http://www.whitakerwellness.

com/health-concerns/diabetestreatment/what-is-alpha-lipoic-acid/
Amazing Alpha Lipoic Acid
Julian Whitaker, MD
The term miracle drug has been loosely applied to everything from
aspirin and penicillin to statins and COX-2 inhibitors. But I want to tell
you about a nutritional supplement that truly is miraculous: alpha
lipoic acid (also called lipoic acid or ALA).
Lipoic acid is a potent antioxidant that, unlike most antioxidants, is
both water- and fat-soluble, making it active in virtually every cell in
the body. In addition to neutralizing harmful free radicals, lipoic acid
regenerates and increases levels of vitamin C, vitamin E, coenzyme
Q10, and glutathione.
But thats not all. Lipoic acid is also a mitochondrial powerhouse. It
not only protects your energy-producing factories from free radical
damage, it also helps prep the fuel burned in the mitochondria and
increases the amount of energy generated. Furthermore, it has a
unique ability to neutralize toxins, chelate heavy metals, and protect
against DNA damage. These multiple actions make lipoic acid a
valuable ally against diabetes, liver damage, cancer, and a host of
other diseasesit even slows down aging.
Diabetics Best Friend
If I had to limit lipoic acid to just one use, it would be for the
treatment of diabetes. This supplement not only improves insulin
sensitivity and lowers blood sugar, it is also an excellent treatment for
deterioration of the arteries, eyes, and especially the nerves that
plague so many patients with diabetes.
Bill, a Health & Healing subscriber, had such severe diabetic
neuropathy that he had constant pain and limited sensation in his
limbs, his left leg dragged when he walked, and he was continually
dropping things. He started taking lipoic acid after reading about it in
this newsletter. Shortly thereafter, the pain subsided, his sensation
improved, and his coordination returned.
Incredible as this may seemespecially for a condition that patients
are told cannot be treatedits an everyday occurrence at the
Whitaker Wellness Institute. Used intravenously or as an oral
supplement, lipoic acid very effectively reduces pain, numbness,
burning, and other unpleasant sensations of neuropathy.
A Lifesaver for Failing Livers
Lipoic acid also shines in the treatment of liver problems. This is most
dramatically illustrated by the story of John and Eunice, who were
admitted to the hospital in acute liver failure after inadvertently
eating Amanita verna, the highly toxic Destroying Angel wild
mushroom.
Lucky for them, their care was turned over to Burton Berkson, MD,
PhD, a medical resident and one of the few doctors in the US at the
time who was familiar with the use of lipoic acid for the treatment of
liver failure. Although he had been told by the hospitals chief doctor

that nothing could be done for them and that John, who had eaten
several mushrooms, would definitely die, Dr. Berkson tracked down
some lipoic acid and treated John and Eunice with IV infusions. Within
days, they left the hospital completely well. I interviewed them 20
years after this incident, and both were doing just fine.
By using this unconventional treatment, Dr. Berkson ruffled a few
feathers. The chief doctor dismissed the role of lipoic acid stating,
They would have come around anyway. He also refused to allow Dr.
Berkson to administer lipoic acid to another couple with the same
diagnosis soon thereafter. Dr. Berkson treated them anyway, and it
saved their lives. For this good deed, he was rewarded with a furious
admonition and labeled a troublemaker.
Rejuvenate Your Liver With Lipoic Acid
We need more troublemakers like Dr. Berkson. Today, he is an
internationally recognized clinical expert in the use of lipoic acid, and
has helped thousands of patients with liver problems such as hepatitis
B and C, autoimmune hepatitis, primary biliary cirrhosis, and primary
sclerosing cholangitis. We use several of his protocols here at
Whitaker Wellness, including triple therapy, a combination of lipoic
acid, silymarin, and selenium that reliably lowers liver enzymes and
viral loads and improves symptoms.
A few years ago, I told a teacher at my kids school who had hepatitis
C and was not responding to conventional treatments about triple
therapy. Within a couple of weeks of starting on it, he began to feel
much better, and his blood workup showed marked improvements.
His doctors response when he told him what he was doing? That
cant be true.
Cancer Fighter?
As I mentioned earlier, lipoic acid counteracts toxins and free radicals
that damage DNA, which is considered to be the first step in the
uncontrolled growth of cancer cells. It also modifies gene expression
and appears to put the brakes on cells that are genetically
programmed to become cancerous. In addition, it promotes apoptosis,
or programmed cell death, in some cancerous cells. This makes lipoic
acid an excellent supplement for anyone looking to sidestep cancer.
But treating cancer? As I was doing research for this article, I came
across a case history published in Integrative Cancer Therapies. It was
about a patient with metastatic pancreatic cancer, a routinely fatal
disease with an average survival time of three to six months after
diagnosis. According to the journal article, The patient was told by a
reputable university oncology center in October 2002 that there was
little hope for his survival. Today, January 2006, however, he is back
at work, free from symptoms, and without appreciable progression of
his malignancy. His treatment included IV lipoic acid and low-dose
naltrexone, a drug used in much larger doses to help with heroin
withdrawal.
Intrigued, I wanted to talk to the author of this paper, and it turned
out to be my old friend, Dr. Berkson. He told me this protocol helps
many, although not all, cancer patients, and it is also extremely
effective for rheumatoid arthritis, multiple sclerosis, lupus, and

other autoimmune disorders. This is a fascinating therapy that I am

currently investigating and will write more about in a future issue.
Want to Retard Aging? Take Lipoic Acid
Theres one more thing you need to know about lipoic acid: Because
of its multiple roles in the mitochondria, it is one of the most
promising anti-aging therapies yet discovered. Bruce Ames, PhD,
professor of biochemistry and molecular biology at the University of
California, Berkeley, and one of Americas most highly honored
scientists, believes that mitochondrial dysfunction is a primary cause
of aging and age-related diseases. When your energy factories cease
to function at their peak, your lights begin to dim and eventually go
out.
When Dr. Ames and his research team gave older rats lipoic acid and
acetyl-L-carnitine (another amino acid derivative with multiple
benefits) for several weeks, it turned the lights back on. Old, lethargic
animals had more pep and energy, they looked younger, and they
performed better on memory tests. The conclusion was that lipoic
acid and acetyl-L-carnitine tuned up the mitochondria, and this had
profound anti-aging effects. Human studies on this combo are
currently underway, and the early results are very promising.
Many More Benefits
A short article can barely scratch the surface of this remarkable
supplement. Lipoic acid is also an excellent preventive and adjunct
therapy for cardiovascular disease, AIDS and immunosuppression,
vision problems such as cataracts and glaucoma, and
neurodegenerative disorders such as Parkinsons and Alzheimers
disease. Other current areas of research include lipoic acids ability to
increase energy, decrease appetite, and inhibit inflammation-related
bone loss.
For all of these reasons and more, I recommend that everyone over
age 45, no matter how healthy they are, include alpha lipoic acid in
their daily supplement regimen.
Recommendations
The suggested dose of lipoic acid for prevention and anti-aging
purposes is 400 mg per day. For patients with diabetes or liver
disease, 800-1,600 mg is recommended, taken in divided doses half
an hour to an hour before eating for optimal absorption. Controlledrelease lipoic acid has some advantages, especially for patients with
diabetes, since it stays in the system much longer.
Triple therapy for liver disease consists of 600 mg lipoic acid,
900 mg silymarin (from the herb milk thistle), and 400 mcg selenium
(an antioxidant mineral), taken in divided doses twice a day.
Dr. Ames anti-aging regimen includes 400 mg of lipoic acid and
1,000 mg of acetyl-L-carnitine. (Look for a combination product
containing these dosages or purchase these supplements separately
at your local health food store.)
If you cant find these supplements in a store near you, order by
calling (800) 810-6655.

