alfa alpha lipoic acid review

8/18/2019 Alfa Alpha Lipoic Acid Review

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http://www.whitakerwellness.com/health-concerns/diabetes-treatment/what-is-alpha-lipoic-acid/

Amazing Alpha Lipoic Acid

Julian Whitaker, MD The term “miracle drug” has been loosely applied to eerything !romaspirin and penicillin to statins and "#$-% inhibitors. &ut ' want to tellyou about a nutritional supplement that truly is miraculous: alphalipoic acid (also called lipoic acid or ALA).Lipoic acid is a potent antio*idant that+ unlike most antio*idants+ isboth water- and !at-soluble+ making it actie in irtually eery cell inthe body. 'n addition to neutralizing harm!ul !ree radicals+ lipoic acidregenerates and increases leels o! itamin "+ itamin ,+ coenzyme+ and glutathione.&ut that0s not all. Lipoic acid is also a mitochondrial powerhouse. 'tnot only protects your energy-producing !actories !rom !ree radicaldamage+ it also helps “prep” the !uel burned in the mitochondria andincreases the amount o! energy generated. 1urthermore+ it has auni2ue ability to neutralize to*ins+ chelate heay metals+ and protectagainst 34A damage. These multiple actions make lipoic acid aaluable ally against diabetes+ lier damage+ cancer+ and a host o!other diseases5it een slows down aging.Diabetics’ Best Friend'! ' had to limit lipoic acid to 6ust one use+ it would be !or thetreatment o! diabetes. This supplement not only improes insulin

sensitiity and lowers blood sugar+ it is also an e*cellent treatment !ordeterioration o! the arteries+ eyes+ and especially the neres thatplague so many patients with diabetes.&ill+ a Health & Healing subscriber+ had such seere diabeticneuropathy that he had constant pain and limited sensation in hislimbs+ his le!t leg dragged when he walked+ and he was continuallydropping things. 7e started taking lipoic acid a!ter reading about it inthis newsletter. 8hortly therea!ter+ the pain subsided+ his sensationimproed+ and his coordination returned.'ncredible as this may seem5especially !or a condition that patientsare told cannot be treated5it0s an eeryday occurrence at the

9hitaker 9ellness 'nstitute. sed intraenously or as an oralsupplement+ lipoic acid ery e;ectiely reduces pain+ numbness+burning+ and other unpleasant sensations o! neuropathy.A Lifesaver for Failing LiversLipoic acid also shines in the treatment o! lier problems. This is mostdramatically illustrated by the story o! h3+ a medical resident and one o! the !ew doctors in the 8 at thetime who was !amiliar with the use o! lipoic acid !or the treatment o!lier !ailure. Although he had been told by the hospital0s chie! doctor

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that nothing could be done !or them and that


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other autoimmune disorders. This is a !ascinating therapy that ' amcurrently inestigating and will write more about in a !uture issue.Want to Retard Aging# $ake Li!oic Acid There0s one more thing you need to know about lipoic acid: &ecauseo! its multiple roles in the mitochondria+ it is one o! the most

promising anti-aging therapies yet discoered. &ruce Ames+ >h3+pro!essor o! biochemistry and molecular biology at the niersity o!"ali!ornia+ &erkeley+ and one o! America0s most highly honoredscientists+ beliees that mitochondrial dys!unction is a primary causeo! aging and age-related diseases. 9hen your energy !actories ceaseto !unction at their peak+ your lights begin to dim and eentually goout.9hen 3r. Ames and his research team gae older rats lipoic acid andacetyl-L-carnitine (another amino acid deriatie with multiplebene?ts) !or seeral weeks+ it turned the lights back on. #ld+ lethargicanimals had more pep and energy+ they looked younger+ and theyper!ormed better on memory tests. The conclusion was that lipoicacid and acetyl-L-carnitine “tuned up” the mitochondria+ and this hadpro!ound anti-aging e;ects. 7uman studies on this combo arecurrently underway+ and the early results are ery promising.Man% More Bene&tsA short article can barely scratch the sur!ace o! this remarkablesupplement. Lipoic acid is also an e*cellent preentie and ad6uncttherapy !or cardioascular disease+ A'38 and immunosuppression+ision problems such as cataracts and glaucoma+ andneurodegeneratie disorders such as >arkinson0s and Alzheimer0s

disease. #ther current areas o! research include lipoic acid0s ability toincrease energy+ decrease appetite+ and inhibit inDammation-relatedbone loss.1or all o! these reasons and more+ ' recommend that eeryone oerage EF+ no matter how healthy they are+ include alpha lipoic acid intheir daily supplement regimen.Reco''endations

• The suggested dose o! lipoic acid !or preention and anti-agingpurposes is E mg per day. 1or patients with diabetes or lierdisease+ G-+C mg is recommended+ taken in diided doses hal!an hour to an hour be!ore eating !or optimal absorption. "ontrolled-

release lipoic acid has some adantages+ especially !or patients withdiabetes+ since it stays in the system much longer.

• “Triple therapy” !or lier disease consists o! C mg lipoic acid+H mg silymarin (!rom the herb milk thistle)+ and E mcg selenium(an antio*idant mineral)+ taken in diided doses twice a day.

• 3r. Ames0 anti-aging regimen includes E mg o! lipoic acid and+ mg o! acetyl-L-carnitine. (Look !or a combination productcontaining these dosages or purchase these supplements separatelyat your local health !ood store.)

• '! you can0t ?nd these supplements in a store near you+ order by

calling ()**+ )*-..//.

http://whitakerwellness.com/health-concerns/autoimmune-conditionshttp://whitakerwellness.com/health-concerns/heart-diseasehttp://whitakerwellness.com/health-concerns/parkinsonshttp://whitakerwellness.com/health-concerns/autoimmune-conditionshttp://whitakerwellness.com/health-concerns/heart-diseasehttp://whitakerwellness.com/health-concerns/parkinsons


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References

• &erkson &=+ et al. The long-term surial o! a patient withpancreatic cancer with metastases to the lier a!ter treatment withthe intraenous alpha-lipoic acid/low-dose naltre*one protocol. IntegrCancer Ther . %C =arIF():GJ-H.

