Medical Marijuana: An Extensive Review of Clinical Benefits and Adverse Effects

Date: 
08/21/2015

A recent study by Whiting, et al, (JAMA 2015) performed an extensive literature review using 28 databases and provided assessment of the indications, benefits and adverse effects of medical marijuana and cannabinoids. Using a rating scale to score the quality of evidence, the authors described evidence of moderate quality to support the use of marijuana in treating chronic pain syndromes and spasticity from multiple sclerosis. There was evidence of low quality that cannabinoids were associated with some improvements in chemotherapy-induced nausea and vomiting, sleep disorders, weight gain in HIV infection, and Tourette syndrome. Indications for which cannabinoids showed either very low-quality evidence or no effect included CNS depression, anxiety disorder, psychosis, and intraocular pressure from glaucoma. Adverse effects were reported with the use of cannabinoids, including, among others, dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, drowsiness, confusion, loss of balance and hallucination.

By R.L. Wynn

Study Methods
The Whiting, et al, study was an extensive systematic literature review to evaluate the evidence for the benefits and adverse effects of medical cannabinoids across a broad range of indications. The authors are from University Hospitals NHS Foundation Trust, Whitefriars, Lewins Mead, Bristol, UK. The full report can be accessed at:
Whiting, P.F., et al. “Cannabinoids for medical use: a systematic review and meta-analysis.” JAMA 2015; 313(24):2456-2473.
Twenty-eight databases were searched for relevant studies evaluating cannabinoids in the treatment of various medical conditions. Randomized clinical trials (RCTs) that compared cannabinoids with (1) usual care, (2) placebo, or (3) no treatment in the following indications were eligible:

  • Chemotherapy-induced nausea and vomiting
  • Appetite stimulation in HIV/AIDs patients
  • Chronic pain
  • Spasticity from multiple sclerosis (MS)
  • CNS depression
  • Anxiety disorder
  • Sleep disorder
  • Psychosis
  • Intraocular pressure in glaucoma
  • Movement disorder in Tourette syndrome

The RCTs were independently assessed by two reviewers. If no RCTs were available for a particular indication, then nonrandomized studies including uncontrolled studies, such as case series, with at least 25 patients were eligible.
From the eligible studies and reports, the authors extracted data about baseline characteristics and outcomes which included disease-specific outcomes, activities of daily living, quality of life, global impression of change, and specified adverse events. The numbers of patients with an outcome in each medical category was assessed. For each outcome, mean differences in change from baseline was determined.
A grading scale was used to rate the overall quality of the evidence for risk of bias, imprecision, indirectness, and magnitude of effect. Grade ratings of very low-, low-, moderate-, or high-quality evidence reflected the extent to which the authors were confident that the effect estimates were correct.

Study Results
The literature search identified 505 potentially relevant studies based on title and obtained as full text reports. From that, a total of 79 studies, which included a total of 6,462 participants, were then identified. Publication dates ranged from 1975 to 2015 (median 2004). In those 79 studies, a variety of cannabinoids were evaluated and compared with various different active comparators or placebos. Most studies reported being double blinded.

The identified studies tested the following cannabinoids:

  • Cannabis (the marijuana plant) – Schedule I controlled substance; legal for medical use in 23 states
  • THC (tetrahydrocannabinol – an active cannabinoid part of cannabis) – Schedule I controlled substance; legal for medical use in 23 states
  • Dronabinol (synthetic THC) – Schedule II controlled substance; approved for use in U.S.
  • Nabilone (synthetic cannabinoid derivative) – Schedule II controlled substance; approved for use in U.S.
  • Nabiximols (mix of THC and cannabidiol) – Not currently licensed in U.S .
  • CBD (cannabidiol – an active cannabinoid part of cannabis) – Schedule I controlled substance

Results: Treatment of Chemotherapy-induced Nausea and Vomiting
This was assessed in 28 studies, comprising 37 reports with 1772 participants. All studies suggested a greater benefit of cannabinoids compared with active comparators or placebo. However, the greater benefit did not reach statistical significance in all studies. The most common active comparators were prochlorperazine, chlorpromazine, and domperidone. Most of those studies assessed either THC or nabilone. Further, the average number of patients showing complete response in nausea and vomiting cessation was approximately 4 times greater with cannabinoids (dronabinol or nabiximols) than placebo. Due to the lack of statistical significance, the authors ranked the effects of cannabinoids as low-quality evidence to support their use in treating chemotherapy-induced nausea and vomiting.

