The perils and promise of medical cannabis
BY CHRISTINE KILGORE
There is a small but consistent body of Class 1 evidence that cannabis can reduce patient-reported spasticity symptoms as well as pain, and a belief that commonly studied cannabinoids may someday be proven to have a clinical significant neuroprotective effect for patients with MS—potentially one that could help slow disease progression.
But as neurologist Allen C. Bowling, MD, PhD, cautions, there is little connection between the products studied thus far—almost all of which are standardized research-grade products and not available to be prescribed in the U.S.–and the products sold in U.S. dispensaries.
“There’s a lack of fidelity. You can’t take a study of Sativex, a standardized oral-mucosal preparation prepared in a world-class pharmaceutical facility, and extrapolate findings of benefit for someone to go out to a local dispensary and buy marijuana buds and smoke them,” said Dr. Bowling, a physician associate at the Colorado Neurological Institute (CNI), a clinical professor of neurology at the University of Colorado, and the author of several books on integrative care for MS.
Dr. Allen C. Bowling
Dr. Bowling has been studying the pharmacology, efficacy, and safety of cannabis as part of a project funded by the CNI to develop an evidence-based guide for clinicians and patients. Of 20,000-plus published articles on Cannabis sativa, he has screened more than 1,000. “Cannabis is by far the most complex drug I’ve ever worked with,” he said. “There are more than 100 different pharmacologically active molecules in cannabis, each of which may have 5-15 or even 20 different pharmacologic effects.”
In interpreting research, Dr. Bowling emphasizes, it’s important to appreciate that “cannabis does not equal cannabis does not equal cannabis.”
Research to Date
The highest quality studies thus far, Dr. Bowling said, are those that have utilized one of two formulations of cannabis: Cannador, an oral cannabis extract available to European researchers that contains both THC (tetrahydrocannabinol) and CBD (cannabidiol) in a ratio of about 2:1 (2.5 mg THC, 1.25 mg CBD), or Sativex (generic nabiximols), an oromucosal cannabinoid spray that contains almost equal amounts of THC and CBD (2.7 mg THC, 2.5 mg CBD). Sativex is approved in other countries for MS pain/spasticity and cancer pain, but it is not approved in the U.S.
There’s “growing scientific thought,” moreover, that patients with MS and other neurologic disorders “might get the most benefit from CBD, and not as much from THC,” he added. “But in the case of MS, we don’t know this until we’ve done more research. And thus far, there have been no studies of a high-CBD formulation…Research is still very much in its infancy and there are many questions not answered on the efficacy side.”
By Dr. Bowling’s count, 6 of the 19 randomized controlled trials (RCTs) conducted thus far of the efficacy of cannabis in MS have been Class 1 studies; 4 have been Class II and 9 have been Class III, per the American Academy of Neurology’s (AAN) classification scheme for therapeutic studies. Most of these 19 trials have used extracts (Sativex or Cannador), 6 have used THC/Marinol, and 2 have involved smoked cannabis as the route of delivery.
Most of the 19 RCTs have looked at spasticity, pain, or both. And across the Class I studies in particular, Dr. Bowling said, reductions in the “subjective sense of spasticity” have been consistent, as have reductions in pain.
The AAN published two documents in 2014 that similarly honed in on the evidence. One was a systematic review of the efficacy and safety of medical marijuana in MS, epilepsy and movement disorders. The reviewers identified 34 papers that met their inclusion criteria, including 8 Class 1 studies (for all conditions combined). Regarding MS, they offered several conclusions.
For spasticity, they said, oral cannabis extract (OCE)—Cannador in most studies—“is effective,” and nabiximols/Sativex and THC (dronabilol/Marinol) are “probably effective” for reducing patient-centered measures of spasticity. Additionally, both OCE and THC are “possibly effective” for reducing objective measures as well at 1 year.
For pain, including spasticity-related pain and excluding neuropathic pain, they concluded that OCE is effective and that THC and nabiximols are “probably effective.” And with respect to bladder dysfunction, nabiximols is “probably effective” for reducing bladder voids/day, and THC and OCE are “probably ineffective” for reducing bladder complaints (Neurology 2014;82:1556-1563).
In its second 2014 paper, the Academy addressed the use of cannabis in MS as part of a broader guideline on complementary and alternative medicine (CAM) for the disease. The guideline’s strongest recommendation on cannabis, supported by Level A quality of evidence, is that that clinicians “might offer” OCE for spasticity symptoms and pain (excluding neuropathic pain). Other recommendations (Level B or C) are that clinicians “might offer” THC for spasticity symptoms and pain, and Sativex for spasticity, pain and urinary frequency.
Clinicians should counsel patients that these agents are probably ineffective for urinary incontinence, the guidelines say (Neurology 2014;82:1083-1092). “There may be some efficacy with bladder dysfunction,” said Dr. Bowling, one of the authors of the AAN guideline on CAM for MS. “But the evidence is not quite as good.”
