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Meta-Analysis
. 2020 May 19;5(5):CD004192.
doi: 10.1002/14651858.CD004192.pub4.

Dietary interventions for multiple sclerosis-related outcomes

Natalie E Parks  1 , Caitlin S Jackson-Tarlton  1 , Laura Vacchi  2 , Roah Merdad  3 , Bradley C Johnston  4
Affiliations
Meta-Analysis

Dietary interventions for multiple sclerosis-related outcomes

Natalie E Parks et al. Cochrane Database Syst Rev. .

Abstract

Background: Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system. Although the exact pathogenesis remains unknown, the leading theory is that it results from immune system dysregulation. Approved disease-modifying therapy appears to modulate the immune system to improve MS-related outcomes. There is substantial interest in the ability of dietary interventions to influence MS-related outcomes. This is an update of the Cochrane Review 'Dietary interventions for multiple sclerosis' (Farinotti 2003; Farinotti 2007; Farinotti 2012).

Objectives: To assess the effects of dietary interventions (including dietary plans with recommendations for specific whole foods, macronutrients, and natural health products) compared to placebo or another intervention on health outcomes (including MS-related outcomes and serious adverse events) in people with MS.

Search methods: On 30 May 2019, we searched CENTRAL, MEDLINE, Embase, and Web of Science. We also searched ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (ICTRP), and Networked Digital Library of Theses and Dissertations (NDLTD). We checked reference lists in identified trials and requested information from trial authors to identify any additional published or unpublished data.

Selection criteria: We included any randomized controlled trial (RCT) or controlled clinical trial (CCT) examining the effect of a dietary intervention versus placebo or another intervention among participants with MS on MS-related outcomes, including relapses, disability progression, and magnetic resonance imaging (MRI) measures.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. Planned primary outcomes were number of participants experiencing relapse and change in disability progression, according to a validated disability scale at the last reported follow-up. Secondary outcomes included MRI activity, safety, and patient-reported outcomes. We entered and analysed data in Review Manager 5.

Main results: We found 41 full-text articles examining 30 trials following full-text review. Participants were adults with MS, defined by established criteria, presenting to MS clinics in Europe, North America, and the Middle East. Study design varied considerably, although all trials had at least one methodological issue leading to unknown or high risk of bias. Trials examined: supplementation to increase polyunsaturated fatty acids (PUFAs) (11 trials); a variety of antioxidant supplements (10 trials); dietary programmes (3 trials); and other dietary supplements (e.g. acetyl L-carnitine, biotin, creatine, palmitoylethanolamide, probiotic, riboflavin) (6 trials). In three trials comparing PUFAs with monounsaturated fatty acids (MUFAs), the evidence was very uncertain concerning difference in relapses (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.20; 3 studies, 217 participants; 75% in the PUFA group versus 74% in the MUFA group; very low-certainty evidence). Among four trials comparing PUFAs with MUFAs, there may be little to no difference in global impression of deterioration (RR 0.85, 95% CI 0.71 to 1.03; 4 studies, 542 participants; 40% in the PUFA group versus 47% in the MUFA group; low-certainty evidence). In two trials comparing PUFAs with MUFAs (102 participants), there was very low-certainty evidence for change in disability progression. None of the PUFA versus MUFA trials examined MRI outcomes. In one trial comparing PUFAs with MUFAs (40 participants), there were no serious adverse events; based on low-certainty evidence. In two trials comparing different PUFAs (omega-3 versus omega-6), there may be little to no difference in relapses (RR 1.02, 95% CI 0.62 to 1.66; 2 studies, 129 participants; 30% in the omega-3 versus 29% in the omega-6 group; low-certainty evidence). Among three trials comparing omega-3 with omega-6, there may be little to no difference in change in disability progression, measured as mean change in Expanded Disability Status Scale (EDSS) (mean difference (MD) 0.00, 95% CI -0.30 to 0.30; 3 studies, 166 participants; low-certainty evidence). In one trial comparing omega-3 with omega-6, there was likely no difference in global impression of deterioration (RR 0.99, 95% CI 0.51 to 1.91; 1 study, 86 participants; 29% in omega-3 versus 29% in omega-6 group; moderate-certainty evidence). In one trial comparing omega-3 with omega-6 (86 participants), there was likely no difference in number of new T1- weighted gadolinium-enhancing lesions, based on moderate-certainty evidence. In four trials comparing omega-3 with omega-6, there may be little to no difference in serious adverse events (RR 1.12, 95% CI 0.38 to 3.31; 4 studies, 230 participants; 6% in omega-3 versus 5% in omega-6 group; low-certainty evidence). In four trials examining antioxidant supplementation with placebo, there may be little to no difference in relapses (RR 0.98, 95% CI 0.59 to 1.64; 4 studies, 345 participants; 17% in the antioxidant group versus 17% in the placebo group; low-certainty evidence). In six trials examining antioxidant supplementation with placebo, the evidence was very uncertain concerning change in disability progression, measured as mean change of EDSS (MD -0.19, 95% CI -0.49 to 0.11; 6 studies, 490 participants; very low-certainty evidence). In two trials examining antioxidant supplementation with placebo, there may be little to no difference in global impression of deterioration (RR 0.99, 95% 0.50 to 1.93; 2 studies, 190 participants; 15% in the antioxidant group versus 15% in the placebo group; low-certainty evidence). In two trials examining antioxidant supplementation with placebo, the evidence was very uncertain concerning difference in gadolinium-enhancing lesions (RR 0.67, 95% CI 0.09 to 4.88; 2 studies, 131 participants; 11% in the antioxidant group versus 16% in the placebo group; very low-certainty evidence). In three trials examining antioxidant supplementation versus placebo, there may be little to no difference in serious adverse events (RR. 0.72, 95% CI 0.17 to 3.08; 3 studies, 222 participants; 3% in the antioxidant group versus 4% in the placebo group; low-certainty evidence).

