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MDMA, Microdosing LSD, THC & Memory, Human Psychopharmacology | Harriet de Wit | #96

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Harriet de Wit 4:33

okay, well, I'm at the University of Chicago. I'm in a department of psychiatry, but I'm not a psychiatrist. I'm an experimental psychologist, and I've been here at the University of Chicago since I got my PhD several many decades ago. And I do research looking at the effects of psychoactive drugs of all kinds in healthy human volunteers under circumstances where they don't know what they're getting. So we do all our studies under double blind conditions. And we look, we tell them, they might get any one of a number of different classes of drug. And so I'm interested in how drugs affect human behavior and human experiences. And the research has mainly been funded over the years by the National Institute on Drug Abuse. So the main focus of the studies in the past has been drugs that have some potential to be used for non medical purposes. And only recently have I gotten interested, I would say in the last six or so years or eight years in drugs that well, it's it's interesting that these drugs that we're studying now,

were originally known as recreational drugs, and they're we're now discovering that they might also have some therapeutic effects. So I'm not sure what the question was, you asked me I think I probably already be answered, you asked me what do I do? I'm a, I'm a, I'm an experimental psychologist, I do studies with human volunteers and study behavioral effects of drugs. And so this change that you mentioned, you know, focusing on drugs with some abuse potential, and looking at that side of things, and then shifting focus to, you know, potential positive benefits of drugs, including drugs that we thought, you know, some people thought, you know, we're just recreational or just potential drugs of abuse, looking at them on the other side of the equation, what they might be used for in terms of like medical applications, which drugs are you talking about there? And what sort of prompted that shift.

It is a shift and I referred to it as a shift. We were really just, we were interested to know, what the drugs do to behavior. And I think what the drug that really got me interested to begin with was MDMA. So I have spent many years studying amphetamine and D amphetamine and methamphetamine in healthy volunteers. And MDMA is very similar in many respects to prototypic stimulants, but there's also something that's different. And I saw it as my challenge to see what it is behaviorally that's different about MDMA that gives it this reputation for having pro social effects or pathogenic effects. So it's almost as though some of the same effects behavioral effects of a drug might continue might support the non medical use as also supporting medical use. So it's not as though I'm making a huge transition. It's more I want to know how the drugs affect behavior. And that might be relevant in a in a therapeutic context, or it might be relevant in a in a more recreational context.

Nick Jikomes 7:51

And so, you know, for MDMA, you mentioned, I think there's probably a lot of people who don't realize what MDMA stands for that it is basically a type of amphetamine. So how is it different? Or in similar to, to just amphetamine? How does what makes MDMA different pharmacologically? And what kind of what kind of effects does it have that that something like speed does not have?

Harriet de Wit 8:17

I think the main differences is in the mechanism of action that that so D, amphetamine and methamphetamine act mainly on dopamine and serotonin, they act both as an or Coke, or cocaine for that matter, they act as they they release the neurotransmitters or they block the reuptake of the transmitters. And the distinctive thing about MDMA is that it adds preferentially more on serotonin receptors. So that's thought to account for the distinct effects of the two distinctive effects of the prototypic stimulants and an MDMA. That's what I've spent the last several years looking at trying to find out whether there are measures on which the two kinds of drugs are different than whether other measures that are the same. So they're the same in many ways. Both stimulant drugs and MDMA, other stimulants and MDMA, make people feel more social, they make fewer people feel more energetic, they make people feel sometimes more confident. Then if you get into ratings of dis, adjectives, how they describe how they feel when there's also a couple of adjectives that distinguish that that are true for MDMA, that increase with MDMA and not with stimulants are more than with MDMA. And one is a measure of loving, how loving Do you feel? And how playful Do you feel? So there you start both the amphetamines also show an increase there but the MDMA a little bit more than we've done. Do you want me to just get into the studies that we've done or do you want to wait and ask me question to direct me?

No, no, go go for it. If you feel like there's interesting studies that speak to what we're talking about now, just just jump right in.

So, when you think about what is empathy, for example, it could be, are you able to detect emotions in other people? Are you? Does the drug? Make you better able to see whether somebody's sad or happy? Or does it increase your response to the emotion and other people? Or does it make you just feel more social in general. So those are some of the studies that we've done. So we can look at, we can look at people's ability to detect an emotional expression in a face that we present to them. And so actually, MDMA increases the threshold for detecting anger and fear. So that means you need to show more of the expression of the facial expression for the subject to be able to detect the emotion correctly, compared to something like, happy for example, I see. So that's one,

Nick Jikomes 10:56

when someone takes MDMA, you're saying that if someone has like an angry face, someone on MDMA will, will be less likely to pick up on that, or the face will need to be angrier for them to pick up on it.

