Psychedelics for the Treatment of Cluster and Migraine - Spotlight on Migraine - Episode 31

Summary

Dieses Podcast-Episode des Spotlight on Migraine, moderiert von der Association of Migraine Disorders, beleuchtet die heutige Forschung an der Yale University zur Behandlung von Migräne und Cluster-Kopfschmerzen mit psychedelischen Pilzen. Dr. Christopher Gottschalk, ein Kopfschmerz-Spezialist, teilt Erkenntnisse über die potenziellen Vorteile von Substanzen wie Psilocybin und LSD und ihre Verwendung als Therapieansätze. Er diskutiert auch die Veränderungen in der Behandlung von Kopfschmerzen und die Notwendigkeit, Stereotypen und Fehlinformationen um diese erschwerenden Krankheit zu bekämpfen. Die Diskussion umfasst die Charakteristika von Cluster-Kopfschmerzen, die Intensität des Schmerzes, die Selbstberichte von Patienten und die Ergebnisse kontrollierter Studien mit psychedelischen Substanzen. Die Zuhörer erfahren auch über die derzeitigen Behandlungsmöglichkeiten für Cluster-Kopfschmerzen und die Hoffnung auf zukünftige Fortschritte durch innovative Therapieansätze.

Takeaways

• 🌟 Die Behandlung von Kopfschmerzen wie Migräne und Cluster-Kopfschmerzen befindet sich in einer revolutionären Phase mit vielen neuen Behandlungsansätzen.
• 🍄 Forschungen an der Yale University untersuchen die Verwendung von psychedelischen Pilzen zur Behandlung von Kopfschmerzstörungen.
• 🧪 Psychedelische Substanzen wie Psilocybin und LSD scheinen bei der Behandlung von akuten Kopfschmerzattacken und zur Prophylaxe von Cluster-Kopfschmerzen wirksam zu sein.
• 🏥 Zusammenarbeit zwischen Amgen und Novartis führte zur Entwicklung von bahnbrechenden Therapien für Alzheimer und Migräne.
• 🚫 Die Stereotype und Missverständnisse um Migräne als erschwerende Krankheit müssen überwunden werden.
• 🧬 Die chemische Abstammung von Medikamenten, die zur Behandlung von Migräne und Cluster-Kopfschmerzen verwendet werden, von psychedelischen Substanzen wird diskutiert.
• 📊 Eine Online-Umfrage zu Cluster-Kopfschmerzen zeigt, dass diese extrem schmerzhaft sind und der Suizidrate in dieser Patientengruppe um das Zehnfache höher ist als in der Normalbevölkerung.
• 💊 Aktuelle Behandlungsmöglichkeiten für Cluster-Kopfschmerzen umfassen reine Sauerstoff-Inhalation, Sumatriptan-Injektionen und eine Reihe von Medikamenten zur Langzeittherapie.
• 📈 Eine kontrollierte Studie mit einem nicht-halluzinogenen psychedelischen Wirkstoff zeigte eine signifikante Reduktion der Angriffsanzahl bei Cluster-Kopfschmerzen.
• 🧠 Die Wirkung von psychedelischen Substanzen wird auf die Interaktion mit dem 5-HT_2A-Rezeptor zurückgeführt, was ihre potenzielle Nutzeffektivität erklärt.
• 🇺🇸 An der Yale University laufen derzeit kontrollierte Studien mit Psilocybin-Extrakt für Cluster- und Migränekopfschmerzen, wobei bisher ein gutes Verträglichkeitsprofil beobachtet wurde.

Q & A

Was ist das Hauptthema der in diesem Podcastserie behandelten Episode?

Das Hauptthema der Episode ist die Forschung über die Verwendung von psychedelischen Pilzen zur Behandlung von Migräne und Cluster-Kopfschmerzen.

Welche Universität wird in der Episode als Forschungsstandort genannt?

Die Yale University wird als Forschungsstandort für die Behandlung von Kopfschmerzen mit psychedelischen Pilzen genannt.

Welche Pharmaunternehmen werden in der Episode als Sponsoren erwähnt?

Als Sponsoren werden in der Episode Amgen, Novartis und Alder BioPharmaceuticals genannt.

