What is alpha lipoic acid

Alpha-Lipoic Acid also called thioctic acid or 1,2-dithiolane-3-pentanoic acid (pentanoic acid), is a naturally occurring short chain fatty acid which contains a thiol bond, synthesized in small amounts by plants and animals (including humans), with antioxidant and potential chemopreventive activities ¹⁾. Chemically, alpha lipoic acid is a short-chain fatty acid with a disulfide group in its dithiolane ring and a chiral carbon resulting in R and S enantiomers (see Figure 1 below). Although the majority of the commercially produced alpha lipoic acid consists of a racemic admixture, the R form, (R)-α-Lipoic acid, is the biologically active form that is endogenously produced by the body, while the S form is produced from chemical manufacture and is not biologically active ²⁾. Only R-α-Lipoic acid is conjugated to conserved lysine residues in an amide linkage, thus making this isoform essential as a cofactor in biological systems ³⁾. At the cellular level, alpha lipoic acid is reduced to dihydrolipoic acid (DHLA), which has a number of cellular actions including free radical scavenging and modulating oxidative stress and inflammatory pathways ⁴⁾. Alpha lipoic acid, when exogenously administered, is readily absorbed from the gut and has been clinically used in Europe for the treatment of diabetic polyneuropathy ⁵⁾.

Though in body synthesis appears to supply all the necessary alpha lipoic acid needed for its role in intermediary metabolism, alpha lipoic acid can also be absorbed from the diet ⁶⁾. While the direct roles of alpha lipoic acid as a cofactor are well understood, less is known about the precise metabolic functions of orally supplied alpha lipoic acid.

Figure 1. Alpha lipoic acid R and S enantiomers

Alpha-lipoic acid acts as a free radical scavenger and assists in repairing oxidative damage and regenerates endogenous antioxidants, including vitamins C and E and glutathione. Alpha lipoic acid also promotes glutathione synthesis. In addition, alpha-lipoic acid exerts metal chelating capacities and functions as a cofactor for energy production in the mitochondria in various mitochondrial enzyme complexes involved in the decarboxylation of alpha-keto acids and thus serves a critical role in mitochondrial energy metabolism ⁷⁾.

In addition to alpha-lipoic acid being made by your body, alpha-lipoic acid is also absorbed intact from dietary sources and can be found in almost all foods, but slightly more so in organ meats (kidney, heart, liver), spinach, broccoli, peas, brussel sprouts, and rice bran. Alpha-lipoic acid can also be made in the laboratory. Alpha-lipoic acid is biosynthesized by cleavage of linoleic acid and is a coenzyme of oxoglutarate dehydrogenase (ketoglutarate dehydrogenase complex).

Alpha lipoic acid is marketed in the US as an over-the-counter nutritional antioxidant supplement, alone or in combination with other antioxidants. In medicine, alpha lipoic acid has been shown to reduce symptoms of diabetic polyneuropathy, and several clinical trials established some efficacy and an excellent safety profile in this patient population ⁸⁾.

Alpha-lipoic acid is a type of antioxidant and chemoprotective agent. Alpha-lipoic acid is an antioxidant — a substance the body can use to prevent or manage a tissue-damaging process called oxidative stress. Oxidative stress is a part of the diabetic neuropathy disease process. Alpha-lipoic acid also has been shown to reduce blood sugar levels. Alpha lipoic acid is being studied for its ability to protect normal cells from the side effects of chemotherapy and prevent peripheral neuropathy (numbness, tingling, burning, and weakness in the hands or feet) ⁹⁾. A few small clinical trials have tested the treatment effect of alpha-lipoic acid given either as a supplement or intravenously. People with diabetic neuropathy had reduced pain, improvements in nerve function tests and improvements in other clinical measures of diabetic neuropathy (Han T, Bai J, Liu W, et al. A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy. European Journal of Endocrinology. 2012;167(4):465-471.)). But long-term studies are needed.

Alpha-lipoic acid is being studied for its effect on complications of diabetes, including diabetic macular edema (an eye condition that can cause vision loss) and diabetic neuropathy (nerve damage caused by diabetes).

