View source for Lipoic acid

{{Distinguish|linolenic acid|linoleic acid|α-Linolenic acid{{!}}alpha-Linolenic acid}}
{{Chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477002603
| ImageFile_Ref = {{chemboximage|correct|??}}
| ImageFile = Lipoic acid.svg
| ImageFile1 = Lipoic-acid-3D-vdW.png
| ImageFile2 = File:Lipoic-acid-from-xtal-3D-bs-17.png
| ImageFile3 = Lipoová kyselina.jpg
| IUPACName = (''R'')-5-(1,2-Dithiolan-3-yl)pentanoic acid
| OtherNames = α-Lipoic acid; Alpha lipoic acid; Thioctic acid;  6,8-Dithiooctanoic acid
|Section1={{Chembox Identifiers
| IUPHAR_ligand = 4822
| Beilstein = 81851
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5886
| EINECS = 214-071-2
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C16241
| InChI = 1/C8H14O2S2/c9-8(10)4-2-1-3-7-5-6-11-12-7/h7H,1-6H2,(H,9,10)/t7-/m1/s1
| InChIKey = AGBQKNBQESQNJD-SSDOTTSWBZ
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 134342
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C8H14O2S2/c9-8(10)4-2-1-3-7-5-6-11-12-7/h7H,1-6H2,(H,9,10)/t7-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = AGBQKNBQESQNJD-SSDOTTSWSA-N
| CASNo1_Ref = {{cascite|correct|CAS}}
| CASNo1 = 1200-22-2
| CASNo1_Comment = (''R'')
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 1077-28-7
| CASNo_Comment = (racemate)
| UNII1_Ref = {{fdacite|correct|FDA}}
| UNII1= VLL71EBS9Z
| UNII1_Comment = (''R'')
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 73Y7P0K73Y
| UNII_Comment = (racemate)
| PubChem = 6112
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00166
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 30314
| SMILES = O=C(O)CCCC[C@H]1SSCC1
| MeSHName = Lipoic+acid

 }}
|Section2={{Chembox Properties
| C=8 | H=14 | O=2 | S=2
| Appearance = Yellow needle-like crystals
| Solubility = 0.24 g/L<ref name="pubmed">{{cite web |url= https://pubchem.ncbi.nlm.nih.gov/compound/thioctic_acid#section=Physical-Description|title=Lipoic Acid |author=<!--Not stated--> |website=Pubmed |publisher=NCBI |access-date=October 18, 2018 }}</ref>
| SolubleOther = Soluble
| Solvent = ethanol 50 mg/mL
| Density =
| MeltingPtC = 60-62
| BoilingPtC =
 }}
|Section7={{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt =
 }}
|Section6={{Chembox Pharmacology
| ATCCode_prefix = A16
| ATCCode_suffix = AX01
| Bioavail = 30% (oral)<ref>{{cite journal |last1= Teichert |first1= J |last2= Hermann |first2= R |last3= Ruus |first3= P |last4= Preiss |first4= R |title= Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers |journal= [[The Journal of Clinical Pharmacology]] |volume= 43 |issue= 11 |pages= 1257–67 |date= November 2003 |pmid= 14551180 |doi= 10.1177/0091270003258654 |s2cid= 30589232 }}</ref>
 }}
|Section8={{Chembox Related
| OtherCompounds = [[Lipoamide]]<br />[[Asparagusic acid]]
 }}
}}

'''Lipoic acid''' ('''LA'''), also known as '''α-lipoic acid''', '''alpha-lipoic acid''' ('''ALA''') and '''thioctic acid''', is an [[organosulfur compound]] derived from [[caprylic acid]] (octanoic acid).<ref name="lpi">{{cite web |title=Lipoic acid |url=https://lpi.oregonstate.edu/mic/dietary-factors/lipoic-acid |publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis |access-date=5 November 2019 |date=1 January 2019}}</ref> ALA, which is made in animals normally, is essential for [[aerobic metabolism]]. It is also available as a [[dietary supplement]] or [[pharmaceutical drug]] in some countries. '''Lipoate''' is the [[conjugate base]] of lipoic acid, and the most prevalent form of LA under physiological conditions.<ref name=lpi/> Only the (''R'')-(+)-[[enantiomer]] (RLA) exists in nature. RLA is an essential [[Cofactor (biochemistry)|cofactor]] of many processes.<ref name=lpi/>

==Physical and chemical properties==
Lipoic acid contains two sulfur atoms connected by a [[disulfide bond]] in the [[1,2-dithiolane]] ring. It also carries a carboxylic acid group. It is considered to be oxidized relative to its acyclic relative dihydrolipoic acid, in which each sulfur exists as a thiol.<ref name=lpi/> It is a yellow solid.

(''R'')-(+)-lipoic acid (RLA) occurs naturally, but (''S'')-(-)-lipoic acid (SLA) has been synthesized.

For use in [[dietary supplement]] materials and [[compounding]] pharmacies, the [[United States Pharmacopeia|USP]] established an official monograph for R/S-LA.<ref>{{cite book |title= USP32-NF27 |page= 1042|title-link= United States Pharmacopeia}}</ref><ref>{{cite journal |title=Unavailable First-Time Official USP Reference Standards |author=<!--Staff writer(s); no by-line.--> |journal=Pharmacopeial Forum |volume=35 |page=26 |publisher=USP |date=February 2009 |url=https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/pf-legacy-pdf/pf-2009_vol-35.pdf |language=en |access-date=13 January 2023 |url-status=live |archive-url=https://web.archive.org/web/20220305141903/https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/pf-legacy-pdf/pf-2009_vol-35.pdf |archive-date=5 March 2022 }}</ref>

==Biological function==
Lipoic acid is a cofactor for five [[enzymes]] or classes of enzymes: [[pyruvate dehydrogenase]], [[Oxoglutarate dehydrogenase complex|α-ketoglutarate dehydrogenase]], the [[glycine cleavage system]], [[Branched-chain alpha-keto acid dehydrogenase complex|branched-chain alpha-keto acid dehydrogenase]], and the α-oxo(keto)adipate dehydrogenase. The first two are critical to the [[citric acid cycle]]. The GCS regulates [[glycine]] concentrations.<ref>{{cite journal |doi=10.3389/fgene.2020.00510|doi-access=free |title=Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes |year=2020 |last1=Cronan |first1=John E. |journal=Frontiers in Genetics |volume=11 |page=510 |pmid=32508887 |pmc=7253636 }}</ref>

HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are targets of the reduced form (open dithiol) of (''R'')-lipoic acid.<ref>{{cite journal | doi=10.1038/s41467-023-39151-8 | title=Chemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid | date=2023 | last1=Lechner | first1=Severin | last2=Steimbach | first2=Raphael R. | last3=Wang | first3=Longlong | last4=Deline | first4=Marshall L. | last5=Chang | first5=Yun-Chien | last6=Fromme | first6=Tobias | last7=Klingenspor | first7=Martin | last8=Matthias | first8=Patrick | last9=Miller | first9=Aubry K. | last10=Médard | first10=Guillaume | last11=Kuster | first11=Bernhard | journal=Nature Communications | volume=14 | issue=1 | page=3548 | pmid=37322067 | pmc=10272112 | bibcode=2023NatCo..14.3548L }}</ref>

===Biosynthesis and attachment===
Most endogenously produced RLA are not "[[Free fatty acid|free]]" because octanoic acid, the [[Precursor (chemistry)|precursor]] to RLA, is bound to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is [[Covalent bond|covalently]] attached by an [[amide bond]] to a terminal [[lysine]] [[Residue (chemistry)#Biochemistry|residue]] of the enzyme's lipoyl [[Protein domain|domains]].
The precursor to lipoic acid, [[octanoic acid]], is made via [[Mitochondrial fatty acid synthesis|mitochondrial fatty acid biosynthesis]] in the form of octanoyl-[[acyl carrier protein]].<ref name=lpi/> The octanoate is transferred as a [[thioester]] of [[acyl carrier protein]] from mitochondrial fatty acid biosynthesis to an [[amide]] of the lipoyl domain protein by an [[enzyme]] called an [[Lipoyl(octanoyl) transferase|octanoyltransferase]].<ref name=lpi/> Two [[Hydrogen|hydrogens]] of octanoate are replaced with sulfur groups via a [[radical SAM]] mechanism, by [[lipoyl synthase]].<ref name=lpi/> As a result, lipoic acid is synthesized attached to proteins and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by action of the enzyme [[lipoamidase]].<ref>{{cite journal |last1= Jiang |first1= Y |last2= Cronan |first2= JE |year= 2005 |title= Expression cloning and demonstration of ''Enterococcus faecalis'' lipoamidase (pyruvate dehydrogenase inactivase) as a Ser-Ser-Lys triad amidohydrolase |journal= [[Journal of Biological Chemistry]] |volume= 280 |issue= 3 |pages= 2244–56 |pmid= 15528186 |doi= 10.1074/jbc.M408612200 |doi-access= free }}</ref> Free lipoate can be used by some organisms as an enzyme called [[lipoate protein ligase]] that attaches it covalently to the correct protein. The [[ligase]] activity of this [[enzyme]] requires [[Adenosine triphosphate|ATP]].<ref>{{cite book |last1= Cronan |first1= JE |title= Function, attachment and synthesis of lipoic acid in ''Escherichia coli'' |last2= Zhao |first2= X |last3= Jiang |first3= Y  |year= 2005 |series= Advances in Microbial Physiology |volume= 50 |pages= 103–46 |pmid= 16221579 |doi= 10.1016/S0065-2911(05)50003-1 |isbn= 978-0-12-027750-6 |editor-first= RK |editor-last= Poole}}
</ref>

===Cellular transport===

Along with [[sodium]] and the vitamins [[biotin]] (B7) and [[pantothenic acid]] (B5), lipoic acid enters cells through the [[Sodium-dependent multivitamin transporter|SMVT]] (sodium-dependent multivitamin transporter). Each of the compounds transported by the SMVT is competitive with the others. For example research has shown that increasing intake of lipoic acid<ref>{{Cite journal|pmid = 9278559|year = 1997|last1 = Zempleni|first1 = J.|last2 = Trusty|first2 = T. A.|last3 = Mock|first3 = D. M.|title = Lipoic acid reduces the activities of biotin-dependent carboxylases in rat liver|journal = The Journal of Nutrition|volume = 127|issue = 9|pages = 1776–81|doi = 10.1093/jn/127.9.1776|doi-access = free}}</ref> or pantothenic acid<ref>{{Cite journal|pmid = 23578027|year = 2013|last1 = Chirapu|first1 = S. R.|last2 = Rotter|first2 = C. J.|last3 = Miller|first3 = E. L.|last4 = Varma|first4 = M. V.|last5 = Dow|first5 = R. L.|last6 = Finn|first6 = M. G.|title = High specificity in response of the sodium-dependent multivitamin transporter to derivatives of pantothenic acid|journal = Current Topics in Medicinal Chemistry|volume = 13|issue = 7|pages = 837–42|doi = 10.2174/1568026611313070006}}</ref> reduces the uptake of biotin and/or the activities of biotin-dependent enzymes.

===Enzymatic activity===
Lipoic acid is a [[Cofactor (biochemistry)|cofactor]] for at least five [[enzyme]] systems.<ref name=lpi/> Two of these are in the [[citric acid cycle]] through which many organisms turn nutrients into energy. Lipoylated [[enzymes]] have lipoic acid attached to them covalently. The lipoyl group transfers [[acyl]] groups in [[2-oxoacid dehydrogenase]] complexes, and [[methylamine]] group in the [[glycine cleavage complex]] or [[glycine dehydrogenase]].<ref name=lpi/>