References
Berkson BM, et al. The long-term survival of a patient with
pancreatic cancer with metastases to the liver after treatment with
the intravenous alpha-lipoic acid/low-dose naltrexone protocol. Integr
Cancer Ther. 2006 Mar;5(1):83-9.
(The key therapeutic agents were intravenous "-lipoic acid (ALA) 300
to 600 mg 2 days per week and lowdose naltrexone (LDN), 4.5 mg at
bedtime. In addition,a triple antioxidant regimen consisting of oral
ALA (600 mg/d), selenium (200 #g 2 times per day),and silymarin
(300mg4 times a day) was added to scavenge the products of
oxidative stress that inevitably result from any serious chronic
medical disorder. J.
Berkson BM. The Alpha Lipoic Acid Breakthrough. Prima Health,
Rocklin, CA, 1998.
Hagen TM, et al. Feeding acetyl-L-carnitine and lipoic acid to old
rats significantly improves metabolic function while decreasing
oxidative stress. Proc Natl Acad Sci USA. 2002 Feb 19;99(4):1870-5.
Panneerselvam KE, et al. L-carnitine and alpha-lipoic acid
improves mitochondrial function during ageing process. Clin Nutr.
2006 May 9.
/////////////////////
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///////////////
https://examine.com/supplements/alpha-lipoic-acid/
Summary
All Essential Benefits/Effects/Facts & Information
Alpha-Lipoic Acid (ALA) is a mitochondrial fatty acid that is highly
involved in energy metabolism. It is synthesized in the body and can
be consumed through eating meats and minimally in some
fruits/vegetables.
In supplement form, it has shown benefit against various forms of
oxidation and inflammation. These effects carry on to benefits that
protect one from heart diseases, liver diseases, diabetes, and
neurological decline with age.

It is a potent anti-oxidant compound. It works with mitochondria and

the body's natural anti-oxidant defenses. It is also seen as an antiaging compound since it can reverse some of the oxidant damage
related effects of aging.
Confused about supplements?
Free 5 day supplement course
Things To Know
Also Known As
ALA, thioctic acid, 1, 2-dithiolane-3-pentanoic acid, ala, Tiolepta
Do Not Confuse With
Alpha-Linolenic Acid (omega-3 fatty acid)
Things to Note

Alpha-Lipoic Acid, despite being a fatty acid, appears to be

water soluble in the gut and is absorbed by transporters. Coingestion
with fatty acids in the diet does not appear to be required

Can be bound by avidin, and thus coingestion with raw egg

whites can possibly negate the benefits of supplementation

Is a Form Of
Nootropic
Goes Well With

L-Carnitine
Does Not Go Well With

Monocarboxylic acids (Medium chain triglycerides, Benzoic acid)

as they can compete for absorption
Caution Notice

Examine.com Medical Disclaimer

How to Take
Recommended dosage, active amounts, other details
Standard dosages of Alpha-lipoic acid (ALA) tend to be in the range of
300-600mg; with little differentiation as to whether the racemic
mixture of ALA (S- and R- isomers) or Na-R-ALA results in higher blood
levels.

Alpha-lipoic acid appears to be absorbed via transporter-related

means, and despite being inherently fat-soluble it does not require
dietary fatty acids to be absorbed from the gut. ALA supplementation
can be taken in a fasted state.
Confused about supplements?
Free 5 day supplement course
Human Effect Matrix
The Human Effect Matrix looks at human studies (it excludes
animal and in vitro studies) to tell you what effects alpha-lipoic acid
has on your body, and how strong these effects are.

GRADE

LEVEL OF EVIDENCE

Robust research conducted with repeated double-blind clinical trials

Multiple studies where at least two are double-blind and placebo contr

Single double-blind study or multiple cohort studies

Uncontrolled or observational studies only

LEVEL
OF
EVIDEN
CE
?

OUTCOME

Symptoms
of Diabetic
Neuropath

MAGNITUD
E OF
EFFECT
?

Notab
le

CONSISTENCY OF
RESEARCH
RESULTS
?

VERY HIGHSee 2
studies

NOTES

Not yet compared to

drugs, but it has been
to a meta-analysis an

GRADE

LEVEL OF EVIDENCE

Robust research conducted with repeated double-blind clinical trials

to be more effective t
options for reducing n
associated with diabe
lack of a ref... See mo

Minor

General
Oxidation

Blood
Pressure

Symptoms
of
Intermitten
t
Claudicatio
n

Blood Flow

Notab
le

Minor

HIGHSee all 6
studies

Appears to reduce bio

of oxidation

VERY HIGHSee all

6 studies

The majority of evide

intravenous or oral
supplements fail to fin
influence, and the on
suggest a reduction w
confounded with weig
(known to reduce blo
pressure... See more

VERY HIGHSee
study

The reduction of clau

symptoms appears to
potent with ALA
supplementation, alth
there is not a large bo
evidence overall.

VERY HIGHSee 2
studies

May increase blood fl

although not the a re
degree. Possibly seco
antioxidative effects

GRADE

LEVEL OF EVIDENCE

Robust research conducted with repeated double-blind clinical trials

Minor

MODERATESee all
3 studies

There appears to be a
reducing effect on Hb

Inflammati
on

Minor

MODERATESee 2
studies

Mixed effects depend

what inflammatory bi
or cytokine is measur
practical significance

Lipid
Peroxidatio
n

Minor

VERY HIGHSee 2
studies

Appears to reduce bio

of lipid peroxidation (
mostly)

Nerve
Repair

Minor

VERY HIGHSee
study

May increase nerve

regeneration rates an
aid to nervous system

Protein
Carbonyl
Content

Minor

VERY HIGHSee
study

Appears to reduce pro

carbonylation, which
related to the antioxid
effects

MODERATESee all
4 studies

It is possible that high

(1,800mg) may have
weight reducing effec
persons, but this requ
evidence.

