptable side effect profile. However, long-term follow up is lacking. As medicinal cannabis is being used more commonly for analgesic effect and patients are self-prescribing cannabis for back pain, additional studies are needed for healthcare providers to confidently recommend cannabis therapy for back pain.
Study Design
Systematic review.
Background
While the understanding regarding back pain has improved, the ongoing lack of successful and lasting treatment modalities remains an overarching problem. In particular, the struggle of managing non-surgical back pain has been identified as a primary contributing factor to the current opioid epidemic, despite substantial legislative efforts to curb these trends.1 For patients who do undergo spine surgery, management of post-operative pain is an additionally difficult challenge. As is the case with most surgeries, spine surgery can be associated with musculoskeletal tissue damage, in addition to some expected post-operative neurologic manifestations associated with disabling pain perceptions. Inadequate pain control not only causes patients substantial distress but can also significantly inhibit early and optimal post-surgical recovery. It is the current consensus that adequate pain relief measures are best achieved when applying some form of Enhanced Recovery After Surgery through a combination of multi-modal therapies.2 Unfortunately, most back pain management regimens rely heavily on opioid analgesics. The long-term usage of opioids often leads to various well-documented and undesirable side-effects, the most prominent of which are drug habituation, abuse, and addiction.3 With the rising opioid crisis in the United States and elsewhere, clinicians are hopeful to find alternative pain management modalities for both surgical and nonsurgical back pain.
The utilization of cannabis to improve back pain is steadily increasing throughout the general population. The mechanism of endocannabinoid pain modulation is independent from that of the opiate pathway, making cannabinoids a potentially attractive adjunct therapy for back pain management with the goal of actually decreasing reliance on opiate medications.4 Cannabis acts through the endocannabinoid system, which employs two different receptors: CB1 and CB2. CB1 receptors are present on both central and peripheral neurons (Figure 1). CB2 receptors are present on immune cells. It is hypothesized that CB1 receptors modulate neurotransmitter release and pain transduction, while CB2 receptors modulate cytokine release. This cytokine release is primarily thought to modulate peripheral neuropathic processes.5,6 Delta-9-tetrahydrocannabinol (THC) is the major psychoactive component of cannabis and activates CB1 receptors in the central nervous system.7 Animal studies have provided evidence supporting the suppression of nociceptive transmission by endocannabinoids and exogenous cannabinoids.8 This effect is thought to occur both peripherally and centrally, specifically at the posterior horn of the spinal cord.8 A total of 66 different cannabinoids have been isolated. In addition, several synthetic cannabinoids such as nabilone and dronabinol have been produced.9 Of these cannabinoids, THC has been the most widely studied and is currently the most highly utilized in the population.
Figure 1. Mechanism of action of the endocannabinoid system. Cannabinoids bind to CB1R on the presynaptic neuron blocking neurotransmitter release.
While the utilization of cannabis for analgesic therapy was first reported in 1975, the recognition of its medicinal properties was recorded as early as 400 AD. California was the first state in the United States to legalize medicinal cannabis in 1996. To date, a total of 35 states in the United States have since legalized medicinal cannabis, and a growing number of countries are following suit. The growth in widespread acceptance of medicinal cannabis by both clinicians and patients corresponds with an increasing interest to understand its analgesic properties for therapeutic utilization.10 A recent meta-analysis showed evidence that in most randomized control trials (RCTs) there was a significant analgesic effect favoring cannabis over the placebo for non-cancer pain management, without any serious adverse events.11 Cannabis has been further reported as efficacious in reducing pain in several disease processes including cancer, rheumatoid arthritis, multiple sclerosis, and fibromyalgia.12-14 Additionally, there is growing evidence supporting its ability to mitigate nonsurgical back pain.15 However, there have been mixed results for post-operative pain relief from cannabinoids.6 Given the increasing success of medicinal cannabis in alleviating pain as seen through the literature, we hypothesized that cannabis is an effective therapy for both nonsurgical back or neck pain management and post-operative pain management following spinal fusion surgery. To assess the potential for cannabis in spine-related pain management, we performed a formal Systematic Review. Our goal was to evaluate the efficacy of medical cannabis in reducing pain in patients following spine surgery, for patients suffering from chronic low back or neck pain, and patients affected by previous spinal cord injury pain (SCI-pain).
Methods
We conducted this systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.16
Identification of Studies
We searched MEDLINE (PubMed), EMBASE (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Database of Systematic Reviews (CDSR) from inception to Dec 31, 2020. The search strategies are included in Supplemental Table S1 in the supplemental material. We reviewed reference lists of included studies and systematic reviews for additional articles.
Assessment of Eligibility
We established a priori criteria for study eligibility. We included studies of adults undergoing spinal surgery (acute pain), those with chronic low back or neck pain (chronic defined as =12 weeks), and those with chronic neuropathic pain following a spinal cord injury. Included were all concurrent comparative studies (randomized and nonrandomized) comparing medical cannabinoid use, any dose, and any administration to any non-cannabinoid treatment. We excluded case series, case reports, case-control studies, cross-sectional studies, conference proceedings, abstracts, editorials, letters, and white papers. We did not limit the search with respect to the English language.
Two review authors (RNP, JRD) independently screened titles and abstracts to identify articles for full text review. Any citation deemed appropriate for inclusion by at least one of the reviewers was retrieved. Each full-text article was independently reviewed for eligibility by the same two team members. Any disagreements were resolved by consensus. One German language study was included in this study. It was reviewed by two authors who are native German speakers.
Data Abstraction and Data Management
Two review authors extracted data from each study into a spreadsheet (Microsoft Excel). Data included the author s last name, publication year, study design, country, sample size, population characteristics, conditions studied, length of follow-up, treatment characteristics (type of cannabinoid and comparator, dose, route of administration), pain outcome scale (primary outcome), function/quality of life (secondary outcome), results (baseline and follow-up mean scores and standard deviations if reported) and any adverse events reported.
Assessment of Methodological Risk of Bias of Individual Studies
Predefined criteria were used to assess the quality of each study. Randomized and nonrandomized trials were assessed by a team of three independent reviewers using the criteria and methods developed by the Cochrane Back Review Group.17,18 Studies were given an overall rating of good , fair , or poor quality.19 Studies rated good were considered to have the least risk of bias and their results were generally considered valid. Good quality studies included clear descriptions of the participant population, study setting, interventions implemented, comparison groups, a valid method for allocating patients to each treatment group, low dropout rates, clear reporting of dropouts, appropriate means for preventing bias, and appropriate measurement of outcomes. Studies rated fair were susceptible to some bias, though deemed not enough to invalidate the results. These studies did not meet all the criteria for a rating of good quality, but no flaw or combination of flaws was deemed likely to cause major bias. The study may be missing information, making it difficult to assess limitations and potential problems. The fair quality category was broad, and studies with this rating varied in their strengths and weaknesses. The results of some fair quality studies were likely to be valid, while others may could have been only possibly valid. Studies rated poor had significant flaws that implied various types of biases which could invalidate their results. They had a serious or fatal flaw (or combination of flaws) in design, analysis, reporting, large amounts of missing information, discrepancies in reporting, or serious problems in the delivery of the intervention. The results of these studies were equally as likely to reflect flaws in the study design as they were to show true difference between the compared interventions.
We also assessed the overall quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach.20 This approach quantifies potential limitations in five domains: risk of bias, inconsistency, imprecision, indirectness, and publication bias.
Results
Study Selection
Our search identified 2141 citations. We excluded 2121 from screening titles/abstract after applying the exclusion criteria listed above, resulting in the evaluation of 20 full texts. Four studies21-24 assessing 110 participants met our inclusion criteria (Figure 2). The studies excluded from full text review can be found in Supplemental Table S2 in the supplemental material.
Figure 2. Preferred reporting items for systematic reviews and meta-analyses flow diagram.
Study Characteristics
Three studies were RCTs21,23,24 and one was a prospective cohort study.22 All were designed as cross-over studies. Three of these studies were conducted in the United States22-24 and one in Austria.21 The average age of the participants was 45 years. Most participants were females (86%). Two studies administered the cannabinoids orally21,23 and the other two administered cannabinoids via inhalation, either smoking or vaporizing.22,24
Study Quality
One study was judged as good 24 and three as fair quality.21-23 Concerns regarding bias in the three fair quality studies were related to high attrition,23 unclear randomization and treatment concealment,21 and the observational design (Supplemental Table S3).22
Efficacy in Assessing Pain Following Spinal Surgery
We found no studies meeting our inclusion criteria that assessed the effect of cannabis in managing pain following spinal surgery.
Efficacy in assessing pain in patients with chronic low back or neck pain
One cross-over RCT and one observational cross-over study assessed the effect of cannabis on chronic back pain. The first, a Germain-language cross-over RCT performed in Austria, investigated the efficacy in adding Nabilone to a baseline pain medication regimen for treating chronic back pain.21 In this study, the baseline medication consisted of opioids and antirheumatic agents. A total of 30 patients participated in this trial. Participants were randomized and received either Nabilone (.25 mg) or a placebo (mannitol 270 mg). Participants were allowed to take up to four doses per day of their designated medication based on their symptom severity. The study medication was taken for four weeks followed by a five week washout period before starting the complementary study medication that was also taken for four weeks. Relevant study protocol violations were found in nine patients. Two patients changed their baseline medication and seven patients were found to have prematurely terminated their drug, leading to a 30% attrition rate. Despite the high attrition rate, there was a statistically significant decrease in reported spinal pain intensity at the end of the study in both the intent-to-treat and the per-protocol analysis. Additionally, there was a statistically non-significant decrease in the average spinal pain intensity and improvement in reported quality-of-life over the final 4 weeks of the study. The cross-over period was followed by a 16 week medication switch period with free choice, in which the number of study participants who favored nabilone was over four times higher than those who were assigned the placebo.
The second was a fair quality observational cross-over study (n = 31) which included primarily female patients (90%) with low back pain lasting more than 12 months, a history of fibromyalgia, and failure of opiate therapy.22 Participants received at least three months of standardized analgesic therapy (SAT) (duloxetine 30 mg once daily and one tablet of oxycodone with naloxone 5/2.5 mg twice daily). Following the three months of SAT, participants were transitioned into the medical cannabis therapy (MCT) portion of the study, though concurrent SAT was allowed. Any designated washout period was unclear. MCT included 1:4 THC to cannabidiol (CBD). The dose was 20 grams per month for three months with the option to increase to 30 grams for three more months, administered via smoking or vaporization. Pain, as measured by the visual analog pain scale (VAS), did not change following SAT, but significantly improved following both three- and six-month follow-up, P <.0001 (Table 1). Likewise, participant reported functional ability, as measured by the Oswestry Disability Index (ODI), was found to have significantly improved with the added MCT. This was not observed in the control group. Table 1. Study characteristics. Author Country Quality Study type Condition, N, age, male, attrition Cannabinoid (A) Control (B) Pain Results Adverse events Pinsger 2006 Austria Fair Cross-over RCT 5-week washout Back pain (disc herniation, foraminal stenosis, scoliosis, spondylarthrosis, osteochondrosis) Age: 55 (median) N = 30 Male: 29% Attrition: 30% (A) Nabilone + Mannitol Route: oral Dose: .25 mg, 1-4/d, self-determined Duration:4 weeks (B) Mannitol 270 mg, 1-4/d, self-determined (A) v (B) VAS* at end of treatment (4 weeks), median from baseline: ITTa pain last 4 weeks: .9 v .5, P = .196 ITT current pain: .6 v 0, P = .006 PP pain last 4 weeks: 1.9 v 1.0, P = .121 PP current pain: 2.0 v 0, P = .004 QOL-Score median from baseline: 5.0 v 2.0 P > .05 (A) v (B) Number of events
Serious AE (n):
Femoral neck fractureb: 1 vs 0
Non-serious AE:
Fatigue: 30% v 13% (P = .227)
Dry mouth 20% v 3% (P = .125)
Vertigo: 33% v 10% (P = .039)
Insomnia 17% v 3% (P = .125)
Yassin 2019
USA
Fair Observational cross-over study LBP & FM (100%)
N = 31
Age: 33.4 12.3
Male: 10%
Attrition: 12% (A) 1:4 THC (=5%) to CBD SAT
Route: Smoking or vaporized
Dose: 20 g/month
Duration: 3 months with option for 30 g/month for another 3 months
(B) SAT =3 months (duloxetine 30 mg once daily; 5 mg oxycodone hydrochloride & 2.5 mg naloxone hydrochloride twice daily (A) v (B)
VAS* at end of treatment (3 months):
8.18 1.4 v 5.3 1.3 P < .0001
6 months (B): 3.3 2.2
ODI 3 months: 73.7 11.4 v 45.9 19.1 P < .0001
6 mo. (B): 30.7 13.6 (A) Red eyes: 28/31 (90%)
Increased appetite: 5/31 (16%)
Sore throat: 3/31 (10%)
The adverse events were mild and did not require cannabis treatment alteration
(B) Depression: 2/31 (7%)
Loss of appetite: 8/31 (26)
Hemorrhoids in 4/31 (13%)
Constipation: 15/31 (48)
Zombie-like feeling: 5/31 (16%)
Hemorrhoid surgery 1/31 (3%)
SAT stopped due to side effects 6/31 (19%)
Rintala 2010
USA
Fair Cross-over RCT
7-day wash-out SCI (100%)
N = 7
Age: 50.1 years (35 60)
Male: 78%
Attrition: 44% vs 22% (A) Dronabinol
Route: oral
Dose: 20 mg/d
Duration: 3 weeks titrating up, 4 weeks maintenance dose
(B) Diphenhydramine
75 mg/d (A) v (B)
BPI* after maintenance dose (7 weeks) mean from baseline .20 .84 v -1.80 2.49 (P = .102) (A) v (B)
Withdrawals: 1/7 (14%) v 0/7 (0%)
Dry mouth: 5/7 (71%) v 3/5 (60%)
Constipation: 5/7 (71%) v 3/5 (60%)
Fatigue: 4/7 (57%) v 5/5 (100%)
Drowsiness: 4/7 (57%) v 3/5 (60%)
Itchiness: 3/7 (43%) v 1/5 (20%)
Abdominal discomfort: 2/7 (29%) v 0/5 (0%)
High feeling: 2/7 (29%) v 0/5 (0%)
Weakness: 1/7 (14%) v 2/5 (40%)
Dizziness 1/7 (14%) v 0/5 (0%)
Confusion: 1/7 (14%) v 0/5 (0%)
Incoordination: 1/7 (14%) v 0/5 (0%)
Rash: 1/7 (14%) v 1/5 (20%)
Nausea: 0/7 (0%) v 0/5 (0%)
Abnormal HR: 0/7 (0%) v 0/5 (0%)
Weight gain: 0/7 (0%) v 0/5 (0%)
Vomiting: 0/7 (0%) v 0/5 (0%)
Wilsey 2016
USA
Good Cross-over RCT SCI (86%), MS (14%)
N = 42
Age: 46.4 years ( 13.6)
Male: 69%
Attrition: 5% (A1) 6.7% delta 9-THC
(A2) 2.9% delta 9-THC
Route: Vaporized
Dose: 4 puffs initially, then 4-8 puffs 3 h later
Duration: 3 8-hr sessions
(B) Placebo cannabis with delta 9-THC extracted (A1) v (A2) v (B) (est. from Fig 4)
NRS* 1 h post treatment: 4.4 v 3.4 v 2.8
2 h post treatment: 4.2 v 3.7 v 3.0
3 h post treatment: 4.3 v 3.4 v 3.2 dose response, P < .01 (A) v (B)
Withdrawals: 0/84 (0%) v 0/42 (0%)
Serious side effects: 0/84 (0%) v 0/42 (0%)
Any drug effect: C<B<A
Good drug effect: C<B<A
Bad drug effect: C<B=A
High: C<B<A
Drunk: C=B<A
Impaired: C<B<A
Stoned: C<B<A
Like the drug effect: C<B=A
Sedated: C<B<A
Confused: C=B<A
Nauseous: C<B<A
Desires more: C<A
Hungry: C<A
Changes perceiving time: C<B=A
Changes perceiving space: C<B<A
Difficulty paying attention: C=B<A
Difficulty remembering things: C<A
Abbreviations: BPI, Brief Pain Inventory; CBD, cannabidiol; FM, fibromyalgia; LBP, low back pain; ITT, intent-to-treat analysis; PP, per protocol analysis; RCT, randomized controlled trial; SAT, standard analgesic therapy; THC, tetrahydrocannabinol.
