Harriet de Wit, PhD. September 2023

September 16, 2023

Information

Title: Microdosing: Fact or Fiction?

Description: Microdosing of psychedelic drugs remains an extremely popular practice in the general population, and users claim a wide range of beneficial effects. However, it has been difficult to verify these benefits in controlled studies. This presentation will review some of the findings from controlled studies with microdoses of LSD, and identify some of the methodological challenges.

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00:05Thank you everyone for being
00:06here on our first meeting for
00:08this academic year of our monthly
00:10seminar and Psychedelic Science.
00:12It's great to see such a
00:13a varied and large group.
00:15I'm sure we'll have more joining and
00:17we'll also as always be recording this,
00:19so as as almost always be recording
00:20this so we can get to an even broader
00:23audience within the old community.
00:25We are really privileged today to
00:27have Harriet do it speaking with us,
00:30someone who who really needs
00:31no introduction in this group.
00:32And so I'll be very brief.
00:34She's Professor of Psychiatry
00:36and Behavioral Neuroscience at
00:38the University of Chicago and
00:39she's been active in this space
00:41for longer than than most of us,
00:43certainly longer than me.
00:44And a lot of lot of interesting and
00:47provocative work over the years
00:49including work in microdoses recently
00:51which is something that where that I
00:53think that the ratio of use to data
00:55is vastly broader than than in even in
01:00the other the the macro dosing field.
01:04So really excited to have you here.
01:06Harriet thank you for joining us and very,
01:09very excited we have to share with us today.
01:12All right, great.
01:13It's a real pleasure to be here.
01:15And let me just make sure that.
01:30How's that? Is that all right?
01:32Can you see it? Yep. All right.
01:33Well, it's a real pleasure to be here.
01:35And, you know, I'm a little
01:37intimidated by this audience,
01:39so I'm happy to turn it into
01:41a discussion as we go along.
01:43I think there's lots of just
01:45interesting issues that come along
01:47all along the way that interest us.
01:49Also, please feel free to
01:52interrupt and contribute your
01:54thoughts and knowledge and ideas.
01:56So I am gonna talk a little bit about
01:58our work with micro dosing and I have
02:00a few disclosures here that are not
02:02really relevant to the LSD studies.
02:06I just gotta get rid of this.
02:09There we go. So what is micro dosing?
02:11I'm sure you're all familiar with
02:13the idea that it's the use of
02:16low doses of LSD and sometimes
02:18other psychedelic drugs as well.
02:20People take it once every three or four days,
02:23and they claim that it improves their mood,
02:25their cognition, their created creativity,
02:28and lots of other response measures as well.
02:32The doses that people take are about a
02:36tenth of the tripping psychedelic dose,
02:39and the practice is extremely widespread
02:41and it's had a lot of publicity,
02:44positive publicity.
02:46On the other hand,
02:48as was just mentioned,
02:49there have been very few controlled
02:52studies to really validate
02:53whether these claims have merit.
03:00Here are some of the popular So again
03:03it's been really popular in the media.
03:06And here are a few of the books that
03:09have been published specifically
03:10about micro dosing and the claims
03:12that they make are very broad.
03:14So here's one, the first one there is to
03:17improve your physical and mental health.
03:20Another one is safe, sacred journeys,
03:23another to upgrade your life and
03:25another one to improve your mood,
03:27your marriage and your life.
03:28So these are pretty general claims
03:31to kind of put to scientific test.
03:34So our question when we got into this work,
03:38I'm sorry something
03:42light touch. So the question
03:43that we put to ourselves is,
03:45is really does it work and it's
03:47something that we can look at
03:49under laboratory conditions.
03:50And there are reasons both to be
03:53optimistic about whether it actually
03:55works at a pharmacological levels and
03:57also there is reasons to be skeptical.
04:00From the point of view of does
04:02up to be optimistic.
04:04The fact that so many people are using
04:06it and claiming benefits from it
04:09suggests that there's something there.
04:11It seems like if it's completely
04:13a snake oil then people would
04:15drop off and their enthusiasm.
04:17So the the widespread use is one reason to
04:20think that there might be something there.
04:22There are also plausible neural
04:24mechanisms that you are probably
04:27more familiar with than I am.
04:29Of course,
04:30LSD acts on serotonin receptors,
04:32which is the same as receptor system
04:34that antidepressant drugs work on,
04:37and there's evidence that it might
04:39have antiinflammatory effects and
04:41it might have neurogenic effects.
04:42So there's some plausible neural
04:45mechanisms by which it might have
04:47some sort of antidepressant effect.
04:49There are also very promising
04:52clinical reports with high doses
04:54of LSD that high doses of LSD
04:56reduce symptoms of depression in
04:59treatment resentment patients,
05:00and there's also some
05:02evidence from animal models.
05:06There are also reasons to be
05:08skeptical about the claims.
05:09First of all, and most importantly,
05:11the users claims are deeply
05:14confounded by their expectancies.
05:16Nobody uses a drug like this on a
05:18regular basis without expecting
05:19some sort of beneficial effects
05:22and they'll continue to take it.
05:24And any effects that they do experience
05:26are then interpreted often as as
05:29being beneficial or or supportive.
05:31And so it's it's really difficult
05:33to determine whether it's really
05:35the pharmacological effects
05:37or the expectancy effects.
05:38Secondly,
05:39the pharmacology of these very
05:41low doses is poorly understood.
05:43We don't know what the optimal
05:45doses are for micro dosing.
05:46We don't know what the receptor
05:48actions of these very low doses are.
05:51So without knowing the pharmacology well,
05:53it's hard to really go into a a
05:56clinical investigation of of and
05:59possible antidepressant effects.
06:00And one of the things that concerns
06:02me is the heterogeneity of the of
06:05the claimed and apparent benefits.
06:07And here's just a brief listing of
06:09some of the claims that people have
06:11made along the way. They improve.
06:13They claim that the drug improves
06:16their creativity,
06:16which actually turns out to
06:18be very difficult to measure.
06:20That improves energy, productivity, focus.
06:22I won't read them all,
06:23but you can see that there's quite
06:25a variety spiritual awareness,
06:27leadership, develop wisdom,
06:28so all these claims,
06:30so it's our job as pharmacologist,
06:32psychopharmacologist to figure out
06:34which of these have an empirical basis
06:38and then of course decreased depression,
06:40anxiety and even menopausal symptoms.
06:42So it seems unlikely that one
06:44drug could do all of these things.
06:47And so it's our job to try and
06:49figure out what does it do.
06:51So there's a need for controlled studies.
06:54What are its effects on either mood
06:57or objective behavioral measures?
06:58Who benefits? So does it.
