Alpha-Lipoic Acid

ALA is a naturally occurring compound with the chemical name 1,2-dithiolane-3-pentanoic acid, sometimes referred to as thioctic acid.^[1]

ALA can be found in food, mostly meat like organ tissue, and in some fruits and vegetables.^[2][3] Some specific contents include:

• Spinach at 3.14+/-1.11mcg/g dry weight as lipoyllysine^[4][5]
• Kidney at 2.64+/-1.23mcg/g dry weight as lipoyllysine^[4][5]
• Liver at 1.51+/-0.75mcg/g dry weight as lipoyllysine^[4][5]
• Broccoli at 0.94+/-0.25mcg/g dry weight as lipoyllysine^[4][5]
• Heart Tissue at 0.86+/-0.33mcg/g dry weight as lipoyllysine^[4][5]
• Tomatoes at 0.56+/-0.23mcg/g dry weight as lipoyllysine^[4][5]

Lipoyllysine is a lipoic acid molecule bound to a lysine amino acid, and is a food storage form of alpha-lipoic acid that is bound to the proteins.^[6] It is separated into lipoic acid and lysine via the glycoprotein enzyme lipoamidase (sometimes referred to as lipoyllysine hydrolase), which circulates in human serum.^[7]

Lipoic acid is found in a variety of food sources, but the levels found in food tend to be significantly lower than standard supplemental dosages.

Alpha-Lipoic Acid (ALA) is a naturally occurring dithiol compound created in the mitochondria from octanoic acid as a precursor, with a good deal of synthesis occurring in the liver's mitochondria.^[8][3]

Its main biological role is as a cofactor in mitochondrial enzymes such as alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase.^[9] ALA also appears to be involved in the production of acetyl-CoA, via oxidative decarboxylation of pyruvate.^[10]

Supplementation has been found to provide protective benefits against oxidation, inflammation, diabetes, and cognitive decline.^[9]

Alpha-Lipoic Acid (ALA) possesses a chiral center carbon and thus can exist in an S or R isomer. Unspecified ALA is a 'racemic' solution of both, while R-ALA is often sold as well, commonly bound to sodium (Na-R-ALA).

The disulfide bond in alpha-lipoic acid can be homolytically cleaved by near UV light and heat^[11][12] during which the dithiolane ring structure forms two thiyl radicals and self-polymerizes into a linear chain of disulfides known as PBCPD. The full name is poly{3-(n-butane carboxylic acid)propyl}disulfide.^[13] This polymerization is seen as reversible, with conversion back into ALA in alkaline solution or with coincubation with reducing agents such as dithiothreitol and β-mercaptoethanol.^[14] It has been suggested that naturally occurring ALA may be a racemic mixture including a PBCPD content.^[15]

In vivo, ALA can be reduced to dithiol form (where the ring structure is broken), dihydrolipoic acid (DHLA).^[3] In cells with mitochondria, this reduction is mediated by lipoamide dehydrogenase and is an NADH-dependent reaction. In cells without mitochondria, this reduction occurs via NADPH with glutathione and thioredoxin reductases.^[16]

ALA has a melting point of 63°C when in racemic solution and 50°C as the R-ALA isomer, and pairing with salts with higher boiling points may enhance stability, a common venture for patents.^[17][18]

Orally ingested Alpha-Lipoic Acid (ALA) is rapidly taken up in the gut in a pH dependent manner by monocarboxylic acid transporters (MCTs). Coingestion with monocarboxylic acids such as medium-chain triglycerides or benzoic acid inhibits ALA uptake.^[19] There is also the potential for ALA to be taken up by the sodium-dependent multivitamin transporter (SMVT).^[20][21] In the gut, some ALA converts into dihydrolipoic acid. The overall bioavailability of ALA supplementation is approximately 30%^[22][9] due to high liver extraction.^[23] The Na-R-ALA form of ALA is completely soluble in water.^[24] Although the R-enantiomer has higher intestinal uptake rates in vivo,^[25] the S-enantiomer may stabilize uptake by preventing polymerization.^[9]

ALA is taken up moderately well, uses the MCT transporter, and may not be absorbed as well if taken alongside medium-chained triglycerides.

