#406 ‒ Migraine, cluster headache, and tension headache: symptoms, causes, prevention, and treatment | Brian Grosberg, M.D.

22:06I think you elicited one person who is bedridden, but many people with migraine are significantly impacted and walking around. And you'd never know necessarily that they're impacted unless you're asking them or seeing their behaviors by the way they dim the lights or try to end up pushing through. A lot of people with an invisible disease, I think back to a famous comedian, Rodney Dangerfield, that I don't get respect. I think that's migraine, right? Where most people think of it just as a headache without realizing it's a neurologic disease. And it disproportionately affects women three times more often than men.

22:43Peter Attia:Oh, wow. So 12 % is aggregate. Correct. But if you do the math. 18%. Yeah, it's disproportionately women. So almost one in five women. Correct. I'm actually amazed it's that high. Yes. And the hard part is that demand for outstrip supply, right? So demand for headache care, the number of people, number of clinicians across the country that are providing and able to provide headache care, there's just not enough just because of the numbers. Yeah, there's not enough Bryans. There's not enough Bryans or other people. Yeah, yeah. And then the training also is very different. So I'm very fortunate not only to have had great mentorship, but to be able to mentor the next generation of headache specialists, but there are 50 or so minted a year.

23:24It's just not enough.

23:25Peter Attia:There are only 50 fellowship-trained headache neurologists that are coming out of training a year-ish. Ish. Amazing. For a condition that affects 10, 12 % of the population. Correct. Yeah. We could almost come up with some interesting parallels there in terms of how many dermatologists would be trained that could treat a dermatologic issue that affects 12 % of the population. And the spectrum of migraine is so broad because we're just talking about migraine as a disease, but there are people who have episodic migraine and then there are people who have chronic migraine. So episodic migraine is where people have less than 15 days of migraine per month.

24:04Chronic migraine is where people experience 15 or more days of headache per month. That's most of the people that I'm fortunate to care for. And that's about one to 2 % of the population that experience 15 or more days.

24:17Peter Attia:These people are thoroughly debilitated. Half their time is in a state of headache. Correct. Okay. So 10 % of the population is experiencing up to 50 % of their time in headache. One to 2 % of the population experiences chronic migraine where they have more than 50 % of the time experiencing headaches. So the vast majority of people experience episodic migraine, but that episodic migraine is a range, right? It could be a couple of times a year to... Up to 50 % of the month. Up to 50 % of the month. Yeah. Okay. Before we get into treatments and other things I want to talk about, well, we could talk about them now.

24:52Peter Attia:Tell me a little bit about genetic susceptibility. Obviously, genetics matter given the fact that women are three times more likely than men. That always makes the first thing one might think as well, is it hormonal? How much does it relate to estrogen, progesterone? We know that there are receptors for these things in the brain. Does the frequency of this type of headache, is it higher during the reproductive years? Is it higher during the menopausal years? That would give us a clue as to the role of hormones. And then if during the reproductive years, is it higher during any part of the cycle?

25:22Peter Attia:That's a lot of information packed. I will try to tease that apart. And so ultimately, yes, hormones plays a role. Yes, genetics plays a role. But migraine is multifactorial in the sense that genetic environmental factors play a role in experiencing migraine. So if somebody has a family history of migraine, they're more likely to end up experiencing migraine. And through a woman's reproductive cycle and across hormonal milestones, migraine can certainly have a predilection around times of puberty, around times of menses, pregnancy, lactation, perimenopause and menopause. And so across these hormonal milestones, migraine certainly will fluctuate, if you will.

26:08I would say about two-thirds of women will experience migraines with perimenstrual attacks, with a nodal association of migraine around their menstrual period. And that association comes in two possible forms. One is women who experience pure menstrual migraine, where they experience menses and headaches and migraine occurring around their menses, solely around their menses, but not at other times of the month. That's less common. That That occurs in probably less than 10 % of women who experience what's called pure menstrual migraine, where the migraine are just around the menstrual period, usually a couple of days before and a couple of days into.

26:45Peter Attia:Which of course is the lowest period of hormones, which suggests hormone deprivation is driving that subset. Correct. And then menstrual-related migraine, which is present in about 50 % of women, is where they experience migraine not only in temporal association with their menstrual period, but at other times of the month. And so this is a very common occurrence for women. The estrogen, that dates back to the 1970s, studies that were looked at that natural decline in estrogen in the late luteal phase and the development of migraine. If we fast forward in time, what we know from studies is that it's the faster rate of estrogen decline in that late luteal phase that is unique in women who experience migraine.

27:36So it's this more rapid rate of decline in estrogen. I'm very proud because one of the people I was fortunate to mentor actually did those studies.

27:45Peter Attia:I'm surprised that we don't also see that post-ovulation because you also have a very sharp decline in estradiol post-ovulation. They kind of have two. They're sharp after ovulation and then not as sharp at the end of the luteal phase, did they see anything mid-cycle? So interestingly, around ovulation, there doesn't necessarily seem to be a much higher risk of developing migraine. And I think that's in part to this more rapid, faster rate of decline of estrogen in that late luteal phase, which is the unique part. Yeah. It could also be the progesterone because we don't see, progesterone hasn't risen in ovulation.

28:24Peter Attia:You know this, but just for the listener. So we don't see a progesterone crash post-ovulation, whereas post-luteal, we're seeing both estrogen and progesterone come down. So is it possible that it's the combination of them or the progesterone that's causing the problem? Right now, the belief is really the estrogen, that decline of estrogen, not the decline per se, but the degree and rapidity of decline that is unique mostly in women who experience migraine. The other couple of things to end up thinking about is we know estrogen can have effects on serotonin transmission. And so serotonin is involved in migraine, right?

29:00If I go back to the 1940s when serotonin was first discovered in blood, and then fast forward, serotonin was identified and noticed to be lower in blood during migraine attacks, and then the recovery phase would increase. Those studies ended up leading to the development of tryptans. So estrogen has a number of different roles to play in the pain pathways.

29:24Peter Attia:Has the experiment been done where you take susceptible women and you selectively give them estrogen during the period of time in anticipation of that? So for example, seven days post-ovulation, which would be peak estrogen as it's about to crash into menses, you give them physiologic estrogen replacement levels and does that mitigate any of this risk? Yeah, so estrogen has been given, those studies have been done. The hard part is predicting necessarily who is going to respond. So there are some women that will get improvement in migraine. There are some women, they may not get improvement. And there are some women who will take combined hormonal contraceptives and they may get worsening of their migraine.

30:10And so it's very hard to tease apart and know who's the individual that will necessarily respond. And in caring for those patients, one of the things that I try to do that's unique is actually in a collaborative care model, work with a gynecologist who is a specialist on hormones. And so working together, we actually try to end up mapping out a plan for individual patients.

30:31Peter Attia:What else do we know genetically about predispositions? Are people whose parents sufferers of migraines more likely to be sufferers themselves? Yes. People ask me why they have migraine. If there are parents in the room, I usually point to them and I say, you're the cause. Not to place blame. No, of course. But we think it's very, very highly genetic then. Correct. But there are many genes that have been identified for migraine. So it's not a specific gene. So it's polygenic, but highly hereditary. Correct. And the nervous system, if you will, of people who have migraine is more hyper excitable than people who don't have migraine.

31:08So it's not that there's more lighter sound, but the perception, if you will, the sensitivity has just increased.

31:16Peter Attia:Maybe a silly question you haven't thought of, but is there an evolutionary benefit to it? Not that this would have weighed heavily in selection, but is there an upside to the hyper excitability? Does it manifest itself in other positive traits during the period of time when the individual is not suffering? My question is through the lens of like, hey, if we're on a continuum of excitability and when the thing goes too far, you end up with a headache and that's bad. But if you pull back just a little bit from the brink, is there some benefit to that state? So a colleague of mine ended up writing about this a number of years ago where she postulated that the evolutionary benefit to women in particular may have been, if they're the caregivers of their family, that they would know if there was inclement weather coming, rainy storms, if they had end up, signs of danger.

32:05And so that may be one of the evolutionary benefits. The other thing is, you know, if I think about the neural networks in men versus women, women generally have to multitask much more than men in general. And so the question is whether the neural networks, if you will, are better.

32:20Peter Attia:That is super interesting. So one of those says, look, women might be more wired to be better at multitasking. And the migraine is just a manifestation of an extreme, more extreme version of that, which you're going to get if you shift the population over that way? And then the second issue is presumably through changes in barometric pressure. Is that the most common weather-related triggering event? Triggers are not the cause of the headache. Triggers are factors that will elicit a headache in somebody who's biologically predisposed. So meaning if somebody is not biologically predisposed to having migraine, then there may be a weather storm that's coming through and they may not experience a migraine.

33:01But in somebody who has migraine, they may have one or more triggers. Some people with migraine have no triggers. Others have multiple triggers, changes in weather, the letdown phenomenon after stress, drinking or eating certain types of foods that may trigger. And it's usually a combination of two or more triggers that will precipitate an attack of migraine.

33:22Peter Attia:Do you have a sense of what subset of patients are indeed triggered by weather patterns and changing barometric pressure? It varies from person to person. My patient population is one that generally suffers more because it's more so in the people who are experiencing 15 or more days of headache per month. And so that reporting bias may occur. I may hear that more often than others may. That kind of makes sense. The more severely impacted people would presumably have more diversity in their triggers as well? Correct. They may, but not necessarily. And that's what makes migraine very nuanced, if you will.

