Methylfolate Makes Depression WORSE! How Is This Possible?

Finding out you have an MTHFR mutation can be exciting, in it’s own strange way, because all of a sudden there is hope that you can actually help yourself and fix how you’re feeling, so it really feels like being kicked in the gut if you start taking 5-LMTHF and the methylfolate makes depression worse.  Have no fear, there is an explanation and also some possible solutions. Read on my friends.

Methylfolate makes depression worse! Don't worry - there is a solution. Great photo by © Philippe Ramakers | Dreamstime Stock Photos

Methylfolate makes depression worse! Don’t worry – there is a solution. Great photo by © Philippe Ramakers | Dreamstime Stock Photos

Why Does Methylfolate Make Depression Worse?

We recently talked about the terms “undermethylated” vs. “overmethylated” and although there aren’t great lab tests to show your status, typically you can determine your general tendency through their symptom picture.  Depression, however, can be ambiguous because it can happen in people who are undermethylated, overmethylated or people with totally normal methylation.  Although having the MTHFR mutation pushes many people into the undermethylated category, having the mutation itself isn’t enough to tell you if you’re under, over or normal. I myself am a compound heterozygous MTHFR mutant, but happen to have other genetic factors that make me an overmethylator – go figure.

5-L methyltetrahydrofolate (5-LMTHF) is suggested for everyone with a methylation issue – over or undermethylators.  It’s the first line of defence because it can actually help both groups to balance their methylation in different ways.  Also for depression specifically, folic acid or 5-LMTHF supplementation can be extremely helpful even without a known methylation issue because folate deficiency is a common cause of depression – so really for most people folate is beneficial. There is one group, however, who doesn’t respond well at all that that is undermethylated people with depression.

Let me clarify – anyone starting 5-LMTHF for the first time, or even increasing a dose, may notice some side effects for the first few days.  Starting to methylate differently can be messy and so this first few days isn’t enough time to know if you actually have a bad reaction. This is why we talk so much about starting with a low dose and easing your way up. If you’ve started with a low dose and you’re easing into it, but your depression gets worse and stays worse beyond the first week or so, then chances are you have undermethylated depression. This means methylfolate, folic acid and even folate rich foods are probably always going to make your depression worse.    Here’s why:

The link between Methylfolate and Serotonin

This is complicated because typically boosting your methylation cycle also helps your body to make more neurotransmitters via BH4 (we don’t need to go into it, but if you want a refresher you can read about it here). So 5-LMTHF is supposed to fix depression by boosting levels of serotonin, dopamine and other key neurotransmitters.  The problem is that 5-LMTHF, folic acid and folate all have a second effect on neurotransmitters, which is to depress serotonin through an epigenetic mechanism.

Epigenetics is essentially the study of how external factors (like nutrition, stress, oxidative damage, etc…) influence the way our genes express themselves. Folate and folic acid, according to the Walsh Research Institute, have an epigenetic effect on the SERT transporter.  The SERT transporter helps to reuptake serotonin after it’s been released. SERT is the target for many pharmaceutical antidepressants (SSRIs, or Selective Serotonin Reuptake Inhibitors). SSRIs work because they interfere with SERT and so serotonin stays active longer, which means you get more benefit from this happy neurotransmitter. Methylfoate, folate from foods and folic acid, while they increases serotonin production through BH4, also increase SERT via an epigenetic effect.  This means they help your brain to clear out serotonin faster, thereby reducing the amount of serotonin that is available for you to use. Essentially this makes folate the anti-anti-depressant.  Sigh.

As a brief reality check – Walsh Research Institute is convinced this is happening (see the link to their presentation above), many MTHFR websites are convinced this is happening, and it certainly explains a lot of what I’ve seen clinically, but for whatever reason I can’t find any published research that says definitively that this is happening so please take this with a grain of salt.

Methylfolate Makes Depression Worse For Me – Now What?

Don’t worry – you have a couple of options.  If you’re sure this isn’t just your body adjusting to methylfolate (the symptoms last beyond the first week of moderate supplementation) then it’s time to check to see if you fit the profile of an undermethylator. If that sounds like you, and your depression is getting worse, then let’s look at your choices.

