The Broadening Exploration of Potential Uses for Psychedelics: Dr. Fred Barrett, Associate Director of The Johns Hopkins Center for Psychedelic and Consciousness Research

Shiv Gaglani: Hi I’m Shiv Gaglani and today I’m actually recording a special episode in person.
I'm here with Dr. Fred Barrett, Associate Director at the Johns Hopkins Center for Psychedelic and Consciousness Research. As listeners of this podcast know, we've been really excited about the research coming out of their lab around these psychedelic substances for a whole array of mental health disorders ranging from obsessive-compulsive disorder to major depressive disorder as well as some of the work they're doing in human flourishing and wellbeing. So, Dr. Barrett, thanks for taking the time to be with us today.

Dr. Fred Barrett: Thanks a lot, Shiv, for having me on.

Shiv: We always like to ask our guests in their own words to tell us what got them interested in science, and in your case, going into neuroscience and medicine.

Dr. Barrett: Well, it's an interesting question. It's a little circuitous, so bear with me for a moment. I started my academic life as a music educator. Coming out of high school I had experience with computers and I'd been playing music for a while. I decided that at that time I didn't want to sit behind a computer for the rest of my life, and look at me now. 

Shiv: (laughs)

Dr. Barrett: But I also naively thought that there would always be jobs for music teachers. I knew I loved playing music, so I went into a program at Temple University for Music Education. 

It was a really wonderful music education program. The music school at Temple is a tiny conservatory within a large state school atmosphere. One thing led to the other, and in my penultimate semester at Temple, I started getting into classes and realizing how much of a challenge it would be to try to be a successful educator. How many other struggles students --especially in parts of the inner city in Philadelphia -- would face? 

I began to wonder whether I was really cut out to do that and at the same time, I was taking my psychology core courses at Temple, and I got really into them. I thought, well, maybe if I get a minor in psychology, I can somehow be a better human to these kids that I'm going to be teaching. So, I stayed an extra year, and I got a minor in psychology. 

By the end of that, I thought maybe instead of being a music teacher, I can be a psychologist and actually more directly help people, and decided to get a double major in psychology and music education. So, I stayed an extra year, and by the end of that final year, I said, well, maybe I don't want to be a psychologist. I really started to get into research and really got excited about the idea of generating new knowledge and really diving in and dissecting the mind. 

I realized I'd taken a couple of large shifts in my career in a short period of time, so at that point I graduated and I secured a job as a research assistant at the Schizophrenia Research Center at the University of Pennsylvania. That's where I really began to learn more about the brain, the scientific study of emotion. Half of what I did was to code the backend of an online neuro-psych evaluation tool, which was a neat experience. The other half of what I did was help to conduct studies in patients with schizophrenia, looking at different levels of emotional dysfunction and brain dysfunction. That's where it came together for me. 

I realized I was really interested in the brain and I realized in retrospect that my love of music was, in some part, driven by my interest in and love of using music to explore myself emotionally and to communicate with others emotionally. Also, performing on stage leads to its own really unique and remarkable altered state of consciousness. I was really interested in that as well, so I started to look around at grad schools, and I finally found a graduate school at UC Davis where I could bring it full circle.

I found the lab of Petr Janata at the Center for Mind and Brain at UC Davis, where I could use music as a tool to study the brain. Petr's lab was studying music cognition and music perception, and we used computational models of music cognition to interrogate brain regions that were active and supporting the process of experiencing music. I thought, well, this is fascinating. This is what I need to be doing with my life, bringing my two loves together -- music and the mind and the brain -- and why weren't we using music as a tool to study emotion? Music is such a wonderful, naturally embedded, ecologically valid stimulus for exploring emotions. So many people around the world use music every day to regulate their emotions. Why aren't we using this tool for science? 

And so that's what motivated me to get into grad school and turns out that music is complicated because people are complicated. We have these tricky things called preferences and idiosyncratic relationships with songs and genres, or by artists that we may not otherwise have any interest in or actually might actively dislike, except that one song is a trigger for a deeply meaningful memory that you may have of some time when you were younger or someone that you knew -- a loved one, or a crush, or best friends in high school or something like that. 

So, acknowledging that it can be difficult to precisely select a piece of music that will reliably evoke a specific emotion in a given individual at a certain point in time is actually a very challenging thing to do. I was getting frustrated with that, but along the way at Davis, there was another grad student a couple of years ahead of me, Katherine MaClean, and she was studying the effects of meditation on attention. She graduated, came here to work with Dr. Roland Griffiths on psychedelics and they got funding from the Heffter Research Institute and Bill Linton to conduct a study looking at the interaction of psilocybin and people with a long-term meditation practice.

One of the questions there was, is there any truth or any kind of basis for claims that seem to have been made for quite some time that psychedelics and Buddhism can bring you to certain similar altered states of consciousness? They also got funding along the way to do brain imaging within this study. They decided that they would do brain imaging the day after psychedelic experiences to look possibly at the afterglow. 

