Setting the record straight - Challenging the competition

GeroNova Research Inc. (The Lipoic Acid Company) responds to critics over whether or not R-lipoic acid requires stabilization to be an effective nutrient.  

"There are none as blind as those who will not see" 

 Summary: A representative of Insulow contends without any scientific evidence that it is unnecessary to stabilize R-lipoic acid (aka; RLA, dextro lipoic acid, lipoic acid (R-form) and that GeroNova Research, a company specializing in R-lipoic acid manufacturing & products for nutraceutical applications is using the “stabilization issue” as a ploy which they claim is without merit. Insulow also contends on their website that the “rotation” is the ONLY way to test RLA (see Insulow's website).

David A Carlson, Co-Founder & Director of R&D of GeroNova Research, Inc will respond to Insulow’s contentions and demonstrate the necessity for stabilization of R-lipoic acid to increase the shelf life and to significantly improve the bioavailability.

One of the great things about being alive in the 21^st century is the availability and wide spread use of the internet which allows many voices to be expressed and heard. One of the great challenges of the internet for the non-specialist is discriminating truth from falsehood in that much of what is said may be either wrong, through ignorance or by blatant disinformation which may perpetuate errors and misconceptions.

Although this blog concerning the R-lipoic acid stability issue was originally posted in March 2007, it was forwarded to me by a customer in Nov 2008. I held off on posting my reply but decided to do so now since the question recently came up again. Since the person posting this used the opportunity to take a few “cheap shots” at GeroNova Research (and my work for the last 11 yrs), and since almost every line is filled with inaccuracies, I feel that it is worth the time to try to set the record straight. My approach & philosophy concerning R-lipoic acid (and life) has been to educate and not to denigrate but in this case most of the statements are filled with errors so forgive me if I take a few jabs.

 The GeroNova Research Challenge to Insulow:

Talk is cheap; Put your money where your mouth is!

I would like to put out a challenge to Insulow & Glucorell or any other company advocating the “free-acid” form of R-lipoic acid over one of its salts. To resolve this issue and to set the record straight, GeroNova Research proposes a binding arbitration in the San Francisco Bay Area to judge Insulow’s claims versus those of GeroNova Research. I suggest that the parties choose a neutral entity, preferably a retired judge, to oversee the proceedings and that each party choose three published experts (the criteria for expert is at least one peer reviewed publication) on lipoic acid to act as a fact finding panel or “jury.” In the case of a “jury” deadlock, the neutral would make the final decision. The parties shall split the fees for the neutral and shall be responsible for the fees and costs of their own representatives and chosen experts. If Insulow prevails, GeroNova Research will retract all its claims, start selling the “free-acid” form of R-lipoic acid and make a public apology. If GeroNova Research prevails, Insulow will make a public apology about its incorrect claims, including written apologies to GeroNova Research for the disparaging comments which will be posted on-line. Insulow will also agree to immediately stop selling their unstabilzed R-lipoic acid product as well as to make corrected statements on their website within 7days. 

The italicized comments below were excerpted from a dialog on a blog. I did not correct the typos. Apparently the writers were too busy to use) spell check and “fact check”.

 Insulow makes a good product my meter says its good, but insulow also has to stablize the R-ALA , The germans have been using this stuff for a very long time and in the old east  germany they used it in their sports programs, along with a bunch of other stuff. I realize that good manufactures have a hard time, as all the supplements out on the market will drive almost all of us carzy, but please realize my final check on almost any thing i eat or med's or supplements i put in my body is my meter.

It would be a more objective gauge to test blood levels and even better to include a reliable blood marker than to rely on a subjective hunch that the internal “meter” is accurate. Having said this, many people do report an almost immediate sense of energy and well being from K-RALA (especially the liquid) we have had people report that they felt nothing from taking pure R-lipoic acid and hoped that it might be doing something for them. This is what I call “faith-based nutrition.” We have shown this lack of effect from the free-acid form of R-lipoic acid is due to extremely low blood levels.

An Evaluation of the Stability and Pharmacokinetics of R-lipoic Acid and R-Dihydrolipoic Acid Dosage Forms in Plasma from Healthy Carlson DA, Young KL, Fischer SJ, Ulrich H. Chapter 10 in: Packer L, Patel M, eds. Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects. London, England: Taylor & Francis Publishers; 2008:235-270

In our preliminary pharmacokinetic studies of R-lipoic acid and R- dihydrolipoic acid, we showed that the maximum plasma level of the “free-acid” form of RLA was barely distinguishable from baseline levels. In other words it was hard to know if the subject had consumed the product or not.