Authors' conclusions: There are a variety of controlled trials addressing the effects of dietary interventions for MS with substantial variation in active treatment, comparator, and outcomes of interest. PUFA administration may not differ when compared to alternatives with regards to relapse rate, disability worsening, or overall clinical status in people with MS, but evidence is uncertain. Similarly, at present, there is insufficient evidence to determine whether supplementation with antioxidants or other dietary interventions have any impact on MS-related outcomes.

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Conflict of interest statement

Natalie E Parks has provided consulting services to Biogen, EMD Serono, Roche, and Sanofi Genzyme. She has accepted funds from Biogen and Roche for travel to a scientific conference. She has acted as site sub‐investigator for clinical trials for Biogen, MedDay, Sanofi Genzyme, and Roche. She is the recipient of a Killam Predoctoral Scholarship, Nova Scotia Graduate Scholarship, and Dalhousie Medical Research Foundation Multiple Sclerosis Graduate Studentship.

Caitlin S Jackson‐Tarlton: nothing to declare Laura Vacchi: nothing to declare Roah Merdad: nothing to declare Bradley C Johnston: As part of his recruitment to Texas A&M University, BCJ received a start‐up grant from Texas A&M AgriLife Research to fund investigator‐initiated research related to saturated and polyunsaturated fats. The grant was from Texas A&M AgriLife institutional funds from interest and investment earnings, not a sponsoring organization, industry, or company.