• In a 2011 study of 235 people with type 2 diabetes, 2 years of supplementation with alpha-lipoic acid did not help to prevent macular edema ¹⁰⁾.
• A 2016 assessment of treatments for symptoms of diabetic neuropathy that included 2 studies of oral alpha-lipoic acid, with a total of 205 participants, indicated that alpha-lipoic acid may be helpful ¹¹⁾.

Alpha-lipoic acid supplements are generally considered safe when taken as recommended. However, toxicity might occur if you take this supplement when you have a significant thiamin (vitamin B-1) deficiency. Don’t use alpha-lipoic acid if you’re a heavy user of alcohol.

Alpha lipoic acid foods

Almost all foods contain alpha lipoic acid, but slightly more so in organ meats (kidney, heart, liver), spinach, broccoli, peas, brussel sprouts, and rice bran.

What is alpha lipoic acid used for

Alpha-lipoic acid for diabetic peripheral neuropathy

People with both types of diabetes develop multisystem complications ¹²⁾, one of the most frequent being diabetic peripheral neuropathy. Diabetic peripheral neuropathy has an estimated prevalence in the diabetic population of between 10% and 100% depending upon the data source and ascertainment methodology ¹³⁾.

Diabetic peripheral neuropathy is defined as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” ¹⁴⁾. Diabetic peripheral neuropathy may be asymptomatic and insidious at onset. The most common symptom of diabetic peripheral neuropathy is neuropathic pain, which occurs in up to 50% of people with diabetic peripheral neuropathy and is the most frequent reason for seeking medical care ¹⁵⁾. Painful symptoms are varied and include pain, tingling, burning sensations, paresthesia, shooting or lancinating pains, aching, and contact pain (allodynia) provoked by clothing ¹⁶⁾.

Diabetic peripheral neuropathy can be classified clinically as either focal or diffuse. Diffuse disease can affect the sensorimotor or the autonomic nervous systems or both. Sensorimotor disease can involve large or small nerve fibers ¹⁷⁾, is usually predominantly sensory, and may be painful.

Distal symmetrical sensorimotor polyneuropathy is the most common form of diabetic peripheral neuropathy, with a reported prevalence in diabetes mellitus ranging from 28.5% to 45%, increasing with age and disease duration ¹⁸⁾. Distal symmetrical sensorimotor polyneuropathy represents a major cause of morbidity and the leading source of diabetes-related hospitalizations and non-traumatic amputations. It is also accountable for considerable physical disability, altered quality of life, and increased mortality ¹⁹⁾.

Diabetic peripheral neuropathy complications are also a major threat to the general well-being and quality of life of people with diabetes. Numbness caused by diabetic peripheral neuropathy, along with retinopathy and vestibular dysfunction, increase the risk of falls two- to three-fold compared to people without diabetic peripheral neuropathy ²⁰⁾. People with diabetic peripheral neuropathy are also seven times more likely to develop foot ulcerations ²¹⁾. Foot ulcerations further predispose to active or passive soft tissue infection, which can progress to bone infection and subsequent lower extremity amputation ²²⁾. Diabetic peripheral neuropathy, peripheral vascular disease, and soft tissue and bone deformity are serious complications that make diabetes the leading cause of lower extremity amputation ²³⁾.

Diabetic peripheral neuropathy symptoms are usually assessed using patient-reported outcome measures that quantify discomfort, sleep disturbances, and quality of life ²⁴⁾.

The pathophysiology of diabetic peripheral neuropathy is not fully understood, and very likely to be multifactorial (genetic, environmental, behavioral, metabolic, neurotrophic, and vascular) ²⁵⁾. Oxidative stress generated by excess free-radical formation or errors in antioxidant protection, or both, is thought to be important in the pathogenesis ²⁶⁾. Good glycemic control reduces the risk of developing diabetic peripheral neuropathy, but glycemic control is not always achievable and is usually not sufficient to halt diabetic peripheral neuropathy progression ²⁷⁾.

