Medically reviewed by Drugs.com. Last updated on Mar 29, 2018.
Scientific Name(s): 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3-valeric acid, 5-(1,2-dithiolan-3-yl) valeric acid, 6,8-thioctic acid
Common Name(s): Acetate replacing factor, Alpha-lipoic acid, Biletan, Lipoic acid, Lipoicin, Thioctacid, Thioctan, Thioctic acid
Alpha-lipoic acid (ALA) has been used as an antioxidant for the treatment of diabetes and HIV. It also has been used for cancer, liver ailments, and various other conditions.
Oral dosage of alpha-lipoic acid given in numerous clinical studies ranges from 200 to 1,800 mg daily. It also is given intravenously at similar daily dosages.
Contraindications have not yet been determined.
Information regarding safety and efficacy in pregnancy and lactation is lacking.
None well documented.
No adverse reactions have been reported; however, hypersensitivity reactions have occurred.
Fatal multiorgan failure occurred in a 14 year-old girl at a dose of 6 g (greater than 130 mg/kg).
Alpha lipoic acid (ALA) is a fat-soluble, sulfur-containing, vitamin-like antioxidant. It is not a true vitamin because it can be synthesized in the body and is not necessary in the diet of animals. ALA functions in the same manner as many B-complex vitamins. Good sources of ALA are yeast and liver.1, 2 Other sources include spinach, broccoli, potatoes, kidney, heart, and skeletal muscle.3
In the 1930s, it was found that a certain potato growth factor was necessary for growth of some bacteria.3 In 1951, a fat-soluble coenzyme factor was discovered from lactic acid bacteria. Researchers isolated and identified ALA and found it to be an important growth factor for many bacteria and protozoa.4 It is the most active form of lipoic acid.
ALA is a naturally occurring dithiol compound that functions as a cofactor for many mitochondrial enzymes involved in energy metabolism. Endogenous ALA is bound to proteins and is involved in acyl-group transfer reactions. Both in vivo and in vitro studies demonstrate that ALA exhibits the ability to scavenge free radicals, chelate redox-active transition metals, regulate the detoxification of heavy metals, and modulate various signal transduction pathways in physiological and pathological conditions.5
ALA is an 8-carbon sulfur containing fatty acid that has the International Union of Pure and Applied Chemistry name of 5-([3R]-dithiolan-3-yl) pentanoic acid, and is also known as thioctic acid, ALA, and lipoate. It is synthesized de novo from octanoic acid by lipoic acid synthase in most prokaryotic and eukaryotic microorganisms, plants, and animals. ALA can also be absorbed from the diet, and natural food sources, as well as from nutritional supplements.5
Two liopate enatiomers (R and S) exist as a consequence of a chiral center at the C6 location; however only R-ALA is endogenously synthesized.5
ALA can be oxidized and reduced, whereby the disulfide-containing ring is opened to form dihydrolipoic acid (DHLA) by the mitochondrial enzyme lipoamide dehydrogenase. ALA/DHLA is recognized as an essential cofactor for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and other mitochondrial enzymes, thus making ALA a necessary cofactor in catabolic and metabolic processes.1, 5
Numerous studies have demonstrated the ability of ALA to stimulate various signal transduction pathways and activate transcription factors including activation of G-protein coupled receptors and adenosine 3',5'-cyclic phosphate production, mitogen activated protein kinase signaling cascade, insulin signaling, and protein kinase B and nuclear factor kappa B.5
ALA interacts with and recycles endogenous glutathione (GSH).
Pharmacokinetics and bioavailability of both enantiomers of ALA have been studied in 12 subjects.6
ALA appears to be readily absorbed orally and converted to its reduced form, DHLA, in many tissues of the body. The effects of ALA and DHLA are present both intra- and extracellularly. R-ALA is bound to a protein where it functions as an essential cofactor for several mitochondrial enzyme complexes in energy production and the catabolism of alpha-keto acids and amino acids.7 Nutritional supplements of ALA are generally made up of R-ALA alone or a racemic mixture of the 2 isomers. Human studies using the oral racemic mixture have demonstrated plasma concentration of R-ALA to be higher than that of S-ALA.6, 8 One study found that following oral administration, the maximum plasma concentrations of R-ALA were double that of S-ALA.8
Uses and Pharmacology
The pharmacology of ALA has been studied in the chelation of transition and heavy metals, CNS conditions, oxidation, diabetes, AIDS, cancer, and liver ailments.
