Alpha-Lipoic Acid

1. What conditions has Alpha-Lipoic Acid been studied for?

• Peripheral arterial disease (PAD) with intermittent claudication (600 mg/day for 3 months; walking tolerance and claudication pain outcomes).

• Dementia of the Alzheimer type in adults with Down syndrome (600 mg/day ALA as part of a combined antioxidant regimen with vitamin E and vitamin C for 2 years).

• Rheumatoid arthritis (RA) (ALA 900 mg/day for 4 weeks in a crossover trial; inflammatory cytokines and symptom scores).

• Obesity / pre-obesity and weight loss

  • Large randomized trial in obese adults: 1200 or 1800 mg/day for 20 weeks.

  • Open-label/observational-style intervention in pre-obese and obese adults: 800 mg/day for 4 months.

• Impaired glucose tolerance (IGT) in obesity (1 g/day ALA for 12 weeks, alone vs combined with exercise; oxidative/LDL oxidation outcomes and metabolic markers).

• Type 2 diabetes mellitus (T2DM) (dose-ranging 300–1200 mg/day for 6 months; glycemic markers and oxidative stress biomarkers).

• Diabetes-related oxidative stress and glycation (small volunteer study) using a combined antioxidant supplement including ALA (90 mg/day) for 6 weeks; HbA1c and antioxidant capacity.

• Acute mountain sickness (AMS) prevention as part of a combined antioxidant regimen including ALA 600 mg/day during ascent to 5200 m.

2. Does it work in treating those conditions? Summarize the evidence.

• PAD / claudication: Mixed and inconclusive. In a small randomized, double-blind trial (n=28), the ALA group improved within-group for initial claudication pain time and peak pain ratings (both p<0.05), but the key group-by-time interaction was not significant (p>0.05), meaning superiority vs placebo was not clearly demonstrated. Inflammation (CRP) and oxidative stress (lipid hydroperoxides) were not different between groups at 3 months.

• Down syndrome with Alzheimer-type dementia (ALA as part of antioxidants): Negative. A 2-year randomized, double-blind, placebo-controlled trial (n=53) found no improvement or stabilization in cognitive outcomes vs placebo, despite good compliance and increased plasma vitamin E levels.

• Rheumatoid arthritis: Negative over the studied timeframe. In a randomized, placebo-controlled, double-blind crossover trial (n=20), ALA (900 mg/day for 4 weeks) produced no significant differences vs placebo in TNF-α, IL-1β, IL-6, CRP, or disease severity scores (KHAQ, VAS).

• Obesity / weight loss:

  • Randomized trial evidence: In a 20-week randomized, double-blind, placebo-controlled trial (n=360), 1800 mg/day ALA produced a modest but statistically significant weight loss vs placebo (about 2.1% greater loss; P<.05). The 1200 mg/day dose is mentioned but the abstract highlights significance for 1800 mg/day.

  • Non-randomized/less controlled evidence: A large 4-month intervention (800 mg/day) reported substantial reductions in weight, BMI, blood pressure, and waist circumference in pre-obese and obese participants (p<0.001). However, because the abstract does not describe randomization/placebo control, the magnitude of effect is harder to interpret (potential confounding from diet, lifestyle changes, regression to the mean, etc.).

• Obesity with impaired glucose tolerance (IGT): Concerning signals when ALA is used without exercise. In a randomized study (n=24), ALA-only (1 g/day) was associated with a greater rate of LDL oxidation post-intervention (p<0.05 vs pre-intervention), although total oxidant status decreased. When ALA was combined with exercise, LDL oxidation was attenuated and total antioxidant capacity increased (p<0.05). There were no selective treatment differences in glycemic regulation (p>0.05).