Systemic pharmacokinetics of ALA are fairly rapid. After rapid intestinal uptake, it is quickly partitioned to tissues that uptake ALA (brain, heart, and muscle) which includes a transient liver storage of ALA.^[9][26] ALA accumulates in the brain as soon as an hour after ingestion^[27] and is stored in various brain regions.^[28]

After oral ingestion of 600mg ALA racemic mixture, the C_max appears to be 6.86+/-1.29µg/mL with a T_max of 50.8 minutes and an overall 8 hour AUC of 5.65+/-0.79µg/mL/h.^[29]

In cells, ALA is primarily metabolized via beta-oxidation.^[30] The main metabolites are bisnorlipoate, tetranorlipoate, β-hydroxy-bisnorlipoate, or the bis-methylated mercapto derivatives of these compounds^[26] and dihydrolipoic acid, which undergoes rapid cellular excretion.^[16]

ALA is also rapidly excreted by filtration in the kidneys, with 98% of digested ALA excreted within 24 hours^[23]. However, most orally ingested ALA is lost in fecal excretion prior to intestinal uptake.^[30] For these reasons, ALA is not stored long-term. According to Shay et al.^[9] the average AUC is approximately 160+/-35ug/ml/min and the average C_max is 2.8+/-1.5 for a 600mg oral dose of both enantiomers. These results rival Na-R-ALA for AUC (despite R-ALA showing higher peak values and faster excretion) but are well ahead of S-ALA in isolation.^[25]

The majority of supplemental ALA does not appear to be stored for longer than a day.

Alpha-Lipoic Acid (ALA) as well as its metabolite dihydrolipoic acid bind to metals in vitro, with the former binding to copper, lead, and zinc while the reduced form of dihydrolipoic acid binds to those three as well as mercury and iron(III).^[31] Due to selenium and manganese deficiency being symptoms of ALA toxicity^[32], it seems ALA or its metabolites can bind to these two metals as well.

In vivo, ALA has been observed to reduce iron levels in the brain and liver, but only when the iron level is above normal.^[33][34] These results preliminarily suggest that ALA does not negatively affect the mineral status of the body.

It has been hypothesized that the longevity promoting aspects of ALA are due to PPAR gamma cofactor 1 (PCG-1a) activation,^[35] a mechanism shared by Pyrroloquinoline Quinone.

In liver cells, alpha-lipoic acid has been found to increase oxygen consumption to 189% of baseline when given to old rats at 0.5% of the diet while it nonsignificantly increase oxygen consumption to 104% of baseline in younger rats.^[36] Initially the older rats had 59% of the level of oxidation relative to younger rats, and after supplementation there were no significant differences.^[36] This normalization of mitochondrial oxygen capacity has been recorded in neural tissue as well, where increased oxygen consumption coupled with increased anti-oxidative potential improved neural consequences of aging (such as memory loss) in old rats fed 0.5%/1.5% ALA/ALCAR (a form of L-Carnitine).^[37][38]

This increased oxygen consumption is associated with fewer parameters of oxidation when ALA at 0.5% of feed is supplemented or a combination of ALA and L-Carnitine (as ALCAR) is supplemented. ALCAR at 1.5% of feed in isolation can increase oxidation.^[39] The 30.8% increase in oxidation seen with aging (relative to control) in this study was abolished with combination therapy and normalized to the level of youthful rats. Aging was measured by MDA, Ascorbate, and 2',7'-dichlorofluoresin appearance.^[39] This decrease in oxidation is also associated with a lesser decline of mitochondrial enzymes, which appears as an increase from pre-supplementation levels.^[40][41]

Supplementation of Alpha-Lipoic Acid (ALA) alone increases oxidative consumption (indicative of metabolic activity) in a similar manner to L-Carnitine in aged animals, which improves functional performance. ALA can also curb the pro-oxidative effects of L-Carnitine, demonstrating practical synergism.

A rat study assessing Alpha-Lipoic Acid (ALA) and diet interactions concluded, after following 12 groups of rats for their lifetimes, that supplementation at a dose that does not interfere with food intake (1.5g/kg in rats) does not appear to augment the efficacy of caloric restriction nor enhance ad libitum (no control) feeding per se, but that (1) although rats that switch to caloric restriction after 12 months of age (30% of lifespan) show similar life extension to lifelong caloric restriction, rats previously fed ad libitum with ALA did not, and (2) switching from caloric restriction to ad libitum feeding at 12 months normally attenuates the life extension effects of caloric restriction, but this was not seen when refeeding occurred with ALA despite an increase in growth rates.^[5] The former inhibition of longevity and promotion of longevity (respectively) were lesser in magnitude with a shorter supplementation time.^[5]

One study simply administering ALA to immunosuppressed mice found that both isomers of ALA were able to increase longevity with the S-isomer at 75mg/kg daily and the R-isomer at 9mg/kg daily. High doses of 350mg/kg appeared to act to reduce lifespan.^[42]

