MTHFR and depression – what is the link here?

MTHFR mutation is becoming kind of the “in” thing to have at the moment and it seems like everyone talks about MTHFR and anxiety, MTHFR and heart disease, MTHFR and depression. The question is, why does a gene for the enzyme that activates folic acid have anything at all to do with those things?  First off, if this sounds like gibberish, then here’s some background reading on MTHFR and on MTHFR and folate. Now – lets see if we can decode the link between MTHFR and depression, because understanding this can hopefully help a lot of people who are struggling start to regain some normal and some happy in their lives.

What is the Link Between MTHFR and Depression?

At the simplest most basic level, your body needs methylated folate (which is what you don’t make very well if you have the MTHFR mutation) in order to manufacture the neurotransmitters serotonin, dopamine, epinephrine and norepinephrine and also the neurohormone melatonin (which helps with sleep among other things). The methylated folate isn’t used directly for these neurotransmitters, but it helps to make something called BH4, or tetrahydrobiopterin if you want to be technical about it. BH4 is then used to help the neurotransmitters building blocks (which are amino acids) to be converted to the active neurotransmitters that your body uses for brain cell signaling.

This is the link between MTHFR and depression, in not so plain english. Great diagram from Dr. Rostenberg, in this post which goes into the subject in more detail. Dr. R was kind enough to give me permission to use this!

This is the link between MTHFR and depression, in not so plain english. Great diagram from Dr. Rostenberg, in this post which goes into the subject in more detail. Dr. R was kind enough to give me permission to use this!

Um… Still Not Following.

Right – so I honestly don’t think it is hugely beneficial when you’re trying to fix MTHFR  issues in yourself to actually dive too deep into the biochemistry of what is happening because it gets overwhelming really quickly.  Suffice to say that your body has trouble making neurotransmitters if it can’t make BH4 because there just isn’t enough methylfolate. When your body has trouble making neurotransmitters, then you can start to see symptoms including these.

Symptoms of Low Serotonin (Think Negativity and Anxiety):

  • Negative thinking – Pessimistic, cynical or distrusting thoughts.
  • Craving for sweets and starches – Bring on the bread. With a side of fries. These foods temporarily boost serotonin levels in the brain, so you might reach for these more frequently
  • Sleep trouble – You need to make serotonin before you make melatonin (your primary sleep hormone) so this can be a big issue.
  • Low self esteem – Serotonin is one of the chemicals that helps you to feel good about you. Without it, you might feel socially anxious, inferior, or incapable.
  • Anxiety – worry, apprehension, obsessive thoughts and panic attacks are all more likely when your serotonin is low.
  • Aggression – Violence, aggression and suicidal thoughts or actions (violence against yourself) are all symptoms of low serotonin.
  • Impulsive behaviour – Low serotonin can reduce your ability to control impulses.

Symptoms of Low Dopamine (Think No Motivation and No Reward):

  • Lack of Motivation – No real “reason” to do things that matters to you. This also shows up in difficulty getting going in the morning and outright fatigue.
  • Joylessness – Dopamine helps you to actually feel the positive effects of enjoyable things. Without it, everything is a little blah. You have a hard time experiencing pleasure.
  • Memory Loss – Forgetfulness, lack of focus and outright memory loss.

Symptoms of Low Epinephrine and Norepinephrine In the Brain (Think Get Up and Go Got Up and Went)

  • Mentally Worn Out – Mental energy is lacking. All mental effort feels like far too much.
  • Inattention – Can’t really focus on anything.
  • Lack of Excitement – Yeah. Another day in paradise.

The short version of all of this is that without MTHFR you have trouble methylating folate. Without methylated folate, your body lacks Bh4. Without enough BH4, you have low levels of these neurotransmitters and with low levels of these neurotransmitters, everything feels pretty yucky. Like sad, apathetic, anxious, joyless yucky. Is there hope? Hell yes! This isn’t the post for it, but here’s some info about finding the right dose of methylfolate for you, and here’s one about foods that are high in natural sources of folate. It’s a great place to start. Even if you have depression but haven’t confirmed that you have a MTHFR mutation this can be a really great place to start.

12 thoughts on “MTHFR and depression – what is the link here?

  1. Tamera Shoemaker

    I left a comment on another post of yours… I found out 5 years ago I had this mutation but my NP at psychiatrists office just gave me methyl- folate and sent me on my way. I’ve been on an antidepressant for 9 years and have been struggling. After finding your site and wealth of information, I’m wondering what to do if I’m making healthy food choices, taking Thorne Methyl-Guard do I still have to take the AD?? It’s 50 mg pristiq. And now I’m concerned of what that may be doing to my health…
    Many thanks!!

    1. amyneuzil Post author

      Hi Tamera,
      Yeah – this is such a difficult question, and I think one that just about everyone who takes antidepressants long-term wrestles with at some point. I would say if you’re still struggling with depression, even while taking the antidepressant and making good choices, then maybe it’s time to go back to the prescribing physician and see if they will work with you to taper off, increase, or switch medications. I am a big fan of feeling good, and if you’re doing things right, taking care of yourself, taking a medication and still not feeling well then something isn’t right and needs adjusting. Does that make sense?

  2. Pauline Price

    hi – I gather things might be too complex to make conclusions based on the presence of a few polymorphisms, versus my symptoms/experience L). But by any off-chance do you have some sense of how my having the three following polymorphisms might play out, since it seems like they all impact BH4 level? In particular with regard to the best routes to combat depression/anxiety/obsessiveness/perfectionism. I’ve been on paxil for some years and am tapering off, so anticipating issues… Thank you!

