Importance Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. Objective To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. Data Sources Twenty-eight databases from inception to April 2015. Study Selection Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. Data Extraction and Synthesis Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. Main Outcomes and Measures Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. Results A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. Conclusions and Relevance There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

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Cannabinoids for Medical Use: A Systematic Review and Meta-analysis.

Cannabis sativa has been cultivated throughout human history as a source of fiber, oil and food, and for its medicinal and intoxicating properties. Selective breeding has produced cannabis plants for specific uses, including high-potency marijuana strains and hemp cultivars for fiber and seed production. The molecular biology underlying cannabinoid biosynthesis and other traits of interest is largely unexplored. We sequenced genomic DNA and RNA from the marijuana strain Purple Kush using shortread approaches. We report a draft haploid genome sequence of 534 Mb and a transcriptome of 30,000 genes. Comparison of the transcriptome of Purple Kush with that of the hemp cultivar 'Finola' revealed that many genes encoding proteins involved in cannabinoid and precursor pathways are more highly expressed in Purple Kush than in 'Finola'. The exclusive occurrence of Δ9-tetrahydrocannabinolic acid synthase in the Purple Kush transcriptome, and its replacement by cannabidiolic acid synthase in 'Finola', may explain why the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) is produced in marijuana but not in hemp. Resequencing the hemp cultivars 'Finola' and 'USO-31' showed little difference in gene copy numbers of cannabinoid pathway enzymes. However, single nucleotide variant analysis uncovered a relatively high level of variation among four cannabis types, and supported a separation of marijuana and hemp. The availability of the Cannabis sativa genome enables the study of a multifunctional plant that occupies a unique role in human culture. Its availability will aid the development of therapeutic marijuana strains with tailored cannabinoid profiles and provide a basis for the breeding of hemp with improved agronomic characteristics.

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The draft genome and transcriptome of Cannabis sativa

Cannabis, or marijuana, has been used for medicinal purposes for many years. Several types of cannabinoid medicines are available in the United States and Canada. Dronabinol (schedule III), nabilone (schedule II), and nabiximols (not U.S. Food and Drug Administration approved) are cannabis-derived pharmaceuticals. Medical cannabis or medical marijuana, a leafy plant cultivated for the production of its leaves and flowering tops, is a schedule I drug, but patients obtain it through cannabis dispensaries and statewide programs. The effect that cannabinoid compounds have on the cannabinoid receptors (CB1 and CB2) found in the brain can create varying pharmacologic responses based on formulation and patient characteristics. The cannabinoid Δ9-tetrahydrocannabinol has been determined to have the primary psychoactive effects; the effects of several other key cannabinoid compounds have yet to be fully elucidated. Dronabinol and nabilone are indicated for the treatment of nausea and vomiting associated with cancer chemotherapy and of anorexia associated with weight loss in patients with acquired immune deficiency syndrome. However, pain and muscle spasms are the most common reasons that medical cannabis is being recommended. Studies of medical cannabis show significant improvement in various types of pain and muscle spasticity. Reported adverse effects are typically not serious, with the most common being dizziness. Safety concerns regarding cannabis include the increased risk of developing schizophrenia with adolescent use, impairments in memory and cognition, accidental pediatric ingestions, and lack of safety packaging for medical cannabis formulations. This article will describe the pharmacology of cannabis, effects of various dosage formulations, therapeutics benefits and risks of cannabis for pain and muscle spasm, and safety concerns of medical cannabis use.

https://accpjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/phar.1187

The Pharmacologic and Clinical Effects of Medical Cannabis

Practical considerations in medical cannabis administration and dosing

PurposeTo provide evidence-based guidance on the optimum management of chronic pain in adult cancer survivors.MethodsAn ASCO-convened expert panel conducted a systematic literature search of studies investigating chronic pain management in cancer survivors. Outcomes of interest included symptom relief, pain intensity, quality of life, functional outcomes, adverse events, misuse or diversion, and risk assessment or mitigation.ResultsA total of 63 studies met eligibility criteria and compose the evidentiary basis for the recommendations. Studies tended to be heterogeneous in terms of quality, size, and populations. Primary outcomes also varied across the studies, and in most cases, were not directly comparable because of different outcomes, measurements, and instruments used at different time points. Because of a paucity of high-quality evidence, many recommendations are based on expert consensus.RecommendationsClinicians should screen for pain at each encounter. Recurrent disease, second malignancy, or lat...

https://ascopubs.org/doi/pdf/10.1200/jco.2016.68.5206

Management of Chronic Pain in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