HbA1c

Weight

Minor

GRADE

LEVEL OF EVIDENCE

Robust research conducted with repeated double-blind clinical trials

AntiOxidant
Enzyme
Profile

Blood
Glucose

LOWSee 2 studies

Mixed effects on antio

enzymes, with decrea
glutathione peroxidas
increases in catalase
effect on SOD

VERY HIGHSee
study

A small decrease in b
glucose is noted with
supplementation of A
related to the glucose
properties

C-Reactive
Protein

MODERATESee 2
studies

Although there may b

reduction of C-Reactiv
in some populations,
most part ALA does n
significantly effective
reducing this inflamm
biomarker of cardiova
dise... See more

Heart Rate

VERY HIGHSee
study

No significant interac
between ALA and hea
has been noted

VERY HIGHSee
study

No significant influen
insulin sensitivity has
noted

Insulin
Sensitivity

GRADE

LEVEL OF EVIDENCE

Robust research conducted with repeated double-blind clinical trials

VERY HIGHSee
study

Insufficient evidence
a reduction in motion
with ALA supplement

Symptoms
of
Rheumatoi
d Arthritis

VERY HIGHSee
study

No significant interac
between ALA supplem
and symptoms of rhe
arthritis

Treatment
of
Dementia

VERY HIGHSee
study

No significant rehabil
effect of ALA on cogn
decline has been note

VERY HIGHSee
study

Has been associated

augmentingCreatine
into muscle cells acut
term influence unkno

Motion
Sickness

Muscle
Creatine
Content

Minor

Oxidation
of LDL

Minor

VERY HIGHSee
study

Appeared to increase
of LDL according to o
which was abolished
exercise but noted to
concern during rest.

Skin
Quality

Minor

VERY HIGHSee
study

May improve skin qua

topically applied

GRADE

LEVEL OF EVIDENCE

Robust research conducted with repeated double-blind clinical trials

Glycemic
Control

VERY HIGHSee
study

Studies Excluded from Consideration

1.
1.
2.
3.
2.
1.
2.
3.
4.
5.
3.
1.
2.
4.
1.
2.
3.
4.
5.
6.
7.
8.
5.
1.
2.
3.
6.

Excluded due to being intravenous injections and not oral

supplementation[1]
Disagree? Join the Alpha-Lipoic Acid Discussion
Scientific Research
Table of Contents:
1 Sources and Synthesis
1.1 Sources
1.2 Biosynthesis
1.3 Structure and Stability
2 Pharmacology
2.1 Absorption
2.2 Serum
2.3 Metabolism
2.4 Elimination
2.5 Metal Chelation
3 Life Extension and Longevity
3.1 Mechanisms
3.2 Animal Interventions
4 Neurology and the Brain
4.1 Appetite
4.2 Mechanisms
4.3 Glutaminergic Neurotransmission
4.4 Cholinergic Neurotransmission
4.5 Dopaminergic Neurotransmission
4.6 Serotonergic Signalling
4.7 Adrenergic (Adrenaline) Signalling
4.8 Oxidation
5 Nerve function
5.1 General
5.2 Carpal Tunnel Syndrome
5.3 Diabetic Neuropath
6 Interactions with the Liver

No significant practic
on glycemic control n

1.
7.
1.
2.
3.
8.
1.
2.
9.
1.
2.
3.
10.
1.
2.
11.
1.
2.
12.
1.
2.
13.
1.
14.
1.
2.
3.
15.
1.
2.

6.1 Mechanisms
7 Interactions with Obesity and Body Fat
7.1 Mechanisms
7.2 Energy Expenditure
7.3 Interventions
8 Interactions with Skeletal Muscle
8.1 Mechanisms
8.2 Glucose Uptake
9 Interactions with Cardiac Health
9.1 Platelet Function
9.2 Endothelium
9.3 Triglycerides and Lipoproteins
10 Interactions with Glucose Metabolism
10.1 Insulin
10.2 Usage in Diabetes
11 Interactions with Oxidation
11.1 Mechanisms
11.2 Interventions
12 Inflammation and Immunology
12.1 Mechanisms
12.2 Rheumatoid Arthritis
13 Interactions with Hormones
13.1 Leptin
14 Nutrient-Nutrient Interactions
14.1 L-Carnitine
14.2 Sesamin
14.3 Avidin
15 Toxicity and Safety
15.1 General
15.2 Interventions

1Sources and Synthesis

1.1. Sources
ALA is a naturally occurring fatty acid with the chemical name of 1,2dithiolane-3-pentanoic acid and sometimes simply referred to as
thioctic acid.[2]
ALA can be found in foods, mostly meats such as organ tissue and in
some fruits and vegetables.[3][4]Some select contents include:

Spinach at 3.14+/-1.11mcg/g dry weight as lipoyllysine[5][6]

Kidney at 2.64+/-1.23mcg/g dry weight as lipoyllysine[5][6]

Liver at 1.51+/-0.75mcg/g dry weight as lipoyllysine[5][6]

Broccoli at 0.94+/-0.25mcg/g dry weight as lipoyllysine[5][6]

Heart Tissue 0.86+/-0.33mcg/g dry weight as lipoyllysine[5][6]

Tomatoes at 0.56+/-0.23mcg/g dry weight as lipoyllysine[5][6]

Lipoyllysine is a lipoic acid molecule bound to a lysine amino acid, and

is a food storage form of alpha lipoic acid that is bound to the
proteins.[7] It is separated into lipoic acid and lysine via the
glycoprotein enzyme lipoamidase (sometimes referred to
as lipoyllysine hydrolase), which circulates in human serum.[8]
Lipoic Acid is found in a variety of food sources, but the levels found
in food tend to be significantly lower than standard supplemental
dosages
1.2. Biosynthesis
Alpha-Lipoic acid (ALA) is a naturally occurring dithiol compound
created in the mitochondria from octanoic acid as a precursor, with a
good deal of synthesis occurring in the liver's mitochondria.[9][4]
Its main biological role is as a cofactor in mitochondrial enzymes such
as alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase.
[10]
ALA also appears to be involved in the production of Acetyl-CoA,
via oxidative decarboxylation of pyruvate.[11]
Supplementation has been found to carry benefits against oxidation,
inflammation, diabetes, and cognition.[10]
1.3. Structure and Stability
Alpha-Lipoic Acid possesses a chiral center carbon and thus can exist
in an S or R isomer; unspecified ALA is a 'racemic' solution of both
whereas R-ALA is commonly sold as well, commonly bound to sodium
(Na-R-ALA).
The disulfide bond in Alpha-Lipoic Acid can be homolytically cleaved
by near UV light and heat[12][13]in where the dithiolane ring structure
forms two thiyl radicals and self-polymerizes into a linear chain of
disulfides known as PBCPD, full name of poly{3-(n-butane carboxylic
acid)propyl}disulfide.[14] This polymerization is seen as reversible, with
conversion back into ALA in alkaline solution or with coincubation with
reducing agents such as dithiothreitol and -mercaptoethanol.[15] It
has been suggested that naturally occurring ALA may be a racemic
mixture including a PBCPD content.[16]
In vivo, ALA can be reduced to dithiol form (where the ring structure is
broken), dihydrolipoic acid (DHLA).[4] In cells with mitochondria this
reduction is mediated by lipoamide dehydrogenase and is an NADH-

dependent reaction, and cells without mitochondria this reduction

occurs via NADPH with glutathione and thioredoxin reductases.[17]
ALA has a melting point of 63C when in racemic solution and 50C as
the R-ALA isomer, and pairing with salts with higher boiling points
may enhance stability (a common venture for patents[18][19])