In regard to an anti-aging phenotype (giving the appearance of youth without impacting median of maximal lifespan), supplementation of ALA has been demonstrated to increase the metabolic rate and activity levels of older rats, to a greater extent than seen in younger rats. Due to increasing activity levels more in older rats than younger rats, ALA supplementation reduced the differences between groups.^[39]

Alpha-Lipoic Acid (ALA) has been demonstrated to inhibit AMPK in the hypothalamus (as opposed to other areas of the body, where it has a stimulatory effect) and due to mimicking a caloric surplus can suppress appetite. These effects may be secondary to increasing glucose uptake into the hypothalamus, and are reversed upon AMPK activation in the hypothalamus.^[43] ALA at 0.25, 0.5, and 1% of the overall food intake of rats over 2 weeks and when tested over the period of 14 weeks was able to reduce body weight relative to unsupplemented control.^[43] The reduction in food intake in rats does not appear to be secondary to a conditioned taste aversion, which should be noted due to ALA's sharp taste.^[43] Another rat study using 200mg/kg oral intake found that this suppression of hypothalamic AMPK paired with adipose expression of AMPK helped to normalize changes in fat mass associated in a model of menopause.^[44]

In older rats fed 0.75% ALA, this reduction in food relative to control has been quantified at ranges of 18%^[45] to 30%,^[46] and many other studies that note food intake as secondary observations tend to note decreases that reach statistical significance^{[47][48][44][49][46][50][51]} or trends towards significance.^[52] The reproducability of this seems to be high enough that, in some trials irrelevant to food intake, a third 'pair-fed' group is planned at the onset to match the experimental group for intake and control for the effects of ALA against the effects of food deprivation per se.^{[53][54][55][56]}

This suppression of appetite seems to influence both low-fat and high-fat diets, as one rat study that supplemented ALA to both groups noted non-significant differences in overall weight loss (-24% and -29% in low and high fat; respectively and relative to high fat control)^[46]

The only human study to be conducted on ALA at 600mg and appetite was conducted in schizophrenic patients and confirmed appetite suppression with increased energy (subjective rating), but had a very low sample size.^[57]

ALA appears to be a potent appetite suppressant in research animals, and is consistent in the appetite suppressing effects. It is surprisingly underresearched in humans, but may have the same effects.

Some studies do note an attenuation of appetite suppression (less significance) about two weeks after consumption, so these effects may be short term and they do not seem to be fully abolished.

Alpha-lipoic acid has been noted to reduce oxidative damage in neuronal cells^[58] and aged rats at 100mg/kg,^[28] which is thought to underlie the reductions in age-related cognitive decline.^{[59][60][37][61]}

It has been noted that ALA does not alter basal calcium concentrations in a neuron at lower concentrations (5-50μg/mL) nor did it augment the calcium response to glutamate, yet 500μg/mL is able to increase basal calcium influx and suppress glutamate induced signaling.^[62]

ALA has also been found to inhibit T-currents (specifically, via the Ca_V3.2 channel) with an IC₅₀ of 3+/-1μM, reaching maximal inhibition of around 40% at 100-1,000μM. This appears to be mediated via a REDOX reaction on the calcium channel.^[63]

Alpha-lipoic acid (0.05-1µM) appears to facilitate the calcium-dependent release of glutamate from the synapse via a PKA/PKC dependent mechanism, the magnitude of which reached around 27.3+/-3.1%.^[64]

ALA may facilitate the release of glutamate at the presynatic level, which would theoretically enhance signaling through glutaminergic receptors.

It has been noted that incubation of glial cells with alpha-lipoic acid (10-50μM) increases glutamine synthetase activity in astrocytes and increases glutamate uptake by around 20% (and subsequent glutathione production by 40%),^[65] a mechanism similar to resveratrol. This appears to be mediated via PKC but not PI3K.^[65]

ALA appears to stimulate glutamate uptake into glial cells for conversion into glutamine, which theoretically suppresses signaling.

ALA does not appear to alter the synaptic membrane potential of glutamate signaling^[64] and when investigating the NDMA receptors, researchers found alpha-lipoic acid to both suppress signaling (as ALA) or enhance signaling (as the reduced form DHLA).^[66]

Interestingly, the age-related deficits in NMDA receptor B_max appear to be normalized with alpha-lipoic acid in aged mice.^[67]

Alpha-lipoic acid is able to modulate the REDOX site of the NMDA receptor, but since it works in both directions its overall actions on receptor signaling are unclear. However, at least one study suggest a possible increase in NMDA receptor density in older subjects.