Was ist das Ziel von Amgen und Novartis bei ihrer Zusammenarbeit?

Amgen und Novartis arbeiten zusammen, um bahnbrechende Therapien für Alzheimer und Migräne zu entwickeln und um Migräne und die umliegenden Vorurteile und Missverständnisse zu bekämpfen.

Wie wird ein Cluster-Kopfschmerz definiert?

Ein Cluster-Kopfschmerz ist eine Form von primärer Kopfschmerzstörung, die unilaterale Schmerzanfälle mit anderen Symptomen wie bei Migräne hat, aber zu den trigeminus-autonomen Kopfschmerzen gehört, was bedeutet, dass es Schmerzanfälle auf einer Seite des Gesichts gibt, die mit Veränderungen der autonomen Nerven verbunden sind.

Was ist die Prävalenz von Cluster-Kopfschmerzen?

Die Prävalenz von Cluster-Kopfschmerzen liegt zwischen 1 in 1.000 und 1 in 5.000.

Wie wird der Schmerz von Cluster-Kopfschmerzen im Vergleich zu anderen Schmerzen wie Migräne, Gicht oder Geburt beschrieben?

Der Schmerz von Cluster-Kopfschmerzen wird als extrem intensiv beschrieben und ist auf einer Schmertschkala von 1 bis 10 höher als Schmerzen durch Migräne, Gicht und Geburt.

Welche Behandlungsoptionen werden für Cluster-Kopfschmerzen genannt?

Behandlungsoptionen für Cluster-Kopfschmerzen umfassen Inhalation von reinem Sauerstoff, Sumatriptan-Injektionen, Verapamil, Lithium, Krampfmittel wie Topamax und Depakote, Steroide, Methylergonovine und Vagus-Nerv-Stimulatoren.

Was ist die aktuelle Haltung der Studierenden und Forscher bezüglich der Verwendung von psychedelischen Substanzen in der Behandlung?

Die Studierenden und Forscher sind der Meinung, dass psychedelische Substanzen aufgrund ihres potenziellen Nutzens in der Behandlung von Kopfschmerzen untersucht werden sollten, unabhängig von ihren hallucinogenen Eigenschaften.

Welche Art von Studien werden derzeit an der Yale University durchgeführt?

An der Yale University werden kontrollierte Studien durchgeführt, die die Wirksamkeit von Psilocybin-Extrakten oder Placebos bei Patienten mit Cluster-Kopfschmerzen und Migräne untersuchen.

Was ist das Nebenwirkungsprofil der in den Studien verwendeten Psilocybin-Dosen?

Das Nebenwirkungsprofil der Psilocybin-Dosen ist sehr günstig, mit einigen Fällen von Übelkeit, vorübergehendem Unwohlsein, Schwindel, Aufregung und Kopfschmerzen, jedoch ohne schwerwiegende Nebenwirkungen.

Outlines

00:00

🎤 Einführung in die Migränenforschung

Dieses Kapitel stellt die Podcast-Serie 'Spotlight on Migraine' vor, die von der Association of Migraine Disorders moderiert wird. Der Schwerpunkt liegt auf persönlichen Geschichten und Interviews mit Experten, die die Auswirkungen von Migräne untersuchen. Dr. Christopher Gottschalk spricht über die aktuellen Forschungen an der Yale University, die sich mit der Verwendung von psychedelischen Pilzen bei der Behandlung von Migräne und Cluster-Kopfschmerzen beschäftigen. Er vergleicht auch die Derivate und Eigenschaften von derzeit verwendeten Migräne-Medikamenten mit psychedelischen Substanzen. Die Zusammenarbeit von Amgen und Novartis seit 2015 im Bereich Alzheimer und Migränetherapien wird erwähnt, ebenso wie das gemeinsame Ziel, Migräne und die umliegenden Vorurteile zu bekämpfen.

