Alpha-Lipoic Acid

Health Care Professional Information

Scientific Name
1,2-dithiolane-3-pentanoic acid
Common Name

Thioctic acid, lipoate, lipoic acid, 1,2 dithilpolane-3-valeric acid, 6,8 thioctic acid, ALA, thioctan

Clinical Summary

Endogenous cofactor found in all eukaryotic and prokaryotic cells that can be obtained in the diet. Patients take this supplement to treat and prevent cancer and to treat diabetes, diabetic neuropathies, HIV/AIDS, and liver disease. Alpha-lipoic acid is an essential cofactor in the production of energy and acts as a potent antioxidant and exerts apoptotic effects on tumor cell lines (1) (2) (3).
In human studies, alpha-lipoic acid improved insulin sensitivity, vasodilation, and polyneuropathy in patients with diabetes mellitus (5) (6). A meta-analysis of clinical trials of alpha-lipoic acid in diabetic patients showed a significant reduction in neuropathic symptoms (7). Studies have also been conducted to determine its role in reversing neuropathies (8) (9) and liver disease (10) (11) but the results are mixed.
Current data suggest protective effects of antioxidants against Alzheimer's disease, but a new study did not find such benefits with a combination of Coenzyme Q, vitamins C, E, and lipoic acid (20). Topical application of creams containing alpha-lipoic acid may help prevent photoaging of facial skin (12).

High doses of alpha-lipoic acid can cause hypoglycemic symptoms (4). The antioxidant activity of alpha-lipoic acid may antagonize the effects of chemotherapy and radiation therapy.

Food Sources

Organ meats, spinach, broccoli, tomato, peas, Brussels sprouts, rice bran

Purported Uses
  • Cancer prevention
  • Cancer treatment
  • Diabetes
  • Diabetic neuropathy
  • AIDS
  • Liver disease
Mechanism of Action

Alpha-lipoic acid acts as a lipophilic free radical scavenger. Dihydrolipoic acid (DHLA), a reduced form of lipoic acid, has more potent antioxidant effects. It can assist in repairing oxidative damage and regenerate endogenous antioxidants such as vitamin C, vitamin E, and glutathione. Both DHLA and lipoic acid also have metal chelating capacities. As a lipoamide, alpha-lipoic acid functions as a cofactor in various multienzyme systems involved in the decarboxylation of alpha-keto acids such as pyruvate. (13) (14) (15) Alpha-lipoic acid caused cell cycle arrest in G0/G1 in FaDu and Jurkat human tumor cell lines (1). Alpha lipoic acid was also found to scavenge reactive oxygen species in MCF-7 breast cancer cells (16). Reduction of reactive oxygen species was then followed by cancer cell growth arrest and apoptosis (16).

Pharmacokinetics

Absorption:
Endogenous synthesis of lipoic acid takes place in humans and animals. Lipoic acid is bound to proteins in food, specifically lysine. It appears that digestive enzymes do not effectively cleave the peptide bond between lipoic acid and lysine. Oral bioavailability for a 200 mg dose of alpha-lipoic acid is estimated to be 30%. De novo synthesis from fatty acids and cysteine also yields lipoic acid.
Distribution:
Small amounts of lipoic acid enter the circulation from food or endogenous biosynthesis. After oral administration of supplements, high levels of free lipoic acid can be detected in the serum, and it is this form that is thought to be most important therapeutically. Free lipoic acid distributes widely throughout the body and can be detected in body tissues. The mean plasma half-life is approximately 30 minutes. An absolute bioavailability value has been calculated to be approximately 20% to 38% depending on the isomer and the formula administered.
Metabolism/Excretion:
Enzymatic reduction of lipoic acid takes place in the mitochondria and cytosol. Mitochondrial beta-oxidation also occurs. In general, a variety of reductive enzymes in body tissues contribute to the high clearance of lipoic acid. Urine appears to be the major excretory pathway with some fecal loss. The metabolism of lipoic acid in humans has not been studied extensively.
(13) (14) (15) (17) (18) (19)

Adverse Reactions

Reported: Hypoglycemia
(4) (13)

Herb-Drug Interactions

May have synergetic effects with hypoglycemic agents (7).

Literature Summary and Critique

Gu XM, et al. Efficacy and safety of high-dose á-lipoic acid in the treatment of diabetic polyneuropathy. Zhonghua Yi Xue Za Zhi. 2010 Sep;90(35):2473-2476. This randomized, double-blind, placebo-controlled, multicenter study enrolled 236 patients with symptomatic polyneuropathy. Subjects were treated with 600 mg three times a day alpha lipoic acid (n=117) or placebo (n=119) for 12 weeks. The primary outcome measure was total symptom score (TSS); secondary measures included nerve conduction velocity, individual symptom score, HbA1C, and safety parameters. This study found that 73.27% of the patients with symptomatic polyneuropathy improved after treatment with alpha lipoic acid, compared to 18.27% receiving placebo. Total symptom score in alpha lipoic acid-treated patients also decreased quickly and by a greater amount than placebo at 2 weeks (p<0.05). Scores for individual symptoms, including pain, numbness of extremities, burning sensation, or abnormal resting sensations were also significantly diminished compared to both baseline and placebo (p<0.05). Patients treated with alpha lipoic acid were also found to have significantly decreased levels (p<0.05) of HbA1C at study end. Adverse effects were observed in 25.4% vs 11.8% of the treatment and control groups, respectively. The most common adverse event was a burning sensation from throat to stomach (11.8%). The investigators concluded that 600 mg tid alpha lipoic acid has marked efficacy and reasonable safety in patients with diabetic polyneuropathy.

