June 19, 2023 • 32 mins
Lab Rat Chat - Episode 33 with Dr. Alejando Torrado-Pacheco
What if psychedelics could hold the key to improving mental health? Join us for an inspiring conversation with Dr. Alejandro Torrado-Pacheco, a postdoc from Oregon Health Sciences University, as we journey through the world of psychedelics and their potential therapeutic applications. Alejandro shares his unique background, from growing up in Europe and studying physics, to ultimately transitioning into neuroscience and then behavioral neuroscience. We also learn about his current research in Dr. Bita Moghaddam's lab, which focuses on the fascinating potential of psychedelics to enhance mental well-being.
Dr. Torrado-Pacheco provides valuable insights into the history of psychedelics, the importance of set and setting for these experiences, and how animal research can help us better understand their biological mechanisms. Don't miss this opportunity to learn about the potential therapeutic benefits of these fascinating compounds and how they could reshape our understanding of mental health treatment in the near future.
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- Moghaddam Laboratory – Oregon Health & Science University
- Acute psilocybin enhances cognitive flexibility in rats | Neuropsychopharmacology (nature.com)
- MAPS.org - Support Psychedelic Science - Multidisciplinary Association for Psychedelic Studies - MAPS
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Jeff Marshall (00:05):
This podcast is supported by Americans for
Medical Progress and was foundedand created through the Michael
D Hare Fellowship, awardedannually to support projects
that inform and educate thepublic about the critical role
of animal research in furtheringmedical progress.
The Fellowship honors the lateDr Michael Hare, a renowned
board-certified laboratoryanimal veterinarian who
dedicated his career toscientific and medical
(00:25):
advancements and who was deeplycommitted to animal welfare and
advocacy.
Hey everyone, and welcome in tothis month's edition of Labrat
Chat.
(00:45):
Thanks for joining us and, asalways, please take a second
pause.
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(01:06):
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If you ever have, you know,suggestions, comments, just for
us personally, danielle and Iwill respond to them labratchat
at gmailcom.
So thanks everyone again fortuning in.
Today we have an exciting guest.
His name is Dr AlejandroTirado-Pacheco.
He's from Oregon HealthSciences University.
(01:28):
He's a postdoc up there, a labthat focuses on want to know if
the lab focuses on it.
But what we're talking to himtoday about is the use of kind
of psychedelics and how that canbenefit mental health.
Especially with the last month,may, being mental health
awareness month, we thought it'dbe a cool idea to actually talk
to someone that does researchin that field and how it can
(01:52):
possibly benefit us and how theuse of animals help, you know,
accomplish that goal.
So, if you will, drTirado-Pacheco, just tell us a
little bit.
You know about yourself.
We got you interested inscience and research and then in
this kind of field,particularly if you would just
tell us a little bit about that.
Alejandro Torrado-Pacheco (02:09):
Yeah, well, first of all, thanks a
lot for having me on.
It's really exciting to be ableto talk to the public about
this research.
I don't get the chance to dothat a lot, so I'm really really
glad to be here.
So I guess, yeah, my story is abit of a bit of a wandering
path to get to where I am today.
I grew up in Europe and I wasreally into science from a young
age and the system, the way itworks in Britain, which is where
(02:31):
I went to university, is thatyou apply to university when
you're very young, like 16, 17,and you don't have a major.
You just apply for something.
And so I applied for a physicsprogram and you go in and you
only do that.
So I started this physicsprogram and two years in I was
basically ready to quit becauseyou know, as you can imagine,
choosing a career when you're 17years old, the chances that
(02:52):
that works out are pretty slim.
But then I got introduced tothese ideas about graph theory
and dynamical systems, so allthese like mathematical methods
that you could use to modelthings in the world.
The problem I had with physicswas it was too abstract.
I couldn't really relate whatwas going on in the math to the
real world.
But when I got introduced tothese ideas and especially to
(03:14):
the fact that you can modelsomething like the brain using
these mathematical tools, thatwas really fascinating right,
that you can use these tools tothink about cognition, behavior
and even emotion, and so thatwas kind of my entry point into
neuroscience.
So I did a computationalneuroscience master's at
University College London And itwas actually a physics master's
(03:35):
, but I did a computationalneuroscience thesis in a lab
over there, peter Latham's labAnd I decided I would go to grad
school for neuroscience.
And so I ended up going toBrandeis University, which is in
Massachusetts, for my PhD.
And that was another choicethat was dictated by the
difference which might beinteresting to your listeners,
differences between the Europeanand the American system.
In the American system you comeinto grad school and you have a
(03:58):
couple of years of classes andyou get to sort of explore
different labs and then choosewhat you're going to do.
In a lot of places in Europe,the way it works, you as you
find a professor and you sort ofask them.
You know I would like to workwith you on this topic, so you
have to really have a good ideaof what you want to do.
But because I came in from thesides basically and you know I
(04:19):
didn't have any biologybackground, i applied only to
the US because I wanted thatopportunity to explore different
topics And I thought I wasgoing to do computational
neuroscience but I ended upfalling in love with experiments
, especially experiments withfreely behaving animals.
I just love the techniques andwhat you can learn from those.
So I joined Gina Torrigiano'slab at Brandeis.
(04:41):
Over there I studied sleep andplasticity, so how brain
plasticity is affected by sleep.
So, as you can see, kind ofnone of this has anything to do
with mental health orpsychedelics, but the way I
thought about it, i alwayswanted to work with psychiatric
disorders And the way I thoughtabout it was my PhD was an
opportunity to learnneuroscience and learn
techniques and then apply thoselater on in the next step, and
(05:04):
so that's what I'm doing now.
Like you said in yourintroduction, i am a postdoc in
Bita Mogadam's lab in theBehavioral Neuroscience
Department, ohsu.
What we're studying is broadly.
The lab is interested in theneurobiology of psychiatric
illnesses.
Bita has, you know, 30 years ofexperience working in this
field and she's done a lot ofwork with schizophrenia, and
(05:25):
when I contacted her aboutworking in her lab, she offered
me this project that she wasinterested in to pursue research
on psychedelics and especiallypsilocybin, because of the
really promising data in humans,and we can talk about that
later.
But yeah, so now that's whatI'm studying, looking at
psilocybin and major depressivedisorder.
Jeff Marshall (05:44):
Yeah, it's crazy that you apply to a university
when you're 16, 17, and you haveto pick what you want to do.
I mean, it's kind of similar, iguess, in a way, in the
American system You go tocollege when you're 18.
And if you have a scholarship Ithink a lot of scholarships,
state-sponsored scholarshipsrequire you to pick a major by
the end of your first semesteror first year or something in
order to keep your scholarship.
And so even then, like 18, 19,you don't know what you wanted.
(06:06):
It took me, i mean, look, iwent back to school at 32.
So I didn't know.
It took me a while to likeactually get into a career or
some sort of job that I wasinterested in and then to
explore that further, so thenbreak it down and figure out
what I really wanted to dowithin that field.
And so it's kind of crazy thatat 16, 17, that you're forced to
try to make that decision.
Alejandro Torrado-Pacheco (06:28):
Yeah, it's pretty wild.
And the thing is there's nomajor or minor, so you just go
in, and so I took no collegelevel classes in biology,
chemistry, anything else.
That wasn't even science, likejust physics.
So I really think it's limiting.
Danielle Dady (06:42):
I don't know.
that sounds kind of nice,though I just remember in my
undergrad having to take likesociology and Greek mythology
and you're just like I don'twant to learn this.
This is so far better.
Jeff Marshall (06:51):
Greek mythology is pretty cool.
I like Greek mythology.
I took it because I thought itwould be cool.
It's not cool, it's not whenyou have to write a paper, yeah
right, when you have to write afive-page paper.
Danielle Dady (06:58):
I immediately regretted that decision.
But I have a quick questionjust about, like, what
psychedelics are, because when Ithink about that I think of
mushrooms.
So I'm sure, well I don't know.
Are there other means of wherethe compounds come from?
I guess, what exactly ispsilocybin, some of the other
psychedelic compounds that youwork with?
where do they come from?
How do you even obtain them?