33:58That's why the history needs to be detailed. So the questionnaire that people are filling out for me are 15 pages, pretty extensive in trying to end up determining if I'm dealing with a primary or secondary headache. And then if it's migraine, how does it present? Because a headache diary is probably the most important thing that your listeners can do for not only themselves, because it really empowers patients. But for a clinician like me to understand, because the patterns may be different from person to person.

34:25Peter Attia:Do you have an online version on your website that patients can download? Yes. Okay. So we'll link to that in the show notes so that anybody listening to this who wants to actually have a diary and know what things to put in the diary, they can do it. I agree. It's funny. We live in this world where we're so obsessed with really high-tech things and sleep trackers and all these things, but honestly, like a sleep doctor, if you go and see a sleep physician, they're going to want you to do a really good pen and paper sleep diary. And we still give those to our patients who are in the biggest distress around sleep because the information it captures is so much more rich, so much more temporally related to what's happening.

35:06Peter Attia:And two weeks of painstakingly doing this will offer more than two years of tracker data. Sounds like very similar for you in getting a good diary? Obviously, it might take more than two weeks given the frequency of the headache. Yeah, usually we're looking at a period of several months, particularly if it's a woman who's reporting a relationship between their migraine and menstrual period, because ultimately to make a diagnosis of probably menstrual migraine, whether it's pure menstrual or menstrual-related migraine, that association is known in at least two out of three cycles. obviously thinking about the patient that first connected us 10 years ago one of the things that stands out about me because she was a menopausal patient this was a woman who at the time was in her probably late 50s early 60s she did better on hormones but it couldn't be too much there was a very very fine line in other words we ended up having to use estradiol and progesterone as you do in perimenopausal women, but less than you would normally have treated someone.

36:10Peter Attia:In other words, we couldn't take her to full therapeutic dose. Is that common in menopausal women? Those transitions, if you will, from perimenopause to menopause, not only are hormonal fluctuations are occurring in perimenopause, but so is migraine. And so in a patient like that during perimenopause, there are women that will experience a significant worsening of migraine. Probably about two-thirds of women who, after they've transitioned to menopause, they've finished perimenopause, they will notice improvement in migraine. But 10 to 20 % may actually either continue or get worse. I find that there's a fallacy where some patients are told that once you hit menopause, you're finished and you're not going to have migraine anymore.

36:51And the hard part becomes is it's not only the hormonal fluctuations, but the impact on others' symptoms. So there may be sleep disruption, there may be other pains, joint pains. And so there are risk factors that put one at greater risk for more frequent migraine. If somebody experiences five or more days of headache per month, they're at greater risk. Sleep disturbance, changes in mood, which can end up happening in perimenopause, going into menopause. So all of these things have either direct or indirect impacts potentially.

37:23Peter Attia:I mean, this just makes it a very complicated thing because now, in addition to all the reasons you would consider HRT, you have to then consider if you're in that group of women who are improving in menopause, presumably adding hormones makes you worse. Not always. I mean, unless you figure out that sweet spot like we did in this patient where we could still give hormones to maybe two-thirds of the level without making it worse and then still capturing two-thirds of the benefit or something. Yeah, there are, just like in this patient, there are some women who will not necessarily need HRT or hormone-related therapy, and there are others that, despite best efforts with non-medication and medication approaches, will need HRT.

38:06The hard part becomes is, like you're pointing out, it becomes very individualized. What may work, what dose may work for one person may not work for another, and too much may potentially exacerbate versus too little may not end up providing the relief that's needed.

38:22Peter Attia:Yeah. Anything else about presentation and susceptibility of migraine? I want to then talk briefly about, see if we have anything to finish on tension and then get the cluster. Yeah. So I think presentation of migraine is, I spoke about a couple of the phases, and not all people with migraine have all the phases of migraine. So the first phase is that premonitory phase, the calm before the storm, and a quarter to a third of people experience the aura. And then it's the migraine phase, but it's not just the pain. It is potentially a constellation of symptoms, that light sensitivity, the sound sensitivity, nausea.

38:54It may be autonomic symptoms. So if somebody has tearing or redness of the eyes or congestion running of the nose, often people think that they have, quote, a sinusetic. But there's no such thing as a sinusetic. There's acute rhinosinusitis. There's chronic rhinosinusitis. But based on the pathophysiology of migraine, there is involvement of an aspect of the parasympathetic nervous system that has a connection, if you will, with the nerve called the trigeminal nerve, which is the main nerve that's involved in the experience of migraine and headache. And when people's parasympathetic nervous system becomes activated, people may experience tearing or redness of the eye or congestion or running of the nostrils, which is pretty common in people with migraine, and they think they have, quote, a sinus headache.

39:39And then ultimately, at the end of the day, after the pain is gone, they can experience a post-trome, which is the pain is gone, but I don't feel back to myself. I feel hungover. And that can last for hours. up to even a couple of days. And so when I take a history of migraine, I want to understand what's the total impact? Meaning if they experience all the phases, what is the duration of each of them? What's the personal impact? Because we just focus on the pain, but not necessarily the impact in totality. The other thing is the interictal burden. One of the things that you pointed out, I really appreciate it, is how are people thinking about their plans, their daily activities in anticipation of experiencing a migraine, meaning I'm not experiencing a migraine now, but I don't know when it's going to come.

40:27How am I going to plan that vacation? That's what's referred to as interictal burden.

40:31Peter Attia:Interictal meaning between the pain bouts. Between the pain bouts. And so that's where when I'm eliciting all these pieces of history, I'm thinking about how am I thinking about their acute treatment plan? How am I thinking about their preventive treatment plan if they need that? How am I thinking about non-medication approaches? And then combining the picture together, obviously with the patient driving the decision-making once they understand the rationality of how I'm putting it together. Can you say a little bit more about some of those post-ictal experiences? What fraction of migraine sufferers, once the pain is gone, are largely able to resume activity versus those that have that post-ictal period where they're not back to normal for a day or more?

41:17There are population-based studies and there are clinic-based studies that have been done. So population-based studies, looking at the general population, clinic-based studies, like somebody would do an academic headache program like my own, those numbers can range anywhere from like 60 % to in the high 80s.

41:32Peter Attia:But it's still a big number. It's a big number. The same thing with the premonitory symptoms, kind of that calm before with the storm. Okay. Now you said, by the way, for everything we're talking about here, 12 % of the population, three to one women to men, going back to tension, which we talked about very briefly, you said that's the single most common cause. It's the anti-migraine. So it's all the things that are in my migraine. What's the prevalence of that? Lifetime incidents maybe or lifetime? That's pretty high. Yeah. A lot of people are going to experience that. Yes. Okay. Female to male difference?

42:01Peter Attia:Pretty evenly split. What are some of the triggers and how genetic is it? I think the name lends people to think necessarily that it's just tension or stress that causes the headache. And that's not necessarily the case. That's why it's referred to as tension-type headache. And so that's the experience where people have that lighter sound sensitivity, mild to moderate pain, that can be around the head, the muscles around the head, the muscles in the neck, and the nerves that are involved. The anatomy and physiology, there's overlapping, if you will, because the nerves that supply sensation to the face and the head of the neck are similar to what's involved in migraine.

42:40There are genetic factors that are responsible, there are environmental factors, and then there's pericranial or around the head muscle nerve tenderness, if you will, that's a contributing factor as well.

42:51Peter Attia:If a person has a tension headache and they take a thousand milligrams of Tylenol and they get better, do they have a tension headache? Or in other words, could it respond to something as simple and over-the-counter as that? Yes. Okay. Yeah. As long as we know that that's what it is, that it's a tension-type headache, because making any diagnosis not only meets criteria, but also that it's not attributable to something else. Okay. And obviously, we're going to come and talk about the potential treatments for these things. So let's round it out with cluster then. So what's a cluster headache? So cluster headache is relatively uncommon, pretty rare relative to migraine and tension-type headache, but it's one of the most painful disorders known in the world.

43:31I have a woman patient who's likened it to giving birth to 100 babies at the same time without an epidural. I mean, that's the exquisite nature of the pain. And so it's pretty distinctive in its presentation. It disproportionately affects men more often than women. So that ratio that is now about three to four to one. It has characteristics where people may have a circadian periodicity or circadian periodicity. By that, I mean the longest and shortest days of the year, January and February and July and August. People can experience cluster periods where they may have daily or near daily attacks, sometimes multiple attacks per day.

44:09And this pain often is conceptualized as in and around or behind one eye. It's usually almost exclusively side-locked, so just on one side of the head or the face. The rapidity of onset is very quick. Unlike migraine, which generally will gradually build up, cluster headaches peak within about 5 to 15 minutes. The attacks generally last anywhere from 15 minutes up to 3 hours and can be characterized as stabbing, boring, exquisite nature. And then as soon as it came can often be as soon as it goes. And with the pain, people can end up getting very characteristic features. About 97 % of patients can experience a droop of the eyelid on that side, a tearing or redness of the eye on that side, congestion or running of the nostril.

45:01And so not only can you see the experience on the person's face, but you could actually see the visual symptoms often. And about 90 % of people with cluster headache can experience a sense of restlessness with the attacks where they can't sit still. They need to move about. That's in contrast to migraine where the vast majority prefer to be still or lie down in a dark, quiet room. And so the presentations are very, very distinctive. And where cluster headache has also been nicknamed suicide headache, not only because of the intensity of the pain, but the frequency of which these attacks occur.

