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Alpha-Lipoic Acid
Indications
Alpha-lipoic acid (ALA) is a caprylic acid-derived antioxidant. The compound is synthesized in the mitochondria and is a cofactor in the enzymatic nutrient breakdown.[1] ALA is also available in red meat, beets, carrots, potatoes, spinach, and broccoli. ALA consists of a dithiol functional group that eliminates reactive oxygen species (ROS) by reducing the oxidized forms of other antioxidants.[2] The organosulfur compound was discovered in 1937 when scientists found a type of bacteria that uses potato juice for reproduction.[3]
ALA has recently gained a reputation as an antioxidant. In the reduced form, dihydrolipoate reacts and neutralizes ROS, such as superoxide radicals, singlet oxygen, and hydroxyl radicals. Thus, ALA is highly beneficial in several oxidative-stress-associated conditions such as ischemia-reperfusion or radiation injury.[4]
Secondly, numerous studies have strongly supported the role of ALA in treating diabetic neuropathy. ALA does so by enhancing nitric oxide-mediated endothelium-dependent vasodilation, improving microcirculation in patients with diabetic polyneuropathy.[5] Additionally, when taken with avocado or soybean unsaponifiable compounds, ALA is shown to significantly suppress prostaglandin E-2 production, a key cytokine in the pathogenesis of inflammation.[6]
ALA possesses an excellent iron-chelation property. The thiol groups in ALA are responsible for chelating irons. By increasing the glutathione levels inside the cells, ALA and dihydrolipoate excrete toxins, especially toxic metals, into the body. Lipoic acid preferentially binds to Zn, Pb, and Cu. On the other hand, dihydrolipoate forms complexes with Fe, Zn, Hg, Pb, and Cu.[7]
So far, ALA has the most substantial evidence of the therapeutic effect in diabetic neuropathy and oxidative stress conditions. There is still a need for more studies on the benefits of other conditions such as HIV/AIDS, liver disease, and weight loss. According to the FDA, ALA is safe and effective, and promising uses can be explored in future studies.
FDA-Approved Indications
ALA has no approved indication as a dietary supplement available over the counter.
Mechanism of Action
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Mechanism of Action
The dithiolane ring dictates ALA's chemical reactivity. Two forms of ALA are oxidized lipoic acid (LA) and reduced dihydrolipoic acid (DHLA). Both are capable of scavenging a variety of ROS. DHLA is a potent antioxidant that can neutralize free radicals. Furthermore, ALA simultaneously regenerates other antioxidant factors, such as vitamins C and E, increasing glutathione synthesis.[7] ALA is generally involved in keto acid oxidative decarboxylation processes and is a growth factor for some organisms.[8]
In the pathogenesis of inflammation, factor NF-kB modulates inflammatory cytokines, including interleukins (ILs) such as IL-1β and IL-6. ALA inhibits I Kappa B kinase, suppressing the activation of inflammatory cytokines.[9]
Pharmacokinetics: Absorption, volume of distribution, metabolism, and excretion are not well-established for ALA.
Administration
ALA is available as an oral supplement and intravenous injection. Studies postulate promising therapeutic properties in several conditions, including type 1 and 2 diabetes mellitus (DM), neuropathy, and ischemic-perfusion injury.
Oral: Data demonstrates that daily oral supplementation of 300 mg of ALA over 3 months maintains and improves functional vision in type 1 and type 2 diabetes mellitus patients.[10] However, ALA can be orally dosed between 600 mg and 1800 mg daily for up to 6 months.
Intravenous injection: The study shows evidence for IV treatment of 600 mg daily in improving positive neuropathic symptoms and neuropathic deficits.[11]
Special Patient Populations
Hepatic impairment: No research has examined the effects of hepatic impairment on ALA dosing. Research has examined ALA's role in treating certain liver conditions.[12][13]
Renal impairment: There is no research documenting dose adjustments of ALA for patients with renal impairment. Some research has examined the role of ALA and other compounds in reducing oxidative stress in diabetic nephropathy.[14]
Pregnant women: To date, research shows ALA supplementation during pregnancy is safe.[15] More data is needed to establish the role of ALA supplementation in pregnancy.
Breastfeeding women: There is a lack of reliable data regarding the safety of alpha-lipoic use during breastfeeding.
Pediatric and older patients: There is no data regarding the use of ALA in these specific patient populations.
Adverse Effects
ALA is considered a safe supplementation without any adverse effects. One study supports the safety of the drug, and an adult can take up to 2400 mg without experiencing any harmful adverse effects.[16] High doses of ALA are not recommended as higher doses provide no additional benefits. The most common adverse effects reported with ALA are headache, heartburn, nausea, and vomiting.[17]
A 1996 ALA study on 6 rhesus monkeys showed that excess lethal doses in primates would cause hepatic necrosis. Researchers noted that 3 out of 6 monkeys that received 90 mg/kg to 100 mg/kg of intravenous ALA exhibited large necrotic areas in the muscles of their thighs, the liver, the heart, and the kidneys. This situation led the researchers to conclude that exceptionally high doses of IV ALA can produce the same symptoms that smaller doses prevent.[18]
Contraindications
Box Warning
There are no box warnings for ALA.