Harriet de Wit 11:09

Exactly. And so that kind of, we hadn't predicted that we didn't know that. But that kind of behavioral process could account for the drugs use both in non medical uses in like in, in social settings, where if you if you're interacting with strangers, and and somehow, you know, when you're interacting with strangers, you're always afraid of being judged or, and so if this drug decreases this perception that you have other people judging you or being angry at you, and if it decreases that, then it might make it easier to socialize, for example, so it might help if you're in a in a, you know, bar or raves situation where you're taking the drug and and it helps you to overcome any constraints that you might have, because you're feeling judged, or you feeling that somebody, there's whether there is or is not an angry expression, that you're, it's your perception of it. But then on the other hand, even if now they're using it in psychotherapy, and it could be even in psychotherapy, that there you have to make yourself very vulnerable. And you have to interact with a therapist. And again, if you if you are less sensitive to any perceived negative expression in the therapists face that make it make it easier for you to reveal things. So that kind of phenomenon might that kind of behavioral process might influence both recreational use and medical use. And so extensive,

Nick Jikomes 12:35

yeah, so in addition to, to making it harder to pick up on like these negative cues, and these negative emotions, MDMA is also you know, because it's an amphetamine, it is also having a stimulating quality on top of that, right?

Harriet de Wit 12:50

That's true, that's true, and increases feelings of well being and energy and makes you more focused. So it's doing all those things that amphetamines do as well. One other study that we did not too long ago was looking at pleasantness of social touch. So it turns out there, there are many MDMA users claim that their sense of touch is improved. And they and that somehow makes the drug more pleasant. And so it turns out, there's a standardized measure of pleasantness of touch, if you stroke somebody's hand, we use a brush and you stroke it at one rate, it's considered to be social touch, if you do the same stroking, but do it faster. It's not social touch. And this has been there's a whole there's a whole discipline on this sense of social touch. And we want to know whether the MDMA would increase this pleasantness of social touch, and MDMA does in a dose dependent way. So the higher you give the drug, the more pleasant the social touch was, and methamphetamine didn't do that. So there was an interesting one where there's a distinction between a methamphetamine and the MDMA.

Nick Jikomes 13:58

So even though they're both stimulants, and they're both probably changing thresholds for basic sensory detection, there is the specificity to MDMA for social touch that that isn't enhanced by a regular amphetamine.

Harriet de Wit 14:12

Exactly, exactly.

Nick Jikomes 14:13

And when you say dose, when you see dose dependent here, can you talk a little bit about the doses that you're talking about? What kind of doses do you use in your studies? And how does that compare to what people are using out in the wild so to speak?

Harriet de Wit 14:27

Yeah, right. We have used doses sometimes we give the dose by bodyweight. So that's point seven five milligrams per kilogram of body weight at or so point seven, five, and the highest we give is 1.5 milligrams per kilogram. And that's a substantial dose that's a that's about as high as most people would want to go in an in a recreational setting. Right now we're doing studies with just a fixed dose just because it's easier we're giving 100 milligrams and that's used in a lot of other studies as well. So how does it make Make them feel it. It's, I don't know how to describe it, I guess, I guess some of the effects are really just detectable if you have these subtle behavioral measures, looking at responses to emotional stimuli, and so on, I think for the immediate effect is really like a stimulant in many ways.

I see. And so you mentioned that there is this effect with MDMA, where it's harder to pick up on these negative emotional cues that people might give you, you know, looking at an angry face or something like this, it becomes harder to detect that so you're less you're less inhibited, or you're less, you know, affected by by those negative qualities that you might perceive in other people's faces. Is the flip side also true? Does it become easier to detect positive emotions or do people?

That's a good question, we have an In one study, we found a decrease in the threshold of detecting, detecting happy, and in another study, we didn't. So that's it's it's, the review is mixed on that one. I see.

Nick Jikomes 16:09

So maybe there's some enhanced ability to detect happy faces or whatever. But but it's unclear. But definitely what's happening, it seems, is that you're, you're less inhibited, you're less encumbered by the negative aspect that you might pick up. So you're sort of dis inhibiting people in a sense.

Harriet de Wit 16:27

Exactly, exactly. And it's actually working on your ability to detect. So it's not even your response to it. It's you just don't you don't see it. So it's a it's a very basic kind of perceptual process. Interestingly, when you asked a little bit about how MDMA works, the the effect on serotonin is also thought to result in an increased release of oxytocin. So oxytocin is a bonding hormone that's involved in Mother Child bonding, it's also involved in bonding between men and women. And MDMA, especially at the higher doses produces a significant increase in plasma levels of oxytocin. So it's tempting to think that it's the oxytocin, that accounts for this. So it's, it's the effects that we see can easily be foot fit into a kind of schema of feeling more connected or feeling more bonded with and socially in which what might you might want with mother child interactions, whether it's actually related to the oxytocin remains to be determined, there could be other actions of serotonin, for example, that could have the same result.

And, you know, you mentioned that you're using, you know, in the ballpark of 100 milligrams, which is, you know, roughly speaking, it's a full dose, it's a dose that someone would choose to take in a recreational setting, it's a dose, approximately that that is used in a lot of studies. There's this phenomenon now with psychedelics, in particular of micro dosing, the idea that you could take very small amounts of something that has very little or even no discernible psychoactive effects, then maybe it'll have some some beneficial effects, despite the fact that you're your sub threshold for the psychoactive effects. Have you done that? Has anyone done with MDMA at all, where they look at like, lower doses or I think, yeah,

it's a good question. I don't know of any scientific studies that have done I've heard him, but as we sort of just anecdotal reports, and I haven't seen any studies that have done that, basically. Yeah.

And, you know, sticking with MDMA just for a minute, one thing I want to ask about is, how much is too much do we know anything about, you know, toxicity, cytotoxicity, or neuro toxicity that can come from MDMA, either by taking too much or by doing it over a number of years? Does it cause any damage?

That's a really hard question to answer. I think any drug that you take on a very regular basis at high doses is going to produce damage. So, you know, not recommended that there was a controversy some maybe 20 years ago now, about neurotoxicity of MDMA in particular, it hasn't held up that much, it's not doesn't seem to be that different from other stimulant drugs that you also shouldn't take in high doses on a regular basis over a long period of time, so so that it had a reputation for neurotoxic effects it hasn't, hasn't completely held up.

Nick Jikomes 19:22

And when you give, you know, when you give 100 milligrams, give or take in a experimental setting, one thing that people often talk about in recreational settings is, you know, they'll go out to a party or whatever, they will be taking MDMA. And sometimes at least some people report that the next day they kind of feel depleted, like they feel a little bit depressed and they attribute that to like, you know, all of their serotonin kind of getting used up and needing to be replenished. Do you observe that kind of thing in experimental patients when you give them MDMA?

Harriet de Wit 19:56

We have looked for it and a number of other people have looked for it and we don't see it. Some people call it like the Monday morning effect or Tuesday morning effect or something. Of course, there's a lot of other things that happen on Monday morning, after you've had a weekend of partying. So I'm skeptical that I mean, I think yes, if you took it in high doses for a number of days in a row, then you'd be just like with amphetamine, you'd be exhausted at the end of that. But whether there's a really predictable dip in mood, we haven't seen it, we have asked our subjects like 24 or 48 hours later how they feel, and they feel just fine. So now we're talking about a single dose at a time. So it could be that people are taking much higher doses in their party situations.

Nick Jikomes 20:38

Yeah, I mean, that makes sense to me. I mean, you guys are giving, you know, lab grade tested, MDMA that, you know, is pure, you're giving it at a very well specified dose, you know, one time so to the extent that that phenomenon is true, you're saying it's likely that people are taking too much, or they're taking it for multiple days in a row, something like that.

Harriet de Wit 20:58

Or they're not used to getting up to go to work in the morning, or they took a lot of other drugs, they drank, they didn't sleep enough, they didn't eat enough, you know, a lot of things are happening.

Yeah, yeah, that makes sense. And so I know that you've done some work recently to looking at psychedelics like LSD. So how long? Have you been looking at psychedelics? And what are some of the major research questions that your lab has started to grapple with? Recently?