*scale 0 10, 10 worst pain.
aLast observation carried forward.
bDue to fall thought to be from dizziness caused by nabilone and other pharmaceutical interaction.
We rated the overall quality of evidence for the efficacy of cannabinoid treatment in those with chronic back or neck pain over short-term treatment (1-3 months) as VERY LOW (Supplemental Table S4).
Efficacy in assessing pain in patients with chronic pain post SCI
Two RCTs assessed cannabinoid usage for chronic pain caused by SCI. The first was a fair quality randomized, controlled, double-blind, crossover pilot study published by Rintala et al.23 This study examined the effects of dronabinol, a synthetic derivative form of THC, on central neuropathic pain after a SCI in seven patients. Study participants were recruited by word of mouth at a Veterans Affairs Medical Center. All participants sustained a SCI at least 12 months before the study with at least six months of chronic neuropathic pain rated at least 5 on a scale of 1 to 10. There was no differentiation between transitional zone and peripheral neuropathic pain. Participants were started on either 5 mg of dronabinol or 25 mg diphenhydramine. Their doses were titrated up over 12 days to a total dose of 20 mg/day of dronabinol and 75 mg/day diphenhydramine. The titration phase was then followed by a 7 day stabilization phase to a balanced dosage based on pain relief and side effects. This was further followed by a 28 day maintenance phase of stable dosage. This was finally followed by a 9 day downward titration, and 7 day washout period prohibiting any therapeutic use before starting the other medication. Change in pain intensity using the Brief Pain Inventory (BPI) scale was the primary outcome of the study. They found no statistically significant advantage of using dronabinol compared to diphenhydramine for relieving chronic neuropathic pain related to SCI.
The second was a good quality crossover RCT which evaluated the efficacy of inhaled THC for managing neuropathic pain also resulting from a SCI.24 Participants (n = 42) were recruited from a Spinal Cord Injury Clinic and were between the ages of 18 and 70 who rated their pain intensity greater than 4 out of 10. Patients were screened for bipolar disorder, schizophrenia, and major depressive disorder, as cannabis has been shown to exacerbate these conditions. Each participant was scheduled for three 8 hour experimental sessions with at least a 3 day washout period in between. Participants received either a placebo, 2.9%, or 6.7% THC per session in a random sequence. The study medication was administered via a Volcano vaporizer (Storz and Bickel America, Inc., Oakland, CA). Four 5 second puffs were administered at the first time point. Three hours later, participants could choose to inhale anywhere from four to eight puffs.
The primary outcome was pain intensity measured on an 11-point numerical rating scale (0 10). At all time-points during the 8 hour session, there was a statically significant reduction in pain in both THC groups when compared to the placebo group. There was no statistical difference between the two THC doses, suggesting the lower dose is just as effective as the higher dose. Psychoactive and other subjective side-effects were dose dependent. The number of puffs needed-to-treat to achieve a clinically significant reduction (30% or more) of pain intensity during the 8 hour period was determined to be four. Additional neuropsychological performance measurements were attempted, but were inconclusive given the range of disabilities throughout the study participants.
The overall quality of evidence for the effect of cannabinoid treatment in chronic pain following spinal cord injury was rated as LOW for its immediate effect (1 3 hours), and VERY LOW for its short-term effect (7 weeks), Supplemental Table S4.
Adverse Events
AEs were reported in all studies, and most were categorized as non-serious. With respect to cannabinoid use, one serious AE was reported: one participant sustained a femoral neck fracture following a fall thought to be due to an interaction between nabilone and a separate pharmaceutical agent.21 One participant receiving dronabinol withdrew from their study due to self-reported unacceptable side effects.23 No other withdrawals were noted among cannabinoid users. Other non-serious side effects varied among studies and are listed in Table 1.
Discussion
In this Systematic Review, we evaluated the efficacy of cannabis as an analgesic for surgical and non-surgical back pain. Exhaustive database searches for RCTs and cohort studies revealed only four studies that formally studied cannabis use for nonsurgical back pain. Two studies each focused on general back pain or post-SCI back pain. No studies specifically evaluated cannabis utilization for post-surgical back pain. Overall, the studies were well-performed. No studies demonstrated excessive or outright bias. A total of 110 participants were involved in the four studies. In three out of four studies, there was a statistically significant reduction in pain reported in the cannabinoid group when compared to the control group. The singular study which found no difference between cannabinoid versus control pain management included only seven patients. While there was a positive trend supporting pain improvement in the cannabinoid group, the study likely lacked significant power to prove statistical significance. Given the heterogeneity of the included studies, a meta-analysis of cannabis efficacy for treating back pain could not be performed.
Several different cannabinoids used in the studies were included in this review. Nabilone and Dronabinol are synthetic cannabinoids available via prescription. Typically prescribed for their anti-emetic properties, over the recent years they have gained wider indications for their potential ability to manage neuropathic pain. With regards to pharmaceutical delivery systems, there have been well-documented deleterious effects of inhaled cannabis preparations on the respiratory system, resulting in many experts recommending against such applications.25 Thus, oral synthetic cannabinoids appear to be a more appealing delivery approach. There remains a debate regarding whether the inhalation delivery of whole plant cannabis produces superior analgesic effects when compared to ingesting oral synthetics.26 In addition to these differing routes of administration, synthetic compounds may lack certain key chemicals present in whole cannabis plants which aid in its absorption and the activation of cannabinoid receptors.27 Some studies suggest that self-titrating cannabis through inhalation may result in more potent dosages, thus optimizing pain control. To our knowledge, there have been no studies which directly compare oral versus inhaled cannabis for pain control. Establishing a deeper understanding regarding the pharmacokinetic differences between oral and inhaled forms of cannabis is necessary to provide the most accurate formal recommendations towards a preferred mode of delivery for pain control.
The duration of follow-up for these studies was also quite varied and ranged from 4 weeks in the 2006 Austrian study by Pinsger to 6 months in the study by Yassin et al from 2019, but also charted hourly changes in the study by Wilsey et al from 2016. Longer term treatment benefits or adverse side effects beyond the 6 month paradigm can therefore not be inferred, these follow up ranges, however, are very much within the typical range of pharmaceutical analgesics studies. No serious adverse events directly attributed to cannabis use were reported in the four studies analyzed in this review. While the lack of serious short-term side effects is encouraging, long-term follow-up would be necessary to document any long-term side effects of cannabis use. The longest study follow-up in the studies utilized for this Systematic Review was 6 months. Clearly longer-term follow-up of sequelae such as opiate recidivism and functional recovery would be very desirable in the context of a general overhaul of post-operative pain management. There have been some concerns raised regarding the growing utilization of cannabis throughout the population. The legal status of Cannabis varies heavily among countries around the world, and remains heavily stigmatized and sometimes actively prohibited even for medicinal use in many legal codes even beyond the actively restricted status of opiate analgesics present around the world. Some longer-term adverse side effects of more open access to cannabis may still be emerging as further experience with its wider spread use in the United States is still emerging. For instance, in Washington State, an increase in the rate of de novo spinal infections has been reported since the legalization of recreational cannabis, which may have directly or indirectly resulted in growing substance abuse.28 Patients should be extensively counseled by care provider on the potential risk of abuse of cannabis if used to treat back pain. Cannabis use has also been associated with higher suicide rates in individuals with depression, increased risk for psychosis, and rates of other affective disorders, again increasing the onus on medical professionals to raise awareness of such undesirable side effects in general and specifically in case of medical applications. Thus, assessing possible cognitive effects of long-term cannabis use would be useful.29,30 Cannabis is not recommended for patients with mental health disorders.31 As such, we recommend screening for mental health disorders and/or suicidal ideation before recommending cannabis for back pain management.
Back pain is understood as a multi-faceted condition and is difficult to manage. Novel therapeutic approaches are highly sought after, including a reappraisal of pharmaceuticals used, to improve the wellbeing of the affected population. Conventional wisdom which heavily relied on opiate analgesics has clearly been an unfavorable option with severe downsides. Indeed cannabis, with its alternate neurochemical transmitter pathway may provide a compelling alternative. Three out of the four studies in this Systematic Review showed significant back pain improvement in patients who utilized cannabis instead of a placebo. Interestingly, cannabis remains more heavily stigmatized than opiates in the eyes of many patients, medical providers and legislatures around the world. As the legalization of both medicinal and recreational cannabis continues expanding worldwide, the use of cannabis as an adjunct for back pain management is likely to increase as well. Coupled with an acceptable side effect profile and low addiction potential, cannabis could become a preferable alternative over other types of medications, including opiate analgesics. This is further supported by recent data which suggests cannabis use for pain management leads to decreased opiate utilization.32 Opiates and cannabis operate through distinctly different neurochemical pathways, providing a physiologic explanation which supports the addition of cannabis as an adjunct to opiates for pain management.33
Reducing opiate use is a strongly pursued goal in the context of the United States opioid epidemic. Overall, there is growing evidence that cannabis may be efficacious in managing back pain, however, given the current level of evidence, a conclusion recommending the routine utilization of cannabis as an alternative to opioids cannot be made at this time. We were disappointed to have found no studies that met our search criteria regarding cannabis use in post-surgical back pain. Therefore, we are not able to assess efficacy in this population. There has been no direct evaluation of the efficacy of different routes of cannabis administration or related dosing with respect to its analgesic properties. Studies that address possible combination multimodality therapies, which could include the addition of cannabis to conventional pain management regimens to decrease opiate analgesic usage, are certainly of future interest. As the legalization of cannabis continues to evolve alongside its steadily diminishing social stigma, we anticipate more studies will emerge, further advancing our understanding regarding the potential for cannabis to manage back pain.”
https://journals.sagepub.com/doi/full/10.1177/20451253221116240,”First published online September 20, 2022
Clinical outcome analysis of patients with autism spectrum disorder: analysis from the UK Medical Cannabis Registry
Simon Erridge https://orcid.org/0000-0001-5871-6501, Jess Kerr-Gaffney, [ ], and James J. Rucker [email protected]+9View all authors and affiliations
All Articles
https://doi.org/10.1177/20451253221116240
Contents
Abstract
Introduction
Methods
Results
Discussion
Conclusion
Acknowledgments
ORCID iD
Footnotes
References
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Abstract
Introduction:
Cannabis-based medicinal products (CBMPs) have been identified as a promising novel therapeutic for symptoms and comorbidities related to autism spectrum disorder (ASD). However, there is a paucity of clinical evidence of their efficacy and safety. Objective: This case series aims to assess changes to health-related quality of life and the incidence of adverse events in patients treated with CBMPs for associated symptoms of ASD enrolled on the UK Medical Cannabis Registry (UKMCR).
Methods:
Patients treated with CBMPs for ASD-related symptoms for a minimum of 1 month were identified from the UKMCR. Primary outcomes were changes in validated patient-reported outcome measures [Generalised Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), 5-level version of the EQ-5D (EQ-5D-5L) index values] at 1, 3 and 6 months compared with baseline. Adverse events were recorded and analysed. Statistical significance was determined by p < 0.050.
Results:
Seventy-four patients with ASD were included in the analysis. The mean age of participants was 32.7 ( 11.6) years. There were significant improvements in general health-related quality of life and sleep as assessed by the EQ-5D-5L, SQS and GAD-7 at 1 and 3 months, with sustained changes in EQ-5D-5L and SQS at 6 months (p < 0.010). There were 180 (243.2%) adverse events reported by 14 (18.9%) participants. If present, adverse events were commonly mild (n = 58; 78.4%) or moderate (n = 81; 109.5%), rather than severe (n = 41; 55.4%).
Conclusion:
This study demonstrated an associated improvement in general health-related quality of life, and anxiety- and sleep-specific symptoms following initiation of treatment with CBMPs in patients with ASD. These findings, while promising, are limited by the confines of the study which lacks a control arm and is subject to attrition bias. Therefore, further evaluation is required with randomised controlled trials.
Introduction
Autism spectrum disorder (ASD) is a heterogeneous pervasive developmental disorder defined according to deficits in social communication and interaction, in addition to the presence of restricted, repetitive behaviours.1 ASD is estimated to affect 1 in 132 individuals globally, and its incidence is increasing.2 Individuals with ASD are affected by a higher incidence of comorbid irritability, challenging behaviours, self-injury and psychiatric conditions.3,4 Challenging behaviours, such as irritability, destructiveness, aggression and hyperactivity, are estimated to affect anywhere between 56% and 94% of children with a diagnosis of ASD.3 These behaviours, except for hyperactivity, have been observed as persisting into adulthood.3 ASD is also associated with a higher incidence of physical comorbidities and sleep disturbance in adults.5 7 Consequently, ASD has been associated with reduced quality of life for both adult and paediatric patients.4,8
Management of the core symptoms of ASD is predominantly via a psychological approach.9 However, there is paucity of high-quality research to delineate the effectiveness of different psychological approaches.4 At present, there are no established pharmacological treatments for the core symptoms of ASD. Medications, such as monoamine reuptake inhibitors, have been used in the treatment of comorbid psychiatric illnesses, although the efficacy in people with ASD compared with the general population is not well-known.4 Atypical neuroleptics, such as risperidone and aripiprazole, have demonstrated efficacy in treating irritability and aggression in children and adolescents.10 However, these medications are poorly tolerated due to their side effect profile,10 and their efficacy in an adult population with ASD is again unknown. Consequently, there is an unmet clinical need to identify novel therapeutics for the core symptoms of ASD, other associated symptoms or comorbid diagnoses.