2Pharmacology
2.1. Absorption
Orally ingested Alpha-Lipoic Acid (ALA) is rapidly taken up in the gut
in a pH dependent manner by monocarboxylic acid transporters
(MCTs). Coingestion with monocarboxylic acids such as medium-chain
triglycerides or benzoic acid inhibits ALA uptake.[20] There is also the
potential for ALA to be taken up by the sodium-dependent
multivitamin transporter (SMVT).[21][22] In the gut, some ALA converts
into dihydrolipoic acid. The overall bioavailability of ALA
supplementation is ~30%[23][10] due to high liver extraction.[24] The NaR-ALA form of ALA is completely soluble in water.[25] Although the Renantiomer has higher intestinal uptake rates in vivo[26] the Senantiomer may stabilize uptake by preventing polymerization. [10]
Taken up moderately well, uses the MCT transporter and may not be
absorbed as well if taken alongside medium-chained triglycerides
2.2. Serum
Systemic pharmacokinetics of ALA are fairly rapid. After rapid
intestinal uptake it is quickly partitioned to tissues that uptake ALA
(brain, heart, and muscle) and includes a transient liver storage of
ALA.[10][27] ALA accumulates in the brain as soon as an hour after
ingestion[28] and is stored in various brain regions.[29]
After oral ingestion of 600mg ALA racemic mixture, the Cmax appears
to be 6.86+/-1.29g/mL with a Tmax of 50.8 minutes and an overall 8
hour AUC of 5.65+/-0.79g/mL/h.[30]
2.3. Metabolism
In cells, ALA is primarally metabolized via beta-oxidation.[31] The main
metabolites are bisnorlipoate, tetranorlipoate, -hydroxybisnorlipoate, or the bis-methylated mercapto derivatives of these
compounds[27] and dihydrolipoic acid, which undergoes rapid cellular
excretion.[17]
2.4. Elimination
ALA is also rapidly excreted by filtration in the kidneys, with 98% of
digested ALA excreted within 24 hours[24]. However, most orally

ingested ALA is lost in fecal excretion prior to intestinal uptake.[31] For

these reasons, ALA is not stored long-term. According to Shay et al.
[10]
the average AUC is approximately 160+/-35ug/ml/min and the
average Cmax is 2.8+/-1.5 for a 600mg oral dose of both enantiomers.
These results rival Na-R-ALA for AUC (despite R-ALA showing higher
peak values and faster excretion) but are well ahead of S-ALA in
isolation.[26]
The majority of supplemental ALA does not appear to be stored for
longer than a day
2.5. Metal Chelation
Alpha-Lipoic Acid (ALA) as well as its metabolite dihydrolipoic acid
bind to metals in vitro, with the former binding to copper, lead,
and Zinc while the reduced form of dihydrolipoic acid binds to those
three as well as mercury and iron(III).[32] Due to Selenium and
manganese deficiency being symptoms of ALA toxicity[33], it seems
ALA or its metabolites can bind to these two metals as well.
In vivo, ALA has been observed to reduce iron levels in the brain and
liver, but only when the iron level is above normal.[34][35] These results
preliminarily suggest that ALA does not negatively affect the mineral
status of the body.

3Life Extension and Longevity

3.1. Mechanisms
It has been hypothesized that the longevity promoting aspects of ALA
are due to PPAR gamma cofactor 1 (PCG-1a) activation,[36] a
mechanism shared by Pyrroloquinoline quinone.
In liver cells, alpha-lipoic acid has been found to increase oxygen
consumption to 189% of baseline when given to old rats at 0.5% of
the diet while it nonsignificantly increase oxygen consumption to
104% of baseline in younger rats.[37] Initially the older rats has 59%
the level of oxidation relative to younger rats, and after
supplementation there were no significant differences.[37] This
normalization of mitochondrial oxygen capacity has been recorded in
neural tissue as well where increased oxygen consumption coupled
with increased anti-oxidative potential improved neural consequences
of aging in old rats fed 0.5%/1.5% ALA/ALCAR (a form of L-Carnitine)
such as memory loss.[38][39]
This increased oxygen consumption is associated with less
parameters of oxidation when ALA at 0.5% of feed is supplemented or
a combination of ALA and L-Carnitine (as ALCAR) is supplemented,
ALCAR at 1.5% of feed in isolation can increase oxidation.[40] The
30.8% increase in oxidation seen with aging (relative to control) in

this study was abolished with combination therapy, and normalized to

the level of youthful rats, and was measured by MDA, Ascorbate, and
2',7'-dichlorofluoresin appearance.[40] This decrease in oxidation is also
associated with a lesser decline of mitochondrial enzymes, which
appears as an increase from pre-supplementation levels.[41][42]
Supplementation of Alpha-Lipoic Acid alone increases oxidative
consumption (indicative of metabolic activity) in a similar manner
to L-Carnitine in aged animals, which improves functional
performance. ALA can also curb the pro-oxidative effects of LCarnitine, demonstrating practical synergism
3.2. Animal Interventions
A rat study assessing Alpha-Lipoic Acid and diet interactions
concluded, after following 12 groups of rats for their lifetimes, that
supplementation at a dose that does not interfere with food intake
(1.5g/kg in rats) does not appear to augment the efficacy of caloric
restriction nor enhance ad libitum(no control) feeding per se, but that
(1) although rats that switch to caloric restriction after 12 months of
age (30% of lifespan) show similar life extension to lifelong caloric
restriction, rats previously fedad libitum with ALA did not, and (2)
switching from caloric restriction to ad libitum feeding at 12 months
normally attenuate the life extension effects of caloric restriction, this
was not seen when refeeding occurred with ALA despite an increase
in growth rates.[6] The former inhibition of longevity and promotion of
longevity (respectively) were lesser in magnitude with a shorter
supplementation time.[6]
One study simply administering ALA to immunosuppressed mice
found that both isomers of ALA were able to increase longevity, but
the S-isomer at 75mg/kg daily and the R-isomer at 9mg/kg daily; high
doses of 350mg/kg appeared to act to reduce lifespan. [43]
In regards to an anti-aging phenotype (giving the appearance of
youth without impacting median of maximal lifespan),
supplementation of Alpha-Lipoic Acid has been demonstrated to
increase the metabolic rate and activity levels of older rats, to a
greater extent as seen in younger rats. Due to increasing activity
levels more in older rats than younger, ALA supplementation reduced
the differneces between groups.[40]

4Neurology and the Brain

4.1. Appetite
ALA has been demonstrated to inhibit AMPK in the hypothalamus (as
opposed to other areas of the body where it stimulates) and due to
mimicking a caloric surplus can suppress appetite; these effects may
be secondary to increasing glucose uptake into the hypothalamus,

and are reversed upon AMPK activation in the hypothalamus.[44] ALA

at 0.25, 0.5, and 1% of the overall food intake of rats over 2 weeks
and when tested over the period of 14 weeks was able to reduce body
weight relative to unsupplemented control.[44] The reduction in food
intake in rats does not appear to be secondary to a conditioned taste
aversion, which should be noted due to ALAs sharp taste.[44] Another
rat study using 200mg/kg oral intake found that this suppression of
hypothalamic AMPK paired with adipose expression of AMPK helped to
normalize changes in fat mass associated in a model of menopause.
[45]