07:00The are the effects of the drug
07:03dependent on the either psychiatric
07:05symptoms or personality or
07:07preexisting state of the individual?
07:09Who's taking it?
07:11At what doses is the drug effective
07:13and for how long?
07:14And what exactly is the role of
07:17the expectancies?
07:18So the expectancies you could get
07:22apparently beneficial effects
07:23purely from expectancy,
07:25or it could be that the expectancy
07:28could interact with the pharmacological
07:31effects to produce some desired outcome.
07:34Some of the preclinical evidence
07:35that you as a group are probably
07:38very familiar with that.
07:39For example,
07:40repeated LSD normalized active
07:42avoidance learning,
07:43which is a model of depression,
07:46antidepressant effect,
07:47and reverse signaling abnormalities.
07:50In the olfactory balbectomy model
07:53of depression neurogenesis,
07:55LSD reportedly increases indicators of
07:59neural neuronal growth social behavior.
08:02Repeated LSD increased social behavior
08:04in my since a series of very elegant
08:08studies coming from McGill and also
08:10similarly stress induced anxiety.
08:12Repeated LSD reversed stress into
08:15induced anxiety like behavior in mice.
08:18So these are all very promising
08:20bits of preclinical evidence.
08:22And I I I'd like to just say that
08:25one of my particular interests is
08:27to try and bridge what gets found in
08:30the animal studies and what we can
08:32study in humans. So I I I see that
08:36there's a need for really parallel,
08:38closely parallel studies in the
08:40animals and in the humans to as
08:42sort of a proof of concept to go on
08:45to figure out what the mechanisms
08:47are underlying these drug effects.
08:49So a number of studies have been published
08:52with humans and there is one whole
08:55category of survey, self report study.
08:57So these are usually Internet studies,
09:00online studies where they ask you are you
09:02a micro doser and do you like the effects,
09:05Do you get beneficial effects?
09:07And you can see that there
09:08might be a real bias in there.
09:10Those studies,
09:11those survey questionnaires rarely reveal
09:15lack of effect or negative effects,
09:18are almost always positive.
09:19And so again,
09:20they're very much influenced by
09:22expectancies and then by selection bias.
09:25That is,
09:25the people who report on them are generally
09:28enthusiastic about the drug effects.
09:30There was a very interesting citizen
09:33science study by Zaghetti in 2021
09:36where they allowed micro dosers to
09:39blind their own Drug Administration
09:42in their own home environment.
09:45So they used their own drug and they were
09:48at the the researchers allowed them to
09:53sort of formulate put their drugs into
09:55envelope so that they didn't know what
09:57they were getting but the researchers
09:59didn't know what they were getting.
10:01So that then they over a period of
10:03several weeks they got either placebo
10:05or a low dose or a higher dose of
10:07their preferred micro dose drug.
10:09And it was. It's an elegant study.
10:11And basically though their
10:14conclusion was that they saw some
10:17beneficial effects of micro dosing.
10:18But when they took into account
10:21the people who recognized that
10:23they had received an active drug,
10:25the if the beneficial effects disappeared.
10:28And so they concluded from this
10:31that they were unable to exclude the
10:35possibility that people's expectancies,
10:37that is their idea that they
10:39might have beneficial effects,
10:41could have accounted for
10:42the beneficial effects.
10:43Now researchers have come up with this idea
10:46that for something to be a true micro dose,
10:50it has to be below the
10:53detectable threshold of effects.
10:55So and so that this is a very
10:58stringent criterion.
10:59So you're giving a drug and you see no
11:01self reported effects and they're hoping
11:03that it will have beneficial effects.
11:05From my point of view,
11:07I think this is too stringent criterion.
11:09I think it's possible that people who
11:12are micro dosing out in the world
11:14are actually experiencing some subtle
11:16drug effects and so it might be unfair
11:19to exclude them completely and you
11:21might be excluding the very people
11:23who might get beneficial effects.
11:24It's a very difficult,
11:27troublesome methodological issue to overcome.
11:31In any case,
11:32the citizen science study was was good.
11:34It showed some beneficial effects,
11:36but not if you excluded the people who
11:39correctly identified the drug that they got.
11:41So then we've done a series of
11:45laboratory based studies under
11:46double-blind conditions and I'll
11:48describe those to you here.
11:52These are done with healthy
11:54volunteers for the most part.
11:56They're also done under
11:58double-blind conditions.
11:59And in our laboratory we are
12:01able to administer drugs under
12:03truly double-blind conditions.
12:05So we tell the participants that
12:07they might receive any of a
12:08wide range of drugs so that we
12:10say you might get a stimulant,
12:11you might get a tranquilizer,
12:12you might get a hallucinogen,
12:14A placebo and some studies and
12:16antihistamine or a or a alcohol.
12:18So we give them a whole range of
12:21different possible categories of drugs.
12:22So they really don't know what kind of
12:25drug they're going to get in the study.
12:27And we believe and I think there's
12:29good reason to think that if you just
12:31told them either alcohol or placebo or
12:33only MDMA or placebo then or LSD or placebo,
12:37then they're going to be very much biased
12:39that any drug effect that they experience,
12:41they're going to attribute to the drug.
12:42So we go to a lot of trouble to
12:45really do this extra blinding.
12:46Most of our studies have been with
12:49single doses of the drugs and
12:51we measure behavioral responses,
12:53so measure different tasks and
12:57different mood measures.
12:58We also have done some studies
13:00with EE G and FM RI and then we've
13:03done one study where we give,
13:05we gave repeated doses in the same people.
13:08So I'll describe those studies to
13:09you and I'll also very briefly at
13:11the end describe a recent study
13:13that was published by Murphy at
13:14all where they used both laboratory
13:16and naturalistic settings.
13:22So just to kind of go over the what
13:24we've done in our laboratory studies,
13:26single doses of LSD, their doses are
13:29odd doses of 6.513 and 26 micrograms.
13:34We measure subjective and behavioral effects.
13:36I just said that already healthy volunteers
13:38and most recently we've also looked at
13:40depressed participants and I'll show
13:42you the results of that and then that.
13:44So most of them are single doses and then
13:48one study was done with repeated doses
13:50of either placebo or 13 or 16 micrograms.
13:58I've already said they were double.
13:59The studies are double-blind
14:01and placebo-controlled.
14:01So all the in, in with one exception,
14:04all the studies,
14:06in all the studies it's within the subject.
14:07So the same subjects get drug and placebo
14:10in or or actually in two of the studies.
14:12Now that's between subjects.
14:13So, But they're all placebo-controlled.
14:15The participants are healthy men and women.
14:18We exclude anyone with psychiatric,
14:21serious psychiatric background and
14:25anyone with substance use history,
14:27anyone who's taking any kind of medication.
14:29They had to be 18 to 35.
