Advertisement

The effect of emerging nutraceutical interventions for clinical and biological outcomes in multiple sclerosis: A systematic review

Published:November 02, 2019DOI:https://doi.org/10.1016/j.msard.2019.101486

      Highlights

      • 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.

      Keywords

      1. Introduction

      Multiple sclerosis (MS) is characterized by the development of central nervous system inflammatory demyelination and neurodegeneration resulting in irreversible axonal loss and gliosis (
      • Reich D.S.
      • Lucchinetti C.F.
      • Calabresi P.A
      Multiple sclerosis.
      ). 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 (
      • Simpson Jr., S.
      • Tan H.
      • Otahal P.
      • Taylor B.
      • Ponsonby A.L.
      • Lucas R.M.
      • Blizzard L.
      • Valery P.C.
      • Lechner-Scott J.
      • Shaw C.
      • Williams D.
      • van der Mei I
      Anxiety, depression and fatigue at 5-year review following CNS demyelination.
      ), a meta-analysis concluded that current pharmacotherapy has little effect on MS-related fatigue (effect size 0.07 (95%CI −0.22, 0.37); p = 0.63) (
      • Asano M.
      • Finlayson M.L.
      Meta-Analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication.
      ).
      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) (
      • Lassmann H.
      Pathology and disease mechanisms in different stages of multiple sclerosis.
      ) 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 (
      • Farinotti M.
      • Vacchi L.
      • Simi S.
      • Di Pietrantonj C.
      • Brait L.
      • Filippini G
      Dietary interventions for multiple sclerosis.
      ;
      • Zheng C.
      • He L.
      • Liu L.
      • Zhu J.
      • Jin T
      The efficacy of vitamin D in multiple sclerosis: a meta-analysis.
      ;
      • Yadav V.
      • Bever Jr., C.
      • Bowen J.
      • Bowling A.
      • Weinstock-Guttman B.
      • Cameron M.
      • Bourdette D.
      • Gronseth G.S.
      • Narayanaswami P
      Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology.
      ;
      • McLaughlin L.
      • Clarke L.
      • Khalilidehkordi E.
      • Butzkueven H.
      • Taylor B.
      • Broadley S.A
      Vitamin D for the treatment of multiple sclerosis: a meta-analysis.
      ). 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 (
      • Zheng C.
      • He L.
      • Liu L.
      • Zhu J.
      • Jin T
      The efficacy of vitamin D in multiple sclerosis: a meta-analysis.
      ;
      • McLaughlin L.
      • Clarke L.
      • Khalilidehkordi E.
      • Butzkueven H.
      • Taylor B.
      • Broadley S.A
      Vitamin D for the treatment of multiple sclerosis: a meta-analysis.
      ). Similarly, a Cochrane review reported that omega-3 supplementation provided no significant improvements to disease progression (
      • Farinotti M.
      • Vacchi L.
      • Simi S.
      • Di Pietrantonj C.
      • Brait L.
      • Filippini G
      Dietary interventions for multiple sclerosis.
      ).
      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.

      ;
      • Claflin S.B.
      • van der Mei I.A.F.
      • Taylor B.V
      Complementary and alternative treatments of multiple sclerosis: a review of the evidence from 2001 to 2016.
      ). 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 (
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gøtzsche P.C.
      • Ioannidis J.P.A.
      • Clarke M.
      • Devereaux P.J.
      • Kleijnen J.
      • Moher D
      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 (
      • Farinotti M.
      • Vacchi L.
      • Simi S.
      • Di Pietrantonj C.
      • Brait L.
      • Filippini G
      Dietary interventions for multiple sclerosis.
      ;
      • Zheng C.
      • He L.
      • Liu L.
      • Zhu J.
      • Jin T
      The efficacy of vitamin D in multiple sclerosis: a meta-analysis.
      ).

      2.2 Data extraction

      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.

      2.3 Assessment of study risk of bias

      Risk of bias was assessed using the Jadad Scale (
      • Jadad A.R.
      • Moore R.A.
      • Carroll D.
      • Jenkinson C.
      • Reynolds D.J.
      • Gavaghan D.J.
      • McQuay H.J
      Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
      ). 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).
      Table 1Summary table of included studies.
      Author/DateStudy detailsSample detailsInterventionOutcomesResultsJadad score
      Alpha Lipoic acid
      • Khalili M.
      • Soltani M.
      • Moghadam S.A.
      • Dehghan P.
      • Azimi A.
      • Abbaszadeh O
      Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients: a randomized clinical trial.
      Study design: RCTMS diagnosis: Relapse remittingAlpha lipoic acid (1200 mg/day)ADMA, EDSSNo significant between-group differences reported.5
      Country: IranAge in years (mean): 32
      Sample size (n): 31
      Total study period (weeks): 12
      • Spain R.
      • Powers K.
      • Murchison C.
      • Heriza E.
      • Winges K.
      • Yadav V.
      • Cameron M.
      • Kim E.
      • Horak F.
      • Simon J.
      • Bourdette D
      Lipoic acid in secondary progressive MS: a randomized controlled pilot trial.
      Study design: RCTMS diagnosis: Secondary progressiveAlpha Lipoic Acid (1200 mg/day)Annualized percent change brain volume, mobility, QoL (using the RAND 36-Item Short Form Health Survey), cognition, EDSSAnnualized PCBV was significantly less in the intervention group compared to placebo (p = 0.002).5
      Country: USAAge in years (median): 57.9 (intervention), 59.7 (control)No other significant between-group differences reported
      Sample size (n): 54
      Total study period (years): 2
      • Khalili M.
      • Azimi A.
      • Izadi V.
      • Eghtesadi S.
      • Mirshafiey A.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Sanoobar M.
      • Eskandari G.
      • Farhoudi M.
      • Amani F
      Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Khalili M.
      • Eghtesadi S.
      • Mirshafiey A.
      • Eskandari G.
      • Sanoobar M.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Moftakhar S.
      • Azimi A
      Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.
      )
      Study design: RCTMS diagnosis: Relapse remittingAlpha lipoic acid (1200 mg/day)Total antioxidant capacity, superoxide dismutase, glutathione peroxidase activity, malondialdehyde,Total antioxidant capacity significantly improved in the intervention group compared to placebo (p < 0.004)5
      Country: IranAge in years (mean): 30
      Sample size (n): 52
      Total study period (weeks): 12
      • Khalili M.
      • Azimi A.
      • Izadi V.
      • Eghtesadi S.
      • Mirshafiey A.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Sanoobar M.
      • Eskandari G.
      • Farhoudi M.
      • Amani F
      Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Khalili M.
      • Eghtesadi S.
      • Mirshafiey A.
      • Eskandari G.
      • Sanoobar M.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Moftakhar S.
      • Azimi A
      Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.
      )
      Study design: RCTMS diagnosis: Relapse remittingAlpha lipoic acid (1200 mg/day)TGF-β,INF-γ, VCAM-1, ICAM-1, IL-4, TNF-α, IL-6, EDSS, MMP-9TGF-β,INF-γ, VCAM-1, ICAM-1, IL-4, significantly improved in the intervention group compared to placebo (p < 0.01)5
      Country: IranAge in years (mean): 30
      Sample size (n): 52
      Total study period (weeks): 12
      • Khallli M.
      • Eskandari G.
      • Ghajarzadeh M.
      • Azimi A.
      • Eghtesadi S.
      • Sahraian M.A.
      • Motevalian A.
      • Hashemi H.
      • Mirshafiey A.
      • Norouzi A
      Lipoic acid and multiple sclerosis: a randomized controlled conical trial.
      Study design: RCTMS diagnosis: Relapse remittingAlpha lipoic acid (1200 mg/day)Fatigue (using the Fatigue Severity Scale), EDSS, plaque formation (via MRI)No significant between-group differences reported.4
      Country: IranAge in years (mean): 32In participants with a baseline EDSS >0, there was a significant decrease in EDSS (p = 0.036)
      Sample size (n): 39
      Total study period (weeks): 12
      • Yadav V.
      • Marracci G.
      • Lovera J.
      • Woodward W.
      • Bogardus K.
      • Marquardt W.
      • Shinto L.
      • Morris C.
      • Bourdette D.N
      Lipoic acid in multiple sclerosis: a pilot study.
      Study design: RCTMS diagnosis: Mixed diagnosesAlpha Lipoic Acid 1200mg (either once or twice per day), 2400mg (1200mg twice per day)MMP-9, TIMP-1,No significant between-group differences reported.5
      Country: USAAge in years (median): 49sICAM-1A dose response relationship was observed for mean change in sICAM-1 (p = 0.03)
      Sample size (n): 37
      Total study period (weeks): 2
      Ginkgo Biloba
      • Brochet B.
      • Guinot P.
      • Orgogozo J.M.
      • Confavreux C.
      • Rumbach L.
      • Lavergne V
      Double blind placebo controlled multicentre study of ginkgolide B in treatment of acute exacerbations of multiple sclerosis. The Ginkgolide Study Group in multiple sclerosis..
      Study design: RCTMS diagnosis: RRMSginkgolide B (240  mg/day or 360 mg/day)EDSS, Hauser ambulation index, fatigue (using the FSS)No significant between-group differences reported.4
      Country: FranceAge in years (mean): 35
      Sample size (n): 104
      Total study period (days): 7

      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.