The excitotoxicity seen with excess glutamate appears to be reduced with alpha-lipoic acid (100µM or above), which seems to be secondary to preserving glutathione concentrations in the neuron.^[68][69][70] A reduction in NMDA-induced lesions has also been confirmed in rats injected with 10mg/kg ALA for 10 days, reaching about a halving in lesion size.^[71]

Alpha-lipoic acid appears to be neuroprotective against glutamate-induced toxicity secondary to supporting the glutathione pool (its depletion precedes cellular death), a mechanism similar to N-acetylcysteine.

In pilocarpine-induced seizures, an intraperitoneal injection of 10mg/kg alpha-lipoic acid is able to normalize the increase in glutamate seen with pilocarpine.^[72] This was associated with a preservation of taurine^[72] and aspartate^[73] concentrations as well.

The increase in glutamate seen with cyanide toxicity (which releases glutamate^[74], while neurotoxicity is thought to be mediated via the NMDA receptor^[75]) appears to be attenuated with 25-100mg/kg ALA.^[76]

The elevation in glutamate concentrations seen in pathological conditions or toxin administration appears to be able to be attenuated with preadministration of alpha-lipoic acid.

An animal study assessing the interactions of ALA and pilocarpine (a cholinergic agonist capable of inducing seizures) found that 10mg/kg ALA was able to reduce pilocarpine-induced seizures by 50% and prolong time to seizure by 112% if it was unable to outright prevent a seizure.^[77]

A study in which rats were fed low doses (10, 20, or 30mg/kg bodyweight) ALA found that 20mg/kg bodyweight was able to increase dopamine levels in the hippocampus by about 9% 24 hours after ingestion, yet the other two doses (10 and 30mg/kg) were not significantly different than control.^[78] Another study using 10mg/kg found no effect.^[77]

Alterations in dopamine (decrease) and dopamine metabolite (increase) levels associated with pilocarpin-induced seizures has been normalized with 10mg/kg pre-treatment ALA.^[77]

A study in rats found a decrease in hippocampal serotonin by 9% and its main metabolite, H-IAA, by 21% when consumed at 20mg/kg bodyweight (but not 10 or 30) and measured 24 hours later.^[78] Another study using 10mg/kg found no effect.^[77]

A rat study found 11% increased noradrenaline levels in the hippocampus associated with 20mg/kg ALA supplementation after 24 hours, while the other two tested doses (10 and 30mg/kg) were not significantly different than control.^[78] Another study using 10mg/kg found no effect.^[77]

A significant reduction in noradrenaline levels in the brain associated with pilocarpine (experimental seizure inducer) has been abolished by pre-treatment with ALA at 10mg/kg in rats.^[77]

In an aforementioned study noting alterations in monoamines at 20mg/kg oral dose yet not 10mg/kg nor 30mg/kg, a reduction of lipid peroxidation was observed that also only occurred at this dose.^[78] The study has been duplicated in the literature.^[79]

One study has been conducted with ALA on people with compressive radiculopathy syndrome from disc-nerve root conflict. Researchers found that 600mg of ALA daily (paired with 360mg gamma-linoleic acid) in conjunction with a physical rehabilitation program was synergistic with the physical rehabilitation program and promoted nerve recovery over 6 weeks.^[80]

Carpal Tunnel Syndrome (CTS), at least in the early stages of disease progression, has been shown to be slowed in terms of disease progression and symptoms of CTS (when CTS is at a moderate-severe level) after supplementation of an ALA multinutrient (main confound was gamma-linoleic acid) at 600mg and 360mg, respectively, over the source of 90 days.^[81]

One study paired ALA with oral superoxide dismutase (an anti-oxidant enzyme) and found significant reductions in diabetic neuropathy as assessed by subjective pain and electroneurographic parameters.^[82]

A 4-year trial of ALA on diabetic neuropathy using 600mg ALA daily failed to show a significant difference in primary outcomes between groups (Neuropathy Impairment Score, neurophysiological tests) yet the ALA group showed significant improvements relative to their own baseline value.^[83] This trial could not establish a protective effect of ALA, however, since placebo did not deteriote over time.^[83]