The only studies I've done have addressed this question that you just raised about micro dosing. So I haven't done any studies with full dose of LSD. I was curious about micro dosing, because there are so many claims, so many people claim to be using it and benefiting from it. And the claims are very diverse. I mean, people claim so many different things with micro dosing, they can't claim, you know, physical, athletic performance, leadership, antidepressant, anti anxiety, pain, really, they just in every part, you know, marital improvements, all kinds of things, a couple, you know, so I'm set up to do studies under double blind conditions. And we're talking very low doses. And I thought, this is something I could do, I could look at what these very low doses do with the most sensitive possible measures under completely double blind conditions, because you just have in the, in the real world situation, we have no idea how much of it is expectancy, nobody does micro dosing or takes drugs, in any case, without having some sort of expectation that it's going to have some beneficial effects. So I think that's kind of what I do I study that just the purely pharmacological effects of drugs. So we started out just kind of seeing what kind of dose we might give that might be testable. And it turns out to be it's very challenging, for several reasons. One is if you if you don't see any effect at all, with micro dosing, if there's no self reported effect of the drug, then you don't know if you're high enough. And whether you're doing anything, if you do detect an effect, then you might be so high that expectancies kick in and then whatever they thought that was going to happen, influences their their results. So it's a very tricky thing that you have to find a dose that you think is just below what might be a detectable effect. The other thing is that people vary a lot in their sensitivity to LSD. So some people, you need a higher dose to see any effects. Some people report effects at very low, lower doses. And we have wait, we can't predict that ahead of time. Some of that has to do with the absorption and what they call pharmacokinetic properties, like how much of the drug gets to the brain. And some of that has just to do with differences in sensitivity to the drug. So it makes it a very, very challenging topic to study. But we went ahead and did it and we tested doses of six and 13 and 26 micrograms. The dose that people use to really trip is 100 micrograms, or 200 micrograms. And so we're the micro dosing range is around a 10th of that, basically. So we started looking at, we looked at some EEG measures, we looked at some brain activity with fMRI, we looked at how it makes them feel. And so it produces effects. As you might expect, as you increase the dose, there's more and more kind of psychedelic perceptual kinds of effects. We don't, but the main subjective effect that we really get from the low doses is a feeling of stimulation, so that that increases ratings and how vigorous they feel. There's a little bit of antidepressant effect as well. But in our most recent study, we gave the drug on four occasions. So we gave the drug first just on one occasion to kind of select a dose and then in a separate study we gave, one group of people got four doses of placebo. One group of people got four doses of 13 micrograms, and another group got four doses of 26 micrograms, so we wanted to see whether there were lasting effects and whether the effects changed over repeated doses. The effects did change over repeated doses. They became smaller. So that's consistent with what they call in pharmacology tolerance. But just so you see an effect on the first session, and then less and less and less as with repeated sessions. So we saw that for anti decrease in in depression, and we also saw it for increase in vigor, so a feeling of energy, but by the fourth session that wasn't there anymore. We measured all kinds of emotional responses, cognitive responses, we measured things after the four sessions. And we really saw nothing else other than those things. So at these doses in these people for this number of sessions, we didn't see any support, strong support for the idea of micro dosing improving anything, but you know, we never, you just don't know whether maybe you didn't have the right people, maybe you need to get really depressed people to start with, maybe we didn't have the right outcome measures, maybe we didn't measure exactly the right thing that would detect the effect, maybe there's a lot of variability across individuals and what they feel. And so we wouldn't get that with standardized measures. We had, I think, 18 or 19 people in each of our three groups. And maybe we didn't go long enough. So that's another possibility. Maybe you have to do it for three months in order to see an effect. So yeah, go ahead. I

was just gonna ask. So what kind of people were in the study? Were these people that had past experience with psychedelics? Were they sounds like they were not people with major depression or some other psychiatric condition? What were the what were the inclusion criteria?

Yeah, sort of a middle ground, I didn't want to be the first person to give these people LSD. So we selected people who had at least reported ever having tried some kind of either MDMA or, or a psychedelic of some kind. So that was one thing. And a lot of them, a lot of people have tried them once or twice, and so to not have an adverse response. We also tried to get people who were high on self reported feelings of depression or anxiety. So we got people who were high on a questionnaire measure of negative mood states, because we thought the drug might improve that, it turned out that all three of our groups, whether they got placebo, or or either of the doses of the drug, all three of the groups improved over time. So the placebo group improved just as much as the drug treated groups

Nick Jikomes 27:13

I see. And I guess this is the entire point of doing these double blind placebo controlled studies is, so what you're saying is the people who got micro doses of LSD, either 13 or 26 micrograms, they did report a mood boost, but the people who got no LSD also reported a mood boost.

Harriet de Wit 27:28

Yes, yes. And this is a phenomenon that's plagues, a lot of psychiatry, pharmacological research in psychiatry that there's this large, sometimes they call it a placebo effect. I don't like to call it that, because it can mean so many different things. But at least patients who enroll in in a in a treatment study where they get some attention, basically improve over time anyway.

But something was happening, because you said that there was this tolerance, you saw session by session. And that was the sort of the invigorating effects that people were reporting, how much time was between sessions?

Three to four days.

Nick Jikomes 28:04

I see. Okay, so that makes a lot of sense. So three or four days between sessions, and with each session, he basically saw some, some drop off in that effect that LSD was having at those low doses.

Harriet de Wit 28:17

Yes. And, and, and tolerance has been often reported with LSD. So it was not at some level, it was not a surprise. But we didn't know we didn't know whether something might emerge with repeated doses. It could be also that there's some accumulation of drug and so something might appear that wasn't there in the first session. So we didn't know.

And, you know, there's this question of, you know, the subjective side, how do people say they feel when they take a drug or they take a micro dose of LSD in this case? There's also objective measures that don't depend on the self reports of these people, did you look at any objective measures of things that were changing in the brain or anything?

In that study, we didn't look at changes in the brain, we did these behavioral tasks, like the task I mentioned, where you detect emotions in people's faces in in faces, I didn't change that. We did a number of cognitive tasks like go no go performance and brief memory tests. And a couple of we did a whole battery of different tests because some people claim that they that they have improved cognition when they're microdosing. Now that that impression of improved cognition could also come from this kind of increased in increase in vigor and arousal and alertness that people the our people reported in the first couple of sessions. So, you know, there's some drug effects could lead people to interpret it in some way, in a way. So

I see. So basically, so for the doses you looked at or for sessions, 13 and 26 micrograms, roughly speaking, this is you know about a 10th Give or take of what someone will take and record Rational setting to have a full psychedelic trip on LSD. And you're not seeing anything obvious in terms of cognitive or perceptual effects, correct? Correct. Right. Um, and then you did these other studies that that I took a peek at where you were looking at brain activity. So was when you look at the brain activity of people taking micro doses, do you see any detectable change that the drug causes?

