Medical Marijuana: Where's the Evidence?

July 06, 2015

With many US states now having laws in place to facilitate access to medical marijuana for a variety of medical conditions, two new reviews have highlighted the lack of evidence to support its use in most indications.

An editorial also raises questions about the legal implications for doctors prescribing such products.

The reviews, published in the June 23/30 issue of JAMA, note that 23 states and the District of Columbia have enacted laws to allow prescription of medical marijuana for certain medical conditions.

Reviewing the medical literature on medical marijuana, the two papers come to similar conclusions — that some evidence supports the use of marijuana for nausea and vomiting related to chemotherapy, specific pain syndromes, and spasticity from multiple sclerosis. But for most other indications such as hepatitis C, Crohn's disease, Parkinson's disease, or Tourette's syndrome, they found that the evidence supporting its use is of poor quality.

A third paper in the same issue of JAMA highlights the large variability in specific cannabinoids in various medical marijuana products and finds that contents did not conform to what was advertised on the labelling.

In an accompanying editorial, Deepak Cyril D'Souza, MBBS, and Mohini Ranganathan, MD, Yale University School of Medicine, New Haven, Connecticut, note that for most of the conditions that qualify for medical marijuana use, the evidence fails to meet US Food and Drug Administration (FDA) standards.

They call for government support to conduct high-quality trials. Until such trials are available, they suggest it may be prudent to wait before widely adopting use of marijuana. "Perhaps it is time to place the horse back in front of the cart," they conclude.

Legal implications Unclear

The editorialists point out that for physicians, the legal implications of certifying patients for medical marijuana remain unclear given the differences between the views of state vs federal government.

They emphasize that the prescription, supply, or sale of marijuana is illegal by federal law, and it is not known to what extent a physician who certifies a patient for medical marijuana may be liable for negative outcomes, and whether malpractice insurance will cover any liability.

In one of the review papers, Kevin P. Hill, MD, McLean Hospital, Belmont, Massachusetts, examined 28 randomized clinical trials of cannabinoids in various indications.

He notes that there are two cannabinoids (dronabinol and nabilone), which are FDA approved for nausea and appetite stimulation.

Apart from these two indications, Dr. Hill found that use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence.

Six trials that included 325 patients examined chronic pain, 6 trials that included 396 patients investigated neuropathic pain, and 12 trials that included 1600 patients focused on multiple sclerosis. Several of these trials had positive results, suggesting that marijuana or cannabinoids may be efficacious for these indications.

The other review paper, by a team led by Penny F. Whiting, PhD, University Hospitals Bristol NHS Foundation Trust, United Kingdom, evaluated 79 trials of cannabinoids in a total of 6462 participants. Indications included 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's syndrome.

There was better evidence of efficacy in nausea and vomiting (with 47% of patients showing a complete response vs 20% placebo in 3 trials), pain (with 37% of patients reporting a reduction vs 31% on placebo in 8 trials), and spasticity (with an average reduction in the Ashworth spasticity scale of –0.36 in 7 trials).

Both reviews report an increased risk for short-term adverse effects, including dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, hallucination, addiction, and worsening of psychiatric illnesses, such as anxiety and mood disorders.

Inaccurate Labeling

For the dosing paper, a team led by Ryan Vandrey, PhD, Johns Hopkins University School of Medicine in Baltimore, Maryland, report that of 75 products purchased (47 different brands), 17% were accurately labeled, 23% were underlabeled, and 60% were overlabeled with respect to tetrahydrocannabinol content.

"Edible cannabis products from 3 major metropolitan areas, though unregulated, failed to meet basic label accuracy standards for pharmaceuticals," the authors write. "Because medical cannabis is recommended for specific health conditions, regulation and quality assurance are needed," they conclude.

In their editorial, Dr D'Souza and Dr Ranganathan note inconsistencies in how medical conditions are qualified for medical marijuana use within a state and between states. For example, in Connecticut, psoriasis and sickle cell disease but not Tourette's syndrome qualify, even though the supporting evidence for all three conditions is uniformly of very low quality. Similarly, post-traumatic stress disorder is approved as a qualifying condition in some, but not all, US states.

They also point out that marijuana is a complex of more than 400 compounds, including up to 70 cannabinoids that have individual or interactive effects, and that the composition of cannabis preparations can vary substantially.

The editorialists advise that because of the risk for psychosis with marijuana, there needs to be explicit contraindications for use in patients with schizophrenia, bipolar disorder, or substance dependence, along with measures to minimize their access to it. They suggest that follow-up programs should be introduced to monitor long-term outcomes in patients taking medical marijuana.

Given that cannabinoid exposure during critical periods of brain development is associated with long-lasting changes in behavior and cognition, they say careful consideration is needed to determine at what age exposure to medical marijuana is justifiable.

JAMA. 2015;313:2474-2483, 2456-2473, 2491-2493, 2431-2432. Hill review paper Whiting review paper Dose study Editorial

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