14:31They had to report using at least
14:33one one lifetime use of psychedelic
14:36and that was really to reassure
14:38ourselves we didn't want to be
14:40the first ones to administer a
14:42drug like this to healthy people.
14:44That'd be normal.
14:45Weight that to have a high school
14:46education fluent in English.
14:47So they're they're very,
14:50very thoroughly screened to be
14:53healthy participants.
14:54Our sessions are conducted in
14:57the laboratory for between 4:00
15:00and at the longest 8 hours in
15:03comfortable living room like room,
15:05so with couches and and televisions and
15:08movies to watch and that kind of thing.
15:11So the four studies I'll talk about here
15:13are one where we the first study where
15:15we looked at single low doses of LSD,
15:17we gave the same subjects
15:19got 06.513 or 26 micrograms.
15:21The second study I'll describe here,
15:24we looked at brain measures of
15:26reactivity to rewards and in that
15:28study we used zero and 26 micrograms.
15:31In the third study I'll describe,
15:32we gave repeated doses of zero,
15:3413 and 36 and that is between
15:38subjects design.
15:39And then finally,
15:40I'll describe the results of our recent
15:42study with people with depressed mood.
15:47I've already said all this healthy men
15:50and women within subject design this,
15:52this was our first study.
15:53So we actually had eight hour sessions
15:55in our laboratory environment because we
15:57didn't know how long the drug would last.
16:00As I'm sure you know,
16:01LSD has a long duration of effect
16:03and in the end at these low doses,
16:05we don't have to keep them in quite so long.
16:07But in this first study,
16:08they stayed in for 8 hours at a time.
16:10So this kind of gives you an outline
16:12of what happens in a typical session.
16:14They do all kinds of screening,
16:15pregnancy and drug,
16:16urine tests before they participate
16:18and they get the drug and then we
16:22get cardiovascular and subjective
16:23subjective ratings every half hour or
16:25hour for the duration of the session.
16:28And then at the time of peak drug effect,
16:30we get behavioral tasks or scan as
16:32the case might be or EE G measures
16:35as the case might be.
16:39So just to give you an idea of
16:43the is, do you see this thing?
16:47We can see your cursor.
16:48Yeah, we can see the Finder,
16:49but OK. So anyway,
16:51I'll take that into account.
16:52There's, it's hiding something there.
16:54OK. Just to give you an idea of
16:56the doses that we're giving over
16:58on the left are ratings of how
17:00much people feel a drug effect when
17:03they get full psychedelic doses.
17:05So 100 and 200 micrograms of LSD,
17:07this is the group in Switzerland.
17:09These are the ratings of how much drug
17:11effect the the scale goes up to 100.
17:13And so you can see that it's close
17:16to maximal at both 100 and and 200.
17:18Actually interestingly there
17:19aren't very clear dose dependent
17:21effects when you get this high.
17:23So both 100 and 200 produce
17:25fairly high effects.
17:29Then over on the right you can see the
17:31ratings on this same sort of questionnaire.
17:33How much do you feel a drug effect at
17:36the doses that we gave in that single
17:38low dose administration and the,
17:40the lightest line is the placebo session,
17:43this is the ratings of field drug over
17:46time during the session you can say
17:48that the lightest one at the bottom
17:50there is placebo and then you get
17:52the lower dose and then the higher
17:54middle dose and the highest dose.
17:55And so at the highest dose here we're getting
17:58ratings that are less than 50% of maximal.
18:01So and that's not happening
18:02in all the subjects.
18:04And so this this sort of formed the basis
18:07for trying to find a threshold dose.
18:10Again, finding a dose that's either threshold
18:13or below threshold is extremely difficult.
18:16One of the problems is that people vary
18:18a lot in their responses to the drug.
18:21So what's a detectable dose to one person
18:24might be below threshold to another person.
18:27And the other problem as I sort of
18:29referred to before is that if you're
18:31if you're repeatedly giving doses
18:33that are not even detectable then
18:35you're you're investing a lot of
18:37time and energy into something,
18:38into a study where you might
18:40not see anything.
18:41So it's nice to be able to get
18:43at least some kind of reportable
18:46subjective effect from the drug anyway.
18:48So this is where we are in the in the
18:50the range of doses that we're answering.
18:53Yeah,
18:54can I, can I ask you a question
18:55going back to that slide.
18:56So just for perspective
19:01on the right hand side, the low dose,
19:03very low doses of LST, what would you,
19:06what kind of drug effects are
19:08you are people reporting with,
19:10say some of your other studies
19:12with drugs like, I don't know,
19:15antihistaminics or just for comparison,
19:19you mean how much do people report feeling
19:21a drug if we gave them, say, amphetamine
19:25or an antihistaminic or?
19:28Well, we actually haven't
19:30given antihistamines.
19:31That happens to be one that
19:33we used as a distractor.
19:34Yeah. OK. So it would depend
19:36on the drug and the dose.
19:39OK, All right. Thanks.
19:41But typically in our studies
19:44where we use amphetamine or THC,
19:46we would see like ratings of field
19:49drug of 70 or 80 something like that
19:52or MDMA again it depends on the dose.
19:59OK. So then we come up with a
20:01challenge of what to measure.
20:02So we're we've got these threshold
20:04doses and and many of our usual
20:07questionnaires for measuring drug
20:08effects except for do you feel
20:10a drug effect overall are not
20:11designed for psychedelic drugs.
20:13And so we're struggling with
20:15what exactly to measure.
20:17And so someone has to
20:19design this questionnaire,
20:20the five dimensional altered states
20:22of consciousness questionnaire,
20:23which has these at least.
20:25For scales and and there are other
20:27versions of it as well which is
20:29a series of questions that appear
20:31to be sensitive to the effects of
20:33psychedelic drugs and so and and
20:35more sensitive to any of our other
20:37measures of acute subjective effects.
20:40So we in our other studies we use
20:42something called the addiction
20:43Research Center inventory or we
20:44use the profile of mood States and
20:46some of those things are just don't
20:48detect these really unique effects
20:49of the of the psychedelic drugs.
20:52So this is kind of new territory
20:54for us as psychopharmacologist.
20:56So measures like reports like I
20:58felt one with my surroundings or I
21:01experienced a touch of eternity.
21:04It's getting into territory that we're
21:07not used to measuring or studying.
21:10It's it's just such a subtle and and
21:13and abstract kind of conceptual experience.
21:16But as it turns out this people are
21:18able to answer these questions and we
21:20are able to quantify the the responses.
21:22So I I still struggle with the idea
21:25that how do you even for yourself how
21:28do you rate something like experience
21:31of awe or experience of inner peace.
21:34It's just it's just a real challenge
21:35to come up with and I and I think we
21:38as a field still need to work on that.