05:03

🧬 Cluster-Kopfschmerzen: Charakteristika und Behandlung

In diesem Abschnitt werden Cluster-Kopfschmerzen als eine eigenständige Form von Kopfschmerzen mit unilateralem Schmerz und Autonomen Symptomen charakterisiert. Es wird erwähnt, dass sie seltener als Migräne vorkommen und hauptsächlich bei Männern auftreten. Die Schmerzintensität wird durch eine Online-Umfrage untersucht, bei der Cluster-Kopfschmerzen als besonders schmerzhaft eingestuft werden. Die Behandlungsmöglichkeiten umfassen Sauerstoffinhalation, Sumatriptan-Injektionen, Verapamil, Lithium, Carbamazepin, Steroide und andere Medikamente. Neuere Ansätze wie CGRP-Antagonisten und Nervenstimulation werden auch erwähnt.

10:05

🍄 Psychedelika in der Behandlung von Kopfschmerzen

Dieser Abschnitt konzentriert sich auf die Verwendung von psychedelischen Pilzen und verwandten Substanzen bei der Behandlung von Kopfschmerzen. Es wird über die Erfahrung eines Patienten berichtet, der durch die Einnahme von Psilocybin-Extrakt die Häufigkeit seiner Cluster-Kopfschmerz-Anfälle reduzieren konnte. Es wird auf frühere Studien und Patientenberichte eingegangen, die die Wirksamkeit von Psilocybin und LSD bei akuten Anfällen und zur Verhinderung von Anfällen hinweisen. Die Unterschiede zwischen psychedelischen Substanzen und anderen Klassen von Drogen wie Empathogenen oder Dissoziativen werden betont, und es wird betont, dass die Studien nicht auf hallucinogene Effekte abzielen, sondern auf die potenziellen Vorteile der Substanzen.

15:06

🧪 Psychedelika: Chemie und Wirkungsweise

Der Abschnitt erklärt die chemische Zusammensetzung von psychedelischen Substanzen und ihre Wirkung auf das Gehirn. Es werden die Hauptgruppen, Tryptamine und Ergoline, sowie Phenethylamine erläutert. Albert Hofmanns Arbeit an der Synthese von LSD und anderen Derivaten aus dem Mutterkornpilz wird erwähnt. Es wird betont, dass die hallucinogenen Effekte von LSD und Psilocybin nicht der Hauptgrund für ihre Untersuchung sind, sondern ihre potenziellen therapeutischen Vorteile. Die Wirkung von Psychedelika an der 5-HT_2A-Rezeptorstelle wird beschrieben, und ihre vergleichsweise geringe Toxizität wird hervorgehoben.

20:10

🧫 Yale-Studien zu Psychedelika bei Kopfschmerzen

In diesem letzten Kapitel werden kontrollierte Studien an der Yale University vorgestellt, die die Wirksamkeit von Psilocybin bei der Behandlung von Cluster-Kopfschmerzen und Migräne untersuchen. Es werden die Einschluss- und Ausschlusskriterien für die Studienteilnehmer erläutert, und es wird berichtet, dass bisher 20 Patienten eingeschlossen und 14 Studien abgeschlossen haben. Die Nebenwirkungen der Studie, einschließlich Übelkeit, vorübergehender Angst und Schwindel, werden als gering eingeschätzt. Da die Studien noch nicht entblindet wurden, können keine Ergebnisse berichtet werden, aber die Studien werden fortgesetzt, um die Dosierung zu optimieren und die am meisten ansprechenden Patientengruppen zu identifizieren.

Keywords

💡Migräne

Migräne ist eine neuropatische Erkrankung, die durch wiederkehrende Anfälle heftigen Kopfschmerzes gekennzeichnet ist, die mit anderen Symptomen wie Übelkeit und Erbrechen einhergehen können. Im Video wird die Migräne als ein zentrales Thema behandelt, das durch persönliche Geschichten und Experteninterviews erkundet wird.

💡Cluster-Kopfschmerz

Cluster-Kopfschmerz ist eine Form von primarem Kopfschmerz, der durch wiederkehrende, einseitige Schmerzanfälle charakterisiert ist, die oft mit autonomen Symptomen wie Tränenabgang oder Rotsein der Augen auf der schmerzbetroffenen Seite einhergehen. Im Video wird dieser als besonders heftiger Kopfschmerz dargestellt, der schwerwiegende Auswirkungen auf das Leben der Betroffenen hat.

