Serotonin and MTHFR

MTHFR can come with a whole host of mental health issues including depression, anxiety, obsessive-compulsive traits, and more major states like bipolar disorder or schizophrenia.

Culturally, we tend to jump to the idea that all mental health issues are neurotransmitter problems and that the only way to solve them is by boosting your neurochemistry. We’ll explore this in a series of posts.

That idea, however neat and tidy, is just not true. With MTHFR especially, it is most important to look first to your methylation and work on balancing that because balancing your methylation will produce tremendous changes in your mental health state. There are other areas to explore too, like estrogen dominance (this is an issue for us MTHFR folks), low testosterone, or thyroid dysfunction. Still, once you’ve looked at the rest of your health, you may still want to examine those neurotransmitters. So let’s dive in and learn what we can about the highs and lows of particular neurotransmitter states. Especially since MTHFR ties directly into neurotransmitter formation via the BH4 pathway.


Serotonin helps to stabilize and modulate your mood, gives you feelings of well-being, and boosts joyfulness. It’s also involved in processes such as memory, feeling of reward, learning, and cognition. Interestingly, serotonin also has a heavy impact on digestion, with 80 – 90% found in the gut helping to regulate intestinal motility. Serotonin is also involved in such diverse processes as vasoconstriction and clotting. Given that it has so many functions, it is easy to see why problems show up vividly.

Symptoms of Low Serotonin and MTHFR

  • Depression – Although people think of this as an obvious statement, the research on serotonin and depression is actually quite mixed. Also, life events that typically cause depression, like chronic stress and trauma, have been shown to deplete serotonin levels. So while low serotonin might be a causative factor in depression, it might also be a consequence of difficult life events that cause depression.
  • Chronic Pain – Low serotonin is highly correlated with chronic pain states like fibromyalgia and many people with fibromyalgia report benefits from serotonin-boosting supplements or drugs. This could be because serotonin has the ability to strengthen the brain’s signals to the muscles. Also, conversely, if it’s in too large amounts it can make muscles like the muscles in your legs feel heavy.
  • Memory or Learning Issues – Sudden issues with memory or learning could signal a drop in serotonin.
  • Anxiety – Anxiety that appears without an obvious trauma or stressor, or anxiety that includes an obsessive-compulsive component, could well be a serotonin issue.
  • Internal Clock Problems – Serotonin along with its metabolite melatonin help to regulate your circadian rhythm. Not sleeping according to a regular schedule, having difficulty keeping a regular schedule of hunger and eating, or feeling chronically tired or constantly hyper might indicate a serotonin deficiency.
  • Sleep Trouble – Because of its relationship with your internal clock and your sleep hormone melatonin, serotonin is all tied up with your sleep. Serotonin deficiency may show up as chronic insomnia, unusual sleep patterns, chronic fatigue, or consistently vivid dreams might have low serotonin.
  • Appetite Irregularity including Eating Disorders – Low serotonin symptoms may include overeating, not eating enough, or alternating between those two states.
  • Dementia – Because of its link with memory and cognition, serotonin may play a role in dementia as well. Studies certainly show a link with early dementia but it is unclear whether low serotonin is a cause or a symptom.
  • Hyperactivity – A link exists between serotonin and ADD or ADHD People with low serotonin might fidget constantly, feel restless or agitated, or be chronically bored.

Obviously, serotonin is a big deal for your body and certainly something that you want to have enough of. In good news, working with serotonin and MTHFR gives you some really direct routes to addressing issues. The biggest and most important step for MTHFR folks is going to be balancing your methylation. That means following the To Health WIth That Plan – eliminating folic acid, getting a background of good B vitamins without any folate or B12, then slowly adding in methyl folate and a good form of B12 one at a time. All of this while using your symptom tracker. If the plan is new to you, we’ve got a great “Start Here” resource for you.

Once you’ve got your methylation levels where you want them with methyl folate or folate alternatives if you don’t tolerate folate, it’s time to address serotonin specifically. Here are some things you can try.

  • Melatonin at bedtime – Melatonin is made from serotonin, so if you’re supplementing at bedtime, it can leave you with more serotonin left over. Plus, it helps to improve sleep quality and makes falling asleep easier. It’s also a great antioxidant that crosses the blood-brain barrier, which is a total bonus.
  • SAMe – If you’re already working on methylation, SAMe might already be something you’re familiar with. If it isn’t, it can be a good boost to the BH4 pathway that helps your body to crank out the neurotransmitters. Just be careful and raise your dosage slowly because, just like methylated B vitamins, SAMe can cause reactions for MTHFR folks if we take too much, too quickly.
  • St John’s Wort – This potent herb has been incredibly well documented as an aid in depression, and it is documented to raise serotonin. In fact, research shows that when you compare St. John’s Wort to conventional SSRI medications, which are the most frequently prescribed medications for depression in North America, the results are very similar.
  • Aerobic exercise – Serotonin is made from an amino acid called tryptophan, and doing light cardio that you enjoy triggers the release of tryptophan into your blood and decreases the levels of other amino acids, hence getting more tryptophan to your brain. For an added boost, do something that makes you happy.
  • Sunshine or a light therapy box – Bright light boosts serotonin, and research has been suggesting that some might be made in our skin in response to light. If you combine your exercise with sunshine it could give you a double whammy, but if that isn’t possible, there are also light therapy boxes that can help if you have a hard time getting into the sun.
  • Massage – This doesn’t have to be anything fancy. A study of depressed pregnant women showed that 20 minutes of massage from a partner twice a week boosted their serotonin and dopamine levels and decreased the stress hormone, cortisol (along with back and leg pain).

