- Welcome everyone to Wednesday Nite @ the Lab.
I'm Tom Zinnen.
I work at the University of Wisconsin-Madison
Biotechnology Center.
I also work for the Division of Extension, Wisconsin 4-H.
And on behalf of those folks
and our other co-organizers, PBS Wisconsin,
the Wisconsin Alumni Association,
and the UW-Madison Science Alliance,
thanks again for coming to Wednesday Nite @ the Lab.
We do this every Wednesday night, 50 times a year.
Tonight it's my pleasure to introduce to you Cody Wenthur.
He's an assistant professor in the School of Pharmacy here.
He was born in Cedarburg, Wisconsin
and went to Cedarburg High School.
Then he went to Purdue University
to get his doctorate in pharmacy,
and then went to Vanderbilt University
to get his PhD in pharmacology.
He post doc'ed at the Scripps Research Institute
in La Jolla, California.
Tonight, he's gonna speak with us
about his research on psychedelics
and how they're a catalyst for change
in the area of mental health.
Please join me in welcoming Cody Wenthur
to Wednesday Nite @ the Lab.
- Thank you very much, Tom, for that introduction.
And thank you for the opportunity to give this talk.
I'm excited to speak to you about psychedelics
and mental health, but in order or for us to understand
what I'm talking about throughout this talk,
the first question we need to answer is,
what are psychedelics?
And the first place that we see the word psychedelic come up
is in a quote by Humphry Osmond from 1957,
where he says, "To fathom hell or soar angelic,
just take a pinch of psychedelic."
And this was a new word penned at that time.
And it's derived from two Greek roots, psyche,
meaning mind or delos to make manifest.
So together, psychedelic means to make the mind manifest.
Because one of the things that these compound seem to do
is enhance the salience of thoughts
and to bring them to the surface
in ways that might not otherwise be obvious.
Now, there is a pharmacological definition
of what a psychedelic is, and here on this plot
we can see compounds like LSD,
psilocybin, and dimethyltryptamine,
which are formally psychedelics.
But in this talk, we'll also be talking about compounds
like ketamine and MDMA, which are dissociatives
or empathogens, respectively.
And the reason that we're going to see
some of these compounds that aren't formally psychedelics
being discussed in this talk,
is because in modern clinical usage,
some of the same approaches have been applied
to these compounds that are also being applied
to the classical psychedelics like LSD and psilocybin.
So we have both a pharmacological definition,
but then you'll often see in literature
and in the public parlance, a little bit looser definition
that includes some of these associated compounds.
And although we saw the word psychedelic cropping up
for the first time in the mid 20th century,
the history of these compound themselves
actually goes back much, much longer.
And although the timeline shown on this slide
is encompassing a swath of approximately the last 80 years,
human use of psychedelics is actually ancient
and prehistorical, where 99% of human experience
with compounds like psilocybin, which is in magic mushrooms
and DMT, which is in ayahuasca,
actually occur for more than 6,000 years.
So that's 99% of our experience
is not encompassed on this timeline.
That being said, the 20th century has been an era
of proliferation for new psychedelic compounds,
including the first synthesis
of naturally occurring compounds, like mescaline.
First time they were synthesized in the lab,
as well as the synthesis of new compounds, like LSD,
which aren't naturally occurring,
but are derived from natural precursors.
And then as we enter the 21st century,
we see the application of these compounds clinically.
And indeed, this 21st century application is a resurgence
of what we saw in the middle of the 20th century,
where there was a great deal of interest by psychiatrists
in the clinical application of these compounds
that were branded psychedelics, but due to schedule I placement
in the Controlled Substances Act,
which is the most restrictive schedule
that says both these compounds have a risk of abuse
and also no accepted medical use,
there was a period of diminished research
on their clinical applications.
Further on in this talk, we'll see the ways
in which we're currently re-exploring the potential
in some of the clinical outcomes
that have been seen to date.
In the second half of the talk title was mental health.
So we talked about what psychedelics are.
Let's also talk about what the current status
of mental health is in the United States of America today.
And presently, mental health in the United States
faces some significant challenges.
There are nearly 50 million Americans,
or almost 20% of American adults,
that experienced a mental illness in 2019.
And almost 5% of adults
report having serious thoughts of suicide.
This is a number that's increased every year since 2011.
Likewise in youth populations,
15% are experiencing a major depressive episode
in the past year, and access to mental health treatment
remains a serious challenge for many U.S. adults.
If we look at other features
contributing to negative mental health,
like alcoholism and drug overdose,
we see there's a really staggering number
of excess deaths
that are occurring because of these outcomes.
That is, there are almost 850,000 people that have died
from a drug overdose since 1999 in the United States.
And these numbers continue to go up in recent years,
with 28.5% increase in the number
of drug overdose deaths recently.
In Wisconsin, we see similar trends,
where alcohol-attributable deaths over time
have been increasing in recent years,
and we have about 3,000 deaths.