If we're looking at emotional function, Katherine thought, well, why don't we use music to do that? I know a guy. So, she sent me this series of emails and said, "How did you collect your data? How'd you analyze your data? How'd you design your study?" All these things. I kind of tongue in cheek replied, hire me and I'll do it for you. She said, okay. I was like, of course, yes. I mean, music is complicated, but we know all sorts of things about drugs, and psychedelics are such powerful drugs. Those are the tools that we need to be using to study emotion and memory in the brain. 

So, I was hired as a postdoctoral fellow and continued on to a faculty position and here I am. It turns out that I thought music is complicated because people are complicated. It turns out drugs are also complicated because people are complicated. But now I find myself in this really remarkable and incredible position to be able to study the effects of these drugs on the mind and the brain. And if along the way, we can help somebody -- and it's starting to look more and more every day, like we may be able to help people with this -- then I feel like I almost have a moral obligation to continue. It feels like this makes it even more important for us all to be good stewards of this science because of the potential that may be there for actually helping lots of people.

Shiv: One hundred percent. There are so many threads to pull on, in just that intro. One is I remember listening to your podcast with Scripps a couple of months ago and hearing that story about how you wound up at Hopkins by just kind of tongue in cheek saying, "Hey, hire me as a postdoc." I'm sure you were like 50% or 90% kidding, but then it happened. I love that story because I think so much of one's career is serendipitous and maybe just asking for something you want. I want our audience to learn that and remember that, because my mom would just tell me, "If you don't ask, the answer is, always no by default."

The second thread is, I think maybe on that same podcast or in your USC presentation when people asked you for advice on how to get into psychedelic research or science, your advice was, don't get into it. Come in through a different angle.  In your case, it was being a neuroscientist, knowing functional MRI really well, volumetric analysis, and music...you know, this eclectic background. 

Certainly, it seems like the Center you've built, and the people you've assembled and enroll, is a very eclectic group of people. I want to go back to the music in a bit, but let's dive into the Center. Tell us about how it got started and then maybe a bit about the current research and why you're so excited about the different threads and the faculty you've brought together.

Dr. Barrett: One of the remarkable things about psychedelics is that they can touch so many different fields. There are so many different directions from which you can try to study psychedelics. There are so many different ways in which psychedelics may contact people and help move them. This really provides a rich environment and a rich landscape for collaboration and for multidisciplinary research. 

In some ways, the Psychedelic Center is composed of an incredibly diverse faculty. In other ways, the Psychedelic Center is composed of very restricted faculty in that we all try to take a bit of a clinical trial or empirical research approach to studying psychedelics. But within that framework, we do have a wide diversity of opinions and perspectives and expertise that's brought to bear here.

I, myself, am a cognitive neuroscientist. I fashion myself as a cognitive neuroscientist and some of the questions that really motivate me are really looking at the interface of the hardware and the software. How do the brain and the mind interact to produce these experiences and how do psychedelics kind of perturb that? So, some of the studies that I'm conducting are really focused on that. They're focused on trying to understand moment-to-moment changes in brain dynamics that occur when people are watching movies. 

I'm collaborating with a colleague in the Department of Psychological and Brain Sciences, Janice Chen, and with our joint grad student, Brian Winston. We're really exploring the acute effects of psychedelics on people and their minds and brains while they're watching a variety of movies that evoke different emotions and have different scenes and social contexts. We believe there's a lot to unpack there in terms of brain dynamics and how we can better understand how psychedelics perturb those brain dynamics.

Other studies we're conducting are one with my postdoctoral fellow, Ceyda Sayali. We're looking at creativity and insight, and also Ceyda's an expert in studying cognitive control, so we're trying to better understand the effects of psychedelics on cognitive control. Cognitive control may represent a really important trans-diagnostic, therapeutic target of psychedelics. We can think of depression as in part a disorder of cognitive control and really cognitive flexibility. 

Often when people are depressed, they get stuck in a rut of thinking. One of the ways of describing this is with the cognitive triad: "It's my fault, there's nothing I can do about it, and it affects everything in my life." If you get stuck in a rut of negative self-thought and negative ruminations that are held together by those three kinds of core ideas, then it's really something that's almost inescapable. 

This happens often in patients who are suffering from depression, and that becomes the trap within which our minds are held. But if you had an intervention that could increase your capacity for cognitive flexibility, your psychological flexibility, increase your capacity for changing the way that you think about yourself and your place in the world and your relationships, then maybe that could help you to break free of that trap. We have evidence now that psychedelics may be doing that. So, Ceyda and I are working on a lot more studies to disentangle that.

Shiv: Is that specifically the neuroplasticity effects, like up-regulating BDNF (Brain-derived Neurotrophic Factor), or is it other kinds of methods?

Dr. Barrett: Yes. Well, it's possible. And this is one of the remarkable things about psychedelics is yes, that is a compelling story, and that's a compelling kind of explanation here where so many people in this space are working at different levels of analysis. So, you have the work of David Olson at UC Davis, and Alex Kwan, who's at Yale and they're really working almost like at a neuronal level to begin to disentangle these questions of brain plasticity and the markers of that plasticity and the other mechanisms through which that plasticity may be occurring, that psychedelics may be engaging. 

You'll also have Gul Dölenwho's looking at critical windows of learning and opening of critical windows. All of these things at the neuronal molecular level and also at the animal behavioral level are consistent with the story that we're trying to tell at the human brain systems and psychological functioning level. It's a much different level of analysis, but I think that all of these lines are beginning to converge and they're likely all related, right?

Shiv: Yeah, that makes sense. Yeah.

Dr. Barrett: Yeah. That's Ceyda's work. Manoj Doss is a postdoctoral fellow who's an expert in episodic memory and he's working on the ways that psychedelics may impact memory acutely during the acute drug effect and then in a persistent fashion. Those are all of the interests that I have and that my trainees and my colleagues are closely working on. 

But we have, of course, lots of other folks in the center. Al Garcia-Romeu is actually doing a remarkable job now of breaking us into a series of other indications. The lion's share of evidence for any therapeutic effect right now with psilocybin can be found in the treatment of mood disorders in various kinds of presentations or in substance use disorders. So far, the published data really are pointing towards smoking and alcohol use, but Al's conducting a number of studies. He's also breaking into a study, hopefully soon, in patients with cannabis use disorder. He's also actively conducting studies in patients with Alzheimer's dementia, post-treatment Lyme disease syndrome, and he has a few other ideas in his pocket that he's hopefully going to pull out soon. 

Al's been remarkable in being able to really pull off a number of early-stage proof of concept trials in indications that may not seem completely obvious immediately but really fit a clear mold of psychedelics being able to treat some measure of mood and existential crisis that accompanies really intractable disorders.

Oftentimes when people are diagnosed with Alzheimer's dementia, they really go through an existential crisis. It's a bit of a death sentence for the mind for some, and it can be really devastating to receive that diagnosis. There are cognitive deficits that accompany the progression from mild cognitive impairment into Alzheimer's dementia, but some of those are exacerbated or accelerated by the depression that can also come with that. So, Al is really trying to target that experience. A similar story can be told with post-treatment, Lyme disease syndrome. 

So, I think we're at an important time in psychedelic science where we really need to know the limits of the indication space. Some people like to describe psychedelics as a cure-all..."it'll cure what ails ‘ya." I'm just waiting for that study to come out with psychedelics and gout or like emphysema. 

Shiv: (laughs)

Dr. Barrett: Like, we shouldn't expect psychedelics to do everything. We really shouldn't, and I don't believe they will. But if you can make a compelling story or case for why we should extend a psychedelic into an indication, I think we also have an obligation to at least track that down at a pilot stage and see, "Well, is there anything there?" And so, Al's really kind of pushing the limits there, which is wonderful. 

We also have Sandeep Nayak, who's now breaking into a study in patients with opioid use disorder. Sandeep is a psychiatrist. Al's really interesting and remarkable in that he's trained in transpersonal psychology. Sandeep is trained as a traditional psychiatrist. He has a great deal of interest in patients who are suffering from substance use disorders. 

The first study that he's going to get off the ground is a really important population, especially in Baltimore, those with opioid use disorder. He's pairing psilocybin therapy with a particular induction on buprenorphine to see that if we can get people at that stage in their treatment and their recovery to prolong their adherence to medications and really see if we can make an impact that is meaningful, especially to underserved communities in the Baltimore region.

Shiv: This one's interesting. All of these are interesting, but this one -- I'll stop and interrupt you if you don't mind -- because so much of this research has been done, as with most clinical trials, on higher socioeconomic status and white populations who have the time to go through this pretty intensive therapy which includes multiple hours of talk therapy beforehand followed by an eight-hour session twice or three times. So, not everyone can do that. But, obviously, the traditional opioid-use population tend to be of lower socioeconomic status. So, that's really interesting. I'm glad that's gotten funded or getting funded.

Dr. Barrett: Yeah. That's going to be conducted within the framework of the Psychedelic Research Center. It's an incredibly important population. It'll hopefully represent an increase in the representation and diversity of the samples that are being studied with psychedelics. It's a really important point that you raise there. 

Sandeep is also working on putting together two additional studies: one in patients with with PTSD; and another in people who are interested in micro-dosing. The PTSD angle is very interesting because people like to broadly identify a number of different compounds as psychedelic. One of the closest compounds to psychedelics that people are studying right now is MDMA. It's not quite like psilocybin or LSD, but of course, MAPS (Multidisciplinary Association for Psychedelic Studies) has had an awful lot of success in really pushing forward a number of clinical trials to study the effects of MDMA in treating patients with PTSD.

But an interesting kind of artifact within this space is that MDMA has been studied almost exclusively for PTSD, whereas nearly nothing has been done with classic psychedelics like psilocybin and LSD for the treatment of PTSD. Similarly, there's been a lot done with psilocybin for mood and substance use disorders, but nearly nothing is done with MDMA in those indications. So, now that MAPS is close to the starting line for MDMA, I do believe more folks are interested in figuring out whether MDMA can be used for the indications that psilocybin has been studied for and vice versa. 

Sandeep is hopefully going to be getting approval soon for a study in patients with PTSD with psilocybin. But it's going to be a tricky thing, too, because psilocybin experiences can be vastly different than MDMA experiences. And whereas MDMA may help people to approach their index trauma or traumatic experiences from a more objective space -- in a way that they can engage with them without being overwhelmed by the emotional kind of charge of those experiences -- psilocybin experiences can be very different. They can force you to confront things fully emotionally charged.

One question is whether that will be safe for patients who are suffering from Post-Traumatic Stress Disorder. But this is something that we're going to be exploring very carefully in as safe of a container as possible. 

The microdosing question is obviously a big one. There have been a few studies of microdoses have been conducted in the lab. By and large, very, very little has been shown in terms of any effect of a microdose of psilocybin or LSD on tension or cognitive processing, emotional function, wellbeing...these things. One could rightfully criticize most of those papers by suggesting that that's not how micro-dosing works. If you're going to follow the Jim Fadiman model, you have to have a certain amount of LSD or psilocybin once every two or three days for six to eight weeks, and then things get better and that's not necessarily what people have studied. 

But the closest we've come to that as a field has been the Imperial College study -- the citizen science, self-blinding study -- that I believe showed, if anything, an effect of expectancy and maybe a stronger effect in the placebo condition in some outcomes than in the active drug condition. That really is a bit of a damning outcome. But still, this hasn't been studied quite with the exact formula in the lab. That's one of those things that Sandeep is going to try to do.

Shiv: That's fascinating because the microdosing has gotten a lot of attention and anecdotal evidence. We've had Jim Fadiman on the podcast before. It's unclear. I'm speaking to David Yaden in the Center later and in his book, The Varieties of Spiritual Experience, he talks about one of the main mediators potentially for therapeutic effects for psychedelics is having these peak experiences or spiritual experiences. In microdosing, the whole point is to not reach that point. Like, you aren't getting any perceptual changes. It could just be neurotropic or something. It's unclear. And potentially it has the negative effect of hitting the serotonin 2B receptors in the heart with chronic use. So it's definitely interesting.

I'm very impressed with how people are trying to design studies around all these different aspects. Your center is well-known for not only reigniting the psychedelic renaissance, as they say, but also having all these very interesting study designs. As far as novel study designs, we had Manish Agrawal at Sunstone Therapies on the podcast talking about the caregiver and the patient with cancer together taking some psilocybin to see if that reduces anxiety and improves the prosocial connection between them. 

Another one that comes to mind -- I don't know if it's been done -- is at least in the field, a lot of people are combining multiple entactogens like MDMA and entheogens like psilocybin. They're doing both at the same time. Are there any studies about those kinds of things?

Dr. Barrett: We have a lot of ideas. (laughs)

Shiv: I'm sure. (laughs) 

Dr. Barrett:  It's a really interesting space. One of the challenges sometimes with designing studies of that nature is that you almost have an infinite parameter space. Oftentimes, people -- when they're beginning to consider study designs like that -- they will go to underground therapists or what's being done recreationally. 

One of the founders of the behavioral pharmacology research unit here, within which the Center exists, is George Bigelow. George is known for saying that humans are really good pharmacologists. Like, we're usually pretty good at knowing what makes us feel good, knowing what doesn't make us feel good, and then at a certain point figuring out how to use drugs in order to make us feel good. And sometimes that gets us into real trouble, right?  But there's a lot to be said about using patterns of recreational use as a template or hypothesis-generating space for how we could study things in the lab. 

The questions include, but are not limited to, when would MDMA and psilocybin and LSD be administered in relation to each other, and what doses should we expect to be active in what ways? The problem then becomes that people don't always do exactly the same thing out in the world. I think that a lot of us are beginning to ask that question, how can we use psychedelics together in concert? 

One of the terms is candy flipping. Right?

Shiv: Yeah.

Dr. Barrett: Is that LSD and MDMA?

Shiv: There's a hippie flip and a candy flip. I forgot what...

Dr. Barrett: Hippie flipping is mushrooms and MDMA. So, what dose of LSD do you use? What dose of MDMA do you use? You can imagine a dose-effect study where you're looking at multiple doses of LSD and multiple doses of MDMA. But then if you just pick fifty, 100, 200 micrograms of LSD and then forty, eighty, and 120 milligrams of MDMA, that right there is a three-by-three study trial design. That's nine different sessions. 