      Study design: RCTMS diagnosis: Mixed diagnosesGinkgo Biloba (Egb 761 extract, 240 mg/day)Visual-spatial memory, attention/concentration, processing speed, verbal intrusionsProcessing 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: USAAge in years (mean): 50.75
      Sample size (n): 23
      Total study period (weeks): 4
      Johnson et al. (2013)Study design: RCTMS diagnosis: Mixed diagnosesGinkgo 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.5
      Country: USAAge in years (mean): 50.75
      Sample size (n): 23
      Total study period (weeks): 4
      • Lovera J.F.
      • Kim E.
      • Heriza E.
      • Fitzpatrick M.
      • Hunziker J.
      • Turner A.P.
      • Adams J.
      • Stover T.
      • Sangeorzan A.
      • Sloan A.
      • Howieson D.
      • Wild K.
      • Haselkorn J.
      • Bourdette D
      Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial.
      Study design: RCTMS diagnosis: Mixed diagnosesGinkgo Biloba (Egb 761 extract; 240 mg/day)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.5
      Country: USAAge in years (mean): 52
      Sample size (n): 120
      Total study period (weeks): 12
      • Lovera J.
      • Bagert B.
      • Smoot K.
      • Morris C.D.
      • Frank R.
      • Bogardus K.
      • Wild K.
      • Oken B.
      • Whitham R.
      • Bourdette D
      Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial.
      Study design: RCTMS diagnosis: Mixed diagnosesGinkgo Biloba (Egb 761 extract; 240 mg/day)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.5
      Country: USAAge in years (mean): 49
      Sample size (n): 43
      Total study period (weeks): 12
      Inosine
      • Markowitz C.E.
      • Spitsin S.
      • Zimmerman V.
      • Jacobs D.
      • Udupa J.K.
      • Hooper D.C.
      • Koprowski H
      The treatment of multiple sclerosis with inosine.
      Study design: RCT with a cross-over placebo armMS diagnosis: Relapse remittingInosine (2-3g/day), administered with interferonEDSS, MRINo significant between-group differences reported.5
      Country: USAAge in years (mean): not listed
      Sample size (n): 16
      Total study period (years): 1
      • Gonsette R.E.
      • Sindic C.
      • D'Hooghe M B.
      • De Deyn P.P.
      • Medaer R.
      • Michotte A.
      • Seeldrayers P.
      • Guillaume D
      Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
      Study design: RCTMS diagnosis: Relapse remittingInosine, Individualized dose based on serum uric acid levelsEDSS, Multiple Sclerosis Functional Composite, relapse rateNo significant between-group differences reported.5
      Country: BelguimAge in years (mean): 37
      Sample size (n): 159
      Total study period (years): 2
      • Munoz Garcia D.
      • Midaglia L.
      • Martinez Vilela J.
      • Marin Sanchez M.
      • Lopez Gonzalez F.J.
      • Arias Gomez M.
      • Dapena Bolano D.
      • Iglesias Castanon A.
      • Alonso Alonso M.
      • Romero Lopez J
      Associated inosine to interferon: results of a clinical trial in multiple sclerosis.
      Study design: RCTMS diagnosis: Relapse remittingInosine (3g/day), administered with interferonMRINo significant between-group differences reported.4
      Country: SpainAge in years (mean): 32
      Sample size (n): 36
      Total study period (years): 1
      Acetyl L Carnitine
      • Ledinek A.H.
      • Sajko M.C.
      • Rot U
      Evaluating the effects of amantadin, modafinil and acetyl-L-carnitine on fatigue in multiple sclerosis - Result of a pilot randomized, blind study.
      Study design: RCTMS diagnosis: Relapse remittingAcetyl L Carnitine (2000 mg/day)Fatigue (using the Modified Fatigue Impact Scale), QoL (using the 36-item Short Forum Health Survey Questionnaire)No significant between-group differences reported.2
      Country: USAAge in years (mean): 39
      Sample size (n): 30 (medication groups not included)
      Total study period (weeks): 4
      • Tomassini V.
      • Pozzilli C.
      • Onesti E.
      • Pasqualetti P.
      • Marinelli F.
      • Pisani A.
      • Fieschi C
      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.
      Study design: RCT-cross overMS diagnosis: Primary progressive or secondary progressiveAcetyl 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: ItalyAge in years (mean): 44No other significant between-group differences reported.
      Sample size (n): 93
      Total study period (months): 6 (6-month open label extension phase not extracted)
      Biotin
      • Tourbah A.
      • Gout O.
      • Vighetto A.
      • Deburghgraeve V.
      • Pelletier J.
      • Papeix C.
      • Lebrun-Frenay C.
      • Labauge P.
      • Brassat D.
      • Toosy A.
      • Laplaud D.A.
      • Outteryck O.
      • Moreau T.
      • Debouverie M.
      • Clavelou P.
      • Heinzlef O.
      • De Seze J.
      • Defer G.
      • Sedel F.
      • Arndt C
      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.
      Study design: RCTMS diagnosis: Mixed diagnosesBiotin (MD1003; 300 mg/day)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 scaleNo significant between-group differences reported.5
      Country: France/UKAge in years (mean): 41
      Sample size (n): 93
      Total study period (weeks): 24 (6-month open label extension phase no extracted)
      • Tourbah A.
      • Lebrun-Frenay C.
      • Edan G.
      • Clanet M.
      • Papeix C.
      • Vukusic S.
      • De Seze J.
      • Debouverie M.
      • Gout O.
      • Clavelou P.
      • Defer G.
      • Laplaud D.A.
      • Moreau T.
      • Labauge P.
      • Brochet B.
      • Sedel F.
      • Pelletier J
      MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study.
      Study design: RCTMS diagnosis: Primary progressive or secondary progressiveBiotin (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: FranceAge in years (mean): 51In 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): 154Intervention 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)No other significant between group differences.
      Green tea extract
      • Lovera J.
      • Ramos A.
      • Devier D.
      • Garrison V.
      • Kovner B.
      • Reza T.
      • Koop D.
      • Rooney W.
      • Foundas A.
      • Bourdette D
      • Polyphenon E.
      Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
      Study design: RCTMS diagnosis: Relapse remittingPolyphenon E (Epigallocatechin-3-gallate Green tea extract)NAA (using magnetic resonance spectroscopic imaging), EDSS, MSFCNot assessed, trial halted early due to adverse liver events5
      Country: SloveniaAge in years (mean): 48
      Sample size (n): 13 (halted early)
      Total study period (weeks): 52
      • Mahler A.
      • Steiniger J.
      • Bock M.
      • Klug L.
      • Parreidt N.
      • Lorenz M.
      • Zimmermann B.F.
      • Krannich A.
      • Paul F.
      • Boschmann M
      Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial.
      Study design: RCT Cross-overMS diagnosis: Relapse remittingEpigallocatechin-3-gallate (600 mg/day)Postprandial increase in fat oxidation, efficiency of muscle work, postprandial profiles of plasma glucose, insulin, and free fatty acidsThe 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: GermanyAge in years (mean): 42
      Sample size (n): 20
      Total study period (weeks): 16 weeks per intervention
      Retinyl palmitate
      Bitarfen et al. (2016)Study design: RCTMS diagnosis: Relapse remittingRetinyl 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: IranAge in years (mean): 31.3Total 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
      Sample size (n): 101
      Total study period (months): 12
      • Mohammadzadeh Honarvar N.
      • Harirchian M.H.
      • Abdolahi M.
      • Abedi E.
      • Bitarafan S.
      • Koohdani F.
      • Siassi F.
      • Sahraian M.A.
      • Chahardoli R.
      • Zareei M.
      • Salehi E.
      • Geranmehr M.
      • Saboor-Yaraghi A.A
      Retinyl palmitate supplementation modulates T-bet and interferon gamma gene expression in multiple sclerosis patients.
      Study design: RCTMS diagnosis: RRMSRetinyl palmitate (25,000IU/day)IFN-γ and T-bet gene expressionIFN-γ (p = 0.002) and T-bet (p = 0.001) gene expression improved in the intervention group compared to placebo.4
      Country: IranAge in years (mean): 32.2
      Sample size (n): 39
      Total study period (weeks): 24
      Melatonin
      • Drake M.J.
      • Canham L.
      • Cotterill N.
      • Delgado D.
      • Homewood J.
      • Inglis K.
      • Johnson L.
      • Kisanga M.C.
      • Owen D.
      • White P.
      • Cottrell D
      Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS).
      Study design: RCT-cross overMS diagnosis: Mixed diagnosesMelatonin (sustained release, 2 mg/day)Nocturia episodes, subjective severity, QoL (using the MS Quality of Life Scale), sleep quality (using the Pittsburgh Sleep Quality Index), EDSS, urinary tract symptomsNo significant between-group differences reported.5
      Country: UKAge in years (mean): 54.8
      Sample size (n): 34
      Total study period (weeks): 12 (6 weeks per intervention phase)
      • Roostaei T.
      • Sahraian M.A.
      • Hajeaghaee S.
      • Gholipour T.
      • Togha M.
      • Siroos B.
      • Mansouri S.
      • Mohammadshirazi Z.
      • Aghazadeh Alasti M.
      • Harirchian M.H
      Impact of melatonin on motor, cognitive and neuroimaging indices in patients with multiple sclerosis.
      Study design: RCTMS diagnosis: Relapse remittingMelatonin (3 mg/day)Relapse rate, EDSS, number and volume of brain lesion, Fatigue (using the Modified Fatigue Impact Scale), Depression (using the Beck Depression Inventory-II), Multiple Sclerosis Functional CompositeNo significant between-group differences reported.5
      Country: IranAge in years (mean): 33.9
      Sample size (n): 26
      Total study period (weeks): 52
      Creatine monohydrate
      • Malin S.K.
      • Cotugna N.
      • Fang C.S
      Effect of creatine supplementation on muscle capacity in individuals with multiple sclerosis.
      Study design: RCT Cross-overMS diagnosis: MS subtype not statedCreatine monohydrate 20grams (first week), 5grams (second week)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: USAAge in years (mean): 44
      Sample size (n): 11
      Total study period (weeks): 2 weeks per intervention
      • Lambert C.P.
      • Archer R.L.
      • Carrithers J.A.
      • Fink W.J.
      • Evans W.J.
      • Trappe T.A
      Influence of creatine monohydrate ingestion on muscle metabolites and intense exercise capacity in individuals with multiple sclerosis.
      Study design: RCTMS diagnosis: Relapse remittingCreatine monohydrate (20g/day)Body composition, exercise capacity and muscle metabolites (phosphocreatine, ATP, total creatine)No significant between-group differences reported.3
      Country: USAAge in years (mean): 40.3
      Sample size (n): 16
      Total study period (days): 5
      Lemon Verbena
      Mauritz et al. (2015)Study design: RCTMS diagnosis: Mixed diagnosesLemon Verbena (600mg) standardized to 10% verbascosideIFN-y, IL-12, IL-23, IL-6, TNF-a, TGF-a, IL-4 and IL-10, CRPSecondary progressive MS- supplemented participants had significantly lower CRP (p < 0.005) and IFN-y (p < 0.003) and higher IL-4 and IL-10 compared to placebo (p < 0.05).3
      Country: SpainAge in years (mean): 49IL-12 was reduced in the relapsing-remitting supplemented group compared to placebo (p < 0.05).
      Sample size (n): 32IFN-y levels decreased for all MS-treated groups
      Total study period (weeks): 4
      Probiotics
      • Kouchaki E.
      • Tamtaji O.R.
      • Salami M.
      • Bahmani F.
      • Daneshvar Kakhaki R.
      • Akbari E.
      • Tajabadi-Ebrahimi M.
      • Jafari P.
      • Asemi Z
      Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
      Study design: RCTMS diagnosis: Relapse remittingProbiotics (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, glutathioneEDSS (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.5
      Country: IranAge in years (mean): 34
      Sample size (n): 60
      Total study period (weeks): 12
      Curcumin
      • Dolati S.
      • Ahmadi M.
      • Aghebti-Maleki L.
      • Nikmaram A.
      • Marofi F.
      • Rikhtegar R.
      • Ayromlou H.
      • Yousefi M
      Nanocurcumin is a potential novel therapy for multiple sclerosis by influencing inflammatory mediators.
      Study design: RCTMS diagnosis: RRMSCurcumin (nano-encapsulated, 80 mg/day)Gene expression levels of miR-32, miR-16, miR-45. mRNA expression of genes (NF-κB, AP-1, STAT-1, STAT5, IL-1β, IL-6, IL-8, TNF-α, IFN– γ, CCL2 and CCL5) miRNA-dependent targets (FoxP3, PDCD1, Sirtuin1, Sox2), Serum inflammatory cytokines (IFN–γ, CCL5, CCL2, , IL-1β, IL-6, IL-8, TNF-α), EDSSmiR-45 (p < 0.001), miR-32 (p = 0.0039), IFN–γ (p = 0.0025), CCL5 (p = 0.0003), CCL2 (p = 0.0029), FoxP3 (p = 0.02), PDCD1 (p = 0.0012), Sirtuin1 (p = 0.0062), Sox2 (p = 0.0032), STAT1 (p = 0.0001), STAT5 (p = 0.0001), NFKB (p < 0.0001), AP-1 (p = 0.047) significantly improved in the intervention group compared to placebo.4
      Country: IranAge in years (mean): 34.9No 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 overMS diagnosis: Relapse remitting or Secondary progressiveMS14, 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: IranAge in years (mean): 30.8
      Sample size (n): 38
      Total study period (weeks): 3
      Coenzyme Q10
      Sanoobar et al. (2015)Study design: RCTMS diagnosis: Relapse remittingCoenzyme 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 group3
      Country: IranAge in years (mean): 32
      Sample size (n): 48
      Total study period (weeks): 12
      Cranberry extract
      • Gallien P.
      • Amarenco G.
      • Benoit N.
      • Bonniaud V.
      • Donze C.
      • Kerdraon J.
      • de Seze M.
      • Denys P.
      • Renault A.
      • Naudet F.
      • Reymann J.M
      Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter, randomized, placebo-controlled, double-blind trial.
      Study design: RCTMS diagnosis: Mixed diagnosesCranberry 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 consumptionNo significant between group differences except at month 9 where placebo group had higher QoL compared to intervention (p = 0.02)5
      Country: FranceAge in years (mean): 49
      Sample size (n): 171
      Total study period (years): 1
      Glucosamine sulphate
      • Shaygannejad V.
      • Janghorbani M.
      • Savoj M.R.
      • Ashtari F
      Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial.
      Study design: RCTMS diagnosis: Relapse remittingGlucosamine sulphate (1000 mg/day)EDSS progression, relapse rateNo significant between-group differences reported.5
      Country: IranAge in years (mean): 30.25
      Sample size (n): 97
      Total study period (months): 6
      Gamma-tocopherol
      • Pantzaris M.C.
      • Loukaides G.N.
      • Ntzani E.E.
      • Patrikios I.S
      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.
      Study design: RCTMS diagnosis: Relapse remittingGamma-tocopherol (760 mg/day)Annualized relapse rate, EDSS progression, T2 lesions progressionNo significant between-group differences reported.5
      Country: CyprusAge in years (mean): 37.9
      Sample size (n): 40 (omega 3 groups not included)
      Total study period (months): 30
      Riboflavin
      • Naghashpour M.
      • Majdinasab N.
      • Shakerinejad G.
      • Kouchak M.
      • Haghighizadeh M.H.
      • Jarvandi F.
      • Hajinajaf S
      Riboflavin supplementation to patients with multiple sclerosis does not improve disability status nor is riboflavin supplementation correlated to homocysteine.
      Study design: RCTMS diagnosis: Relapse remitting or secondary progressiveRiboflavin (10 mg/day)EDSS, serum homocysteineNo significant between-group differences reported.4
      Country: IranAge in years (mean): 33
      Sample size (n): 29
      Total study period (months): 6 with 3 months washout
      Andrographis paniculata
      • Bertoglio J.C.
      • Baumgartner M.
      • Palma R.
      • Ciampi E.
      • Carcamo C.
      • Caceres D.D.
      • Acosta-Jamett G.
      • Hancke J.L.
      • Burgos R.A
      Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study.
      Study design: RCTMS diagnosis: Relapse remittingAndrographis paniculata (340 mg/day, total andrographolides: 170 mg)Fatigue (using the FSS), EDSSFatigue was significant improvement in the intervention group compared to placebo (p value not reported). No other significant between-group differences reported.5
      Country: ChileAge in years (mean): 37
      Sample size (n): 24
      Total study period (years): 1
      Ginseng
      • Etemadifar M.
      • Sayahi F.
      • Abtahi S.H.
      • Shemshaki H.
      • Dorooshi G.A.
      • Goodarzi M.
      • Akbari M.
      • Fereidan-Esfahani M
      Ginseng in the treatment of fatigue in multiple sclerosis: a randomized, placebo-controlled, double-blind pilot study.
      Study design: RCTMS diagnosis: Relapse remittingGinseng (500 mg/day)Fatigue (using the Modified Fatigue Impact Scale) and QoL (using the Multiple Sclerosis Quality Of Life QuestionnaireFatigue (p = 0.046) and QoL (p ≤ 0.0001) were significantly improved in the intervention group compared to placebo.4
      Country: IranAge in years (mean): 33
      Sample size (n): 60
      Total study period (months): 3
      ADMA, asymmetric dimethylarginine; CCL, Chemokine Ligand; CRP, C reactive protein; EDSS, Expanded Disability Status Scale; HOMA IR, Homeostatic model assessment insulin resistance; IFN, interferon; IL, interleukin; MMP-9, MRI, Magnetic resonance imaging; Matrix metallopeptidase 9; MSFC, Multiple Sclerosis Functional Composite; NAA, N-acetyl aspartate; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; OCT, optical coherence tomography; PCBV, percent change brain volume; PDCD1, Programmed Cell Death 1; QOL, quality of life; RNFL, retinal nerve fiber layer; sICAM-1, Soluble intercellular adhesion molecule-1; TIMP-1, Tissue inhibitor matrix metalloproteinase 1; TGF-alpha, transforming growth factor alpha; TNF-alpha, Tumor necrosis factor alpha; UTI, Urinary Tract infection; VEPs, visual evoked potentials.