Likewise, there are about 8,000 deaths due to all drugs
in the state of Wisconsin annually.
We mentioned suicide as a problem in the United States,
and this slide gives us some further information
about the serious issue of suicide.
There are about 50,000 people that have died of suicide
in 2019 and recent years.
That's one death every 11 minutes.
And this is now the 10th leading cause of death
in the United States,
after undergoing a 40% increase since 1999.
Although people often think of suicide as being a problem
that's distant from them,
the reality is that almost every person
probably knows someone who has considered suicide.
And there is an elevation in suicide rates in jobs
like mining, quarrying, oil and gas extraction,
construction, automotive repair, forestry,
farming, and others that form the backbone
of our economy and our society,
which is a giant problem across the United States,
but especially here in Wisconsin,
where those jobs and those individuals
make up a large percentage of our population.
These deaths due to drug overdose,
alcoholism, and suicide
are often called deaths of despair.
And in the data,
we can see that the United States is currently an outlier
when it comes to these deaths of despair.
In comparison to other countries like Germany, France,
Sweden, Canada, the United Kingdom, and Australia,
there have been many more deaths of despair
in the United States,
particularly among white non-Hispanic adults,
than in these comparator countries
since the turn of the 21st century.
And these deaths are especially elevated
in individuals with no college degree,
both individuals with white and Black identities.
And so there are many working families
who are struggling with alcohol, drug abuse,
and suicidality that are in need of some improvements,
in need of some new ideas about how to reconnect them
to their communities, how to reinvigorate their lives,
and how to help them out of this mental health crisis.
Another group that's been disproportionately impacted
by these negative mental health outcomes are our veterans.
And the number of veterans with PTSD,
or post traumatic stress disorder,
is certainly higher than the average population,
but it does vary somewhat from service era to service era.
We can see somewhere between 12-15% of individuals
that were in the Gulf War and the Vietnam War
having been diagnosed with PTSD.
Likewise, the rate of suicide in our veterans
is about twice as high among veterans
as in the general population.
Because of this, there's been a special interest in uptake
in the use of
psychedelic-assisted psychotherapy approaches,
such as the ones we'll be talking about today,
for treatment of veterans' populations.
And finally, the last word on the state of mental health
that we'll talk about is access.
And this map shows us health professional shortage areas
across the United States, and you can see in the dark blue,
these are areas where the whole county is a shortage area,
in the medium blue, where part of the county
is a shortage area, and in the light blue,
those areas where none of the county is a shortage area.
And most of the United States
is considered a health professional shortage area.
If we look at Wisconsin and look at shortage areas
for mental health care, you can see a large majority
of our counties fall within this shortage area definition.
So not only do we have a problem with increasing burdens
of negative mental health outcomes,
we also have a big challenge to meet that,
in terms of bringing mental health care
to the folks that need it most.
With that understanding of a little bit
about where psychedelics come from
and what the challenges that we're trying to meet,
the next question we want to talk about is
how might psychedelics actually act on the brain
in order to affect changes in mental health?
And the first thing we wanna know about psychedelics
is that they are agonists at the serotonin 2A receptor.
This is a particular protein in your brain
that normally responds to the neurotransmitter serotonin,
which is a common target
for other antidepressant medications, like Prozac.
These compounds, psychedelics,
as you can see in the structures on the slide,
actually often bear a structural similarity to serotonin,
and so it's perhaps not surprising
that they're binding to some of the same places
that these natural neurotransmitters bind.
That being said, in addition to the serotonin 2A receptor,
the psychedelics have several other sites of action.
They have sites of action at other serotonin receptors,
as well as often at dopamine receptors,
and others in the brain.
So the question is,
if serotonin is normally binding to these receptors
and psychedelics are binding to these receptors,
why are they having such a profoundly different effect
on our perception than serotonin?
Psychedelics induce hallucinations
and a completely altered sense of perception,
while serotonin doesn't.
And the reasons we think
that serotonin doesn't affect these changes,
but psychedelics do, is that there may be something
called biased agonism happening.
That is, when you bind to these receptors,
when a compound binds to these receptors,
it can elicit not just one outcome,
but one of several different outcomes.
And we can see here, from the comparison of lisuride,
a non-psychedelic compound,
and LSD, which is a classical psychedelic drug.
They're very structurally similar, and indeed,
they both do bind to that serotonin 2A receptor.
But evidence has shown
that they may elicit different downstream outcomes.
And in the plot that's shown on this slide,
we're looking at the expression of different genes
occurring after these drugs have been administered,
and you can see a cluster of outcomes for those compounds
that are psychedelic in the black.
So mescaline is a psychedelic, psilocybin, LSD, DOI.
These are all psychedelic compounds,
and they're having a similar type of effect
on these downstream genetic outcomes.
