S3:Ep9 – Magic Mushrooms? What You Need to Know About Psychedelics for Migraine



Voice-over: Welcome to Spotlight on Migraine, hosted by the Association of Migraine Disorders. Join us for fresh perspectives by medical experts and advocates as we explore the spectrum of migraine and dig deeper into this complex disease.


This episode is brought to you in part by our generous sponsors Amgen and Novartis.


Molly O’Brien: Hi there, and welcome to Spotlight on Migraine. I’m your host, Molly O’Brien. Today we’re going to talk all about psychedelic drugs for migraine and cluster, and we do want to give a reminder that these drugs are illegal.


I’d like to say hello and welcome to our guest, Dr. Peter McAllister. He’s a board-certified neurologist, and he’s the director of the New England Institute for Neurology and Headache. Dr. McAllister, thank you so much for joining us today.


Dr. Peter McAllister: It’s a pleasure. Thanks for having me.


Molly: Super excited to talk to you today and get some of your insight. We’re going to talk a little bit about psychedelic use for migraine and cluster treatment, and we do want to say that using psychedelics is not legal yet, so we’re kind of talking in theory and about the latest research out there.


Dr. McAllister: Right.


Molly: Wonderful. Well, thank you again for joining us. As we dive in here, let’s just kind of take a broad look, with some of the basics. What are psychedelics, and how do they work?


Dr. McAllister: So psychedelics are a group of compounds, chemicals, that are hallucinogenic — that is, when used in sufficient dose, trigger what we call a nonordinary state of consciousness. They work specifically on serotonin, which is one of the main neurotransmitters in the brain, and we’ve even gotten more specific to know that the psychedelics work on serotonin 2A, which is a subtype receptor. And it increases serotonin dramatically in areas of the cortex, which is the higher-thinking part of the brain.


Some folks might think of psychedelics such as LSD, psilocybin, which is the compound in mushrooms, mescalin, peyote, etc., and think, “Boy, that sounds like very dangerous stuff.” But actually, when you look into the science of it, these drugs are remarkably safe. So the interesting thing is medicines or drugs like psilocybin, LSD, etc., have no lethality; that is, there is no ability to overdose and accidentally kill yourself. There’s no addiction or dependence. So compared to other compounds that we think of that might be safer, such as alcohol and tobacco, actually, I think that psilocybins would win that, as would LSD and the others.


The main problem was these were used in research in the 1950s, ’60s, and into the ’70s, but what happened was the counterculture, hippies, Timothy Leary, dropping acid and dropping out, and it got the government really quite scared. And so they legislated to make these illegal, such that even physicians can’t prescribe them. And all that research that was very fruitful in depression and other disorders kind of came to a grinding halt. And only recently now have we opened up the gates a little bit and gotten some permission to do clinical trials for a number of different states with these drugs.


Molly: It’s absolutely fascinating to learn more about what the drugs are, how they impact the brain, and, like you said, don’t have any lethality to them. So it’s fascinating to learn that.


So you mentioned, Dr. McAllister, a couple different types of psychedelics that people might be familiar with — you said psilocybin, peyote — so maybe a little bit more common. But can you tell us a little bit about the different types of psychedelic drugs that could impact migraine and cluster, and kind of how those work?


Dr. McAllister: Sure. You can look at psychoactive substances in general, and there are many things that are psychoactive. Caffeine is psychoactive. Nicotine is psychoactive. Alcohol is psychoactive. When we talk about psychedelics, we’re really referring to that subgroup of psychoactive substances that works on the serotonin 2A receptor.


The quintessential one is LSD. LSD was originally synthesized as a high-blood pressure drug in Germany, and Dr. Hofmann, who was the scientist trying to find a good blood-pressure drug actually accidentally got some on his membranes as he was handling it, and his bicycle ride home was basically an acid trip. That was the first, really, recorded acid trip. And then we kind of [went?] into a whole host of research over the next few decades on LSD.