21:40What are we measuring and what are the
21:43the core dimensions of these experiences?
21:46But as it turns out, so this scale,
21:48this is scale can go up to 100.
21:50Oops.
21:54These are the ratings in that
21:56study of the zero, the low,
21:58medium and higher dose of LSD on these
22:02on 4 scales, experience of unity,
22:04spiritual experience,
22:05blissful state and insightfulness.
22:06The black bar on the left of each
22:09foursome is the placebo and then the
22:12rightmost one is the higher dose.
22:14And you can see that there is a dose
22:17dependent increase on ratings of
22:19these questionnaires on these scales.
22:22The the I've we've expanded the scale
22:25here so this only goes up to 20 and
22:28the scale itself goes up to 100 and
22:30when you give high doses of psychedelic
22:32drugs then they do approach 100.
22:34So these are very subtle,
22:36but at least we're seeing qualitative
22:39effects that are kind of resemble the
22:41doses that you see that the effects
22:43that you see with higher doses.
22:45So we did see detectable effects.
22:48You know again this is,
22:49I'm sorry this is very sensitive.
22:51The very lowest dose I'd have to
22:53say didn't maybe on insightfulness
22:55it increased in effect,
22:56but so it's but we're just a
22:59marginal dose effect there.
23:02OK.
23:02So that was sort of a proof of
23:05concept and and it was also a
23:08way to determine what doses we
23:10should use in our other studies.
23:12So we kind of went on from there
23:14and the the studies that we've
23:16done from there have been either
23:19at 13 or 26 micrograms.
23:21So the second study that I'll describe
23:23to you is 1 on the effects of LS,
23:26these low doses of LSD on
23:28brain response to reward.
23:30So one possibility that in is
23:32intriguing is whether low doses
23:34of LSD or other psychedelic drugs
23:36can alter brain function even at
23:38doses that produce minimal effects.
23:40So it could be that the reason we're
23:43not seeing anything on the subjective
23:45effects is or that we that it might be.
23:47It's possible that you could see
23:50some longterm beneficial effect
23:52on psychological function or or
23:54or feelings of wellbeing even at
23:57doses that that don't produce
24:00acute subjective effects.
24:01But then you're you're it's it's
24:03you're you're really taking a risk.
24:06And as a scientist in running that study,
24:08if there's no if,
24:09you see no effects at all,
24:10no physiological effects,
24:11no subjective effects.
24:12So we want to know whether that we
24:14could detect an effect on brain function
24:16even at doses that were produced,
24:17hardly any subjective effects.
24:19So we selected the brain reward signal.
24:22That's called rue P That's measured with
24:25EEG during the monetary incentive delay task.
24:28So in the Monitor,
24:29I'm sure you're familiar with the
24:30monetary incentive delay task.
24:31It's a it's a simple behavioral
24:33task where people get cues that
24:34either signal that they're going
24:36to have a win or a loss,
24:37and then there's some delay,
24:38and then they actually get a win or a loss.
24:40And there's a lot of interest,
24:41especially anticipatory,
24:42in their brain responses to the
24:45to the anticipation cue and
24:47then also to the feedback queue.
24:49It turns out that people who have depression
24:52have a smaller rupee by this EE G measure.
24:55And so we might predict that if this
24:58drug increases, makes people more
25:01sensitive to reward that we might see
25:04a larger rupee response even acutely.
25:07And so that's what we saw.
25:09So this is the brains signal.
25:12This is time in milliseconds after a a,
25:15a queue actually this feed,
25:17this queue happens to be the feedback queue.
25:19So it's the report that the the signal
25:22that people actually won something
25:24or lost something or that there was
25:26something neutral and the solid line
25:29here corresponds to the people's brain,
25:33the signal after the under the placebo
25:36condition and then the broken lines.
25:38First of all that the middle one there
25:40is the lower dose of LSD and then
25:42this one is the higher dose of LSD.
25:44And you can see that both the lower dose
25:46and the higher dose increase the brain's
25:49response to this receipt of reward signal.
25:52So that's consistent at least with this
25:56idea that the drug is affecting reactivity
25:59to reward basically at at a neural level.
26:03And so this is definitely something that
26:05needs to be replicated and extended.
26:09So we found here that the doses of LSD
26:13that are too low to be detected by
26:15selfreport measures could produce subtle
26:17and alterations as it happens in this study,
26:20the 13, both the 13 and the 26 micrograms,
26:23they did produce a little bit
26:25of subjective effect.
26:25So we still haven't,
26:27we still haven't shown that that there's
26:29a brain response at a dose where there's
26:32absolutely no subjective response.
26:33So that's still to be to be determined.
26:37Harriet,
26:37yes,
26:38you mentioned at the beginning
26:39that you use active controls in
26:41some of the studies and that would
26:42it was that done in this study,
26:44was there an amphetamine control or anything
26:48not in this study. But we have,
26:50we have looked at amphetamine on this
26:55mid task with EEG in a separate group
26:58of subjects and I don't think I have the
27:00results fully put together to tell you
27:07so. Then the other question,
27:08important question is whether these
27:10alterations in neural function
27:12are change with repeated dosing.
27:14So even if we don't see anything
27:15at this thing after a single dose,
27:17it could be that somehow gradually over
27:20time with repeated doses this changes.
27:23So the next study that I'll
27:25describe is a repeated dose study.
27:26This was a between subjects.
27:28So most of our studies are within subjects,
27:29this one's between subjects.
27:31So people were randomly assigned
27:32to either be in the placebo group
27:34or 13 or 26 microgram group.
27:36They got their dose on 4 separate
27:39occasions separated by three or four days.
27:41So session 123 and four are dosing
27:44days where they came into the lab and
27:46they sat there for four hours for I
27:49think it was four or five hours and
27:51got this either placebo or the drug.
27:53And then some number of days after that,
27:55I think it was a week afterwards or
27:57or four days after that they had a
27:59post test to see whether anything had
28:01changed as a function of receiving
28:03these four doses.
28:05Yes, I have a question.
28:07Yes, why did you choose just three
28:09to four days between sessions?
28:12Oh, because that's what people
28:13do when they micro dose,
28:15this is oh I see this is kind of modeling
28:17what people do when they're micro
28:19dosing that's exactly what they do.
28:21OK. But because you might expect that those
28:24effects of LST might last much longer on EEG,
28:28might last longer than three to four days,
28:32that's an interesting question.
28:36There's no evidence from our studies or from
28:39other people's studies that at these doses,
28:42the pharmacological, that there's any
28:44measurable effect or pharmacological
28:46effect left at three or four days.
28:49But you're right, there could be some
28:51lasting neural changes and that would
28:53be interesting to know that and how that
28:56changes across the four sessions, right.