Whereas the non-psychedelic compounds
that are structurally related have a different profile,
giving us some indication that these compounds
are actually having a different effect
at the molecular level.
Another important thing to know about psychedelics
that's come out in recent work by David Olson and other groups,
is that psychedelics seem to promote actual restructuring
of neurons.
So unlike other cells in our body,
which may turn over on average as often as every seven years,
neurons don't tend to turn over all that often in our life.
There are some areas of the brain
where we do have new neuronal growth, but generally,
neurons are with you for the vast majority of your life.
And so change in the brain is often manifest
through the restructuring of these neurons.
Each of them are making connections with other neurons,
which is how the brain is talking to itself
at these functional synapses.
And when you form new structures and new synapses,
this is often a correlate of memory and of new learning.
And when compounds like DOI or DMT or LSD
have been administered to cultured neurons,
those are neurons that are growing in a dish.
What has been observed
is that new neural outgrowth is occurring.
That is, new branches are coming off of that neuron,
making new opportunities to connect with other neurons.
Likewise, it's been seen that there's formation
of new spines, which are the structural components
on which synapses form, and that we see expression
of key proteins like PSD-95 and VGLUT1,
that are supporting the expression
of new functional synapses.
So psychedelics are inducing
new structural and functional plasticity in the brain.
The other fascinating thing
about the way that psychedelics act in the brain
is that they change the way the brain talks to itself
on a larger level.
There are networks, like the default mode network,
the executive control network, the visual network,
the salience network, and so forth,
where there are certain regions of the brain that are likely
to communicate with one another more frequently
than they are to communicate with other regions
of the brain, and these form sort of standing groups of areas
in the brain that have common communication patterns.
And on the right-hand side of this slide,
what we see are two network connectivity diagrams.
One of these is the diagram
underneath the placebo condition.
And in this diagram, those networks that are standing
are colored similarly to one another.
So in the purple dots, for example,
that represents one standing network.
Whereas the red dots represent another standing network,
and the lines between them are showing the strength
of connection between each of these regions of the brain.
And what we see from the placebo plot is that as we expect,
if there are these standing networks,
most of the communication is happening
within the same network,
with relatively fewer crossings between networks.
But following the administration of psilocybin,
during the acute psychedelic experience,
we see far more connections between these networks,
a sort of anarchic breakdown
of the hierarchical structure of the brain.
So the way that it's normally communicating with itself
is kind of disintegrated underneath this experience,
and this has been proposed as one of the reasons
that people often have, for example, synesthetic effects,
where they can taste sounds, for example,
underneath the influence of classical psychedelics.
But this also might have implications
for their potential therapeutic activity.
The last thing to note about the psychedelic actions
on the brain of course, is the experience itself,
where psychedelics are most known
for introducing an altered state of consciousness.
People are having alterations
of their visual processing, with visual hallucinations.
They may have those audio-visual synesthesia.
They often have very vivid imagery.
They think there's high levels of insight,
and there's changed meanings
to the things in their environment.
Sometimes people will report disembodiment
or impaired control or cognition.
Frequently, there are experiences of unity
and loss of the sense of a personal ego.
And while all of these things are fairly difficult to reduce
to a single dimension or to quantify,
there are clinical scales available,
things like the 5-Dimension
Altered States of Consciousness Questionnaire
that have been used to reproducibly show
that specific psychedelics have specific
and dose-dependent changes across these dimensions
of the altered state of consciousness.
And by using these different scales,
we can begin to understand, and importantly,
can begin to reproducibly introduce an altered state
of consciousness in ways that isn't possible
in the absence of psychedelics,
which may make them a uniquely powerful tool
for influencing mental health.
Together, these changes
in molecular and cellular signaling,
the changes in structural plasticity,
the changes in network connectivity,
and then these changes in perception and meaning,
seem to come together to form a catalyst
for long-term change,
following the application of psychedelics.
But that demands the question,
although these drugs are doing all these interesting
and unique things in the brain,
is a drug really enough to produce long-term changes
in mental health, all on its own?
And as currently used,
psychedelics are not following this model.
Psychedelics are embedded
within a psychotherapeutic component.
That is, in addition to getting the drug
in clinical trials using psychedelics,
people are also getting psychotherapy.
And looking at the slide we have here,
there's one model of how psychedelics could induce
long-term improvements in mental health,
together with psychotherapy.
Thinking back to that network diagram
and those connections between different sections
of the brain, here we have a simplified version
of that plot.
And we can conceptualize someone with depression,
for example, is where their connections
between certain areas of the brain are stronger
than they otherwise would be
because of overuse of that circuit.
There's a relatively well-trialed idea
in neuroscience
that those neurons that fire together wire together,
which means that if you use a circuit often in enough,
you'll actually get those physical changes
where they have stronger connections between them.
This can also result in not just physical changes
in the brain, but clearly,
those behavioral changes that might put you
in the type of rut that someone would describe
when they're having a depressive episode.