Psilocybin has been used since before the written word. It’s been used by ancient Indians and other Indigenous tribes for their religious ceremonies. In fact, psilocybin in some cultures translates into the “food of God,” because of the hallucinogenic experience.


Another one commonly used is dimethyltryptamine, which is DMT. DMT’s got a very short half-life, and it can be inhaled, but if you mix DMT with something that slows down its metabolism — you can have it in a tea or even in a soup or a broth, and we call that ayahuasca.


So ayahuasca, LSD, and principally psilocybin, based off of magic mushrooms, is probably the most used and the most commented on in the migraine and cluster world for treating those conditions.


Molly: And so the way that those drugs work, are they all kind of acting on the same mechanism of involving those serotonin receptors?


Dr. McAllister: Yes. Some work very specifically on the serotonin 2A receptor. Some work on that but are what we call “dirty,” or the other fun term is “promiscuous,” meaning they can bind to other receptors as well, not just the 2A. It also depends on where in the brain it binds. So these are very similar and overlapping, but they have some differences, so.


But, really, it is the serotonin — serotonin in the cortex has a lot to do with our perception of consciousness. It’s hard to conceptualize because day to day, we just look out and we see the world as we view it. But that’s really just our interpretation of it based on our brain. It’s kind of an odd thought, but when you do psychedelics in a hallucinogenic dose — which is called macrodosing, as opposed to microdosing — that consciousness that we take for granted gets completely altered. And it’s led to a lot of fascinating insights.


And one of the ways it’s worked for conditions like depression — another one called “existential fear of death” — let’s say, sadly, you had terminal cancer. Now, some people just kind of live out their time and have a good time with their family, etc., and then they pass. And some folks are so fearful of dying, they have no quality of life at the end. So a study looked at these mind-altering psychedelics, and once someone did what we would call a hallucinogenic trip, they kind of connected to the cosmos and big terms like that, such that they didn’t feel the fear of death anymore. And the study showed that one hallucinogenic trip completely improved the quality of life right up until the point they died.


Now, interestingly, you can also microdose. So microdosing means you take it at a subhallucinogenic amount or vaguely hallucinogenic. I’ve had people use these drugs for cluster where they can hold a conversation and all, but the walls are shimmering a bit. It’s not a full-on hallucinogenic trip.


Interestingly, for pain states, for cluster, for migraine, etc., you don’t need the hallucinogenic part. So people who say, “I’m afraid of that; I don’t want to have a trip,” you don’t need it. Microdosing — mind you, again, the caveat that this is still unfortunately illegal — but microdosing has been the mainstay of busting cluster, and now there’s new research on chronic migraine as well.


Molly: And you mentioned a couple studies that had involved using psychedelics — either macro-, microdosing — for other conditions. Can we talk a little bit more about some research that’s been happening on the migraine and headache disorder side? In fact, there was a recent study published just in 2020. There was a small-scale study but seemed to have some really good insight on how these drugs can impact migraine. Can you just tell us a little bit about that?


Dr. McAllister: Sure. So they were first looked at, these hallucinogenic drugs, for cluster, and then only later migraine, particularly the 15-or-more-headache-days-a-month thing we call chronic migraine. For cluster, that dates back to an accidental observation, so before the hard science came, of somebody who had cluster and was also a recreational user of these type of drugs, and noticed that when he took his LSD — it was, actually, for this guy — it completely obliterated his cluster. And like many things in science, it’s a serendipitous discovery, accidental.


He wrote about that, back before blogging was in, but wrote about it, got it online, and more people took up the mantle. And then groups formed, and then there were informal surveys, if you look at Clusterbusters or other kind of chat rooms and things. And people say, “If I do X — psilocybin, LSD, etc. — twice a week during my cluster, it just vanishes.” And so that then led scientists and physicians to take this all very seriously. It wasn’t just that these people were getting “high”; they were actually affecting their pain.