In older rats fed 0.75% ALA, this reduction in food relative to control
has been quantified at ranges of 18%[46] to 30%,[47] and many other
studies that note food intake as secondary observations tend to note
decreases that reach statistical significance[48][49][45][50][47][51][52] or trends
towards significance.[53] The reproducability of this seems to be high
enough that, in some trials irrelevant to food intake, a third 'pair-fed'
group is planned at the onset to match the experimental group for
intake and control for the effects of ALA against the effects of food
deprivation per se.[54][55][56][57]
This suppression of appetite seems to influence both low-fat and highfat diets, as one rat study that supplemented ALA to both groups
noted non-significant differences in overall weight loss (-24% and
-29% in low and high fat; respectively and relative to high fat control)
[47]

The only human study to be conducted on Alpha-Lipoic Acid at 600mg

and appetite was conducted in Schizophrenic patients and confirmed
appetite suppression with increased energy (subjective rating), but
had a very low sample size.[58]
Appears to be a potent appetite suppressant in research animals, and
is consistent in the appetite suppressing effects. Surprisingly
underresearched in humans, but may have the same effects
Some studies do note an attenuation of appetite suppression (less
significance) about two weeks after consumption, so these effects
may be short term and they do not seem to be fully abolished
4.2. Mechanisms
Alpha-lipoic acid has been noted to reduce oxidative damage in
neuronal cells[59] and aged rats at 100mg/kg[29] which is thought to
underlie the reductions in age-related cognitive decline.[60][61][38][62]
It has been noted that ALA does not alter basal calcium
concentrations in a neuron at lower concentrations (5-50g/mL) nor
did it augment the calcium response to glutamate, yet 500g/mL is
able to increase basal calcium influx and suppress glutamate induced
signalling.[63]

ALA has also been found to inhibit T-currents (specifically, via the
CaV3.2 channel) with an IC50 of 3+/-1M, reaching maximal inhibition
of around 40% at 100-1,000M. This appears to be mediated via a
REDOX reaction on the calcium channel.[64]
4.3. Glutaminergic Neurotransmission
Alpha-lipoic acid (0.05-1M) appears to facilitate the calciumdependent release of glutamate from the synapse via a PKA/PKC
dependent mechanisms, the magnitude of which reached around
27.3+/-3.1%.[65]
May facilitate the release of glutamate at the presynatic level, which
would theoretically enhance signalling through glutaminergic
receptors
It has been noted that incubation of glial cells with alpha-lipoic acid
(10-50M) increases glutamine synthetase activity in astrocytes and
increases glutamate uptake by around 20% (and subsequent
glutathione production by 40%),[66] a mechanism similar
to Resveratrol. This appears to be mediated via PKC but not PI3K.[66]
Appears to stimulate glutamate uptake into glial cells for conversion
into Glutamine, which theoretically suppresses signalling
It does not appear to alter synaptic membrane potential of glutamate
signalling[65] and when investigating the NDMA receptors alpha-lipoic
acid has been found to both suppress signalling (as ALA) or enhance
signalling (as the reduced form DHLA).[67]
Interestingly, the age-related deficits in NMDA receptor Bmax appear to
be normalized with alpha-lipoic acid in aged mice.[68]
Alpha-lipoic acid is able to modulate the REDOX site of the NMDA
receptor, but since it works in both directions its overall actions on
receptor signalling are unclear. However, at least one study suggest a
possible increase in NMDA receptor density in older subjects
The excitotoxicity seen with excess glutamate appears to be reduced
with alpha-lipoic acid (100M or above), which seems to be secondary
to preserving glutathione concentrations in the neuron.[69][70][71] A
reduction in NMDA-induced lesions has also been confirmed in rats
injected with 10mg/kg ALA for 10 days, reaching about a halving in
lesion size.[72]
Alpha-lipoic acid appears to be neuroprotective against glutamateinduced toxicity secondary to supporting the glutathione pool (its
depletion precedes cellular death), a mechanism similar to Nacetylcysteine

In pilocarpine induced seizures, an intraperitoneal injection of

10mg/kg alpha-lipoic acid is able to normalize the increase in
glutamate seen with pilocarpine.[73] This was associated with a
preservation of Taurine[73] and aspartate[74] concentrations as well.
The increase in glutamate seen with cyanide toxicity (which releases
glutamate[75] and neurotoxicity is thought to be mediated via the
NMDA receptor[76]) appears to be attenuated with 25-100mg/kg ALA.
[77]

The elevation in glutamate concentrations seen in pathological

conditions or toxin administration appears to be able to be attenuated
with preadministration of alpha-lipoic acid
4.4. Cholinergic Neurotransmission
An animal study assessing the interactions of ALA and pilocarpine (a
cholinergic agonist capable of inducing seizures) found that 10mg/kg
ALA was able to reduce pilocarpine-induced seizures by 50% and
prolong time to seizure by 112% if unable to outright prevent.[78]
4.5. Dopaminergic Neurotransmission
A study in which rats were fed low doses (10, 20, or 30mg/kg
bodyweight) ALA found that 20mg/kg bodyweight was able to
increase dopamine levels in the hippocampus by about 9% 24 hours
after ingestion yet the other two doses (10 and 30mg/kg) were not
significantly different than control.[79]Another study using 10mg/kg
found no effect.[78]
Alterations in dopamine (decrease) and dopamine metabolite
(increase) levels associated with pilocarpin-induced seizures has been
normalized with 10mg/kg pre-treatment ALA.[78]
4.6. Serotonergic Signalling
A study in rats found a decrease in hippocampal serotonin by 9% and
its main metabolite, H-IAA, by 21% when consumed at 20mg/kg
bodyweight (but not 10 or 30) and measured 24 hours later.[79]Another
study using 10mg/kg found no effect.[78]
4.7. Adrenergic (Adrenaline) Signalling
A rat study found 11% increased noradrenaline levels in the
hippocampus associated with 20mg/kg ALA after 24 hours, while the
other two tested doses (10 and 30mg/kg) were not significantly
different than control.[79] Another study using 10mg/kg found no
effect.[78]

A significant reduction in noradrenaline levels in the brain associated

with pilocarpine (experimental seizure inducer) has been abolished by
pre-treatment with ALA at 10mg/kg in rats.[78]
4.8. Oxidation
In an aforementioned study noting alterations in monoamines at
20mg/kg oral dose yet not 10 nor 30, a reduction of lipid peroxidation
was observed that also only occurred at this does,[79] the study has
been duplicated in the literature.[80]

