Interesting, thanks for posting this summary and review. Would be fascinating to hear a video/podcast conversation between you and Dr. Burt Berkson talking about ALA and how it functions, clinical use, etc. He has treated patients for years with it, conditions related to liver disease, cancer treatment, autoimmune, and some others, and he has some remarkable published case studies. I heard he advises b complex injections after ALA infusions due to it depleting their levels in some way, but I couldn’t find a citation for that claim to know the mechanism of how that happens.
Hopefully the complex includes good doses of methyl donors! He probably means by increasing utilization in energy metabolism but perhaps he is also referring to this dynamic.
So fascinating - thank you. I just listed to your podcast on niacin as well and deeply appreciate your insight on how these two supplements can have a huge negative impact on methylation.
I have been taking 480mg of R-Lipoic Acid (Life extension brand) daily for almost 8 years now, all at breakfast. I am always grumpy and my strength levels have not been improving in years. Last year, I fasted before my blood test and homocysteine was just over 9 (so that would be the leftover from the day before). After reading your article, I asked my doc if I could test your hypothesis and he said yes, so I fasted except I took the 480mg of R-Liopic acid 1 hour and 5 mins before the blood test was drawn. I'll post here when I see the homocysteine results, but might be a few weeks.
I got the results back. Homocysteine was 10.2. Up from 9.6 the year before; and the year before the blood test was 24 hours after taking the dose. So my best guess is that the blood levels stay elevated for more than a day after taking the stuff. The only other anomaly I noted was Alanine Aminotransferase (ALT) was 34 last year, and this year 1 hour after taking the R-Lipoic acid ALT was up to 78, and flagged as being high.
I will ask the Dr if I can do more tests, but medicine in Canada is socialized, and unless the Dr has a good reason he will not be allowed to do extra testing. I stopped doing the R-Lipoic acid once the blood sample was taken, and that was 3 weeks ago now, I am sleeping better but strength recovery is still far below where it should be. I am hoping that if the R-Lipoic acid levels decrease sleeping increased further and recovery time decreases, will see over the next few months.
Interesting! I've been taking 600mg/day of the Jarrow product for oh, must be 25+ years now. It's evidently racemic, since it doesn't say otherwise, and is 2/3 sustained-release. I haven't noticed any of the symptoms you mentioned, but I'll keep an eye out for them.
Very interesting, Chris. Thanks for this. I have been toying a bit with Dmitry Kats' protocol since I have long Covid from a delta infection in early January, and one thing I've noticed is significantly decreased muscle mass, exercise capacity, and even my skin is looking wrinkly and bad, all of which are unusual. I already dropped the niacin dosage significantly because I was already concerned about depleting methyl groups (I'm taking 50mg of nicotinic acid BID now) but I had no idea that the 600mg of Na-R-ALA that I've been taking was also likely depleting methyl groups! I am so glad that I read this because I'm going to switch gears and focus on increasing Methionine, Choline, TMG, Creatine, etc now, which feels like a much better tactic since the NA/ALA protocol is not helping my energy or exercise capacity! : )
According to this article food decreases absorption by 30%, why do you suggest spreading it with meals? Gleiter, C. H., Schug, B. S., Hermann, R., Elze, M., Blume, H. H., and Gundert-Remy, U. Influence of food intake on the bioavailability of thioctic acid enantiomers. Eur.J Clin Pharmacol. 1996;50(6):513-514
Very interesting! I'm thinking people have had SNPs that affect methylation for generations and lived very well, without consequences associated with poor methylation. Why it's such an issue now is heavy metals, including mercury, further impede the methylation cycle. The dithiol group is what chelates mercury. Given the difficulty in getting DMSA and DMPS as mercury chelators, could ALA be more beneficial to methylation in the long run as a mercury chelator?
Also, I'm reading Sean Carson's comment below and it seems he's taking the approach of supplementing at each step of the methylation cycle (methionine, TMG, creatine, etc.) to make sure all his bases are covered. What do you think of that approach?
That’s an interesting hypothesis, although I think there’s more to it. For example MTHFR might not be any lower in activity with ancestral riboflavin intakes. A lot of people who report sensitivities to vitamins and swings in methylation states have defects in glycine buffering likely driven by iron or vitamin A.
Methionine’s SH is covered by a methyl group so isn’t going to bind metals. But I do think metals will hurt energy metabolism and lower the ATP needed to activate methionine.
I don’t think he’s trying to hit each different point but rather use creatine to lower methyl demand and TMG to raise methyl supply, which is an approach that I believe I pioneered or at least popularized with my audience. It’s tailored for low methylfolate levels but would help deal with low SAM as well.
Very interesting and insightful article. You mention that one of the effects in the rat study was "The SAH in the plasma increased 10-20-fold" so it seems like impact on SAH was a much more pronounced effect than homocysteine. I was wondering whether you'd see this study (S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects https://pubmed.ncbi.nlm.nih.gov/35388610/ ...it was in Caenorhabditis elegans so very preliminary).
I give zero credence to C elegans longevity studies as the main way to lengthen its life is to put it into a state of dormancy, which has no relevance to humans at all, whose life will be lengthened primarily by preventing osteoporosis, diabetes, CVD, and cancer.
Methylation activates MTOR and I think it’s pretty well established that C elegans gets a longevity benefit from anything that is on the side of fasting state signaling, opposite to MTOR.
I am sure there are too many variables to consider this, but taken as a standalone supplementation issue, is there any factor, axiom or even a shaky suggestion as to what dose of TMG would be prophylaxis for methyl depletion/mg R-ALA?
This is an interesting aspect of ALA. How would you predict individuals with low homocysteine (range of 4-5) to react with ALA with partially impaired methylation (heterozygous 677T)? Any recommendations?
Interesting, thanks for posting this summary and review. Would be fascinating to hear a video/podcast conversation between you and Dr. Burt Berkson talking about ALA and how it functions, clinical use, etc. He has treated patients for years with it, conditions related to liver disease, cancer treatment, autoimmune, and some others, and he has some remarkable published case studies. I heard he advises b complex injections after ALA infusions due to it depleting their levels in some way, but I couldn’t find a citation for that claim to know the mechanism of how that happens.
Hopefully the complex includes good doses of methyl donors! He probably means by increasing utilization in energy metabolism but perhaps he is also referring to this dynamic.
So fascinating - thank you. I just listed to your podcast on niacin as well and deeply appreciate your insight on how these two supplements can have a huge negative impact on methylation.
You’re welcome and thank you for your appreciation!
Awesome info! Thank you for writing this article! What do you think about ALA as a heavy metal chelator?
It does chelate metals, but I'm not well versed in using it that way clinically so I'd prefer not to comment further on it.
I have been taking 480mg of R-Lipoic Acid (Life extension brand) daily for almost 8 years now, all at breakfast. I am always grumpy and my strength levels have not been improving in years. Last year, I fasted before my blood test and homocysteine was just over 9 (so that would be the leftover from the day before). After reading your article, I asked my doc if I could test your hypothesis and he said yes, so I fasted except I took the 480mg of R-Liopic acid 1 hour and 5 mins before the blood test was drawn. I'll post here when I see the homocysteine results, but might be a few weeks.
Very interesting. For the best results you should do at least 3 tests with and 3 tests without in random order and run a t-test on them.
I got the results back. Homocysteine was 10.2. Up from 9.6 the year before; and the year before the blood test was 24 hours after taking the dose. So my best guess is that the blood levels stay elevated for more than a day after taking the stuff. The only other anomaly I noted was Alanine Aminotransferase (ALT) was 34 last year, and this year 1 hour after taking the R-Lipoic acid ALT was up to 78, and flagged as being high.
I will ask the Dr if I can do more tests, but medicine in Canada is socialized, and unless the Dr has a good reason he will not be allowed to do extra testing. I stopped doing the R-Lipoic acid once the blood sample was taken, and that was 3 weeks ago now, I am sleeping better but strength recovery is still far below where it should be. I am hoping that if the R-Lipoic acid levels decrease sleeping increased further and recovery time decreases, will see over the next few months.
Interesting! I've been taking 600mg/day of the Jarrow product for oh, must be 25+ years now. It's evidently racemic, since it doesn't say otherwise, and is 2/3 sustained-release. I haven't noticed any of the symptoms you mentioned, but I'll keep an eye out for them.
Very interesting, Chris. Thanks for this. I have been toying a bit with Dmitry Kats' protocol since I have long Covid from a delta infection in early January, and one thing I've noticed is significantly decreased muscle mass, exercise capacity, and even my skin is looking wrinkly and bad, all of which are unusual. I already dropped the niacin dosage significantly because I was already concerned about depleting methyl groups (I'm taking 50mg of nicotinic acid BID now) but I had no idea that the 600mg of Na-R-ALA that I've been taking was also likely depleting methyl groups! I am so glad that I read this because I'm going to switch gears and focus on increasing Methionine, Choline, TMG, Creatine, etc now, which feels like a much better tactic since the NA/ALA protocol is not helping my energy or exercise capacity! : )
Sorry to hear your struggling, but that’s very interesting how it lines up with what I wrote here!
I used to measure the ratio between SAH and SAM...in mice livers. Now I am an out of work molecular biologist. Good article!
Would MSM help?
I wouldn’t expect it to, or at least it wouldn’t be very well targeted toward helping.
According to this article food decreases absorption by 30%, why do you suggest spreading it with meals? Gleiter, C. H., Schug, B. S., Hermann, R., Elze, M., Blume, H. H., and Gundert-Remy, U. Influence of food intake on the bioavailability of thioctic acid enantiomers. Eur.J Clin Pharmacol. 1996;50(6):513-514
Reducing the amount methylated and lost.
Very interesting! I'm thinking people have had SNPs that affect methylation for generations and lived very well, without consequences associated with poor methylation. Why it's such an issue now is heavy metals, including mercury, further impede the methylation cycle. The dithiol group is what chelates mercury. Given the difficulty in getting DMSA and DMPS as mercury chelators, could ALA be more beneficial to methylation in the long run as a mercury chelator?
Also, I'm reading Sean Carson's comment below and it seems he's taking the approach of supplementing at each step of the methylation cycle (methionine, TMG, creatine, etc.) to make sure all his bases are covered. What do you think of that approach?
That’s an interesting hypothesis, although I think there’s more to it. For example MTHFR might not be any lower in activity with ancestral riboflavin intakes. A lot of people who report sensitivities to vitamins and swings in methylation states have defects in glycine buffering likely driven by iron or vitamin A.
Methionine’s SH is covered by a methyl group so isn’t going to bind metals. But I do think metals will hurt energy metabolism and lower the ATP needed to activate methionine.
I don’t think he’s trying to hit each different point but rather use creatine to lower methyl demand and TMG to raise methyl supply, which is an approach that I believe I pioneered or at least popularized with my audience. It’s tailored for low methylfolate levels but would help deal with low SAM as well.
Very interesting and insightful article. You mention that one of the effects in the rat study was "The SAH in the plasma increased 10-20-fold" so it seems like impact on SAH was a much more pronounced effect than homocysteine. I was wondering whether you'd see this study (S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects https://pubmed.ncbi.nlm.nih.gov/35388610/ ...it was in Caenorhabditis elegans so very preliminary).
I give zero credence to C elegans longevity studies as the main way to lengthen its life is to put it into a state of dormancy, which has no relevance to humans at all, whose life will be lengthened primarily by preventing osteoporosis, diabetes, CVD, and cancer.
Methylation activates MTOR and I think it’s pretty well established that C elegans gets a longevity benefit from anything that is on the side of fasting state signaling, opposite to MTOR.
Thank you for taking the time to explain your thoughts.
I am sure there are too many variables to consider this, but taken as a standalone supplementation issue, is there any factor, axiom or even a shaky suggestion as to what dose of TMG would be prophylaxis for methyl depletion/mg R-ALA?
Also see footnote 2.
I directly addressed this in the article.
Yes you do! Sorry, I see you do suggests a 1:1 for Alpha Lipoic and TMG.
MTHFR imo is the body trying to unmethylate and block B6 pyroxidine which is rocket fuel for leukemia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389897/
So maybe alpha lipoic acid can help block B6 or stub leukemia?
Yes kinda:
https://pubmed.ncbi.nlm.nih.gov/27461609/
I don’t understand your first comment at all.
This is an interesting aspect of ALA. How would you predict individuals with low homocysteine (range of 4-5) to react with ALA with partially impaired methylation (heterozygous 677T)? Any recommendations?
I’d want to see the rest of the methylation data to see why homocysteine is low. Genova Methylation Panel is good.