Histamine is a hot topic in the migraine community. In this episode of Spotlight on Migraine, host Molly O’Brien speaks with neurologist Dr. Lauren Natbony to explore the relationship between histamine and migraine. Learn how histamine works in the body, why allergies and migraine often overlap, and whether antihistamines or low-histamine diets may help some people with migraine.

They also discuss mast cells, seasonal allergies, the gut-brain connection, and some misconceptions about migraine and histamine. 

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TRANSCRIPT

Molly O’Brien: There’s been a lot more conversation about the relationship between histamine and migraine, but what is histamine? What role does it play in the body? How does it work? Hi, I’m Molly O’Brien, and this is Spotlight on Migraine. In today’s episode, we’re going to break down this very complex topic of histamine and get a better understanding of how it works in our body and the role it may play in migraine. 

To help us break it all down, I’d like to introduce our guest, Dr. Lauren Natbony. Dr. Lauren Natbony is a board-certified neurologist and fellowship-trained headache specialist. She is the founder and medical director of Integrative Headache Medicine of New York, a boutique neurology practice focused on migraine, facial pain, and complex overlapping neurologic conditions, including autonomic dysfunction and hypermobility spectrum disorders. She serves as an assistant clinical professor of neurology at the Icahn School of Medicine at Mount Sinai, where she previously directed the headache fellowship. Thanks so much for joining us.

 

Dr. Lauren Natbony: Thank you so much for having me. 

 

O’Brien: Let’s start out just laying the foundation. What is histamine? 

 

Natbony: Very simple. Histamine is a naturally occurring chemical. It acts as a signaling molecule, so it signals other things to happen in the body. Most people think of it as this allergy chemical – that it has to do with allergies – but it actually has roles across the entire immune system, the gut, and the brain. That’s its basic overview. And when we think about histamine, we think about mast cells. So we talk a lot about mast cells, and that’s what produces histamine. And these are cells that sit in your blood vessels, near your nerves, and on different mucosal surfaces, and they are strategically positioned in places to respond to environmental triggers. So think about the mast cell, which holds the histamine. That all sits next to these areas that can be exposed to triggers in the environment. 

 

O’Brien: Can you break that down a little bit more? What is its role in the body? What does it do? Maybe give us some examples. 

 

Natbony: So histamine does a lot of things. I think of it as an army of defense. It’s part of the immune system’s first response – its first line of defense. So let’s say the body detects something like pollen, infection, or injury. That increases histamine release from mast cells, which then increases blood flow and makes blood vessels more permeable so immune cells can get to that area. It’s kind of like the soldiers marching into that area. And then it also stimulates the stomach to produce acid for digestion, so it helps with digestion. When we think about the brain, it’s involved in alertness, wakefulness, and attention. So if we think of antihistamines making us really tired, histamine is part of that attention pathway. So there are different histamine receptors. There are four, and they all do different things. So when we look at blocking them, I think it’s important to know what they do. 

 

O’Brien: Yes. 

 

Natbony: So H1 – the histamine 1 receptor – is involved in allergy and blood vessel dilation. H2 is involved in gastric acid secretion, so medications we use for reflux can target H2. H3 is in more neurotransmitter regulation. This is where some of the migraine work has been. And then H4 is immune modulation. So the medications that we have out there are mostly H1 and H2. 

 

O’Brien: Okay. That’s where they target to block histamine. Is that right? 

 

Natbony: Block histamine, yes. So if we think about it in migraine, histamine basically mediates the neuroimmune axis, and that’s what gets dysregulated in migraine. We know about the gut-brain connection. We know about blood vessel dilation. It’s basically sitting at that mediator between all of these different processes – the gut, the immune system, and the brain. 

 

O’Brien: This is so fascinating to me because it seems like histamine has a vital role in our body, but in everyday life we might just think of histamine as, okay, well, now I have itchy skin, I have a bug bite, or I have allergies from pollen, so my eyes are watery and itchy and red, or my nose is stuffy. But it sounds like histamine is responsible for a lot more than just these problem things. 

 

Natbony: So it’s funny. I think about it and I think about the pollen and I’m like, oh, my mast cells are degranulating right now. 

 

O’Brien: Yes. 

 

Natbony: That’s as a doctor, but I feel like, yes, the histamine release. That’s why I think taking an antihistamine is going to stop those mast cells from releasing the histamine, I’m going to be all good, and I’m going to feel better. So I think of it in that regard. 

 

O’Brien: It’s so cool to learn about what’s actually happening in our body. We talked about histamine as naturally occurring. It’s a messenger, it signals different systems within our body, and we have these receptors. So it’s there for a reason and we have it, but sometimes this can become a problem. So can you kind of explain how that goes? When, how, and why does histamine become a problem? Is it that we have too much? Is it that we don’t have enough? How does that work? When does it become a problem? 

 

Natbony: So as with everything, I frame it in a migraine context. 

 

O’Brien: Perfect. 

 

Natbony: It’s when instability and imbalance happen. So it becomes a problem if there is an imbalance between how much histamine is present and how well the body can break it down. So normally histamine is metabolized very quickly by enzymes. There’s diamine oxidase – DAO – which is in the gut, and then there’s also one that breaks it down inside cells. But when this system becomes overwhelmed and it becomes impaired, then histamine can accumulate. 

So this can happen with allergies. We talk about the gut microbiome, gut inflammation, reflux, certain medications, and alcohol. We talk about it in the context of migraine, maybe high-histamine foods. So some people might have this reduced ability to also break histamine down, and it becomes more of a problem.

There are problems with increased release of histamine and problems with decreased breakdown. So things that cause increased release are allergies, infections, stress, hormones, and hormonal shifts; and then things that reduce its breakdown include decreased DAO activity in the gut, certain medications because they impair gastric acid, and alcohol. So I sort of look at it in those two categories of drivers.

And then for migraine, I look at histamine as a threshold-lowering factor. It’s not the cause, but you take a person who’s already sensitive to change, and then you take something that’s getting more imbalanced, and you create a cascade of events that’s a problem.

 

O’Brien: It seems like there’s been a lot more chitchat about this. Do we know why that is? Or do you have a thought on why that is? 

 

Natbony: I think, first of all, with migraine, all the symptoms overlap. So migraine symptoms and excess histamine go into this big web of overlapping symptoms. You can get headache, dizziness, brain fog, fatigue, nausea, bloating – all of it. So how we differentiate is really difficult, and I think it’s not about necessarily differentiating. As I said, migraine is there, and then you lower the threshold. So what symptoms you’re having are probably histamine symptoms, but they’re being triggered by a migraine-sensitive brain. I sort of look at it as they kind of go together. 

And then for the focus on histamine and migraine now, I think there are a few reasons. I remember when I was a baby little/big fellow and was still figuring things out, but now we have a better understanding of obviously the biology of migraine, especially the role of CGRP. Histamine and CGRP actually interact and they can amplify each other. So I think with talking more about CGRP, histamine has sort of evolved there. So that’s number one. 

I think, secondly, there’s been more interest in mast cells and neuroinflammation. Obviously, COVID has brought a lot of attention to the neuroimmune axis, and then I think there’s been more talk about mast cells. And then I think also there’s been more awareness of all these overlapping conditions of allergies, autonomic dysfunction, hypermobility, and mast cell activation. Again, since COVID, it seems like this has become more of a conversation, which is good. I’m glad that this is happening. So I think that that’s why it’s just become more in focus right now. 

And I also think everyone wants to relate the whole gut-brain connection, and I totally agree. The gut and brain are connected, but how do we modify that? And then in relation to diet, diet has not been, in my opinion, great for migraine because I feel like it blames the patient, it’s very hard to do, and it really hasn’t had such profound impacts in most patients. So I think when I talk about if someone wants to go on a specific diet – a low-histamine diet – how that works with the gut, and talking through the pros and cons, I think there’s a lot more awareness about that now, and people want to talk about it. 

So overall, I feel like histamine was kind of fringy. I don’t know. It was more sort of on the outskirts of what we talked about, but I think now it’s being more recognized as a contributor to things in certain patients. It’s still not the primary driver, but it’s part of that stacking up of the threshold in the right patient. 

 

O’Brien: I love that explanation, and I really do appreciate it. How does histamine play a role within migraine? You’ve talked a little bit about how there are all these different systems at play. What do we know about putting it all together? 

 

Natbony: So mast cells are in the meninges. The meninges are the coating of our brain, and that’s where pain signaling comes from. So mast cells in the meninges can release histamine. And as I said, the mast cells live near where important things are, so those are near trigeminal nerve fibers, and trigeminal nerve fibers are important in migraine. So then when the mast cells degranulate and the histamine is released, it can activate and sensitize pain pathways. 

