Alpha-lipoic acid

ALA (also called thioctic acid) is made by plants, animals and humans. Inside mitochondria it is a cofactor for the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes, two key steps in turning food into energy. As a drug it is used, in racemic form, for the pain and pins-and-needles of diabetic polyneuropathy [1].

Diabetic neuropathy is where the evidence is strongest. A meta-analysis of intravenous ALA at 600 mg a day for three weeks found meaningful improvements in symptoms and nerve deficits, with adverse events no different from placebo [3]. A broader meta-analysis of 15 intravenous trials found faster nerve conduction, though the trials were of poor quality [7]. For oral ALA, a 2023 meta-analysis of 10 randomised trials (1,242 patients) found improved symptom scores with a dose-response trend, but no benefit on several objective nerve measures [2].

Elsewhere the effects are modest. ALA produced about 1.3 kg more short-term weight loss than placebo [4]. In type 2 diabetes, oral ALA lowered HbA1c, weight and triglycerides, but every effect fell below the threshold for clinical importance [5].

ALA is a natural mitochondrial cofactor, and in supplement doses it is also a strong antioxidant [1]. The neuropathy benefit is thought to come from reduced oxidative stress and improved blood flow to nerves [2].

R-ALA, S-ALA and Na-R-ALA. ALA has a chiral centre, so it exists as R and S forms. The drug form, like most supplements, is the racemic mix of both [1]. The R form shows better pharmacokinetics, including higher bioavailability, than the S form [1]. In a crossover study of racemic tablets and solution, both enantiomers were absorbed within about 20 to 30 minutes, and the solution delivered noticeably more R-ALA than tablets [8]. Pure R-ALA tends to polymerise. Na-R-ALA (sodium R-lipoate) was developed to fix that. It is fully water-soluble, less prone to polymerising, and gave higher peak levels and total exposure than R-ALA or racemic ALA in healthy volunteers [6].

In the neuropathy trials adverse events were no more common than on placebo [3], and no serious adverse events were seen in the intravenous meta-analysis [7].

The notable rare risk is insulin autoimmune syndrome (Hirata disease). ALA's sulfur groups can alter insulin in people who carry particular HLA genes (HLA-DRB1*04:06, 04:03 or 04:04), leading them to make antibodies against their own insulin. The result is recurrent low blood sugar, sometimes alternating with high blood sugar after meals [9]. The first European cases were reported in 2014, and hypoglycaemia eased after ALA was stopped [10].

ALA lowers blood sugar modestly [5], so people on glucose-lowering drugs should watch for lows. Anyone who develops unexplained hypoglycaemia while taking ALA should consider insulin autoimmune syndrome [9].