💡Psychedelische Pilze

Psychedelische Pilze, wie Psilocybin, werden im Video als Teil der Behandlungsforschung für Kopfschmerzzustände wie Migräne und Cluster-Kopfschmerz erwähnt. Sie sind Substanzen, die traditionell für ihre hallucinogenen Eigenschaften bekannt sind, aber in medizinischer Forschung für ihre möglichen therapeutischen Vorteile untersucht werden.

💡Serotonin

Serotonin ist ein Neurotransmitter, der bei der Regulation von Stimmung, Wachheit und Schmerz empfunden wird. Im Video wird Serotonin als Ausgangspunkt für die Entwicklung einiger Medikamente erwähnt, die für die Behandlung von Kopfschmerzen verwendet werden, wie zum Beispiel Indomethasin, das aus Serotonin abstammt.

💡Sumatriptan

Sumatriptan ist ein Medikament, das zur Behandlung von Migräneanfällen verwendet wird. Es wird im Video als Beispiel für einen Wirkstoff diskutiert, der aus der Struktur von DHE (Dihydroergotamin) entwickelt wurde und eng mit Melatonin verwandt ist.

💡CGRP-Antagonisten

CGRP-Antagonisten sind ein neuerer Typ von Medikamenten, die zur Behandlung von Migräne entwickelt wurden. Sie blockieren den Calcitonin-Gen-veränderten-Peptid-Rezeptor (CGRP), der in der Schmerzübertragung involviert ist. Im Video werden sie als eine der Optionen für die Behandlung von Kopfschmerzen erwähnt.

💡Vagusnerv-Stimulator

Ein Vagusnerv-Stimulator ist ein medizinisches Gerät, das verwendet wird, um Schmerzanfälle zu stoppen oder zu verhindern. Im Video wird erwähnt, dass es eine Option für die Behandlung von Cluster-Kopfschmerzen ist, indem es den Nerv im Hals reizt.

💡5-HT_2A-Rezeptor

Der 5-HT_2A-Rezeptor ist ein Art von Serotonin-Rezeptor, an dem psychedelice Substanzen wie LSD und Psilocybin ihre Wirkung ausüben. Im Video wird er als der spezifische Wirkungsort dieser Substanzen beschrieben, um ihre potenziellen therapeutischen Eigenschaften zu erklären.

💡St. Anthony's Fire

St. Anthony's Fire ist ein historischer Begriff für die Symptome, die durch die Intoxikation mit dem Schimmelpilz Ergot bewirkt werden, der auf Weizenbrot wächst. Im Video wird dieser als historischer Kontext für die heutige Verwendung von Ergot-Extrakten wie Dihydroergotamin in der Behandlung von Kopfschmerzen genannt.

💡Methysergide

Methysergide ist ein Medikament, das aus Ergotamin abgeleitet wurde und ursprünglich zur Prophylaxe von Migräne verwendet wurde. Im Video wird erwähnt, dass es als erster Wirkstoff zur Verhütung von Migräneanfällen auf dem Markt war, bevor es aufgrund von Bedenken hinsichtlich der Fibrose-Entwicklung vom Markt genommen wurde.

💡Selbstbericht von Patienten

Der Selbstbericht von Patienten bezieht sich auf die Erfahrungen und Berichte von Menschen, die unter bestimmten Erkrankungen leiden und über ihre Symptome und Behandlungsergebnisse berichten. Im Video wird dies als wichtige Quelle der Informationen für die Forschung und Behandlung von Kopfschmerzen genutzt.

Highlights

Dr. Christopher Gottschalk discusses the revolutionary ideas and applications in the treatment of headache disorders at Yale University.

Research on the use of psychedelic mushrooms in treating migraine and cluster headache is being conducted at Yale.

Derivatives and characteristics of current migraine and cluster treatment drugs are compared to psychedelics.

Amgen and Novartis collaborate to develop therapies for Alzheimer's and migraine diseases.

Cluster headache is part of the trigeminal autonomic cephalalgias, characterized by unilateral pain and autonomic nerve changes.

The prevalence of cluster headaches is lower than migraines and is more common in men.

Pain intensity of cluster headaches is highly subjective and has been compared to other types of pain through an online questionnaire.

