Alpha-Lipoic Acid (ALA)
1. Identity: Chemical Names, Natural Sources, and Common Forms
1.1 Chemical Identity
Alpha-lipoic acid, also known as thioctic acid or ALA, is a naturally occurring, sulfur-containing fatty acid of great pharmacological importance. It is commonly known as thioctic acid and its systematic IUPAC name is (–)-(R)-5-(1,2-dithiolan-3-yl)pentanoic acid. Other synonyms include 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3-valeric acid, 5-(1,2-dithiolan-3-yl) valeric acid, and 6,8-thioctic acid. Its molecular formula is C₈H₁₄O₂S₂.
Alpha-lipoic acid has a chiral carbon atom and occurs in two enantiomeric forms. The (R)-ALA isoform is considered biologically active and is naturally present in the human body, where it plays crucial roles in energy metabolism and neutralising reactive oxygen species. In contrast, the artificially synthesised (S)-ALA enantiomer has no recognised biological function and may even inhibit the action of (R)-ALA by competing for cell receptors or transporters. Studies have shown that (R)-ALA has greater bioavailability and therapeutic efficacy compared to DL-ALA, especially in conditions associated with oxidative stress, such as diabetic neuropathy. Even so, the racemic form is widely used in commercial supplements, mainly for reasons of stability and lower production costs.
Due to its amphiphilic structure, ALA is soluble in both aqueous and lipidic environments. This extremely advantageous feature allows its distribution throughout the body, including the central nervous system, as it can cross the blood–brain barrier. In vivo, ALA can be reduced to the dithiol form (where the ring structure is broken) called dihydrolipoic acid (DHLA).
1.2 Natural Sources
Being an organosulfur and biological antioxidant, alpha-lipoic acid is produced normally in plants, animals, and human beings, forming covalent bonds with proteins and playing a vital role in the Krebs cycle. Good sources of ALA are yeast and liver. Other sources include spinach, broccoli, potatoes, kidney, heart, and skeletal muscle. In plant material studied, lipoyllysine content was highest in spinach (3.15 μg/g dry weight; 92.51 μg/mg protein). When expressed as weight per dry weight of lyophilized vegetables, the abundance of naturally existing lipoate in spinach was over three- and five-fold higher than that in broccoli and tomato, respectively.
ALA is not a true vitamin because it can be synthesized in the body and is not necessary in the diet of animals. Naturally, ALA is located in mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. Although synthesized by the human body in low amounts, the ALA quantities produced are not enough to fulfill the energy requirement of the cell.
1.3 Common Forms and Preparations
ALA marketed as a food supplement, when not otherwise specified, is a racemic solution of both the S and R isomers, while R-ALA, the naturally occurring form of biologically active ALA, is commonly bound to sodium (Na-R-ALA) as a sodium salt. It has not yet been clearly established which of R-ALA, Na-R-ALA, or the racemic solution is the most suitable form for its use. It has been hypothesized that R-ALA would be the most appropriate form of commercial supplement; however, it is prone to polymerization and is absorbed to an even lower extent than racemic-ALA. Nutritional supplements of ALA are generally made up of R-ALA alone or a racemic mixture of the 2 isomers.
Available oral commercial dosage forms include capsules (100 mg, 200 mg, 300 mg, 600 mg) and tablets (50 mg, 100 mg, 300 mg). ALA is also administered intravenously in clinical settings. ALA has been approved for the treatment of diabetic peripheral neuropathy for many years in Germany, and is commonly used at doses of 200–600 mg and is available over-the-counter.
2. Historical and Scientific Discovery
The organosulfur compound was discovered in 1937 when scientists found a type of bacteria that uses potato juice for reproduction. ALA was first isolated as an amphipathic molecule from liver tissue in 1951 by Reed et al. and was originally identified as an enzymatic cofactor of dihydrolipoate acyltransferase in the mitochondrial tricarboxylic acid cycle that manages gene transcription. Researchers isolated and identified ALA and found it to be an important growth factor for many bacteria and protozoa.