    –1 copy of C677T allele of MTHFR
    — MTHFR A1298C
    –gs224 – Two copies of GCH1 variant associated with lower levels of tetrahydrobiopterin You have two copies of a GCH1 variant associated with lower levels of tetrahydrobiopterin (BH4) and total biopterins.

    1. amyneuzil Post author

      Hi Pauline,
      Yeah – you’ve got a lot going on there. Honestly, I would say go S.L.O.W.L.Y with everything. Both the taper off of paxil (slower than normal, please!) and also introducing supplements for MTHFR. Start with really low doses – probably a multivitamin with the methylfolate in it would be a great first step and possibly not the full dose. Also, something to look into that might be helpful for your particular type of anxiety is inositol. I keep meaning to write a post about it specifically for obsession-type anxiety. I’ve seen it be very helpful. Also check with the doctor who prescribed the paxil just to make sure he or she is okay with it before you start anything. Good luck!

  3. Diana

    Under what circumstances could eating folate in plants (like lentils, kale, chard) lead to depression? Is there another path along the folate pathway that could be compromised?

    1. amyneuzil Post author

      Hi Diana,
      People who are intolerant to folate or for whom it makes the depression worse are typically undermethylated depressives with low serotonin. The folate helps the methylation issue, but actually reduces serotonin in the brain, so overall doesn’t help. I could be totally wrong because I don’t know anything about your daughter, but this could be a guess! Nice and simple right? (Groan).

  4. Diana

    We are waiting for 23andme and NutrEval results for my 12 year old daughter. I suspect it will show some impairment of the folate metabolism. While we’re waiting, I made a meal of lentil pasta, with tomato blended with kale/chard. The lentil pasta said that it delivered 50% of folate RDA, but it only listed lentils as the one ingredient so did not appear to be fortified. The next two days she was really depressed. Does any link come to mind? I’m trying to keep things as stable as possible while we wait for results.

    1. amyneuzil Post author

      Hi Diana,
      It’s really difficult to say, although typically if folate is listed on the label it is fortified (I could be wrong, of course but it would be my first guess). So potentially she got a significant dose of folic acid. It is also possible that she’s an undermethylated depressive. In this case it sounds like folate should be a good idea, but using some of the Walsch Institute’s research we’re finding that it isn’t. The folate DOES help with the methylation issue, but also reduces bioavailable serotonin in the brain, which makes the depression worse. In this case we actually don’t want her to have 5-LMTHF or even other folate. Keep me posted when you get her results and in the interim I’ll write about over vs. undermethylation.

  5. KathyP

    Hello Dr. Amy… I am homozygous C677T and also have anxiety and depression (amongst many other issues possibly related to methylation and absorption). I am 52 and also in menopause. My integrative doctor recommended Deplin a few months ago which was too expensive so I purchased Methyl Pro’s 5-MTHF Extrafolate-S® 15mg. My anxiety and depression seemed to get worse but I keep thinking it was my hormones (or lack of) causing the increase. But now I’m wondering if I am over methylating. I’ve read here and at Dr. Lynch’s website that 15 mg of methylfolate is very high. What are your thoughts? Do we eventually adjust to the 15 mg dosage, or can that dose be too high and cause increase in anxiety and depression as long as we’re on it?? I am also taking a few other supplements and feel pretty good physically (still somewhat fatigued and have some minor brain fog), but emotionally I’m a complete mess and considering going back on Prozac. Any input is greatly appreciated!

    1. amyneuzil Post author

      Hi Kathy,
      Ack! Yes – for lots of people 15 mg is just too big a dose. And even if it’s the right dose for you (eventually) it might just be too much to start with. Honestly, for most people I suggest starting with a small dose and working your way up. Small meaning 400 mpg or even 200 mpg for people who are really sensitive. I know that sounds like nothing, but methylfolate, as much as we need it, can be completely crazy-making if you flood your system. I wrote a post about starting slowly here, just because it’s such a common question that people have. It’s like your body tries to do all the things it hasn’t been able to do all at once and gets log jammed. I’d cut WAY back and work your way up to whatever dose feels right for your body. Maybe give your body a few days off before you start again though – sounds like this has been a bit much! I’d love to hear how it goes for you – keep me posted if you get a chance!

      1. KathyP

        Thank you! I am going to take your advice and take a few days off, and order a new dosage. What are your thoughts on anxiety, depression and menopause (along with MTHFR, and other health issues most likely related to malabsorption and poor gut motility)? I’ve tried so many things to try and feel better and happy, but can’t seem to get there!! I’ve been diagnosed with Dysthymia and moderate single current episode of major depression.

        1. amyneuzil Post author

          Ha! Too many thoughts to list Kathy! Honestly, it’s all connected. It’s not like you can “treat anxiety” without looking at the rest of the body – the gut, the hormones, the inflammation, the diet. You are only one human and of course your health in every area is connected to your health in every other area. This is a hard concept because I think culturally we’re sort of trained to look for the 1 miracle pill – the penicillin model of health. In my experience it doesn’t work that way – what you need to find is the way of living that suits your body in particular. That might include some supplements, maybe some pharmaceutical drugs, certainly a particular way of eating and having activity in your life and probably some supportive activities like meditating or taking stress breaks or whatever. It’s the process of getting to know your body and your particular needs. Does that make sense at all?

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