Figures

1
1
PRISMA Diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Forest plot of comparison: 1 PUFA versus MUFA, outcome: 1.1 Relapse.
5
5
Forest plot of comparison: 1 PUFA versus MUFA, outcome: 1.2 Global impression of deterioration.
6
6
Forest plot of comparison: 2 PUFA (omega‐3) versus PUFA (omega‐6), outcome: 2.1 Relapse.
7
7
Forest plot of comparison: 2 Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), outcome: 2.2 Progression (change in EDSS).
8
8
Forest plot of comparison: 3 Antioxidant versus placebo, outcome: 3.1 Relapse.
9
9
Forest plot of comparison: 3 Antioxidant versus placebo, outcome: 3.2 Progression (change in EDSS).
10
10
Forest plot of comparison: 3 Antioxidant versus placebo, outcome: 3.4 Gadolinium‐enhancing lesions.
1.1
1.1. Analysis
Comparison 1: Polyunsaturated fatty acid versus monounsaturated fatty acid, Outcome 1: Relapse
1.2
1.2. Analysis
Comparison 1: Polyunsaturated fatty acid versus monounsaturated fatty acid, Outcome 2: Global impression of deterioration
2.1
2.1. Analysis
Comparison 2: Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), Outcome 1: Relapse
2.2
2.2. Analysis
Comparison 2: Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), Outcome 2: Progression (change in EDSS)
2.3
2.3. Analysis
Comparison 2: Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), Outcome 3: Global impression of deterioration
2.4
2.4. Analysis
Comparison 2: Polyunsaturated fatty acid (omega‐3) versus polyunsaturated fatty acid (omega‐6), Outcome 4: Serious adverse event
3.1
3.1. Analysis
Comparison 3: Antioxidant versus placebo, Outcome 1: Relapse
3.2
3.2. Analysis
Comparison 3: Antioxidant versus placebo, Outcome 2: Progression (change in EDSS)
3.3
3.3. Analysis
Comparison 3: Antioxidant versus placebo, Outcome 3: Global impression of deterioration
3.4
3.4. Analysis
Comparison 3: Antioxidant versus placebo, Outcome 4: Gadolinium‐enhancing lesions
3.5
3.5. Analysis
Comparison 3: Antioxidant versus placebo, Outcome 5: Cognition
3.6
3.6. Analysis
Comparison 3: Antioxidant versus placebo, Outcome 6: Fatigue
3.7
3.7. Analysis
Comparison 3: Antioxidant versus placebo, Outcome 7: Serious adverse event
4.1
4.1. Analysis
Comparison 4: Sensitivity analysis, Outcome 1: Polyunsaturated fatty acid versus monounsaturated fatty acid: relapse
4.2
4.2. Analysis
Comparison 4: Sensitivity analysis, Outcome 2: Omega‐3 versus omega‐6: relapse
4.3
4.3. Analysis
Comparison 4: Sensitivity analysis, Outcome 3: Antioxidant versus placebo: relapse
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Yadav 2016 {published data only}
    1. Yadav V, Maracci G, Kim E, Spain R, Cameron M, Overs S, et al. Effects of a very low fat, plant-food based diet on fatigue in multiple sclerosis: Report of a pilot trial [abstract]. Multiple Sclerosis Journal 2014;20(S1):91.
    1. Yadav V, Marracci G, Kim E, Spain R, Cameron M, Overs S, et al. Effects of a low fat plant based diet in multiple sclerosis (MS): results of a 1-year long randomized controlled (RC) study [abstract]. Neurology 2014;82(S10):P6.152.
    1. Yadav V, Marracci G, Kim E, Spain R, Cameron M, Overs S, et al. Low-fat, plant-based diet in multiple sclerosis: A randomized controlled trial. Multiple Sclerosis and Related Disorders 2016;9:80-90. [PMID: ] - PubMed
Zandi‐Esfahan 2017 {published data only}
    1. Zandi-Esfahan S, Fazeli M, Shaygannejad V, Hasheminia J, Badihian S, Aghayerashti M, et al. Evaluating the effect of adding Fish oil to Fingolimod on TNF-alpha, IL1beta, IL6, and IFN-gamma in patients with relapsing-remitting multiple sclerosis: A double-blind randomized placebo-controlled trial. Clinical Neurology and Neurosurgery 2017;163:173-8. [PMID: ] - PubMed

