Introduction

Alpha lipoic acid has been described as the ‘universal anti-oxidant’ because it not only has anti-oxidant powers itself but also has the unique ability to regenerate other anti-oxidants such as glutathione, vitamin C and vitamin E. As worldwide sales in alpha lipoic acid rise, the term ‘universal’ is also beginning to take on a new and different meaning relating to its ‘universal’ reach (aka sales).

Existing blogs on the health benefits of alpha lipoic acid derive much of their data from animal studies (without explicitly saying so) and claim that alpha lipoic acid is a natural treatment for diabetes, memory loss and eye health. Are there human studies to support any of these claims?

What Is Alpha Lipoic Acid (ALA)?

Just a clarification to start. The abbreviation ALA is used for both alpha lipoic acid and alpha linoleic acid. In this article, ALA refers to alpha lipoic acid.

ALA (thioctic acid, 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3-valeric) contains a sulfur group and as such is classified as a thiol.

Free radicals are the waste products of cell metabolism which can damage other cells, tissues and organs. Anti-oxidants are compounds that neutralize the damaging effects of these free radicals.

ALA is a potent anti-oxidant made by any cell in the body that metabolizes glucose.

It is hypothesized that ALA acts in the following ways:

  • directly as an anti-oxidant itself
  • indirectly by regenerating and recycling other antioxidants which usually get used up as they neutralize free radicals e.g. glutathione, vitamins E and C
  • as an anti-inflammatory and
  • as a metal chelator (iron, zinc and copper).

It acts at both intracellular and extracellular levels. The other unique selling proposition for ALA (apart from its ability to regenerate other anti-oxidants) lies in its ability to work in both aqueous and lipid environments. When we compare ALA to other anti-oxidants such as vitamin E (which is limited to lipid environments) and vitamin C (which is limited to aqueous environments), ALA is the winner.

ALA is reduced to dihydrolipoic acid (DHLA) following uptake into cells and tissues. DHLA has an even higher antioxidant capacity than the ALA parent compound.

From a biochemical perspective, there are two enantiomers (optical isomers) of ALA. The R-enantiomer is of most relevance in clinical practice.

ALA has a low bioavailability of just 30% (meaning that only 30% of the dose taken orally is absorbed). Absorption is reduced about 40% by food which underscores the recommendation that ALA should be taken 30 minutes before food. All of this is of relevance as we will see that some studies look at intravenous formulations of ALA in order to optimize the bioavailability. It also has a short half-life which means that it is quickly cleared from the body

Historically, R-lipoic acid was discovered by investigators at the University of Wisconsin and was initially identified as a potato extract required for cell growth. The compound was subsequently formally identified in 1951 by investigators at the University of Texas. It was first used in clinical practice in 1959 for the treatment of amanita phalloides (death cap mushroom) poisoning.

Fast forward to today, when there are 514 ALA products for sale on Amazon and it costs approximately $0.06 per 600mg.

Can You Get Alpha Lipoic Acid From Food?

ALA is created endogenously by plants and animals and can be found in vegetables (spinach, broccoli and tomatoes) and animal viscera. It is difficult to get accurate assessments of the ALA content of common foods.

Is There Any Research?

There are 4676 publications relating to ALA which include 257 human clinical trials. The sections that follow focus on human data and explicitly state if animal or in vitro data are being quoted at any time. Using a generally accepted hierarchy of source material, systematic reviews of human clinical trials trump data from an individual human clinical trial which trumps observational human data which trumps animal data which in turn trumps laboratory data.

Some bloggers seem to think that animal data can be given the same weight as human data – either they don’t know any better or they are just being irresponsible.

Does Alpha Lipoic Acid Help Diabetes?

The following summary of the literature shows the importance of following the generally accepted hierarchy for source data.

Laboratory Data: Experimental models suggest that ALA may help diabetic neuropathy via improvements in oxidative stress with downstream benefits on nerve blood flow and nerve conduction velocity. That would be a yes vote for ALA in diabetic neuropathy (if we were that type of blogger).

Single Randomized Study: A large German study randomised 509 diabetic patients to induction therapy with ALA 600mg intravenously for 3 weeks followed by ALA 600mg three times daily for six months or induction therapy with ALA 600mg intravenously for 3 weeks followed by placebo three times daily or induction therapy with placebo intravenously for 3 weeks followed by placebo three times daily (1).

The aim of the study was to evaluate the effect of ALA on diabetic neuropathy. The study showed no significant differences between the groups suggesting that ALA had no significant effect on diabetic neuropathy. That would be a no vote for ALA in diabetic neuropathy (if we were that type of blogger).