5Nerve function
5.1. General
One study has been conducted with ALA on persons with compressive
radiculopathy syndrome from disc-nerve root conflict, and found that
600mg of ALA daily (paired with 360mg Gamma-Linoleic Acid) in
conjunction with a physical rehabilitation program was synergistic
with the physical rehabilitation program and promoted nerve recovery
over 6 weeks.[81]
5.2. Carpal Tunnel Syndrome
Carpal Tunnel Syndrome (CTS), at least in the early stages of disease
progression, has shown benefit to disease progression and symptoms
of CTS (when CTS is at a moderate-severe level) associated with an
Alpha-Lipoic Acid multinutrient (main confound was Gamma-Linoleic
Acid) at 600mg and 360mg, respectively, over the source of 90 days.
[82]

5.3. Diabetic Neuropath

One study paired Alpha-Lipoic Acid with oral Superoxide Dismutase
(an anti-oxidant enzyme) and found significant reductions in diabetic
neuropathy as assessed by subjective pain and electroneurographic
parameters.[83]
A 4 year trial of ALA on diabetic neuropathy using 600mg ALA daily
failed to show a significantly difference in primary outcomes between
groups (Neuropathy Impairment Score, neurophysiological tests) yet
the ALA group showed significant improvements relative to their own
baseline value.[84]This trial could not establish a protective effect of
ALA, however, since placebo did not deteriote over time.[84]

6Interactions with the Liver

6.1. Mechanisms
Alpha-Lipoic Acid can induce triglyceride lipase expression in liver
cells (responsible for decreasing triglyceride strorages in these
cells[85]) secondary to AMPK activation, which decreased lipid
accumulation in vitro.[86] AMPK was activated in a time and
concentration dependent manner, and was able to do so despite high
glucose (30mM) and palmitate (0.1mM) concentrations at
concentrations of 0.25-1mM.[86] These AMPK interactions are
independent of Sirtuin proteins, and appears to circumvent insulins
actions on the nuclear transcription factor FOXO1 by preventing
nuclear exclusion, which appears to be secondary to AMPK as well.
[86]
When fed to genetically obese rats, 2.4% ALA of the diet for 5
weeks (about 40mg/kg bodyweight in this study after controlling for
20% bioavailability) is able to reduce triglyceride accumulation in liver
tissue (-26%) and increase glycogen content (+27%); relative to
calorically restricted rats, the LA group had larger livers without
abnormal biomarkers, possibly due to the glycogen content.[54]
Superoxide Anion production in the liver of rats fed 1% ALA also
appears to be reduced relative to control, and the increase in
superoxide production in response to added glucose to the diet, for
the most part, abolished.[49]
AMPK is not the sole mechanism of reducing fat accumulation in the
liver, and can inhibit the genetic actions of pro-lipogenic proteins LXR
and specificity protein 1.[87] Alpha-Lipoic Acid may increase the protein
content of PPAR receptors when fed at 1% of the diet over a period
of 14 weeks and was negatively correlated (r=0.8) with blood free
fatty acid levels.[49]
Although the beneficial effects of ALA on liver physiology in
aforementioned models are well-established, one study comparing
the effects of long-vs short term ALA supplementation in healthy mice
suggests that regular, long term supplementation may cause liver
damage, and should be considered with caution.[88]
To examine the effect of short- vs long term ALA supplementation on
the liver, black 6 mice (C57BL6/J, a common laboratory mouse
strain) were treated with 20mg/kg ALA for 4 or 74 weeks.[88]After the
treatment period, mice were euthanized followed by liver tissue
analysis for lipid and cholesterol metabolism. Short and long term ALA
supplementation caused an increase in -oxidation and decreased
lipogenesis. In contrast, both short and long term ALA treatment
increased liver cholesterol content by 70% and 110%, respectively,
and increased triglyceride levels, inducing systemic triglyceridemia.
Moreover, in spite of the fact that short term ALA treatment
decreased lipogenic gene expression, it also caused fat accumulation
in the liver. Long-term ALA treated mice showed a worse phenotype,

with extensive fat accumulation leading to hepatic steatosis and

extensive liver damage.[88]
Notably, the above study was unique in that it investigated the effects
of long term ALA treatment in otherwise healthy mice. In contrast,
other studies that have shown a beneficial effect of longer term ALA
treatment were conducted in rodent disease models, including high
fat diet fed rats[87] and Zucker Diabetic Fatty (ZDF) rats.[89] Thus, longterm ALA treatment in healthy animal models may be liver toxic,
causing a phenotype that closely resembles that of non-alcoholic fatty
liver disease.[90][91]It should be noted that the dose of ALA in the
healthy mouse study[88] of 20mg/kg is equivalent to approximately 1.8
grams/day in a 200 lb human. Although this is a relatively high dose
of ALA, it is close enough to standard doses that caution may be
warranted for long term supplementation.
Although ALA has been shown to decrease oxidative stress and
improve lipid metabolism in animal disease models, one study in
healthy mice suggests that long term treatment may be liver toxic,
causing damage that resembles non-alcoholic fatty liver
disease. CAUTION: The effects of long term ALA supplementation in
healthy humans have not been studied, so it is not currently known
whether long-term high dose ALA may have similar detrimental
effects. Since ALA supplements are widely used by healthy individuals
in an effort to limit oxidative stress and lipogenesis that occurs during
aging, caution is warranted when taking higher doses for longer
periods of time unless under the supervision of a physician.

7Interactions with Obesity and Body Fat

7.1. Mechanisms
The following mechanisms are those that are independent of appetite
suppression. As evidence by the appetite summary (Neurology
Header, subsection 1) ALA has potent effects on reducing appetite.
However, even when a third group has their energy intake restricted
to match the intake of a group with appetite suppression (known as
pair-fed feeding) ALA appears to induce some manner of weight loss
beyond mere appetite suppression (although appetite suppression
appears to be the most potent influencing factor).[50] At least one pairfed study (control group, group fed ALA, third group fed only the
amount of calories the ALA group wanted to consume) found that the
statistically significant weight loss became insignificantly different
between pair fed and ALA supplemented.[54]
Most significant factor influencing alpha-lipoic acid's weight reducing
effects is the reduction of appetite, and pair-fed studies suggest this
may account for 80-90% (rough estimate derived from charts) of the
overall weight-reducing effects secondary to ALA