  • SAMe – Ultimately the end product of the entire methylation cycle is SAMe, so it can be a helpful work around for people who can’t take 5-LMTHF.  This is where all that methylfolate is going and although it doesn’t entirely cover the necessity for methylated folate, it does help with the depression. This is partly because SAMe is a very slow acting serotonin reuptake inhibitor – just like the pharmaceutical drugs only much less powerful. As with any methylation issue, start with a low dose and work your way up.
  • Methionine – This amino acid is a direct precursor to SAMe in the body, and uses the MATI/II enzyme (coded by the gene of the same name) to go through the conversion.  Because this turns into SAMe it can be a much more cost effective way to get the same benefits, which again is as a slow acting serotonin reuptake inhibitor.  The only situation in which that isn’t going to be helpful is if your MATI/II gene has an issue or something is interfering.  Most people find methionine to be effective though, so this can be a far less expensive solution. Again, start with a lower dose and work your way up.
  • St. John’s Wart – This has nothing to do with methylation, only with serotonin.  Happily, St. John’s wart shows similar effectiveness to SSRI medications for major depressive disorder, with significantly fewer adverse events.  Here’s the research study, from the Annals of Family Medicine that compares St John’s Wart (referred to by it’s latin name, hypericum) with SSRIs and other anti depressant medications as well as placebo. Go nature!

It should be said that while SAMe and Methionine will help to augment the methylation cycle, they still aren’t providing folate of any kind, so they won’t protect against the more folate dependent issues like neural tube defects in babies and issues with pregnancy and fertility.  If you have undermethylated depression and are considering getting pregnant it is vital to work closely with a doctor who can help you to get the folate that you need and also help you to offset the depressive symptoms that might come with that. Even though methylfolate makes depression worse,  in pregnancy it might still be necessary so please consult a physician.

19 thoughts on “Methylfolate Makes Depression WORSE! How Is This Possible?

  1. Lucas

    Hi Dr. Amy

    A year ago, I ordered a genetic test and found out I had an MTHFR mutation, and my nutritionist prescribed 400mcg methylfolate (plus active b6 and b12). I’ve always been a bit antisocial and moody, but I got much worse after that. In 5 months I developed severe depression, with suicidal thoughts. I didn’t knew the supplement was the culprit, because my nutritionist and all the resources about methyl-folate I found at that time said it was beneficial for depression, so I feared stopping and getting even worse.

    After that, I had a consult with a functional medicine doctor, also unaware of these potential risks of methyl-folate supplements. He prescribed an SSRI that I’ve been taking for 2 months. I feel better now, but I also feel that the medication could not be necessary if I stopped the folate sooner.

    Thank you so much for the eye opening article, I hope more practioners consider that possibility and stop hurting their patients.

    1. amyneuzil Post author

      Hi Lucas,
      I’m so very sorry you had to go through all of that. It’s been a while since you posted this comment – have you chosen to stay on the SSRI? I”d love to hear how you’re doing now. Thanks for being here and taking a look!

  2. Michael

    Dr. Amy,
    Thank you so much for all your great information. I’m sure it helps tons of people trying to regain their health. I suffer from bad anxiety and depression all my life and have a a double homozygous snp at the MTHFR 6779 gene. Anyways I do a lot of research and trial and error to try to figure what best helps my situation. I’m just curious because half the specialists in the field believe methylfolate is best for undermethylators and the other half agree with Dr. Walsh believe SamE/methionine is best and to avoid folates becuas of their epigenetic actions involving clearing out serotonin fast. I couldn’t really find any research on this belief besides Dr. Walsh’s experience. Anyway I’m just curious why we see so many people that fit the characteristics on the internet as undermethylators and being chronically depressed thrive so well on low of high dose methylfolate, saying it “changed their life and eliminated depression”. How could that be so if Dr. Walsh’s belief is correct?

    1. amyneuzil Post author

      Hi Michael,
      Sorry for the delay – I’ve only just stumbled across a handful of comments that haven’t been addressed. Apologies! Yes – that is a good question, and my particular belief and experience doesn’t match up with Dr. Walsch’s, but that doesn’t actually mean that Dr. Walsch is incorrect and I think until there is more research about treating and mitigating the risks of MTHFR, instead of just quantifying the risks, we won’t really know. Unfortunately, most of the current research helps us to understand the risks that MTHFR mutation might pose or the conditions that are somehow associated with it, but there isn’t really much at all about how to mitigate those risks or approach the problem clinically. We’re all flying a bit blind in that area and have to rely on our own experience. Dr. Walsch’s experience has been different than mine, but they are equally valid. At the end of the day, my honest belief is that the MTHFR mutation interacts with so many other possible genetic polymorphisms that there isn’t going to be an easy one-size-fits-all approach and that it will remain difficult to make blanket statements with any accuracy. I hope this is helpful!

  3. lisa adorna

    Does this apply to anxiety as well? My sons anxiety has resurfaced badly in the last fortnight. He is heterozygous 677-TT and been on Methylfolate for years. Eats loads of avocados.