Meta-analysis: A 2012 systematic review of ALA in diabetic neuropathy interrogated data from 15 trials of 1058 patients (2). Only studies of intravenous ALA at a dose of 300-600mg for 2 to 4 weeks were considered in the review.

The reviewers found that ALA was associated with significant improvements in efficacy and nerve velocity outcomes.  Of note, the overall quality of the trials was deemed to be poor – most had very small sample sizes and failed to report their methods of randomization.

As you can see, the conclusions differed radically depending on the which source data was used. It gets even more complex.

That was just looking at diabetic neuropathy which is just one clinical manifestation of diabetes. What about other manifestations of diabetes?

Let’s start with glycemic control and oxidative stress.

An Iranian study compared ALA 300 mg daily to placebo in a randomised controlled 8 week trial. (3) Significant decreases in blood glucose, post prandial glucose, insulin resistance and glutathione peroxidase were noted in the ALA arm.

A total of 38 patients with type 2 DM were recruited and randomly assigned to either placebo or treatment at various doses of ALA (300, 600, 900, and 1200 mg/day) for 6 months (4).

Results showed  a non-significant decrease in fasting blood glucose, HbA1c in a dose-dependent manner. Urinary PGF2α-Isoprostanes (F2α-IsoP) is a marker of lipid peroxidation and was noted to increase in placebo but not in the ALA-treated groups. 8-Hydroxy-2′-deoxyguanosine (8-OHdG) is a marker of oxidative damage due to hyperglycemia and was similar in both placebo and ALA groups.

Overall (despite what the authors of the study say) this is a negative outcome for ALA in diabetes as the results did not reach the level of statistical significance.

An Italian study looked at a food supplement containing ALA 600mg plus L-carnosine, zinc and vitamins or placebo in 105 patients with diabetes over three months and found significant improvements in glycemic control, lipid profile and oxidative stress markers (5). As always with combinations of foods or herbs, it is impossible to isolate out the impact of any single component.

Cardiac dysfunction is seen in patients with diabetes. Egyptian investigators found that ALA significantly increases glutathione levels and improved ventricular function in a cohort of patients with diabetes (6). The authors concluded that ALA may prevent or delay the risk of heart failure in patients with diabetes.

An overused cliche from the  self-help industry goes something like ‘If you want a better answer, then ask a better question’.

Well, that might just be true on this occasion. It is entirely daft to ask if ALA can help diabetes. That is way too simplistic. Which part of diabetes are we talking about? As we have seen, diabetes is a very complex problem with a myriad of manifestations.

Bottom Line

It is too simplistic to ask if ALA can help diabetes  as diabetes is a complex condition with a myriad of manifestations.  ALA may help with diabetic neuropathy but not other aspects of the disease.

Does It Help Your Eyes?

A Russian study looked at 45 patients (which the authors clarified as 90 eyes) with glaucoma who were given ALA 75 mg, ALA 150mg or topical hypotensive therapy for 1 month (7).

The original article is in Russian which limits us to the details in the abstract. It is unclear whether all patients received the local hypotensive therapy. The results showed that there was an improvement in biochemical parameters, visual function, and of the coefficient of efficacy of liquid discharged in the ALA 150mg group.

A study in 235 patients with diabetes evaluated ALA 600 mg per day or placebo for two years and found no benefits in terms of prevention of macular edema (8).

Another study looked at ALA versus placebo in 100 patients with the dry form of age-related macular  degeneration(9). The study showed that ALA treatment significantly improved vision-related quality of life in patients with dry age-related macular degeneration probably by increasing antioxidant activity.

That is the extent of human data on ALA in ophthalmology.

Bottom Line

There is no science to support a role for ALA in ophthalmology apart from age related macular degeneration.

Does It Prevent Memory Loss or Cognitive Decline?

ALA freely crosses the blood brain barrier which certainly makes it a potential candidate for brain health.

A group of British reviewers undertook a Cochrane review of ALA in dementia but found no clinical trials that met the selection criteria (10) . Not unreasonably they concluded that ‘until data from trials become available for analysis, ALA cannot be recommended for people with dementia’.

A study of omega-3 versus omega-3 plus ALA versus placebo in 39 patients with Alzheimer’s Disease showed that the combination of omega-3 plus ALA slowed cognitive and functional decline in AD over 12 months (11).

Another study looked at ALA supplementation (600mg) in 43 patients with Alzheimer’s Disease over an observation period of up to 48 months and found a slower than expected rate of progression (12). However this was just an observational study and as such is very limited in terms of its generalizability.

