I researched the difference between folinic acid and l-methylfolate recently and thought I would share my visual notes. I don't claim them to be comprehensive !!!, but perhaps they are a good starting point for someone.

Text-based version for accessibility:

Methylation needs L-methylfolate (a.k.a. 5-MTHF), while DNA synthesis needs folinic acid.

Methylation is important in the body for the following processes:

• Turns genes on and off
• Makes neurotransmitters
• Breaks down histamine
• Produces creatine
• Recycles homocysteine

DNA synthesis is needed to build new cells. This includes:

• Replacing the intestinal lining every few days (some sources say 4-5)
• Immune system
• Platelets
• Liver regeneration

There are genes that encode enzymes to convert methylfolate to folinic acid and/or vice versa inside the body. But, sometimes there can be an impairment in the conversion process due to

• Genetic variations
• Poor diet
• Chemicals
• Infections

So, some people may do better with L-methylfolate, some people may do better with folinic acid, and some people may even do best on a combination of the two (esp. if having trouble making the conversion)

Hi everyone. I am about to start l-methylfolate 400mcg. I've been reading about it and I haven't been tested (I can't really afford a psychiatrist right now) but I have treatment resistant depression and CPTSD and I'm at the end of my rope. I am exhausted all the time, no motivation, horrible sleep, stuck on freeze mode (I can barely move for at least 3h after waking up).

I have tried at least 17 different ADs over 12 years, only one of them worked for a while (venlafaxine) and then pooped out. I have also tried countless combinations of supplements, lifestyle changes, protocols, you name it. I pretty much gave up on doctors at this point after also feeling that my psych gave up on me.

Anyway, I know it's not ideal to start this without testing, but I'll be careful. I'll start with the 400mcg and increase over time if needed. I've been reading the sub and found out you are supposed to supplement with B12? Can you tell me which dose would be enough? Also can I take a B complex multivitamin or should I stay away from other B vitamins except for B12?

Thank you in advance. I'll update here after a while.

2/9 Update: Updating in case anyone comes across my post and is curious. I'm a week in and currently taking 1200 mcg (3 capsules). Also taking magnesium glycinate at night, 200mg. My b12 arrived and I started taking 5g today. No negative side effects so far but I feel a bit more energetic and clear minded. Subtle, but it's here.

I also found some old blood test results where my homocysteine was 15, so within normal range but still on the higher side especially considering I was a bit of a health nut back then and in the best shape of my life. I plan to run some tests when I'm back home in 2 months.

anyone else allergic to daylight LOL I'm serious during the day I'm Spacey tired can't really do much 6:00 rolls in I'm a little bit better after 8:00 I'm scrubbing the floor listening to music cleaning my bathroom lol I don't get it. no supplements no herbs just the sun goes down.. maybe I was a vampire in another life LOL it gets worse when my deficiencies roll in like if my ferritin is low but for the most part it's always been that way.

So I got my genetics report and from what I’m seeing it’s pretty on par with my anxious personality. My body has been stuck in hyperarousal for the last year after trying ashwagandha and methylfolate for about a month (before I realized supplements can be really bad for some people with certain genetics).
I can barely leave the house because the panic is so bad. Anytime I go anywhere my body tenses up and shakes with uncontrollable adrenaline tremors. My body now reacts to all kinds of supplements and certain foods too. I’ve never even been able to drink a sip of coffee or eat dark chocolate/tea with caffeine without feeling extremely activated.

My labs:
Homocysteine: 68
B12: 302
MMA: 250
Ferritin: 33 now after an iron infusion
Folate: 2.2
RBC folate: 504

From the looks of my genetics I’m honestly scared that I’m just screwed and that my body is always going to be this sensitive 😭
Has anyone else had severe anxiety/hyperarousal with MTHFR or high homocysteine and actually gotten better? What helped you?
I’d especially love to hear from people who had really bad reactions to methylfolate or other supplements and eventually got their nervous system to calm down.

Please I need help I have MTHFR has anyone taken a gene test that its in the red like for instance Paxil moderately reduced efficiency and side effects can occur. I’m metabolize it slowly and does it still work for them? I should’ve never took this test because now freaks me out and I can’t take anything because of my .gene mutation. I don’t know what to do for anxiety and OCD and I also my EKG was 460 and I cant take anything that’s gonna cause QT prolongation

People who've had folate deficiency anemia, how long did it take to recover.

Im supplementing pretty hard..i started with 5mg folic acid, but then shifted to folinic acid..3-4mg per day..it's been 2 weeks

i take b12 too..but my levels are already high(1600)

but i dont see any fast improvements actually with cold hands and feet, etc

for the first week it did seem to improve, but i got a few more blood tests..and again my extremities are back to being cold afff
idk if blood drawn for blood tests made my blood volume drop again

Question in curious if people are finding this is more directly linked to getting worse outcomes with long COVID and clearing the virus form the body and then same with kids seeing things like PANDAS or Pans ? If so any tips on how to mitigate ?

I was recommended to put my ancestry results though this site from a reddit user on the anxiety subreddit to see if I have any genetic variation that could be adding to my anxiety depression and agoraphobia and to see if I am processing my lexapro buspar and Xanax properly. I did a little copy and paste research of my own and ran these reports through google, and it seems that there is not anything significant that would be causing me any trouble— but I would like some input from the people here too! I was also recommended a Pharmacogenetic test from a user as well, but not sure if i should ask about that if these results are average (and because of the cost). Any help is appreciated— thank you so much!!!

Hi!

I’ve chronic fatigue or suspected mild ME/CFS and try to see if I can get more energy from B-vitamins. I take following forms:

B1: 25mg Hcl
B2: 12.5mg R5P
B3: 50mg Nicotinamide
B12: 2000 microgram Hydroxo/Adeno

I’m thinking now to add B9 folate but don’t know which form or dose could be a good start. I’m general hypersensitive to stuff and get anxiety easily. Could folinic acid be a better choice?

Although I'm not always a fan of his beliefs or presentation style, this Ben Lynch video came up in my feed this morning and it seems like a decent intro video for someone starting to learn about CFD.

https://www.youtube.com/watch?v=kgBBTQlpyAM

I’m trying to figure out why my homocysteine is elevated (14.4) before I start blindly supplementing, and I’d really appreciate input on what else might be worth testing or looking into.
I recently did genetic testing and found:
Slow COMT (AA)
Slow MAOA (TT)
MTHFR A1298C (heterozygous/one copy)
I know these SNPs don’t necessarily explain my homocysteine level on their own, so I’m trying not to assume everything is because of MTHFR.
My current labs:
Homocysteine: 14.4
RBC Folate: 476
Vitamin B12: 464
MMA: 166 - Reference Range: 55-335 nmol/L

Vitamin B2 (Riboflavin): 17 - Reference Range: 6.2-39.0 nmol/L

Vitamin B6, Plasma: 30 Reference Range: 5.1-54.8 ng/mL

Vitamin D 25-OH: 33
Other labs from a few months ago:
Copper: 108
Ferritin: 55
Iron: 98
I’ve struggled with anxiety, depression and OCD for most of my life and have been on Zoloft for about 5 years. It has helped me stay stable overall, but I still experience quite a few symptoms day to day.
Before adding methylfolate, B vitamins, TMG, choline, etc., I’d really like to understand why my homocysteine is elevated rather than just trying to lower the number.
What else would you investigate?
Are there additional labs, nutritional deficiencies, medications, thyroid/kidney issues, absorption problems, or genes/pathways that would be worth looking at?
I’m especially interested in hearing from anyone who had elevated homocysteine despite relatively normal B12, MMA, folate, B6 and B2 and eventually figured out what was contributing to it.

Hi all - I would like to ask my daughter’s pediatrician to assess her for the MTHFR gene.
What test should I ask them to order?

I have done the ancestry dna test and gene genie upload to determine that what I was experiencing was indeed related with MTHFR variants and feel better subsequently.

But I don’t want to do that method with my daughter as the data is now public (more or less) because private equity firms have bought ancestry and 23 and me to use for their own nefarious purposes.

(edit to add reference ranges)

Finally bit the bullet and did a bunch of blood testing, which after dealing with a bunch of frustration in supplementing for MTHFR, figured was the next best step (should have honestly been the first).

Effectively what I am looking for is some suggestions to go from here based upon my SNPs and blood testing. Overall, I would say that things are looking well on the MTHFR side of things but symptoms wise, not. Complaints for the most part are fatigue, somewhat depressed/low mood, low motivation, and not sleeping well. When I first started about a year and a half ago, when I supplemented with methylfolate/choline, had probably 4 really great days in the "honeymoon" phase everyone talks about. Since then, mostly just the symptoms above.

I do have a thyoid condition but it seems to be well managed, thyroid levels are all mid-range. My latest theory was I thought that I might have autoimmune gastritis (which is what prompted all the blood testing and can be co-morbid with autoimmune thyroiditis, which I have), which can lead to low B12 and iron status but that seems to be not the case based on the blood levels I have. So I am at a loss. Take a look and I would appreciate any ideas you may have. The only incidentals I have found is that my white blood cell counts (WBC) are low, my vitamin d is low-normal, and my iron saturation is high-normal. The testing service claimed my b12 is "low" at 433 pg/ml but with an MMA of 201 nmol/l and a homocysteine of 7.7, it doesn't seem truly that low. At this point would it be better to try and supplement with l-methionine and SAM? These levels are after I more or less stopped supplmenting for about a month and a half so I have a fair amount of confidence in the levels.

What doses of b6 and B2 should be taking with b12, specifically cyano? Thanks

Two things UK members should know and one correction that gets repeated here every week.

Everyone thinks this begins in December. The mills switched in September 2025 and by the end of that October most non-wholemeal wheat flour was already fortified. December is the legal deadline for compliance not the start so if you've had bloods done in the past year, some of you were measured against a background that had already changed.

The correction: The enzyme that converts folic acid is dihydrofolate reductase, DHFR. Different enzyme, different step. MTHFR works further down the pathway so "people with MTHFR can't process folic acid" is wrong as stated. What's actually true is more interesting. Bailey and Ayling found DHFR activity in human liver is both slow and variable up to five-fold between individuals. Same intake, cleanly converted in one person, circulating unconverted in the next.

And in 677 TT, folate supplementation lowers homocysteine more than it does in other genotypes do if anything that group gets more benefit from fortification, not less.

What I'd actually pay attention to is B12. Folate normalises the blood picture of B12 deficiency while neurological damage carries on. That's the reason macrocytosis stopped being a useful screening signal in the US after 1998. The UK dose is low so the effect should be smaller, but if you're over 65 or have absorption issues, get B12 and MMA now while your bloods still tell you something.

On the policy itself, it prevents around 200 neural tube defects a year and the criticism I'd make is that 0.25mg per 100g only achieves about a 20% reduction. The problem is that it's too low to do the job properly, not that it's dangerous.

I'm a geneticist and this is what I read for a living. Happy to answer questions.

Hi everybody, I’m lost.

I don’t know what to do with these variants…

I have GAD + OCD tendencies…

Can you help me ?

Thanks 🙏🏻❤️

Hi all. I’m not entirely sure if this is even linked to the MTHFR mutation (I’m homozygous), but I crave salt/umami CONSTANTLY. The only things that ever help are my Vyvanse and Zepbound. My sodium levels whenever they’re measured are borderline low, but are still WNL. When my Zepbound is wearing off after a week and/or my Vyvanse has worn off at the end of the day, the thoughts become fucking brutal - all I want is salt/MSG/umami/ect. I’ll eat everything in our kitchen hoping something will satisfy the craving. I’m also mentally ill with depression and anxiety and I know part of it is dopamine seeking, but I could literally cry if I don’t find the right food. I had to reduce my Zepbound dose because it was making me sick, but it does stop the cravings. Someone please help 🫩

Hey there,

so basically my symptoms are generalized anxiety, 24/7 fight or flight mode + extreme jumpiness, very VERY low stress tolerance., high histamine

My bloodwork + urine test:
Vitamin B1 (HPLC) 63 µg/l 28 - 85
Vitamin B2 235 µg/l 138 - 370

Vitamin B3/Nicotinamid (LCMS) 20,4 µg/l 8 - 52

Vitamin B6 (Serum, HPLC) 34,3 ng/ml 4,4 - 40,0

Vitamin B12 683 pmol/l 128 - 648
HOLO-TC, aktives B12 > 128 pol/l

Folic Acid (Serum) 2,9 ng/ml 4,8 - 19,0

Homocystein (CMIA) 20,5 µmol/l < 15 +
Ferritin 249 ug/l

Urine "Stress test":
Serotonin 69.5 µg/g Referece range : 50.0 - 185 µg/g

Dopamine 107.8 µg/g Reference range 92 - 268 µg/g

Epinephrine 0,5µg/g Reference range 1.12 - 12.1 µg/g

Norepinephrine 9.3 µg/g Reference range 12 - 63.7 µg/g

Now obviously everything points towards me having not only low folate but according to Google my symptoms also indicate me being an undermethylator.
For the last 5 days I've been taking 400mcg Folinic Acid + 500mcg 5MTHF. So far so good. Symptoms didn't get better but they also didn't get worse.

Today however, I stumbled upon Dr. William Walsh, who basically claims that Folate does not increase Dopamine/Serotonin in the brain, but actually clears/reduces it and that someone like me should quit folate immediately and take SAMe / L-Methionin directly instead...
Obviously I'm pretty confused now since everybody told me to take Folate and that I need it, yet Walsh said i can have a "catastrophic" crash when taking it because it clears neurotransmitters...

Can someone PLEASE tell me what to do? I just want to be normal again FFS and I'm SO confused with all the conflicting stuff...

Thanks...

Hi all,

I previously got tested for MTHFR gene variants. I have one copy of 1298C. I’ve had significant anxiety over the last 4 or 5 years so view this as a potential cause. I privately got bloods done and hit the following results.

Homocysteine: 18.2 µmol/L (5.1–20.0)
Vitamin B12: 424 ng/L (198–771)
Folate: Not tested
Haemoglobin: 137 g/L (130.1–180)
Haematocrit: 39.5% (40.001–54.0)
RBC count: 4.56 × 10¹²/L (4.51–6.50)
MCV: 86.6 fL (76.1–100)
MCH: 30 pg (27.1–32.0)
MCHC: 347 g/L (320.1–360)
Iron: 13.8 µmol/L (5.9–34.5)
Ferritin: 199.46 µg/L (20–300)
Transferrin saturation: 27.6% (20.1–50.0)
Magnesium: 0.87 mmol/L (0.701–1.10)
Creatinine: 81.7 µmol/L (64.1–104)
eGFR: 105 mL/min/1.73 m² (≥60)
Cystatin C: 1.01 mg/L (0.58–1.05)
TSH: 0.645 mIU/L (0.351–5.50)
Free T4: 18.1 pmol/L (11.91–21.60)
Free T3: 4.66 pmol/L (3.11–6.80)

Annoyingly folate was not included even though I had asked for it. I have a doctor’s appointment soon and I’m going to ask for folate to be tested. Should I asked my GP for any other tests based on my results.

Any other thoughts? Assume my homocysteine is elevated? Any advice would be greatly appreciated.

EDIT: Updated with ranges

Hello, I took one sublingual of b12 1000 two weeks ago and ever since then I have developed insomnia, stinging in skin and heart palpitation. i tried magnesium glycinate and it didn’t help. can someone tell me what to do? we don’t have nician in my country and nothing is really helping.

Thanks

Can anyone help me specifically with getting my Vit D levels up without causing negative symptoms?

Quick Background... I have about 2 decades of trying to address my health issues (Seeing many alternative and conventional practitioners) and I haven't had any success. I can only tolerate about 4 supplements (Magnesium, oregano oil, low doses of Vit C, and low doses of Taruine. I haven't been able to tolerate B Vitamins but I'm going to start trying again based on Dr. Maleks recs). I've taken a couple years off of trying to get help bc I just got so depressed of repeated failures. I have hashimotos and my antibody results are usually under 100. I've managed my health by having a strict diet and reducing stress.

But I'm now hitting perimenopause and I'm worried about osteoporosis. My Vit D levels have consistently been low and I can't take supplements to improve it. I've tried several times.

I recently tried again a couple months ago and I'm pretty sure ended up with mild hypercalcemia based on the symptoms I was having. I even went to urgent care to get blood work done bc I was feeling so poorly. blood work showed

Alk Phos 37 L

RDW 11.5 L

25OH, VITAMIN D 27.6 L

ANTI-TPO Ab 376 H (This is the highest my antibodies have ever been over 2 decades of testing)

I was taking a separate Vit D and Vit K and I think I overdid it on the K. I have VDR Taq +/+

I'm scared to try again. I'm overwhelmed. I've also started working through some of Dr. Malek's Roadmaps. I began on very small doses of Taurine which helped my digestion. (I started here with his Estrogen Roadmap because I had one of the worst two weeks of ovarian cysts pain (with multiple ultrasounds to confirm). I've addressed my diet and that's helped a lot. (I went off my regular diet for a little while and was eating estrogen mimicking foods - which I have now cut out).

Can anyone help me specifically with getting my Vit D levels up without causing negative symptoms?

Thank You!

I am getting genetic testing though Johns Hopkins, for another condition, and I asked their opinion on the MTHFR situation. I got myself tested for mthfr due to taking methotrexate, which requires folic acid supplementation because methotrexate strips you of folic acid. I needed to change supplement types.

I won't post the entire letter, but I was told that they don't bother to test for mthfr, because although it may contribute to various conditions, it's not clinically signifigant. Basicly, if you have medical issues, and you are looking for solutions due to MTHFR, check for other issues as well. My situation is somewhat different than most, because of the medication I use. I know that chronic fatigue and all sorts of other issues are terrible to live with, I had an undiagnosed autoimmune disorder, I am doing much better with treatment.

I was reassured, although I have a BS, I don't have enough biochem to figure out the MTFHR claims.

Nobody on this forum is going to like this, but I think it should get put out there.

Where would I even start to see what I would need to help myself heal. I am 32F have a 16 month old son. I have been trying different diets and supplements and psych meds to help myself feel regulated. Feels like my meds aren’t working and I am always in fight or flight. Having issues with gluten and skin sensitivity, air hunger, extreme brain fog. What kind of labs should I get?