Cannabinoids Mildly Effective for Multiple Sclerosis Symptoms

Batya Swift Yasgur, MA, LSW

October 17, 2018

Medicinal cannabinoids are helpful for treatment of spasticity, pain, and bladder dysfunction for patients with multiple sclerosis (MS), although their efficacy is "limited," new research suggests.

Mari Carmen Torres-Moreno, PhD, and colleagues at the Universitat Autònoma de Barcelona, Spain, reviewed and analyzed 17 trials comparing medicinal cannabinoids to placebo in a more than 3000 patients with MS and found that cannabinoids produced a "limited and mild reduction of subjective spasticity, pain, and bladder dysfunction....

"To our knowledge, this is the most complete systematic review and meta-analysis of the effect of cannabinoids on MS," the authors write.

Moreover, "they can be considered safe drugs, as the analysis of serious adverse events did not show statistical significance, although the total number of adverse events is higher than in placebo for the treatment for symptoms in patients with MS," they add.

The study was published online October 12 in JAMA Network Open.

Incomplete Data

"Cannabinoids act as neuromodulators of the endocannabinoid system," the authors write.

A mixture of cannabinoids (nabiximols) has been approved in some countries for the symptomatic treatment of MS spasticity and neuropathic pain in cases in which previous medication has proved ineffective, they note.

Nabiximols combine δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in an approximate 1:1 ratio.

The efficacy of these agents in treating symptoms of spasticity, pain, and bladder dysfunction in patients with MS is unclear, because previous systematic reviews and meta-analyses of the impact of cannabinoids on MS have been "relatively incomplete."

The investigators therefore set out to evaluate the therapeutic efficacy and tolerability of medicinal cannabinoids in treating these symptoms by performing a systematic review and meta-analysis of randomized, double-blind, and placebo-controlled trials.

The researchers analyzed 17 randomized controlled trials, which included a total of 3161 patients.

To qualify for inclusion, a study had to evaluate the effect of medicinal cannabinoids, administered by oral or oromucosal route, on the symptoms of spasticity, pain, or bladder dysfunction in adult patients.

The studies were required to be randomized, placebo-controlled, double-blind, or parallel or crossover trials; the length of treatment in the studies had to be 2 weeks or longer; and results of the trials had to be specified by means of an estimated effect size, or the trials must have provided information sufficient to calculate an estimated effect size.

Spasticity findings consisted of both objective and subjective measures. Objective measures were obtained via observed-completed Ashworth and Modified Ashworth Scales; subjective measures were obtained via patients' self-reported assessments.

Few Adverse Effects

The researchers selected a total of 82 results from clinical assessment tools and converted them to standard mean differences (SMDs), from which 17 combinations were carried out.

A negative SMD denoted clinical effect in favor of the experimental treatment, whereas a positive value was considered to favor placebo.

Statistically significant results were considered to be favorable for cannabinoids or placebo whenever the confidence interval (CI) of the results did not exceed the value of no effect (0 in case of the SMD).

Significant findings for the efficacy of cannabinoids vs placebo for spasticity (subjective patient assessment data), pain, and bladder dysfunction were as follows: SMD = -0.25 SD; 95% CI, -0.38 to -0.13 SD; SMD = -0.17 SD; 95% CI, -0.31 to -0.03 SD; and SMD = -0.11 SD; 95% CI, -0.22 to -0.0008 SD, respectively, with results that favored cannabinoids.

"However, none of the interventions demonstrated a clear efficacy in the treatment of spasticity when valuated in a more objective form (ie, the Ashworth and Modified Ashworth scales)," the authors note.

The researchers analyzed a total of 5357 adverse events and calculated serious adverse events (death or threat to a patient's life or functioning); 325 events were included.

A rate ratio (RR) >1 denoted higher risk in the experimental treatment, whereas an RR <1 denoted higher risk for placebo.

Results were considered statistically significant with higher risk in cannabinoids or placebo whenever the CI of the results did not exceed the value of no effect (1 in the case of the RR).

The researchers also analyzed tolerability and found an RR of 1.72 patient-years (95% CI, 1.46 - 2.02 patient-years) in the total adverse events analysis and 2.95 patient-years (95% CI, 2.14 - 4.07 patient-years) in withdrawals due to adverse events.

These findings pointed to a higher risk for cannabinoids; however, the serious adverse events meta-analysis showed no statistical significance.

The investigators found a high risk for bias regarding blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. The greatest percentage of high risk for bias concerned blinding of outcome assessment and incomplete outcome data.

Publication bias was detected in studies that were both for and against cannabinoids.

Given the concern regarding the potential impact of industry funding on the outcomes of industry-funded studies, the investigators performed an additional analysis that excluded those studies.

The additional analysis showed no differences between nabiximols and placebo in all the efficacy outcomes.

Nevertheless, in the analysis for cannabinoids, only the results for bladder dysfunction changed in statistical significance, becoming nonsignificant.

"It seems that sponsored studies favored active treatment," the authors note.

Real-World Recommendations

Commenting on the study for Medscape Medical News, Thorsten Rudroff, PhD, assistant professor in the Department of Health and Human Physiology, University of Iowa, Iowa City, who was not involved with the study, said that although it is "a good study overall, it is not new," inasmuch as a similar study with similar findings was published in 2014.

Additionally, "I'm not so sure they [the investigators] covered all the studies available on the subject," he said.

However, he agreed with the study's conclusions, with the caveat that they are based on subjective measurements, so "there is no strong evidence."

He added that this study assessed medications from pharmaceutical companies. "But in the real world, many people are not using these drugs but are going to dispensaries and obtaining products with higher TCH content, so we need more studies of what these patients are taking in the real world."

He encouraged those who recommend cannabinoids to patients with MS to "pay attention to THC content and recommend products with less THC and higher CBD, since it is THC that is associated with psychosocial and cognitive effects, and people with MS already have impairments in cognition."

Also commenting on the study for Medscape Medical News, Jacquelyn Bainbridge, PharmD, FCCP, MSCS, professor, Department of Clinical Pharmacy and Neurology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz, who was not involved with the study, agreed that more research is needed on the subject, using objective measures.

She emphasized that clinicians who recommend cannabinoids should "go with a reputable manufacturer when choosing a product."

She recommended "starting with a CBD-rich product and adding in THC to a ratio where the patient gets results."

She pointed out that industrial hemp is a "safe product to start with, since it is CBT with no more than 3% THC."

She added that one cannabidiol has been approved by the US Food and Drug Administration (Epidiolex, GW Pharmaceuticals), but only for two rare, severe forms of epilepsy. It is a Schedule V drug.

The authors state that they could find no studies that compared the safety of cannabinoids with that of other treatments for MS.

"Research into the greater possible combination of cannabinoids and other therapies, therefore, might bring about greater synergy benefits than in an individual form," they conclude.

The study was funded in part by grants from the Ministerio de Sanidad, Servicios Sociales e Igualdad. The authors, Dr Rudroff, and Dr Bainbridge have disclosed no relevant financial relationships.

JAMA Open Network. Published online October 12, 2018. Full text

For more Medscape Neurology news, join us on Facebook and Twitter.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: