Lipoic acid is a water- and fat-soluble antioxidant. Synonyms for lipoic acid include alpha-lipoic acid, thioctic acid, and 6,8-dithiooctanoic acid.
Dihyrolipoic acid (DHLA), has more antioxidant activity than lipoic acid. DHLA is also called reduced lipoic acid and 6,8-dimercaptooctanoic acid.
In addition to antioxidant activities, alpha-lipoic acid may affect health by increasing glutathione synthesis, insulin signaling, and modulating the activity of other cell signaling molecules and transcription factors.
Alpha-lipoic acid is found in nearly all foods but is almost always covalently bound to proteins and therefore has low bioavailability.1,2
All supplemental lipoic acid is synthetic. Although R-alpha-lipoic acid is the active form, most supplements contain mixtures of the R and S forms.
Alpha-lipoic acid is bound to proteins and free lipoic acid has not been found in humans.
Alpha-lipoic acid has been used in Germany for several decades for the treatment of acute painful diabetic neuropathy.3
Protein-bound alpha-lipoic acid and free alpha-lipoic acid have distinct functions in the body. Endogenously synthesized alpha-lipoic acid is protein bound. Free alpha-lipoic acid in undetectable in humans except for during brief periods of time after consumption of alpha-lipoic acid supplements or intravenous injection of alpha-lipoic acid.
The activities of native, protein-bound alpha-lipoic acid are related to its functions as an enzyme cofactor. In this role, alpha-lipoic acid is involved in energy production and the breakdown of alpha-keto acids and amino acids.
Protein-bound alpha-lipoic acid:
Energy production: Alpha-lipoic acid has a role in enhancing energy production (ATP synthesis) through several mitochondrial enzymes. Alpha-lipoic acid is a cofactor for the enzymes responsible for the catabolism of alpha-keto acids and for amino acids.4
Nucleic acid synthesis: Through the glycine cleavage system and formation of 5,10-methylene tetrahydrofolate, alpha-lipoic acid is involved in nucleic acid synthesis. 5
Supplemental alpha-lipoic acid transiently increases concentrations of free alpha-lipoic acid in the body. Free alpha-lipoic acid has antioxidant, metal-chelating, and signal transduction activities.
Free alpah-lipoic acid:
Antioxidant: Alpha-lipoic acid and its reduced form, dihydrolipoic acid, may quench various reactive oxygen and nitrogen species (e.g. hydroxyl radicals, hypochlorous acid, peroxynitrite, and singlet oxygen).1
Regeneration of antioxidants: Dihydrolipoic acid can regenerate antioxidants including vitamin C and glutathione in vitro.6 It is not known whether these functions are relevant under physiological conditions. In in vitro and animal studies, alpha-lipoic acid has been found to stimulate glutathione synthesis.7,8
Metal binding: As a chelator, lipoic acid can trap free metals thus preventing cellular damage. In vitro and animal studies have shown that alpha-lipoic acid can chelate iron and copper.9,10,11,12
Signal transduction: Alpha-lipoic acid can activate the insulin signaling system although not through binding to insulin receptors.13,14,15 Alpha-lipoic acid activates the PKB/Akt-dependent signaling system and has been found to increase survival of neurons in vitro.16
Two-hundred to 400 mg alpha-lipoic acid daily appears to be safe and efficacious for healthy adults. For people with diabetes or Alzheimer’s disease, 600 to 1,200 mg alpha-lipoic acid daily has been studied and found to be safe and well-tolerated.
Few serious side effects have been reported with alpha-lipoic acid. Minor side effects include an allergic reaction (e.g. skin rash, hives, or itching) or gastrointestinal symptoms (e.g. abdominal pain, nausea, vomiting, or diarrhea). People taking at least 1,200 mg alpha-lipoic acid daily have sometimes reported changes in urine smell.
One report indicated a case of severe cholestatic hepatitis attributed to 600 mg daily alpha-lipoic acid. Liver enzymes returned to normal levels after stopping the supplement.17
Nearly all foods contain alpha-lipoic acid bound to proteins. This form is not very bioavailable. Alpha-lipoic acid is also synthesized in the human body. Supplemental alpha-lipoic acid is provided as capsules or tablets and almost always contain mixtures of R-alpha-lipoic acid (active form) and L-alpha-lipoic acid.
People with diabetes who are taking insulin or anti-diabetic agents should use caution when starting to take alpha-lipoic acid. Alpha-lipoic acid may improve insulin-mediated glucose utilization and could increase risk of hypoglycemia.18
Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.
Impact of therapy with alpha-lipoic acid (ALA) on the oxidative stress in the controlled NIDDM: a possible preventive way against the organ dysfunction?
A randomized, double-blind, placebo-controlled trial investigated the effects of alpha-lipoic acid on lipid profile, oxidative stress, and inflammation for people with non-insulin dependent diabetes mellitus. Fourteen people with stable type 2 diabetes participated in the four week trial. Participants were at least 50 years of age at the beginning of the trial and had been diagnosed with diabetes at least five years before the beginning of the trial. Participants were randomly assigned to receive either 400 mg alpha-lipoic acid or a placebo daily during the parallel group trial. Oxidative stress was evaluated using the d-ROMs test and biological antioxidant potential. Both demonstrated significant difference between the groups (d-ROMs p=0.03; biological antioxidant potential p=0.04); biological antioxidant potential was higher in the alpha-lipoic acid participants at the end of the trial (p=0.06). LDL cholesterol was reduced in the alpha-lipoic acid group (p=0.07). Total cholesterol, triglycerides, and C-reactive protein were not different between the alpha-lipoic acid and placebo groups (0.65, 0.78, and 0.96, respectively). The results of this small study suggest that alpha-lipoic acid may help to moderate oxidative stress for people with well-controlled type 2 diabetes.19
Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials.