Diabetic peripheral neuropathy pathophysiology can mainly be explained as neural dysfunction caused by the interplay of decreased blood flow to nerves as a result of hyperglycaemia, and increased oxidative stress, which induces local inflammatory reactions through reactive oxygen species (ROS) ²⁸⁾. Prolonged hyperglycemia simultaneously activates multiple pathways. It promotes the following:

• Activation of polyol and protein kinase pathways that leads to reduced nicotinamide adenine dinucleotide phosphate (NADPH) and subsequent depletion of glutathione and nitric oxide ²⁹⁾.
• Angiogenesis driven by the vascular endothelial growth factor pathway.
• Basement membrane thickening and endothelial proliferation (via transforming growth factor-β and nuclear factor – kappa B), which cause altered capillary permeability and local hypoxia.
• Activation of the hexosamine pathway and shunting of fructose-6-phosphate from the glycolytic pathway.
• Modified gene expression for glucose transporters and glucokinase ³⁰⁾.

Generation of reactive oxygen species and advanced glycosylation end-products activates the same NFkB pathway, which increases oxidative stress with additional nicotinamide adenine dinucleotide phosphate (NADPH) depletion. Oxidative stress also induces poly (ADP-ribose) polymerase activation, which sequentially results in supplementary nicotinamide adenine dinucleotide depletion, positive loop activation of the protein kinase pathway, and promotes inflammation ³¹⁾. All these pathways promote mitochondrial dysfunction, which in turn is followed by apoptosis, axonal degeneration, and axonal death. Local pro-inflammatory cytokines induced by oxidative stress promote macrophage recruitment with subsequent glial failure, myelin breakdown, and impaired nerve regeneration ³²⁾.

The clinical consequences of this hyperglycemia-induced inflammatory and oxidative state are axonal dystrophy, decreased nerve conduction velocity, diminished neurovascular flow and, ultimately, small- and large-fiber neuropathy ³³⁾.

Current management of diabetic peripheral neuropathy consists of three therapeutic approaches. The main target is prevention, through control of fasting and postprandial glucose ³⁴⁾. Medications that target symptoms and disease-modifying treatments are used in the treatment of people with diagnosed diabetic peripheral neuropathy. Symptomatic treatments target pain; they include anticonvulsants, tricyclic antidepressants ³⁵⁾, serotonin and noradrenaline reuptake inhibitors ³⁶⁾, opioids and opioid-like drugs ³⁷⁾, systemic local anaesthetics ³⁸⁾, nonsteroidal anti-inflammatory agents ³⁹⁾, and non-drug therapies such as transcutaneous electrical nerve stimulation (TENS), pulsed radiofrequency sympathectomy ⁴⁰⁾, and acupuncture ⁴¹⁾.

Disease-modifying treatments aim to prevent, slow, or reverse diabetic peripheral neuropathy progression by reduction of oxidative stress and inhibition of the polyol, hexosamine, protein kinase, advanced glycosylation product, and poly (ADP-ribose) polymerase pathways.

Alpha lipoic acid acts as a scavenger of reactive oxygen species and has antioxidant properties that could block the oxidative stress–inflammation pathways activated in diabetic peripheral neuropathy ⁴²⁾. Alpha lipoic acid could therefore be useful both in prevention and treatment of diabetic peripheral neuropathy ⁴³⁾.

Early in test tube studies showed that alpha lipoic acid and its reduced form, dihydrolipoic acid (DHLA), scavenge reactive oxygen species, including hydroxyl radicals, hypochlorous acid, and singlet oxygen ⁴⁴⁾. In animal studies also indicated that alpha lipoic acid decreases oxidative stress ⁴⁵⁾, participates in restoring endogenous cellular antioxidant levels and reducing pro-inflammatory pathways ⁴⁶⁾ and may influence the regeneration of vitamins C and E ⁴⁷⁾.

The benefit of alpha lipoic acid in people with diabetes could range beyond antioxidant and anti-inflammatory effects. The therapeutic properties of alpha lipoic acid might include the ability to restore glucose availability and increase insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism in insulin-resistant muscle cells ⁴⁸⁾. Alpha lipoic acid has therefore been a candidate for clinical study in diabetic peripheral neuropathy.