Then, you also have a placebo condition. You can maybe have zero, fifty, 100, 200 micrograms of LSD and then zero, forty, eighty, and 120 milligrams of MDMA. That's sixteen sessions that you're putting someone through. That's not even to think about the enduring effects of any of these conditions. I mean, you could end up learning that giving someone 200 micrograms of LSD and 120 milligrams of MDMA leads to really powerful experiences, maybe overpowering experiences, maybe really wildly transformative experiences, but then how long will it take for a person to recover from that to the degree that they would want to try to engage in another drug condition not knowing what's coming next in your blinded double-blind study design? I think there's a remarkable potential here for a lot of scientific discovery. We just have to think about what the best study designs are going to be and then just approach that carefully.

Shiv: Totally. You guys have been very methodical, and that's why I think you've pushed the field as far along as you have over the past twenty years now. When you look ahead to the next twenty years, what are you most excited about? And you can even say the next two years, but I'm just curious where you see the field going and what are the things that get you up every day very excited about this?

Dr. Barrett: Well, I think that there's the obvious goal of trying to determine whether psilocybin can be approved as a medicine to treat depression and substance use disorder. I think that we have an obligation to really push as hard as we can to find out if psilocybin really is effective in that way and if it can be approved. But beyond that, there are so many other questions. 

I do think that psychedelics are very powerful tools that we can use to try to understand the brain basis of cognition, the brain basis of behavior. And I think that while we may not be able to break the hard problem of consciousness open, there are still plenty of other very noble kinds of questions to ask including but not limited to, what is really the basis of emotional function, the basis of emotional dysfunction? How do we play with receptor systems to help push around altered states of consciousness? How do we get people into the flow state? How do we get people out of the flow state?

I think something that's remarkable that can sometimes get lost in the excitement over medical uses of psychedelics is that the very first few studies at Hopkins with psilocybin were conducted in healthy -- as we noted, high socioeconomic status, very well-educated, mostly white people -- but these were healthy people who...I don't want to say despite being healthy, but even in the context of being healthy really endorsed a substantial increase in well-being and life satisfaction, decreases in anxiety, increase in positive affect that lasted not only a day or a couple of days afterward, but weeks, months, and for more than fourteen months in most cases. 

I like to say, "Well, you had this really peculiar experience on a couch in a small building in East Baltimore. Great. What happens when you go back to getting stuck in traffic and paying your taxes?" And people say, no... that was it. One of the most remarkable findings that Roland Griffiths encountered early on was that people would endorse the statement that they had one of the top five or the single most personally meaningful and spiritually significant experiences of their lives. And it really gets you thinking...you know, we all exist on a spectrum. No one is perfect, or hardly anybody, and we all have an opportunity for growth. We can all use a bit more flourishing, and this is something that is hard to fit within a medical model of anything.

There are certainly people for whom psychedelics are not something to be encountered. That challenge for the field is really finding the hard limits of the safety space. There's growing evidence to suggest that maybe we should not be giving these drugs to anybody who has a personal or family history of bipolar disorder or psychosis. That may be a very bad idea. There are case reports of patients with bipolar, or that may have had a vulnerability to psychosis, taking mushrooms and then having a pretty traumatic and damaging manic episode. It's clear that there are sure to be people for whom psychedelics will not be safe.

Shiv: Same goes for meditation, or any sort of intervention, but certainly this one's more repeatable. It seems a more powerful version of that.

Dr. Barrett: Yes. No one's arguing that these are not powerful drugs and no one I think is arguing, at least in the scientific space, that you shouldn't treat these drugs with respect. But I think the idea is that with properly screened individuals in the appropriate setting with the appropriate preparation and support, that these compounds and this approach may have benefits for those who are otherwise well...people who don't meet the criteria for a DSM-5 diagnosis of any significant clinical severity yet still may be able to increase in their flourishing after having one of these experiences. What are the opportunities for spiritual growth? What are the opportunities for flourishing? What are the opportunities for increasing well-being?

I think it's a very tricky question to ask, especially in a culture, in a society where drug use overall is frowned upon or prohibited or criminalized. And what's the answer? I don't want to make any claims about criminalization or decriminalization. I don't want to try to make any policy statements here. I'm not a policy person at all, but I just want to acknowledge that there's an opportunity for exploration here that, if we're very careful, may have utility and value outside of the medicalization of these compounds.

Shiv: Yeah, totally. We're going to drop the link to your talk at USC a couple of months ago in the show notes. I remember one of the slides that really resonated -- and I think our audience would be interested in because they lump Schedule 1 drugs all in the same category even though they're very different, for instance, opioids and cocaine are highly addictive substances -- but I think one of the points you made is there are studies of animals being given psychedelic compounds and not necessarily continuing to try ingesting them. And also the LSD scale. I think you had mentioned in that talk about how there is actually a scale that this is not addictive. People will self-regulate because generally they won't always have a positive experience and want to keep doing it.

Dr. Barrett: Well, there, there are a couple of important points to make here. One is that there are absolutely people who meet the criteria for substance use disorder as applied to hallucinogens or psychedelics. That's clear. Those people absolutely exist. That is a risk. But the rates at which people meet those criteria are far lower than for what we would consider typically misused drugs, and the patterns of use and the kind of presentation of those people are vastly different than what you'd expect with typical misused drugs. 

