At the forefront of alternative medicine is Alpha-lipoic acid (ALA), also known as thioctic acid, which has been studied to treat various medical conditions, including type-2 diabetes, burning mouth syndrome, fibromyalgia, chronic fatigue syndrome, neuropathy, cancer, and atherosclerosis.

Type-2 Diabetes

Type-2 diabetes is associated with high levels of oxidative stress. Specifically, diabetes impairs endothelial nitric oxide synthase activity and increases the production of reactive oxygen species, thus resulting in diminished nitric oxide bioavailability and increased oxidative stress. Alpha-lipoic acid is a disulfide compound produced in small quantities in cells and serves as an antioxidant at pharmacological doses. It has been shown to improve insulin sensitivity in type-2 diabetic patients due to its anti-inflammatory and hypoglycemic properties.

In one recent open-label study in which lean and obese individuals with type-2 diabetes were administered 600 mg ALA by mouth twice per day for four weeks, treatment with ALA was associated with increased glucose effectiveness in both lean and obese diabetics relative to non-diabetic lean and obese controls.

Lean diabetic patients were also found to have a higher degree of insulin sensitivity and lower fasting glucose. Furthermore, after ALA treatment, lactate and pyruvate before and after glucose loading were approximately 45% lower in obese and lean diabetics, leading researchers to conclude that treatment with ALA prevents hyperglycemia-induced increments serum lactate and pyruvate levels and increases glucose sensitivity. As the result of another study, researchers concluded that oral treatment with 800 mg/day for 4 months might improve cardiac autonomic dysfunction in type-2 diabetics. Intravenous administration of ALA has also been beneficial in type-2 diabetes. In a small, randomized, controlled trial, 13 patients received either 1000 mg ALA or normal saline in small, randomized, controlled trial. Both groups were comparable in age, BMI, and duration of diabetes. They also had similar degrees of insulin resistance at baseline. After administration of ALA, patients experienced a significant increase in insulin-stimulated glucose disposal. The metabolic clearance rate for glucose rose by about 50% in the treatment group, while the control group did not experience any significant change. Similar results, specifically a 30% increase in insulin-stimulated glucose disposal, were demonstrated in an uncontrolled pilot trial administered 500 mg ALA intravenously per day over 10 days.

In another study, while both oral and intravenous administration of ALA led to improvements in insulin sensitivity, the gains associated with oral administration were minimal (about 20%) compared to the improvements seen with intravenous administration. The intravenous route of administration remained superior, despite higher doses of oral ALA (up to 1800 mg) and longer treatment time (30 days oral vs. 10 days IV).

Burning Mouth Syndrome

As the name implies, burning mouth syndrome (BMS) is a chronic condition characterized by burning in the oral cavity. The syndrome is frequently associated with hyposalivation, xerostomia, and taste disturbances. While the exact etiology is unknown, BMS has been related to psychological factors such as anxiety, depression, and cancer phobia, as well as systemic conditions such as menopause, nutrient deficiencies (B vitamins including folate, iron), hypothyroidism, diabetes mellitus (type-2 more than type-1), and pharmacological use of anti-hypertensive agents. Recent studies have also suggested that the cause of BMS may be neurological and that BMS may be neuropathy.11 Because of ALA’s role in treating diabetes and diabetic neuropathy, researchers have explored its use in BMS management.

One double-blind, randomized, placebo-controlled trial administered 400 mg ALA or 400 mg ALA plus vitamins to two treatment groups and placebo to a control group over 8 weeks. At the end of the study, all three groups had significant reductions in the visual analog scale (VAS) and the mixed affective/evaluative subscale of the McGill Pain Questionnaire (MPQ). No significant differences were observed between the three groups, leading researchers to conclude that there may be no therapeutic role for ALA in BMS management. Another randomized, controlled trial showed no significant differences between the ALA group (800 mg per day for 8 weeks) and the placebo group. In contrast to these studies, several other studies have assessed the efficacy of ALA in the treatment of BMS, and results have been promising. In one study, 64% of ALA patients reported clinical benefit at a dosage of 600 mg per day, while 27.6% of the placebo group demonstrated a reduction in BMS symptoms.