      3.2 Trial characteristics

      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 (
      • Tomassini V.
      • Pozzilli C.
      • Onesti E.
      • Pasqualetti P.
      • Marinelli F.
      • Pisani A.
      • Fieschi C
      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) (
      • Khalili M.
      • Azimi A.
      • Izadi V.
      • Eghtesadi S.
      • Mirshafiey A.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Sanoobar M.
      • Eskandari G.
      • Farhoudi M.
      • Amani F
      Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Khalili M.
      • Eghtesadi S.
      • Mirshafiey A.
      • Eskandari G.
      • Sanoobar M.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Moftakhar S.
      • Azimi A
      Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.
      ,
      • Khalili M.
      • Soltani M.
      • Moghadam S.A.
      • Dehghan P.
      • Azimi A.
      • Abbaszadeh O
      Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients: a randomized clinical trial.
      ;
      • Khallli M.
      • Eskandari G.
      • Ghajarzadeh M.
      • Azimi A.
      • Eghtesadi S.
      • Sahraian M.A.
      • Motevalian A.
      • Hashemi H.
      • Mirshafiey A.
      • Norouzi A
      Lipoic acid and multiple sclerosis: a randomized controlled conical trial.
      ;
      • Spain R.
      • Powers K.
      • Murchison C.
      • Heriza E.
      • Winges K.
      • Yadav V.
      • Cameron M.
      • Kim E.
      • Horak F.
      • Simon J.
      • Bourdette D
      Lipoic acid in secondary progressive MS: a randomized controlled pilot trial.
      ;
      • Yadav V.
      • Marracci G.
      • Lovera J.
      • Woodward W.
      • Bogardus K.
      • Marquardt W.
      • Shinto L.
      • Morris C.
      • Bourdette D.N
      Lipoic acid in multiple sclerosis: a pilot study.
      ), ginkgo biloba (n = 5) (
      • Diamond B.J.
      • Bailey M.R
      Ginkgo biloba. indications, mechanisms, and safety.
      ;

      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.

      ;
      • Lovera J.
      • Bagert B.
      • Smoot K.
      • Morris C.D.
      • Frank R.
      • Bogardus K.
      • Wild K.
      • Oken B.
      • Whitham R.
      • Bourdette D
      Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial.
      ;
      • Lovera J.F.
      • Kim E.
      • Heriza E.
      • Fitzpatrick M.
      • Hunziker J.
      • Turner A.P.
      • Adams J.
      • Stover T.
      • Sangeorzan A.
      • Sloan A.
      • Howieson D.
      • Wild K.
      • Haselkorn J.
      • Bourdette D
      Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial.
      ;
      • Brochet B.
      • Guinot P.
      • Orgogozo J.M.
      • Confavreux C.
      • Rumbach L.
      • Lavergne V
      Double blind placebo controlled multicentre study of ginkgolide B in treatment of acute exacerbations of multiple sclerosis. The Ginkgolide Study Group in multiple sclerosis..
      ), inosine (n = 3) (
      • Gonsette R.E.
      • Sindic C.
      • D'Hooghe M B.
      • De Deyn P.P.
      • Medaer R.
      • Michotte A.
      • Seeldrayers P.
      • Guillaume D
      Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
      ;
      • Markowitz C.E.
      • Spitsin S.
      • Zimmerman V.
      • Jacobs D.
      • Udupa J.K.
      • Hooper D.C.
      • Koprowski H
      The treatment of multiple sclerosis with inosine.
      ;
      • Munoz Garcia D.
      • Midaglia L.
      • Martinez Vilela J.
      • Marin Sanchez M.
      • Lopez Gonzalez F.J.
      • Arias Gomez M.
      • Dapena Bolano D.
      • Iglesias Castanon A.
      • Alonso Alonso M.
      • Romero Lopez J
      Associated inosine to interferon: results of a clinical trial in multiple sclerosis.
      ), acetyl-L-carnitine (n = 2) (
      • Tomassini V.
      • Pozzilli C.
      • Onesti E.
      • Pasqualetti P.
      • Marinelli F.
      • Pisani A.
      • Fieschi C
      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.
      ;
      • Ledinek A.H.
      • Sajko M.C.
      • Rot U
      Evaluating the effects of amantadin, modafinil and acetyl-L-carnitine on fatigue in multiple sclerosis - Result of a pilot randomized, blind study.
      ), biotin (n = 2) (
      • Tourbah A.
      • Gout O.
      • Vighetto A.
      • Deburghgraeve V.
      • Pelletier J.
      • Papeix C.
      • Lebrun-Frenay C.
      • Labauge P.
      • Brassat D.
      • Toosy A.
      • Laplaud D.A.
      • Outteryck O.
      • Moreau T.
      • Debouverie M.
      • Clavelou P.
      • Heinzlef O.
      • De Seze J.
      • Defer G.
      • Sedel F.
      • Arndt C
      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.
      ;
      • Tourbah A.
      • Lebrun-Frenay C.
      • Edan G.
      • Clanet M.
      • Papeix C.
      • Vukusic S.
      • De Seze J.
      • Debouverie M.
      • Gout O.
      • Clavelou P.
      • Defer G.
      • Laplaud D.A.
      • Moreau T.
      • Labauge P.
      • Brochet B.
      • Sedel F.
      • Pelletier J
      MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study.
      ), green tea extract (n = 2) (
      • Lovera J.
      • Ramos A.
      • Devier D.
      • Garrison V.
      • Kovner B.
      • Reza T.
      • Koop D.
      • Rooney W.
      • Foundas A.
      • Bourdette D
      • Polyphenon E.
      Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
      ;
      • Mahler A.
      • Steiniger J.
      • Bock M.
      • Klug L.
      • Parreidt N.
      • Lorenz M.
      • Zimmermann B.F.
      • Krannich A.
      • Paul F.
      • Boschmann M
      Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial.
      ), retinyl palmitate (n = 2) (
      • Bitarafan S.
      • Saboor-Yaraghi A.
      • Sahraian M.A.
      • Soltani D.
      • Nafissi S.
      • Togha M.
      • Moghadam N.B.
      • Roostaei T.
      • Honarvar N.M.
      • Harirchian M.H
      Effect of Vitamin A supplementation on fatigue and depression in multiple sclerosis patients: a double-blind placebo-controlled clinical trial.
      ;
      • Mohammadzadeh Honarvar N.
      • Harirchian M.H.
      • Abdolahi M.
      • Abedi E.
      • Bitarafan S.
      • Koohdani F.
      • Siassi F.
      • Sahraian M.A.
      • Chahardoli R.
      • Zareei M.
      • Salehi E.
      • Geranmehr M.
      • Saboor-Yaraghi A.A
      Retinyl palmitate supplementation modulates T-bet and interferon gamma gene expression in multiple sclerosis patients.
      ), melatonin (n = 2) (
      • Drake M.J.
      • Canham L.
      • Cotterill N.
      • Delgado D.
      • Homewood J.
      • Inglis K.
      • Johnson L.
      • Kisanga M.C.
      • Owen D.
      • White P.
      • Cottrell D
      Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS).
      ;
      • Roostaei T.
      • Sahraian M.A.
      • Hajeaghaee S.
      • Gholipour T.
      • Togha M.
      • Siroos B.
      • Mansouri S.
      • Mohammadshirazi Z.
      • Aghazadeh Alasti M.
      • Harirchian M.H
      Impact of melatonin on motor, cognitive and neuroimaging indices in patients with multiple sclerosis.
      ), creatine monohydrate (n = 2) (
      • Malin S.K.
      • Cotugna N.
      • Fang C.S
      Effect of creatine supplementation on muscle capacity in individuals with multiple sclerosis.
      ;
      • Lambert C.P.
      • Archer R.L.
      • Carrithers J.A.
      • Fink W.J.
      • Evans W.J.
      • Trappe T.A
      Influence of creatine monohydrate ingestion on muscle metabolites and intense exercise capacity in individuals with multiple sclerosis.
      ), lemon verbena (n = 1) (
      • Mauriz E.
      • Vallejo D.
      • Tunon M.J.
      • Rodriguez-Lopez J.M.
      • Rodriguez-Perez R.
      • Sanz-Gomez J.
      • Garcia-Fernandez Mdel C
      Effects of dietary supplementation with lemon verbena extracts on serum inflammatory markers of multiple sclerosis patients.
      ), a multi-strain probiotic (n = 1) (
      • Kouchaki E.
      • Tamtaji O.R.
      • Salami M.
      • Bahmani F.
      • Daneshvar Kakhaki R.
      • Akbari E.
      • Tajabadi-Ebrahimi M.
      • Jafari P.
      • Asemi Z
      Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
      ), curcumin (n = 1) (
      • Dolati S.
      • Ahmadi M.
      • Aghebti-Maleki L.
      • Nikmaram A.
      • Marofi F.
      • Rikhtegar R.
      • Ayromlou H.
      • Yousefi M
      Nanocurcumin is a potential novel therapy for multiple sclerosis by influencing inflammatory mediators.
      ), MS14 (a propriety herbal formulation; n = 1) (
      • Nabavi S.M.
      • Naseri M.
      • Rezaeezadeh H.
      • Ghareguzli K.
      • Shayegannejad V.
      • Ghafarpoor M.
      • Faghihzadeh S
      A double-blind, placebo-controlled, study of oral MS14, a herbal-marine drug, on walking ability in multiple sclerosis patients.
      ), coenzyme Q10 (n = 1) (
      • Sanoobar M.
      • Dehghan P.
      • Khalili M.
      • Azimi A.
      • Seifar F
      Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: a double blind randomized clinical trial.
      ), cranberry extract (n = 1) (
      • Gallien P.
      • Amarenco G.
      • Benoit N.
      • Bonniaud V.
      • Donze C.
      • Kerdraon J.
      • de Seze M.
      • Denys P.
      • Renault A.
      • Naudet F.
      • Reymann J.M
      Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter, randomized, placebo-controlled, double-blind trial.
      ), glucosamine sulphate (n = 1) (
      • Shaygannejad V.
      • Janghorbani M.
      • Savoj M.R.
      • Ashtari F
      Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial.
      ), and gamma-tocopherol (n = 1) (
      • Pantzaris M.C.
      • Loukaides G.N.
      • Ntzani E.E.
      • Patrikios I.S
      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 (n = 1) (
      • Naghashpour M.
      • Majdinasab N.
      • Shakerinejad G.
      • Kouchak M.
      • Haghighizadeh M.H.
      • Jarvandi F.
      • Hajinajaf S
      Riboflavin supplementation to patients with multiple sclerosis does not improve disability status nor is riboflavin supplementation correlated to homocysteine.
      ), Andrographis paniculata (n = 1) (
      • Bertoglio J.C.
      • Baumgartner M.
      • Palma R.
      • Ciampi E.
      • Carcamo C.
      • Caceres D.D.
      • Acosta-Jamett G.
      • Hancke J.L.
      • Burgos R.A
      Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study.
      ), and ginseng (n = 1) (
      • Etemadifar M.
      • Sayahi F.
      • Abtahi S.H.
      • Shemshaki H.
      • Dorooshi G.A.
      • Goodarzi M.
      • Akbari M.
      • Fereidan-Esfahani M
      Ginseng in the treatment of fatigue in multiple sclerosis: a randomized, placebo-controlled, double-blind pilot study.
      ).