( The key therapeutic agents were intraenous K-lipoic acid (ALA) Jto C mg % days per week and lowdose naltre*one (L34)+ E.F mg atbedtime. 'n addition+a triple antio*idant regimen consisting o! oralALA (C mg/d)+ selenium (% g % times per day)+and silymarin(JmgE times a day) was added to scaenge the products o!o*idatie stress that ineitably result !rom any serious chronicmedical disorder. rima 7ealth+Mocklin+ "A+ HHG.

• 7agen T=+ et al. 1eeding acetyl-L-carnitine and lipoic acid to old

rats signi?cantly improes metabolic !unction while decreasingo*idatie stress. Proc Natl Acad Sci USA. %% 1eb HIHH(E):GN-F.

• >anneerselam O,+ et al. L-carnitine and alpha-lipoic acidimproes mitochondrial !unction during ageing process. Clin Nutr .%C =ay H.

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http://de!ymedical.com/serices/%-serices/%-nutrients-and-nutritional-supplements

• L-0lutathione %mg/ml Jml122• L-"arnosine %mg/ml Jml1..

• Al!ha Li!oic Acid (ALA+ %Fmg/ml Jml1..

• AL"AR (Acet%l-L-"arnitine+ %mg/ml Jml1..

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https://e*amine.com/supplements/alpha-lipoic-acid/

3u''ar%

All 4ssential Bene&ts546ects5Facts 7 8nfor'ation

Alpha-Lipoic Acid (ALA) is a mitochondrial !atty acid that is highlyinoled in energy metabolism. 't is synthesized in the body and canbe consumed through eating meats and minimally in some!ruits/egetables.

'n supplement !orm+ it has shown bene?t against arious !orms o!o*idation and inDammation. These e;ects carry on to bene?ts thatprotect one !rom heart diseases+ lier diseases+ diabetes+ andneurological decline with age.

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't is a potent anti-o*idant compound. 't works with mitochondria andthe bodyPs natural anti-o*idant de!enses. 't is also seen as an anti-aging compound since it can reerse some o! the o*idant damagerelated e;ects o! aging.

"onfused about su!!le'ents# Free / da% su!!le'ent course$hings $o 9no:Also 9no:n As

ALA+ thioctic acid+ + %-dithiolane-J-pentanoic acid+ ala+ Tiolepta

Do ;ot "onfuse With

Alpha-Linolenic Acid (omega-J !atty acid)

$hings to ;ote

• Alpha-Lipoic Acid+ despite being a !atty acid+ appears to bewater soluble in the gut and is absorbed by transporters. "oingestionwith !atty acids in the diet does not appear to be re2uired

• "an be bound by aidin+ and thus coingestion with raw eggwhites can possibly negate the bene?ts o! supplementation

8s a For'


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Alpha-lipoic acid appears to be absorbed ia transporter-relatedmeans+ and despite being inherently !at-soluble it does not re2uiredietary !atty acids to be absorbed !rom the gut. ALA supplementationcan be taken in a !asted state.

"onfused about su!!le'ents# Free / da% su!!le'ent course=u'an 46ect Matri>

The =u'an 46ect Matri> looks at human studies (it e*cludesanimal and in vitro studies) to tell you what e;ects alpha-lipoic acidhas on your body+ and how strong these e;ects are.

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. . =echanismsN. 2 8nteractions :ith


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• &roccoli at .HEU/-.%Fmcg/g dry weight as lipoyllysineSFSC

• 7eart Tissue .GCU/-.JJmcg/g dry weight as lipoyllysineSFSC

• Tomatoes at .FCU/-.%Jmcg/g dry weight as lipoyllysineSFSC

Lipoyllysine is a lipoic acid molecule bound to a lysine amino acid+ andis a !ood storage !orm o! alpha lipoic acid that is bound to theproteins.SN 't is separated into lipoic acid and lysine ia theglycoprotein enzyme lipoamidase (sometimes re!erred toas lipo%ll%sine h%drolase)+ which circulates in human serum.SG

Lipoic Acid is !ound in a ariety o! !ood sources+ but the leels !oundin !ood tend to be signi?cantly lower than standard supplementaldosagesC Bios%nthesis

Alpha-Lipoic acid (ALA) is a naturally occurring dithiol compoundcreated in the mitochondria !rom octanoic acid as a precursor+ with agood deal o! synthesis occurring in the lierPs mitochondria.SHSE

'ts main biological role is as a co!actor in mitochondrial enzymes suchas alpha-ketoglutarate dehydrogenase and pyruate dehydrogenase.S ALA also appears to be inoled in the production o! Acetyl-"oA+ia o*idatie decarbo*ylation o! pyruate.S

8upplementation has been !ound to carry bene?ts against o*idation+inDammation+ diabetes+ and cognition.S

3tructure and 3tabilit%

Alpha-Lipoic Acid possesses a chiral center carbon and thus can e*istin an 8 or M isomerI unspeci?ed ALA is a PracemicP solution o! bothwhereas M-ALA is commonly sold as well+ commonly bound to sodium(4a-M-ALA).

