Ketogenic Diet Results in Reduced Weight, Fatigue, and Depression in Relapsing Multiple Sclerosis


In a recent phase 2 study, 6-months of ketogenic diet for people with relapsing multiple sclerosis resulted in a significant reduction in weight, fatigue, and depression, and improved quality of life.

James Nicholas Brenton, MD, assistant professor, division of pediatric neurology, department of neurology, the University of Virginia, in Charlottesville

James Nicholas Brenton, MD

A recent phase 2 study (NCT03718247) on ketogenic diet in relapsing multiple sclerosis (MS) resulted in participants exhibiting a significant reduction in fat mass as well as a 50% decline in self-reported fatigue and depression scores.1 This study’s findings suggest that ketogenic diets have potential clinical benefits, as dietary changes impact human physiology and immune function, serving as therapeutic strategies.

After implementing the ketogenic diet, MS Quality of life (QoL) scores significantly improved from 67 (±16) at baseline to 79 (±12; P <.001) at 6 months. Additionally, these patients saw mental health scores improved from 71 (±17) to 82 (±11; P <.001) over the same time period with the MS Qol scale.

Notably, there were also significant improvements in the Expanded Disability Status Scale scores (2.3 [±0.9] vs 1.9 [±1.1]; P <.001), 6-minute walk time (1631 [±302] vs 1733 [±330];P <.001) and for the Nine-Hole Peg Test scores (21.5 [±3.6] vs 20.3 [±3.7]; P <.001).

Additionally, the serum leptin with participants was lower, with amounts of 25.5 ng/mL (±15.7) at baseline vs 14.0 ng/mL (±11.7; P <.001) at the end of the treatment period. Additionally, the adiponectin was higher (11.4 µg/mL [±7.8] vs 13.5 µg/mL [±8.4] P =.002) on the ketogenic diets. Based on these results, lead investigator Nicholas Brenton, MD, assistant professor of neurology, Division of Child Neurology, University of Virginia, and colleagues conclude that ketogenic diets are, “safe and tolerable over a 6-month study period and yield improvements in body composition, fatigue, depression, QoL, neurological disability and adipose-related inflammation in persons living with relapsing MS.”

Brenton and colleagues also noted that their overall results support the rationale for a large-scale study of ketogenic diets as a complementary treatment for MS. However, their data does not support the widespread adoption of ketogenic diets as a therapeutic strategy for MS outside of a clinical trial.

Notably, the limitation for this study was the lack of a matched control group monitored on a regular or standard diet. Brenton et al wrote, “while the current study lacks controls, the findings herein are essential for next-step phase 3 trial design.” In addition to the lack of control group, another limitation included enrollment which was restricted to patients with clinically-stable relapsing MS. Hence, their findings are not generalizable to a population with active relapsing or progressive MS, which may be focused on in future studies.

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During the 6-month prospective intervention study, 65 participants with relapsing MS were enrolled, with adherence monitored daily via urine ketone testing. In addition to MS-related clinical outcome metrics and fasting adipokines, investigators collected data at baseline on fatigue, depression and QoL scores. At 3 and/or 6 months on-diet, the baseline metrics were repeated for measure comparisons. Using established adherence criteria, 83% of participants successfully adhered to the diet for the duration of 6 months, which exceeded prior data reported in the epilepsy population, where this diet is commonly used, and among those undergoing weight loss intervention.2,3

Other findings from Brenton et al showed that the Vitamin D levels in those on the ketogenic diet increased, while leptin significantly declined. The study demonstrated at 6 months, participants had a significant increase in adiponectin levels, which were changes that correlated in body mass index over time.

They added, “Based on the 6-month intervention study findings, those with good adherence in the first month had higher odds of adhering, therefore future trials should also include study visits within the first month of intervention to reinforce adherence. Futural trial designs need to consider diet adherence such as barriers and include qualitative interviews with participants at multiple time points. Research in the future should also aim to study ketogenic diets as a complementary therapeutic approach to treating MS.”

This phase 2 trial demonstrated that the ketogenic diets are, “tolerable, safe, and promotes improvements in body composition, MS-related QoL, and significant reductions in adipose-related inflammation,” Brenton et al noted.

1. Brenton JN, Lehner-Gulotta D, Woolbright E, et al. Phase II study of ketogenic diets in relapsing multiple sclerosis: safety, tolerability and potential clinical benefits. J Neurol Neurosurg Psychiatry. 2022;93(6):637-644. doi:10.1136/jnnp-2022-329074
2. Cervenka MC, Henry BJ, Felton EA, Patton K, Kossoff EH. Establishing an Adult Epilepsy Diet Center: Experience, efficacy and challenges. Epilepsy Behav. 2016;58:61-68. doi:10.1016/j.yebeh.2016.02.038
3. Lemstra M, Bird Y, Nwankwo C, Rogers M, Moraros J. Weight loss intervention adherence and factors promoting adherence: a meta-analysis. Patient Prefer Adherence. 2016;10:1547-1559. doi:10.2147/PPA.S103649

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