With respect to smoked marijuana, the AAN noted in a statement about its guideline, research studies “have not produced enough evidence to assess its effectiveness or safety for treating MS symptoms including spasticity, pain, balance, posture, and cognition.”
Implications of Current Research
In practice, Dr. Bowling believes, the current research findings on efficacy must be balanced against several realities: For one, there have been no formal clinical studies of the efficacy of products sold in U.S dispensaries. Nor have any products sold in U.S. dispensaries undergone detailed pre-clinical or human safety evaluation.
“It’s the crude plant products and extracts of the crude plant products that are being sold in U.S. dispensaries. And it’s very hard to know what’s in those,” said Dr. Bowling. “As I’ve become more knowledgeable, I’ve become less and less confident [about dispensary products] in terms of potential contamination [such as solvents, pesticides, and heavy metals] and in terms of the labelling process.”
He points to a study published several years ago in the Journal of the American Medical Association as emblematic of the problems with labeling accuracy (JAMA 2015;313(24):2491-93). Researchers analyzed 75 edible cannabis products purchased in California and Washington with a physician’s letter and found that 83% were inaccurately labeled (23% under-labeled and 60% over-labeled with respect to THC content).
Overall, the clinical trials of cannabis in MS and other neurologic conditions suggest that cannabis products have been generally well tolerated. However, the safety of cannabis is still poorly understood, and there are a host of documented side effects of neurological relevance–from visual difficulties and leg weakness to seizures, strokes and cognitive problems—that are potentially concerning for patients with MS, Dr. Bowling said. (Pro-convulsant effects appear to be associated with THC, he noted.)
In its guideline addressing cannabis, the AAN takes note of the range of potential side effects and emphasizes that patients with MS should be counseled about the potential for both neurocognitive and psychiatric adverse effects (e.g. depression and predisposal to psychosis). Moreover, Dr. Bowling said, it is still “underappreciated” by clinicians that cannabis can be addictive. “There’s a 9% addition rate in adults overall, and if use is daily, that rate jumps to 25-50%,” he said.
So what does the current research mean, practically speaking? For Dr. Bowling, it’s all about informed decision-making—balancing the evidence from clinical trials with what’s known and unknown about safety and product quality in the real world. “In spite of all the disadvantages, I do have some patients who’ve benefitted….typically those who have pain and/or spasticity that’s not fully responsive to medications, that breaks through [later in the day],” he said. “A little bit of cannabis can help them get through the afternoon or evening. And for some, it helps with sleep.”
Sleep was not part of the AAN’s evidence-based review or addressed in the AAN’s guideline, but according to a 2017 National Academy of Sciences (NAS) report on “The Health Effects of Cannabis and Cannabinoids,” the NAS found “moderate evidence” that cannabinoids, primarily nabiximols, are effective for improving short-term sleep outcomes in individuals with sleep disturbances associated with MS, in addition to “conclusive or substantial” evidence for improvements in patient-reported MS spasticity symptoms.
The Future of Research
There is much to be learned about cannabinoids’ mechanisms of action–both those that explain the benefits seen thus far in published MS clinical studies, and those that, given the right product development, could drive further benefits, Dr. Bowling said.
Recent evidence indicates, for instance, that particular cannabinoids open up intracellular potassium channels—an action that may drive at least some of the improvement seen in spasticity symptoms, Dr. Bowling said.
And in the longer term, there is “real potential” for clinically significant neuroprotection. Certain cannabinoids have been shown to decrease the activity of glutamatergic neurons, for instance, “which is very exciting because a calming of excessive glutamate activity could decrease the glutamate neurotoxicity” that likely contributes to neurodegeneration in MS, he said. Additionally, “certain cannabinoids have effects on calcium flux—on decreasing intracellular calcium. And, they have antioxidant effects. That’s three potentially neuroprotective mechanisms right there.”
Researchers are also discovering ways to inhibit the enzymes that degrade endogenous cannabinoids made by the body, Dr. Bowling notes. The National Institute of Health’s portfolio of research on cannabinoids describes such efforts, citing, for instance, how the activity of endogenous cannabinoids anandamide (AE) and 2-arachidonoylglycerol (2-AG) can be manipulated by inhibiting their corresponding hydrolases FAAH or MAGL.
The key to future research and the best use of cannabis in MS, Dr. Bowling said, lies in honing in on specific cannabinoid compounds and their mechanisms of action, and “on developing clean products with correct labels and no contaminants [that are tested through] randomized controlled trials.”
He’s optimistic, especially given the “ever-growing number of trials each year” and given the Food and Drug Administration’s approval in June 2018 of Epidiolex, a drug containing purified CBD, for the treatment of seizures associated with two uncommon forms of epilepsy. “This new drug is a huge step forward for the development of pharmaceutical-grade cannabis products,” he said.