A meta-analysis of randomized placebo controlled trials investigated the use of alpha-lipoic acid for people with peripheral neuropathy stemming from diabetes mellitus. Data were pooled from four randomized, placebo-controlled clinical trials of oral or intravenous alpha-lipoic acid. Evaluation of pooled data included determination of a total symptom score (TSS). TSS was reduced by alpha-lipoic acid administration (-2.26; confidence interval -3.12 to -1.41; P=0.00001). For oral alpha-lipoic acid only, TSS was reduced by -1.78 (CI: -2.45 to -1.10; P=0.00001). For intravenous administration only, TSS was reduced by -2.81 (CI: -4.16 to -1.46; P=0.0001). The authors concluded that alpha-lipoic acid, particularly from intravenous administration, was helpful for symptoms of peripheral neuropathy. Further trials are recommended to evaluate these results particularly since only four trials were sufficiently well-designed to meet inclusion criteria.20
Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction study.
A randomized, double-blind, placebo controlled trial investigated the efficacy of irbesartan, alpha-lipoic acid, or both on endothelial function and inflammation in metabolic syndrome. Fifty-eight people with metabolic syndrome participated in the four week trial. Participants were randomly assigned to one of four groups: irbesartan only (an angiotensin receptor blocker; 150 mg/day; n=14), alpha-lipoic acid only (300 mg/day; n=15), both (n=15), or placebo (n=14). Relative to placebo, endothelium-dependent flow-mediated vasodilation (brachial artery) was increased in the irbesartan (67%), alpha-lipoic acid (44%), and both irbesartan and alpha-lipoic acid groups (75%) (P<0.005 after four weeks). Serum levels of IL-6 were reduced in all three groups compared with placebo after four weeks: irbesartan (25%, P<0.01), alpha-lipoic acid (15%, P<0.01), and both irbesartan plus alpha-lipoic acid (40%, P<0.001). Serum plasminogen activator-1 levels were reduced relative to placebo after four weeks by 19% (irbesartan, P<0.001), 14% (alpha-lipoic acid, P<0.001), and 27% (both irbesartan and alpha-lipoic acid, P<0.001). Irbesartan and alpha-lipoic acid, alone and in combination, improved endothelial function and reduced proinflammatory markers in this study. These results suggest that alpha-lipoic acid may be beneficial for reducing inflammation in people with metabolic syndrome. Further studies are needed to evaluate these results.21
Effects of alpha-lipoic acid supplementation in peripheral arterial disease: a pilot study.
A randomized, double-blind, placebo-controlled parallel-design study investigated the efficacy of alpha-lipoic acid supplements for pain in peripheral artery disease. Twenty-eight people with peripheral artery disease participated in the three month trial. Participants were randomly assigned to receive 600 mg alpha-lipoic acid daily or a daily placebo during the trial. Efficacy was assessed through evaluation of walking tolerance (6-minute walk test distance, 4-meter walk time, initial claudication pain time, distance, and peak claudication pain). Initial claudication pain time increased in both groups (34.4% and 15%, respectively; not significantly different, p>0.05). Initial claudication distance was reduced in both groups (40.5% and 18%, respectively; significantly different, p<0.05). Peak pain ratings were reduced in both groups (93% and 7%, respectively; significantly different, p<0.05). Results of this study suggest that alpha-lipoic acid was effective for reduction of pain for people with peripheral artery disease. Larger and longer trials are necessary to investigate this application of alpha-lipoic acid.22
A randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis.
A randomized, double-blind, placebo controlled, parallel design trial investigated the efficacy of alpha-lipoic acid for migraine prevention. Fifty-four people enrolled in the trial; forty-four people completed the trial after the one month run in period. Participants were migraine sufferers with a mean age of 38 years (+/- 8 years); seven of the participants were male. The study design included a single-blind one-month run in period followed by a three month double-blind trial period. Participants were randomly assigned to receive 600 mg alpha-lipoic acid or a placebo daily during the three-month trial. Attack frequency was reduced in the alpha-lipoic acid group relative to the placebo group (P=0.06). However, the proportion of 50% responders (people who had at least a 50% reduction in attacks between run-in and three months) was not different between the alpha-lipoic acid and placebo groups (30.8% and 27.8%, respectively). Attack frequency, headache days, and headache severity were significantly reduced in the alpha-lipoic acid group in within-group analysis (P=0.005, P=0.009, and P=0.03, respectively). Attack frequency, headache days, and headache severity were unchanged in the placebo group. This small study indicates that alpha-lipoic acid may be helpful for those with migraine headaches. A larger trial is needed to confirm these results.23
Burning mouth syndrome (BMS): double blind controlled study of alpha-lipoic acid (thiotic acid) therapy.
A double-blind, placebo-controlled trial investigated the use of alpha-lipoic acid for burning mouth syndrome. Burning mouth syndrome is a type of chronic mouth pain with unknown causes. Sixty people with burning mouth syndrome participated in the two month trial. Participants were randomly assigned to receive either alpha-lipoic acid (200 mg pills, three times daily) or a cellulose starch pill (three times daily). Ninety-seven percent of people taking alpha-lipoic acid experienced symptomatic improvement with during the two month trial while 40% of people in the placebo group reported improvement. In the alpha-lipoic acid group, 87% reported decided improvement or resolution of pain; no participants in the placebo reported resolution of pain or decided improvement. The authors concluded that these results support the hypothesis that burning mouth pain is a neurological disorder and that alpha-lipoic acid may be useful for pain improvement. Larger clinical trials are needed to investigate these findings.24
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