So the initial cluster studies done in the late 1990s into the 2000s were all small because, as we said, this is what we call a Schedule 1 drug. So doctors can write out controlled substances in lower schedules — Schedule 2, 3, 4, and 5. Schedule 1 specifically means you can’t write this drug. And to do a study, it takes basically an act of Congress, pretty much.


So these little studies, when they were done, were all amazingly effective in both knocking out a cluster once it starts and then keeping clusters at bay. In fact, there was a small study that looked at one and only one LSD taking completely eliminated cluster from recurring again, at subhallucinogenic doses.


Now, the study you’re referring to was done just down the road from me at Yale. It’s an ongoing study they have on chronic migraine, and it was only 10 patients, I believe. The total number was 24, but they looked at, I think, 10 patients and found a 70 percent reduction in the number of migraines, and then also a number of quality-of-life measures that dramatically went up.


This was subhallucinogenic, so people didn’t have to trip. It turns out that if you’re treating depression, anorexia, addiction, the hallucinating is a big part of that. But when you’re treating pain, such as migraine and cluster, you don’t have to hallucinate. So microdosing — which has been used for ages for creativity and other things out in Silicon Valley, in particular — is perfectly fine, and that’s all you need to effect the change that you want.


Molly: Do you think that that was one of the most important takeaways from that study, to know that you didn’t have to have the trip in order to see benefits?


Dr. McAllister: Yeah, because once you take away that — which some people either find fascinating, exciting, but a fair amount of people find it scary and not something they want to do — yes. Otherwise, the side effects of mild sedation, a little bit of dizziness, I mean, it’s comparable or better than the medicines we have now. And, mind you, we have medicines for cluster, but they don’t always work all the time, and they have their own set of side effects, etc. So we need more research on this.


I wrote an article on a true story of a patient of mine who had episodic cluster, so he would just cluster in and cluster out. And we were able to help him through those, as awful as they were. But then he switched to chronic cluster, meaning he never had a remission. So every day of his life was the worst pain on the planet, as a hot poker jammed through his eye. And when nothing could help him, although he was not depressed — he clearly states that — his answer was to kill himself.


Molly: Oh, God.


Dr. McAllister: Yeah, and he bought a gun, but then got information on the use of psilocybin. And he did a particular dose, and he did it twice a week. And after he did it for about three weeks, his headaches reverted back to episodic cluster and became very mild, and he basically got his life back.


Molly: It’s incredible to think that someone can live through that extraordinary amount pain and still research and advocate for themselves. It’s overwhelming to think that someone’s living through that.


Dr. McAllister: Yeah, and I think that, again, going back to the ethics of withholding that from people, it gets very dicey. And perhaps one of the things that come out of as many people who listen to and view this blog as possible, to try to get active in the headache community, talk to their legislators, write to their legislators. Let us use these medicines in controlled clinical trials so that it can be done safely, we can get the real, hard science, and then we can get useful medications out to these very, very desperate patients.


Molly: My goodness, all great points there. And I read the article that you’re referring to. You mentioned a little bit that it’s important to talk about psychedelic drug use with patients. Patients bring it up. But then also you just mentioned that there is ethical obstacles that kind of murky the waters. So as a physician, how can you start or how can patients start a conversation that doesn’t have murky waters about psychedelics?


Dr. McAllister: Yeah, well, in my mind, there’s no ethical dilemma. It’s a legal dilemma. Yeah, so I don’t bring it up straight away. I’m a very science-based clinical researcher and clinician. This is what I do for a living. So we can get a fair number of patients better. I was involved in one of the trials of galcanezumab, also known as Emgality, and we got that approved to treat cluster attacks. So there are still plenty of legit, FDA-approved ways to go after this terrible condition.


But it’s that group that nothing works or they have intolerable side effects. I had somebody who I put on verapamil, and it caused a big conduction problem with their heart, such that they were going to need a pacemaker. So that wasn’t going to work, and that was the only drug that was effective for him.