Background: Chronic neuropathic pain affects 1%‐2% of the adult population and is often refractory to standard pharmacologic treatment. Patients with chronic pain have reported using smoked cannabis to relieve pain, improve sleep and improve mood. Methods: Adults with post-traumatic or postsurgical neuropathic pain were randomly assigned to receive cannabis at four potencies (0%, 2.5%, 6% and 9.4% tetrahydrocannabinol) over four 14-day periods in a crossover trial. Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle, followed by a nine-day washout period. Daily average pain intensity was measured using an 11-point numeric rating scale. We recorded effects on mood, sleep and quality of life, as well as adverse events. Results: We recruited 23 participants (mean age 45.4 [standard deviation 12.3] years, 12 women [52%]), of whom 21 completed the trial. The average daily pain intensity, measured on the 11-point numeric rating scale, was lower on the prespecified primary contrast of 9.4% v. 0% tetrahydrocannabinol (5.4 v. 6.1, respectively; difference = 0.7, 95% confidence interval [CI] 0.02‐1.4). Preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief. Participants receiving 9.4% tetrahydrocannabinol reported improved ability to fall asleep (easier, p= 0.001; faster, p< 0.001; more drowsy, p= 0.003) and improved quality of sleep (less wakefulness, p= 0.01) relative to 0% tetrahydrocannabinol. We found no differences in mood or quality of life. The most common drug-related adverse events during the period when participants received 9.4% tetrahydrocannabinol were headache, dry eyes, burning sensation in areas of neuropathic pain, dizziness, numbness and cough. Conclusion: A single inhalation of 25 mg of 9.4% tetrahydrocannabinol herbal cannabis three times daily for five days reduced the intensity of pain, improved sleep and was well tolerated. Further long-term safety and efficacy studies are indicated. (International Standard Randomised Controlled Trial Register no. ISRCTN68314063)

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Smoked cannabis for chronic neuropathic pain: a randomized controlled trial

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 nonserious 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.

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Adverse effects of medical cannabinoids: a systematic review

https://www.alchimiaweb.com/blogfr/wp-content/uploads/2015/10/PIIS1526590015008378.pdf

Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS)

Anastrozole is a third‐generation aromatase inhibitor that exerts potent anti–breast cancer effects. This trial aimed to explore the pharmacokinetics (PK) and safety with bioequivalence of orally administered anastrozole provided by 2 sponsors in healthy volunteers.Two separate open‐label, randomized, single‐dose, crossover‐design studies consisting of a fasting study (n = 23) and a fed study (n = 23, 1 participant withdrew before taking medication) were conducted. In each study, healthy volunteers were randomized to receive the test product (Haizheng Pharmaceutical Group) followed by the reference drug (AstraZeneca Pharmaceuticals LP), or vice versa. Each study subject received a 1‐mg anastrozole tablet with a 21‐day washout. The plasma concentrations of anastrozole were measured with liquid chromatography–tandem mass spectrometry, and PK parameters were determined by noncompartmental analysis. Forty‐six healthy female volunteers were enrolled. For patients enrolled in the fasting study, the mean age was 55.0 years, mean weight was 57.1 kg, mean body mass index was 23.6 kg/m2, and mean height was 155.5 cm. For patients enrolled in the fed study, the mean age was 54.2 years, mean weight was 55.9 kg, mean body mass index was 23.9 kg/m2, and mean height was 152.8 cm. All PK end points met the predefined criteria for PK equivalence. In fasting subjects, the median maximum plasma concentration was 23.4 and 22.6 at 1 hour for test and reference formulations, respectively. The maximum plasma concentration in fed subjects was 18.7 and 18.5 at 4 hours for test and reference formulations, respectively. Both fasting and fed studies achieved plausible bioequivalence. Anastrozole was well tolerated and exhibited a favorable safety profile at the prescribed doses. The severity of observed adverse events assessed according to the Common Terminology Criteria for Adverse Events (version CTCAE4.03) was mild, and some of the adverse events were not caused by anastrozole. Furthermore, the results of our study under fasting and fed conditions demonstrated bioequivalence of the test and reference products.

Tongtong Wang

Papers

Smoked cannabis for chronic neuropathic pain: a randomized controlled trial

Adverse effects of medical cannabinoids: a systematic review

Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS)

Evaluation of Pharmacokinetics and Safety With Bioequivalence of Anastrozole in Healthy Chinese Volunteers: Bioequivalence Study Findings