      3.3 Trial results

      3.3.1 Alpha lipoic acid

      Six studies investigated the use of alpha lipoic acid (
      • Khalili M.
      • Azimi A.
      • Izadi V.
      • Eghtesadi S.
      • Mirshafiey A.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Sanoobar M.
      • Eskandari G.
      • Farhoudi M.
      • Amani F
      Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Khalili M.
      • Eghtesadi S.
      • Mirshafiey A.
      • Eskandari G.
      • Sanoobar M.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Moftakhar S.
      • Azimi A
      Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.
      ;
      • Khalili M.
      • Soltani M.
      • Moghadam S.A.
      • Dehghan P.
      • Azimi A.
      • Abbaszadeh O
      Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients: a randomized clinical trial.
      ;
      • Khallli M.
      • Eskandari G.
      • Ghajarzadeh M.
      • Azimi A.
      • Eghtesadi S.
      • Sahraian M.A.
      • Motevalian A.
      • Hashemi H.
      • Mirshafiey A.
      • Norouzi A
      Lipoic acid and multiple sclerosis: a randomized controlled conical trial.
      ;
      • Spain R.
      • Powers K.
      • Murchison C.
      • Heriza E.
      • Winges K.
      • Yadav V.
      • Cameron M.
      • Kim E.
      • Horak F.
      • Simon J.
      • Bourdette D
      Lipoic acid in secondary progressive MS: a randomized controlled pilot trial.
      ;
      • Yadav V.
      • Marracci G.
      • Lovera J.
      • Woodward W.
      • Bogardus K.
      • Marquardt W.
      • Shinto L.
      • Morris C.
      • Bourdette D.N
      Lipoic acid in multiple sclerosis: a pilot study.
      ). All studies used a dose of 1200 mg per day, with one trial including an additional arm that received 2400 mg per day.
      • Yadav V.
      • Marracci G.
      • Lovera J.
      • Woodward W.
      • Bogardus K.
      • Marquardt W.
      • Shinto L.
      • Morris C.
      • Bourdette D.N
      Lipoic acid in multiple sclerosis: a pilot study.
      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 (
      • Spain R.
      • Powers K.
      • Murchison C.
      • Heriza E.
      • Winges K.
      • Yadav V.
      • Cameron M.
      • Kim E.
      • Horak F.
      • Simon J.
      • Bourdette D
      Lipoic acid in secondary progressive MS: a randomized controlled pilot trial.
      ). One 12-week trial (n = 39) found alpha lipoic acid improved EDSS in patients with a baseline EDSS >0 (p = 0.036) (
      • Khallli M.
      • Eskandari G.
      • Ghajarzadeh M.
      • Azimi A.
      • Eghtesadi S.
      • Sahraian M.A.
      • Motevalian A.
      • Hashemi H.
      • Mirshafiey A.
      • Norouzi A
      Lipoic acid and multiple sclerosis: a randomized controlled conical trial.
      ). Another 12-week trial (n = 54) reported that 1200 mg of alpha lipoic acid improved serum total antioxidant capacity, transforming growth factor-β (TGF-β), Interferon-gamma (IFN-y), vascular cell adhesion molecule-1, Intercellular Adhesion Molecule-1 (ICAM-1), and interleukin-4 compared to placebo but not superoxide dismutase, glutathione peroxidase activity, and malondialdehyde (
      • Khalili M.
      • Azimi A.
      • Izadi V.
      • Eghtesadi S.
      • Mirshafiey A.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Sanoobar M.
      • Eskandari G.
      • Farhoudi M.
      • Amani F
      Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Khalili M.
      • Eghtesadi S.
      • Mirshafiey A.
      • Eskandari G.
      • Sanoobar M.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Moftakhar S.
      • Azimi A
      Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.
      ). Four 12-week studies reported no significant between-group difference in one or more of the following measures: EDSS (
      • Khallli M.
      • Eskandari G.
      • Ghajarzadeh M.
      • Azimi A.
      • Eghtesadi S.
      • Sahraian M.A.
      • Motevalian A.
      • Hashemi H.
      • Mirshafiey A.
      • Norouzi A
      Lipoic acid and multiple sclerosis: a randomized controlled conical trial.
      ), fatigue (
      • Khallli M.
      • Eskandari G.
      • Ghajarzadeh M.
      • Azimi A.
      • Eghtesadi S.
      • Sahraian M.A.
      • Motevalian A.
      • Hashemi H.
      • Mirshafiey A.
      • Norouzi A
      Lipoic acid and multiple sclerosis: a randomized controlled conical trial.
      ), plaque formation (
      • Khallli M.
      • Eskandari G.
      • Ghajarzadeh M.
      • Azimi A.
      • Eghtesadi S.
      • Sahraian M.A.
      • Motevalian A.
      • Hashemi H.
      • Mirshafiey A.
      • Norouzi A
      Lipoic acid and multiple sclerosis: a randomized controlled conical trial.
      ), and serum measures including asymmetric dimethylarginine (
      • Khalili M.
      • Soltani M.
      • Moghadam S.A.
      • Dehghan P.
      • Azimi A.
      • Abbaszadeh O
      Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients: a randomized clinical trial.
      ), tumor necrosis factor-alpha (TNF-α) (
      • Khalili M.
      • Azimi A.
      • Izadi V.
      • Eghtesadi S.
      • Mirshafiey A.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Sanoobar M.
      • Eskandari G.
      • Farhoudi M.
      • Amani F
      Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Khalili M.
      • Eghtesadi S.
      • Mirshafiey A.
      • Eskandari G.
      • Sanoobar M.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Moftakhar S.
      • Azimi A
      Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.
      ), interleukin-6 (IL-6) (
      • Khalili M.
      • Azimi A.
      • Izadi V.
      • Eghtesadi S.
      • Mirshafiey A.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Sanoobar M.
      • Eskandari G.
      • Farhoudi M.
      • Amani F
      Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Khalili M.
      • Eghtesadi S.
      • Mirshafiey A.
      • Eskandari G.
      • Sanoobar M.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Moftakhar S.
      • Azimi A
      Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.
      ), tissue inhibitor of metalloproteinases-1 (
      • Yadav V.
      • Marracci G.
      • Lovera J.
      • Woodward W.
      • Bogardus K.
      • Marquardt W.
      • Shinto L.
      • Morris C.
      • Bourdette D.N
      Lipoic acid in multiple sclerosis: a pilot study.
      ), sICAM-1 (
      • Yadav V.
      • Marracci G.
      • Lovera J.
      • Woodward W.
      • Bogardus K.
      • Marquardt W.
      • Shinto L.
      • Morris C.
      • Bourdette D.N
      Lipoic acid in multiple sclerosis: a pilot study.
      ), and matrix metallopeptidase-9 (
      • Khalili M.
      • Azimi A.
      • Izadi V.
      • Eghtesadi S.
      • Mirshafiey A.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Sanoobar M.
      • Eskandari G.
      • Farhoudi M.
      • Amani F
      Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Khalili M.
      • Eghtesadi S.
      • Mirshafiey A.
      • Eskandari G.
      • Sanoobar M.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Moftakhar S.
      • Azimi A
      Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.
      ;
      • Yadav V.
      • Marracci G.
      • Lovera J.
      • Woodward W.
      • Bogardus K.
      • Marquardt W.
      • Shinto L.
      • Morris C.
      • Bourdette D.N
      Lipoic acid in multiple sclerosis: a pilot study.
      ).

      3.3.2 Ginkgo biloba

      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 (
      • Brochet B.
      • Guinot P.
      • Orgogozo J.M.
      • Confavreux C.
      • Rumbach L.
      • Lavergne V
      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 (
      • Diamond B.J.
      • Bailey M.R
      Ginkgo biloba. indications, mechanisms, and safety.
      ;

      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.

      ;
      • Lovera J.
      • Bagert B.
      • Smoot K.
      • Morris C.D.
      • Frank R.
      • Bogardus K.
      • Wild K.
      • Oken B.
      • Whitham R.
      • Bourdette D
      Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial.
      ;
      • Lovera J.F.
      • Kim E.
      • Heriza E.
      • Fitzpatrick M.
      • Hunziker J.
      • Turner A.P.
      • Adams J.
      • Stover T.
      • Sangeorzan A.
      • Sloan A.
      • Howieson D.
      • Wild K.
      • Haselkorn J.
      • Bourdette D
      Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial.
      ). 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 (
      • Lovera J.
      • Bagert B.
      • Smoot K.
      • Morris C.D.
      • Frank R.
      • Bogardus K.
      • Wild K.
      • Oken B.
      • Whitham R.
      • Bourdette D
      Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial.
      ). 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) (
      • Lovera J.F.
      • Kim E.
      • Heriza E.
      • Fitzpatrick M.
      • Hunziker J.
      • Turner A.P.
      • Adams J.
      • Stover T.
      • Sangeorzan A.
      • Sloan A.
      • Howieson D.
      • Wild K.
      • Haselkorn J.
      • Bourdette D
      Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial.
      ).