When you get those people in, I then just review the science. So I think if you start with science, you’re not advocating it, you’re not telling him to go out and do something illegal. You say, “You know, cluster headache has a lot to do with serotonin. There are some drugs that are not commercially available but have been shown in small studies and a whole host of surveys to be highly effective, and here they are.” And I do refer them often to the Clusterbusters website. I think that’s a clearinghouse of a lot of useful information.


I also tell them that this discussion is privileged doctor-patient information and what goes on in this room stays in this room, so their comfort level is high. The problem is — and it’s just awful that it’s still, in 2021, has to be this way — the only access they can to try this out is to sort of know a guy who knows a guy who can get something on the streets. And that’s terrible for a 63-year-old accountant who really doesn’t have contacts like that. But at least I open their eyes to it, and then they, then, can make their own decisions based on the information I provide.


Molly: It’s so good to hear that there is a way to have this kind of conversation, to have open and honest communication with your healthcare provider while still knowing that, yeah, these substances are illegal. And you mentioned advocating, reaching out to your representatives to make sure that we can have access to clinical trials with these types of drugs. So I think you make some really good points about the patient side of things and how they can advocate for themselves. So I really appreciate that insight.


So let’s back up a little bit. You mentioned the psychedelic drug DMT, and we’re starting to see a little bit more buzz around DMT for migraine use. Can you tell us a little bit more about that specific drug, kind of how it works, and what we know so far, and what we might know in the future?


Dr. McAllister: Sure. DMT is a very potent psychedelic. It’s hard to microdose DMT. It really is designed to be hallucinogenic. And in its pure form, DMT is generally inhaled, and then there’s a very, very quick onset — within minutes, virtually — and it’s out of you in pretty short order too. If you use a chemical with it, as I mentioned earlier, which has a chemical term, a monoamine oxidase inhibitor, you block some of the breakdown, so now it doesn’t get out of you so rapidly. And then that can be in a broth or a tea, which is ayahuasca.


DMT is now undergoing clinical trials from a small company in the Bay Area of California for a number of different disease states, including depression, anorexia nervosa, body dysmorphic syndrome. And I don’t know of any migraine studies, although I’m sure they’re working on that. I’ve done some consulting with them on the idea that working on this for severe pain states like chronic migraine and chronic cluster would be worth their while. I mean, not only would it be ethically good and have a real population who could use it; it probably would be financially a good idea for the company too, since if you look at — cluster is fairly uncommon, but chronic migraine is really common, just given the sheer number of total migraine sufferers, which is in the tens of millions, and a billion around the world.


So, yeah, I think the leading country is the United Kingdom. So England has relaxed their hallucinogenic research laws a bit because of some amazing scientists who have really just pioneered it and literally pushed the government. So they’re a bit ahead of us, having access to hallucinogenic compounds even at microdose to use in studies for cluster and for migraine and for depression and for post-traumatic stress disorder, etc. The United States is — we got a small number, but, again, it really takes effort to get these things up and running. And my hope, again, is that the barriers will start to come down and we can actually do this properly.


Molly: I have two questions from what you mentioned. Do you think that the United States can kind of see how the UK navigates this? Does that offer some promise that a country that we’re fairly close with can give insight and kind of lead the way, and maybe the United States can trail a little bit?


Dr. McAllister: If they can show that the floodgates are not going to be opened and you’re going to have zombies hallucinating all over the streets of London — which they have not seen, mind you — I think that will come to pass here as well. At least, I hope so.


The other thing is, again, because the hallucinogenic part is not needed for the pain, there is something called bromo-LSD, which basically takes the hallucinogenic potential out of LSD but keeps the pain-fighting properties. So there is a company that’s now bought the rights to it, and we really hope — it’s been hanging around for a few years, but we really hope that someone’s going to come forward with this bromo-LSD so that you can have a compound that can be written by doctors that won’t have hallucinogenic properties.