Well, i imagine they're likecontrolled substances, but maybe
(07:21):
you could just talk a littlebit about the compounds
themselves.
Alejandro Torrado-Pacheco (07:24):
Sure, i guess I'll start with what
they are.
There's three main classes ofpsychedelics and they're just
like, biochemically slightlydifferent, but I'm not a
biochemist myself, so thosethings don't really mean much to
me.
But essentially all of them arevery closely related to
serotonin and they act onserotonin receptors in the brain
.
And then they have slightlydifferent pharmacological
(07:45):
profiles.
You know, some are naturalcompounds, like psilocybin, like
you mentioned, is found inmushrooms.
Another very popular one is DMT, or dimethyl tryptamine, which
is found in some species oftoads and in some plants as well
.
And then a lot of them are justsynthetic compounds, for
example LSD, the most famous oneof them all.
So the interesting thing is alot of them are controlled
(08:08):
substances and they are like atthe highest level, So they're
schedule one substances.
So psilocybin is schedule one,lsd is schedule one, and so,
yeah, it takes a while to getthem.
You have to have a license witha DEA Luckily I don't, but my
boss does And it takes a longtime to get that and then it
takes a long time to get thecompound.
The National Institutes ofHealth has a drug supply program
(08:30):
through the National Instituteon Drug Abuse.
So basically the idea is wewant to study these
quote-unquote drugs of abuse tounderstand them better.
They can give you small amountsof these drugs when you request
them.
There's a lot of paperworkinvolved and you have to
obviously justify why you wantit, what you're going to do with
it and how this is going tobenefit the public.
There are other compounds thatare actually not scheduled, even
(08:53):
though they're extremelysimilar.
So one of them is DOI, and ifyou look up psychedelic research
, you'll see this DOI pop up allthe time, and that's because
you can just buy it, and so Idon't know what it feels like to
take it.
I don't know how similar it isto LSD or psilocybin, but it's
freely available and it's kindof used as a proxy for
psychedelic effects.
I personally think it's notexactly the same, but we can get
(09:15):
into that if we want to lateron.
Jeff Marshall (09:17):
Is that also something that comes from
mushrooms?
That's just like a syntheticcompound someone's made.
Alejandro Torrado-Pachec (09:21):
That's synthetic.
And actually I should mentionthe psilocybin that we get and
that everyone gets is at thispoint synthetic.
So it's made in a lab, becausewhen you extract it from
mushrooms you get a lot ofimpurities.
Jeff Marshall (09:34):
Okay, So it's a process of extraction.
You can't go out and just findthe mushroom and eat it and get
the psilocybin effects.
It's kind of like, I don't know, I guess like cocaine.
If you will, You got likethere's a process to make it
into cocaine And I guess there'sa process to make psilocybin.
I'm not trying to giveinformation on how to make it,
or process it.
Danielle Dady (09:51):
You're teaching people how to do that.
Jeff Marshall (09:52):
Well, my biochemistry book in school
detailed the process of how tomake crack detailed.
Oh my gosh that's hilarious.
It's like the protocol on howto do it Probably no longer in
publication And I didn't try itjust for the record.
Danielle Dady (10:04):
Either way, people should not go out and
just eat mushrooms, because youhave no idea.
Jeff Marshall (10:08):
Yeah.
So I guess if they're scheduledone drugs, if it's something
that you could just go out andget in nature, or if it takes a
pretty like advanced process toactually get the compound out of
it, You know, for lab researchwe want to make sure it's a pure
compound, so we use thesynthetic version.
Alejandro Torrado-Pacheco (10:23):
But yeah, it's naturally available.
And I should mention you knowit's been used for millennia by
people all over the world,especially in what is currently
Mexico.
So in Mesoamerica people havebeen using psychedelic mushrooms
for religious and otherimportant cultural ceremonies
for a long, long time.
Jeff Marshall (10:40):
Good to know.
It seems like there'sdefinitely a lot of positive use
for it.
I think it seems like when Iwas a kid I remember talks about
mushrooms and how people wouldhallucinate.
I just remember conversationsabout if you took them you're
going to hallucinate and go jumpoff a building and all the side
effects and how awful they areand how they need to be banned
from society.
But now it's nice that there'skind of maybe the little bit of
(11:02):
shift coming on in society andfinding a positive use for it.
And I think in order to get tothat understanding, research
needs to be done, and I thinkthat's kind of where you guys
come in.
I know there's lots of humanresearch in there out there as
well, but in order to really geta good understanding, i think
it's important that we do someof the animal research.
So if you would, can you justtell us a little bit about your
(11:23):
research?
Which animal model do you guysuse once you get that synthetic
psilocybin compound In order tostudy it?
you've had a lot of findings,but what's like a broad spectrum
approach to some of thefindings that you've been able
to discover using that animalmodel?
Alejandro Torrado-Pacheco (11:40):
Yeah.
So we use rats in the lab andthere's a very specific reason,
and the reason is that we areinterested in the behavioral
effects of psilocybin.
So I'm going to back up alittle and tell you a bit about
the human data, because thatwill kind of bring it into
context why we're doing whatwe're doing.
There's a lot of phase oneclinical trials and even a few
phase two clinical trials thatshow incredibly promising
(12:02):
results for psilocybin.
And to kind of tell you whatthat means, incredibly promising
.
I'm talking about two doses ofpsilocybin three weeks apart
having a stronger effect inameliorating symptoms of
depression than a six-weekcourse of a standard medication,
which would be a selectiveserotonin reuptake inhibitor,
you know, like prozac or lexapro.
(12:22):
That's crazy, it's verystriking, it's fast-acting and
it's long-lasting.
So people have looked up to sixmonths after one or two doses
and you still see an effect.
Yeah, that's incredible.
And it's really important tosort of underscore the fact that
, while accessorizer are amazingand I can probably say that
they've saved countless livesThey have a lot of side effects
(12:44):
and adverse effects and you knowpeople end up having to take
this medication every day.
So it's you know you get sortof problems with people taking
it.
We've been on the hunt for abetter treatment for depression
for six decades or so, so it'sreally cool that we now have a
few options like ketamine is one, and now psychedelics are
emerging as a really promisingoption.
Jeff Marshall (13:03):
Ketamine- is one I didn't know that Yeah, we use
ketamine all the time.
I don't know it was used in themental health realms.
I thought it was more just inthe realm of like just an
addictive kind of like cocaine,heroin type of drug.
But I guess it has use as well.
I know that's not the focus ofyour research, but that's just
not that interesting.
Alejandro Torrado-Pacheco (13:20):
Yeah yeah, ketamine is interesting
because the different doses dovery different things.
So at high doses it's ananesthetic I know it's used in
animals for anesthesia but atlow doses it has this weird
antidepressant effect, and soit's actually pretty close to
FDA approval, i think Awesome.
Jeff Marshall (13:37):
Okay, that's cool .
Yeah, i mean, we use it quite abit and cats that want to try
to kill us while at work, whenthey're hissing at you, you can
score a little bit in the mouth.
It calms them down a little andthey do a little anesthetic
properties, like you said.
But yeah, that's cool, good toknow as well.
Alejandro Torrado-Pacheco (13:51):
Yeah, so going back to I guess the
reason I talked about all thatis because psychedelics have an
interesting history.
You know they were used in the50s and 60s in research.
Then they you know researchstopped because the control
substances act made themschedule one substances.
And now we have all this humandata, but we have a real gap of
knowledge in terms of thebiological mechanism, and that's
(14:12):
where the animal research comesin.
We want to understand why arethey so effective?
right, what is happening in thebrain when you take psilocybin,
and you know later on you feelbetter.
And so to do that, we have tobe able to see an effect.
Is the animal actually feelingpsilocybin and perhaps does it
have an antidepressant likeeffect?
and then what is happening inthe brain?
(14:33):
So we have to be able to usetechniques that you wouldn't be
able to use in humans, that areinvasive, that you can do in
animals.
And so in our research, what wereally sort of noticed is that
in the polyclinical trials youknow you might have heard this
phrase set and setting in termsof psychedelic use, where you
know the mental set, so yourexpectations coming in your
(14:53):
current mood, your history, yourgenetics, that plays a part,
and also the environment plays apart, right, so you're the
peers who is present during thatexperience, the kind of support
you have, even just thephysical environment.
