Original article| Volume 75, 104743, July 2023

Association of serum homocysteine, folate, and vitamin B12 and mood following the Swank and Wahls elimination dietary interventions in relapsing-remitting multiple sclerosis: Secondary analysis of the WAVES trial


      • Both diets had significant improvements in anxiety and depression scores.
      • Serum levels of homocysteine were reduced, and folate and vitamin B12 increased.
      • No association of depressive symptoms changes with serum homocysteine or vitamin B12.



      Depression and anxiety are common psychiatric comorbidities among people with multiple sclerosis (MS). Emerging data suggest abnormal serum homocysteine, vitamin B12, and folate levels in people with MS, which are related to a range of neurological disorders, including mood and mental illnesses. Evidence suggests that dietary interventions could affect mood disorders via several pathways. This study aimed to evaluate the impact of the low-saturated fat (Swank) and modified Paleolithic elimination (Wahls) diets, along with a supplement regimen, on mood as assessed by Hospital Anxiety and Depression Scale (HADS), and Mental Health Inventory (MHI). The secondary objective was to identify changes in serum levels of homocysteine, folate, and vitamin B12 and the association and mediation effects between their changes and HADS and MHI scores and their subscales among people with relapsing-remitting MS (RRMS).


      In a previously conducted randomized parallel-arm trial, participants with RRMS (n = 77) were randomly allocated to either the Swank or Wahls diets at baseline and followed for 24 weeks. Blood was drawn at four study visits spaced 12 weeks apart: (1) run-in, (2) baseline, (3) 12 weeks, and (4) 24 weeks. Serum vitamin B12, folate, and homocysteine were analyzed. HADS and MHI questionnaires were also completed by participants at the four study visits to assess symptoms of depression and anxiety, behavioral control and positive affect respectively.


      Significant improvement in severity of depression (HADS-D) and anxiety (HADS-A) symptoms, MHI total, and MHI subscores were seen at 12 and 24 weeks in each diet group. Further, a significant within-group reduction in serum homocysteine and a significant increase in serum vitamin B12 level were observed in both groups at 12 and 24 weeks compared to corresponding baseline values (p ≤ 0.05 for all). All participants exceeded the analytical maximum threshold for folate of 20 nmol/L at 12 and 24 weeks. Changes in serum levels of homocysteine and vitamin B12 were not associated with and did not mediate changes in HADS depression, anxiety, MHI total and four subscales scores (p > 0.05).


      Participants on both Swank and Wahls dietary interventions, including folate and vitamin B12 supplements, showed significant improvement in mood. However, the favorable effects of both diets on mood were not associated with or mediated by the effect of the diets on serum levels of homocysteine, folate, and vitamin B12 (p > 0.05).


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