33. Over-Methylation Explained: COMT, Estrogen, Mood & Inflammation

In this episode of the Histamine Well Podcast, Joanne Kennedy explains why over-methylation is becoming increasingly common, especially among women, and how it’s closely linked to COMT enzyme activity, estrogen dominance, mood disorders, and inflammation.

This episode breaks down the biochemistry of methylation in a clear, practical way—exploring how estrogen affects COMT, why some people react badly to methylated B vitamins, and how over-methylation can drive symptoms such as anxiety, irritability, insomnia, nervous system overload, and chronic inflammation.

Joanne also introduces the Mood Sense test as a real-time tool for assessing methylation status, helping practitioners and individuals move away from guesswork and toward personalized, symptom-aware support. With insights inspired by James Bradshaw, this episode is essential listening for anyone navigating estrogen-related symptoms, mood instability, or complex supplement reactions.

What you’ll learn in this episode:

• Why over-methylation is becoming more common, especially in women
• How COMT enzyme activity influences mood, stress tolerance, and neurotransmitter
• The connection between estrogen dominance and over-methylation
• Common emotional and inflammatory symptoms linked to over-methylation
• Why methylated supplements can worsen symptoms for some people
• How the Mood Sense test can help assess methylation status in real time
• Key considerations for supporting estrogen balance and calming the nervous system