The endocannabinoid system has been implicated in the pathophysiology of ASD, as well as is a potential pharmaceutical target. Cannabinoid type 1 receptors (CB1Rs) are predominantly located in the central nervous system and at increased density within the basal ganglia, hippocampus and cerebellum.11 Moreover, CB1Rs are principally expressed at pre-synaptic terminals of -aminobutyric acid (GABA)ergic and glutaminergic neurons.12 Endogenous agonists of CB1Rs, such as anandamide, cause inhibition of either GABA or glutamate synaptic release.12 Subsequently, the endocannabinoid system has been implicated in the regulation of anxiety, mood, motor coordination and social behaviour.11 13 Children with ASD have been found to have lower circulating levels of anandamide compared with the general population.14
Cannabidiol (CBD), a major phytocannabinoid, is an inhibitor of anandamide reuptake and breakdown, a negative allosteric modulator of CB1Rs and is an agonist of 5-HT1a serotonin receptors.12 (-)-trans- 9-tetrahydrocannabinol ( 9-THC), another active pharmaceutical ingredient of the cannabis plant, is an agonist of CB1Rs.12 Cannabis-based medicinal products (CBMPs), containing these phytocannabinoids, have therefore been highlighted as a potential class of medications for utilisation across the broad potential symptom profile of ASD. In the United Kingdom, CBMPs may be considered for these symptoms if licensed treatments have failed to produce a sufficient clinical response or are not tolerated.15 In 2019, Schleider et al.16 published a series of outcomes from 188 children and adolescents treated with CBMPs. In this study they demonstrated an improvement in quality of life, mood, sleep and challenging behaviours. However, they did not utilise any validated measures to assess for symptom prevalence and change over time.16 At present, there is a paucity of randomised controlled trials and other high-quality evidence on the efficacy and safety of CBMPs in the treatment of ASD-associated symptoms. Importantly, there are no published clinical studies of the outcomes of adult patients treated with CBMPs. Herein, the primary aim of this study is to report the general health-related quality of life outcomes and adverse event incidence of patients prescribed CBMPs for ASD enrolled on the UK Medical Cannabis Registry.”
https://journals.sagepub.com/doi/full/10.1177/20451253221116240,”First published online September 20, 2022
Clinical outcome analysis of patients with autism spectrum disorder: analysis from the UK Medical Cannabis Registry
Simon Erridge https://orcid.org/0000-0001-5871-6501, Jess Kerr-Gaffney, [ ], and James J. Rucker [email protected]+9View all authors and affiliations
All Articles
https://doi.org/10.1177/20451253221116240
Contents
Abstract
Introduction
Methods
Results
Discussion
Conclusion
Acknowledgments
ORCID iD
Footnotes
References
PDF / ePub
Cite article
Share options
Information, rights and permissions
Metrics and citations
Figures and tables
Abstract
Introduction:
Cannabis-based medicinal products (CBMPs) have been identified as a promising novel therapeutic for symptoms and comorbidities related to autism spectrum disorder (ASD). However, there is a paucity of clinical evidence of their efficacy and safety. Objective: This case series aims to assess changes to health-related quality of life and the incidence of adverse events in patients treated with CBMPs for associated symptoms of ASD enrolled on the UK Medical Cannabis Registry (UKMCR).
Methods:
Patients treated with CBMPs for ASD-related symptoms for a minimum of 1 month were identified from the UKMCR. Primary outcomes were changes in validated patient-reported outcome measures [Generalised Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), 5-level version of the EQ-5D (EQ-5D-5L) index values] at 1, 3 and 6 months compared with baseline. Adverse events were recorded and analysed. Statistical significance was determined by p < 0.050.
Results:
Seventy-four patients with ASD were included in the analysis. The mean age of participants was 32.7 ( 11.6) years. There were significant improvements in general health-related quality of life and sleep as assessed by the EQ-5D-5L, SQS and GAD-7 at 1 and 3 months, with sustained changes in EQ-5D-5L and SQS at 6 months (p < 0.010). There were 180 (243.2%) adverse events reported by 14 (18.9%) participants. If present, adverse events were commonly mild (n = 58; 78.4%) or moderate (n = 81; 109.5%), rather than severe (n = 41; 55.4%).
Conclusion:
This study demonstrated an associated improvement in general health-related quality of life, and anxiety- and sleep-specific symptoms following initiation of treatment with CBMPs in patients with ASD. These findings, while promising, are limited by the confines of the study which lacks a control arm and is subject to attrition bias. Therefore, further evaluation is required with randomised controlled trials.
Introduction
Autism spectrum disorder (ASD) is a heterogeneous pervasive developmental disorder defined according to deficits in social communication and interaction, in addition to the presence of restricted, repetitive behaviours.1 ASD is estimated to affect 1 in 132 individuals globally, and its incidence is increasing.2 Individuals with ASD are affected by a higher incidence of comorbid irritability, challenging behaviours, self-injury and psychiatric conditions.3,4 Challenging behaviours, such as irritability, destructiveness, aggression and hyperactivity, are estimated to affect anywhere between 56% and 94% of children with a diagnosis of ASD.3 These behaviours, except for hyperactivity, have been observed as persisting into adulthood.3 ASD is also associated with a higher incidence of physical comorbidities and sleep disturbance in adults.5 7 Consequently, ASD has been associated with reduced quality of life for both adult and paediatric patients.4,8
Management of the core symptoms of ASD is predominantly via a psychological approach.9 However, there is paucity of high-quality research to delineate the effectiveness of different psychological approaches.4 At present, there are no established pharmacological treatments for the core symptoms of ASD. Medications, such as monoamine reuptake inhibitors, have been used in the treatment of comorbid psychiatric illnesses, although the efficacy in people with ASD compared with the general population is not well-known.4 Atypical neuroleptics, such as risperidone and aripiprazole, have demonstrated efficacy in treating irritability and aggression in children and adolescents.10 However, these medications are poorly tolerated due to their side effect profile,10 and their efficacy in an adult population with ASD is again unknown. Consequently, there is an unmet clinical need to identify novel therapeutics for the core symptoms of ASD, other associated symptoms or comorbid diagnoses.
The endocannabinoid system has been implicated in the pathophysiology of ASD, as well as is a potential pharmaceutical target. Cannabinoid type 1 receptors (CB1Rs) are predominantly located in the central nervous system and at increased density within the basal ganglia, hippocampus and cerebellum.11 Moreover, CB1Rs are principally expressed at pre-synaptic terminals of -aminobutyric acid (GABA)ergic and glutaminergic neurons.12 Endogenous agonists of CB1Rs, such as anandamide, cause inhibition of either GABA or glutamate synaptic release.12 Subsequently, the endocannabinoid system has been implicated in the regulation of anxiety, mood, motor coordination and social behaviour.11 13 Children with ASD have been found to have lower circulating levels of anandamide compared with the general population.14
Cannabidiol (CBD), a major phytocannabinoid, is an inhibitor of anandamide reuptake and breakdown, a negative allosteric modulator of CB1Rs and is an agonist of 5-HT1a serotonin receptors.12 (-)-trans- 9-tetrahydrocannabinol ( 9-THC), another active pharmaceutical ingredient of the cannabis plant, is an agonist of CB1Rs.12 Cannabis-based medicinal products (CBMPs), containing these phytocannabinoids, have therefore been highlighted as a potential class of medications for utilisation across the broad potential symptom profile of ASD. In the United Kingdom, CBMPs may be considered for these symptoms if licensed treatments have failed to produce a sufficient clinical response or are not tolerated.15 In 2019, Schleider et al.16 published a series of outcomes from 188 children and adolescents treated with CBMPs. In this study they demonstrated an improvement in quality of life, mood, sleep and challenging behaviours. However, they did not utilise any validated measures to assess for symptom prevalence and change over time.16 At present, there is a paucity of randomised controlled trials and other high-quality evidence on the efficacy and safety of CBMPs in the treatment of ASD-associated symptoms. Importantly, there are no published clinical studies of the outcomes of adult patients treated with CBMPs. Herein, the primary aim of this study is to report the general health-related quality of life outcomes and adverse event incidence of patients prescribed CBMPs for ASD enrolled on the UK Medical Cannabis Registry.”
https://journals.sagepub.com/doi/full/10.1177/20451253221116240,”First published online September 20, 2022
Clinical outcome analysis of patients with autism spectrum disorder: analysis from the UK Medical Cannabis Registry
Simon Erridge https://orcid.org/0000-0001-5871-6501, Jess Kerr-Gaffney, [ ], and James J. Rucker [email protected]+9View all authors and affiliations
All Articles
https://doi.org/10.1177/20451253221116240
Contents
Abstract
Introduction
Methods
Results
Discussion
Conclusion
Acknowledgments
ORCID iD
Footnotes
References
PDF / ePub
Cite article
Share options
Information, rights and permissions
Metrics and citations
Figures and tables
Abstract
Introduction:
Cannabis-based medicinal products (CBMPs) have been identified as a promising novel therapeutic for symptoms and comorbidities related to autism spectrum disorder (ASD). However, there is a paucity of clinical evidence of their efficacy and safety. Objective: This case series aims to assess changes to health-related quality of life and the incidence of adverse events in patients treated with CBMPs for associated symptoms of ASD enrolled on the UK Medical Cannabis Registry (UKMCR).
Methods:
Patients treated with CBMPs for ASD-related symptoms for a minimum of 1 month were identified from the UKMCR. Primary outcomes were changes in validated patient-reported outcome measures [Generalised Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), 5-level version of the EQ-5D (EQ-5D-5L) index values] at 1, 3 and 6 months compared with baseline. Adverse events were recorded and analysed. Statistical significance was determined by p < 0.050.
Results:
Seventy-four patients with ASD were included in the analysis. The mean age of participants was 32.7 ( 11.6) years. There were significant improvements in general health-related quality of life and sleep as assessed by the EQ-5D-5L, SQS and GAD-7 at 1 and 3 months, with sustained changes in EQ-5D-5L and SQS at 6 months (p < 0.010). There were 180 (243.2%) adverse events reported by 14 (18.9%) participants. If present, adverse events were commonly mild (n = 58; 78.4%) or moderate (n = 81; 109.5%), rather than severe (n = 41; 55.4%).
Conclusion:
This study demonstrated an associated improvement in general health-related quality of life, and anxiety- and sleep-specific symptoms following initiation of treatment with CBMPs in patients with ASD. These findings, while promising, are limited by the confines of the study which lacks a control arm and is subject to attrition bias. Therefore, further evaluation is required with randomised controlled trials.
Introduction
Autism spectrum disorder (ASD) is a heterogeneous pervasive developmental disorder defined according to deficits in social communication and interaction, in addition to the presence of restricted, repetitive behaviours.1 ASD is estimated to affect 1 in 132 individuals globally, and its incidence is increasing.2 Individuals with ASD are affected by a higher incidence of comorbid irritability, challenging behaviours, self-injury and psychiatric conditions.3,4 Challenging behaviours, such as irritability, destructiveness, aggression and hyperactivity, are estimated to affect anywhere between 56% and 94% of children with a diagnosis of ASD.3 These behaviours, except for hyperactivity, have been observed as persisting into adulthood.3 ASD is also associated with a higher incidence of physical comorbidities and sleep disturbance in adults.5 7 Consequently, ASD has been associated with reduced quality of life for both adult and paediatric patients.4,8
Management of the core symptoms of ASD is predominantly via a psychological approach.9 However, there is paucity of high-quality research to delineate the effectiveness of different psychological approaches.4 At present, there are no established pharmacological treatments for the core symptoms of ASD. Medications, such as monoamine reuptake inhibitors, have been used in the treatment of comorbid psychiatric illnesses, although the efficacy in people with ASD compared with the general population is not well-known.4 Atypical neuroleptics, such as risperidone and aripiprazole, have demonstrated efficacy in treating irritability and aggression in children and adolescents.10 However, these medications are poorly tolerated due to their side effect profile,10 and their efficacy in an adult population with ASD is again unknown. Consequently, there is an unmet clinical need to identify novel therapeutics for the core symptoms of ASD, other associated symptoms or comorbid diagnoses.
The endocannabinoid system has been implicated in the pathophysiology of ASD, as well as is a potential pharmaceutical target. Cannabinoid type 1 receptors (CB1Rs) are predominantly located in the central nervous system and at increased density within the basal ganglia, hippocampus and cerebellum.11 Moreover, CB1Rs are principally expressed at pre-synaptic terminals of -aminobutyric acid (GABA)ergic and glutaminergic neurons.12 Endogenous agonists of CB1Rs, such as anandamide, cause inhibition of either GABA or glutamate synaptic release.12 Subsequently, the endocannabinoid system has been implicated in the regulation of anxiety, mood, motor coordination and social behaviour.11 13 Children with ASD have been found to have lower circulating levels of anandamide compared with the general population.14
Cannabidiol (CBD), a major phytocannabinoid, is an inhibitor of anandamide reuptake and breakdown, a negative allosteric modulator of CB1Rs and is an agonist of 5-HT1a serotonin receptors.12 (-)-trans- 9-tetrahydrocannabinol ( 9-THC), another active pharmaceutical ingredient of the cannabis plant, is an agonist of CB1Rs.12 Cannabis-based medicinal products (CBMPs), containing these phytocannabinoids, have therefore been highlighted as a potential class of medications for utilisation across the broad potential symptom profile of ASD. In the United Kingdom, CBMPs may be considered for these symptoms if licensed treatments have failed to produce a sufficient clinical response or are not tolerated.15 In 2019, Schleider et al.16 published a series of outcomes from 188 children and adolescents treated with CBMPs. In this study they demonstrated an improvement in quality of life, mood, sleep and challenging behaviours. However, they did not utilise any validated measures to assess for symptom prevalence and change over time.16 At present, there is a paucity of randomised controlled trials and other high-quality evidence on the efficacy and safety of CBMPs in the treatment of ASD-associated symptoms. Importantly, there are no published clinical studies of the outcomes of adult patients treated with CBMPs. Herein, the primary aim of this study is to report the general health-related quality of life outcomes and adverse event incidence of patients prescribed CBMPs for ASD enrolled on the UK Medical Cannabis Registry.”
https://journals.sagepub.com/doi/full/10.1177/23247096221140251,”First published online November 22, 2022
Suspected Cannabis Vaping Induced Pericardial Effusion
Nicole Maharaj, MBBS, Steven Swarath, MBBS, [ ], and Naveen Anand Seecheran, MBBS (MD), MSc https://orcid.org/0000-0002-7779-0181 [email protected]+2View all authors and affiliations
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https://doi.org/10.1177/23247096221140251
Contents
Abstract
Introduction
Case Report
Discussion
Conclusion
Ethics Approval
Informed Consent
Declaration of Conflicting Interests
Funding
ORCID iD
Data availability statement
References
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Abstract
Pericardial effusions refer to an excess accumulation of fluid within the pericardial cavity. The etiology is diverse, with most cases being idiopathic in nature. We report a case of suspected cannabis vaping induced pericardial effusion in a 31-year-old South Asian patient, which was successfully managed with high-dose aspirin, colchicine therapy, and cannabis vaping cessation.
Key Clinical Message: Clinicians should be aware of the possible cardiovascular complications of cannabis vaping.
Introduction
Pericardial effusions refer to an excess accumulation of fluid within the pericardial cavity. The etiology is diverse, with most cases being idiopathic in nature.1-3 Cannabis is a widely used recreational and therapeutic drug with potentially adverse cardiovascular complications, including myopericarditis and myocarditis.4,5
Currently, to the authors knowledge, there are no case reports describing cannabis vaping and pericardial effusions. We report a case of suspected cannabis vaping induced pericardial effusion in a 31-year-old South Asian patient, which was successfully managed with high-dose aspirin, colchicine therapy, and cannabis vaping cessation.
Case Report
A 31-year-old South Asian man with no significant medical history presented to the emergency department with a 1-week duration of worsening dyspnea. He did not report any angina, orthopnea, paroxysmal nocturnal dyspnea, or syncope. His social history revealed that he vaped large quantities of cannabis daily (half of a cartridge 1.5 mg, 95% tetrahydrocannabinol) or the prior 2 months without tobacco, alcohol, or illicit drug use. He did not have any recent travel history, nor did he have any pets. He did not display any antecedent viral symptoms and denied any sick contacts.
On admission to the emergency department, his vital signs included a blood pressure of 115/82 mmHg, a pulse of 88 beats per minute, and regular pulse oximetry of 98% on ambient air. On physical examination, he appeared comfortable without cardiopulmonary distress, with a mildly distended jugular venous pressure of 9 cm of water, and normal heart sounds without a pericardial friction rub on auscultation. He had no crackles upon auscultation of the lung fields, and no peripheral edema was noted.