All of that really affects theexperience and the outcome.
And so in these clinical trialspeople are usually in a very,
very safe feeling environment.
(15:14):
They're usually on a bed withrelaxing music and sometimes eye
shades, and there's usually twosupport staff who are often
trained psychologists ortherapists, and the idea is not
to give, like it's non-directive, supportive therapies, what
they call it, so it's not reallylike therapy session, but there
is that sort of support.
And so we thought maybe what'shappening is that the effect of
(15:36):
psilocybin is to sort of primepeople to get the most out of
that experience, and so reallythe effects while the drug is on
board are important to study.
We decided to do that in ratsAnd broadly what we found is
that, very surprisingly, ratscan be better at some tasks that
require cognitive flexibility,so the ability to switch between
(15:58):
different behavioral strategiesdepending on the environment,
while they are essentially highon psilocybin.
And you might ask, what doesthat have to do with depression,
what you've been talking about?
Well, cognitive flexibilityfirst of all, is associated with
greater mental health.
Cognitive inflexibility, so kindof rigid thinking and rigid
patterns of behavior, are seenin a lot of psychiatric
(16:21):
disorders, including depressionand anxiety disorders, and
higher cognitive flexibility,which is measured in humans with
tasks very similar to the oneswe use in rodents, is associated
with greater mental health andalso better responsiveness to
treatment for depression.
So there's a very strong linkthere, and basically the idea is
that the hypothesis that wehave, and others that propose as
(16:43):
well, is that psychedelicspromote a state of higher
flexibility that then allowspeople to break out of ingrained
patterns of thought, ofingrained sort of negative
perceptions of the self or theenvironment.
Our research in animals sort ofsupports that idea And also,
well, currently and in the nearfuture, we're trying to also
(17:04):
understand how this is happening, so that we can first of all
get an understanding of thatprocess in the brain which would
be great And also perhapsdesign compounds that can better
target the specific therapeuticaction that we're looking for,
as opposed to something likepsilocybin, which is perhaps
having a lot of effects that aremaybe undesirable or even just
(17:25):
unnecessary.
Danielle Dady (17:26):
I have a question about why rats would be the
best animal for this, Because,now that I'm thinking about it,
all the places I've worked wherethere is like a psychology
department or something, itseems like rats are always the
go-to model And I didn't know ifthere was a particular reason.
Is it maybe just because theirbrains are bigger than mouse
brains?
or maybe they can learndifferent tasks easier?
But I guess what's the draw torats for this type of work?
Alejandro Torrado-Pacheco (17:47):
Yeah, that's a great question, And it
really boils down to the factthat they're just smarter than
mice.
This is what it is, the taskthat we use.
Mice would just not be able todo it.
Danielle Dady (17:57):
Okay, interesting .
Jeff Marshall (17:58):
Were you guys planning on using, like higher
level species, like you plan ongoing into monkeys or something
like that to do this, or is thatsomething that's not necessary?
Alejandro Torrado-Pacheco (18:07):
I think it could be interesting,
but our lab is not equipped forthat.
I wouldn't be surprised ifsomeone started doing research
with psychedelics and monkeys.
I think the things you canlearn from all the different
species are a little bitdifferent, you know, and so all
levels of research are valuable.
But even in mice people do alot of research with
psychedelics and they just lookat different things.
(18:28):
So for us, with the behavioralfocus that we have, rats are a
really optimal choice.
Danielle Dady (18:33):
That kind of lends itself to my next question
, because we like to ask ourguests to kind of get their take
on this.
In your opinion, is there a wayto conduct this research, or
maybe preliminary research,using computer models or organs
on a chip or any otheralternative, without using
animals?
We just kind of like to getdifferent opinions on that.
Alejandro Torrado-Pacheco (18:52):
I think, for what we are
specifically trying to do.
What we're trying to understandis how does the brain produce a
certain behavior and how doesthis external agent, this drug,
change brain activity?
that then changes the behavior,and so if you don't have the
behavior part, you're reallysort of losing a whole level of
analysis.
So I don't think we could dothe research we're doing using a
(19:12):
computer model or a brain in avat.
Essentially, that said, i thinkthat those types of techniques
or those types of models arereally valuable, because our
goal with animal research isalways to keep the number of
animals that we're using at aminimum.
We always want to try tominimize the number of animals
and that can be done withcareful study, design and
repeated measures, designs andstuff.
(19:33):
But of course, if your questionis answerable without using an
animal, then I think it shouldbe, and I think it would be
really cool to see somepsychedelics research done in,
for example, brain organoids,which I don't know maybe for
some of the listeners who arenot familiar, what these are is.
You can take human stem cellsand then differentiate them into
(19:54):
neurons in a dish And itbecomes essentially a human
brain in a dish.
Obviously it's not a real humanbrain, it's not the same thing,
but it's been used to studyhuman brain development from a
genetic standpoint, and I thinksomething like that would be
great to answer some questionsabout what psychedelics do, for
example, to specific cell typesthat are found in a human brain
but not in the brain of a rat.
Jeff Marshall (20:16):
I've been asking, speaking about the brain and
looking at changes in cell type,and maybe you said it and I
mentioned.
But when someone takespsilocybin, like in these
clinical trials, and then theylook at the brain, or when you
guys are looking at your rats,are there permanent changes to
the brain that psilocybin causes, like give the long lasting
kind of effects that are like?
are they permanent changes tothe brain or are they just
(20:37):
something that they'retemporarily changes to the brain
that alleviate the signs ofdepression, that then eventually
reverse back to normal celltypes, or should just have
changes to do with like synapsesor just psilocybin just have
like a long half life in thebody that's causing the side
effect that we see, if you know,alleviating signs of depression
.
Alejandro Torrado-Pacheco (20:55):
Yeah, that's a fantastic question And
it's not a settled one.
There are definitely longlasting changes for psilocybin.
So one of the things that hascome up we mentioned ketamine
before and this is true also forketamine.
These compounds causeplasticity.
They cause growth of synapses,essentially in the brain.
When people have looked andthat can be something that's
fairly long lasting We don'thave the data to look, let's say
(21:19):
a year after administration butit does seem to be a persistent
increase in the potentialnumber of synapses in some parts
of the brain after psilocybin,after ketamine.
Whether that is directly relatedto the depressive symptoms,
it's hard to confirm for sure,but that's definitely a leading
hypothesis about why.
The other option, which is kindof like our angle, is a bit
(21:42):
more that this plasticity isperhaps a direct correlate of
the increased flexibility Andthen it's kind of a resetting of
the ability to make newconnections, and so maybe you
can think of it as rewiring yourbrain in a way.
So instead of being stuck inthis loop of negative self
perception and perception of theenvironment, you can rewrite
all that and come to a differentstate after that experience.
(22:04):
Perhaps it's not a lastingphysical state, it's a physical
state that lasts a little bitand allows you to change other
things, but it's also possiblethat there are changes that are,
for example, gene expression,that are very, very long lasting
, and we just don't know yet.
So I would say it's an openquestion, but it's definitely
something that people arelooking into and that is a very
(22:26):
promising avenue for research.
Jeff Marshall (22:28):
Yeah, absolutely, and we always like to help our
listeners kind of understand thepotential applications of the
research that you're doing.
Maybe it's like when we haveguests on the show and how
that's going to affect oursociety, and so you've said a
lot already about how I thinkyour research has helped advance
our understanding of the use ofthese psychedelics,
particularly psilocybin.
(22:48):
Do you think in our lifetimeeven which I mean I think we're
all relatively young, but do youthink in our lifetime we're
going to see these compoundsbeing accepted as a powerful
therapeutic tool, something thatdoesn't require people
suffering from PTSD ordepression to enroll in a
clinical trial, like, do youthink psychiatrists will
(23:09):
eventually be able to use it inpractice, like regularly,
outside of clinical trials?
That's what I'm getting at, iguess.
Alejandro Torrado-Pacheco (23:16):
I think that's definitely where
the momentum is going.