A number of animal studies have demonstrated that ALA improves age-associated cognitive dysfunction associated with neurodegenerative diseases. ALA improved cognitive function in healthy older mice, as well as longer-term memory of aged female nuclear magnetic resonance imaging mice. ALA also demonstrated improvement with cognitive function in senescence-accelerated mice and in chemically-induced, aging-accelerated mice. ALA improved hippocampal-dependent memory deficits of Tg2576 mice, a transgenic model of cerebral amyloidosis associated with Alzheimer disease. It also showed improvement of cognitive function in X-irradiation-induced memory impaired in mice.9
Small studies utilizing ALA in Alzheimer disease have been reported. Nine patients with Alzheimer-related dementias were given ALA 600 mg for an average of 337 days. The treatment led to stabilization of cognitive function as measured by the Mini-Mental State Examination and the Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-cog).11 Though the study was small and not randomized, it suggests that treatment with ALA is a possible neuroprotective therapy option for Alzheimer disease and related dementias.
In a follow-up study, analysis was extended to 37 patients over an observation period of 49 months. The study confirmed that ALA treatment slowed the progression rate of dementia dramatically, compared with the rate in untreated patients or patients receiving cholinesterase inhibitors.12
A small, 16-week, randomized, double-blind, placebo-controlled trial compared ALA 900 mg/day combined with vitamins C and E to coenzyme Q10 (CoQ10). Patients were randomized to one of the active treatments or matching placebo. The study’s primary outcome measures were changes from baseline in cerebrospinal fluid biochemical markers A-beta-42, tau, phosphorylated tau, and F2-isoprostane. The group receiving ALA/ vitamin C/vitamin E had a significantly greater reduction in F2-isoprostane, but no other biomarker results were significantly different. The group receiving ALA/vitamin C/vitamin E had a significantly greater decline in Mini-Mental State Examination (MMSE) scores compared with CoQ10 and placebo.47 A 12-month randomized, double-blind, placebo-controlled comparator trial (n = 39) in patients with probable mild Alzheimer disease (MMSE 15-26; Clinical Dementia Rating Scale 0.5-1) found no difference in F2-isoprostane levels in patients receiving combination therapy of ALA (600 mg/day) plus omega-3 fatty acids (docosahexamenoic acid [DHA] 675 mg/day, eicosapentaenoic acid [EPA] 975 mg/day), monotherapy with omega-3 fatty acids, or placebo (that contained 5% fish oil). However, over 12 months, the combination therapy significantly decreased cognitive and functional decline (MMSE and Instrumental Activities of Daily Living, respectively).53
Mechanism of action
ALA's antioxidant properties have been demonstrated. It has the ability to chelate metals and to scavenge free radicals.16 ALA is easily absorbed and transported across cell membranes; thus, free radical protection occurs both inside and outside of cells. It is water- and fat-soluble, which makes it more effective against a broader range of free radicals than vitamin C (water-soluble) and vitamin E (fat-soluble) alone.2 ALA administration also increases intracellular levels of glutathione, an important antioxidant.17
ALA regenerates or recycles antioxidant vitamins C and E.3 However, in one report it had no effect on vitamin E tissue concentration in animals, contradicting this effect.18 The body routinely converts ALA to DHLA, a more effective antioxidant. Both forms can quench peroxynitrite radicals, which are responsible in part for heart, lung, and neurological disease, as well as for inflammation.19 In oxidative stress models, such as ischemia, reperfusion injury, and radiation injury, ALA was beneficial.20, 21
The antioxidant ability of ALA has been demonstrated in studies with diabetic patients. It has been shown in diabetic children with subclinical left ventricular dysfunction to improve biochemical markers, such as glutathione and malondialdhyde, which indirectly reflect oxidative stress. Additionally, it has demonstrated significant antioxidant benefit in diabetic patients with poor glycemic control.51
Burning mouth syndrome
Burning mouth syndrome (BMS) refers to chronic oral pain diagnosed in the absence of any visible mucosal abnormality and where psychogenic factors are a possible cause.
