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MTHFR and Pain Medications – NSAIDS, Opiates, and Alternatives.

This whole week’s topic stemmed from a call-in question from Jane Turner that piqued my curiosity, so thanks, Jane! Here’s the question:

I just found out that I’m an MTHFR mutant… I have some pain issues, and I was wondering how NSAIDs or other pain medications that are tempting to use might be influenced by MTHFR, and if there are better choices that I should be considering?

– Jane Turner on the To health with that! Podcast

This is so relevant because pain is an experience that is shared by a lot of MTHFR folks. We have a higher tendency toward inflammation than average and that can be a big source of physical and structural pain, but we also have tendencies towards altered neurochemistry and with some neurochemical imbalances, the perception of pain is also heightened. Just to add to that, many of us MTHFR folks have a tendency to push ourselves to extremes – extreme competition athletics (especially in undermethylators), extreme expressive athletics like dance (in both over and under methylators), and extremes of ignoring self-care in favor of artistic, professional or athletic goals ( in both over and under methylators). Add to this all of this the sensitivities and toxicities which can contribute additionally to inflammation, pain is part of the MTHFR experience.

MTHFR and Pain Medications

Let’s start this off by saying, as I so often find myself doing, that research is limited. Very limited. We will go through different pain medications individually.

What is the risk of MTHFR mutations and pain medications?
In the case of pain medications and MTHFR mutations, what are the risks associated with them?

MTHFR and Tylenol

Tylenol (or paracetamol, or acetaminophen) is one of the most common pain killers used globally and is sold in most places without a prescription. The exact mechanism of action isn’t known, but it may act to reduce prostaglandins in the brain, thus decreasing the sensation of pain. It is not like most commonly sold pain medications, an NSAID (which stands for non-steroidal anti-inflammatory) because it is not known to be strongly anti-inflammatory.

Tylenol has been shown to reduce levels of glutathione, which could be part of why Tylenol overdose is one of the most common causes of fatal poisonings worldwide. This could also present more sensitivity for MTHFR mutants than for other folks. With an MTHFR mutation, our glutathione production is compromised to varying degrees (via the BH4 pathway). Glutathione production depends on many factors, not just MTHFR so this isn’t a cause for total avoidance, more just a cause for caution about prolonged or high-dose use. There is absolutely no research on Tylenol specifically with MTHFR – literally not one study, so it isn’t a well-documented issue. This is more of a theoretically potential issue, but something to be aware of if you take Tylenol on a regular basis. Also, it’s good to consider other factors that can deplete glutathione, like smoking or alcohol use.

MTHFR and NSAIDS – Ibuprophane, Naproxen Sodium, Etc…

Again, not even one study exists on this topic. I did stumble across a fascinating study about residual NSAIDs in water supplies increasing oxidative stress in a tiny water creature called Hyalella, but it would be hard to leap to any conclusions from that. At the end of the day, this one is a big unknown.

As far as I’m aware there aren’t any specific risks to MTHFR folks with this category of medications, but of course, all medications should be treated with caution.

MTHFR and Opiates

Opiates, especially lately in North America, have been the topic of extensive research because there is such a huge potential for abuse and also fatal overdose. As pain medications, opiates are highly effective and overlap into psychiatric and mental/emotional pain relief, which makes them especially helpful to many people. Unfortunately, there is a higher risk of opiate dependency for people with MTHFR polymorphisms, and research is only beginning to explore MTHFR as a factor in other addictions.

The unfortunate fact with opioids, is that many of the people with addictions started out with legitimate pain, and legitimate reasons to take legitimate medications. This isn’t the shadowy criminal underworld, this is just people looking for answers to medical problems.

There is a lot of controversy surrounding MTHFR and pain medications - are opiates really worth the risk?
MTHFR and pain medications – are opiates worth the risk?