References to studies excluded from this review

Bisaga 2011 {published data only}
    1. Bisaga GN, Odinak MM, Boiko AN, Melnik IuB, Popova NF. Possibilities of treatment of multiple sclerosis exacerbations without corticosteroids: A role of metabolic and antioxidant therapy. Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova 2011;111(2):44-8. [PMID: ] - PubMed
Bisaga 2012 {published data only}
    1. Bisaga GN, Odinak MM, Boiko AN, Melnik YB, Popova NF. Treatment of exacerbations of multiple sclerosis without the use of corticosteroids: the role of metabolic and antioxidant therapy. Neuroscience and Behavioral Physiology 2012;42(2):123-7.
Bitarafan 2013 {published data only}
    1. Bitarafan S, Harirchian MH, Sahraian MA, Keramatipour M, Beladi Moghadam N, Togha M, et al. Impact of vitamin A supplementation on RAR gene expression in multiple sclerosis patients. Journal of Molecular Neuroscience 2013;51(2):478-84. [PMID: ] - PubMed
Bittner 2016 {published data only}
    1. Bittner F, Murchison C, Bourdette D, Spain R. The pharmacokinetics of lipoic acid at baseline and 48 weeks in secondary progressive multiple sclerosis patients. Annals of Neurology 2016;80(S20):S117.
Cendrowski 1982 {published data only}
    1. Cendrowski W. Unsaturated fatty acids in the immunology and therapy of multiple sclerosis. Polski Tygodnik Lekarski 1982;37(8):225-7. - PubMed
Cignarella 2017 {published data only}
    1. Cignarella F, Cantoni C, Ghezzi L, Zhou Y, Cross AH, Piccio L. Intermittent fasting in experimental autoimmune encephalomyelitis and multiple sclerosis. Multiple Sclerosis Journal 2017;23(S1):69.
Coe 2017 {published data only}
    1. Coe S, Axelsson E, Murphy V, Collett J, Clegg M, Izadi H, et al. The effect of high flavonoid cocoa on fatigue in people with multiple sclerosis. Multiple Sclerosis Journal 2016;22(S3):823. - PubMed
    1. Coe S, Axelsson E, Murphy V, Santos M, Collett J, Clegg M, et al. Flavonoid rich dark cocoa may improve fatigue in people with multiple sclerosis, yet has no effect on glycaemic response: An exploratory trial. Clinical Nutrition ESPEN 2017;21:20-5. [PMID: 30014865 ] - PubMed
Dworkin 1981 {published data only}
    1. Dworkin RH. Linoleic acid and multiple sclerosis. Lancet 1981;1(8230):1153-4. [PMID: ] - PubMed
Dworkin 1984 {published data only}
    1. Dworkin RH, Bates D, Millar JH, Paty DW. Linoleic acid and multiple sclerosis: A reanalysis of three double-blind trials. Neurology 1984;34(11):1441-5. [PMID: ] - PubMed
Eghtesadi 2015 {published data only}
    1. Eghtesadi S, Khalili M, Azimi A, Mirshafiey A, Sahraian M, Motevalian A, et al. Study of the effect of lipoic acid consumption on cytokine profile: A double-blind randomized clinical trial. Annals of Nutrition and Metabolism 2015;67(S1):301.
Field 1979 {published data only}
    1. Field EJ. Polyunsaturated fatty acids and colchicine in multiple sclerosis. British Medical Journal 1979;1(6160):411-12. [PMID: ] - PMC - PubMed
Fitzgerald 2017 {published data only}
    1. Fitzgerald K, Vizthum D, Henry-Barron B, Baer D, Sullivan P, Cassard S, et al. Calorie restriction diets and changes in the metabolome in people with multiple sclerosis. Multiple Sclerosis Journal 2017;23(S3):664-5.
    1. Fitzgerald K, Vizthum D, Henry-Barron B, Baer D, Sullivan P, Cassard S, et al. Concomitant changes in weight and in sleep quality among people with multiple sclerosis. Multiple Sclerosis Journal 2017;23(S3):761.