ALA was isolated by Reed in 1951 as an acetate replacing factor, and its first clinical use dates from 1959 in the treatment of acute poisoning by Amanita phalloides, also known as the death cap mushroom. Until the 1980s it was considered a vitamin, and only later was it recognized primarily as an antioxidant. It is commonly known to function as a powerful antioxidant and is manufactured as a medicine or supplement to prevent aging. In addition, ALA is used in antidiabetic treatments because of its excellent glycemic control. It has been approved for the treatment of diabetic polyneuropathy in Germany.
Because ALA is synthesized endogenously and has no established essential dietary requirement in humans, it does not have a history of use in traditional herbal or botanical medicine systems in the same manner as plant-derived botanical ingredients. Its applications are rooted entirely in 20th-century biochemistry and clinical pharmacology. The compound's transition from a recognized enzyme cofactor to a therapeutic agent occurred through the systematic investigation of oxidative stress in the latter half of the 20th century.
3. Key Constituents, Chemistry, and Established Mechanisms of Action
3.1 The ALA/DHLA Redox Pair
The oxidized form ALA and its active reduced counterpart DHLA, two of the major powerful antioxidants present in nature, have been demonstrated to fight oxidative stress by quenching a variety of reactive oxygen species (ROS). Among antioxidant substances, alpha-lipoic acid is unique as it maintains protective functions in both its oxidized (ALA) and reduced (DHLA) forms, although the latter is more effective in performing antioxidant functions.
The ALA/DHLA combination represents an ideal antioxidant since it can quench radicals, is able to chelate metals, is amphiphilic, and has no major adverse effects. This unique system is able to scavenge reactive oxygen species, exerting a major effect on tissue levels of reduced forms of other antioxidants, including glutathione. For this reason, ALA is also known as the "antioxidant of antioxidants."
3.2 Regeneration of Endogenous Antioxidants
Physiologically, ALA acts as a coenzyme of the oxidative decarboxylation of α-keto carboxylic acid (e.g., pyruvates) and as an antioxidant, and it is able to regenerate vitamin C, vitamin E, glutathione, and coenzyme Q10. Both ALA and DHLA prevent protein carbonyl formation, and DHLA alone can regenerate the oxidized forms of vitamins E and C and neutralize free radicals. DHLA reduces the oxidized form of ubiquinone (CoQ10), which can additionally reduce the alpha-tocopheroxyl radical.
3.3 Metal Chelation
ALA and its reduced form DHLA have many biological functions in different intracellular systems, resulting in a wide range of actions such as antioxidant protection, chelation of metal ions, regeneration of other antioxidant agents such as vitamin C, E, and glutathione. The ability to chelate transition metals such as iron and copper, which catalyze free radical chain reactions, contributes importantly to ALA's antioxidant profile.
3.4 Modulation of NF-κB and Inflammatory Signaling
Alpha-lipoic acid is a pleiotropic medication with anti-inflammatory and antioxidant properties, of which the effects are exerted through the modulation of NF-κB. NF-κB modulates inflammatory cytokines, including interleukin (IL) IL-1β and IL-6, in different cell types and tissues. LA has also been shown to improve glucose and ascorbate handling, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-κB.
3.5 Nrf2 Activation and Phase II Detoxification
ALA also boosts the antioxidant defense system through Nrf2-mediated antioxidant gene expression and by modulation of peroxisome proliferator-activated receptor (PPAR)-regulated genes. LA, acting as a pro-oxidant, may increase Nrf2-dependent transcriptional activity by forming lipoyl-cysteinyl mixed disulfides on Keap1, the protein that sequesters Nrf2 and bridges it to ubiquitin ligases.
3.6 Insulin Signaling and AMPK Activation
ALA, with its documented potent antioxidant properties, has been shown to enhance insulin sensitivity and glucose uptake by activating the PI3K/Akt pathway, a crucial signaling pathway for cellular glucose metabolism. Additionally, ALA influences energy homeostasis and fatty acid oxidation via the activation of AMPK. In the hypothalamus, ALA-mediated activation of AMPK plays a significant role in appetite regulation and energy expenditure, with an overall effect on metabolism.
