ALA has several plausible mechanisms for slowingALS progression, including enhancing energy pro-duction, reducing oxidative stress as a potent anti-oxidant and anti-inflammation. Preclinical studiesdemonstrated better motor function and improvedsurvival. One open-label study suggested improvedQOL and fatigue when administered as a palla-dium lipoic acid complex, but motor function wasnot assessed. Several PALS in the ALS online community reported improved muscle strengthwhen taking ALA as part of extensive supplementregimens, but most did not. Therefore, it isunclear whether the reported improvement wasdirectly related to ALA. Although one clinical trialwas completed in PALS, the result has not beenpublished. ALA was safe and well-tolerated basedon self-report from PALS and in clinical trials forother disease conditions at 600 mg daily. Given theabove, we cannot endorse ALA as an effectivetherapy for PALS. We support more research onthe efficacy of ALA in slowing ALS progression.
Mechanistic plausibility
Caffeine
Caffeine is inexpensive, reasonably safe at doses of under 400 mg daily, and has plausible mechanisms by which it could slow ALS progression. However, data from pre-clinical models are contradictory and a two cohort studies showed no clear relationship between caffeine intake and ALS progression. Based on all this, we cannot endorse caffeine as anALS treatment.
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
Melatonin
Melatonin has plausible mechanisms, some positive (and some negative) pre-clinical data, and two case reports in which it was part of a cocktail of treatments associated with recovery of lost motor function. As we have stated previously, there are
multiple possible explanations for cases like these. There was also a very small, flawed retrospective study suggesting that PALS taking it progressed more slowly and lived longer than PALS were not taking it. Melatonin appears safe at high doses, but evidence is lacking for a proven benefit in slowing disease progression in ALS. Furthermore, an optimal dose and route of administration have not been established. Based on this data, a pilot trial of melatonin in PALS would be reasonable, but we cannot yet recommend it as an ALS treatment.
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.
Proprionyl-L-Carnitine
There are good theoretical mechanisms for carnitines, some pre-clinical evidence for LC and ALCAR, and a single clinical trial that suggested ALCAR could slow disease progression in PALS. All three carnitines appear to be well-tolerated, generally safe and inexpensive. We believe that there is a need for future clinical trials of carnitines in PALS to further elucidate their efficacy. Until there is further data, we cannot endorse any of these supplements as a definite way to slow ALS progression; however, oral ALCAR at 1000mg three times daily (3000 mg total daily dose) appears to be a theoretically promising supplement available for PALS whom would like to self-experiment.