MTHFR and Aspirin

This area is absolutely fascinating. Aspirin is a pain medication, of course, but also a well-known blood thinner. While there isn’t any research on aspirin medication for pain in MTHFR folks at this moment, there is some great research on aspirin for MTHFR families who have a history of repeat miscarriages. This study compared treatment with 100 mg aspirin + 5 mg folic acid daily with 100 mg aspirin + 5 mg folic acid + low molecular weight heparin (another, stronger anticoagulant). It showed a significant difference between the groups – with the triple therapy group having more positive pregnancy outcomes than the double therapy group. My only complaint is that the control group (the group that receives no therapy) were women without a history of repeat miscarriages or MTHFR mutations, so it’s difficult to see how much of an improvement from baseline it is for both groups.

This also suggests to me that micro-clotting, which is thought to be the mechanism that is interfering with these pregnancies in the first place, might be more of a routine issue for MTHFR folks than we realize. A similar study was done in women who were not tested for MTHFR mutations, which found that both aspirin and aspirin + heparin were effective in increasing pregnancy outcomes.

MTHFR and pain medications - the benefits of aspirin might surprise you
If you have MTHFR gene mutations and take pain medications, you might be surprised to learn how beneficial aspirin can be

Aspirin may also reduce the risk of colorectal cancer in MTHFR mutants, but the evidence, in this case, is really mixed.

MTHFR and Nitrous Oxide

Nitrous Oxide is not a conventional pain therapy, but it is used as an anesthetic, often for dental procedures or other minor surgeries. This is a really interesting case and it deserves its own post because there is a lot of information, but the quick and dirty version is that Nitrous oxide is not the best choice for MTHFR folks because it lowers plasma vitamin B12 concentrations (this study has a great discussion of how exactly that happens), which can, in turn, raise homocysteine levels. Elevated homocysteine and low B12 are factors that a lot of MTHFR mutants struggle with anyway, so this is doubly bad for us. Bad enough to be fatal in the most extreme cases, and also to cause blood clotting and it’s secondary effects (like heart attack and stroke).

For MTHFR-safe options for pain management, look for fewer drug-based treatments and more hands-on pain control methods. We’ll do a whole post about it in the future, but the most well-documented and researched therapies are:

  • Therapies that break up fascial adhesions like gua-sha, myofascial therapy, fascia scraping and any bodywork technique like Rolfing.
  • Light therapies like 660 – 670 nm/850 nm red light therapy
  • Cognitive behavioral therapy for chronic pain
  • Acupuncture
  • Cold laser therapy
  • Magnet therapy
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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.

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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.

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    • My pleasure, Jane!
      It’s all very personal – I have my own MTHFR issues, so it makes me really happy to pass on knowledge to other mutants. Thanks for a great question. 🙂

  1. I’m a mthfr mutation and I had 4 miscarriages the first month because I was taking folic acid and it was no longer suitable for me and now I’m taking folate, is it possible to have a normal pregnancy while taking methyl folate and blood transfusions?
    Or is it necessary to do microscopic insemination

    • Hi Maha,
      I’m sorry to hear about the miscarriages. For most people with MTHFR mutations conceiving isn’t the problem, it’s carrying a child to term that is the difficult part. So typically, intervention isn’t needed to get pregnant, but careful management of the pregnancy can be helpful. From your story, it sounds like you get pregnant reasonably easily, so I would think a normal pregnancy is possible, but the doctor you are working with will be able to tell you more because there is a lot I don’t know about your particulars (like why you’re doing the transfusions.) I hope this helps and all the best to you on your baby journey!

  2. Thank you!! So much confusion in this area. I looking at 3 surgeries in the near future. Is there anything I need to let the doctor and anesthesiologist know?
    Thank your for all your insite and knowledgeable.

    • Hi Angela,
      I would certainly let them know that you have an MTHFR polymorphism, and the particular one you have if you happen to know. Anesthesiologiests should be familiar because it does change the way we process certain medications. Thanks for the question!

