ALA is a fatty acid that exists in the mitochondria and is involved in energy metabolism. Commonly taken with L-Carnitine supplements as they are related in mechanisms. ALA gives a short but potent reduction of oxidation by increasing anti-oxidant enzymes, and may decrease Blood Glucose acutely.
This page features 131 unique references to scientific papers.
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Alpha-Lipoic Acid (ALA) is a mitochondrial fatty acid that is highly involved in energy metabolism. It is synthesized in the body and can be consumed through eating meats and minimally in some fruits/vegetables.
In supplement form, it has shown benefit against various forms of oxidation and inflammation. These effects carry on to benefits that protect one from heart diseases, liver diseases, diabetes, and neurological decline with age.
It is a potent anti-oxidant compound. It works with mitochondria and the body's natural anti-oxidant defenses. It is also seen as an anti-aging compound since it can reverse some of the oxidant damage related effects of aging.
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ALA, thioctic acid, 1,2-dithiolane-3-pentanoic acid, ala, Tiolepta
Alpha-Linoleic Acid (omega-3 fatty acid)
Standard dosages of 300-600mg of ALA are used; with little differentiation as to whether the racemic mixture of ALA or Na-R-ALA results in higher blood levels.
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The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Alpha-Lipoic Acid has in your body, and how strong these effects are.
| Grade | Level of Evidence |
|---|---|
| A | Robust research conducted with repeated double blind clinical trials |
| B | Multiple studies where at least two are double-blind and placebo controlled |
| C | Single double blind study or multiple cohort studies |
| D | Uncontrolled or observational studies only |
| Level of Evidence | Effect | Change | Magnitude of Effect Size | Scientific Consensus | Comments |
|---|---|---|---|---|---|
| B | General Oxidation |   Minor | Appears to reduce biomarkers of oxidation | ||
| B | Blood Pressure | The majority of evidence using intravenous or oral supplements fail to find an influence, and the one study to suggest a reduction was also confounded with weight loss... show | |||
| B | Symptoms of Diabetic Neuropathy | Notable | 100% See 2 studies | Not yet compared to reference drugs, but it has been subject to a meta-analysis and appears to be more effective than other options for reducing nerve pain associated with... show | |
| C | Weight | Minor | It is possible that high doses (1,800mg) may have a body weight reducing effect in obese persons, but this requires more evidence. | ||
| C | C-Reactive Protein | Although there may be a reduction of C-Reactive protein in some populations, for the most part ALA does not seem significantly effective in reducing this inflammatory biomarker... show | |||
| C | Treatment of Dementia | 100% See study | No significant rehabilitative effect of ALA on cognitive decline has been noted | ||
| C | Insulin Sensitivity | 100% See study | No significant influence on insulin sensitivity has been noted | ||
| C | Lipid Peroxidation | Minor | 100% See 2 studies | Appears to reduce biomarkers of lipid peroxidation (MDA mostly) | |
| C | Inflammation | Minor | Mixed effects depending on what inflammatory biomarker or cytokine is measured; practical significance unknown | ||
| C | Symptoms of Rheumatoid Arthritis | 100% See study | No significant interaction between ALA supplementation and symptoms of rheumatoid arthritis | ||
| C | Motion Sickness | 100% See study | Insufficient evidence to support a reduction in motion sickness with ALA supplementation | ||
| C | Protein carbonyl content | Minor | 100% See study | Appears to reduce protein carbonylation, which may be related to the antioxidative effects | |
| C | Anti-oxidant Enzyme Profile | Mixed effects on antioxidant enzymes, with decreases in glutathione peroxidase and increases in catalase with no effect on SOD | |||
| C | Symptoms of Intermittent Claudication | Notable | 100% See study | The reduction of claudication symptoms appears to be fairly potent with ALA supplementation, although there is not a large body of evidence overall. | |
| C | HbA1c | Minor | There appears to be a slight reducing effect on HbA1c | ||
| C | Nerve Repair | Minor | 100% See study | May increase nerve regeneration rates and be of aid to nervous system injury | |
| C | Blood glucose | Ineffective | 100% See study | A small decrease in blood glucose is noted with oral supplementation of ALA, related to the glucose disposal properties | |
| C | Heart Rate | 100% See study | No significant interaction between ALA and heart rate has been noted | ||
| C | Blood Flow | Minor | 100% See 2 studies | May increase blood flow, although not the a remarkable degree. Possibly secondary to antioxidative effects | |
| D | Oxidation of LDL | Minor | 100% See study | Appeared to increase oxidation of LDL according to one study, which was abolished by exercise but noted to be a concern during rest. | |
| D | Glycemic control | 100% See study | No significant practical benefit on glycemic control noted | ||
| D | Skin quality | Minor | 100% See study | May improve skin quality when topically applied | |
| D | Muscle Creatine Content | Minor | 100% See study | Has been associated with augmenting Creatine uptake into muscle cells acutely; long term influence unknown |
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ALA is a naturally occurring fatty acid with the chemical name of 1,2-dithiolane-3-pentanoic acid and sometimes simply referred to as thioctic acid.[2]
ALA can be found in foods, mostly meats such as organ tissue and in some fruits and vegetables.[3][4] Some select contents include:
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.[7] It is separated into lipoic acid and lysine via the glycoprotein enzyme lipoamidase (sometimes referred to as lipoyllysine hydrolase), which circulates in human serum.[8]
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 occuring dithiol compound created in the mitochondria from octanoic acid as a precursor, with a good deal of synthesis occurring in the liver's mitochondria.[9][4]
Its main biological role is as a cofactor in mitochondrial enzymes such as alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase.[10] ALA also appears to be involved in the production of Acetyl-CoA, via oxidative decarboxylation of pyruvate.[11]
Supplementation has been found to carry benefits against oxidation, inflammation, diabetes, and cognition.[10]
Alpha-Lipoic Acid possesses a chiral center carbon and thus can exist in an S or R isomer; unspecified ALA is a 'racemic' solution of both whereas R-ALA is commonly 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[12][13] in where the dithiolane ring structure forms two thiyl radicals and self-polymerizes into a linear chain of disulfides known as PBCPD, full name of poly{3-(n-butane carboxylic acid)propyl}disulfide.[14] 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.[15] It has been suggested that naturally occurring ALA may be a racemic mixture including a PBCPD content.[16]
In vivo, ALA can be reduced to dithiol form (where the ring structure is broken), dihydrolipoic acid (DHLA).[4] In cells with mitochondria this reduction is mediated by lipoamide dehydrogenase and is an NADH-dependent reaction, and cells without mitochondria this reduction occurs via NADPH with glutathione and thioredoxin reductases.[17]
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[18][19])
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.[20] There is also the potential for ALA to be taken up by the sodium-dependent multivitamin transporter (SMVT).[21][22] In the gut, some ALA converts into dihydrolipoic acid. The overall bioavailability of ALA supplementation is ~30%[23][10] due to high liver extraction.[24] The Na-R-ALA form of ALA is completely soluble in water.[25] Although the R-enantiomer has higher intestinal uptake rates in vivo[26] the S-enantiomer may stabilize uptake by preventing polymerization.[10]
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) and includes a transient liver storage of ALA.[10][27] ALA accumulates in the brain as soon as an hour after ingestion[28] and is stored in various brain regions.[29]
After oral ingestion of 600mg ALA racemic mixture, the Cmax appears to be 6.86+/-1.29µg/mL with a Tmax of 50.8 minutes and an overall 8 hour AUC of 5.65+/-0.79µg/mL/h.[30]
In cells, ALA is primarally metabolized via beta-oxidation.[31] The main metabolites are bisnorlipoate, tetranorlipoate, β-hydroxy-bisnorlipoate, or the bis-methylated mercapto derivatives of these compounds[27] and dihydrolipoic acid, which undergoes rapid cellular excretion.[17]
ALA is also rapidly excreted by filtration in the kidneys, with 98% of digested ALA excreted within 24 hours[24]. However, most orally ingested ALA is lost in fecal excretion prior to intestinal uptake.[31] For these reasons, ALA is not stored long-term. According to Shay et al.[10] the average AUC is approximately 160+/-35ug/ml/min and the average Cmax 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.[26]
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).[32] Due to Selenium and manganese deficiency being symptoms of ALA toxicity[33], 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.[34][35] 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,[36] 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.[37] Initially the older rats has 59% the level of oxidation relative to younger rats, and after supplementation there were no significant differences.[37] 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 in old rats fed 0.5%/1.5% ALA/ALCAR (a form of L-Carnitine) such as memory loss.[38][39]
This increased oxygen consumption is associated with less 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.[40] 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, and was measured by MDA, Ascorbate, and 2',7'-dichlorofluoresin appearance.[40] This decrease in oxidation is also associated with a lesser decline of mitochondrial enzymes, which appears as an increase from pre-supplementation levels.[41][42]
Supplementation of Alpha-Lipoic Acid 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 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 attenuate the life extension effects of caloric restriction, this was not seen when refeeding occurred with ALA despite an increase in growth rates.[6] The former inhibition of longevity and promotion of longevity (respectively) were lesser in magnitude with a shorter supplementation time.[6]
One study simply administering ALA to immunosuppressed mice found that both isomers of ALA were able to increase longevity, but 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.[43]
In regards to an anti-aging phenotype (giving the appearance of youth without impacting median of maximal lifespan), supplementation of Alpha-Lipoic Acid has been demonstrated to increase the metabolic rate and activity levels of older rats, to a greater extent as seen in younger rats. Due to increasing activity levels more in older rats than younger, ALA supplementation reduced the differneces between groups.[40]
ALA has been demonstrated to inhibit AMPK in the hypothalamus (as opposed to other areas of the body where it stimulates) 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.[44] 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.[44] The reduction in food intake in rats does not appear to be secondary to a conditioned taste aversion, which should be noted due to ALAs sharp taste.[44] 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.[45]