Results: Appetite Stimulation in HIV/AIDS Infection
This was assessed in four studies, comprising four reports with 255 participants. All studies tested dronabinol, and there was some evidence that it was associated with an increase in weight when compared against a placebo. The authors also described limited evidence from single studies showing that dronabinol may also be associated with increased appetite, greater percentage of body fat, and reduced nausea in HIV/AIDS subjects. These associations, however, did not reach a level of statistical significance. One trial that evaluated marijuana and dronabinol found significantly greater weight gain with both forms of cannabinoid compared to placebo. All in all, however, the authors concluded that there was low-quality evidence that cannabinoids caused weight gain in HIV infection.

Results: Chronic pain
The authors uncovered 28 chronic pain studies, including 63 reports and 2454 participants. The types of marijuana evaluated were nabiximols, smoked THC, nabilone, THC oromucosal spray, dronabinol, oral THC, and vaporized cannabis. The conditions causing chronic pain included neuropathic pain, cancer pain, diabetic peripheral neuropathy, fibromyalgia, and HIV-associated sensory neuropathy. In addition, one study for each of the following types of pain was uncovered: refractory pain due to MS, rheumatoid arthritis, non-cancer neuropathic pain, musculoskeletal problems, and chemotherapy-induced pain.
According to the authors, the studies collectively suggested improvement in pain measures associated with cannabinoids, but did not reach statistical significance in most individual studies. The average number of patients who reported a reduction in pain of at least 30% was greater with cannabinoids than with placebo (approximately 1.5 times greater). One trial assessed smoked THC and reported an effect of over 3 times greater pain relief. Nabiximols seemed to have an overall effect in pain reduction in seven trials. Pain conditions evaluated in the smoked THC and nabiximol trials were neuropathic pain and cancer pain. The authors concluded that there was moderate-quality evidence to support the use of for the treatment of chronic pain.
Results: Spasticity
The authors retrieved 14 studies involving 33 reports and 2280 subjects relative to treatment of spasticity due to multiple sclerosis or paraplegia. In general, the studies suggested that cannabinoids were associated with improvements in spasticity, but failed to reach statistical significance in the majority of studies. The average number of patients who reported an improvement on a global impression of change score was approximately 1.5 times greater with the nabiximol cannabinoid compared to placebo. The authors concluded that there was moderate-quality evidence to support the use of cannabinoids for the treatment of spasticity.

Results: Sleep Disorder
There were 19 placebo-controlled studies included for chronic pain and MS that also evaluated sleep as an outcome. There was evidence that cannabinoids improved sleep in these patient groups. The cannabinoids (mostly nabiximols) were associated with a greater average in improvement of sleep quality and sleep disturbance. Two studies consisting of five reports and 54 subjects evaluated cannabinoids solely for the treatment of sleep problems. These studies showed improvements in sleep disturbance and insomnia. The authors concluded that there was low-quality evidence to support the use of cannabinoids for the treatment of sleep disorders.

Results: Other Disorders
There was low-quality evidence that cannabinoids were associated with improvements in movement disorders in patients with Tourette syndrome (two trials, four reports, 36 subjects) and very low-quality evidence for improvement in anxiety assessed using a public speaking test (one trial). There was low-quality evidence for no effect on psychosis (two studies, nine reports, 71 subjects) and very low-quality evidence for no effect on CNS depression (five studies included for other indications reporting depression as an outcome measure). For glaucoma, one trial found no difference between placebo and cannabinoids on measures of intraocular pressure in patients with glaucoma.

Cannabinoid-induced Adverse Effects
Adverse effects were reported in 62 studies consisting of 127 reports. In general, cannabinoids were associated with a much greater risk of any adverse effect and patient withdrawal of medication due to the specific adverse reaction. No studies evaluating the long-term effects of cannabinoids were identified. There were 14 specific adverse effects with at least 2 times or greater incidence compared to control.

  • Approximately 5x greater likelihood:
    • Dizziness
    • Disorientation
  • Approximately 4x greater likelihood:
    • Euphoria
    • Confusion
  • Approximately 3x greater likelihood:
    • Dry mouth
    • Drowsiness
  • Approximately 2x greater likelihood:
    • Asthenia
    • Paranoia
    • Hallucination
    • Balance
    • Anxiety
    • Somnolence
    • Fatigue
    • Nausea

There was no evidence of any difference in association of adverse effects based on the type of cannabinoids or mode of administration.

Authors’ Comments
More studies are needed to confirm the effects of cannabinoids (i.e., on chronic pain and spasticity). Further, the authors indicated that large, robust RCTs are needed on weight gain in patients with HIV/AIDS, depression, sleep disorders, anxiety disorders, psychosis, glaucoma, and Tourette syndrome. They also recommended more studies on cannabis (marijuana plant) itself are needed, since there is very little evidence on the effects or adverse reactions to cannabis.

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