The disul?de bond in Alpha-Lipoic Acid can be homolytically cleaed

by near @ light and heatS%SJin where the dithiolane ring structure!orms two thiyl radicals and sel!-polymerizes into a linear chain o!disul?des known as >&">3+ !ull name o! polyVJ-(n-butane carbo*ylicacid)propylWdisul?de.SE This polymerization is seen as reersible+ withconersion back into ALA in alkaline solution or with coincubation withreducing agents such as dithiothreitol and X-mercaptoethanol.SF 'thas been suggested that naturally occurring ALA may be a racemicmi*ture including a >&">3 content.SC

In vivo+ ALA can be reduced to dithiol !orm (where the ring structure isbroken)+ dihydrolipoic acid (37LA).SE 'n cells with mitochondria thisreduction is mediated by lipoamide dehydrogenase and is an 4A37-

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dependent reaction+ and cells without mitochondria this reductionoccurs ia 4A3>7 with glutathione and thioredo*in reductases.SN

ALA has a melting point o! CJY" when in racemic solution and FY" asthe M-ALA isomer+ and pairing with salts with higher boiling points

may enhance stability (a common enture !or patentsSGSH)

%Ehar'acolog%C Absor!tion

#rally ingested Alpha-Lipoic Acid (ALA) is rapidly taken up in the gutin a p7 dependent manner by monocarbo*ylic acid transporters(="Ts). "oingestion with monocarbo*ylic acids such as medium-chaintriglycerides or benzoic acid inhibits ALA uptake.S% There is also thepotential !or ALA to be taken up by the sodium-dependentmultiitamin transporter (8=@T).S%S%% 'n the gut+ some ALA conertsinto dihydrolipoic acid. The oerall bioaailability o! ALAsupplementation is ZJ[S%JS due to high lier e*traction. S%E The 4a-M-ALA !orm o! ALA is completely soluble in water.S%F Although the M-enantiomer has higher intestinal uptake rates in vivoS%C the 8-enantiomer may stabilize uptake by preenting polymerization.S

Taken up moderately well+ uses the ="T transporter and may not beabsorbed as well i! taken alongside medium-chained triglycerides

CC 3eru'

8ystemic pharmacokinetics o! ALA are !airly rapid. A!ter rapidintestinal uptake it is 2uickly partitioned to tissues that uptake ALA(brain+ heart+ and muscle) and includes a transient lier storage o!ALA.SS%N ALA accumulates in the brain as soon as an hour a!teringestionS%G and is stored in arious brain regions. S%H

A!ter oral ingestion o! Cmg ALA racemic mi*ture+ the "ma* appearsto be C.GCU/-.%H\g/mL with a Tma* o! F.G minutes and an oerall Ghour A" o! F.CFU/-.NH\g/mL/h.SJ

C Metabolis'

'n cells+ ALA is primarally metabolized ia beta-o*idation.SJ The mainmetabolites are bisnorlipoate+ tetranorlipoate+ X-hydro*y-bisnorlipoate+ or the bis-methylated mercapto deriaties o! thesecompoundsS%N and dihydrolipoic acid+ which undergoes rapid cellulare*cretion.SN

C 4li'ination

ALA is also rapidly e*creted by ?ltration in the kidneys+ with HG[ o!digested ALA e*creted within %E hoursS%E. 7oweer+ most orally

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ingested ALA is lost in !ecal e*cretion prior to intestinal uptake.SJ 1orthese reasons+ ALA is not stored long-term. According to 8hay et al.S the aerage A" is appro*imately CU/-JFug/ml/min and theaerage "ma* is %.GU/-.F !or a Cmg oral dose o! both enantiomers. These results rial 4a-M-ALA !or A" (despite M-ALA showing higher

peak alues and !aster e*cretion) but are well ahead o! 8-ALA inisolation.S%C

The ma6ority o! supplemental ALA does not appear to be stored !orlonger than a dayC/ Metal "helation

Alpha-Lipoic Acid (ALA) as well as its metabolite dihydrolipoic acidbind to metals in vitro+ with the !ormer binding to copper+ lead+and ]inc while the reduced !orm o! dihydrolipoic acid binds to thosethree as well as mercury and iron(''').SJ% 3ue to 8elenium andmanganese de?ciency being symptoms o! ALA to*icitySJJ+ it seemsALA or its metabolites can bind to these two metals as well.

In vivo+ ALA has been obsered to reduce iron leels in the brain andlier+ but only when the iron leel is aboe normal.SJESJF These resultspreliminarily suggest that ALA does not negatiely a;ect the mineralstatus o! the body.

JLife 4>tension and Longevit% Mechanis's

't has been hypothesized that the longeity promoting aspects o! ALAare due to >>AM gamma co!actor (>"Q-a) actiation+SJC amechanism shared by >yrrolo2uinoline 2uinone.

'n lier cells+ alpha-lipoic acid has been !ound to increase o*ygenconsumption to GH[ o! baseline when gien to old rats at .F[ o!the diet while it nonsigni?cantly increase o*ygen consumption toE[ o! baseline in younger rats.SJN 'nitially the older rats has FH[

the leel o! o*idation relatie to younger rats+ and a!tersupplementation there were no signi?cant di;erences.SJN Thisnormalization o! mitochondrial o*ygen capacity has been recorded inneural tissue as well where increased o*ygen consumption coupledwith increased anti-o*idatie potential improed neural conse2uenceso! aging in old rats !ed .F[/.F[ ALA/AL"AM (a !orm o! L-"arnitine)such as memory loss.SJGSJH

This increased o*ygen consumption is associated with lessparameters o! o*idation when ALA at .F[ o! !eed is supplemented ora combination o! ALA and L-"arnitine (as AL"AM) is supplemented+AL"AM at .F[ o! !eed in isolation can increase o*idation.SE TheJ.G[ increase in o*idation seen with aging (relatie to control) in

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this study was abolished with combination therapy+ and normalized tothe leel o! youth!ul rats+ and was measured by =3A+ Ascorbate+ and%P+NP-dichloroDuoresin appearance.SE This decrease in o*idation is alsoassociated with a lesser decline o! mitochondrial enzymes+ whichappears as an increase !rom pre-supplementation leels.SESE%

8upplementation o! Alpha-Lipoic Acid alone increases o*idatieconsumption (indicatie o! metabolic actiity) in a similar mannerto L-"arnitine in aged animals+ which improes !unctionalper!ormance. ALA can also curb the pro-o*idatie e;ects o! L-"arnitine+ demonstrating practical synergismC Ani'al 8nterventions