And what psychedelics might do, through those molecular actions,
is to acutely weaken the old connections
to help form new connections between those areas
of the brain that aren't always talking to one another
and thus, potentially allow cognitive escape.
If you think about a snowy field,
the first person to walk across that field
has many choices of how to get from point A to point B.
But after they've crossed it,
the next person is probably more likely to follow
in their tracks because it's simpler.
And it's not until there's a new snowfall
that those old paths will go away.
And so some people have conceptualized psychedelics
as kind of shaking up the snow globe of the brain
and allowing new connections and new paths to be formed.
But that psychedelic-assisted psychotherapy component
is the key point toward understanding
how we could actually use this in a therapeutic approach,
because there's nothing that says that just shaking up
the snow globe and forming new paths
should necessarily cause your behavior to be any better
than it was in the past.
And indeed, it's been conceived
that the role of the mental state in psychedelics
just puts you into a pivotal mental state
where you're poised for change.
Things can get better, they could get worse,
and that you need some influence of psychotherapy
and support in order for those new patterns of behavior
and improved patterns of behavior to take hold.
Because of this, others who have been doing clinical trials
incorporate very rigorous structures
around the psychotherapy component.
In this example, we're looking at a training session
and therapeutic sessions from the MDMA
or ecstasy-assisted psychotherapy trial for PTSD.
And each of these colored blocks represents a visit
of the participant in that trial.
There are three times that the individuals get the drug,
but overall, there are 16 times that they come in.
This includes preparation sessions
to allow the person to understand what to expect
when they're receiving the drug,
and it also includes integration sessions
that help people process the insights that come up
during the MDMA experience itself.
As part of this, there are two guides or therapists
in the room together with the individual
while they're having the experience,
and also therapeutic support throughout the full process.
So we can see here that there's much more to this therapy
than just the drug itself.
And in addition to those therapeutic components,
there's also a unique set and setting.
That is, the preparation and integration sessions
are designed to put individuals in a calm mindset,
to be accepting of insights, and to be willing to work
with the material that comes up during a psychedelic session.
There's also a unique built environment
with comfortable furniture, soft lighting, music tracks,
for example, that help people look inward
to help support the psychedelic experience itself.
So with all of this effort being put into generating
an effective psychedelic experience,
and then following that psychedelic experience up
with therapy and attempts
to understand the insights generated,
do we have evidence that this actually could work?
And all the data I'm about to show you in this section
was generated by other researchers,
and you'll see later how my lab is trying
to work on building from this exciting data set.
So some of the first insights that we had
into potential new therapies for the treatment of depression
come from ketamine treatments.
Ketamine, as we saw very early in this talk,
is not a classical psychedelic.
It's a dissociative compound,
but it has been used in ketamine-assisted psychotherapy,
and is also interestingly used
as a therapy on its own in the absence of psychotherapy
that nevertheless does seem to act in some ways
by altering the plasticity of the brain.
And here, we're going to look at some data
for its use in treatment-resistant depression
and reductions in suicidal ideation.
On the left-hand plot, what we're looking at
is a comparison between ketamine and placebo
at a couple different time points.
The studies in the top half are looking at the effect
of ketamine on treatment-resistant depression
24 hours after being administered,
and those in the bottom half are looking seven days
after the ketamine has been administered.
And the way that these data are shown
is that anything to the right
of the red line that I'm showing you there,
indicates that ketamine had a greater effect
than that of placebo.
Anything to the left
indicates that the placebo performed better.
And we can see across all of these time points
and all of these studies that placebo overall
is having a positive effect in reduction
of treatment-resistant depression symptoms.
Likewise, in suicidal ideation, if we look at several trials
with intravenous ketamine or trials with an intranasal form
of S-ketamine, a single enantiomer,
that likewise, we see the effect is favoring ketamine.
If we look at a similar type of data set
for classical psychedelic compounds,
we can see that in short-term effects,
which are on the top,
medium-term effects, which are in the middle,
and long-term effects, which are on the bottom,
that these trials, relatively consistently,
indicate that psychedelics are superior to placebo
in reducing depressive symptoms and improving mood.
And this does vary a bit from trial to trial
and drug to drug.
Here, we're seeing the compounds psilocybin,
LSD, and the concoction ayahuasca, which includes DMT,
all independently being studied.
But when we look at the combined data, the all data,
in every case throughout these time points,
it appears that there is a more positive effect
from the psychedelic than from placebo,
which is a very encouraging sign.
In a very recent phase two clinical trial
using psilocybin for treatment-resistant depression,
basically the biggest study of its kind to date,
psilocybin at two different doses,
either 10 or 25 milligrams, was compared to placebo.
And overall in this study,
we're looking at approximately 225 individuals.