ALA inhibits nuclear factor kappa B and activates AMPK in skeletal muscles, which in turn have a plethora of metabolic consequences. Beneficial effects are accomplished with low micromolar levels of alpha-lipoic acid, suggesting that its therapeutic potential extends beyond the precise definition of an antioxidant agent.
3.7 Endothelial Function
The elasticity of the vessel wall is regulated by nitric oxide (NO), a gas produced by endothelial nitric oxide synthase (eNOS). Loss of eNOS activity causes endothelial dysfunction due to NO limitation, and is characterized by reduced vasodilation, a proinflammatory milieu, and a prothrombic state. Oxidative stress has been implicated in endothelial dysfunction on the basis that antioxidants, such as ascorbate and LA, improve the redox state of the plasma and endothelium-dependent NO-mediated vasodilation.
3.8 Mitochondrial Cofactor Function
Biologically, lipoate exists as lipoamide in at least five proteins where it is covalently linked to a lysyl residue. Four of these proteins are found in α-ketoacid dehydrogenase complexes, the pyruvate dehydrogenase complex, the branched chain keto-acid dehydrogenase complex, and the α-ketoglutarate dehydrogenase complex.
4. Pharmacokinetics and Bioavailability
Data suggests that ALA has a short half-life and bioavailability (about 30%) triggered by its hepatic degradation, reduced solubility as well as instability in the stomach. The absolute bioavailabilities (oral vs. intravenous in humans) of 200 mg of LA in aqueous solution have been estimated to be 38% for the R form and 28% for the S form.
The R enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability, as compared to its S enantiomer. In one study, volunteers given 600 mg of R,S-LA had plasma concentrations of R-LA that were 40–50% higher than S-LA, the latter of which was apparently more rapidly cleared than R-LA. These results suggest that the R-enantiomer would be the most appropriate form to provide as oral supplements; however, S-LA in the racemic mixture may prevent the polymerization of R-LA and thereby enhance overall bioavailability.
When ALA is taken with food, maximum blood levels are achieved 30–60 minutes after ingestion. Peak levels in the cortex, retina, and optic nerve are achieved around the same time. The use of various innovative formulations has greatly improved ALA bioavailability. 600 mg racemic ALA exhibits a good safety profile in both softgel and tablet dose forms along with rapid absorption and good bioavailability.
5. Scientific Evidence by Area of Use
5.1 Diabetic Peripheral Neuropathy
Evidence strength: Strong for symptomatic improvement (intravenous); moderate for oral routes. This is ALA's most extensively documented clinical application.
ALA has various properties, among them great antioxidant potential, and is widely used as a racemic drug for diabetic polyneuropathy-associated pain and paresthesia. The clinical evidence for diabetic neuropathy is built on a structured program of randomized controlled trials — collectively referred to as the ALADIN (Alpha-Lipoic Acid in Diabetic Neuropathy), SYDNEY (Symptomatic Diabetic Neuropathy), and NATHAN (Neurological Assessment of Thioctic Acid in Neuropathy) trial series.
Four trials — ALADIN I, ALADIN III, SYDNEY, and NATHAN II — comprised 1,258 patients (alpha-lipoic acid n=716; placebo n=542) and were included in a meta-analysis based on the intention-to-treat principle. These were randomized, double-masked, placebo-controlled, parallel-group trials using alpha-lipoic acid infusions of 600 mg i.v. per day for 3 weeks in diabetic patients with positive sensory symptoms of polyneuropathy scored by the Total Symptom Score (TSS) in the feet. Their results indicated that the intravenous treatment was safe and significantly alleviated positive neuropathic symptoms.
Oral treatment with alpha-lipoic acid for five weeks improved neuropathic symptoms and deficits in 187 patients with diabetic symmetrical polyneuropathy. This is an encouraging finding as deficits are major risk factors in the development of neuropathic foot ulcer. An oral dose of 600 mg once daily seems to provide the optimum risk-to-benefit ratio in the SYDNEY 2 trial. The adverse effects (mainly nausea) with the 1,200 mg dose daily occurred in 21% of patients, somewhat higher than that observed in the ALADIN I (15%) and ALADIN II study (7%) with the same dose of alpha-lipoic acid.
