Alpha-lipoic acid (ALA), also called thioctic acid, is a small sulfur-containing fatty acid that the body makes in small amounts and uses as a cofactor for key energy-producing enzymes in mitochondria. As a concentrated pill or infusion it is used in two very different ways: as a licensed medicine for diabetic nerve damage in Germany and several other countries, and as a widely used nutritional supplement (Gullo et al., Clin Endocrinol 2014).
The most solid evidence is in diabetic neuropathy, where short courses of 600 mg/day given intravenously improved symptoms in randomized trials. Effects on weight and blood sugar are statistically measurable but small. The main safety signal is rare but real: ALA can trigger insulin autoimmune syndrome, an antibody-driven cause of severe low blood sugar.
This page summarizes what the clinical trials, meta-analyses and European regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Class | Endogenous enzyme cofactor; dithiol antioxidant |
| Other names | Thioctic acid; R-lipoic acid (the R-form only) |
| Forms | R-(+) (natural form), S-(−) (made only by chemical synthesis), racemic 50:50 mixture |
| Medicinal status | Licensed for diabetic sensorimotor polyneuropathy in Germany and several other countries |
| Route | Oral tablets; intravenous infusion (used in the neuropathy trials) |
| Doses in key trials | 600 mg/day IV for 3 weeks; 600 mg/day oral for up to 4 years |
| Half-life | About 30 minutes in plasma |
| Oral bioavailability | About 30% (high first-pass liver extraction) |
| Main safety signal | Insulin autoimmune syndrome (hypoglycemia), linked to specific HLA genotypes |
What it is
ALA is an eight-carbon fatty acid with a five-membered ring containing two sulfur atoms (formula C₈H₁₄O₂S₂, molecular weight 206.3 g/mol). One carbon in that ring is chiral, so ALA exists as two mirror-image forms, R-(+) and S-(−) (EFSA, 2021).
In the body, the R-form is attached to enzyme proteins and acts as an essential cofactor of the mitochondrial pyruvate dehydrogenase complex, which feeds carbohydrate fuel into the citric acid cycle (Hermann et al., Clin Pharmacol 2014). ALA and its reduced form, dihydrolipoic acid, form a redox pair with antioxidant activity (Teichert et al., J Clin Pharmacol 2003). The neuropathy trials were designed around the idea that this antioxidant action could counter oxidative stress in diabetic nerves (Ziegler et al., Diabetologia 1995).
R-, S- and racemic ALA
| Form | What it is | Key points |
|---|---|---|
| R-(+)-ALA | The naturally occurring form | The body can make it from octanoic acid and cysteine. Less chemically stable than the racemic mixture. Sold as “R-lipoic acid”. |
| S-(−)-ALA | The mirror-image form | Not made by the body; arises from chemical synthesis. |
| Racemic (R,S)-ALA, thioctic acid | 50:50 mixture of both | EFSA assumes most industrially produced ALA is racemic. The licensed medicine and the major neuropathy trials used racemic ALA. |
Sources: EFSA, 2021; Hermann et al., 2014; Ametov et al., Diabetes Care 2003.
After a racemic dose, plasma levels of the R-form are higher than those of the S-form: peak levels about 40–50% higher (Breithaupt-Grögler et al., Eur J Pharm Sci 1999) and roughly twofold higher bioavailability (Hermann et al., 2014). A small pilot study comparing 500 mg of R-ALA with 500 mg of racemic ALA found that absorption of either form varied widely between older adults, with no consistent advantage for either (Keith et al., Pharmacol Res 2012). Clinical benefit in the neuropathy trials was shown with the racemic drug; the trials cited here did not test pure R-ALA.
Food contains only small amounts of ALA, mostly bound to protein. Pig heart, one of the richest sources, contains about 1.1–1.6 mg/kg. Supplements are usually sold at 300–600 mg/day (EFSA, 2021).
