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Acetyl-L-carnitine (ALCAR) has been studied in ALS for its ability to reduce neuromuscular degeneration and extend lifespan in animal models. A retrospective observational study in ALS patients reported improved 24-month survival (71.1% vs 48.9%) and a slower ALSFRS-R decline in treated subjects. It protects motor neuron cultures from excitotoxicity and decreases oxidative stress markers.

Alpha-lipoic acid is a potent antioxidant that boosts intracellular glutathione, chelates metals, and protects neurons against glutamate-induced excitotoxicity relevant to ALS pathology. In a mouse model of ALS, lipoic acid administration improved survival. It is studied as an adjunct antioxidant intervention in ALS.

Astragaloside IV, a saponin from Radix astragali (Astragalus membranaceus), is used traditionally in China for ALS treatment and has strong preclinical antioxidant evidence. It protects PC-12 neuronal cells from H2O2-induced oxidative stress, activates HO-1, suppresses intracellular ROS, and reduces apoptotic cell death in ALS-relevant models.

CoQ10 is an antioxidant and mitochondrial cofactor studied in ALS because of mitochondrial dysfunction and oxidative stress in disease pathology. In SOD1 transgenic mice, CoQ10 extended survival by 6 days. A Phase II multi-center RCT (n=185) testing doses of 1,800–2,700 mg/day found CoQ10 did not improve ALSFRS-R decline sufficiently to justify a Phase III trial.

Creatine has been extensively studied in ALS due to its role in mitochondrial energy metabolism and neuroprotection. Multiple placebo-controlled clinical trials tested 5–10 g/day in ALS patients, but a Cochrane review of three trials (n=386) found no significant benefit on survival or ALSFRS-R progression. Animal models showed promising survival benefit, but this did not translate to humans.

Curcumin has been tested in ALS via a pilot randomized clinical trial using a nanocurcumin formulation added to riluzole. The 12-month double-blind trial (n=54) reported significantly improved survival probability in the nanocurcumin group (3.7% events vs. 22.2% in placebo, p=0.036), though functional scores did not differ. Preclinical data show curcumin protects motor neurons from TDP-43 toxicity and oxidative damage.

Diallyl trisulfide (DATS), an organosulfur compound from garlic (Allium sativum), is identified in peer-reviewed reviews as having ALS activity. It crosses the blood-brain barrier, activates heme oxygenase-1 (HO-1), downregulates glial fibrillary acidic protein expression, and protects motor neurons from TDP-43-induced neurotoxicity via lysosomal degradation and antioxidant responses.

EGCG, the principal catechin in green tea, is identified in multiple peer-reviewed reviews as a phytochemical with ALS activity. It reduces oxidative stress and protects motor neurons in organotypic spinal cord cultures relevant to ALS. EGCG modulates iron homeostasis, inhibits protein aggregation, and activates Nrf2 antioxidant pathways. Evidence is primarily preclinical.

Fisetin preserves mitochondrial SOD1, resists mitochondrial DNA breakage, and restores proteasome activity in cell and animal models of ALS. It protects motor neurons in NSC-34 cell lines and was included in a multi-disease neuroprotective review.

Genistein, a soy isoflavone, is identified in multiple peer-reviewed reviews as a phytochemical possessing ALS activity. It acts via antioxidant and anti-apoptotic mechanisms, including upregulation of Bcl-2, suppression of intracellular ROS, and antioxidant enzyme modulation. Evidence is primarily preclinical from in vitro and animal model studies.

L-serine has been proposed as a neuroprotective therapy for ALS based on the hypothesis that the environmental neurotoxin BMAA (β-methylamino-L-alanine) can be misincorporated into proteins in place of L-serine, causing protein misfolding. A Phase I FDA-approved randomized double-blind clinical trial in 20 ALS patients found L-serine safe at up to 30 g/day and demonstrated a dose-related 34% reduction in ALSFRS-R functional decline slope. A Phase II trial is ongoing.