Heinisch BB, et al. Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial. Eur J Clin Invest. 2010 Feb;40(2):148-54. This randomized, controlled, parallel group trial studied the effect of alpha lipoic acid treatment on endothelial-dependent and -independent vasodilation in patients (n=30) with type 2 diabetes. Forearm blood flow (FBF) responses to intra-arterial acetylcholine (ACH) and glycerol trinitrate (GTN) were measured before and after intravenous therapy with 600 mg alpha lipoic acid or placebo. Treatment with alpha lipoic acid was found to significantly increase endothelium-dependent vasodilation in response to ACH (p<0.05), but not to GTN in comparison to baseline. Treatment was found to be well-tolerated, with no adverse effects observed. The investigators concluded that intravenous alpha lipoic acid treatment improves endothelium vasodilation in patients with type 2 diabetes in the absence of effects on vasomotor function. Whether this action translates into vascular risk reduction remains unclear.

Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet.Med 2004;21:114-21.
A meta-analysis of clinical trials of alpha-lipoic acid and symptomatic polyneuropathy. Four trials met the stringent inclusion criteria (randomized, double-blind, placebo, using 600 mg i.v. per day for three weeks, except for weekends, in diabetic patients with positive sensory symptoms of polyneuropathy scored by the Total System Score in the feet on a daily basis). The analysis included 1258 patients following an intention-to-treat principle. Improvement was first noted after eight days of treatment. After three weeks, responder rates for patients receiving alpha-lipoic acid was 53% versus 37% for placebo. The difference was statistically significant. Rates of adverse events did not differ between groups. Researchers suggest that alpha-lipoic acid may be clinically meaningful as a treatment for diabetic polyneuropathy.

Dosage (Inside MSKCC Only)
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References
  1. van de MK, Chen JS, Steliou K, Perrine SP, Faller DV. Alpha-lipoic acid induces p27Kip-dependent cell cycle arrest in non-transformed cell lines and apoptosis in tumor cell lines. J Cell Physiol 2003;194:325-40.
  2. Simbula G, Columbano A, Ledda-Columbano GM, et al. Increased ROS generation and p53 activation in alpha-lipoic acid-induced apoptosis of hepatoma cells. Apoptosis 2007 Jan;12(1):113-23.
  3. Shi DY, Liu HL, Stern JS, et al. Alpha-lipoic acid induces apoptosis in hepatoma cells via the PTEN/Akt pathway. FEBS Lett. 2008 May 28;582(12):1667-71.
  4. Jacob S, et al. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med 1999;27:309-14.
  5. Gu XM, Zhang SS, Wu JC, et al. Efficacy and safety of high-dose á-lipoic acid in the treatment of diabetic polyneuropathy. Zhonghua Yi Xue Za Zhi. 2010 Sep;90(35):2473-2476.
  6. Heinisch BB, Francesconi M, Mittermayer F, et al. Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial. Eur J Clin Invest. 2010 Feb;40(2):148-54.
  7. Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet.Med 2004;21:114-21.
  8. Ziegler D, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999 Aug;22(8):1296-301.
  9. Ruhnau k, et al. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med. 1999 Dec;16(12):1040-3.
  10. Marshall AW, et al. Treatment of alcohol-related liver disease with thioctic acid: a six month randomized double-blind trial. Gut 1982;23:1088-93.
  11. Park KG, Min AK, Koh EH, et al. Alpha-lipoic acid decreases hepatic lipogenesis through adenosine monophosphate- activated protein kinase (AMPK)-dependent and AMPK-independent pathways. Hepatology 2008 Nov;48(5):1477-86.
  12. Beitner H. Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoageing of facial skin. Br J Dermatol 2003;149:841-9.
  13. Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol 1997;29:315-31.
  14. Packer L. alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kB signal transduction and protects against oxidative injury. Drug Metab Rev 1998;30:245-75.
  15. Schupke H, et al. New metabolic pathways of a-lipoic acid. Drug Metab Disp 2001;29:855-62.
  16. Dozio E, Ruscica M, Passafaro L, et al. The natural antioxidant alpha-lipoic acid induces p27(Kip1)-dependent cell cycle arrest and apoptosis in MCF-7 human breast cancer cells Eur J Pharmacol. 2010 Sep 1;641(1):29-34.
  17. Sen CK, Packer L. Thiol homeostasis and supplements in physical exercise. Am J Clin Nutr 2000;72(suppl):653S-69S.
  18. Teichert J, et al. Investigations on the pharmacokinetics of alpha-lipoic acid in healthy volunteers. Int J Clin Pharmacol Ther 1998;36:625-8.
  19. Breithaupt-Grogler K, et al. Dose-proportionality of oral thioctic acid - coincidence of assessments via pooled plasma and individual data. Eur J Pharm Sci 1999;8:57-65.
  20. Galasko DR, Peskind E, Clark CM, et al; for the Alzheimer's Disease Cooperative Study. Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures. Arch Neurol. 2012 Mar 19. [Epub ahead of print]