Pharmacokinetics
Oral ALA is absorbed quickly and cleared within a few hours.
| Parameter | Finding | Source |
|---|---|---|
| Time to peak (oral) | 0.33–0.5 h (600 mg tablets or solution, fasted); 0.5–1 h (50–600 mg) | Hermann 2014; Breithaupt-Grögler 1999 |
| Elimination half-life | ≈0.5 h; no difference between R- and S-forms | Breithaupt-Grögler 1999; EFSA 2021 |
| Dose proportionality | Linear across 50–600 mg | Breithaupt-Grögler 1999 |
| Absolute oral bioavailability | About 30% (20–40% depending on form and formulation), due to high first-pass liver extraction | Teichert 2003; EFSA 2021 |
| Metabolism | S-methylation and beta-oxidation (the same pathway that breaks down fatty acids) | Teichert 2003 |
| Urinary excretion | 12.4% of the dose recovered in urine within 24 h as ALA plus metabolites; no accumulation over 4 days of 600 mg/day | Teichert 2003 |
| Sex | Exposure (AUC) 20–32% higher in women after weight adjustment; authors judged no dose change needed | Hermann 2014 |
The short half-life means plasma levels after a single oral dose fall steeply within hours. This is one reason trials compared intravenous dosing (which avoids first-pass loss) with oral dosing.
Medical use and regulatory status
ALA is approved for the treatment of diabetic sensorimotor polyneuropathy in Germany (McIlduff and Rutkove, Ther Clin Risk Manag 2011). The NATHAN 1 authors describe the brand Thioctacid as an over-the-counter drug widely prescribed in Germany for decades (Ziegler et al., Diabetes Care 2011). A 2023 review states that ALA is authorized for treatment of diabetic peripheral neuropathy in several countries (Ziegler, Diabetes Res Clin Pract 2023).
In the European Union, ALA is used as an active ingredient in medicines, mainly for diabetic neuropathy, and is also sold as a food supplement. In 2015 the European Medicines Agency’s safety committee (PRAC) recommended adding insulin autoimmune syndrome as a warning and side effect in the product information of thioctic acid medicines. After concerns raised by Danish and Belgian authorities, the European Commission asked EFSA to assess the risk of ALA in food supplements (EFSA, 2021).
What the research shows
Diabetic neuropathy: the trial program
Most of the controlled data come from a series of multicenter, double-blind, placebo-controlled trials of racemic ALA, led largely by German investigators. The designs differed in an important way: some tested short intravenous courses, others tested oral tablets.
| Trial | Patients (n) | Route and dose | Duration | Main result |
|---|---|---|---|---|
| ALADIN (Ziegler 1995) | 328, type 2 diabetes | IV 100, 600 or 1200 mg/day vs placebo | 3 weeks | Foot symptom score fell 63.5% (600 mg) and 58.6% (1200 mg) vs 38.4% (placebo); 100 mg no better than placebo |
| ALADIN III (Ziegler 1999) | 509, type 2 diabetes | IV 600 mg/day for 3 weeks, then oral 600 mg three times daily or placebo | 7 months | No clinically meaningful difference in symptoms; small benefit on neuropathy impairment score |
| SYDNEY (Ametov 2003) | 120 | IV 600 mg/day on weekdays, 14 infusions | 3 weeks | Total symptom score improved 5.7 vs 1.8 points (p under 0.001) |
| SYDNEY 2 (Ziegler 2006) | 181 | Oral 600, 1200 or 1800 mg once daily vs placebo | 5 weeks | Symptom score fell 51%, 48% and 52% vs 32% on placebo (all p under 0.05) |
| NATHAN 1 (Ziegler 2011) | 460, mild-to-moderate neuropathy | Oral 600 mg once daily vs placebo | 4 years | Primary composite endpoint not met (p = 0.105); some secondary impairment scores better on ALA |
Intravenous trials. In ALADIN, the 600 mg dose gave the best balance: 82.5% of patients responded (at least 30% symptom improvement) vs 57.6% on placebo, and adverse events occurred in 18.2% vs 20.7%. The 1200 mg dose was not more effective and had the highest adverse event rate (32.6%) (Ziegler et al., 1995). SYDNEY confirmed a rapid symptom benefit of 14 infusions of 600 mg, with improvements in each symptom (stabbing and burning pain, numbness, prickling) and in neuropathy signs (Ametov et al., 2003).
