Psychiatry & Psychotherapy Podcast - Microdosing LSD & Psilocybin: The Future of Psychiatry or Placebo?

Episode Date: April 19, 2023

The idea of using psychedelics to treat psychiatric symptoms has been approaching mainstream popularity thanks to podcasters like Joe Rogan, Tim Ferris, and Sam Harris. As interest in these substances continues to grow, so does the size of the online communities centered around this topic. While there is undoubtedly value in recognizing some of the claims being made about microdosing, it's important to recognize where the literature currently stands and to identify where there are gaps in understanding. In this episode, Dr. David Puder and Liam Browning discuss the state of Microdosing in current research. By listening to this episode, you can earn 1.25 Psychiatry CME Credits. Link to blog. Link to YouTube video.  

All right, welcome to the podcast. I am joined today with soon-to-be Dr. Liam Browning. He did an excellent job summarizing and working with me on this episode on microdosing LSD and psilocybin. We will be looking at the current state of the science and microdosing being, you know, one-tenth to one-twentieth of a normal, maybe singular dose. And so today we are going to be talking about what is going on in pop culture? What are they saying? What are we hearing on different sort of podcasts from other people? What is some of the history of it? What are some of the early studies? And then what are some of the newer studies? And, you know, it's funny we're, I was running some of these questions through chat GPT. And I was, I was, I, I, I, I,

Liam, you have done such, you have beat chat GPT by far. In this summary, if anyone goes to our website, Psychiatrypodcast.com, you can see this for free. All of our literature is for free. Every episode has an article. And you're a listener. Is that correct? Yeah, that's right. Big fan of the show. What kind of episodes have you enjoyed prior? Like, what's your genre that you're interested in? Well, I'm interested in practicing psychotherapy once I become a psychiatrist. So hearing some of the episodes about like transference, that was pretty interesting. And pretty much any psychotherapy-related podcast, I'm really listening intently into. Awesome.

Awesome. Okay. So, yeah, let's talk about the why. Why is this important to talk about now? Yeah, so like you said, we're hearing about podcasters, sort of singing the gospels of psychedelics. and really spreading the idea of, you know, using psychedelics for psychiatric disorders. So the mainstream culture is really picking up on it.

And it's catching a lot of traction in sort of online communities, especially Reddit. And so these online communities are starting to pick up practices like microdosing. And they're sort of making claims that microdosing is more beneficial than traditional psychiatric treatments for treating ADHD, anxiety, depression, PTSD. And a lot of these podcasters, Joe Rogan especially, is a big proponent of microdressing.

So there's definitely a lot of sort of positivity going around there. And I definitely think it's important to be critical of what they're saying and see if there's any signs to actually support the claims that they're making. Yeah, so I asked you to look at some of these quotes. So, you know, you got Joe Rogan saying things like, like people are using psilocybin these days in what they call microdosing, taking very small doses and seeing these profound benefits. You know, one of the things that I'm aware of is these kickboxers using it.

And kickboxers are using it. A good buddy of mine is using it and says he can see things happen before they happen. Yeah, he's in the matrix. He's in the matrix. Well, he's exited the matrix is what's going on. It's beyond the Matrix. There's a couple of quotes here. Any that you want to read?

Yeah, another Joe Rogan quote that he said recently in a podcast is he says, it just puts me in this very appreciative, thankful, low-anxiety state. And there's another person who's sort of famous for being a big proponent of microdosing. And that's like an author. Her name's Islet Waldman. She wrote a book about microdosing. And her book titled A Really Good Day, How Microdosing Made a Mega Diffrance in My mood. my marriage and my life. She says, quote, for the first time in so long, I feel happy,

not giddy or out of control, just at ease with myself in the world. When I think about my husband and my children, I feel a gentle sense of love and security. I'm not anxious for them or annoyed with them. When I think of my work, I feel optimistic, griving with ideas, yet not spilling over. Yeah. I think I first heard about it from Tim Ferriss. We don't have any quotes from him, but there's been this kind of push in the coding community in Silicon Valley. Yeah, for productivity. Yeah, so this is a quote from Paul Stannitz. I think this is on the Joe Rogan experience when he was a guest on it.

He says, quote, coders in Silicon Valley from the biggest computer companies that we all know, they do it. This is not only a fashion, but a tool that they're seeing an increased ability for coming up with codes. And it's a competitive advantage in the capitalistic system. So there's definitely this general idea that it helps productivity. Yeah. So, yeah, who has this guy, Dr. James Faddyman? Who's he and what's his background here? Yeah, so Dr. Faddyman, he was a researcher in the first wave of psychedelic research in the 50s and 60s.

He was a Harvard researcher. He researched LSD. and when psychedelic research was sort of put under wraps in the 70s, he sort of started focusing on other things. But when research came back, he sort of wrote a book called The Psychedelic Explorer's Guide. And in this book, he sort of coins the term microdosing and gives a protocol for how someone can microdose. And that protocol is called the Fadiamen Protocol. and that involves taking a microdose every third day to sort of account for tolerance effects that might happen. But this vitamin protocol is pretty much the most widely adopted microdosing protocol that's raised now.

Okay, so they're using, so normal dose of like LSD is 100 to 200 micrograms. They're using like 10 to 20 micrograms of LSD. Is that correct? Yeah, that's right. So like you mentioned, it's about 110th to 120th, the normal dose of, dose. So for LSD, that would be 10 to 20 micrograms and up to 26 micrograms you'll see in the research. And then for psilocybin mushrooms, the recreational dose might be around two to five microgram or two to five grams. And that would mean a microdose would be about 0.1 to 0.7

grams. Okay. I think it might be interesting to just kind of like go back a little bit further into the history of rituals and how microdoses were used. Do you want to give a brief overview of that. Yeah, sure. Not micro doses, actually. Macrodoses, right, yeah. Because micro doses weren't used until recently, right?

Very recently, yeah. Traditionally, psychedelics have been used within tribes and indigenous cultures for the purpose of rights of passage and for enhancing religious experiences. So some example of these could be like the Mazatex. They use psilocybin mushrooms in Mexico. There's the Shepibo that use ayahuasca and Amazon.

And another Amazonian tribe, two Amazonian tribes are Ibine and Yanomami, I think. They use DMT. And there's also people in Africa. They use the Ibidame, the beweedy people. And then even in Japan, there's the Ainu people. They use mushrooms. And of course, there's North American Indians who use peyote. So traditionally, you know,

You know, these were used for very ritualistic settings and not to be used every day. It was more of a once in a lifetime or sort of once every so often experience, not something you're taking every day. Yeah. One of the interesting things I found when I was looking at this was the history of the CIA's use and the CIA funding initially LSD research and the goal being mind control. And you may hear this and you're like, really? Like, are you kidding me?

No, like, this is actually stuff that has come out from, you know, freedom of information acts, MK Ultra. Like, it's a real thing. It's not a conspiracy theory. That actually happened. Using LSD on non-consenting people as part of torture, as part of prostitution to see, you know, if they could gain control of people's minds.

in order to, you know, like, you hear that and it sounds absolutely awful, and it is awful. A lot of it was done in the name of national pride almost. Like, how can we do this before other people so that we're not the ones that don't have this technology of mind control? Yeah, do you want to mention anything from that? Yeah, so most of these experiments by the CIA were done on non-consentienting. people. So people, oftentimes they didn't even know that they're taking a psychedelic and they would be interrogated. Oftentimes they'd be tortured to try to, you know, access some sort of mind control state. Yeah. And there were, there were even some people, there was a book that

detailed this and that I read and I knew you read and detailed how some people got to the point of even dying from potentially either a large dose or it's unclear if they were killed, you know, so to speak. Yeah. So. Yeah, especially some of these people, they were dosed for days, every single day for months. So you think about just the impact that can have on someone. Yeah.

And then I think there's another book which is a little, like, it seems like it's on the fringe of thought, but the way that that. the reporter puts it is with a skeptical mind. So it's called Chaos Charles Manson, the CIA, and the secret history of the 60s. And he finds that, or he potentially looks at how Charles Manson used LSD as part of his ability to control the minds of his followers. You know, they ended up murdering people.

The murders themselves seem to be more of meth. that they were using meth during the time of the murders. But the mind control aspects seem to be a combination of his ability to persuade people and use LSD and sex and all sorts of things like that. Any thoughts on reading that book or your reflections on that? Well, I didn't actually read the book, but I've heard many interviews from the author. and I thought it's very interesting to see that the CIA sort of backed Charles Manson, or at least he assumes that they backed him because he sort of could evade his prison statements. And despite all the sort of things that he's doing with his cult,

it's sort of suggested by the author that he was actually using LSD to be able to have sort of a mind control effect on his following. And the CIA was obviously interested in that. So that's why they sort of backed him in that. Yeah. So anyway, it's kind of a historical curiosity. But I think it's important to understand, you know, the history and how these things have been used or abused in the past because, you know, it teaches us, one, it's a good sort of ethical study.

It would be a good ethical discussion for, like, medical students like, I mean, it's not that hard to figure out why it would be unethical. Anyways, let's keep moving. So Dr. James Fottieman came out with the Psychedelics Explorer Guide, which kind of ignited this interest in this topic of microdosing specifically. And then that sort of catapulted, you know, the Silicon Valley and these online forums discussing it. antidotes of it working. And then he published a paper in 2019.

And tell me about that. Yeah. So he was sort of collecting all these anecdotal reports through an online sort of platform that he created where people could track their moon and give their anecdotes about their experiences. And from this, from these anecdotes, he published a paper in 2019. And sort of in this paper and then a lot of the talks that he gives, he sort of claims that because of the anecdotes that they're making, they're saying that they're seeing improvements in anxiety, general anxiety, academic anxiety, party anxiety, all sorts of anxiety, Asperger's mood for depression and bipolar disorder. They're seeing improvements in focus, learning, habit formation, and also improvements in physical elements like headaches, premenstrual syndrome, concussions, trauma.

So a whole load of different claims being made in this paper, and then also from some detoxies giving. And you can go on Reddit, and on the Reddit community, there's over, I think there's 240,000 people now on the microdressing community. So you can go on Reddit and see people are making these claims too, and they're saying that they're improving their ADHD, PTSD, anxiety. And the fact that there's not really much literature up until this point, there's some sort of studies, like the early observational studies that we saw, like the Fadiman paper, they have some statistically significant results. So that definitely sort of pushed the idea that there's something to microdosing.

You know, I was thinking if I was on the Joe Rogan podcast and he was saying to me, well, why would you discount this study? Right. It's of a thousand people. you know they're taking micro doses of 10 micrograms of LSD you know it's multiple countries why would you discount it and and value maybe more recent studies over it and I was thinking well you have number one a self-selected group of people these are people who are already in the community that have read his book that are you know curious enough to kind of like buy into this, right? These are self-selecting people. And it's not that we discount studies like this,

but they may provide interesting antidotes that are positive, but we have to do randomized trials with placebos to see what the placebo effect is doing versus what the actual microdose is doing. Right. And the fact that, you know, you mentioned that people are self-selecting, But all of these people in these studies, they are already microdosing. So there are people going out of their way to get oftentimes an illegal substance to actually participate in these studies. And they're going out of their way sort of on the online communities to find where these substances are sort of attracting people and getting their participants.

So you definitely need some sort of placebo control and also in people who don't necessarily have some sort of affiliation towards microdosing. So there are recent, you know, I did two episodes or three episodes on, you know, psychedelics in the past. There are studies that are promising on macrodosing or promising as in they have a positive, you know, effect size. Any comment on those studies as we kind of bridge into the smaller microdosing studies? Yeah. So most of the sort of clinical trials that have been conducted mainly through sort of the labs from Howard Harris and Roland Griffiths, these sort of studies have been very controlled with high doses

and with a lot of high contact with the sort of a monitor or a therapist in that setting. So a lot of people are taking these studies to say, yes, there's definitely some effect with psychedelics. So that means all doses of psychodots are going to work, right? Okay. And then what are some of the other online surveys that you found? And what did they say? Yeah, so a lot of these online surveys, as you mentioned, they're mostly from 2018 to 2020.

