In the study, published in Annals of Neurology, investigators revealed that the identified treatments included acetyl-L-carnitine, antiretrovirals, clenbuterol, L-serine, methylcobalamin, nicotinamide riboside/pterostilbene, quinidine/dextromethorphan, and tamoxifen. Among these treatments, six targeted neuroinflammation, five targeted oxidative stress, four targeted mitochondrial dysfunction, six affected the gut microbiome, and three inhibited retroviruses.
Several treatments demonstrated significant clinical benefits in trials. Methylcobalamin at 50 mg twice weekly improved ventilator-free survival by more than 600 days compared with placebo and significantly improved ALSFRS-R decline (P = .003) in patients with early-stage disease. In a trial of 25 patients, clenbuterol showed 90% slowing in FVC progression (P = .02) using doses from 40 μg daily to 80 μg twice daily.
A crossover trial of Nuedexta (n = 60) reported significant improvements in speech (P = .003), swallowing (P = .009), sialorrhea (P = .004), and overall bulbar function (P < .001). The antiretroviral Triumeq showed 21.8% slower ALSFRS-R progression compared with baseline in a 40-patient trial.
Two large trials were actively recruiting at the time of publication: an antiretroviral trial (n = 390, ClinicalTrials.gov identifier NCT05193994) and a nicotinamide riboside/pterostilbene trial (n = 380, ClinicalTrials.gov identifier NCT04562831).
The treatments varied in accessibility. Methylcobalamin was available in low over-the-counter oral doses, with higher injected doses requiring a prescription through compounding pharmacies. Clenbuterol was available by prescription outside of the United States. Tamoxifen was prescribed at 40 to 80 mg daily, while Nuedexta, containing quinidine sulfate (10 mg) and dextromethorphan (20 mg), was approved by the U.S. Food and Drug Administration for pseudobulbar affect.
The review noted several limitations, including small sample sizes ranging from 15 to 82 patients, lack of randomization or placebo controls in some trials, and high dropout rates. These limitations complicated the interpretability of the efficacy results across treatments and emphasized the need for more rigorous studies. For instance, in the acetyl-L-carnitine trial, 21 of 82 participants did not meet eligibility criteria, which may have affected the study’s outcomes.
The investigators suggested that combinations of these treatments might hold potential as a result of their overlapping mechanisms, which could address amyotrophic lateral sclerosis (ALS)’s complex pathology more effectively than single-target approaches. Given the disease's multifactorial nature, future research focusing on combination therapies targeting diverse mechanisms may offer new therapeutic directions.
The research was conducted by investigators from Duke University, University of North Carolina, National Institutes of Health, and Barrow Neurological Institute, with funding from the ALS Association.
Disclosures: Two authors received funding from the ALS Association, one author reported consulting support from a pharmaceutical company with an ALS drug in trials, and one author reported support from a probiotics manufacturer. Full disclosures are available in the published study.