    1. amyneuzil Post author

      Hi Lisa,
      This doesn’t apply to anxiety as much, although mixed anxiety with depression could be serotonin-related. If he’s been on the methylfolate for years and tolerated it well, then my guess is that it is unrelated. Have you explored life triggers – some source of stressor, relationship situation or even health situation (like a virus – I know that sounds crazy, but being physically ill can make anxiety or depression worse). Can your son pinpoint anything in particular? Of course, if you can’t find anything then maybe eliminate his methylfolate for a couple of weeks and see if that helps, but it wouldn’t be my first guess as a culprit. I hope this is helpful and good luck!

  4. Leigh

    Hi Dr. Amy,

    Thanks for this article, which finally seems to explain what I’ve been experiencing! My serotonin is low, based on an OAT test. I’ve managed depression well with inositol in the last year. I started feeling down again after two weeks on methylfolate, and now 3 weeks later, it’s still challenging. Time to stop the methylfolate! But boosting methylation has been noticeably helpful in other ways, so looking for alternatives.

    Any thoughts on TMG (trimethylglycine / betaine) as another strategy, in lieu of methylfolate or SAMe, to boost serotonin and methylation?

    1. amyneuzil Post author

      Hi Leigh,
      Yeah – it’s hard to balance the benefits with the depression that happens for some people. My experience with things like TMG or SAMe is that the response varies widely and I don’t have any specific thing to point to in terms of who will respond positively and who won’t. I think both are worth a try, or the methionine, but I have no great way to predict how they will work for you. Also, other serotonin boosters are worth looking into (good old St. John’s Wort and the like). Sometimes if you can boost your serotonin enough then you can tolerate small doses of the methylfolate. Plus, if it took two weeks for you to start feeling down, I think you’ve got a shot of raising your serotonin enough to tolerate it. I have seen clients who drop like a stone on day one, so although it doesn’t feel good for you, I would consider this on the milder end of the reaction spectrum. Keep me posted and let me know if you find something that is great for you!

  5. Julie

    This might explain a BIG problem with recent depression. I was doing great, little depression even though I’ve had struggles with it life-long. Hadn’t taken anything for it in several years. I started supplementing with methylated folate, didn’t start low, just started taking the amount in the capsule alternating with a B complex pill. Then I started taking it everyday and not the B complex. I ended up with terrible crying at the drop of a hat depression that lasted a couple months. Then, we went out of town and I only took the B complex with me, not the methylated folate for a week. I’ve felt fine like I’m over the big depression which is such a relief. Somehow I stumbled upon your article, thank GOD and I believe this could have been my problem!! Now I am back to alternating with the B complex and I empty half the capsule before taking it. I still feel fine. I so appreciate your insight. I pray it was my problem because it hit me totally off guard.

    1. amyneuzil Post author

      Hi Julie,
      Yes – isn’t that crazy? Your body needs the methylfolate, but WOW does it feel bad. I’m so glad you found this and if you get a chance, keep us posted – I think lots of people would like to hear about your journey.

  6. Robin

    Thank you for making a confusing problem more understandable. I have 677(TT) and probably an undermethylater with depression. After some messy trial and error, I’ve been taking 400 mcg of methylfolate with other b vitamins for a week and I’m feeling worse. If this doesn’t change soon should I add SAM-e or replace the methylfolate with it? What could I try next? Thanking for sharing with us.

    1. amyneuzil Post author

      Hi Robin,
      Have you tried food sources of folate? That can be a really great test to find out if any methylfolate makes you feel worse, or if you just haven’t found the right supplements yet. I would do a trial. Stop the B vitamins and methylfolate and have a week of really clean eating with lots of food sources of folate and see how you feel. If you STILL feel worse (especially the depression) then it means you are probably not going to be able to tolerate any methylfolate at all, and then we’d try the SAMe and that sort of thing instead. If the food sources don’t make you feel worse (even if they don’t make you feel better) then you can probably tolerate some methylfolate, we’ll just have to play with doses to see how things go. Does that make sense?

      1. Heather


        Question–I thought people with MTHFR gene mutation could not process folate found in food correctly? If so, wouldn’t food folate be totally different to that person than methylfolate?

        Thank you!

        1. amyneuzil Post author

          Hi Heather,
          Great question! So – natural folate doesn’t need to go through the MTHFR enzyme to be usable, so food that has naturally occurring folate is actually usable by MTHFR mutants. This is things like lentils, beans, nutritional yeast, avocados, dark green leafy veggies. The big problem comes in when people eat food that has been “fortified” with folic acid. This food does need the MTHFR enzyme and so us mutants don’t do well with this at all. This includes bread, pasta, flour, and now corn flour products. It can be really confusing, so I wrote a whole post about it here. I hope this helps!