A rat study assessing Alpha-Lipoic Acid and diet interactionsconcluded+ a!ter !ollowing % groups o! rats !or their li!etimes+ thatsupplementation at a dose that does not inter!ere with !ood intake(.Fg/kg in rats) does not appear to augment the eRcacy o! caloricrestriction nor enhance ad liitum(no control) !eeding per se+ but that() although rats that switch to caloric restriction a!ter % months o!age (J[ o! li!espan) show similar li!e e*tension to li!elong caloricrestriction+ rats preiously !edad liitum with ALA did not+ and (%)switching !rom caloric restriction to ad liitum !eeding at % monthsnormally attenuate the li!e e*tension e;ects o! caloric restriction+ thiswas not seen when re!eeding occurred with ALA despite an increasein growth rates.SC The !ormer inhibition o! longeity and promotion o!longeity (respectiely) were lesser in magnitude with a shorter

supplementation time.SC

#ne study simply administering ALA to immunosuppressed mice!ound that both isomers o! ALA were able to increase longeity+ butthe 8-isomer at NFmg/kg daily and the M-isomer at Hmg/kg dailyI highdoses o! JFmg/kg appeared to act to reduce li!espan.SEJ

'n regards to an anti-aging phenotype (giing the appearance o!youth without impacting median o! ma*imal li!espan)+supplementation o! Alpha-Lipoic Acid has been demonstrated toincrease the metabolic rate and actiity leels o! older rats+ to a

greater e*tent as seen in younger rats. 3ue to increasing actiityleels more in older rats than younger+ ALA supplementation reducedthe di;erneces between groups.SE

E;eurolog% and the Brain A!!etite

ALA has been demonstrated to inhibit A=>O in the hypothalamus (asopposed to other areas o! the body where it stimulates) and due tomimicking a caloric surplus can suppress appetiteI these e;ects maybe secondary to increasing glucose uptake into the hypothalamus+

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and are reersed upon A=>O actiation in the hypothalamus.SEE ALAat .%F+ .F+ and [ o! the oerall !ood intake o! rats oer % weeksand when tested oer the period o! E weeks was able to reduce bodyweight relatie to unsupplemented control.SEE The reduction in !oodintake in rats does not appear to be secondary to a conditioned taste

aersion+ which should be noted due to ALAs sharp taste.SEE Anotherrat study using %mg/kg oral intake !ound that this suppression o!hypothalamic A=>O paired with adipose e*pression o! A=>O helped tonormalize changes in !at mass associated in a model o! menopause.SEF

'n older rats !ed .NF[ ALA+ this reduction in !ood relatie to controlhas been 2uanti?ed at ranges o! G[SEC to J[+ SEN and many otherstudies that note !ood intake as secondary obserations tend to notedecreases that reach statistical signi?canceSEGSEHSEFSFSENSFSF% or trendstowards signi?cance.SFJ The reproducability o! this seems to be highenough that+ in some trials irreleant to !ood intake+ a third Ppair-!edPgroup is planned at the onset to match the e*perimental group !orintake and control !or the e;ects o! ALA against the e;ects o! !ooddepriation per se.SFESFFSFCSFN

This suppression o! appetite seems to inDuence both low-!at and high-!at diets+ as one rat study that supplemented ALA to both groupsnoted non-signi?cant di;erences in oerall weight loss (-%E[ and-%H[ in low and high !atI respectiely and relatie to high !at control)SEN

The only human study to be conducted on Alpha-Lipoic Acid at Cmgand appetite was conducted in 8chizophrenic patients and con?rmedappetite suppression with increased energy (sub6ectie rating)+ buthad a ery low sample size.SFG

Appears to be a potent appetite suppressant in research animals+ andis consistent in the appetite suppressing e;ects. 8urprisinglyunderresearched in humans+ but may hae the same e;ects8ome studies do note an attenuation o! appetite suppression (lesssigni?cance) about two weeks a!ter consumption+ so these e;ects

may be short term and they do not seem to be !ully abolishedC Mechanis's

Alpha-lipoic acid has been noted to reduce o*idatie damage inneuronal cellsSFH and aged rats at mg/kg S%H which is thought tounderlie the reductions in age-related cognitie decline.SCSCSJGSC%

't has been noted that ALA does not alter basal calciumconcentrations in a neuron at lower concentrations (F-F^g/mL) nordid it augment the calcium response to glutamate+ yet F^g/mL isable to increase basal calcium inDu* and suppress glutamate inducedsignalling.SCJ

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ALA has also been !ound to inhibit T-currents (speci?cally+ ia the"a@J.% channel) with an '"F o! JU/-^=+ reaching ma*imal inhibitiono! around E[ at -+^=. This appears to be mediated ia aM,3#$ reaction on the calcium channel.SCE

0luta'inergic ;eurotrans'ission

Alpha-lipoic acid (.F-\=) appears to !acilitate the calcium-dependent release o! glutamate !rom the synapse ia a >OA/>O"dependent mechanisms+ the magnitude o! which reached around%N.JU/-J.[.SCF

=ay !acilitate the release o! glutamate at the presynatic leel+ whichwould theoretically enhance signalling through glutaminergicreceptors

't has been noted that incubation o! glial cells with alpha-lipoic acid(-F^=) increases glutamine s%nthetase actiity in astrocytes andincreases glutamate uptake by around %[ (and subse2uentglutathione production by E[)+SCC a mechanism similarto Meseratrol. This appears to be mediated ia >O" but not >'JO.SCC

Appears to stimulate glutamate uptake into glial cells !or conersioninto Qlutamine+ which theoretically suppresses signalling

't does not appear to alter synaptic membrane potential o! glutamate

signallingSCF

and when inestigating the 43=A receptors alpha-lipoicacid has been !ound to both suppress signalling (as ALA) or enhancesignalling (as the reduced !orm 37LA).SCN