45:35So on average, people can experience three attacks per day. The criteria allow people to have one attack every other day, up to eight attacks per day. And these cluster periods could be, depending on the person, weeks to months, sometimes longer. So depending on if somebody has episodic cluster headache, where they get this cluster period and then a break in time, or chronic cluster headache, where they have no break at all. They're just having multiple attacks per day.

46:00Peter Attia:Does the term suicide headache stem from the fact that people will take their life if it's extreme enough? Yes. That's terrifying. Does that suggest that the drive to move provides some relief? I don't know if the drive to move provides relief as much as the areas in the brain that are involved during the attack of cluster headache can cause manifestation of symptoms. And one of those manifestation of symptoms is a sense of restlessness or agitation. What else do we know about these things? How genetic are these? We know that there are genetics that play into cluster headache as well. First-degree relatives may be at higher risk.

46:40Like I said, it's not common, but these are very highly motivated patients, just like migraine, but maybe even more so because of the exquisite nature. They also, like migraine, often go underdiagnosed or misdiagnosed because of the presentation of pain, because it can be a predilection for attacks to occur January and February. So people may come into their doctor at that period of time, say that I have pain, I have nasal congestion, and they may be told, oh, you have a sinus infection, then receive an antibiotic. July and August, they may come to their doctor and say, I have pain, tearing or redness of the eye, and they may be told, you have allergies, you need allergy shots.

47:19Some people will have pain that's around the teeth or the face, and they have had teeth pult or major dental surgery or sinus surgery without realizing that the presentation is actually cluster headache.

47:33Peter Attia:Part of the log that people can download from your site that allows them to take an accurate history, is that something they could take into their primary care physician if they're having a headache? And does it highlight enough for the doctor the flag that says, hey, this might actually be a cluster headache and this might be one of the times when even though it's hard to get to headache specialists because of the frequency or the low number of them, it's worth taking the time to get the right clinician on board before we make a mistake and treat you for something you don't have. Yes. I think that becomes very important.

48:07I think about my primary care colleagues and the number of things that they have to address in a relatively short period of time.

48:15Peter Attia:And headache may be just one of them. And I think that's the hard part. So we want to kind of arm patients with a ton of data so that when they meet their PCP, they can do the lifting for them. The 10 minutes that that primary care doc has, they're not going to be able to do the detailed history you would do. But if they can walk in with it, hopefully the doctor is receptive and says, oh gosh, yeah, I wouldn't have had the time to elicit this or wouldn't have even had the knowledge base to elicit. I was about to say, it's not only receptive, it's the time. It's also having the knowledge and education experience to make the diagnosis and then offer the appropriate treatments.

48:50All the stars need to align, if you will. Most people with headache, if they're coming in, they're not coming to me for the first time. Sometimes they do, but they're often going to their primary care. So that's the gateway, if you will. The hard part becomes is kind of navigating afterwards the gateway, particularly if they don't have a diagnosis or they're misdiagnosed.

49:08Peter Attia:And patients come and see you from all over the place. All over the world. Yeah. That means that obviously a lot of them can't see you when they're in the throes of suffering. Does that matter? So for patients with cluster headache, that's kind of the password, if you will, in my office, in the sense that if somebody who's either an established patient or somebody who's trying to get in, they will say that they have cluster headache. And if in fact, they, at least on the basis of their questionnaire, seem to check off information that alludes to that possibility, then yes, they're seen quicker in general, just because it's been nicknamed suicide headache.

49:42Peter Attia:Is there a benefit to you seeing them while suffering to make a diagnostic or treatment decision? Yes. And the reason why is often patients with cluster headache require multiple treatments. One could be acute treatment, meaning when they experience the attack, they're using a treatment to rapidly abort the pain. The other is a preventive treatment. So they're taking something, one or more things to prevent attacks because often these patients with cluster are You're experiencing frequent attacks a day over a period of potentially weeks to months. And then transitional treatment. The preventive treatments often take weeks to months to build up, even for migraine.

50:22And so what is being done in the transitional period?

50:26Peter Attia:Sorry to interrupt, Brian. When you say preventive treatments, do you mean lifestyle preventive treatments like changing diet? Or do you mean actual pharmacologic prophylactic drugs that you need to just have on board to reduce the probability of an attack? Yeah, so a multidisciplinary approach. So meaning for patients with cholesterol headaches, some of the examples would be avoiding alcohol, avoiding foods with nitrates, not taking naps during the day, preferably if they have a sleep apnea, addressing that because hypoxia can sometimes be associated with it as well. And then at the same time, preventive treatment is taking a pharmacological, right, a medication treatment that may take time to build up.

51:08And while that is being built up, offering something to try to rapidly suppress the attacks until those preventive treatments kick in. Yeah.

51:16Peter Attia:Well, let's use that to pivot to the first thing that you talked about there, which is what are the modifiable lifestyle interventions that you would keep in your playbook for these patients? And are they the same across all the headaches? Everything you just said, for example, around correcting sleep apnea, minimizing alcohol, avoiding naps during the day. would you give that advice to any person suffering from headache or are you really narrowing that on the cluster patient whereas the migraine patient you have a different playbook? Migraine itself has certain identified risk factors. Even the subtypes of migraine may have their own identified risk factors.

51:58So if we know from studies that were done that if somebody is experiencing at least one migraine a week more than that may put them at greater risk for more frequent attacks of migraine. So the higher the frequency of attacks at baseline maybe lead to chronification or transformation of more frequent migraine. Somebody who has stressful life events, right? We all do, but that's a risk factor as well. Sleep disturbance. That may be insomnia. That may end up being sleep apnea. So once again, modifiable. Person's mood, depression, anxiety, or comorbid with migraine. They coexist at a higher than expected by chance.

52:38and there's a bidirectional relationship between mood disorders and migraine. And so addressing those, that's why I try to explain to patients that all the stars kind of need to align. It's not just taking care of your pain, but we need to end up addressing these risk factors. People frequently using acute pain medications. So there are some classes of pain medications where if they're used two or more days per week on a regular basis over an extended period of time, that can actually create more frequent headaches. It doesn't happen for everybody.

53:06Peter Attia:That could be NSAIDs and acetaminophen or opioids. It could be nonsteroidal anti-inflammatories, simple analgesics. It could even be triptans, migraine-specific medications. It could be barbitric-containing combination analgesics, medications like fioracetofioranol, opioids. And then if somebody has other pain disorders, obesity is a risk factor for more frequent migraine. And the greater the degree of obesity, the greater the risk. And do you think that's inflammatory? Do you think it's insulin-related? It's probably multifactorial as well. Migraine itself has a pro-inflammatory component to its pathophysiology.

53:41And so there may be shared mechanisms that underlie that.

53:45Peter Attia:And is this modifiable if a person is... So first of all, do you know what the hazard ratio is or the increase in relative risk with obesity versus not with respect to the headaches? So people who are morbidly obese are at five times higher risk for more frequent migraine. Oh, so it's not subtle. It's not subtle. This is dramatic. And there are studies with weight loss, surgical and non-surgical, showing improvement in migraine, not uniformly across the board for every individual, but certainly showing improvement. Modifying that risk factor is very helpful as well. Some of these numbers are shocking.

54:18Peter Attia:The women being three to one is not shocking with my lived experience because when I stop to think about it, almost all of the people I've encountered with migraines, or most of them, are women. I get that. The obesity is 5X. That is surprising. Morbidly obese. Okay, so morbidly obese. Meaning 35 BMI? Yeah, yeah. But what about obese? What about 30 to 35? Great risk. How much? 2X? 2X. Okay, still a big deal. Yeah. So in other words, if you're looking for a reason to correct obesity, there are plenty of them on a health perspective as it pertains to chronic disease like heart disease and cancer.

54:56Peter Attia:But when you think about two dramatic things that improve the quality of your life, one would be orthopedic. You just have less wear and tear in your joints. And then another could be for the susceptible individual, these headaches. Correct. And then having other pain disorders, which you just alluded to, whether joint pain, neck pain, back pain. Which leads you to more of the medications that then also become the trigger. And has that been corrected for in the analysis? Yes. Having other pain disorders in and of itself puts one at greater risk. having the presence of nausea, nausea that's not optimally treated.

55:27If a migraine attack is suboptimally treated, also greater risk. So when I'm listening to history, I'm almost doing this computational analysis and then explaining to people, here's how I'm thinking about it. This is why your treatment plan is being designed this way. And no two people are going to necessarily have the same treatment plan. That's what you were asking in terms of migraine versus cluster. Cluster headaches, certainly we're going to talk about lifestyle modifications, but it may be things that are particular triggers, whether it's the food, the nitrates, the sleep apnea, taking naps during the day.

56:02With migraine, it's what are those risk factors and how do we address not only the disease migraine, but also those risk factors to try to prevent progression. Okay.

56:11Peter Attia:Just to play that back, make sure I heard it. Prophylaxis on the cluster side is around identifying the triggers. What's the thing that's making it happen? On the migraine side, it's because there are fewer acute triggers that we are aware of, it's more just generally reducing probability of it happening? Let me clarify. So for cluster headache, it's not the triggers. Those are things, lifestyle changes that I may suggest to them. It's the pathophysiology and the mechanisms that are underlying cluster headache that will precipitate attacks potentially at different times of the year and different times of the day or the night because there's involvement of the sleep-wake cycle.