Alpha-Lipoic Acid (ALA) can induce triglyceride lipase expression in liver cells (responsible for decreasing triglyceride strorages in these cells^[84]) secondary to AMPK activation, which decreased lipid accumulation in vitro.^[85] AMPK was activated in a time- and concentration-dependent manner, and was able to do so despite high glucose (30mM) and palmitate (0.1mM) concentrations at concentrations of 0.25-1mM.^[85] These AMPK interactions are independent of Sirtuin proteins, and appear to circumvent insulins actions on the nuclear transcription factor FOXO1 by preventing nuclear exclusion, which appears to be secondary to AMPK as well.^[85] When fed to genetically obese rats, 2.4% ALA of the diet for 5 weeks (about 40mg/kg bodyweight in this study after controlling for 20% bioavailability) is able to reduce triglyceride accumulation in liver tissue (-26%) and increase glycogen content (+27%). Relative to calorically restricted rats, the LA group had larger livers without abnormal biomarkers, possibly due to the glycogen content.^[53]

Superoxide anion production in the liver of rats fed 1% ALA also appears to be reduced relative to control, and the increase in superoxide production in response to added glucose to the diet, for the most part, abolished.^[48]

AMPK is not the sole mechanism of reducing fat accumulation in the liver, and can inhibit the genetic actions of pro-lipogenic proteins LXR and specificity protein 1.^[86] ALA may increase the protein content of PPARα receptors when fed at 1% of the diet over a period of 14 weeks and was negatively correlated (r=0.8) with blood free fatty acid levels.^[48]

Although the beneficial effects of ALA on liver physiology in aforementioned models are well-established, one study comparing the effects of long- vs. short-term ALA supplementation in healthy mice suggests that regular, long term supplementation may cause liver damage, and should be considered with caution.^[87]

To examine the effect of short- vs. long-term ALA supplementation on the liver, “black 6” mice (C57BL6/J, a common laboratory mouse strain) were treated with 20mg/kg ALA for 4 or 74 weeks.^[87] After the treatment period, mice were euthanized followed by liver tissue analysis for lipid and cholesterol metabolism. Short- and long-term ALA supplementation caused an increase in β-oxidation and decreased lipogenesis. In contrast, both short and long term ALA treatment increased liver cholesterol content by 70% and 110%, respectively, and increased triglyceride levels, inducing systemic triglyceridemia. Moreover, in spite of the fact that short-term ALA treatment decreased lipogenic gene expression, it also caused fat accumulation in the liver. Long-term ALA treated mice showed a worse phenotype, with extensive fat accumulation leading to hepatic steatosis and extensive liver damage.^[87]

Notably, the above study was unique in that it investigated the effects of long term ALA treatment in otherwise healthy mice. In contrast, other studies that have shown a beneficial effect of longer term ALA treatment were conducted in rodent disease models, including high fat diet fed rats^[88] and Zucker Diabetic Fatty (ZDF) rats.^[89] Thus, long-term ALA treatment in healthy animal models may be liver toxic, causing a phenotype that closely resembles that of non-alcoholic fatty liver disease.^[90][91] It should be noted that the dose of ALA in the healthy mouse study^[87] of 20mg/kg is equivalent to approximately 146 mg/day in a 200 lb human. Although this is a relatively high dose of ALA, it is close enough to standard doses that caution may be warranted for long-term supplementation.

Although ALA has been shown to decrease oxidative stress and improve lipid metabolism in animal disease models, one study in healthy mice suggests that long term treatment may be liver toxic, causing damage that resembles non-alcoholic fatty liver disease. Since the effects of long term ALA supplementation in humans have not been studied, it is not currently known whether long-term high dose ALA may have similar detrimental effects in humans.

The following mechanisms are those that are independent of appetite suppression. As evidence by the appetite summary (Neurology Header, subsection 1) ALA has potent effects on reducing appetite. However, even when a third group has their energy intake restricted to match the intake of a group with appetite suppression (known as pair-fed feeding) ALA appears to induce some manner of weight loss beyond mere appetite suppression (although appetite suppression appears to be the most potent influencing factor).^[49] At least one pair-fed study (control group, group fed ALA, third group fed only the amount of calories the ALA group wanted to consume) found that the statistically significant weight loss became insignificantly different between pair fed and ALA supplemented.^[53]

The most significant factor influencing alpha-lipoic acid's weight reducing effects is the reduction of appetite, and pair-fed studies suggest this may account for 80-90% (rough estimate derived from charts) of the overall weight-reducing effects secondary to ALA.