Research reveals no animal data for the use of ALA for BMS.
Sixty patients with BMS were randomized to receive either ALA 200 mg 3 times daily or placebo for 2 months. Statistically significant improvement was seen with ALA (97%) compared with placebo (40%) over 2 months without any notable adverse reactions. Follow-up after 12 months showed that improvement achieved with ALA was maintained completely in 73% of patients, whereas all patients receiving placebo who had improved during the course of the study had deteriorated to some extent.15
There is limited information available concerning ALA's role in cancer. Its mechanism of action and anticarcinogenic and cytoprotective effects have been addressed.35
ALA administration, in conjunction with cyclophosphamide, lowered the toxic effects of this anticancer drug when tested in animals.36
Research reveals no clinical data regarding the use of ALA in cancer treatment.
Chelation of transition and heavy metals
Under physiological conditions, metal ions such as iron, copper, and zinc are important and necessary cofactors for normal function of many proteins. Transition metal deficiency or excess can lead to or affect the progression of diseases. Both ALA and DHLA have been shown to chelate metal ions by forming stable complexes with the ions. Consequently, ALA may have therapeutic potential in transition metal-mediated cellular toxicity in diseases. In addition, ALA and DHLA contribute to heavy metal detoxification. More recently, it has been suggested that ALA may be useful to protect against and reverse arsenic-induced cell toxicity.5
Increasing evidence shows that mitochondrial dysfunction due to the oxidation of lipids, proteins, and nucleic acids plays an important role in brain aging and neurodegenerative diseases such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Mitochondria provide energy for basic metabolic processes, produce oxidants as inevitable by-products, and decay with age, impairing cellular metabolism and leading to cellular decline. Various mechanisms of LA's positive effects on cognitive function have been suggested, including improvement of memory-related signaling pathways, reduction of oxidative stress, and improvement of mitochondrial function. ALA may also restore the activity of acetylcholinesterase and Na+, K+-ATPase. The activity of acetylcholinesterase was decreased in the cerebral corex, cerebellum, striatum, hippocampus, and hypothalamus in aged rats, while administration of ALA reversed the decrease in the activity in the discrete brain regions. Treatment with ALA also protected cortical neurons against cytotoxicity induced by beta-amyloid or hydrogen peroxide.
A combination of nonsteroidal anti-inflammatory drugs and appropriate levels and types of micronutrients may be more effective than the individual agents in the prevention and treatment of Alzheimer disease. Based on epidemiological, laboratory, and clinical studies, using the optimal combinations of ALA and other mitochondrial nutrients to target mitochondrial dysfunction may provide an effective strategy in delaying aging, and preventing and treating cognitive dysfunction.9
ALA has been shown to be beneficial in types 1 and 2 diabetes, preventing various pathologies associated with the disease, such as reperfusion injury, macular degeneration, cataracts, and neuropathy.2, 3, 20, 22
Overproduction of reactive oxygen species in mitochondria induced by hyperglycemia is central to the pathogenesis of endothelial damage in diabetes. Several experimental and clinical trials have shown that antioxidants fail to protect against diabetic vascular damage. However, R-ALA is thought to be an exception.23
ALA reduced diabetic neuropathy in a rat model in a dose-dependent manner. In part, the mechanism was suggested to be a reduction of the effects of oxidative stress.22
The retina is markedly sensitive to oxygen free radical damage, due to its high levels of polyunsaturated lipids. A study in mice tested the effect of ALA on the retina after a short diabetic insult. The results showed that after 3 weeks of diabetes, malondialdehyde (MDA) levels in the retina were increased when compared with controls and that ALA was able to prevent this effect. MDA is a well-accepted oxidative stress marker for pathological processes.24 Another study in rats has shown that treatment with R-ALA reduced oxidative stress, preventing microvascular damage through normalized pathways downstream of mitochondrial overproduction of reactive oxygen species and preserving pericyte coverage of retinal capillaries, which may provide additional endothelial protection.23