  3. I would be a perfect case study on opiates and Homozygous C677T. I was prescribed them for years by a doctor for menstrual relief and the associated leg, hip and lower back pain. It turned into a physical dependency and I’m now 42, trying to quit suboxone, smoking (drinking anything, even a glass of wine with dinner, just randomly lost its appeal to me one day 8-10 years ago) and just found out I have to copies of C677T. I went through severe menopause between 35-37 to the point I was labeled suicidal and just before that I went hyperthyroid and was very skinny and very sick. No form of HRT has been my friend ever and I’ve been sick since December of 2021. I have an appointment with an integrative medical provider this coming Tuesday because I’m tired, numb and my life is a mess of merely existing. That and I’m not arguing with my PCP any more on my incomplete lab orders missing serum folate, homocysteine and early antigen for EBV or the fact that she firmly believes homozygous (which literally means 2 identical copies) C677T detected means one copy.
    I Wake every 2 hours to pee and every 3 to dry off from night sweats and just utterly exhausted but can never sleep (thyroid is trending down again). I was gathering historical and recent lab data today and saw a high a.m. cortisol and other things that were never even really followed as well. The nighttime jaw clenching and 5am headaches are especially fun.
    I’m working on diet, my gut is wrecked because sleep (and I’ve been on 40mgs of Nexium since 1999) sugar and carbs are my kryptonite, especially after midnight.
    I’ve started biocidin drops, a complete mag supplement, drinking more water and less sugar, added greens (powder, raw and cooked in the a.m. and again with dinner), collagen type I and III and my favorite is Barleans gut restore with Activated charcoal, aloe, flax and goldenseal. I’ve also started a digestive enzymes supplement. That’s all so far and I feel terrible. I’ve stopped all HRT patches and cut my suboxone dose from 16mgs daily to 4mg eod. And I am attempting to quit smoking.

    Thank you for the wealth of information you’ve gone above and beyond to provide. The biggest keys are the basics. Diet, sleep and attempting to stop adding to the list of toxic items my body tries to remove.

    • Oh wow, Jennifer! What a rollercoaster ride. First off, I would love to give you a big hug and a pat on the back for getting down to 4 mg suboxone eod. That is amazing and you should be incredibly proud of yourself. I’m really glad to see you added the magnesium as well – that’s a big step and remember magnesium is dose dependent so if you aren’t seeing the result you want (especially with things like the jaw clenching) you can up the dose. If you end up with loose stools then back it down, or split it into multiple doses.

      You are doing amazing – just keep putting one foot in front of the other and please be gentle with yourself. You’re working on a lot of big changes at once, so give yourself the grace to make mistakes and be human and then get back on track. You are a total rockstar! I hope your new integrative doc is awesome and can help you to weed through all the crazy to get feeling better. Thanks for being here and if you have any questions, just reach out!

  4. Thank you for this article. I have one copy of the MTHFR gene variant. I had a knee repair surgery from which I suffered for months without any reduction in pain. I now need a total knee replacement. I didn’t take any nsaids for the last surgery, abd zicdm wondering if my inflammation prevented healing. I do want to take an nsaid this time. Your thoughts?

    • Hi Gisele,
      I certainly think NSAIDS to reduce inflammation after surgery are a good idea, with or without the MTHFR mutation. In this case, the benefits of keeping inflammation down while you’re healing far outweigh any risks. With something like this, you’re planning on using the drugs for a specific period of time for a specific purpose (it’s not like open-ended use for something like arthritis where people end up taking high doses of NSAIDS for years, or at least while their stomachs hold out.) Does that make sense? Good luck with the surgery!

    • Hi Tammy,
      Great idea – actually, in Genetic Rockstars (the MTHFR community) we got into a low dose naltrexone kick and added an article to the MTHFR Library about it. The short version is that I’m a huge fan of LDN for pain and many other conditions (autoimmunity, chronic fatigue, so much more) and there isn’t any contraindication for MTHFR folks, so it’s usually a big win. I have seen people have side effects, but most tolerate it really well. We’d love for you to join us in genetic rockstars! Find us at

    • Which mutation do you have, Cassie? The MTHFR mutation means you have a lower than average conversion of other forms of folate to L-methyl folate, and also that taking the methyl folate bypasses the problem, so to speak. But are you talking about a different mutation?

        • Hi Mary,
          Tylenol is safe as long as you’re taking lowe doses for short periods of time (not high doses or every day use). NSAIDS like ibuprophen, naproxen, etc…are safe as long as you follow dosing guidelines. They do have some stomach side effects, so again they aren’t for long-term use. Aspirin seems to be safe for us, but like everything else – not for every day. I hope this helps!

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