Cannabidiol-associated hepatotoxicity: A systematic review and meta-analysis.

BACKGROUND: Findings of liver enzyme elevations in recent cannabidiol studies have raised concerns over liver safety. This study aimed to determine the association between cannabidiol use, liver enzyme elevation, and drug-induced liver injury (DILI). METHODS: In this systematic review and meta-analysis, a search of EMBASE, CENTRAL, CINAHL, Clinicaltrials.gov, Medline, medRxiv, and Web of Science of records up to February 2022 was conducted. Clinical trials initiating daily cannabidiol treatment with serial liver enzyme measures were included. The proportion of liver enzyme elevations and DILI were independently extracted from published reports. Pooled proportions and probability meta-analyses were conducted. RESULTS: Cannabidiol use was associated with an increased probability of liver enzyme elevation (N = 12 trials, n = 1229; OR = 5.85 95% CI = 3.84-8.92, p < 0.001) and DILI (N = 12 trials, n = 1229; OR = 4.82 95% CI = 2.46-9.45, p < 0.001) compared to placebo controls. In participants taking cannabidiol (N = 28 trials, n = 1533), the pooled proportion of liver enzyme elevations was 0.074 (95% CI 0.0448-0.1212), and DILI was 0.0296 (95% CI 0.0136-0.0631). High-dose CBD (≥1000 mg/day or ≥20 mg/kg/day) and concomitant antiepileptic drug use were identified as risk factors. No cases were reported in adults using cannabidiol doses <300 mg/day. No cases of severe DILI were reported. CONCLUSIONS: Cannabidiol-associated liver enzyme elevations and DILI meet the criteria of common adverse drug events. Clinicians are encouraged to screen for cannabidiol use and monitor liver function in patients at increased risk.

Cannabidiol as a Harm Reduction Strategy for People Who Use Drugs: A Rapid Review.

OBJECTIVE: The drug poisoning crisis throughout North America necessitates novel harm reduction approaches. Emerging evidence suggests that cannabidiol (CBD) may have some utility as a harm reduction modality for those with problematic substance use. This rapid review aimed to synthesize available evidence on CBD as a potential harm reduction tool for people who use drugs while providing clinical and research insights. METHOD: A systematic search in EMBASE, MEDLINE, CENTRAL, and CINAHL was completed in July 2022. For inclusion, studies had to meet the following criteria: (1) drawn from an adult population of people who use drugs; (2) investigates CBD as an intervention for problematic substance use or harm reduction-related outcomes; (3) be published after the year 2000 and in English; and (4) be primary research or a review article. A narrative synthesis was used to group outcomes relevant to harm reduction and provide clinical and research insights. RESULTS: We screened 3,134 records, of which 27 studies (5 randomized trials) were included. The evidence remains limited, but available studies support the potential utility of CBD to reduce drug-induced craving and anxiety in opioid use disorder. There were low-quality studies suggesting that CBD may improve mood and general well-being of people who use drugs. Evidence suggests that CBD monotherapy may not be an adequate harm reduction strategy for problematic substance use but rather an adjunct to the standard of care. CONCLUSION: Low-quality evidence suggests that CBD may reduce drug cravings and other addiction-related symptoms and that CBD may have utility as an adjunct harm reduction strategy for people who use drugs. However, there is a significant need for more research that accurately reflects CBD dosing and administration regimens used in a real-world context.

Clinical Application of Cannabis Vaporization: Examining Safety and Best Practices.

Introduction: Cannabis vaporization is useful for individuals requiring fast-acting method of cannabis administration and for individuals using smoked cannabis as a harm reduction tool. There is a need for guidance on how to assess if a patient is a vaporization candidate and how to safely initiate and monitor cannabis vaporization. Methods: An overview of safe cannabis vaporization, including practical guidance and tactics to promote the lowest-risk use, is provided. This review was developed through a combination of expert clinical opinion and reviewing the available literature. Results: Dried cannabis vaporizers and metered-dose inhalers are recommended to be used over other vaporization devices. Assessing the benefit versus risks of vaporized cannabis and providing guidance for choosing a vaporization device, choosing a cannabis chemovar, and employing a mindful vaping technique are important steps in the safe utilization of vaporized cannabis. Dosing optimization and monitoring to limit adverse events and improve symptom control are essential. Discussion: The utilization of cannabis vaporization presents an important opportunity for clinicians and other health professionals to help facilitate safer cannabis administration and reduce the prevalence of smoked cannabis.