'nterestingly+ the age-related de?cits in 4=3A receptor &ma* appear tobe normalized with alpha-lipoic acid in aged mice.SCG

Alpha-lipoic acid is able to modulate the M,3#$ site o! the 4=3Areceptor+ but since it works in both directions its oerall actions onreceptor signalling are unclear. 7oweer+ at least one study suggest apossible increase in 4=3A receptor density in older sub6ects

The e*citoto*icity seen with e*cess glutamate appears to be reducedwith alpha-lipoic acid (\= or aboe)+ which seems to be secondaryto presering glutathione concentrations in the neuron.SCHSNSN Areduction in 4=3A-induced lesions has also been con?rmed in ratsin6ected with mg/kg ALA !or days+ reaching about a haling inlesion size.SN%

Alpha-lipoic acid appears to be neuroprotectie against glutamate-induced to*icity secondary to supporting the glutathione pool (itsdepletion precedes cellular death)+ a mechanism similar to 4-acetylcysteine

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'n pilocarpine induced seizures+ an intraperitoneal in6ection o!mg/kg alpha-lipoic acid is able to normalize the increase inglutamate seen with pilocarpine.SNJ This was associated with apreseration o! TaurineSNJ and aspartate SNE concentrations as well.

The increase in glutamate seen with cyanide to*icity (which releasesglutamateSNF and neuroto*icity is thought to be mediated ia the4=3A receptorSNC) appears to be attenuated with %F-mg/kg ALA.SNN

The eleation in glutamate concentrations seen in pathologicalconditions or to*in administration appears to be able to be attenuatedwith preadministration o! alpha-lipoic acid "holinergic ;eurotrans'ission

An animal study assessing the interactions o! ALA and pilocarpine (acholinergic agonist capable o! inducing seizures) !ound that mg/kgALA was able to reduce pilocarpine-induced seizures by F[ andprolong time to seizure by %[ i! unable to outright preent.SNG

/ Do!a'inergic ;eurotrans'ission

A study in which rats were !ed low doses (+ %+ or Jmg/kgbodyweight) ALA !ound that %mg/kg bodyweight was able toincrease dopamine leels in the hippocampus by about H[ %E hoursa!ter ingestion yet the other two doses ( and Jmg/kg) were not

signi?cantly di;erent than control.SNH

Another study using mg/kg!ound no e;ect.SNG

Alterations in dopamine (decrease) and dopamine metabolite(increase) leels associated with pilocarpin-induced seizures has beennormalized with mg/kg pre-treatment ALA.SNG

. 3erotonergic 3ignalling

A study in rats !ound a decrease in hippocampal serotonin by H[ andits main metabolite+ 7-'AA+ by %[ when consumed at %mg/kg

bodyweight (but not or J) and measured %E hours later.SNHAnotherstudy using mg/kg !ound no e;ect.SNG

2 Adrenergic (Adrenaline+ 3ignalling

A rat study !ound [ increased noradrenaline leels in thehippocampus associated with %mg/kg ALA a!ter %E hours+ while theother two tested doses ( and Jmg/kg) were not signi?cantlydi;erent than control.SNH Another study using mg/kg !ound noe;ect.SNG

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A signi?cant reduction in noradrenaline leels in the brain associatedwith pilocarpine (e*perimental seizure inducer) has been abolished bypre-treatment with ALA at mg/kg in rats.SNG

) idation

'n an a!orementioned study noting alterations in monoamines at%mg/kg oral dose yet not nor J+ a reduction o! lipid pero*idationwas obsered that also only occurred at this does+SNH the study hasbeen duplicated in the literature.SG

F;erve function/ 0eneral

#ne study has been conducted with ALA on persons with compressieradiculopathy syndrome !rom disc-nere root conDict+ and !ound thatCmg o! ALA daily (paired with JCmg Qamma-Linoleic Acid) incon6unction with a physical rehabilitation program was synergisticwith the physical rehabilitation program and promoted nere recoeryoer C weeks.SG

/C "ar!al $unnel 3%ndro'e

"arpal Tunnel 8yndrome ("T8)+ at least in the early stages o! disease

progression+ has shown bene?t to disease progression and symptomso! "T8 (when "T8 is at a moderate-seere leel) associated with anAlpha-Lipoic Acid multinutrient (main con!ound was Qamma-LinoleicAcid) at Cmg and JCmg+ respectiely+ oer the source o! H days.SG%

/ Diabetic ;euro!ath

#ne study paired Alpha-Lipoic Acid with oral 8upero*ide 3ismutase(an anti-o*idant enzyme) and !ound signi?cant reductions in diabeticneuropathy as assessed by sub6ectie pain and electroneurographic

parameters.SGJ

A E year trial o! ALA on diabetic neuropathy using Cmg ALA daily!ailed to show a signi?cantly di;erence in primary outcomes betweengroups (4europathy 'mpairment 8core+ neurophysiological tests) yetthe ALA group showed signi?cant improements relatie to their ownbaseline alue.SGE This trial could not establish a protectie e;ect o!ALA+ howeer+ since placebo did not deteriote oer time.SGE

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C8nteractions :ith the Liver. Mechanis's

Alpha-Lipoic Acid can induce triglyceride lipase e*pression in liercells (responsible !or decreasing triglyceride strorages in these

cellsSGF) secondary to A=>O actiation+ which decreased lipidaccumulation in vitro.SGC A=>O was actiated in a time andconcentration dependent manner+ and was able to do so despite highglucose (Jm=) and palmitate (.m=) concentrations atconcentrations o! .%F-m=.SGC These A=>O interactions areindependent o! 8irtuin proteins+ and appears to circument insulinsactions on the nuclear transcription !actor 1#$# by preentingnuclear e*clusion+ which appears to be secondary to A=>O as well.SGC 9hen !ed to genetically obese rats+ %.E[ ALA o! the diet !or Fweeks (about Emg/kg bodyweight in this study a!ter controlling !or%[ bioaailability) is able to reduce triglyceride accumulation in liertissue (-%C[) and increase glycogen content (U%N[)I relatie tocalorically restricted rats+ the LA group had larger liers withoutabnormal biomarkers+ possibly due to the glycogen content.SFE