They weren't really controlled. A lot of them. And they, like we had mentioned as well, that they're self-selecting. you know, they're participants from these online communities. That's where they're attracting their participants. But again, despite the fact that they weren't controlled and there is no sort of a blinding, the fact that they had statistically significant results, I think that further propelled the movement because people were seeing online, oh, look, it's a study, it's statistically significant.

It proves depression. So I'm going to take a microdose. Yeah. Yeah, and so we will, in our paper on our website, show all these studies. You can look at them. And, yeah, a lot of them were very positive, very positive observational studies, right? Self-selecting people in these online communities, looking at the people, what they're doing, what they're finding. Okay. So there have only been several randomized control trial. to date on microdosing. And, you know, we may be coming back three years from now and seeing 10 more studies, but to date, we are going to talk about the ones that have been published and go through each one. So this is our deep dive. Let's go. Okay. So yeah, I wanted to mention first that

although there are randomized controlled trials, all of them, except for two, have been in healthy populations so not in clinical populations right so the first two studies that we're going to discuss they're in clinical populations but they used the microdose as the active control versus a macrodose so that kind of limits our ability to say like okay the long-term effects of microdosing compared to a placebo but i still think they're pretty useful to actually look into Okay. Yeah, let's talk about gasser at all 2014. This is on the safety and efficacy of LSD for anxiety associated with life-threatening disease, which is interesting because actually this is a population that I treat in the IOP partial that I run. We treat people with medical issues and psychiatric issues, people who would score very poorly. on mental health and physical health. So walk me through this study.

Okay, so this study was a randomized control trial where 11 cancer patients, who scored positively on the state trait anxiety inventory, and actually half of them met diagnostic criteria for GAD based on the DSM4. So these 11 participants were randomized to two psychotherapy sessions in which they received either 200 micrograms, so the high-dose condition, or 20 micrograms, which is the microdose condition of LSD.

So they did two psychotherapy sessions split apart between two to three weeks, and then after two months, the 20 microgram group, the low-dose group, they crossed over to the high-dose condition. So in between these sessions, they also received a lot of psychotherapy. So they received two preparatory sessions prior to the treatment sessions. and then three psychotherapy sessions after each experimental session. So they had quite a bit of contact with a therapist in addition to these treatments. So for the results, two months after the first block of sessions, so before the crossover,

the high dose group showed significantly lower scores on state and trait anxiety compared to the low dose group. And the effect sizes were pretty high at 1.2 and 1.1.1. And three out of eight participants in the high-dose group, they drop below the threshold for the state-trade anxiety in the tortient, for both state and trade-anxiety. While this is interesting here, all three participants in the low-dose group had higher trait-anxiety scores and two had higher state-anxiety scores. So the low-dose group had higher anxiety and the high-dose group had lower anxiety. Despite the therapy.

Yeah, despite the therapy. Despite the therapy, which is interesting. So the low-dose group, some of them got worse, is what you're saying. Right. But again, this study is pretty small. There's only three people in the low-dose group. So should be cautious about making claims about it. Sure, sure.

But it's not like both groups got better, a lot better. Oh, no. Because sometimes with placebo, with like medication placebo, you'll see, you know, actually the placebo did pretty good. like it actually made an impact. The effect size, you know, how many standard deviations do they shift from each other? So the high-dose group shifted about one standard deviation from the low-dose group.

And then that's an effect size of one, basically. Interestingly, in the IOP partial that I run, which is a lot more therapy, right, and medication management. And, you know, they're seeing me weekly or our NP. and they're doing group group therapy starts off seven hours a day, five days a week, and then it goes down to three hours a day, three days a week. So it goes down from partial to IOP.

RFX sizes are somewhere between two and three after about 30 sessions. So a lot more therapy, you know, 30 sessions of three hours. That's like 90 hours of therapy, right? So a lot more hours of therapy, but just to give you kind of like a, And it's not state trait anxiety. We don't measure that. We measure a couple of them, a couple other well-established measures,

but just to give you an idea of comparatives. You can't compare it. It's comparing apples and oranges, of course. But that being said, there's, you know, this is not the only treatment that we know for people with anxiety and cancer. That is helpful. Okay.

Right. Do you want to make any comments on this study before we move on. Yeah, I just wanted to mention that they also measured secondary outcomes, like quality of life, psychiatric symptoms according to the SCL 90R scale. I don't know what that is, but, and then also anxiety and depression. And the participants only improved after they received the high dose. And this was maintained at 12-month follow-up as well.

So even the low-dose participants who had increased anxiety, once they received the macrodose, then they actually improved. And, you know, I think if I was an advocate of low dose after this study, I would say, well, this is only a couple doses, like, of low dose. Like, I would, you know, and is really, and also I would argue the expectation effect was for the high dose. Like, people thought the high dose was going to be what changed them. And so there's actually a negative expectation effect on the low dose. So if I was wanting to sort of defend against why this doesn't disprove lotus, those are the things I would say. What do you think about that?

Yeah, definitely. Like if you're expecting to receive a psychedelic and you take a pill and there's like no effect, then you're going to be like, okay, what the heck? I want the high dose. So you might actually say like, okay, I'm more anxious because I know I'm not receiving the treatment that I want. Despite the therapy, which I would expect the therapy itself to be helpful. Okay. Let's talk about Griffin's at all 2016. And it is called psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life, threatening cancer,

or randomized double-blind trial, which I don't know how blind you would be. Okay, but go ahead. Yeah. We could talk about that. So this was a double-blind crossover randomized control trial where 51 cancer patients in various stages of cancer with comorbid DSM-4 diagnosis of either depression and or anxiety disorder. They are randomized to first receive either a low that is 1 to 3 milligrams or high, 22 to 30 milligrams of oral psilocybin.

And they followed this by the opposite dose five weeks later. So just like in the previous study, the active control is the... the microdose condition here. And also like the previous study, they met with monitors. The participants met with monitors before, after, and between sessions for a mean total of about 15 hours. So a lot of contact with this study too, I would say.