56:54And that's why people have this circanual periodicity and this circadian periodicity because there's involvement of the hypothalamus and the pineal gland and the changing of the clock for daylight savings time. So I know when the clock has changed, I'm going to hear from people with cluster headache. In both spring and fall? Yeah. I mean, I have patients, I have a patient from Australia who, when he travels there, he'll get cluster attacks because the season's changing when he comes here, if he comes at the differences.

57:19Peter Attia:And how much of that do you think is fixable with circadian rigidity? In other words, if you said to a patient, look, Bob, I don't care that we're going to change the light. We're going to get a 50 ,000 lux light in your home. And we are going to make sure that your pituitary, your hypothalamus, your pineal gland, every part of your brain is seeing light and darkness at the exact same. Again, I'm using this as a thought experiment, We are going to completely control your light environment independent of the seasons. Would that have an impact? I don't think that's going to eliminate a person's cluster headaches.

57:59I think what it will do is if somebody is not necessarily going to areas or time zones where there may be seasonal changes, they may not necessarily experience cluster attacks, but that's not a certainty.

58:14Peter Attia:And how often do you just take an empirical approach to this and say, look, we're going to throw the kitchen sink at this two interventions at a time until we find things that work? I mean, for example, we do this all the time with dietary sensitivities. So you get a patient who's just got debilitating bloating and GI issues, autoimmune conditions that aren't otherwise easy to identify. And one path is I'm going to run a bunch of blood tests on you that are totally bogus and bullshit and made up and have no verifiable causes. And I'm going to come up with a bunch of silly recommendations and give you a bunch of dumb supplements.

58:48Peter Attia:Obviously, that's not our approach, as you can tell by my language. An alternative approach that seems way less scientific, but frankly works a lot more is we're going to do an elimination diet. We're going to hypothesize that something in your diet is causing this, and we are going to selectively and ruthlessly pull things out of your diet until we find the trigger, which means pull it out, wait for an improvement, reintroduce it one at a time and watch to see if we can precipitate it. And this is how we will figure out the role of dairy, alcohol, caffeine, wheat, all of these things. Again, seems less scientific, way more practical than using bogus metrics that don't mean anything.

59:27Peter Attia:Do you ever do the same thing in the headache landscape? Yeah, so a big focus of what I do is on lifestyle. How do we modify things that will set that person up for best success that may be triggers or that help reduce risk factors? I try to take a very calculated approach. I also try to understand the person who's sitting in front of me. Right. How willing are they to be empirical? So it's, what's the diagnosis? What are their coexisting medical conditions? What's their preference? What are their expectations? Before I start a visit, I ask people, what are the one or two most important questions I can answer today?

1:00:02I want to understand that person's perspective. It's not enough to end up giving them the medical information, but I want to make sure it aligns with how they're thinking about it. And then it becomes very tailored. If I'm thinking about lifestyle modification, we're focusing on diet, routine meals a day that are not delayed. And if there are particular food triggers, asking them to track with the headache. Unless I understand the individual, I don't necessarily ask them to eliminate everything at the same time. I also want to know if there's a family history of either gluten sensitivity or celiac disease.

1:00:34And so that may lead me down the path to end up thinking about them getting tested for that. But there are certain, like you said, certain foods that may be triggers for certain people. Alcohol may be triggers, but not everyone. And that's why I say it's very individualized. And then the importance of sleep, hormones, environmental factors, exercise, and reducing trigger burden. So meaning if somebody knows that I may be set up for an attack at this particular time, then I may say, okay, you may be able to mitigate that risk by doing X, Y, and Z. And an example of that is when people keep headache diaries and they may experience attacks on the weekend.

1:01:15I'll say, okay, so what happens during the week? You go very hard, endorphin levels go up and then they drop down. And then you go to sleep later on Friday night and you wake up later on Saturday and your caffeine intake is delayed. That's three triggers. And so then people have like the aha moment. Oh, I didn't realize that.

1:01:33Peter Attia:And this is especially valuable when they're doing the log because you can see during the week, I have my coffee at six in the morning. On Saturday, I'm not even getting up till eight o 'clock in the morning and having coffee at nine. And you wouldn't think of that. Right. And those are the nuances that I point out. And usually the diaries that I ask people to keep are a month view. And so that way I'm able to quickly glance and I actually pull the diary off into patients and I'll say, okay, here's how I'm thinking about and interpreting this. This is why we're going to end up using these treatments.

1:02:02And so an example would be if someone experienced menstrual migraine, which is quite common, I may say, oh, okay, so your menses, how long does it last? What's the intercycle length? What's the length in between the cycles? What's the characterization of the flow? When do you experience headaches in relationship to that? I see that it is the same every single time. Because of that, that timing, we may be able to use preemptive treatment. We may be able to actually start treatment in advance and then carry it through the days that you would normally anticipate it. The diary, it's an effort that not only empowers patients, but it really helps guide decision-making.

1:02:40Yeah.

1:02:40Peter Attia:I like that you're talking about this because it's a great call out to patients for why you want to invest in this effort. Let's admit it. It's a bit of a pain to have to fill out one of these diaries. You have to write down what time you go to bed, what time you wake up, when your period starts, how long it lasts, what the characteristics of it are, when you have caffeine, when you have alcohol, when you work. I mean, that's a lot to keep track of. It's a 20 minute added burden every day. And I thank people for it. I said, listen, I know you're putting in effort. But it pays huge dividends. We don't need to go through every single lifestyle adjustment because all the ones that are in the obvious category are worth stating.

1:03:17Peter Attia:Everyone who has sleep apnea should have it corrected. Everyone should exercise. Everyone should moderate alcohol intake. Everyone should be sleeping a certain period of time. Everyone should be trying to fix bedtime and wake-up time relatively. Everybody should be doing circadian health, etc. Is there any non-obvious lifestyle thing that you can think of? A couple of things that I would think about that. So one is, I'm not sure when I see patients whether every risk factor is weighted the same way. There may be some that if somebody is not getting enough sleep and insomnia is quite common in people with migraine that we may be able to try the best medications in the world, but if they're not addressing that, it's going to get harder to get that under control.

1:04:03I think the regularity, migraine has that hypersensitivity. And so if people are adhering to routine meals, drinking enough water, exercise, getting appropriate sleep, which is not so easy because sometimes they have to employ non-medication approaches, which are hard to do, but ultimately pay dividends. I think the important also thing that people may not think about is that stress reduction, whether it's meditation, biofeedback, cognitive behavioral techniques. Autonomic control. Correct. I think people, not everybody, but I think some people sometimes focus on the medications and don't realize it's a holistic approach.

1:04:42It's looking at the whole individual and trying to kind of present those lifestyles in the way of being able to end up helping their migraine and making them feel better overall. Yeah.

1:04:53Peter Attia:And as you said right there, it's a double win because if we get those things right, you're getting a benefit it outside of the realm of your headache. All those things are actually just better for your risk of chronic disease, your health span, and other capacities as well. So let's now talk a little bit about pharma through both lenses. The prophylactic lens, the things that you would have somebody take all the time to reduce the probability or severity of an attack. After that, we'll talk about the treatments that you would use acutely as a rescue medication. We're going to do it by class of drug?

1:05:25Peter Attia:We can talk about it by class. We can also then talk about it by pros and cons of each drug's success rate or things like that. I think I would start off first by saying, what are the goals of preventive therapy? Because I think that's important for your listeners to know. The idea of using prophylaxis or prevention is not to cure headache, is not to cure migraine, but to ultimately reduce the frequency, intensity, or duration of attacks. It also helps improve potentially responsiveness to acute treatments. It can, by using prevention, you can reduce disease burden. You can end up reducing progression of migraine.

1:06:01So as I said, people who experience more frequent migraine are a greater risk for developing even more frequent migraine attacks. It could end up improving other comorbidities. So some prevention may be helpful with sleep. Some prevention may lead to potential for weight loss. And so you may be able to leverage some of those benefits as well. The other thing is it improves functionality and quality of life, which is obvious. But it also ends up helping reduce interictal burden. So that was one of the things I was talking about where people have this almost anticipatory anxiety. So there are multiple goals for using prevention.

1:06:38The indications for using a preventive medication are as if somebody is experiencing frequent attacks or attacks that are very disabling. even despite acute treatment. If somebody has rare types of migraine or headaches that may limit their ability to use certain acute treatments, or if acute treatments are either contraindicated, poorly tolerated, or ineffective. And so that's where some of the indications for preventive therapy, the preventive therapy come into a number of classes, which you're alluding to.

1:07:10Peter Attia:Before we do that, Brian, just to close the loop on that point, overall, all comers of people who suffer from migraine, what percentage do you think do not meet criteria to justify the drug burden of a preventive drug? So I would say probably about 40 % or so of people with migraine may be eligible for prevention. Eligibility is, I don't just mean through the lens of reimbursement on insurance, but in your mind, medically justified. 40%, yes, 60%. They don't have it enough or it's not severe enough to justify and we can do enough good with an acute medication. Once again, looking at population-based studies.

1:07:50Peter Attia:Yeah, your population is going to be totally discute. My population, the vast majority. The hard part is that the discrepancy or the gap, if you will, where 40 % of people may be eligible based on indications for migraine prevention, but only like 16 or 17 % are actually receiving preventive therapy. And how much of that is economic where their insurance companies don't cover? These drugs can be pretty expensive. Yeah, so I think it's varied. I think it may end up being that it's not recognized by the treating clinician and it may be economic. So I think there are a number of different factors.

