S2:Ep23 – Psychedelics, Serotonin & Migraine




Voice-over: Welcome to Spotlight on Migraine: The Professional Series, a podcast hosted by the Association of Migraine Disorders. Join us as we dive deeper into migraine topics with guests from the medical field. This episode includes educational content intended for medical professionals, but may be useful or interesting for patients as well. This episode is brought to you by our generous sponsor, Lundbeck.


Dr. Franklin King describes historic applications of psychedelic therapies, explores possible biological and psychological mechanisms of these compounds and how they may be beneficial for migraine.


Lundbeck is a global pharmaceutical company that is committed to improving the lives of people living with brain diseases. Lundbeck is pleased to offer a treatment option for migraine prevention. To learn more, visit LundbeckUS.com.


Franklin King: Hi, I’m Franklin King, and I’m a psychiatrist at Mass General in Boston, and I am going to talk with you today about psychedelics and migraine and some possible mechanisms. Just a little bit of background — so this is an area I’ve been following really closely — psychedelics in general, that is — since medical school. And very excited to kind of see how quickly things have been developing in the last couple of years.


At Mass General, I have a number of different clinical roles, but just listing here my newest role, which is director of training and education at our brand-new Center for the Neuroscience of Psychedelics. So let’s get started.


So psychedelics actually have quite a rich history in medicine; it’s just not Western medicine. And it turns out that they’ve been used for healing purposes for thousands of years across many different continents around the world, and that ranges from ayahuasca in the jungles of the Amazon to peyote cactus in the American Southwest, psilocybin mushrooms in Mexico, amanita mushrooms in Siberia, and the iboga plant in West Africa. But their potential use as medicines wasn’t “discovered” by the West until the 1950s. There were a couple of discoveries at that point that ushered in a short but intense focus of research for purposes of treating anxiety, depression, and alcohol use disorder, and a few other things.


What happened in the late 1960s is there was a very significant media and cultural backlash against psychedelics, which ultimately culminated in the federal government pretty abruptly reversing course. They were funding tons of studies, and then in the early 1970s, they withdrew all the funding and they shut everything down. And that kind of brought in this Dark Ages of psychedelic research, where really there was no clinical or human studies for about 30 years, until resuming in earnest until around the early 2000s. Really over the last few years, there’s been a pretty significant surge in publications and new studies involving psychedelics for various conditions.


Before going any further, I just want to kind of orient everyone to what I mean when I’m talking about psychedelics, because psychedelics encompass a variety of different compounds. The ones that we’re going to be mostly talking about today is this second column, the tryptamine psychedelics. And those include probably the best-known compounds in the overarching class, so LSD; psilocybin, which is in magic mushrooms; ayahuasca, which contains DMT. And these are the psychedelics, really, that when people in these sort of migraine communities talk about taking for their migraines, it’s usually the tryptamines.


Occasionally the phenethylamines, which are pretty similar in terms of how they have effects — so there’s MDMA and mescaline — are the two most common of those. I’m not really going to talk about ketamine, which is being researched for depression and suicidal thoughts. I’m not really going to talk about ibogaine either, which is a powerful psychedelic and is being researched for treating opioid use disorder. So really just sticking mostly with tryptamines when I say the term psychedelics.


Just a little bit about safety — so we have a lot of clinical data at this point from studies that shows that psychedelics actually, when administered in clinical settings — and I stress that — when administered in clinical settings, psychedelics actually are quite safe. So they’ve been medically well-tolerated, even in some fairly sick patient populations. There’s been a couple of very nicely designed studies looking at end-of-life-related anxiety and depression in cancer patients with a lot of medical illness, and they’ve been quite well-tolerated there.


They’re actually not addictive because dependence is biologically not possible. So psychedelics are actually interesting in the fact that they generate a very quick induction of tachyphylaxis. So if someone takes a psychedelic three or four days in a row, they just very quickly get locked out and they can’t actually get any drug effect after a few days. So you can’t actually get dependent on psychedelics.