And for the results, five weeks after the first dosing session, only the high dose group showed significant decreases in clinical questionnaires. They used the ham D and the ham A. But there's actually a slight trend in the low dose group, but it didn't reach, uh, statistical significance. But for the low dose groups, there's actually a 32% response rate, which they used as a 50% decrease relative to baseline. And there's a 16% remission on the HAMD.

So 32% response rate on the HAMD for the low dose group, but compared to the high dose group, the high dose group had a 92% response rate on the HAMD and a 60% remission rate. And the microdose group also improved on the HAMA. They had a 3rdose group, they had a 24% response rate and a 12% remission rate. And compared to the high dose group, the high dose group had a 76% response rate and a 52% remission rate. Right. So unlike the previous study,

you're seeing sort of improvement with a microdose group. So if I was some, you know, podcast where I said, see, it's making some impact, you know, look at that, 32, 16% response, you know, that's impact. It's not the full dose, you know, so it's not the 92% response rate. But like, what would you say to that person? You said that. Well, what can you compare that to? The 32% response rate in the low microdose group, how do you know you can see that same response rate in a placebo with the same sort of therapy, right? Oh, so you're saying the therapy alone could have caused

potentially that 32% and we don't know. Is that where you're saying? Yeah, potentially, yeah. Okay. I think I remember from this study as well, the subjects who received the high dose knew that they were probably receiving the high dose. Was that documented in the study? Like most of them knew what they were receiving, right? I think it's pretty easy to tell if you're taking a psychedelic. You can probably feel the effects, right? Especially with the high dose like this. You're going to be able to tell, okay, I definitely didn't receive the placebo. So the blinding, like you mentioned, it's sort of iffy, especially like the experimental raiders who were supposed to be saying whether the participant took a low dose or a microdose group, or a low dose or a high dose, they can definitely tell who took the macrodose. I think that's a pretty big problem for the entire field of psychedelics where you can't really control that well or blind that well.

Yeah, it's really hard to blind when you don't, like what could you blind them with? maybe a super high dose of Benadryl or something, you know, that's going to cause. But then you know, it's like LSD psilocybin, it's such a profound, impacting, you know, mind-altering moment that it's just, how do you control that? Right. You need to control it with another drug that's federally regulated, and that makes it so much harder for these studies to get approved. Okay.

Okay, so yeah, another issue with this study was the population. Tell me about that. Yeah, so this population was actually highly educated, very homogenous, and they also had favorable attitudes towards psychedelics. So they actually did like a survey before beginning the study, and most of the participants actually had favorable attitudes about psychedelics or had psychedelic experience. Okay, now we're going to jump to some of these sort of lab-based controlled trials. and walk me through those. Right. So in the following years after this Griffith study,

there have been eight lab-based controlled trials of microdosing that have addressed mood or symptoms of anxiety and depression as one of their outcome measures. So pretty much all these lab-based studies, they're in healthy volunteers. And most volunteers have had previous exposure with psychedelics. That was actually the inclusion criteria for a lot of them. but the basic design of a lot of these studies is that the participants basically came into the lab

and they're randomized to receive either a placebo or a low dose microdose, a medium dose, or a high dose microdose. And they essentially had them do some sort of clinical questionnaires and then some cognitive assessments. And then they'd have a washout period and then cross them over to gather doses. Okay. Yeah. And what do they find from these studies? So I'm going to break down these studies, at least going by the questionnaires that they use, because a lot of the studies there was overlap in the questionnaire that they used. So I think it makes a little bit easier to digest. So the first questionnaire that I'm going to talk about is the PANAS, which actually was the sort of mood tracking tool that Dr. Fidaman used in his 2019 study. So two lab-based studies I used this tool, and one of them was LSD, and one of them was a psilocybin study.

and they found no significant effect on the PANAS. And for the next questionnaire is the POMS, which is the profile of mood states. So it measures different dimensions of mood swings. So it has subscales related to anxiety, depression, anger. So four studies use this tool. And of those four studies, two observe a significant increase in anxiety subscale on the palms during the acute effects of the highest dose. And then two studies actually found no effect on any of the subscales of the palms.

And one of these studies that didn't find any effect found a dose-dependent increase in anxiety and a subscale of another questionnaire that they used, which is the 5D ASC. And one of the studies that observed an increase in anxiety, they also found an increase in elation and positive mood in the highest dose group. So for the next questionnaire, we have the BSI 18. this is a symptom scale with subscales of somatization, anxiety, and depression. And compared to baseline during the acute effects of dosing, the highest dose group showed increases in average anxiety and somatization subscale scores, and there are no changes in the depression subscale.

So those studies were all essentially exposing participants to different doses at random, and then they would measure the acute effects. but the next studies that I'm going to talk about were more so repeating the doses. So instead of just the one dose of the same dose, they had multiple sessions with the same dose. Okay. What are those fine? So the first study is by Kavana at all in 2022, and they studied the effect of microdosing 0.5 grams of psilocybin and found no change in acute anxiety using the state-trade anxiety inventory during the effects of microdose. So in this study, they basically had participants microdose for one week and then

use a placebo dose for another week. And obviously, they randomized it and did crossover. So they had 34 participants take two doses once Wednesday and once Friday. And they measured state trade anxiety on, I think it was Friday or Wednesday and then Sunday. So Sunday was a non-dosing day and they use depth to measure if there are any changes in anxiety. So compared to the weeks that they'd taken a placebo, there are no differences when they'd taken a microdose. Interesting. Yeah. Yeah, they concluded that expectation underlies at least some of the antidotal benefits attributed to microdosing with psilocybin mushrooms. That was their conclusion. Right. Yeah. Okay. Go on to the next one. Yeah, the next study is by DeWitt at all.

This is another 2022 study, and they had 56 participants randomized to take four doses of either placebo, 13 micrograms of LSD, or 26 micrograms of LSD. And they separated the doses by three to four days. So that's sort of similar to what you'd see with the Vodombin protocol, which is the most commonly used protocol where it's every three days. So after completing the four doses, all the groups showed significant reductions on the DAS, which is the depression, anxiety, and stress skill.

And they improved in all the subskills, depression, anxiety, stress, and the total score as well. But there are no group differences observed. So the placebo group improved as well as the microdose conditions. So there was no difference between the placebo or the microdose. Is that what you're saying? Right. Yeah, they all improves.

They all improved a little bit. yeah okay and um that one was probably the closest that i've heard to the the protocol that's used out in the wild so to speak right yeah that was one of them they definitely you need to have for pedidosis and actually have it look like what people are using in the real world yeah okay yeah so the next study actually also used a similar protocol uh they actually had participants follow the vitamin protocol. So this study was by Marshall-It-all in 2022, and this was a double-blind crossover with 52 participants, where the participants were randomized to first take capsules containing either 0.7 grams of psilocybin truffles or non-psychotic mushrooms. And they essentially

gave participants bags of the doses, and that they were instructed to take it every third day, so following the vitamin protocol. And they did this for three weeks. And, and they did this for three weeks, And after the three weeks, they were then crossed over to the opposite condition. So after the first block of doses, they measured the DAS, just like the previous study, and they saw that they were significantly lower scores in both the microdose group and the placebo group. So there was lower scores, but was it significantly different? Yeah, but there's no significantly, there's no significant differences, between the two groups.

Between the two groups, right? Okay. So basically you're saying the placebo and the microdose were equivalent from this study. Right. Yeah, they both improves. Okay. Yeah, any takeaways? How do you, like limitations of these studies in your mind?

Yeah. First of all, this is sort of a problem with the observational studies as well, is that most of these participants were recruited from online forums or from psychedelic conferences. And like I mentioned, they had prior experience with psychedelics. So that can sort of influence the results of the placebo condition as well as the microdose condition, right? Yeah, that was one of the conclusions of this, the most recent study we talked about is like further research in a substance naive population with clinical range, anxiety, and depressive symptoms is needed to substantiate the potential beneficial effects of microdosing. That was their

like conclusion. So yeah, so if you use it on people that are not naive and that know a lot about psychedelics or believe in them, it might make a different impact or might have, or people who have clinical grades of depression and anxiety, that's what they were saying. Is that what you're saying as well? Yeah, I'm saying like there could be some sort of impact on their beliefs about what psychedelics do in terms of like how that affects their symptoms. But they're But then again, I think the main limitation with these studies is that these were healthy people. They didn't have clinically significant scores on any sort of depression questionnaires or anxiety. So I think before we make any conclusions about the effects of microdosing, they need to be studied in a clinical population.

Yeah, I see that as well with like SSRIs. SSRIs, SNRIs, like work a lot better, the more severe the depression. So when you go up from like mild to moderate to severe depression, the placebo does about the same impact, but the medication does more impact as it gets more severe. So I could see that criticism and that need to study a more severe population. Right. Yeah, anything else? Any other takeaways? Yeah, another takeaway I had was that you could expect a lot of people to say, oh, well, for a lot of these studies, you didn't give them enough time to actually see an antidepressant effect because the longest study here was, I think, three weeks.

So you'd expect with like SSRIs, the effect doesn't kick in until oftentimes up to six to eight weeks with a lot of people. but the main criticism I have about that point is it's generally accepted within the microdosing community that microdoses work within sort of the first week and then people actually stop dosing after a couple weeks because either they develop a tolerance or they have some headaches or nausea. So the fact that these studies weren't longer than three weeks, I think that's not a limitation. You know, I don't really see a limitation of these studies being that they weren't like naive to the to the idea of psychedelics because I would think that there would be a believer effect actually of like people if they believed in psychedelics and they're at these conferences,

well then they're going to have a bigger response actually. Do you have any thoughts on that? Yeah, I definitely think that. but at the same time, the sealing effects are still pretty substantial. So if they're already very low on depression and anxiety, then it's kind of hard to have any meaningful statistical difference between the placebo and microdose condition. Yeah, I agree. Okay. Let's go on.

There's this other study in 2021, self-blinding citizen science to explore psychedelic microdosing. Tell me about that one. Yeah, although this isn't necessarily a lab-based study, I thought it's very intriguing because it's technically the largest placebo-controlled trial to date. So this was a naturalistic study where they had 191 participants learn a self-blinding procedure with their own microdoses. So what they did is essentially they had the participants prepare their microdoses,

put them in capsules, and then put them in envelopes, and they also had placebo pills to put in envelopes. And they shuffled the envelopes. They had directions on how to do this, and there is also QR codes on the envelopes so that their shuffling process was enabled them to have three groups emerge, three different dosing conditions. So there's one group that was dosing, microdosing for four weeks, twice a week, and then with two placebo doses within those weeks. and then there's another group with four weeks of all placebo doses and then there's another group that had two weeks of microdosing and then two weeks of placebo and you know this is a 191 participants self-blinding with microdosis so yeah what happened yeah so in terms of like what

they actually took they took lSD 84% took lSD and then 14% took cilocybin i think that's important to mention so in terms of the results After five weeks, the microdosing group improved on self-reported psychological outcomes related to well-being, mindfulness, life satisfaction, and paranoia. And they also reduced their Big Five neuroticism and increased openness. And the placebo group and a half-and-half group also improved in mindfulness and paranoia. But unlike the microdose group, they didn't improve for well-being or life satisfaction. Then also for the placebo condition, the neuroticism decreased.

And on days when they took a microdose, the participants reported significantly higher scores of mood, energy, creativity, and drug effects, and also higher PANS positive mood. They also observed statistically significant decreases in state anxiety, state trait anxiety, in the microdose group, while measures of depression, mental well-being, social connection, those were insignificant, actually. Now, the thing with this study is they actually controlled for belief effects. So what they did is they essentially had participants guess the number of times they had a microdose every day that they took a dose, they had them guess.

And they summed up the number of guesses, and they used that as a covariate in their statistical models. And when they included this covariate, they observed that almost all of their effects dropped out of statistical significance. And the only thing that maintained was the subjective drug effects, like if they felt like they were experiencing the effect of a drug. And actually this covariate of the number of guesses, of the number of times they'd guessed they'd taken a microdose, that was statistically significantly correlated with increases in Big Five of groups. freeableness, openness, and increases in well-being and mindfulness. So what you're saying is that once they controlled for the belief effect, the impact of the changes no longer were as important? Yeah, that's right. Or they were no longer important at all?