      3.3.3 Inosine

      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 (
      • Gonsette R.E.
      • Sindic C.
      • D'Hooghe M B.
      • De Deyn P.P.
      • Medaer R.
      • Michotte A.
      • Seeldrayers P.
      • Guillaume D
      Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
      ;
      • Markowitz C.E.
      • Spitsin S.
      • Zimmerman V.
      • Jacobs D.
      • Udupa J.K.
      • Hooper D.C.
      • Koprowski H
      The treatment of multiple sclerosis with inosine.
      ;
      • Munoz Garcia D.
      • Midaglia L.
      • Martinez Vilela J.
      • Marin Sanchez M.
      • Lopez Gonzalez F.J.
      • Arias Gomez M.
      • Dapena Bolano D.
      • Iglesias Castanon A.
      • Alonso Alonso M.
      • Romero Lopez J
      Associated inosine to interferon: results of a clinical trial in multiple sclerosis.
      ). Doses were either 2–3 g/day or individually determined based on serum uric acid levels. EDSS (
      • Gonsette R.E.
      • Sindic C.
      • D'Hooghe M B.
      • De Deyn P.P.
      • Medaer R.
      • Michotte A.
      • Seeldrayers P.
      • Guillaume D
      Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
      ;
      • Markowitz C.E.
      • Spitsin S.
      • Zimmerman V.
      • Jacobs D.
      • Udupa J.K.
      • Hooper D.C.
      • Koprowski H
      The treatment of multiple sclerosis with inosine.
      ), MRI (
      • Markowitz C.E.
      • Spitsin S.
      • Zimmerman V.
      • Jacobs D.
      • Udupa J.K.
      • Hooper D.C.
      • Koprowski H
      The treatment of multiple sclerosis with inosine.
      ;
      • Munoz Garcia D.
      • Midaglia L.
      • Martinez Vilela J.
      • Marin Sanchez M.
      • Lopez Gonzalez F.J.
      • Arias Gomez M.
      • Dapena Bolano D.
      • Iglesias Castanon A.
      • Alonso Alonso M.
      • Romero Lopez J
      Associated inosine to interferon: results of a clinical trial in multiple sclerosis.
      ), functional capacity (
      • Gonsette R.E.
      • Sindic C.
      • D'Hooghe M B.
      • De Deyn P.P.
      • Medaer R.
      • Michotte A.
      • Seeldrayers P.
      • Guillaume D
      Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
      ), inflammatory markers (
      • Markowitz C.E.
      • Spitsin S.
      • Zimmerman V.
      • Jacobs D.
      • Udupa J.K.
      • Hooper D.C.
      • Koprowski H
      The treatment of multiple sclerosis with inosine.
      ), and relapse rate (
      • Gonsette R.E.
      • Sindic C.
      • D'Hooghe M B.
      • De Deyn P.P.
      • Medaer R.
      • Michotte A.
      • Seeldrayers P.
      • Guillaume D
      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 (
      • Tomassini V.
      • Pozzilli C.
      • Onesti E.
      • Pasqualetti P.
      • Marinelli F.
      • Pisani A.
      • Fieschi C
      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 (
      • Ledinek A.H.
      • Sajko M.C.
      • Rot U
      Evaluating the effects of amantadin, modafinil and acetyl-L-carnitine on fatigue in multiple sclerosis - Result of a pilot randomized, blind study.
      ).

      3.3.5 Biotin

      Two randomized controlled trials by the same research group investigated the use of 300 mg/day of a biotin formulation (MD1003) (
      • Tourbah A.
      • Gout O.
      • Vighetto A.
      • Deburghgraeve V.
      • Pelletier J.
      • Papeix C.
      • Lebrun-Frenay C.
      • Labauge P.
      • Brassat D.
      • Toosy A.
      • Laplaud D.A.
      • Outteryck O.
      • Moreau T.
      • Debouverie M.
      • Clavelou P.
      • Heinzlef O.
      • De Seze J.
      • Defer G.
      • Sedel F.
      • Arndt C
      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.
      ;
      • Tourbah A.
      • Lebrun-Frenay C.
      • Edan G.
      • Clanet M.
      • Papeix C.
      • Vukusic S.
      • De Seze J.
      • Debouverie M.
      • Gout O.
      • Clavelou P.
      • Defer G.
      • Laplaud D.A.
      • Moreau T.
      • Labauge P.
      • Brochet B.
      • Sedel F.
      • Pelletier J
      MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study.
      ). The first trial (n = 154) was a 12-month randomized, double-blind, placebo-controlled trial with a subsequent open-label 12-month extension phase (
      • Tourbah A.
      • Lebrun-Frenay C.
      • Edan G.
      • Clanet M.
      • Papeix C.
      • Vukusic S.
      • De Seze J.
      • Debouverie M.
      • Gout O.
      • Clavelou P.
      • Defer G.
      • Laplaud D.A.
      • Moreau T.
      • Labauge P.
      • Brochet B.
      • Sedel F.
      • Pelletier J
      MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, 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 (
      • Tourbah A.
      • Gout O.
      • Vighetto A.
      • Deburghgraeve V.
      • Pelletier J.
      • Papeix C.
      • Lebrun-Frenay C.
      • Labauge P.
      • Brassat D.
      • Toosy A.
      • Laplaud D.A.
      • Outteryck O.
      • Moreau T.
      • Debouverie M.
      • Clavelou P.
      • Heinzlef O.
      • De Seze J.
      • Defer G.
      • Sedel F.
      • Arndt C
      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 (
      • Lovera J.
      • Ramos A.
      • Devier D.
      • Garrison V.
      • Kovner B.
      • Reza T.
      • Koop D.
      • Rooney W.
      • Foundas A.
      • Bourdette D
      • Polyphenon E.
      Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
      ,
      • Mahler A.
      • Steiniger J.
      • Bock M.
      • Klug L.
      • Parreidt N.
      • Lorenz M.
      • Zimmermann B.F.
      • Krannich A.
      • Paul F.
      • Boschmann M
      Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial.
      ). 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 (
      • Mahler A.
      • Steiniger J.
      • Bock M.
      • Klug L.
      • Parreidt N.
      • Lorenz M.
      • Zimmermann B.F.
      • Krannich A.
      • Paul F.
      • Boschmann M
      Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial.
      ). 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) (
      • Lovera J.
      • Ramos A.
      • Devier D.
      • Garrison V.
      • Kovner B.
      • Reza T.
      • Koop D.
      • Rooney W.
      • Foundas A.
      • Bourdette D
      • Polyphenon E.
      Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
      ).

      3.3.7 Retinyl palmitate (Vitamin A)

      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 (
      • Bitarafan S.
      • Saboor-Yaraghi A.
      • Sahraian M.A.
      • Soltani D.
      • Nafissi S.
      • Togha M.
      • Moghadam N.B.
      • Roostaei T.
      • Honarvar N.M.
      • Harirchian M.H
      Effect of Vitamin A supplementation on fatigue and depression in multiple sclerosis patients: a double-blind placebo-controlled clinical trial.
      ). 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 (
      • Mohammadzadeh Honarvar N.
      • Harirchian M.H.
      • Abdolahi M.
      • Abedi E.
      • Bitarafan S.
      • Koohdani F.
      • Siassi F.
      • Sahraian M.A.
      • Chahardoli R.
      • Zareei M.
      • Salehi E.
      • Geranmehr M.
      • Saboor-Yaraghi A.A
      Retinyl palmitate supplementation modulates T-bet and interferon gamma gene expression in multiple sclerosis patients.
      ).

      3.3.8 Melatonin

      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 (
      • Roostaei T.
      • Sahraian M.A.
      • Hajeaghaee S.
      • Gholipour T.
      • Togha M.
      • Siroos B.
      • Mansouri S.
      • Mohammadshirazi Z.
      • Aghazadeh Alasti M.
      • Harirchian M.H
      Impact of melatonin on motor, cognitive and neuroimaging indices in patients with multiple sclerosis.
      ). 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 (
      • Drake M.J.
      • Canham L.
      • Cotterill N.
      • Delgado D.
      • Homewood J.
      • Inglis K.
      • Johnson L.
      • Kisanga M.C.
      • Owen D.
      • White P.
      • Cottrell D
      Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS).
      ).

      3.3.9 Creatine monohydrate

      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 (
      • Malin S.K.
      • Cotugna N.
      • Fang C.S
      Effect of creatine supplementation on muscle capacity in individuals with multiple sclerosis.
      ). 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 (
      • Lambert C.P.
      • Archer R.L.
      • Carrithers J.A.
      • Fink W.J.
      • Evans W.J.
      • Trappe T.A
      Influence of creatine monohydrate ingestion on muscle metabolites and intense exercise capacity in individuals with multiple sclerosis.
      ).

      3.3.10 Lemon verbena

      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) (
      • Mauriz E.
      • Vallejo D.
      • Tunon M.J.
      • Rodriguez-Lopez J.M.
      • Rodriguez-Perez R.
      • Sanz-Gomez J.
      • Garcia-Fernandez Mdel C
      Effects of dietary supplementation with lemon verbena extracts on serum inflammatory markers of multiple sclerosis patients.
      ). 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 (
      • Kouchaki E.
      • Tamtaji O.R.
      • Salami M.
      • Bahmani F.
      • Daneshvar Kakhaki R.
      • Akbari E.
      • Tajabadi-Ebrahimi M.
      • Jafari P.
      • Asemi Z
      Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
      ).

      3.3.12 Curcumin

      One 6-month trial (n = 51) reported that curcumin (80 mg/day) modulated gene expression of the following inflammatory and immune markers: micro-RNA 45 (p < 0.001), micro-RNA 32 (p = 0.0039), IFN–γ (p = 0.0025), Chemokine ligand (CCL) 5 (p = 0.0003), CCL2 (p = 0.0029), forkhead box P3 (FOXP3; p = 0.02), Programmed Cell Death 1 (PDCD1; p = 0.0012), Sirtuin1 (p = 0.0062), sex determining region Y box-2 (Sox2; p = 0.0032), Signal transducer and activator of transcription (STAT) 1 (p = 0.0001), STAT5 (p = 0.0001), nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB; p < 0.0001), Activator protein 1 (AP-1; p = 0.047) (
      • Dolati S.
      • Ahmadi M.
      • Aghebti-Maleki L.
      • Nikmaram A.
      • Marofi F.
      • Rikhtegar R.
      • Ayromlou H.
      • Yousefi M
      Nanocurcumin is a potential novel therapy for multiple sclerosis by influencing inflammatory mediators.
      ). 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 (
      • Nabavi S.M.
      • Naseri M.
      • Rezaeezadeh H.
      • Ghareguzli K.
      • Shayegannejad V.
      • Ghafarpoor M.
      • Faghihzadeh S
      A double-blind, placebo-controlled, study of oral MS14, a herbal-marine drug, on walking ability in multiple sclerosis patients.
      ).

      3.3.14 Co-enzyme Q10

      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) (
      • Nabavi S.M.
      • Naseri M.
      • Rezaeezadeh H.
      • Ghareguzli K.
      • Shayegannejad V.
      • Ghafarpoor M.
      • Faghihzadeh S
      A double-blind, placebo-controlled, study of oral MS14, a herbal-marine drug, on walking ability in multiple sclerosis patients.
      ).

      3.3.15 Cranberry extract

      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 (
      • Gallien P.
      • Amarenco G.
      • Benoit N.
      • Bonniaud V.
      • Donze C.
      • Kerdraon J.
      • de Seze M.
      • Denys P.
      • Renault A.
      • Naudet F.
      • Reymann J.M
      Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter, randomized, placebo-controlled, double-blind trial.
      ).