In vitro, lipoic acid was able to induce apelin secretion from fat cells (an adipokine that may regluate glucose metabolism) but was deemed to be unrelated to changes seen in vivo.^[47]

In regard to AMPK, at least one study has seen results that suggest AMPK inhibition could be at play in 3T3-L1 adipocytes, but the study was not designed to answer these questions.^[47] Two other studies note that in white adipose tissue AMPK is both activated and its mRNA upregulated.^[54][44]

When investigating the interactions of ALA and nutrient absorption, supplemental ALA for 56 days was able to reduce carbohydate uptake secondary to inhibiting the SGLT1 transport (sodium dependent glucose transporter) by approximately a third, when the jujenum was excised and tested in vitro with alpha-methylglucose.^[49] When tested in vivo at 0.5% ALA though, there are no significant differences in the caloric content of the feces with ALA (assessed by bomb calorimetry).^[46]

ALA has the potential to inhibit nutrient uptake, but does not appear to be potent enough to be meaningful.

In animals fed 0.5% of food intake as ALA when caloric intake was controlled (as ALA may suppress appetite), energy expenditure as assessed by indirect calorimetry increased by day 3 and continued to be elevated for the 21 tested days.^[43] These rats showed increased expression of UCP1 in brown adipose tissue and ectopic expression of UCP1 in white adipose tissue, thought to be a reason for the increased metabolic rate.^[43] In older rats administered 0.75% ALA for 4 weeks, an increased metabolic rate has also been observed through an AMPK/PGC-1a dependent mechanism. This metabolic rate (paired with an 18% reduction in food intake) resulted in 15.8% total weight lost.^[45] Oxygen consumption and carbon dioxide production in these older rats fed 0.75% ALA increased by 27% and 38%, respectively.^[45]

One study conducted on 228 people (360 at the start with a high dropout rate) who were either obese or overweight paired with metabolic abnormalities (metabolic syndrome) given 1,200mg or 1,800mg of ALA (in three daily doses before meals) for 20 weeks noted that there was a significant decrease in weight in the 1,800mg group when all groups were subject to a 600kcal deficit.^[92] Average weight loss was 0.94+/-0.45kg in placebo, 1.49+/-0.38kg in 1,200mg, and 2.76+/-0.53kg in 1,800mg.^[92]

In aged rats, improvements in GLUT4 and PGC-1a mRNA content was increased by 105% and 80% (respectivly) after 4 weeks of 0.75% ALA ingestion.^[45]

One rat study noted that with ALA injections at 30mg/kg, heat shock proteins 72 and 25 were induced in the high fat (60%) but not the low fat (10%) diet, which was able to reduce pro-inflammatory signaling via JNK and NF-kB (reported elsewhere^[93][94]) and to improve fatty-acid induced insulin resistance.^[52] ALA has previously been implicated (alongside other anti-oxidants, Vitamin C and Vitamin E) in reducing the activity of IRS-1 and improving insulin sensitivity by this mechanism.^[95]

Increased markers of lipid metabolism have been noted as well, namely increased phosphorylation of AMPK, ACC, FAS, and ATGl. The effect of these increased β-oxidation and decreased lipid accumulation.^[96] Increased SIRT1 expression has been noted in myotubes secondary to AMPK and an increased NAD/NADH ratio, yet knockdown of SIRT1 with siRNA reduces the β-oxidixing of AMPK in these cells.^[96] These effects were nonsignificantly more potent than resveratrol, a known PDE4 inhibitor that influences AMPK.^[96] ALA at 0.5% of the diet has been shown to reduce lipid accumulation in fat cells, but this study attributed that to anorexic (appetite suppressing) effects rather than via AMPK.^[46]

When looking at the mechanism of AMPK upregulation, it has been shown this can occur independently of the AMP:ATP ratio (countering a previous study suggesting LKB1 activation was the cause^[96]) and secondary to increased intra-cellular calcium concentration at 200uM and 500uM.^[97] Chelating intracellular calcium can abolish the effects of ALA on AMPK, as can inhibiting the CaMKK enzyme, which releases calcium into myocytes.^[97]

One study noted that in chow-fed rats (10% fat) ALA was unable to stimulate glucose uptake into muscle cells in vivo, but was able to improve the 54.7% reduction in glucose uptake seen in the high-fat (60%) fed rats (relative to chow) by 55.7%.^[52]

ALA appears to be able to inhibit platelet aggregation secondary to PPAR agonism, where incubation with ALA caused activation of PPARα and PPARγ and a subsequent inhibition of arachidonic acid induced platelet aggregation possibly secondary to PKCα association and inhibtion of calcium accumulation.^[98] Incubation with either a PPARα or PPARγ antagonist abolished these effects.^[98]

One study has noted that, secondary to AMPK activation, ALA may reverse an impairment of relaxation seen in obese rats.^[99]