Lipoic acid is the cofactor of the following enzymes in humans:<ref>{{Cite journal |last1=Mayr |first1=Johannes A. |last2=Feichtinger |first2=René G. |last3=Tort |first3=Frederic |last4=Ribes |first4=Antonia |last5=Sperl |first5=Wolfgang |date=2014 |title=Lipoic acid biosynthesis defects |url=https://onlinelibrary.wiley.com/doi/10.1007/s10545-014-9705-8 |journal=Journal of Inherited Metabolic Disease |language=en |volume=37 |issue=4 |pages=553–563 |doi=10.1007/s10545-014-9705-8 |pmid=24777537 |s2cid=27408101 |issn=0141-8955|url-access=subscription }}</ref><ref>{{Cite journal |last1=Solmonson |first1=Ashley |last2=DeBerardinis |first2=Ralph J. |date=2018 |title=Lipoic acid metabolism and mitochondrial redox regulation |journal=Journal of Biological Chemistry |language=en |volume=293 |issue=20 |pages=7522–7530 |doi=10.1074/jbc.TM117.000259 |doi-access=free |pmc=5961061 |pmid=29191830}}</ref><ref>{{Cite journal |last1=Nemeria |first1=Natalia S. |last2=Nagy |first2=Balint |last3=Sanchez |first3=Roberto |last4=Zhang |first4=Xu |last5=Leandro |first5=João |last6=Ambrus |first6=Attila |last7=Houten |first7=Sander M. |last8=Jordan |first8=Frank |date=2022-07-26 |title=Functional Versatility of the Human 2-Oxoadipate Dehydrogenase in the L-Lysine Degradation Pathway toward Its Non-Cognate Substrate 2-Oxopimelic Acid |journal=International Journal of Molecular Sciences |language=en |volume=23 |issue=15 |page=8213 |doi=10.3390/ijms23158213 |doi-access=free |issn=1422-0067 |pmc=9367764 |pmid=35897808}}</ref>
{| class="wikitable"
|+
!EC-number
!Enzyme
!Gene
!Multienzyme complex
!Role of the complex
|-
|[[Enzyme Commission number|EC]] [https://enzyme.expasy.org/EC/2.3.1.12 2.3.1.12]
|[[dihydrolipoyl transacetylase]] (E2)
|[[DLAT]]
|[[pyruvate dehydrogenase complex]] (PDC)
|Connection of [[glycolysis]] with the [[citric acid cycle]]
|-
| rowspan="2" |EC [https://enzyme.expasy.org/EC/2.3.1.61 2.3.1.61]
| rowspan="2" |[[Dihydrolipoyllysine-residue succinyltransferase|dihydrolipoyl succinyltransferase]] (E2)
| rowspan="2" |[[DLST]]
|[[oxoglutarate dehydrogenase complex]] (OGDC)
|[[Citric acid cycle]] enzyme
|-
|[[2-oxoadipate dehydrogenase complex]] (OADHC)
|[[Lysine]], [[tryptophan]] and [[hydroxylysine]] degradation
|-
|EC [https://enzyme.expasy.org/EC/2.3.1.168 2.3.1.168]
|[[dihydrolipoyl transacylase]] (E2)
|[[DBT (gene)|DBT]]
|[[Branched-chain alpha-keto acid dehydrogenase complex|branched-chain α-ketoacid dehydrogenase complex]] (BCKDC)
|[[Leucine]], [[isoleucine]] and [[valine]] degradation
|-
|
|[[GCSH|H-protein]]
|[[GCSH]]
|[[glycine cleavage system]] (GCS)
|[[Glycine]] and [[serine]] metabolism, [[folate]] metabolism
|}
The most-studied of these is the pyruvate dehydrogenase complex.<ref name=lpi/> These complexes have three central subunits: E1-3, which are the decarboxylase, lipoyl transferase, and [[dihydrolipoamide dehydrogenase]], respectively. These complexes have a central E2 core and the other subunits surround this core to form the complex. In the gap between these two subunits, the lipoyl domain ferries intermediates between the active sites.<ref name=lpi/> The lipoyl domain itself is attached by a flexible linker to the E2 core and the number of lipoyl domains varies from one to three for a given organism. The number of domains has been experimentally varied and seems to have little effect on growth until over nine are added, although more than three decreased activity of the complex.<ref>{{cite journal |last1= Machado |first1= RS |last2= Clark |first2= DP |last3= Guest |first3= JR |title= Construction and properties of pyruvate dehydrogenase complexes with up to nine lipoyl domains per lipoate acetyltransferase chain |journal= FEMS Microbiology Letters |year= 1992 |pages= 243–8 |volume= 79 |issue= 1–3 |doi= 10.1111/j.1574-6968.1992.tb14047.x |pmid= 1478460|doi-access= free }}</ref>

Lipoic acid serves as co-factor to the [[acetoin dehydrogenase]] complex catalyzing the conversion of [[acetoin]] (3-hydroxy-2-butanone) to acetaldehyde and [[acetyl coenzyme A]].<ref name=lpi/>

The [[glycine cleavage system]] differs from the other complexes, and has a different nomenclature.<ref name=lpi/> In this system, the H protein is a free lipoyl domain with additional helices, the L protein is a dihydrolipoamide dehydrogenase, the P protein is the decarboxylase, and the T protein transfers the [[methylamine]] from lipoate to [[tetrahydrofolate]] (THF) yielding methylene-THF and ammonia. Methylene-THF is then used by serine hydroxymethyltransferase to synthesize [[serine]] from [[glycine]]. This system is part of plant [[photorespiration]].<ref>{{cite journal |last1= Douce |first1= R |last2= Bourguignon |first2= J |last3= Neuburger |first3= M |last4= Rebeille |first4= F |title= The glycine decarboxylase system: A fascinating complex |journal= [[Trends (journals)|Trends in Plant Science]] |year= 2001 |pages= 167–76 |volume= 6 |issue= 4 |doi= 10.1016/S1360-1385(01)01892-1 |pmid= 11286922|bibcode= 2001TPS.....6..167D }}</ref>

===Biological sources and degradation===
Lipoic acid is present in many foods in which it is bound to lysine in proteins,<ref name=lpi/> but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.<ref>{{cite journal |last1= Durrani |first1= AI |last2= Schwartz |first2= H |last3= Nagl |first3= M |last4= Sontag |first4= G |title= Determination of free [alpha]-lipoic acid in foodstuffs by HPLC coupled with CEAD and ESI-MS  |journal= [[Food Chemistry (journal)|Food Chemistry]] |date= October 2010 |pages= 38329–36 |volume= 120 |issue= 4 |doi= 10.1016/j.foodchem.2009.11.045}}</ref> Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources.<ref name=lpi/> In addition, the amount of lipoic acid present in dietary sources is low. For instance, the purification of lipoic acid to determine its structure used an estimated 10 tons of liver residue, which yielded 30&nbsp;mg of lipoic acid.<ref>{{cite journal |last= Reed |first= LJ |title= A trail of research from lipoic acid to alpha-keto acid dehydrogenase complexes  |journal= [[Journal of Biological Chemistry]] |date= October 2001 |pages= 38329–36 |volume= 276 |issue= 42 |pmid= 11477096 |doi= 10.1074/jbc.R100026200 |doi-access= free }}</ref> As a result, all lipoic acid available as a supplement is chemically synthesized.{{cn|date=November 2024}}

