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By Carrie Decker, ND
Founder and Medical Director, Blessed Thistle, Madison, WI
Dr. Decker reports no financial relationships relevant to this field of study.
Lipoic acid (LA) is a supplement that has much current interest for a variety of therapeutic reasons. Historically, its use as an antioxidant has been known for a long period of time. Current research has elaborated on what we know about the antioxidant function of this compound, its availability in the body, and how it may function to improve diabetic peripheral neuropathy, insulin resistance, and reduce obesity. In addition to these topics, research has also shown improvements in endothelial function, lipid profiles, Alzheimer’s disease, and multiple sclerosis, with mechanisms attributed mainly with its antioxidant function. Ongoing research continues to investigate the use of LA for disease conditions including hepatic injury, Parkinson’s disease, traumatic brain injury, migraines, and other disease states, which include pathology attributed to oxidative damage and mitochondrial dysfunction. Collectively, these conditions affect a large portion of individuals seeking medical care and mandate further attention to the possible uses of LA in clinical practice.
BIOAVAILABILITY AND METABOLISM
Also known as thioctic acid, 6,8-thioctic acid, 6,8-dithioctane acid, and 1,2-dithiol-3-valeric acid, LA is a molecule with two possible isomers: R-(+)-LA and S()-LA (referred to herein as R-LA and S-LA). A small amount of LA is made by de novo synthesis and obtained from dietary sources (as lipoyllysine), with the greatest abundance found in organ meat,1 red meat, spinach, broccoli, and tomatoes.2,3 The highest level of lipoyllysine found in animal and vegetable sources are 3.67 and 3.15 mcg/g dry weight in kidney and spinach, respectively.1,2 When utilized therapeutically, LA is most commonly supplied by supplement form.
Maximum plasma levels of LA have been observed between 10-60 minutes post oral administration, with a plasma half-life of 30 minutes.4,5 When supplemented orally as thioctic acid (a racemic mixture of R-LA and S-LA), maximum plasma concentrations of R-LA were observed to be 40-50% higher than S-LA.4 Maximum bioavailability of oral LA has been observed to be 38% as R-LA and 28% as S-LA.6 Higher plasma levels of LA may be available when it is supplied as a sodium salt form7 and when taken away from food.8 LA is converted to its reduced form dihydrolipoic acid (DHLA) by different enzymes within the mitochondria and cytosol and from DHLA to further metabolites. A low level of excretion of LA and these primary metabolites are recovered in human urine (12%) compared to animal studies (80%).5
MECHANISMS OF ACTION
Antioxidant. As an oxidant couple, LA and DHLA has a reduction potential of () 0.32V and has both lipophilic and hydrophilic properties.9 Both the reduced and oxidized forms have the capability of acting as an antioxidant (with DHLA being the more active form10) and together have the capability of reducing a multitude of free radical species.10,11 LA has been shown to be a regenerator of other antioxidants, interacting with ascorbate, vitamin E, ubiquinol, and glutathione.10,11 The LA/DHLA duo also may act as an antioxidant as a metal chelator, with some evidence for the chelation of copper, zinc, lead, mercury, and iron.11,12 LA crosses the blood-brain barrier and its central nervous system antioxidant function is the primary mechanism by which disease conditions such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury may experience improvements.13 Some of the effects seen with LA supplementation are observed up to 24 hours after oral administration, particularly pertaining to antioxidant status.14
Insulin Resistance. There are multiple mechanisms by which LA may affect insulin resistance and blood sugar regulation. LA has been found to increase glucose uptake in muscle cells dependent on phosphatidylinositol 3-kinase (PI3K) and associated with a redistribution of glucose transporters to the plasma membrane.15 The greatest effects seen on glucose uptake were with R-LA compared to the racemic mixture or S-LA, with other studies showing supplementation with the reduced DHLA form to have no effect.14 Improvements in insulin-stimulated glucose uptake via R-LA have also been associated with increased insulin receptor substrate 1 expression.16 Non-PI3K-dependent effects have also been seen with glucose uptake in skeletal muscle.17 LA also may affect muscle glucose uptake by activation of the AMP-activated protein kinase,18 a primary regulator of skeletal muscle metabolism.19