In vitro, lipoic acid was able to induce apelin secretion from fat cells
(an adipokine that may regluate glucose metabolism) but was
deemed to be unrelated to changes seen in vivo.[48]
In regards to AMPK, at least one study has seen results that suggest
AMPK inhibition could be at play in 3T3-L1 adipocytes but was not
designed to answer these questions;[48] two other studies note that in
white adipose tissue AMPK is both activated and its mRNA
upregulated.[55][45]
When investigating the interactions of ALA and nutrient absorption,
supplemental ALA for 56 days was able to reduce carbohydate uptake
secondary to inhibiting the SGLT1 transport (sodium dependent
glucose transporter) by approximately a third, when the jujenum was
excised and testedin vitro with alpha-methylglucose.[50] When
tested in vivo at 0.5% ALA though, there are no significant differences
in the caloric content of the feces with ALA (assessed by bomb
calorimetry).[47]
Has the potential to inhibit nutrient uptake, does not appear to be
potent enough to be meaningful
7.2. Energy Expenditure
In animals fed 0.5% of food intake as ALA when caloric intake was
controlled (as ALA may suppress appetite), energy expenditure as
assessed by indirect calorimetry increased by day 3 and continued to
be elevated for the 21 tested days.[44] These rats showed increased
expression of UCP1 in brown adipose tissue and ectopic expression of
UCP1 in white adipose tissue, thought to be a reason for the increased
metabolic rate.[44] In older rats at 0.75% ALA for 4 weeks, an increased
metabolic rate has also been observed through an AMPK/PGC-1a
dependent mechanisms and this metabolic rate (paired with an 18%
reduction in food intake) resulted in 15.8% total weight lost.
[46]
Oxygen consumption and Carbon Dioxide production in these older
rats fed 0.75% ALA increased by 27% and 38%, respectively.[46]
7.3. Interventions
One study conducted on 228 persons (360 at the start, high dropout
rate) who were either obese or overweight paired with metabolic
abnormalities (metabolic syndrome) given 1,200mg or 1,800mg
Alpha-Lipoic Acid (in three daily doses before meals) for 20 weeks
noted that there was a significant decrease in weight in the 1,800mg
group when all groups were subject to a 600kcal deficit.[92]Average
weight loss was 0.94+/-0.45kg in placebo, 1.49+/-0.38kg in 1,200mg,
and 2.76+/-0.53kg in 1,800mg.[92]

8Interactions with Skeletal Muscle

8.1. Mechanisms
In aged rats, improvements in GLUT4 and PGC-1a mRNA content was
increased by 105% and 80% (respectivly) after 4 weeks of 0.75% ALA
ingestion.[46]
One rat study noted that with ALA injections at 30mg/kg, Heat Shock
Proteins 72 and 25 were induced in high fat (60%) but not low fat
(10%) diet, which was able to reduce pro-inflammatory signalling via
JNK and NF-kB (reported elsewhere[93][94]) and to improve fatty-acid
induced insulin resistance.[53] ALA has previously been implicated
(alongside other anti-oxidants, Vitamin C andVitamin E) in reducing
the activity of IRS-1 and improving insulin sensitivity by this
mechanism.[95]
Increased markers of lipid metabolism have been noted as well,
namely increased phosphorylation of; AMPK, ACC, FAS, and ATGl. The
effect of these was increased -oxidation and decreased lipid
accumulation.[96] Increased SIRT1 expression has been noted in
myotubes secondary to AMPK and an increased NAD/NADH ratio, yet
knockdown of SIRT1 with siRNA reduces the -oxidixing of AMPK in
these cells.[96] These effects were nonsignificantly more potent
than Resveratrol, a known PDE4 inhibitor that influences AMPK.[96] ALA
at 0.5% of the diet has been shown to reduce lipid accumulation in fat
cells, but this study attributed that to anorexic (appetite suppressing)
effects rather than via AMPK.[47]
When looking at the mechanism of AMPK upregulation, it has been
shown this can occur independently of the AMP:ATP ratio (countering
a previous study suggesting LKB1 activation was the cause[96]) and
secondary to increased intra-cellular calcium concentration at 200uM
and 500uM.[97]Chelating intracellular calcium can abolish the effects of
ALA on AMPK as can inhibiting the CaMKK enzyme, which releases
calcium into myocytes.[97]
8.2. Glucose Uptake
One study noted that in chow fed rats (10% fat) that ALA was unable
to stimulate glucose uptake into muscle cells in vivo, but was able to
improve the 54.7% reduction in glucose uptake seen in the high-fat
(60%) fed rats (relative to chow) by 55.7%.[53]

9Interactions with Cardiac Health

9.1. Platelet Function
ALA appears to be able to inhibit platelet aggregation secondary to
PPAR agonism, where incubation with ALA caused activation of PPAR

and PPAR and a subsequent inhibition of arachidonic acid induced

platelet aggregation possibly secondary to PKC association and
inhibtiion of calcium accumulation.[98] Incubation with either a PPAR
or PPAR antagonist abolished these effects.[98]
9.2. Endothelium
One study has noted that, secondary to AMPK activation, may reverse
an impairment of relaxation seen in obese rats.[99]
In human interventions, ALA supplementation appears to improve
endothelial dysfunction and blood flow as assessed by flow-mediated
vasodilation after 3 weeks of supplementation in persons with
subclinical hypothyroidism[100] and either type II diabetes[101] or merely
impaired fasting glucose either over the long term[1] or during an
acute glucose tolerance test.[102]
9.3. Triglycerides and Lipoproteins
One intervention seeing how ALA affects weight loss noted that 1,200
and 1,800mg daily ALA for 20 weeks did not influence resting
triglycerides or HDL cholesterol at either dose compared to placebo.
[92]

10Interactions with Glucose Metabolism

10.1. Insulin
Oral supplementation of 1,800mg ALA for 2 weeks does not appear to
influence insulin secretion rates in healthy but overweight/obese men.
[103]

The impairment of insulin sensitivity seen with high blood

triglycerides does not appear to be alleviated with ALA at 1,800mg
daily for 2 weeks.[103]
10.2. Usage in Diabetes
Alpha-Lipoic Acid has been investigated for oral usage at doses of
300, 600, 900, and 1,200mg of a racemic mixture over a period of 6
months in persons with confirmed type II diabetes (some on antihyperglycemic therapy) and it was shown that a dosedependent trend towards reduced fasting blood glucose and HbA1c at
each dose, and significant reductions when all groups were pooled
and when subjects were compared to baseline.[104] A longer trial of 4
years with 600mg ALA found a greater decrease in HbA1c associated
with ALA (0.67 1.41%) than placebo (0.48 1.46%), but did not
reach significance.[84]

11Interactions with Oxidation

11.1. Mechanisms
Alpha-Lipoic Acid (ALA) is a multi-modal antioxidant, capable of
decreasing oxidation that is a result of metal peroxidation, increasing
glutathione levels in the body, or by directly acting on anti-oxidants
(like ascorbate) or by itself.
As a metal-chelator, ALA can reduce peroxidation in neural tissue
induced by mercury[105] and via iron(III) and copper(II) chelation has
shown benefits in the pathophysiology of Alzheimer's disease.[35]
ALA's ability to upregulate expression of glutathione[106] (one of the
body's intrinsic anti-oxidant systems) comes from hepatic expression
of Nrf2 (as evidenced by being elevated 24 hours after exposure,
rather than acutely[107]). During aging intrinsic expression
of Nrf2 (which mediates genes of the anti-oxidant response element
(ARE)) declines, which results in less ARE activity and subsequently
reduced levels of glutamyl cysteine ligase (GCL)--the rate-limiting
enzyme in glutathione synthesis. ALA has been observed to
upregulate the synthesis of both GCL subunits viaNrf2 binding to ARE,
and restore age-depleted glutathione levels.[108]
The hypothesized mechanism of the above is that ALA irreversibly
binds to the Keap1 protein, which normally binds to Nrf2 and signals
for its destruction.[109] By forming lipoyl-cysteine bridges with
Keap1[110] ALA preserves Nrf2 function.[111][112]
ALA has been observed to induce an increase in ascorbate (Vitamin C)
levels in the liver[113] and heart[114] of aged rats, or which levels decline
due to possibly a reduction in the sodium-dependent vitamin C
transporter in the liver.[115] ALA supplementation may also induce
more vitamin C uptake from the blood into the mitochondria for
usage, thus acting as a potentiator.[116]
ALA can also act as a direct anti-oxidant, at least in vitro. However,
due to its rapid excretion rates and lack of AUC in a cell it is suspected
that this pathway is negligible.
11.2. Interventions
Supplementation of 300-1,200mg ALA daily for 6 months is associated
with reduced urinary levels of F2-isoP, which suggests that ALA
reduces lipid peroxidation in vivo for type II diabetics.[104]Consumption
of 600mg ALA in type 1 diabetics over 5 weeks does not appear to
significantly reduce this biomarker, however.[117]