L-Threonine has been evaluated in multiple clinical trials as a symptomatic treatment for ALS, based on its role as a glycine precursor to counteract excitatory neurotoxicity. However, controlled trials at 2–4 g/day for up to 12 months did not demonstrate meaningful slowing of ALS progression or symptom reduction, and one trial raised concerns about potential worsening of lung function. The hypothesis was scientifically grounded but the clinical evidence does not support efficacy.

Multiple randomized controlled trials, including the large LiCALS phase 3 trial, have tested lithium in ALS. While lithium has neuroprotective effects in cell and animal ALS models, and an initial Italian pilot study showed dramatic benefit, all subsequent adequately powered human trials found no significant improvement in survival or functional decline.

Ultra-high-dose MeCbl has been investigated as a disease-modifying therapy for ALS across multiple clinical trials in Japan. The Phase III JETALS trial showed a significant 43% reduction in ALSFRS-R score decline in early-stage patients. MeCbl received regulatory approval in Japan for ALS in 2024 following JETALS results.

NAC is a glutathione precursor and direct antioxidant studied in ALS because ALS patients have elevated oxidized glutathione levels and reduced antioxidant capacity. Weekly NAC infusions in ALS patients reduced inflammatory cytokine levels in peripheral blood. Preclinical data show NAC increases glutathione levels and protects motor neurons from degeneration in ALS models.

Nicotinamide riboside (NR), a form of vitamin B3 and NAD+ precursor, was tested in a registered clinical trial (NCT03489200) in ALS patients supplementing a Mediterranean diet. The trial assessed NR combined with pterostilbene versus placebo on anthropometric variables in 40 ALS subjects. NR's rationale is based on combating oxidative stress and mitochondrial dysfunction in ALS.

Quercetin is identified in multiple peer-reviewed experimental reviews as a phytochemical with anti-ALS activity. It has been explored computationally and experimentally as a potential ALS therapeutic. A 2024 in vivo study demonstrated that rutin (quercetin-3-rutinoside) reduced SOD1 aggregation and neuroinflammation, improved motor function in ALS mice, supporting the broader quercetin class. Evidence is primarily preclinical.

Resveratrol, a polyphenol from plants including Polygonum cuspidatum and grapes, is identified in peer-reviewed reviews as possessing ALS activity through antioxidant and anti-neuroinflammatory mechanisms. It inhibits pro-inflammatory cytokines in microglial cells and was among top-performing antioxidant compounds in an in vitro ALS motor neuron screening assay. Evidence is primarily preclinical.

SPMs have demonstrated efficacy in preclinical ALS models. Neuroinflammation—a core ALS pathomechanism—is a primary target of SPM action. SPMs are listed among validated preclinical disease applications by Serhan et al. (Cold Spring Harbor Perspectives, 2015), one of the defining references in the field.

ALS patients have significantly lower serum 25-hydroxyvitamin D levels than controls, and a Mendelian randomization study found higher genetically predicted vitamin D levels associated with reduced ALS risk. A systematic review of 13 studies found discordant results for vitamin D supplementation on ALS outcomes, with some showing small functional improvement. The relationship is under active investigation.

Vitamin E (alpha-tocopherol) is one of the most studied antioxidants in ALS, investigated because ALS patients exhibit lipid peroxidation susceptibility and ROS-driven motor neuron death. A placebo-controlled trial of high-dose vitamin E (5000 IU/day) as add-on to riluzole in ALS showed no significant benefit. Epidemiological studies suggest higher vitamin E intake may be associated with reduced ALS risk.

Withanolides, the principal bioactive steroidal lactones from Ashwagandha (Withania somnifera), are identified in published experimental reviews as phytoconstituents with anti-ALS activity. They exhibit neuroprotective, anti-inflammatory, and antioxidant effects relevant to ALS motor neuron pathology. Evidence is preclinical from cell and animal model studies.