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.
Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)
Grade C: One or more peer-reviewed publication(s) reporting benefits in flawed studies.
Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.
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
Vitamin C is safe and inexpensive. As an antioxidant, it has a plausible mechanism for influencing the course of neurodegenerative diseases. Two flawed preclinical studies by the same group showed benefits in a mouse model of familial ALS. There are two case reports in which it was associated with improvement. However, there are multiple possible explanations for the improvement in these cases. It is not clear which if any dose of vitamin C might be beneficial for PALS; a small clinical trial using oral vitamin C at 2,000 mg daily was unable to demonstrate benefits in PALS. Based on this negative trial, we currently advise against using vitamin C to treat ALS.
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.
Light therapy has not yet been convincingly shown to help people with ALS. However, at specific wavelengths and energy densities, LT appears safe and has theoretically plausible mechanisms. There is a single case report suggesting benefits for light therapy in ALS, but it contains in sufficient detail to independently confirm diagnosis or treatment benefit. Further studies are needed to determine whether LT is useful for people with ALS, and via what specific protocols.
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.
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.
Vitamin E (a-tocopherol) is perhaps the most studied supplement in the history of ALS and was taken by one of the most famous ALS patients. Vitamin E has mechanistic potential in ALS as an antioxidant but appears in the SOD1 mutant mouse model to only have an effect on delaying disease onset. This bears out in human populations as large prospective cohorts show that long-duration vitamin E supplementation may decrease the risk of ALS, but randomized clinical trials show that even high dose vitamin E does not benefit the disease once ALS has been diagnosed. Although it is inexpensive and safe, we do not recommend vitamin E to slow, stop or reverse ALS
based on the lack of efficacy in clinical trials.