The NATHAN 1 trial aimed to analyze the impact of baseline factors on the efficacy of α-lipoic acid (ALA) over 4 years, involving 460 diabetic patients with mild-to-moderate polyneuropathy using ALA 600 mg once daily or placebo. The NATHAN 1 trial demonstrated an improvement of neuropathic signs (deficits, impairments) after four years in asymptomatic diabetic peripheral neuropathy. Based on the results of the NATHAN 1 trial, ALA (600 mg daily) can also be considered for long-term use of ≥ 4 years in asymptomatic patients.
ALA is the most established adjunctive metabolic therapy for symptomatic diabetic peripheral neuropathy, although no study has demonstrated structural nerve regeneration or a definitive disease-modifying effect. A Cochrane systematic review (Baicus et al., 2024; Cochrane Database of Systematic Reviews, 2024 Jan 11;1(1):CD012967) was published evaluating the evidence base for ALA in diabetic peripheral neuropathy. Although ALA is frequently used for diabetic peripheral neuropathy, there is currently no established universal consensus on its usage.
In multiple randomised controlled studies, alpha-lipoic acid was found to dramatically enhance neuropathic pain and nerve conduction velocity. The evidence for intravenous ALA at 600 mg/day is considered stronger than for oral administration, owing to the higher and more consistent plasma concentrations achieved parenterally.
5.2 Blood Glucose and Insulin Sensitivity
Evidence strength: Moderate. Multiple RCTs and meta-analyses show modest but significant effects on glucose parameters.
Alpha lipoic acid, a naturally occurring dithiol compound which plays an essential role in mitochondrial bioenergetic reactions, has gained considerable attention as an antioxidant for use in managing diabetic complications. ALA has been shown to enhance insulin sensitivity and glucose uptake by activating the PI3K/Akt pathway, a crucial signaling pathway for cellular glucose metabolism.
Many conflicting data have been found concerning the clinical use of alpha-lipoic acid in the treatment of diabetes and of diabetes-related chronic complications such as retinopathy, nephropathy, neuropathy, wound healing, and diabetic cardiovascular autonomic neuropathy. The most frequent clinical condition in which alpha-lipoic acid has been studied was in the management of diabetic peripheral neuropathy in patients with type 1 as well as type 2 diabetes.
ALA activates the insulin receptor by binding to it extracellularly and can also traverse the cell membrane to activate AMPK, which enhances GLUT4 expression and glucose uptake. This leads to increased glycolysis and initiates the Krebs cycle via interaction with pyruvate dehydrogenase. While mechanistic evidence is well established from preclinical data, the magnitude of blood-glucose lowering in human clinical trials is generally modest, and the clinical relevance in well-controlled diabetes remains under active investigation.
5.3 Obesity and Body Weight
Evidence strength: Modest. Meta-analyses show small statistically significant reductions in weight and BMI, but clinical significance is debated.
Previous studies observed improvements in components of metabolic syndrome with the supplementation of ALA. In particular, three recent systematic reviews and meta-analyses of randomized controlled clinical trials summarized the effects of ALA supplementation on anthropometric (body weight, BMI, and waist circumference), metabolic, and inflammatory indices among adult subjects. The first systematic review and meta-analysis revealed that ALA supplementation slightly but significantly decreased body weight and BMI.
ALA influences energy homeostasis and fatty acid oxidation via the activation of AMPK. In the hypothalamus, ALA-mediated activation of AMPK plays a significant role in appetite regulation and energy expenditure, with an overall effect on metabolism.
The benefits of ALA are likely more pronounced in individuals with higher baseline metabolic risk, such as those with elevated oxidative stress, insulin resistance, or dyslipidaemia. Future clinical trials should focus on populations with metabolic syndrome or diabetes, where the effects of ALA might be more easily detected owing to greater baseline dysfunction. The dosage and duration of ALA supplementation varied significantly across included studies, with doses ranging from 300 to 1800 mg/day and intervention periods spanning from 8 to 24 weeks.