• Type 2 diabetes (glycemic control and oxidative stress): Suggestive but not definitive. In a 6-month randomized, double-blind, placebo-controlled dose-ranging trial (n=38), fasting glucose and HbA1c trended downward in a dose-dependent manner. Placebo showed increased urinary F2α-isoprostanes while ALA-treated groups did not, suggesting possible suppression of lipid peroxidation. However, several endpoints were unchanged (e.g., 8-OHdG, microalbumin, creatinine), and the abstract describes effects as trends rather than clearly significant for all comparisons.

• Acute mountain sickness prevention (ALA as part of antioxidants): Negative. In a double-blind randomized trial during ascent to 5200 m (n=83), the antioxidant regimen including ALA showed no difference vs placebo in AMS incidence or severity (e.g., Day 2 at 5200 m: 69% vs 66%, P=0.74), nor in oxygen saturation or pulmonary artery systolic pressure.

• Diabetes oxidative stress / HbA1c (ALA as part of antioxidants): In a very small study (n=8 diabetics) using a combined antioxidant supplement including ALA 90 mg/day for 6 weeks, HbA1c decreased during supplementation and rose again after stopping; plasma antioxidant capacity improved. Because this was not described as randomized and used a combination product, it cannot isolate ALA’s effect.

3. What health benefits does it have?

• Modest weight loss (adjunctive): In a large randomized trial, 1800 mg/day produced a statistically significant but modest additional weight loss vs placebo over 20 weeks (~2.1% difference).

• Possible improvement in claudication pain measures in PAD: The PAD trial showed within-group improvements in initial claudication pain time and peak pain ratings with ALA, though superiority vs placebo was not established by interaction testing.

• Potential improvements in oxidative stress markers in metabolic disease (context-dependent):

  • In T2DM, ALA groups did not show the placebo-associated rise in urinary F2α-isoprostanes (a lipid peroxidation marker), suggesting possible suppression of lipid peroxidation.

  • In obese IGT participants, ALA plus exercise increased total antioxidant capacity; ALA alone lowered total oxidant status but increased LDL oxidation (a potentially adverse tradeoff).

• Possible glycemic benefit in T2DM (signal, not definitive): The 6-month dose-ranging trial reported dose-dependent downward trends in fasting glucose and HbA1c.

4. Does it have any downsides or side effects?

• Skin reactions (noted in obesity RCT): In the 20-week randomized trial, urticaria and itching were the most common adverse events in ALA groups; generally mild and transient.

• Potential adverse lipid oxidation effect in IGT when used without exercise: In obese IGT participants, ALA-only increased the rate of LDL oxidation post-intervention (p<0.05 vs pre-intervention), and authors cautioned it may increase atherogenicity when taken in isolation of exercise.

• Minor side effects in T2DM dose-ranging trial: ALA was described as well tolerated with some minor side effects (not specified in the abstract).

• No serious adverse events reported in several trials: PAD trial (600 mg/day, 3 months) reported no serious side effects; Down syndrome dementia antioxidant trial reported no serious adverse events attributed to treatment; AMS antioxidant trial did not report benefit and did not highlight serious harms in the abstract.

• Laboratory assay interference (important for monitoring): One study noted in vivo conversion of ALA to DHLA caused potent interference with a standard fructosamine assay, limiting its use for that measurement in their study context.

5. Is it beneficial or harmful for any genetic variations (pharmacogenomics)?

The provided abstracts do not evaluate outcomes by genotype, nor do they report pharmacogenomic analyses (e.g., variants affecting ALA transport, metabolism, antioxidant pathways, or diabetes/obesity risk genes). Therefore:

• No evidence from these abstracts that ALA is specifically beneficial or harmful for particular genetic variants.

• The Down syndrome dementia trial involves a genetic condition (trisomy 21), but it tested a combined antioxidant regimen and found no cognitive benefit; this does not establish a genotype-specific ALA response, only that this antioxidant approach was ineffective in that population.