8upero*ide Anion production in the lier o! rats !ed [ ALA alsoappears to be reduced relatie to control+ and the increase insupero*ide production in response to added glucose to the diet+ !orthe most part+ abolished.SEH

A=>O is not the sole mechanism o! reducing !at accumulation in the

lier+ and can inhibit the genetic actions o! pro-lipogenic proteins L$Mand speci?city protein .SGN Alpha-Lipoic Acid may increase the proteincontent o! >>AM_ receptors when !ed at [ o! the diet oer a periodo! E weeks and was negatiely correlated (r`.G) with blood !ree!atty acid leels.SEH

Although the bene?cial e;ects o! ALA on lier physiology ina!orementioned models are well-established+ one study comparingthe e;ects o! long-s short term ALA supplementation in healthy micesuggests that regular+ long term supplementation may cause lierdamage+ and should be considered with caution.SGG

To e*amine the e;ect o! short- s long term ALA supplementation onthe lier+ “black C” mice ("FN&LC/


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with e*tensie !at accumulation leading to hepatic steatosis ande*tensie lier damage.SGG

4otably+ the aboe study was uni2ue in that it inestigated the e;ectso! long term ALA treatment in otherwise healthy mice. 'n contrast+

other studies that hae shown a bene?cial e;ect o! longer term ALAtreatment were conducted in rodent disease models+ including high!at diet !ed ratsSGN and ]ucker 3iabetic 1atty (]31) rats. SGH Thus+ long-term ALA treatment in healthy animal models may be lier to*ic+causing a phenotype that closely resembles that o! non-alcoholic !attylier disease.SHSH't should be noted that the dose o! ALA in thehealthy mouse studySGG o! %mg/kg is e2uialent to appro*imately .Ggrams/day in a % lb human. Although this is a relatiely high doseo! ALA+ it is close enough to standard doses that caution may bewarranted !or long term supplementation.

Although ALA has been shown to decrease o*idatie stress andimproe lipid metabolism in animal disease models+ one study inhealthy mice suggests that long term treatment may be lier to*ic+causing damage that resembles non-alcoholic !atty lierdisease. "A@$8


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In vitro+ lipoic acid was able to induce apelin secretion !rom !at cells(an adipokine that may regluate glucose metabolism) but wasdeemed to be unrelated to changes seen in vivo.SEG

'n regards to A=>O+ at least one study has seen results that suggest

A=>O inhibition could be at play in JTJ-L adipocytes but was notdesigned to answer these 2uestionsISEG two other studies note that inwhite adipose tissue A=>O is both actiated and its mM4Aupregulated.SFFSEF

9hen inestigating the interactions o! ALA and nutrient absorption+supplemental ALA !or FC days was able to reduce carbohydate uptakesecondary to inhibiting the 8QLT transport (sodium dependentglucose transporter) by appro*imately a third+ when the 6u6enum wase*cised and testedin vitro with alpha-methylglucose. SF 9hentested in vivo at .F[ ALA though+ there are no signi?cant di;erencesin the caloric content o! the !eces with ALA (assessed by bombcalorimetry).SEN

7as the potential to inhibit nutrient uptake+ does not appear to bepotent enough to be meaning!ul2C 4nerg% 4>!enditure

'n animals !ed .F[ o! !ood intake as ALA when caloric intake wascontrolled (as ALA may suppress appetite)+ energy e*penditure asassessed by indirect calorimetry increased by day J and continued to

be eleated !or the % tested days.SEE

These rats showed increasede*pression o! "> in brown adipose tissue and ectopic e*pression o!"> in white adipose tissue+ thought to be a reason !or the increasedmetabolic rate.SEE 'n older rats at .NF[ ALA !or E weeks+ an increasedmetabolic rate has also been obsered through an A=>O/>Q"-adependent mechanisms and this metabolic rate (paired with an G[reduction in !ood intake) resulted in F.G[ total weight lost.SEC #*ygen consumption and "arbon 3io*ide production in these olderrats !ed .NF[ ALA increased by %N[ and JG[+ respectiely. SEC

2 8nterventions

#ne study conducted on %%G persons (JC at the start+ high dropoutrate) who were either obese or oerweight paired with metabolicabnormalities (metabolic syndrome) gien +%mg or +GmgAlpha-Lipoic Acid (in three daily doses be!ore meals) !or % weeksnoted that there was a signi?cant decrease in weight in the +Gmggroup when all groups were sub6ect to a Ckcal de?cit.SH%Aerageweight loss was .HEU/-.EFkg in placebo+ .EHU/-.JGkg in +%mg+and %.NCU/-.FJkg in +Gmg.SH%

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G8nteractions :ith 3keletal Muscle) Mechanis's

'n aged rats+ improements in QLTE and >Q"-a mM4A content wasincreased by F[ and G[ (respectily) a!ter E weeks o! .NF[ ALA

ingestion.SEC

#ne rat study noted that with ALA in6ections at Jmg/kg+ 7eat 8hock>roteins N% and %F were induced in high !at (C[) but not low !at([) diet+ which was able to reduce pro-inDammatory signalling ia O as can inhibiting the "a=OO enzyme+ which releasescalcium into myocytes.SHN

)C 0lucose @!take

#ne study noted that in chow !ed rats ([ !at) that ALA was unableto stimulate glucose uptake into muscle cells in vivo+ but was able toimproe the FE.N[ reduction in glucose uptake seen in the high-!at(C[) !ed rats (relatie to chow) by FF.N[.SFJ

