Lipoic Acid: R vs. S

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Lipoic Acid: R vs. S

Postby NHE » Wed Aug 22, 2007 9:42 pm

I recently posted this information in another thread but I thought that it might be a good idea for it to be in its own thread in the Natural Approach forum.

Lipoic acid is an antioxidant which some researchers are investigating as a possible treatment therapy for MS. Many people refer to lipoic acid by the name 'Alpha Lipoic Acid' however synthetic lipoic acid usually contains two isomers in a 50/50 mix known as the R and S forms. These are mirror images of each other which are nonsuperimposible much as our hands are mirror images of each other. The R and S isomers arise due to there being a chiral carbon in the molecule. A chiral carbon is one which can have the same atoms attached to it arranged in 3 dimensional space such that it exists in nonsuperimposible mirror images of itself.

Anyways, what's important about the above discussion of lipoic acid's chemistry is that the R isomer is the natural isomer found in the body while the S isomer is not. Some formulations of lipoic acid are sold as being purified R-lipoic acid and their manufacturers typically make the claim that the R form is better or more effective. In reality, there is actually a negative physiological cost to consuming the S form. It's not only not as effective as the R form but also has some undesirable effects.

The following review paper discusses some of these differences between the R and S forms. The quotes I've listed below are pulled from the full paper as the abstract did not go into the full details.

I hope that this information helps to answer any questions that people may have about lipoic acid as there have been some recent inquiries about it on the forum.


Molecular Aspects of Lipoic Acid in the Prevention of Diabetes Complications
Nutrition. 2001 Oct;17(10):888-95.
The polyol pathway is known as the primary cause of cataractogenesis in diabetes. Lipoic acid can exert protective effects in different ways. The reduction of R-lipoic acid by lipoamide reductase depends on NADH. Accordingly, intramitochondrial reduction of R-lipoic acid can alleviate NADH surplus in diabetes. In a model of glucose-induced lens opacity in vitro, stereospecific protection by lipoic acid was observed. Although R-lipoic acid completely protected the lens, addition of racemic lipoic acid decreased damage only by about one-half, whereas S-lipoic acid potentiated deterioration of the lens.

Insulin resistance is typical for type II diabetes. Therapeutic intervention to enhance glucose uptake by skeletal muscle is potentially important for the prevention and treatment of non–insulin-dependent diabetes. As early as 1970, lipoic acid was shown to enhance glucose uptake into rat tissues. Subsequently, obese Zucker rats, an animal model of insulin resistance, were used to investigate the effects of acute and chronic intravenous treatments with R,S-lipoic acid on glucose transport in isolated skeletal muscle. Lipoic acid markedly increased net glucose uptake, which was associated with a significant enhancement of glycogen synthesis. This observation was supported by a separate experiment in vitro from the same group showing an increased glucose uptake into muscle from lean (insulin-sensitive) or obese (insulin-resistant) Zucker rats. In the same model, the effect of the individual enantiomers of lipoic acid on glucose disposal, hyperinsulinemia, and dyslipidemia was studied. Obese Zucker rats were treated acutely or chronically by intraperitoneal injection with R- or S-lipoic acid. Acute treatment with R-lipoic acid increased insulin-mediated glucose transport by 64%, whereas the S form showed no significant effect. Chronic R-lipoic acid administration reduced plasma insulin and free fatty acids, whereas S-lipoic acid increased insulin and had no effect on plasma free fatty acids. Further, R-lipoic acid improved insulin-stimulated glycogen synthesis and glucose oxidation. The level of glucose transporter-4 protein was not altered after chronic treatment with R-lipoic acid but was reduced by S-lipoic acid.

The effect of lipoic acid on glucose uptake into heart muscle also has been investigated. Glucose uptake into Langendorff hearts of insulin-resistant Zucker was measured with the [ 14 C] 3-O-methylglucose washout method. Glucose uptake rate increased 1.6-fold with R,S-lipoic acid, 1.8- fold with the R form, and was negatively influenced by the S-enantiomer (-50%).