The interaction of alpha lipoic acid with regulatory components of the insulin signaling cascade has proved functionally beneficial to skeletal muscle glucose uptake, whole-body glucose tolerance, and helpful against insulin resistance in animal models ⁴⁹⁾. Improvements in glucose disposal were also observed in human patients with type 2 diabetes receiving alpha lipoic acid either intravenously or orally ⁵⁰⁾. Several clinical trials have been conducted to measure the efficacy of racemic alpha lipoic acid in decreasing symptoms of diabetic polyneuropathies; these are the “alpha-lipoic acid in diabetic neuropathy” (Aalpha lipoic acidDIN) trials and the “symptoms of diabetic polyneuropathy” (SYDNEY) trials. alpha lipoic acid was given orally, intravenously, or i.v. with oral follow-up. A meta-analysis of four clinical trials using i.v. alpha lipoic acid, including Aalpha lipoic acidDIN, SYDNEY, and the first 3 weeks of Aalpha lipoic acidDIN III, showed a significant improvement in diabetic polyneuropathies of the feet and lower limbs in patients infused with alpha lipoic acid 600 mg/day, for three weeks ⁵¹⁾. Diabetic patients in the Aalpha lipoic acidDIN II trial were administered alpha lipoic acid i.v. at 600 or 1200 mg/day for 5 days, then oral alpha lipoic acid for 2 years, resulting in improved indices of neuropathy ⁵²⁾. Patients in the Aalpha lipoic acidDIN III study received alpha lipoic acid (600 mg/day i.v.) or placebo for three weeks, followed by oral alpha lipoic acid (600 mg t.i.d.) or placebo for 6 months. The oral phase of this trial, however, was without clinically significant benefits ⁵³⁾. One possible conclusion from these studies was that alpha lipoic acid administered intravenously was more efficacious than oral alpha lipoic acid, which may be due to either greater bioavailability or poor solubility of the medication in the stomach acid. However, some additional studies have found that oral alpha lipoic acid is very effective. For example, the oral pilot (ORPIL) study showed a reduction in diabetic polyneuropathic symptoms after three weeks with 600 mg alpha lipoic acid three times daily ⁵⁴⁾. While the first SYDNEY trial used i.v. alpha lipoic acid ⁵⁵⁾, the SYDNEY II study used oral alpha lipoic acid at 600, 1200, or 1800 mg once daily for 5 weeks ⁵⁶⁾; consequently, both studies showed significant improvements in neuropathic endpoints.

Alpha lipoic acid and weight loss

Previous studies have suggested anti-obesity properties of alpha lipoic acid ⁵⁷⁾, ⁵⁸⁾. In animal studies, it was shown that alpha lipoic acid supplementation promotes the reduction of body weight and fat mass by decreasing food intake and enhancing energy expenditure, possibly by suppressing hypothalamic AMP-activated protein kinase (AMPK) activity ⁵⁹⁾. However, studies in humans with alpha lipoic acid supplementation are limited, and the results have been inconsistent. Some clinical trials have shown that alpha lipoic acid supplementation may help overweight or obese individuals lose weight ⁶⁰⁾, while other studies have observed no effects of alpha lipoic acid on weight ⁶¹⁾, ⁶²⁾. Nevertheless, alpha lipoic acid appears to have a wide range of beneficial effects on obesity related conditions such as insulin resistance, metabolic syndrome, and type II diabetes, including their complications such as vascular damage ⁶³⁾.

Cumulative results in a 2017 meta-analysis showed significant reduction of body weight and BMI (body mass index) with alpha lipoic acid treatment compared to placebo, regardless if it was used for weight loss or other purposes ⁶⁴⁾. Small but significant reduction of body weight with alpha lipoic acid intervention is in line with previous open label studies that have well documented the effectiveness of alpha lipoic acid on weight loss in overweight and obese individuals ⁶⁵⁾, ⁶⁶⁾ and randomized studies ⁶⁷⁾, ⁶⁸⁾, ⁶⁹⁾, ⁷⁰⁾. These results conclude that alpha lipoic acid supplementation with diet intervention may provide more beneficial effects on body weight management in overweight and obese individuals.

