Alpha-Lipoic Acid (ALA) | Supplementopedia

Overview

Alpha‑lipoic acid (ALA) is a naturally occurring dithiol compound that functions as a vital co‑factor for mitochondrial enzymes involved in aerobic metabolism. In supplement form, it is used primarily for its antioxidant properties and its ability to modulate glucose and oxidative pathways, which underlies many of its therapeutic applications.

Benefits

Metabolic regulation: 600‑1200 mg/day improves insulin‑stimulated glucose uptake and reduces fasting blood glucose and HbA1c in people with type‑2 diabetes (J Diabetes Metab 2021).
Neuropathic pain: 600 mg/day for 3 months reduces diabetic peripheral neuropathy pain scores by ~30 % (Cochrane 2020).
Cognitive support: Small RCTs show modest improvements in memory and executive function in older adults receiving 300–600 mg/day (NeuroSci 2022).
Antioxidant protection: ALA increases plasma total antioxidant capacity and reduces lipid peroxidation markers in healthy volunteers (J Nutr 2020).
Weight management: Adjunctive ALA (300‑600 mg) can modestly enhance weight loss when combined with calorie restriction (Obesity 2021).

How It Works

Redox activity: ALA is reduced intracellularly to dihydrolipoic acid (DHLA), creating a potent redox pair that scavenges reactive oxygen and nitrogen species.
Antioxidant regeneration: It regenerates other antioxidants (vitamin C, vitamin E, glutathione) by donating electrons, thereby restoring cellular redox balance.
Mitochondrial function: In mitochondria, ALA is a co‑factor for pyruvate dehydrogenase and α‑ketoglutarate dehydrogenase, facilitating conversion of pyruvate to acetyl‑CoA and supporting ATP production.
Nrf2 activation: ALA activates the transcription factor Nrf2, up‑regulating endogenous antioxidant enzymes (SOD, catalase, heme‑oxygenase‑1).
Insulin signaling: It enhances insulin signaling by promoting GLUT4 translocation via AMPK activation, which improves glucose uptake in skeletal muscle.
Combined effects: These combined actions account for its metabolic, neuroprotective, and anti-inflammatory effects.

Dosage

Typical regimens: Oral ALA regimens range from 300 mg to 1,200 mg per day divided into 1–3 doses.
Metabolic support: For metabolic support (e.g., glucose control) 600‑1,200 mg divided BID is most common.
Neuropathic pain/neuro-cognitive benefit: For neuropathic pain or neuro‑cognitive benefit, 300‑600 mg twice daily has the strongest evidence.
Administration: ALA is best taken with food to reduce gastrointestinal upset and to improve absorption (the R‑enantiomer is better absorbed on an empty stomach, but the racemic mixture is usually taken with meals).
Weight loss protocols: In weight‑loss protocols, 300 mg before meals is often used.
Dose escalation: Dose escalation should be gradual (e.g., 300 mg for 1 week, then increase) to monitor tolerance.

Safety & Side Effects

General tolerance: ALA is generally well‑tolerated; the most common adverse effects are mild gastrointestinal complaints (nausea, abdominal discomfort) and occasional skin rash.
Contraindications: Known hypersensitivity to ALA.
Cautions: Caution in patients with thyroid disease (ALA can influence thyroid hormone metabolism) and pregnant or lactating women (limited safety data).
Drug interactions: ALA may potentiate the hypoglycaemic effect of insulin or oral hypoglycemics, increasing the risk of hypoglycaemia; it may also lower plasma levels of certain chemotherapeutics (e.g., bortezomib) and interfere with the absorption of minerals (iron, zinc).
Renal/Hepatic impairment: Patients with renal or hepatic impairment should start at the low end of dosing and be monitored.

Chemistry

IUPAC name: Alpha‑lipoic acid (IUPAC: (R)-5-(1,2‑dithiolan-3-yl)pentanoic acid).
Molecular formula: C₈H₁₄O₂S₂
Molecular weight: 185.33 g mol⁻¹
Structure: It is a cyclic disulfide with an eight‑carbon chain terminating in a carboxylic acid.
Redox activity: The disulfide ring confers redox activity; reduction yields the dithiol dihydrolipoic acid (DHLA).
Enantiomers: The molecule exists as two enantiomers: the biologically active R‑(+) form and the less active S‑(–) form; most supplements contain the racemic mixture, although the R‑form shows higher bio‑availability.
Solubility: ALA is water‑soluble at low pH but becomes more lipophilic at physiological pH, allowing both intracellular and extracellular distribution.

Sources & Quality

Natural sources: Natural ALA is found in small amounts in organ meats (liver, kidney), spinach, broccoli, and potatoes.
Commercial production: Commercial supplements are primarily produced via chemical synthesis of the R‑ and S‑enantiomers, followed by racemization; some “natural” products are extracted from yeast‑grown or plant‑derived sources, but the final product is chemically identical.
Quality considerations:
- Purity (≥ 95 % for pharmaceutical‑grade; > 98 % for research‑grade)
- Enantiomeric ratio (R‑enantiomer is more bio‑active)
- Absence of heavy‑metal or pesticide residues
- Stability (ALA oxidizes to a less active form; good packaging uses amber glass or nitrogen‑flushed capsules.
Third-party testing: Third‑party testing (e.g., USP, NSF) is recommended to verify label claims and ensure batch‑to‑batch consistency.