In preparing for the Anxiety Summit I put out a call for questions for my methylfolate interview with Dr. Ben Lynch: How Methylfolate can make you Feel Worse and even Cause Anxiety, and What to do about it This question was posted on my blog and since it’s a big topic I feel it deserves a separate blog post
This is the question that Paula posted:
If my understanding is correct, William Walsh of the Walsh Research Institute explains that folates of any kind (methylfolate, folic acid, etc) will cause there to be less serotonin activity at the synapse because folates promote the expression of the SERT enzyme which increases serotonin reuptake. He warns that those who are undermethylators should not take folate if they have cognitive/mood issues, as it will make their anxiety or depression worse. Since those with the MTHFR gene defect are likely undermethylators, his advice contradicts Dr Lynch’s advice regarding the use of folate. Could you ask Dr Lynch if he has any opinion regarding this?
Dr. Walsh has treated over 30,000 patients with mental health problems and has one of the largest lab chemistry data bases in the world. It would be great to see the top doctors collaborating on the methylation cycle as it seems to be a large piece of the puzzle for so many people. Maybe a methylation summit? It’s such a complicated and confusing subject and there seems to be some contradictory information out there.
This was my response:
These are excellent questions you bring up!
The terminology can be confusing so I will recap my understanding here:
Undermethylators/high histamine/histadelia = folate not good
Overmethylators or low folate/low histamine/histapenia = folate helps symptoms
This is from the work of Carl Pfeiffer (his book “Nutrition and Mental Illness” is excellent) and is also written about in Joan Matthews Larson’s wonderful book “Depression-Free Naturally” and Eva Edelman’s “Natural Healing for Schizophrenia.”
As you’re aware Dr. Walsh uses this terminology too. His book is “Nutrient Power.” Here is a snippet from a powerpoint of his called The Role of Epigenetics in Mental Health
Undermethylated mental patients are intolerant to folic acid, but most overmethylated mental patients improve after folic acid supplements.
Folic Acid generates acetylase enzymes that alter histones, promoting expression of SERT and DAT transporter proteins. SERT and DAT enhance reuptake at serotonin and dopamine synapses…. thus reducing NT activity.
For undermethylators, the harmful impact of folic acid at NT synapses greatly exceeds the benefits of normalizing methylation.
So there is a place for methylfolate. I don’t know anything about SERT and DAT transporter proteins so can’t comment on that aspect, but look forward to learning more.
You say “Since those with the MTHFR gene defect are likely undermethylators.” I don’t know that this is a true statement. I would love to see a source for this? It’s certainly not the case with me – I have the MTHFR 1298C defect and have low histamine/histapenia/overmethylation (using the Carl Pfeiffer terminology).
As far as I’m aware Dr Walsh does NOT feel the MTHFR defects play a role in all of this. I hope to learn more and interview him on a future Anxiety Summit.
I have not seen Dr. Lynch write about histapenia and histadelia or the work of Carl Pfeiffer, although some recent comments in this blog refer to Walsh and Dr. Lynch says he’ll check it out.
Dr. Lynch is not a big fan of the terms overmethylation and undermethylation. And when he talks about overmethylation and undermethylation I think he is referring to the methylation process being more effective/speeding up and being less effective/slowing down within a few days of adding methylfolate supplements.
So I feel we have some terminology differences AND some differences of opinions.
Both Dr. Walsh and Dr. Lynch see amazing results with their patients/clients but I agree with you – I’d love to clear up some of the confusion. I’m going send this question and my answer to Dr. Lynch for our interview next Friday. Since he may need to do some additional prep/research, we may have to do a deeper dive into this question on a future summit. Hopefully he’ll be able to add something to the discussion this time.
I did also interview Yamsina (www.thelowhistaminechef.com) for this summit and she too was not familiar with the work of Carl Pfeiffer so it’s exciting that we can all learn from each other and advance the field.
Finally, this is not all bad because it gets us thinking and asking questions and digging deeper.
Paula then has this follow-up question:
The following quote from this link gave me the impression that the MTHFR mutation usually caused undermethylation, but farther down it also references where Dr Walsh says it’s possible to have MTHFR and not be undermethylated.
In your opinion, do people fall into either an overmethylated or undermethylated status or can you be an undermethylator in certain areas of the methylation cycle and an overmethylator in other areas of the cycle? If someone has some traits of an undermethylator and some traits of an overmethylator, what would you recommend?
Dr. Walsh: Based on my massive chemistry database, about 22% of the population is undermethylated and 8% overmethylated. These are inborn tendencies that usually persist throughout life. Undermethylation usually results from single nucleotide polymorphisms (SNPs) that weaken MTHFR or other enzymes in the methylation cycle. Overmethylation is generally caused by enzyme weaknesses (SNPs) in the SAMe utilization pathways.
What are your thoughts on using genetic testing, such as “23 and Me” to create an individual methylation roadmap/treatment plan.
Dr. Walsh: Genetic testing is quite inexpensive, highly accurate, reliable, and will certainly grow in importance in future years. These tests can already identify predispositions for many disorders such as breast cancer and Alzheimer’s and may soon obsolete the need for pap smears. However the reliability of genetic testing for assessing methylation is quite limited at present.
Identifying SNP weaknesses in MTHFR and other methylation-cycle enzymes does not necessarily mean that individual is undermethylated. There is a “tug-of-war” competition between enzyme SNPs that weaken methylation and SNPs in the SAMe utilization pathway that can produce overmethylation.
I believe you’re right Trudy in saying this is not all bad because it gets everyone thinking and digging deeper. I think both Dr Lynch and Dr Walsh bring invaluable information to the discussion, each adding something that can further illuminate how this complicated process works. Thanks again to you for providing us an opportunity to ask questions.
And this is my response:
This is a perfect summary of Dr Walsh’s approach – thank you!
This part is interesting: “Undermethylation usually results from single nucleotide polymorphisms (SNPs) that weaken MTHFR or other enzymes in the methylation cycle. Overmethylation is generally caused by enzyme weaknesses (SNPs) in the SAMe utilization pathways.” I’d love to know which ones… and then he says “However the reliability of genetic testing for assessing methylation is quite limited at present”
His percentages are also interesting and I would challenge this saying it’s very likely based on the people he has worked with: 22% of the population is undermethylated (high histamine) and 8% overmethylated (low histamine).
When I worked with Julia Ross we saw way more low histamine and that is likely because we worked with more women who seem to be prone to low histamine.
This is also what Carl Pfeiffer found: “These are inborn tendencies that usually persist throughout life” and was my understanding until I started learning from Dr Lynch 2 years ago. Now I’m confused too!
Here is a nice post by Chris Kresser: Methylation – What it is and why should you care. I’m going to paraphrase some of it. He says yes do the 23and me testing but: “genetics do not always predict functional methylation capacity”…”I really believe that we need to be testing both”… “There are different ways to test functional methylation capacity. Doctor’s Data has a methylation panel blood test. Health Diagnostics and Research Institute has a Methylation Pathways Panel that’s good and I tend to use in my practice. Genova has a Complete Hormones profile that, among other things, looks at the ability to convert proliferative estrogen metabolites into less proliferative metabolites, and those conversions are methylation dependent. So if you see poor conversion happening there, that’s a methylation issue. The urine organics acids profile from Genova has some methylation markers, active folate and B12 deficiency. And then a urine amino acids profile can be helpful to look at taurine levels and levels of other metabolites in the methylation cycle.”
This above blog has comments about Dr. Walsh and Dr. Lynch too so they are worth a read.
Of course Dr. Lynch supports the fact that just because you have a defect it doesn’t mean you are affected by it so the additional functional testing makes total sense. And he recommends this additional testing too.
I feel it’s time to mesh the old research and prior work Carl Pfeiffer did, the work Dr. Walsh is doing, Dr. Lynch’s work and the new methylation research. And the wisdom from other practitioners like Chris Kresser and people like you who are digging and reading and asking questions
We clearly all have lots to learn! I know I don’t have the answers! This topic has been front and center in my mind for awhile so it’s good to get it down in writing here (so thanks Paula, for asking this question!)
I encourage you to listen in to my interview with Dr. Lynch. We talk about this and acknowledge that we all have gaps and that getting together to talk about all this would be an excellent idea!
And finally, please share if you have had your histamine levels tested (whole blood histamine)? Low or high? and have you found results with the Pfeiffer protocol?
I have tested mine and have low histamine/histapenia and absolutely do benefit from the low histamine protocol.