All of this boosting is great, but I do want to give you a quick warning about serotonin syndrome, which can happen if you take serotonin-boosting supplements on top of some antidepressants, or even too many supplements. Serotonin syndrome is serious and can be life-threatening if untreated. If you’re already taking an antidepressant, or if you wish to swap out your current medication for natural methods, please talk with your doctor to develop a safe plan to do so.

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What To Expect When You’re Breaking A Mental Bad Habit

Last week we started our conversation about the “bad habit” component, called neuroplasticity, of depression, anxiety, intrusive thoughts, and obsessive or compulsive thoughts. This is, of course, only part of the picture. Neurotransmitter balance is a factor along with the often overlooked physical contributors to depression and other states.

We discussed three main methods for breaking mental bad habits. Those are:

  1. The Fantasy
  2. The Stop and Drop
  3. The Distraction

When you’re first trying this, it can be really helpful to try all three strategies at different times to see what works the best for you. You’ll know it works when you are able to pop yourself out of your mental bad habit – to feel different in your body and to let go of whatever thought pattern it is that you’re working on.

Stages of Resolution With Mental Bad Habits

  1. Learning. In this phase, you’re actually learning to pay attention to your thoughts and that takes more time than you would think. You may find a particular “warning” signal for you – it could be a behavior (like when I’m starting to feel this way I always log on to Facebook and click links that make me angry or I start craving XYZ food. It could also be a physical feeling – a headache in a particular place, a clenching in your belly, pain in your neck or shoulders. It could also be something more subtle like tuning into your mood more frequently.
  2. Out of Control. This phase feels like you’re moving backward. You’ve started tuning in and now you’re actually noticing how much your brain does this thing and it’s a ton! It will seem like your brain is a wild horse racing ahead of you, and it feels like the bad habit is happening more, not less.  That is a GREAT sign because the reality is that you aren’t doing the bad thing more, you’re just noticing more and that is the first step to actually changing it. This can take a few months of diligent attention, but don’t get discouraged – you’re doing it and you’re making progress.
  3. Quietening. In this phase, you start to make tangible progress and you’ll notice that the mental bad habit becomes softer somehow. Quieter.  The thoughts/feelings are still there and they still affect you, but you’re learning to let them go more quickly and it’s easier not to get pulled in by them. 
  4. Maintenance. This phase is amazing.  One day you’ll notice your mental bad habit pop up and the first thought you’ll have is “Oh! I haven’t seen that for a while.” and you’ll dismiss it and move on. This is the phase where you have the freedom to move on to something else because that bad habit is mostly gone.  It’s a good idea to still take proactive action when it pops up, but it is popping up so much less frequently that it becomes almost a curiosity when it’s there.

Great! So I’ll be mentally healthy by next week, right?

Absolutely not. I would love to say it was easy and took no time or effort, but that would be a bald-faced lie. It’s a challenge and it takes time. You’ve probably had this mental bad habit for years if not for your entire adult life, so it will take some time to break it too. And some time doesn’t mean a couple of weeks, it means months and maybe even a year. This isn’t quick, but it is SO. WORTH. IT.

Does This Work Every Time?

This works every time if you stick with it, and when there isn’t some other major imbalance. If your serotonin is actually so low it’s living in the sub basement, then this will still help fix the habit part of it, but it won’t completely normalize the serotonin (but it will bring it up – research shows these techniques are associated with higher levels of both serotonin and melatonin). Although, every day we’re learning more about what this can actually accomplish.

What IS This Witchcraft? It’s Mindfulness.

Yup. That thing that hippies and new-agey types do. Also, everybody who studies neurology and neuroscience of any sort, because as it turns out the effects are so powerful as to be almost unbelievable.

Among the many documented effects of any form of mindfulness are:

  • Increased wellbeing
  • Reduced cognitive reactivity (so external things don’t affect you so much)
  • Reduced inflammation
  • Reduced reactivity of the autonomic nervous system (you don’t get an adrenaline spike every time something bad happens)
  • Higher serotonin
  • Higher melatonin
  • increased telomerase activity (anti-aging)
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I Can’t Take Folate – Now What?

