Cannabinoids

Orally administered cannabinoids (cannabis extract, synthetic tetrahydrocannabinol [THC]), mucosal delivered cannabinoids (cannabis THC and cannabidiol [CBD] extract oral spray, nabiximols (trade name Sativex)) and smoked cannabis have all been studied for therapeutic effects in MS.

Based on available evidence, cannabinoids may relieve spasticity and/or pain in people with MS; however, no marijuana-derived medication is approved by the US Food and Drug Administration (FDA) for the treatment of MS. Sativex (equal blend of THC and CBD) has received regulatory approval in several European countries, including Spain and Canada for the treatment of spasticity (muscle stiffness/spasms) due to MS.

There is insufficient data to determine whether smoking marijuana relieves symptoms of MS. In addition, the psychoactive properties and other potential adverse effects must be considered.

What does the research show?

• ONE 2022 Cochrane review of 25 randomized controlled trials involving a total of 3,763 participants found that, compared with placebo, nabiximol is likely to reduce the severity of spasticity in the short term in people with MS. The assessors were less certain about the effect on chronic neurological pain and health-related quality of life. ONE 2018 systematic review and meta-analysis of 17 trials involving a total of 3,161 participants found limited efficacy of cannabinoids such as THC, CBD, THC:CBD formulations, pharmaceutical cannabinoids (dronabinol and nabilone), smoked cannabis, and oral cannabinoid extracts for the treatment of spasticity, pain, and bladder dysfunction in patients with bladder MS. Another 2018 systematic review of 11 reviews providing data from 32 studies (including 10 randomized controlled trials of moderate to high quality) found sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Results from a 2024 randomized controlled trial involved 68 participants did not indicate a significant treatment effect on spasticity using a clinician-rated measure of velocity-dependent lower extremity muscle tone.
• Oral cannabinoids. The 2014 evidence-based guidelines issued by the American Academy of Neurology, which was confirmed in 2023, concluded that oral cannabis extract is established as effective in reducing patient-reported spasticity symptoms and pain. This subjective service may be retained for 1 year. The guidelines also concluded that THC is probably effective to reduce patient-reported symptoms of spasticity and pain. This subjective service may be retained for 1 year. However, the guidelines state that oral cannabis extract and THC are probably ineffective to reduce both objective measures of spasticity and MS-related tremor symptoms. Oral cannabis extract and THC are possibly effective for reduction of symptoms and objective measures of spasticity over 1 year.
• Oromucosal cannabinoid spray. The 2014 American Academy of Neurology evidence-based guidelineswhich was confirmed in 2023 concluded that Sativex oromucosal cannabinoid spray is probably effective for the improvement of subjective spasticity symptoms and is probably ineffective for reduction of objective spasticity measures over 6 weeks or bladder incontinence episodes over 10 weeks. Further, the guidelines state that Sativex oral cavity spray is possibly ineffective to reduce MS-related tremor over 15 weeks. In addition, one 2010 meta-analysis reported on 666 patients with MS who received either nabiximol (363) or placebo (303); all patients had spasticity that was not well controlled using existing treatments. The results showed that effects of nabiximol are typically seen within 3 weeks. Also, about a third of the MS patients given nabiximol had a 30 percent improvement from baseline. The authors noted that the treatment appeared reasonably safe.
• Smoked hashish. Based on two small studies 2014 evidence-based guidelines issued by the American Academy of Neurologywhich was confirmed in 2023, concluded that data are insufficient to determine the safety or effectiveness of smoked cannabis used for spasticity/pain, balance/posture, and cognition.

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• In the studies that formed the basis of 2014 American Academy of Neurology guidelineswhich was confirmed in 2023, cannabinoids were generally well tolerated, although some serious side effects were reported. Mild or moderate side effects including dizziness, somnolence, somnolence, vertigo, memory impairment, and difficulty concentrating were more common in participants given cannabinoids compared to placebo. Less common side effects included increased appetite, nausea, vomiting, constipation, dry/sore mouth, myalgia, seizures, and others. The guidelines noted that because cannabinoids have known psychoactive properties, their potential for psychopathological and neurocognitive side effects is a concern, particularly in a patient population that may be vulnerable due to underlying disorders.
• The guidelines recommend that clinicians counsel patients about the potential for psychopathological/cognitive and other adverse effects associated with cannabinoids. Sativex oromucosal cannabinoid spray is not approved by the FDA and is not available in the United States. Further, the guidelines suggest that caution be exercised in extrapolating results from trials with standardized oral cannabis extract (which is not commercially available) to other non-standardized, unregulated cannabis extracts (which may be commercially available in states with medical marijuana laws).
• Although people sometimes think that CBD products are completely safe, they may not be. Unlike Epidiolex (the purified CBD product sold as an FDA-approved prescription drug), over-the-counter CBD products may contain more or less CBD than stated on their labels and, due to inadequate quality control, may also contain contaminants such as THC.

