Lipoate is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions.

As a cofactor, RLA is covalently attached by an amide bond to a terminal lysine residue of the enzyme's lipoyl domains.

[3] Two hydrogens of octanoate are replaced with sulfur groups via a radical SAM mechanism, by lipoyl synthase.

The number of domains has been experimentally varied and seems to have little effect on growth until over nine are added, although more than three decreased activity of the complex.

[16] Lipoic acid is present in many foods in which it is bound to lysine in proteins,[3] but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.

[citation needed] Baseline levels (prior to supplementation) of RLA and R-DHLA have not been detected in human plasma.

[23] Both synthetic lipoamide and (R)-lipoyl-L-lysine are rapidly cleaved by serum lipoamidases, which release free (R)-lipoic acid and either L-lysine or ammonia.

[3][24] Degradation to tetranorlipoic acid, oxidation of one or both of the sulfur atoms to the sulfoxide, and S-methylation of the sulfide were observed.

[24] Degradation of lipoic acid is similar in humans, although it is not clear if the sulfur atoms become significantly oxidized.

[32][33][34][35] Advances in chiral chemistry led to more efficient technologies for manufacturing the single enantiomers by both classical resolution and asymmetric synthesis and the demand for RLA also grew at this time.

At the current time, most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in Italy, Germany, and Japan.

Both stereospecific and non-stereospecific reactions are known to occur in vivo and contribute to the mechanisms of action, but evidence to date indicates RLA may be the eutomer (the nutritionally and therapeutically preferred form).

[38][39] A 2007 human pharmacokinetic study of sodium RLA demonstrated the maximum concentration in plasma and bioavailability are significantly greater than the free acid form, and rivals plasma levels achieved by intravenous administration of the free acid form.

Lipoic acid in a cell seems primarily to induce the oxidative stress response rather than directly scavenge free radicals.

[38] Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription, which improve the antioxidant status of the cell.

[42][44][46] All the disulfide forms of LA (R/S-LA, RLA and SLA) can be reduced to DHLA although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems.

[47][48][49][50][51][52][53] Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.

[54] RLA may function in vivo like a B-vitamin and at higher doses like plant-derived nutrients, such as curcumin, sulforaphane, resveratrol, and other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents.

[58][59][60][61][62] R/S-LA and RLA are widely available as over-the-counter nutritional supplements in the United States in the form of capsules, tablets, and aqueous liquids, and have been marketed as antioxidants and pertaining to cellular glucose utilization for metabolic disorders and type 2 diabetes.

Maximum blood levels of LA are achieved 30–60 minutes after dietary supplementation, and it is thought to be largely metabolized in the liver.

[65] As of 2015, intravenously administered ALA is unapproved anywhere in the world except Germany for diabetic neuropathy, but has been proven reasonably safe and effective.

[67] A 2018 review recommended ALA as an anti-obesity supplement with low dosage (< 600 mg/day) for a short period (<10 weeks).