Peripheral Neuropathy. Oxidative stress, promoted by hyperglycemia through various mechanisms, is thought to be one of the primary factors associated with the development of peripheral neuropathy.20 It is speculated that improvements in peripheral neuropathy may be due to various mechanisms including increased blood flow to the nerve due the antioxidant effects of LA, associated with decreased lipid peroxidation and increased reduced glutathione levels.21
Obesity. One of the possible ways that LA may mediate anti-obesity effects is via suppressing hypothalamic adenosine monophosphate-activated protein kinase (AMPK).22 The normal function of AMPK is to activate when cellular energy is depleted, and has been shown to be activated by triiodothyronine23 and inhibited by leptin, insulin, high glucose, and refeeding.24
Lipids. LA has been observed to reduce dyslipidemia associated with a high-fat diet by decreasing gene expression associated with cholesterol synthesis and by increasing those associated with ß-oxidation (fatty acid breakdown).25 LA has been observed to effect hepatic triglyceride metabolism by inhibiting lipogenic gene expression, lowering triglyceride secretion, and stimulating clearance of triglyceride-rich lipoproteins.26
Alzheimer’s Disease. Multiple pathways associated with CNS antioxidant and mitochondrial function have shown LA may have an effect on Alzheimer’s disease.27 Glucose uptake in the brain, insulin signaling, and other pathways associated with mitochondria biogenesis and energy homeostasis have been shown in animal models to be altered with aging.28 These changes have been shown to be improved with R-LA supplementation. LA has also been shown in animal models to have an insulin mimetic effect on the brain, activating insulin receptor substrate and improving synaptic plasticity.29 Additionally, DHLA has been shown to be essential in the activity of choline acetyl transferase, an enzyme necessary for acetylcholine synthesis.30
Multiple Sclerosis. Inflammatory pathways may be an additional means by which LA has an effect on conditions such as multiple sclerosis, diabetes, and various sequela of metabolic syndrome. Cyclic adenosine monophosphate (cAMP) is a second messenger that regulates aspects of immune response.31 LA has been observed in vivo to increase cAMP production and to inhibit IL-6 and IL-17 production and T-cell proliferation and activation in vitro.32 An increase in soluble intercellular adhesion molecule-1 and matrix metalloproteinase-9 has also been associated with multiple sclerosis and the inflammatory aspects of other pathologies and has been shown to be reduced with LA supplementation.33
Unless otherwise mentioned, the form of LA utilized in studies (L- vs R- form) has not been specified, and a racemic mixture should be assumed.
Diabetes and Metabolic Syndrome. Individuals with type-2 diabetes (T2DM) had a significant increase in insulin-stimulated glucose disposal compared to placebo (P < 0.01; 95% confidence interval [CI] NR) when supplemented with 600 mg of LA orally one to three times per day for 4 weeks, with no significant difference seen with dosage.34 In a larger study, individuals with T2DM who were supplemented with 300 mg of LA (orally once daily before food consumption) had a significant reduction in fasting blood glucose and insulin resistance index (P = 0.001 and 0.006, respectively; CI NR) after 8 weeks compared to placebo.35
Obese individuals with impaired glucose tolerance who received intravenous treatment with 600 mg of LA once daily for 2 weeks experienced a significant decrease in postprandial plasma glucose, total cholesterol, LDL, VLDL, small dense LDL, and triglycerides, as well as a significant increase in HDL (P < 0.01 vs before treatment and placebo; CI NR). Insulin sensitivity also significantly increased after LA treatment (P < 0.01; CI NR).36
Decreases in both BMI and HbA1c (P < 0.01; CI NR) were seen in males with T2DM randomized to LA treatment (600 mg intravenously for 7 days followed by 600 mg per day orally) or 50 mg of transdermal testosterone per day after a period of 12 weeks.37 Improvement in all parameters associated with sexual function (P < 0.05; CI NR) were also seen. Weight loss of obese patients was significantly increased after 20 weeks of supplementation with 1800 mg of LA (divided doses, 30 minutes before meals) compared to placebo (2.1%; 95% CI, 1.4-2.8%; P < 0.05), but not significantly increased at the 1200 mg (divided) dosage.38 All groups (including placebo) were also subject to caloric restriction of 600 calories a day during this period. Flow-mediated dilation in individuals with metabolic syndrome was significantly increased (P < 0.005; CI NR) and markers of inflammation (interleukin-6 and plasminogen activator inhibitor-1) were significantly reduced (P = 0.01 and P < 0.001, respectively; CI NR) compared to placebo after 4 weeks of treatment with 300 mg/day of LA.39