Ten of the ALA patients who reported benefit, 68.75% maintained their improvement one month after treatment. Another study revealed significant improvement in BMS symptomatology at a dosage of 600 mg per day orally for 20 days followed by 200 mg per day for 10 days. Up to 66% of ALA patients reported benefit, while 15% of the placebo group reported benefit, and 66% of those who tried the placebo then switched to ALA also reported benefit. In a retrospective review of medical records, 35% of patients reported benefit from taking ALA.

Researchers found that duration of the syndrome, intensity of symptoms,10, and previous treatment with psychotropic medication16 influence the likelihood of benefit with ALA in the management of BMS.


Fibromyalgia is a functionally disabling disorder characterized by widespread pain and frequently accompanied by sleep disturbance, fatigue, depression, and cognitive dysfunction. The commonly prescribed analgesics provide incomplete relief, possibly due to insufficient efficacy and dose-limiting adverse events. Specifically, the side effects of the drugs aggravate some symptoms of the disease they are prescribed to treat, namely fatigue and cognitive dysfunction. These complications have led researchers to search for new treatment options. While the exact etiology of fibromyalgia is unknown, recent studies have provided evidence that oxidative stress and inflammation play a role in the pathophysiology of fibromyalgia. Alpha-lipoic acid, which acts as a potent antioxidant at pharmacologic doses, has also been demonstrated to have anti-inflammatory effects on the body.

ALA is rarely present in tissues above micromolar levels and is unlikely to function as a primary cellular antioxidant when administered orally. Instead, its potent antioxidant properties appear to be attributable to the fact that ALA increases cellular glutathione levels by regulating glutathione synthesis and alleviating oxidative stress. ALA may exert its anti-inflammatory effects by scavenging free radicals and down-regulating pro-inflammatory redox-sensitive signal transduction processes, including nuclear factor kappa B translocation, leading to decreased release of other free radicals and cytotoxic cytokines. While no randomized controlled trials evaluating the efficacy of ALA in the treatment of fibromyalgia has been completed, one is currently underway, and the research that we do have available suggests that its results will be favorable.

Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS), also referred to as myalgic encephalomyelitis, is an illness characterized by debilitating and relapsing fatigue and often accompanied by neuropsychiatric concerns, such as depression, irritability, sleep disorders, autonomic symptoms, and neurocognitive defects, as well as psychosomatic concerns, such as malaise, hyperalgesia, irritable bowel, and muscle pain and tension. Some have suggested that CFS should be renamed better to reflect the oxidative and inflammatory nature of the condition. Oxidative stress and inflammation25 play essential roles in the pathogenesis of CFS. Some have also suggested that mitochondrial dysfunction may play a role in the disease. Researchers have studied ALA in CFS treatment because of its antioxidant and anti-inflammatory properties and its role in mitochondrial function. ALA is rarely present in tissues above micromolar levels and is unlikely to function as a primary cellular antioxidant when administered orally. Instead, its potent antioxidant properties appear to be attributable to the fact that ALA increases cellular glutathione levels by regulating glutathione synthesis and alleviating oxidative stress.

ALA may exert its anti-inflammatory effects by scavenging free radicals and down-regulating pro-inflammatory redox-sensitive signal transduction processes, including nuclear factor kappa B translocation, leading to decreased release of other free radicals and cytotoxic cytokines. Evidence implicates mitochondrial dysfunction, impaired oxidative phosphorylation, and abnormally high lactate levels in the pathophysiology of CFS. ALA is a critical cofactor in mitochondrial alpha-ketoacid dehydrogenases, including pyruvate dehydrogenase.

As a result, it is essential in mitochondrial oxidative-decarboxylation reactions and plays a crucial role in mitochondrial activity and energy metabolism.28 Furthermore, supplementation with ALA has been demonstrated to lead to a decrease in abnormally elevated lactate levels, likely due to its role in stabilizing and regulating pyruvate dehydrogenase and other mitochondrial 2-ketoacid dehydrogenase complexes. Although no randomized controlled trials are using ALA to treat chronic fatigue syndrome, when we consider its widespread use as a safe nutrient with the ability to reduce oxidative stress, decrease inflammation, and support mitochondrial function, its use in addressing chronic fatigue syndrome appears to be justified.