In the working rat heart during reoxygenation, R-lipoic acid improved aortic flow, reaching 70% of normoxic conditions at nanomolar concentrations, whereas 1 µM of the S form was needed to achieve only 60%. In the same study, R-lipoic acid added to the perfusion medium increased mitochondrial ATP synthesis of the working rat heart, whereas ATP synthesis remained unaltered in response to S-lipoic acid.


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Postby jimmylegs » Thu Aug 23, 2007 6:47 am

love that kind of info nhe, good one
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Postby dignan » Thu Aug 23, 2007 9:55 am

Thanks for the interesting info NHE. Do you know what kind of LA they are using in the studies they are doing in Oregon? (eg study below)


Mult Scler. 2005 Apr;11(2):159-65.

Lipoic acid in multiple sclerosis: a pilot study.

Yadav V, Marracci G, Lovera J, Woodward W, Bogardus K, Marquardt W, Shinto L, Morris C, Bourdette D.
Department of Veterans Affairs Medical Center, Portland, OR, USA.

Lipoic acid (LA) is an antioxidant that suppresses and treats an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis. The purpose of this study was to determine the pharmacokinetics (PK), tolerability and effects on matrix metalloproteinase-9 (MMP-9) and soluble intercellular adhesion molecule-1 (sICAMP-1) of oral LA in patients with MS. Thirty-seven MS subjects were randomly assigned to one of four groups: placebo, LA 600 mg twice a day, LA 1200 mg once a day and LA 1200 mg twice a day. Subjects took study capsules for 14 days. We found that subjects taking 1200 mg LA had substantially higher peak serum LA levels than those taking 600 mg and that peak levels varied considerably among subjects. We also found a significant negative correlation between peak serum LA levels and mean changes in serum MMP-9 levels (T = -0.263, P =0.04). There was a significant dose response relationship between LA and mean change in serum sICAM-1 levels (P =0.03). We conclude that oral LA is generally well tolerated and appears capable of reducing serum MMP-9 and sICAM-1 levels. LA may prove useful in treating MS by inhibiting MMP-9 activity and interfering with T-cell migration into the CNS.
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Postby gwa » Sat Jan 19, 2008 9:39 am

This is an excerpt from a research article I read this week about ALA.

http://www.medicalnewstoday.com/articles/94031.php


"Alpha lipoic acid is a naturally occurring nutrient found at low levels in green leafy vegetables, potatoes and meats, especially organ meats such as kidney, heart or liver. The amounts used in this research would not be obtainable by any normal diet, researchers said, and for human consumption might equate to supplements of about 2,000 milligrams per day. Even at low, normal, dietary levels, the compound can play a key role in energy metabolism. "


I have been taking 200mg of R-ALA for months, but cannot figure out how to translate the 2000mg amount done in the research into R-ALA. The research definitely shows reasons to take this supplement.

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Postby cheerleader » Sat Jan 19, 2008 9:49 am

Hi GWA-
My husband is on ALA (rec. by neuro) and he takes 600 mg. daily. After I posted my husband's protocol on the regimen forum, NHE sent me to this thread, and brought to my attention that there are R and S formations of this drug. I'll do some more research and post here if I learn any more.
best,
AC
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Postby gwa » Sat Jan 19, 2008 10:45 am

I knew that R-ALA is better absorbed and more potent than regular ALA, but have not found any info that tells how much of R-ALA is needed instead of ALA.

Hope that you find some info on this.

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Re: Lipoic Acid: R vs. S

Postby NHE » Sat Jan 19, 2008 2:07 pm

Hi GWA,

gwa wrote:I knew that R-ALA is better absorbed and more potent than regular ALA, but have not found any info that tells how much of R-ALA is needed instead of ALA.

Hope that you find some info on this.


From one of my first posts to the forum...
NHE wrote:The biological activity of R lipoic acid is also reported to be roughly 6-12 fold higher than S lipoic acid if I remember correctly.


I believe that the author's name that you'll want to search PubMed for is Packer however I'm having difficulty reaching the PubMed site right now so I can't list any abstracts.