Oral trials. SYDNEY 2 showed that oral doses also improved symptoms over 5 weeks. Response rates (at least 50% symptom reduction) were 62%, 50% and 56% for 600, 1200 and 1800 mg vs 26% for placebo. Nausea, vomiting and vertigo rose with dose, and the authors concluded that 600 mg once daily gave the best benefit-to-risk balance (Ziegler et al., 2006). ALADIN III, which followed 3 weeks of IV treatment with 6 months of oral 1800 mg/day, did not show a clinically meaningful symptom effect, which the authors attributed partly to variability between study centers (Ziegler et al., 1999).
Long-term oral treatment. NATHAN 1 ran at 36 centers in the US, Canada and Europe. Its primary endpoint combined a lower-limb neuropathy impairment score with seven nerve tests. This endpoint did not differ between groups, partly because the placebo group did not worsen measurably over 4 years. ALA did better on the neuropathy impairment score (p = 0.028) and its lower-limb version (p = 0.05), and fewer patients on ALA showed progression (Ziegler et al., 2011).
Neuropathy meta-analyses
| Meta-analysis | Trials (patients) | Regimen | Result |
|---|---|---|---|
| Ziegler et al., Diabet Med 2004 | 4 trials: ALADIN I, ALADIN III, SYDNEY, NATHAN II (1258) | IV 600 mg/day for 3 weeks | Symptom score 24.1% better than placebo (95% CI 13.5–33.4); responders 52.7% vs 36.9%; adverse event rates similar |
| Han et al., Eur J Endocrinol 2012 | 15 RCTs | IV 300–600 mg/day for 2–4 weeks | Nerve conduction velocity improved (e.g. median motor +4.63 m/s, 95% CI 3.58–5.67); odds ratio for overall efficacy 4.03 (95% CI 2.73–5.94); most trials of poor methodological quality |
The 2004 analysis was based on the sponsor’s trial database. The 2012 authors cautioned that most included trials were of poor quality, so the evidence “may not be strong”. Overall, the case for a short-term symptom benefit from IV ALA is consistent; the case for long-term oral treatment slowing neuropathy is weaker.
Weight loss
Several meta-analyses of randomized trials found a statistically significant but small effect on body weight.
| Meta-analysis | Trials | Weight difference vs placebo | BMI difference |
|---|---|---|---|
| Kucukgoncu et al., Obes Rev 2017 | 10 | 1.27 kg greater loss (CI 0.25–2.29) | −0.43 kg/m² (CI −0.82 to −0.03) |
| Namazi et al., Clin Nutr 2018 | 12 | −0.69 kg (95% CI −1.27 to −0.10) | −0.38 kg/m² (95% CI −0.53 to −0.24) |
| Mohammadi et al., Nutr Metab Cardiovasc Dis 2026 | 63 (all cardiometabolic outcomes) | −0.64 kg (95% CI −1.04 to −0.24) | −0.27 kg/m² (95% CI −0.44 to −0.10) |
Kucukgoncu and colleagues found no relationship between ALA dose and weight change. Namazi and colleagues found no significant effect on waist circumference and judged that ALA “cannot be cost-effective” as a weight-loss aid. In all three analyses the average difference was under 1.5 kg.
Blood sugar and insulin resistance
| Meta-analysis | Population | Outcome | Effect |
|---|---|---|---|
| Jibril et al., Endocr Connect 2022 | Type 2 diabetes; 16 trials, 1035 patients | HbA1c per 500 mg/day oral ALA | −0.17% (95% CI −0.30 to −0.05); moderate certainty |
| Same | Same | Body weight per 500 mg/day | −0.68 kg (95% CI −0.71 to −0.64) |
| Mohammadi et al., 2026 | Mixed; 63 RCTs | HbA1c | −0.40% (95% CI −0.66 to −0.14) |
| Same | Same | Fasting glucose | −5.28 mg/dL (95% CI −7.21 to −3.35) |
| Same | Same | HOMA-IR (an insulin-resistance index) | −0.74 (95% CI −1.17 to −0.31) |
HbA1c (glycated hemoglobin) reflects average blood sugar over about 3 months. Jibril and colleagues set 0.5% as the smallest clinically important HbA1c change and concluded that, despite statistical significance, none of ALA’s effects in type 2 diabetes reached a clinically important size. These effects are much smaller than those of prescription diabetes drugs such as metformin. Readers comparing supplements marketed for blood sugar may also see the berberine page, which has its own, separate evidence base.