We have a number of assays that we can use to try to determine the abuse liability of novel or known compounds. Some of those methods have been developed here but they're widely known in the field. Those methods include drug substitution, self-administration rates, and then other things like does the drug induce craving or withdrawal syndrome? And so if you have a novel compound and you can train an animal to self-administer that compound, the rate of self-administration then can become a proxy of abuse liability.

One of the classic examples is cocaine. You can train a rodent to self-press a lever to get cocaine. If you allow a rodent free access to cocaine, they will eventually select cocaine over water or food and they will self-administer cocaine to death, which is tragic and terrifying, but reality.  I think that's a good example of the self-administration assay and how it can be used to determine the abuse liability of a novel compound. 

On the other hand, you essentially have to bend over backward to trick animals into self-administering psychedelic drugs. There was a paper published in 2004 by William Fantegrossi where he essentially was able to get primates to self-administer psychedelics. But I believe that the rates of self-administration were far lower than you'd expect with a classic misused drug. He had to go to some lengths to coerce them, in my opinion, into self-administering these drugs. 

Drug substitutions are a good proxy. If you have a known drug that can be misused, you train an animal to reliably respond to receive that drug, and then you give them a choice between that drug and another drug. If there's a drug that is similar enough in its effects and/or abuse liability -- imagine oxycodone or hydromorphone -- and then you allow them access to fentanyl, they'll switch to using fentanyl. If another drug can substitute in behaviorally, then that's a marker that it could have similar abuse liability to another known drug. Right?

Shiv: Right.

Dr. Barrett: So, psychedelics don't substitute for known drugs of abuse use. People don't typically develop craving or withdrawal syndromes after the use of psychedelic drugs. People may have one of the most powerful experiences of their life, and you ask, "Well, do you want to do that tomorrow? And they say, "Of course not. No, maybe never again, maybe once was enough." 

Even for folks who self-administer psychedelics on a regular basis, the rate of re-administration of psychedelics is usually incredibly low and there are long periods of time between when people will re-administer psychedelic drugs. 

And that goes to the kind of compulsive drug-seeking which can be easily observed with typical drugs of abuse and misuse. This is often related to craving withdrawal syndromes. The more you use a compound the more tolerance you build up to it, the more tolerance you build, the greater the withdrawal and the craving syndromes, which lead to reuse. You get a shift of a person initially using for kind of hedonic purposes, possibly then moving to a kind of maintenance schedule so that they are avoiding the negative effects of not using. That really is the development and maintenance of substance use disorder. That's the cycle of misuse and abuse. Psychedelics typically don't engender any of that.

The final point was from the Addiction Research Center inventory. This is a questionnaire that was developed by the Addiction Research Center here in Maryland a long time ago. It's a questionnaire with lots of different items. Once you're exposed to a drug condition, you can use this to rate the strength of all of these different aspects of your experience. There are subscales within the questionnaire that really describe stimulant effects and sedative-like effects and things like this. 

One of the scales is the LSD scale within the Addiction Research Center inventory. It mostly describes the dysphoric effects of a drug. A compound that scores highly on the LSD scale is expected to be somewhat self-limiting. Those kinds of dysphoric effects are limiting the abuse potential of whatever compound you've administered to people. 

That's a really important point as well, that psychedelic experiences are not all fun and games. They're not all kinds of fuzzy flowers and pastels and kaleidoscopic imagery. They can be terrifying. They can be panic-stricken. They can involve the deepest depth of grief that you can imagine, or maybe past that, they can be harrowing experiences and it's not for the faint of heart at all. You can experience incredible euphoria, but that's absolutely not guaranteed. It's a very different state of consciousness and landscape than people are typically used to experiencing with other kinds of other drugs and substances. 

The experience of the psychedelic is not similar to being intoxicated on alcohol. It's not similar to being intoxicated with cannabinoids or being high, if you will. It's in ways somewhat similar and somewhat different than experiences people can encounter with MDMA. So, they're really not like other drugs. These experiences are not to be entered into blithely or without a lot of care and preparation. 

So, they don't act like typical drugs of abuse or misuse. They don't come with the same risks. But we should also acknowledge that they don't come without risks.

Shiv: That's very helpful. I think it's something our audience should definitely take away because they're going to encounter people who are not only interested in this field, but any drugs, really. 

If you go back to the 1990s when Oxycontin was starting to get to be prescribed regularly there was one very short paper in the New England Journal Medicine saying that Oxycontin is not addictive. It was done in a hospital setting following these patients for months, and the conclusion was it was not addictive. That's very different than, "Hey, here's some Oxycontin, take it home." 

The continuing medical education companies, in part funded by Purdue Pharma and others, wound up pushing this narrative too. But doctors are busy, nurses are busy, clinicians are busy, and so they may not fully understand the ramifications of any substances.