As a potent antioxidant, ALA appears to retard or reverse the progression of peripheral diabetic neuropathy. Diabetic neuropathy, which is diagnosed in diabetic patients with peripheral nerve dysfunction when other causes of neuropathy have been excluded, is believed to be due to increased flux through the polyol pathway, leading to accumulation of sorbitol, a reduction in myoinositol, and an associated reduced Na+-K+-ATPase activity, as well as nitric oxide inactivation by increased oxygen free radical activity leading to endoneurial microvascular damage and hypoxia. In a study designed to assess the efficacy of ALA in the improvement of sural nerve conduction velocity and amplitude in patients with diabetic neuropathy, participants were administered 600 mg ALA per day. After the study, ALA failed to improve sural nerve conduction velocity and amplitude; however, researchers noted that their study results should be interpreted with caution due to the study’s uncontrolled nature, researchers’ failure to assess patient compliance, small sample size, and short study duration.

Several studies demonstrate the beneficial effects of ALA in the management of peripheral neuropathy. In one study that compared results of patients who were administered 600 mg, 1200 mg, and 1800 mg ALA by mouth, patients reported significant improvements in stabbing and burning pain (subset of total symptom score, or TSS), the Neuropathy Symptoms and Change (NSC) score, and the patients’ global assessment of efficacy. Benefits were not remarkably different between the three groups, suggesting that oral dosage of 600 mg provides the most favorable cost-benefit ratio.

One systematic review of the literature concluded that, when administered intravenously at a dosage of 600 mg per day for 3 weeks, ALA leads to a significant and clinically relevant reduction in neuropathic pain (grade of recommendation A). In another study that administered ALA orally at a dosage of 600 mg per day for 40 days, ALA administration was found to be associated with reductions in neuropathic symptoms [as demonstrated by reduced Neuropathy Symptom Score (NSS), Subjective Peripheral Neuropathy Screen Questionnaire (SPNSQ), and douleur neuropathic (DN4) questionnaire scores at day 40 versus baseline] and in triglycerides. These researchers also studied orally administered ALA and stated that it was unclear whether or not the improvements seen after 3-5 weeks at an oral dosage of 600 mg were clinically relevant.

Other systematic reviews maintained that oral and intravenous administration might provide similar benefits. For example, one stated that an oral or intravenous ALA dose of at least 600 mg per day resulted in a 50% reduction in the TSS35. A more recent (2018) systematic review on ALA in the management of diabetic peripheral neuropathy concluded that current data provide evidence for the benefits of ALA in diabetic peripheral neuropathy treatment at a dose of 600 mg per day, either intravenously or orally, for at least 3 weeks with minimal side effects.


Most cancer cells utilize aerobic glycolysis, which is the preferential conversion of glucose to lactate for ATP generation, even when oxygen is present. This phenomenon, referred to as the Warburg effect, can be seen in cancer cells of different origins. Because aerobic glycolysis is grossly inefficient, producing only two molecules of ATP per molecule of glucose, cancer cells metabolize large amounts of glucose to keep up with their energy demands. Researchers hypothesized that by shifting cancer cell metabolism toward complete oxidation of glucose and away from aerobic glycolysis, they could effectively reduce the proliferation of cancer cells.

Because ALA is a cofactor of pyruvate dehydrogenase, it was a crucial consideration in nutrients that can steer energy production away from aerobic glycolysis and toward complete glucose oxidation, resulting in a decrease in lactate production and inhibition of glycolysis. Pre-clinical studies designed to investigate ALA’s role in this capacity demonstrated that ALA could reduce cancer cell viability and proliferation, as well as lactate production. ALA also induced apoptosis in the following cell lines: neuroblastoma cell lines Kelly, SK-N-SH, Neuro-2a, and the breast cancer cell line SkBr3. ALA also inhibits cancer cell proliferation and induces apoptosis by other mechanisms. The nutrient was found to inhibit cell proliferation and induce apoptosis in MDA-MB-231 breast cancer cell lines and to inhibit the colony-forming ability of the highly invasive MDA-MB-231 and 4T1 breast cancer cells. ALA inhibited the migration and invasion of metastatic breast cancer cells, at least in part through inhibiting ERK1/2 and AKT signaling.