Side effects and risks
General tolerability
In the pooled intravenous neuropathy trials (600 mg/day for 3 weeks), adverse event rates did not differ from placebo (Ziegler et al., 2004). Higher oral doses (1200–1800 mg) caused dose-dependent nausea, vomiting and vertigo (Ziegler et al., 2006). In type 2 diabetes supplement trials, reported side effects were mostly mild gastrointestinal complaints, with itching and rash leading to withdrawal in one trial (Jibril et al., 2022).
In the 4-year NATHAN 1 trial, serious adverse events were more frequent on ALA (38.1%) than placebo (28.0%). The authors found no clear explanation: only 2 patients on ALA and 1 on placebo stopped treatment because of a likely drug-related event, cardiovascular serious events were not significantly different (14.7% vs 12.0%, p = 0.394), and deaths were fewer on ALA (3 vs 6) (Ziegler et al., 2011).
Insulin autoimmune syndrome and hypoglycemia
Insulin autoimmune syndrome (IAS, or Hirata disease) is a rare condition in which the body makes antibodies against its own insulin. The antibodies bind insulin after meals and release it later, causing high insulin levels and hypoglycemia (low blood sugar), typically 2–6 hours after eating. It occurs in people who have never injected insulin, and it is linked to sulfur-containing (sulfhydryl) drugs (EFSA, 2021).
EFSA’s 2021 review of the published cases found:
- 49 case reports of IAS after ALA taken as a medicine or supplement; 41 of the 49 were women, aged 28–82.
- Onset 7–120 days after starting ALA, at reported intakes of 200–800 mg/day.
- Resolution in all cases within weeks to months of stopping ALA. One woman developed IAS three times, each time on 600 mg/day.
- Genetic risk: susceptibility is tied to the HLA alleles DRB1*04:06 (common in Japanese and Korean people) and DRB1*04:03 (found in Europeans, more often in southern Europe). People at risk cannot be identified without genetic testing.
- No safe threshold: EFSA concluded that a dose below which IAS will not occur cannot be determined from the available data.
In a series of six white European patients taking 600 mg/day, hypoglycemic symptoms began 30–120 days after starting ALA. Five carried the DRB1*04:03 allele and one carried DRB1*04:06; episodes decreased after ALA was stopped, with glucose and prednisone treatment (Gullo et al., Clin Endocrinol 2014).
Outside IAS, controlled studies have not shown that ALA itself causes low blood sugar. In healthy volunteers, single 600 mg doses did not change insulin or glucose levels or alter the effect of the sulfonylurea glibenclamide (glyburide) or acarbose (Gleiter et al., Br J Clin Pharmacol 1999).
Thiamine (vitamin B1)
The only direct evidence found on this question is from animals. In a 1965 study in thiamine-deficient rats, the S-(−) form of ALA was selectively toxic, and giving thiamine reversed the toxicity (Gal, Nature 1965). No human data on this interaction were found, so its relevance to people is unknown.
Related supplements
ALA is often discussed alongside other sulfur-containing or “mitochondrial” supplements. See NAC (N-acetylcysteine), another thiol antioxidant, and carnitine, whose page covers acetyl-L-carnitine and its own nerve-damage trials. Evidence for one compound does not transfer to another.
Key takeaways
- Two forms, one tested drug. R-ALA is the natural form; the licensed medicine and the major trials used racemic thioctic acid.
- A licensed neuropathy drug in some countries. ALA is approved for diabetic polyneuropathy in Germany and authorized in several other countries; it is also sold as a supplement.
- Best evidence is for short IV courses. IV 600 mg/day for 3 weeks improved neuropathy symptoms by about a quarter vs placebo; 4 years of oral 600 mg/day missed its primary endpoint in NATHAN 1.