Yeah, they're actually not statistically significant. So you started out the study, and if they wouldn't have looked at belief effects, effects, we would have thought very positively about this study. We would have thought like, oh, wow, look at that. Look at those effect sizes. You know, there is a change here. But what you're saying is that once they controlled for that belief effect, it wasn't. Yeah, exactly.

A lot of these effects actually dropped away. The effects dropped away. Yeah, the only one that maintained was the, whether they actually felt the effects of a drug. That was the, so, so this is another negative study is what you're saying. Right. And it seems to be pretty well done. I mean, you know, how many people are in it? 191.

It's quite a bit more than before the length of time, four weeks, which we would expect to see an impact in four weeks. So they controlled for belief. Okay. You know, I mean, I've talked about placebo. I have an episode on placebo. I talked about placebo a lot in the social anxiety. anxiety study as well. And placebo is incredibly powerful. And so if you're listening to this and you're

like, but no, Dr. Peter, like, I've done this. It's really helpful to me. I would say, man, I hate to tell you, but it's probably going to be less helpful after this because, you know, your belief probably has decreased from reading this, listening to this. And like there was that one study I talked about on eschatalopram for social anxiety, where they gave everyone eschatopram. One group, they told that they were giving this medication that would cause the same side effects of esotelabram, but it wasn't the act of medication. But everyone got eschatelopram. So you would expect both groups to do better on social anxiety. And both groups did better on social anxiety, but the group that believed that they were getting the active drug did considerably better than the group

that believed that they were not getting the active drug. That would be an interesting study to run on this kind of population as well, right? It's a deception study. So you deceive half the group to think that they're not getting it, but they actually are getting it. Any other thoughts coming up to you before we move on? Yeah. I think that would be pretty interesting. But then again, there is a high break-blind rate with microdosing studies.

So specifically in this study, if someone had taken a microdose, I think there was 70% accurate at guessing whether they're taking the microdose or not. So there's definitely some sort of like you feel a drug, even though you're not sure if it's placebo or microdose. And if you took a placebo, then there's still that 70% accuracy in guessing that you're taking a placebo. So I think you definitely need some sort of active control because you, you know, traditionally you see microdoses.

You think of them as subperceptual, but in reality, a lot of these studies are showing that there is some sort of perception, perceptual changes. So I need some sort of active control with a similar subperceptual change or perceptual change. Okay. Nice. Yeah, let's move on to this, Cartner-E-L-E-L-2021. Positive expectations predict improved mental health outcomes linked to psychedelic microdosing. Yeah, so this was another naturalistic online study.

This is actually not controlled, but I thought it was meaningful to improve it. It's one of the most highly cited articles in the microdosing literature. So this was a naturalistic study with 253 participants who were planning to begin microdosing. And actually, 46% of participants have been diagnosed with a psychiatric disorder in the past, with MDD being the most common and anxiety disorder as well. And participants, they were not instructed on a particular microdosing regimen, and they were free to choose the dose and the substance of their microdose.

and 48% chose to microdust with psilocybin, 42% chose LSD, and the remaining 10% chose another psychedelic. And after they continue this study for four weeks, and most of the participants actually chose the Fadamine Protocol for this week, or for these four weeks. So after the four weeks, the participants showed significant improvements in self-supported well-being, symptoms of depression and anxiety, emotional stability, and the great differences in these metrics were observed after the first week. But I think what's interesting about this study is that when they controlled for baseline expectations of the long-term benefits of psychedelics, so essentially they did a survey before beginning the study and measured what they think about psychedelics, are there going to be any improvements? They found a significant correlation with well-being, depressive symptoms, and anxiety. And although these were sort of

smaller correlations, the R value was like 0.2. I still think it's pretty interesting to look at and say like, okay, yeah, their expectations of improvement was significantly correlated with their actual improvements. Yeah, I think this study is a little bit, wait, what is this dropout rate on this? Yeah, 68%. What does that mean? So I think the author is kind of discharges.

described it as the difficulties of getting an illegal substance probably contributed to the dropout rate because obviously they enroll and have to keep getting the doses. Oh, okay. So this study is less exciting for me, honestly, because there's no placebo, there's, you know, there's no comparative, you know, it has a small correlation, 0.3, around 0.2 to 0.3 with, like, belief and, you know, did they improve? But that's not huge, you know? Right. Because the stated belief is different than I think I'm actually taking something, you know, belief, like in the prior study. So in this study, it's like they were asked to survey of how much they believe,

and they correlated that with outcome, which, you know, it's positively or negatively correlated, but it's not huge. Whereas in the prior study, they actually were measuring, do you believe you took an active or not an active medication essentially. And so that is, measures as well, unconscious belief, right? Measures all like, like, you know, the stuff that you're not, like you can trick yourself into believing that you don't believe it, you know, and you're skeptical, but you really do believe it type of thing. So just measuring, did they believe that they took it or not, and using that as the control and that washing out any of the impact of it, I think that's more significant in my mind.

Yeah, I agree. I definitely think it's important to sort of include at least one measure of like if they had taken a microdose or not, some sort of guess. I think that's really important. Yeah. But if everyone's taking a microdose, like in this study, you don't really know, you know, what's causing what. And so you really do need a placebo.

And ideally a placebo that can be confused for the microdose, but it's not the same mechanism of the microdose. Okay. Yeah, any other things that you wanted to draw out? Yeah, I thought the authors of the study actually had a pretty interesting conclusion about sort of the effects of microdosing. Like, what is the mechanism of action of microdosing? So the author suggested that given the context sensitivity of psychedelics,

that is the influence of set and setting. So the individual's mindset is their set, and then the physical location that they're in, their environment is the setting. So given the context sensitivity of microdosing or of psychedelics, they say that microdosing can serve as accurate, to placebos, while amplifying the expectations due to the plasticity promoting nature of the drug effects.