His electrocardiogram revealed sinus rhythm, a rate of 83 beats per minute with small voltage complexes, and nonspecific ST-T changes such as T-wave inversions in leads V5-V6, II, III, and (aVF) (Figure 1). The chest radiograph did not indicate any acute cardiopulmonary disease. Pertinent diagnostic laboratory investigations revealed a normal troponin I 0.05 ng/mL (normal range: 0.0-0.08 ng/mL) and NT-pro-brain natriuretic peptide 105 pg/mL (normal range < 125 pg/mL). His complete blood count, renal, hepatic, and thyroid function tests were normal. A glycosylated hemoglobin and lipid panel were also normal. A 2-dimensional transthoracic echocardiogram (2D-TTE) revealed a moderate circumferential pericardial effusion ( anterior dimension of 13 mm, posterior dimension of 8 mm) with no impending tamponade physiology and preserved left ventricular function (Figure 2).
Figure 1. The patient s electrocardiogram indicating sinus rhythm, a rate of 83 beats per minute with small voltage complexes, and nonspecific ST-T changes such as T-wave inversions in leads V5-V6, II, III, and aVF.
Figure 2. The patient s 2-dimensional transthoracic echocardiography on admission and outpatient follow-up: (A) Parasternal long-axis view The red stars indicate the circumferential pericardial effusion on admission. (B) Apical 4-chamber view The red star indicates the pericardial effusion on admission. (C) Parasternal long-axis view There is complete interval resolution of the pericardial effusion on the 4-week outpatient follow-up visit. (D) Apical 4-chamber view There is complete interval resolution of the pericardial effusion on the 4-week outpatient follow-up visit.
He was admitted to the cardiology ward and was administered high-dose aspirin (325 mg every 8 hours), colchicine (0.5 mg every 12 hours), and pantoprazole (40 mg every 12 hours). No oral or intravenous glucocorticoids were administered. Diagnostic pericardiocentesis was not performed as there was no evident tamponade physiology, and it was not deemed in the patient s risk-benefit favor. During his ensuing 1-week hospitalization, he remained hemodynamically stable, and a repeat 2D-TTE indicated a significant interval improvement in the pericardial effusion (Figure 2). No pericardiocentesis or advanced thoracic imaging was performed.
Further detailed work-up included a negative interferon- release assay (QuantiFERON-TB Gold Plus), hepatitis panel, HIV, enzyme-linked immunosorbent assay (ELISA), RNA, polymerase chain reaction (PCR), and respiratory pathogen panel (BioFire) tests. Inflammatory markers (erythrocyte sedimentation rate and high-sensitivity C-reactive protein) were normal. A comprehensive rheumatologic and immunologic panel was unremarkable. Coronavirus 2019 PCR and rapid antigen tests were negative, in addition to blood cultures and urinalysis. He was extensively counseled with respect to the possibility of his cannabis vaping being implicated in the etiology of the pericardial effusion and subsequently discharged for routine outpatient follow-up with a surveillance 2D-TTE.
Discussion
The pericardium is a fibroelastic sac that surrounds the heart and normally contains a thin layer of fluid. A pericardial effusion is considered present when the accumulated fluid within the sac exceeds the small amount that is normally present. There is a diverse spectrum of etiologies for pericardial effusions, including neoplasia, infections, inflammatory conditions, systemic diseases, drugs, and toxins, and in many cases, no specific cause is ascertained; it is either deemed idiopathic or presumed viral.1-3
Cannabis vaping is increasing in popularity, and its use has nearly doubled in the last decade.6 Vaping devices can be divided into dab pens or vaporizers. In both devices, the desired substance, contained in a reservoir or cartridge, is heated in a vaporization chamber to produce an aerosol and then inhaled via a mouthpiece. Dab pens use cannabis concentrates referred to as butane hash oil or butane honey oil. Vaporizers can utilize dried or liquid forms of cannabis as well as cannabis concentrates.7 There is still much to be discovered about the adverse effects of vaping cannabis, but thus far, there have been reports of E-cigarette or vaping-associated lung injury (EVALI) occurring in users.8 The known cardiovascular effects of cannabis use include tachycardia, hypertension, and orthostatic hypotension, and in rare cases, it can precipitate acute coronary syndromes.9,10 There have been case reports of myopericarditis and myocarditis in cannabis users, although no causal link has been established, and it remains ambiguous whether cannabis or contaminants of the substance may have played a role in the pathophysiology.4,5
Our patient reported daily vaping of dried cannabis herb for the prior 2 months (half of a cartridge 1.5 mg, 95% tetrahydrocannabinol). Our tentative differential diagnosis suspected that the patient developed pericarditis with an associated effusion, despite the normal inflammatory markers.11 The patient s symptomatology also coincided with the onset of his new habit, and the pericardial effusion resolved soon after cannabis cessation, alluding to a temporal link that may have been confounded by his 4-week therapeutic course. It is entirely plausible that routine vaping of cannabis was implicated in the development of the pericardial effusion; however, it remains unknown whether other constituents or contaminants could have contributed. The sale of cannabis is not regulated in Trinidad and Tobago; thus, the drug s purity is not assured.
Our patient also underwent comprehensive diagnostic testing, including for rheumatologic disease, which ultimately proved unrevealing. As aforementioned, diagnostic pericardiocentesis was deferred as the patient did not display overt tamponade physiology, and the anterior effusion was 13 mm and was considered in the risk-benefit analysis. Most idiopathic pericardial effusions are presumed to be viral in origin, and an in-depth work-up of viral causes is usually not performed. However, an extensive assay for common respiratory pathogens (coronavirus, Enterovirus, rhinovirus, influenza, parainfluenza, respiratory syncytial viruses, Bordetella, Mycoplasma, and chlamydia) was negative in this case, although it does not entirely exclude an atypical pathogen. Ideally, further advanced cardiac imaging with cardiac computed tomography (CCT) or magnetic resonance imaging (cMRI) could have been performed; however, the patient swiftly responded to the conventional therapies of high-dose aspirin and colchicine evidenced by significant interval echocardiographic resolution between 1 week and 1 month, respectively.
Conclusion
We report a case of suspected cannabis vaping-induced pericardial effusion in a 31-year-old South Asian patient, which was successfully managed with high-dose aspirin, colchicine therapy, and cannabis vaping cessation. Clinicians should be aware of the possible cardiovascular complications of cannabis vaping.”
ProfessorGPT paper on Epilepsy using 2022 and 2023 data,”Introduction Epilepsy is a neurological disorder characterized by recurrent seizures resulting from abnormal brain activity. It affects millions of people worldwide and often proves challenging to manage with conventional antiepileptic drugs (AEDs). However, recent research has shown promising results regarding the use of cannabis-based treatments for epilepsy. This paper aims to explore the effectiveness of medicinal cannabis in treating epilepsy based on research papers from 2022 and 2023. Cannabis and Epilepsy Cannabis contains numerous active compounds called cannabinoids, with delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being the most well-known. THC is primarily responsible for the psychoactive effects of cannabis, while CBD exhibits various therapeutic properties without inducing a “”high.”” Both cannabinoids have shown potential in managing epileptic seizures. Research Findings 1. Efficacy of CBD: A study published in the New England Journal of Medicine in 2018 examined the use of CBD in patients with Dravet syndrome, a severe form of epilepsy. The trial found that CBD significantly reduced seizure frequency compared to a placebo group. Similar positive results were reported in subsequent studies involving other forms of treatment-resistant epilepsy. 2. Combination Therapy: In some cases, combining CBD with other AEDs has demonstrated enhanced efficacy. A study published in Epilepsia in 2022 evaluated the impact of adding CBD to existing treatment regimens for patients with refractory epilepsy. The results showed a significant reduction in seizure frequency compared to baseline, suggesting a potential synergistic effect. 3. Long-Term Safety: Another critical aspect of cannabis-based treatments is their long-term safety profile. A systematic review published in Frontiers in Neurology in 2023 analyzed the safety data from multiple studies involving pediatric patients with epilepsy treated with CBD. The review concluded that CBD was generally well-tolerated, with mild side effects such as drowsiness and gastrointestinal disturbances. 4. Mechanisms of Action: Understanding the mechanisms underlying the antiepileptic effects of cannabinoids is crucial for optimizing treatment strategies. A study published in Epilepsia in 2023 investigated the impact of CBD on neuronal excitability using a mouse model of epilepsy. The findings suggested that CBD exerts its antiseizure effects by modulating calcium channels, potassium channels, and glutamate receptors. Conclusion The research papers from 2022 and 2023 provide further evidence supporting the use of medicinal cannabis, particularly CBD, in the treatment of epilepsy. CBD has shown efficacy in reducing seizure frequency, even in cases resistant to conventional AEDs. Additionally, combining CBD with existing treatments may enhance its antiepileptic effects. Moreover, long-term studies have demonstrated a favorable safety profile for CBD use in epilepsy patients. However, it is important to note that more research is needed to fully understand the optimal dosing, long-term effects, and potential drug interactions associated with cannabis-based treatments. Healthcare professionals should carefully evaluate each patient’s unique circumstances and consider the legal and regulatory aspects before recommending medicinal cannabis for epilepsy management.”
https://doi.org/10.1177/20503245231172535,”Research article
First published online May 25, 2023
Medicinal cannabis for pain: Real-world data on three-month changes in symptoms and quality of life
Kylie O Brien [email protected], Justin Beilby, [ ], and David Nutt+6View all authors and affiliations
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https://doi.org/10.1177/20503245231172535
Contents
Abstract
Introduction
Methods
Results
Discussion
Conclusion
Acknowledgements
Declaration of conflicting interests
Funding
References
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Abstract
Background
Internationally, one of the most common conditions for which people seek medicinal cannabis (MC) is chronic pain. However, relatively little is known about the effectiveness of cannabis for reducing pain in Australia. Medicinal cannabis was made legally available in Australia in 2016. Project Twenty21 Australia is an observational study that follows patients prescribed MC for chronic pain, anxiety, PTSD and multiple sclerosis for up to 12 months. It commenced recruitment in February 2022. This paper describes some preliminary findings for a cohort of patients with chronic pain.
Method
Participants seeking treatment for chronic pain are prescribed MC from within a Project Formulary, and complete questionnaires at baseline then three monthly for up to 12 months. Pain severity and interference are assessed using the Brief Pain Index while standardised measures of quality of life, mood and sleep quality are also applied.
Results
By 30 November 2022, 55 participants with chronic pain had completed the first three-month follow-up. Patients reported a low quality of life and high levels of co-morbidity. Three-month data indicate that MC use was associated with significant reductions in self-reported pain intensity and pain interference (Effect sizes = 0.66 [95% CI = 0.34 0.98] and 0.56 [0.24 0.88], respectively). Additionally, there were significant improvements in quality of life, general health, mood/depression and sleep (Effect sizes = 0.53 0.63). One adverse reaction was reported which was mild in nature.
Conclusions
Preliminary evidence suggests that MC may be effective in reducing both pain severity and pain interference while also improving quality of life, general health, mood and sleep in patients with chronic pain. Increasing uptake of MC coupled with growing evidence of both the effectiveness and safety of these medications indicate a need both to make MC more widely available and to reduce financial costs associated with its use.
Introduction
Chronic pain is one of the leading indications for which people use medicinal cannabis (MC) (Lintzeris et al., 2018, 2022; Sexton et al. 2016). The Australian Therapeutic Goods Administration (TGA) figures for prescriptions approved under the Special Access Scheme B in 2021 also indicate chronic pain to be the number one condition for which they have approved applications for MC (TGA 2021).
Many systematic reviews, long considered the gold standard of evidence in medicine (though a position now challenged) (Moore et al. 2022), also support the contention that MC is efficacious in the treatment of chronic pain (Aggarwal 2013; Boychuk et al. 2015; Hill 2015; Lynch and Campbell 2011; Lynch and Ware 2015; Martin-Sanchez et al. 2009; McDonagh et al. 2022; Mucke et al. 2018; TGA 2017; Wang et al. 2021; Whiting et al. 2015). The National Academies of Sciences, Engineering and Medicine’s 2017 report on cannabis and cannabinoids used only evidence from systematic reviews and randomised controlled trials (RCTs) to ascertain whether MC or cannabinoids were efficacious in a range of clinical conditions. The report concluded that there is conclusive or substantial evidence that cannabis or cannabinoids are effective for the treatment of chronic pain in adults (cannabis) . (National Academies of Sciences, Engineering and Medicine 2017). The TGA’s guidance document on the use of MC in the treatment of chronic non-cancer pain in Australia concluded, through meta-analysis of 49 RCTs, that there is evidence of effectiveness of MC in reducing pain scores and pain intensity ratings compared with placebo (TGA 2017). In contrast, a recent review by Stockings and colleagues (2018) concluded that evidence for the use of MC for chronic non-cancer pain was limited.
However, RCTs and systematic reviews have their limits methodologically. RCTs typically have strict inclusion and exclusion criteria, often conducted over short timeframes, and may use fixed dosing regimes which do not reflect the real-world use of cannabis and limit generalisability to the wider population. Other research methods including case studies and observational studies are able to assess effectiveness and safety over extended time periods, reflecting its real-world use which includes individualisation of dosage, use of multiple products and in many cases concurrent western medicines and complementary medicines. Such data has been termed real-world data (RWD) (Sakal et al. 2021; Schlag et al., 2022).
Project Twenty21 Australia is an observational study that follows patients prescribed MC for chronic pain, anxiety, PTSD and multiple sclerosis (MS) for up to 12 months. Participants are prescribed products from within the project formulary containing cannabis oils and flowers. At baseline and every three months, participants complete a condition-specific questionnaire and general questionnaires assessing sleep, mood/depression and quality of life. In addition, at the three month follow-up visits, they also complete a questionnaire that measures global impression of change, a Cannabis-Based Medicines Questionnaire (CBMQ) and a symptom questionnaire. The detailed methodology has been described elsewhere (O Brien et al. 2023). This paper describes, briefly, the methodology in relation to chronic pain participants, and some preliminary data at the three-month follow-up mark.
Methods
Study design
Project Twenty21 Australia study is a single-arm open-label, prospective observational cohort study investigating the effectiveness of MC in alleviating symptoms of four clinical conditions (chronic pain, anxiety, PTSD and MS). MC products are individualised to the participants.
Ethics approval
Approval from the National Institute of Integrative Medicine Human Research Ethics Committee was granted on 20 December 2021. The study is registered with the Australia and New Zealand Clinical Trials Registry.
Recruitment and consent
Participants are patients who have consulted doctors at Releaf Clinics within Australia, have indicated interest in participating in the study and have one of four conditions (chronic pain, anxiety, PTSD and MS). All participants have consented to be part of the study (informed consent forms are signed). Further details about the recruitment process can be found at O Brien et al. (2023).
Study objectives in relation to chronic pain
The following is the study s primary and secondary objectives in relation to chronic pain that are reported on in this paper. There are other primary and secondary objectives, described in O Brien et al. 2023, that will be reported on in subsequent papers and include analysing subcategories of cannabis products.
Primary objective: To investigate whether MC as a whole alleviates chronic pain
Secondary objectives: To investigate whether MC as a whole improves tolerable quality of life, sleep and depression/mood for patients with chronic pain, and if it is safe and tolerable.
Hypotheses
The study s null hypotheses in relation to the above objectives are as follows:
MC as a whole will not alleviate chronic pain.
MC as a whole will not improve quality of life, sleep and depression/mood in patients with chronic pain.
MC as a whole is not safe and tolerable.
Inclusion/exclusion criteria
Inclusion and exclusion criteria are set out in Table 1. Note that not all participants are strictly cannabis-naive in the sense of never having used cannabis (see Table 1).
Table 1. Study inclusion and exclusion criteria.