      3.3.16 Glucosamine sulphate

      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 (
      • Shaygannejad V.
      • Janghorbani M.
      • Savoj M.R.
      • Ashtari F
      Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial.
      ).

      3.3.17 Gamma-tocopherol

      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 (
      • Pantzaris M.C.
      • Loukaides G.N.
      • Ntzani E.E.
      • Patrikios I.S
      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.
      ).

      3.3.18 Riboflavin (Vitamin B2)

      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 (
      • Naghashpour M.
      • Majdinasab N.
      • Shakerinejad G.
      • Kouchak M.
      • Haghighizadeh M.H.
      • Jarvandi F.
      • Hajinajaf S
      Riboflavin supplementation to patients with multiple sclerosis does not improve disability status nor is riboflavin supplementation correlated to homocysteine.
      ).

      3.3.19 Andrographis paniculata

      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 (
      • Bertoglio J.C.
      • Baumgartner M.
      • Palma R.
      • Ciampi E.
      • Carcamo C.
      • Caceres D.D.
      • Acosta-Jamett G.
      • Hancke J.L.
      • Burgos R.A
      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 (
      • Etemadifar M.
      • Sayahi F.
      • Abtahi S.H.
      • Shemshaki H.
      • Dorooshi G.A.
      • Goodarzi M.
      • Akbari M.
      • Fereidan-Esfahani M
      Ginseng in the treatment of fatigue in multiple sclerosis: a randomized, placebo-controlled, double-blind pilot study.
      ).

      3.4 Adverse events

      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 (
      • Spain R.
      • Powers K.
      • Murchison C.
      • Heriza E.
      • Winges K.
      • Yadav V.
      • Cameron M.
      • Kim E.
      • Horak F.
      • Simon J.
      • Bourdette D
      Lipoic acid in secondary progressive MS: a randomized controlled pilot trial.
      ). 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 (
      • Spain R.
      • Powers K.
      • Murchison C.
      • Heriza E.
      • Winges K.
      • Yadav V.
      • Cameron M.
      • Kim E.
      • Horak F.
      • Simon J.
      • Bourdette D
      Lipoic acid in secondary progressive MS: a randomized controlled pilot trial.
      ). 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) (
      • Munoz Garcia D.
      • Midaglia L.
      • Martinez Vilela J.
      • Marin Sanchez M.
      • Lopez Gonzalez F.J.
      • Arias Gomez M.
      • Dapena Bolano D.
      • Iglesias Castanon A.
      • Alonso Alonso M.
      • Romero Lopez J
      Associated inosine to interferon: results of a clinical trial in multiple sclerosis.
      ). Another study reported that n = 4 of the 16 participants receiving inosine experienced kidney stones (
      • Markowitz C.E.
      • Spitsin S.
      • Zimmerman V.
      • Jacobs D.
      • Udupa J.K.
      • Hooper D.C.
      • Koprowski H
      The treatment of multiple sclerosis with inosine.
      ). 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) (
      • Lovera J.
      • Ramos A.
      • Devier D.
      • Garrison V.
      • Kovner B.
      • Reza T.
      • Koop D.
      • Rooney W.
      • Foundas A.
      • Bourdette D
      • Polyphenon E.
      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%) (
      • Tourbah A.
      • Gout O.
      • Vighetto A.
      • Deburghgraeve V.
      • Pelletier J.
      • Papeix C.
      • Lebrun-Frenay C.
      • Labauge P.
      • Brassat D.
      • Toosy A.
      • Laplaud D.A.
      • Outteryck O.
      • Moreau T.
      • Debouverie M.
      • Clavelou P.
      • Heinzlef O.
      • De Seze J.
      • Defer G.
      • Sedel F.
      • Arndt C
      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 (
      • Tourbah A.
      • Lebrun-Frenay C.
      • Edan G.
      • Clanet M.
      • Papeix C.
      • Vukusic S.
      • De Seze J.
      • Debouverie M.
      • Gout O.
      • Clavelou P.
      • Defer G.
      • Laplaud D.A.
      • Moreau T.
      • Labauge P.
      • Brochet B.
      • Sedel F.
      • Pelletier J
      MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study.
      ). 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 (
      • Bertoglio J.C.
      • Baumgartner M.
      • Palma R.
      • Ciampi E.
      • Carcamo C.
      • Caceres D.D.
      • Acosta-Jamett G.
      • Hancke J.L.
      • Burgos R.A
      Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study.
      ).

      4. Discussion

      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 (
      • Tomassini V.
      • Pozzilli C.
      • Onesti E.
      • Pasqualetti P.
      • Marinelli F.
      • Pisani A.
      • Fieschi C
      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.

      ;
      • Bitarafan S.
      • Saboor-Yaraghi A.
      • Sahraian M.A.
      • Soltani D.
      • Nafissi S.
      • Togha M.
      • Moghadam N.B.
      • Roostaei T.
      • Honarvar N.M.
      • Harirchian M.H
      Effect of Vitamin A supplementation on fatigue and depression in multiple sclerosis patients: a double-blind placebo-controlled clinical trial.
      ;
      • Kouchaki E.
      • Tamtaji O.R.
      • Salami M.
      • Bahmani F.
      • Daneshvar Kakhaki R.
      • Akbari E.
      • Tajabadi-Ebrahimi M.
      • Jafari P.
      • Asemi Z
      Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
      ;
      • Sanoobar M.
      • Dehghan P.
      • Khalili M.
      • Azimi A.
      • Seifar F
      Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: a double blind randomized clinical trial.
      ;
      • Bertoglio J.C.
      • Baumgartner M.
      • Palma R.
      • Ciampi E.
      • Carcamo C.
      • Caceres D.D.
      • Acosta-Jamett G.
      • Hancke J.L.
      • Burgos R.A
      Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study.
      ;
      • Etemadifar M.
      • Sayahi F.
      • Abtahi S.H.
      • Shemshaki H.
      • Dorooshi G.A.
      • Goodarzi M.
      • Akbari M.
      • Fereidan-Esfahani M
      Ginseng in the treatment of fatigue in multiple sclerosis: a randomized, placebo-controlled, double-blind pilot study.
      ). Clinical improvements in EDSS were reported in three trials, involving biotin, alpha lipoic acid, and probiotics (
      • Khallli M.
      • Eskandari G.
      • Ghajarzadeh M.
      • Azimi A.
      • Eghtesadi S.
      • Sahraian M.A.
      • Motevalian A.
      • Hashemi H.
      • Mirshafiey A.
      • Norouzi A
      Lipoic acid and multiple sclerosis: a randomized controlled conical trial.
      ;
      • Tourbah A.
      • Lebrun-Frenay C.
      • Edan G.
      • Clanet M.
      • Papeix C.
      • Vukusic S.
      • De Seze J.
      • Debouverie M.
      • Gout O.
      • Clavelou P.
      • Defer G.
      • Laplaud D.A.
      • Moreau T.
      • Labauge P.
      • Brochet B.
      • Sedel F.
      • Pelletier J
      MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study.
      ;
      • Kouchaki E.
      • Tamtaji O.R.
      • Salami M.
      • Bahmani F.
      • Daneshvar Kakhaki R.
      • Akbari E.
      • Tajabadi-Ebrahimi M.
      • Jafari P.
      • Asemi Z
      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 (
      • Khalili M.
      • Azimi A.
      • Izadi V.
      • Eghtesadi S.
      • Mirshafiey A.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Sanoobar M.
      • Eskandari G.
      • Farhoudi M.
      • Amani F
      Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
      ,
      • Khalili M.
      • Eghtesadi S.
      • Mirshafiey A.
      • Eskandari G.
      • Sanoobar M.
      • Sahraian M.A.
      • Motevalian A.
      • Norouzi A.
      • Moftakhar S.
      • Azimi A
      Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.
      ;
      • Mohammadzadeh Honarvar N.
      • Harirchian M.H.
      • Abdolahi M.
      • Abedi E.
      • Bitarafan S.
      • Koohdani F.
      • Siassi F.
      • Sahraian M.A.
      • Chahardoli R.
      • Zareei M.
      • Salehi E.
      • Geranmehr M.
      • Saboor-Yaraghi A.A
      Retinyl palmitate supplementation modulates T-bet and interferon gamma gene expression in multiple sclerosis patients.
      ;
      • Mauriz E.
      • Vallejo D.
      • Tunon M.J.
      • Rodriguez-Lopez J.M.
      • Rodriguez-Perez R.
      • Sanz-Gomez J.
      • Garcia-Fernandez Mdel C
      Effects of dietary supplementation with lemon verbena extracts on serum inflammatory markers of multiple sclerosis patients.
      ;
      • Kouchaki E.
      • Tamtaji O.R.
      • Salami M.
      • Bahmani F.
      • Daneshvar Kakhaki R.
      • Akbari E.
      • Tajabadi-Ebrahimi M.
      • Jafari P.
      • Asemi Z
      Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
      ;
      • Dolati S.
      • Ahmadi M.
      • Aghebti-Maleki L.
      • Nikmaram A.
      • Marofi F.
      • Rikhtegar R.
      • Ayromlou H.
      • Yousefi M
      Nanocurcumin is a potential novel therapy for multiple sclerosis by influencing inflammatory mediators.
      ).
      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 (
      • Motl R.W.
      • Mowry E.M.
      • Ehde D.M.
      • LaRocca N.G.
      • Smith K.E.
      • Costello K.
      • Shinto L.
      • Ng A.V.
      • Sullivan A.B.
      • Giesser B.
      • McCully K.K.
      • Fernhall B.
      • Bishop M.
      • Plow M.
      • Casaccia P.
      • Chiaravalloti N.D
      Wellness and multiple sclerosis: The National MS Society establishes a Wellness Research Working Group and research priorities.
      ). 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 (
      • O'Connor K.
      • Weinstock-Guttman B.
      • Carl E.
      • Kilanowski C.
      • Zivadinov R.
      • Ramanathan M
      Patterns of dietary and herbal supplement use by multiple sclerosis patients.
      ). 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 (
      • Sato F.
      • Martinez N.E.
      • Shahid M.
      • Rose J.W.
      • Carlson N.G.
      • Tsunoda I
      Resveratrol exacerbates both autoimmune and viral models of multiple sclerosis.
      ). 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 (
      • Isomura T.
      • Suzuki S.
      • Origasa H.
      • Hosono A.
      • Suzuki M.
      • Sawada T.
      • Terao S.
      • Muto Y.
      • Koga T
      Liver-related safety assessment of green tea extracts in humans: a systematic review of randomized controlled trials.
      ;
      • Molinari M.
      • Watt K.D.S.
      • Kruszyna T.
      • Nelson R.
      • Walsh M.
      • Huang W.-.Y.
      • Nashan B.
      • Peltekian K
      Acute liver failure induced by green tea extracts: case report and review of the literature.
      ). In another trial, incidence of relapse was almost four-fold higher in the group that received a biotin formulation than in the placebo group (
      • Tourbah A.
      • Gout O.
      • Vighetto A.
      • Deburghgraeve V.
      • Pelletier J.
      • Papeix C.
      • Lebrun-Frenay C.
      • Labauge P.
      • Brassat D.
      • Toosy A.
      • Laplaud D.A.
      • Outteryck O.
      • Moreau T.
      • Debouverie M.
      • Clavelou P.
      • Heinzlef O.
      • De Seze J.
      • Defer G.
      • Sedel F.
      • Arndt C
      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.
      ). However, this was not replicated in a post hoc analysis of another trial that used the same biotin formulation (
      • Tourbah A.
      • Gout O.
      • Vighetto A.
      • Deburghgraeve V.
      • Pelletier J.
      • Papeix C.
      • Lebrun-Frenay C.
      • Labauge P.
      • Brassat D.
      • Toosy A.
      • Laplaud D.A.
      • Outteryck O.
      • Moreau T.
      • Debouverie M.
      • Clavelou P.
      • Heinzlef O.
      • De Seze J.
      • Defer G.
      • Sedel F.
      • Arndt C
      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.
      ;
      • Tourbah A.
      • Lebrun-Frenay C.
      • Edan G.
      • Clanet M.
      • Papeix C.
      • Vukusic S.
      • De Seze J.
      • Debouverie M.
      • Gout O.
      • Clavelou P.
      • Defer G.
      • Laplaud D.A.
      • Moreau T.
      • Labauge P.
      • Brochet B.
      • Sedel F.
      • Pelletier J
      MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, 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 (
      • Marx W.
      • Isenring E.A.
      • Lohning A.E
      Determination of the concentration of major active anti-emetic constituents within commercial ginger food products and dietary supplements.
      ). 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 (
      • Lan M.
      • Tang X.
      • Zhang J.
      • Yao Z
      Insights in pathogenesis of multiple sclerosis: nitric oxide may induce mitochondrial dysfunction of oligodendrocytes.
      ). Others have suggested that in the early neuroinflammatory process, axonal mitochondrial trafficking dynamics could be affected, with consequent perturbation of local energy levels (
      • Errea O.
      • Moreno B.
      • Gonzalez-Franquesa A.
      • Garcia-Roves P.M.
      • Villoslada P
      The disruption of mitochondrial axonal transport is an early event in neuroinflammation.
      ). 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 (
      • Pereira C.
      • Chavarria V.
      • Vian J.
      • Ashton M.M.
      • Berk M.
      • Marx W.
      • Dean O.M
      Mitochondrial agents for bipolar disorder.
      ).
      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 (
      • Lim C.K.
      • Bilgin A.
      • Lovejoy D.B.
      • Tan V.
      • Bustamante S.
      • Taylor B.V.
      • Bessede A.
      • Brew B.J.
      • Guillemin G.J
      Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression.
      ). 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 (
      • Strasser B.
      • Geiger D.
      • Schauer M.
      • Gostner J.M.
      • Gatterer H.
      • Burtscher M.
      • Fuchs D
      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.
      ;
      • Marques C.
      • Fernandes I.
      • Meireles M.
      • Faria A.
      • Spencer J.P.E.
      • Mateus N.
      • Calhau C
      Gut microbiota modulation accounts for the neuroprotective properties of anthocyanins.
      ).
      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 (
      • Berer K.
      • Gerdes L.A.
      • Cekanaviciute E.
      • Jia X.
      • Xiao L.
      • Xia Z.
      • Liu C.
      • Klotz L.
      • Stauffer U.
      • Baranzini S.E.
      • Kümpfel T.
      • Hohlfeld R.
      • Krishnamoorthy G.
      • Wekerle H
      Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice.
      ). 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 (
      • Kouchaki E.
      • Tamtaji O.R.
      • Salami M.
      • Bahmani F.
      • Daneshvar Kakhaki R.
      • Akbari E.
      • Tajabadi-Ebrahimi M.
      • Jafari P.
      • Asemi Z
      Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
      ), further studies are required to confirm these results.
      Several nutraceuticals including polyphenol compounds such as apigenin
      • Ginwala R.
      • McTish E.
      • Singh N.
      • Raman C.
      • Nagarkatti M.
      • Jain P.
      • Khan Z.K
      Apigenin, a natural flavonoid, attenuates EAE severity through modulation of dendritic and other immune cell functions.
      , and naringenin
      • Wang J.
      • Niu X.
      • Meydani S.
      • Wu D
      Dietary supplementation with naringenin attenuates experimental autoimmune encephalomyelitis in mice.
      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)