1:08:20Peter Attia:And then what about on the cluster side of things? At the population level, what percentage of patients, does it make sense for them to be on prophylactic therapy? Again, in your population, I'm sure it's much higher. I'm going to say even outside of my patient population, the vast majority. So unless the cluster period is a week, which is not the norm, If it's going on weeks, months, yes, the vast majority of those people are going to need, every one of them, I would say, are going to end up requiring a preventive therapy. And then on tension headaches, presumably none? So it depends. So there are people who experience episodic tension type headache less than 15 days per month.

1:09:00And then there are people who experience chronic tension type headache. Oh, I didn't realize that. That experience 15 or more days of tension type headache per month. It depends on the frequency responsiveness to acute treatments that are being used or other modalities and then functionality and impact on quality of life. Okay.

1:09:18Peter Attia:Let's talk about some of the drugs that are used to reduce risk here. So let's start with beta blockers. That's literally one of the only things I remember is the triptans and the beta blockers, but I think the triptans are for acute. But anyway, let's start with beta blockers. I remember that from USMLE studying. Is that still used? Yeah. Okay. Beta blockers are a class of blood pressure medications. The exact mechanism how they work isn't known. It's postulated that it may have effects on the sympathetic aspect of the nervous system. And so two of the beta blockers that are FDA approved are propanolol and timolol, but there are other beta blockers that are used as well.

1:09:54They can be very effective for people. Once again, there's caution if somebody has asthma. So there are different types of beta blockers. so it can potentially exacerbate asthma. Potential side effects include lowering of blood pressure, heart rate, or exercise intolerance. That's the other reason why I say it's really important to understand the person so that you're using a preventive treatment that aligns with that person, their lifestyle, their risk factors, their comorbidities. But yes, that can end up being helpful.

1:10:20Peter Attia:And that's mostly for migraine. Correct. And then what about antidepressants? Yeah, so antidepressants have been used for years. Which is a dumb term, by the way. I can't stand, And I cannot stand that that class of drug is called antidepressant. I'll save that rant for another day. No, I think it's an important rant. And what I explain to patients is there are supplements or medications that are used for prevention of migraine that weren't specifically designed for migraine prevention, but through serendipity or studies were found to be helpful for migraine prevention. And by using one of these medications, it doesn't mean that they have high blood pressure.

1:10:57It does not mean that they have depression. Yes, we know depression or anxiety can exist at a higher than expected by chance in migraine, but please, they should not assume that that's the indication that I'm using it for.

1:11:10Peter Attia:My gripe goes even further, Brian, because I actually think some of the things that antidepressants quote unquote work best for are not even depression. It's not even dysthymia, anhedonia. I actually think when you look at mood stabilization, anxiety, migraines, those are places where they can really work. And the stigma that goes around the drug prevents people from utilizing it. It's just infuriating. I agree with you. Migraine itself has its own stigma. But yes, I think there's a high degree of stigma. And that's why I explain to patients, even in using this class of medications, this antidepressants, the doses that are often being used are not even doses that would be starting doses to treat depression.

1:11:52And so that's why I like to make that distinction, let them know that if we're using a medication like amitriptyline and nortriptyline, often the doses we're using are much lower than what would be needed to treat depression. And rarely are these medications used to treat depression anymore. So they can be very effective. One of the potential side effects could be some tiredness. And so usually there are medications that are taken before they go to sleep. And because if somebody has difficulty falling asleep, that potential side effect of tiredness may actually be helpful, not for every patient, but for a number of people with migraine who have insomnia.

1:12:26Peter Attia:Do we have a sense of why? Presumably it ties to serotonin and norepinephrine. Is that basically our belief? Yes. Okay. And then what about on the anti-epileptic side? Talk about getting a patient anxious, right? It's like, we're going to give you a drug for epilepsy. Yeah. Yeah. Is that GABA related? What do we think is the pathway there? I think it depends on the anti-seizure medications, two that are FDA approved are topiramate, which is known as Topamax, and valproic acid known as Depakote. These medications have different mechanisms of action. So for topiramate or Topamax, that can work on particular channels, which is what you spoke about early on, but also has effects on glutamate and GABA.

1:13:08And so glutamate is the excitatory neurotransmitter in the brain. GABA is the suppressor, if you will. That can be very effective for people who have migraine

1:13:17Peter Attia:Enhance GABA and suppress glutamate, presumably? Yeah. That can be very effective for people, but it does have, like every other medication, potential side effects. And then valproic acid or Depakote, once again, can have effects on GABA as well. That medication also may be helpful, but also has potential side effects. And it's really important that we go back to the patient population where I have migraines, I'm not only sympathetic, but empathetic, but the vast majority of people who have migraine are women. And so it really becomes important when we're thinking about women during their reproductive years, if they're sexually active, what form of contraceptive they're on.

1:13:54That's another piece of information that becomes important in setting a preventive plan. I'm trying to avoid then or at least counsel patients on the possibility that some of these medications may not be safe during pregnancy. So I want to understand that piece.

1:14:10Peter Attia:I didn't realize you had migraines, by the way. So did you have them even at the time when you were a neurology resident? Do you think that's part of what allowed you to take such a good history? So I did have them when I was a neurology resident. I'm not sure that ended up giving me a leg up on taking a history. And the reason why is many people that I see with migraine who experience it, they know what it feels like. Often it's hard for them to put into words. They have to like pause, reflect, think about their answers. Not always, but some people. I really like the fact that it's a group of people that I can really help.

1:14:45And sadly, there are not a lot of people that have the knowledge or information on how to do that in a systematic fashion.

1:14:53Peter Attia:Okay. The class of drug that I remember when it came about were these monoclonal antibodies. In fact, the patient that we keep referring to, I remember being one of the first patients on it because you got her into a clinical trial. And it was a resounding success. Can you say a little bit more about these drugs and their utility today? The class of what are called CGRP or calcitonin gene-related peptides, I think in order to be able to speak about the class, I'd probably have to give a little bit of background on the path of physiology of migraine. Absolutely. And this is a podcast where we don't shy away from depth.

1:15:29Peter Attia:So treat this as though you're giving a lecture. Okay. Always trying to understand my audience. I'll speak a little medicalese and speak English at the same time. We're 25 % physician by audience, by the way, it's crazy. I love it. The brain itself is insensate. It's not pain sensitive, but the coverings around the brain, like the meninges or specifically the dura and the blood vessels that are both within the durian and the brain have pain sensitive nerve terminals, nerve endings. and the main nerve that's involved in migraine is the trigeminal nerve. If we go back in time to probably the 1940s, the thought of migraine is that there was a vascular hypothesis where the thought about migraine is it was purely a vascular phenomenon.

1:16:12There was dilation of blood vessels that occurred during the pain phase and then a constriction that occurred during the, so to speak, recovery phase, if you will. With the advent of increasing research, particularly over the past, I would say 50 years, we know that that model is just too simplistic. So now we know that it's a neurovascular phenomenon. And so that there's involvement of not only the nervous system, but the cranial blood vessels as well. And so what ends up happening is that these nociceptive or pain-sensitive information is conveyed from these pain-sensitive structures. So the dura mater, that covering around the brain and the dural and intracranial blood vessels.

1:16:51And then it's laid back centrally along a nerve called the trigeminal nerve that has three branches, primarily along the first division, the ophthalmic division of the trigeminal nerve, passes through an area called the trigeminal ganglion, and then synapses or connects in an area of the brainstem called the trigeminal nucleus cordalis. That pain sense of information is carried back there. At the same time, nerves that supply sensation to the back of the head, the neck, and the shoulders from the upper cervical roots in the neck, so C1, C2, C3, carries information back primarily C2 and C3 into the same area of the brainstem, which is why people with migraine often will have associated neck pain, or people with tension diapetic will have associated neck pain, where they may not realize that it's a referral pain pattern because of this convergence of information.

1:17:43Now, when those nerves become stimulated, people can experience peripheral sensitization. If they're turning their head or bending down, they can get a throbbing type of feeling that can occur early into a migraine. And when pain-sensitive information goes back to the brainstem, if there's sustained firing of nerve cells, people can get central sensitization. And one clinical marker for that, that presentation, is the phenomenon of allodynia, that uncomfortable sensation to things that normally aren't uncomfortable. That's the putting the hair back in the tight ponytail and brushing hair that generally will kick in about 30 to 60 minutes or so into a migraine headache.

1:18:24And then using tripped hands during that time may be less effective. So that's the reason why knowing if somebody experiences that with their migraine becomes important when you're advising them when to treat. And we'll come back to the triptans when we talk about acute treatments. And then that pain sense of information then travels from the brainstem to the thalamus, which is kind of the sensory processing area of the brain. So there's some nuclei like ventropostomal medial thalamic nuclei that are involved. And then from there, gnosis of the information then goes to the sensory cortex of the brain and then other pain matrix areas of the brain.

1:18:59Now, while this is all occurring, there's a cascade of events that occurs. So that trigeminal nerve information has a reflex with that parasympathetic information in the brainstem, which is why people can experience those autonomic symptoms, the tearing, the redness of the eye, the congestion or running of the nostril. At the same time, parasympathic innervation is relayed to the cranial blood vessels, the blood vessels within that dura mater, with that covering around the brain and the intracranial blood vessels. And people can experience dilation of blood vessels and the release of chemical messengers or neurotransmitters.

1:19:36So things like substance P, neurokinin.