    1. Fitzgerald KC, Vizthum D, Henry-Barron B, Cassard S, Sullivan P, Baer D, et al. Effects of intermittent calorie restriction on weight, fat mass, lean mass, visceral adipose tissue: Results from a pilot controlled-feeding study in multiple sclerosis patients. Neurology 2017;88(S16):P3.390.
    1. Fitzgerald SK, Vizthum D, Barron B, Sullivan P, Baer D, Mowry EM. Calorie restriction diets and changes in the metabolome in people with multiple. Annals of Neurology 2017;82(S21):S191.
Gasperini 2011 {published data only}
    1. Gasperini C, Sormani MP, Galgani S, Stromillo ML, Scagnolari C, Solaro C, et al. Evaluation of efficacy of an add-on therapy with cianocobalamine (Vitamin B12) plus calcium levofolinate in relapsing-remitting multiple sclerosis patients already in treatment with interferon beta over a period of 24 months for a better longterm outcome (ADVANCE). Multiple Sclerosis Journal 2011;17:S208-9.
Harbige 2007 {published data only}
    1. Harbige LS, Sharief MK. Polyunsaturated fatty acids in the pathogenesis and treatment of multiple sclerosis. British Journal of Nutrition 2007;98(S1):S46-S53. [PMID: ] - PubMed
Holmoy 2013 {published data only}
    1. Holmoy T, Loken-Amsrud KI, Bakke SJ, Beiske AG, Bjerve KS, Hovdal H, et al. Inflammation markers in multiple sclerosis: CXCL16 reflects and may also predict disease activity. PLoS One 2013;8(9):e75021. [PMID: ] - PMC - PubMed
Jafarirad 2012 {published data only}
    1. Jafarirad S, Siassi F, Harirchian MH, Sahraian MA, Eshraghian MR, Shokri F, et al. The effect of vitamin A supplementation on stimulated T-cell proliferation with myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Journal of Neurosciences in Rural Practice 2012;3(3):294-8. [PMID: ] - PMC - PubMed
Jafarirad 2013 {published data only}
    1. Jafarirad S, Siassi F, Harirchian M, Amani R, Bitarafan S, Saboor-Yaraghi A. The effect of vitamin A supplementation on biochemical parameters in multiple sclerosis patients. Iranian Red Crescent Medical Journal 2013;15(3):194-8. [PMID: ] - PMC - PubMed
Kouchaki 2018 {published data only}
    1. Kouchaki E, Afarini M, Abolhassani J, Mirhosseini N, Bahmani F, Masoud SA, et al. High-dose ω-3 fatty acid plus vitamin D3 supplementation affects clinical symptoms and metabolic status of patients with multiple sclerosis: a randomized controlled clinical trial. Journal of Nutrition 2018;148(8):1380-6. - PubMed
Lambert 2003 {published data only}
    1. Lambert CP, Archer RL, Carrithers JA, Fink WJ, Evans WJ, Trappe TA. Influence of creatine monohydrate ingestion on muscle metabolites and intense exercise capacity in individuals with multiple sclerosis. Archives of Physical Medicine and Rehabilitation 2003;84(8):1206-10. [PMID: ] - PubMed
Lieben 2017 {published data only}
    1. Lieben CK, Blokland A, Deutz NE, Jansen W, Han G, Hupperts RM. Intake of tryptophan-enriched whey protein acutely enhances recall of positive loaded words in patients with multiple sclerosis. Clinical Nutrition 2018;37(1):321-8. [PMID: ] - PubMed
Loder 2002 {published data only}
    1. Loder C, Allawi J, Horrobin D. Treatment of multiple sclerosis with lofepramine, L-phenylalanine and vitamin B12: Mechanism of action and clinical importance: roles of the locus coeruleus and central noradrenergic systems. Medical Hypotheses 2002;59(5):594-602. [PMID: ] - PubMed
Lopes De Carvalho 2012 {published data only}
    1. Lopes De Carvalho L, Francavilla G, Motta R, Brichetto G. D-mannose, cranberry and Vitamin C are effective in preventing urinary tract infections in multiple sclerosis subjects. Multiple Sclerosis Journal 2012;18(5):S12-S13.