The Plasma Pharmacokinetics of R-(+)-Lipoic Acid Administered as Sodium R-(+)-Lipoate to Healthy Human Subjects.Carlson DA, Smith AR, Fischer SJ, Young KL, Packer L. Alt Med Rev 2007;12(4) 343-351.

 I could not find any published literature indicating the East Germans used R-Lipoic acid in their sports programs, so I asked a reliable source who asked to remain anonymous and below are his comments:

“I know that the former GDR used racemic or (+/-)-alpha-lipoic acid together with other nutritional compounds and steroids in an attempt to improve performance and recovery in elite athletes. I got this information from 2 sports physicians, who worked in sports medicine after they deserted from the East German team.

They told me, that it had been discussed that they might achieve better results with R-Lipoic Acid but before their desertion they had no chance to get the pure R-enantiomer. After this time I have no solid information about what the East Germans used in their doping cocktails”.

I have heard rumors (and found one published study) that veterinarians have used racemic (+/-)-lipoic Acid to improve performance and recovery in racing dogs and race horses.

Williams CA, Hoffman RM, Kronfeld DS, Hess TM, Saker KE, Harris PA. Lipoic acid as an antioxidant in mature thoroughbred geldings: a preliminary study. J Nutr. 2002 Jun;132(6 Suppl 2):1628S-31S

I also reviewed the early drafts of a study just published indicating rac-LA increased the expression of heat shock proteins in horses and improved several metabolic parameters.

Alpha-Lipoic acid modulates thiol antioxidant defences and attenuates exercise-induced oxidative stress in standardbred trotters. Kinnunen S, Oksala N, Hyyppa S, Sen CK, Radak Z, Laaksonen DE, Szabo B, Jakus J, Atalay M. Free Radic Res. 2009 Jun 22:1-9.

 R-ALA is made up of two enantiomers, S and R. The S part is of no use to us because it has been found to inhibit ATP production in muscle tissue.

Technically, this is incomplete and incorrect. R-ALA is one of the enantiomers, the other is S-ALA or S-lipoic acid. The 50:50 mixture of the two is called a racemic mixture and is the usual form of lipoic acid found in commerce. While I have championed R-Lipoic Acid (R-ALA) for 11 yrs now and have done so because I believe the evidence to date confirms the superiority of R-Lipoic Acid over S-Lipoic Acid or R/S-Lipoic Acid, SLA obviously has some value and in some isolated experiments was superior to R-Lipoic Acid. One of Hagen’s early papers showed that R-Lipoic Acid increased ATP levels in heart muscle whereas S-Lipoic Acid decreased it. It is a widespread misconception and gross oversimplification that only the R-Lipoic Acid component of the racemic mixture is responsible for all the therapeutic effects of alpha-lipoic acid.

The R part gives us all of the beneficial effects, including increasing ATP production, lowering oxidative stress, improving metabolic activity and cellular metabolism.

Technically, this is incorrect. S-Lipoic Acid also has benefits such as reacting with a variety of free radicals but in other cases it can act as a competitive inhibitor of R-Lipoic Acid. Therefore it is best removed since these cases represent the limiting criteria in vivo. In our preliminary comparative pharmacokinetic (PK) study where we compared blood levels of R-Lipoic Acid vs S-Lipoic Acid and R/S-Lipoic Acid in the same three subjects we surprisingly found that S-Lipoic Acid was better at short term reduction of blood glucose than R-Lipoic Acid even though the plasma levels were considerably lower.   view study here

 Unfortunately, the R form is extremely sensitive and becomes unstable when there are even the smallest changes in light, air, moisture, and temperature. These changes cause it to decay and polymerize into a sticky, rubbery, or glue like substance which is useless in the human body within hours of ingestion. R-ALA is so unstable that is needs to be shipped in dry ice and stored in a cool and dry place at all times. This instability renders the R-ALA orally inactive. Another problem associated with R-ALA is that it is a waxy material that has a tendency to trap high amounts of residual toxic chemicals and waste from manufacturing, including the carcinogenic solvents dichloromethane, ethylene dichloride, MTBE, acetonitrile, cyclohexane, toluene, methanol and ethyl acetate.

Note: Most of the above was taken from the GeroNova Research website. Underlined below was the slanderous response from the Insulow representative that resulted in my detailed reply.

 I have not read the Geronova garbage in a long time. I didn't realize they were still using those tactics to push their product. It's a shame. 

What is really a shame is a person passing themselves off as a lipoic acid expert as well as an analytical chemist because they read a few articles and put the product someone else made in a capsule. The level of ignorance and arrogance is laughable in light of the numerous errors espoused by this self proclaimed expert.