ALA may prevent formation of experimentally induced cataracts by increasing glutathione, ascorbate, and vitamin E levels. In turn, ALA restores glutathione, peroxidase, catalase, and ascorbate free radical-reductase activity. The effect was seen in the lenses of 60% of rats treated with L-buthionnine sulfoximine, an inhibitor of glutathione synthesis.25 The efficacy of ALA in delaying the development and progression of cataracts in rats with streptozotocin-induced diabetes has also been demonstrated.26
ALA improves the diabetic condition by facilitating more efficient conversion of sugar into energy, therefore improving blood sugar metabolism.2 A study investigated the efficacy of ALA in preventing diabetes mellitus in diabetes-prone obese rats. At 40 weeks, glycosuria occurred in 78% of untreated rats compared with none of the ALA treated animals. Compared with results in untreated rats, ALA reduced body weight and protected pancreatic beta-cells from destruction. ALA also reduced triglyceride accumulation in skeletal muscle and pancreatic islets.27
In 13 noninsulin-dependent diabetes mellitus patients, ALA increased insulin-stimulated glucose disposal. The metabolic clearance rate for glucose rose 50% in the treated group compared with the control group.28 ALA improves blood flow to peripheral nerves and stimulates regeneration of nerve fibers.2 In a German study evaluating patients with autonomic nervous system damage due to diabetes, treatment with ALA 800 mg/day was compared with placebo. After 4 months, sympathetic systems showed improvement and autonomic nerve disorders decreased in the ALA group.29
In general, antioxidants may lead to regression of diabetic complications. When ALA was compared with the antioxidant vitamin E, results failed to justify the higher cost of ALA over less expensive and equally effective nutritional antioxidants.2
In numerous studies, ALA has improved signs and symptoms of diabetic neuropathy. In a meta-analysis of 4 placebo-controlled studies that randomized more than 1,200 patients, ALA 600 mg/day improved the total symptom score in patients with diabetic neuropathy.30 Both pain and burning were improved in the ALA group as compared with those receiving placebo. The disadvantage of ALA in this meta-analysis was that it had to be given intravenously (IV). In one study, there was no difference in symptoms between patients administered oral ALA or placebo, after both groups had received an initial 3 weeks of IV treatment.31 A later study used oral doses of ALA 1.8 g/day or less. This study suggested that ALA may be effective for alleviating some neuropathic symptoms (stabbing and burning pain).32 A 2013 meta-analysis that included 15 studies and 1,106 diabetic patients found combination therapy for 2 to 4 weeks with IV ALA 300 to 600 mg/day plus IV methylcobalamin 500 to 1,000 mg/day to be superior to methylcobalamin monotherapy for improving nerve conduction.48 Similarly, combination therapy with prostaglandin E1 (10 or 20 mcg IV) and methylcobalamin (500 to 1,500 mcg IV/IM) plus lipoic acid (300 or 600 mg/day IV) provided significantly improved nerve conduction velocity compared with combination therapy without the lipoic acid in a 2015 meta-analysis of 18 randomized clinical trials (N = 1,410) involving patients with diabetic peripheral neuropathy.58
In a randomized controlled trial (n = 45), biochemical markers (ie, glutathione levels, malondialdhyde, nitric oxide, tumor necrosis factor-alpha, Fas ligand) associated with the development of diabetic cardiomyopathy were significantly improved in children and adolescents 10 to 14 years of age with asymptomatic type 1 diabetes who received ALA 300 mg twice daily in addition to insulin compared with those who received insulin alone.51
Age-related hearing loss is the most common form of hearing impairment in adults. As levels of ALA have been found to decrease with age, dietary supplementation with this compound may moderate age-related alterations in mitochondria.
A study in DBA mice found that those fed ALA exhibited preserved hearing during early-onset, age-related hearing loss, possibly caused by decreased reactive oxygen species production and enhanced antioxidant status in aged mice. Although hearing preservation was time dependent in that mice fed ALA sooner after birth had superior hearing than those fed ALA later in life, the latter mice had less hearing loss than control mice, perhaps indicating that feeding less ALA relatively late in life still has beneficial effects.13
Research reveals no clinical data for the use of ALA for hearing loss.