We all know that MTHFR mutations are differences in the way your body processes folate, so obviously the answer is to take more or better folate supplements like 5-LMTHF or folinic acid just like every doctor out there talks about. It’s so exciting to have a solution to the health issues that you’ve been struggling with! The problem is, there is a significant chunk of MTHFR folks out there who just don’t tolerate folate and never will. Truly, never. If you’re not sure why not being able to tolerate folate would matter in MTHFR, then read the Start Here Guide to MTHFR.

Who Can’t Take Folate?

Typically these people are in the group of MTHFR folks who tend toward undermethylation. Undermethylators make up about 45% of the population and while some of them do tolerate folate in low doses in foods or even a very tiny dose in a supplement, many of them don’t tolerate any folate at all, not even in food. There are exceptions, of course including low-serotonin overmethylators.

Now How Do I Deal With MTHFR Issues?

You’ll recall that the whole methylation cycle is mostly accomplishing two goals. One is converting homocysteine to methionine (to avoid homocysteine buildup), and the other is making SAMe (a methyl-donor).

the MTHFR lifestyle matters because of the way these cycles all interconnect.

Bypass the Cycle

So, if you can’t convert homocysteine to methionine, and you can’t make SAMe, you can still get the cycle and all related processes going by taking methionine and SAMe. It’s a bit of a cheat, but it helps to solve that one very basic problem and for most people, boosts their mood tremendously.

But Why Is This Happening In The First Place?

For most undermethylators who don’t tolerate folate, it’s happening because their serotonin is just so low. This can happen to overmethylators too, but it’s far less common. The key issue is typically LOW SEROTONIN and folate of any kind makes the depressive symptoms of low serotonin worse.

The basic trouble is that folate, 5-LMTHF, and folinic acid (also folic acid, but I know you don’t allow any of that into your body because of this) have an epigenetic effect on the SERT transporter.

The SERT Transporter

The SERT transporter helps to re-uptake serotonin after it has been released, This is the target for the popular antidepressants called SSRIs – that stands for Selective Serotonin Reuptake Inhibitor (it’s essentially a SERT inhibitor).

Taking an SSRI or inhibiting SERT doesn’t change the amount of serotonin you have, but it changes how long it stays out there as a signal. The longer it’s out there, the more effect it has and the happier you feel.

Folate boosts serotonin production, but also speeds up reuptake so may actually net decrease the amount of benefit (happiness) you get from that serotonin.

Folate in all of it’s forms actually boosts SERT function so even though folate helps your body manufacture more serotonin through the BH4 pathway, it boosts re-uptake more, so the net effect feels like lower serotonin.

Boosting Serotonin Naturally (Or Less Naturally)

The great news is that often the people who don’t respond well to folate, do typically respond really well to supplements and often drugs that boost serotonin. These include:

  • St. John’s Wort
  • SAMe (so if depression is your primary concern, focus on finding the optimal dose of SAMe before you add other serotonin boosters).
  • Melatonin (which boosts serotonin indirectly by both helping sleep and also reducing serotonin conversion to melatonin.)
  • Tryptophan
  • SSRI Medications (although you may still experience side-effects).

Where Do I Start?

  1. Folic Acid – Like everyone else with MTHFR issues, start at the beginning, which is getting the toxic folic acid out of your diet. If you don’t tolerate high-folate foods or folate supplements, then foods fortified with folic acid are extra harmful to you.
  2. HIgh natural-folate foods – you might find you can tolerate some high-folate foods once the folic acid is gone. If not, that’s fine too, but it’s worth it to try. This gets you out of stage 1 of MTHFR balancing, which is the general stuff that is typically good for all mutants. If you want more detail, check here.
  3. Other B vitamins – a B supplement or multivitamin that doesn’t include folate or B12. The only ones I know of are from Seeking Health and can be purchased from Fullscript using the sidebar link. This is an affiliate link so I will get a small commission on the referral and I will offer you a 10% discount.
  4. Methionine – 500 mg at bedtime can make a world of difference on its own.
  5. SAMe – this can help with depression and energy levels so it’s a good next choice. (Methionine and SAMe can also be purchased from the link on the side, but they are also pretty easy to find in local health food stores.) As with everything else with MTHFR, start at a lower dose, and increase slowly. A good starting dose is 200 mg twice daily.
  6. Move to Stage 3 of MTHFR balancing – this is all working with your own individual symptom picture, so it very much depends on what you are working with right now.

What If Low Serotonin Doesn’t Sound Like Me?

Sometimes, even without low serotonin some MTHFR folks just don’t do well with high-folate foods or supplements like 5-LMTHF. In this scenario, it is still a good idea to try the steps above and if low serotonin (which usually feels like depression) isn’t the issue then you might be able to try a tiny dose of folinic acid, which for some reason is better tolerated in this situation. It still might not be right, but it is worth a try to see if we can get that cycle moving just a little bit. Otherwise, follow the Start Here for MTHFR guide.

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