And then there’s this feedback loop with mast cells and CGRP. So mast cells get released and then CGRP, and it sort of goes in this loop. And then histamine can cause the blood vessels to dilate more, and it can also influence other pathways in the hypothalamus that are involved in the initiation of a migraine attack. So basically it becomes this self-amplifying cycle of inflammation and pain signaling, that sort of continuous cycle that just feeds on itself. 

But I think the main thing to know is there are mast cells in the meninges that can release histamine near structures that are responsible for migraine and set off a whole cascade of events. 

 

O’Brien: It sounds like the spinning wheel of doom on your computer that just goes around. 

 

Natbony: I still have the spinning wheel of doom sometimes, and I’m like, is this an antiquated thing? But yes, it is. It’s that spinning wheel, but that cycle doesn’t have to go and spin and spin.

But I think understanding it and saying that it’s the triggering force that keeps it spinning, but it’s not causal. How can we remove it or decrease it as a triggering force?

 

O’Brien: It seems like there are possible ways to break up that loop to reduce histamine in our body, I think. So let’s start off with antihistamines. People take allergy medicines. Sometimes people take allergy shots. Then there are potential antihistamines in a migraine IV cocktail that you might get at the ER. So can you talk to us a little bit about antihistamines, what they do, and the role that they might be able to play in migraine – either management, treatment, or just overall with histamine? 

 

Natbony: First important thing, antihistamines are not primary migraine treatments, but they definitely can play a role in specific situations. So there is a breakdown of the different antihistamines. First, we have the first generation. That’s like diphenhydramine and cyproheptadine, and these cross into the brain and are very sedating. So I feel like those are the ones where you’re going to get really tired because histamine helps with wakefulness. They can help with the associated symptoms of migraine like nausea. They can also help with sleep, and we know sleep is restorative to the brain. Getting someone to sleep can actually be helpful in sort of stopping that migraine. We also use them in pediatric migraine, especially cyproheptadine, because that does work on histamine, which is also involved in the pain pathways. I have seen it work for pain as well, but I think we think of them as helping with associated symptoms, which calms down the entire system. 

And when we give antihistamines in the emergency room, usually we’re using them in addition to other medications to mitigate side effects, but also just the sleep part of it – just promoting sleep and helping with nausea, sort of takes something about that inflammation and just kind of settling things down. So I will add diphenhydramine to someone’s regimen to sort of help with that process. 

For the second generation, those are like cetirizine or loratadine. They are less sedating but not really clear migraine benefit because they don’t cross [into the] brain. And then the H2 blockers, which are used for reflux, really don’t help with migraine, per se. I do have some patients who say I have really bad reflux. And the reflux is a trigger, so if we’re reducing the reflux and sort of talking about that gut-brain axis. But in terms of a direct role, there really isn’t one. 

Like I was saying, there also is some research going on for H3 receptors. Those are the ones that regulate histamine in the brain, but it’s still really early. 

 

O’Brien: I think that’s really helpful to understand how these different types of antihistamines work and how they may help in reducing that triggering effect but taking your daily antihistamine because it’s allergy season isn’t going to stop migraine because, as we know, migraine is much more complicated than that. But it could support you maybe not going into that attack. Is that kind of a good summary? 

 

Natbony: Absolutely. I think about myself the other night when my eyes are so itchy, I can’t sleep, and my throat feels like it’s itching. My sleep is then disrupted. It sort of triggers the whole thing. Then that morning, I wake up with a headache. So in that situation, I started taking an antihistamine before bed, and it stopped that loop. So it’s not so much direct, but looking at it as how can this set off a cascade of events that I could prevent. 

 

O’Brien: Okay. That makes a ton of sense. I really do enjoy this conversation. It’s so interesting to me. I kind of want to stay on that topic, being cognizant of time here. It’s on this topic – it’s not written on our question list – but say you have someone who has seasonal allergies who does have really bad reflux and they also have migraine. Does it make sense that treating these things separately could also help support migraine management? 

