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

https://doi.org/10.1016/j.msard.2019.101486Get rights and content

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.

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 et al., 2018). 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 et al., 2016), 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 and Finlayson, 2014).

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, 2013) 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 et al., 2012; Zheng et al., 2018; Yadav et al., 2014; McLaughlin et al., 2018). 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 et al., 2018; McLaughlin et al., 2018). Similarly, a Cochrane review reported that omega-3 supplementation provided no significant improvements to disease progression (Farinotti et al., 2012).

Clinical trials that have investigated other nutraceutical interventions are emerging and the use of such nutraceuticals is of considerable interest to patients (Dunn et al., 2015; Claflin et al., 2018). 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 et al., 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.

Section snippets

Literature search

In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Liberati et al., 2009) 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

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).

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

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)

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

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

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