So they sort of think that psychedelics could enhance any sort of placebo effect that is going into it. If they have high expectations, then perhaps the plasticity of the psychedelics, of the microdose, it help enhance any of the sort of behavioral and mood outcomes of the placebo. Hmm. Maybe. I don't know. I mean, from the ketamine studies that I've seen, there seems to be increased plasticity. There's also increased plasticity from exercise, from SSRI. So there's different things that increase plasticity in the brain, BDNF, you know, increase BDNF and stuff like that. I do think that it seems that people on LSD are more suggestible, dating back to, you know, some of those early sort of CIA. studies you know it seems like um and just just case reports too you know like um sam harris on the jo rogan podcast talked about how he came to his idea that there was no such thing as free will during a trip and when he came out of the trip then he kind of like you know wrote the book

against free will and he so it's kind of like he he developed this idea in the midst of a trip and then um it developed a very strongly cherished belief that then his like cognitive mind came around later which you know if you've listened to my episodes on free will i think there's a good argument to say that believing in a sense that you have the ability to change things in your environment is what we would call good internal locus of control which a ton of good mental health benefits come from right internal locuses of control or belief in free will so um you know does it increase your suggestibility? Probably. Do microdoses increase suggestibility? I don't know. I haven't been

convinced of that yet. Or does it do microdoses increase your belief or your plasticity? I haven't seen any data to support that yet. Yeah. In terms of plasticity, some studies have shown increase in BDNF after microdoses and for macrodosis too. But in terms of the setting, like in, in what, yeah, tell me about that. So increased plasma BDNF from. Yeah, increased plasma BDNF from a microdose of LSD. So I think in this study, they use 20 micrograms and they observe an increase. I don't know if it was a dose-dependent increase, but they observed an increase in plasma BDNF.

But then again, is BDNF an actual proxy for neuroplasticity? I don't know if that's really been confirmed yet. I think it's a good proxy. I mean, serum BDNF, you know, cerebral spinal fluid BDNF probably is more accurate to plasticity. I'm looking at the figure on this. it does seem to have increased BD and F a little bit. Okay. Interesting.

Yeah. And yeah, to your comment about whether microdoses could influence suggestibility, I think I'm a little bit critical of that because I think the sort of suggestibility from large doses of psychedelics comes from the fact that the set and setting are extremely important. So the individual's environment, so at least in terms of anecdotal sort of data on this, people are saying that if you take someone who's having a bad psychedelic experience and then you simply just change their environment that they're in, if you change the music or take off their blindfolds, then that completely changes the experience.

Right. So you're seeing that the person is increased. they have increased suggestibility of their mindset and their beliefs. And that's sort of being shaped by their environment. But in terms of microdosing, I don't think you get to that same level of sort of brain activity. So you're not going to have that huge change in sort of their beliefs and their context dependency. So I was just talking to a provider who is helping someone in a K-hole, you know, giving ketamine and they were the patient thought that they were dead like they thought they were

in this like state of like death and the provider was holding their hand trying to calm them and had to you know had to stay with them for like 30 minutes while they were in this state of this really scary place so yeah may i don't know if it's as easy as changing the music when you're in that state of absolute fear in these um psychedelic experiences. But it does, yeah, I see what you're saying, that suggestibility seems to be a lot higher in the higher doses. Is that what you're saying?

Yeah, that's pretty much what I'm saying. You can sort of guide the experience a lot more easily. So with these clinical trials that we're seeing with the high doses, pretty much all of them are using blindfolds and then the same sort of music. It's like a low-intensity music with drums, sort of what you'd expect to see you with, like, spiritual ceremonies. So you're seeing a very, like, homogenous sort of, like, setting and context that they give these people. And they can sort of guide their expectations about what the psychedelic is going to do for them. So if you have, like, a positive environment and a positive therapist and a good relationship with a therapist that you're doing this,

this drug with, then you're probably more likely to have a positive experience, right? Versus if you have a negative experience, like, say if someone is telling you that you come across, let's say you come across like a demon when you're taking the psychedelic. So if you have the person with you that tells you, okay, this demon is actually a threat to your soul and you have to like try to run from it. And you have to take this feather and spring with assault around you in a circle and your soul is going to be protected. This person is going to be coming out of this experience, probably traumatized because the belief within the psychedelic experience is so high. A lot of these people believe that they're actually dying, like you'd mentioned.

So the fact that they believe so strongly that they're in danger, that their soul is in danger. You can expect, because there's probably increased plasticity too, that this person will come away from the experience, having some sort of delusional beliefs, some sort of avoidance behavior because of this negative experience. And especially if they sort of guide those with them is telling them, yeah, this was a sign that your soul's in danger, you should really be careful after this experience. So this demon is going to attack you. And they might actually develop these delusional sort of thoughts for a long period of time.

versus if you have a positive guide and a positive experience like you're seeing in these controlled trials, you can sort of have that person say, okay, this is going to be a challenging experience. You're going to have some negative emotions that will come up, but I'll be here with you. And whatever you see is just like a construct of what your mind is coming up with. So instead of when they see that demon, the guide can kind of tell them, okay, turn towards the demon. It's okay. Just relax. Just approach it.

and see what happens. And then that can sort of precipitate some insight from the person. So the demon can turn into sort of like their abuser or something when they're younger. And then they can sort of transform that demon into like the abuse is getting yelled at from someone or being mistreated. So then they can sort of get the inside of like generational trauma. And they can sort of develop some sort of empathy for themselves from that experience and for other people. So just the effect of having a guide there can statistically, like can significantly influence the person's outcomes on the psychedelic.

So, yeah, I think the context and the environment can definitely influence an individual's sort of suggestability to developing certain beliefs. But whether microdosing has enough impact there, I'm not too sure of. Right. Yeah, well, I'm, you know, I'm aware from listening to a podcast where, you know, the person therapist or, you know, underground therapist abused the person, you know, in some way. And so, you know, having an unethical role in someone's trip can potentially really impact things as well. I had one patient, I'll change the variables, but her guide during her trip was very, very narcissistic towards her. And it really became like a micro trauma of sorts because it was a very sort of, she felt very isolated, scared and alone.