Warnings and Precautions
There are very few studies on the contraindications of ALA supplementation. However, due to the adverse effects of ALA on animals and due to ALA's physiological effects, one should consult with a doctor if they have the following conditions:
- Liver disease
- Consumption of large amounts of alcohol
- Diabetes (ALA is known to lower blood sugar)
- Thyroid disorder
- Thiamine deficiency
Also, one should stop using ALA immediately if an allergic reaction occurs, such as skin rash, nausea, or vomiting. There is no established contraindication for using ALA in pregnant women and infants.
Monitoring
Though ALA intoxication is extremely rare, close monitoring is necessary for children who are around diabetic patients. A case of ALA intoxication was reported in which the patient attempted to commit suicide. Therefore, it is vital to monitor ALA use in people who have suicidal thoughts or psychological issues.[19] Patients admitted to the emergency room with acute ALA poisoning usually present with tachycardia, neurologic effects, metabolic acidosis, and T wave inversion in the EKG.[20]
There is no established therapeutic index of ALA in humans. However, studies show that safety dosage is defined in animals. The experimental values are 400 mg/kg to 500 mg/kg for dogs, 30 mg/kg for cats, and 500 mg/kg for mice. In animal studies, high levels of ALA were reported to cause hepatotoxicity, apathy, confusion, and hypokinesis.[7] Therefore, patient monitoring may be advisable when under high doses of ALA.
Toxicity
ALA is generally considered a safe drug. A daily dose of 200 mg/day to 2400 mg/day of ALA is deemed safe without significant adverse effects. However, there is no reported safe dose in children.[21]
A notable case in literature demonstrated status epilepticus (SE) that subsided within a few days. The seizures were treated per normal standards for SE.[22]
In the last 2 decades, there have been few reported cases of ALA toxicity in humans. Most of these cases occur in children and are treatable. Though there is no established lethal dosage of ALA for humans, studies have shown that a high dose of 121 mg/kg body weight/day was associated with alterations in liver enzymes and liver function.[16] Therefore, there are potentially harmful adverse effects from overdosing on ALA, and more studies are necessary to determine the toxicity.
Enhancing Healthcare Team Outcomes
Effective and safe use of ALA supplements require communication between healthcare team members, including primary care clinicians and pharmacists. Patients should consult their primary clinician before using ALA, and these frontline resources can provide patients with the proper dosage and safety information. ALA is a generally safe supplement that can be purchased over the counter, but clinicians can monitor and treat any adverse events. It is essential to have appropriate cooperation between interprofessional team members to ensure that the patient receives optimal benefits from ALA supplementation.
References
Packer L, Cadenas E. Lipoic acid: energy metabolism and redox regulation of transcription and cell signaling. Journal of clinical biochemistry and nutrition. 2011 Jan:48(1):26-32. doi: 10.3164/jcbn.11-005FR. Epub 2010 Dec 29 [PubMed PMID: 21297908]
Golbidi S, Badran M, Laher I. Diabetes and alpha lipoic Acid. Frontiers in pharmacology. 2011:2():69. doi: 10.3389/fphar.2011.00069. Epub 2011 Nov 17 [PubMed PMID: 22125537]
Pirlich M, Kiok K, Sandig G, Lochs H, Grune T. Alpha-lipoic acid prevents ethanol-induced protein oxidation in mouse hippocampal HT22 cells. Neuroscience letters. 2002 Aug 9:328(2):93-6 [PubMed PMID: 12133563]
Level 3 (low-level) evidencePacker L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. Free radical biology & medicine. 1995 Aug:19(2):227-50 [PubMed PMID: 7649494]
Level 3 (low-level) evidenceVallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic Acid and diabetic neuropathy. The review of diabetic studies : RDS. 2009 Winter:6(4):230-6. doi: 10.1900/RDS.2009.6.230. Epub 2009 Dec 30 [PubMed PMID: 20043035]
Frondoza CG, Fortuno LV, Grzanna MW, Ownby SL, Au AY, Rashmir-Raven AM. α-Lipoic Acid Potentiates the Anti-Inflammatory Activity of Avocado/Soybean Unsaponifiables in Chondrocyte Cultures. Cartilage. 2018 Jul:9(3):304-312. doi: 10.1177/1947603516686146. Epub 2017 Jan 10 [PubMed PMID: 29156944]
Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochimica et biophysica acta. 2009 Oct:1790(10):1149-60. doi: 10.1016/j.bbagen.2009.07.026. Epub 2009 Aug 4 [PubMed PMID: 19664690]
Level 3 (low-level) evidencePark S, Karunakaran U, Jeoung NH, Jeon JH, Lee IK. Physiological effect and therapeutic application of alpha lipoic acid. Current medicinal chemistry. 2014:21(32):3636-45 [PubMed PMID: 25005184]
Li G, Fu J, Zhao Y, Ji K, Luan T, Zang B. Alpha-lipoic acid exerts anti-inflammatory effects on lipopolysaccharide-stimulated rat mesangial cells via inhibition of nuclear factor kappa B (NF-κB) signaling pathway. Inflammation. 2015 Apr:38(2):510-9. doi: 10.1007/s10753-014-9957-3. Epub [PubMed PMID: 24962643]
Level 3 (low-level) evidenceGębka A, Serkies-Minuth E, Raczyńska D. Effect of the administration of alpha-lipoic acid on contrast sensitivity in patients with type 1 and type 2 diabetes. Mediators of inflammation. 2014:2014():131538. doi: 10.1155/2014/131538. Epub 2014 Feb 10 [PubMed PMID: 24665163]
Level 2 (mid-level) evidenceZiegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabetic medicine : a journal of the British Diabetic Association. 2004 Feb:21(2):114-21 [PubMed PMID: 14984445]
Level 1 (high-level) evidenceYu Y, Xu J, Li H, Lv J, Zhang Y, Niu R, Wang J, Zhao Y, Sun Z. α-Lipoic acid improves mitochondrial biogenesis and dynamics by enhancing antioxidant and inhibiting Wnt/Ca(2+) pathway to relieve fluoride-induced hepatotoxic injury. Chemico-biological interactions. 2023 Nov 1:385():110719. doi: 10.1016/j.cbi.2023.110719. Epub 2023 Sep 20 [PubMed PMID: 37739047]
Dugbartey GJ, Alornyo KK, Adams I, Atule S, Obeng-Kyeremeh R, Amoah D, Adjei S. Targeting hepatic sulfane sulfur/hydrogen sulfide signaling pathway with α-lipoic acid to prevent diabetes-induced liver injury via upregulating hepatic CSE/3-MST expression. Diabetology & metabolic syndrome. 2022 Oct 13:14(1):148. doi: 10.1186/s13098-022-00921-x. Epub 2022 Oct 13 [PubMed PMID: 36229864]
Darenskaya M, Kolesnikov S, Semenova N, Kolesnikova L. Diabetic Nephropathy: Significance of Determining Oxidative Stress and Opportunities for Antioxidant Therapies. International journal of molecular sciences. 2023 Aug 3:24(15):. doi: 10.3390/ijms241512378. Epub 2023 Aug 3 [PubMed PMID: 37569752]
Parente E, Colannino G, Bilotta G, Espinola MSB, Proietti S, Oliva MM, Neri I, Aragona C, Unfer V. Effect of Oral High Molecular Weight Hyaluronic Acid (HMWHA), Alpha Lipoic Acid (ALA), Magnesium, Vitamin B6 and Vitamin D Supplementation in Pregnant Women: A Retrospective Observational Pilot Study. Clinics and practice. 2023 Sep 15:13(5):1123-1129. doi: 10.3390/clinpract13050100. Epub 2023 Sep 15 [PubMed PMID: 37736936]
Level 2 (mid-level) evidenceCremer DR, Rabeler R, Roberts A, Lynch B. Safety evaluation of alpha-lipoic acid (ALA). Regulatory toxicology and pharmacology : RTP. 2006 Oct:46(1):29-41 [PubMed PMID: 16904799]
Level 3 (low-level) evidenceTheodosis-Nobelos P, Papagiouvannis G, Tziona P, Rekka EA. Lipoic acid. Kinetics and pluripotent biological properties and derivatives. Molecular biology reports. 2021 Sep:48(9):6539-6550. doi: 10.1007/s11033-021-06643-z. Epub 2021 Aug 22 [PubMed PMID: 34420148]
Vigil M, Berkson BM, Garcia AP. Adverse effects of high doses of intravenous alpha lipoic Acid on liver mitochondria. Global advances in health and medicine. 2014 Jan:3(1):25-7. doi: 10.7453/gahmj.2013.011. Epub [PubMed PMID: 24753992]
Level 3 (low-level) evidenceHadzik B, Grass H, Mayatepek E, Daldrup T, Hoehn T. Fatal non-accidental alpha-lipoic acid intoxication in an adolescent girl. Klinische Padiatrie. 2014 Sep:226(5):292-4. doi: 10.1055/s-0034-1372622. Epub 2014 May 8 [PubMed PMID: 24810749]
Level 3 (low-level) evidenceEmir DF, Ozturan IU, Yilmaz S. Alpha lipoic acid intoxicatıon: An adult. The American journal of emergency medicine. 2018 Jun:36(6):1125.e3-1125.e5. doi: 10.1016/j.ajem.2018.03.022. Epub 2018 Mar 13 [PubMed PMID: 29559356]
Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Möller W, Tritschler HJ, Mehnert H. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free radical research. 1999 Sep:31(3):171-9 [PubMed PMID: 10499773]
Level 1 (high-level) evidenceTolunay O, Çelik T, Kömür M, Gezgin AE, Kaya MS, Çelik Ü. A rare cause of status epilepticus; alpha lipoic acid intoxication, case report and review of the literature. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2015 Nov:19(6):730-2. doi: 10.1016/j.ejpn.2015.07.002. Epub 2015 Jul 18 [PubMed PMID: 26216607]
Level 3 (low-level) evidence