Lipoic Acid
Lipoic acid, also known as alpha-lipoic acid and thioctic acid, is an antioxidant that exists widely in nature. It is inconsistently produced by the human body and therefore is recommended to be obtained food and/or dietary supplements1. It functions as a cofactor for several important mitochondrial multienzyme complexes and is thus essential for aerobic metabolism2. Supplementation is considered to be a promising approach to improving outcomes in MS3.
In a live EAE animal model of MS, intravenous administration of lipoic acid was associated with less severe disease as indicated by degree of limb weakness and paralysis4. In a later EAE study, lipoic acid at a dose of 100 mg/kg was associated with less neuropathic pain and sensitivity to cold5.
In cells isolated from RRMS patients, lipoic acid was associated with a less inflammatory profile of monocytes and macrophages, including inhibition of monocyte secretion of cytokines relevant to MS (tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1β), likely due to increased levels of the immunomodulator cyclic AMP (cAMP)6.
In a randomized clinical study with MS patients, lipoic acid at a dose of 1200 mg per day was associated with improved antioxidant7 and anti-inflammatory activity7, as well as a good safety profile. The same dose was found to reduce inflammatory marker levels after 14 days, and to inhibit autoimmune cell movement into the CNS8. In SPMS patients, lipoic acid 1200 mg/day increased production of cAMP9.
There have been successful randomized clinical studies evaluating the effect of lipoic acid 1200 mg/day on mobility in SPMS patients. In one, lipoic acid was associated with improved “timed up and go”* test outcome, particularly with regard to turning time compared to pre-treatment and placebo10. In another, timed 25-foot walk was better, and there were significantly fewer falls with lipoic acid. Further, after two years of supplementation, yearly brain volume loss (also known as “atrophy”) was significantly less compared with placebo. Side effects were gastrointestinal upset and one case of unexpected renal failure that was resolved with discontinuation of lipoic acid11.
When lipoic acid 122 mg/day (370 mg/kg/day) was provided to pregnant rats in drinking water, it appeared to protect the adult offspring from developing metabolic symptoms associated with high fructose intake12. Other pregnant rat studies have shown maternal lipoic acid intake to be protective against the negative developmental effects in offspring the toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin13 and the medication valproic acid14. In humans, lipoic acid at doses of up to 800 mg/day has been used to improve fertility in men15-17 and women18 and to improve outcomes in high-risk pregnancies, e.g., preventing miscarriage, spontaneous abortion, or preterm delivery with oral doses ranging from 100 mg/day to 300 mg twice/day1. When administered to pregnant women managing gestational diabetes, lipoic acid up to 300 mg/day was not associated with risk to the fetus19-21. A 2020 systematic review and meta-analysis of randomized placebo-controlled clinical trials concluded that lipoic acid does not present a danger in pregnancy22.
Lipoic acid exists primarily in two forms: natural R-lipoic acid and synthetic S-lipoic acid, which are often combined. The combination is most commonly available in supplement form, but the natural R form can be increasingly found (and tends to be a bit more expensive). In a randomized crossover study in SPMS and PPMS patients, the R form was found to be better tolerated by the gastrointestinal system and more bioavailable, especially when taken 600 mg at a time23.
Food sources of lipoic acid include animal foods such as red and organ meats and plant foods like broccoli, tomatoes, spinach, and Brussels sprouts.
References
1.Petca A, Bot M, Maru N, et al. Benefits of alpha-lipoic acid in high-risk pregnancies (Review). Exp Ther Med. Nov 2021;22(5):1232. doi:10.3892/etm.2021.10666
2.Institute. LP. Lipoic Acid. Micronutrient Information Center https://lpi.oregonstate.edu/mic/dietary-factors/lipoic-acid
3.Xie H, Yang X, Cao Y, Long X, Shang H, Jia Z. Role of lipoic acid in multiple sclerosis. CNS Neurosci Ther. Dec 28 2021;doi:10.1111/cns.13793
4.Jones RE, Moes N, Zwickey H, Cunningham CL, Gregory WL, Oken B. Treatment of experimental autoimmune encephalomyelitis with alpha lipoic acid and associative conditioning. Brain Behav Immun. May 2008;22(4):538-43. doi:10.1016/j.bbi.2007.10.017
5.Dalenogare DP, Theisen MC, Peres DS, et al. TRPA1 activation mediates nociception behaviors in a mouse model of relapsing-remitting experimental autoimmune encephalomyelitis. Exp Neurol. Jun 2020;328:113241. doi:10.1016/j.expneurol.2020.113241