In older rats fed 0.75% ALA, this reduction in food relative to control has been quantified at ranges of 18%[46] to 30%,[47] and many other studies that note food intake as secondary observations tend to note decreases that reach statistical significance[48][49][45][50][47][51][52] or trends towards significance.[53] 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.[54][55][56][57]
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)[47]
The only human study to be conducted on Alpha-Lipoic Acid 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.[58]
Appears to be a potent appetite suppressant in research animals, and is consistent in the appetite suppressing effects. 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
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 unable to outright prevent.[59]
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.[60] Another study using 10mg/kg found no effect.[59]
Alterations in dopamine (decrease) and dopamine metabolite (increase) levels associated with pilocarpin-induced seizures has been normalized with 10mg/kg pre-treatment ALA.[59]
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.[60] Another study using 10mg/kg found no effect.[59]
A rat study found 11% increased noradrenaline levels in the hippocampus associated with 20mg/kg ALA after 24 hours, while the other two tested doses (10 and 30mg/kg) were not significantly different than control.[60] Another study using 10mg/kg found no effect.[59]
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.[59]
In an aforementioned study noting alterations in monoamines at 20mg/kg oral dose yet not 10 nor 30, a reduction of lipid peroxidation was observed that also only occurred at this does,[60] the study has been duplicated in the literature.[61]
One study has been conducted with ALA on persons with compressive radiculopathy syndrome from disc-nerve root conflict, and 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.[62]
Carpal Tunnel Syndrome (CTS), at least in the early stages of disease progression, has shown benefit to disease progression and symptoms of CTS (when CTS is at a moderate-severe level) associated with an Alpha-Lipoic Acid multinutrient (main confound was Gamma-Linoleic Acid) at 600mg and 360mg, respectively, over the source of 90 days.[63]
One study paired Alpha-Lipoic Acid with oral Superoxide Dismutase (an anti-oxidant enzyme) and found significant reductions in diabetic neuropathy as assessed by subjective pain and electroneurographic parameters.[64]
A 4 year trial of ALA on diabetic neuropathy using 600mg ALA daily failed to show a significantly difference in primary outcomes between groups (Neuropathy Impairment Score, neurophysiological tests) yet the ALA group showed significant improvements relative to their own baseline value.[65] This trial could not establish a protective effect of ALA, however, since placebo did not deteriote over time.[65]
Alpha-Lipoic Acid can induce triglyceride lipase expression in liver cells (responsible for decreasing triglyceride strorages in these cells[66]) secondary to AMPK activation, which decreased lipid accumulation in vitro.[67] 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.[67] These AMPK interactions are independent of Sirtuin proteins, and appears to circumvent insulins actions on the nuclear transcription factor FOXO1 by preventing nuclear exclusion, which appears to be secondary to AMPK as well.[67] 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.[54]
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.[49]
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.[68] Alpha-Lipoic Acid 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.[49]
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).[50] 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.[54]
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.[48]
In regards to AMPK, at least one study has seen results that suggest AMPK inhibition could be at play in 3T3-L1 adipocytes but was not designed to answer these questions;[48] two other studies note that in white adipose tissue AMPK is both activated and its mRNA upregulated.[55][45]
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.[50] 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).[47]
Has the potential to inhibit nutrient uptake, 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.[44] 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.[44] In older rats at 0.75% ALA for 4 weeks, an increased metabolic rate has also been observed through an AMPK/PGC-1a dependent mechanisms and this metabolic rate (paired with an 18% reduction in food intake) resulted in 15.8% total weight lost.[46] Oxygen consumption and Carbon Dioxide production in these older rats fed 0.75% ALA increased by 27% and 38%, respectively.[46]
One study conducted on 228 persons (360 at the start, high dropout rate) who were either obese or overweight paired with metabolic abnormalities (metabolic syndrome) given 1,200mg or 1,800mg Alpha-Lipoic Acid (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.[69] 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.[69]
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.[46]
One rat study noted that with ALA injections at 30mg/kg, Heat Shock Proteins 72 and 25 were induced in high fat (60%) but not low fat (10%) diet, which was able to reduce pro-inflammatory signalling via JNK and nF-kB (reported elsewhere[70][71]) and to improve fatty-acid induced insulin resistance.[53] 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.[72]
Increased markers of lipid metabolism have been noted as well, namely increased phosphorylation of; AMPK, ACC, FAS, and ATGl. The effect of these was increased β-oxidation and decreased lipid accumulation.[73] 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.[73] These effects were nonsignificantly more potent than Resveratrol, a known PDE4 inhibitor that influences AMPK.[73] 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.[47]
