We found several new publications since this review was published in 2019 which warrant TOE Grade changes.
Resveratrol has now been shown to restore SIRT1/AMPK activity in mesenchymal stem cells derived from people living with ALS (Yun YC, Jeong S-G, Kim SH, Cho G-W. Reduced sirtuin 1/adenosine monophosphate-activated protein kinase in amyotrophic lateral sclerosis patient-derived mesenchymal stem cells can be restored by resveratrol. J Tissue Eng Regen Med. 2019; 13: 110–115. https://doi.org/10.1002/term.2776). Thus we change our Mechanisms grade from B to A.
With regard to pre-clinical models, one of the studies we initially used in our grading has since been retracted (BioMed Research International. Retracted: Resveratrol Ameliorates Motor Neuron Degeneration and Improves Survival in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis. Biomed Res Int. 2019 Oct 29;2019:4729651. doi: 10.1155/2019/4729651. PMID: 31781618; PMCID: PMC6855073). We found another newer study showing that resveratrol had no benefit on multiple measurements in the G93A mutant SOD1 mouse model (Nagy JA, Semple C, Lo P, Rutkove SB. Assessing the therapeutic impact of resveratrol in ALS SOD1-G93A mice with electrical impedance myography. Front Neurol. 2022 Dec 22;13:1059743. doi: 10.3389/fneur.2022.1059743. PMID: 36619925; PMCID: PMC9813785). Based on these updates, we change our Pre-Clinical grade from B to C.
With regard to trials, we found one (Martín-Ruiz J, Maset-Roig R, Caplliure-Llopis J, Villarón-Casales C, Alarcón-Jiménez J, de Bernardo N, Proaño B, Menargues-Ramírez R, Selvi-Sabater P, de la Rubia-Ortí JE. Enhanced Acute Muscle Activation in ALS Patients Following Liposomal Curcumin, Resveratrol, and Dutasteride Administration. Pharmaceuticals (Basel). 2025 Mar 28;18(4):497. doi: 10.3390/ph18040497. PMID: 40283933; PMCID: PMC12030179.). While this was randomized, double-blind, and placebo controlled, it was very small (37 patients in the intervention and 37 in the control group) and the duration of treatment was short (2 months). While the main outcome measures (muscle activation and muscle fasciculations) were said to improve in the intervention group relative to the placebo group, these are not widely accepted as useful or predictive of clinical benefit. We therefore change our Trials grade from U to D.
With regard to risks, a meta-analysis reviewing previous human trials reported no serious adverse events (LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Resveratrol. [Updated 2024 Nov 30]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548465/). Minor side effects were said to include minor gastrointestinal upset, nausea, headache and fatigue and possible supplement-drug interactions with estrogens and anticoagulants. Based on this report, we change our Risks grade from U to C. We caution that the side effect profile of this compound in people with ALS is not known and may differ from that of patients with other conditions.
Key Information
Resveratrol is a dietary supplement that likely activates SIRT1 cellular pathways and may alter the gut microbiome. These are interesting mechanisms that may potentially alter the progression of ALS and do confer benefit in animal models of one type of familial ALS; however, to-date, there have been no trials of resveratrol in PALS. Some trials in other populations show frequent gastrointestinal adverse events, including weight loss, and one trial showed a high risk of serious renal toxicity. Given the unknown benefit of resveratrol in PALS and the possible risks, we cannot recommend resveratrol as an ALS treatment at this time. We hope to see well-designed clinical trials of resveratrol and other SIRT1 modulators in the near future.
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