The only studies we've done so far have been with a single dose of the drug. So most recently, we used a measure of something called it's called evoked potential, it's what the brain does immediately after you it receives a signal. And there's when it receives a sort of an unexpected reward, there's a particular signal that the brain has. And this particular signal is dampened in people that are who are depressed. So it's, it's thought to be a measure of reward sensitivity. And accordingly, people who are depressed have a dampened one of this. And the LSD in our study increased that reward signal. So suggests that it increased the brain's responses to an unexpected reward. So that's, I guess, consistent with an increase in feeling of well being, we only did it with a single dose. It's also consistent with this feeling of stimulation and increased vigor and things. So kind of an energizing feeling.

What was the dose that you used for that 126 micrograms? That was 26 micrograms,

single dose or 26? micrograms? Yeah. So it, I guess it remains to be seen. And I think other people are doing that if if you administer the drug repeatedly over an extended period of time, whether there are lasting changes, that might look like antidepressant effects, and presumably, somebody else will be doing that.

So So in other words, you have a non invasive way to measure brain activity. So you're, you're measuring brain activity, you're you're putting people in an experimental situation where you can detect the response the brain has to some kind of reward. And this response, this particular response that you measure is higher when you give 26 micrograms of LSD. Yes. And when you give the 26 Micro dose of LSD, are they in that such they have this heightened reward response? Are they perceiving that they have gotten the drug? Do they realize that they have gotten the drug? Or is it is it causing undetectable psychoactive effects for the person?

That's a good question. And I'm not sure we've looked at it quite in that way. I would say that of the 24 people that were in that study, some people probably identified the drug correctly, and other people didn't. And I don't know whether that brain response was highly correlated with whether they detected it or not. And that would be an interesting question to look

Nick Jikomes 32:58

at. I see. So I'm So on balance, like what you know, so you've done this research, Has any one else looked at micro dosing LSD or psilocybin? And if so, what are they generally find do they generally find results kind of like what you've seen where the cognitive and perceptual changes are minimal or absent or to have other people found things that that are impacted by microdosing.

Harriet de Wit 33:24

The, the studies that have been the largest and, and kind of best designed in some way, have used what they call citizen blinding. So they let people use their people who this The subjects are people who are micro doses anyway. And they somehow the experimenters arrange for the subjects to blind their own doses so that they don't know whether they're getting active drug or placebo. And again, there they have, and then they arrange it so that the subjects get some of what some of the subjects get placebo threw out, some of them get a low dose throughout, and some of them get a higher dose throughout. And there they saw some beneficial effects, but only in the people who correctly identified the drug as the psychedelic drug. So they said they could not rule out expectancies from that. So they weren't that was specifically what they were interested in whether there were any effects, if people were not able to detect it, and and they basically all their account, their results were accounted for by people who correctly identified the psychedelic, and they were micro dosing and they were using their own drugs. So there's a bias there for you know, for people to support their their expectations. Now, the there is a possibility that there are beneficial effects, but you need some kind of detectable effect in order to in order to achieve them. So I don't know how to solve that problem. So on the one hand, the detection can invalidate the results, because it can be then it can be attributed to their expectancies, but on the other And it might be that you need a little bit of a detectable effect in order to get the beneficial effects. So I don't know how to resolve that one. And this question of blinding drugs in Psychedelic Studies is haunting the field right now, especially with higher doses worth impossible to blind them.

Yeah. So but with these, so one thing that strikes me is, these low doses of these micro doses of LSD have the sort of stimulating invigorating effect, even though they're not causing full blown psychedelic effects? Is it possible to use like an active placebo to give people like a little bit of amphetamine or something so that they're not sure if they got? Like, how is that possible? Has anyone done that?

That would be that would be a good thing, that would be a good thing to do. That would be an interesting, good thing to do. You know, amphetamine, also, it used to be used as an antidepressant. So you have to be careful with something like that. If you give repeated low doses of amphetamine, that might have some pharmacological effects in itself.

I see. Yeah. But I guess Yeah, but the basic idea would be, you know, for the for those listening that aren't familiar, instead of like a regular placebo, where you're giving someone nothing like a sugar pill or something, you actually give them, you know, one group, the drug, in this case, it would be your micro dose of LSD. And then the other group gets an active placebo. So it's actually another drug that does have some detectable effect, but it's going to be distinct from the drug use and studying. And that that sounds like maybe it's a way to tease out some of these difficulties.