1:19:40Peter Attia:I haven't heard substance P in years. I'm happy to bring you back. I'm happy to bring you back. and then calcitonin gene-related peptide, or what's known as CGRP. At the same time, there's a pro-inflammatory response that occurs, what's called neurogenic inflammation, and then a release of histamine, male cells, nitric oxide. Once again, a full cascade of events. This becomes important because through studies that have been done over the years, studies that looked at jugular venous blood noted elevations of CGRP during migraine, that calcitonin gene-related peptide. Those studies led to the possibility that this may be a target for migraine treatments.

1:20:19And then when sumatriptan or imatrex came on the market, there were studies that looked at patients who were treated with it and what happened to their CGRP or calcitonin gene-related peptide levels, and they normalized. So meaning they were increased during migraine and then the use of sumatriptan would end up normalizing levels. And so there It was like that aha moment. And that's what led to the class of what are known as CGRP antagonists. And the CGRP antagonists are kind of broken down into two buckets. One are what are called large monoclonal antibodies, which is the medication that our patient was placed on, and then small molecules, what are known as G-pants.

1:21:02So that's kind of the history that led into the formulation of that class of medication.

1:21:07Peter Attia:These are drugs that are administered intravenously at what frequency? The CGRP antagonists, the large monoclonal antibodies, three of them are self-injection medications, almost like EpiPens. And those medications have a long half-life, so roughly about 28 days. They're administered in a monthly fashion or every 28 days, and that's the three of them. There's one that's actually given quarterly as an infusion every three months. Any difference in efficacy? Varies from person to person. There are no large head-to-head studies of these medications. That's the challenge with being able to end up using data to end up answering that question.

1:21:52Peter Attia:So basically, you might start with the home-use pen because it's easier. I assume it's cheaper. If they're failing those things, you would have to just go with the quarterly infusion. Right. So that's one reason. The other reason is what the insurance will dictate in terms of what they will allow me, the clinician, to prescribe. These have changed the game, though. Obviously, I'm biased perhaps by my small, small sample set of the patients I know that have had a significant improvement with these. But across your clinic, which is very high risk, but obviously very diverse, how much have these been an improvement in mitigating onset and severity?

1:22:29Peter Attia:Significant improvement. The biggest change you've seen in your clinical practice? Yes. Wow. It doesn't mean that they work for everyone. For what fraction of patients do they not work? So they probably work for up to 60 % or so of patients with migraine. That's why I say sometimes there is trial and error. The other thing is there are some people that will be much quicker responders than others. So some people will get benefit within the first month with these medications. Other people may take up to three to four months. And when you say 60 % success, does that mean 60 % of patients who take this drug regularly will no longer suffer migraines?

1:23:06No, there's a spectrum.

1:23:08Peter Attia:Uh-huh. So it's like oncology where success is a partial response, a complete response, and you're including the partial response in here as well. Correct. In oncology, a partial response has a very specific definition, which I won't bore listeners with. How are you defining a partial response? Based on what information the patients are providing me. Doesn't have to be at least a 50 % reduction. Correct. That would be wonderful if I could end up providing people who have 30 days of headache per month for 20 years, a 50 % reduction. But sometimes the timeline, and once again, it's usually a multidisciplinary approach that I'm employing in order to be able to continue for building on incremental gains.

1:23:48Peter Attia:As difficult as it might be to get this data from a patient, unless they're very good at logging it and their temporal history is very consistent, Are there people in the 40 % group that we're considering non-responders who have no abatement in frequency, but severity does go down and or responsiveness to acute treatments improves? Or does that automatically put them in the 60 % bucket? For me, I'd probably put that group into the 60 % bucket. But once again, there are people that will get variable ways of getting improvement. That's where the diaries become very important to understand. Yeah.

1:24:24Peter Attia:Sorry to just harp on this, but given the importance of it, when a patient does not have success on this drug, do you have a sense that most people will have the ability to progress through all of them so that we know that, hey, if you're going to fail this treatment, you've failed the class? No. I'm very happy that you're raising this point. If somebody doesn't respond to one of the treatments within the class, that does not dictate that they're not going to respond to another treatment in the class. And the challenge becomes is I can't tell by looking at somebody if they're going to respond to one medication in the class versus another.

1:25:00We don't have biomarkers and so we can't end up telling. But ultimately, I do tell people that if one may not work, another one may.

1:25:09Peter Attia:Again, it's an important lesson, I think, for clinicians, although I would hope most people understand this. Whenever you're using these monoclonal antibodies, by definition, because different drugs have different patents, they have to have different IP, meaning they can't be the same molecule, which means they could be binding to different parts of the epitope. And therefore, when you look at a person's genetics, and not everybody has the same receptor, as an example, and therefore, just because one drug doesn't bind perfectly doesn't mean another one won't. We see this, by the way, with PCSK9 inhibitors in the lipid space, where if you don't respond to one, you might respond to the other and vice versa.

1:25:45Peter Attia:Super interesting. You mentioned the oral equivalent of these as well? Yes. So there are oral medications that are known as G-pants that are small molecule CGRP antagonists. These medications have shorter half-lives and there are fewer of them. There are a couple that are oral and there's one that is a nasal spray. These medications can be used acutely when somebody ends up having a migraine. One of them has an indication both for acute and preventive treatment. Yeah, that's autogepent or something like that? Atojapant. I can't even pronounce the drug. That's okay. That's okay. That is for preventive treatment.

1:26:28Peter Attia:That's not one that you can use acutely. No, that would not be used acutely. Remedjapant, or what's known as NERTEK, has an indication for preventive and acute treatment. Gubrogepant or Ubrelvi, which is another medication in that class, has an FDA approval for acute treatment of migraine. Got it. Do you have a sense, by the way, what the out-of-pocket cost on these drugs is? They're expensive. All of these medications are expensive. Thousands of dollars a year, I'm assuming, if it's based on other monoclonal antibodies. And then do you have a sense of what patients that come to see you do have insurance coverage on these?

1:27:01It's variable because there are so many plans. And then within the plans, there are high deductible, low deductible, big copays, low copays. Yeah. That's the biggest frustration, I would say, both for patients and for people like myself who are caring for them.

1:27:15Peter Attia:Yeah. And if it's like every other drug in the United States, we're paying probably three to 10x what the rest of the world pays for the same drug. Yes. Some of these drugs get so expensive that it's cheaper to fly out of the country to get the drug and bring it back. I have patients who do that and I have patients who live outside the country. they have an easier time in some respects of getting these medications and paying for them. I used to take care of a patient with type 1 diabetes who used to fly to Europe to buy his insulin. And it was still cheaper to fly first class to Europe, stay at the Four Seasons, buy his three months of insulin, put it in a cooler, fly back.

1:27:58Peter Attia:He saved money doing this. Can you just imagine the absurdity of this? Uh, sadly, yes, because I have patients who fall into that category. I think the hard part also is maybe the short side, if you will, meaning the cost of these medications may be very expensive, but it's trivial compared to the economic cost, the personal costs, the trips to emergency rooms, the loss costs and insurance of people at work, lost work time and productivity. I mean, it's just, It's short-sighted, I think. Rounding out this list, calcium channel blockers and Botox, correct? Yeah. Yeah, let's talk a little bit about those two.

1:28:39So calcium channel blockers doesn't have as much data for prevention of migraine. More classically, it's used for prevention of a headache like cluster headache. But still, people may end up using calcium channel blockers, which is a blood pressure medication for prevention of migraine. And they're doing this at a lower dose, I'm assuming, as well?

1:29:01Peter Attia:A lower dose, but sometimes the doses are increased, particularly in patients with cluster headache. So what do you do if you have a normotensive person with cluster headaches? How do you treat them with verapamil? There are some patients that I have where, usually in collaboration with a cardiologist, there's one patient I'm thinking of that I just recently saw where this person was on, at one point, over a thousand milligrams of verapamil. And for your audience to know, that is an exceedingly high dose. Once again, EKGs need to be checked, blood pressure, pulse needs to be checked, tolerability needs to be checked.

1:29:32But that was the dose that was needed and that person tolerated it amazingly.

1:29:36Peter Attia:And obviously it reduced significantly the frequency of cluster headaches. Correct. This is the trade-off in pharmacology, right? Right. Nothing comes without a side effect, but the side effect can often be well worth it. And then you mentioned Botox. Botox. When I think about Botox, I think about tension headaches, but does it also play a role in migraines and clusters? Surprisingly, Botox doesn't work well for tension-type headache. Okay. Yeah. It's a good thing I'm not a neurologist. Okay. You have me on set, so I'm more than happy to help. Serendipitous finding that Botox was helpful for migraine.

1:30:08There was a plastic surgeon, Bill Binder, in California who was giving it to patients cosmetically and then was told by patients that, you know, my headaches are getting better. My migraines are getting better. And that's actually what led to Botox or anabotulinum toxin being studied for prevention of migraines, specifically chronic migraine. So that's whereby people experiencing 15 or more days of headache per month, that's where Botox has mostly been studied and where it has the current FDA approval for that. And so it's not by cosmetic effects that it works, but actually it interferes with the release of certain SNARE and SNAP proteins, certain proteins, and also involvement in CGRP, calcitonin gene-related peptide.

1:30:57Once again, we come back to this.

1:30:59Peter Attia:Because of systemic delivery? So it has effects on pain pathways. Pardon my ignorance. Okay. So obviously this was discovered probably on the face and forehead because that's where he was administering it. Is that how it's administered today? So the protocol went through a number of iterations until the current protocol, which is called the preempt protocol, which is standard across the world, where injections are given in the forehead, on the sides of the head, the back of the head, the neck, and the shoulders. And they're given around areas where there are superficial nerves. The postulated mechanism is that it may have interference in the release of certain vesicles and certain proteins called SNR and SNAP proteins, as well as CGRP, which is that chemical messenger, that neuropeptide we were talking about heavily involved in migraine.