      Appendix. Supplementary materials

      References

        • Asano M.
        • Finlayson M.L.
        Meta-Analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication.
        Mult. Scler. Int. 2014; 2014798285
        • Berer K.
        • Gerdes L.A.
        • Cekanaviciute E.
        • Jia X.
        • Xiao L.
        • Xia Z.
        • Liu C.
        • Klotz L.
        • Stauffer U.
        • Baranzini S.E.
        • Kümpfel T.
        • Hohlfeld R.
        • Krishnamoorthy G.
        • Wekerle H
        Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice.
        Proc. Natl Acad. Sci. 2017; 114: 10719-10724
        • Bertoglio J.C.
        • Baumgartner M.
        • Palma R.
        • Ciampi E.
        • Carcamo C.
        • Caceres D.D.
        • Acosta-Jamett G.
        • Hancke J.L.
        • Burgos R.A
        Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study.
        BMC Neurol. 2016; 16: 77
        • Bitarafan S.
        • Saboor-Yaraghi A.
        • Sahraian M.A.
        • Soltani D.
        • Nafissi S.
        • Togha M.
        • Moghadam N.B.
        • Roostaei T.
        • Honarvar N.M.
        • Harirchian M.H
        Effect of Vitamin A supplementation on fatigue and depression in multiple sclerosis patients: a double-blind placebo-controlled clinical trial.
        Iran. J. Allergy Asthm Immunology. 2016; 15: 13-19
        • Brochet B.
        • Guinot P.
        • Orgogozo J.M.
        • Confavreux C.
        • Rumbach L.
        • Lavergne V
        Double blind placebo controlled multicentre study of ginkgolide B in treatment of acute exacerbations of multiple sclerosis. The Ginkgolide Study Group in multiple sclerosis..
        J. Neurol. Neurosurg. Psychiatr. 1995; 58: 360-362
        • Claflin S.B.
        • van der Mei I.A.F.
        • Taylor B.V
        Complementary and alternative treatments of multiple sclerosis: a review of the evidence from 2001 to 2016.
        J. Neurol. Neurosurg. Psychiatry. 2018; 89: 34
        • Diamond B.J.
        • Bailey M.R
        Ginkgo biloba. indications, mechanisms, and safety.
        Psychiatr. Clin. N. Am. 2013; 36: 73-83
      1. 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.

        • Dolati S.
        • Ahmadi M.
        • Aghebti-Maleki L.
        • Nikmaram A.
        • Marofi F.
        • Rikhtegar R.
        • Ayromlou H.
        • Yousefi M
        Nanocurcumin is a potential novel therapy for multiple sclerosis by influencing inflammatory mediators.
        Pharmacol. Rep. 2018; 70: 1158-1167
        • Drake M.J.
        • Canham L.
        • Cotterill N.
        • Delgado D.
        • Homewood J.
        • Inglis K.
        • Johnson L.
        • Kisanga M.C.
        • Owen D.
        • White P.
        • Cottrell D
        Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of Nocturia in adults with multiple sclerosis (MeNiMS).
        BMC Neurol. 2018; 18 (107–)
      2. 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.

        • Errea O.
        • Moreno B.
        • Gonzalez-Franquesa A.
        • Garcia-Roves P.M.
        • Villoslada P
        The disruption of mitochondrial axonal transport is an early event in neuroinflammation.
        J. Neuroinflammation. 2015; 12: 152
        • Etemadifar M.
        • Sayahi F.
        • Abtahi S.H.
        • Shemshaki H.
        • Dorooshi G.A.
        • Goodarzi M.
        • Akbari M.
        • Fereidan-Esfahani M
        Ginseng in the treatment of fatigue in multiple sclerosis: a randomized, placebo-controlled, double-blind pilot study.
        Int. J. Neurosci. 2013; 123: 480-486
        • Farinotti M.
        • Vacchi L.
        • Simi S.
        • Di Pietrantonj C.
        • Brait L.
        • Filippini G
        Dietary interventions for multiple sclerosis.
        Cochrane Database Syst. Rev. 2012; 12 (Cd004192)
        • Gallien P.
        • Amarenco G.
        • Benoit N.
        • Bonniaud V.
        • Donze C.
        • Kerdraon J.
        • de Seze M.
        • Denys P.
        • Renault A.
        • Naudet F.
        • Reymann J.M
        Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter, randomized, placebo-controlled, double-blind trial.
        Mult. Scler. 2014; 20: 1252-1259
        • Ginwala R.
        • McTish E.
        • Singh N.
        • Raman C.
        • Nagarkatti M.
        • Jain P.
        • Khan Z.K
        Apigenin, a natural flavonoid, attenuates EAE severity through modulation of dendritic and other immune cell functions.
        J. Neurovirol. 2015; 21: S24-SS5
        • Gonsette R.E.
        • Sindic C.
        • D'Hooghe M B.
        • De Deyn P.P.
        • Medaer R.
        • Michotte A.
        • Seeldrayers P.
        • Guillaume D
        Boosting endogenous neuroprotection in multiple sclerosis: the Association of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.
        Multiple sclerosis (Houndmills, Basingstoke, England). 2010; 16: 455-462
        • Isomura T.
        • Suzuki S.
        • Origasa H.
        • Hosono A.
        • Suzuki M.
        • Sawada T.
        • Terao S.
        • Muto Y.
        • Koga T
        Liver-related safety assessment of green tea extracts in humans: a systematic review of randomized controlled trials.
        Eur. J. Clin. Nutr. 2016; 70: 1221
        • Jadad A.R.
        • Moore R.A.
        • Carroll D.
        • Jenkinson C.
        • Reynolds D.J.
        • Gavaghan D.J.
        • McQuay H.J
        Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
        Control. Clin. Trials. 1996; 17: 1-12
      3. 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.