Lovera 2015 {published data only}
    1. Lovera J, Ramos A, Devier D, Garrison V, Kovner B, Reza T, et al. Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: Phase I single group and phase II randomized placebo-controlled studies. Journal of Neurological Sciences 2015;358(1-2):46-52. [PMID: ] - PMC - PubMed
Mauriz 2013 {published data only}
    1. Mauriz E, Laliena A, Vallejo D, Tuñón M, Rodriguez-López J, Rodriguez-Pérez R, et al. Effects of a low-fat diet with antioxidant supplementation on biochemical markers of multiple sclerosis long-term care residents. Nutricion Hospitalaria 2013;28(6):2229-35. [PMID: ] - PubMed
Mauriz 2014 {published data only}
    1. Mauriz E, Vallejo D, Tuñón M, Rodriguez-López J, Rodriguez-Pérez R, Sanz-Gómez J, et al. Effects of dietary supplementation with lemon verbena extracts on serum inflammatory markers of multiple sclerosis patients. Nutricion Hospitalaria 2014;31(2):764-71. [PMID: ] - PubMed
Mertin 1973 {published data only}
    1. Mertin J, Shenton BK, Field EJ. Unsaturated fatty acids in multiple sclerosis. British Medical Journal 1973;2(5869):777-8. [PMID: ] - PMC - PubMed
Meyer‐Rienecker 1976 {published data only}
    1. Meyer-Rienecker JH, Jenssen HL, Kohler H, Field EJ, Shenton BK. Effect of gamma-linolenate in multiple sclerosis. Lancet 1976;2(7992):966. - PubMed
Millar 1984 {published data only}
    1. Millar H. Preliminary-results of double-blind linoleic-acid treatment trials in multiple-sclerosis carried out in Belfast, Newcastle-Upon-Tyne and London, Ontario. Irish Journal of Medical Science 1984;153(4):153.
Moccia 2019 {published data only}
    1. Moccia M, Capacchione A, Lanzillo R, Carbone F, Micillo T, Perna F, et al. Coenzyme Q10 supplementation reduces peripheral oxidative stress and inflammation in interferon-β1a-treated multiple sclerosis. Therapeutic Advances in Neurological Disorders 2019;12:1756286418819074. [PMID: ] - PMC - PubMed
Mohammadzadeh Honarvar 2013 {published data only}
    1. Mohammadzadeh Honarvar N, Harirchian M, Koohdani F, Siassi F, Abdolahi M, Bitarafan S, et al. The effect of vitamin A supplementation on retinoic acid-related orphan receptor γt (RORγt) and interleukin-17 (IL-17) gene expression in Avonex-treated multiple sclerotic patients. Journal of Molecular Neuroscience 2013;51(3):749-53. [PMID: ] - PubMed
Mohammadzadeh Honarvar 2016 {published data only}
    1. Mohammadzadeh Honarvar N, Harirchian MH, Abdolahi M, Abedi E, Bitarafan S, Koohdani F, et al. Retinyl palmitate supplementation modulates T-bet and interferon gamma gene expression in multiple sclerosis patients. Journal of Molecular Neuroscience 2016;59(3):360-5. [PMID: 27122150] - PubMed
Saboor‐Yaraghi 2015 {published data only}
    1. Saboor-Yaraghi A, Harirchian M, Mohammadzadeh HN, Bitarafan S, Abdolahi M, Siassi F, et al. The effect of vitamin A supplementation on FoxP3 and TGF-β gene expression in avonex-treated multiple sclerosis patients. Journal of Molecular Neuroscience 2015;56(3):608-12. [PMID: ] - PubMed
Salari 2015 {published data only}
    1. Salari S, Khomand P, Arasteh M, Yousefzamani B, Hassamzadeh K. Zinc sulphate: A reasonable choice for depression management in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled clinical trial. Pharmacological Reports 2015;67(3):606-9. [PMID: ] - PubMed
Saresella 2017 {published data only}