Here in Oregon, there was aballot question and it ended up
resulting in the approval ofpsilocybin as a medication.
essentially, it's a complicatedlegal and logistical framework,
but it's definitely going thatdirection.
To answer your question of willit happen in our lifetime, i
think so, but I want to be alittle bit cautious.
(23:37):
There's a great paper from acouple of the people that have
been doing a lot of the clinicaltrials, like Roland Griffith
and David Yead.
In this little, very short paperthey talk about the bursting of
the psychedelic bubble.
Their idea is when you havesomething that has so much hype
behind it, it creates thisbubble of expectations.
It's kind of like you getsensationalists, news articles
(23:58):
and this is the miracle cure foreverything and it's going to
cure depression for everybody.
It's our role as scientists tobe realistic and cautious and to
not feed into that, becausewhat can happen is that you then
get a pushback when all theseincredibly high expectations
don't materialize and then youget very negative coverage and
(24:18):
very negative landscape forfunding and for continuing to do
this research.
This is kind of what happenedin the 50s and 60s.
People were so had such highexpectations on these compounds,
which were not illegal at thetime, that they first of all
promoted them as they were goingto be the cure-all for the
world and for all the ailmentsin the world.
But also they did very, verysloppy research and that,
(24:41):
combined with popular culture,the use of these compounds, but
definitely the poor research,contributed to these substances
being kind of written off themap of research for several
decades with the ControlSubstances Act of 1970.
And so I think it's importantto be cautious about our
expectations.
It's unlikely that we're goingto ever find a complete cure,
pharmacological cure, fordepression.
(25:02):
That said, the more tools wehave in our toolbox, the better.
I really think thatpsychedelics are going to be one
of those tools, and it willtake time.
Ketamine has had kind of asimilar progression and it's
taken more than 20 years to gofrom the first promising
research to almost FDA approvaland there are actually ketamine
clinics out there.
So I think it will happen andhopefully we can sort of temper
(25:24):
expectations and be careful withour research and really get
these compounds accepted as whatthey are, which is another
potential tool in treating thesedisorders that are very, very
hard to treat and that reallyaffect people's lives.
Jeff Marshall (25:38):
But yeah, i hope that made sense Makes perfect
sense, and I think it'simportant too that if they do
become more widely accepted andare able to start being used,
that they have to be usedcorrectly, right?
Because you talked about someof the negative side effects,
but we didn't really talk aboutwhat the negative side effects
were, and if people were usingthem irresponsibly or at higher
doses that were too high for thehuman body to handle, then they
(26:00):
could have obviously verynegative consequences as well,
right?
Alejandro Torrado-Pacheco (26:04):
Of course, safety is a big concern
with these things.
I don't think it's ever goingto be the kind of medication
that your doctor hands you, theprescriptions like, yeah, one
type of acid every three weeks.
that's just not how it's goingto work.
More likely than not it's goingto be the way the clinical
trials have been done.
So there's a preparatorysessions and there's a very
specific sort of protocol forhaving the experience with
(26:28):
psychological support, and thena debriefing session and then
another experience.
You know it's all very, verystandardized and the support is
essential.
So I think that's probably howit's going to go.
And yet, when done that way,the adverse effects and side
effects are actually veryminimal.
That's a good thing, yeah,absolutely.
Danielle Dady (26:47):
One question that we always like to ask our
guests, and I think you mighthave an interesting answer, just
based on your unique research.
How do you go about describingto strangers what you do for a
living, so like if you're at aparty or trapped on an airplane
next to someone like, how do youbring up that you work with
research, animals and, on top ofthat, psychedelics.
It's kind of a uniquecombination.
Alejandro Torrado-Pacheco (27:09):
It's funny because the psychedelics
part most people think, oh wow,that's so cool, so that part is
easy.
And then, yeah, the animal partis.
I recognize that it's adifficult sort of a delicate
subject for some people, and soyou know, i've asked people how
they feel about animal research,because it's kind of a
sensitive subject, and,interestingly, most of the time
the response I get from justpeople who are not scientists at
(27:32):
all.
It's kind of the same thingthat I feel, which is that we're
making this sort of ethicalbargain where animal research is
necessary because we are tryingto alleviate suffering and
trying to come up withtreatments for all these
different disorders, And even ata basic science level, we need
to understand the biology to beable to get back to the
(27:52):
translational level.
I feel like everyone has anunderstanding of that
intuitively.
It makes it a little bit easierto talk about that, but I find
that people don't actually,while they have this
understanding, they don't reallyknow in practice what that
looks like, and so I'd reallytry to make the point that we
obviously try to do this, whilewe do everything in the most
(28:13):
humane way possible.
We have very standardizedprotocols that are checked by
veterinarians, we use steriletechnique and anesthesia and all
this when we do surgeries onour animals, for example.
But also we try to minimizeanimal use.
So we can use statisticalanalysis and careful study
design And, like you said,potentially alternative model
(28:33):
organisms or even computermodeling to minimize how many
animals we use And so kind oftrying to make the point that we
understand we're trying to dothis in the most ethical way
possible.
I feel like people are reallyreceptive and interested when
they actually learn how ithappens in practice.
Jeff Marshall (28:48):
Yeah, absolutely, and that's great that you make
that point to kind of explainall that, because once I mean,
of course, like you said, try tominimize the use, it'd be great
not to have to use animals, butunfortunately we still need
those animals to makediscoveries that are going to
benefit both humans and animals.
And taking the time to explainit I think helps, because 99% of
us have never been inside of ananimal or a research laboratory
(29:12):
and seen kind of how it goesdown or been a part of an
eye-cook meeting and hear thediscussions that they have and
how it's all about.
You have to have humaneendpoints to ensure they're not
suffering and yada-yada.
We've had the whole eye-cookdiscussion down here before
about protocol breakdown andwhat goes into the protocols.
So if you want more informationon the approval process and how
that goes, you can go back toone of our earlier episodes and
(29:32):
hear all of that.
But it's great that you takethe time to do that Before we
wrap up this episode.
Do you have any other finalstatements or thoughts about
anything that we haven't coveredor anything you want to
reiterate, just kind of eitherwhether or not it's about just
the animal research side ofthings or about your research,
or about the use of psychedelicsor any other topic.
Alejandro Torrado-Pacheco (29:51):
And, sir, you gave me that
opportunity.
I would like to make a couplepoints, if I may.
One of them is related to yourlast question and it's something
I wanted to mention that Iforgot.
I really want to make the pointthat as scientists, we are
accountable to the public,because most of the time, we are
funded by taxpayer dollars, andso I really appreciate what you
guys are doing here, andbecause we want the public to
(30:12):
see the value of animal research, i want people to see the value
of the research that they'refunding and get people behind
funding for translational andbasic science, and so thanks for
doing this And, yeah, i thinkthat's an important part of
science.
Communication is to really makethat point.
And then the other thing Iwanted to say is that if you're
interested in psychedelicresearch, i really would like to
(30:32):
recommend the MAPS organization.
So MAPS is theMultidisciplinary Association
for Psychedelic Science, andthey are sort of a broad
consortium of scientists andpeople who work in field who are
conducting a lot of theclinical trials.
I'm not part of them, but Ithink it's a great thing to look
in terms of seeing whatpsychedelic research is about,
and so if you want to check themout there at mapsorg and
(30:53):
they're been actually behind alot of the trials with MDMA
which we haven't talked aboutbut which will very likely be
approved as a treatment for PTSD.
So I just wanted to give ashout out to them.
Oh and sorry.
One more thing, if you want tocheck us out our lab is you can
look up the Moga Down Lab atOHSU.
Jeff Marshall (31:09):
We really appreciate your time.
I've learned a lot.
I think all of our listenershave probably learned a lot
after listening to this wholeepisode.
So thank you for you beingwilling to come on and talk to
us and break all this down.
For us And it's, like we said,kind of a topic that doesn't
seem to be discussed a whole lot, but hopefully we start hearing
more about it, because anythingwe can do to help benefit
mental health and especiallydepression and PTSD and all that
(31:32):
If we can do anything to helpthose people suffering from that
, it's fantastic.