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Postby dignan » Sat Jan 19, 2008 6:32 pm

NHE, So 'r' is 6-12 times more potent than 's'. Got it...and regular "alpha lipoic acid" is 50-50 'r' and 's'? Is that right? So if they recommend 2,000mg of ALA, then that would be 1,000mg of r lipoic acid? Is that right?
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Re: Lipoic Acid: R vs. S

Postby NHE » Tue Jan 22, 2008 7:33 am

Dignan wrote:NHE, So 'r' is 6-12 times more potent than 's'. Got it...and regular "alpha lipoic acid" is 50-50 'r' and 's'? Is that right?

Yes. Both stereoisomers are present in equal amounts. In my reading of papers, I've found that unless the paper specifically mentions one optical isomer or the other, then it's best to assume that they are referring to racemic lipoic acid, i.e., both R and S in equal amounts. Moreover, another point of confusion encountered when reading papers is the distinction between dihydrolipoic acid (DHLA), the reduced form, and alpha lipoic acid (ALA), which is usually the oxidized form. Most papers discuss using ALA though a few mention DHLA. My understanding is that supplements, either R or racemic, are the oxidized ALA form and then the body converts it to DHLA so that it can function as an antioxidant.
So if they recommend 2,000mg of ALA, then that would be 1,000mg of r lipoic acid? Is that right?

I really don't know. That might be true if the S isomer was simply just ineffective, but as the paper I pulled quotes from at the top of the thread points out, the S isomer can actually have a negative physiological cost. Thus, at this time, I'm really not sure how to go about figuring out what an equivalent dose of R might be in terms of the racemic form. Such an equivalence conversion might also depend on the specific biochemistry one is interested in as well. For example, lipoic acid is known to inhibit NF-kB, a transcription factor for proinflammatory cytokines, and it's also known to inhibit matrix metalloproteinases (MMP). It could very well be the case that the difference in activity between the R isomer and the racemic form is different for these two biochemical activities.

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Postby dignan » Tue May 06, 2008 11:59 am

I have an unhappy addition to this thread (especially since I take r-lipoic acid):

Due to its tendency to polymerize, RLA is relatively unstable and suffers poor aqueous solubility, leading to poor absorption and low bioavailability.


After reading the abstract below, it struck me that all the info I've seen on r-lipoic acid is in test tube or rat studies where they administer it intraveneously. I'm hoping somebody knows more about this and can convince me I'm not wasting my money on r-lipoic acid...


The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects.

Altern Med Rev. 2007 Dec;12(4):343-51.
Carlson DA, Smith AR, Fischer SJ, Young KL, Packer L.
GeroNova Research, Inc., 4677 Meade St, Richmond, California 94804, USA. david@geronova.com

BACKGROUND: The racemic mixture, RS-(+/-)-alpha-lipoic acid (rac-LA) has been utilized clinically and in a variety of disease models. Rac-LA and the natural form, R-lipoic acid (RLA), are widely available as nutritional supplements, marketed as antioxidants. Rac-LA sodium salt (NaLA) or rac-LA potassium salt (KLA) has been used to improve the aqueous solubility of LA.

STUDY RATIONALE: Several in vitro and animal models of aging and age-related diseases have demonstrated efficacy for the oral solutions of LA salts in normalizing age-related changes to those of young animals. Other models and studies have demonstrated the superiority of RLA, the naturally occurring isomer over rac-LA. Despite this, RLA pharmacokinetics (PK) is not fully characterized in humans, and it is unknown whether the concentrations utilized in animal models can be achieved in vivo. Due to its tendency to polymerize, RLA is relatively unstable and suffers poor aqueous solubility, leading to poor absorption and low bioavailability. A preliminary study demonstrated the stability and bioavailability were improved by converting RLA to its sodium salt (NaRLA) and pre-dissolving it in water. The current study extends earlier findings from this laboratory and presents PK data for the 600-mg oral dosing of 12 healthy adult subjects given NaRLA. In addition, the effect of three consecutive doses was tested on a single subject relative to a one-time dosing in the same subject to determine whether plasma maximum concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) values were comparable to those in animal studies and those achievable via intravenous infusions in humans.

