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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.

In this episode Dr. Emmanuelle Schindler presents data from a pilot study that investigated the effects of the psychedelic drug psilocybin in ten people with migraine. She discusses the results of a single micro-dose of the drug, side effects, safety information and more.

Emmanuelle Schindler, MD, PhD: Here are my disclosures, some of which are relevant to what I’ll be talking about today. I wanted to first give some background on what psychedelics are. Psychedelics are compounds that bind to serotonin 2A receptor and have characteristic acute effects known as the psychedelic effects.

There are two major classes. There are the indoleamines that look more like serotonin, and the phenethylamines that look more like dopamine. In the indoleamine class there are the simpler tryptamine compounds that include psilocybin there along with some other examples, DMT and 5-methoxy-DMT, more complex ergolines include LSD, the maker of which is shown there, a Dr. Albert Hoffman.

And on the phenethylamine side the most commonly known one would be mescaline and there are some other compounds that are used, mostly in research, to study the serotonin 2A receptor.

What you notice here is that you don’t see MDMA or cannabis or ketamine on this list because those are pharmacologically very different compounds. They don’t have as their primary, or even any of their actions, a serotonin 2A receptor agonist. When I talk about psychedelics I’m talking about these classic psychedelics which are 2A receptor agonists.

Looking at two of the more commonly known ones, psilocybin and LSD, if you put them up next to conventional headache medications, you see that there’s a lot of overlap. For psilocybin, you have, which is an indolamine compound, melatonin and sumatriptan look almost identical with a couple of things added on or taken off. Melatonin is, of course, used as a preventive in certain headache conditions, and sumatriptan as an abortive.

Comparing LSD, you have DHE, which is used both acutely and as a transitional treatment and methysergide, which was actually developed off of LSD, very effective migraine preventive and also cluster headache preventive. But it was taken off the market for some side effects. And this is kind of a warning sign for psychedelics because they’re so chemically related.

So, it should not be a big surprise that psychedelics would have effects in headache disorders. And, in fact, for decades now, that has been reported. Sometimes the report is on a different topic and it’s buried in there, that the subject happened to have migraine and they found relief for weeks or months. But most of these reports are in cluster headache and that’s perhaps in part because cluster headache has relatively few treatment options. And patients are willing to do and take anything and everything to help with that condition.

The discovery of the effects of psychedelics in cluster headache happened by accident where a patient in the late ‘90s found that after doing LSD one summer that, that kept his normal annual cycle at bay.

So here’s an example of what cluster headache patients have found with psilocybin. Here’s a headache diary of a cluster headache patient and most patients will have an annual cycle lasting weeks to months. And so this is one where on the X-axis there are the days of his cycle. So his is about two months long. And then each attack he shows as a box, the height of which is the duration and on the Y-axis there’s the time of day. And the color of which is the intensity of the headache. So, the blues and greens are less severe and the reds and blacks are really severe.

So, as his typical cycle goes, it starts off with fewer attacks and they’re less severe and then they ramp up to very frequent attacks that are more severe and then it tapers back down. So, that’s a typical cycle.

This patient happened to have biannual cycle. So the next time he had a cycle, here he is, he starts to have his cycle, the attacks ramp up and he heard about using psilocybin mushrooms to help with cluster headache. So he tried .5 grams of the mushroom, that’s a pretty low dose, but immediately, for a couple of days, he’s got reduced number and intensity of attacks.

They ramp back up, and so he takes a whopping dose of psilocybin mushroom, he was probably talking to God at this point, and his cycle completely stops after a couple of days of some minor attacks.

Psilocybin is rapidly metabolized. It’s out of his blood by the following day. There’s nothing else in headache medicine that you can take by mouth that’s metabolized out of your body that has such a profound effect.

So, this is what makes psychedelics so exciting in headache disorders. That there’s nothing like it.

What has been reported that patients using psilocybin mushrooms for cluster use very low doses, .1 grams up to much higher doses. So, there’s a range. Not everybody needs to have the higher doses. And then there are also many reports of patients using sub-psychedelic doses of LSD in cluster headache as well. And again, most of these anecdotal data are in cluster. But we can take from that and we can apply it to other headache disorders as well.

Since there really wasn’t a whole lot out there on migraine, perhaps just some case reports and patients telling us of their experiences, I wanted to do an exploratory study in migraine. Really basic question, what happens after a single dose and compare it to a placebo.

We enrolled patients who had migraine with about two attacks a week or more, up to age 65. And like with all psychedelic studies we excluded patients who have significant medical disease, psychiatric disease, and substance use history. And that’s a little schedule of the study. It was very short term.

We had patients keep a diary for about six weeks and then two weeks apart they got two different drugs. Between placebo and psilocybin and we compared the differences in the diary. We’re interested in those changes such as frequency, the duration of attacks, and some other measures there.

And then during the test days when patients get the psilocybin, we looked at changes in vital signs, how they generally felt on the drug, and then there’s a specialized scale, the 5-Dimensional Altered States of Consciousness scale that measures the psychedelic effects. And then, of course, adverse events.