Inclusion criteria Exclusion criteria
Patients, females and males, aged 18 years and over with a diagnosis which falls under one of the following four study categories: chronic pain, anxiety, PTSD and MS and who are prescribed medicinal cannabis as per standard clinical practice by a clinician at Releaf Clinics.
In the professional opinion of the treating clinician, the patient is eligible to be prescribed medicinal cannabis in Australia.
Ability to fully understand the potential side effects associated with medicinal cannabis, and the fact that driving with any amount of THC in your system is an offence under Australian driving laws in all states and territories
Ability to fully understand the requirements of participation in the study.
Provide written informed consent to participate in the study and are willing to comply with the study procedures.
Agree to be prescribed medicinal cannabis products from the Project Formulary.
Patients currently using recreational cannabis (where use is chronic and more than three days per week for the past 2 months) or currently using medicinal cannabis for medical reasons.
Evidence of clinically relevant haematological, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic or psychiatric disorder which in the opinion of the medical practitioner should preclude them from participating in the study.
Known allergy to medicinal cannabis, CBD or any of the components of the medicinal cannabis products in the Project Formulary.
Pregnancy or active breast feeding.
Clinically significant abnormalities in baseline laboratory test results including liver function and kidney function: Creatinine > 1.5 times upper limit of normal; ALT, AST or ALP > 2 times upper limit of normal.
Taking warfarin or any other blood thinning medication (which may interact adversely with CBD).
Have participated in a clinical trial or receipt of an experimental therapy within 30 days prior to inclusion.
Unwilling or unable to provide written informed consent.
Project formulary: MC products
Project Twenty21 Australia is supported by five MC companies. The Project Formulary contains 26 MC products categorised in terms of level of CBD or THC, set out in Table 2.
Table 2. Types of MC products in project formulary.
High CBD Balanced CBD/THC High THC
Oils 3 5 5
Flower 0 0 10
Tablets 2 0 1
A participant may have cannabis products prescribed outside of the formulary also, however, they must be taking at least one product from within the Project Formulary to be included and remain in the study.
Overview of the study process and outcome variables reported for chronic pain cohort
Following recruitment into the study, participants complete various assessments at baseline and every three months, up to 12 months. Each participant receives a condition-specific questionnaire (e.g., specific to the condition nominated as their primary complaint, which is chronic pain, anxiety, PTSD or MS) plus general questionnaires which assess other factors, as described below. As part of the preliminary data collected about participants, participants can record details about their medical history including concomitant medications. They are also required to record their MC product details including dosage at baseline (and if there is a change in medication, they can update this in their three-month reporting).
In the case of those study participants who have nominated chronic pain as their primary complaint, each study participant completes a pain questionnaire and six questionnaires common to all participants which address the secondary outcome variables of the study. The pain questionnaire is administered at five time-points of the study: baseline, and thereafter three months up to a maximum of 12 months. Three questionnaires common to all participants are conducted at baseline, then three months thereafter: a health-related quality of life questionnaire, a sleep questionnaire and a depression/mood questionnaire. This paper will report on the results of these questionnaires in a cohort at the first three-month follow-up mark.
Three more questionnaires are also conducted at the follow-up visits only: a questionnaire that measures global impression of change, and CBMQ and a symptom questionnaire that both collect data on symptoms, adverse effects and behavioural changes associated with MC. Blood pathology tests (safety data, including liver function tests) are measured at baseline, 6 months and 12 months. Details of these additional questionnaires can be found in O Brien et al. (2023). The results of these additional questionnaires will not be reported in this paper.
Pain Questionnaire: Brief Pain Inventory Short Form
The primary outcome measure for patients with chronic pain is the Brief Pain Inventory Short Form (BPI-SF), a commonly used, validated measurement tool that evaluates chronic pain, including pain severity and interference of pain on feeling and function (Cleeland, 1991; Keller et al. 2004). It asks participants to rate pain severity (four items: worst pain, least pain, average pain and pain now, each scored on a scale of 0 10). It also asks individuals to rate aspects of pain interference (seven items: interference with general activity, mood, walking ability, normal work, relation to other people, sleep and enjoyment of life, each on a 0 10 scale) (Cleeland, 2009). BPI pain severity is scored as the mean of the four severity items, each scored on a scale of 0 10. These can be summed (total scores 0 40) or alternatively, the mean rating across the four items can also be calculated (range of 0 10) which is how we have reported results in Table 3. The BPI Pain Interference is scored as the total of the seven interference items, each scored on a scale of 0 10 (range 0 70) or alternatively, the mean rating across the seven items can be calculated (range 0 10) which is how we have reported results in Table 3 (Cleeland, 2009).
Table 3. Comparison of self-reported health at treatment entry and three-month follow-up for chronic pain patients.
Measure Mean baseline (std dev) Mean 3 months (std dev) T* Effect size (Cohen’s d, 95% CI)
Pain Severity (BPI) (mean) (range 0 10) 5.54 (1.76) 4.33 # (2.04) 4.63 d = 0.66 (0.34, 0.98)
Pain Interference (BPI) (mean) (range 0 10) 6.24 (2.09) 4.98 # (2.56) 4.49 d = 0.56 (0.24, 0.88)
Quality of life (EQ-5D-5L) (weighted score range -0.285 1.0) 0.54 (0.25) 0.67 # (0.25) -3.60 d = -0.53 (-0.85, -0.21)
General Health Index (EQ-5D-5L VAS) (range 0 100) 52.79 (19.16) 64.25 # (16.03) -4.41 d = -0.63 (-0.95, -0.30)
Mood/Depression (PHQ-9) (range 0 -27) 12.35 (6.28) 8.73# (5.52) 4.83 d = 0.60 (0.28, 0.92)
Sleep Quality (range 0 20) 12.47 (3.66) 10.50 # (3.76) 3.88 d = 0.53 (0.21, 0.85)
Note. CI = confidence interval.
N = 55 participants.
#
probability value p < 0.01.
- T = T-value (Student t test).
Health-related quality of life questionnaire: EQ-5D-5L Summary Index
The Euro Quality of Life 5 Dimensions (EQ-5D-5L) is a widely used, validated and reliable health-related quality of life tool that measures quality of life, by assessing the severity of five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item is scored on a five-point Likert scale (1 5): no problems (score = 1), slight problems (score = 2), moderate problems (score = 3), severe problems (score = 4) and extreme problems (score = 5) (EuroQol Research Foundation 2019).
The EQ-5D-5L Summary Index is a summary score derived from the individual dimension scores by applying a formula that attaches values or weights to each of the levels in each dimension. These values or weights are typically country-specific (obtained by consensus) (EuroQol Research Foundation 2019). For these analyses, we calculate Index Values using values from Devlin et al. (2016). The weighted score is a minimum of -0.285 and maximum of 1.0 (indicative of optimal health) (Schrag et al., 2000).
The EQ-5D-5L also contains a visual analogue scale (VAS) that is a measure of perceived general health (overall health). Individuals rate their current health (on a visual scale from 0 100; 0 = worst health imaginable, 100 = best health imaginable) (EuroQol Research Foundation 2019).
Depression/mood questionnaire: PHQ-9 questionnaire
Depression or mood is measured with the Patient Health Questionnaire (PHQ-9; Kroenke et al. 2001, a reliable and valid measure of depression severity (Rancans et al., 2018). There are nine items, and participants are asked to self-rate the frequency of depressive symptomatology during the previous two weeks on a four-point Likert scale (0 = not at all; 1 = several days; 2 = over half the days; 3 = nearly every day) (Rancans et al. 2018). An overall measure of severity of depressive symptomatology is gained by adding the scores for each item (total maximum score of 27). The interpretation of the total score is as follows (Kroenke et al., 2001):
1 4 Minimal depression
5 9 Mild depression
10 14 Moderate depression
15 19 Moderately severe depression
20 27 Severe depression
Sleep questionnaire
A sleep questionnaire adapted from the widely used Pittsburgh Sleep Quality Index (Buysee et al., 1989) was developed with four items, each assessed on a five-point scale. The first item asks: How much sleep patterns are interfering with daily activities (1 = not at all, 2 = a little, 3 = somewhat, 4 = much, 5 = very much)? The other three items assess: difficulties falling asleep, difficulties staying awake and waking up too early, each on a five-point scale (1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe). The total maximum score is 20 (higher scores indicate worse sleep quality).
Safety data and adverse events
Safety and tolerability data is collected via a Symptom Questionnaire and the CBMQ as part of the follow-up visits. Objective safety data is collected in the form of results of blood tests including liver function tests (AST, ALT, ALP, GGT and bilirubin) and kidney function tests (EGFR, urea, creatinine, albumin and total protein), conducted at baseline and every six months thereafter. Since this paper only presents preliminary three-month data, pathology tests are not reported here.
All participants are advised by their treating clinicians at Releaf Clinics to contact them if they do have any side effects, in particular those which may be more serious in nature, as part of normal patient care. In the event that a study participant experiences an adverse event or serious adverse event, participating clinicians are instructed to contact the Study Coordinator immediately, and doctors are also required to report adverse events to the TGA (as for any medicine).
Statistical analysis
Mean ratings in the following questionnaires: BPI-SF, EQ-5D (quality of life) score, general health VAS score, PHQ-9 Questionnaire score and sleep score are compared at baseline and three months using paired sample t tests, with Cohen’s d reported to assess the effect size.
Results
Sample characteristics
As of 30 October 2022, a total of 113 individuals had been recruited into the study and completed the three-month follow-up. Nearly half (n = 55, 48.7%) of these patients identified chronic pain as their primary condition; 53.6% of this pain sample were female, and 46.4% were male. Their average age was 43.7 years (range = 23 74).
A total of 73.2% of those with chronic pain , as their primary condition/complaint, reported at least one additional comorbid or secondary condition. The mean number of comorbid conditions reported across this cohort was 2.20 (range = 0 9); 16.1% of the sample reported one comorbid condition, 44.6% reported two to four and 12.5% reported five or more (comorbid) secondary conditions. The most commonly reported secondary conditions were: back and/or neck pain (28.6%), stress (28.6%) and Generalized Anxiety Disorder (23.2%). Including back and/or neck pain as secondary conditions simply allows for further stratification of data at a later time to investigate the effectiveness of these more specific areas of pain.
Cannabis product characteristics
Across the cohort of 55 participants (64.3%) received one product, 30.4% received two products and 5.36% received three or more products. The majority of products prescribed were oils (68.1%), with 31.9% being flower (which were all high THC). Of the oils prescribed, the majority were high CBD oils (89.4%) with the remaining being balanced CBD/THC oils (10.6%).
Chronic pain: BPI SF scores
The mean rating across the four severity items from the BPI was 5.54 (SD = 1.76) at baseline and 4.33 (SD = 2.04) at three months. The mean rating across the seven pain interference items was 6.24 (SD = 2.09) at baseline and 4.98 (SD = 2.56) at three months (see Table 3).
Secondary outcome measures
Table 3 also summarises mean scores for quality of life (EQ-5D-5L Index), perceived general health (EQ-5D-5L VAS), mood/depression (PHQ-9) and sleep quality (sleep 4-item scale) at baseline and at three-month follow-up.
Effect sizes, assessed using Cohen’s d, ranged from 0.53 to 0.63 and in all cases indicated significant improvements in quality of life, general health, mood and sleep.
Reported adverse events
According to the Australian National Health and Medical Research Council, an adverse reaction is defined as Any untoward and unintended response to an investigational medicinal product related to any dose administered and further, that All adverse events judged by either the reporting investigator or the sponsor as having a reasonable possibility of a causal relationship . In contrast, an adverse event is defined as any untoward medical occurrence in a patient or clinical trial participant administered a medicinal product and that does not necessarily have a causal relationship with this treatment (NHMRC, 2016).
In this cohort of 55 chronic pain patients who had completed the three-month follow-up, there was one participant who experienced what was considered by his treating doctor as a mild adverse reaction. He is a 29-year-old male who was prescribed a flower product at a dosage of 0.2 0.3 g PRN for chronic pain. He reported dry eyes and feeling cold; this resolved on the same day.
Discussion
We have described the baseline and three-month follow-up data for 55 participants recruited into Project Twenty21 Australia who identified chronic pain as the primary condition for which they were seeking treatment with MC.
Overall, measures of pain severity and interference improved significantly over three months of treatment with MC. Sleep, mood/depression and overall quality of life measures also significantly improved over the three months. Effect sizes in all cases were moderate to strong.
Comorbidities
A feature of this cohort of chronic pain patients was their relatively poor health, in relation to quality of life (including many of its dimensions), level of mood and sleep quality and comorbidities. For example, 41 (73.2%) of the study sample reported at least one additional comorbid or secondary condition and the mean number of comorbid conditions reported across the entire sample was 2.20 (range = 0 9), with 7 (12.5%) reporting five or more (comorbid) secondary conditions.
The most commonly reported secondary conditions were: back and/or neck pain (28.6%), stress (28.6%) and Generalized Anxiety Disorder (23.2%). This is perhaps not surprising as chronic pain, anxiety, depression and insomnia are often comorbid (Arrow et al. 2006; Baglioni et al., 2011; Finan and Smith, 2013; Khurshid, 2018; O Brien and Blair, 2021; Pollack, 2005; Russo et al., 2007; Taylor et al., 2005; van Mill et al., 2010). Compared with the general population, chronic pain sufferers are up to four times more likely to meet diagnostic criteria for mood and anxiety disorders (Arrow et al. 2006).
Pain
Pain severity and interference improved significantly over three months of treatment with MC. The literature largely supports the contention that MC is efficacious for the treatment of chronic pain. Indeed there is evidence that the endocannabinoid system plays a role in the regulation of pain and analgesia and that components of MC including THC and CBD have analgesic effects (Hill et al. 2017). Table 4 lists some of the key systematic reviews reported in the literature since 2009. These largely support the contention that MC is efficacious for the treatment of chronic pain.
Table 4. Systematic reviews investigating Cannabis for chronic pain.
Year Key findings Reference
2009 18 RCTs comparing any cannabis preparation to placebo: cannabis treatment moderately efficacious Martin-Sanchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med. 2009;10:1353 1368.
2011 18 RCTs, n = 925 participants, non-cancer pain: 15/18 RCTs confirmed cannabis/cannabinoids had significant positive analgesic effects (studies included neuropathic pain, RA, fibromyalgia, mixed chronic pain) Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol 2011;72:735 744.
2013 38 RCTs, n = 2423 patients: 27/38 RCTs confirmed cannabis/cannabinoids had a significant positive analgesic effect. Aggarwal SK. Cannabinergic pain medicine: a concise clinical primer and survey of randomized controlled trial results. Clin J Pain 2013; 29: 162 171.
2015 Chronic non-cancer pain, 11 RCTs, n = 1135 participants: 7/11 significant analgesic effects of cannabis/cannabinoids compared with controls (in the 7 positive studies, pain conditions included overuse headache, diabetic neuropathy, MS pain, muscle stiffness & spasticity pain, neuropathic pain with allodynia, neuropathic pain). Lynch ME, Ware MA. Cannabinoids for the treatment of chronic non-cancer pain: An updated systematic review of randomized controlled trials. J Neuroimmune Pharmacol. 2015;10:293 301.
2015 79 trials involving cannabis/cannabinoids, 28 in chronic pain: concluded moderate quality evidence to support use for chronic pain and spasticity. Compared with placebo, cannabis/cannabinoids associated with reduction in pain and greater average reduction in numerical scale pain assessment and average reduction Ashworth spasticity scale. Whiting PF, Wolffe RF, Deshpande M et al. Cannabinoids for medical use:a systematic review and meta-analysis. JAMA 2015; 313(24): 2456 2473.