H8nteractions :ith "ardiac =ealthG Elatelet Function

ALA appears to be able to inhibit platelet aggregation secondary to>>AM agonism+ where incubation with ALA caused actiation o! >>AM_

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and >>AM and a subse2uent inhibition o! arachidonic acid inducedplatelet aggregation possibly secondary to >O"_ association andinhibtiion o! calcium accumulation.SHG 'ncubation with either a >>AM_or >>AM antagonist abolished these e;ects.SHG

GC 4ndotheliu'

#ne study has noted that+ secondary to A=>O actiation+ may reersean impairment o! rela*ation seen in obese rats.SHH

'n human interentions+ ALA supplementation appears to improeendothelial dys!unction and blood Dow as assessed by Dow-mediatedasodilation a!ter J weeks o! supplementation in persons withsubclinical hypothyroidismS and either type '' diabetes S or merelyimpaired !asting glucose either oer the long termS or during anacute glucose tolerance test.S%

G $rigl%cerides and Li!o!roteins

#ne interention seeing how ALA a;ects weight loss noted that +%and +Gmg daily ALA !or % weeks did not inDuence restingtriglycerides or 73L cholesterol at either dose compared to placebo.SH%

8nteractions :ith 0lucose Metabolis'* 8nsulin

#ral supplementation o! +Gmg ALA !or % weeks does not appear toinDuence insulin secretion rates in healthy but oerweight/obese men.SJ

The impairment o! insulin sensitiity seen with high bloodtriglycerides does not appear to be alleiated with ALA at +Gmgdaily !or % weeks.SJ

*C @sage in Diabetes

Alpha-Lipoic Acid has been inestigated !or oral usage at doses o!J+ C+ H+ and +%mg o! a racemic mi*ture oer a period o! Cmonths in persons with con?rmed type '' diabetes (some on anti-hyperglycemic therapy) and it was shown that a dose-dependent trend towards reduced !asting blood glucose and 7bAc ateach dose+ and signi?cant reductions when all groups were pooledand when sub6ects were compared to baseline.SE A longer trial o! Eyears with Cmg ALA !ound a greater decrease in 7bAc associatedwith ALA (.CN .E[) than placebo (.EG .EC[)+ but did notreach signi?cance.SGE



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8nteractions :ith idation Mechanis's

Alpha-Lipoic Acid (ALA) is a multi-modal antio*idant+ capable o!decreasing o*idation that is a result o! metal pero*idation+ increasingglutathione leels in the body+ or by directly acting on anti-o*idants(like ascorbate) or by itsel!.

As a metal-chelator+ ALA can reduce pero*idation in neural tissueinduced by mercurySF and ia iron(''') and copper('') chelation hasshown bene?ts in the pathophysiology o! AlzheimerPs disease.SJF

ALAPs ability to upregulate e*pression o! glutathioneSC (one o! thebodyPs intrinsic anti-o*idant systems) comes !rom hepatic e*pressiono! Nr'" (as eidenced by being eleated %E hours a!ter e*posure+rather than acutelySN). 3uring aging intrinsic e*pressiono! Nr'" (which mediates genes o! the anti-o*idant response element(AM,)) declines+ which results in less AM, actiity and subse2uentlyreduced leels o! glutamyl cysteine ligase (Q"L)--the rate-limitingenzyme in glutathione synthesis. ALA has been obsered toupregulate the synthesis o! both Q"L subunits iaNr'" binding to AM,+and restore age-depleted glutathione leels.SG

The hypothesized mechanism o! the aboe is that ALA irreersibly

binds to the Oeap protein+ which normally binds to Nr'" and signals!or its destruction.SH &y !orming lipoyl-cysteine bridges withOeapS ALA preseres Nr'" !unction. SS%

ALA has been obsered to induce an increase in ascorbate (@itamin ")leels in the lierSJ and heart SE o! aged rats+ or which leels declinedue to possibly a reduction in the sodium-dependent itamin "transporter in the lier.SF ALA supplementation may also inducemore itamin " uptake !rom the blood into the mitochondria !orusage+ thus acting as a potentiator.SC

ALA can also act as a direct anti-o*idant+ at least in vitro. 7oweer+due to its rapid e*cretion rates and lack o! A" in a cell it is suspectedthat this pathway is negligible.

C 8nterventions

8upplementation o! J-+%mg ALA daily !or C months is associatedwith reduced urinary leels o! 1%_-iso>+ which suggests that ALAreduces lipid pero*idation in vivo !or type '' diabetics. SE"onsumptiono! Cmg ALA in type diabetics oer F weeks does not appear tosigni?cantly reduce this biomarker+ howeer.SN

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9hen measuring G-#7dQ+ an o*idatie 34A byproduct !ound in theurine+ there was no signi?cant inDuence.SE

%8nHa''ation and 8''unolog%C Mechanis's

=ost anti-inDammatory e;ects o! Alpha-Lipoic Acid (ALA) aremediated through its ability to inhibit 41-k&+ a nuclear transcription!actor that+ upon its actiation+ induces an inDammatory cascade.SGALA inhibits upregulation o! '"A=- and @"A=-+ two pro-adhesioncytokines+ in models o! spinal in6ury at concentrations o! %F-ug/mL(doses seen as therapeutic+ and well-aboe the typically Cmg aday).SHS% ALA may also inhibit e*pression o! metalloproteinase-HS% and osteoclast !ormation by this same mechanism. S%%

The mechanism by which ALA inhibits 41-k& actiity seems to be!urther upstream than T41-alpha inhibition+ which is the stage manyanti-o*idants act on. ALAPs anti-inDammatory e;ects are independento! T41-alpha modulation.S%J

'n humans+ a clinical trial noted a F[ serum reduction in leels o!interleukin-C (an inDammatory marker) !ollowing E weeks o! Jmgracemic ALA supplementation.S%E