Baseline levels (prior to supplementation) of RLA and R-DHLA have not been detected in human plasma.<ref>{{cite journal | doi = 10.1016/0928-0987(95)00045-3 |last1= Hermann |first1= R |year= 1996 |title= Enantioselective pharmacokinetics and bioavailability of different racemic formulations in healthy volunteers |journal= [[European Journal of Pharmaceutical Sciences]] |volume= 4 |issue= 3 |pages= 167–74 |last2= Niebch |first2= G |last3= Borbe |first3= HO |last4= Fieger |first4= H |last5= Ruus |first5= P |last6= Nowak |first6= H |last7= Riethmuller-Winzen |first7= H |last8= Peukert |first8= M |last9= Blume |first9= H |display-authors= 4}}</ref> RLA has been detected at 12.3−43.1&nbsp;ng/mL following acid hydrolysis, which releases protein-bound lipoic acid. Enzymatic hydrolysis of protein bound lipoic acid released 1.4−11.6&nbsp;ng/mL and <1-38.2&nbsp;ng/mL using [[subtilisin]] and [[alcalase]], respectively.<ref>{{cite book |doi= 10.1016/S0076-6879(97)79019-0 |pmid= 9211267 |last1= Teichert |first1= J |last2= Preiss |first2= R |chapter= High-performance liquid chromatography methods for determination of lipoic and dihydrolipoic acid in human plasma |title= Vitamins and Coenzymes Part I |volume= 279 |year= 1997 |pages= 159–66 |series= [[Methods in Enzymology]] |isbn= 978-0-12-182180-7}}</ref><ref>{{cite journal |doi= 10.1016/0378-4347(95)00225-8 |pmid= 8581134 |last1= Teichert |first1= J |last2= Preiss |first2= R |title= Determination of lipoic acid in human plasma by high-performance liquid chromatography with electrochemical detection |journal= [[Journal of Chromatography B]] |volume= 672 |issue= 2 |date= October 1995 |pages=277–81}}</ref><ref>{{cite journal |pmid= 1490813 |last1= Teichert |first1= J |last2= Preiss |first2= R |title= HPLC-methods for determination of lipoic acid and its reduced form in human plasma |journal= International Journal of Clinical Pharmacology, Therapy, and Toxicology |volume= 30 |issue= 11 |date= November 1992 |pages= 511–2}}</ref>

Digestive proteolytic enzymes cleave the R-lipoyllysine residue from the mitochondrial enzyme complexes derived from food but are unable to cleave the lipoic acid-<small>L</small>-[[lysine]] amide bond.<ref>{{cite journal |pmid= 9378235 |last1= Biewenga |first1= GP |last2= Haenen |first2= GR |last3= Bast |first3= A |title= The pharmacology of the antioxidant lipoic acid |journal= General Pharmacology |volume= 29 |issue= 3 |date= September 1997 |pages=315–31 |doi= 10.1016/S0306-3623(96)00474-0}}</ref> Both synthetic lipoamide and (''R'')-lipoyl-<small>L</small>-lysine are rapidly cleaved by serum lipoamidases, which release free (''R'')-lipoic acid and either <small>L</small>-lysine or ammonia.<ref name=lpi/> Little is known about the degradation and utilization of aliphatic sulfides such as lipoic acid, except for [[cysteine]].<ref name=lpi/>

Lipoic acid is metabolized in a variety of ways when given as a dietary supplement in mammals.<ref name=lpi/><ref name="ReferenceA">{{Cite journal  |last1= Schupke |first1= H |last2= Hempel |first2= R |last3= Peter |first3= G |last4= Hermann |first4= R |last5= Wessel |first5= K |last6= Engel |first6= J |last7= Kronbach |first7= T |display-authors= 4 |title= New metabolic pathways of alpha-lipoic acid |journal= [[Drug Metabolism and Disposition]] |volume= 29 |issue= 6 |pages= 855–62 |date= June 2001 |pmid= 11353754}}</ref> Degradation to tetranorlipoic acid, oxidation of one or both of the sulfur atoms to the sulfoxide, and S-methylation of the sulfide were observed. Conjugation of unmodified lipoic acid to glycine was detected especially in mice.<ref name="ReferenceA"/> Degradation of lipoic acid is similar in humans, although it is not clear if the sulfur atoms become significantly oxidized.<ref name=lpi/><ref>{{Cite journal |last1= Teichert |first1= J |last2= Hermann |first2= R |last3= Ruus |first3= P |last4= Preiss |first4= R |title= Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers |journal= [[The Journal of Clinical Pharmacology|Journal of Clinical Pharmacology]] |volume= 43 |issue= 11 |pages= 1257–67 |date= November 2003 |doi= 10.1177/0091270003258654 |pmid= 14551180|s2cid= 30589232 }}</ref> Apparently mammals are not capable of utilizing lipoic acid as a sulfur source.

== Diseases ==

=== Combined malonic and methylmalonic aciduria (CMAMMA) ===
In the metabolic disease [[combined malonic and methylmalonic aciduria]] (CMAMMA) due to [[ACSF3]] deficiency, [[mitochondrial fatty acid synthesis]] (mtFAS), which is the precursor reaction of lipoic acid biosynthesis, is impaired.<ref>{{Cite journal |last1=Levtova |first1=Alina |last2=Waters |first2=Paula J. |last3=Buhas |first3=Daniela |last4=Lévesque |first4=Sébastien |last5=Auray-Blais |first5=Christiane |author-link5=Christiane Auray |last6=Clarke |first6=Joe T.R. |last7=Laframboise |first7=Rachel |last8=Maranda |first8=Bruno |last9=Mitchell |first9=Grant A. |last10=Brunel-Guitton |first10=Catherine |last11=Braverman |first11=Nancy E. |date=2019 |title=Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort |url=https://onlinelibrary.wiley.com/doi/10.1002/jimd.12032 |journal=Journal of Inherited Metabolic Disease |language=en |volume=42 |issue=1 |pages=107–116 |doi=10.1002/jimd.12032 |issn=0141-8955 |pmid=30740739 |s2cid=73436689|url-access=subscription }}</ref><ref name=":0">{{Cite journal |last1=Wehbe |first1=Zeinab |last2=Behringer |first2=Sidney |last3=Alatibi |first3=Khaled |last4=Watkins |first4=David |last5=Rosenblatt |first5=David |last6=Spiekerkoetter |first6=Ute |last7=Tucci |first7=Sara |date=2019-11-01 |title=The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism |url=https://www.sciencedirect.com/science/article/pii/S1388198119301349 |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1864 |issue=11 |pages=1629–1643 |doi=10.1016/j.bbalip.2019.07.012 |pmid=31376476 |s2cid=199404906 |issn=1388-1981|url-access=subscription }}</ref> The result is a reduced [[Post-translational modification#PTMs involving addition of functional groups|lipoylation]] degree of important mitochondrial enzymes, such as [[pyruvate dehydrogenase complex]] (PDC) and [[Oxoglutarate dehydrogenase complex|α-ketoglutarate dehydrogenase complex]] (α-KGDHC).<ref name=":0" /> Supplementation with lipoic acid does not restore mitochondrial function.<ref>{{Cite journal |last1=Hiltunen |first1=J. Kalervo |last2=Autio |first2=Kaija J. |last3=Schonauer |first3=Melissa S. |last4=Kursu |first4=V.A. Samuli |last5=Dieckmann |first5=Carol L. |last6=Kastaniotis |first6=Alexander J. |date=2010 |title=Mitochondrial fatty acid synthesis and respiration |url=https://linkinghub.elsevier.com/retrieve/pii/S000527281000112X |journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics |language=en |volume=1797 |issue=6–7 |pages=1195–1202 |doi=10.1016/j.bbabio.2010.03.006|pmid=20226757 |url-access=subscription }}</ref><ref name=":0" />