So thank you for everythingthat you're doing and thank you
for taking the time to talk tous today.
We truly appreciate it.
Alejandro Torrado-Pachec (31:42):
Thanks so much, it was my pleasure.
Jeff Marshall (31:44):
Absolutely.
Thanks, guys.
Thanks, be sure to go writereview our show again If you're
still listening.
Hopefully you made it this far.
Write review us.
It does help us and we willcatch everyone next time.
Thanks everyone.
This podcast is supported by Americans for
Medical Progress and was foundedand created through the Michael
D Hare Fellowship, awardedannually to support projects
that inform and educate thepublic about the critical role
of animal research in furtheringmedical progress.
The Fellowship honors the lateDr Michael Hare, a renowned
board-certified laboratoryanimal veterinarian who
dedicated his career toscientific and medical
(00:25):
advancements and who was deeplycommitted to animal welfare and
advocacy.
Hey everyone, and welcome in tothis month's edition of Labrat
Chat.
(00:45):
Thanks for joining us and, asalways, please take a second
pause.
If you can go into Spotify,press the star rate, review our
podcast.
That really does help.
You know other people find ourpodcast.
If you can go into iTunes orApple podcasts and actually
write a written review, that'seven better.
Wherever you can write andreview the podcast on any
(01:06):
platform that you're using, wedo appreciate it.
It really does help.
And again, our email.
If you ever have, you know,suggestions, comments, just for
us personally, danielle and Iwill respond to them labratchat
at gmailcom.
So thanks everyone again fortuning in.
Today we have an exciting guest.
His name is Dr AlejandroTirado-Pacheco.
He's from Oregon HealthSciences University.
(01:28):
He's a postdoc up there, a labthat focuses on want to know if
the lab focuses on it.
But what we're talking to himtoday about is the use of kind
of psychedelics and how that canbenefit mental health.
Especially with the last month,may, being mental health
awareness month, we thought it'dbe a cool idea to actually talk
to someone that does researchin that field and how it can
(01:52):
possibly benefit us and how theuse of animals help, you know,
accomplish that goal.
So, if you will, drTirado-Pacheco, just tell us a
little bit.
You know about yourself.
We got you interested inscience and research and then in
this kind of field,particularly if you would just
tell us a little bit about that.
Alejandro Torrado-Pacheco (02:09):
Yeah, well, first of all, thanks a
lot for having me on.
It's really exciting to be ableto talk to the public about
this research.
I don't get the chance to dothat a lot, so I'm really really
glad to be here.
So I guess, yeah, my story is abit of a bit of a wandering
path to get to where I am today.
I grew up in Europe and I wasreally into science from a young
age and the system, the way itworks in Britain, which is where
(02:31):
I went to university, is thatyou apply to university when
you're very young, like 16, 17,and you don't have a major.
You just apply for something.
And so I applied for a physicsprogram and you go in and you
only do that.
So I started this physicsprogram and two years in I was
basically ready to quit becauseyou know, as you can imagine,
choosing a career when you're 17years old, the chances that
(02:52):
that works out are pretty slim.
But then I got introduced tothese ideas about graph theory
and dynamical systems, so allthese like mathematical methods
that you could use to modelthings in the world.
The problem I had with physicswas it was too abstract.
I couldn't really relate whatwas going on in the math to the
real world.
But when I got introduced tothese ideas and especially to
(03:14):
the fact that you can modelsomething like the brain using
these mathematical tools, thatwas really fascinating right,
that you can use these tools tothink about cognition, behavior
and even emotion, and so thatwas kind of my entry point into
neuroscience.
So I did a computationalneuroscience master's at
University College London And itwas actually a physics master's
(03:35):
, but I did a computationalneuroscience thesis in a lab
over there, peter Latham's labAnd I decided I would go to grad
school for neuroscience.
And so I ended up going toBrandeis University, which is in
Massachusetts, for my PhD.
And that was another choicethat was dictated by the
difference which might beinteresting to your listeners,
differences between the Europeanand the American system.
In the American system you comeinto grad school and you have a
(03:58):
couple of years of classes andyou get to sort of explore
different labs and then choosewhat you're going to do.
In a lot of places in Europe,the way it works, you as you
find a professor and you sort ofask them.
You know I would like to workwith you on this topic, so you
have to really have a good ideaof what you want to do.
But because I came in from thesides basically and you know I
(04:19):
didn't have any biologybackground, i applied only to
the US because I wanted thatopportunity to explore different
topics And I thought I wasgoing to do computational
neuroscience but I ended upfalling in love with experiments
, especially experiments withfreely behaving animals.
I just love the techniques andwhat you can learn from those.
So I joined Gina Torrigiano'slab at Brandeis.
(04:41):
Over there I studied sleep andplasticity, so how brain
plasticity is affected by sleep.
So, as you can see, kind ofnone of this has anything to do
with mental health orpsychedelics, but the way I
thought about it, i alwayswanted to work with psychiatric
disorders And the way I thoughtabout it was my PhD was an
opportunity to learnneuroscience and learn
techniques and then apply thoselater on in the next step, and
(05:04):
so that's what I'm doing now.
Like you said in yourintroduction, i am a postdoc in
Bita Mogadam's lab in theBehavioral Neuroscience
Department, ohsu.
What we're studying is broadly.
The lab is interested in theneurobiology of psychiatric
illnesses.
Bita has, you know, 30 years ofexperience working in this
field and she's done a lot ofwork with schizophrenia, and
(05:25):
when I contacted her aboutworking in her lab, she offered
me this project that she wasinterested in to pursue research
on psychedelics and especiallypsilocybin, because of the
really promising data in humans,and we can talk about that
later.
But yeah, so now that's whatI'm studying, looking at
psilocybin and major depressivedisorder.
Jeff Marshall (05:44):
Yeah, it's crazy that you apply to a university
when you're 16, 17, and you haveto pick what you want to do.
I mean, it's kind of similar, iguess, in a way, in the
American system You go tocollege when you're 18.
And if you have a scholarship Ithink a lot of scholarships,
state-sponsored scholarshipsrequire you to pick a major by
the end of your first semesteror first year or something in
order to keep your scholarship.
And so even then, like 18, 19,you don't know what you wanted.
(06:06):
It took me, i mean, look, iwent back to school at 32.
So I didn't know.
It took me a while to likeactually get into a career or
some sort of job that I wasinterested in and then to
explore that further, so thenbreak it down and figure out
what I really wanted to dowithin that field.
And so it's kind of crazy thatat 16, 17, that you're forced to
try to make that decision.
Alejandro Torrado-Pacheco (06:28):
Yeah, it's pretty wild.
And the thing is there's nomajor or minor, so you just go
in, and so I took no collegelevel classes in biology,
chemistry, anything else.
That wasn't even science, likejust physics.
So I really think it's limiting.
Danielle Dady (06:42):
I don't know.
that sounds kind of nice,though I just remember in my
undergrad having to take likesociology and Greek mythology
and you're just like I don'twant to learn this.
This is so far better.
Jeff Marshall (06:51):
Greek mythology is pretty cool.
I like Greek mythology.
I took it because I thought itwould be cool.
It's not cool, it's not whenyou have to write a paper, yeah
right, when you have to write afive-page paper.
Danielle Dady (06:58):
I immediately regretted that decision.
But I have a quick questionjust about, like, what
psychedelics are, because when Ithink about that I think of
mushrooms.
So I'm sure, well I don't know.
Are there other means of wherethe compounds come from?
I guess, what exactly ispsilocybin, some of the other
psychedelic compounds that youwork with?
where do they come from?
How do you even obtain them?
Well, i imagine they're likecontrolled substances, but maybe
(07:21):
you could just talk a littlebit about the compounds
themselves.
Alejandro Torrado-Pacheco (07:24):
Sure, i guess I'll start with what
they are.
There's three main classes ofpsychedelics and they're just
like, biochemically slightlydifferent, but I'm not a
biochemist myself, so thosethings don't really mean much to
me.
But essentially all of them arevery closely related to
serotonin and they act onserotonin receptors in the brain
.