28:58So the drug is certainly cleared by the
29:00three or four days that we were a little bit
29:02worried that there might be accumulation,
29:04but there's no evidence at all that
29:06there's any accumulation of drug.
29:15So we looked at both acute responses to
29:17the drug at each of the doses using mood,
29:20emotional reactivity.
29:21So having them look at emotional faces
29:23and looking at emotional pictures,
29:25we had lots of measures of cognition
29:28and go no go tasks, all kinds of
29:30things that are cognitive measures.
29:32And then we also looked at the
29:33lasting effects after the four doses.
29:35And this was without the drug present
29:37to see whether there were any lasting
29:39effects on any of these measures.
29:41This side summarizes 2 of the measures.
29:44This is depression.
29:45And then what's this other one?
29:47Vigor. This one is vigor.
29:49So sense of energy on the
29:51profile of mood states this.
29:53It shows their responses during
29:55each of the four sessions,
29:57session 1234 and I'm showing
29:59you here the placebo session is
30:01the open bar and then I'm sorry,
30:03the placebo group is the open bar,
30:05the the 13 microgram group is the middle
30:08one and then the darker one is the
30:13the darker one is the 26 microgram group.
30:16And this is across the four sessions.
30:18So you can see on session one we see a
30:21nice apparent antidepressant effect that
30:24is the highest dose compared to placebo.
30:27People show a decrease in depression and
30:29it's a little bit there on session 2:00 and
30:33basically it disappears by session four.
30:35And I should say also that their their
30:37ratings on these scales before getting
30:39the drug on the four days don't change.
30:42So there's no shift in the baseline
30:44of depression scores.
30:45But so we see a quite a pronounced
30:47effect on the first day that they get
30:49their dose and that that basically
30:51there's apparently tolerance to it or it
30:53dissipates across the other four sessions.
30:56That was also true for these
30:58reports of vigor.
30:59So people,
30:59this is a change score from pre from
31:01at the beginning of the session.
31:03Pre capsule or it's not a capsule,
31:06it's actually a liquid,
31:07but so pre drug to the highest point,
31:10it's a peak change.
31:11So it's the highest point during the session.
31:13So you can see there's a significant
31:15increase in vigor and that's there
31:17on sessions 1-2 and three and
31:20basically disappears by session 4:00.
31:22So we found that the first dose decreased
31:25depression and increased vigor,
31:26but that these effects declined
31:28with repeated doses.
31:29There were no effects on measures of
31:32creativity or psychomotor function,
31:33and there were no lasting changes
31:35on on any of our measures.
31:37So mood measures measures,
31:39responses to emotional stimuli
31:42or psychomotor effects.
31:43And we had a I think the measure of
31:46creativity was something like the
31:49some kind of associations task
31:51where they're supposed to come
31:53up with words that are related
31:55or unrelated to other words.
31:56Anyway, it's a standardized kind of
31:58word based measure of creativity,
32:01but we saw no drug effects on that.
32:06So this was a little bit discouraging
32:09that that we saw these effects at the
32:11beginning and the effects that we saw
32:13on that first session are similar to
32:14effects that we saw in the previous
32:16studies across all of our studies.
32:18But that it really disappears
32:19across the four days.
32:21We, I mean we might we could equally as
32:24well have seen the opposite that effects
32:27might emerge over repeated sessions,
32:29but they didn't, they declined.
32:32Yes. Sorry,
32:33quick question. Did you have
32:35any physiological measure like
32:37heart rate or blood pressure?
32:39And did you see a similar profile?
32:42And do you think this is
32:44some kind of tachyphylaxis?
32:47I should know the answer to that for sure.
32:49We had heart rate and blood pressure and
32:51I can't remember exactly how whether or
32:53how it changed across the four sessions.
32:55I'll follow up on it with you.
32:58But yes, it does seem to be tolerance,
33:02but you know tolerance can develop at
33:04different rates to different measures.
33:06So it depending on them,
33:07I'm sure you know, depending on the
33:09mechanism by which the drug acts.
33:11So it could be that there's tolerance
33:15to this, these CNS effects and not
33:17not tolerance to the heart rate,
33:19blood pressure effects.
33:19Anyway, I'll get back to you
33:21on that whether it was true.
33:22But there's another thing I want to say
33:24about these and and that's the the,
33:26the quality of the effects here
33:27and that that's that the drug
33:29effects are mainly stimulantlike.
33:31So the drug is increasing people's
33:33feeling of energy and vigor and
33:35we're seeing this across the studies
33:37and it could very well be that that
33:39kind of feeling and and the and the
33:41reports are not dissimilar from what
33:43we see when we give amphetamine
33:44a low dose of amphetamine.
33:46So it could be that that experience
33:48of kind of energy and vigor and and
33:51that that and sort of confidence
33:53that amphetamine gives could give
33:57the impression that people are
33:58performing better in their lives.
34:00It's kind of like a mild
34:02antidepressant effect in a sense.
34:03You know,
34:03I mean amphetamines were used as
34:05antidepressants for some period of time.
34:06So it could be that the,
34:08the,
34:08the reports of microdosing could
34:11be related to this a self report
34:13measure of feeling increased bigger.
34:17Going back to serials
34:19question about tachyphylaxis,
34:20there's a preclinical literature
34:21which I don't know as well as I
34:24should about the down regulation
34:25of 2A receptors after exposure
34:27to a classic psychedelic.
34:29And I'm wondering if there's any
34:30literature on the dose dependence of
34:32that and if there's any like if there's
34:34a potential mechanism there at these doses.
34:36I wonder if anyone knows that
34:38preclinical but like if that's
34:40been looked at preclinical
34:42there's it definitely there's LSD is
34:46reportedly there's there's clear components
34:48to many of the effects of LSD and I
34:50wasn't aware that that was related to
34:52down regulation of the two a receptor.
34:55You know we don't know for sure
34:57that these low doses exactly act
34:59on that and not on other receptors.
35:01So there's nobody's really had any
35:03particular interest in the very low doses.
35:06So, but that would that would be a
35:10reasonable to explanation and I guess
35:13you'd have to do some kind of pet study
35:15to really determine that in people.
35:17Some somewhat related to that,
35:19Rick Strassman did a study
35:22where he repeated DMT doses
35:24four times within a single day.
35:27Oh, and he failed to find any evidence
35:30of tolerance and tachyphylaxis
35:33really. Yeah, but it's specific to DMT.
35:36Sure, there is a,
35:37there is no tolerance to DMT.
35:39But with other psychedelics,
35:40there is some tolerance,
35:42Okay clinically reported by users.
35:47Okay. That's interesting.
35:48Yeah, So suggest different mechanisms.
35:53Yeah. But it hasn't been like
35:55super studied like it's more
35:56like about what people say.