In human interventions, ALA supplementation appears to improve endothelial dysfunction and blood flow as assessed by flow-mediated vasodilation after 3 weeks of supplementation in people with subclinical hypothyroidism^[100] and either type II diabetes^[101] or merely impaired fasting glucose either over the long term^[102] or during an acute glucose tolerance test.^[103]

One intervention designed to determine how ALA affects weight loss noted that 1,200 and 1,800mg daily ALA for 20 weeks did not influence resting triglycerides or HDL cholesterol at either dose compared to placebo.^[92]

Oral supplementation of 1,800mg ALA for 2 weeks does not appear to influence insulin secretion rates in healthy but overweight or obese men.^[104]

The impairment of insulin sensitivity seen with high blood triglycerides does not appear to be alleviated with ALA at 1,800mg daily for 2 weeks.^[104]

ALA has been investigated for oral usage at doses of 300, 600, 900, and 1,200mg of a racemic mixture over a period of 6 months in people with confirmed type II diabetes (some on anti-hyperglycemic therapy). Researchers found a dose-dependent trend toward reduced fasting blood glucose and HbA1c at each dose, and significant reductions when all groups were pooled and when subjects were compared to baseline.^[105] A longer trial of 4 years with 600mg ALA found a greater decrease in HbA1c associated with ALA (0.67 ± 1.41%) than placebo (0.48 ± 1.46%), but did not reach significance.^[83]

Alpha-Lipoic Acid (ALA) is a multi-modal antioxidant, capable of decreasing oxidation that is a result of metal peroxidation, increasing glutathione levels in the body, or by directly acting on anti-oxidants (like ascorbate) or by itself.

As a metal-chelator, ALA can reduce peroxidation in neural tissue induced by mercury^[106] and via iron(III) and copper(II) chelation has shown benefits in the pathophysiology of Alzheimer's disease.^[34]

ALA's ability to upregulate expression of glutathione^[107] (one of the body's intrinsic anti-oxidant systems) comes from hepatic expression of Nrf2 (as evidenced by being elevated 24 hours after exposure, rather than acutely^[108]). During aging, intrinsic expression of Nrf2 (which mediates genes of the anti-oxidant response element (ARE) declines, which results in less ARE activity and subsequently reduced levels of glutamyl cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis. ALA has been observed to upregulate the synthesis of both GCL subunits via Nrf2 binding to ARE, and restore age-depleted glutathione levels.^[109]

The hypothesized mechanism for the above is that ALA irreversibly binds to the Keap1 protein, which normally binds to Nrf2 and signals for its destruction.^[110] By forming lipoyl-cysteine bridges with Keap1,^[111] ALA preserves Nrf2 function.^[112][113]

ALA has been observed to induce an increase in ascorbate (vitamin C) levels in the liver^[114] and heart^[115] of aged rats, in which levels decline due to a possible reduction in the sodium-dependent vitamin C transporter in the liver.^[116] ALA supplementation may also induce more vitamin C uptake from the blood into the mitochondria for usage, thus acting as a potentiator.^[117]

ALA can also act as a direct anti-oxidant, at least in vitro. However, due to its rapid excretion rates and lack of AUC in a cell it is suspected that this pathway is negligible.

Supplementation of 300-1,200mg ALA daily for 6 months is associated with reduced urinary levels of F2α-isoP, which suggests that ALA reduces lipid peroxidation in vivo for type II diabetics.^[105] Consumption of 600mg ALA in type 1 diabetics over 5 weeks does not appear to significantly reduce this biomarker, however.^[118]

When measuring 8-OHdG, an oxidative DNA byproduct found in urine, there was no significant influence.^[105]

Most anti-inflammatory effects of Alpha-Lipoic Acid (ALA) are mediated through its ability to inhibit NF-kB, a nuclear transcription factor that, upon its activation, induces an inflammatory cascade.^[119] ALA inhibits upregulation of ICAM-1 and VCAM-1, two pro-adhesion cytokines, in models of spinal injury at concentrations of 25-100ug/mL (doses seen as therapeutic, and well-above the typical 600mg a day).^[120][121] ALA may also inhibit expression of metalloproteinase-9^[122] and osteoclast formation by this same mechanism.^[123]

The mechanism through which ALA inhibits NF-kB activity seems to be further upstream than TNF-alpha inhibition, which is the stage many anti-oxidants act on. ALA's anti-inflammatory effects are independent of TNF-alpha modulation.^[124]

In humans, a clinical trial noted a 15% serum reduction in levels of interleukin-6 (an inflammatory marker) following 4 weeks of 300mg racemic ALA supplementation.^[125]