 

Natbony: Yes. I think migraine is so multifaceted, and that’s why I feel like I preach this multimodal, sort of integrative approach that we have to look at the factors and the variables that go into each person’s individualized migraine attacks and migraine experience. We know that there’s a link between allergies and migraine. So in supporting the allergy part of it, can we downstream affect migraine? Absolutely, and I think that’s why migraine is so complex, because it’s not just one thing. There are a lot of influences that go into it. But I think treating the allergies can reduce the trigger burden. So you’re treating the trigger, not the migraine itself, but that trigger is really important. And not everyone is going to be triggered by it. I think that’s the other thing – a trigger is individualized. 

So I think in terms of treatment, sometimes it’s hard to know is this actually helping migraine or not. So I think there has to be a clear, okay, maybe my attacks number is not decreasing, but I feel less vulnerable to the attack happening. So I always like to say to my patients, what are we looking for in terms of measuring if this is helpful or not? 

 

O’Brien: I like that way of looking at it. Maybe you’re not seeing a reduction in attacks, but I’m less vulnerable to an attack happening.

 

Natbony: Yes. There’s this «I’m just on the verge» feeling. I don’t know if you ever feel it, but there’s a lot of description of it’s on the verge, and that’s a very disconcerting feeling because it’s like what feels destabilized in that moment. But if you can take away that feeling and it’s a more clear-cut attack versus this on the edge, I still think that helps decrease overall migraine disability and burden. 

 

O’Brien: Absolutely. And then if you also can bring that down a notch, then you’re…

 

Natbony: Yes. 

 

O’Brien: …not stressed out about like, well, all these things happen in my life, I’m going to get… So you’re just bringing everything down. 

 

Natbony: Exactly. 

 

O’Brien: You mentioned that, yes, allergies have a connection with migraine. We’re talking about seasonal allergies or possibly if you’re allergic to cats, dogs – whatever it is. What do we know…

 

Natbony: Allergic rhinitis. That is the…

 

O’Brien: Okay. 

 

Natbony: Yes. 

 

O’Brien: Okay, fair. Let’s start there. What do we know about that connection? 

 

Natbony: We looked at linkage and comorbid conditions. We know that people with allergic rhinitis are significantly more likely to have migraine. That association doesn’t mean causation. It just means that there is some tied linkage. But if we sort of think about what we talked about – how histamine plays a role in different parts of the body, as do a lot of migraine chemicals – I feel like it makes sense that there are these linkages with other conditions. 

 

O’Brien: If you do have allergies, that’s not the cause of migraine, which you mentioned, but you might be more likely to have both conditions. So if someone has migraine and they also have allergies, and it’s allergy time of year, how can we tell the difference if we’re right in the middle of all the pollen flooding us? Or maybe a stuffy nose, watery eyes, and head’s hurting a little bit, is that migraine, or is it an allergy headache – whatever you want to call it? How can we tell? 

 

Natbony: That’s such a good question. And it’s so hard because when we think about migraine, we think of it as specifically pounding, moderate-to-severe headache, light and sound sensitivity, nausea, worse with activity. But that’s not the case for everyone all the time. When we think about allergies, there’s this itching, sneezing, congestion, but migraine can cause the autonomic symptoms of all of it. In the headache world, there is no such thing as a sinus headache. 

So I look at it as you’re having those allergy triggers sort of flooding your system and you’re having the symptoms of the allergy, which could be a precursor to the migraine. It’s all working on the same sort of migraine nerves and migraine chemicals. That’s the beginning part of what might evolve into a migraine. So they’re kind of all along the same pathway, but feeling more congested, sneezing and itching alone is not migraine – we need the other components to it – but it’s still something that I would want to treat as a potential lead-up into it. It’s very hard and it’s very nuanced, and I think that there is no great answer, but a lot of times it’s both. It’s sort of that circle of one going into the other. 

So then trying to say how can I reduce potential allergies, like looking at what can I do for overall life and does that help at all. I think even from our environment, just trying to reduce our exposure, air filters, bedding. I think changing your bed sheets is something that can really help. Obviously if you’re outside in the pollen, taking a shower, getting the pollen off, controlling environment – those are some more simple ways. If you notice that you are having a clear pattern of allergies, start there. Then introducing some allergy treatment, do I feel that is significantly helping my allergy symptoms…

 

O’Brien: Yes. 

 

Natbony: …first of all? Because allergy treatment will help the allergy symptoms – it won’t necessarily help the migraine – so separating those. 