35:58Yeah, right, right, right.
36:01Honestly, I don't know about
36:02the cardiovascular effect,
36:03the heart rate and blood pressure,
36:04whether that's mediated
36:05peripherally or or or through a
36:08twoway receptor or you know I just
36:10or or where or how that works.
36:12And so I don't know how I
36:14would interpret dissociation
36:15between the subjective effect
36:17and the cardiovascular effect.
36:21Harriet. Just to weigh in on my Harriet,
36:25it's Emmanuel Schindler.
36:27Back in the grad school I used rabbits
36:29as my subjects and with chronic
36:32administration of psychedelics,
36:34there were decreases of the
36:36serotonin 2A receptor but not
36:38the serotonin 2C receptor.
36:40We looked at some dopamine receptors as well.
36:42I can't recall right offhand what
36:44happened to the dopamine receptors,
36:45but there were differences.
36:47And at least those two serotonin
36:49receptor subtypes in terms of
36:51their other down regulation,
36:54well that suggests some ways to kind of
36:56look at this tolerance with different
36:58you in animal models with different
37:01drugs and looking at the at the
37:04neurotransmitter receptors regulation.
37:05That sounds great.
37:06That's interesting. Thank you.
37:09Somebody has to look do more with dopamine
37:11and the and the psychedelic drugs,
37:12I think because this really looks
37:14like a dopaminergic effect.
37:18All right. Study four,
37:20most recently we've looked at people.
37:22So we thought, well, after all these
37:25relatively negative kind of outcomes,
37:27maybe it's because our volunteers are
37:30healthy and maybe we would see something
37:32in people who report depressed mood.
37:34So we compared healthy adults to people
37:36who had higher than average scores
37:38on the back depression inventory.
37:40But they're still not, they're not far,
37:43they're far from clinically depressed.
37:45We just gave the,
37:46we have difficulty finding
37:47people who are really depressed.
37:49So we gave them the back depression
37:51inventory and we included people who
37:53scores of greater than 17 in our high
37:55depressed group and less than 17 in
37:57our low depression group and we gave
38:00them 26 micrograms versus placebo.
38:02So we wanted to know whether
38:04single dose of LSD would produce
38:06different effects in these people
38:08with and without depressed mood.
38:13And this is what we found.
38:14Interestingly, we did find that there was
38:16a difference in the subjective effects.
38:18So this is the low BDI group here on
38:21the the green is the low group and
38:23the purple is the high BDE group.
38:26This is their ratings of positive
38:28mood on the profile of mood states
38:30before they took the capsule and
38:32or the drug and then post so on.
38:34When they got placebo of course no change
38:36and when the healthy the when the low
38:39BDI people got LSD there was no change.
38:41But you can see over on the
38:43right that the high BDA group,
38:45BDI group first of all had lower
38:47positive moods towards to begin with
38:49which is what you might expect if
38:51they have high high depression and
38:53that the LSD preferentially increased
38:55improve their positive mood scores
38:58only in the high BD die group.
39:00So this is kind of interesting it
39:03suggests that the the mood effects of LSD
39:08might depend on the baseline mood states.
39:12There's there's no question of here
39:15of ceiling effects of course that
39:17the positive mood in the healthy
39:18people it's it's can go up to.
39:20I think I have got the scale from
39:22-10 to plus 10 here but it can go
39:24substantially higher than that.
39:25And in fact we a lot of other are
39:28other drugs that we administer
39:29amphetamine or alcohol or other
39:31drugs that that it clearly the drugs
39:34clearly increase positive mood.
39:35So here it was preferential
39:37to the high BDI people.
39:39So it's kind of interesting this
39:40to me this is the first evidence,
39:42it's kind of a just one small step
39:45forward that we are seeing some
39:47difference in the in the depressed
39:49people and this should be extended
39:51by someone to look in really more
39:54depressed people and to look at different
39:56doses and to look at repeated doses
40:00and this is their scores on the five DASC.
40:03Again, this is this experience of
40:04unity and spiritual experience,
40:06and again, we're seeing on this
40:08measure of psychedelic effects.
40:10That the high BDI group.
40:12So here the low BDI group is green
40:15and the high BDI group is purple.
40:18And you can the solid lines are
40:20the drug sessions and the hatched
40:21lines of the placebo sessions.
40:22And if you go start with the left,
40:24you can see that there's a small
40:26increase in experience of unity after
40:28LSD in the low BDI group and a larger
40:31difference in the high BDI group and
40:34then similarly in each of the measures,
40:37spiritual experience,
40:38blissful state,
40:39insightfulness and total FIDLSD.
40:42Then on on all of these the BDI,
40:45I'm sorry,
40:46the high BDI group seems to be more
40:48sensitive to the psychedelic effects of LSD.
40:51Very interesting and it still it's also
40:54remains to be seen whether there there's
40:57it's something about this population
40:59and their tendency to report internal states.
41:02So, so it could be that they're more likely
41:06to report or more sensitive to reporting.
41:08So we've never looked at this
41:10group of people with other drugs.
41:11So that would be an important
41:14comparison condition as well.
41:15Anyway was it's encouraging to us to
41:17see something like this where there
41:19is a different where there is an
41:21effect of preexisting mood states.
41:26So LSD may have more pronounced
41:28pronounced effect on certain measures.
41:29I should say interestingly that these this
41:33increased higher sensitivity in the high
41:35BDI group was not there on all measures.
41:37If you looked at their ratings
41:39of field drug effect that overall
41:41global they were identical.
41:42So they're reporting the same magnitude of
41:45drug effect but they have qualitatively
41:47different responses on the drug.
41:50So they they have uncertain measures.
41:52They reported greater drug effects
41:54needs to be replicated with patients
41:57with more severe symptoms and then
41:59we need to know whether it's related
42:02to other life events like early
42:04life trauma for example.
42:06And I finally,
42:06I just want to just go over
42:08this one nice study that Murphy
42:09at all has recently published.
42:11They actually gave LSD or placebo
42:14for six weeks, which is much longer
42:16than anyone else has done.
42:17They gave the first dose in the laboratory
42:20and then the subsequent doses at home.
42:22So, and that's useful because then
42:23you can look at the concordance
42:25between their responses in the
42:26laboratory and their responses at home.
42:28Interestingly,
42:28it turned out that the responses
42:30at home were greater than their
42:32responses in the laboratory.
42:33So it's something about the laboratory
42:35environment might have actually
42:36dampened the responses a little bit.
42:38They looked at safety,
42:39effectiveness of blinding and expectancies.
42:41They gave questionnaires and
42:43psychometrics and cognitive tasks.
42:46They found that acutely it increased
42:48self ratings of creativity,
42:50happiness and energy.