And then they have slightlydifferent pharmacological
(07:45):
profiles.
You know, some are naturalcompounds, like psilocybin, like
you mentioned, is found inmushrooms.
Another very popular one is DMT, or dimethyl tryptamine, which
is found in some species oftoads and in some plants as well
.
And then a lot of them are justsynthetic compounds, for
example LSD, the most famous oneof them all.
So the interesting thing is alot of them are controlled
(08:08):
substances and they are like atthe highest level, So they're
schedule one substances.
So psilocybin is schedule one,lsd is schedule one, and so,
yeah, it takes a while to getthem.
You have to have a license witha DEA Luckily I don't, but my
boss does And it takes a longtime to get that and then it
takes a long time to get thecompound.
The National Institutes ofHealth has a drug supply program
(08:30):
through the National Instituteon Drug Abuse.
So basically the idea is wewant to study these
quote-unquote drugs of abuse tounderstand them better.
They can give you small amountsof these drugs when you request
them.
There's a lot of paperworkinvolved and you have to
obviously justify why you wantit, what you're going to do with
it and how this is going tobenefit the public.
There are other compounds thatare actually not scheduled, even
(08:53):
though they're extremelysimilar.
So one of them is DOI, and ifyou look up psychedelic research
, you'll see this DOI pop up allthe time, and that's because
you can just buy it, and so Idon't know what it feels like to
take it.
I don't know how similar it isto LSD or psilocybin, but it's
freely available and it's kindof used as a proxy for
psychedelic effects.
I personally think it's notexactly the same, but we can get
(09:15):
into that if we want to lateron.
Jeff Marshall (09:17):
Is that also something that comes from
mushrooms?
That's just like a syntheticcompound someone's made.
Alejandro Torrado-Pachec (09:21):
That's synthetic.
And actually I should mentionthe psilocybin that we get and
that everyone gets is at thispoint synthetic.
So it's made in a lab, becausewhen you extract it from
mushrooms you get a lot ofimpurities.
Jeff Marshall (09:34):
Okay, So it's a process of extraction.
You can't go out and just findthe mushroom and eat it and get
the psilocybin effects.
It's kind of like, I don't know, I guess like cocaine.
If you will, You got likethere's a process to make it
into cocaine And I guess there'sa process to make psilocybin.
I'm not trying to giveinformation on how to make it,
or process it.
Danielle Dady (09:51):
You're teaching people how to do that.
Jeff Marshall (09:52):
Well, my biochemistry book in school
detailed the process of how tomake crack detailed.
Oh my gosh that's hilarious.
It's like the protocol on howto do it Probably no longer in
publication And I didn't try itjust for the record.
Danielle Dady (10:04):
Either way, people should not go out and
just eat mushrooms, because youhave no idea.
Jeff Marshall (10:08):
Yeah.
So I guess if they're scheduledone drugs, if it's something
that you could just go out andget in nature, or if it takes a
pretty like advanced process toactually get the compound out of
it, You know, for lab researchwe want to make sure it's a pure
compound, so we use thesynthetic version.
Alejandro Torrado-Pacheco (10:23):
But yeah, it's naturally available.
And I should mention you knowit's been used for millennia by
people all over the world,especially in what is currently
Mexico.
So in Mesoamerica people havebeen using psychedelic mushrooms
for religious and otherimportant cultural ceremonies
for a long, long time.
Jeff Marshall (10:40):
Good to know.
It seems like there'sdefinitely a lot of positive use
for it.
I think it seems like when Iwas a kid I remember talks about
mushrooms and how people wouldhallucinate.
I just remember conversationsabout if you took them you're
going to hallucinate and go jumpoff a building and all the side
effects and how awful they areand how they need to be banned
from society.
But now it's nice that there'skind of maybe the little bit of
(11:02):
shift coming on in society andfinding a positive use for it.
And I think in order to get tothat understanding, research
needs to be done, and I thinkthat's kind of where you guys
come in.
I know there's lots of humanresearch in there out there as
well, but in order to really geta good understanding, i think
it's important that we do someof the animal research.
So if you would, can you justtell us a little bit about your
(11:23):
research?
Which animal model do you guysuse once you get that synthetic
psilocybin compound In order tostudy it?
you've had a lot of findings,but what's like a broad spectrum
approach to some of thefindings that you've been able
to discover using that animalmodel?
Alejandro Torrado-Pacheco (11:40):
Yeah.
So we use rats in the lab andthere's a very specific reason,
and the reason is that we areinterested in the behavioral
effects of psilocybin.
So I'm going to back up alittle and tell you a bit about
the human data, because thatwill kind of bring it into
context why we're doing whatwe're doing.
There's a lot of phase oneclinical trials and even a few
phase two clinical trials thatshow incredibly promising
(12:02):
results for psilocybin.
And to kind of tell you whatthat means, incredibly promising
.
I'm talking about two doses ofpsilocybin three weeks apart
having a stronger effect inameliorating symptoms of
depression than a six-weekcourse of a standard medication,
which would be a selectiveserotonin reuptake inhibitor,
you know, like prozac or lexapro.
(12:22):
That's crazy, it's verystriking, it's fast-acting and
it's long-lasting.
So people have looked up to sixmonths after one or two doses
and you still see an effect.
Yeah, that's incredible.
And it's really important tosort of underscore the fact that
, while accessorizer are amazingand I can probably say that
they've saved countless livesThey have a lot of side effects
(12:44):
and adverse effects and you knowpeople end up having to take
this medication every day.
So it's you know you get sortof problems with people taking
it.
We've been on the hunt for abetter treatment for depression
for six decades or so, so it'sreally cool that we now have a
few options like ketamine is one, and now psychedelics are
emerging as a really promisingoption.
Jeff Marshall (13:03):
Ketamine- is one I didn't know that Yeah, we use
ketamine all the time.
I don't know it was used in themental health realms.
I thought it was more just inthe realm of like just an
addictive kind of like cocaine,heroin type of drug.
But I guess it has use as well.
I know that's not the focus ofyour research, but that's just
not that interesting.
Alejandro Torrado-Pacheco (13:20):
Yeah yeah, ketamine is interesting
because the different doses dovery different things.
So at high doses it's ananesthetic I know it's used in
animals for anesthesia but atlow doses it has this weird
antidepressant effect, and soit's actually pretty close to
FDA approval, i think Awesome.
Jeff Marshall (13:37):
Okay, that's cool .
Yeah, i mean, we use it quite abit and cats that want to try
to kill us while at work, whenthey're hissing at you, you can
score a little bit in the mouth.
It calms them down a little andthey do a little anesthetic
properties, like you said.
But yeah, that's cool, good toknow as well.
Alejandro Torrado-Pacheco (13:51):
Yeah, so going back to I guess the
reason I talked about all thatis because psychedelics have an
interesting history.
You know they were used in the50s and 60s in research.
Then they you know researchstopped because the control
substances act made themschedule one substances.
And now we have all this humandata, but we have a real gap of
knowledge in terms of thebiological mechanism, and that's
(14:12):
where the animal research comesin.
We want to understand why arethey so effective?
right, what is happening in thebrain when you take psilocybin,
and you know later on you feelbetter.
And so to do that, we have tobe able to see an effect.
Is the animal actually feelingpsilocybin and perhaps does it
have an antidepressant likeeffect?
and then what is happening inthe brain?
(14:33):
So we have to be able to usetechniques that you wouldn't be
able to use in humans, that areinvasive, that you can do in
animals.
And so in our research, what wereally sort of noticed is that
in the polyclinical trials youknow you might have heard this
phrase set and setting in termsof psychedelic use, where you
know the mental set, so yourexpectations coming in your
(14:53):
current mood, your history, yourgenetics, that plays a part,
and also the environment plays apart, right, so you're the
peers who is present during thatexperience, the kind of support
you have, even just thephysical environment.
All of that really affects theexperience and the outcome.
And so in these clinical trialspeople are usually in a very,
very safe feeling environment.
(15:14):
They're usually on a bed withrelaxing music and sometimes eye
shades, and there's usually twosupport staff who are often
trained psychologists ortherapists, and the idea is not
to give, like it's non-directive, supportive therapies, what
they call it, so it's not reallylike therapy session, but there
is that sort of support.