2015 6 studies in chronic pain (n = 325 participants), 6 trials neuropathic pain (n = 396 participants), 12 trials MS (n = 1600 participants): concluded use of cannabis for chronic pain, neuropathic pain and spasticity due to MS supported by high-quality evidence. Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: A clinical review. JAMA. 2015;313:2474 2483.
2015 13 trials of cannabis extracts/cannabinoids for chronic non-malignant neuropathic pain: concluded these may provide effective analgesia in conditions refractory to other treatments. Boychuk DG, Goddard G, Mauro G, Orellana MF. The effectiveness of cannabinoids in the management of chronic non-malignant neuropathic pain: a systematic review. J Oral Facial Pain Headache. 2015;29:7 14.
2017 Review of 102 studies including 26 parallel RCTs, 23 cross-over RCTs and 53 observational studies in chronic non-cancer pain. Meta-analysis of the (49) RCTs indicated that medicinal cannabis was more likely than placebo to produce 30% and 50% reductions in pain scores and more likely than placebo to produce significantly greater reduction in pain intensity ratings. Evidence strongest for nabiximols (most likely cannabinoid to be associated with reduction in overall pain scores); studies of lesser quality suggest nabilone, cannabis sativa, THC:CBD extracts and ajulemic acid may be more effective than placebo in producing a 30% reduction in pain, though evidence limited (small no. studies and small sample sizes). Therapeutic Goods Administration. Guidance for the use of medicinal cannabis in the treatment of chronic non-cancer pain in Australia. Canberra, ACT: TGA, 2017
2018 16 studies, 2 26 weeks long, n = 1750 participants. All studies compared cannabis-based medicines with placebo except one (synthetic THC cf dihydrocodeine); studies compared an oro-mucosal spray with plant-derived combination of THC & CBD (10 studies), inhaled herbal cannabis (2 studies), synthetic THC (nabilone) (2 studies) & plant-derived THC (dronabinol) (2 studies).
Results: All cannabis-based medicines (any dose) pooled together superior to placebo for substantial (50% and more) (low-quality evidence) & moderate (30% and more) pain relief (moderate-quality evidence), for global improvement (very low-quality evidence), & in reduction of mean pain intensity (low-quality evidence), sleep problems (low-quality evidence) and psychological distress (low-quality evidence).
The effect sizes of mean pain intensity, sleep problems and psychological distress were clinically relevant. Mucke M et al. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database of Systematic Reviews 2018, Issue 3. Art. No.: CD012182. DOI: 10.1002/14651858.CD012182.pub2.
2018 104 studies (n = 9958 participants): n = 76 where pain was the primary indication, n = 28 where pain was a secondary indication); 47 RCTs and 57 observational studies. N = 48 studies neuropathic pain, n = 7 studies fibromyalgia, n = 1 rheumatoid arthritis, and n = 48 other chronic non-cancer pain (13 MS-related pain, 6 visceral pain, 29 samples with mixed or undefined chronic non-cancer chronic pain.
Concluded: moderate evidence for a reduction in pain for cannabinoids. Pooled analyses suggest a 30% reduction in pain was reported by 29.0% in those taking cannabinoids compared with 25.9% for placebo. A 50% reduction in pain was reported by 18.2% in cannabinoid treatment groups compared with 14.4% in placebo groups (no statistically significant difference). Also concluded that number needed to treat to benefit is high and no. needed to treat for harm is low. Stockings E, Campbell G, Hall WD, Nielson S, Zagic D et al. Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. Pain 2018; 159(10):1932 1954.
2021 32 trials (n = 5174 participants), 29 of which compared medical cannabis or cannabinoids with placebo. Medical cannabis administered orally (n = 30) or topically (n = 2 studies). Clinical populations: chronic non-cancer pain (28 trials) and cancer-related pain (4 studies). Follow-up 1 5.5 months.
Concluded: moderate to high certainty evidence that non-inhaled medical cannabis or cannabinoids results in a very small to small improvement in pain relief, physical functioning and sleep quality in patients with chronic pain, along with several transient side effects, in comparison with placebo. Wang L, Hong PJ, May C et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ 2021;8: 374.
2022 18 randomised placebo-controlled trials (n = 1790 participants) plus 7 cohort studies (n = 13095 participants). Studies mostly short term (1 6 months), 56% of participants with neuropathic pain.
Concluded: oral synthetic cannabis products with high THC-CBD ratios and sublingual extracted cannabis products with comparable THC-CBD ratios associated with short-term improvements in chronic pain, but also increased risk dizziness and sedation. Longer term studies required. McDonagh MS, Morasco BJ, Wagner J et al. Cannabis based products for chronic pain. Annals Internal Med 2022; https://doi.org/10.7326/M21-4520
There are some differences found when comparing the results of RCTs compared with observational studies. For example, Stockings et al. (2018) reviewed 104 studies of which 47 were RCTs and 57 were observational studies. When considering the RCTs, there was a significant difference in pooled ev”
https://journals.sagepub.com/doi/full/10.1177/87551225231180796,”First published online June 24, 2023
The Effectiveness and Adverse Events of Cannabidiol and Tetrahydrocannabinol Used in the Treatment of Anxiety Disorders in a PTSD Subpopulation: An Interim Analysis of an Observational Study
Sophie K. Stack, BPharm, Nial J. Wheate, PhD, DSc https://orcid.org/0000-0002-0505-1363, [ ], and Elise A. Schubert, BPharm [email protected]+3View all authors and affiliations
Volume 39, Issue 4
https://doi.org/10.1177/87551225231180796
Contents
Abstract
Introduction
Methods
Results
Discussion
Conclusions
Ethics Approval
Declaration of Conflicting Interests
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ORCID iD
References
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Abstract
Background: Anxiety is a condition for which current treatments are often limited by adverse events (AEs). Components of medicinal cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC), have been proposed as potential treatments for anxiety disorders, specifically posttraumatic stress disorder (PTSD). Objective: To evaluate quality-of-life outcomes after treatment with various cannabis formulations to determine the effectiveness and associated AEs. Methods: An interim analysis of data collected between September 2018 and June 2021 from the CA Clinics Observational Study. Patient-Reported Outcomes Measurement Information System-29 survey scores of 198 participants with an anxiety disorder were compared at baseline and after treatment with medicinal cannabis. The data of 568 anxiety participants were also analyzed to examine the AEs they experienced by the Medical Dictionary for Regulatory Activities organ system class. Results: The median doses taken were 50.0 mg/day for CBD and 4.4 mg/day for THC. The total participant sample reported significantly improved anxiety, depression, fatigue, and ability to take part in social roles and activities. Those who were diagnosed with PTSD (n = 57) reported significantly improved anxiety, depression, fatigue, and social abilities. The most common AEs reported across the whole participant cohort were dry mouth (32.6%), somnolence (31.3%), and fatigue (18.5%), but incidence varied with different cannabis formulations. The inclusion of THC in a formulation was significantly associated with experiencing gastrointestinal AEs; specifically dry mouth and nausea. Conclusions: Formulations of cannabis significantly improved anxiety, depression, fatigue, and the ability to participate in social activities in participants with anxiety disorders. The AEs experienced by participants are consistent with those in other studies.
Introduction
As defined by Craske and Stein,1 anxiety is a response that individuals have to situations they perceive as threatening, and anxiety disorders occur when this response is overactive to the point that it impairs a person s functioning. The exact pathophysiology of anxiety is unknown; however, it is thought to arise from an imbalance of neurotransmitters such as serotonin and noradrenaline and abnormalities in brain structures including the amygdala and prefrontal cortex.2 The major types of anxiety disorders are generalized anxiety disorder, social anxiety, panic disorder, phobic disorder, posttraumatic stress disorder (PTSD), and obsessive compulsive disorder.1 The initial treatment for anxiety disorders is usually nonpharmaceutical, such as cognitive behavioral therapy, and when this is not suitable or successful, pharmacological treatment may be considered.3,4
Benzodiazepines are effective anxiolytics; however, they are limited to short-term or acute crisis use due to the risk of dependence, daytime sedation, and memory problems.3,4 The various antidepressants indicated for anxiety disorders, such as serotonin reuptake inhibitors, are only effective in 60% of people with PTSD and can be inconsistent in terms of efficacy.5,6 Due to the limited efficacy of some of these medications, clinicians take adverse event (AE) profiles and patient preference into consideration when prescribing these treatments.3 As such, there is a continuing need for new medications for anxiety disorders that have both favorable safety and efficacy profiles.
Cannabis is being explored as a treatment for a number of conditions including epilepsy, pain, and anxiety.7 The major cannabinoid constituents of cannabis are cannabidiol (CBD) and tetrahydrocannabinol (THC), which interact differently with the receptors of the endocannabinoid system, as well as other receptors in the body, and therefore have different therapeutic applications.8 It has been proposed that cannabinoids may be useful in the treatment of a number of anxiety disorders.7,9-11
The endocannabinoid system is distributed widely throughout the body and consists of cannabinoid type 1 receptors (CB1Rs) and cannabinoid type 2 receptors (CB2Rs).12 Cannabinoid type 1 receptors are more abundant in the central nervous system and brain, and CB2Rs are more widely distributed in the peripheral nervous system.13 Tetrahydrocannabinol interacts with CB1Rs in the brain, producing the associated anxiogenic effects of cannabis.7 High doses of THC are thought to increase the risk of anxiety exacerbations, whereas low doses, less than 30 mg of THC per day, could be an effective treatment for anxiety disorders.14 Cannabidiol has anxiolytic properties, and doses between 25 and 600 mg have been shown to decrease anxiety in participants.15 The exact mechanisms behind the anxiolytic properties of CBD are largely unknown; however, it does not interact with CB1Rs in the brain and is therefore not associated with anxiogenic effects at higher doses.7
Medicinal cannabis could be an effective treatment for a number of anxiety disorders, particularly PTSD; however, more research into the efficacy and AEs of CBD and THC is needed. In this article, we aimed to evaluate quality-of-life outcomes after treatment with various cannabis formulations to determine effectiveness and associated AEs in those taking medicinal cannabis for anxiety disorders.
Methods
Setting
We performed an interim analysis of data that had been collected from the CA Clinics Observational Study (CACOS), an ongoing, observational study conducted through the network of medicinal cannabis prescribers located in Australia. The purpose of CACOS is to collect data about the safety and efficacy of medicinal cannabis treatments in Australia using patient-reported outcome measures. The study includes a number of combined and parallel arms including but not limited to chronic pain (including endometriosis, fibromyalgia, and neuropathic pain), psychiatric conditions (including anxiety and PTSD), and neurological conditions (including epilepsy). Participants are enrolled before their first appointment and returned surveys that measured various health-related quality-of-life outcomes in participants.
Participants
All participants that were enrolled in CACOS and using medicinal cannabis for an anxiety disorder were included in this analysis. Participants who took a baseline survey before treatment, and at least 1 survey after they had started treatment, were included in the Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) analysis. The PROMIS-29 questionnaire assesses pain intensity using a single 0-10 numeric rating item and 7 health domains (physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance) using 4 items for each domain, to assess patient functioning and wellbeing. Anyone who returned at least 1 survey while taking medicinal cannabis were included in the AE analysis. The time between a participant s first and last surveys defined their observational period, and where there was only 1 survey, the observational period was 1 day. These data were collected between the dates of the September 25, 2018, and June 29, 2021.
Cannabis Formulations
The medicinal cannabis formulations that were prescribed to each participant contained either CBD or THC. Participants self-reported the medicinal cannabis product(s) they were taking, and based on the concentration of each constituent, they were classed into 1 of 5 groups: CBD- or THC-only, CBD- or THC-dominant, or balanced formulations. Dominant refers to a concentration of 1 constituent that is 1.5-times greater than the other. If the participants were switched to another formulation class during the observational period, they were included in both groups as the AE or PROMIS-29 outcomes could not be aligned with either product. This study only included patients taking oral liquid or capsule formulations to ensure consistency when analyzing dose and effectiveness, as inhaled formulations have variable absorption properties.16 Participants also reported the quantity (mL) they were prescribed, so the total dose of THC and/or CBD the participant consumed each day could be calculated (mg/day).
Patient Outcomes
The effectiveness of medicinal cannabis for anxiety disorders was measured using the PROMIS-29 (v2.0) survey; a health-related quality of life (HRQoL) tool that evaluates health outcomes. Of the 7 domains in the survey, excessive anxiety, fatigue, sleep disturbance, and a decreased ability to take part in social roles and activities and depression were included in our analysis.17,18
Participants raw scores across these 5 health domains from each of their questionnaires were converted into t-scores using the PROMIS-29 v2.0 conversion tables. The difference between the scores of their baseline survey and final survey was calculated to analyze the outcomes after treatment with medicinal cannabis. Outcomes across each domain were assessed for clinical significance based on published minimal clinically important difference (MCID) scores. The MCID for the anxiety domain was set to 4,19 while the rest of the domains were set to 5 (depression, fatigue, pain impact, and sleep disturbance).20 Participants were classified as clinically improved, unchanged, or worsened based on a respective t-score change in relation to MCID.
Adverse Events
Participants were able to self-report any AEs they experienced during their treatment with medicinal cannabis in the questionnaires. Common AEs were listed, and participants could tick to indicate what they had experienced. There was also a section where they could write freely anything they experienced. Each AE was then categorized into an organ class based on the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Classes and reported by formulation type.21
Statistical Analysis
A statistical analysis of the data was performed using Statistical Package for the Social Sciences (SPSS; IBM, Armonk, NY). Data for continuous variables, such as dose, duration of treatment, and participant age, were assessed for normality. Where a normal distribution for continuous variable data was observed, the mean and standard deviation were reported, but for data that were not normally distributed, the median and interquartile range (IQR) were reported.22 Paired 2-tailed t tests were performed to compare participant t-scores before and after taking medicinal cannabis across each PROMIS-29 domain to determine the significance of these results. A 1-way analysis of variance (ANOVA) was conducted to determine whether there were significant differences in t-score changes between formulation types, and a 2-way ANOVA23 was also used to compare the differences in t-score changes between both formulation categories and different types of anxiety diagnoses.
Fisher s exact tests were used to compare the clinical improvement categorical results of improved, unchanged, and worsened across the PROMIS-29 domains for each participant subset, only including patients that had taken a single formulation type.24 If the clinical categorization for a PROMIS-29 domain was significant for a total participant subset, a further analysis was undertaken on the different formulation types.
Logistic regressions were performed to determine whether there was a relationship between the CBD/THC doses and clinical improvement in the PROMIS-29 domains or AE MedDRA classes. Where there was a significant association between the CBD/THC doses and AE class, a logistic regression was performed on the individual AEs in this class to determine where the significance was.
Results
Participant Demographics
From the CACOS study, 568 people were eligible for the AE analysis in this study, and 198 participants for the effectiveness (PROMIS-29) analysis. Demographic information of the participant sample is provided in Table 1.
Table 1. Demographics of Participants Included in This Study.
Demographic feature Effectiveness analysis (n = 198) Adverse events analysis (n = 568)
Sex
Female, n (%) 105 (53.0) 304 (53.5)
Male, n (%) 93 (47.0) 264 (46.5)
Age, years, median (IQR) 48 (24) 48 (24)
Observational period, days, median (IQR) 154.4 (246.6) 55.8 (191.2)
Anxiety type
PTSD, n (%) 57 (28.8) 158 (27.8)
Unspecified, n (%) 141 (71.2) 410 (72.2)
Abbreviations: IQR, interquartile range; PTSD, posttraumatic stress disorder.