CC Rheu'atoid Arthritis

#ne study has been conducted on ALA (Jmg) !or E weeks inpersons with rheumatoid arthritis noted that lipoid acid !ailed tosigni?cantly reduce 'L-C+ 'L-X+ or T41-_ and !ailed to signi?cantlyreduce pain associated with rheumatoid arthritis.S%F

J8nteractions :ith =or'ones Le!tin

Alpha-Lipoic Acid+ through suppressing hypothalamic A=>O yetactiating peripheral A=>O+ shares mechanistic similarities to thehormone leptinI when tested in mice howeer+ those with and withoutleptin receptors still e*perience these e;ects+ suggesting ALA acts asa leptin mimetic in results (but not mechanisms) and may help inoercoming leptin resistance by bypassing the receptor.SEE

9hen gien to rats prone to 4on-alcoholic 1atty Lier 3isease(4A1L3)+ ALA can suppress the disease pathology and e*pected risein leptinS%C and increased leptin leels in a model o! type diabetes+which e*periences a decrease in leptin.S%N 9hen gien at .%F[ o!the diet to otherwise normal and healthy rats+ a decrease in



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circulating leptin and leptin mM4A is seen a!ter G weeks+ and wascorrelated (r`.HG) with leels o! white adipose tissue.SF% 'solatedadipocytes !rom these rats a!ter G weeks sub6ect to %Fu= ALAincreased conersion o! glucose to lactate (resulting in a signi?cantincrease in lactate by EE[ at Fu=) and this increase in lactate was

correlated with a decreased secretion o! leptin.SF% Lipoic acid appearsto be associated with increased phosphorylation o! 8p+ a nucleartranscription !actor induced by glucose that stimulates leptinI itsphorphorylation preents its actions in the nucleus+ and ALAPs actionswere mimicked by >'JO inhibitors.SF%

E;utrient-;utrient 8nteractions L-"arnitine

9hen placed in isolated adipocytes (!at cells)+ Alpha-Lipoic Acidappears to be synergistic with L-"arnitine supplementation+ with aconcentration o! .umol/L o! both molecules outper!ormingumol/L o! either molecule (and interesting+ umol/L o! bothmolecules) in increasing mitochondrial density.S%G umol/L o! bothappeared to be the most e;ectie at increasing mitochondrial density+more than J-!old that o! control cells.S%G

'n a model o! lipoto*icity+ while "arnitine was e;ectie at increasingmM4A leels o! ">T- and >>AMy in mitochondria the addition o! Lipoic

Acid !urther augmented the increases in mM4A.S%H

These synergisticincreases in mM4A hae been reported elsewhere+ and appear toa;ect >>AMa as well.S%G

C 3esa'in

8esamin is a mi*ture o! lignans !rom sesame seeds that may increaselipid o*idation and decrease lipid synthesis in the lier+ an e;ectsimilar to ALA. >airing the two appears to be additie in regards toreducing circulating lipid leels+ but the combination con!er noadditional bene?t in reducing triglyceride storage in the lier.SJ The

combination additiely decreased !atty acid o*idation+ but ALAappeared to normalize the increase in !atty acid o*idation seen with8esamin.SJ

Avidin

Aidin is a protein !ound predominately in raw (but not cooked) eggwhites which is known to potently bind to and se2uester &iotin+leading to biotin de?ciency i! more biotin is not ingested.SJSJ% &iotinhas a similar structure to ALA+ and aidin binds to biotin ia the parto! the molecule that is structurally similarSJJ meaning that aidin canalso se2uester ALA.SJJ

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9hile it is not prudent to consume raw egg whites anyways due to theaidin content+ they could not be consumed alongside ALA as theaidin in the egg whites has the potential to se2uester and inactiatethe ingested ALA be!ore it can be absorbed

F$o>icit% and 3afet%/ 0eneral

ALA supplementation is relatiely sa!e in the doses consumed inhumans. 8tudies in rats hae established a Cmg/kg bodyweight dosein which no aderse side e;ects are notedSJE and acute harm beingnoted at %mg/kg a day.S 'n humans+ doses o! Gmg/kgbodyweightSJF and %Emg/kg bodyweight SJC !ailed to hae any side-e;ects oer a C-N month period.

'n these to*ic doses+ ALA has been !ound to increase o*idation leels(ia hydropero*ide) in the organs it acts inSJNSJG as well as take itsmetal-chelating abilities to the e*treme and induce mineralde?ciencies.SJJ These e;ects were seen at the human e2uialent o! J-Fg o! ALA a day+ well below the leel used in human trials thatobsered no side e;ects.

/C 8nterventions

1or interentions that note side e;ects+ one was a E-year blinded trialo! ALA at Cmg !or the purpose o! aiding diabetic neuropathy wherethe aderse side e;ects were higher in ALA (at JG.[) than inplacebo (at %G[)+ and were dubbed to be Pcardiac relatedP or urinaryin nature. These aderse e;ects did not deter the authors !romdetermining that ALA was well tolerated+ possibly due to signi?cantdi;erences in global rating.SGE

#ther trials note that common side e;ects are nausea (deemed minorand related to appetite suppression)SFG and an itching sensation o! theskin assocaited with higher (+%-+Gmg) doses.SH%

3cienti&c 3u!!ort 7 Reference "itationsReferences

. _ -lipoic acid can improe endothelial dys!unction in sub6ectswith impaired !asting glucose

%. Lipoic Acid &iosynthesis: LipA 's an 'ron8ul!ur >roteinJ. Akiba 8+ et al Assay o! protein-bound lipoic acid in tissues by a

new enzymatic method . Anal Biochem. (HHG)E. 9ollin 83+ < Alpha-lipoic acid and cardioascular

disease . ( Nutr . (%J)F. =oini 7+ >acker L+ 8aris 4, Antio*idant and proo*idant actiities

o! alpha-lipoic acid and dihydrolipoic acid . To)icol Appl Pharmacol.(%%)

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alfa alpha lipoic acid review

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