==Chemical synthesis==
[[Image:(R)-Liponic Acid Structural Formula V.1.svg|200px|R-isomer]] [[Image:(S)-Liponic Acid Structural Formula V.1.svg|200px|S-isomer]]

SLA did not exist prior to chemical synthesis in 1952.<ref>{{cite journal |last1= Hornberger  |first1= CS |last2= Heitmiller |first2= RF |last3= Gunsalus |first3= IC |last4= Schnakenberg |first4= GHF |last5= Reed |first5= LJ |display-authors= 4 |title= Synthesis of DL—lipoic acid |journal= [[Journal of the American Chemical Society]] |volume= 75 |issue= 6 |pages= 1273–7 |year= 1953 |doi= 10.1021/ja01102a003}}</ref><ref>{{cite journal |last1= Hornberger |first1= CS |last2= Heitmiller |first2= RF |last3= Gunsalus |first3= IC |last4= Schnakenberg |first4= GHF |last5= Reed |first5= LJ |display-authors= 4 |title= Synthetic preparation of lipoic acid |journal= [[Journal of the American Chemical Society]] |volume= 74 |issue= 9 |page= 2382 |year= 1952 |doi= 10.1021/ja01129a511|bibcode= 1952JAChS..74.2382H }}</ref> SLA is produced in equal amounts with RLA during achiral manufacturing processes. The racemic form was more widely used clinically in Europe and Japan in the 1950s to 1960s despite the early recognition that the various forms of LA are not bioequivalent.<ref name="Kleeman" /> The first synthetic procedures appeared for RLA and SLA in the mid-1950s.<ref>{{cite journal |pmid= 13294188 |last1= Fontanella |first1= L |title= Preparation of optical antipodes of alpha-lipoic acid |journal= Il Farmaco; Edizione Scientifica |volume= 10 |issue= 12 |year= 1955 |pages= 1043–5}}</ref><ref>{{cite journal |last1= Walton |first1= E |last2= Wagner |first2= AF |last3= Bachelor |first3= FW |last4= Peterson |first4= LH |last5= Holly |first5= FW |last6= Folkers |first6= K |display-authors= 4 |title= Synthesis of (+)-lipoic acid and its optical antipode |journal= [[Journal of the American Chemical Society]] |volume= 77 |issue= 19 |pages= 5144–9 |year= 1955 |doi= 10.1021/ja01624a057 }}</ref><ref>{{cite journal |last1= Acker |first1= DS |last2= Wayne |first2= WJ |title= Optically active and radioactive α-lipoic acids |journal= [[Journal of the American Chemical Society]] |volume= 79 |issue= 24 |pages= 6483–6487 |year= 1957 |doi= 10.1021/ja01581a033}}</ref><ref>{{cite journal |pmid= 14207116 |last1= Deguchi |first1= Y |last2= Miura |first2= K |title= Studies on the synthesis of thioctic acid and its related compounds. XIV. Synthesis of (+)-thioctamide |journal= Yakugaku Zasshi |volume= 84 |issue= 6 |date= June 1964 |pages= 562–3|doi= 10.1248/yakushi1947.84.6_562 |doi-access= free }}</ref> Advances in chiral chemistry led to more efficient technologies for manufacturing the single enantiomers by both classical resolution and [[asymmetric synthesis]] and the demand for RLA also grew at this time. In the 21st century, R/S-LA, RLA and SLA with high chemical and/or optical purities are available in industrial quantities. At the current time, most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in Italy, Germany, and Japan. RLA is produced by modifications of a process first described by Georg Lang in a Ph.D. thesis and later patented by DeGussa.<ref>{{cite thesis |last= Lang |first= G |title= In Vitro Metabolism of a-Lipoic Acid Especially Taking Enantioselective Bio-transformation into Account |degree= Ph.D. |publisher= University of Münster |location= Münster, DE |year= 1992}}</ref><ref>{{cite patent |inventor1-last= Blaschke |inventor1-first= G |inventor2-last= Scheidmantel |inventor2-first= U |inventor3-last= Bethge |inventor3-first= H |inventor4= R Moeller, Beisswenger, T Huthmacher |title= Preparation and use of salts of the pure enantiomers of alpha-lipoic acid |country= US |number= 5281722 |status= patent |gdate= 1994-01-25 |assign1= DeGussa |fdate= 1992-11-12 |pridate= 1991-11-16 |postscript= .}}</ref> Although RLA is favored nutritionally due to its "vitamin-like" role in metabolism, both RLA and R/S-LA are widely available as dietary supplements. Both [[stereospecific]] and non-stereospecific reactions are known to occur ''in vivo'' and contribute to the mechanisms of action, but evidence to date indicates RLA may be the [[eutomer]] (the nutritionally and therapeutically preferred form).<ref name=Carlson08/><ref>{{cite journal |pmid= 11684397 |last1= Packer |first1= L |last2= Kraemer |first2= K |last3= Rimbach |first3= G |title= Molecular aspects of lipoic acid in the prevention of diabetes complications |journal= Nutrition |volume= 17 |issue= 10 |date= October 2001 |pages= 888–95 |doi= 10.1016/S0899-9007(01)00658-X}}</ref>

==Pharmacology==

===Pharmacokinetics===
A 2007 human [[pharmacokinetic]] study of sodium RLA demonstrated the maximum concentration in plasma and bioavailability are significantly greater than the free acid form, and rivals plasma levels achieved by intravenous administration of the free acid form.<ref name="ReferenceB">{{cite journal |last1= Carlson |first1= DA |last2= Smith |first2= AR |last3= Fischer |first3= SJ |last4= Young |first4= KL |last5= Packer |first5= L |display-authors= 4 |title= The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects |journal= Alternative Medicine Review |volume= 12 |issue= 4 |date= December 2007 |pages= 343–51 |pmid= 18069903 |url= http://www.altmedrev.com/publications/12/4/343.pdf |access-date= 2014-07-06 |archive-date= 2017-08-08 |archive-url= https://web.archive.org/web/20170808231646/http://altmedrev.com/publications/12/4/343.pdf }}</ref> Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.<ref name="ReferenceB"/>

The various forms of LA are not bioequivalent.<ref name="Kleeman">{{cite conference |last1= Kleeman |first1= A |last2= Borbe |first2= HO |last3= Ulrich |first3= H |chapter= Thioctic Acid-Lipoic Acid |title= Thioctsäure: Neue Biochemische, Pharmakologische und Klinische Erkenntnisse zur Thioctsäure |trans-title= Thioctic Acid. New Biochemistry, Pharmacology and Findings from Clinical Practice with Thioctic Acid |pages= 11–26 |editor1-last= Borbe |editor1-first= HO |editor2-last= Ulrich |editor2-first= H |conference= Symposium at Wiesbaden, DE, 16–18 February 1989 |date= 1991 |location= Frankfurt, DE |publisher= Verlag |isbn= 978-3-89119-125-5}}</ref> Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.<ref name="ReferenceB"/>