My worry -- and I think all of our worry -- is that any substance can be misused or used correctly, it's just a matter of the context, the set and setting, if you will. What we don't want happening is this going the way of oxycontin, or Timothy Leary back in the day. So we need to protect against that. 

Everything I've seen coming out of your center has been very methodical. Sometimes, I'm sure for you guys, it's painfully slow because the government still hasn't changed things, but hopefully we're coming across this nucleation effect in the next couple of years where the research foundation you all have built will lead to some real-life therapeutic applications. 

My last two questions for you -- and I'm sorry for taking so much of your time -- 

Dr. Barrett: Sure.

Shiv: One is, going back to your music roots...when we spoke the first time, I remember you mentioned you'd worked with Charles Lamb -- I remember his great ENT lecture about jazz creativity and rap creativity with fMRI scanners. I would love to hear your thoughts as a musician and as a neuroscientist about creativity and just any general thoughts on creativity and maybe any examples of studies you've done in this space and maybe can that be applied beyond music creativity to other forms of creativity? For example, research design is creativity or starting a company is creativity. There are a lot of forms of creativity...

Dr. Barrett: I mentioned a little while ago how I think psychedelics may help to increase cognitive flexibility and the capacity for cognitive flexibility. I think that story works quite well when thinking about creativity. What is creativity except for some form of cognitive flexibility? A paper that Ceyda and I just published in Neuron is essentially kind of a review and synthesis of a few different kinds of literature all in service of proposing that psychedelics may have their therapeutic effects by altering the balance of meta-control in the brain. 

Meta control is a series of processes by which we adapt our behavior and our behavioral strategies in order to best respond to a given demand in the environment at a time. Within the meta-control framework, you essentially have a balance of cognitive flexibility or stability. You may imagine certain tasks that would be more efficiently conducted with one or the other. 

If you have to sit down and focus and write a paper or conduct an analysis, you're really going to benefit from an awful lot of stability but at the cost of flexibility and the cost of being able to respond flexibly to other things. So, if you can approach that task with a lot of cognitive stability, you're going to be a lot more efficient and focused in conducting and finishing that task.

But you can imagine you know lots of situations in which cognitive flexibility could be helpful...maybe in responding to questions at the end of a scientific lecture. You don't know what questions are going to come at you. You have to be able to think fast, think on your feet, and adapt to a quickly shifting environment. Whereas if you were deeply entrenched in some kind of stability space, you may not be able to as efficiently and effectively respond to whatever questions are going to be lobbed at you. 

And so, we go about the world humaning, and as we're humaning, we're balancing these things throughout. But you can imagine people getting into a rut of being stuck in one or the other. It may be that people who are suffering from some form of psychosis are stuck in a flexibility mode that they can't get out of to the kind of detriment of any stability or ability to adapt to the environment in the way that's necessary to behave in an appropriate way. You could also imagine disorders or psychiatric illnesses that are marked by stability, over-stability -- depression and substance use disorder. A real reduction of your behavioral repertoire, a reduction of your cognitive repertoire, psychological repertoire, stuck in a rut of responding in only a certain way or really referencing your behaviors in a certain way.

So, the theory goes that psychedelics may acutely bias us towards flexibility in a way that is then adaptive and instructive. We're building more and more evidence to suggest that psychedelics may really tip the scales heavily in favor of increased cognitive flexibility. That may be one of the reasons that psychedelics present a risk for people who have a vulnerability for psychosis. Maybe that's a little too much. 

But after that experience, you can imagine someone who is in a state of overemphasized stability or overweighted stability being administered psychedelics acutely and temporarily rebalancing the scales in the other direction. Through that experience, people can learn the value of meta control or learn the value of cognitive flexibility.  Along the way, in a neuroplastic period that follows -- given the right context and framing and the right integration and psychotherapy -- people may be able to then integrate that into a more balanced strategy overall.

But how does this relate to creativity? Well, that may also be the process through which people -- if they do increase creativity acutely or sub acutely -- that that's the context and the mechanism through which it happens. This hits on a point that my postdoc fellow and colleague Manoj likes to try to make, which is that we don't really know. 

People like to say that under the effects of psychedelic drugs, they have insights. From clinical spaces, we do believe that it's possible that people have personally meaningful psychological insights during their psychedelic experience that really form the basis of their healing. You know, "Wow. I realized this was the aspect of my relationship that I need to fix, and that's what I'm going to fix moving forward." 

In fact, that happened to a patient in a study that I'm conducting in patients with major depressive disorder and co-occurring alcohol use disorder. After this experience, one of the participants in the study came back the next day for integration.

During integration, the first thing we do is ask a person to just walk through what they think happened. This individual said, "At one point, myself went away. I went away. But then I saw myself through the eyes of a number of my loved ones --through the eyes of my child, through the eyes of my spouse, through the eyes of my ex-spouse. I began to really see how much they love me and how much they're trying to help me." 

As they said, they finally saw how their behaviors were destructive and how they could begin to adjust their behaviors and respond more appropriately to their loved ones and their life. They said, like, "I get it. I finally know what I need to fix it. I want to fix it. I never knew before. I had no idea."