And so we thought maybe what'shappening is that the effect of
(15:36):
psilocybin is to sort of primepeople to get the most out of
that experience, and so reallythe effects while the drug is on
board are important to study.
We decided to do that in ratsAnd broadly what we found is
that, very surprisingly, ratscan be better at some tasks that
require cognitive flexibility,so the ability to switch between
(15:58):
different behavioral strategiesdepending on the environment,
while they are essentially highon psilocybin.
And you might ask, what doesthat have to do with depression,
what you've been talking about?
Well, cognitive flexibilityfirst of all, is associated with
greater mental health.
Cognitive inflexibility, so kindof rigid thinking and rigid
patterns of behavior, are seenin a lot of psychiatric
(16:21):
disorders, including depressionand anxiety disorders, and
higher cognitive flexibility,which is measured in humans with
tasks very similar to the oneswe use in rodents, is associated
with greater mental health andalso better responsiveness to
treatment for depression.
So there's a very strong linkthere, and basically the idea is
that the hypothesis that wehave, and others that propose as
(16:43):
well, is that psychedelicspromote a state of higher
flexibility that then allowspeople to break out of ingrained
patterns of thought, ofingrained sort of negative
perceptions of the self or theenvironment.
Our research in animals sort ofsupports that idea And also,
well, currently and in the nearfuture, we're trying to also
(17:04):
understand how this is happening, so that we can first of all
get an understanding of thatprocess in the brain which would
be great And also perhapsdesign compounds that can better
target the specific therapeuticaction that we're looking for,
as opposed to something likepsilocybin, which is perhaps
having a lot of effects that aremaybe undesirable or even just
(17:25):
unnecessary.
Danielle Dady (17:26):
I have a question about why rats would be the
best animal for this, Because,now that I'm thinking about it,
all the places I've worked wherethere is like a psychology
department or something, itseems like rats are always the
go-to model And I didn't know ifthere was a particular reason.
Is it maybe just because theirbrains are bigger than mouse
brains?
or maybe they can learndifferent tasks easier?
But I guess what's the draw torats for this type of work?
Alejandro Torrado-Pacheco (17:47):
Yeah, that's a great question, And it
really boils down to the factthat they're just smarter than
mice.
This is what it is, the taskthat we use.
Mice would just not be able todo it.
Danielle Dady (17:57):
Okay, interesting .
Jeff Marshall (17:58):
Were you guys planning on using, like higher
level species, like you plan ongoing into monkeys or something
like that to do this, or is thatsomething that's not necessary?
Alejandro Torrado-Pacheco (18:07):
I think it could be interesting,
but our lab is not equipped forthat.
I wouldn't be surprised ifsomeone started doing research
with psychedelics and monkeys.
I think the things you canlearn from all the different
species are a little bitdifferent, you know, and so all
levels of research are valuable.
But even in mice people do alot of research with
psychedelics and they just lookat different things.
(18:28):
So for us, with the behavioralfocus that we have, rats are a
really optimal choice.
Danielle Dady (18:33):
That kind of lends itself to my next question
, because we like to ask ourguests to kind of get their take
on this.
In your opinion, is there a wayto conduct this research, or
maybe preliminary research,using computer models or organs
on a chip or any otheralternative, without using
animals?
We just kind of like to getdifferent opinions on that.
Alejandro Torrado-Pacheco (18:52):
I think, for what we are
specifically trying to do.
What we're trying to understandis how does the brain produce a
certain behavior and how doesthis external agent, this drug,
change brain activity?
that then changes the behavior,and so if you don't have the
behavior part, you're reallysort of losing a whole level of
analysis.
So I don't think we could dothe research we're doing using a
(19:12):
computer model or a brain in avat.
Essentially, that said, i thinkthat those types of techniques
or those types of models arereally valuable, because our
goal with animal research isalways to keep the number of
animals that we're using at aminimum.
We always want to try tominimize the number of animals
and that can be done withcareful study, design and
repeated measures, designs andstuff.
(19:33):
But of course, if your questionis answerable without using an
animal, then I think it shouldbe, and I think it would be
really cool to see somepsychedelics research done in,
for example, brain organoids,which I don't know maybe for
some of the listeners who arenot familiar, what these are is.
You can take human stem cellsand then differentiate them into
(19:54):
neurons in a dish And itbecomes essentially a human
brain in a dish.
Obviously it's not a real humanbrain, it's not the same thing,
but it's been used to studyhuman brain development from a
genetic standpoint, and I thinksomething like that would be
great to answer some questionsabout what psychedelics do, for
example, to specific cell typesthat are found in a human brain
but not in the brain of a rat.
Jeff Marshall (20:16):
I've been asking, speaking about the brain and
looking at changes in cell type,and maybe you said it and I
mentioned.
But when someone takespsilocybin, like in these
clinical trials, and then theylook at the brain, or when you
guys are looking at your rats,are there permanent changes to
the brain that psilocybin causes, like give the long lasting
kind of effects that are like?
are they permanent changes tothe brain or are they just
(20:37):
something that they'retemporarily changes to the brain
that alleviate the signs ofdepression, that then eventually
reverse back to normal celltypes, or should just have
changes to do with like synapsesor just psilocybin just have
like a long half life in thebody that's causing the side
effect that we see, if you know,alleviating signs of depression
.
Alejandro Torrado-Pacheco (20:55):
Yeah, that's a fantastic question And
it's not a settled one.
There are definitely longlasting changes for psilocybin.
So one of the things that hascome up we mentioned ketamine
before and this is true also forketamine.
These compounds causeplasticity.
They cause growth of synapses,essentially in the brain.
When people have looked andthat can be something that's
fairly long lasting We don'thave the data to look, let's say
(21:19):
a year after administration butit does seem to be a persistent
increase in the potentialnumber of synapses in some parts
of the brain after psilocybin,after ketamine.
Whether that is directly relatedto the depressive symptoms,
it's hard to confirm for sure,but that's definitely a leading
hypothesis about why.
The other option, which is kindof like our angle, is a bit
(21:42):
more that this plasticity isperhaps a direct correlate of
the increased flexibility Andthen it's kind of a resetting of
the ability to make newconnections, and so maybe you
can think of it as rewiring yourbrain in a way.
So instead of being stuck inthis loop of negative self
perception and perception of theenvironment, you can rewrite
all that and come to a differentstate after that experience.
(22:04):
Perhaps it's not a lastingphysical state, it's a physical
state that lasts a little bitand allows you to change other
things, but it's also possiblethat there are changes that are,
for example, gene expression,that are very, very long lasting
, and we just don't know yet.
So I would say it's an openquestion, but it's definitely
something that people arelooking into and that is a very
(22:26):
promising avenue for research.
Jeff Marshall (22:28):
Yeah, absolutely, and we always like to help our
listeners kind of understand thepotential applications of the
research that you're doing.
Maybe it's like when we haveguests on the show and how
that's going to affect oursociety, and so you've said a
lot already about how I thinkyour research has helped advance
our understanding of the use ofthese psychedelics,
particularly psilocybin.
(22:48):
Do you think in our lifetimeeven which I mean I think we're
all relatively young, but do youthink in our lifetime we're
going to see these compoundsbeing accepted as a powerful
therapeutic tool, something thatdoesn't require people
suffering from PTSD ordepression to enroll in a
clinical trial, like, do youthink psychiatrists will
(23:09):
eventually be able to use it inpractice, like regularly,
outside of clinical trials?
That's what I'm getting at, iguess.
Alejandro Torrado-Pacheco (23:16):
I think that's definitely where
the momentum is going.
Here in Oregon, there was aballot question and it ended up
resulting in the approval ofpsilocybin as a medication.
essentially, it's a complicatedlegal and logistical framework,
but it's definitely going thatdirection.
To answer your question of willit happen in our lifetime, i
think so, but I want to be alittle bit cautious.
(23:37):
There's a great paper from acouple of the people that have
been doing a lot of the clinicaltrials, like Roland Griffith
and David Yead.