The suicide rate among cluster headache sufferers is at least 10 times higher than the normal population rate.

Current treatments for cluster headaches include inhaled pure oxygen and sumatriptan injections.

A patient's diary shows a dramatic reduction in cluster headache attacks with the use of psilocybin.

Citizen science and patient self-reports indicate potential benefits of psychedelics in treating cluster headaches.

A controlled trial with a non-hallucinogenic agent shows a significant decrease in the number of cluster headache attacks.

Psychedelics, including psilocybin and LSD, are being studied for their potential benefits beyond their hallucinogenic effects.

The chemical structure of sumatriptan, a common migraine medication, is closely related to psilocybin.

The 5-HT_2A receptor is a specific site of action for psychedelics, which is understood in terms of their effects.

Yale University is conducting controlled trials with psilocybin for cluster and migraine headaches.

The side effect profile of psilocybin in the trials is very favorable with no serious adverse events reported.

The study is still blinded, and further recruitment and optimization of dosage are ongoing.

Transcripts

Welcome to Spotlight on Migraine, a podcast series hosted by the Association of Migraine

Disorders.

Through personal stories and interviews with experts, we expose the true scope of migraine

by exploring symptoms, treatments, research topics, and more.

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

Alder BioPharmaceuticals.

In this episode, Dr. Christopher Gottschalk gives a presentation explaining research currently

being done at Yale University on the use of psychedelic mushrooms in the treatment of

migraine and cluster headache.

Additionally, he explains the derivatives and characteristics of drugs currently being

used for migraine and cluster treatment and how they compare to psychedelics.

Since 2015, Amgen and Novartis have been working together to develop pioneering therapies in

Alzheimer's disease and migraine.

Together, Amgen and Novartis share in a mission to fight migraine and the stereotypes and

misconceptions surrounding this debilitating disease.

Dr. Christopher Gottschalk: It's a great pleasure to be here, and I found those talks that you've

already heard very, very exciting.

The best thing about being a headache physician right now and in the last 10 or 20 years is

that this is an extraordinary period of revolutionary ideas and applications, devices and medications

for this group of people that have been standing in the dark for way too long.

And speaking of that, I'd like to speak a little bit about some of the research that

we're currently doing at Yale and the use of psychedelics in the treatment of headache

disorders.

So we're here talking about a slightly different but related phenomenon.

You've been hearing about mostly migraine so far and, in some cases, things that could

be applied to both, but just a quick review.

Cluster headache is a distinct form of what we call a primary headache disorder, meaning

it is attacks of pain with other symptoms, like migraine.

But as opposed to migraine, it is part of what we call the trigeminal autonomic cephalalgias,

which simply means it is diseases that have unilateral pain attacks associated with weird

changes in your eye or your nose or your ear on the same side, indicating to us that there

is something that is affecting the what we call autonomic nerves on the same side of

the head as your trigeminal nerve where you're getting the pain sensation.

So there's a list here of diseases that fall under that category, and by far, the first

member of that group, cluster headache, is the most common type.

The rest -- paroxysmal hemicranias, hemicrania continua, SUNCT, and SUNA -- are very rare

disorders, although very interesting, and actually, as a group, the latter ones tend

to respond to one specific medication called indomethacin, which I think we don't understand

well enough.

But one thing you can say about that chemical is that it was derived from serotonin, and

as far as anybody can tell, that's as good a reason as any why it is effective in those

diseases.

Cluster headache, the one that we'll talk about right now, has a prevalence that is

far lower than migraine, somewhere between 1 in 1,000 and 1 in 5,000, and as opposed

to what I was taught when I trained in neurology -- that the prevalence was 8 times more common

in men -- it's probably a lot closer to 3 or 4 times more common in men, which is another

example of the kind of biased thinking that all of us have been guilty of for a long time,

basically things like, "Well, if you're a guy, you must have cluster attacks, and if

you're a woman, you couldn't possibly.

You must have migraine."

So that thinking, fortunately, is evolving.

One of the characteristics of cluster is that it is described as intensely painful attacks.

Well, up until recently, no one has taken a new approach to try to understand exactly

what that means by "intensely painful."