The adherence of the Insulow representative to the “free-acid form” of R-Lipoic Acid over other forms is without merit and the GeroNova Research “tactics” include published human pharmacokinetic trials and clinical feedback from 100’s of physicians. I will discuss in detail below.

 Thanks for writing all that. Since I was the one who brought R+ ALA to the US for the first time and was the first to make it available to the public I can assure you that I know more about it than you do.

AOR and Insulow have both publicly claimed to be “the” company who introduced R-Lipoic Acid to the nutraceutical market. To me, this is like claiming they built the first rocket to the moon. Pay no attention to the fact it blew up on the launch pad. The above person claiming to be the “one” who introduced RLA to the US is in error again. Italian made (Labochim, Milan) was available by special order in 2000 for $1100/kg in 20 kg drums. While I do not claim to be first, I can certainly claim to be amongst the first since I started the bench chemistry in 1998 and commercial production in 2000 in an attempt to get the price down so that it was affordable for use as a supplement. I can claim to be the first to stabilize R-lipoic acid and make a highly bioavailable product on the industrial scale and bring it to market. My lab continues to this day making R-Lipoic Acid, R-Lipoic Acid salts, lipoic acid metabolites and lipoic acid derivatives and is constantly seeking to improve the chemistry making it more “green” (eco-friendly) and cost effective as well as trying to make ever better products for the consumer.

GeroNova Research was also one of the first companies to develop and perfect a large scale manufacturing process and the first specialized American based Lipoic acid company selling R-lipoic acid and derivatives in bulk.  GeroNova Research has been focused on R-lipoic acid process development and stabilized dosage forms ever since, while other companies are simply profiting by putting powder with known lack of efficacy in capsules. GeroNova Research has been involved in every step of the R&D, manufacturing and testing of R-lipoic acid and its intermediates. Consumers of the free-acid form of R-lipoic acid should contact the manufacturers and ask them about the stability and bioavailability of their products. To most companies R-lipoic acid is just a “widget”.

We currently supply most of the companies selling R-lipoic acid or stabilized R-lipoic acid have two published peer reviewed papers a book chapter in the latest LA book and several more papers and studies in progress.

In addition, GeroNova Research is involved in numerous collaborations with world class academic and industrial lipoic acid researchers and has provided R-lipoic acid sodium salt products for (in process) federally funded (NIH and NIA) clinical trials. What has Insulow contributed to the scientific knowledge base? Where is the evidence supporting ANY of their contentions?

Your post is by a company trying to defend the K-R-ALA that you posted about using. K-R-ALA was invented by the Chinese a few years back because they have no air conditioning in their manufacuring plants. This means they can only make R+ for 6 months of the year. This was okay the first few years but they needed to find an answer to their unique problem. They found it. They attach K to it so they can make it year round. This is clearly in their favor because there is no way to test it for purity so they don't need to worry about quality testing and they can sell it cheaper because there is no need to turn out a pure product.

The above contention is blatantly wrong & illogical. If R-lipoic acid can only be produced for 6 months, then they would have to stockpile R-lipoic acid which is not heat stable (it would polymerize in the hot summer months) in order to keep making the more stable salt form all year. Most Chinese manufacturers of R-lipoic acid and the salts still only produce it 6 months out of the year and stockpile the stable salt to meet the demands of the year, not the R-lipoic acid starting material.

The R-lipoic acid raw material going into Na-RALA or K-RALA has the same chemical and specific rotation (an indication of chiral purity) as that sold by Insulow. We have verified the chemical purity by NMR and LC/MS and the enantiomeric purity by polarimetry and chiral HPLC.  view here

Our starting material has the same specific rotation as that being sold by Insulow. The salts can also be tested for specific rotation which we do routinely. GeroNova Research was responsible for the Chinese companies raising their standards for R-lipoic acid products by broadcasting the solvent impurity, polymer, stability and adulteration issues. We have seen numerous products being offered as R-lipoic acid which in fact contain the inexpensive R/S-lipoic acid.

THAT's the history and truth behind K-R-ALA. And I know that from the inside. We would not use a material that is impossible to test for purity. Other companies, like the one that wrote that junk, do. 

Everything written in the 2 paragraphs above are misleading and incorrect. He “knows that from the inside”? Inside what, his own head? While K-RALA was mentioned in the peer reviewed & old patent literature and was frequently made in solution, on the spot for in vitro studies, I could find no record in Chemical Abstracts of it having been isolated or characterized, even though a Chem Abstracts Reference number (CAS #) was assigned [344904-53-6].

