Lipoic acid, homocysteine and methylation burden
Question: A recent rat study in Free Radical Biology & Medicine indicated lipoic acid increased plasma homocysteine and S-adenosyl homocysteine levels and suggested this could be a previously unreported adverse effect of lipoic acid consumption. Could you please comment as this could be relevant to regular users of lipoic acid products?
(DAC) I saw the full text of the Stabler et al study the day it was posted online and we have been working on clearing up this issue for the last two months. Like you I was particularly concerned after reading the study due to the strong warning language used and the fact they used our PK paper to justify their conclusions.
I will write to Stabler et al and FRB&M since I believe the peer reviewers and journal should have made them tone down the language or prove this preliminary rat study has any relevance to humans prior to publication. I don’t think fear based language belongs in a scientific journal without significant data to support the contentions. Stabler et al failed on this point but probably gained interest in getting funding for the next study.
When I first saw the Stabler et al study, I wrote Dr. Anthony Smith for his opinion. He also felt the language was unwarranted since Stabler et al could show no statistical correlation between lipoic acid concentration and HCy and SAH (despite the doubling of HCy concentrations) and since they only looked at a single time point. Even if the same pattern occurs in humans, the effect of a transient spike in HCy and SAH is unknown. Many factors may transiently alter HCy output and metabolism that may not correlate to normal/average baseline levels or pose any additional risk to the consumer.
The newest member of our team, Dr. Anthony Sanchez has been working on an HPLC method to measure blood levels of R-lipoic acid (RLA) as well as Homocysteine (HCy) and other amino thiols such as cysteine, glutathione and cysteinylglycine simultaneously. This way we can see if the HCy levels are altered overall in humans (higher or lower) or if it only occurs when RLA is transiently present in blood, which we suspect. Remember RLA/NaRLA reaches high blood levels fast and clears quickly (most within 0.5 hr and almost all in <1 hr). We plan to run another NaRLA PK study with simultaneous measurements of Hcy at each time point and even after RLA has cleared from the blood.
I do believe patients receiving blood panels should advise their doctors as to whether or not they recently ate lipoic acid since it can give artificially high Hcy levels. When we first started testing lipoic acid in the blood 5 years ago I did see a transient spike in my HCy from the average of ~7 uM up to to ~15 uM (a doubling effect similar to Stabler's model) but I didn’t know if it was an artifact or a real effect since red blood cells (RBCs) can export significant amounts of Hcy if the sample is not processed quickly and properly. The elevation in HCy occurred only at Cmax for RLA (1 gram of K-RALA was consumed). When I later tested my Hcy it was back to the normal level of ~7uM where it has stayed for years despite the fact I consume 1-2 grams of our R-lipoic acid products/day with loads of methyl donors. When I get my Hcy measured now I make sure the RLA content of my blood is low by waiting at least 24 hrs after the last consumption.
I do not think any LA/RLA products in the normally used dosages (50-600 mg/day) will cause any long term health problems due to "methylation stress" particularly if consumed with methyl donors (betaine, phosphatydyl choline, carnitine, acetyl carnitine, methylcobalamin etc as well as B6 and B12) which most lipoic acid users take concurrently or as a regular part of their supplement programs.
Lipoic acid consumers with genetic variations (SNPs) in the 5-MTHFR gene might be at greater risk than the normal population but I believe even this can be easily compensated for by increased consumption of methyl factors. I have 2 SNPs in the 5-MTHFR gene which can reduce methylation by 50% of normal and yet my HCy levels are "normal".
Another issue not considered by Stabler is that although 1 lipoic acid molecule acquires in theory up to two methyl groups during metabolism, these methylated metabolites might themselves provide methyl groups to further downstream targets (even HCy) and thus negate any net methyl group depletion. This is supported by the Schupke study that showed only 12.4% of the methylated metabolites appeared in the 24 hr urine.
Thanks for you question and interest in our products. Keep checking my lipoic acid research blog since I will have a lot more to say on this topic in the weeks and months ahead.