To Health With That!

Schedule a free 15 minute consult now
Follow us :

S2E14: What To Do for MTHFR When You Don’t Tolerate 5-LMTHF

A couple of weeks ago we talked about two different dealbreaker scenarios where you did everything right with the methylfolate start, but you just couldn’t tolerate it. So let’s talk about what the next steps could be if you find yourself in this scenario.

5-LMTHF Nontolerator – Low Doses Feel Too High

If you were in this group, you started with a low dose of 5-LMTHF and immediately felt the symptoms of too high a dose. That usually feels like agitation, restlessness, wound-up energy, anxiety, intrusive thoughts, panic attacks, or something along those lines. Like way too much caffeine. There are a few things to do here.

If you do not tolerate 5-LMTHF for MTHFR, here are some things you should do

Evaluate the dose you started with – Because methylfolate is available in so many giant dosage sizes, people tend to go bigger than they need to. I’ve had conversations with plenty of people who say “I started with 1000 mcg – that’s a low dose.” Actually, it’s a bit of a high dose. Even 400 mcg, which is the recommended daily allowance in most countries, is not a low dose. If the dose you started with was anything more than 200 mcg, reevaluate your definition of low and try again. The best thing to do is give your body a week away from any methylfolate and try again at a much lower dose.

My dose really was low! – This happens too. Plenty of people take a low dose – 200 or even 100 mcg – and it’s still too much. In this case, I want you to think about whether or not you tolerate food sources of natural folate.

I tolerate food sources fine. In this situation we can really work on boosting food sources of folate and maybe add a low dose folinic acid for a while. Food sources of natural folate and folinic acid both still need to go through the MTHFR enzyme, so it’s especially important in this scenario to be folic acid free. Because they still depend on the enzyme, your body makes 5-LMTHF slowly so you don’t get that big rush of methylfolate that feels like too much. This might also mean that you’re short on methyl groups. Take methylated B12 if you tolerate it, and also think about trying a methyl-donor like SAMe or TMG, which stands for trimethylglycine. Trimethylglycine, or betaine, can donate methyl groups just like SAMe can and help to move the pathway forward. With both SAMe and TMG, start the dose low and don’t change anything else for a week or two. Symptom track and let your body tell you how it’s doing. Also, don’t start those two things at the same time – try one or the other, you probably don’t need both. After a few months of this routine, it’s a good idea to try a low dose of 5-LMTHF again because chances are you’ll be able to tolerate it in the end.

I don’t do well with food sources of natural folate – This indicates that you likely won’t tolerate 5-LMTHF, maybe even ever. That’s ok – there are work-arounds in every scenario. These folks should try a low dose folinic acid, then wait a couple of weeks to make sure you tolerate that before moving on to a TMG (trimethylglycine). If you don’t tolerate folinic acid either, then we’ll keep doing the other B vitamins, try to get a methyl B12 if you can, and skip folate all together. Just go for TMG at a low dose and if you can later on, we’ll add in SAMe as well. If you don’t tolerate TMG, then choline can be a good substitute. It isn’t methylated, but it still helps. This scenario needs a lot of trial and error to find what works best for your body, but there is always a way forward. Just take it one day at a time.

If you don’t tolerate methylfolate your options are:
natural folate from foods
folinic acid

The Second Scenario – 5-LMTHF Makes Me Depressed

This is a very particular scenario that happens only, as far as I know, to undermethylators with extremely low serotonin. It isn’t common, but when it does happen it’s extremely vivid. Folate normally has a beneficial effect on depression, and technically it also helps you make more serotonin, but in this scenario it has a net negative effect. The reason is that folate boosts something called SERT. SERT is a serotonin transporter and it carries serotonin back into the neuron, or brain cell, that released it. Serotonin can only produce signals when it’s between neurons in what is called the synaptic cleft, and SERT is busy cleaning it out of the synaptic cleft for recycling and reuse. For this tiny group of people who fall into a deep dark hole when they take folate, the boosted activity of SERT overwhelmed the benefits of taking folate.