- Small metabolic effects. Weight loss averaged under 1.5 kg vs placebo, and HbA1c changes fell below the threshold for clinical importance.
- Very short half-life. Plasma half-life is about 30 minutes, and only about 30% of an oral dose reaches the circulation unchanged.
- Rare but serious hypoglycemia risk. ALA can trigger insulin autoimmune syndrome in genetically susceptible people; EMA’s safety committee recommended adding it to product warnings, and EFSA could not identify a dose below which it will not occur.
Sources
- Turck D, Castenmiller J, de Henauw S, et al. (EFSA Panel on Nutrition, Novel Foods and Food Allergens). Scientific opinion on the relationship between intake of alpha-lipoic acid (thioctic acid) and the risk of insulin autoimmune syndrome. EFSA J. 2021;19(6):e06577. PubMed.
- Hermann R, Mungo J, Cnota PJ, Ziegler D. Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms. Clin Pharmacol. 2014;6:195–204. PubMed.
- Teichert J, Hermann R, Ruus P, Preiss R. Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers. J Clin Pharmacol. 2003;43(11):1257–1267. PubMed.
- Breithaupt-Grögler K, Niebch G, Schneider E, et al. Dose-proportionality of oral thioctic acid–coincidence of assessments via pooled plasma and individual data. Eur J Pharm Sci. 1999;8(1):57–65. PubMed.
- Keith DJ, Butler JA, Bemer B, et al. Age and gender dependent bioavailability of R- and R,S-α-lipoic acid: a pilot study. Pharmacol Res. 2012;66(3):199–206. PubMed.
- Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995;38(12):1425–1433. PubMed.
- Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999;22(8):1296–1301. PubMed.
- Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003;26(3):770–776. PubMed.
- Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365–2370. PubMed.
- Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34(9):2054–2060. PubMed.
- Ziegler D, Nowak H, Kempler P, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21(2):114–121. PubMed.
- Han T, Bai J, Liu W, Hu Y. A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy. Eur J Endocrinol. 2012;167(4):465–471. PubMed.
- McIlduff CE, Rutkove SB. Critical appraisal of the use of alpha lipoic acid (thioctic acid) in the treatment of symptomatic diabetic polyneuropathy. Ther Clin Risk Manag. 2011;7:377–385. PubMed.
- Ziegler D. Pathogenetic treatments for diabetic peripheral neuropathy. Diabetes Res Clin Pract. 2023;206(Suppl 1):110764. PubMed.
- Kucukgoncu S, Zhou E, Lucas KB, Tek C. Alpha-lipoic acid (ALA) as a supplementation for weight loss: results from a meta-analysis of randomized controlled trials. Obes Rev. 2017;18(5):594–601. PubMed.
- Namazi N, Larijani B, Azadbakht L. Alpha-lipoic acid supplement in obesity treatment: A systematic review and meta-analysis of clinical trials. Clin Nutr. 2018;37(2):419–428. PubMed.
- Jibril AT, Jayedi A, Shab-Bidar S. Efficacy and safety of oral alpha-lipoic acid supplementation for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized trials. Endocr Connect. 2022;11(10):e220322. PubMed.
- Mohammadi S, Ashtary-Larky D, Alaghemand N, et al. Effects of alpha-lipoic acid supplementation on cardiometabolic risk factors: A systematic review and dose-response meta-analysis. Nutr Metab Cardiovasc Dis. 2026;36(2):104370. PubMed.
- Gullo D, Evans JL, Sortino G, et al. Insulin autoimmune syndrome (Hirata Disease) in European Caucasians taking α-lipoic acid. Clin Endocrinol (Oxf). 2014;81(2):204–209. PubMed.
- Gleiter CH, Schreeb KH, Freudenthaler S, et al. Lack of interaction between thioctic acid, glibenclamide and acarbose. Br J Clin Pharmacol. 1999;48(6):819–825. PubMed.
- Gal EM. Reversal of selective toxicity of (-)-alpha-lipoic acid by thiamine in thiamine-deficient rats. Nature. 1965;207(996):535. PubMed.