Bottom Line

There are no data to support ALA for dementia and only very small, poor quality studies of ALA in Alzheimer’s Disease.

Does it Boost Gluthianone (and does that matter?)?

Glutathione is a sulfur tripeptide containing glutamate, cysteine and glycine and is a potent anti-oxidant. ALA is often referred to as a ‘glutathione-replenishing disulfide’ which gives us a hint that ALA boosts glutathione. In fact, DHLA which is the reduced from of ALA raises the levels of glutathione intracellularly.

A longitudinal study was carried out in children with severe kwashiorkor (severe malnutrition) (13).  Red blood cell glutathione is reduced in children with kwashiorkor. The study hypothesis was that the oral administration of glutathione, α-lipoic acid, and N-acetylcysteine would support the restoration of intracellular glutathione concentrations and would confer a survival advantage.

The children were randomized to either standard nutritional supplements or standard nutritional supplements plus glutathione or standard nutritional supplements plus N-acetyl cysteine or standard nutritional supplements plus ALA 100mg. Blood glutathione levels increased in the glutathione and ALA arms and correlated positively with survival rates. The authors concluded that  anti-oxidants such as glutathione and ALA should be added to the WHO treatment protocol for severe malnutrition.

In the discussion section of the paper, the authors suggest that ALA acts by mimicking glutathione and caution that ALA may not replace all the functions of glutathione at a cellular level. This is interesting as this is quite different to the general consensus on the mechanism of action of ALA in relation to glutathione which relates to recycling of glutathione.

Another key study looked at the effect of ALA on glutathione levels in 33 HIV infected patients (14). Patients were either given placebo or ALA 300mg three times daily for six months.

The study found a statistically significant increase in glutathione in the ALA treatment arm.

Bottom Line

ALA has been shown to increase glutathione levels but there is limited information about the clinical importance of this in the general population apart from what we know can infer about glutathione as an antioxidant.

Does It Help Protect Skin?

An in vivo study found that ALA possessed moderate antioxidant capacity on the human stratum corneum but compared poorly to vitamins E and C which have excellent antioxidant activity (15).

Vitiligo is a skin disorder which involves depigmentation of the skin and is associated with oxidative stress. Narrowband UVB in used in the treatment of vitiligo. ALA was tested in 35 patients with vitiligo who were randomized to either placebo or a blend of ALA, fatty acids and vitamins C and E (16) . The ALA containing blend was associated with a statistically significantly higher response to UVB therapy (repigmentation) and a significant reduction in oxidative stress.

Bottom Line

There is very limited data on ALA in dermatology and as such it is not possible to make any meaningful evidence based recommendations at this time.

Does It Help with Weight Loss?

A 2017 meta-analysis of ALA supplementation for weight loss identified 10 relevant articles (17). The review found that ALA was associated with a statistically significant 1.27 kg weight loss and a -0.43kg/square meter change in BMI compared to placebo.

There was no significant association between ALA dose and changes in BMI or weight.

Bottom Line

ALA has been shown to be associated with a small but significant weight loss as compared to placebo.

Does It Help Metabolic Syndrome?

An open label randomized study in 40 patients with dual diagnoses of psoriasis and the metabolic syndrome looked at etanercept versus etanercept plus a blend of co-enzyme Q, krill oil, lipoid acid, resveratrol, vitamin E plus selenium (18).

The investigators report a statistically significant difference in HDL, cholesterol and triglycerides in favor of the herbal blend intervention arm. All very interesting but it is too complex to begin to unravel all the confounders in order to isolate out the effect of ALA in the general population of people with the metabolic syndrome.

Bottom Line

There is no clear evidence linking ALA to the metabolic syndrome.

Is Alpha Lipoic Acid (and or Supplementation) Safe?

Standard oral doses of ALA range between 300 and 600mg daily. The safe upper limit has not been defined but doses of up to 1800mg per day have been used safely.

Side effects are usually mild and transient and include nausea, urticaria and itching. ALA can increase the risk of hypoglycaemia in patients taking blood sugar lowering medications. It can also lower levels of thyroid hormone replacement therapies and levels of vitamin B1.

Conclusion

There is very limited generalizable human clinical data available on ALA. There is even less high quality positive science linking ALA to positive human health benefits.

That does not give anyone a license to upgrade in vitro or animal data as a basis for recommending ALA for any particular patient population.

There are lots of unanswered questions in medicine but I would rather live with the uncertainty than have a blogger or s0-called guru fill in the blanks for me.

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