  7. Peggy Seracuse

    Very interesting article. My daughter who has been struggling with anxiety and depression has just found out she has a A1298C mutation – 2 copies. She’s tried several antidepressants in the past with no help and one definitely made the depression worse. We’re excited to find some kind of reason for why she feels this way, but I’m concerned about your discussion about how taking methylfolate may increase her depression. Her homocysteine is high (12.6). She’s been taking SAMe but can barely tolerate an 800 mg dose because it makes her stomach cramp, so she often just takes the 400 dose. I understand that the effective dose is much higher – like 1600. I’m wondering if you are saying in this article that people who have the mutation and are depressed will definitely find their depression increase when taking methylfolate. Or if the increased depression happens only to a subset of people who have depression and the mutation? I’m also wondering if you try to supplement past the MTHFR gene, if you don’t still have problems with increased homocysteine levels and the inability of your body to make glutathione? Thanks for any help you can give in clarifying this confusing new bit of information we know have.

    1. amyneuzil Post author

      Hi Peggy,
      Great question! And NO, most people with depression and MTHFR issues are greatly benefitted by taking methylfolate – although it is important to start with a lower dose and work your way up. This article is mostly for the small group of people who have tried methylfolate and notice an increase in their symptoms. It is uncommon, but it can happen so I wanted people to have some explanation for it. So as you say, it’s a subset of the population. In terms of supplementing with methylfolate – I feel like if people have a known mutation then supplementation is a good idea even if they don’t have symptoms. It could be unnecessary, but it’s also a low-risk and reasonably low-cost venture. For people with no symptoms I usually just suggest switching their multivitamin to one with methylfolate or their B-complex if they take one. Does that make sense?

      1. Mary

        Hi Dr. Amy,

        I’ve been reading your articles and appreciate them. I’m hoping you can help me. Until a few months ago, I had been on phenelzine (Nardil, an MAO-I) for about 14 years and it worked well for depression and anxiety. I’m having problems with both again since being off the medication. Since the medication worked for me and for so long, does that mean that the issues weren’t from the MTHFR mutations? I had tried many SSRIs before being put an an MAO-Inhiitor and got side effects from them all. I’m sensitive to medicines it seems. My dr recently tried me on only 5mg of Fluoxetine (Prozac) for 6.5 weeks and I had side effects from it so stopped taking it. I think it may have helped some things a very tiny bit. I had tried a small amount of SAMe before when on nothing else, and it made my heart beat more forceful which I didn’t like. Phenelzine made me gain 25 pounds which quickly came off when I was off it for awhile combined with my appetite loss from the depression returning. I did try liquid methyl b12 before with no issues. I felt it gave me more energy. I tried Parnate, a different MAO-I. It gave me energy and made my heart beat more forceful but no improvement in mood. I take Plaquenil to keep my mixed connective tissue disease from progressing. I also have fibromyalgia. I’m considering trying a tiny dose of l-methylfolate but am scared. Below are my recent test results for tests I asked doctors for.
        Any thoughts?
        Thank you, Mary

        This patient has two copies of the MTHFR A1298C mutation,
        while C677T was not detected.

        >20.0 ng/mL (my result)
        NORMAL RANGES >2.8 ng/mL
        SERUM DEFICIENT 1.0-2.8 NG/ML

        8.4 (my result)
        Normal: 5.0-15.0 mcmol/L
        Optimal: 0.0-12.0 mcmol/L

        Vitamin B-12
        275 pg/mL (my result)
        Standard range: 239 – 931 pg/mL

        Thyroid Stimulating Hormone (TSH)
        1.00 u[IU]/mL (my result)
        Standard range: 0.46 – 4.68 u[IU]/mL

        Free T4
        1.1 ng/dL (my result)
        Standard range: 0.8 – 2.2 ng/dL

        1. amyneuzil Post author

          Hi Mary,
          First off – the issues could certainly be related to MTHFR, even though the medication worked. Many anxiety and depression medications can work for MTHFR mutants, but everyone is different. For some of us, adding methylfolate can make a medication unnecessary and some of us find that methylfolate helps, but they still need a medication to get the results they want to see. You’ve got a lot going on with the mixed connective tissue disorder and fibromyalgia as well as anxiety and depression, plus several medications in the mix. I think you’d be best to work with a practitioner who can help you to introduce a methylfolate supplement slowly and work closely with you to make sure it isn’t making anything else more difficult. If you had no issues with the liquid B12 and your doctors were comfortable with you taking it then starting that again sounds like a good idea because your B12 numbers are certainly low. Still, given how complex your situation is I think finding someone locally would help. Here’s a link to a look up a doc near you page from the American Assoication of Natuorpathic Physicians that might be helpful.

Comments are closed.