Zinc has plausible mechanisms for modulating ALS progression, specifically with its roles in oxidative stress reduction and stabilization of SOD1 structure and function. Preclinical data has demonstrated potential benefits in slowing ALS progression at moderate doses in mouse models, but high doses without additional supplementation of copper were shown to be harmful. Clinical data on zinc supplementation in PALS is limited, but numerous case reports and a small pilot trial provide some insight. The case reports indicated no benefit from zinc supplementation, while the pilot trial reported potential benefits in slowing ALS progression. However, this trial lacked statistical analyses and had a very small sample size, which significantly limits the strength of its findings. Based on the current lack of substantial clinical evidence supporting the potential benefits of zinc supplementation in PALS, we cannot endorse zinc supplementation as a treatment for ALS at this time.
Mechanistic plausibility
Ashwagandha
WS appears reasonably safe, has plausible mechanisms by which it might slow ALS progression, and has promising data obtained in multiple different clinical models of ALS. While there are also some interesting self-reports from PALS and one verified ALS reversal on a compound containing WS, these must be interpreted with caution because of the variable natural history of ALS progression. We conclude that WS is a reasonable compound for ALS trials, and we look forward to the results of the one trial that is underway.
Lions Mane
While Lion’s Mane may have neuroprotective, neurotrophic, antioxidant, and anti-inflammatory properties that could, at least in theory, potentially help ALS, there are still no studies in ALS-relevant cell or animal models, nor in humans with ALS. Therefore, we do not have enough information to support the current use of Lion’s Mane for treating ALS. We hope to see the validation of its neuroprotective and anti-inflammatory benefits in ALS disease models, which may ultimately lead to clinical trials in PALS.
Nuedexta
Nuedexta has plausible mechanisms for improving bulbar function in PALS. Some PALS reported concomitant improvement in bulbar function for at least a short period when taking Nuedexta for PBA. A well-designed phase II trial in PALS demonstrated the efficacy of Nuedexta in patient-reported bulbar function, and the preliminary result of another trial showed improvement in bulbar physiology. However, its long-term effect on bulbar function is unclear, and one open-label study showed a lack of benefit in one year. There is no evidence suggesting Nuedexta slows down progression or prolongs survival. Nuedextacauses mild to moderate side effects, but severe side effects directly caused by Nuedexta have not been reported. It should be avoided in patients with a known history of prolonged QT interval. Given all this, we feel there is sufficient evidence to consider Nuedexta treatment for bulbar dysfunction in ALS patients with and without PBA. Financial burden and periodic assessment of its efficacy should be considered for the latter.
Ketogenic Diets
Ketogenic diets have plausible mechanisms for treating ALS. One flawed preclinical study and two PatientsLikeMe participants reported benefits; these were not independently verified. Two other PatientsLikeMe participants and one patient under
the care of an ALSUntangled investigator did not show benefits. A trial of a ketogenic diet was only able to enroll a single patient and their experience cannot be interpreted due to the lack of any control group. We hope to see another trial of a ketogenic diet in people with ALS. Until then, given the frequent side effects, we do not advise such diets for the treatment of ALS
Resveratrol
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.
Click here to download the complete review.
Perampanel
Perampanel is a drug currently used to treat seizures which has a mechanism of action that theoretically could be useful in treating patients with ALS. A single flawed study in a mouse model of ALS showed some benefits of perampanel, but data from humans with ALS is quite limited. Due to the lack of data in PALS, the failure of the closely related drug talampanel in ALS clinical trials, and several serious safety concerns, including an increased fall risk and serious psychiatric adverse effects, we cannot recommend off-label use of perampanel for ALS at this time. We look forward to the results of the on-going clinical trials of perampanel in ALS and we will update our TOE grades accordingly when these results become available.
Click here to download the complete review.
RT001
RT001 has a novel mechanism for reducing oxidative stress that could theoretically work better than more traditional antioxidants. In the small trial of patients with Friedreich’s ataxia, it seems to be safe and well-tolerated at lower dosages but can cause nausea and diarrhea at higher doses. At the time of this writing, there is very little efficacy or safety data in PALS. An expanded access program is underway which allows PALS at certain clinics to try this compound free of charge. Data resulting from this expanded access program will help the planning of a possible future clinical trial.
Click here to download the complete review.