The toxic dose of LA in cats is much lower than that in humans or dogs and produces hepatocellular toxicity.<ref>{{cite journal |last1= Hill |first1= AS |last2= Werner |first2=JA |last3= Rogers |first3= QR |last4= O'Neill |first4= SL |last5= Christopher |first5= MM |display-authors= 4 |title= Lipoic acid is 10 times more toxic in cats than reported in humans, dogs or rats |journal= Journal of Animal Physiology and Animal Nutrition |volume= 88 |issue= 3–4 |date= April 2004 |pages= 150–6 |pmid= 15059240 |doi= 10.1111/j.1439-0396.2003.00472.x}}</ref>

===Pharmacodynamics===
The mechanism and action of lipoic acid when supplied externally to an organism is controversial. Lipoic acid in a cell seems primarily to induce the oxidative stress response rather than directly scavenge free radicals. This effect is specific for RLA.<ref name= "Shay08"/> Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.<ref name="Packer1995">{{cite journal |doi= 10.1016/0891-5849(95)00017-R |pmid= 7649494 |last1= Packer |first1= L |last2= Witt |first2= EH |last3= Tritschler |first3= HJ |title= Alpha-lipoic acid as a biological antioxidant |journal= [[Free Radical Biology and Medicine]] |volume= 19 |issue= 2 |date= August 1995 |pages= 227–50}}</ref> LA is able to scavenge reactive oxygen and reactive nitrogen species in a biochemical assay due to long incubation times, but there is little evidence this occurs within a cell or that radical scavenging contributes to the primary mechanisms of action of LA.<ref name= "Shay08"/><ref name="ReferenceC">{{cite journal |pmid= 19664690 |pmc= 2756298 |last1= Shay |first1= KP |doi= 10.1016/j.bbagen.2009.07.026 |last2= Moreau |first2= RF |last3= Smith |first3= EJ |last4= Smith |first4= AR |last5= Hagen |first5= TM |display-authors= 4 | title = Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential |journal= [[Biochimica et Biophysica Acta (BBA) - General Subjects]] |volume= 1790 |issue= 10 |date= October 2009 |pages= 1149–60}}</ref> The relatively good scavenging activity of LA toward [[hypochlorous acid]] (a bactericidal produced by neutrophils that may produce inflammation and tissue damage) is due to the strained conformation of the 5-membered dithiolane ring, which is lost upon reduction to DHLA. In cells, LA is reduced to dihydrolipoic acid, which is generally regarded as the more bioactive form of LA and the form responsible for most of the antioxidant effects and for lowering the redox activities of unbound iron and copper.<ref>{{cite journal |last1= Haenen |first1= GRMM |last2= Bast |first2= A |year= 1991 |title= Scavenging of hypochlorous acid by lipoic acid |journal= [[Biochemical Pharmacology (journal)|Biochemical Pharmacology]] |pmid= 1659823 |volume= 42 |issue= 11 |pages= 2244–6 |doi= 10.1016/0006-2952(91)90363-A }}</ref> This theory has been challenged due to the high level of reactivity of the two free sulfhydryls, low intracellular concentrations of DHLA as well as the rapid methylation of one or both sulfhydryls, rapid side-chain oxidation to shorter metabolites and rapid efflux from the cell. Although both DHLA and LA have been found inside cells after administration, most intracellular DHLA probably exists as mixed disulfides with various cysteine residues from cytosolic and mitochondrial proteins.<ref name=Carlson08>{{cite book |last1= Carlson |first1= DA |last2= Young |first2= KL |last3= Fischer |first3= SJ |last4= Ulrich |first4= H|title=Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects|chapter= Ch. 10: An Evaluation of the Stability and Pharmacokinetics of R-lipoic Acid and R-Dihydrolipoic Acid Dosage Forms in Plasma from Healthy Human Subjects |pages= 235–70 |editor1=Mulchand S. Patel |editor2=Lester Packer |date=2008}}</ref> Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription, which improve the antioxidant status of the cell. However, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.<ref name= "Shay08"/><ref name="ReferenceC"/><ref name="Shay in Packer"/>

All the [[disulfide]] forms of LA (R/S-LA, RLA and SLA) can be reduced to [[DHLA]] although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems. At least two cytosolic enzymes, [[glutathione reductase]] (GR) and [[thioredoxin reductase]] (Trx1), and two mitochondrial enzymes, [[lipoamide dehydrogenase]] and [[thioredoxin reductase]] (Trx2), reduce LA. SLA is stereoselectively reduced by cytosolic GR whereas Trx1, Trx2 and lipoamide dehydrogenase stereoselectively reduce RLA. (''R'')-(+)-lipoic acid is enzymatically or chemically reduced to (''R'')-(-)-dihydrolipoic acid whereas (''S'')-(-)-lipoic acid is reduced to (''S'')-(+)-dihydrolipoic acid.<ref>{{cite journal |pmid= 8769129 |last1= Arnér |first1= ES |doi= 10.1006/bbrc.1996.1165 |last2= Nordberg |first2= J |last3= Holmgren |first3= A |title= Efficient reduction of lipoamide and lipoic acid by mammalian thioredoxin reductase |journal= [[Biochemical and Biophysical Research Communications]] |volume= 225 |issue= 1 |date= August 1996 |pages= 268–74}}</ref><ref>{{cite journal |doi= 10.1667/0033-7587(2003)159[0484:RROCDA]2.0.CO;2 |pmid= 12643793 |last1= Biaglow |first1= JE |last2= Ayene |first2= IS |last3= Koch |first3= CJ |last4= Donahue |first4= J |last5= Stamato |first5= TD |last6= Mieyal |first6= JJ |last7= Tuttle |first7= SW |display-authors= 4 |title= Radiation response of cells during altered protein thiol redox |journal= Radiation Research |volume= 159 |issue= 4 |date= April 2003 |pages= 484–94   |bibcode= 2003RadR..159..484B |s2cid= 42110797 }}</ref><ref>{{cite journal |doi= 10.1016/S0891-5849(96)00400-5 |pmid= 8981046 |last1= Haramaki |first1= N |last2= Han |first2= D |last3= Handelman |first3= GJ |last4= Tritschler |first4= HJ |last5= Packer |first5= L |display-authors= 4 |title= Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid |journal= [[Free Radical Biology and Medicine]] |volume= 22 |issue= 3 |year= 1997 |pages= 535–42}}</ref><ref>{{cite journal |doi= 10.1016/0006-2952(95)00084-D |pmid= 7632170 |last1= Constantinescu |first1= A |last2= Pick |first2= U |last3= Handelman |first3= GJ |last4= Haramaki |first4= N |last5= Han |first5= D |last6= Podda |first6= M |last7= Tritschler |first7= HJ |last8= Packer |first8= L |display-authors= 4 |title= Reduction and transport of lipoic acid by human erythrocytes |journal= [[Biochemical Pharmacology (journal)|Biochemical Pharmacology]] |volume= 50 |issue= 2 |date= July 1995 |pages= 253–61}}</ref><ref>{{cite journal |pmid= 16650819 |last1= May |first1= JM |doi= 10.1016/j.bbrc.2006.04.065 |last2= Qu |first2= ZC |last3= Nelson |first3= DJ |title= Cellular disulfide-reducing capacity: An integrated measure of cell redox capacity |journal= [[Biochemical and Biophysical Research Communications]] |volume= 344 |issue= 4 |date= June 2006 |pages= 1352–9}}</ref><ref>{{cite journal |doi= 10.1016/S0891-5849(02)00862-6 |pmid= 12086686 |last1= Jones |first1= W |last2= Li |first2= X |last3= Qu |first3= ZC |last4= Perriott |first4= L |last5= Whitesell |first5= RR |last6= May |first6= JM |display-authors= 4 |title= Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells |journal= [[Free Radical Biology and Medicine]] |volume= 33 |issue= 1 |date= July 2002 |pages= 83–93}}</ref><ref>{{cite journal |last1= Schempp |first1= H |last2= Ulrich |first2= H |last3= Elstner |first3= EF |title= Stereospecific reduction of R(+)-thioctic acid by porcine heart lipoamide dehydrogenase/diaphorase |journal= [[Zeitschrift für Naturforschung C]] |volume= 49 |issue= 9–10 |pages= 691–2 |year= 1994 |pmid= 7945680 |doi= 10.1515/znc-1994-9-1023 |doi-access= free }}</ref> Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, [[thiol-disulfide exchange|thiol-disulfide exchange reactions]].<ref>{{cite book |last1= Biewenga |first1= GP |last2= Haenen |first2= GRMM |last3= Bast |first3= A |chapter= Ch. 1: An Overview of Lipoate Chemistry |editor1-last= Fuchs |editor1-first= J |editor2-last= Packer |editor2-first= L |editor3-last= Zimmer |editor3-first= G |title= Lipoic Acid In Health & Disease |publisher= [[CRC Press]]  |year= 1997 |pages= [https://books.google.com/books?id=ksWdMbxa5FkC&pg=PA1 1–32] |isbn= 978-0-8247-0093-5}}</ref>