        • Khalili M.
        • Azimi A.
        • Izadi V.
        • Eghtesadi S.
        • Mirshafiey A.
        • Sahraian M.A.
        • Motevalian A.
        • Norouzi A.
        • Sanoobar M.
        • Eskandari G.
        • Farhoudi M.
        • Amani F
        Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial.
        NeuroImmunoModulation. 2014; 21: 291-296
        • Khalili M.
        • Eghtesadi S.
        • Mirshafiey A.
        • Eskandari G.
        • Sanoobar M.
        • Sahraian M.A.
        • Motevalian A.
        • Norouzi A.
        • Moftakhar S.
        • Azimi A
        Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.
        Nutr. Neurosci. 2014; 17: 16-20
        • Khalili M.
        • Soltani M.
        • Moghadam S.A.
        • Dehghan P.
        • Azimi A.
        • Abbaszadeh O
        Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients: a randomized clinical trial.
        Electron. Physician. 2017; 9: 4899-4905
        • Khallli M.
        • Eskandari G.
        • Ghajarzadeh M.
        • Azimi A.
        • Eghtesadi S.
        • Sahraian M.A.
        • Motevalian A.
        • Hashemi H.
        • Mirshafiey A.
        • Norouzi A
        Lipoic acid and multiple sclerosis: a randomized controlled conical trial.
        Curr. Top Nutraceutical Res. 2012; 10: 95-100
        • Kouchaki E.
        • Tamtaji O.R.
        • Salami M.
        • Bahmani F.
        • Daneshvar Kakhaki R.
        • Akbari E.
        • Tajabadi-Ebrahimi M.
        • Jafari P.
        • Asemi Z
        Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
        Clin. Nutr. (Edinburgh, Scotland). 2017; 36: 1245-1249
        • Lambert C.P.
        • Archer R.L.
        • Carrithers J.A.
        • Fink W.J.
        • Evans W.J.
        • Trappe T.A
        Influence of creatine monohydrate ingestion on muscle metabolites and intense exercise capacity in individuals with multiple sclerosis.
        Arch. Phys. Med. Rehabil. 2003; 84: 1206-1210
        • Lan M.
        • Tang X.
        • Zhang J.
        • Yao Z
        Insights in pathogenesis of multiple sclerosis: nitric oxide may induce mitochondrial dysfunction of oligodendrocytes.
        Rev. Neurosci. 2018; 29: 39-53
        • Lassmann H.
        Pathology and disease mechanisms in different stages of multiple sclerosis.
        J. Neurol. Sci. 2013; 333: 1-4
        • Ledinek A.H.
        • Sajko M.C.
        • Rot U
        Evaluating the effects of amantadin, modafinil and acetyl-L-carnitine on fatigue in multiple sclerosis - Result of a pilot randomized, blind study.
        Clin. Neurol. Neurosurg. 2013; 115: S86-SS9
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • Mulrow C.
        • Gøtzsche P.C.
        • Ioannidis J.P.A.
        • Clarke M.
        • Devereaux P.J.
        • Kleijnen J.
        • Moher D
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
        PLoS Med. 2009; 6e1000100
        • Lim C.K.
        • Bilgin A.
        • Lovejoy D.B.
        • Tan V.
        • Bustamante S.
        • Taylor B.V.
        • Bessede A.
        • Brew B.J.
        • Guillemin G.J
        Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression.
        Sci. Rep. 2017; 7: 41473
        • Lovera J.
        • Bagert B.
        • Smoot K.
        • Morris C.D.
        • Frank R.
        • Bogardus K.
        • Wild K.
        • Oken B.
        • Whitham R.
        • Bourdette D
        Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial.
        Mult. Scler. 2007; 13: 376-385
        • Lovera J.
        • Ramos A.
        • Devier D.
        • Garrison V.
        • Kovner B.
        • Reza T.
        • Koop D.
        • Rooney W.
        • Foundas A.
        • Bourdette D
        • Polyphenon E.
        Non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies.
        J. Neurol. Sci. 2015; 358: 46-52
        • Lovera J.F.
        • Kim E.
        • Heriza E.
        • Fitzpatrick M.
        • Hunziker J.
        • Turner A.P.
        • Adams J.
        • Stover T.
        • Sangeorzan A.
        • Sloan A.
        • Howieson D.
        • Wild K.
        • Haselkorn J.
        • Bourdette D
        Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial.
        Neurology. 2012; 79: 1278-1284
        • Mahler A.
        • Steiniger J.
        • Bock M.
        • Klug L.
        • Parreidt N.
        • Lorenz M.
        • Zimmermann B.F.
        • Krannich A.
        • Paul F.
        • Boschmann M
        Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial.
        Am. J. Clin. Nutr. 2015; 101: 487-495
        • Malin S.K.
        • Cotugna N.
        • Fang C.S
        Effect of creatine supplementation on muscle capacity in individuals with multiple sclerosis.
        J. Diet Suppl. 2008; 5: 20-32
        • Markowitz C.E.
        • Spitsin S.
        • Zimmerman V.
        • Jacobs D.
        • Udupa J.K.
        • Hooper D.C.
        • Koprowski H
        The treatment of multiple sclerosis with inosine.
        J. Altern. Complem. Med. (New York, NY). 2009; 15: 619-625
        • Marques C.
        • Fernandes I.
        • Meireles M.
        • Faria A.
        • Spencer J.P.E.
        • Mateus N.
        • Calhau C
        Gut microbiota modulation accounts for the neuroprotective properties of anthocyanins.
        Sci. Rep. 2018; 8: 11341
        • Marx W.
        • Isenring E.A.
        • Lohning A.E
        Determination of the concentration of major active anti-emetic constituents within commercial ginger food products and dietary supplements.
        Eur. J. Integr. Med. 2017; 10: 19-24
        • Mauriz E.
        • Vallejo D.
        • Tunon M.J.
        • Rodriguez-Lopez J.M.
        • Rodriguez-Perez R.
        • Sanz-Gomez J.
        • Garcia-Fernandez Mdel C
        Effects of dietary supplementation with lemon verbena extracts on serum inflammatory markers of multiple sclerosis patients.
        Nutr. Hosp. 2014; 31: 764-771
        • McLaughlin L.
        • Clarke L.
        • Khalilidehkordi E.
        • Butzkueven H.
        • Taylor B.
        • Broadley S.A
        Vitamin D for the treatment of multiple sclerosis: a meta-analysis.
        J. Neurol. 2018; 265: 2893-2905
        • Mohammadzadeh Honarvar N.
        • Harirchian M.H.
        • Abdolahi M.
        • Abedi E.
        • Bitarafan S.
        • Koohdani F.
        • Siassi F.
        • Sahraian M.A.
        • Chahardoli R.
        • Zareei M.
        • Salehi E.
        • Geranmehr M.
        • Saboor-Yaraghi A.A
        Retinyl palmitate supplementation modulates T-bet and interferon gamma gene expression in multiple sclerosis patients.
        J. Mol. Neurosci. 2016; 59: 360-365
        • Molinari M.
        • Watt K.D.S.
        • Kruszyna T.
        • Nelson R.
        • Walsh M.
        • Huang W.-.Y.
        • Nashan B.
        • Peltekian K
        Acute liver failure induced by green tea extracts: case report and review of the literature.
        Liver Transpl. 2006; 12: 1892-1895
        • Motl R.W.
        • Mowry E.M.
        • Ehde D.M.
        • LaRocca N.G.
        • Smith K.E.
        • Costello K.
        • Shinto L.
        • Ng A.V.
        • Sullivan A.B.
        • Giesser B.
        • McCully K.K.
        • Fernhall B.
        • Bishop M.
        • Plow M.
        • Casaccia P.
        • Chiaravalloti N.D
        Wellness and multiple sclerosis: The National MS Society establishes a Wellness Research Working Group and research priorities.
        Multiple sclerosis (Houndmills, Basingstoke, England). 2018; 24: 262-267
        • Munoz Garcia D.
        • Midaglia L.
        • Martinez Vilela J.
        • Marin Sanchez M.
        • Lopez Gonzalez F.J.
        • Arias Gomez M.
        • Dapena Bolano D.
        • Iglesias Castanon A.
        • Alonso Alonso M.
        • Romero Lopez J
        Associated inosine to interferon: results of a clinical trial in multiple sclerosis.
        Acta Neurol. Scand. 2015; 131: 405-410
        • Nabavi S.M.
        • Naseri M.
        • Rezaeezadeh H.
        • Ghareguzli K.
        • Shayegannejad V.
        • Ghafarpoor M.
        • Faghihzadeh S
        A double-blind, placebo-controlled, study of oral MS14, a herbal-marine drug, on walking ability in multiple sclerosis patients.
        J. Neurol. 2012; : S153
        • Naghashpour M.
        • Majdinasab N.
        • Shakerinejad G.
        • Kouchak M.
        • Haghighizadeh M.H.
        • Jarvandi F.
        • Hajinajaf S
        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
        • O'Connor K.
        • Weinstock-Guttman B.
        • Carl E.
        • Kilanowski C.
        • Zivadinov R.
        • Ramanathan M
        Patterns of dietary and herbal supplement use by multiple sclerosis patients.
        J. Neurol. 2012; 259: 637-644
        • Pantzaris M.C.
        • Loukaides G.N.
        • Ntzani E.E.
        • Patrikios I.S
        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.
        BMJ Open. 2013; 3
        • Pereira C.
        • Chavarria V.
        • Vian J.
        • Ashton M.M.
        • Berk M.
        • Marx W.
        • Dean O.M
        Mitochondrial agents for bipolar disorder.
        Int. J. Neuropsychopharmacol. 2018; 21: 550-569
        • Reich D.S.
        • Lucchinetti C.F.
        • Calabresi P.A
        Multiple sclerosis.
        N. Eng. J. Med. 2018; 378: 169-180
        • Roostaei T.
        • Sahraian M.A.
        • Hajeaghaee S.
        • Gholipour T.
        • Togha M.
        • Siroos B.
        • Mansouri S.
        • Mohammadshirazi Z.
        • Aghazadeh Alasti M.
        • Harirchian M.H
        Impact of melatonin on motor, cognitive and neuroimaging indices in patients with multiple sclerosis.
        Iran J. Allergy Asthma Immunol. 2015; 14: 589-595
        • Sanoobar M.
        • Dehghan P.
        • Khalili M.
        • Azimi A.
        • Seifar F
        Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: a double blind randomized clinical trial.
        Nutr. Neurosci. 2016; 19: 138-143
        • Sato F.
        • Martinez N.E.
        • Shahid M.
        • Rose J.W.
        • Carlson N.G.
        • Tsunoda I
        Resveratrol exacerbates both autoimmune and viral models of multiple sclerosis.
        Am. J. Pathol. 2013; 183: 1390-1396
        • Shaygannejad V.
        • Janghorbani M.
        • Savoj M.R.
        • Ashtari F
        Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial.
        Neurol. Res. 2010; 32: 981-985
        • Simpson Jr., S.
        • Tan H.
        • Otahal P.
        • Taylor B.
        • Ponsonby A.L.
        • Lucas R.M.
        • Blizzard L.
        • Valery P.C.
        • Lechner-Scott J.
        • Shaw C.
        • Williams D.
        • van der Mei I
        Anxiety, depression and fatigue at 5-year review following CNS demyelination.
        Acta Neurol. Scand. 2016; 134: 403-413
        • Spain R.
        • Powers K.
        • Murchison C.
        • Heriza E.
        • Winges K.
        • Yadav V.
        • Cameron M.
        • Kim E.
        • Horak F.
        • Simon J.
        • Bourdette D
        Lipoic acid in secondary progressive MS: a randomized controlled pilot trial.
        Neurol. Neuroimmunol. Neuroinflammation. 2017; 4: e374
        • Strasser B.
        • Geiger D.
        • Schauer M.
        • Gostner J.M.
        • Gatterer H.
        • Burtscher M.
        • Fuchs D
        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.
        Nutrients. 2016; 8: 752
        • Tomassini V.
        • Pozzilli C.
        • Onesti E.
        • Pasqualetti P.
        • Marinelli F.
        • Pisani A.
        • Fieschi C
        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.
        J. Neurol. Sci. 2004; 218: 103-108
        • Tourbah A.
        • Gout O.
        • Vighetto A.
        • Deburghgraeve V.
        • Pelletier J.
        • Papeix C.
        • Lebrun-Frenay C.
        • Labauge P.
        • Brassat D.
        • Toosy A.
        • Laplaud D.A.
        • Outteryck O.
        • Moreau T.
        • Debouverie M.
        • Clavelou P.
        • Heinzlef O.
        • De Seze J.
        • Defer G.
        • Sedel F.
        • Arndt C
        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.
        CNS Drugs. 2018; 32: 661-672
        • Tourbah A.
        • Lebrun-Frenay C.
        • Edan G.
        • Clanet M.
        • Papeix C.
        • Vukusic S.
        • De Seze J.
        • Debouverie M.
        • Gout O.
        • Clavelou P.
        • Defer G.
        • Laplaud D.A.
        • Moreau T.
        • Labauge P.
        • Brochet B.
        • Sedel F.
        • Pelletier J
        MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study.
        Mult. Scler. 2016; 22: 1719-1731
        • Wang J.
        • Niu X.
        • Meydani S.
        • Wu D
        Dietary supplementation with naringenin attenuates experimental autoimmune encephalomyelitis in mice.
        FASEB J. Conf. 2015; 29
        • Yadav V.
        • Bever Jr., C.
        • Bowen J.
        • Bowling A.
        • Weinstock-Guttman B.
        • Cameron M.
        • Bourdette D.
        • Gronseth G.S.
        • Narayanaswami P
        Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology.
        Neurology. 2014; 82: 1083-1092
        • Yadav V.
        • Marracci G.
        • Lovera J.
        • Woodward W.
        • Bogardus K.
        • Marquardt W.
        • Shinto L.
        • Morris C.
        • Bourdette D.N
        Lipoic acid in multiple sclerosis: a pilot study.
        Multiple Sclerosis. 2005; 11: 159-165
        • Zheng C.
        • He L.
        • Liu L.
        • Zhu J.
        • Jin T
        The efficacy of vitamin D in multiple sclerosis: a meta-analysis.
        Mult. Scler. Relat. Disord. 2018; 23: 56-61