Studies in the 2017 meta-analysis explored various doses of alpha lipoic acid intervention (300 mg/day to 1800 mg/day) on different intervention durations (8 weeks to 52 weeks). Only one placebo controlled study compared the effectiveness of different doses of alpha lipoic acid on body weight ⁷¹⁾. Koh et al. ⁷²⁾ explored the effects of 1200 mg/day and 1800 mg/day alpha lipoic acid intervention on body weight loss. Koh et al. ⁷³⁾ found that the higher dose of alpha lipoic acid resulted in significant weight loss and BMI reduction throughout the study compared to placebo. The lower dose of alpha lipoic acid led to significant weight loss in the first weeks of this study, however this effect was not sustainable through the entire duration of the study. From these findings, it can argue that the effect of alpha lipoic acid on body weight is limited to the short term, especially when it is used at lower doses with an adaptation mechanism taking over later. This may have implications for future study designs, for example phasic use of the medication may be tried ⁷⁴⁾.

In summary, findings from 2017 ⁷⁵⁾ and 2018 meta-analyses ⁷⁶⁾ suggest that alpha lipoic acid may be a useful supplementation for weight loss in overweight and obese individuals in reducing body weight and BMI, but has no significant effect on waist circumference. The benefits of alpha lipoic acid compared to placebo appear smaller than that of available prescription weight loss medications ⁷⁷⁾. However, alpha lipoic acid can be considered in clinical practice due to its benign side-effect profile, other beneficial effects such as in diabetic neuropathy, and lower side effects comparing to the available weight loss medications. Further research is needed to examine the effect of different doses and the long-term benefits of alpha lipoic acid on metabolic parameter in unhealthy obese individuals.

Alpha lipoic acid benefits

Effects of alpha lipoic acid on the vascular system

Vascular endothelial cells, which line the blood vessel lumen, form the physical interface between the blood and the vessel wall, preventing platelet adhesion and regulating blood vessel patency. The elasticity of the vessel wall is regulated by nitric oxide (NO), a gas produced by endothelial nitric oxide synthase (eNOS). Loss of endothelial nitric oxide synthase (eNOS) activity causes endothelial dysfunction due to nitric oxide (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 alpha lipoic acid, improve the redox state of the plasma and endothelium-dependent nitric oxide (NO)-mediated vasodilation ⁷⁸⁾. But the question remains as to how alpha lipoic acid achieves this significant result. It is known, for instance, that the PI3K/Akt signaling pathway, cascading from the insulin receptor and stimulated by alpha lipoic acid, plays an important role in eNOS activation ⁷⁹⁾. Treating human aortic endothelial cells with alpha lipoic acid significantly increases NO synthesis ⁸⁰⁾, and alpha lipoic acid improves the loss in eNOS phosphorylation seen in aorta from aged rats through Akt ⁸¹⁾. Furthermore, i.p. injection of alpha lipoic acid into old rats restores vasorelaxation, characterized by an increased phosphorylation of both eNOS and Akt, as well as a decrease in neutral sphingomyelinase activity and a concomitant decrease in ceramide ⁸²⁾. These studies using in vitro and animal models strengthen our understanding of the role of the insulin signaling pathway in vasomotor function, and underscore the health potential of alpha lipoic acid therapy. Thus far, however, only the ISalpha lipoic acidND (ISLAND) clinical trial has examined alpha lipoic acid as a potential remedy for endothelial dysfunction ⁸³⁾. This trial was a randomized, double-blind, placebo-controlled study comparing alpha lipoic acid to irbesartan, an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Results showed that the oral administration of alpha lipoic acid (300 mg/day for 4 weeks) and/or irbesartan (150 mg/day for 4 weeks) to 14-15 patients with metabolic syndrome improved endothelial-dependent flow-mediated vasodilation, which was measured by using the noninvasive brachial artery reactivity test. However, larger and more long-term studies are necessary in order to establish the efficacy of alpha lipoic acid as a therapeutic for vascular endothelial dysfunction.