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[73]) and secondary to increased intra-cellular calcium concentration at 200uM and 500uM.[74] Chelating intracellular calcium can abolish the effects of ALA on AMPK as can inhibiting the CaMKK enzyme, which releases calcium into myocytes.[74]
One study noted that in chow fed rats (10% fat) that 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%.[53]
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 inhibtiion of calcium accumulation.[75] Incubation with either a PPARα or PPARγ antagonist abolished these effects.[75]
One study has noted that, secondary to AMPK activation, may reverse an impairment of relaxation seen in obese rats.[76]
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 persons with subclinical hypothyroidism[77] and either type II diabetes[78] or merely impaired fasting glucose either over the long term[1] or during an acute glucose tolerance test.[79]
One intervention seeing 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.[69]
Oral supplementation of 1,800mg ALA for 2 weeks does not appear to influence insulin secretion rates in healthy but overweight/obese men.[80]
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.[80]
Alpha-Lipoic Acid 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 persons with confirmed type II diabetes (some on anti-hyperglycemic therapy) and it was shown that a dose-dependent trend towards reduced fasting blood glucose and HbA1c at each dose, and significant reductions when all groups were pooled and when subjects were compared to baseline.[81] 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.[65]
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[82] and via iron(III) and copper(II) chelation has shown benefits in the pathophysiology of Alzheimer's disease.[35]
ALA's ability to upregulate expression of glutathione[83] (one of the bodies intrinsic anti-oxidant systems) comes from hepatic expression of Nrf2 (as evidenced by being elevated 24 hours after exposure, rather than acutely[84]). 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.[85]
The hypothesized mechanism of the above is that ALA irreversibly binds to the Keap1 protein, which normally binds to Nrf2 and signals for its destruction.[86] By forming lipoyl-cysteine bridges with Keap1[87] ALA preserves Nrf2 function.[88][89]
ALA has been observed to induce an increase in ascrobate (Vitamin C) levels in the liver[90] and heart[91] of aged rats, or which levels decline due to possibly a reduction in the sodium-dependent vitamin C transporter in the liver.[92] ALA supplementation may also induce more vitamin C uptake from the blood into the mitochondria for usage, thus acting as a potentiator.[93]
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.[81] Consumption of 600mg ALA in type 1 diabetics over 5 weeks does not appear to significantly reduce this biomarker, however.[94]
When measuring 8-OHdG, an oxidative DNA byproduct found in the urine, there was no significant influence.[81]
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.[95] 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 typically 600mg a day).[96][97] ALA may also inhibit expression of metalloproteinase-9[98] and osteoclast formation by this same mechanism.[99]
The mechanism by 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.[100]
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.[101]
One study has been conducted on ALA (300mg) for 4 weeks in persons with rheumatoid arthritis noted that lipoid acid failed to significantly reduce IL-6, IL-1β, or TNF-α and failed to significantly reduce pain associated with rheumatoid arthritis.[102]
Alpha-Lipoic Acid, 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.[44]
When given to rats prone to Non-alcoholic Fatty Liver Disease (NAFLD), ALA can suppress the disease pathology and expected rise in leptin[103] and increased leptin levels in a model of type 1 diabetes, which experiences a decrease in leptin.[104] 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.[52] 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.[52] 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.[52]
When placed in isolated adipocytes (fat cells), Alpha-Lipoic Acid 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 interesting, 100umol/L of both molecules) in increasing mitochondrial density.[105] 10umol/L of both appeared to be the most effective at increasing mitochondrial density, more than 3-fold that of control cells.[105]
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.[106] These synergistic increases in mRNA have been reported elsewhere, and appear to affect PPARa as well.[105]
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 regards to reducing circulating lipid levels, but the combination confer no additional benefit in reducing triglyceride storage in the liver.[107] The combination additively decreased fatty acid oxidation, but ALA appeared to normalize the increase in fatty acid oxidation seen with Sesamin.[107]
ALA supplementation is relatively safe in the doses consumed in humans. Studies in rats have established a 60mg/kg bodyweight dose in which no adverse side effects are noted[108] and acute harm being noted at 2000mg/kg a day.[10] In humans, doses of 1800mg/kg bodyweight[109] and 2400mg/kg bodyweight[110] 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[111][112] as well as take its metal-chelating abilities to the extreme and induce mineral deficiencies.[33] 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.
For interventions that note side effects, one 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.[65]
Other trials note that common side effects are nausea (deemed minor and related to appetite suppression)[58] and an itching sensation of the skin assocaited with higher (1,200-1,800mg) doses.[69]
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