I first made K-RALA in the US in 2000 and commercial production was done in New York, USA not in China. The Chinese did not invent it. After our success with K-RALA, the Chinese jumped in on the action with a spin-off and by possibly violating Bruce Ames’ patent for the potassium-nicotinamide salt of R-lipoic acid. Ames decided not to market it through Juvenon because of potential health issues associated with high doses of nicotinamide. One Chinese manufacturer now makes K-RALA without nicotinamide.

Once again Insulow is mistaken in that it is just as easy to test the specific rotation of potassium R-lipoate (K-RALA), sodium R-lipoate (Na-RALA), and R-lipoic acid tromethamine salt (trade name Dexlipotam, the form developed by Asta Medica in Germany as a drug due to the poor stability & bioavailability of RLA) as the “free-acid” form of R-lipoic acid.

The specific rotation of K-RALA is [a]_D²⁰ [+90.5], c=1 in water, Na-RLA= [a]_D²⁰ [+75.5], c=1 in water, and RLA tromethamine salt, [a]_D²⁰ [+71.6], c=1 in ethanol.

We still offer 10% aqueous solutions of K-RALA (one of our top selling products) but now prefer R-lipoic acid sodium salt (NaRLA) for solid dosage forms due to good batch to batch consistency and the highest blood levels (62% absolute bioavailability).

When we did contract with a Chinese lab to make R+ ALA we have to send our own chemist there from Chicago. Then when it was done we have to send a sample to the Univ of Wisconsin to be tested for purity because the Chinese are unable to do the optical rotation testing needed.

This is absurd and completely false. I have spent many days and nights in the lab and the production facility in China monitoring reactions and working with the chemists and engineers. The measurement of the specific rotation is routine and I find it hard to believe anyone would suggest that the Chinese chemists who have the skill & capability to make R-lipoic acid on an industrial scale (not easy) are unable to test it. All three of the major Chinese R-lipoic acid manufacturers have polarimeters (as do all 1^st semester organic chemistry labs), HPLC’s and now I have introduced our manufacturing partner to chiral HPLC (view here) so we have multiple methods of monitoring the enantiomeric/chiral purities of each intermediate as well as the final products.

So it's a lot of hassle for us. But it's certainly better than buying K-R-ALA and pushing it as "a stable R+ ALA" to people who don't know any better. 

Apparently this person knows no better and must have failed basic organic chemistry! Ignorance is bliss and the world is flat! The above “expert” has claimed that the “only way” to analyze R-lipoic acid is by specific rotation and is apparently unaware that measuring the specific rotation without testing the product purity by HPLC, Mass Spec or NMR is meaningless. This is taught in basic organic and analytical chemistry.

The specific rotation ([a]_D )of a compound is a characteristic of that compound only after its chemical purity has been determined by another method. For example it is possible to get a rotation of [+120] deg (the “gold-standard” according to Insulow) by mixing a compound with a higher rotation with one of a lower rotation. Therefore the specific rotation is a secondary measurement, not primary as suggested.  If one looks at the literature, there is a wide range of reported values for R-lipoic acid. If the rotation of [+120] is the ONLY way to test the R-lipoic acid purity, then what are we to make of the following from the peer reviewed, reference and patent literature? Should we infer that even the material isolated from natural sources contained the un-natural S-lipoic acid?

Technically it is essential to report both the solvent used and the concentration as well, since the number by itself is meaningless. Interestingly we have done detailed work comparing the solvent effects & concentrations with the specific rotations as well as to the chiral HPLC method and surprisingly have found no peaks from S-lipoic acid detectable even with rotations as low as [+112] and found no difference whether the solvent was benzene or alcohol (the solvent used by Insulow).

The Italian made Active Pharmaceutical Ingredient (API) R-Lipoic Acid has a reported specific rotation ranging from [+112] to [+119]. Should we reject this material as impure even though it is pure enough for the European pharmaceutical market and shown to be enantiomerically pure by chiral HPLC?

R+ ALA is not unstable to where it needs to be shipped on dry ice unless it's going to be subjected to temperatures over 103 degrees. 

Insulow has never had a single box returned because the contents became unstable or melted into wax. This can happen. This can happen to many supplements. So don't leave supplements in the car in the summer time. 

All supplements should be stored in a cool dry place and it says so on most bottles. 