Peripheral Neuropathy. Multiple clinical trials have assessed the effect of LA on diabetic peripheral neuropathy. A meta-analysis was performed to assess the effectiveness of intravenous LA for diabetic neuropathy, dosed at 600 mg, 5 days a week for 3 weeks.40 Four randomized, double-blind, placebo-controlled studies met the inclusion criteria for this analysis, with the relative difference (pooled data) in favor of LA over placebo in total symptom score (TSS) of 24.1% (95% CI, 13.5-33.4; P < 0.05) and neuropathy impairment score of the lower limbs of 16.0% (95% CI, 5.7-25.2; not significant in all studies), as well as response rates (≥ 50% reduction in TSS) of 52.7% in the LA group compared with 36.9% in the placebo group (P < 0.05 for pooled data but not significant in all studies; CI NR). Oral supplementation of LA at doses of 600 mg, 1200 mg, and 1800 mg daily for a period of 5 weeks was found to significantly improve TSS by 51%, 48%, and 52%, respectively, compared with 32% with placebo (P < 0.05, CI NR) with response rates of 62%, 50%, and 56%, respectively, compared with 26% in placebo (P < 0.05, CI NR).41
Alzheimer’s Disease. Individuals with probable Alzheimer’s disease receiving a combination of 600 mg of LA and 3 g of omega-3 fatty acids (containing 675 mg docosahexaenoic acid and 975 mg eicosapentaenoic acid, triglyceride form) had a lower decline in the mini-mental state examination and Instrumental Activities of Daily Living scores compared to placebo after a 12-month period (P < 0.01 and P = 0.01, respectively), while the group receiving only the omega-3 fatty acids had a lower decline in the later score.42
Multiple Sclerosis. Improved oxidative status and other markers of pathology associated with multiple sclerosis have been shown to improve with oral supplementation of LA;32,33,43 however, clinical studies assessing the effects of LA on multiple sclerosis symptomatology and disease course have not been shown.
Oral dosing of LA ranges from 300-1800 mg daily. Commonly, for diabetic neuropathy, Alzheimer’s disease cognitive dysfunction, and sexual dysfunction, 600 mg daily is used. A lower dose of 300 mg could be used to increase insulin sensitivity, whereas higher doses (600 mg two or three times daily) could be used to affect lipids or support weight loss. The duration of treatment ranges, but some benefits are seen as early as 2 weeks for diabetic neuropathy. Treatment should be continued for 4-8 weeks for insulin sensitivity, and 12 weeks or longer to support weight loss and reduce Alzheimer’s disease-related cognitive dysfunction. Although some studies have used intravenous LA, other studies have found a benefit with the above doses used orally.
No serious adverse effects of LA supplementation were observed with intravenous dosing at 600 mg daily for 3 weeks,44 oral dosing to 2400 mg (1200 mg twice daily) for 2 weeks,33 or 1800 mg (600 mg three times/day) for 6 months.44 The most common side effects reported were urticaria or itching sensation,38 nausea, gastrointestinal discomfort, vomiting, and vertigo. One isolated event of an allergic rash and mild thrombocytopenia was observed.33 Treatment emergent adverse events of nausea, vomiting, and vertigo were observed to increase with increasing oral dosage.41 Animal studies have shown evidence of increased oxidative damage at higher doses equivalent to 5-10 g/day in humans.45
A complication that is rare yet worthy of mention due to the diabetic population in which LA may most often be used in is the development of insulin autoimmune syndrome (IAS, Hirata disease). This syndrome is characterized by spontaneous hypoglycemia, with lab findings of high serum insulin levels and high autoantibody titers. Substances containing sulfhydryl compounds can initiate the development of IAS in genetically susceptible individuals having the HLA-DRB1*04:06 or HLA-DRB1*04:03 allele.46,47
Supplement quality and cost are both primary considerations. When serum pharmacokinetics were compared after supplementation with three different brands of LA at a single dose of 1200 mg, it was found that only two the three formulations achieved the target serum levels.48 Retail pricing of supplement brands that have been shown to achieve therapeutic levels ranges from $0.70-1.50 for 600 mg.
CONCLUSION AND RECOMMENDATIONS
Improvements in some of the underlying pathological markers and clinical symptoms of diabetes and metabolic syndrome have been observed with supplementation of LA. Controlled clinical studies showing the benefits of LA for Alzheimer’s disease and multiple sclerosis are lacking. Therapeutic dosages have been shown to be achievable with oral supplementation. Minimal adverse effects in the general population have been observed with treatment, and may be dose dependent; however, if spontaneous hypoglycemia occurs, the possibility of IAS must be considered. With the multiplicity of benefits shown for the conditions of diabetes and metabolic syndrome, LA is recommended as an integral aspect of treatment.