HIV and AIDS
Patients with HIV have a compromised antioxidant defense system, which may benefit from ALA's antioxidant effect.2
Mechanism of action
Several reports have suggested that impaired antioxidant defenses, particularly glutathione deficiency, may play a role in the immunopathogenesis of HIV infection. Glutathione is the major redox buffering thiol within cells and a central molecule for lymphocytic function. It is necessary for T-cell activation, interleukin-2-dependent proliferation, and antibody/cell-mediated cytotoxicity. Both HIV-infected and AIDs patients manifest depressed systemic glutathione levels. Because several immunologic functions relevant to HIV infection are dependent on adequate intracellular total glutathione balance, glutathione-replenishing compounds have been suggested in the treatment of HIV infection.33
ALA suppressed HIV replication in cultured cells and enhanced helper T cells in mice. ALA inhibits replication of HIV by reducing the activity of reverse transcriptase, the enzyme responsible for manufacturing the virus from the DNA of lymphocytes.2 In another report, ALA inhibited activation of nuclear factor kappa-B, which is involved in AIDS progression.34
A small pilot study was conducted administering ALA 150 mg 3 times daily to 10 HIV-infected patients. ALA increased glutathione in all patients and vitamin C in most patients. In addition, it improved the T-helper lymphocyte to T-helper suppressor cell ratio in 6 patients.2
Another study was carried out in 33 HIV-infected patients with a history of highly active antiretroviral treatment (HAART) unresponsiveness (ie, viral load greater than 10,000 copies per cm3 despite HAART), to test the hypothesis of whether supplementation with ALA would increase blood total glutathione and improve immune T-cell function. After 6 months of treatment, the mean whole blood total glutathione level in the ALA-treated group increased significantly (P = 0.03) compared with placebo. Lymphocyte proliferative response was either stabilized or enhanced in the ALA-treated group, depending on the mitogen used. In response to the CD3 monoclonal antibody, lymphocyte proliferation decreased approximately 66% in the placebo group over 6 months, compared with approximately a 3.7-fold enhancement in the anti-CD3 response in the ALA-treatment group. No difference was seen between the ALA-treatment group and the placebo group for viral load, CD4, or CD8 count.33
The effect of ALA on dry age-related macular degeneration was investigated in 100 older adults in China enrolled in a randomized single-blind, placebo-controlled trial. Diabetes and hypertension were among the exclusion criteria. ALA 200 mg/day administered for 3 months was found to significantly increase contrast sensitivity at middle or low spatial frequency compared to baseline as well as antioxidant activity (ie, superoxide dismutase) and quality of life.61
ALA has been studied as an effective therapy in a rat model of multiple sclerosis and experimental autoimmune encephalomyelitis. ALA dose dependently prevented the development of clinical signs in this model. ALA has a protective effect on encephalomyelitis development not only by affecting the migratory capacity of monocytes, but also by stabilizing the blood-brain barrier.10
Mouse studies have shown that ALA suppresses the migration of T cells across the blood-brain barrier in the spinal cord. Additionally, ALA inhibited expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by CNS endothelial cells in experimental autoimmune encephalomyelitis. ALA was also effective in preventing experimental autoimmune encephalomyelitis development in a dose-dependent fashion. It was shown that reactive oxygen species are important mediators of injury in experimental autoimmune encephalomyelitis and that generation of reactive oxygen species can be decreased by ALA. ALA also decreased the migration of monocytes across the blood-brain barrier, which correlated with clinical improvement seen in experimental autoimmune encephalomyelitis. In other studies, ALA decreased the phagocytosis of myelin by macrophages by inhibiting the generation of reactive oxygen species.5
A placebo-controlled phase 1 clinical trail of 37 subjects studied the effects of oral racemic ALA in multiple sclerosis. Subjects were randomly assigned to 4 groups, including placebo. The other 3 groups received ALA 600 mg twice a day, 1,200 mg once a day, or 1,200 mg twice a day, for 14 days. The study found ALA to be generally well tolerated, but peak plasma levels of ALA varied among subjects. As would be expected in a short duration study, there was no change in disability caused by multiple sclerosis as assessed by the Expanded Disability Status Score. The study found that stable blood levels of ALA required a dose of 1,200 mg, and treatment was associated with changes in serum immunologic markers associated with T-cell migration into the CNS. Longer-duration trials with a larger number of multiple sclerosis subjects are needed to establish the ability of ALA to decrease disease activity.5
Reduction of drug toxicity
The potential protective effect of ALA against acetaminophen-induced hepatotoxicity and nephrotoxicity has been investigated. Pretreatment of rats with oral ALA 100 mg/kg protected against hepatotoxicity and nephrotoxicity induced by an acute oral toxic dose of acetaminophen 2.5g/kg, as assessed by biochemical measurements and histopathological examination. Similarly, daily treatment of rats with a smaller dose of ALA 25 mg/kg concurrently with a smaller toxic dose of acetaminophen 750 mg/kg for 1 week protected against acetaminophen-induced hepatotoxicity and nephrotoxicity.39
Research reveals no clinical data for ALA in reducing drug toxicity.