In this little, very short paperthey talk about the bursting of
the psychedelic bubble.
Their idea is when you havesomething that has so much hype
behind it, it creates thisbubble of expectations.
It's kind of like you getsensationalists, news articles
(23:58):
and this is the miracle cure foreverything and it's going to
cure depression for everybody.
It's our role as scientists tobe realistic and cautious and to
not feed into that, becausewhat can happen is that you then
get a pushback when all theseincredibly high expectations
don't materialize and then youget very negative coverage and
(24:18):
very negative landscape forfunding and for continuing to do
this research.
This is kind of what happenedin the 50s and 60s.
People were so had such highexpectations on these compounds,
which were not illegal at thetime, that they first of all
promoted them as they were goingto be the cure-all for the
world and for all the ailmentsin the world.
But also they did very, verysloppy research and that,
(24:41):
combined with popular culture,the use of these compounds, but
definitely the poor research,contributed to these substances
being kind of written off themap of research for several
decades with the ControlSubstances Act of 1970.
And so I think it's importantto be cautious about our
expectations.
It's unlikely that we're goingto ever find a complete cure,
pharmacological cure, fordepression.
(25:02):
That said, the more tools wehave in our toolbox, the better.
I really think thatpsychedelics are going to be one
of those tools, and it willtake time.
Ketamine has had kind of asimilar progression and it's
taken more than 20 years to gofrom the first promising
research to almost FDA approvaland there are actually ketamine
clinics out there.
So I think it will happen andhopefully we can sort of temper
(25:24):
expectations and be careful withour research and really get
these compounds accepted as whatthey are, which is another
potential tool in treating thesedisorders that are very, very
hard to treat and that reallyaffect people's lives.
Jeff Marshall (25:38):
But yeah, i hope that made sense Makes perfect
sense, and I think it'simportant too that if they do
become more widely accepted andare able to start being used,
that they have to be usedcorrectly, right?
Because you talked about someof the negative side effects,
but we didn't really talk aboutwhat the negative side effects
were, and if people were usingthem irresponsibly or at higher
doses that were too high for thehuman body to handle, then they
(26:00):
could have obviously verynegative consequences as well,
right?
Alejandro Torrado-Pacheco (26:04):
Of course, safety is a big concern
with these things.
I don't think it's ever goingto be the kind of medication
that your doctor hands you, theprescriptions like, yeah, one
type of acid every three weeks.
that's just not how it's goingto work.
More likely than not it's goingto be the way the clinical
trials have been done.
So there's a preparatorysessions and there's a very
specific sort of protocol forhaving the experience with
(26:28):
psychological support, and thena debriefing session and then
another experience.
You know it's all very, verystandardized and the support is
essential.
So I think that's probably howit's going to go.
And yet, when done that way,the adverse effects and side
effects are actually veryminimal.
That's a good thing, yeah,absolutely.
Danielle Dady (26:47):
One question that we always like to ask our
guests, and I think you mighthave an interesting answer, just
based on your unique research.
How do you go about describingto strangers what you do for a
living, so like if you're at aparty or trapped on an airplane
next to someone like, how do youbring up that you work with
research, animals and, on top ofthat, psychedelics.
It's kind of a uniquecombination.
Alejandro Torrado-Pacheco (27:09):
It's funny because the psychedelics
part most people think, oh wow,that's so cool, so that part is
easy.
And then, yeah, the animal partis.
I recognize that it's adifficult sort of a delicate
subject for some people, and soyou know, i've asked people how
they feel about animal research,because it's kind of a
sensitive subject, and,interestingly, most of the time
the response I get from justpeople who are not scientists at
(27:32):
all.
It's kind of the same thingthat I feel, which is that we're
making this sort of ethicalbargain where animal research is
necessary because we are tryingto alleviate suffering and
trying to come up withtreatments for all these
different disorders, And even ata basic science level, we need
to understand the biology to beable to get back to the
(27:52):
translational level.
I feel like everyone has anunderstanding of that
intuitively.
It makes it a little bit easierto talk about that, but I find
that people don't actually,while they have this
understanding, they don't reallyknow in practice what that
looks like, and so I'd reallytry to make the point that we
obviously try to do this, whilewe do everything in the most
(28:13):
humane way possible.
We have very standardizedprotocols that are checked by
veterinarians, we use steriletechnique and anesthesia and all
this when we do surgeries onour animals, for example.
But also we try to minimizeanimal use.
So we can use statisticalanalysis and careful study
design And, like you said,potentially alternative model
(28:33):
organisms or even computermodeling to minimize how many
animals we use And so kind oftrying to make the point that we
understand we're trying to dothis in the most ethical way
possible.
I feel like people are reallyreceptive and interested when
they actually learn how ithappens in practice.
Jeff Marshall (28:48):
Yeah, absolutely, and that's great that you make
that point to kind of explainall that, because once I mean,
of course, like you said, try tominimize the use, it'd be great
not to have to use animals, butunfortunately we still need
those animals to makediscoveries that are going to
benefit both humans and animals.
And taking the time to explainit I think helps, because 99% of
us have never been inside of ananimal or a research laboratory
(29:12):
and seen kind of how it goesdown or been a part of an
eye-cook meeting and hear thediscussions that they have and
how it's all about.
You have to have humaneendpoints to ensure they're not
suffering and yada-yada.
We've had the whole eye-cookdiscussion down here before
about protocol breakdown andwhat goes into the protocols.
So if you want more informationon the approval process and how
that goes, you can go back toone of our earlier episodes and
(29:32):
hear all of that.
But it's great that you takethe time to do that Before we
wrap up this episode.
Do you have any other finalstatements or thoughts about
anything that we haven't coveredor anything you want to
reiterate, just kind of eitherwhether or not it's about just
the animal research side ofthings or about your research,
or about the use of psychedelicsor any other topic.
Alejandro Torrado-Pacheco (29:51):
And, sir, you gave me that
opportunity.
I would like to make a couplepoints, if I may.
One of them is related to yourlast question and it's something
I wanted to mention that Iforgot.
I really want to make the pointthat as scientists, we are
accountable to the public,because most of the time, we are
funded by taxpayer dollars, andso I really appreciate what you
guys are doing here, andbecause we want the public to
(30:12):
see the value of animal research, i want people to see the value
of the research that they'refunding and get people behind
funding for translational andbasic science, and so thanks for
doing this And, yeah, i thinkthat's an important part of
science.
Communication is to really makethat point.
And then the other thing Iwanted to say is that if you're
interested in psychedelicresearch, i really would like to
(30:32):
recommend the MAPS organization.
So MAPS is theMultidisciplinary Association
for Psychedelic Science, andthey are sort of a broad
consortium of scientists andpeople who work in field who are
conducting a lot of theclinical trials.
I'm not part of them, but Ithink it's a great thing to look
in terms of seeing whatpsychedelic research is about,
and so if you want to check themout there at mapsorg and
(30:53):
they're been actually behind alot of the trials with MDMA
which we haven't talked aboutbut which will very likely be
approved as a treatment for PTSD.
So I just wanted to give ashout out to them.
Oh and sorry.
One more thing, if you want tocheck us out our lab is you can
look up the Moga Down Lab atOHSU.
Jeff Marshall (31:09):
We really appreciate your time.
I've learned a lot.
I think all of our listenershave probably learned a lot
after listening to this wholeepisode.
So thank you for you beingwilling to come on and talk to
us and break all this down.
For us And it's, like we said,kind of a topic that doesn't
seem to be discussed a whole lot, but hopefully we start hearing
more about it, because anythingwe can do to help benefit
mental health and especiallydepression and PTSD and all that
(31:32):
If we can do anything to helpthose people suffering from that
, it's fantastic.
So thank you for everythingthat you're doing and thank you
for taking the time to talk tous today.
We truly appreciate it.
Alejandro Torrado-Pachec (31:42):
Thanks so much, it was my pleasure.
Jeff Marshall (31:44):
Absolutely.
Thanks, guys.
Thanks, be sure to go writereview our show again If you're
still listening.
Hopefully you made it this far.
Write review us.
It does help us and we willcatch everyone next time.
Thanks everyone.
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