ARTICLE IN BRIEF
The AAN's new systematic review of evidence on medical marijuana, including 34 studies that met inclusion criteria, is discussed here, as well as the challenges the Guideline Development Subcommittee faced in evaluating the data.
Medical marijuana appears to help alleviate spasticity and central or spasm-related pain and some other multiple sclerosis symptoms, but there is little evidence of efficacy in treating epilepsy or movement disorders, and there are serious concerns about side effects, according to a new systematic review from the AAN Guideline Development Subcommittee, which was published in Neurology on April 29.
The author panel systematically reviewed all studies and articles on medical marijuana published from 1948 through November 2013 for evidence of efficacy in treating symptoms of multiple sclerosis (MS), Huntington's disease (HD), epilepsy, Parkinson's disease (PD), cervical dystonia, and Tourette's syndrome.
Neurology Today asked lead author Barbara Koppel, MD, FAAN, professor of neurology at New York Medical College and chief of neurology at Metropolitan Hospital in New York City, to discuss the systematic review.
WHAT WERE THE MAJOR FINDINGS?
We found that oral cannabis extract (OCE) is effective, and that nabiximols [Sativex] — an oral spray containing both tetrahydrocannabinol (THC) and cannabidiol — as well as pure THC — are probably effective, in reducing spasticity based on patient reports, and that it is possible that both OCE and THC are effective for reducing both patient-centered and objective measures at one year.
We also concluded that OCE is effective in reducing central pain, and that THC and nabiximols are probably effective in helping with painful spasms, including spasticity-related pain. It was suggested that some of the improvement in spasticity and in walking time may have been due to pain relief allowing improved mobility. Also, that more improvements were seen in subjective measures can possibly be explained in part by overall improved feelings of well-being provided by marijuana's effects.
For urinary problems, nabiximols is probably effective in reducing the number of voids each day, but not other bladder complaints, and THC and OCE are probably ineffective for bladder complaints.
For MS-related tremor, THC and OCE are probably ineffective, and nabiximols is possibly ineffective.
In addition, we found that THC is probably ineffective for treating dopa-induced dyskinesias in PD patients. The efficacy of oral cannabinoids is unknown in treating non–chorea-related symptoms of HD, Tourette syndrome tics, or cervical dystonia. There were no studies above Class IV that examined cannabinoids for seizure frequency in epilepsy, so no conclusion was drawn.
HOW MUCH RESEARCH HAS BEEN PUBLISHED AND WHAT IS THE QUALITY OF THE DATA?
A total of 34 studies met inclusion criteria, including eight that were rated Class I studies, the highest level of evidence. There were four Class I and four Class II studies on spasticity in MS patients, as well as nine Class III studies. Each study was graded using AAN's classification system for rating therapeutic studies. But because these studies used different preparations and doses, the overall results were possibly confusing, so we presented our analysis by the type of cannabinoid preparation. [A table of the different cannabinoid formulations, by trade name, manufacturer, dosage and components, as well as study is available at http://bit.ly/1p48NzT.]
WHAT PROBLEMS WERE THERE IN COMPARING STUDIES?
Most of the Class I data came from two large studies in the United Kingdom, and several smaller studies in Europe, but again, comparing these data is difficult because the studies used four different oral drug combinations with differing amounts of THC and cannabidiol. Some used pills, one was an oral/mucosal spray, and some used vaporized or smoked marijuana.
Other studies have shown subjective but not objective improvement in shorter durations, such as 12–15 weeks. In all of these studies, subjects continued to receive standard medical therapy, so we were unable to comment on the comparative effectiveness.
Also, many patients in randomized trials are able to guess which arm of the study they are in due to the psychoactive effects, especially if the subjects had used marijuana before, which potentially confounds any findings.
WHAT RESEARCH HAS BEEN DONE IN THE US?
There have been very few studies in the US for neurologic disorders because it is difficult to get permission [to proceed with the trials.] The US Food and Drug Administration (FDA) has only approved medical marijuana in pill form for treating nausea in chemotherapy patients and weight loss in patients with HIV, and only dronabinol (Marinol), an oral synthetic THC, and nabilone (Cesamet), may be prescribed.
Of course some states have legalized or decriminalized marijuana, and even in states where marijuana remains illegal, there is a lot of self-treatment going on. Some parents of children with epilepsy have begun using “medical marijuana” in a totally unsupervised or systematic way. My understanding is the “prescriber” gives a document saying they approve the patient's use for their medical condition and then the patient or parent goes to a marijuana dispensary, but they do not receive the carefully examined pills and sprays we looked at in this guideline.
WHAT ABOUT THE SIDE EFFECTS?
The risk of overuse and/or dependence is one important reason why the FDA is cautious about marijuana research, and why doctors may resist using cannabinoid preparations. We feel that the risks and potential benefits of medical marijuana must be weighed carefully. In highly potent recreational use, cognitive impairment, which may be permanent and not just immediate, is well known. Marijuana's immediate effects on judgment, which would cause prescribers to worry about patients' engaging in risky behaviors such as driving while using it, also contribute to our caution.
The occurrence of serious adverse psychopathologic effects in the studies we examined was nearly 1 percent, which may be somewhat low, given the preparations we studied deliberately contained less THC and more of the nonpsychoactive cannabidiol. Unfortunately, we need to reach a certain dose to test efficacy, and that dose may result in psychoactive effects that are unacceptable for some patients.
It is also important to remember that many neurological disorders also cause cognitive impairment, and adding marijuana may cause more trouble. That is why it is so important that we know the potency of each of these preparations. In the future, I believe that certain treatment centers will become more knowledgeable about prescribing these compounds and about better identifying which patients might benefit from medical marijuana.
WHAT ADDITIONAL RESEARCH IS NEEDED?
We need studies using formulations that are available and familiar, and we need to study the effects of smoking (or vaporizing) marijuana as well as the oral or THC preparations that we looked at in the included studies. Marijuana vaporizing devices are available that may eliminate some of the harmful effects of smoke while still delivering the active forms of cannabis. But remember, non-medicinal marijuana today has been bred to be much more potent than it was in the 1960s and 70s. At that time the THC content was around one percent, but today it is often up to nine percent or even higher.
LINK UP FOR MORE INFORMATION:
•. Koppel BS, Brust JCM, Fife T, et al. Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders. Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology
•. Zajicek JP, Hobart JC, Slade A, et al. for the MUSEC Research Group. Multiple sclerosis and extract of cannabis: results of the MUSEC trial. J Neurol Neurosurg Psych
•. Collin C, Ehler E, Waberzinek G, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res
•. Collin C, Davies P, Mutiboko IK, Ratcliffe S, et al. for the Sativex Spasticity in MS Study Group. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 2007;14:290–296.
•. Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psych
•. Zajicek JP, Fox P, Sanders H, et al..; UK MS Research Group. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): Multicentre randomized placebo-controlled trial. Lancet
•. Armstrong MJ, Miyasaki JM. Evidence-based guideline: Pharmacologic treatment of chorea in Huntington disease. Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology