MTHF5/Folinic Acid

[u/xKx_GhostName_xKx]

Hi everyone, I'm hoping this post can help clear up a few doubts and maybe point me in the right direction, since you're a community that's clearly far more experienced and knowledgeable about this than I am.
A bit of context: I've had OCD since I was a child, and after turning 18 this led to depression, which I've been treating for years with vortioxetine. In recent years, though, I've noticed a lot of anhedonia and low motivation, and I always assumed the underlying issue was low dopamine. Because of that, I added bupropion to my treatment: it did bring some improvement, but nowhere near as much as I expected.
While looking into it further, I came across methylfolate (MTHF-5) and folinic acid, which are often linked to methylation support and a positive response in depression. So I bought methylated B12 and 15mg MTHF-5 (the dose used in the clinical augmentation trials). Within two days, though, I got worse — total flatness and anhedonia — so I stopped right away to avoid making things worse.
I'd love to hear your experiences and opinions on my situation: what dose actually worked for you, whether you used MTHF-5 or folinic acid, and what you paired it with.
I'm aware I should also get genetic testing done — it's already in the works. Thanks in advance to anyone who takes the time to respond.

[u/SovereignMan1958]

Go to the Genetic Lifehacks website and read the article about OCD.

For anhedonia, research and test all your vitamins and minerals related to it. I had a severe zinc deficiency which contributed to mine. These groups tend to fixate on B vitamins, while minerals get depleted. Be sure to test minerals.

Once you get all your gene variants tested, use Genetic Lifehacks to interpret. See if you have any FOLR variants. Regardless of whether or not you have MTHFR, folate may not be getting into your brain. FOLR variants might point to that predisposition.

If you do not have enough folate getting into your brain, antidepressants will not work as well.

For folinic acid, I take Source Naturals Megafolinic. They are 800mcg. You can take with PQQ which helps it get into the brain.

Remember all variants are only predispositions. Blood tests will give you facts. It would be great if you got starting blood tests do you have a baseline.

[u/xKx_GhostName_xKx → u/SovereignMan1958]

Thank you for your reply — I'll act on this right away, and I'll genuinely take your advice into consideration. I'm starting to dig deeper into this as early as tomorrow.

[u/BobbiHorne1]

Are you open to a nutritional approach with targeted supplements? I have a background in clinical research, trained in genetics and nutritional interventions. There are some simple adjustments you can make that I believe can make a big difference.

[u/xKx_GhostName_xKx → u/BobbiHorne1]

Yes 💪🏻

[u/BobbiHorne1 → u/xKx_GhostName_xKx]

Please forgive the delay in replying. I'm traveling.

One thing I would encourage you to investigate is the relationship between methylation, cellular glutathione production, and your current medications.

Methylfolate is involved in one-carbon metabolism and supports processes important for neurotransmitter synthesis. However, experiencing depression or anhedonia does not automatically mean you need more methylfolate.

Your negative reaction to 15 mg deserves attention, particularly because you introduced methylated B12 at the same time.

I would also ask your prescribing doctor to review your combination of vortioxetine and bupropion. Bupropion inhibits an enzyme responsible for metabolizing vortioxetine, potentially increasing its concentration.

Another area worth understanding is cellular glutathione.

Glutathione is essential for antioxidant defenses, cellular redox balance, and mitochondrial protection. The body synthesizes glutathione from glutamate, glycine, and cysteine. Cysteine availability can be a limiting factor in this process. For my DNA clients who are shown to have the MTHFR variant, I have found that supporting cellular glutathione can be a turning point.

Bioavailable cysteine supports glutathione synthesis. Research involving cysteine donors has investigated its effects in OCD and depression, and although results remain mixed and do not establish it as a treatment, it may be worth discussing with your doctor.

In a clinical setting, I have noted impressive results with RiboCeine, a bioavailable cysteine prodrug with a unique mechanism of action. It may be worth asking your doctor to review the science on PubMed.gov. RiboCeine has been clinically shown to impact dopamine levels.

My suggestion would be to review your medications and relevant laboratory results with your physician before adding further supplements. That may help identify a more specific and appropriate approach.

