Despite the facts that millions of people are affected by multiple sclerosis (MS), and that in some countries medicinal cannabinoids have been approved for the treatment of MS symptoms, evidence for the efficacy of cannabinoids for MS symptoms is limited. Torres-Moreno et al1 conducted a meta-analysis in which 4 different medicinal cannabinoids were evaluated for MS-associated symptoms of spasticity, pain, and bladder spasms. They identified 17 studies involving 3161 patients that satisfied the eligibility criteria (randomized, placebo-controlled, double-blind, and parallel/crossover-designed trials for a minimum length of treatment of 2 weeks). Small but statistically significant differences were found in favor of cannabinoids for all 3 symptoms. Although cannabinoids were associated with more adverse effects and more withdrawals due to adverse effects, no statistically significant difference in serious adverse effects was noted. The authors conclude that cannabinoids provide a mild reduction in subjective outcome assessment of uncertain clinical significance and that they are safe.
Cannabinoids include more than 100 unique molecules. The most common cannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC), but plant-based products contain many other cannabinoids, including cannabigerol and turpenes.2 Receptors that bind to cannabinoids can be found in many tissues, with most being expressed in the nervous and immune systems. The 2 predominant receptors are CB1 and CB2.3 Tetrahydrocannabinol mediates its effects through binding with the CB1 receptors expressed throughout the nervous system. Cannabidiol binds to CB1 receptors and also to CB2 receptors, which are heavily implicated in immune response (important because MS is characterized by immune-mediated neuron changes). Cannabidiol has a much lower affinity for its receptors than THC, but this may be overcome by increasing the dose of CBD. In mouse models, both receptors have been found to play a role in moderating spasticity, a common symptom of MS.4
To better understand the potential role for cannabinoids in treatment of MS-related symptoms, the authors have carried out a rigorous analysis following international standards (eg, use of the Preferred Reporting Items for Systematic Reviews and Meta-analyses [PRISMA] Statement and the Cochrane Risk of Bias Tool). To our knowledge, this study represents the most comprehensive systematic review and meta-analysis on this topic to date. Standardization of the measures used to determine the effect of cannabis in the studies allowed pooled estimates of several outcomes, which sets this review apart from other literature. As expected for an intervention designed to improve symptoms, the effect measures in primary studies were largely patient-reported outcomes, and interpretation of results hinges on minimally important differences associated with validated rating scales. While the pooled estimates provide a high-level assessment of statistical significance, clinical significance is less apparent. In pooling standardized results from many rating scales, the extent to which patients with MS experience meaningful changes in symptoms is not clear.
It is notable that the only objective outcome measure studied related to spasticity. No benefit from cannabinoids was observed, and this was discordant with the subjective measures of the same symptom. This is consistent with some sparse literature as well as anecdotal accounts that cannabinoids in treating pain have not always decreased the pain as reported on pain scales even as patients report feeling better.5 The explanation of this phenomenon is unclear but may be related to effects of cannabinoids binding at higher cortical levels in the nervous system.
Any systematic review and meta-analysis is heavily influenced by the quality of the trials included, and the validity of conclusions is based on the strength of the evidence synthesized. In a meta-analysis, ideally the trials that are pooled should have similar study populations, interventions, and end points. However, if the trials that are pooled are very different (ie, heterogeneous), the validity of the final results of the meta-analysis can be of concern. In the meta-analysis by Torres-Moreno and colleagues,1 heterogeneity is an issue. Among the primary trials analyzed there were differences in study designs (eg, randomized vs crossover), study populations (eg, little detail provided regarding treatment-naive vs treatment refractory and MS subtype), and variability of cannabinoid agents studied, duration of treatment, and outcome measures.
Let us consider the potential impact of variation in cannabinoid used on the integrity of the analysis result. Four types of cannabinoids were studied for spasticity, 3 for pain, and 2 for urinary retention. Two of the formulations consisted entirely of THC or a THC analogue, whereas the other 2 consisted of a fixed ratio of THC to CBD of either 2:1 or 1:1 dose. For all 3 symptoms, the results slightly favored treatment with cannabinoids over placebo, with some cannabinoids being more effective than others. This may be related to the difference in composition of the treatments. Additionally, there was a range of doses of each of the cannabinoids used, which is not accounted for but may affect the outcome. Variability in the compounds studied also influences interpretation of tolerability results. Treatment groups in this meta-analysis showed statistically significant differences in adverse effects and withdrawals due to adverse effects in the treatment groups compared with placebo. It seems increasingly clear, however, from the literature on medicinal cannabinoids used for a variety of symptoms, that THC has dose-limiting adverse effects occurring at a much lower range (15-30 mg) than CBD, which can be dosed up to several hundred milligrams without treatment withdrawal.6,7
In the Discussion section, the authors review current strategies for managing spasticity, pain, and bladder dysfunction in patients with MS, highlighting a lack of effective treatments. Many current therapies have associated risks and adverse effects and can be invasive. This paradigm holds true for many clinical situations. For example, existing therapies for chemotherapy-induced peripheral neuropathy and intractable seizures have been shown to be either minimally effective or associated with a significant burden to the patient.8,9 It is therefore not surprising that researchers may be tempted to study cannabinoids, which are generally well tolerated and safe, in the hopes of finding more effective therapy to relieve suffering. It is critical that researchers gain a deeper understanding of both of the major (THC and CBD) and minor components of this therapy to unlock its full potential. Historically, THC, which binds with high affinity to CB1 receptors at multiple levels along the nociceptive pathway, has been highlighted as the key to symptom relief. Newer information suggests that higher doses of CBD may in fact be more important in realizing the potential of this category of therapy.10
Torres-Moreno et al1 have conducted a methodologically sound meta-analysis; however, this does not overcome the limitation of the relatively weak trials that were included. In light of uncertainty around clinically meaningful benefit and heterogeneity of the studies and results, they appropriately avoid drawing strong conclusions regarding the role for cannabinoids in managing symptoms of MS. Given the relative safety of these agents, lack of strong evidence of other effective treatment options, and increasing access in some jurisdictions, it may seem appealing to include cannabinoids in the armamentarium of therapies for MS. But carefully conducted, high-quality studies with thought given to the biologic activity of different cannabis components are still required to inform on the benefits of cannabinoids for patients with MS.
Published: October 12, 2018. doi:10.1001/jamanetworkopen.2018.3484
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Slaven M et al. JAMA Network Open.
Corresponding Author: Marissa Slaven, MD, Juravinski Cancer Centre, 699 Concession St, Hamilton, ON L8V 5C2, Canada (email@example.com).
Conflict of Interest Disclosures: None reported.
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Slaven M, Levine O. Cannabinoids for Symptoms of Multiple Sclerosis: Benefits to Patients Still Unclear. JAMA Netw Open. 2018;1(6):e183484. doi:10.1001/jamanetworkopen.2018.3484
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