Ginkgo biloba

According to clinical practice guidelines issued by the American Academy of Neurology in 2014 and confirmed in February 2023, there is strong evidence that Ginkgo biloba is ineffective in improving cognitive function in people with MS. The guidelines also state that there is weak evidence that Ginkgo biloba may be effective in reducing fatigue.

What does the research show?

• The 2014 evidence-based guidelines from the American Academy of Neurology, which was confirmed in February 2023, concluded that Ginkgo biloba is ineffective in improving cognitive function in people with MS, but that it may be effective over 4 weeks in reducing fatigue in MS. These conclusions are based on four small studies.
• ONE 2012 randomized controlled trial involved 120 participants with MS with some cognitive impairment found that Ginkgo biloba twice daily for 12 weeks did not improve cognitive performance.
• ONE 2013 Cochrane review of four randomized controlled trials evaluated pharmacological treatments, including Ginkgo biloba, for memory disturbances in MS. The reviewers concluded that, based on the available evidence, there is no convincing evidence to support the use of Ginkgo biloba as an effective treatment for memory disturbances in MS patients.

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• Side effects of ginkgo may include headache, nausea, gastrointestinal disturbances, diarrhea, dizziness, or allergic skin reactions. More severe allergic reactions have occasionally been reported.
• There are some data from animal models suggesting that ginkgo may have an effect on the pharmacokinetics of several drugs; however, currently available clinical evidence suggests that low doses do not pose a risk of clinically relevant herb-drug interactions.
• Fresh ginkgo seeds contain large amounts of ginkgotoxin, which can cause serious side effects, including seizures and death. Roasted seeds can also be poisonous. Products made from standardized ginkgo leaf extracts contain little ginkgotoxin and appear to be safe when used orally and properly.
• National Toxicology Program (NTP) studies found that rats and mice developed tumors after being given a specific ginkgo extract for up to 2 years. Further studies are needed to find out which substances in ginkgo caused the tumors and whether taking ginkgo as a dietary supplement affects the risk of cancer in humans.

Omega-3 fatty acid supplements

Although some studies of omega-3 fatty acid supplementation have shown some beneficial effects on relapse rate, inflammation, and improving quality of life, there is currently insufficient evidence to rate any real beneficial effects of omega-3 fatty acid supplementation on MS.

Evidence-based guidelines from the American Academy of Neurology, issued in 2014 and reaffirmed in February 2023, concluded that a low-fat diet with fish oil supplementation is likely to be ineffective in reducing MS-related relapses, disability, or magnetic resonance imaging (MRI) lesions or in improving quality of life.

What does the research show?

• The 2014 evidence-based guidelines of the American Academy of Neurology concluded that, based on three reviewed studies, a low-fat diet with fish oil supplementation is probably ineffective in reducing MS-related relapses, disability, or MR lesions, or in improving fatigue or quality of life.
• ONE 2020 Cochrane review of 30 trials examining dietary interventions including polyunsaturated fatty acids (PUFAs) and dietary plans with recommendations for specific whole foods, macronutrients, and natural health products concluded that PUFA administration may not differ from alternatives in terms of relapse rate, worsening of disability, or overall clinical status in people with MS; however, evidence is inconclusive.

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• Omega-3 fatty acid supplements usually do not have negative side effects. When side effects occur, they typically consist of minor gastrointestinal symptoms.

Vitamin D

To date, the results of studies have been conflicting as to whether vitamin D may provide a therapeutic benefit for people with MS. A 2018 Cochrane review found very low-quality evidence suggesting no benefit of vitamin D for important patient outcomes among people with MS.

What does the research show?

• ONE 2024 systematic review and meta-analysis of 9 studies involving 867 participants found that vitamin D supplementation had no significant impact on clinical outcomes in people with MS.
• ONE 2018 Cochrane review of 12 randomized controlled trials involving a total of 933 participants with MS found very low-quality evidence suggesting no benefit of vitamin D for patient-important outcomes. The reviewers concluded that vitamin D appears to have no effect on recurrence of relapse, worsening of disability and MR lesions. Effects on health-related quality of life and fatigue were unclear.
• Results of a large, 5-year randomized trial in 468 participants with MS suggests that low blood levels of vitamin D may be a risk factor for long-term disease activity and progression. In addition, higher levels of serum levels of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, was associated with lower degree of MS activity, MRI lesion burden, brain atrophy and clinical progression during the 5 years of follow-up. However, more controlled studies are needed to determine whether additional supplementation of already adequate vitamin D levels is therapeutic in any way that may affect disease course and progression.

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• Limited intervention studies in MS suggest that vitamin D supplementation is generally well tolerated in MS.
• High doses can cause fatigue, stomach cramps, nausea, vomiting, kidney damage and other side effects.