Yeah, definitely, if you could come up with the right control drug to do because, again, you don't want a drug that that might have a beneficial effects. You want something that just produces that it's just, it's just hard to come up with a drug that that would really not be expected to have any antidepressant effects in itself. If you think about caffeine, well, I might have anti depressant, and Fadiman that might, so it's hard to come up with something

Nick Jikomes 36:54

I see. And so basically, I mean, is it fair to say, you know, based on the EEG studies you've done based on these other studies that you've done, those microdoses are doing something they're having physiological effects, we know that some of these EEG signals that you're measuring from the brains of these people are changing, but there's been no clear sort of bonafide cognitive or perceptual or emotional benefit. That is clear, meaning that you can rule out Expectancy Effects.

Harriet de Wit 37:25

Correct? That's right. That's kind of where we are right now. So there could still be something there and and we haven't been able to detect it. You know, one of the things I thought I'd when I first started doing this research, so LSD also has its primary effects on serotonin. And antidepressant drugs, also act on serotonin. And for the longest time, when you first start taking antidepressant effects, they don't have any detectable effect. And somehow over a period of weeks or months, as you take the drug, the your your symptoms somehow are alleviated. And I thought so that's in theory, then I thought LSD, a very low dose, CT might be doing something similar. So if you gave something that was sub threshold that people couldn't even detect, and you gave it over a long period of time, then it might have an antidepressant effect, not unlike the SSRIs. So that was kind of I thought that was from the point of view of mechanism of action there that there was some reason to be optimistic. And it still might be it still might be something like that.

I see. Yeah, you would just have to do a more long term study where you were giving LSD repeatedly over probably weeks or months even. Right. Is there any research on there? Is there any concern there about micro dosing something like LSD chronically?

Not to my knowledge, it's a quite a safe drug. I mean, just to my knowledge that I don't see any obvious cardiovascular problems or toxic neurotoxicity or anything like that. So, you know, if you've got an audience, I wouldn't recommend that anybody do it, partly because they can't. It's so hard to get pure drug, that anytime you have a drug that you've gotten from a source, you're not really confident it could have other constituents in it. So I would be worried about that.

Yeah, I mean, one thing that other people have talked to me on the subject about is, you know, on the one hand, most of these classic psychedelics LSD, psilocybin DMT, they're very safe from the perspective of like toxicity, they don't really cause cellular toxicity or any damage in that sense. But one thing that people have alerted me to is, you know, the psychedelic effects come from the serotonin to a receptor, but apparently there's this other serotonin receptor to be and it's expressed in the heart and other places. And I get I forget the name of it, but there was some prescription medication back in the day, that was a serotonin to be agonist an activator of that receptor. And I guess that drug About I don't remember, that could have been. But anyways, this drug got pulled because it was causing heart issues heart valve issues that were dependent on this five inch T to be receptor stimulation. And no one has shown I don't think that that happens with psychedelics, but their concern is because LSD and psilocybin I think also hit that receptor, that that's at least a possibility.

definitely possible. And I should be careful, careful when I say drug is safe, completely safe? Of course, we don't know.

Um, so what other things? What are some of the other things that your lab is working on right now that are really interesting.

Let's see, one of the things I got kind of interested in MDMA has to do with the social effects of drugs. So usually, when people when we study drugs, we study the participants alone. And yet the the main effect of the drug is a social effect. So we've gotten into studying, we did it, we just finished a study and it's been submitted now for publication on the effects of MDMA, on feelings of connectedness. So we had subjects we gave them MDMA or placebo. And when they had to have a conversation with another, actually, it wasn't another it was a Confederate wasn't another participant, they had just a casual conversation over 45 minutes. And at the end of the 45 minutes, they rated how meaningful the conversation was, how connected they felt, how close they felt, and how much they liked their partner. And the MDMA significantly increased their feeling of connectedness and their liking of the partner, then, maybe, unfortunately, we went on and did the same study with amphetamine with methamphetamine. And it did exactly the same thing. So it made people feel more connected with their partner, they liked them more, they thought the conversation was more meaningful. So that was kind of, you know, it's it's one of these things we might have just stopped with, with MDMA. And it would have confirmed our beliefs, our pre existing beliefs, that there's something that this is unique to MDMA. But then I thought it was also important to show that we could do that the same effect occurred, an impediment does make people more social. And so but this is just it was interesting to us. So,

yeah, go ahead, go ahead, good.

I'm just interested in other aspects of how drugs affect social interactions, you know, it hasn't been studied very well. So we're thinking about doing the same thing. Now with alcohol, again, alcohol tends to make people feel more connected with each other. And then it also gets really complicated, because it depends on what the other whether the other person is also intoxicated. And we've done a little bit of that with MDMA, giving it to people, either alone or with another person, or with another person who's also under the influence of the drug and see what how that changes, it gets really complicated, because it's such a bi directional thing, that the experimenters we don't have a lot of control over how they're interacting, how they're responding, the other person is responding back to them. But clearly, I mean, that's it's, it's, it's important. It's, there's some sort of interaction between the therapist and the patient when the patient is under the influence and somehow that the drug is affecting the interaction. And so I think there's a lot there to be learned.