1:31:52Peter Attia:How many patients that qualify for this are able to get insurance coverage? Because this would be even more expensive than monoclonal antibodies. I mean, Botox must be insanely expensive. So not necessarily relative to the monoclonal antibodies, because the monoclonal antibodies... I guess you're taking them every week, whereas you do this maybe quarterly. Right. And the Botox is administered quarterly. Yeah. Okay. The insurance companies won't let me say, oh, of course, Dr. Grossberg, you can end up prescribing Botox. You think this person has chronic migraine. Often they will ask me or mandate that I have to try at least two or three conventional non-migraine-specific preventive therapies and either try and fail or been poorly intolerant to them before they let me end up looking at Botox for prevention of chronic migraine.

1:32:41Got it.

1:32:42Peter Attia:Okay, so let's talk about the rescue drugs. You're now in the throes of a headache. What can you do? So there are many classes that we end up using. There are non-migraine-specific classes, and then there migraine-specific classes, non-migraine-specific. So analgesics like acetaminophen, non-steroidal anti-inflammatory drugs like NSAIDs. Do opioids play any role here? Notwithstanding the loaded nature of addiction and things like that or dependency. We go back to the risk factors for migraine chronification. And one of the risk factors is medication overuse. And the two largest culprits for the possibility of medication overuse are opiates and barbitric-containing combination analgesics like fioracet or fioranol, which is even banned in some countries in the world.

1:33:28Opioids or this class of medications, the barbitric containing combination analgesics, even used a handful of times per month, even if it's not for migraine. The nervous system, once again, may not like that, and they have a particularly high risk for medication overuse.

1:33:44Peter Attia:Is the issue that? In other words, is the issue that if we give patients these drugs, the probability of excessive use becomes high enough, which is itself a trigger? Yes. Or a potentiating mechanism. I see. Okay. So in other words, you would not prescribe these in your practice. You have enough other tools that you're not going to do that. Once again, opioids for me are a last line after people have explored everything, if you will. Even in the emergency room, we really tried staying away from opioids just because of this potential. In terms of migraine-specific medications, triptans were the first class that was specifically designed for the acute treatment of migraine.

1:34:30What predated that were the agonamines, which are still used. And so these are medications that come from a particular type of fungus that have effects on serotonin, which is heavily involved in migraine. And so they work on not only serotonin receptors, but they work on other receptors as well. Whereas tryptans work specifically on certain subtypes of migraine receptors, namely what is called 5-HT1B, 1D receptors. And the 1B receptors have different effects. Those are on smooth muscle cells. And so they are involved on that aspect. and the 5-HT1D are involved in some of the chemicals that are neurotransmitters that are released.

1:35:13And so tryptans, the advent of them really ended up was a game changer for migraine. And even now - 20, what, 30 years ago? We're probably going back to the 1990s. Yeah, mid-90s maybe. Yeah. Ultimately, sumatriptan was the first one. It was in tablet and injection form. It's also available in nasal spray. And then since that time, there are six more that came along. So there are seven triptans in total.

1:35:36Peter Attia:Are these drugs like statins or GLP-1 agonists where each new version gets more effective and has fewer side effects? Not necessarily. So there are plenty of people, sumatriptan was the first one. Some people may be sensitive to sumatriptan versus some of the later triptans. One of the potential side effects of triptans is a sense of warmth or heat or tightness anywhere in the body. It's usually short-lived, but for some people, it's extremely uncomfortable. Flush, like a niacin flush? Yeah, like a flushing. And then other people use simitriptan, no issues whatsoever, right? Like, God made this for me.

1:36:16Some of the half-lives of the triptans may be different. So there may be some that are quicker onset, some that may last longer. And so that's where the decision-making may come in. Some may be tablet versus a melt versus a nasal spray versus an injection. And so depending, once again, going back to that attack profile, presence of nausea, we know that both during and in between attacks of migraine, there can be delayed gastric motility or gastric stasis. So absorption of medications may be slowed. And so if I need to think about absorption and rapidity of onset of attack and speed of the treatment and trying to bypass the gut.

1:36:56I may be trying to choose one formulation over another. So all of these factors help me kind of hone in on the decision-making.

1:37:06Peter Attia:Intuitively, my gut says, no pun intended, the intranasal would have more efficacy than the oral. Like it would go intranasal, I am, then oral in terms of the speed with which they respond. Is there any truth to that? I'm going to switch the order a little bit. So I am, intramuscular is actually quicker. The sumatriptan is available, injectable. So the quicker onset sometimes needs to be balanced versus the, so to speak, if somebody experiences a side effect, it may be more heightened than what they're taking as a nasal spray or as a tablet. So they may feel that flush into me. So the oral would have the lowest amount of that given that pharmacokinetics...

1:37:49Peter Attia:Because of the pharmacokinetics. And that may be potentially, obviously. This may be different if I'm, let's say, treating somebody with migraine versus cluster headache. So cluster headache, if I'm using sumatriptan, I'd really love to end up using the injection because the median time to pain relief may be like nine minutes. So for somebody who really needs quick onset because they're having a rapidly onset attack, that's like God made this for me. It's a preloaded pen that they can carry around with them. So often it's a preloaded pen that they give themselves an injection. Or if somebody's experiencing a migraine attack at night that wakes them up from sleep or builds up quickly.

1:38:24The nasal spray, that bioavailability that you were talking about, doesn't pan out for all the nasal sprays. So the sumatriptan nasal spray, and there are a couple of them, but we'll talk about the, not a brand form of sumatriptan nasal spray, but the, so to speak, the generic or the form of sumatriptan nasal spray, the bioavailability is not so great.

1:38:45Peter Attia:It's higher in Imatrex than it is for generic sumatriptan, you're saying? The nasal spray itself, there are other brand formulations of sumatriptan, like nasal powder, if you will. The nasal spray of sumatriptan, the bioavailability across the nasal mucosa is not so good. So the absorption sometimes is actually by swallowing something that doesn't taste so good. The zomitriptan, which is known as zomig nasal spray, which is a triptan, and zavagipan or zavzapret, which is a G-pant. Once again, that's in the class that we were talking about, that CGRP antagonists. Those bioavailabilities are higher.

1:39:25And so that's where somebody may end up getting faster relief. Okay.

1:39:30Peter Attia:Success rate for these across all comers? So looking at triptans, or for any acute treatment, I'm looking at speed of onset, improvement in associated symptoms, functionality, which is very, very important. Generally, the mark of time that's used is by two hours. And then what's the rate of recurrence or the rate of return of headache either that day or within 24 hours. And certain triptans may have a higher recurrence than others. And so that's where the decision-making is used based on all the factors that patients tell me about. Okay. Outside of these treatments, what about any sort of electrical stimulation, TENS?

1:40:09Peter Attia:Have any of these other things shown any benefit? Yeah. So you're referring to the class of - Or TMS. I'm sorry. I said TENS, but what I meant was TMS. Yeah. Neuromodulation devices, right? So the idea of neuromodulation is a stimulus is being used and that stimulus may be in various forms. It may be magnetic stimulation, maybe electrical stimulation, that targets some system, if you will, in this case, the nervous system. And there are different forms of neuromodulation that have postulated mechanisms that work on different targets based on the pathophysiology or the anatomy of migraine. So one example would be a device that delivers stimulation to the nerves, the superficial branches of the trigeminal nerve over the eyebrow.

1:40:56So there's a device that will do that. And that works by, so to speak, suppressing pain transmission, if you will, superficially to end up having effects centrally within the nervous system. There are devices that will stimulate electrically the vagus nerve. That can also be helpful for prevention and acute treatment of migraine. What I'm talking about are external devices. These are devices that can be applied or held, not necessarily implanted. I think that becomes an important point of distinction. A device like remote electrical neuromodulation, which is an armband device called Nervio that is worn on the arm that's operated by an app on the phone that delivers a level of stimulation to a nerve in the arm that relays messages to the brain that uses the brain's own natural mechanisms to downregulate pain.

1:41:45And that's used as a prevention or a treatment? That particular device has an indication for prevention and acute treatment of headache.

1:41:54Peter Attia:How successful is it in each domain? Across neuromodulation, there are varying successes. There are no head-to-head studies of these devices where medications have to be FDA approved, devices get FDA cleared. Our headache center was actually the lead site in the world that led to that FDA clearance for that armband device. And so once again, depending on the study, the benefits are pretty significant depending on the patient and the attack profiles, if you will. Are these devices expensive? They can be depending on the devices. So some of them are bought, like the device that's worn on the head that delivers stimulation.

1:42:30The device that applies vagal nerve stimulation is actually kind of like rented or leased. And so there's a monthly payment for that. The armband device has a certain number of treatments within a month. And so that's purchased or gets some reimbursement through insurance. And then there's another device that delivers stimulation both to the nerves in the front of the head as well as the nerves in the back of the head that can be purchased or, quote, rented or leased as well.

1:42:56Peter Attia:Are you under the impression that a lot of patients who are suffering from headaches don't even know these devices exist and therefore they're missing out on another therapeutic opportunity? Yes. The devices themselves may be used either as first line or in conjunction or as rescued, depending on the person and their attack profiles. I think the hard part becomes is some people are coming in waiting for a prescription in the form of a medication. Some people, because of the cost prohibition, may not want to end up looking at devices. But there may be other people that have preferences. I prefer not to be on a prescription medication to the extent possible.