Molly: That’s very exciting. And I just want to touch back to one thing that you mentioned before, that — small scale, again, but a group out in San Francisco was looking into different types of uses for psychedelic drugs. Is it possible that — even though it’s not directly looking at psychedelic drug use with migraine and cluster, could we see some overlap? Because some of the disorders you mentioned are comorbidities of migraine. So could we kind of stumble, again, saying, “Hey, yeah, this isn’t what we’re looking into, but we do have evidence that it helps”?


Dr. McAllister: It’s a great point. So, as you’re alluding to, depression and anxiety are strongly comorbid with migraine. I mean, it’s the same sort of serotonergic fragility complex in the brain. So, yes, I think that if they are going after a depression indication, a severe anxiety, OCD, post-traumatic stress disorder, many particularly chronic migraineurs have unfortunately been the victims of trauma and have PTSD, so that would be great. We then would have access to it for our migraineurs with those comorbid conditions.


Molly: In fact, I think we’ve seen quite a few treatments, we just stumble upon it, like Botox, for example. Oh! Someone got this cosmetically, but it also helped their migraines, so, hey —


Dr. McAllister: Yeah, no, that’s exactly how it works. Botox was originally in the neurologists’ toolbox for a spasm of the face and eyes, but then we noticed people looked younger. And then it became a cosmetic thing, and then a group that was getting it cosmetically said, “Oh, I look younger and great, but I used to have these horrible headaches. I don’t have them anymore.” So it was just one after the other serendipitous finding.


So, yeah, I hope that we’ll come to see that once these start and then we really look at the what we call “safety and tolerability” — because when you have a new compound, you want to look at how well it works. That’s called the efficacy. And then you want to look at the safety and tolerability, and that’s how dangerous it is or isn’t and how much side effects you have. And if we find that these things work — and I think all the evidence points to that, so there’s going to be good efficacy. Once we demonstrate scientifically that it’s got safety and tolerability as good or better than other products out there, I think the government will relax a bit. I certainly hope so.


Molly: Wonderful. Well, we don’t want to take up too much more of your time. This has been such a great conversation. I know I’ve learned a ton. If you’re willing to, we do have a couple viewer questions we’d like to get your insight on.


Dr. McAllister: Sure.


Molly: So you mentioned a few studies that either happened that you’ve been a part of or that are happening. Do you know how people, if they’re interested, might be able to participate in one of these studies?


Dr. McAllister: Yeah, I think the best way to get a handle on what’s out there and where is to go to ClinicalTrials.gov. And then it looks like a Google search engine where you can put in a disease state, say migraine or cluster, or you can do what I just tried this morning, is under — just below that, you can put in the word psychedelics. And if you just put in the word psychedelics and nothing else, what pops up is 237 studies for all sorts of indications. Some of them I’ve mentioned. And then when you click on it, you can find what the study is about and where the locations are around the country. So that’s great.


Clusterbusters’s website, if they can go to that, does have an email to sign up for. And if you want to get notifications about studies that are geographically close to you, they can do that as well.


Molly: Wonderful. And we have some good friends over at Clusterbusters. They do amazing work, so we’re always thankful to work alongside them.


You mentioned earlier that psychedelics aren’t necessarily dangerous in terms of addiction, but one of our followers wanted to know, “Could it be safe for someone that’s in recovery from drugs and alcohol to use a psychedelic substance?”


Dr. McAllister: As far as we know, the answer generally seems to be yes. In fact, if you look at the guy who founded Alcoholics Anonymous, he cured himself of alcohol with a psychologist-guided hallucinogenic LSD trip.


Molly: Wow.


Dr. McAllister: Yeah, so they do not seem to have addiction potential, dependency. Certainly, we mentioned, there’s not lethality. So I think that if somebody’s in recovery from another substance that has those properties, a — particularly — microdose to treat pain is not going to trigger their old habits back. In fact, it may help them because it’s been used for, as I mentioned, alcohol, quitting tobacco, and other substances.


