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.
Patient case reports
Astaxanthin
There are theoretical mechanisms supporting the potential role of astaxanthin in the treatment of ALS, however, there are no ALS-specific pre-clinical data exploring this treatment. One verified“ALS reversal” occurred while taking astaxanthin in the setting of a cocktail of various other therapies—an association that does not prove causality. There have been no clinical trials of astaxanthin in PALS. Natural astaxanthin appears to be generally safe and inexpensive. We believe there is a need for further pre-clinical and/or clinical trials of natural astaxanthin in disease models and PALS, respectively, to further elucidate efficacy.
Ozone
Ozone therapy has possible mechanisms for treating ALS. A preclinical study in very small numbers of mTDP43 mice (which has yet to be peerreviewed) suggested benefits on motor function and survival (21,22); however, these benefits were not seen in mSOD1 mice (20). One verified “ALS reversal” occurred on a cocktail of alternative therapies including ozone (24); an association such as this does not prove causality. There have been no trials of ozone therapy in PALS. There may be potentially serious side effects associated with ozone therapy, depending on the dose (31). Based on all this, we support further investigation of ozone therapy in ALS cell or animal models, but we cannot yet recommend it as an ALS treatment.
Butyrates
Butyrates have plausible mechanisms for slowing ALS progression and positive pre-clinical studies. One trial suggests that sodium phenylbutyrate (NaPB) in combination with Tauroursodeoxycholic acid (TUDCA) can slow ALS progression and prolong survival, but the specific contribution of NaPB toward this effect is unclear. Butyrates appear reasonably safe for use in humans. Based on the above information, we support a trial of a butyrate in PALS, but we cannot yet recommend one as a treatment.
https://www.tandfonline.com/doi/pdf/10.1080/21678421.2022.2045323
Tamoxifen
Tamoxifen is reasonably safe, has plausible mechanisms for treating ALS, and has at least one positive preclinical study. One case report and 2 small human trials suggested an association between tamoxifen (at higher doses) and slower ALS progression but this is not enough evidence to recommend this medication as an ALS treatment. Moving forward, we would like to see a larger human ALS clinical trial of tamoxifen at 80mg daily. Interestingly, one study suggests that tamoxifen may decrease a person’s risk for getting ALS. We hope to see this independently replicated.
RCH4
RCH4 is an unlicensed, unapproved product reported to “probably slow the progression of your ALS” (6) on a website. The only peer reviewed publication we found on this product is a single abstract which was never presented at a meeting. We have been unable to determine RCH4’s structure or chemical class, and its purported mechanism is one that has never been shown to be useful in treating PALS before. We have been unable to independently verify RCH4’s reported efficacy or even safety. Thus, at this time, we cannot advise PALS to use this product. We hope the proponents of RCH4 will someday present more useful information about their product at a scientific meeting or in a peer reviewed publication.
We believe that regulatory oversight is important for optimizing patient safety on experimental drugs, and that independent peer review and replication are fundamentals of good science. Caution should be exercised around any product being developed and in clinical use without these safeguards and fundamentals in place.
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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.
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Hyperbaric Oxygen
Although there are plausible mechanisms by which HBOT could work in ALS and a flawed pre-clinical study showing benefit in a mouse model, the best available human trial of HBOT showed no benefit. Given this negative human trial and the fact that HBOT has potentially serious complications, we do not recommend HBOT for patients with ALS at this time.
Kim Cherry’s ALS reversal, which occurred on HBOT and several other alternative treatments, appears very interesting. We do not think this is due to HBOT alone. There are other rare examples of ALS reversals on different (or sometimes no) treatments (28). Other explanations for these reversals include undetected ALS mimics syndromes or endogenous mechanisms that confer resistance to the disease (28). We look forward to further study of cases like this (29).
Declaration of interest: ALSUntangled is sponsored by the ALS Association and the Motor Neurone Disease Association.
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