1:43:35Can we try nutraceuticals or supplements? Could we end up trying neuromodulation devices? If it's somebody who may be looking to get pregnant, we may for that, aside from patient preference, but if we're looking for people who are in that period of time and during that time, even though the devices have not necessarily been studied during pregnancy, one of them has, for acute treatment. Knowing their mechanisms of action, they're not associated with medication, it's presumed that their safety and tolerability would be okay during that period of time.

1:44:09Peter Attia:Do we know anything about THC or cannabis directly? It's interesting that you ask that. I hear mixed things, right? Yeah. So we actually ended up doing one of the largest studies looking at use in our patient population, an academic headache program of people using cannabinoids. And what we found, which was about a third of our patient population are using cannabinoids. And so the hard part becomes it's not, not everybody's using. And in the study, did you standardize the vehicle or was it an outpatient? Outpatient survey study. It's next to impossible because We have no idea what they're using.

1:44:44Roots, formulations, combinations, right? It's very hard. The other challenge becomes is even those people who say that they may get benefit, the question becomes is... What else are they doing? Right. What else are they doing? Is it direct benefit for headache? Is it indirect benefit by helping with sleep or anxiety that may be comorbid with migraine? So I think that's the hard part to tease apart. The other challenge is sometimes it's hard to advise patients because we don't know about the potential drug-drug interactions.

1:45:10Peter Attia:So no one's done or is doing an RCT where you're using a pharmacologic consistent grade of THC and trying to identify the actual effect of the active agent delivered in a standardized way. There is a study that was done that looked at it for acute treatment of an attack using one formulation. Because of regulatory concerns, these are really hard studies to implement. There's a company right now that is also looking at doing larger studies in the future on this. So I think those studies will come, but they're going to be very slow. But these have to be done as almost, I think you almost have to have the patients come in to be administered the drug because it's schedule one.

1:45:52Correct. Yeah. The feasibility is not so easy. Yeah.

1:45:55Peter Attia:Brian, is there anything we haven't talked about as far as headaches that people should know from a primary perspective? So I think from a primary perspective, what I would end up saying is people should have hope in the sense that it's very important to be as empowered as possible by keeping a log of information, by providing their clinicians or the treating physicians or providers with the details of their headache and recognizing the importance of those lifestyle factors, which can't be overstated. I often think about an equation of expectations over reality, E over R. What is their reality?

1:46:34What are their expectations? How do I try to match it as long as the expectations aren't necessarily exceeding reality? I think it's important for people to take ownership, which is not so easy. Some people will say, you're the doctor, you tell me what to do. I have to say, well, we're partnering together. This is a partnership. Recognizing that preventive medications may take weeks to months. I often say that this is not Amazon Prime. I know we live in Amazon Prime society. You know, everybody's used to next day delivery, but Often good things come to those who wait. We're building on incremental gains.

1:47:06And so I'm sometimes cheerleading people, if you will. Then in thinking about the overall frequency of attacks, knowing that preventive options, sometimes people need one or more preventive medications. It's not one size that fits all. So it really is a very tailored approach for acute treatment. And it's also knowing and for clinicians to know that not everybody is necessarily going to respond to one acute treatment. They may need a backup. They need a rescue treatment. So I think that's important. For patients who are very debilitated, there are also intravenous medications that can sometimes be used to try to suppress a prolonged attack that may be known as status migranosis, where a migraine is occurring for longer than three days, like that first patient I was you about who had a prolonged migraine for six weeks, and then recognizing that ultimately at the end of the day, it's a marathon, not a sprint.

1:48:02Peter Attia:I just want to spend a minute on secondary causes because I want to make sure that people understand that if you're having a headache for the first time or a headache that's not well characterized and documented as one of the ones we've spent the last couple hours on, you're not missing something medically. So when a person experiences a headache, not to create fear because I'm guessing most of the time 99 times out of 100 it is not going to be a mass effect or a vascular lesion or something but I'll give you an example of something that has now come across my radar twice meaning I've known two people in the last year who have had CSF leaks one was traumatic so they fell skiing and then over the ensuing months they just kept getting these headaches and it took months to figure out, oh my God, you have a leak of the CSF and we're going to go down the path of fixing it.

1:48:53Peter Attia:In the other case, it was an individual who had a spontaneous CSF leak. And you can imagine how long it took to figure that out, which says nothing of how difficult it was to treat that. So I don't know, do you want to say anything about CSF leaks? My bias is like, oh my God, these are occurring all the time, but they're clearly not, but they're debilitating and they're easy to miss. I think maybe if I could provide some pieces through the mnemonic that people should be aware of that may raise concern. So if somebody is having new onset headaches or a change in the headache pattern, that may be something that they want to speak to their doctor about.

1:49:33If they're having associated fevers, rashes, a headache that's painful to flex their head and touch their chin to their chest, that may be signs of something that's concerning. If somebody is having unintended weight loss, that may be a reason too. So those systemic symptoms. If somebody is having new types of headaches or change in a headache pattern during pregnancy, once again, migraine can occur during pregnancy, but as a general rule, migraine without aura improves during pregnancy. And so probably about 47 % people notice and women notice improvement in the first trimester and then 80 to 87 percent or so in the second and third trimester.

1:50:13I think that's estrogen related, presumably. Yeah. Once again, if it's worsening, there are people who can have new onset migraine where migraine may not improve. But if that's the case, that would be something that I would look at a little bit more closely. If people are on medications that suppress their immune system and they're starting to have headaches or experiencing more frequent headaches, I'd look at that. If somebody is having neurologic symptoms with the headache, so weakness, numbness, problems with speech or language, double vision, loss of vision, problems with balance. If somebody is older than the age of 50 with a new type of headache or a change in the pattern, we have to think about secondary conditions, one of them being temporal otoritis.

1:50:53Most people who experience this are older, but sometimes the misconception is that the pain is just in the temple because it's called temporal otoritis, but the pain of that headache could be anywhere in the head or face. And then is the headache thunderclap? Does the pain peak at maximal intensity within seconds to a minute? That can be what's referred to as a thunderclap presentation. Sometimes a CSF leak can actually present as that if it's a spontaneous leak, not always. And then we get to the other factors like, is the headache specifically provoked by cough, exertion, sexual activity or sleep, or if there's a positional component.

1:51:29Often people with a CSF or cerebrospinal fluid leak may have a positional component to their headache, such that if they sit up or stand either right away or a, quote, second half of the day syndrome, meaning as the day goes on, they start developing a headache, that can be issues. Sometimes people with a CSF leak can have intrascapular pain, so pain that develops in between the scapula. There are a myriad of manifestations which makes it so difficult to diagnose and treat. It's people like myself, ultimately, and others, other colleagues of mine, that may be seeing patients like this. That's why Duke has a CSF program, right?

1:52:10That's one of the programs that's dedicated specifically for patients like them.

1:52:14Peter Attia:Well, Brian, this was really interesting. Incredibly grateful for the work you're doing with patients, but also just really grateful for you taking the time to come out here and be away from those patients for a couple of days to have this discussion, because I think a lot of people are going to benefit from this. I'm sure a number of them are going to want to come and see you. What is the waitlist like for people to come and see you? Obviously, when there's only so few doctors doing what you're doing, I know how difficult it is to get in to see you. Yeah. So me personally, when I moved to Connecticut about 10 years ago from New York, I would say probably the vast majority of those patients I was seeing in New York who were driving or flying are now just coming to Connecticut, which is humbling and flattering.

1:52:51The hard part becomes is I want to take care of everybody, but it's hard. So my personal wait list is actually quite long, but there is a link that people can go on. Often if people live out of the state or out of the country, I'll ask them just to have like a local physician that can help with prescribing medications and be able to help implement the plans. Thankfully, I have other great colleagues as well. And so - In your practice? In my practice. Yeah. Yeah. We're probably one of the largest programs in the country.

1:53:18Peter Attia:Got it. Okay. People can get in the door into your practice. And if it's anything like my practice, seeing one of my colleagues is no different than seeing me. Right. Is it the same with you? I have great colleagues who have the same philosophy. I was very fortunate to have great mentors. And so can they curbside you? Yes, they can curbside you. Yeah, that's sort of what I mean. It's an open system. It's a collaborative system. It's a collaborative system. Yeah, yeah. Awesome. And then again, I think encouraging people to go to the site will link to your headache journal so that anybody, whether they're going to see their local doctor or ultimately coming to see you should really, really, as you said, put in the time, the effort, 10 to 15 minutes, 20 minutes a day that it would take to really accurately log this for a month, because you're going to get better treatment.

1:54:00At the end of the day, it's just going to improve the quality of your care and your outcomes.

1:54:03Peter Attia:So Brian, thank you again. This was really exciting. Thank you so much. Both for the physicians listening, but I think of the hundreds of thousands of people that are not physicians that are going to be hearing this on their podcast player, something I encourage you to do with other podcasts is get a good podcast player and find the time when you're exercising or driving to listen. Please share those with me. I will. I will share for sure. All right. Thank you, Peter. Thank you, Brian. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com forward slash show notes if you want to dig deeper into this episode.

1:54:38Peter Attia:You can also find me on YouTube, Instagram, and Twitter, all with the handle peteratiamd. You can also leave us review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment.

1:55:15Peter Attia:Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peteratiamd.com forward slash about where I keep an up-to-date and active list of all disclosures.