5.4 Cardiovascular and Metabolic Syndrome
Evidence strength: Preliminary to moderate. Individual RCTs and meta-analyses show improvements in some biomarkers, but findings are not yet consistent across studies.
Alpha-lipoic acid is a commonly used dietary supplement exerting anti-oxidant and anti-inflammatory effects. Investigators have examined whether a three-month treatment with ALA improves endothelial function, as assessed by flow-mediated dilation (FMD) of the brachial artery, and clinical and metabolic risk factors in overweight/obese youths. At three months, within the ALA and placebo groups, FMD did not change significantly. However, the basal and peak diameter of the brachial artery significantly increased after ALA treatment as compared to placebo.
There is no definitive consensus regarding the impacts of alpha-lipoic acid supplementation on the risk factors of cardiometabolic syndrome. The ISLAND study (Irbesartan and Lipoic Acid in Endothelial Dysfunction) examined ALA in combination with irbesartan and found improvements in endothelial function and markers of inflammation in metabolic syndrome. These above-mentioned actions have been shown in experimental studies emphasizing the use of alpha-lipoic acid as a potential therapeutic agent for many chronic diseases with great epidemiological as well as economic and social impact, including cardiovascular disease and hypertension.
5.5 Neurological Applications: Alzheimer's Disease and Cognitive Function
Evidence strength: Preliminary. Preclinical evidence is promising; human clinical trial evidence is limited and mixed.
Preclinical research suggests that ALA scavenges free radicals, reduces inflammation, and may protect brain cells from conditions such as stroke, multiple sclerosis, and Alzheimer's disease. Preclinical studies also indicate that ALA or a combination of ALA and regular exercise may improve certain aspects of learning and memory. However, no clinical studies suggest that ALA can prevent dementia or improve cognition.
In clinical trials, ALA treatment for mild cognitive impairment and Alzheimer's patients has shown mixed results. Alpha-lipoic acid is a disulfide molecule with antioxidant properties that has positive effects on glucose metabolism and insulin resistance. One study evaluated the effect of ALA treatment (600 mg/day) on cognitive performance in AD patients; 126 patients with Alzheimer's disease were divided into two groups according to the presence or absence of diabetes.
ALA plays many different roles in pathogenic pathways of dementia, acting as a neuroprotective agent. It increases acetylcholine production, inhibits hydroxyl radical production, and increases the process of getting rid of reactive oxygen species. By the same ways, ALA promotes downregulation of redox-sensitive inflammatory processes.
The results obtained demonstrated that the progression of the disease in patients treated with ALA is significantly lower than that in untreated patients or those treated with cholinesterase inhibitors. Although both these studies are very preliminary, the data obtained suggested that ALA treatment could be a successful "neuroprotective" treatment option for Alzheimer's disease and related dementias. There are no official recommended doses for ALA supplements, but clinical trials with Alzheimer's patients have used doses ranging from 600 to 900 mg/day for up to 2 years without reporting serious side effects.
5.6 Multiple Sclerosis
Evidence strength: Preliminary. Phase 2 trials are ongoing or recently completed; evidence of benefit for walking function is negative, but brain atrophy findings are exploratory.
Lipoic acid (LA) is an endogenous antioxidant that exists widely in nature. Supplementation with LA is a promising approach to improve the outcomes of patients with multiple sclerosis (MS). A systematic review included 20 studies reporting LA effects in cell and mouse models of MS and 12 studies reporting LA effects in patients with MS. Cell experiments revealed that LA protected neurons by inhibiting the expression of inflammatory mediators and activities of immune cells.