Cannabis vaporisation: Understanding products, devices and risks.

ISSUES: Vaporisation is a common method of cannabis administration. Inconsistent terminology and jargon regarding vaporisation has led to confusion. The increasing public interest and access to cannabis, combined with possible safety concerns associated with certain cannabis vaping products, warrants improved consumer and public and health care professional knowledge. APPROACH: To improve this knowledge, we conducted a review of the common terminology, regulatory status, products and device types related to cannabis vaporisation. KEY FINDINGS: Cannabis vaporisation devices can be separated into nine types. While vaporisation reduces respiratory risks associated with cannabis combustion, not all vaping products and device types carry the same level of safety. Metered dose inhalers and dried product vaporisers present the lowest safety risk due to a lower risk of toxin exposure and the use of lower tetrahydrocannabinol potency products. IMPLICATIONS: As both vaping and cannabis use increase in popularity, focusing on accurate health education will help facilitate health promotion to encourage lower risk use. The current lack of understanding on risk differences between types of cannabis vaporisation is a missed opportunity for harm reduction. Increased opportunities for public health and health care professional education on different cannabis vaporisation devices and associated risks are warranted. Improvements to health warning labelling may also be beneficial. CONCLUSION: Not all cannabis vaporisation devices and products carry the same level of risk. A better understanding of risk differentiation is needed among consumers and health professionals. Continued research, policy development and health education can lead to safer cannabis vaporisation.

Does acute cannabidiol (CBD) use impair performance? A meta-analysis and comparison with placebo and delta-9-tetrahydrocannabinol (THC).

Cannabidiol (CBD) is widely used and believed to be non-intoxicating, lacking acute performance effects (e.g., non-impairing). However, a synthesis of data has not evaluated this. This meta-analysis synthesized data from controlled human laboratory studies that evaluated if acute CBD use impairs performance. Performance on objective and subjective measures of cognitive and psychomotor function were used as markers for potential performance changes and impairment. Studies were identified through systematic database searches. Adult clinical trials measuring acute CBD effects (within 0-8 h of administration) were included. The primary outcome was the peak mean difference in performance measures between CBD and placebo. A secondary analysis utilizing delta-9-tetrahydrocannabinol (Δ9-THC) as a positive control for comparison to CBD was completed. Pooled Hedges' g estimates were calculated using robust variance estimation (RVE) meta-regression. The omnibus RVE meta-analysis indicated a statistically significant, but small effect size (Hedge's g < 0.2) for impaired performance following acute CBD consumption compared to placebo (N = 16 trials, Hedges' g = 0.122, 95% CI: 0.023-0.221, p = 0.019). Measure type was a significant moderator with larger mean differences between CBD and placebo when subjective measures, specifically self-reported sedation, were used versus objective performance tasks (Hedges' gSubjective = 0.288 versus Hedges' gObjective = 0.048). Δ9-THC had a significantly greater magnitude of impairment compared to CBD (N = 8, Hedges' g = 0.416, 95% CI: 0.017-0.816, p = 0.043). In summary, acute CBD consumption was associated with a small increase in subjective ratings of sedation, but no difference from placebo was observed across multiple domains of objectively assessed cognitive or psychomotor performance. These findings suggest that acute CBD alone is unlikely to significantly impair daily functioning or workplace performance.

A Clinical Framework for Evaluating Cannabis Product Quality and Safety.

Increase in medical cannabis use, along with available products, warrants the need for clinicians to be knowledgeable in evaluating the quality of any cannabis product presented in clinical practice. Determining whether a product is regulated within the region is key in assessing overall quality and safety. Regulated products are held to a higher standard including independent testing, contamination mitigation, and concentration limits. Here, we present a clinical framework in evaluating cannabis products to ascertain the quality and regulation level of the product. Evaluation includes assessing the source company, reviewing product details (e.g., type, cannabinoid content, and labeling), and assessing quality control variables such as manufacturing and decontamination processes. The quality of products patients use is an important part of mitigating cannabis-related harms, especially in medically vulnerable patients. Currently, there is a great need to implement widespread standardization and regulations to ensure product quality and safety.