When measuring 8-OHdG, an oxidative DNA byproduct found in the

urine, there was no significant influence.[104]

12Inflammation and Immunology

12.1. Mechanisms
Most anti-inflammatory effects of Alpha-Lipoic Acid (ALA) are
mediated through its ability to inhibit NF-kB, a nuclear transcription
factor that, upon its activation, induces an inflammatory cascade.
[118]
ALA inhibits upregulation of ICAM-1 and VCAM-1, two pro-adhesion
cytokines, in models of spinal injury at concentrations of 25-100ug/mL
(doses seen as therapeutic, and well-above the typically 600mg a
day).[119][120] ALA may also inhibit expression of metalloproteinase9[121] and osteoclast formation by this same mechanism.[122]
The mechanism by which ALA inhibits NF-kB activity seems to be
further upstream than TNF-alpha inhibition, which is the stage many
anti-oxidants act on. ALA's anti-inflammatory effects are independent
of TNF-alpha modulation.[123]
In humans, a clinical trial noted a 15% serum reduction in levels of
interleukin-6 (an inflammatory marker) following 4 weeks of 300mg
racemic ALA supplementation.[124]
12.2. Rheumatoid Arthritis
One study has been conducted on ALA (300mg) for 4 weeks in
persons with rheumatoid arthritis noted that lipoid acid failed to
significantly reduce IL-6, IL-1, or TNF- and failed to significantly
reduce pain associated with rheumatoid arthritis.[125]

13Interactions with Hormones

13.1. Leptin
Alpha-Lipoic Acid, through suppressing hypothalamic AMPK yet
activating peripheral AMPK, shares mechanistic similarities to the
hormone leptin; when tested in mice however, those with and without
leptin receptors still experience these effects, suggesting ALA acts as
a leptin mimetic in results (but not mechanisms) and may help in
overcoming leptin resistance by bypassing the receptor. [44]
When given to rats prone to Non-alcoholic Fatty Liver Disease
(NAFLD), ALA can suppress the disease pathology and expected rise
in leptin[126] and increased leptin levels in a model of type 1 diabetes,
which experiences a decrease in leptin.[127] When given at 0.25% of
the diet to otherwise normal and healthy rats, a decrease in

circulating leptin and leptin mRNA is seen after 8 weeks, and was
correlated (r=0.908) with levels of white adipose tissue.[52] Isolated
adipocytes from these rats after 8 weeks subject to 250uM ALA
increased conversion of glucose to lactate (resulting in a significant
increase in lactate by 44% at 500uM) and this increase in lactate was
correlated with a decreased secretion of leptin.[52] Lipoic acid appears
to be associated with increased phosphorylation of Sp1, a nuclear
transcription factor induced by glucose that stimulates leptin; its
phorphorylation prevents its actions in the nucleus, and ALA's actions
were mimicked by PI3K inhibitors.[52]

14Nutrient-Nutrient Interactions
14.1. L-Carnitine
When placed in isolated adipocytes (fat cells), Alpha-Lipoic Acid
appears to be synergistic with L-Carnitine supplementation, with a
concentration of 0.1umol/L of both molecules outperforming
100umol/L of either molecule (and interesting, 100umol/L of both
molecules) in increasing mitochondrial density.[128] 10umol/L of both
appeared to be the most effective at increasing mitochondrial density,
more than 3-fold that of control cells.[128]
In a model of lipotoxicity, while Carnitine was effective at increasing
mRNA levels of CPT-1 and PPARy in mitochondria the addition of Lipoic
Acid further augmented the increases in mRNA.[129] These synergistic
increases in mRNA have been reported elsewhere, and appear to
affect PPARa as well.[128]
14.2. Sesamin
Sesamin is a mixture of lignans from sesame seeds that may increase
lipid oxidation and decrease lipid synthesis in the liver, an effect
similar to ALA. Pairing the two appears to be additive in regards to
reducing circulating lipid levels, but the combination confer no
additional benefit in reducing triglyceride storage in the liver.[130] The
combination additively decreased fatty acid oxidation, but ALA
appeared to normalize the increase in fatty acid oxidation seen with
Sesamin.[130]
14.3. Avidin
Avidin is a protein found predominately in raw (but not cooked) egg
whites which is known to potently bind to and sequester Biotin,
leading to biotin deficiency if more biotin is not ingested.[131][132] Biotin
has a similar structure to ALA, and avidin binds to biotin via the part
of the molecule that is structurally similar[133] meaning that avidin can
also sequester ALA.[133]

While it is not prudent to consume raw egg whites anyways due to the
avidin content, they could not be consumed alongside ALA as the
avidin in the egg whites has the potential to sequester and inactivate
the ingested ALA before it can be absorbed

15Toxicity and Safety

15.1. General
ALA supplementation is relatively safe in the doses consumed in
humans. Studies in rats have established a 60mg/kg bodyweight dose
in which no adverse side effects are noted[134] and acute harm being
noted at 2000mg/kg a day.[10] In humans, doses of 1800mg/kg
bodyweight[135] and 2400mg/kg bodyweight[136] failed to have any sideeffects over a 6-7 month period.
In these toxic doses, ALA has been found to increase oxidation levels
(via hydroperoxide) in the organs it acts in[137][138] as well as take its
metal-chelating abilities to the extreme and induce mineral
deficiencies.[33] These effects were seen at the human equivalent of 35g of ALA a day, well below the level used in human trials that
observed no side effects.
15.2. Interventions
For interventions that note side effects, one was a 4-year blinded trial
of ALA at 600mg for the purpose of aiding diabetic neuropathy where
the adverse side effects were higher in ALA (at 38.1%) than in
placebo (at 28%), and were dubbed to be 'cardiac related' or urinary
in nature. These adverse effects did not deter the authors from
determining that ALA was well tolerated, possibly due to significant
differences in global rating.[84]
Other trials note that common side effects are nausea (deemed minor
and related to appetite suppression)[58] and an itching sensation of the
skin assocaited with higher (1,200-1,800mg) doses.[92]

1.
2.
3.
4.
5.

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