One study has been conducted on ALA (300mg) for 4 weeks in people with rheumatoid arthritis. It noted that lipoic acid failed to significantly reduce IL-6, IL-1β, or TNF-α and failed to significantly reduce pain associated with rheumatoid arthritis.^[126]

Alpha-Lipoic Acid (ALA), through suppressing hypothalamic AMPK yet activating peripheral AMPK, shares mechanistic similarities to the hormone leptin. When tested in mice however, those with and without leptin receptors still experience these effects, suggesting ALA acts as a leptin mimetic in results (but not mechanisms) and may help in overcoming leptin resistance by bypassing the receptor.^[43]

When given to rats prone to non-alcoholic fatty liver disease (NAFLD), ALA can suppress the disease pathology and expected rise in leptin^[127] and increase leptin levels in a model of type 1 diabetes, which causes a decrease in leptin.^[128] When given at 0.25% of the diet to otherwise normal and healthy rats, a decrease in circulating leptin and leptin mRNA is seen after 8 weeks, and was correlated (r=0.908) with levels of white adipose tissue.^[51] Isolated adipocytes from these rats after 8 weeks subject to 250uM ALA increased conversion of glucose to lactate (resulting in a significant increase in lactate by 44% at 500uM) and this increase in lactate was correlated with a decreased secretion of leptin.^[51] Lipoic acid appears to be associated with increased phosphorylation of Sp1, a nuclear transcription factor induced by glucose that stimulates leptin. Its phorphorylation prevents its actions in the nucleus, and ALA's actions were mimicked by PI3K inhibitors.^[51]

When placed in isolated adipocytes (fat cells), ALA appears to be synergistic with L-Carnitine supplementation, with a concentration of 0.1umol/L of both molecules outperforming 100umol/L of either molecule (and interestingly, 100umol/L of both molecules) in increasing mitochondrial density.^[129] In fact, 10umol/L of both appeared to be the most effective at increasing mitochondrial density, more than 3-fold that of control cells.^[129]

In a model of lipotoxicity, while carnitine was effective at increasing mRNA levels of CPT-1 and PPARy in mitochondria, the addition of lipoic acid further augmented the increases in mRNA.^[130] These synergistic increases in mRNA have been reported elsewhere, and appear to affect PPARa as well.^[129]

Sesamin is a mixture of lignans from sesame seeds that may increase lipid oxidation and decrease lipid synthesis in the liver, an effect similar to ALA. Pairing the two appears to be additive in regard to reducing circulating lipid levels, but the combination confers no additional benefit for reducing triglyceride storage in the liver.^[131] The combination additively decreased fatty acid oxidation, but ALA appeared to normalize the increase in fatty acid oxidation seen with sesamin.^[131]

Avidin is a protein found predominately in raw (but not cooked) egg whites, which is known to potently bind to and sequester biotin, leading to biotin deficiency if more biotin is not ingested.^[132][133] Biotin has a similar structure to ALA, and avidin binds to biotin via the part of the molecule that is structurally similar,^[134] meaning that avidin can also sequester ALA.^[134]

While it is not prudent to consume raw egg whites due to the avidin content, they should not be consumed alongside ALA as the avidin in the egg whites has the potential to sequester and inactivate the ingested ALA before it can be absorbed.

ALA supplementation is relatively safe in the doses consumed by people. Studies in rats have established a 60mg/kg bodyweight dose in which no adverse side effects are noted^[135] and acute harm observed at 2000mg/kg a day.^[9] In humans, doses of 1800mg/day ^[136] and 2400mg/day^[137] failed to have any side effects over a 6-7 month period.

In these toxic doses, ALA has been found to increase oxidation levels (via hydroperoxide) in the organs it acts in^[138][139] as well as take its metal-chelating abilities to the extreme and induce mineral deficiencies.^[32] These effects were seen at the human equivalent of 3-5g of ALA a day, well below the level used in human trials that observed no side effects.

One intervention that resulted in a side effect was a 4-year blinded trial of ALA at 600mg for the purpose of aiding diabetic neuropathy where the adverse side effects were higher in ALA (at 38.1%) than in placebo (at 28%), and were dubbed to be 'cardiac related' or urinary in nature. These adverse effects did not deter the authors from determining that ALA was well tolerated, possibly due to significant differences in global rating.^[83]

Other trials note that common side effects are nausea (deemed minor and related to appetite suppression)^[57] and an itching sensation of the skin associated with higher (1,200-1,800mg) doses.^[92]