Differences in those who prefer smoking cannabis to other consumption forms for mental health: what can be learned to promote safer methods of consumption?

Smoking cannabis in medical users is associated with exposure to harmful toxins. It is important to characterize cannabis-use profiles and risk-factors for medical cannabis users who smoke cannabis. 100 members of a medical cannabis dispensary with mental health concerns were interviewed in detail about their cannabis use. Forty seven percent of participants preferred smoking only, 18% preferred vaporizing, 25% preferred both smoking and vaping, and 10% preferred oral ingestion methods. Smokers differed from other users in multiple ways, including a greater preference for THC-dominant chemovars, and more frequent and greater amount of cannabis consumption. Smoking was also associated with greater rates of alcohol use disorder. These results may inform harm-reduction approaches to decrease the number of individuals smoking cannabis and use less harmful methods of medical cannabis ingestion.

Why a distinct medical stream is necessary to support patients using cannabis for medical purposes.

BACKGROUND: Since 2001, Canadians have been able to obtain cannabis for medical purposes, initially through the Access to Cannabis for Medical Purposes Regulations (ACMPR). The Cannabis Act (Bill C-45) came into force on October 17, 2018, replacing the ACMPR. The Cannabis Act enables Canadians to possess cannabis purchased from a licensed retailer without authorization for either medical or nonmedical purposes. The Cannabis Act is currently the guiding legislation which governs both medical and nonmedical access. The Cannabis Act contains some improvements for patients but is essentially the same as its previous legislation. Beginning in October 2022, the federal government is conducting a review of the Cannabis Act and is questioning whether a distinct medical cannabis stream is still required, given the ease of access to cannabis and cannabis products. Although there is overlap in the reasons for medical and recreational cannabis use, the distinct legislation of medical versus recreational use of cannabis in Canada may be under threat. MAIN BODY: A large segment of the medical, academic, research, and lay communities agree that there is a need for distinct medical and recreational cannabis streams. Perhaps most importantly, separation of these streams is necessary to ensure that both medical cannabis patients and healthcare providers receive the required support needed to optimize benefits while minimizing risks associated with medical cannabis use. Preservation of distinct medical and recreational streams can help to ensure that needs of different stakeholders are met. For example, patients require guidance in the form of assessing the appropriateness of cannabis use, selection of appropriate products and dosage forms, dosing titration, screening for drug interactions, and safety monitoring. Healthcare providers require access to undergraduate and continuing health education as well as support from their professional organizations to ensure medical cannabis is appropriately prescribed. Although there are challenges in conducing research, as motives for cannabis use frequently straddle boundaries between medical versus recreational cannabis use, maintenance of a distinct medical stream is also necessary to ensure adequate supply of cannabis products appropriate for medical use, to reduce stigma associated with cannabis in both patients and providers, to help enable reimbursement for patients, to facilitate removal of taxation on cannabis used for medical purposes, and to promote research on all aspects of medical cannabis. CONCLUSION: Cannabis products for medical and recreational purposes have different objectives and needs, requiring different methods of distribution, access, and monitoring. HCPs, patients, and the commercial cannabis industry would serve Canadians well to continue to advocate to policy makers to ensure the continued existence of two distinct streams and must strive to make ongoing improvements to the current programs.

Therapeutic use of psilocybin: Practical considerations for dosing and administration.

The interest in psilocybin as a therapeutic approach has grown exponentially in recent years. Despite increasing access, there remains a lack of practical guidance on the topic for health care professionals. This is particularly concerning given the medical complexity and vulnerable nature of patients for whom psilocybin-assisted psychotherapy may be considered. This article aims to provide health care professionals with an overview of practical considerations for psilocybin therapy, rooted in a patient safety focus. Within this piece we will review basic psilocybin pharmacology and pharmacokinetics, indications, practical therapeutic strategies (e.g., dosing, administration, monitoring) and safety considerations (e.g., contraindications, adverse events, and drug interactions). With this information, our goal is to increase the knowledge and comfort of health care professionals to discuss and counsel their patients on psilocybin therapy, ultimately improving patient care and safety.

