In How Energy Deficiency Hurts Methylation, I covered the ways that low ATP and a low NAD+/NADH ratio will sap your methylation, and the patterns to look for on a Genova Methylation Panel to verify this is happening.
Fascinating post. Appreciate brushing back up on this topic - I'd forgotten how supplementing with creatine and sunflower lecithin can ease the methylation demand in our body and allow SAM to be used for other purposes. Interesting to hear about the need to transport SAM into the mitochondria and how important methylation is to the production of all mitochondrial proteins that are synthesized within the mitochondria. Also fascinating that all of complex ii is synthesized by the nuclear genome. Thanks very much as always!
I've actually started the base methylation protocol last week and two very interesting things happened:
1. My sleep has instantly improved by an incredible degree. No night wake ups, feeling good sleepiness, remembering lots of dreams suddenly, and not awaking up in the morning feeling like i have been run over by a car. (Note: my sleep improved with glycine alone in the past but never this much and it become worse after a few days so i stopped)
2. I became absolutely massively depressed within a day. Zero motivation, no energy, instantly overwhelmed by everything, high anxiety/irritability, and everything feels wrong. The worse i've had it in a long time.
So i was taking 2 x 500mg TMG, around 3-5g of creatine, 2x 200mg of Magnesium Glycinate, 100mg of b2 (since it is lowest capsule, but also tried swapping with 25mg riboflavin 5 phosphate and couldn't tell a difference), and 2 x 400mcg of methylfolate L-5-MTHF/DFE.
I then saw tweets by Dr Walsh (and a few mentions on reddit) that methylfolate increases the serotonin reuptake transporter, which for people with low serotonin could perhaps cause/increase depressive symptoms.
Yesterday i removed the folate from the protocol and today i feel significantly better, but my sleep last night was not as good.
Chris, I'm curious if this explanation tracks for you or if you think there is another reason for the sudden sharp depressive symptoms. And if it is the folate (for SERT expression reasons or other), what would be an alternative if any, or how should the protocol change to accommodate? Would just glycine, b2, tmg, and creatine be work fine without the folate? Any insights in general would be appreciated.
I’ll change the protocol to a layering strategy. I think putting in 5 things at once is a bad idea for this reason, it’s impossible to know which thing is doing what. Simplest explanation is it’s a temporary sharp increase in methyl groups lowering dopamine.
Here's some things that worked for me that you could give a shot:
1. Your methylfolate dose is pretty high. I went very slowly - week 1 was 50mcg/day, week 2 was 2x 50mcg/day, week 3 was 3 x 50mcg/day. I'm now taking 2 x 200mcg. There's a couple supplements out there that are drops instead of capsules to help with this dosing. This potentially is needed to give your methylation system and neurotransmitters a chance to adjust (or some other mechanism).
2. Make sure your diet is dialed in to address all of the other nutrients involved in methylation (lots of veggies and fruits, superfoods such as eggs, oysters, and liver). Personally, no methylation protocol worked for me until I was eating oysters and liver specifically (possibly copper, zinc, or retinol deficient).
3. I also use a bit of B12.
Finally, I find taking too much riboflavin causes fatigue and depression symptoms, but I think this may be connected to another genetic impairment for me and unrelated to methylation. I personally don't take any riboflavin and just make sure I'm getting enough from diet.
1-Chris, the paper you cite describes what I might characterize inelegantly as "serious mutations" in the gene that codes for the SLC25A6 transport protein. These mutations led to very sad outcomes at early ages.
Might lesser problems, SNPs, in the gene lead to a more subtle but meaningful impact in the form of impaired energy metabolism even in the context of adequate SAM production?
2-"The key sign that you need to optimize your energy metabolism is that you aren’t dead yet." !!!!!
Hi Chris, you site here SLC25A6 deficiency for SAM transporter disfunctions. How about SLC19A1 (+/-), that shows in your choline calculator, would that also have the same effect?
I was thinking along the same lines. However the paper that Chris cites doesn't refer to SNPs in the gene. Rather it is describing what I guess what would be called "mutations." ( I am not up on the lingo.)
I asked elsewhere about the implications of SNPs in the gene. By looking through an analysis of my whole genome sequencing I have a heterozygous SNP at rs7205. I am pretty sure a gene analysis short of whole genome sequencing won't reflect this particular SNP.
Thank you, Bennett, for sharing your insight and results. I looked at my same rs7205 and I have homozygous GG. Does this presumeably means that I have reduced enzyme activity? in other words I wonder, do I benefit from adding methyl donors in my supplement regimee…? ( I`ve been testing adding 1000 mg of folate to the basic methylation protocol and the change in my mood and wellbeing has been very positive).
According to the below "GG" is in fact the common or wild base pair at that location. (My result for that is GA). The implication is that your SLC25A6 activity is not impaired.
thank you, Bennett! I appreciate it a lot that you shared the data with me. this was positive and encouraging news for me. this also gave me more insight to better interpret the snp's in my database. I would be interested to hear if you somehow take your spn into account in your supplimentregimee?
There is in fact a supplement "SpectrumNeeds" that is marketed for people with autism spectrum disorders. It includes CoQ10 and Creatine (and tons of other good things). It is a powder and the dose (3 "scoops" twice a day) for someone over 130lbs would include about 375mg of CoQ10 and 1.9 grams of creatine. Probably not enough creatine. Here is the product: https://www.ourkidsasd.com/products/spectrumneeds-powder
I feel the same way generally but just today I saw a video describing a study concerning the positive impact of multivitamins on cognition. Here it is if you are interested... https://www.youtube.com/watch?v=rSuog4QsJrM
How do people generally get the blood sample for this test? If I try to get my dr to order it I feel I'm going to get major brush off, but I don't know how to independently get phlebotomy?
Thanks for the reply. I have the mthfr C677T. I had gotten my homocysteine down to a decent level but it has gone up recently. I have been taking niacin to reduce cholesterol but the homocysteine has gone up again even though I am taking betaine. Should I stop niacin? Also my liver enzymes are up which probably is from the niacin also. Any recommendations?
My SAM is low, SAH high, high taurine and choline, and glutathione tanked. I’ve had dizziness and awful anxiety for 3 years. Hoping to figure my issues. Some say chronic hidden infections such as strep, Lyme can impair methylation. I was also told the antibiotics for Lyme could have made my methylation symptoms even worse. Hopefully I will find the solution soon
I’m sorry if I should not ask this here, but I can’t get an answer from emailing or your site. I have filled out the application for a consult with you and I never heard back. I’ve tried emailing several times but no reply. Can you tell me how to do that? I had one with you and when I tried to get another I couldn’t. Thanks!
Fascinating post. Appreciate brushing back up on this topic - I'd forgotten how supplementing with creatine and sunflower lecithin can ease the methylation demand in our body and allow SAM to be used for other purposes. Interesting to hear about the need to transport SAM into the mitochondria and how important methylation is to the production of all mitochondrial proteins that are synthesized within the mitochondria. Also fascinating that all of complex ii is synthesized by the nuclear genome. Thanks very much as always!
I've actually started the base methylation protocol last week and two very interesting things happened:
1. My sleep has instantly improved by an incredible degree. No night wake ups, feeling good sleepiness, remembering lots of dreams suddenly, and not awaking up in the morning feeling like i have been run over by a car. (Note: my sleep improved with glycine alone in the past but never this much and it become worse after a few days so i stopped)
2. I became absolutely massively depressed within a day. Zero motivation, no energy, instantly overwhelmed by everything, high anxiety/irritability, and everything feels wrong. The worse i've had it in a long time.
So i was taking 2 x 500mg TMG, around 3-5g of creatine, 2x 200mg of Magnesium Glycinate, 100mg of b2 (since it is lowest capsule, but also tried swapping with 25mg riboflavin 5 phosphate and couldn't tell a difference), and 2 x 400mcg of methylfolate L-5-MTHF/DFE.
I then saw tweets by Dr Walsh (and a few mentions on reddit) that methylfolate increases the serotonin reuptake transporter, which for people with low serotonin could perhaps cause/increase depressive symptoms.
Yesterday i removed the folate from the protocol and today i feel significantly better, but my sleep last night was not as good.
Chris, I'm curious if this explanation tracks for you or if you think there is another reason for the sudden sharp depressive symptoms. And if it is the folate (for SERT expression reasons or other), what would be an alternative if any, or how should the protocol change to accommodate? Would just glycine, b2, tmg, and creatine be work fine without the folate? Any insights in general would be appreciated.
I’ll change the protocol to a layering strategy. I think putting in 5 things at once is a bad idea for this reason, it’s impossible to know which thing is doing what. Simplest explanation is it’s a temporary sharp increase in methyl groups lowering dopamine.
Here's some things that worked for me that you could give a shot:
1. Your methylfolate dose is pretty high. I went very slowly - week 1 was 50mcg/day, week 2 was 2x 50mcg/day, week 3 was 3 x 50mcg/day. I'm now taking 2 x 200mcg. There's a couple supplements out there that are drops instead of capsules to help with this dosing. This potentially is needed to give your methylation system and neurotransmitters a chance to adjust (or some other mechanism).
2. Make sure your diet is dialed in to address all of the other nutrients involved in methylation (lots of veggies and fruits, superfoods such as eggs, oysters, and liver). Personally, no methylation protocol worked for me until I was eating oysters and liver specifically (possibly copper, zinc, or retinol deficient).
3. I also use a bit of B12.
Finally, I find taking too much riboflavin causes fatigue and depression symptoms, but I think this may be connected to another genetic impairment for me and unrelated to methylation. I personally don't take any riboflavin and just make sure I'm getting enough from diet.
An idea would be to try folinic acid instead of the methylfolate.
1-Chris, the paper you cite describes what I might characterize inelegantly as "serious mutations" in the gene that codes for the SLC25A6 transport protein. These mutations led to very sad outcomes at early ages.
Might lesser problems, SNPs, in the gene lead to a more subtle but meaningful impact in the form of impaired energy metabolism even in the context of adequate SAM production?
2-"The key sign that you need to optimize your energy metabolism is that you aren’t dead yet." !!!!!
Hi Chris, you site here SLC25A6 deficiency for SAM transporter disfunctions. How about SLC19A1 (+/-), that shows in your choline calculator, would that also have the same effect?
That’s a folate transporter.
What snps in SLC25A6 should be paid attention? I’ve signed in SelfDecode and it shows quite a lot snps related to SLC25A6.
I was thinking along the same lines. However the paper that Chris cites doesn't refer to SNPs in the gene. Rather it is describing what I guess what would be called "mutations." ( I am not up on the lingo.)
I asked elsewhere about the implications of SNPs in the gene. By looking through an analysis of my whole genome sequencing I have a heterozygous SNP at rs7205. I am pretty sure a gene analysis short of whole genome sequencing won't reflect this particular SNP.
Thank you, Bennett, for sharing your insight and results. I looked at my same rs7205 and I have homozygous GG. Does this presumeably means that I have reduced enzyme activity? in other words I wonder, do I benefit from adding methyl donors in my supplement regimee…? ( I`ve been testing adding 1000 mg of folate to the basic methylation protocol and the change in my mood and wellbeing has been very positive).
According to the below "GG" is in fact the common or wild base pair at that location. (My result for that is GA). The implication is that your SLC25A6 activity is not impaired.
https://www.ncbi.nlm.nih.gov/snp/rs7205
thank you, Bennett! I appreciate it a lot that you shared the data with me. this was positive and encouraging news for me. this also gave me more insight to better interpret the snp's in my database. I would be interested to hear if you somehow take your spn into account in your supplimentregimee?
You are welcome! This genetics stuff is complicated. So far I haven't learned if my SNP is actionable so... not yet.
maybe you should market a CoQ10 + Creatine combo
There is in fact a supplement "SpectrumNeeds" that is marketed for people with autism spectrum disorders. It includes CoQ10 and Creatine (and tons of other good things). It is a powder and the dose (3 "scoops" twice a day) for someone over 130lbs would include about 375mg of CoQ10 and 1.9 grams of creatine. Probably not enough creatine. Here is the product: https://www.ourkidsasd.com/products/spectrumneeds-powder
thanks
not a fan of these throw everythng but hte kitchen sink supps
I feel the same way generally but just today I saw a video describing a study concerning the positive impact of multivitamins on cognition. Here it is if you are interested... https://www.youtube.com/watch?v=rSuog4QsJrM
How do people generally get the blood sample for this test? If I try to get my dr to order it I feel I'm going to get major brush off, but I don't know how to independently get phlebotomy?
Look for a local phlebotomist who deals with functional medicine doctors.
Hello, Does nicotine acid raise homocysteine levels?
Probably.
Thanks for the reply. I have the mthfr C677T. I had gotten my homocysteine down to a decent level but it has gone up recently. I have been taking niacin to reduce cholesterol but the homocysteine has gone up again even though I am taking betaine. Should I stop niacin? Also my liver enzymes are up which probably is from the niacin also. Any recommendations?
Ditch the niacin.
Thanks. That is what I was thinking. I am going to add sunflower lecithin to my diet for the choline and the cholesterol lowering effects instead.
My SAM is low, SAH high, high taurine and choline, and glutathione tanked. I’ve had dizziness and awful anxiety for 3 years. Hoping to figure my issues. Some say chronic hidden infections such as strep, Lyme can impair methylation. I was also told the antibiotics for Lyme could have made my methylation symptoms even worse. Hopefully I will find the solution soon
I’m sorry if I should not ask this here, but I can’t get an answer from emailing or your site. I have filled out the application for a consult with you and I never heard back. I’ve tried emailing several times but no reply. Can you tell me how to do that? I had one with you and when I tried to get another I couldn’t. Thanks!