A prospective, open-label clinical trial evaluated the protective effect of ALA on contrast media-induced nephropathy (CIN) in patients with renal dysfunction (creatinine clearance ≤ 60 mL/min) undergoing coronary angiography and/or percutaneous coronary intervention. Iso-osmolar, low-osmolar, or iobitridol contrast media were utilized containing 320, 300, or 350 mg iodine/mL, respectively. No significant differences were noted in mean maximum increase of serum creatinine, and a nonstatistically significant difference was noted in favor of ALA in rate of contrast-induced nephropathy.52 A systematic review and meta-analysis on the effect of antioxidants on contrast-induced nephropathy identified the above trial plus 1 additional randomized controlled trial (n=78) that investigated ALA. Pooled data revealed no significant decrease on the incidence of CIN (odds ration [OR], 0.5; 95% confidence interval [CI], 0.2 to 1.68; P=0.3).62
The effect of ALA on cyclophosphamide-induced testicular toxicity has been investigated in rats. Two groups of male rats were administered cyclophosphamide 15 mg/kg once a week for 10 weeks to induce testicular toxicity. One of these groups received ALA treatment (35 mg/kg) 24 hours before cyclophosphamide administration once a week for 10 weeks.
The rats exposed to cyclophosphamide showed an increase in testicular reactive oxygen species along with a decrease in cellular thiol levels. The activities of testicular marker enzymes such as gamma-glutamyl transferase, beta-glucuronidase, acid phosphatase, and alkaline phosphatase were increased, whereas the activities of sorbitol dehydrogenase and lactate dehydrogenase-X were decreased in animals treated with cyclophosphamide. However, those pretreated with ALA showed normal marker enzyme patterns and normal levels of reactive oxygen species and thiols. Testicular protection with ALA is further supported by normal histological findings, compared with those of cyclophosphamide-treated rats.37
A study in adult male Wistar rats demonstrated that administration of cyclophosphamide resulted in abnormal elevation of serum lipids. In cardiac tissue, the levels of free cholesterol, esterified cholesterol, and triglycerides were increased, while the levels of phospholipids and free fatty acids were reduced. Serum low density lipoprotein and very low density lipoprotein cholesterol increased, while high density lipoprotein cholesterol decreased when compared with controls. ALA supplementation reverted these abnormalities in the lipid levels and activities of lipid metabolizing enzymes to near healthy levels after cyclophosphamide administration.40
Cyclosporine A is associated with a variety of adverse reactions, the most important being nephrotoxicity. It has been speculated that different mechanisms are responsible for cyclosporine-induced nephrotoxicity, with oxidant stress playing a central role as a pathogenetic factor. Cyclosporine A-induced nephrotoxicity was assessed in terms of increased serum marker enzyme, alkaline phosphatase, acid phosphatase, and lactate dehydrogenase activity. An apparent rise in the activities of N-acetyl-beta-D-glucosaminidase, beta-glucuronidase, and cathepsin D activity was seen in the renal tissue of rats given cyclosporine A, which was reversed upon treatment with ALA. Cyclosporine A administration elevated lipid peroxidation along with abnormal levels of enzymic and nonenzymic antioxidants in the kidney. ALA administration improved renal function by bringing about a decrease in peroxidative levels and an increase in antioxidant status.38
An oral daily dose of 1,800 mg ALA (600 mg 3 times daily) given continuously for 24 weeks was not found to provide benefit in reducing oxaliplatin- or cisplatin-induced peripheral neuropathy. Poor compliance suggested a lack of feasibility for this intervention.54
Other drug effects
Animal studies have also demonstrated that the combination of ALA and nitroglycerin can efficiently counteract nitroglycerin tolerance.41
ALA and vitamin E have shown synergistic effects against lipid peroxidation by oxidant radicals in several pathological conditions, such as thromboembolic stroke model in rats from neurological functions, glial reactivity, and neuronal remodeling.9
Research reveals no animal data for the use of ALA for wound management.
