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Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, AustraliaMurdoch Children's Research Institute, Royal Children's Hospital, Australia
Murdoch Children's Research Institute, Royal Children's Hospital, AustraliaDepartment of Paediatrics, University of Melbourne, Parkville, Melbourne, Australia
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, AustraliaFlorey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, AustraliaUniversity of Melbourne, Department of Psychiatry, Level 1 North, Main Block, Royal Melbourne Hospital, Parkville, Australia
School of Medicine and Public Health, University Newcastle, AustraliaDepartment of Neurology, John Hunter Hospital, Hunter New England Health, Newcastle, Australia
National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, Canberra, AustraliaCentre for Ophthalmology and Visual Sciences, University of Western Australia, Perth, Australia
Murdoch Children's Research Institute, Royal Children's Hospital, AustraliaNational Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, Canberra, Australia
Thirty-seven RCTs, investigating fourteen nutraceuticals, were included in the review.
•
Some interventions improved biological and/or clinical outcomes in multiple sclerosis.
•
Most trials were relatively small and there were few studies per nutraceutical.
•
There is only preliminary support for the use of nutraceuticals in MS.
Abstract
Background
Due to the considerable burden of multiple sclerosis (MS)-related symptoms and the need to identify effective interventions to prevent disease progression, various nutraceutical interventions have been trialed as adjunctive treatments. The aim of this review was to investigate the efficacy and safety of nutraceutical interventions for clinical and biological outcomes in people with MS.
Methods
In accordance with PRISMA reporting guidelines, a systematic literature search was conducted using three electronic literature databases. Risk of bias was assessed using the Jadad scale.
Results
Thirty-seven randomized controlled trials, investigating fourteen nutraceuticals, were included in the review. Trials that investigated alpha lipoic acid (n = 4/6), ginkgo biloba (n = 3/5), vitamin A (n = 2/2), biotin (n = 1/2), carnitine (n = 1/2), green tea (n = 1/2), coenzyme Q10 (n = 1/1), probiotics (n = 1/1), curcumin (n = 1/1), Andrographis paniculata (n = 1/1), ginseng (n = 1/1), and lemon verbena (n = 1/1) were reported to improve biological (e.g. MRI brain volume change, antioxidant capacity) and/or clinical (e.g. fatigue, depression, Expanded Disability Status Scale) outcomes in multiple sclerosis compared to control. However, most trials were relatively small (average study sample size across included studies, n = 55) and there were few replicate studies per nutraceutical to validate the reported results. Furthermore, some nutraceuticals (e.g. green tea and inosine) should be used with caution due to reported adverse events. Risk of bias across most studies was low, with 31 studies receiving a score between 4 and 5 (out of 5) on the Jadad Scale.
Conclusion
The existing literature provides preliminary support for the use of a number of nutraceutical interventions in MS. However, sufficiently powered long-term trials are required to expand the currently limited literature and to investigate unexplored nutraceuticals that may target relevant pathways involved in MS such as the gut microbiome and mitochondrial dysfunction. Prospero ID: CRD42018111736.
Multiple sclerosis (MS) is characterized by the development of central nervous system inflammatory demyelination and neurodegeneration resulting in irreversible axonal loss and gliosis (
). While highly effective therapies for MS are now available for early active disease, later-stage disease is more refractory to therapy. Persistent MS-related symptoms are a significant problem for many people with MS and effective symptomatic therapies are not always available. For example, despite fatigue affecting up to 80% of people with MS (
Due to the considerable burden of MS-related symptoms and the need to identify effective interventions to prevent or limit disease progression, various nutraceutical interventions that target specific pathways implicated in MS pathology (such as inflammation, oxidative stress, and mitochondrial dysfunction) (
) have been trialed for their efficacy as adjunctive treatments in MS. The most well explored nutraceutical interventions are omega-3 fatty acids and vitamin D, which have been covered in previous systematic reviews and meta-analyses (
Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology.
). A meta-analysis of 12 randomized controlled trials (n = 950 participants) of vitamin D supplementation reported no significant improvement in the Expanded Disability Status Scale (EDSS), annualized relapse rate, T2 MRI lesions, or gadolinium-enhancing MRI lesions compared to placebo (
Clinical trials that have investigated other nutraceutical interventions are emerging and the use of such nutraceuticals is of considerable interest to patients (
Dunn M., Bhargava P., Kalb R. Your patients with multiple sclerosis have set wellness as a high priority—and the National Multiple Sclerosis Society is responding. Your Patients with Multiple Sclerosis have Set Wellness as a High Priority—And the National Multiple Sclerosis Society is Responding. 2015.
). For example, vitamin or dietary supplement-related queries were the third most common in a recent analysis of terms used by MS-related social media, websites, and call centers conducted by the National Multiple Sclerosis Society (
Dunn M., Bhargava P., Kalb R. Your patients with multiple sclerosis have set wellness as a high priority—and the National Multiple Sclerosis Society is responding. Your Patients with Multiple Sclerosis have Set Wellness as a High Priority—And the National Multiple Sclerosis Society is Responding. 2015.
). With a need to inform both clinical interest and research directions, the aim of this review is to investigate the efficacy and safety of emerging nutraceutical interventions for clinical and biological outcomes in people with MS.
2. Methods
2.1 Literature search
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
) and as registered on PROSPERO (CRD42018111736), relevant studies were retrieved from PubMed, Embase, and The Cochrane Library for articles published since journal inception up to August 2018. Google Scholar and the Natural Medicines Database were also searched. Search terms related to commonly used nutraceuticals (e.g. carnitine, alpha lipoic acid) and multiple sclerosis were used (Supplementary Material 1).
To be included in this review, studies needed to meet each of the following eligibility criteria: used a randomized, parallel or cross-over trial study design; investigated a nutraceutical as a stand-alone intervention either as an adjunctive to standard medication or as a monotherapy; recruited only participants with MS; measured any biological or clinical outcome related to multiple sclerosis pathology or symptoms.
Interventions that investigated nutraceuticals in combination with other medical or lifestyle interventions (e.g. diet or exercise) were excluded. Studies that investigated vitamin D or omega-3 polyunsaturated fatty acids were excluded due to the extensive systematic review literature already published on these interventions (
Screening of the publication title and abstract for individual studies was conducted in duplicate by three authors (WM, AJM or MH) with disagreements resolved by consensus. Articles deemed eligible for full-text review were assessed for eligibility independently by three authors (WM, AJM, MH). The following parameters were extracted from included studies: author and date, study design, sample size, total study period, sample characteristics (including age, gender, EDSS score), intervention characteristics (including type of nutraceutical, dose), length of follow up and outcomes.
). This is a five-item scale that assesses risk of bias due to randomization, blinding, and follow up. Studies can receive a score between zero and five, with lower scores indicating a higher risk of bias.
2.4 Data analysis
Due to the heterogeneous data included in this review and the small number of trials per nutraceutical, a meta-analysis was not conducted. Instead, all results reported in this review are based on between-group differences in the end-of-intervention measures, unless otherwise indicated. Data were considered statistically significant if the reported p-value was <0.05.
3. Results
3.1 Study selection
As represented in Fig. 1, the search strategy resulted in 4532 de-duplicated studies that were screened to identify 37 eligible studies for inclusion (see Table 1).
Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
Double blind placebo controlled multicentre study of ginkgolide B in treatment of acute exacerbations of multiple sclerosis. The Ginkgolide Study Group in multiple sclerosis..
Diamond B.J., Johnson S.K., Kaufman M., Shiflett S.C., Graves L. A randomized controlled pilot trial: the effects of EGb 761 on information processing and executive function in multiple sclerosis. Explore (New York, NY). 2013;9(2):106–7.
Processing speed (p = 0.05) and verbal intrusions (p = 0.03) improved in the intervention group compared to the placebo group. No other significant between-group differences reported.
5
Country: USA
Age in years (mean): 50.75
Sample size (n): 23
Total study period (weeks): 4
Johnson et al. (2013)
Study design: RCT
MS diagnosis: Mixed diagnoses
Ginkgo Biloba (Egb 761 extract, 240 mg/day)
Depression (using the Center for Epidemiologic Studies of Depression Scale), anxiety (using the State-Trait Anxiety Inventory)Fatigue (using the Modified Fatigue Impact Scale), symptom severity (using the Symptom Inventory) and functional performance (using the Functional Assessment of Multiple Sclerosis)
Fatigue significantly improved in the intervention group (p = 0.024), compared to the placebo group. No other significant between group differences.
California Verbal Learning Test II, Stroop Test, Controlled Oral Word Association Test, Paced Auditory Serial Addition Task, Perceived Cognitive deficits, Perceived Cognitive deficits (using the Sclerosis Neuropsychological Screening Questionnaire), Social integration (using the Community Integration Questionnaire), Fatigue (using the Modified Fatigue Impact Scale), Depression (using the Beck Depression Inventory II)
No significant between-group differences reported.
Working memory and sustained attention, phonemic fluency, information processing speed and visual tracking, visual information processing, divided attention and selective attention, which measures cognitive processing speed, concentration, selective attention, mental flexibility and interference susceptibility, verbal memory and learning, depression (using the Beck Depression Index II), QoL (using the MS Quality of Life Index)
Stroop Color and Word Test (p = 0.015) and the Retrospective Memory Scale subscale of quality of life (p = 0.015), improved in the intervention group compared to the placebo group. No other significant between-group differences reported.
Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial.
MS diagnosis: Primary progressive or secondary progressive
Acetyl L Carnitine (1000 mg/day)
Fatigue (using the Fatigue Severity Scale and the Fatigue Impact Scale), depression (using the Beck Depression Inventory), social interaction (using the Social Experience Checklist)
Fatigue significantly improved in the intervention group compared to placebo. (p = 0.039)
3
Country: Italy
Age in years (mean): 44
No other significant between-group differences reported.
Sample size (n): 93
Total study period (months): 6 (6-month open label extension phase not extracted)
MD1003 (High-Dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, Placebo-Controlled Study.
Impairment of the optic nerve, VEPs, automated perimetry, and OCT including RNFL and thickness, QoL (using the Multiple Sclerosis Quality of Life-54 and the National Eye Institute 25-Item Visual Function Questionnaire), patient- and clinician evaluated global impression scale
No significant between-group differences reported.
5
Country: France/UK
Age in years (mean): 41
Sample size (n): 93
Total study period (weeks): 24 (6-month open label extension phase no extracted)
MS diagnosis: Primary progressive or secondary progressive
Biotin (MD1003; 300 mg/day)
Improved disability, EDSS, clinician global impression of change, patient impression of change, QOL (using the Short Form 36 Health Survey), fatigue (using the modified Fatigue Impact Scale)
MS-related disability (p = 0.005), EDSS (p = 0.01), CGI scores (p < 0.001), SGI scores (p = 0.009) significantly improved in the intervention group compared to placebo.
4
Country: France
Age in years (mean): 51
In as post-hoc analysis, there were significantly more participants with >20% improvement in TW25 times at month 9, compared with the placebo group (p = 0.03)."
Sample size (n): 154
Intervention group reported significantly worse on general health QOL subscale (p = 0.03)
Total study period (months): 12 (12-month open label extension phase not extracted)
Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
Postprandial increase in fat oxidation, efficiency of muscle work, postprandial profiles of plasma glucose, insulin, and free fatty acids
The intervention group had a significantly lower postprandial energy expenditure during exercise than placebo (p = 0.004). No other significant between-group differences reported.
4
Country: Germany
Age in years (mean): 42
Sample size (n): 20
Total study period (weeks): 16 weeks per intervention
Retinyl palmitate
Bitarfen et al. (2016)
Study design: RCT
MS diagnosis: Relapse remitting
Retinyl palmitate (25000 IU/d and 10000 IU/d for 6 months each)
Depression (using the Beck Depression Inventory-II), fatigue (using the modified fatigue impact scale)
Depression significantly improved significantly in the intervention group, compared to the placebo group (p = 0.01).
5
Country: Iran
Age in years (mean): 31.3
Total fatigue (p = 0.004) and subscales for physical (p = 0.02), cognitive (p = 0.02), and psychosocial (p = 0.02) function significantly improved in the intervention group, compared to the placebo group
Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS).
Nocturia episodes, subjective severity, QoL (using the MS Quality of Life Scale), sleep quality (using the Pittsburgh Sleep Quality Index), EDSS, urinary tract symptoms
No significant between-group differences reported.
5
Country: UK
Age in years (mean): 54.8
Sample size (n): 34
Total study period (weeks): 12 (6 weeks per intervention phase)
Fatigue (using the Fatigue Severity Scale), rates of perceived exertion, knee extension total work, muscle power (knee extension), muscle power (knee flexion)
No significant between-group differences reported.
4
Country: USA
Age in years (mean): 44
Sample size (n): 11
Total study period (weeks): 2 weeks per intervention
Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
Probiotics (Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum and Lactobacillus fermentum, 2 x 10^9 CFU/g each)
EDSS, QoL(using the general health questionnaire), depression and anxiety (using the Beck Depression Inventory and the Depression Anxiety and Stress Scale), CRP, nitric oxide metabolites, malondialdehyde, insulin, HOMA IR, beta cell function, total/HDL cholesterol, insulin sensitivity check index, HDL cholesterol, BMI, total antioxidant capacity, fasting plasma glucose, glutathione
EDSS (p = 0.001), QOL (p < 0.001), Depression and anxiety (p < 0.001), CRP (p = 0.01), Nitric oxide metabolites (p = 0.002), malondialdehyde (p = 0.04), insulin, HOMA IR (p = 0.001), beta cell function (p < 0.001), total/HDL cholesterol (p = 0.02), insulin sensitivity check index (p < 0.001), HDL cholesterol (p = 0.02) improved in the intervention group compared to the placebo group. No other significant between group differences.
No other significant between-group differences reported.
Sample size (n): 50
Total study period (months): 6
MS14, a proprietary herbal formulation
Nabavi et al. (2009)
Study design: RCT-cross over
MS diagnosis: Relapse remitting or Secondary progressive
MS14, a proprietary herbal formulation containing 90% Penaeus latisculatus, 5% Apium graveolens and 5% Hypericum perforatum (50 mg/kg/day)
QoL (using the Hamburg quality of life questionnaire on multiple sclerosis)
Lower limb mobility sub score significantly improved in the intervention group (p = 0.048), compared to the placebo group. No other significant between-group differences reported.
3
Country: Iran
Age in years (mean): 30.8
Sample size (n): 38
Total study period (weeks): 3
Coenzyme Q10
Sanoobar et al. (2015)
Study design: RCT
MS diagnosis: Relapse remitting
Coenzyme Q10 (500 mg/day)
Fatigue (using the Fatigue Severity Scale), depression (using the Beck Depression Inventory)
Fatigue (p < 0.001) and depression (p < 0.001) was significantly decreased in participants receiving the intervention compared to the placebo group
Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter, randomized, placebo-controlled, double-blind trial.
Cranberry extract (36mg proanthocyanidins per day)
First symptomatic urinary tract infection, number of UTIs, QoL (using the Qualiveen scale), EDSS, symptomatology of urinary disorders, relapses antibiotic consumption
No significant between group differences except at month 9 where placebo group had higher QoL compared to intervention (p = 0.02)
Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial.
A novel oral nutraceutical formula of omega-3 and omega-6 fatty acids with vitamins (PLP10) in relapsing remitting multiple sclerosis: a randomised, double-blind, placebo-controlled proof-of-concept clinical trial.
Riboflavin supplementation to patients with multiple sclerosis does not improve disability status nor is riboflavin supplementation correlated to homocysteine.
Int. J. Vitamin Nutr. Res. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung Journal international de vitaminologie et de nutrition.2013; 83: 281-290
Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study.
Andrographis paniculata (340 mg/day, total andrographolides: 170 mg)
Fatigue (using the FSS), EDSS
Fatigue was significant improvement in the intervention group compared to placebo (p value not reported). No other significant between-group differences reported.
All studies were randomized controlled trials with 31 being parallel designs and 6 being cross-over. Most studies were conducted in Iran (n = 13) or the USA (n = 10). The most common trial duration was 12 weeks, with the longest trial running for 3 years. Sample sizes ranged from 11 to 171 participants with an average of 55 participants. All but one trial compared the nutraceutical intervention to placebo (
Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial.
). Risk of bias across most studies was low with 31 studies receiving a score between 4 and 5 (out of 5) on the Jadad Scale.
The average age of participants was 40 years old. Most participants were women (71%). Studies mostly recruited a cohort of mixed MS types (n = 12) or relapsing remitting only (n = 21), with an average EDSS of 3. In order of frequency, the interventions investigated in the included studies were alpha lipoic acid (n = 6) (
Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
Johnson S.K., Diamond B.J., Rausch S., Kaufman M., Shiflett S.C., Graves L. The effect of Ginkgo biloba on functional measures in multiple sclerosis: a pilot randomized controlled trial. Explore (New York, NY). 2006;2(1):19–24.
Double blind placebo controlled multicentre study of ginkgolide B in treatment of acute exacerbations of multiple sclerosis. The Ginkgolide Study Group in multiple sclerosis..
Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial.
MD1003 (High-Dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, Placebo-Controlled Study.
Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS).
Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter, randomized, placebo-controlled, double-blind trial.
Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial.
A novel oral nutraceutical formula of omega-3 and omega-6 fatty acids with vitamins (PLP10) in relapsing remitting multiple sclerosis: a randomised, double-blind, placebo-controlled proof-of-concept clinical trial.
Riboflavin supplementation to patients with multiple sclerosis does not improve disability status nor is riboflavin supplementation correlated to homocysteine.
Int. J. Vitamin Nutr. Res. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung Journal international de vitaminologie et de nutrition.2013; 83: 281-290
Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study.
Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
In a 2-year trial, participants (n = 54) that received alpha lipoic acid had a significantly lower percentage change in brain volume compared to placebo (p = 0.002) but there was no effect on quality of life (using the RAND 36-Item Short Form Health Survey), mobility, cognition (using the single digit modality test), or EDSS (
Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
Five studies investigated the use of ginkgo biloba extracts. One study investigated the use of 240 mg/day or 360 mg/day of ginkgolide B over a 7-day period in 104 participants experiencing a relapse (
Double blind placebo controlled multicentre study of ginkgolide B in treatment of acute exacerbations of multiple sclerosis. The Ginkgolide Study Group in multiple sclerosis..
). No significant between-group differences were reported for all outcomes: EDSS, the Hauser ambulation index, and fatigue.
In the four remaining studies, the use of a standardized extract (29.7 mg of flavoglycosides and 7.3 mg of terpene lactones per 120 mg) of ginkgo biloba, EGb 76, was investigated at a dose of 240 mg per day (
Johnson S.K., Diamond B.J., Rausch S., Kaufman M., Shiflett S.C., Graves L. The effect of Ginkgo biloba on functional measures in multiple sclerosis: a pilot randomized controlled trial. Explore (New York, NY). 2006;2(1):19–24.
). One 4-week trial (n = 23) reported an improvement in fatigue using the Modified Fatigue Impact Scale (p = 0.024) but no significant difference in depression, anxiety, symptom severity, and functional capacity (
Johnson S.K., Diamond B.J., Rausch S., Kaufman M., Shiflett S.C., Graves L. The effect of Ginkgo biloba on functional measures in multiple sclerosis: a pilot randomized controlled trial. Explore (New York, NY). 2006;2(1):19–24.
). Using the same dataset, another study reported improvements in processing speed (using the Visual Threshold Serial Addition Test; p = 0.05) and performance on the California Verbal Learning Test (p = 0.03) compared to the placebo group (
Diamond B.J., Johnson S.K., Kaufman M., Shiflett S.C., Graves L. A randomized controlled pilot trial: the effects of EGb 761 on information processing and executive function in multiple sclerosis. Explore (New York, NY). 2013;9(2):106–7.
). A 12-week trial (n = 43) reported significant improvements in a quality of life sub-score, retrospective memory (p = 0.015), and measures of concentration using the Stroop Color-Word test (p = 0.015) but no benefits for other cognitive measures (
). There were no significant differences between the ginkgo and placebo group on visual-spatial memory and attention/concentration (using the Rey-Osterreith Complex Figure Test and digit span test, respectively) (
Diamond B.J., Johnson S.K., Kaufman M., Shiflett S.C., Graves L. A randomized controlled pilot trial: the effects of EGb 761 on information processing and executive function in multiple sclerosis. Explore (New York, NY). 2013;9(2):106–7.
). In a larger 12-week follow-up trial (n = 120), no significant difference was reported for any cognitive measure or fatigue (using the Modified Fatigue Impact Scale) and depression (using the Beck Depression Inventory II) (
Three studies investigated the use of inosine, either as a stand-alone intervention or combined with interferon, compared to placebo in 16–159 participants over 1–2 years (
Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
) were measured in at least one study; however, no significant differences were reported in any study.
3.3.4 Acetyl-L-Carnitine
One cross-over trial (3 months per intervention) investigated 1000 mg of acetyl-L-carnitine compared to amantadine in 36 participants. There was improvement in fatigue as measured using the Fatigue Severity Scale (p = 0.039), but not when using the Fatigue Impact Scale (
Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial.
). No significant difference was found for depression (using the Beck Depression Inventory) or social interaction (using the Social Experience Checklist). In contrast, another 4-week trial (n = 30) that investigated the use of 2000 mg of acetyl-L-carnitine reported no improvement in fatigue (using the Modified Fatigue Impact Scale) or quality of life when compared to placebo (
MD1003 (High-Dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, Placebo-Controlled Study.
). This trial reported a significant improvement in the primary outcome, disability reversal (defined as EDSS decrease of ⩾1 point, ⩾0.5 for EDSS 6–7, or a ⩾20% decrease in timed 25-foot walk time, compared to baseline; p = 0.005). The proportion of patients with EDSS progression during the blinded phase was not significantly different across the arms of the trial (p = 0.07). However, there was a significant improvement during the following open-label phase in the group that initially received the intervention compared to those that initially received the placebo (p = 0.005). A post hoc analysis showed that there was a significantly higher number of patients in the treatment group that had >20% improvement in 25-foot walk times from baseline during the blinded phase compared to the placebo group (p = 0.03). The intervention group also had significantly better clinician-assessed Clinical Global Impression Scale scores (p < 0.001) and subject-assessed Clinical Global Impression Scale scores (p = 0.009) at month 12 compared with the placebo-treated participants.
The second trial (n = 93) was also a randomized, double-blind, placebo-controlled trial with an open-label extension phase; however, each phase ran for 6 months instead of 12 (
MD1003 (High-Dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, Placebo-Controlled Study.
). This trial reported no significant difference in measures of visual acuity, quality of life, and subject- or clinician- assessed Clinical Global Impression Scale scores. EDSS was not assessed as a study outcome in this trial.
3.3.6 Green tea extract
Two studies investigated the use of a green tea extract standardized to 600–800 mg/day of epigallocatechin gallate (EGCG), a polyphenol compound abundant in green tea (
Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
). One cross-over trial (n = 20) reported that a 16-week intervention of green tea extract resulted in lower postprandial energy expenditure during exercise than placebo (p = 0.004). The same trial also reported sex differences in energy expenditure in response to EGCG (
). Another trial investigated the effect of a propriety green tea extract (n = 13), Polyphenon E, on N-acetyl aspartate (using brain magnetic resonance spectroscopic imaging), EDSS, and Multiple Sclerosis Functional Composite score, but was halted early due to adverse liver outcomes (See Adverse Events section for further details) (
Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
A trial (n = 101) using retinyl palmitate (25000 IU and 10000 IU per day for 6 months each) reported a significant improvement in depression using the Beck Depression Inventory II and fatigue using the Modified Fatigue Impact Scale (p = 0.004; total score) and its subscales for physical (p = 0.02), cognitive (p = 0.02), and psychosocial (p = 0.02) function compared to placebo (
). A second trial (n = 39) reported that retinyl palmitate (25000 IU per day) significantly improved gene expression of inflammatory markers IFN-γ (p = 0.002) and T-bet (p = 0.001) in a 6-month intervention (
In a 52-week trial that investigated melatonin supplementation (3 mg/day) (n = 26), there were no significant differences between the intervention group and the control group in the following outcomes: relapse rates, EDSS, number and volume of brain lesions, fatigue (using the Modified Fatigue Impact Scale), depression (using the Beck Depression Inventory-II), and Multiple Sclerosis Functional Composite score (
). Similarly, a cross-over trial of 34 participants receiving 2 mg per day of melatonin for 12 weeks reported no significant difference in nocturia episodes, subjective severity of nocturia, quality of life (using the MS Quality of Life Scale), lower urinary tract symptoms, sleep quality (using the Pittsburgh Sleep Quality Index), or EDSS (
Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS).
Two studies investigated the effect of creatine monohydrate. Using a cross-over trial design, the first trial (n = 11) reported that a two-week regimen of creatine monohydrate (20 g/day first week, 5 g/day second week) did not significantly influence fatigue (using the Fatigue Severity Scale), rates of perceived exertion, or muscle power (
). The second (n = 16) found that a 5-day regimen of creatine (20 g/day) did not improve body composition, exercise capacity, or muscle metabolites (phosphocreatine, ATP, total creatine), relative to placebo (
Lemon verbena (600 mg/day, standardized to 10% verbascoside) reduced serum C-reactive protein and IL-4 and IL-10 levels compared to placebo in one 4-week trial in people with secondary progressive MS (n = 32) (
). The same trial reported no significant between-group differences in serum IFN-y, IL-12, IL-23, IL-6, TNF-α, or TGF-β.
3.3.11 Probiotics
One 12-week trial (n = 60) that investigated the use of a multi-strain probiotic formulation (containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum and Lactobacillus fermentum; 2 × 10[9] CFU/g each) reported significant improvement in EDSS (p < 0.001), depression (using the Beck Depression Inventory and the Depression Anxiety and Stress Scale; p < 0.001), quality of life (using the General Health Questionnaire; p < p < 0.001), C-reactive protein (p = 0.01), nitric oxide metabolites (p = 0.002), malondialdehyde (p = 0.04), insulin (p < 0.001), Homeostatic Model Assessment of Insulin Resistance (HOMA IR; p < 0.001), beta cell function (p < 0.001), total/HDL cholesterol (p = 0.02), insulin sensitivity check index (p < 0.001), and HDL cholesterol (p = 0.02). No significant difference was reported for BMI, total antioxidant capacity, fasting plasma glucose, or glutathione (
Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
). There was also an improvement in the following serum inflammatory cytokines: IFN–γ (p = 0.0025), CCL5 (p = 0.0003), CCL2 (p = 0.0029). There were no between-group differences in serum IL-1β, IL-6, IL-8, TNF-α.
3.3.13 MS14, propriety herbal formulation
MS14, a propriety herbal formulation (500 mg/day) containing 90% Penaeus latisculatus, 5% Apium graveolens and 5% Hypericum perforatum, was reported in one 6-week (3 weeks per trial arm) cross-over trial (n = 38) to improve the lower limb motion sub-score (p = 0.048) of a quality of life measure (the Hamburg Quality of Life Questionnaire on Multiple Sclerosis). There was no significant difference in total score or in other subscores of the quality of life measure (
After a 12-week intervention (n = 48) using co-enzyme Q10 (500 mg/day), participants reported reduced fatigue (using the Fatigue Severity Scale), and depression (using the Beck Depression Inventory) compared to the placebo group (p < 0.001) (
No significant differences between placebo and intervention were reported in a one year trial (n = 171) of cranberry extract (36 mg proanthocyanidins per day) for first symptomatic urinary tract infection, number of urinary tract infections, quality of life (using the Qualiveen scale), EDSS, relapses, or antibiotic consumption (
Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter, randomized, placebo-controlled, double-blind trial.
One trial (n = 97) that investigated a 26-week intervention of glucosamine sulphate (1000 mg/day) reported no significant between-group differences in relapse rate and EDSS progression (
Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial.
In one trial (n = 40) that investigated a 30-month intervention of gamma-tocopherol (760 mg/day), there were no significant between-group differences in annualized relapse rate, EDSS progression, and change in T2 lesions (
A novel oral nutraceutical formula of omega-3 and omega-6 fatty acids with vitamins (PLP10) in relapsing remitting multiple sclerosis: a randomised, double-blind, placebo-controlled proof-of-concept clinical trial.
One 6-month study of 29 participants investigated the use of 10 mg/day of riboflavin and reported no significant difference in EDSS (p = 0.25) or homocysteine levels (p = 0.9)_at follow-up (
Riboflavin supplementation to patients with multiple sclerosis does not improve disability status nor is riboflavin supplementation correlated to homocysteine.
Int. J. Vitamin Nutr. Res. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung Journal international de vitaminologie et de nutrition.2013; 83: 281-290
In 24 participants, a 1-year trial investigated the effect of Andrographis paniculata at a dose of 340 mg/day (total andrographolides: 170 mg) and a reported significant between group improvement in fatigue (p-value not reported) but not EDSS in intervention group compared to placebo (
Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study.
). The study also reported that 4 participants that received the placebo had new T2 lesions or new gadolinium-enhancing lesions at 12 months compared to 1 in the intervention group (no statistical analysis reported).
3.3.20 Ginseng
A 3-month study in 60 participants investigated the use of 500 mg/day ginseng and reported significant improvements in fatigue (p = 0.046) and quality of life (p ≤ 0.0001) at follow-up compared to placebo (
In studies that reported adverse events, gastrointestinal-related side-effects such as nausea were most commonly reported. One trial reported vomiting and dehydration requiring hospitalization in one participant receiving alpha lipoic acid; symptoms, resolved once alpha lipoic acid was ceased (
). This trial also reported that two participants who received alpha lipoic acid experienced glomerulonephritis or renal failure. However, the consulting nephrologist did not consider these adverse events to be related to the intervention (
). Two of the three studies that investigated the use of inosine reported adverse events. One study reported renal colic (n = 2 participants) and asymptomatic hyperuricemia (n = 10 participants) (
). One trial that investigated a green tea extract was terminated early due to abnormal liver function test results detected in most participants undergoing the intervention (5 of 6) with one considered a grade 4 serious adverse event (AST and ALT levels 15 times the normal range in conjunction with elevated bilirubin) (
Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
). One trial that investigated biotin reported that the incidence of MS relapse was higher in the intervention group (13.8%) than in the placebo group (3.6%) (
MD1003 (High-Dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, Placebo-Controlled Study.
). Another trial that investigated biotin identified one participant with a mucocutaneous rash, which was considered as possibly relating to the intervention (
). In the one study that investigated the use of Andrographis paniculata, one participant in the intervention arm experienced a skin rash that resolved with anti-histamines (
Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study.
This review identified multiple nutraceutical interventions that have been investigated for their effect on a range of clinical and biological outcomes in people with MS. In sixteen of the 30 included studies, nutraceuticals including alpha lipoic acid, ginkgo biloba, vitamin A, biotin, carnitine, green tea, coenzyme Q10, probiotics, curcumin and lemon verbena were reported to improve biological (e.g. MRI brain volume change, antioxidant capacity) and clinical (e.g. fatigue, depression, EDSS) outcomes in people with MS.
Fatigue and depression were the most commonly reported MS-related symptoms to improve following nutraceutical intervention. Seven studies reported improvement in measures of fatigue and/or depression when investigating coenzyme Q10, retinyl palmitate, probiotics, acetyl L carnitine, ginseng, Andrographis paniculate, or gingko biloba (
Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial.
Johnson S.K., Diamond B.J., Rausch S., Kaufman M., Shiflett S.C., Graves L. The effect of Ginkgo biloba on functional measures in multiple sclerosis: a pilot randomized controlled trial. Explore (New York, NY). 2006;2(1):19–24.
Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study.
Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
). Inflammatory markers were the most commonly reported biological outcomes with five studies reporting significant improvement when using the following interventions: curcumin, probiotics, lemon verbena, retinyl palmitate, or alpha lipoic acid (
Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
Although the existing evidence provides preliminary evidence for the use of nutraceuticals in MS, most trials had relatively small sample sizes and there are few replicate studies per nutraceutical to confirm the reported results. In addition, most included studies have been relatively short-term, which may be unable to capture potential longer-term changes. Until sufficiently powered long-term studies are conducted that can replicate the existing studies, recommendations regarding the use of the included nutraceuticals remains premature. In line with the limited number of trials identified in this review, The National MS Society Wellness Research Working Group has recently stated that the investigation of individual and/or combined nutrients (as well as dietary interventions) in the management of physical health and disease course is a research priority (
). However, despite insufficient evidence of their benefit, the use of commercially available nutraceuticals by people with MS is high with an estimated 82.1% of respondents saying they take at least one dietary supplement per day (
). Due to this high prevalence of existing use, there is a need to improve the evidence-base to inform clinical recommendations.
In addition to further trials to assess efficacy, it will also be important to assess the safety of these interventions within the MS population to ensure they do not interfere with MS-specific medication or exacerbate MS symptoms. For example, resveratrol was reported in one study to exacerbate clinical signs including demyelination and inflammation in an animal model of MS (
). Furthermore, while many nutraceutical compounds are present in food, nutraceutical extracts that deliver compounds far in excess of what is regularly consumed may pose safety concerns. For example, in this review, one trial that investigated green tea extract was halted due to abnormal liver enzymes. Green tea extracts have been reported in other populations to also be associated with liver-related adverse events (
MD1003 (High-Dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, Placebo-Controlled Study.
MD1003 (High-Dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, Placebo-Controlled Study.
In contrast to single-compound nutraceuticals (e.g. coenzyme Q10, Acetyl-L-Carnitine), food-derived extracts (e.g. green tea, lemon verbena) contain a complexity of various bioactive compounds that can significantly differ between products (
). Given the complexity of food-derived nutraceuticals, there is a need for clinical trials to investigate formulations that are standardized to a specific level of bioactive compounds and for researchers to report the level of bioactive compounds to improve between-study comparison.