And what do you make of so I think, you know, MDMA is in phase three clinical trials now for PTSD, are you are you hopeful that it's going to pass through that and sort of be used as a powerful new new tool for treating things like PTSD and other conditions in the context of psychotherapy,

learning is very promising that it's gotten as far as it has, and, and it would be wonderful if it can be captured and incorporated into psychiatric practice. You know, everybody feels that we have to step very carefully. And I think that's true that it doesn't get misused or misdirected or used in ways that then could counter all the progress that's been made. So I think if it holds up, then that would be great to have another tool.

And so how, how has it been like over the past few decades working with controlled substances like this, has it become easier to get the research done? Is it still very difficult for you? Do you have to like get a lot of approvals like like, how easy is it to like, do studies like this where you're working with schedule one, or other scheduled drugs?

I think once you've gotten some approvals, and once you've established yourself as a credible, you know, scientific lab it the the issues are mostly surmountable. So you know, I'm quite conservative in what I request from either the institutional report or review board of my institution or the FDA or the DEA. I don't I don't ask for a lot. I don't think I mean, I'm just I'm quite conservative about it. So. So and these, the the regulatory agencies work with you to try and solve, make things happen. So I don't see them as being a big obstacle. I would say the one exception where I've had to not do the work has been cannabis, that that there, it turns out was very, it was very difficult at the federal level, but then they changed the rules that had to you had to get state approval, and that became insurmountable. So I didn't do any more work on I do a lot of work with THC, the pure THC but not with cannabis for that reason.

I see. And when you get these drugs to do your studies, where do they actually come from? Like, are there government labs that synthesize and provide these? Or where does it actually get manufactured? Where does it come from, and get tested and all that?

comes from a credible pharmaceutical company. And again, I don't use very large quantities, and I got the drugs quite a while ago. And so they've lasted me for a while. It might be more complicated now.

I see. So what kind of research have you done with cannabis or with THC? In particular? Have you done similar studies to the ones that you described for like MDMA? And other things? Or have you looked at other stuff?

Yeah, we've looked at effects of MDM of THC on memory, either memory, consolidation and memory formation, and then memory retrieval. So that was a whole series of studies. We've done THC in most recently in in late adolescence versus young adults. And it turned out the at late adolescence, so 18 year olds were a little bit more sensitive to THC than were the people in their 20s. So that was looking at age related effects. And we've done some of these reward related tasks with with EEG with THC, as well. So again, we're interested in how the drug acts on the brain, we're interested in how it changes behavior, we're interested in how people differ in their responses to the drug. So some people like THC and other people don't like it. And that's one that's very strongly influenced also by expectancy. So if you give people THC, and you don't tell them at all that it's having has anything to do with cannabinoids. They really don't like it. If you tell them it's an active ingredient in cannabis, they like it.

Interesting. So the same people will say I like it or don't like it, depending on how was two

separate groups, one group, one group, we told them, it was they were, they were likely to get a drug that that was an active constituent of cannabis. And the other group, we told them it was going to be any number of a number of classes of drugs, including antiemetic. I think we called it so

Nick Jikomes 48:01

interesting. And like, does that kind of thing influence? Like the cognitive effects of THC? So for example, do the effects it has on things like memory depend on whether the person likes it or doesn't like it?

Harriet de Wit 48:16

Good question. Don't know the answer to that? I don't know the answer to that. It would be testable with our data. So I don't know.

Yeah, interesting. Because, you know, I could imagine that there is an effect there are a lot of people say that, you know, they take cannabis and it helps them do. Whatever helps them do their work helps them focus, then, of course, a lot of people report exactly the opposite. I wonder if there is some kind of interaction that are based on how pleasant the sensations are for people

who could be couldn't be?

And what what do you find generally for the effects on memory? Because, you know, I know that it depends a lot on what exactly you mean by memory, right? And how much of the drug that you're giving. So like, you know, how memory is affected in the moment while you are on the drug? Versus does it affect your ability after that, when the drug is out of your system? What are some of the results you generally found with respect to th is influence on memory.

If you give the THC while people are learning some material, it significantly impairs their their ability to remember it sometime later. If you give it to them only at the time of retrieval, then it can increase their false alarms. So they'll they'll they'll endorse items that they didn't see before. So it can it doesn't impair the memory of what doesn't kind of overall dampen their memory of what they learned, but that you just get more mistakes, basically. So that's probably the main thing. We've looked at it during encoding and during consolidation, and then during retrieval, so there there are definitely more nuances there to the data, those THC memory studies that I can't really go into details here?