Consumer Information

How It Works

Bottom Line: Alpha-lipoic acid is an antioxidant, but there is no proof that it can be used to treat diseases such as diabetes, HIV, liver disease, or cancer in humans.
Alpha lipoic acid is a compound naturally produced by the body that acts as a cofactor in the production of energy. Laboratory studies show that alpha lipoic acid and its metabolite, dihydrolipoic acid (DHLA), have metal-chelating and free radical-scavenging capacities. In addition, DHLA is able to repair oxidative damage and regenerate antioxidants such as vitamin C, vitamin E, and glutathione. However, when taken orally, the amount of alpha lipoic acid delivered to the body varies. Applying a cream containing Alpha-lipoic acid may help prevent wrinkling of skin due to sun exposure.

Purported Uses
  • As an antioxidant
    Laboratory studies support this use.
  • To prevent and treat cancer
    Alpha-lipoic acid is an antioxidant. However, there is no evidence that it can be used to treat cancer.
  • To relieve conditions related to diabetes, such as diabetic neuropathy
    Data from some studies suggest efficacy. But more studies are needed.
  • To treat drug-related toxicity of the auditory nerve
    No clinical trials have been performed to evaluate this use.
  • To treat HIV and AIDS
    No scientific evidence supports this use.
  • To treat liver disease
    A few studies show that alpha-lipoic acid may prevent nonalcoholic liver disease. More research is needed.
Research Evidence

This randomized, double-blind, placebo-controlled, multicenter study enrolled 236 patients with symptomatic polyneuropathy. Subjects were treated with 600 mg tid alpha lipoic acid (n=117) or placebo (n=119) for 12 weeks.  This study found that 73.27% of the patients with symptomatic polyneuropathy improved after treatment with alpha lipoic acid, compared to 18.27% receiving placebo. The most common adverse event was a burning sensation from throat to stomach (11.8%). The investigators concluded that 600 mg tid alpha lipoic acid is safe and can benefit patients with diabetic polyneuropathy.

A randomized, controlled trial studied the effects of alpha lipoic acid treatment on endothelial-dependent and -independent vasodilation in 30 patients with type 2 diabetes. Treatment with alpha lipoic acid was found to significantly increase endothelium-dependent vasodilation. Treatment was found to be well-tolerated, with no adverse effects observed. The investigators concluded that intravenous alpha lipoic acid treatment improves endothelium vasodilation in patients with type 2 diabetes in the absence of effects on vasomotor function.

A meta-analysis of clinical trials of alpha-lipoic acid and symptomatic polyneuropathy. Four trials met the stringent inclusion criteria (randomized, double-blind, placebo, using 600 mg i.v. per day for three weeks, except for weekends, in diabetic patients with positive sensory symptoms of polyneuropathy scored by the Total System Score in the feet on a daily basis). The analysis included 1258 patients following an intention-to-treat principle. Improvement was first noted after eight days of treatment. After three weeks, responder rates for patients receiving alpha-lipoic acid was 53% versus 37% for placebo. The difference was statistically significant. Rates of adverse events did not differ between groups. Researchers suggest that alpha-lipoic acid may be clinically meaningful as a treatment for diabetic polyneuropathy.

A small, prospective, randomized, double-blind evaluation was done using 800 mg alpha-lipoic acid (ALA) or placebo on non-insulin dependent diabetes mellitus (NIDDM) patients with cardiac autonomic neuropathy. Subjects took one tablet four times daily of either 200 mg ALA (n=29) or placebo (n=35) for 4 months.  Following 4 months of supplementation a decrease in heart rate variability (HRV) was seen in the ALA arm while a slight increase occurred in the placebo group, but he difference was not statistically significant. ALA does not appear effective in altering cardiac autonomic neuropathy, but additional studies should be performed.

Side Effects
  • Alpha-lipoic acid can lower blood sugar levels.
Special Point

Taking alpha lipoic acid appears to be relatively safe, but it has yet to be proven beneficial for any of its proposed uses. Diabetic patients should consult their physicians before using alpha lipoic acid.

E-mail your questions and comments to aboutherbs@mskcc.org.