RLA may function ''in vivo'' like a B-vitamin and at higher doses like plant-derived nutrients, such as [[curcumin]], [[sulforaphane]], [[resveratrol]], and other nutritional substances that induce [[Drug metabolism#Phase II – conjugation|phase II detoxification enzymes]], thus acting as cytoprotective agents.<ref name="Shay in Packer">{{cite book |last1= Shay |first1= KP |last2= Shenvi |first2= S |last3= Hagen |first3= TM |chapter= Ch. 14 Lipoic Acid as an Inducer of Phase II Detoxification Enzymes Through Activation of Nr-f2 Dependent Gene Expression|title=Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects|pages= 349–71 |editor1=Mulchand S. Patel |editor2=Lester Packer |date=2008}}</ref><ref>{{cite journal |last1=Lii |first1= CK |last2= Liu |first2= KL |last3= Cheng |first3= YP |last4= Lin |first4= AH |last5= Chen |first5= HW |last6= Tsai |first6= CW |display-authors= 4 |title= Sulforaphane and alpha-lipoic acid upregulate the expression of the pi class of glutathione S-transferase through c-jun and Nrf2 activation |journal= [[Journal of Nutrition]] |volume= 140 |issue= 5 |pages= 885–92 |date= May 2010 |pmid= 20237067 |doi= 10.3945/jn.110.121418 |doi-access= free }}</ref> This stress response indirectly improves the antioxidant capacity of the cell.<ref name= "Shay08">{{cite journal |pmid= 18409172 |last1= Shay |first1= KP |doi= 10.1002/iub.40 |last2= Moreau |first2= RF |last3= Smith |first3= EJ |last4= Hagen |first4= TM |title= Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity |journal= IUBMB Life |volume= 60 |issue= 6 |date= June 2008 |pages= 362–7 |s2cid= 33008376 |doi-access=  }}</ref>

The (''S'')-enantiomer of LA was shown to be toxic when administered to thiamine-deficient rats.<ref>{{cite journal |doi= 10.1016/0003-9861(60)90051-5 |pmid= 13825981 |last1= Gal |first1= EM |last2= Razevska |first2= DE |title= Studies on the in vivo metabolism of lipoic acid. 1. The fate of DL-lipoic acid-S35 in normal and thiamine-deficient rats |journal= [[Archives of Biochemistry and Biophysics]] |volume= 89 |date= August 1960 |pages= 253–61 |issue= 2}}</ref><ref name="Gal1965">{{cite journal |doi= 10.1038/207535a0 |pmid= 5328673 |last1= Gal |first1= EM |title= Reversal of selective toxicity of (-)-alpha-lipoic acid by thiamine in thiamine-deficient rats |journal= [[Nature (journal)|Nature]] |volume= 207 |issue= 996 |date= July 1965 |page= 535|bibcode= 1965Natur.207..535G |s2cid= 4146866 |doi-access= free }}</ref>

Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by [[competitive inhibition]].<ref>{{cite patent |inventor1-last= Ulrich |inventor1-first= H |inventor2-last= Weischer |inventor2-first= CH |inventor3-last= Engel |inventor3-first= J |inventor4-last= Hettche |inventor4-first= H |title= Pharmaceutical compositions containing R-alpha-lipoic acid or S-alpha.-lipoic acid as active ingredient |country= US |number= 6271254 |gdate= 2001-08-07 |status= patent |assign1= ASTA Pharma |fdate= 1998-02-02 |pridate= 1989-11-09 |postscript= .}}</ref><ref>{{cite journal |pmid= 8673020 |last1= Kilic |first1= F |last2= Handelman |first2= GJ |last3= Serbinova |first3= E |last4= Packer |first4= L |last5= Trevithick |first5= JR |display-authors= 4 |title= Modelling cortical cataractogenesis 17: In vitro effect of a-lipoic acid on glucose-induced lens membrane damage, a model of diabetic cataractogenesis |journal= Biochemistry and Molecular Biology International |volume= 37 |issue= 2 |date= October 1995 |pages= 361–70}}</ref><ref>{{cite conference |last1= Artwohl |first1= M |last2= Schmetterer |first2= L |last3= Rainer |first3= G |last4= unknown |display-authors= 3 |date= September 2000|title= Modulation by antioxidants of endothelial apoptosis, proliferation, & associated gene/protein expression |conference= 36th Annual Meeting of the European Association for the Study of Diabetes, 17–21 September 2000, Jerusalem, Israel. |journal= [[Diabetologia]] |volume= 43 |issue= Suppl 1 |page= Abs 274 |publication-date= August 2000 |no-pp= yes |pmid= 11008622}}</ref><ref>{{cite journal |pmid= 9252495 |last1= Streeper |first1= RS |last2= Henriksen |first2= EJ |last3= Jacob |first3= S |last4= Hokama |first4= JY |last5= Fogt |first5= DL |last6= Tritschler |first6= HJ |display-authors= 4 |title= Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle |journal= [[American Journal of Physiology|AJP: Endocrinology and Metabolism]] |volume= 273 |issue= 1 Pt 1 |date= July 1997 |pages= E185–91|doi= 10.1152/ajpendo.1997.273.1.E185 }}</ref><ref>{{cite journal |pmid= 14991456 |last1= Frölich |first1= L |last2= Götz |first2= ME |last3= Weinmüller |first3= M |last4= Youdim |first4= MB |last5= Barth |first5= N |last6= Dirr |first6= A |last7= Gsell |first7= W |last8= Jellinger |first8= K |last9= Beckmann |first9= H |last10= Riederer |first10= P |display-authors= 4 |title= (r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia |journal = Journal of Neural Transmission |volume= 111 |issue= 3 |date= March 2004 |pages= 295–310 |doi= 10.1007/s00702-003-0043-5|s2cid= 20214857 }}</ref>