42:51Now this is again the the measure
42:53of creativity is as is just their
42:55own subjective reports.
42:57And so we don't know what that is.
42:58And it's been difficult to
43:00capture in objective measures.
43:02The effects were most evident
43:03on the first five sessions and
43:06they saw no adverse effects and
43:08they saw no lasting effects.
43:10And this is just one of their figures that
43:13the if you just look up at the top one,
43:15the top left one,
43:17this is daily visual analog scale
43:19measures and you can see how how
43:22much they felt connected or creative
43:25or energetic and that the red line
43:27is the control and then you can see
43:30and then the the the X axis is days
43:34and doses across days basically.
43:36So you can see that whatever
43:38effects there are,
43:39they are really primarily in
43:40the first say 3 or so sessions.
43:43So there's if you look over
43:45at energy in the top right,
43:46you can see there's an apparent
43:48increase in ratings of how energetic
43:50they felt and then that dissipated
43:52across sessions over time,
43:54how happy they felt in the bottom left,
43:56how irritable.
43:56That was a decrease in irritable.
43:59So you can see first of all
44:00there's a lot of variability.
44:01You can see that.
44:02And then also that the effects,
44:04they were subtle and they were
44:06not really very long lasting.
44:11And this is what they concluded.
44:12While microdosing elicited
44:14transient mood elevating effects,
44:15it was not sufficient to produce
44:18produce adhering changes to overall
44:20mood or cognition in healthy adults.
44:23So what can we conclude
44:24from all of these things?
44:25That LSD appears to produce mild
44:28stimulantlike subjective effects
44:30that decline with repeated dosing?
44:32There are no effects on objective measures
44:34of creativity or psychomotor performance.
44:37There is appears to be an increased
44:39brain response to reward,
44:40and there are more pronounced effects on
44:43certain measures in depressed individuals.
44:46Lots of questions remain to be
44:47answered to keep us all busy.
44:49Have we measured the right things?
44:51We don't know.
44:52We don't.
44:52One of the challenges is people are
44:55making all these claims and and we
44:57could easily be missing exactly the
45:00dimension that that the drug acts on.
45:02So we could be missing whatever it is
45:04that it does that improves people's lives.
45:07And are there other ways to
45:08measure the beneficial effect.
45:09So I think here we have to be creative
45:12ourselves to come up with new measures.
45:14Who benefits most from the micro dosing?
45:15So is it more people with
45:18psychiatric conditions or older
45:19people or men versus women?
45:22And we don't know the answers to those.
45:23How long do you have to use
45:24it to get beneficial effects?
45:26And it from the the limited data that
45:28I've shown you here and that we've seen,
45:30it isn't necessarily that more longer
45:32period of time has a better outcome.
45:35If if anything shorter period
45:37has better outcome.
45:38And then what is the role of expectations?
45:40We kind of bend over backwards trying
45:42to rule out expectancies to that
45:44are contributing to the effects.
45:46But of course they could interact
45:48with the pharmacological effects in
45:49the real world in a beneficial way.
45:51Really other questions what are
45:54the neural mechanisms underlying
45:56the effects and are there what are
45:58the relationships to the responses
45:59that people see with high doses
46:01of psychedelic drugs?
46:02So the high doses you just get a
46:04single big dose and then some over
46:06some weeks and months afterwards
46:08you have improved symptomatology
46:09and this does that work by the
46:12same or different mechanisms than
46:14these low dose effects?
46:15And is there any promise for
46:17low dose LSD as a medication?
46:21These are some of the people that
46:23contributed and most of them are
46:25postdoctoral fellows or collaborators.
46:26And the work was funded by the
46:29University of Chicago Institute for
46:31Translational Medicine. And that's all
46:37wonderful. Thank you.
46:41Any questions?
46:43Yeah, I do. I have many, Harriet.
46:45I'll keep it brief.
46:47The first one is did you attempt
46:49to measure expectancy in any of
46:52your studies and do you have any
46:54suggestions about how we might
46:56do that you know moving forward?
46:59I we didn't measure expectancies before.
47:01I'm glad you asked the question.
47:03We did ask them at the end of the
47:05sessions what they thought they got.
47:06This is from the repeated dosing study.
47:08This is the placebo group,
47:09the 13 and the 26 microgram group.
47:11This is sessions 1234 and
47:16we're not seeing your slides
47:18anymore. If you're trying
47:21doing lolly's talking for
47:22nothing, just a second.
47:26This is at least 1000 words in the slide.
47:28Just a second. Sorry about that.
47:32OK, now share. OK, now back up one,
47:36back, back up one. There we go.
47:37OK, what do you think you got
47:39placebo group 13 microgram.
47:41This is the repeated dosing sessions 1234.
47:43The red is people who said they
47:45thought they got a hallucinogen.
47:47So on the placebo group,
47:48these this number of people said they
47:50thought they got a hallucinogen.
47:51And then the Gray here
47:53at the bottom is placebo,
47:54the 13 micrograms,
47:55you can see that a few more people said
47:57they thought they got a hallucinogen and
47:59then the rest were all over the place.
48:01And then the 26 microgram,
48:03a few more said they got hallucinogen.
48:05So
48:08what they thought they were going
48:09to get before, they had no idea that
48:11we told them any one of these all
48:13these different possible categories.
48:14And after the sessions,
48:15this is what they said they got.
48:17And then the depression group,
48:19we did something similar.
48:21This is the high depression group.
48:22This is the low depression group.
48:24This is their. Oh, we've cut off the.
48:26Oh, here they are. Yeah. OK.
48:27This is their LSD session,
48:29their placebo session,
48:30and the black corresponds to
48:32they thought they got placebo.
48:33So not surprisingly on the placebo sessions,
48:36most people thought they got placebo.
48:38And here the hallucinogen is this blue.
48:41And so you can see this is a high
48:44BDI group and the low BDI group.
48:46So that's the number of people who
48:47thought they got a hallucinogen rather
48:49than a stimulant or a sedative,
48:50for example.
48:51So that doesn't exactly answer your question,
48:54but they didn't,
48:55they really didn't have expectancies
48:56beforehand.
48:56They had no clue what they were going to get.
48:59But did you look at the relationship
49:01between what they thought they
49:03got and what their response was?
49:05So in people who thought they got
49:07a hallucinogen, did they have
49:09a bigger response? And yeah,
49:11good question. And we haven't looked at that.
49:15We didn't. We haven't looked
49:16at that. We could. It's yeah,
49:21a related question. I you said that all of
49:23your participants had at least one previous
49:27experience, but do you have any
49:31data on what their attitudes were,
49:33whether that previous experience was
49:36life changing versus pleasant versus
49:39neutral versus lousy, whether that,
49:41whether that influenced their
49:43expected their expectancies? Here
49:46we don't have that information.