A pilot trial of the antioxidant lipoic acid (LA) in secondary progressive MS demonstrated a reduction in whole-brain atrophy, suggesting neuroprotection. A subsequent phase 2, 24-month, randomized, double-blind, placebo-controlled clinical trial (2018–2023) recruited participants from 10 US sites to determine whether LA preserved walking speed, reduced brain atrophy, and was safe in progressive MS. This study provides Class II evidence that in people with primary or secondary progressive MS, oral LA did not improve timed walking speed at 24 months compared with placebo. The apparent reduction of whole-brain atrophy in this trial, even after accounting for the increase in T2-weighted lesion volumes, could suggest neuroprotection. Likewise, the preservation of deep gray matter volumes by LA found in both studies could be interpreted positively as deep gray matter atrophy seems to drive progressive MS disability accumulation.
In a randomized, double-blinded clinical trial, 24 patients with relapsing-remitting MS were divided into a treatment group receiving ALA (1200 mg/day) for 12 weeks and a control group receiving placebo. These findings suggest the need for larger, longer-duration trials to determine whether the potential brain-atrophy benefits of ALA in progressive MS translate into functional and disability outcomes.
5.7 Liver Conditions and Amanita Poisoning
In pathological conditions, lipoic acid is applied in the treatment of diabetic polyneuropathy, liver cirrhosis, and metal intoxications. As noted in the historical record, ALA's first clinical use dates from 1959 in the treatment of acute poisoning by Amanita phalloides (death cap mushroom). Preclinical evidence indicates that ALA can protect liver cells from oxidative injury; however, the evidence from controlled human trials specifically for liver cirrhosis or non-alcoholic fatty liver disease is limited and preliminary.
6. Dosage Forms and Doses Reported in Studies
Oral dosage of alpha-lipoic acid given in numerous clinical studies ranges from 200 to 1,800 mg daily. It is also given intravenously at similar daily dosages.
- Intravenous (diabetic neuropathy): Randomized, double-masked trials used alpha-lipoic acid infusions of 600 mg i.v. per day for 3 weeks, except for weekends, in diabetic patients with symptomatic polyneuropathy.
- Oral (diabetic neuropathy, SYDNEY 2 trial): An oral dose of 600 mg once daily seems to provide the optimum risk-to-benefit ratio in the SYDNEY 2 trial.
- Oral (NATHAN 1 trial, 4-year duration): The NATHAN 1 trial was a 4-year randomized study including 460 diabetic patients with mild-to-moderate polyneuropathy using ALA 600 mg once daily or placebo.
- Oral (Alzheimer's disease trials): Clinical trials with Alzheimer's patients have used doses ranging from 600 to 900 mg/day for up to 2 years.
- Oral (multiple sclerosis): 1200 mg/day for 12 weeks was used in a randomized MS trial.
- Oral (obesity/metabolic syndrome studies): Doses in these studies ranged from 300 to 1800 mg/day with intervention periods spanning from 8 to 24 weeks.
- High-dose oral (safety studies): Clinical studies, including long-term trials (up to four years of oral supplementation), have found that ALA has a strong safety profile with no significant adverse effects at usual doses. An adult may take doses up to about 2400 mg/day of ALA without severe harmful effects in the short term, although higher doses do not necessarily confer additional benefit.
The primary side effects from oral ALA are gastrointestinal and occur at doses of 1200 mg or higher. These gastrointestinal side effects predominantly involve an upset stomach, gastric reflux, and nausea, and can be minimized if ALA is taken in divided doses or with a meal, although concurrent food ingestion may partially reduce bioavailability.
7. Body Systems and Health Areas
Based on the clinical and preclinical evidence, ALA is associated with the following body systems and areas:
- Peripheral Nervous System: Most extensively studied for diabetic peripheral neuropathy, with clinically significant improvements in pain, paresthesia, and nerve conduction.
- Central Nervous System: Neuroprotective effects studied in Alzheimer's disease, MS, and stroke models. Due to its amphiphilic structure, ALA is soluble in both aqueous and lipidic environments, allowing its distribution throughout the body, including the central nervous system, as it can cross the blood–brain barrier.
- Mitochondria and Energy Metabolism: ALA serves as an obligatory enzymatic cofactor in mitochondrial multienzyme complexes central to the Krebs cycle.