We receive drums of R-lipoic acid from China every month and these are just packed with ice-packs and not packed in dry ice. The problem is that sometimes a shipment is held by Customs or the FDA for inspection and sampling. We have received shipments of 100’s of Kilograms that were held in their warehouses for 2-4 weeks and have arrived mostly polymerized. Removing it is like trying to pry a compressed yellow rubber tire from the drum and is obviously useless as a nutrient.

The biggest problem with the above contention and the Insulow website is that the [a]_D and the physical stability are the “bottom line” i.e., the ultimate criteria for efficacy as a nutrient. This is absolutely false as basic pharmacokinetic measurements reveal. In other words it is possible to have a chemically and enantiomerically pure compound that is inferior nutritionally or clinically to one with lower chiral purity. While I believe R-lipoic acid is superior to S-lipoic acid or (+/-)-lipoic acid, the enantiomeric excess (ee) is NOT absolute in terms of therapeutic efficacy. If this were true then R/S-lipoic acid would not be useful, yet there are over 50 clinical trials showing that it is. (for references: The case against controlled release lipoic acid; view here)

Due to differences in the gut absorption between RLA and SLA, I believe it is possible to administer a 90:10 mixture of RLA to SLA and achieve results comparable to the single enantiomer (administered as the salts).

Labochim representatives have suggested to me that even a 75:25 mixture of R-lipoic acid: S-lipoic acid might deliver higher amounts of R-lipoic acid by improving the stability while reducing the negative effects of S-lipoic acid due to lower absorption of the unnatural enantiomer although I’m unaware of any PK testing to prove this. If this proves to be true by further studies then it will provide a way to significantly lower the cost of R-lipoic acid products.

BASF is the largest chemical company in the world. They now manufacture and sell R+ ALA in Germany. They don't seem to have any of the problems you're writing about either. 

Actually, BASF is not producing R-lipoic acid in Germany or marketing R-lipoic acid in the US. They were originally approached by the former Asta Medica in the late 90’s to see if they could lower the manufacturing costs using some of their proprietary asymmetric catalysts while R-lipoic acid tromethamine salt was under pharmaceutical development & abandoned the project after years of work. I have devoted an entire chapter to BASFs work on R-lipoic acid in my forthcoming book. view here

Asta Medica realized early on (in 1984) the inherent problems with R-lipoic acid (poor stability and bioavailability) and planned to launch it into the drug market as the tromethamine salt which can be isolated as a pure yellow crystal, with sharp melting point and defined specific rotation. BASF planned to launch R-lipoic acid as the pyridoxamine salt on the nutraceutical market after the pharmaceutical plans were dropped because of its greater stability and the health benefits of both parts of the salt.

The problem for BASF and the reason they dropped R-lipoic acid was that the market was too small. They were hoping that the market was greater than 50 MT/yr which would make it cost effective for them to recycle their solvents. Unfortunately the entire world market for R-lipoic acid was at the time <10 MT/yr (but is now over 30 MT). Therefore the abandonment of R-lipoic acid and its salts by both the successors of Asta Medica and BASF was a business decision based on high production costs relative to R/S-lipoic acid, Chinese made R-lipoic acid and a small market.

Another problem associated with R-ALA is that it is a waxy material that has a tendency to trap high amounts of residual toxic chemicals and waste from manufacturing, including the carcinogenic solvents dichloromethane, ethylene dichloride, MTBE, acetonitrile, cyclohexane, toluene, methanol and ethyl acetate.

 Insulow’s comment: The last part of that post is complete nonsense. The lab is ISO 9001 and FDA inspected. Those solvents are not even in the building where Insulow is manufactured. What a ridiculous thing to write. 

It’s not a matter of storing the solvents in the same building as finished R-lipoic acid it’s a matter of these solvents being used in the manufacturing of R-lipoic acid. Most of these solvents have boiling points higher than the melting/ sintering point (the temperature at which R-lipoic acid instantly polymerizes which is 46 deg C) and are difficult to remove completely even under high vacuum conditions. We have analyzed many samples of R/S-lipoic acid and R-lipoic acid and have found high amounts of residual solvents. That is why we developed a process where R-lipoic acid is isolated from water and converted into a salt. This increases the heat stability and completely eliminates this problem.

Summary & Conclusion:

 From the above it should be clear that the statements made by Insulow are either inaccurate and/or misleading. GeroNova Research has proven that it is essential to stabilize R-lipoic acid to insure stability, bioavailability and thus nutritional and clinical efficacy.

While the above statements made by me are technically correct and made in good faith, I am willing to discuss or debate these issues and provide data including chromatograms (both chiral and non-chiral) as well as polarimeter readings and expert support in any forum with any non-believing individuals or companies at any time.