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Transcript

0:00

Hi, it's Joanne. Over methylation is more common than you think. In fact, clinically, we've recently seen it far more often in our patient base than under methylation. So what's going on? Why are people over methylating? Stay tuned to learn about COMT, estrogen and the mood and inflammation issues that can arise when methylation goes into overdrive. Welcome to the Histamine Well Podcast. Designed for practitioners and patients alike. This is your trusted source for insights on histamine intolerance, methylation, gut health, women's hormones, and much more. I'm Joanne Kennedy. Your host, naturopath, author, and educator. Passionate about breaking down Complex science into clear, accessible knowledge. Whether you are a health professional or navigating your personal wellness journey, the Histamine Well Podcast bridges the gap between cutting edge research and practical understanding to empower you with the tools to thrive. Hi everyone and welcome back to the Histamine Well. Today's episode is quite short, but super important for practitioners and people dealing with estrogen dominance and mood issues. And that's because we're gonna be talking about over methylation and the COMT enzyme. So since we've been testing methylation at home in real time in our patients using the mood sense test, which is an saliva swab test that you can do from home. It tests what your methylation status is from day to day or from hour to hour, if you like. And what we've surprisingly seen time and time again is that the majority of patients are over methylating rather than under-methylating. This is especially common in our female patients since estrogen really drives over methylation, as you'll learn, but men can also experience it as well. So what's going on? Why do people who have genetic SNPs like MTHFR, BHMT, MTR, and MTRR. Which were often presumed to predispose someone to being underm methylating. Why are they actually over methylating? And the main reason comes down to the COMT enzyme. So before I talk about COMT, I'm gonna just quickly touch on what methylation is for those who are not sure. It's essentially an on off switch in the body. It's a biochemical process where a methyl group, which is simply one carbon atom and three hydrogens attached, and a spare bond. And that moves around the body and that spare bond attaches to neurotransmitters, immune cells, hormones, other COMTounds, turning them on and off. The key processes it's involved in is neurotransmitter balancing, histamine breakdown, detoxification, energy production, estrogen detoxification, proper immune function, and much more. So that's what methylation essentially does. So what is this COMT enzyme I'm talking about? So COMT(Catechol-O-methyltransferase). It's a gene and an enzyme. So we have the gene. It provides the code for the enzyme. It's the enzyme that actually works in real time in our body. And it's a methyl transferase. So a methyl transferase needs a methyl group to work. There are only over 200 methyl transferase enzymes in the body, but COMT seems to be one that when not acting properly(like acting slow or fast) can cause a lot of issues with mood in particular. Here's the key point. If someone has a slow acting COMT enzyme from a gene mutation, often a slow COMT, the enzyme is not working effectively. It's not clearing your dopamine and adrenaline because that's what it does. And it's not clearing your estrogen.'cause that's what it also does. And when it's not clearing and working, it's building up these methyl groups.'cause they're just there to do the job. The enzymes not acting fast enough and these methyl groups aren't being used and they build up. And when they build up, the first thing we see clinically is mood issues. So when these methyl groups build up, it increases dopamine and adrenaline. So patients can feel anxiety, irritability, they can feel really wide but tired. They can have issues with sleeping. A lot of insomnia. They can have sensory overload amongst other things. It is the mood stuff. That's why the test is called mood sense. Because mood is such a key symptom that we see in these people that are over methylating. So what's the estrogen connection? Even if someone does not have a slow COMT but they have high estrogen, that can actually just make that COMT enzyme overloaded with estrogen. And it's just too much to process. This is common in estrogen dominant women. People with gut issues'cause your gut's a big detoxifier of estrogen and histamine. As we know, histamine really increases estrogen levels. So estrogen plays a huge role when it actually comes to over methylating. Now according to James Bradshaw, who is the owner of Mood Sense. He's a PhD scientist. And I interviewed him on my podcast before, but I also got him involved in my histamine and methylation online group coaching course. And he was really helpful in rewriting the methylation module that I had to do since we've been using this test. Practitioners and students, this is the stuff we are looking at in the course. It's cutting edge, it's all the latest research. It's super clinically relevant. So if you're interested in my course, you can join the wait list. You can find that on my website. This is a quote from James. Estrogen has a much greater influence on methylation status than a handful of gene mutations. One of the biggest impacts we see clinically is how strongly estrogen interacts with the COMT gene affecting its transcription, its expression, and its role in estrogen clearance. Since COMT is responsible for phase two metabolism of estrogen. Sluggish COMT activity combined with high estrogen can predispose someone toward over methylating. Though this is never guaranteed, as many factors play a role. Now, the key point is that estrogen alone has an outsized impact. More powerful than any single SNP we currently know of, and therefore deserves special attention in any discussion on methylation balance. Another thing we see clinically, I would say just as much as the mood issues is inflammation in over methylating patients. Inflammation is our patient base. If you're a practitioner listening, you know what I'm talking about. People we see with health issues have chronic inflammation, which definitely drives up histamine. So what's actually going on with over methylating and inflammation. And I've seen this clinically. This is been fascinating to me. People have high histamine symptoms, skin rashes in particular. And they're over methylating. They take niacinamide, which reduces the methyl groups, and it significantly helps with these skin rashes. So what is actually going on? According to James Bradshaw, when methylation is excessive, it can dysregulate gene expression, particularly genes involved in the body's repair mechanisms and inflammatory responses. Elevated samE levels may drive this imbalance leading to an overactive or exaggerated inflammatory reaction. In other words, too much methylation doesn't just affect neurotransmitters and detox pathways. It can also tip the immune system toward inappropriate or heightened responses. So super interesting. cause we know that the histamine and methyl transferase is an enzyme that breaks down histamine. And you need methyl groups for that enzyme to work. But we need to understand that people can have high histamine in the first place because they're over methylating and they can't regulate the inflammation pathways'cause inflammation drives up histamine. So this has been a very interesting thing to see in clinic. So if you're listening and you're unsure, I really encourage you to do the Mood Sense methylation test. It's available through my website. There's a discount code that you can use. I can't remember what it is off the top of my head, but you'll see it there. And this is another quote that I want to leave you, that James provided me with for my course, which I find interesting because there's so much information on methylation online that like, where's it coming from? And when I speak to James, who's a real scientist. There's more questions than answers. Right? And clinically, the relevant information is only starting to become available. And with the use of this test, it allows us to correct methylation in real time. So according to James, when it comes to balancing methylation, the scientific community isn't really approaching it as a whole integrated system. Instead, research often focuses on one pathway or another, rather than looking at how everything connects. That means we don't just have regular systematic studies measuring things like samE Levels alongside other key markers. Hopefully research will catch up to that. For now, what we can do is look at how specific factors, for example, estrogen, influence different parts of the system. Now, the brilliant thing about this test is that it doesn't matter what you are doing. Over exercising. Under exercising. Taking medication. Not taking medication. Premenopausal. Postmenopausal. It tests and tells you what's going on in real time. So that's why it bypasses all the issues and tells you right now this is what's going on with your methylation. So thank you for joining me. I hope you found this episode beneficial. Be sure to subscribe to the histamine well so you don't miss an episode. Leave a review and you can also share this episode with someone who could benefit. If you have any questions you'd like answered. Or have a topic you'd like me to discuss, please go to my website, joanne kennedy naturopathy.com, where you can provide us with that information. Until next time, take care and be well.