Adverse effects of medical cannabinoids : a systematic review
T. Wang, J-P. Collet, S. Shapiro, M.A. Ware,
Canadian Medical Association Journal, 2008,178,13, 1669-1678
Background : The therapeutic use of cannabis and cannabisbased medicines raises safety concerns for patients, clinicians, policy-makers, insurers, researchers and regulators. Although the efficacy of cannabinoids is being increasingly demonstrated in randomized controlled trials, most safety information comes from studies of recreational use.
Methods : We performed a systematic review of safety studies of medical cannabinoids published over the past 40 years to create an evidence base for cannabis-related adverse events and to facilitate future cannabis research initiatives. We critically evaluated the quality of published studies with a view to identifying ways to improve future studies.
Results : A total of 321 articles were eligible for evaluation. After excluding those that focused on recreational cannabis use, we included 31 studies (23 randomized controlled trials and 8 observational studies) of medical cannabis use in our analysis. In the 23 randomized controlled trials, the median
duration of cannabinoid exposure was 2 weeks (range 8 hours to 12 months). A total of 4779 adverse events were reported among participants assigned to the intervention. Most (4615 [96.6%]) were not serious. Of the 164 serious adverse events, the most common was relapse of multiple sclerosis
(21 events [12.8%]), vomiting (16 events [9.8%]) and urinary tract infection (15 events [9.1%]). The rate of nonserious adverse events was higher among participants assigned to medical cannabinoids than among controls (rate ratio [RR] 1.86, 95% confidence interval [CI] 1.57–2.21); the rates of serious adverse events did not differ significantly between these 2 groups (RR 1.04, 95% CI 0.78–1.39). Dizziness was the most commonly reported nonserious adverse event (714 events [15.5%]) among people exposed to cannabinoids.
Interpretation : Short-term use of existing medical cannabinoids appeared to increase the risk of non-serious adverse events. The risks associated with long-term use were poorly characterized in published clinical trials and observational studies. High-quality trials of long-term exposure are required to further characterize safety issues related to the use of medical cannabinoids.
Cannabis (Cannabis sativa) is widely used as a recreational drug, with an estimated worldwide annual
prevalence (defined as use at least once per year) of 160 million.1 Cannabis preparations have also been used medicinally for thousands of years. In the past 40 years the active ingredients of cannabis, Δ-9-tetrahydrocannabinol and cannabidiol, and other derivatives (termed “cannabinoids”) have been identified and characterized,2 and it is becoming clear that cannabinoids have considerable therapeutic potential.3
In Canada, 4 cannabinoid products are currently available for medical use, more than in any other country worldwide. These are: a herbal cannabis extract (marketed as Sativex [GW Pharmaceuticals], which contains Δ-9-tetrahydrocannabinol and cannabidiol in an oromucosal spray); dronabinol (synthetic Δ-9-tetrahydrocannabinol, marketed as Marinol [Solvay Pharmaceuticals]); nabilone (a synthetic derivative of Δ-9- tetrahydrocannabinol, marketed as Cesamet [Valeant Pharmaceuticals International]); and the herbal form of cannabis (available legally through the Medical Marijuana Access Regulations). 4,5 In Canada, dronabinol and nabilone are indicated for chemotherapy-induced nausea and vomiting, dronabinol is approved for HIV-associated anorexia, and oromucosal Δ-9- tetrahydro cannabinol–cannabidiol is conditionally approved for neuropathic pain in multiple sclerosis and cancer pain.
The efficacy of these cannabinoid medicines has been evaluated in randomized controlled trials. In addition, the use of cannabinoids as antiemetics has been systematically reviewed, and potential efficacy has been suggested.6 There has also been considerable interest in the use of cannabinoids as adjunctive therapy for pain management, and several small randomized controlled trials have been published recently. Dronabinol and oromucosal Δ-9-tetrahydrocannabinol– cannabidiol have been proven effective for central neuropathic pain associated with multiple sclerosis.7–11 Oromucosal Δ-9-tetrahydro-cannabinol–cannabidiol reduced pain associated with rheumatoid arthritis,12 and nabilone was effective for pain associated with fibromyalgia.13 A recent review supported further consideration of cannabinoids for chronic pain but was less encouraging for their use in acute pain conditions.3
In addition to the use of prescription cannabinoids, the medical use of smoked herbal cannabis is substantial: an estimated 10%–20% of patients with multiple sclerosis, chronic noncancer pain, HIV/AIDS and epilepsy report smoking cannabis for therapeutic purposes. Smoked cannabis has been found to be safe14 and effective15 for HIV-associated disorders. As of October 2007, 2261 patients in Canada were authorized to use herbal cannabis for medical purposes under the Medical Marihuana Access Regulations.16
With this rising interest in therapeutic use, the safety of cannabinoids is an emerging source of concern for many physicians. The safety of therapeutic agents can be studied by a variety of methodologic approaches, including randomized controlled trials, observational studies and pharmacovigilance studies.17,18 The adverse effects of cannabis have been summarized in several reports,19–24 and systematic reviews have found cannabis to be a risk factor for psychosis,25 cancer26 and neurocognitive
effects,27 but these reports all focused on the recreational use of cannabis.
We report here a systematic review of the published adverse events of medical cannabinoid use. Our primary objective was to create a database of known adverse events related to the medical use of cannabis to inform physicians, policymakers and the public. In addition, we sought to critically
evaluate the quality of published studies to guide future studies on the safety of medical cannabis use.