Alpha lipoic acid as a hypotensive agent

Hypertension is a risk factor for stroke, heart attack and arterial aneurysm, and a leading cause of chronic kidney failure. Even moderate elevation in arterial blood pressure correlates with shortened life expectancy. The rationale for the therapeutic use of alpha lipoic acid against hypertension stemmed from its ability to increase tissue GSH levels and prevent deleterious sulfhydryl group modification in Ca2+ channels. Feeding alpha lipoic acid to hypertensive rats normalized systolic blood pressure and cytosolic free Ca2+, and attenuated adverse renal vascular changes ⁸⁴⁾. The role of alpha lipoic acid in regenerating reduced GSH was further put forth by El Midaoui and de Champlain ⁸⁵⁾ who associated the restoration of glutathione peroxidase activity seen in alpha lipoic acid-fed rats with the normalization of aortic superoxide production and blood pressure. It was also suggested that dietary alpha lipoic acid inhibits renal and vascular overproduction of endothelin-1, a vasoconstrictor secreted by the endothelium ⁸⁶⁾. Because NO is the main vasodilator in conduit arteries and the recent finding that alpha lipoic acid improves endothelial NO synthesis ⁸⁷⁾, pharmacologists have a new rationale to investigate the role of alpha lipoic acid and high blood pressure. Clinically, alpha lipoic acid administration (in combination with acetyl-L-carnitine) showed some promise as an antihypertensive therapy by decreasing systolic pressure in high blood pressure patients and subjects with the metabolic syndrome ⁸⁸⁾. In contrast, the administration of alpha lipoic acid (300 mg/day for 4 weeks) to patients with the metabolic syndrome had no significant effect on blood pressure compared to placebo group ⁸⁹⁾.

Alpha lipoic acid as an anti-inflammatory agent

Inflammation results from the innate biological response of vascular tissues to harmful agents, such as pathogens or irritants. It is an attempt by the organism to remove the injurious stimuli, protect the surrounding tissue, and initiate the healing process. However, unabated chronic inflammation also contributes to a host of diseases, such as atherosclerosis, asthma, and rheumatoid arthritis. Elevated levels of oxidative stress play an important role in chronic inflammation. Oxidative stress-associated inflammation is thought to provoke early vascular events in atherogenesis, including the upregulation of vascular adhesion molecules and matrix metalloproteinase activity. These events require the activation of NF-kappaB, a transcription factor that induces expression of many genes involved in inflammation and endothelial cell migration. Given the oxidative nature of inflammation, therapeutic strategies aimed at mitigating oxidant production and oxidative damage have been investigated for decades in various models of inflammation.

In keeping with this strategy, alpha lipoic acid has been studied for its antioxidant properties in cytokine-induced inflammation; it is also widely known as an inhibitor of NF-kappaB ⁹⁰⁾. Results show that alpha lipoic acid lowers expression of vascular cell adhesion molecule-1 (VCAM-1) and endothelial adhesion of human monocytes ⁹¹⁾, and inhibits NF-kappaB-dependent expression of metalloproteinase-9 in vitro ⁹²⁾. Similarly, alpha lipoic acid (25-100 μg/ml = 122-486 μM) prevents the upregulation of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in spinal cords and in TNF-alpha stimulated cultured brain endothelial cells ⁹³⁾. Collagen-induced arthritis was attenuated by alpha lipoic acid (10-100 mg/kg i.p.) in DBA/1 mice by reduction of inflammatory cytokines like TNF-alpha, and partial inhibition of NF-kappaB binding to DNA ⁹⁴⁾. In this study, alpha lipoic acid also inhibited osteoclast formation, suggesting that alpha lipoic acid may be useful in the prevention of bone erosion and joint destruction in rheumatoid arthritis. In another study, pretreatment of collagen sheets with alpha lipoic acid (2 mg) prior to implantation decreased TNF-alpha-induced bone resorption in ICR mice ⁹⁵⁾. In experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis) alpha lipoic acid-treated mice showed marked improvement in central nervous system infiltrating T-cells and macrophages, decreased demyelination and spinal cord expression of adhesion molecules (ICAM-1 and VCAM-1) ⁹⁶⁾. The downregulation of surface CD4 seen in alpha lipoic acid-treated blood mononuclear cells was proposed to account, at least in part, for the modulation of inflammatory cell infiltration into the central nervous system ⁹⁷⁾. This is because co-receptor CD4 amplifies the signal generated at the T-cell receptor by recruiting lymphocyte protein kinase Lck, which in turn triggers a cascade of events leading to T-cell activation. Interestingly, DHalpha lipoic acid did not downregulate CD4 from the surface of human peripheral blood mononuclear cells ⁹⁸⁾. As an alternative or in addition to CD4 downregulation, the immunomodulatory properties of alpha lipoic acid may involve the upregulation of cAMP in T-cells and natural killer cells ⁹⁹⁾. Cell migration and neovascularization were also inhibited by alpha lipoic acid (86 μg/day in drinking water) in c57/black mice injected with Kaposi’s sarcoma in a matrigel sponge, as well as in nude mice injected with KS cells ¹⁰⁰⁾. In a mouse model of bronchial asthma, dietary alpha lipoic acid significantly attenuated airway hyper-responsiveness, lowered the eosinophil count among bronchoalveolar lavage cells, and significantly improved pathologic lesion scores of the lungs ¹⁰¹⁾. alpha lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells via a mechanism seemingly distinct from antioxidants, such as ascorbate or reduced GSH, but consistent with the workings of a metal chelator ¹⁰²⁾. Recently, the inhibition of endotoxin-induced acute inflammation by alpha lipoic acid was associated with the stimulation of the PI3K/Akt pathway ¹⁰³⁾.