References

1. Effects of alpha-lipoic acid supplementation in peripheral arterial disease: a pilot study
   Heather K Vincent, Cheryl M Bourguignon, Kevin R Vincent, Ann G Taylor (2007)
2. Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation
   Ira T Lott, Eric Doran, Vinh Q Nguyen, Anne Tournay, Elizabeth Head (2011)
3. Effects of antioxidant supplements intervention on the level of plasma inflammatory molecules and disease severity of rheumatoid arthritis patients
   Sang-Cheol Bae, Won-Jin Jung, Eun-Ju Lee, Rina Yu, Mi-Kyung Sung (2009)
4. Effect of α-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose tolerance
   Andrea M McNeilly, Gareth W Davison, Marie H Murphy, Nida Nadeem, Tom Trinick (2011)
5. Alpha-lipoic acid supplementation: a tool for obesity therapy?
   M G Carbonelli, L Di Renzo, M Bigioni, N Di Daniele, A De Lorenzo (2010)
6. Effects of alpha-lipoic Acid on body weight in obese subjects
   Eun Hee Koh, Woo Je Lee, Sang Ah Lee, Eun Hee Kim, Eun Hee Cho (2011)
7. Oral antioxidant supplementation does not prevent acute mountain sickness: double blind, randomized placebo-controlled trial
   J K Baillie, A A R Thompson, J B Irving, M G D Bates, A I Sutherland (2009)
8. A preliminary evaluation of a novel method to monitor a triple antioxidant combination (vitamins E, C and α-lipoic acid) in diabetic volunteers using in vitro methaemoglobin formation
   Michael D Coleman, Sandra Fernandes, Leena Khanderia (2003)
9. Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid: a randomized double-blinded placebo-controlled study
   Supatra Porasuphatana, Suthi Suddee, Atinuch Nartnampong, Julraht Konsil, Busakorn Harnwong (2012)
10. Complementary therapy in diabetic patients with chronic complications: a pilot study
    P Palacka, J Kucharska, J Murin, K Dostalova, A Okkelova (2010)
11. The effects of lipoic acid and α-tocopherol supplementation on the lipid profile and insulin sensitivity of patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial
    Andreia Madruga de Oliveira, Patrícia Helen Carvalho Rondó, Liania Alves Luzia, Francisco Homero D'Abronzo, Vanessa Kristine Illison (2011)
12. Alpha-lipoic acid does not acutely affect resistance and conduit artery function or oxidative stress in healthy men
    James E Sharman, Prasad Gunaruwan, Wade L Knez, Matthias Schmitt, Susan A Marsh (2004)
13. Effects of alpha-lipoic acid supplementation on inflammation, oxidative stress, and serum lipid profile levels in patients with end-stage renal disease on hemodialysis
    Tannaz Khabbazi, Reza Mahdavi, Javid Safa, Parvin Pour-Abdollahi (2012)
14. Alpha-lipoic acid improves endothelial dysfunction in patients with subclinical hypothyroidism
    Xiang G D, Pu J H, Sun H L, Zhao L S (2010)
15. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study
    Srikanth Sola, Muhammad Q S Mir, Faiz A Cheema, Nadya Khan-Merchant, Rekha G Menon (2005)
16. Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome
    D Walter Wray, Abhimanyu Uberoi, Lesley Lawrenson, Damian M Bailey, Russell S Richardson (2009)
17. Effects of supplementation with alpha-lipoic acid on exercise-induced activation of coagulation
    Claus Weiss, Angelika Bierhaus, Peter P Nawroth, Peter Bärtsch (2005)
18. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial
    Dan Ziegler, Phillip A Low, William J Litchy, Andrew J M Boulton, Aaron I Vinik (2011)
19. Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial
    B B Heinisch, M Francesconi, F Mittermayer, G Schaller, G Gouya (2010)
20. Effect of alpha-lipoic acid combined with creatine monohydrate on human skeletal muscle creatine and phosphagen concentration
    Darren G Burke, Philip D Chilibeck, Gianni Parise, Mark A Tarnopolsky, Darren G Candow (2003)