And with in comparison to placebo,
what we see, especially at the 25 milligram dose,
is a significant reduction
in the depressive symptoms very quickly, only on day two,
that's one day after the drug administration,
that seemed to persist up through week six of treatment.
So with a single bout
of psychedelic-assisted psychotherapy,
we see both a rapid reduction in depressive symptoms,
as well as a persistent effect over several weeks.
This stands in contrast
to some of our gold standard therapeutics for depression,
like SSRIs, which may take six to eight weeks
in order to show maximum efficacy in most patients,
and indeed, which ultimately leave
about 1/3 of patients untreated,
even after three to four different attempts
to use multiple types of antidepressant therapy.
And so to see this type of effect
in treatment-resistant depression,
which are patients who have failed several
of these other therapies, is quite encouraging.
That being said, bigger studies are underway
and definitely need to be confirmed
in order to make psilocybin move toward FDA approval.
A couple other areas where psilocybin has shown promise
is in substance use disorders.
So on this slide, we see psilocybin being used
for alcohol use and for tobacco use.
On the left-hand side, we're seeing a measure
of the number of individuals engaging in drinking
on any given day or on heavy drinking on any given day,
following two doses of psilocybin
in conjunction with psychotherapy.
And we can see that after the first,
and especially after the second dose,
that there is a substantial reduction in the percentage
of drinking days and heavy drinking days
that persists out for several weeks afterwards.
Likewise, in the context of tobacco use,
after a single intervention
with psilocybin-assisted psychotherapy,
we see dramatic reductions in the number of cigarettes
that are being smoked per day at 10 weeks.
And for many patients in this data set,
which is fairly small, only about 15 people,
persistence through six months and even a year.
So these are very small data sets,
definitely need to be followed up,
but quite encouraging data
that this could also be an effective approach
in the context of substance use disorders.
Next, we're gonna look at some data
from a patient population that really set off excitement
for the clinical use of psychedelics.
And that is a patient population
facing a very, very difficult situation.
These were patients
who were given end of life cancer diagnosis,
a diagnosis that could be terminal.
They may only have weeks or months to live.
And in many of those patients, unsurprisingly,
we see that they also have mental health challenges
that crop up.
They may actually get diagnosed with depression and anxiety
as a result of being given this life-altering diagnosis
and getting this extremely challenging information.
And we do have palliative care approaches, certainly,
for individuals with end of life cancer,
but the number of interventions that are available
to improve quality of life
and to address those psychiatric consequences
are not as good as we might hope.
In this study, psilocybin again,
was being given to individuals in conjunction
with psychotherapy, and measures of anxiety,
depression, quality of life, and death acceptance
were all taken together,
following the psychedelic experience.
And on the left, we can see the results
from the depression scale.
In this study, people either got a low,
basically inactive dose, of psychedelic first
and then a high dose second or vice versa.
And we can see that after the first dose,
those who got the high dose,
that had the full psychedelic experience,
had dramatic reductions in their depression scores.
There was some effect of the low dose as well,
but that was even significantly bumped further
once they got the high dose in the second session.
And we can see persistence
of these antidepressant-like effects up through six months
in this patient population.
I've also added a line to this graph
that shows the threshold for remission
for these depression scores.
And you can see that on average, actually,
these patients met the threshold for remission,
meaning they no longer met the criteria
for a depression diagnosis after this experience.
We can likewise see very strong increases
in the overall quality of life in this patient population.
The final trial we're going to look at is the use of MDMA,
which is an empathogen or entactogen,
that is also being given in conjunction with psychotherapy
for severe PTSD.
And on this slide, we're looking at a phase three trial,
which is the trial that's immediately preceding
submission to the FDA for approval.
So the biggest type of clinical trial that we have
prior to a drug entering the market.
And in this trial,
what we're looking at is either psychotherapy alone
or psychotherapy plus the use of MDMA.
And in this trial, as we saw from the plot earlier
with all the study visits,
there were three drug sessions and again, 16 visits overall.
And we're looking at reductions
in the clinician-administered PTSD scale,
which is the gold standard for diagnosis of PTSD.
On the left, we can see superiority,
where MDMA is added to the psychotherapy.
Likewise, on the right,
if we look at the Sheehan Disability scale,
which is a tool that's looking at functional outcomes,
like how well is your life going at work,
at school, your social life?
How well are you engaging with your family?
We also see superiority of the MDMA-assisted psychotherapy
and progressive improvements from session one,
to two, to three.
And perhaps most encouragingly of all,
at the end of the study, when we looked at those individuals
who either got the MDMA or did not,
2/3 of the MDMA group no longer met the criteria for PTSD
compared with about 30%
who got the placebo plus psychotherapy.
So in about 1/3 of people, psychotherapy worked,
but in 2/3, we saw a complete loss of diagnostic criteria
for those who also got PTSD.
Notably, 33% or 1/3 of the MDMA group met the criteria
for remission, whereas only 5% of the placebo group
met those criteria.