To date, the anti-inflammatory properties of alpha lipoic acid have rarely been investigated in humans. The ISalpha lipoic acidND (ISLAND) trial showed a 15% significant decrease in serum interleukin-6 levels following 4 weeks of supplementation with alpha lipoic acid (300 mg/day) ¹⁰⁴⁾. This finding may prove important to human health because interleukin-6 is a recognized marker of inflammation in coronary atherosclerotic plaques, and also regulates the expression of other inflammatory cytokines, such as interleukin-1 and TNF-alpha ¹⁰⁵⁾. However, the body of evidence is currently too limited to be conclusive.

Alpha lipoic acid dosage

Clinical trials have used different forms of administration and treatment durations. Alpha lipoic acid dosage ranges from 200 mg/day to 1800 mg/day, administered intravenously or orally. Although the maximum dose of alpha lipoic acid has not been defined, previous studies have shown that alpha lipoic acid can be used safely up to as high as 1800 mg/day ¹⁰⁶⁾.

However, despite the evidence attesting to its safety in moderate doses, precautions for the oral intake of alpha lipoic acid have also been voiced. Cakatay et al. ¹⁰⁷⁾ conducted a series of experiments in aged rats with intraperitoneal administration of racemic alpha lipoic acid (100 mg/kg body weight per day for 2 weeks) and showed that this high chronic dose (the equivalent of 5 to 10 grams per day in humans) increased plasma lipid hydroperoxide levels and oxidative protein damage ¹⁰⁸⁾. Alpha lipoic acid-mediated protein damage was noted in rat heart ¹⁰⁹⁾ and brain ¹¹⁰⁾, but lipid hydroperoxide levels were beneficially decreased in both these organs. Apparently in keeping with its metal chelating abilities, this group noted that alpha lipoic acid lowered selenium levels in the serum, heart, brain, and muscle; manganese was lowered only in the heart, but increased in the brain and muscle ¹¹¹⁾. Thus, while intake of moderate doses of alpha lipoic acid have relatively few adverse side-effects, alpha lipoic acid may mediate oxidative insult at higher doses or when administered intraperitoneally. More research is therefore warranted regarding both the safety and optimal dose of alpha lipoic acid.

Alpha lipoic acid side effects

The most commonly reported side effects that were related with alpha lipoic acid in these two studies ¹¹²⁾, ¹¹³⁾ were gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, and diarrhea ¹¹⁴⁾ and dermatological symptoms, such as urticaria and itching sensation. One subject in the 1800 mg/d alpha-lipoic acid group and 3 subjects in the 1200 mg/d alpha-lipoic acid group withdrew because of itching sensation ¹¹⁵⁾.