    1. Saresella M, Mendozzi L, Rossi V, Mazzali F, Piancone F, LaRosa F, et al. Immunological and clinical effect of diet modulation of the gut microbiome in multiple sclerosis patients: A pilot study. Frontiers in Immunology 2017;8:1391. [PMID: ] - PMC - PubMed
Schultz 1984 {published data only}
    1. Schultz A. Efficacy of cranberry juice and ascorbic acid in acidifying the urine in multiple sclerosis subjects. Journal of Community Health Nursing 1984;1(3):159-69. [PMID: ] - PubMed
Shinto 2008 {published data only}
    1. Shinto L, Calabrese C, Morris C, Yadav V, Griffith D, Frank R, et al. A randomized pilot study of naturopathic medicine in multiple sclerosis. Journal of Alternative and Complementary Medicine 2008;14(5):489-96. [PMID: ] - PMC - PubMed
Simpson 1985 {published data only}
    1. Simpson L, Shand B, Olds R. Dietary supplementation with Efamol and multiple sclerosis. New Zealand Medical Journal 1985;98:1053. - PubMed
Skakonik 1963 {published data only}
    1. Skakonik W, Eisner M. Trials in the treatment of multiple sclerosis with diabetol associated with diets poor in carbohydrates. Annales Academiae Medicae Stetinensis 1963;9:267-70. - PubMed
Spitsin 2010 {published data only}
    1. Spitsin S, Markowitz C, Zimmerman V, Koprowski H, Hooper D. Modulation of serum uric acid levels by inosine in patients with multiple sclerosis does not affect blood pressure. Journal of Human Hypertension 2010;24(5):359-62. [PMID: ] - PubMed
Swank 1990 {published data only}
    1. Swank RL, Bourdillon RB. Multiple sclerosis: assessment of treatment with a modified low-fat diet. Journal of Nervous and Mental Disease 1960;131:468-88. [PMID: ] - PubMed
    1. Swank RL, Dugan BB. Effect of low saturated fat diet in early and late cases of multiple sclerosis. Lancet 1990;336(8706):37-9. [PMID: ] - PubMed
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    1. Swank RL. Multiple sclerosis: Fat-oil relationship. Nutrition 1991;7(5):368-76. [PMID: ] - PubMed
Tamtaji 2017 {published data only}
    1. Tamtaji O, Kouchaki E, Salami M, Aghadavod E, Akbari E, Tajabadi-Ebrahimi M, et al. The effects of probiotic supplementation on gene expression related to inflammation, insulin, and lipids in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled trial. Journal of the American College of Nutrition 2017;36(8):660-5. [PMID: 28922099] - PubMed
Toncev 2006 {published data only}
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Tran 2018 {published data only}
    1. Tran J, Hartung J, Tompkins CA, Frohna P. Effects of high-and low-fat meals on the pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator. Multiple Sclerosis Journal 2016;22(S3):374. - PMC - PubMed
    1. Tran JQ, Hartung JP, Tompkins CA, Frohna PA. Effects of high- and low-fat meals on the pharmacokinetics of ozanimod, a novel sphingosine-1-phosphate receptor modulator. Clinical Pharmacology in Drug Development 2018;7(6):634-40. [PMID: ] - PMC - PubMed
van Rensburg 2006 {published data only}
    1. Rensburg SJ, Kotze MJ, Hon D, Haug P, Kuyler J, Hendricks M, et al. Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis. Metabolic Brain Disease 2006;21(2-3):121-37. [PMID: ] - PubMed
Wade 2002 {published data only}
    1. Wade DT, Young CA, Chaudhuri KR, Davidson DL. A randomised placebo controlled exploratory study of vitamin B12, lofepramine, and L-phenylalanine (the "Cari Loder regime") in the treatment of multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry 2002;73(3):246-9. [PMID: ] - PMC - PubMed