A study in 20 patients investigated the use of ALA supplementation with hyperbaric oxygen therapy for the management of chronic wounds. Down regulation of inflammatory cytokines and growth factors affecting matrix metalloproteinase expression was observed. Disruption of the positive autocrine feedback loop that maintains the chronic wound state promotes progression of the healing process.14
A 2013 randomized controlled trial in Iranian patients on maintenance hemodialysis found that 2 months of supplementation with 400 units vitamin E alone and combined with ALA 600 mg significantly decreased one inflammation biomarker, interleukin-6. Biomarkers for lipid peroxidation, malnutrition, and another inflammation biomarker (C-reactive protein) were not significantly affected. Although subjective nutritional scores increased significantly with supplement monotherapy or combination therapy.55 Supplementation with ALA 600 mg/day × 12 weeks was not shown to be associated with changes in the erythrogram (eg, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration) in patients with systemic arterial hypertension (SAH), without regard to anemia or diabetes. However, in this double-blind, randomized placebo-controlled trial (n=60), a statistically significant increase in neutrophils (P<0.01) and reduction in serum iron (P<0.01) and Transferrin Saturation Index (P=0.01) may reflect the antioxidant and metal chelation activities of ALA. It was calculated that the effects of ALA supplementation on serum iron, transferrin, and total iron binding capacity were clinically significant compared to control. These results, it was speculated, could indicate the potential of undesirable reductions in iron with longer administration of ALA, which could contribute to anemia and potentially the pathological events in SAH.60
A randomized, double-blind, placebo-controlled trial (n = 151) found that 1-year supplementation with ALA with or without vitamin E provided a marginally significant decrease in plasma nonesterified fatty acid concentrations but did not alter insulin or glucose levels in adults with metabolic syndrome.49
Combination therapy with ALA (600 to 1,800 mg/day) plus acetyl-L-carnitine (1,000 to 3,000 mg/day) for 12 weeks did not have antidepressant effects or enhance mitochondrial functioning in adults with bipolar depression in a placebo-controlled randomized clinical trial (n = 20).50
A randomized, double-blind, placebo-controlled, parallel trial (N = 97) conducted in otherwise generally healthy overweight and obese women (body mass index, 27.5 to 40) on a 10-week 30% calorie-restricted diet observed a significant increase in weight lost in the ALA 300 mg/day group (mean, −7 kg; P = 0.032) compared with weight lost by the EPA 1,300 mg/day (EPA + DHA 1,341 mg/day), ALA + EPA, or placebo groups who lost a mean of −5.4 kg, −6.5 kg, and −5.2 kg, respectively. Total cholesterol was significantly reduced in all 4 groups (P < 0.05). No adverse effects were reported and no other significant benefits were demonstrated with ALA on lipid, glucose, leptin or ghrelin levels, or anthropomorphic measurements when adjusted for weight loss. All groups, except for the EPA group, experienced a significant reduction in leptin levels (P < 0.01) along with reduction in fat mass, and a corresponding reduction in resting metabolic rate.57 A 2017 meta-analysis of randomized controlled trials investigating the effect of ALA on weight and body mass index (BMI) identified 11 eligible studies that enrolled 947 participants, including those with diabetes, metabolic syndrome, rheumatoid arthritis, and nonalcoholic fatty liver disease. Doses of ALA ranged from 300 to 1,800 mg/day and were administered between 8 weeks to 1 year. Neither the ALA dose or duration of intervention had a significant effect on weight change; however, intervention duration did significantly affect BMI (P<0.001), with a shorter durations resulting in greater reductions in BMI. However, significant heterogeneity was found among the studies (P<0.001). Incidence of side effects did not differ between treatment and placebo groups; GI (abdominal pain, nausea) and dermatological (urticarial, itching) effects were most commonly associated with ALA. No serious side effects were reported.63
Oral dosage of ALA given in clinical studies ranges from 300 to 1,800 mg daily. It is also given IV at similar daily dosages.29R-ALA is more efficiently absorbed and utilized by the body than the racemate, and lower doses may be effective.42
Pregnancy / Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking.