==Uses==
R/S-LA and RLA are widely available as over-the-counter nutritional supplements in the United States in the form of capsules, tablets, and aqueous liquids, and have been marketed as [[antioxidants]] and pertaining to cellular glucose utilization for metabolic disorders and type 2 diabetes.<ref name=lpi/>

Although the body can synthesize LA, it can also be absorbed from the diet. Dietary supplementation in doses from 200–600&nbsp;mg is likely to provide up to 1000 times the amount available from a regular diet. Gastrointestinal absorption is variable and decreases with the use of food. It is therefore recommended that dietary LA be taken 30–60 minutes before or at least 120 minutes after a meal. Maximum blood levels of LA are achieved 30–60 minutes after dietary supplementation, and it is thought to be largely metabolized in the liver.<ref>{{cite journal |last1=McIlduff |first1=Courtney E |last2=Rutkove |first2=Seward B |date=2011-01-01 |title=Critical appraisal of the use of alpha lipoic acid (thioctic acid) in the treatment of symptomatic diabetic polyneuropathy |journal=Therapeutics and Clinical Risk Management |volume=7 |pages=377–385 |doi=10.2147/TCRM.S11325 |issn=1176-6336 |pmc=3176171 |pmid=21941444 |doi-access=free }}</ref>

In Germany, LA is approved as a drug for the treatment of [[diabetic neuropathy]] since 1966 and is available as a non-prescription pharmaceutical.<ref name="Ziegle">{{cite journal |last1=Ziegle |first1=D. |last2=Reljanovic |first2=M |last3=Mehnert |first3=H |last4=Gries |first4=F. A. |title=α-Lipoic acid in the treatment of diabetic polyneuropathy in Germany |journal=Experimental and Clinical Endocrinology & Diabetes |volume=107 |issue=7 |pages=421–30 |year=1999 |pmid=10595592 |doi=10.1055/s-0029-1212132}}</ref>

==Clinical research==
According to the [[American Cancer Society]] as of 2013, "there is no reliable scientific evidence at this time that lipoic acid prevents the development or spread of cancer".<ref>{{cite web|url=http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/pharmacologicalandbiologicaltreatment/lipoic-acid|title=Lipoic Acid|date=November 2008|publisher=[[American Cancer Society]]|access-date=5 October 2013|archive-date=24 April 2015|archive-url=https://web.archive.org/web/20150424110743/http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/pharmacologicalandbiologicaltreatment/lipoic-acid}}</ref> 

As of 2015, intravenously administered ALA is unapproved anywhere in the world except Germany for [[diabetic neuropathy]], but has been proven reasonably safe and effective.<ref>{{Cite journal |last1=Prado |first1=Mario B. |last2=Adiao |first2=Karen Joy B. |date=2024-01-29 |title=Ranking Alpha Lipoic Acid and Gamma Linolenic Acid in Terms of Efficacy and Safety in the Management of Adults With Diabetic Peripheral Neuropathy: A Systematic Review and Network Meta-analysis |journal=Canadian Journal of Diabetes |volume=48 |issue=4 |pages=S1499–2671(24)00023–6 |doi=10.1016/j.jcjd.2024.01.007 |issn=2352-3840 |pmid=38295879}}</ref> As of 2012, there was no good evidence alpha lipoic acid helps people with [[mitochondrial disorders]].<ref name="pmid22513923">{{cite journal | vauthors = Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF | title = Treatment for mitochondrial disorders | journal = Cochrane Database Syst Rev | issue = 4 | article-number = CD004426 | date = April 2012 | volume = 2012 | pmid = 22513923 | doi = 10.1002/14651858.CD004426.pub3 | pmc = 7201312 }}</ref>

A 2018 review found that ALA had a small effect to reduce body weight, but is not cost-effective as a dietary supplement.<ref name="Namazi">{{cite journal | last1=Namazi | first1=Nazli | last2=Larijani | first2=Bagher | last3=Azadbakht | first3=Leila | title=Alpha-lipoic acid supplement in obesity treatment: A systematic review and meta-analysis of clinical trials | journal=Clinical Nutrition| volume=37 | issue=2 | year=2018 | issn=0261-5614 | doi=10.1016/j.clnu.2017.06.002 | pages=419–428|pmid=28629898}}</ref>

A 2025 study indicated a positive effect in a cellular model of [[Friedreich's_ataxia|Friedreich Ataxia]].<ref>Talaverón-Rey, M., Reche-López, D., Povea-Cabello, S. et al. Alpha–lipoic acid supplementation improves pathological alterations in cellular models of Friedreich ataxia. Orphanet J Rare Dis 20, 453 (2025). https://doi.org/10.1186/s13023-025-03990-z</ref>

==Other lipoic acids==
* β-lipoic acid is a thiosulfinate of α-lipoic acid

==See also==
* [[Aminolevulinic acid]]

==References==
{{Reflist}}

==External links==
* {{Commons category-inline}}

{{Enzyme cofactors}}
{{Chelating agents}}
{{Antioxidants}}
{{Dietary supplement}}

{{Xenobiotic-sensing receptor modulators}}

[[Category:Antioxidants]]
[[Category:Carboxylic acids]]
[[Category:Cofactors]]
[[Category:Drugs developed by Eli Lilly and Company]]
[[Category:Organic disulfides]]
[[Category:1,2-Dithiolanes]]
[[Category:Anti-aging substances]]