I think the most interesting thing about psychedelics is that the primary risks of psychedelics really are not medical; they’re psychological. And in order to protect against that, really, when we talk about — at least in these clinical studies, we’re not just talking about a drug that’s being administered. There’s a whole sort of therapy package, and we’re talking about something called psychedelic-assisted psychotherapy.


And that includes not just having a therapist present as kind of a guide to hold space during the psychedelic experience, but it also includes preparation sessions to get the patient ready and oriented with sort of what they’re getting into, how to negotiate any sort of difficult psychological terrain or things that come up, and then also integration sessions that are done after the psychedelic experience in the following days that are sort of used to help the patient metabolize material that may have come up, solidify any conclusions, sort of understand things more deeply. And it’s really thought that the integration is actually pretty key, at least when used for psychiatric purposes, in sort of ensuring that the psychedelic treatment has this enduring effect.


So most of the studies at this point, or at least the studies that are reported mostly in the media that have generated all this interest with psychedelics, have been geared towards alleviating chronic psychiatric conditions, so things like major depressive disorder, PTSD, alcohol use, substance use disorders, anxiety in serious medical illness, and OCD. We have data in preliminary studies for all of these that psychedelics have been incredibly helpful in reducing symptoms, mostly in treatment-resistant populations.


But psychedelics also appear to induce perhaps more profound changes in psychological characteristics, things that really aren’t thought to change over time. So they’ve been found to increase this trait called openness to experience and to decrease a trait called neuroticism. And these are two of the big five personality factor traits that are thought to basically be traits that once we reach early adulthood, we’re pretty much set. So whether somebody’s depressed or not, they’re going to score more or less the same on scales of openness and neuroticism at any point in their life. And yet psychedelic treatment has been found, even months later after the session has been concluded, to result in these enduring changes in what were once thought to be actually very stable and immutable personality traits.


Similarly, psychedelics seem to also produce an enhanced appreciation for nature and the natural world, decreased orientation towards authoritarian political beliefs, and enhanced spirituality. And so there may be some other positive benefits and byproducts of psychedelic treatment that remain to be more fully explored.


But we’re here to talk about migraine. So what about their use in migraine? Well, it turns out that psychedelics have been used to treat migraine, mostly outside of clinical settings, for decades. The earliest mention that I can find in any literature at all of a psychedelic being used to treat migraine was back from 1963. That was in a book that included a case series where they were treating patients for neuroses, so things like depression and anxiety, as they were called back then. One of the patients had a migraine disorder and had sort of a spectacular recovery with no further migraine following a psychedelic treatment. And that really is actually the only published case of psychedelics being used to treat migraine.


The remainder of the information that we have really comes from surveys of these online communities. And so there’s these large communities of people in the worlds of psychedelics, but also in the worlds of people who suffer from migraines, patient advocacy groups, people looking for complementary and alternative medicine, people looking for treatments of last resort. And so people have gone and done surveys of these populations of people who are using psychedelics to treat their migraines and have actually found that a significant proportion of people who’ve tried this have found success both in prophylaxis of future migraines as well as in acute termination of a migraine attack.


So, unfortunately, clinical studies at this point are lacking. I do mention Yale because Yale University is currently doing a trial using psilocybin — that’s the active ingredient in magic mushrooms — to treat migraine. So in a couple of years, we should see some results from that study. But, certainly, more clinical data is needed rather than just surveys of people in online communities, which we do have to take a little bit with a grain of salt until we have more information.


I would mention just that as somebody working in the field of psychedelics that clinical research is quite difficult. There’s substantial legal hurdles — FDA, DEA hurdles — that have to be gotten over before you can actually start a clinical trial involving psychedelics. So research, despite sort of the increased focus on this, still is actually pretty difficult to conduct.


In terms of the compounds that we’re talking about in these reports from the online communities, usually we’re talking about psilocybin and LSD. So psilocybin comes from magic mushrooms, but floating around in the black market, there’s also synthetic psilocybin that people can get, and then LSD. And by and large, the vast majority of people using psychedelics to treat migraine are using one of those two compounds. As I mentioned earlier, there are some people who’ve used some of the other ones, like people have tried to use DMT or ayahuasca. People have tried to use MDMA and mescaline. And there’s been a smattering of people who’ve reported success with that, but really not enough to sort of make even any conclusions based on these reports.