That personal insight really forms the core of -- if you'll forgive me for the language -- his healing journey after that. It's those personal insights that occur during psychedelic experiences that really seem to push people forward. Manoj's question is, are those insights real? Do we really have insights or do we just reconstruct all of this after the fact and turn it into an insight? 

You can think of parallels with other drug classes. People, when they're intoxicated with alcohol or cannabis, may think that they have really deep insights, but the next day -- even if they write them down -- it may not have been quite as groundbreaking of an idea as they thought they had. 

But do the insights that we think we have with psychedelic drugs...are they vertical? It's possible that we feel like we have insights acutely but people can also experience disorientation and some level of thought disorder during psychedelic experiences. It may be that it's not the acute drug effects that allow us creativity and insight, but the post-acute flexibility that occurs, or neuroplasticity, within which -- if we're careful to shape that neuroplasticity -- we then have really kind of insights and things that then could be applied to an engineering problem or composing an opera or writing a book or whatever creative outlet you have. 

We can be creative, like you said, in all sorts of ways with study designs, with team building exercises, with coming up with a new play that you're going to roll out on the field. I think there's a lot of potential here. If these are kind of creativity-inducing compounds, I think it comes down to meta-control, cognitive flexibility.

Shiv: That's fascinating. I'm learning so much in this podcast, and thanks for going over. Last two questions, I swear. The first is, given the work you're doing here -- the fact that consciousness is in the title of the center -- many people are excited about artificial intelligence and scared by it. I would love to hear your thoughts on how you look at AI -- especially the last couple of months of developments. What does it mean to be human? Obviously, I don't expect you to answer that question, but what does it mean to be human in an age when AI will do a lot of knowledge work better than most humans can?

Dr. Barrett: (pauses) So, I'm reading a book on nihilism. (laughs)

Shiv: (laughs) Great start!

Dr. Barrett: It's remarkable. I think we're going to be really challenged in the way Kant, Hume, Nietzsche and others were challenged to really figure out what we think knowledge is, and are things knowable? 

The thing that terrifies me about AI is the complete obliteration of trust in content. This is something that folks telegraphed a year or more ago. I mean, we're never going to be able to trust a video again. In a time where we are so toxically politically polarized, I fear that the wrong radicalized group of individuals is going to see the right -- or maybe the wrong -- deep fake to just tip us into a really dark place, if we're not there already. 

I think it was Buckminster Fuller who said something like "we have the means to end world hunger and poverty, we just don't have the political will." Now more than ever. Thought workers were the new kind of factory workers. Now, so many programming jobs are going to go away, so many writing jobs are going to go away, so many other jobs. 

I mean, we're still at the point where you can get ChatGPT to write something for you, but you really need a human to go over it and make sense of it and make sure it's accurate and real. I mean, hallucinations in ChatGPT are still a huge problem, right?

Shiv: Right.

Dr. Barrett: One of our research coordinators recently asked ChatGPT to write a summary of a paper, and they actually cited a paper of mine that didn't exist. (laughs)

Shiv: (laughs) Yeah, exactly.

Dr. Barrett: I felt incredibly humbled to be cited by ChatGPT, but for a paper that I had never written.

Shiv: (laughs) Not yet!

Dr. Barrett: (laughs) Well, maybe that's the problem! Wow, the singularity is coming! 

But yeah, I hope that we can eventually somehow use this opportunity to rethink what class structure should be in society and ask openly the question of why we're obsessed with forcing ourselves into profit models and a world in which you need to justify your existence by producing money.

Shiv: Yeah. Four percent growth every year. 

Dr. Barrett: Yeah, forever. And can we move past that? We have the capacity to feed everyone. We have the capacity to treat everyone, if we lived in a different model. 

Shiv: Right.

Dr. Barrett: But we don't live in that model. It could be a fantasy to believe that anything else could exist at this point because we're all so deeply entrenched in the way things are working now if you're the people who won't be able to break out of that and to think of different ways of the world being. But maybe ChatGPT needs to evolve and lead to restructuring all of the ways that we think about jobs for us to get there. I don't know. I'm really deeply speculating now.

Shiv: It's interesting. It's the zeitgeist, and it reminds me of this Einstein quote, which is, you can't solve a problem with the same level of consciousness that created it.  Last question: what advice do you have for our learners in our audience, and then, are there any other thoughts you want to share with us? Obviously, we can talk for hours, but do you have parting words of wisdom?

Dr. Barrett: I think we need to be optimistic, but cautious in this space. We cannot treat psychedelics like a panacea. We need to be skeptical and rigorous in approaching questions about efficacy and safety. But we need to be equally open-minded about the ways that these psychedelics may be helpful to people broadly in the world.

Shiv: Great parting words. Thank you so much for your time, Dr. Barrett. I really appreciate it.

Dr. Barrett: Thank you for inviting me, Shiv. I'm happy to share with your community.