References to studies awaiting assessment

Bock 2015 {published data only}
    1. Bock M, Michaelsen A, Paul F. Ketogenic diet and prolonged fasting improve health related quality of life and blood lipid profile in multiple sclerosis - A randomized controlled trial. Multiple Sclerosis Journal 2015;21(S11):794-5.
Kanter 2014 {published data only}
    1. Kanter J, Keiner E, Biwer A, Coughlin E, DiFabio B, Salmasinia D, et al. A double-blind placebo controlled study of the effect of beta-alanine, a nonessential amino-acid, on neurologic, motor function, quality of life, and fatigue in patients diagnosed with multiple sclerosis. Neurology 2014;82(10 Suppl 1):P7.253.
Khalili 2017 {published data only}
    1. Khalili M, Soltani M, Moghadam SA, Dehghan P, Azimi A, Abbaszadeh O. Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients: A randomized clinical trial. Electronic Physician 2017;9(7):4899-905. [PMID: ] - PMC - PubMed
Loy 2018 {published data only}
    1. Loy BD, Fling BW, Horak FB, Bourdette DN, Spain RI. Effects of lipoic acid on walking performance, gait, and balance in secondary progressive multiple sclerosis. Complementary Therapies in Medicine 2018;41:169-74. [PMID: ] - PMC - PubMed
Shah 2007 {published data only}
    1. Shah PS, O'Riordan JI, Gold L, Houston G, Donnan P. The role of diet in early relapsing remitting multiple sclerosis - A randomised controlled single-blind pilot study (ongoing clinical trial). European Journal of Neurology 2007;14:287-8.
Tourbah 2018 {published data only}
    1. Tourbah A, Arndt C, Vighetto A, Deburghgraeve V, Pelletier J, Papeix C, et al. Effect of MD1003 (high doses of biotin) in chronic visual loss related to optic neuritis in multiple sclerosis (MS-ON): Results of a pivotal randomized double masked placebo controlled study [abstract]. Neurology 2016;86(S16):S49.005.
    1. Tourbah A, Gout O, Vighetto A, Deburghgraeve V, Pelletier J, Papeix C, et al. 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(7):661-72. [PMID: ] - PMC - PubMed

References to ongoing studies

NCT01514370 {published data only}
    1. NCT01514370. Dietary supplement of curcumin in subjects with active relapsing multiple sclerosis treated with subcutaneous interferon Beta 1a. ClinicalTrials.gov/show/NCT01514370 (first received 23 January 2012).
NCT01848327 {published data only}
    1. NCT01848327. Caprylic triglyceride for treatment of cognitive impairments in multiple sclerosis. ClinicalTrials.gov/show/NCT01848327 (first received 7 May 2013).
NCT01915433 {published data only}
    1. NCT01915433. Wahls Paleo diet and progressive multiple sclerosis. ClinicalTrials.gov/show/NCT01915433 (first received 2 August 2013).
NCT02664623 {published data only}
    1. NCT02664623. Personalized nutrition advice for optimizing dietary calcium intake in MS patients. ClinicalTrials.gov/show/NCT02664623 (first received 27 January 2016).
NCT02914964 {published data only}
    1. NCT02914964. Dietary approaches to treat multiple sclerosis-related fatigue study. ClinicalTrials.gov/show/NCT02914964 (first received 26 September 2016).
NCT02936037 {published data only}
    1. NCT02936037. Effect of MD1003 in progressive multiple sclerosis (SPI2). ClinicalTrials.gov/show/NCT02936037 (first received 18 October 2016).
NCT02986893 {published data only}
    1. NCT02986893. Pilot diet study for multiple sclerosis. ClinicalTrials.gov/show/NCT02986893 (first received 8 December 2016).
NCT03322982 {published data only}
    1. NCT03322982. Low fat diet for fatigue in MS. ClinicalTrials.gov/show/NCT03322982 (first received 26 October 2017).
NCT03387046 {published data only}
    1. NCT03387046. A pilot study in subjects with relapsing remitting multiple sclerosis (RR-MS). ClinicalTrials.gov/show/NCT03387046 (first received 29 December 2017).
NCT03508414 {published data only}
    1. NCT03508414. Nutritional approaches in multiple sclerosis. ClinicalTrials.gov/show/NCT03508414 (first received 25 April 2018).

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