In terms of how psychedelics are used, there’s kind of two different ways. So many of you have probably heard of microdosing. Microdosing refers to taking a subperceptual dose of a psychedelic. That means a dose where the person really doesn’t sort of feel the drug effect. They’re just taking such a small dose that they don’t notice anything.


And when people are microdosing, this is not sort of a one-time thing. Usually, people are adhering to some sort of schedule that has to build into that schedule this tachyphylaxis that develops. So people might take the microdose on day 1 through 3, and then have an off day for three days, and then an on day. Or people might take it for five days, and then two days off and five days on, and so on and so forth. But usually people will adhere to a schedule like that for several weeks or months. And that’s kind of a course of microdose, versus a macrodose, which is just taking sort of a full-on psychedelic dose, where the person’s having a complete psychedelic experience.


And at least as far as some of these surveys are concerned, people who suffer from intractable migraines have reported that both methods may be effective. So people have achieved success with microdosing as well as in taking a full dose of psychedelics, which raises the question, Are there kind of two different mechanisms at play here? Is there a biological mechanism that might be more connected with the microdosing strategy where there’s a treatment effect of a drug that they’re taking most of the days of each week, versus something that obviously has a biological underpinning but may induce some psychological changes as well that could actually help the person deal with migraine better when they recur.


So just talking a little bit about serotonin — so serotonin’s obviously at the heart of all of this because psychedelics work through serotonin and most migraine treatments, at least in the 20th century, also work through serotonin. And, unsurprisingly, because they work through serotonin receptors, many migraine drugs as well as all psychedelics have a shared molecular core of this indole structure, which I’ve circled here. On the left, we’re looking at LSD; on the right, we’re looking at sumatriptan. Basically, this is kind of the general picture of all psychedelics. They all have this core that mimics serotonin, as do many migraine treatments. They all have activity within the serotonin system.


What remains to be elucidated is, Is there any overlap in how these two different types of drugs work? Psychedelics work through a different series of subtypes with serotonin. They work with the serotonin 2A receptor primarily, 5HT-2A. And then there’s some downstream effects of the 5HT-1C receptor, whereas triptans and some of the other migraine medications work through a variety of serotonin receptors, but they’re different. So obviously much more research to be done, but just given the fact that there is this sort of shared core structure does make one wonder whether there may be some biological overlap in the pharmacology of these two compounds.


As a psychiatrist, I’m much more interested in the psychological and psychiatric reasons why these might be helpful. So what is worth considering, I think, is that patients with migraines are actually patients who are at much greater risk of things like major depressive disorder, PTSD, and they’re also people who are at much greater risk of developing stress conditions, anxiety disorders around their migraines. And these are actually conditions that psychedelics have been shown to reduce and to assuage. And so perhaps there may be some indirect mechanisms whereby the psychedelic is treating some of the psychiatric conditions, thereby reducing the patient’s negative response to the migraine itself.


I want to focus a little bit more on that and on the idea of this decreased neuroticism. So the personality trait of neuroticism, this stable personality trait that really is supposed to be essentially solidified by early adulthood and not change through one’s life — and that’s irrespective of whether one is depressed or not; they’re going to score the same on neuroticism. But people who score highly on neuroticism scales, these are people who have an increased susceptibility to stress. They’re going to have an increase proneness to developing negative affect in response to stress. They’re going to have a low frustration tolerance. They’re going to be anxious in response to minor provocations. And these are people who are going to somatize. So all of these things are associated with scoring highly on neuroticism, this trait that psychedelics seem to reduce.


Now, going further, scoring highly on neuroticism is a risk factor for developing later in life depression, anxiety disorders, and PTSD, and people who score highly on neuroticism tend to have a more severe manifestation of depression and anxiety and especially of PTSD. People may be more prone to developing PTSD in response to trauma. They may develop a more severe version of PTSD if they score highly on neuroticism. So this is interesting, right?