Pain is one of those things that we measure based on subjective report, so some very clever

researchers -- Drs. Schor, Burish, and Pearson -- have created an online cluster headache

questionnaire in which part of what they ask is, "Well, how does that pain compare to other

pain that you have had?"

So at the time that these slides were prepared, they'd already had over 2,000 people respond,

about two-thirds of them being men, which fits with our perception of what the prevalence

rates are.

The average age of onset for people in this group was about 27, whereas it took at least

6 years for the average person to get diagnosed -- another feature of cluster headache, which

is that it tends to be hidden in some kind of misdiagnosis of a sinus disorder or a variation

of migraine, etc.

In that survey, one of the things they do is present a pain scale, or a set of sliding

pain scales, asking people to rate cluster and other pain that they have experienced.

When you look at the results, one of the things they show is that the most common location

of pain is right around the eye, which is not surprising because that's the most common

location, although it's not limited to that.

But here are some of these initial results: on a scale of 1 to 10, your typical subjective

pain scale, people who'd had shingles rate that at about just under 50%.

People who've had migraine rate that at just over 50%.

People who've had kidney stones, often described as one of the most painful things on the planet,

rate that at about two-thirds.

Childbirth, above that.

Pancreatitis, also described as intensely disabling pain which almost always leads to

hospitalization.

And no surprise to people who have cluster headache or know people who do, that is about

as high as it gets.

So this is a disorder that is intensely painful, and that probably has something to do with

the fact that the suicide rate in this cohort of people is at least 10 times the normal

population rate.

This is a horrendously disabling disorder, and given the fact that attacks typically

occur multiple times a day and often in the middle of the night, I can't really imagine

what it's like to go on living, thinking, "This is probably going to happen once I fall

asleep and over and over again, and why can't anybody do anything about it?"

And that seems to be part of the problem.

So the current definitions of cluster attacks are severe unilateral, usually around the

eye or what we call orbital pain, stabbing in nature, associated with those autonomic

features, meaning changes in the tone of autonomic nerves around the eye and nose and ear and

in the sinuses, and which is typically associated with restlessness.

People, during acute attacks, are often moving around trying to distract themselves, as opposed

to migraine, which tends to be worse with activity and so has people lying quietly.

Unlike migraine, these attacks characteristically are very short -- thank goodness, given what

we've just seen -- but could last as long as 3 hours, but migraine is typically defined

as at least 4 hours -- I cannot literally imagine what it would be like to have something

like that for 3 hours, but so it goes -- and can occur, characteristically, up to 8 times

a day, sometimes more.

There are people out there who, unfortunately, are afflicted with chronic cluster headache,

meaning never get a break of more than a month, and the majority of these patients have periods

of remission lasting weeks to months, sometimes years.

So there is a diurnal variation and a circannual variation, changes in frequency over the course

of a year.

Here's the current state of cluster headache treatments.

We have, in the upper left, agents that are used to stop individual attacks.

Inhaled pure oxygen, amazingly enough, is a phenomenally effective treatment.

Ashley Hattle, sitting in the front row here, I'm assuming, is going to tell us a little

bit about that.

But the bottom line there is if it is prescribed properly and used properly, can be an extraordinarily

effective intervention.

Go figure why it is that the Centers for Medicaid Services in this country refuses to acknowledge

oxygen as a valid treatment for cluster headache despite our years of effort, and that, hopefully,

will change in the next year or two.

The other primary option for acute attacks is taking an injection of sumatriptan, which

fortunately works quite well, and we'll talk more about that in a minute.

For people who are having lots of attacks or for where their cluster periods are going

on for a while, there's a range of medications that have been identified: high doses of verapamil;

lithium, oddly enough, not because it has anything to do with being bipolar, but simply

because it is an effective ion in this condition; seizure drugs sometimes of the same type that

we use in migraine, Topamax and Depakote; steroids; and another that could be on that

list is methylergonovine, the currently existing oral ergot derivative that can be very effective.

Some other options include, probably, these new class of drugs -- the CGRP antagonist

that we'll hear more about later -- and there is now in the upper right a picture of a version

of a vagus nerve stimulator, which has been approved for both stopping acute attacks by

tickling the nerve in your neck and even preventing attacks by using it on a daily basis.

Sometimes, people will have a nerve block.

There is an implantable device, which has been approved in Europe and will probably

be approved here this year, which stimulates the SPG ganglion, that we've just heard about,

on an as-needed basis using an electrical external device to tickle that thing that's

been implanted under your gum -- fairly dramatic, invasive procedure, but fortunately effective

for some.

And there have even been trials of sticking a battery wire all the way deep into your

brain to stimulate the brain -- the hypothalamus of the brain and stop chronic cluster, and

it is effective, although that's about as invasive and dramatic as it can get.

So here is a map -- a diary of a typical cluster headache patient from 15 years ago or more

showing, for each day, the time and the severity of a group of attacks.

So the closer to red or black those little bars are, the more intense the pain, and on

a given day, the number of attacks you can see stacking up.

This is somebody who, a few years later, based on some Internet chatter that was going on

at the time, discovered that there is the possibility that taking an extract of mushroom,

psilocybin, could reduce attacks.

And so there you see a first pass, a small dose of half a gram, which dramatically reduced

the number of attacks, which then built up again over a few days, and then a larger dose

was taken, and the attacks virtually disappeared.

A couple of years later, the same patient produced a map showing that if they took a

dose of this every few months, they could virtually eliminate the possibility of cluster

attacks.

Remarkable.

What is that about?

Well, there have been a series of papers in various ways that have looked at patient self-reports

about the efficacy of these drugs, the first of which was published by Andrew Sewell, who

was a Yale researcher and, unfortunately, died suddenly and unexpectedly a few years

ago.

But in that first paper, they noted that a high percentage of people who said that they

had used either psilocybin or a related hallucinogen -- LSD -- found success with both treating

acute attacks.

So you see in that first arrow, psilocybin 85% effective, LSD 50% effective.

Given the fact that the effects of LSD last so long, that's kind of a tough bargain to

strike.

But as a preventive agent, single doses produced dramatic benefits, even more so for LSD.

And for extending the period of remission from attacks, similarly both very, very effective.

We published a paper just a few years ago looking in more detail at an online cluster

headache survey asking people to report the benefits of various interventions -- on the

left, for abortive treatments; on the right, for preventive -- and the arrows are pointing

to the columns that refer to psilocybin or LSD or related agents, showing that the larger

the column is black, the greater the percentage of people who say these are effective interventions.

So we have a large amount of citizen science telling us that there is something important

here.

Here is a controlled trial which used a related non-hallucinogenic agent, something called

bromo-lysergic acid diethylamide, showing that those lines -- or simply showing that

the number of attacks dramatically decreased after being exposed to one or more doses of

that drug.

Part of my point today is -- and part of the point of this program is to make the point,

the distinction, that although these drugs -- psilocybin and LSD -- are referred to as

psychedelics because they are capable of producing hallucinations, that is not the reason for

studying them and that is not the goal of treatment.

So although these terms exist, the point here is we are not exploring empathogens or dissociatives

or related compounds like cannabinoids.

We are saying that pharmacologically, these are drugs that should be studied because of

their potential benefits.

What are psychedelics?

Well, they encompass many classes.

In terms of organic chemistry, the indoleamine group is broken down into tryptamines and

ergolines, ergolines being more familiar to some people as ergots.

Tryptamines are by and large synthetic agents and also psilocybin.

On the right, there is a picture of Albert Hofmann, the man who, in the early 20th century,

did a lot of chemistry to form derivatives of ergots, which are extracts from plants,

to find agents that could be useful, since those plant extracts had already been found

to be very effective in treating headaches, and produced, among other things, LSD, which

is one of those derivatives, and then some other compounds.

Then the other main class is the phenethylamines, of which mescaline may be familiar to some,

as well as some related synthetic agents.

So here's a picture of wheat with mold growing on it that is typically black, and it is the

extract of that mold which produces extracts called ergot, including the one on the right,

which is dihydroergotamine, a semi-synthetic derivative.

Outbreaks of craziness and gangrene in the 16th, 17th, 18th, and other centuries were

referred to as St. Anthony's fire, and those outbreaks turned out to be due to grain stores

that were infected with this mold.