So yeah, I think, you know, and even in some of these randomized trials where they're looking at MDMA, there was one couple in Canada that, abused, sexually abused, participants in the trial, right? This, the, the, the good or bad that can come from this seems to be amplified, I think is what you're saying. Yeah, exactly. And, you know,

that's, there's some large amounts of respect that I would have, or respect or fear, maybe, you know. It's like, do you come out of this with the delusion that you want or not, right? And it's like, how do you control that? It seems like there's an aspect where it's very, very hard to control that you're not going to come out of this and just be mind altered in a way that you, you know, like, do you, are you consenting to that mind altering? I'm saying delusion. It could be a fixed, cherished belief, right?

And who knows what that fixed, cherished belief will be before you have the experience? is it always aligning with reality or not? I kind of see it similar to how some of my manic patients go into mania and then when they come out, sometimes they have these very fixed, strong delusions about the world that they overvalue, and it's like very rigid and sometimes persists for a long time afterwards. Okay, so I don't know if there was anything else

who wanted to get to in this episode. I think we should definitely kind of wrap up. I know there's like, there's so many more pages of this. But maybe, you know, I think it's good as well. Like maybe we could do, just point people towards the article. There's a lot more there.

Can you summarize it in like three or four sentences, all the other stuff that's in this article? As like to tantalize someone's curiosity. So there's a lot of other studies that also look into creativity and cognition and also perception. So a lot of these studies, they're showing that there's actually not much of a difference between the microdose conditions and the placebo conditions. So you'd expect to see, despite people's claims about creativity, do you think that psychedelics and microdosing will increase creativity? There's nothing really there. And same with

cognition because all these Silicon Valley type people are saying, oh, it helps me, and it helps my ADHD. People are saying on Reddit, they're not really seeing any effect on focus or cognitive performance in general. So I definitely think it is pretty interesting. Their perception of their own internal creativity has increased. Yeah, but their perception is increased. Who's to say their perception has it increased? like they're like yeah I feel a lot more creative I am more creative and then it's like in these studies they're like no that there's no increase in creativity that we're seeing right yeah yeah one comment I wanted to make about safety too is um you know psychedelics are typically considered to be

relatively safe there's not many side effects that people have observed other than sort of the emotional side effects but there's also some side effects that come along with with microdosing that have been observed and that's like headache, fatigue, dizziness, nausea. But then one other side effect that is, I think it's a potential side effect. I don't think it's been observed yet, is the possibility for microdosis to disrupt heart valves. So lead to valveopathies because there's been, the fen-fen was a 5HT2B Agnes that was used for weight loss. and it was withdrawn from the market because it had an effect on heart valves similar to carcinoid syndrome. And other 5HT2B Agnes have also shown the same property where it can increase the heartfowl thickness.

And it's known that psychedelics also activate the same receptor, 5HT2B, that's likely responsible for this effect. So I definitely think that's something that needs to be taken into account before someone, is microdosing and definitely more studies need to be conducted on this okay what I think dissociation depersonalization de-realization those are some of the things that I would be most concerned about what did you find on that yeah there's one study that looked at they were trying to look at pain tolerance and they use microdosis of LSD and they observed increased derelization dissociation depersonalization and even in Indonesia in the highest dose group.

And that was only 20 micrograms, which is still pretty small. But that's a concern. You know, does it ground you in reality or does it take you out of reality? It seems like for one of the side effects is to be taken out of reality, to be more dissociative. Which, you know, like we, you know, like who ends up being trialed on a lot of these new treatments. People with dissociation issues like borderline

person eyes disorder. People with a lot of trauma. So just be wary in that population that you could actually push them further into dissociation. Okay. Yeah, any summative comments from all of your digging on this are, well, would you, if you were a provider,

start giving up microdosing at this point, knowing all that you know? I would say no at this point. Okay. Because we're not really seeing any significant effects. What would be the point at which you would say maybe? I want to see this conducted in a clinical population. And obviously the safety effects also need to be studied too on hard valves.

So yeah, I definitely need to see this done in a clinical population, multiple studies, that account for the belief effects as well. Yeah. I would want a clinical population. So like we're talking about moderate to severe anxiety, depression. And I would want belief effects looked at. I would want it to be randomized as best it could be. And I would want them to look at as well,

dissociation, de-realization, depersonalization, to make sure that that's not worsening, how much it is, what percentage of the population it worsens. so that's that's the stuff I would want so if you're thinking about doing a study on that there you go there's some ideas and if you have done that study and you're listening to this like one year after it's been published uh email it to me and maybe I'll have you on the podcast and we'll talk about your study so always willing to change my mind but you know I think I think there's um in my mind at least as a as a professional As someone not just a researcher, right, like I'm actually seeing clients.

There are treatments that have good effects sizes, right? Psychotherapy. Some medications and different, you know, for different patients, exercise. You know, these all have impacts, you know, the partial IOP. So for me to move to a new treatment, I need to know that it's actually going to make a positive impact, not just a placebo. And that it's not going to cause negative. effects. It's like it's, I sometimes see people who are, uh, recommending different treatments. They're not in the trenches seeing clients. You know, I do this podcast now one day a week. I have

Thursdays blocked off, you know, every other day, eight in the morning to five at night, I'm seeing clients. And it's, I've been doing that for more than a decade now. So, you know, I think it's different when you're in the trenches actually seeing patients than when you are kind of able to at a distance, right, have a select group of people who have had positive experiences that kind of surround you and then continue to sort of give you the feedback that this is something very important. So I will leave it there for today. Thank you, dude. This is amazing. This is probably one of the best handouts. You are going to be applying for psychiatry residency, right? Yeah, hopefully in two years.

Okay. So if you are a program director, this is someone you want in your program. This is truly an excellent summary. And when I saw this, you know, because sometimes I'll have a medical student like yourself, reach out. And they'll be like, hey, I really want to do this project. And we kind of discuss what we're going to do. And then I say, go do a summary. And you came back with this like 40-page, you know, every study that,

that's done. And, and, you know, when I read through it, I'm also like, oh, wow, you're like synthesizing it. I'm looking at the studies. You're not missing things. So really, really well done. Um, thank you. You beat chat, GPT4. Or now. Yeah. Yeah. All right. We'll leave it there for today.