Additionally, ALA has been shown to effectively induce apoptosis in human colon cancer cells (HT-29) by a pro-oxidant mechanism that is initiated by an increased uptake of oxidizable substrates into mitochondria,40 and ALA dramatically decreased non-small cell lung cancer (NSCLC) cell proliferation by down-regulating growth factor receptor-bound protein 2 (Grb2). Studies evaluating the efficacy of ALA in the inhibition/treatment of cancer are limited to experimental data; however, the research appears to be very promising.


Oxidative stress is the primary cause of many cardiovascular diseases, including atherosclerosis. As we age, oxidative stress increases by increasing the production of reactive oxygen species and a decrease in the body’s antioxidant defenses. Improved cardiovascular conditions like atherosclerosis parallel this increase in oxidative stress. Research demonstrates that antioxidants help to decrease the incidence of atherosclerosis. ALA exerts potent antioxidant effects on the body and has been studied in experimental models for its ability to prevent and reverse atherosclerosis.

In one study, Watanabe heritable hyperlipidemic rabbits were fed with high cholesterol chow for 6 weeks and then randomized to receive either high cholesterol diet alone or high cholesterol diet combined with 20 mg/kg/day of ALA for 12 weeks. At the end of the 12 weeks, researchers found that ALA decreased body weight by 15 ± 5% without alterations in lipid parameters and reduced atherosclerotic plaque in the abdominal aorta with morphological analysis revealing reduced lipid and inflammatory cell content. Furthermore, ALA improved vascular reactivity (as indicated by decreased constriction to angiotensin II and increased relaxation to acetylcholine and insulin), inhibited NF-κB activation, and reduced oxidative stress and expression of key adhesion molecules in the vasculature.

An unrelated study demonstrated the cardioprotective effects of ALA. Eighteen adult male New Zealand White rabbits were randomly assigned to three groups for 10 weeks. One group was fed with standard chow (control group), one with a 1% high cholesterol diet to induce hypercholesterolemia, and the third group was fed a 1% high cholesterol diet plus 4.2 mg/bodyweight of ALA. At the end of the study, blood total cholesterol (TCHOL) and low-density lipoprotein (LDL) levels were significantly lower in the ALA group than those that consumed a high cholesterol diet alone. The ALA group also had a less atherosclerotic plaque in their aortas than the group that consumed a high cholesterol diet alone, leading researchers to conclude that, apart from its antioxidant activity, ALA may also exert a lipid-lowering effect on TCHOL and LDL levels and may reduce atherosclerosis formation in rabbits fed a high cholesterol diet.

A similarly designed study conducted on streptozotocin-induced diabetic mice models revealed that ALA completely prevented the increase in TCHOL, atherosclerotic lesions, and the general decline in health typically observed with diabetes, suggesting that ALA is a promising protective agent for reducing cardiovascular complications of diabetes. Studies evaluating the efficacy of ALA in the prevention/treatment of atherosclerosis are limited to experimental data; however, the safety of the supplement and the potential benefits make it a promising intervention in primary care and cardiology settings.

Adverse Effects

While intravenous ALA prevents damage to the membranous structures of cells (including the mitochondria) at typical doses, animal studies suggest that excessively high amounts may result in mitochondrial damage. LD50 studies on six rhesus monkeys demonstrated that doses of approximately 90 mg/kg to 100 mg/kg of intravenous ALA were lethal to three monkeys.45 Researchers extrapolated this data, stating that this dose would likely be fatal to all primates.

Researchers believe this toxicity may be due to the formation of superoxide anions when ALA comes into contact with diatomic oxygen in the mitochondria.46 These damaging free radicals may then react with the unsaturated double bonds in the lipids of the mitochondrial membrane.

Adverse effects associated with therapeutic doses of ALA include adverse gastrointestinal effects such as nausea and vomiting, vertigo, and chest distress (however, researchers noted that this may have been due to the velocity of the IV drip, as it improved the same day after the speed was adjusted). There was no laboratory evidence of iron, vitamins, thyroid function deficiencies, and hyperglycemia associated with ALA supplementation.