6.Fiedler SE, Spain RI, Kim E, Salinthone S. Lipoic acid modulates inflammatory responses of monocytes and monocyte-derived macrophages from healthy and relapsing-remitting multiple sclerosis patients. Immunol Cell Biol. Jan 2021;99(1):107-115. doi:10.1111/imcb.12392
7.Khalili M, Eghtesadi S, Mirshafiey A, et al. Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial. Nutr Neurosci. Jan 2014;17(1):16-20. doi:10.1179/1476830513Y.0000000060
8.Yadav V, Marracci G, Lovera J, et al. Lipoic acid in multiple sclerosis: a pilot study. Mult Scler. Apr 2005;11(2):159-65. doi:10.1191/1352458505ms1143oa
9.Fiedler SE, Yadav V, Kerns AR, et al. Lipoic Acid Stimulates cAMP Production in Healthy Control and Secondary Progressive MS Subjects. Mol Neurobiol. Jul 2018;55(7):6037-6049. doi:10.1007/s12035-017-0813-y
10.Loy BD, Fling BW, Horak FB, Bourdette DN, Spain RI. Effects of lipoic acid on walking performance, gait, and balance in secondary progressive multiple sclerosis. Complement Ther Med. Dec 2018;41:169-174. doi:10.1016/j.ctim.2018.09.006
11.Spain R, Powers K, Murchison C, et al. Lipoic acid in secondary progressive MS: A randomized controlled pilot trial. Neurol Neuroimmunol Neuroinflamm. Sep 2017;4(5):e374. doi:10.1212/NXI.0000000000000374
12.Rabaglino MB, Moreira-Espinoza MJ, Lagares C, et al. Maternal intake of alpha-lipoic acid prevents development of symptoms associated with a fructose-rich diet in the male offspring in Wistar rats. J Dev Orig Health Dis. Oct 2021;12(5):758-767. doi:10.1017/S2040174420001178
13.Yuan M, Sano H, Nishino T, et al. alpha-Lipoic acid eliminates dioxin-induced offspring sexual immaturity by improving abnormalities in folic acid metabolism. Biochem Pharmacol. Apr 2023;210:115490. doi:10.1016/j.bcp.2023.115490
14.Ghoneim FM, Alrefai H, Elsamanoudy AZ, Abo El-Khair SM, Khalaf HA. The Protective Role of Prenatal Alpha Lipoic Acid Supplementation against Pancreatic Oxidative Damage in Offspring of Valproic Acid-Treated Rats: Histological and Molecular Study. Biology (Basel). Aug 20 2020;9(9)doi:10.3390/biology9090239
15.Gamidov SI, Ovchinnikov RI, Popova AY. [Double-blind, randomized placebo-controlled study of efficiency and safety of complex acetyl-L-carnitine, L-carnitine fumarate and alpha-lipoic acid (Spermactin Forte) for treatment of male infertility]. Urologiia. Sep 2019;(4):62-68.
16.Habibi M, Fakhari Zavareh Z, Abbasi B, et al. Alpha-Lipoic Acid Supplementation for Male Partner of Couples with Recurrent Pregnancy Loss: A Post hoc analysis in Clinical Trial. Int J Fertil Steril. Jan 1 2023;17(1):67-74. doi:10.22074/ijfs.2022.543027.1222
17.Scaruffi P, Licata E, Maccarini E, et al. Oral Antioxidant Treatment of Men Significantly Improves the Reproductive Outcome of IVF Cycles. J Clin Med. Jul 23 2021;10(15)doi:10.3390/jcm10153254
18.Novielli C, Anelli GM, Lisso F, et al. Effects of alpha-lipoic acid and myo-inositol supplementation on the oocyte environment of infertile obese women: A preliminary study. Reprod Biol. Dec 2020;20(4):541-546. doi:10.1016/j.repbio.2020.10.002
19.Aslfalah H, Jamilian M, Khosrowbeygi A. Elevation of the adiponectin/leptin ratio in women with gestational diabetes mellitus after supplementation with alpha-lipoic acid. Gynecol Endocrinol. Mar 2019;35(3):271-275. doi:10.1080/09513590.2018.1519795
20.Aslfalah H, Jamilian M, Rafiei F, Khosrowbeygi A. Reduction in maternal serum values of glucose and gamma-glutamyltransferase after supplementation with alpha-lipoic acid in women with gestational diabetes mellitus. J Obstet Gynaecol Res. Feb 2019;45(2):313-317. doi:10.1111/jog.13842
21.Mandani M, Badehnoosh B, Jalali-Mashayekhi F, Tavakoli-Far B, Khosrowbeygi A. Alpha-lipoic acid supplementation effects on serum values of some oxidative stress biomarkers in women with gestational diabetes. Gynecol Endocrinol. Dec 2021;37(12):1111-1115. doi:10.1080/09513590.2021.1963955
22.Fogacci F, Rizzo M, Krogager C, et al. Safety Evaluation of alpha-Lipoic Acid Supplementation: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Clinical Studies. Antioxidants (Basel). Oct 19 2020;9(10)doi:10.3390/antiox9101011
23.Cameron M, Taylor C, Lapidus J, Ramsey K, Koop D, Spain R. Gastrointestinal Tolerability and Absorption of R- Versus R,S-Lipoic Acid in Progressive Multiple Sclerosis: A Randomized Crossover Trial. J Clin Pharmacol. Aug 2020;60(8):1099-1106. doi:10.1002/jcph.1605
* Timed up and go test: 1. Stand up from the chair, 2. Walk to the line on the floor at your normal pace, 3. Turn, 4. Walk back to the chair at your normal pace, 5. Sit down again. (Source: Centers for Disease Control https://www.cdc.gov/steadi/pdf/TUG_test-print.pdf)