And, bringing it back to migraines, patients with migraines in general score more highly on neuroticism than do people in the general population. This is even more significant if they have comorbid depression and anxiety. And so by decreasing neuroticism, you might hypothesize that psychedelics are actually targeting some biopsychological underpinning of something that leads to more distress in people suffering from migraines.


So this is my hypothesis. I think it would be really interesting to study this further, and I think we’re going to get a lot more, particularly — hopefully — from the Yale study and additional studies that may follow. But this is sort of one thing to kind of think about in terms of how psychedelics are working beyond just sort of the serotonin model and the biological impact of what these drugs may do.


So, finally, I want to wrap up and just talk a little bit about harm reduction. So what do we do when a patient comes into our office and they’re like, “I’m going to take a psychedelic, and there’s nothing you can do about it. I’m going to go buy one, and I’m going to take it.” I think it’s important that as physicians, we’re able to have an open and honest conversation about this.


I definitely don’t think we are allowed to — I know we’re not allowed to, and I don’t think we should be recommending psychedelics for anybody because of the obvious risks in nonstructured settings because of legality issues, but I think these are also things that it’s important to be able to talk frankly with patients about. So these are illegal, and even if FDA approves some of these psychedelic-assisted psychotherapy models, that’s not going to be for a couple of years, and it’s not going to be legal in the field the way you can go to a cannabis shop and buy cannabis. So they are illegal, and that poses a legal risk to the patient.


I think of probably greater importance is this idea of drug purity, right? So if somebody is buying a drug on the black market, they really have no way of knowing what they’re truly getting. They buy a sheet of paper, and they think it’s LSD, but every once in a while, somebody at a music festival or a rave ends up having some horrible reaction to a contaminant that was put in and sold as LSD. And so buying drugs in the black market is never safe. It’s never risk-free. And that is also something really to consider.


And then, finally, just this idea that — everything I said in the beginning part of this talk about psychedelic-assisted psychotherapy. We’re really talking about structured clinical settings with preparation. There’s going to be a therapist present when the psychedelic is taken. There’s going to be integration and discussion afterwards. But in nonclinical settings, the majority of people will do fine, but they are certainly not risk-free. These are very powerful drugs, and they can induce some very powerful and different and unfamiliar states of consciousness, and they can bring up really challenging psychological material for people. And so they really aren’t risk-free when used in nonstructured settings, and I think there are some ways to mitigate that.


And so I would just direct anybody who wants to learn more about that to the web page of the Multidisciplinary Association for Psychedelic Studies. They’re actually the group that’s pursuing approval of MDMA-assisted psychotherapy for PTSD. But part of their work, they have a large harm-reduction arm, and there’s a nice page where they talk a lot about kind of set and setting; having a guide, or at least what they call a trip sitter, who can be present to sort of maintain safety for anybody who’s going to do this; and just a lot of information for people who are thinking of embarking on taking a psychedelic so they know what they’re getting into.


And secondly, I mentioned DanceSafe, which is really more of a site that’s associated with the electronic music community, but they have a fairly well-developed harm-reduction page as well. And they sell at very low cost a number of different chemical testing kits that people can order, and they can actually test things that they buy. So they can find out, Is this actually LSD? And they also test for the presence of a number of common compounds that sometimes are mixed into illicit psychedelics that could actually be harmful. So obviously there’s no way to a hundred percent reduce harm, but I think these are some things that we can do as physicians to direct patients to and to help mitigate risk as best we can if they’re going to do it.


So in conclusion, we talked about how psychedelics have shown promise in migraine treatment. Potentially, there may be multiple mechanisms at play. There’s biological, perhaps through serotonin. There may be some indirect mechanisms through depression, anxiety, PTSD; also through producing better coping with illness and symptoms; and then also by reducing neuroticism, which may be one of the sort of underpinnings of all of this. And then finally, we talked a little bit about harm reduction.


And so we are right at time, so I will stop, but thank you again for your time.




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