Molly: That’s incredible. I did not know that. Oh, and then we talked a little bit about how psychedelic drugs impact those serotonin receptors. Another one of our viewers wanted to know if SSRI meds would interfere with or decrease efficacy, or just if we know about any of the two interacting.


Dr. McAllister: Yeah, I think that’s a great question, and when I say that they seem to be remarkably safe, that’s in a vacuum. That’s in an individual not taking other meds. So I think that when and if these drugs become commercially available, we’re going to have to look at other drugs, and there may be warnings.


If you have too much serotonin boosted in your brain, you can have something called serotonin syndrome, which can be dangerous. And your heart is racing, and you’re sweating, and you’re anxious, you can have a seizure, etc. So there’s no evidence that being on an SSRI and taking a hallucinogenic drug does that necessarily. It’s a theoretical risk that would have to be either proved or disproved. And it goes back to what I’ve been saying that we need access to these compounds to do legit research, right? So we will have that answer if we can get our hands on these compounds and do the right research.


Molly: So, Dr. McAllister, is there a right way to take these medications? Is there a proven way for them to work better, whether that’s preventatively or acutely?


Dr. McAllister: Yeah. So an acute drug, you take to knock out the pain that instant or that day, and a preventive drug, you take at a scheduled interval to decrease the intensity and the number of headache days per month, right? So the answer is not based on large studies, because as we mentioned, we don’t have those yet. But anecdotally in small studies, these psychedelics can be used for both. If someone is in a cluster headache and takes a hallucinogenic drug, it can knock that headache out.


But I think they’re better used as preventives, and those folks who have used them and have published on them, etc., they’re not generally taken daily. They’re usually twice a week until the cluster cycle abates, if you’re episodic cluster, or until the migraine is sufficiently down to a small number per month, if you’re a chronic migraine sufferer, and revert back to low-frequency episodic. So I think that most of the research will be pointed toward the preventive side of things.


Molly: Wonderful. And just kind of as we wrap things up here, do you have any other parting thoughts on the use of psychedelic drugs for migraine, cluster treatment, research, anything else you want to share with our followers?


Dr. McAllister: Yeah, I think that we’re getting into a dawn of a new era, that we are looking at compounds that were thought back in the heyday of the hippie movement, etc., to be very dangerous, and coming around to the science of it, not the politics of it. And the science is these drugs are quite safe. Nonserotonin hallucinogenic drugs such as MDMA, known as ecstasy, or ketamine infusions, these are really coming into vogue now for treating the extremes of pain emotionally or physically. So ketamine, for example, is used for severe nerve pain, cluster, migraine, but also PTSD, depression, anxiety.


So we need new compounds, and I think that we have to have an open mind, and we have to sort of push our lawmakers to have an open mind as well. And if we do that, we’re going to have great research and a bunch of new compounds out to help people.


Molly: And science, in fact, rules. Science is legit. So if we all follow the science, then maybe there can be better results lying ahead.


Dr. McAllister: You bet.


Molly: What an excellent conversation that we had here today. I know that I personally have learned a ton, and I hope you at home have learned as well. I’d like to say a big thank you to our guest today, Dr. Peter McAllister. He’s a board-certified neurologist and the directory of the New England Institute for Neurology and Headache. Dr. McAllister, I can’t thank you enough for all of your insight.


Dr. McAllister: Thank you, Molly. It’s a pleasure to do it.


Molly: And we are so happy to have had you.


And that wraps up this episode of Spotlight on Migraine. I’m your host, Molly O’Brien. From myself and from the Association of Migraine Disorders, thank you so much for watching. Bye-bye.




Voice-over: Thank you for tuning in to Spotlight on Migraine. For more information on migraine disease, please visit MigraineDisorders.org.


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