A Clinical Framework for Assessing Cannabis-Related Impairment Risk.

Clinicians play an important role in promoting safe and responsible medical cannabis use. One essential component to safe use is considering a patient's risk of neurocognitive impairment. However, there remains a lack of practical guidance on how clinicians can evaluate this risk for medical cannabis patients. Here, a practical framework is presented for clinicians to assess and stratify cannabis-associated impairment risk. The proposed framework is intended to practically guide healthcare providers in gaining a more comprehensive review of a patient's impairment-related factors. This framework can be used to assess impairment risk for patients currently using or considering medical cannabis and is recommended for all patients who perform safety-sensitive duties. Healthcare providers (HCP) managing patient's medical cannabis or those conducting assessments to determine risk of impairment for safety-sensitive workplaces can utilize this framework to stratify patients' risk of impairment. Such assessments can inform patient-specific needs for support, education, and guidance, to ensure cannabis is used safely and responsibly.

Factors Associated with Problematic Cannabis Use in a Sample of Medical Cannabis Dispensary Users.

Background: With the recent legalization of cannabis for medical purposes in many countries, there has been an increased number of individuals using such products. While there is considerable evidence indicating that cannabis may have therapeutic effects for a range of different conditions, concerns remain about the risk of developing cannabis use disorders for those at risk, or patients without appropriate clinical guidance. The aim of the present study was to determine the prevalence of problematic cannabis use in a cohort of cannabis users who consumed the drug for medical purposes and to identify potential risk factors. Methods: One hundred individuals who self-identified as using cannabis to improve their mental health were recruited from a community dispensary. Extensive details were collected about subjects' patterns of cannabis use and reasons for use. All subjects completed a structured clinical interview with the Mini-International Neuropsychiatric Interview, while information about perceived stress, depressive symptoms, and somatic symptoms were recorded with the Perceived Stress Scale-10, Beck Depression Inventory, and the Patient Health Questionnaire-15. Results: Rates of problematic cannabis use were high, with 30% meeting the criteria. Only 10% of subjects reported medical cannabis use was recommended by their doctor. Significant risk factors for problematic use included earlier age of cannabis initiation, as well as self-reported use of cannabis products for depression. Conclusions: The prevalence of problematic cannabis use in the community dispensary was higher than expected. Specific risk factors for problematic cannabis use may represent important areas for future intervention to ensure safer consumption for medical purposes.

"Is medical cannabis safe for my patients?" A practical review of cannabis safety considerations.

Medical cannabis use is increasing worldwide. Clinicians are commonly asked by patients to provide guidance on its safety and efficacy. Although there has been an increase in research on the role of medical cannabis for a number of different conditions, we found that there was a paucity of clear safety guidance on its use. We aim to address this issue by answering two pertinent clinician safety questions: 1 Can medical cannabis be safely used in this patient? 2. What strategies can be used to ensure that any harms from medical cannabis are mitigated? To address these questions, we reviewed available evidence and provided expert clinical opinion to summarize the fundamental components for evaluating medical cannabis safety and strategies to reduce risk from its use. Our review resulted in a safety-focused framework for medical cannabis initiation and utilization. We provide clear recommendations for patients being considered for cannabis (e.g. precautions, contraindications and drug interactions). Risk mitigation strategies such as appropriate chemovar (strain) selection, routes of administration, and dosing are reviewed. As with any other pharmacotherapy, we review the key components of monitoring and address potential issues that may arise while using medical cannabis. We propose a structured assessment and monitoring strategy that can be used by clinicians recommending cannabis (CRC) to guide patients through each step of their cannabis journey. This framework can be used to ensure that medical cannabis utilization is associated with the lowest possible risk to the patient.

Practical Strategies Using Medical Cannabis to Reduce Harms Associated With Long Term Opioid Use in Chronic Pain.