And enterprising, I guess, alchemists in those days took some of the extracts of those plants

and found that they had really phenomenally potent effects, like getting rid of headache.

But it was Dr. Hofmann who produced derivatives like DHE and then LSD and, because LSD was

so potently hallucinogenic, tried to make less hallucinogenic or non-hallucinogenic

derivatives, like an agent called methysergide.

Fifty-six years ago, methysergide was approved as the first agent for preventing migraine

on the market ever, and it was around for about 40 years until it was pulled because

of some concerns about causing fibrosis, which may or may not be true.

On the left-hand side, on the other hand, is a drug familiar to most headache patients,

sumatriptan, which was derived based on the structure and chemistry of a drug like DHE

and which is very closely related, if you look at it, to melatonin, something we're

all familiar with.

And there's psilocybin, almost indistinguishable in its structure from sumatriptan.

So my point here is that hallucination and euphoria are intrinsic properties of the brain,

and just because a drug can cause those does not mean that it should be forbidden or avoided.

If you take enough of almost any drug, alcohol, anti-cholinergic agents like belladonna, which

were identified hundreds of years ago as being capable of causing hallucinations -- which,

by the way, is where we get the image of witches riding broomsticks, an image I'll never get

out of my mind, having read that book.

But the point is, any drug, Parkinson's drug, can cause this at a given dose.

That does not mean that they are terrible and should be forbidden.

It means they should be studied and understood, and a drug like psilocybin clearly, in my

opinion, fits that criterion.

Here is just a quick map of a neuron synapse, so two neurons communicating with each other

with all of -- or some number of the transmitters that we understand something about and the

receptors that take them up or respond to them, and that the site of action of some

of these, like the so-called psychedelics, is specifically at the 5-HT_2A receptor.

We understand something about how they work and where.

Here's a brief point related to the last one, that if you think about drugs and their toxicity

based on how much it takes to kill you as opposed to how much it takes to have an effect,

then LSD and psilocybin are right at the top of the list of "Boy, do you have to really,

really work hard to get into trouble," as opposed to something like nutmeg, which can

kill you if you overdo it, or a drug that is used every single day by thousands of -- millions

of people and is available over the counter, dextromethorphan or Robitussin.

It's only in the last decade, of course, that those have been placed behind the counter

at CVS because of the number of college and high school students who figured out that

if you drank enough Robitussin and an alcohol at the same time, you can get wildly high.

So again, a point about dose.

So based on that chemistry and the knowledge that we have about what cluster headaches

report in terms of the benefits, a group of investigators at Yale, starting with Dr. Sewell,

wanted to do controlled trials looking at that.

So along with, now, Dr. D'Souza, who's been doing studies of psychotropic drugs at Yale

for years; Emmanuelle Schindler, who is spearheading this study and who came to Yale to work with

Dr. Sewell; and some funding, thank goodness, from the Heffter Research Institute, we are

now looking at studies of both cluster headache and migraine headache or post-traumatic headache.

So we are enrolling people who are willing to be in a study where they might get an extract

of psilocybin or placebo.

We are looking at people who, if they have cluster headache, have at least one attack

a day, who are episodic at the beginning of a cycle -- if you have migraine, having approximately

two attacks a week.

There are certain exclusion criteria, like psychotic or manic disorders, and you can't

be taking an SSRI -- that's probably the most common exclusion reason -- and you have to

limit the amount of triptans.

What I can say about these studies right now is that we've had about 20 patients enrolled

and 14 completed and that the side effect profile, which you see here, is very, very

favorable.

So out of all those patients, we have a few with nausea, a few with transient anxiety,

light-headedness, agitation, etc.; in the migraine studies, a few who reported headache,

which is always seen in migraine studies; and no serious adverse events.

All of the subjects and all of the investigators in these studies are still blinded, so we

don't know who got what, and that's why we can't report anything about the results.

And based on these, we are continuing to recruit subjects, and we will look at optimizing the

dose, looking at which groups are the most responsive, and possibly some other non-hallucinogenic

congeners.

Thank you for your time.

[applause]

Thank you for tuning in to Spotlight on Migraine.

For more information on migraine disease, please visit MigraineDisorders.org.