METHODS: Plasma RLA was separated from protein by a modification of a published method. Standard curves were generated from spiking known concentrations of RLA dissolved in ethanol and diluted in a phosphate-buffered saline (PBS) into each individual's baseline plasma to account for inter-individual differences in protein binding and to prevent denaturing of plasma proteins. Plasma RLA content was determined by the percent recovery using high-performance liquid chromatography (electrochemical/coulometric detection) (HPLC/ECD).

RESULTS: As anticipated from the preliminary study, NaRLA is less prone to polymerization, completely soluble in water, and displays significantly higher Cmax and AUC values and decreased time to maximum concentration (Tmax) and T1/2 values than RLA or rac-LA. In order to significantly extend Cmax and AUC, it is possible to administer three 600-mg RLA doses (as NaRLA) at 15-minute intervals to achieve plasma concentrations similar to those from a slow (20-minute) infusion of LA. This is the first study to report negligible unbound RLA even at the highest achievable plasma concentrations.

Pubmed link
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Re: Lipoic Acid: R vs. S

Postby NHE » Tue May 06, 2008 10:42 pm

I'm familiar with two products which are the stabilized forms of R-lipoic acid. One is made by a company called Hu-Max and the other is made by Doctor's Best. Neither product is inexpensive though some retailers such as Vitamin Shoppe and Super Supplements offer discounts off of the suggested retail price. Hu-Max's r-lipoic acid is the potassium salt whereas Doctor's Best is the sodium salt. In addition, Hu-Max's web site references a study done way back in 1956 which discusses the problems with polymerization. I have made that paper available in PDF for anyone who is interested in it. I should also note that the full paper referenced above by Dignan is available for free from this link. Lastly, due to my current financial situation, I'm not taking either of the products mentioned above. However, when I do purchase R-lipoic acid I take a cooler along with me if it is a warm day and I also store the bottle in the refrigerator. Hopefully, these steps minimize any polymerization.

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Last edited by NHE on Wed Sep 17, 2008 2:01 am, edited 1 time in total.
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Postby dignan » Wed May 07, 2008 8:21 am

Thanks for the info. So I need to get the stabilized form, and keep it in the fridge, ok then.
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Re: Lipoic Acid: R vs. S

Postby NHE » Wed May 07, 2008 5:09 pm

Dignan wrote:Thanks for the info. So I need to get the stabilized form, and keep it in the fridge, ok then.

The websites for both Doctor's Best and Hu-Max indicate that the stabilized form does not need to be refrigerated though I suppose that it couldn't hurt. I was actually referring to regular r-lipoic acid which I get from Source Naturals. These supplements come with a couple of small desiccant packs and I store the bottles in the refrigerator to keep them cool.

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Postby harry1 » Sat Dec 18, 2010 5:43 pm

Hey everyone

I know that i'm digging up an old thread however i didn't want to start a new thread as this one is very informitive especially for any newbies reading this and so i was just reading on the MS Society's web site about this past years research advances and they had mantioned lipoic acid as being beneficial in early studies and so i was wondering for those who've been taking this product for a bit have you noticed any benefits from it or not.

http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=4327

Thanks !
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Re: Lipoic Acid: R vs. S

Postby NHE » Thu Dec 30, 2010 1:59 am

harry1 wrote:I know that i'm digging up an old thread however i didn't want to start a new thread as this one is very informitive especially for any newbies reading this and so i was just reading on the MS Society's web site about this past years research advances and they had mantioned lipoic acid as being beneficial in early studies and so i was wondering for those who've been taking this product for a bit have you noticed any benefits from it or not.

http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=4327

Thanks !
harry


I took it for a while but didn't notice any effects, positive or otherwise, that I could attribute to it. However, when I was taking both r-lipoic acid and acetyl-L-carnitine, I did notice positive improvements in diminished cognitive fatigue.

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