So a substantial increase through the use
of a psychoactive compound to modify the outcomes
of the psychotherapy itself.
So those are some of the good things that we're seeing,
the encouraging signs that this might be helpful.
But you might be asking yourself,
what risks are associated with this approach?
All drugs come with risks.
The word for drug, the initial word pharmacon,
again from the Greek, denotes both therapy,
but also poison, and all drugs have both benefits and risks.
It all depends on getting the right drug
to the right patient in the right dose at the right time.
And these are some of the side effects that we see
in psychedelic clinical trials.
Most individuals will experience a transient increase
in their heart rate and blood pressure
for about the first 60-90 minutes
after they get the psychedelic.
Also, seeing headache is fairly common.
This is generally treated with a standard dose of Tylenol.
Nausea and vomiting are seen in some individuals.
And then MDMA specifically
seems to induce muscle tightness,
can decrease appetite, have sweating and dizziness.
In the context of psychoactive side effects,
about less than 1% of individuals from the trials
that have been reported so far
report potentially risky disorientation
or lingering or delayed psychological effects.
But when we compare psychedelics to other classes
of psychoactive compounds, using a measure of the risk
of harm to the user themself and the harm to others,
here we can see that, for example,
alcohol has a relatively high risk of harm to the user,
as well as significant risk of harm to others.
Whereas compounds like LSD and psychoactive mushrooms
have much lower levels of risk of harm to the user
and harm to others.
But clinical trials are different than real world use,
and one of the things that's often reported by people
who use psychedelics in a recreational
or non-medically supervised context
is that they can have a bad trip,
a very anxiety-inducing and provoking experience.
And they may in fact, report that they're a danger
to themselves or others.
And when we look at surveys asking people
about their worst bad trip, we do see higher rates
of these negative outcomes outside that controlled context
of clinical trials
and without that built-in psychotherapeutic support.
So about 11% report putting themselves or others at risk.
2.5% behave in a physically aggressive manner.
And somewhere around the same percentage
need to get medical help.
Also, 7.5% of people reported seeking treatment
for psychological symptoms
associated with their negative trip,
and relatively small numbers of individuals,
although still notable, has onset of psychotic,
severe symptoms as well as attempted suicide.
So the potential for negative outcomes is there,
but you'll note for certain,
that these outcomes are much higher in this case,
of unsupervised medical use
than what's currently being reported in the clinical trials.
The risk factors that have been shown to support this
potential dangerous behavior outside of the context
of clinical trials are use by individuals
with psychotic disorder,
relative inexperience with the drug,
having poor information about what the drug is likely to do,
by combining psychedelics with other drugs or with alcohol,
and by putting themselves in risky situations
and using with unknown or untrusted individuals.
There are harm reduction options available
for people who are using psychedelics
outside medical context, such as the Zendo Project
and the Fireside Project.
So with all this background, all this wonderful work
that's been done by other researchers in the field,
as well as all the information we've learned
from Indigenous cultures, their elders,
and their sacred practices.
What is my lab doing
and how are we involved in this area of study?
One of the things that we're doing
is assessing combinatorial contributions
to ketamine's antidepressant effects.
Ketamine has many metabolites,
as you can see on the left side of this slide.
That means it's broken down
into a bunch of different compounds inside the body.
And we're using techniques such as development of antibodies
against selective compounds in order to assess
the effects of each of these independently and together,
and also to map the areas in the brain where ketamine
and its metabolites are having these effects.
Unfortunately, we've got a lot of projects,
so that's all you're gonna hear about that project.
Another one that is very exciting to me,
but we don't have the full answers on yet,
is projects in human subjects,
where we're assessing the psychedelic experience
and its therapeutic causality.
Basically asking the question, is the psychedelic experience
that altered state of consciousness,
and particularly the memory of it,
necessary in order for individuals to get better,
or is it possible that people could get better
through the molecular effects alone
and not having any access to the memory
of that altered state of perception
or the potential insights that they may report,
when otherwise coming out of a psychedelic experience?
It's a study I'm very excited about, but stay tuned.
The last two types of work that we're doing
are in a similar domain,
and we're gonna look much more in depth
at a preclinical project in rodents
and a clinical project with human subjects
and community-associated outreach.
And both of these projects are related to the idea
of relating stress self-identity and set and setting,
and how those interact
in psychedelic-assisted psychotherapies.
Classically, as I alluded to the approach
with psychedelic-assisted psychotherapy,
has been to have people be as calm as possible
during the experience and have them ready and prepared
to understand what's happening.
Certainly, we think that preparation
is absolutely essential, but we wonder whether or not
there was a negative or positive role biologically
of the stress response, and whether that's different
than the apparent negative psychological role of the stress
and anxiety response that some people indicate.
And in the first study, we're looking at again,
those markers of biological stress.