None well documented. An early animal study investigating the effect of ALA on thyroid metabolism documented inhibition of T4 to T3 conversion with administration of ALA to mice. ALA reduced both T3 and T4 levels to those of untreated controls.64
Alcohol (Ethyl): Alcohol (Ethyl) may diminish the therapeutic effect of Alpha-Lipoic Acid. Avoid combination.65
Calcium Salts: Calcium Salts may decrease the absorption of Alpha-Lipoic Acid. Alpha-Lipoic Acid may decrease the absorption of Calcium Salts. This interaction applies only to orally administered alpha-lipoic acid and orally administered calcium salts. Consider therapy modification.66
Iron Salts: Iron Salts may decrease the absorption of Alpha-Lipoic Acid. Alpha-Lipoic Acid may decrease the absorption of Iron Salts. This interaction applies only to orally administered alpha-lipoic acid and orally administered iron salts. Consider therapy modification.66
Magnesium Salts: Magnesium Salts may decrease the absorption of Alpha-Lipoic Acid. Alpha-Lipoic Acid may decrease the absorption of Magnesium Salts. This interaction applies only to orally administered alpha-lipoic acid and orally administered magnesium salts. Consider therapy modification.66
No adverse reactions from ALA supplementation have been reported in either animal or human studies, even with large doses or extended use.2 Its use in diabetes may warrant a reduction in insulin or other oral diabetic medications and blood sugar levels should be closely monitored. In addition, ALA use may spare vitamins C and E, as well as other antioxidants.2
Allergic skin conditions have been reported with ALA administration in humans, including delayed hypersensitivity that resulted in a pruritic maculopapular rash.59
A case report of insulin autoimmune syndrome was reported in a woman who regularly took ALA 200 mg/day. After discontinuing ALA, hypoglycemia ceased and the titer of anti-insulin antibodies was markedly decreased.43
Multiorgan failure leading to death was attributed to intentional overdose of ALA by a 14 year-old girl (weight, 45 kg). The dose was estimated to have been 6 g (equivalent to a dosage greater than 130 mg/kg) and yielded plasma levels of 30,900 mcg/L 7 hours after admission. The clinical course was rapid progressive multiorgan failure with subsequent coagulopathy, hemolysis, and seizures. The ALA preparation used was more than 7 years past its expiration date.56
The median lethal dose (LD50) of ALA was 400 to 500 mg/kg after oral dosage in dogs44; however, lower dosages (20 mg/kg) given intraperitoneally to severely thiamine-deficient rats proved fatal. The lethal effect was prevented when thiamine was administered with LA.45 Anecdotal evidence suggests that ALA may be hepatotoxic to cats at doses greater than 20 mg daily.
Long-term toxicity of ALA was tested in Sprague-Dawley rats. Rats were fed either 20, 60, or 180 mg/kg/day of ALA for 24 months. No difference was seen between the control animals and treated animals at 20 or 60 mg/kg/day. In treatment groups, mortality was slightly lower than in the control group. The only notable findings in rats of both sexes dosed at 180 mg/kg/day was a reduction in food intake relative to the controls and a concomitant decrease in body weight. The level at which no adverse reactions were observed is considered to be 60 mg/kg/day. In addition, the study demonstrated that ALA had no carcinogenic potential in rats at doses up to 180 mg/kg/day.46
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