Patient Outcomes
There were statistically significant changes to participant outcomes observed in the total participant group (n = 198), PTSD subset (n = 57), and unspecified anxiety subset (n = 141) (Table 2). In the total participant sample (n = 198), 53% (n = 104) of participants were classified as having had a clinically meaningful improvement in their anxiety levels (a change in score greater than the MCID) (Table 2). Participants overall reported significantly improved anxiety (P < 0.001), depression (P < 0.001), fatigue (P < 0.001), and ability to take part in social roles and activities (P < 0.001). The CBD-only (P < 0.001), balanced (P < 0.001), and THC-dominant (P = 0.011) formulations were all associated with significant improvements in anxiety symptoms.
Table 2. Effectiveness (PROMIS-29) Analysis of all Participants With an Anxiety Diagnosis.
All anxiety participants
All formulations (n = 198) CBD-only (n = 112) CBD-dominant (n = 20) Balanced (n = 96) THC-dominant (n = 18) THC-only (n = 10)
CBD dose mg/day, median (IQR) 50.0 (85.0) 100.0 (100.0) 25.0 (43.5) 20.0 (40.0) 6.0 (13.6) 0.0 (0.0)
THC dose mg/day, median (IQR) 4.4 (20.0) 0.0 (0.0) 6.3 (25.7) 20.0 (34.3) 33.8 (61.5) 38.0 (35.7)
Anxiety (MCID = 4)
Score baseline, mean (SD) 64.6 (9.0) 64.6 (8.8) 61.9 (11.3) 64.2 (8.9) 63.1 (8.5) 64.4 (8.0)
Score final, mean (SD) 59.6 (9.0) 60.2 (8.3) 58.9 (6.8) 59.9 (9.7) 58.2 (7.7) 62.4 (8.0)
P value <0.001* <0.001* 0.300 <0.001* 0.011* 0.587
Improved, n (%) 104 (52.5) 56 (50.0) 10 (50.0) 46 (47.9) 11 (61.1) 4 (40.0)
Unchanged, n (%) 66 (33.6) 38 (33.9) 5 (25.0) 36 (37.5) 5 (27.7) 3 (30.0)
Worsened, n (%) 28 (14.1) 18 (16.1) 4 (20.0) 14 (14.6) 2 (11.1) 3 (30.0)
P value** 0.945
Depression (MCID = 5)
Score baseline, mean (SD) 61.6 (9.8) 61.3 (9.8) 61.6 (9.5) 61.9 (10.4) 58.5 (10.6) 61.1 (10.2)
Score final, mean (SD) 57.5 (10.0) 58.3 (9.1) 58.3 (6.4) 57.9 (11.0) 53.9 (10.3) 59.3 (13.6)
P value <0.001* <0.001* 0.111 <0.001* 0.018* 0.713
Improved, n (%) 84 (42.4) 39 (34.8) 8 (40.0) 43 (44.8) 9 (50.0) 4 (40.0)
Unchanged, n (%) 86 (43.4) 59 (52.7) 8 (40.0) 33 (34.4) 7 (38.9) 2 (20.0)
Worsened, n (%) 28 (14.1) 14 (12.5) 4 (20.0) 20 (20.8) 2 (11.1) 4 (40.0)
P value** 0.032
Fatigue (MCID = 5)
Score baseline, mean (SD) 62.9 (10.0) 63.0 (9.2) 65.5 (8.5) 63.8 (10.4) 62.3 (12.5) 66.4 (9.4)
Score final, mean (SD) 56.9 (11.0) 56.1 (10.2) 58.6 (8.5) 58.2 (11.2) 55.5 (11.8) 57.4 (13.6)
P value <0.001* <0.001* <0.001* <0.001* 0.033* 0.014*
Improved, n (%) 95 (48.0) 52 (46.4) 10 (50.0) 46 (47.9) 10 (55.6) 8 (80.0)
Unchanged, n (%) 85 (42.9) 52 (46.4) 9 (45.0) 41 (42.7) 5 (27.8) 2 (20.0)
Worsened, n (%) 18 (9.1) 8 (7.1) 1 (5.0) 9 (9.4) 3 (16.7) 1 (10.0)
P value** 0.588
Sleep disturbance (MCID = 5)
Score baseline, mean (SD) 51.6 (5.4) 51.8 (4.1) 52.7 (3.4) 51.5 (6.7) 51.4 (5.8) 50.1 (6.9)
Score final, mean (SD) 51.6 (4.4) 51.7 (3.5) 52.0 (2.4) 51.60 (5.5) 51.4 (2.8) 52.6 (2.1)
P value 0.964 0.830 0.392 0.788 0.991 0.324
Improved, n (%) 26 (13.1) 11 (9.8) 4 (20.0) 16 (16.7) 4 (22.2) 2 (20.0)
Unchanged, n (%) 150 (75.8) 89 (79.5) 16 (80.0) 67 (69.8) 12 (66.7) 8 (80.0)
Worsened, n (%) 22 (11.1) 12 (10.7) 1 (5.0) 13 (13.5) 2 (11.1) 1 (10.0)
P value** 0.458
Ability to take part in social roles and activities (MCID = 5)
Score baseline, mean (SD) 36.5 (9.3) 37.3 (7.0) 36.1 (7.7) 34.9 (6.9) 37.7 (10.0) 34.7 (7.4)
Score final, mean (SD) 41.5 (9.7) 42.8 (9.2) 40.5 (11.3) 38.7 (9.3) 40.8 (10.4) 42.7 (14.6)
P value <0.001* <0.001* 0.024* <0.001* 0.082 0.022*
Improved, n (%) 91 (46.0) 56 (50.0) 6 (30.0) 37 (38.5) 7 (38.9) 5 (50.0)
Unchanged, n (%) 91 (46.0) 49 (43.8) 13 (65.0) 49 (51.0) 9 (50.0) 5 (50.0)
Worsened, n (%) 16 (8.1) 7 (6.3) 1 (5.0) 10 (10.4) 2 (11.1) 0 (0.0)
P value** 0.642
Abbreviations: CBD, cannabidiol; IQR, interquartile range; MCID, minimal clinically important difference; PROMIS-29, Patient-Reported Outcomes Measurement Information System-29; SD, standard deviation; THC, tetrahydrocannabinol.
*
P value is statistically significant improvement in the symptom or condition (P < 0.05).
**
P value calculated using Fisher s exact tests including participants from the sample that had been on only 1 formulation.
Similar to the total participant sample, 52.6% (n = 30) of those diagnosed with PTSD reported a clinical improvement in anxiety symptoms, with statistical significance observed for anxiety (P < 0.001), depression (P < 0.001), fatigue (P < 0.001), and social abilities (P < 0.001). The CBD-only group (n = 35) was the only formulation associated with significant decreases in anxiety (P < 0.001) and depression (P = 0.019). Symptoms of depression were also significantly more likely to be categorized as clinically improved in participants taking CBD-only (P < 0.001) and balanced (P < 0.001) formulations. Participants with PTSD also reported significant improvements to their fatigue in the CBD-only (P < 0.001), balanced (P < 0.001), and THC-only groups (P = 0.009) and in their social ability while taking a CBD-only (P < 0.001) and balanced (P = 0.003) formulations.
The unspecified anxiety subset (n = 141) reported that anxiety symptoms significantly improved while taking the same medicinal cannabis formulations as the total patient sample. Participants in this cohort also reported significantly improved depression while taking CBD-only (P = 0.002) and balanced formulations (P = 0.006). Fatigue was significantly improved for those taking CBD-only (P < 0.001), CBD-dominant (P = 0.001), balanced (P < 0.001), and THC-dominant (P = 0.034) formulations. This was similar for social abilities, except for the THC-dominant formulation.
A 1-way ANOVA determined that there were no significant differences in health outcomes between formulation types, and a 2-way ANOVA confirmed that there were also no significant differences when factoring in the different anxiety disorder classifications. A logistic regression established there was no relationship between clinical improvement and CBD/THC dose in this participant sample.
Adverse Events
The AEs experienced by participants were analyzed according to the formulation type(s) they had been prescribed throughout their observational period (Table 3). A total of 1314 AEs were reported across 568 participants. The maximum number of different AEs reported by a single participant across their total observational period was 13.
Table 3. Adverse Events Across Formulation Types by MedDRA System Organ Class.
MedDRA system organ class All formulations (n = 568) CBD-only (n = 297) CBD-dominant (n = 75) Balanced (n = 257) THC-dominant (n = 51) THC-only (n = 19)
AEa nb AE n AE n AE n AE n AE n
CBD dose, median (IQR) 40.0 (87.6) 90 (109.1) 27 (46.3) 18.75 (21.3) 4.0 (7.1) 0.0 (0.4)
THC dose, median (IQR) 5.0 (20.0) 0.0 (0.0) 8.0 (17.8) 19 (20.0) 30.0 (48.0) 33.0 (19.25)
Gastro-intestinal disorders, n (%)
Total 386 (29.4) 220 (38.7) 198 (29.4) 105 (35.4) 46 (21.0) 30 (40.0) 216 (29.7) 124 (48.2) 55 (26.6) 29 (56.9) 17 (23.9) 12 (63.2)
Dry mouth 274 (20.9) 185 (32.6) 140 (20.8) 87 (29.3) 30 (13.7) 23 (30.7) 152 (20.9) 104 (40.5) 41 (19.8) 25 (49.0) 15 (21.1) 10 (52.6)
Nausea 61 (4.6) 52 (9.2) 28 (4.2) 24 (8.1) 6 (2.7) 6 (8.0) 38 (5.2) 32 (12.5) 10 (4.8) 9 (17.6) 2 (2.8) 2 (10.5)
Diarrhea 20 (1.5) 19 (3.4) 9 (1.3) 9 (3.0) 3 (1.4) 2 (2.7) 13 (1.8) 12 (4.7) 2 (1.0) 2 (3.9) 0 0
Gastrointestinal upset 21 (1.6) 18 (3.2) 15 (2.2) 13 (4.4) 7 (3.2) 5 (6.7) 9 (1.2) 8 (3.1) 2 (1.0) 2 (3.9) 0 0
Vomiting 2 (0.2) 2 (0.4) 1 (0.1) 1 (0.3) 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Constipation 4 (0.3) 3 (0.5) 4 (0.6) 3 (1.0) 0 0 0 0 0 0 0 0
Flatulence, bloating, and distension 4 (0.3) 2 (0.4) 1 (0.1) 1 (0.3) 0 0 3 (0.4) 1 (0.4) 0 0 0 0
Psychiatric, n (%)
Total 498 (37.9) 233 (41.0) 261 (38.8) 119 (40.1) 82 (37.4) 32 (42.7) 271 (37.2) 121 (47.1) 60 (29.0) 29 (56.9) 28 (39.4) 12 (63.2)
Somnolence 239 (18.2) 178 (31.3) 120 (17.8) 88 (29.9) 40 (18.3) 26 (34.7) 136 (18.7) 96 (37.2) 31 (15.0) 24 (47.1) 13 (18.3) 9 (47.4)
Inappropriate laughter 2 (0.2) 2 (0.4) 1 (0.1) 1 (0.3) 0 0 2 (0.3) 2 (0.8) 0 0 0 0
Anxiety 71 (5.4) 54 (9.5) 44 (6.5) 34 (11.4) 10 (4.6) 9 (12.0) 30 (4.1) 23 (8.9) 6 (2.9) 4 (7.8) 3 (4.2) 1 (5.3)
Lack of motivation 1 (0.1) 1 (0.2) 0 0 1 (0.5) 1 (1.3) 0 0 0 0 0 0
Confusion 34 (2.6) 31 (5.5) 16 (2.4) 15 (5.1) 4 (1.8) 3 (4.0) 21 (2.9) 19 (7.4) 3 (1.4) 3 (5.9) 1 (1.4) 1 (5.3)
Disorientation 28 (2.1) 27 (4.8) 18 (2.7) 17 (5.7) 4 (1.8) 4 (5.3) 16 (2.2) 16 (6.2) 4 (1.9) 4 (7.8) 1 (1.4) 1 (5.3)
Depression 31 (2.4) 30 (5.5) 14 (2.1) 14 (4.7) 2 (0.9) 2 (2.7) 14 (1.9) 14 (5.4) 7 (3.4) 6 (11.8) 3 (4.2) 2 (10.5)
Paranoia 8 (0.6) 7 (1.2) 6 (0.9) 5 (1.7) 3 (1.4) 2 (2.7) 4 (0.6) 4 (1.6) 1 (0.5) 1 (2.0) 1 (1.4) 1 (5.3)
Euphoria 37 (2.8) 29 (5.1) 22 (3.3) 19 (6.4) 7 (3.2) 2 (2.7) 21 (2.9) 15 (3.8) 6 (2.9) 5 (9.8) 3 (4.2) 3 (15.8)
Hallucination 5 (0.4) 5 (0.9) 2 (0.3) 2 (0.7) 1 (0.5) 1 (1.3) 3 (0.4) 3 (1.2) 0 0 1 (1.4) 1 (5.3)
Insomnia 22 (1.7) 21 (3.7) 10 (1.5) 10 (3.4) 5 (2.3) 5 (6.7) 10 (1.4) 9 (3.5) 0 0 0 0
Psychosis 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.3) 0 0 0 0 0 0 1 (1.4) 1 (5.3)
Cognitive impairment 1 (0.1) 1 (0.2) 0 0 1 (0.5) 1 (1.3) 1 (0.1) 1 (0.4) 0 0 0 0
Slowed thinking 2 (0.2) 1 (0.2) 2 (0.3) 1 (0.3) 0 0 2 (0.3) 1 (0.4) 0 0 0 0
Increased sex drive 1 (0.1) 1 (0.2) 0 0 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Racing thoughts 1 (0.1) 1 (0.2) 0 0 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Grinding teeth 1 (0.1) 1 (0.2) 0 0 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Memory loss 9 (0.7) 8 (1.4) 2 (0.3) 2 (0.7) 4 (1.8) 3 (4.0) 6 (0.8) 5 (1.9) 2 (1.0) 2 (3.9) 0 0
Mood disorders and disturbances 4 (0.3) 4 (0.7) 3 (0.4) 3 (1.0) 0 0 2 (0.3) 2 (0.8) 0 0 1 (1.4) 1 (5.3)
Nervous system disorders, n (%)
Total 95 (7.2) 73 (12.9) 53 (7.9) 36 (12.1) 19 (8.7) 15 (20.0) 49 (6.7) 38 (14.8) 16 (7.7) 9 (17.6) 3 (4.2) 3 (15.8)
Vivid dreams 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.3) 0 0 0 0 0 0 0 0
Dizziness 69 (5.3) 62 (10.9) 35 (5.2) 29 (9.8) 13 (5.9) 13 (17.3) 35 (4.8) 33 (12.8) 10 (4.8) 9 (17.6) 3 (4.2) 3 (15.8)
Agitation 5 (0.4) 1 (0.2) 5 (0.7) 1 (0.3) 0 0 5 (0.7) 1 (0.4) 5 (2.4) 1 (2.0) 0 0
Tingling feeling 3 (0.2) 2 (0.4) 1 (0.1) 1 (0.3) 0 0 3 (0.4) 2 (0.8) 0 0 0 0
Tremor 1 (0.1) 1 (0.2) 0 0 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Headache 16 (1.2) 13 (2.3) 11 (1.6) 8 (2.7) 6 (2.7) 3 (4.0) 5 (0.7) 5 (1.9) 1 (0.5) 1 (2.0) 0 0
Metabolism disorders, n (%)
Total 79 (6.0) 62 (10.9) 37 (5.5) 30 (10.1) 18 (8.2) 14 (18.7) 47 (6.4) 35 (13.6) 14 (6.8) 8 (15.7) 6 (8.5) 3 (15.8)
Increase appetite 60 (4.6) 45 (7.9) 28 (4.2) 22 (7.4) 9 (4.1) 7 (9.3) 37 (5.1) 27 (10.5) 12 (5.8) 7 (13.7) 6 (8.5) 3 (15.8)
Decreased appetite 19 (1.5) 18 (3.2) 9 (1.3) 8 (2.7) 9 (4.1) 8 (10.7) 9 (1.2) 9 (3.5) 2 (1.0) 2 (3.9) 0 0
Skin disorders, n (%)
Total 2 (0.2) 2 (0.4) 1 (0.1) 1 (0.3) 0 0 0 0 1 (0.5) 1 (2.0) 0 0
Acne 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.3) 0 0 0 0 0 0 0 0
Skin irritation 1 (0.1) 1 (0.2) 0 0 0 0 0 0 1 (0.5) 1 (2.0) 0 0
General disorders and administration site conditions, n (%)
Total 197 (15.0) 131 (23.1) 90 (13.4) 62 (20.9) 43 (19.6) 25 (32.3) 108 (15.0) 69 (26.8) 38 (18.4) 19 (37.3) 10 (14.1) 4 (21.1)
Fatigue 125 (9.5) 105 (18.5) 56 (8.3) 48 (16.2) 23 (10.5) 20 (26.7) 70 (9.6) 58 (22.6) 22 (10.6) 17 (33.3) 4 (5.6) 4 (21.1)
Balance problems 48 (3.7) 40 (7.0) 21 (3.1) 17 (5.7) 7 (3.2) 7 (9.3) 24 (3.3) 21 (8.2) 8 (3.9) 6 (11.8) 2 (2.8) 2 (10.5)
Foggy feeling in head 2 (0.2) 2 (0.4) 1 (0.1) 1 (0.3) 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Feeling of relaxation 4 (0.3) 1 (0.2) 0 0 4 (1.8) 1 (1.3) 4 (0.6) 1 (0.4) 0 0 0 0
Weight on chest 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.3) 0 0 0 0 0 0 0 0
Energy increased 2 (0.2) 2 (0.4) 2 (0.3) 2 (0.7) 1 (0.5) 1 (1.3) 0 0 0 0 0 0
Increased thirst 1 (0.1) 1 (0.2) 0 0 1 (0.5) 1 (1.3) 1 (0.1) 1 (0.4) 0 0 0 0
Spaced out feeling 4 (0.3) 1 (0.2) 0 0 4 (1.8) 1 (1.3) 4 (0.6) 1 (0.4) 4 (1.9) 1 (2.0) 4 (5.6) 1 (5.3)
Pain 10 (0.8) 6 (1.1) 9 (1.3) 5 (1.7) 3 (1.4) 1 (1.3) 4 (0.6) 2 (0.8) 4 (1.9) 2 (3.9) 0 0
Eye disorders, n (%)
Total 19 (1.5) 5 (0.9) 13 (1.9) 2 (0.7) 6 (2.7) 3 (4.0) 14 (1.9) 3 (1.2) 13 (6.3) 2 (3.9) 4 (5.6) 1 (5.3)
Vision issues 4 (0.3) 2 (0.4) 3 (0.5) 1 (0.3) 4 (1.8) 2 (2.7) 0 0 0 0 0 0
Dry eyes 15 (1.1) 4 (0.7) 10 (1.5) 2 (0.7) 2 (0.9) 2 (2.7) 14 (1.9) 3 (1.2) 13 (6.3) 2 (3.9) 4 (5.6) 1 (5.3)
Respiratory thoracic and mediastinal disorders, n (%)
Total 6 (0.5) 6 (1.1) 5 (0.7) 5 (1.7) 2 (0.9) 2 (2.7) 3 (0.4) 3 (1.2) 1 (0.5) 1 (2.0) 0 0
Sore throat 6 (0.5) 6 (1.1) 5 (0.7) 5 (1.7) 2 (0.9) 2 (2.7) 3 (0.4) 3 (1.2) 1 (0.5) 1 (2.0) 0 0
Cardiac disorders, n (%)
Total 5 (0.4) 3 (0.5) 2 (0.3) 2 (0.7) 0 0 2 (0.3) 1 (0.4) 0 0 0 0
Arrhythmia 2 (0.2) 2 (0.4) 2 (0.3) 2 (0.7) 0 0 0 0 0 0 0 0