So it's been appreciated for several years now,
including work that we're seeing here from others,
Franz Vollenweider's group, as well as Leah Roseman,
that during the transient period
of altered psychoactive perception
and altered activity in the brain,
that we do see elevations in the stress-associated hormone,
cortisol, at about that 150-minute mark,
which is also where
the so-called peak psychedelic experience is also happening.
It seems to resolve by about the 300 minutes,
but that increase in cortisol is also concurrent
or happening at the same time as increases
in what's called anxious ego dissolution,
or people being worried about the fact
that they're seeming to lose connection with their identity.
And we can see here, going from the left to the right,
that with increasing doses of the psilocybin,
from very low dose to low dose, to medium dose,
to high dose, that there is a dose-dependent effect,
both for the cortisol release
and for the anxious ego dissolution.
And this has been used to suggest that stress
during the time of administration is negative
because on the bottom right plots,
what we see is that the more anxious ego dissolution
that was reported, the less change there was
in depressive symptoms as measured by this scale.
So those individuals who are on the high side of this scale
had greater reductions in their depressive symptoms.
But those who are on the low side of the scale
had lesser effects.
And you'll note that those who have higher dread
of ego dissolution tend to have the lower effects.
But because we're having both a biological effect
and a psychological effect together,
it's hard to disentangle, which may actually be responsible
for blocking the therapeutic outcome
or for modifying that therapeutic outcome.
And so we are using rodent models to look at the
relationship between the stress-associated hormone.
And in this data, we see that like in humans,
psilocybin can induce a transient increase
in stress-associated hormones.
We saw cortisol in humans;
the analog in mice is corticosterone,
and on the right-hand side, we can see a transient increase
in that corticosterone that resolves.
And on the left-hand panel,
what we're looking at is a proxy measure
of hallucinogenic-like activity,
called the head twitch measure in mice,
and we can see that these animals
are having this biological marker
of hallucinogenic-like activity that's basically coterminous
with this spike in corticosterone.
But the interesting observation we've found
is that using a measure called the open field test,
where mice are more likely to stay near the edge
because they feel safe rather than move into the center
of a wide-open arena, we see that psilocybin's acute effects
at this 15-minute time point are inversely correlated
with their post-acute effects in mice.
That is, at the time we have this high corticosterone,
the mice are anxious.
They don't seem to want to enter the center of the arena,
and we have a dose-dependent response there.
But at four hours,
by the time psilocybin has left the system of these mice,
actually we see the opposite,
that at the higher doses of psilocybin,
they now have a seeming rebound effect,
where they're more willing to spend time in the center.
And using another measure of potential anxiety-like behavior,
we see that at that very high dose,
the three milligram per kilogram dose,
that if we put the mice in an environment
where they're motivated to eat a sugary pellet,
but it's also brightly lit, it's an open field,
and they may not normally want to enter
that unusual environment,
that those animals that were treated with psilocybin
actually spend less time until they approach
and begin to eat that pellet,
than animals that didn't receive the psilocybin,
potentially indicating that at these high doses,
there is a real anxiolytic-like or anxiety-reducing effect.
And because it's at those high doses
we saw the spike of corticosterone,
this indicates that biologically,
having that stress response may not inherently be negative.
But what we also see
is that if we modify the response of the stress
in these animals long-term, that this effect can be blunted.
So when we look at anxiety-like effects one week after,
and we have mice that either had no change
in their corticosterone levels,
or where we elevated the corticosterone,
thus simulating an ongoing stress-like response
for a long period of time, for that full week,
we see something very different.
So in the animals
that didn't have a manipulated stress response,
they just had that transient peak,
the psilocybin tended to have an anxiolytic-like effect
up to a week later, which is similar to the types
of observations that have been reported in people.
But in a situation that mimics chronic, unresolved stress,
the psilocybin actually seemed to have a negative effect,
relative to those animals that didn't get the psychedelic,
indicating that unresolved stress at the biological level
may in fact, be a mechanism by which those people
who had strong psychological stress
could be influencing their negative outcomes.
The other study that I want to talk about is a human trial,
where we're looking at the relationship of set and setting,
with representation and generalizability.
It's been noted that ethnic and racial representation
in psychedelic studies is not representative
of the population as a whole.
So whereas the United States in general
has approximately 40% people of color,
psychedelic clinical trials
have only about 11% people of color.
And if we don't have a representative sample
in our trials,
it's harder to make the claim that this therapeutic
will be effective for everyone who comes to use it
in the event that it is approved.
And for this reason, we're interested in understanding
the relationship between self-identity
and therapeutic outcomes.
Earlier, we talked about how set and setting
are a part of these clinical trials.
And the reason we think it's worth understanding
the implications of self-identity
is because if we think that the set and setting
are responsible for influencing the psychedelic efficacy
and that self-identity
influences the mindset and setting,
then the logical output is that self-identity itself
can influence psychedelic treatment efficacy
through this lens.
And an example of this that I like to share
is that in the psychedelic study room,
the people who put the room together had the choice
of what art to put on the walls.
For example, you can put up a medicine wheel
or you could put up a cross.
And obviously, depending on your own self-identity,
your religion particularly, or your spiritual background,
you're going to have a very different reaction
to each of these two items.
And those elements of your self-identity
may directly influence or be mitigating your response
to the art, but other elements of your self-identity,
like your race or your connection to the land
might be likewise influencing your response overall.
And so we're conceptualizing that set and setting
might actually act as a therapeutic modifier,
where if your self-identity is congruent
to the set and setting, you're likely to pass through
and have a therapeutic effect.
And given that most of our trials to date
have had predominantly white subjects,
we might imagine that the set and settings
have sort of evolved to match and maximize
therapeutic effects for the types of participants
that we've already been enrolling,
and the concern is that we might thus
be minimizing or reducing therapeutic effects
for people who don't share those same identities.
In our project that's ongoing,
we're using relationship to art objects as a starting point
to try and develop a fit scale for this set and setting.
Going back to our example of a choice of an art object,
you can imagine that at a site here in Wisconsin,
or at a site in Maryland,
where we're running a psychedelic clinical trial,
there could be two different pieces of art on the wall.
Maybe here in Wisconsin, we have this cheese shop image
and in Maryland, they have this crab picker image,
and depending on a person's background,
they could potentially have very different reactions
to these two objects.
If a person is from Maryland,
they may report that their overall impression
of the cheese shop image
is less than that from someone from Wisconsin.
And likewise, depending on the other elements
of their self identity, it may be more or less connected
to their sense of what it means to be their age,
to have their gender, their own race,
the locality they're at, and their concept
of what the history of psychedelics is.
And by gathering this information
across many different individuals,
what we're trying to do is quantify
how well the set and setting fits individuals
in current psychedelic clinical trial settings,
where a person who has a very good or relatively good fit
to the set and setting might be expected
to have a stronger therapeutic effect
than a person who has a more negative association
with that set and setting.
We can both use this potentially
to quantify and harmonize data across clinical trial sites,
but we can also use this to validate
and permit patient choice in the setting,
where a person with a background that may make them
more receptive to this crab picker image
would be able to have that image brought in
and shown to them during the session,
versus a person who is more receptive
to this cheese shop image.
And by doing that, what we hope to do
is eliminate this hidden variable, this fit score,
to maximize the benefit for all,
that we have a flexible set and setting
that people feel most comfortable with,
minimizes their long-term stress
and maximizes their therapeutic effect.
In our first pilot study
with the Madison Psychedelic Society,
we do see that when measuring perceived connectivity
to the dosing room, across the dimensions
of whether it connects to the local environment,
the history of psilocybin,
or to their own racial and ethnic identity,
that those individuals with any identity
other than non-Hispanic white
actually did significantly report a lower connection
to the dosing room, with regard to their own race.
And what we're looking to do is to expand this
beyond our local environment,
to work with the Milwaukee Psychedelic Society
as well as others across the country,
in order to get a bigger sample set and help understand
and generate this quantitative fit score.
That covers it all for the type of work
we're doing right now.
But I also wanna say we're actively engaged in research
and scholarship as part of this
Transdisciplinary Center for Research
and Psychoactive Substances,
which has many other wonderful members from across campus,
including folks doing the clinical trials
that we talked about,
but also looking into other elements of the history
and cultural applications of psychedelics,
all of whom are fantastic colleagues
and I'm sure you'll hear from them more in the future
if you follow this area.
Likewise, I'm responsible for directing the training
and education initiatives here at UW-Madison,
including the first in the world
Psychoactive Pharmaceutical Investigation masters program,
and an associated capstone certificate program.
In the event that these compounds are approved,
we saw that there is already a challenge
in delivery of mental health,
and we're looking to generate the next generation
of scientists, as well as to educate the next generation
of healthcare providers on how we may potentially
use these compounds and how we may improve them
for future use.
So overall, what did we learn from this talk?
Unfortunately, hundreds of thousands of Americans
are dying each year from mental health-related concerns,
and psychedelic-assisted psychotherapies
have shown promise in treating mental illnesses
in the studies to date.
In contrast to some perceptions,
psychedelics do tend to have very low rates of addiction
and overdose.
That being said, all medicines do have risks.
And by understanding how psychedelic compounds work
at the molecular level, also how they interact
with the non-drug elements of that psychotherapy,
is important for optimizing effectiveness
and maximizing therapeutic access.
There are many people to acknowledge here,
including my collaborators, our funders,
and the other members of the lab.
Thank you very much for taking the time
to listen to my talk.
I hope you found it engaging and interesting.
And remember that mental health is a key community effort.
Taking the time to support those around you
is always time well spent.