49:47I think if it was lousy, they would
49:48not have volunteered for our study.
49:50So there's obviously the big selection
49:51kind of BIOS here of who participates
49:53in this kind of study where we say
49:55we're going to give you something,
49:56we're not going to tell you what it is.
49:58So but it during the screening,
50:00the psychiatric screening interview,
50:01if they had said they had a bad
50:03reaction to any of these drugs,
50:04we wouldn't accept them.
50:09Hi, Harriet, I also have a lot of questions,
50:11but I will pick just one or two.
50:14I can't recall in the beginning
50:16when you had talked about the some
50:19of the evidence that people are
50:21out there micro dosing already.
50:23And I I I wonder, I can't recall are
50:27are these studies from from like
50:29recent times or have people been
50:31doing this since like the 50s and 60s?
50:34Have people been doing it for
50:36ceremonial purposes but for millennia?
50:38I just have a concern that that is a
50:41sort of a a novel new new thing that
50:44I'm afraid that the Netflix documentaries
50:46and such have sort of prompted.
50:48What are your thoughts on that?
50:51I think it's new,
50:52although as the years go by,
50:53it's not so new anymore.
50:55The Fadiman article was one.
50:57James Fadiman was one of the
50:58first people promoting it.
50:59And it must be now 20 years or something
51:01since he's been promoting that and
51:03and that it sort of caught on online.
51:05But it hasn't in the scale of things.
51:07It hasn't been very long.
51:10It sort of came from people
51:11in California, you know,
51:13and and and they talk to each other.
51:15I think that there's a real risk of,
51:19you know, placebo drug use from
51:21this kind of communication.
51:23But anyway,
51:24and is there any suggestion or
51:26any talk either online or in
51:28the literature that you're aware
51:30of of with with chronic use?
51:33In addition to to potential tolerance,
51:36are people having withdrawal symptoms
51:38if they stop or if they don't have
51:41access to their source anymore?
51:43Because this is very different
51:45from the typical infrequent use,
51:47I wonder whether tolerance and
51:49you know perhaps dependence and
51:51addiction and come about over the.
51:55That's a good question.
51:56I have not seen any reports
51:58of any adverse effects when
51:59people stop using again,
52:01they're used they're stopping
52:02of their own volition.
52:04So it's it's hard to know then
52:06how much their expectancies of
52:07experiencing something bad when
52:09they stop using the influences.
52:16Any question. Yeah, go ahead. Yeah.
52:20Thank you for this talk.
52:22My question is about why finally do
52:25we really want people to be blind
52:27about micro dosing why for the
52:31macro dose we never like criticize
52:34so hard that people will have
52:36a strong alicenogenic effect and
52:38that can also that it can drive part
52:42of the of the beneficial effects.
52:44Yeah what are your thoughts about it.
52:46Well it was part of the attraction of
52:49studying micro dosing that you could
52:51you could test its the pharmacological
52:53effects without having to worry
52:55about the confound of expectancies.
52:57So in in some ways that's the
52:59appeal as a as a researcher
53:04but why why did people come up with
53:07that idea that I I think it it
53:10really came from sort of experimental
53:12rigor that they really want to see
53:14if there's a a pharmacological
53:15effect independently of the of the
53:18identification of the drug and the
53:20possibility that people that their
53:21expectancies are influencing it. So
53:26somebody just introduced it as a as a
53:28necessary criterion and and I agree with
53:31you that that the beneficial effects
53:32might be there in this exactly the
53:35people who do experience something.
53:40That's right. There's this sort
53:41of vexing problem in the field.
53:44One is the technical one of how do we blind?
53:46But then there's the conceptual one
53:48of whether the concept of blinding
53:50is simply impossible to apply.
53:54If the dissociating dissociation of the the
53:58subjective effects from the effects is fun,
54:01is impossible and therefore that's just a
54:04miss a misapplication of an older concept.
54:06But I don't. I don't. I don't know.
54:07I think it's a big big. So I'm
54:12I'm kind of drawn to the model of
54:15Ssri's where the Ssri's, they don't
54:18produce any immediate acute effects.
54:20But somehow magically over time,
54:22you take them for several weeks
54:23and somehow the world looks
54:25better and people, you know,
54:26the social anxiety disappears And so,
54:28you know, ideally the low dose LSD
54:30would have worked something like that.
54:35Are you type of question
54:36at these very low doses?
54:37Can you speculate on whether
54:40the receptor binding profile and
54:43all the effects rather on these
54:46different serotonin receptors is
54:47different from what you might get
54:49at the typically higher doses?
54:52No idea. And I would love somebody
54:54to look at that. OK. So any of you
54:56who are binding experts do it.
55:02And one last comment you in your summary
55:05slide you had you know you raised a
55:08number of questions that we should pursue.
55:10And one of them that I, I,
55:13I thought you would have on your in your
55:16summary slide is that we don't know much
55:20about the safety of chronic administration,
55:22chronic use of you know
55:24these drugs at low doses.
55:26We know about very sporadic use
55:29and they're generally safe.
55:30But as Emmanuel keeps reminding me, we,
55:33you know methysagide was withdrawn from
55:36the market because with with repeated
55:38administration it was associated
55:40with fairly serious side effects.
55:46Good question. We haven't seen any sort
55:51of anecdotal reports of adverse effects,
55:53but then we might not,
55:55they might not come to the
55:56attention of the medical community.
55:58So I don't know whether anybody's looked
56:02at something like that in animal models,
56:05different systems where there would
56:07be adverse, you know, toxicity.
56:09So I it's possible.
56:11I don't know the answer.
56:14I know that there are groups who are
56:17trying to find congeners that have
56:20the least to be activity or trying to
56:23take out the serotonin to be affinity
56:26to make them theoretically safer.
56:30Even with methysurgide not everybody
56:32who was on it develop the cardiac valve
56:34fibrosis and and other tissue fibrosis.
56:36But there were enough that when it
56:39was widely used and and this was
56:41not found in the you know in this
56:43in the initial studies this was not
56:44something that was found was found
56:45later once it was used widely.
56:47So it may come it might come about
56:50later if and especially if more and
56:52more people start start doing it.
56:54Yeah right. Yeah good point.
56:56Something to watch out for.
57:05All right. Anything else? Well,
57:08thank you so much, Harriet.
57:09This has been really,
57:10really wonderful to get this,
57:12this overview of your of your
57:14groundbreaking work in this area.
57:15And well, it was a pleasure
57:17you all had. You had good
57:19questions and keep me thinking.
57:20And I look forward to hearing the
57:23results of what you're all doing.
57:25Great. Thanks. Bye. All right.
57:27Thank you very much.