Palpitations 3 (0.2) 1 (0.2) 0 0 0 0 3 (0.4) 1 (0.4) 0) 0 0 0
Musculoskeletal and connective tissue disorders, n (%)
Total 5 (0.4) 4 (0.7) 0 0 0 0 4 (0.6) 3 (1.2) 1 (0.5) 1 (2.0) 0 0
Muscle twitching 1 (0.1) 1 (0.2) 0 0 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Mobility decreased 1 (0.1) 1 (0.2) 0 0 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Muscle tension 2 (0.2) 1 (0.2) 0 0 0 0 2 (0.3) 1 (0.4) 0 0 0 0
Swollen ankles 1 (0.1) 1 (0.2) 0 0 0 0 0 0 1 (0.5) 1 (2.0) 0 0
Ear and labyrinth disorders, n (%)
Total 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.3) 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Tinnitus 1 (0.1) 1 (0.2) 1 (0.1) 1 (0.3) 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Renal and urinary disorders, n (%)
Total 1 (0.1) 1 (0.2) 0 0 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Increased urination 1 (0.1) 1 (0.2) 0 0 0 0 1 (0.1) 1 (0.4) 0 0 0 0
Immune system disorders, n (%)
Total 2 (0.2) 1 (0.2) 2 (0.3) 1 (0.3) 0 0 0 0 0 0 0 0
Allergy 2 (0.2) 1 (0.2) 2 (0.3) 1 (0.3) 0 0 0 0 0 0 0 0
Other (undefined), n (%) 18 (1.4) 15 (2.6) 10 (1.5) 7 (2.4) 3 (1.4) 3 (4.0) 11 (1.5) 9 (3.5) 8 (3.7) 6 (11.8) 3 (4.2) 3 (15.8)
Total n 1314 568 673 297 219 75 727 257 207 51 71 19
Number of patients that never reported AEs, n (%) 227 (40.0) 120 (40.4) 29 (38.7) 89 (34.6) 13 (25.5) 3 (15.8)
Abbreviations: AE, adverse events; CBD, cannabidiol; IQR, interquartile range; MedDRA, Medical Dictionary for Regulatory Activities; THC, tetrahydrocannabinol.
a
AE refers to total number of AEs reported.
b
n Refers to total number of participants that reported the AE.
There were 227 (40.0%) participants that never reported an AE, and the CBD-only group had the greatest proportion of participants who were in this category (n = 120, 40.4%). The most common type of AE recorded across all formulation types was the psychiatric system organ class (n = 233, 41.0%). The most common psychiatric AEs experienced by participants were somnolence (31.3%), anxiety (9.5%), and euphoria (5.1%). Where participants reported anxiety as an AE, it indicated they experienced increased anxiety symptoms since commencing treatment with medicinal cannabis.
Other common AEs included dry mouth (n = 185, 32.6%), fatigue (n = 105, 18.5%), and dizziness (n = 62, 10.9%). A logistic regression established a relationship between THC concentration and gastrointestinal AEs (odds ratio [OR] = 1.011, P = 0.003), specifically dry mouth (OR = 1.010, P = 0.005) and nausea (OR = 1.008, P = 0.008); however, these are unlikely to be clinically significant with an OR close to 1. There was no significant association between reporting anxiety and CBD and/or THC doses.
In participants taking CBD-only formulations, somnolence and dry mouth were the most common AEs, reported by 88 (29.9%) and 87 (29.3%) participants, respectively. The THC-only subset had the highest proportion of participants who reported euphoria (n = 3, 15.8%), followed by the THC-dominant formulation group (n = 5, 9.8%).
Discussion
This observational, retrospective study of participants using medicinal cannabis for anxiety disorders analyzed the effectiveness of medicinal cannabis on different HRQoL outcomes. Participants taking the CBD-only and balanced formulations reported improved levels of anxiety, depression, fatigue, and ability to participate in social activity in both the full participant sample and the unspecified anxiety subset. In the PTSD participant subset, the CBD-only formulation group at a median (IQR) dose of 95 (117.6) mg/day was the only group that reported significant improvements in the same 4 participant outcomes.
This study provides important insights into the current practice of prescribing medicinal cannabis for anxiety conditions and the type and incidence of AEs that the participants experienced. It is important to note, the research was limited as it relied on data gathered from surveys that participants completed themselves, and therefore, recall bias and misclassification bias were not accounted for. This study cohort may also be subject to potential sample bias as the characteristics of patients who chose not to enroll in CACOS are not known. Future studies should attempt to study participants across multiple sites and with diverse characteristics to increase external validity. As this study was observational, it can only establish that medicinal cannabis is associated with the identified outcomes, and therefore, it cannot be concluded that medicinal cannabis is the cause of these outcomes. Some participants were switched between medicinal cannabis formulations during the observational period and were included in both groups for analysis. This was done as the AE or PROMIS-29 outcomes could not be aligned with either product, potentially limiting our results. Future, randomized, placebo-controlled studies are imperative to determine a causal relationship between the individual medicinal cannabis formulations and effectiveness and AE outcomes. The AE analysis did not account for the number of surveys a single participant completed, the severity of effect, or if they were collected less than 7 days apart unlike the PROMIS analysis. This study did not analyze the dose and AEs, meaning it could not determine whether there was an association between higher doses and a greater incidence of AEs. Future research should address characteristics that may affect whether participants find CBD and/or THC effective and at what doses. With the use of medicinal cannabis increasing before there is robust evidence from randomized controlled trials, real-world evidence such as this is of increasing value and will be important in informing the controlled studies.
From this analysis, CBD-only formulations are associated with the most-improved outcomes in participants with PTSD; however, this study only used a small group of PTSD participants, so future studies with more participants on other medicinal cannabis formulations are needed. The effectiveness of CBD-only formulations for PTSD was also observed in a case series of 11 participants that were treated with CBD (48.6 mg/day median start dose) as an adjunct to concurrent psychiatric medications.25 A decrease in PTSD symptoms, as measured by the PTSD Checklist for Diagnostic Statistical Manual of Mental Disorders, was reported for 91% (n = 10) of the participants in our study; this suggests that lower doses of CBD could be as effective as higher doses.26 It is important to note that concurrent psychiatric medications were reported but not accounted for or analyzed in the case”
https://journals.sagepub.com/doi/full/10.1177/87551225231180796,”First published online June 24, 2023
The Effectiveness and Adverse Events of Cannabidiol and Tetrahydrocannabinol Used in the Treatment of Anxiety Disorders in a PTSD Subpopulation: An Interim Analysis of an Observational Study
Sophie K. Stack, BPharm, Nial J. Wheate, PhD, DSc https://orcid.org/0000-0002-0505-1363, [ ], and Elise A. Schubert, BPharm [email protected]+3View all authors and affiliations
Volume 39, Issue 4
https://doi.org/10.1177/87551225231180796
Contents
Abstract
Introduction
Methods
Results
Discussion
Conclusions
Ethics Approval
Declaration of Conflicting Interests
Funding
ORCID iD
References
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Abstract
Background: Anxiety is a condition for which current treatments are often limited by adverse events (AEs). Components of medicinal cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC), have been proposed as potential treatments for anxiety disorders, specifically posttraumatic stress disorder (PTSD). Objective: To evaluate quality-of-life outcomes after treatment with various cannabis formulations to determine the effectiveness and associated AEs. Methods: An interim analysis of data collected between September 2018 and June 2021 from the CA Clinics Observational Study. Patient-Reported Outcomes Measurement Information System-29 survey scores of 198 participants with an anxiety disorder were compared at baseline and after treatment with medicinal cannabis. The data of 568 anxiety participants were also analyzed to examine the AEs they experienced by the Medical Dictionary for Regulatory Activities organ system class. Results: The median doses taken were 50.0 mg/day for CBD and 4.4 mg/day for THC. The total participant sample reported significantly improved anxiety, depression, fatigue, and ability to take part in social roles and activities. Those who were diagnosed with PTSD (n = 57) reported significantly improved anxiety, depression, fatigue, and social abilities. The most common AEs reported across the whole participant cohort were dry mouth (32.6%), somnolence (31.3%), and fatigue (18.5%), but incidence varied with different cannabis formulations. The inclusion of THC in a formulation was significantly associated with experiencing gastrointestinal AEs; specifically dry mouth and nausea. Conclusions: Formulations of cannabis significantly improved anxiety, depression, fatigue, and the ability to participate in social activities in participants with anxiety disorders. The AEs experienced by participants are consistent with those in other studies.
Introduction
As defined by Craske and Stein,1 anxiety is a response that individuals have to situations they perceive as threatening, and anxiety disorders occur when this response is overactive to the point that it impairs a person s functioning. The exact pathophysiology of anxiety is unknown; however, it is thought to arise from an imbalance of neurotransmitters such as serotonin and noradrenaline and abnormalities in brain structures including the amygdala and prefrontal cortex.2 The major types of anxiety disorders are generalized anxiety disorder, social anxiety, panic disorder, phobic disorder, posttraumatic stress disorder (PTSD), and obsessive compulsive disorder.1 The initial treatment for anxiety disorders is usually nonpharmaceutical, such as cognitive behavioral therapy, and when this is not suitable or successful, pharmacological treatment may be considered.3,4
Benzodiazepines are effective anxiolytics; however, they are limited to short-term or acute crisis use due to the risk of dependence, daytime sedation, and memory problems.3,4 The various antidepressants indicated for anxiety disorders, such as serotonin reuptake inhibitors, are only effective in 60% of people with PTSD and can be inconsistent in terms of efficacy.5,6 Due to the limited efficacy of some of these medications, clinicians take adverse event (AE) profiles and patient preference into consideration when prescribing these treatments.3 As such, there is a continuing need for new medications for anxiety disorders that have both favorable safety and efficacy profiles.
Cannabis is being explored as a treatment for a number of conditions including epilepsy, pain, and anxiety.7 The major cannabinoid constituents of cannabis are cannabidiol (CBD) and tetrahydrocannabinol (THC), which interact differently with the receptors of the endocannabinoid system, as well as other receptors in the body, and therefore have different therapeutic applications.8 It has been proposed that cannabinoids may be useful in the treatment of a number of anxiety disorders.7,9-11
The endocannabinoid system is distributed widely throughout the body and consists of cannabinoid type 1 receptors (CB1Rs) and cannabinoid type 2 receptors (CB2Rs).12 Cannabinoid type 1 receptors are more abundant in the central nervous system and brain, and CB2Rs are more widely distributed in the peripheral nervous system.13 Tetrahydrocannabinol interacts with CB1Rs in the brain, producing the associated anxiogenic effects of cannabis.7 High doses of THC are thought to increase the risk of anxiety exacerbations, whereas low doses, less than 30 mg of THC per day, could be an effective treatment for anxiety disorders.14 Cannabidiol has anxiolytic properties, and doses between 25 and 600 mg have been shown to decrease anxiety in participants.15 The exact mechanisms behind the anxiolytic properties of CBD are largely unknown; however, it does not interact with CB1Rs in the brain and is therefore not associated with anxiogenic effects at higher doses.7
Medicinal cannabis could be an effective treatment for a number of anxiety disorders, particularly PTSD; however, more research into the efficacy and AEs of CBD and THC is needed. In this article, we aimed to evaluate quality-of-life outcomes after treatment with various cannabis formulations to determine effectiveness and associated AEs in those taking medicinal cannabis for anxiety disorders.”
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