Background: Chronic non-cancer pain (CNCP) is estimated to affect 20% of the adult population. Current United States and Canadian Chronic non-cancer pain guidelines recommend careful reassessment of the risk-benefit ratio for doses greater than 90 mg morphine equivalent dose (MED), due to low evidence for improved pain efficacy at higher morphine equivalent dose and a significant increase in morbidity and mortality. There are a number of human studies demonstrating cannabis opioid synergy. This preliminary evidence suggests a potential role of cannabis as an adjunctive therapy with or without opioids to optimize pain control. Methods: In 2017, the Canadian Opioid Guidelines Clinical Tool was created to encourage judicious opioid prescribing for CNCP patients and to reevaluate those who have been chronically using high MED. Mirroring this approach, we draw on our clinical experiences and available evidence to create a clinical tool to serve as a foundational clinical guideline for the initiation of medical cannabis in the management of CNCP patients using chronic opioid therapy. Findings: Following principles of harm reduction and risk minimization, we suggest cannabis be introduced in appropriately selected CNCP patients, using a stepwise approach, with the intent of pain management optimization. We use a structured approach to focus on low dose cannabis (namely, THC) initiation, slow titration, dose optimization and frequent monitoring. Conclusion: When low dose THC is introduced as an adjunctive therapy, we observe better pain control clinically with lower doses of opioids, improved pain related outcomes and reduced opioid related harm.

Duration of Neurocognitive Impairment With Medical Cannabis Use: A Scoping Review.

While the recreational use of cannabis has well-established dose-dependent effects on neurocognitive and psychomotor functioning, there is little consensus on the degree and duration of impairment typically seen with medical marijuana use. Compared to recreational cannabis users, medical cannabis patients have distinct characteristics that may modify the presence and extent of impairment. The goal of this review was to determine the duration of acute neurocognitive impairment associated with medical cannabis use, and to identify differences between medical cannabis patients and recreational users. These findings are used to gain insight on how medical professionals can best advise medical cannabis patients with regards to automobile driving or safety-sensitive tasks at work. A systematic electronic search for English language randomized controlled trials (RCTs), clinical trials and systematic reviews (in order to capture any potentially missed RCTs) between 2000 and 2019 was conducted through Ovid MEDLINE and EMBASE electronic databases using MeSH terms. Articles were limited to medical cannabis patients using cannabis for chronic non-cancer pain or spasticity. After screening titles and abstracts, 37 relevant studies were subjected to full-text review. Overall, seven controlled trials met the inclusion/exclusion criteria and were included in the qualitative synthesis: six RCTs and one observational clinical trial. Neurocognitive testing varied significantly between all studies, including the specific tests administered and the timing of assessments post-cannabis consumption. In general, cognitive performance declined mostly in a THC dose-dependent manner, with steady resolution of impairment in the hours following THC administration. Doses of THC were lower than those typically reported in recreational cannabis studies. In all the studies, there was no difference between any of the THC groups and placebo on any neurocognitive measure after 4 h of recovery. Variability in the dose-dependent relationship raises the consideration that there are other important factors contributing to the duration of neurocognitive impairment besides the dose of THC ingested. These modifiable and non-modifiable factors are individually discussed.

Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain: results of a modified Delphi process.

BACKGROUND: Globally, medical cannabis legalization has increased in recent years and medical cannabis is commonly used to treat chronic pain. However, there are few randomized control trials studying medical cannabis indicating expert guidance on how to dose and administer medical cannabis safely and effectively is needed. METHODS: Using a multistage modified Delphi process, twenty global experts across nine countries developed consensus-based recommendations on how to dose and administer medical cannabis in patients with chronic pain. RESULTS: There was consensus that medical cannabis may be considered for patients experiencing neuropathic, inflammatory, nociplastic, and mixed pain. Three treatment protocols were developed. A routine protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg CBD twice daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 2.5 mg and titrate by 2.5 mg every 2 to 7 days until a maximum daily dose of 40 mg/day of THC. A conservative protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg once daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 1 mg/day and titrate by 1 mg every 7 days until a maximum daily dose of 40 mg/day of THC. A rapid protocol where the clinician initiates the patient on a balanced THC:CBD variety at 2.5-5 mg of each cannabinoid once or twice daily and titrates by 2.5-5 mg of each cannabinoid every 2 to 3 days until the patient reaches his/her goals or to a maximum THC dose of 40 mg/day. CONCLUSIONS: In summary, using a modified Delphi process, expert consensus-based recommendations were developed on how to dose and administer medical cannabis for the treatment of patients with chronic pain.

Practical considerations in medical cannabis administration and dosing.

Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.