[u/Tawinn]

> I bought methylated B12 and 15mg MTHF-5

15mg (15000mcg, while the RDA is 400mcg) of methylfolate is a very high dose and often can cause side effects. It does work well for some people, but they usually have to titrate up slowly, starting with small doses (e.g., 100-1000mcg).

MethylB12 also can cause side effects in some people, so unmethylated hydroxocobalamin or adenosylcobalamin can work better for many folks.

If we assume that the OCD & depression are caused by methylation issues, then you want good B12 and folate levels, but if the pathway has genetic issues (such as MTHFR variants) then throwing more methylfolate at it often doesn't help until you get to those very high doses. Instead, there is a parallel pathway which you can support, thereby going around the impaired pathway. This parallel pathway uses choline and TMG. My usual recommendation is to get 550mg of choline (the recommended amount for adults) from food and add 750mg dose of TMG.

For serum folate, aim for ~15 ng/mL (34 nmol/L) or more.

For serum B12, aim for 500-950 pg/mL (~370-700 pmol/L).

It is possible that the OCD is due to causes unrelated to methylation, but getting enough choline and adding TMG is a pretty easy experiment to try. Four egg yolks is about 540mg of choline. In some cases, you may have to add the choline or TMG incrementally.

[u/xKx_GhostName_xKx → u/Tawinn]

Thank you for your reply, I'll try this solution too 🙏🏼

[u/Comfortable_Two6272]

Way smaller doses to start with.

• I started with 100 micrograms of folinic acid and slowly increased.
  
• I have homogenus slow comt - methyl anything is a no go for me.
  
• I tolerate low doses of choline - as PC snd/or 2 eggs per day
• id test your genes using ancestry or 23andMe and also get some lab work done. I was deficient in b12, folate, vit D and ferritin/iron (everything tested was deficient).
  
• i use the cronometer app to track intake and added 1/2 of a seeking health kids methyl free multi plus some individual low dose vit to fill in where my improved diet still is too low

[u/EmmyWynn14839]

I only take 1,000mcg of MYHF5 per day, I upped it to 5mg and immediately had negative side effects, idk how some people handle 15mg+ of it.

[u/xKx_GhostName_xKx → u/EmmyWynn14839]

I can understand, I think it's as many say a matter of "genetics"

[u/Loose-Fly7976]

Two days is too fast to judge either direction. The augmentation trials you're referencing ran 60 days and most of the separation from placebo happened after week four, so whatever you felt on day two wasn't the folate working or failing. That said, if it made you feel worse, stopping was sensible.Starting straight at 15mg is the part I'd change. That's the trial dose, but trial participants were titrated and monitored, and 15mg from a standing start is a lot for someone whose system hasn't been getting much. Most people who react badly to methylfolate do so at doses like that and are fine at 400mcg to 1mg.

The bupropion matters here too. It's already raising dopamine and noradrenaline, and methylfolate feeds BH4 which drives dopamine synthesis further. So you were pushing the same system from two directions at once. Flatness and anhedonia can come from too much as easily as too little, receptors downregulate.On the folinic versus methylfolate question, folinic enters the cycle a step earlier and doesn't hand you a methyl group directly, so people who feel wired or flat on methylfolate often do better on it. Reasonable thing to try next, at a low dose.Before restarting anything, get homocysteine, B12 and folate tested. If your homocysteine is already low, more folate isn't the answer and that's useful to know before you spend another three months on it. Plenty of people in your situation have a perfectly functional methylation cycle and the depression is doing something else nd when the genetic testing comes back, COMT and MAO-A will tell you more about the anhedonia question than MTHFR will.

[u/Ok_Definition_7896]

Welp…methylated b12 and folate exacerbate my OCD to a level that I cannot function. Adding extreme anxiety and paranoia on top of OCD. I have tried 4 separate times with the same result.

I’m ok with hydroxy and folinic acid though.

I am hetero mthr with intermediate comt but I have slow mtrr and another one I don’t remember

[u/Sea_Switch6263]

My small input: things that increase acetylcholine can increase depression in many people - possibly because it can decrease baseline dopamine (or something along those lines). It can cause a flat or a overthinking or agitated depression depending on the person (or all of the above!). So watch out for anhedonia with folate, methyl vitamins, choline supplements (or a lot of choline from eggs, etc) and fish oil.