I see. And when you do those kinds of studies, you said you're using pure THC. I want to ask about dose again. So in those studies, what kind of doses are you using? And how might that compare to you know how much THC is in a joint or something that people out in the world are using.

We use doses that are available in capsule form 7.5 milligrams and 15 milligrams. It's hard to compare to smoked cannabis, because the the, as I said, the pharmacokinetics are very different the drug is when you smoke is absorbed more quickly. And so then you get higher concentrations in the brain at a faster rate. Whereas when it's taken orally, it's absorbed much more slowly, and you overall probably get lower brain levels. But people feel pretty high even with the 15 milligrams oral and and we've had problems going higher than that. So no, we're not, we're not setting very heavy users. So that's another thing that their, that their prior history probably influences their responses to drugs, and we're studying relatively light users. So going to higher than 15 milligrams makes the drug and that people report unpleasant experiences anxiety and nausea, and they don't like it.

And, you know, what are some of the like the major, you know, questions that you think are outstanding, in terms of I want to go back to psychedelics and micro dosing or macro dosing? Are there any new questions that you guys are investigating to build on what you've done already, or things that you're working on or about to work on moving forward?

I don't think so I can't think of any, we're kind of trying to fill in some gaps. We're doing some more studies with people who are more depressed and low doses of LSD to see but there, we're just looking at single doses with EEG again. But again, we we were worried that maybe we didn't get depressed enough people. So now we're extending that with MDMA, again, kind of more of the same using E, EEG and different different kinds of tasks in the EEG. So what are the burning? What are the burning questions? You know, a lot of the questions are just they're, they're difficult to do. So those things like longer term studies, or studies and people who are really troubled, who have serious psychiatric disorders, and that might go on for months that they're huge undertakings, and I'm not going to go and leave them to somebody else to do

I see. What do you make of this whole phenomenon of, you know, psychedelics, just seeing this big resurgence? And all, all the promise that we're that we seem to be seeing, as, as regards their potential for treating things like depression? Like, do you think that there, there really is a lot of potential there? Do you think that this is an area where there's a lot of hype going on, we might get disappointed? What What's your general take on sort of the potential of psychedelics and similar compounds in general as sort of new tools in the in the psychiatric toolkit?

Well, I think the results are very promising. So far, I'm impressed. It's a number of studies. And they're, and they're very encouraging. I think all of us in the field are cautious. And a little bit worried about what might happen and whether this bubble might burst at some point. I think there are some serious issues with expectancies and blinding that are really difficult to overcome. So again, the people that are using these drugs for treatment, they have several preparation sessions, people certainly know what drug they're getting their preparation sessions, they have every expectation that they're going to benefit from it. And so it's really hard to kind of rule out this expectancy. Again, even when we give placebos and we don't give them strong expectancies, they tend to get better. So it's going to, it's just going to be remains to be seen. And people are going to have to come up with clever ways to do the kind of control the expectancy controls. And we thought that micro dosing was maybe one way of doing it. And there are some other interesting ways of doing it.

What are some of those other ways?

Well, one way is to give the drug in such a way that the people don't have a memory of it. So there's a lot of there's a lot of discussion about whether you for the beneficial therapeutic effects, whether you whether you really need the subject, the big subject of experience, whether you need that big trip and the memory of the trip. And so people are trying to figure out ways to kind of make people either not remember the trip or not have the trip and then see whether they still get beneficial effects.

Nick Jikomes 54:48

Wow. So what would that even look like? What would that mean? Like, you know, sedating someone and then giving giving them a psychedelic, interesting. So the idea would be if the subjective effect So the psychedelic trip portion of the drug effects are not critical or not necessary for the therapeutic outcomes. You could sedate someone or give them some kind of memory blocking drug in parallel with the psychedelic so that, you know, the LSD goes through their bloodstream. It gets into their brain, it does its thing, but they don't have that experience. They don't, or at least they don't remember the experience. And if the experience itself is not important for the therapeutic effects, you should see benefit anyway. That's the basic idea. Great, interesting. Well, well, Dr. DeWitt, this has been a really interesting, your lab is doing some interesting work with micro dosing and some of these other substances. Are there any final thoughts you want to leave people with or anything you want to reiterate? Before we go?

Harriet de Wit 55:48

I don't think so. I think it's a it's an exciting field. It's a it's a, you know, it's a blossoming exciting field in psychiatry. For your audience, I would say though, you know, I have an obligation to say, Be careful what you take and what doses you take and where you get what sources you use the drug and, and just just use a lot of caution and wisdom in how you proceed. So I feel obligated to say that, and I believe it. So. No, I think it's an exciting area of research to be in right now.

All right, Dr. Harriet, do it. Thank you for your time.

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Ariel Woods
Ariel Woods
Nov 25, 2023

How does one sign up to be in one of these trials?

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