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.