 

O’Brien: That’s helpful. In the time that we have left, I have a couple other questions for you. Do you want to talk about diet a little bit more? You did mention diet earlier in the conversation, and we have seen a lot of interest in this for several reasons. People are interested in a low-histamine diet or restricting the amount of histamine that they intake. Can you talk to us a little bit about what this is, and is there any evidence that supports trying to focus on such a specific diet actually can help with migraine? 

 

Natbony: I feel like this is one of the most talked-about areas but also one of the most misunderstood. I just want to preface that migraine is not fundamentally a food disorder. It’s a brain disorder. The food part is the trigger. So basically we’re picking and saying that histamine in the food is what’s triggering some of my migraine attacks. What about histamine in other places? But sure, there’s some evidence that high-histamine foods can trigger migraine in the right patient, especially those who might have more of an impaired histamine metabolism. 

Remember we talked about how it’s broken down and overexposure where there are already some regulation issues? But overall, the evidence really is not strong enough to recommend for everyone. How I approach it is, okay, if we want to try it, sure, but making sure that it’s a short and structured trial because there are a lot of different foods. How do you go about doing it? I don’t like long-term restriction. And you also have to reintroduce because you can’t prove that it’s an issue if you just eliminate it without reintroducing it. So you need to get it out of your system and reintroduce to prove the link that it is a trigger. 

I see a lot of patients who then overly restrict, which creates its own anxiety over what to eat and when to eat. This is just one that I find is challenging. I’d rather first try to remove the other sort of potential inputs and then, sure, a trial if somebody really feels – or I feel – that histamine is really an overpowering source. But again, not for everyone. And just because histamine is one person’s trigger does not mean that it’s yours. 

 

O’Brien: I really appreciate you putting that into context. I do agree that it can be really difficult to do such a restrictive diet, and you have to have someone that you’re working with. 

 

Natbony: Yes. 

 

O’Brien: And it’s not a one-size-fits-all and explaining the science behind it. That introduction really needs to be a big part of it. It’s not just you cut this out forever. 

 

Natbony: Usually a trigger is multiple triggers stacked together that set it over the edge. So even if you do a total elimination diet, it doesn’t mean that then that one trigger in that moment is also going to trigger. So it’s very nuanced and very challenging. It’s my life. It’s fascinating, but it’s also very frustrating and I totally get that. But I think bottom line is it’s not a one-size-fits-all, but if you’re going to do it, do it in a way that is structured and that you do reintroduce. 

 

O’Brien: We’ve talked a lot about the role that histamine plays in the body. And not everybody has a good understanding of what histamine is or what it does. Can you talk to us about some of the common myths, misconceptions, or maybe just overall misunderstanding about histamine and its role with migraine? 

 

Natbony: I think the biggest one I see is that histamine is the cause of migraine. If only it was that simple, like we talked about. Migraine is a complex neurologic disorder, and histamine could be a triggering factor, but that is one that I see a lot, just talking about MCAS – mast cell activation – and it’s causal for migraine. It’s not causal. It could be associated. Again, I think that’s a very important differentiation because, one, you are basically saying that this is the cause. The other is you have a genetic neurologic disease that has a threshold for being triggered. 

And I think when we go down that pathway, the myth of then, okay, if it’s all histamine, then antihistamines should treat migraine. Why is it not helping me? Then also that everyone should follow a low-histamine diet. I think it’s all of the blanket statements of everyone should do one thing. I think whenever you hear that, you have to be a little mindful that it’s not one-size-fits-all. 

 

O’Brien: So helpful. Such good insight and expertise. Dr. Natbony, thank you so much for joining us today and helping us understand the very complicated and complex role that histamine plays in our body and within migraine. 

 

Natbony: Well, thank you for having me. And I just want to say to everyone, histamine might be part of your story, but it’s really the entire migraine story. Everyone is different. They have different puzzle pieces that fit together. So could histamine be a part of it? Sure, but it also might not be. So just remembering that everyone is different and approaches should be individualized. 

 

O’Brien: Absolutely. Thank you again for joining us and taking the time today. It was great chatting with you. 

 

Natbony: Thank you. You, too. 

 

O’Brien: And that’s all for this episode of Spotlight on Migraine. We hope you will like and subscribe. With the Association of Migraine Disorders, I’m Molly O’Brien. We’ll see you next time.