- Endocrine/Metabolic System: Documented effects on insulin sensitivity, glucose metabolism, and body weight through PI3K/Akt and AMPK pathway modulation.
- Cardiovascular System: Evidence for improvements in endothelial function, NO bioavailability, and inflammatory markers; data on definitive cardiovascular outcomes remain limited.
- Immune System: The enhanced level of cAMP inside cells reduces the expression of IL-2 and IL-2Rα. Alpha-lipoic acid hampers IFN-γ secretion induced by IL-12/IL-18 and cellular cytotoxicity in NK cells, which enhances cAMP production via G protein-coupled receptors.
- Hepatic System: Historical use in acute hepatotoxic mushroom poisoning; preclinical evidence of hepatoprotective effects.
8. Safety Considerations and Known Interactions
8.1 General Tolerability
Alpha-lipoic acid is considered to be relatively well-tolerated in most adults. Clinical studies, including long-term trials (up to four years of oral supplementation), have found that ALA has a strong safety profile with no significant adverse effects at usual doses. The most common alpha-lipoic acid side effects are gastrointestinal: nausea, mild abdominal discomfort, bloating, and indigestion, typically dose-related and reversible.
8.2 Insulin Autoimmune Syndrome (IAS)
ALA can induce insulin autoimmune syndrome (IAS; also known as Hirata's disease), characterized by hypoglycemia, high concentrations of immunoreactive insulin, and high titers of antibodies to endogenous insulin, even without prior exposure to exogenously administered insulin. ALA may alter insulin by cleaving disulfide bonds, which exposes fragments to the immune system and results in the production of insulin autoantibodies (IAA), contributing to IAS. IAA is a type of IgG antibody with low affinity and high capacity, causing postprandial and nocturnal hypoglycemia in IAS patients.
Overall, it was concluded that the risk of occurrence of this syndrome following consumption of ALA cannot be excluded, but the risk is very low in the French population. Several cases of Insulin Autoimmune Syndrome have been reported in subjects taking ALA.
8.3 Interactions with Antidiabetic Medications
One major interaction concern is with antidiabetic medications (including insulin and oral hypoglycemic agents). ALA can synergistically enhance blood glucose uptake, thereby potentially causing blood sugar to drop more than expected. Patients on medications for diabetes who start ALA therapy should monitor their blood glucose closely and may need dose adjustments of their diabetic medications to prevent hypoglycemia.
8.4 Thyroid Hormone Interactions
Alpha-lipoic acid appears to interfere with the conversion of T4 (thyroxine) to T3 (triiodothyronine), potentially lowering T3 levels. TSH (thyroid-stimulating hormone) may increase as a compensatory response. The interaction with thyroid hormone is rated as moderate: taking alpha-lipoic acid seems to decrease how well thyroid hormone works in the body, and taking alpha-lipoic acid with thyroid hormone might decrease the effectiveness of the thyroid hormone.
8.5 Thiamine (Vitamin B1) and Biotin (Vitamin B7) Interactions
Very large doses of alpha-lipoic acid have caused serious toxicity in thiamin-deficient animals. People taking high doses of alpha-lipoic acid who are at risk for thiamin deficiency — such as those with chronic alcohol use — may require thiamin supplementation. Some diabetics may also be at risk for low thiamin levels.
Chronic use of alpha-lipoic acid may reduce some of the biological activities of biotin. This was demonstrated in a rat study, and co-administering biotin with alpha-lipoic acid eliminated this effect. However, the researchers noted that "even without supplemental biotin, the decreases in enzyme activities are not dramatic and would presumably not cause pathology in patients."
8.6 Regulatory and Safety Status
The Superior Health Council of Belgium noted that ALA may be sold as a medicinal product (e.g., in Germany) used for the treatment of diabetic neuropathy, and that adverse effects of treatment with this substance have been observed. The Council recommended that ALA should be used as a medicinal product instead of a food supplement and consumed under medical supervision.
ALA is metabolized by the liver and is known to be safe in both hepatic and renal disease. Information regarding safety and efficacy in pregnancy and lactation is lacking.
References
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