This study has been published. It was published last year. And there are data from ten subjects who received placebo in the first session and then two weeks later got psilocybin. This dose of .143 mics/kg is roughly 10 mg of the pure psilocybin, which is a relatively low dose. And the final results included three males and seven females with an average age of about 40.

These are some of the main findings. After a single dose, compared to after a single dose of placebo, a single dose of psilocybin reduced the migraine days per week by about half. There was a little dip after placebo, but there’s a big dip after psilocybin.

The pain intensity of the migraine attack ranked from 0 to 3 was also reduced after psilocybin but not after placebo. The duration was also reduced but because it was also reduced after placebo it didn’t meet significance because they both went down. But there was also a reduction in the duration of the migraine attacks that did happen over those next two weeks.

There were also some other measures that were found to be changed. The functional impairment during a migraine was also reduced by about half and then the number of aborted medications taken per week, or the number of days taking an abortive medication was also reduced by about half. And that makes sense if you have 50% fewer migraines, then you’re going to take those medications less.

What was also interesting is that patients had more migraine-free time, so the time to the next attack after the dose of drug was given was pretty much doubled. It was about two days for placebo of the first migraine and it was over five for psilocybin. This missed significance, but the time to the second migraine, that was significantly different between psilocybin and placebo.

Some of the patients in the study didn’t have a single migraine in those two weeks. So we just called their next migraine day 15. This sort of didn’t quite measure when their next migraine could have been, which may have been a month later. There were some patients who had long-term relief.

I told you that during the test days we kept the 5-Dimensional Altered States of Consciousness scale, which is a measure of the psychedelic effect. And there was some, when patients got the placebo, there was a mild, there was a very low rating and there was, of course, a higher rating when patients got psilocybin. When you plot the percent total scores, out of a 100, to the percent reduction in migraine days per week, that’s what’s shown here, all of these, each dot here is one patient. There was no correlation. So, if it was highly correlated the dots would all be very close together, right on top of the line. But they’re all spread out.

Plus, the other thing that’s interesting here is that if you use the line as kind of a guide, even though it’s not significant, it almost looks like those people who had a lower psychedelic experience had a greater reduction in their migraine burden, which was interesting.

In psychedelic research on the mental health side, it’s the opposite. The bigger experience you have during drug dosing, the better the outcome. But for migraine, it didn’t correlate at all. And that’s similar to what cluster headache patients have been saying. They don’t have to take a high dose. They can get the same effect out of a low dose that has minimal or even no psychedelic effects at all.

There were some side effects to taking psilocybin even this low dose; light-headedness and nausea, and anxiety were some of the more common ones during the test sessions. These were all very short lived and they resolved by themselves. We didn’t have to give any medications or anything. The day following the drug administration a lot of people got kind of general kind of hangover headaches. And these were patients who had migraines. So some of them did have migraines also the following day. But that’s not too surprising.

I get asked a lot, don’t psychedelics cause headaches. Well, yes, they can cause one headache, but it’s worth it if it ends up turning off your headaches for weeks or months down the road. So, I say, yes, they can cause a headache, but they can actually treat a headache disorder.

So the conclusions that can be made from this study, keeping in mind that this is a very preliminary study, only ten patients, total in the final analysis, and then this is just after a single dose, looking over a two-week period. So, it’s a very short-term study.

But, in that period we saw that migraine burden, several measures of migraine burden was reduced in that two-week period. It delays the time to the next migraine. So, more migraine-free time. And the clinical effects appear to be independent from the acute psychedelic effects.

This is more relevant for psychedelic research in general, in terms of do you need to have the strong psychedelic effects in order to have therapeutic benefit. And for headache disorders, at least, it doesn’t appear to be necessary.

We demonstrated safety when we controlled for the types of patients we were recruiting for. And making sure that patients, like, for instance, one of our other safety protocols that patients can’t drive themselves home at the end of the test day. So, with all of those safety protocols in place, there were no unexpected or serious side effects.

But, this study is limited. As I mentioned, ten patients, only two weeks. And more research is going to be required.

There are some strengths to the study, though. It was a controlled study. We had both male and female subjects. A wide age range, from the 20s up to the 60s. And we demonstrated safety. But, the sample was small. All subjects happened to be Caucasian, and about half of the patients were chronic, half were episodic. So, this does not represent the disease population in general, because that’s not where the ratio normally is.

We only gave psilocybin once. And there was only one dose that we were studying. So that’s very limiting and we only looked out for a couple of weeks. There was also a high expectation for psilocybin to work. There’s a lot of media coverage out there about psychedelics treating everything and fixing everything, so people have very high expectations. So that factors in as well.

In future studies, we need larger samples, different doses, looking out over the long term. The idea of having to repeat the doses at a certain interval, that has to be studied as well. And all of these other factors.

On the right I list all of the active headache trials that are going on, or that have completed. The one I just mentioned that I just talked about, is the second one. So there are other groups that are also studying psychedelics in headache disorders.

With that, I thank you for your attention, and I look forward to answering questions later.

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

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*The contents of this podcast are intended for general informational purposes only and do not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. The speaker does not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.