What To Do For MTHFR When 5-LMTHF Isn't Tolerable
What To Do For MTHFR When 5-LMTHF Isn’t Tolerable

For these folks, it doesn’t mean you will never be able to take methylfolate, but it does mean we have to get your serotonin out of the tanks before you do. In this situation serotonin is often so profoundly low that a prescription or two might need to be on board to bring it up. If you’re opposed to prescription antidepressants, then we can start with SAMe. SAMe is a methyl donor that can substitute for methylfolate to help your body recycle homocysteine, and it can keep the methyl groups circulating to get all of the downstream pathways moving too. It also helps to boost serotonin.

SAMe by itself is probably not going to be enough, so something like St John’s Wort, which has an incredibly body of research showing that in some cases it boosts serotonin as much as an SSRI medication, can be really helpful. For a person with higher serotonin I wouldn’t suggest trying these two supplements together without professional guidance because too many things that boost serotonin can boost it uncomfortably high, but for poeple whose serotonin is so low that they don’t tolerate any folate, that is far less likely to be a problem. Just be sure you’re working with a professional if you are taking medications and supplements together because it’s important to have someone looking at interactions for you.

The bottom line with this group is that we need to get serotonin levels up before any kind of folate is going to be possible and for some people, it never will be possible. That is ok too – there are work-arounds for our work-arounds.

Another work-around is the amino acid methionine, which is a good option if nothing else is tolerable. Choline bypasses the MTHFR gene as well, but it’s a short-term solution. There are always option because your body has so many redundancies for every system. You and I are made up of layers and layers of fail-safes so that anywhere there is a problem, there are ways to get around it. Your body is a miracle of design and it’s important to always remember how much it is doing for you at every given moment.

Share with friends:

MTHFR is a common genetic mutation that can contribute to anxiety, depression, fatigue, chronic pain, infertility, and more serious conditions like breast implant illness, heart attack, stroke, chronic fatigue syndrome, and some types of cancer. If you know or suspect you have an MTHFR variant, schedule a free 15-minute meet-and-greet appointment with MTHFR expert Dr. Amy today.

Book Your Appointment
Amy Neuzil
Amy Neuzil

Dr. Amy Neuzil, N.D. is a leading expert in MTHFR and epigenetics, and she is passionate about helping people achieve optimal health and wellness for their genetic picture. She has helped thousands of people overcome health challenges using a simple, step-by-step approach that starts with where they are today. Dr. Neuzil's unique approach to wellness has helped countless people improve their energy levels, lose weight, and feel better mentally and emotionally. If you're looking for a way to feel your best, Dr. Amy Neuzil can help. Contact her today to learn more about how she can help you achieve optimal health and wellness.

Articles: 184


  1. What if you’re trying to slow taper from an SSRI that you don’t tolerate well (don’t tolerate any of them), and are also having a hard time tolerating foods with folate and folate or folinic acid and b12 supplements? I just found out about MTHFR, a year after starting tapering from Pax (holding at 9.2 mg now). I think i’m an under-methylator. I cut out all folic acid, am trying different low amount of hydroxo b12, but i’m getting cramping in my left hand and I don’t know why. Ugh frustrating to nail down..

    • Hi Erin,
      It sounds like you really just don’t tolerate folates at all, and that’s ok, we just need to find the right work-arounds. SAMe could be a good place to start – it is not suggested with an SSRI because it can also boost serotonin, so talk with your doctor if you decide to try it, but I think while you’re doing a drug taper it could actually be helpful to smooth out some of the rough edges that are left behind with the lower Paxil dose. Also, choline is a nice stop-gap that kind of detours around the MTHFR enzyme and is really well tolerated by most people. The cramping that you’re experiencing – it could be a minor magnesium deficiency. Sometimes when you get the B vitamins in place and detox and energy production start to ramp up it uncovers little deficiencies elsewhere (or creates them because suddenly your body is doing so much more). Thanks for being here and if you ever need one-on-one help, that’s a possibility.

Leave a Reply

Your email address will not be published. Required fields are marked *