As new evidence uncovers pathways implicated in MS symptoms and severity, there is a need to investigate nutraceuticals that specifically target these pathways. Assessing markers of underlying pathways may also provide insight into inter-individual variations in response to specific nutraceutical interventions. Nitric oxide-mediated impaired mitochondrial dysfunction has been implicated in the pathogenesis and progression of MS. Proposed mechanisms include direct damage of mitochondrial DNA, damage of, or interaction with, respiratory chain complex proteins with consequent impairment of the respiratory chain function, or through damage to mitochondrial membranes (
). Others have suggested that in the early neuroinflammatory process, axonal mitochondrial trafficking dynamics could be affected, with consequent perturbation of local energy levels (
). A recent review identified several nutraceuticals that may target mitochondrial dysfunction including some nutraceuticals that have been trialed in preliminary studies in people with MS such as alpha lipoic acid, vitamin D, and coenzyme Q10 (
Metabolites within the kynurenine pathway have also been implicated in MS as well as other neurological disorders. For example, the metabolites kynurenic acid, quinolinic acid, and tryptophan were critical determinants in predicting MS severity (
). Few studies have evaluated interventions that target the kynurenine pathway in humans. However, probiotics and polyphenols have been demonstrated to affect the kynurenine pathway in non-MS subjects and in animal models (
Probiotic supplements beneficially affect tryptophan–kynurenine metabolism and reduce the incidence of upper respiratory tract infections in trained athletes: a randomized, double-blinded, Placebo-Controlled Trial.
A rapidly expanding area of research has now implicated changes in the composition and function of commensal bacteria within the gut microbiome in MS pathophysiology and symptomology (
). Pro- and pre- biotic interventions that target the gut microbiota are currently being investigated for a wide-range of chronic diseases. While one trial in our review reported a significant improvement in a range of outcomes from probiotic supplementation (
Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
have demonstrated improvements in outcomes in animal models of neuroinflammation used to study MS. However, they have not yet been investigated in people with MS. In addition, composite interventions of selected nutraceuticals that exhibit synergistic effects may provide additional benefit beyond single compound nutraceutical interventions and should be investigated in future trials. Finally, while there have been multiple interventions investigated for their effect on outcomes such as EDSS, fatigue, and depression, other commonly reported outcomes such as cognitive function, quality of life and bowel/bladder/sexual dysfunction have been less explored. It is recommended that these areas be investigated in future trials.
5. Conclusion
The results of this review provide preliminary evidence for the emerging use of nutraceutical interventions in the MS setting. However, due to the small sample sizes and a lack of replication or validation studies using the same agent and outcome measures, recommendations for clinical use are premature. Sufficiently powered trials are required to expand the currently limited literature and to investigate currently unexplored nutraceuticals that may target relevant underlying pathways involved in MS such as the gut microbiota and mitochondrial dysfunction.
We would like to thank and acknowledge the RELIEF trial investigator team for supporting this publication. OMD is supported by the National Health and Medical Research Council (APP 1145634) and gratefully acknowledges their support.
Funding and sponsorship
No direct funding was used to create this manuscript. WM is funded by a Deakin University postdoctoral fellowship. The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. MB is supported by a NHMRC Senior Principal Research Fellowship(APP1059660 and APP1156072). MH is funded by Australian Rotary Health PhD Scholarship. OMD is a R.D. Wright Biomedical Research Fellow (APP 1145634) and has received grant support from the Brain and Behavior Foundation, Simons Autism Foundation, Stanley Medical Research Institute, Deakin University, Lilly, NHMRC and ASBDD/Servier. She has also received in kind support from BioMedica Nutracuticals, NutritionCare and Bioceuticals. ML is funded by a Deakin University PhD Scholarship. FJ has received Grant/Research support from the Brain and Behaviour Research Institute, the National Health and Medical Research Council (NHMRC), Australian Rotary Health, the Geelong Medical Research Foundation, the Ian Potter Foundation, Eli Lilly, Meat and Livestock Australia, The A2 Milk Company, BeFit Foods, Woolworths Limited, Fernwood Foundation, The Wilson Foundation, and The University of Melbourne and has received speakers honoraria from Sanofi-Synthelabo, Janssen Cilag, Servier, Pfizer, Health Ed, Network Nutrition, Angelini Farmaceutica, Eli Lilly and Metagenics. She is supported by an NHMRC Career Development Fellowship(2) (#1108125). Felice Jacka is currently writing two books for commercial publication and has a personal belief that good diet quality is important for mental and brain health. AJM is funded by an Australian Rotary Health/Ten Island Tassie Tag Along Tour Funding Partner PhD Scholarship. RL is funded by a NHMRC Senior Research Fellowship(#1107343)
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Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
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Int. J. Vitamin Nutr. Res. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung Journal international de vitaminologie et de nutrition.2013; 83: 281-290
A novel oral nutraceutical formula of omega-3 and omega-6 fatty acids with vitamins (PLP10) in relapsing remitting multiple sclerosis: a randomised, double-blind, placebo-controlled proof-of-concept clinical trial.
Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial.
Probiotic supplements beneficially affect tryptophan–kynurenine metabolism and reduce the incidence of upper respiratory tract infections in trained athletes: a randomized, double-blinded, Placebo-Controlled Trial.
Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial.
MD1003 (High-Dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: a randomized, double-blind, Placebo-Controlled Study.
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