What the (second) wave of psychedelics research could mean for mental health

In the mid-20th century, psychedelic research to treat conditions like depression began to take off, yet by 1970 almost all of that work came to a screeching halt. But guess what? It’s back, and access to guided therapy to treat various mental health conditions is becoming a reality.

Transcript of this Episode

Sam Jones: Psychedelic plants and fungi have been used for thousands of years throughout much of the world, providing intense, sometimes out-of-body visual and cognitive experiences that many describe as life-changing. But it’s 1938 that’s often pointed to as ‘the year psychedelic research was born.’ It all began with Swiss chemist Albert Hofmann who accidentally synthesized a drug called lysergic acid diethylamide, aka LSD.
 
Deboki Chakravarti: Following his discovery, psychedelic research with LSD and then other compounds like psilocybin began to take off. Although scientists didn’t and still don’t know the exact mechanism behind how these drugs cause such powerful experiences, clinicians and researchers began seeing first hand that they could be really beneficial for people struggling with things like addiction and depression. But in the United States, by 1970, almost all of that work came to a screeching halt.

Deboki: Welcome to Tiny Matters. I’m Deboki Chakravarti and I’m joined by my co-host Sam Jones.

In the last episode of Tiny Matters, we talked about depression—how difficult it can be to treat and where current options like SSRI antidepressants are falling short for so many people living with depression today. If you haven’t listened to the previous episode, I’d suggest checking that out first to get a better sense of the mental health landscape before coming back to this one.

Sam: Today we’re focusing on the possible opportunities that psychedelics—substances like LSD, MDMA, and psilocybin—offer in depression treatments…opportunities that scientists throughout the world were exploring leading up to 1970. Psychedelics are a class of substances that produce changes in the brain that lead to altered perception, mood, thoughts, feelings and behavior. And, funny enough, LSD and psilocybin are known to activate serotonin receptors on our brain cells.

In the 1950s, LSD research and LSD-assisted psychotherapy became quite popular in the United States and UK. Thousands of patients were treated and a huge number of them saw benefits. Patients being treated were mainly ones who had chronic mental health issues and previous treatments they’d received hadn’t worked.

Deboki: In the early 1960s, LSD was still legal in the US, but as LSD became a part of 1960s drug counterculture—which was in part a response to the Vietnam War—the drug also sparked a backlash that led to it becoming illegal in the US in 1968. Much of the world soon followed.  

In 1970, president Richard Nixon signed the Controlled Substances Act, classifying LSD, psilocybin, and other drugs as having a high potential for abuse, making it nearly impossible for anyone to do psychedelics research because of all the regulatory hoops a researcher would need to jump through. There was also stigma attached to this kind of work and really no funding for it.

Sam: But, with time, the stigma began to thaw, and funding started to come in from groups like The Multidisciplinary Association for Psychedelic Studies which was founded in 1986 in California, and the Heffter Research Institute in New Mexico, founded in 1993.

And today, there are more clinical trials in psychedelics happening than ever before. In 2021, the federal government granted researchers funding to study the therapeutic potential of psilocybin. The first time doing that in over 50 years. And just this past month, May, 2023, the American Medical Association approved a billing code for psychedelic assisted therapies, meaning not only is psychedelic research back but guided treatment with psychedelics is being covered by a lot of insurance companies, which means more people will have access to it.

Deboki: Many researchers made this resurgence possible, including Roland Griffiths, the founding director of the Johns Hopkins Center for Psychedelic and Consciousness Research. Over many decades, Griffiths’ work has focused on the effects of psilocybin to help treat various things, like depression and psychological distress in cancer.

David Mathai: Roland is a legend is a big reason why we've had this resurgence and psychedelic research, just really careful methodical science in the late nineties, early two thousands where a lot of people could look at the data and take it more seriously and realize this isn't just sort of a hippie counterculture relic of the sixties and seventies.

Sam: That’s David Mathai who is a postdoctoral research fellow and assistant faculty at Johns Hopkins, in the center that Roland Griffiths founded. We’re bringing up Roland for a couple of reasons. The first is that he has been a pioneer in the field. And the second is that his work is, in some ways, coming full circle.

Roland was diagnosed with stage 4 metastatic colon cancer a couple of months before this episode aired. In doing research for this episode I immediately came across an interview with him that had just come out in the New York Times. We’ve linked to it in the show notes.

Deboki: In the story, Roland talks about how one of the ways he has processed his own diagnosis is with a psychedelic. So Roland and so many other researchers have done and continue to do work that they believe will help people, whether it be processing a cancer diagnosis or finally feeling relief from chronic depression.

If you listened to the last episode of Tiny Matters you’re well aware that first line treatments like SSRIs and cognitive therapy do help a lot of people, but so many experience side effects or no change at all and are left behind. There need to be more options out there.

David Mathai: It doesn't hurt to have a larger toolbox and more tools, thinking about not just side effects and tolerability, but preferences that people may have, for example, to not be on a daily medication that may work for some folks, but not others.

Another big difference is delay in benefit too. You know, when someone's already in a place of being deeply depressed, that's agonizing. Often it's been a couple of weeks, if not longer by the time they seek help. And then to say it's gonna take another four to six weeks for the medication to kick in to be helpful, that's a lot of time to be suffering, and I think one of the unique aspects of medications like psilocybin, ketamine, MDMA, where some of that benefit can be realized much sooner, even in the frame of days to weeks. And I think something unique about psychedelics as an intervention too is how they tend to encourage a more holistic view of health. You know, the focus isn't really on the intervention and adjustments to the intervention that need to happen, but how can this experience lead to changes in wellbeing, not just symptom reduction, but even thinking about what it means for a person to be living in line with their values, with their sense of self. Those kinds of larger psychological questions that I think are really important too.

Sam with David Mathai: One of the things that trips me up about some of the psychedelic research is sort of how things are labeled. Not to be dismissive of this research, because I think it is so cool, but I think sometimes it gets lumped into this sort of quote “woowoo” category, talking about consciousness and altered states of being — that’s what it is, but is that hard to tackle in your research? How do you deal with doing really incredible research but in light of people's perception of talking about things like altered states of consciousness?

David Mathai: Yeah, it is so hard. I think we're really careful to not overstate what it is that the drugs do. Sometimes you might see things like, “achieve a higher state” or “transcend one's consciousness,” which I think can get more in the “woo” territory. What we do more clearly understand are that there are some changes on thinking, feeling, maybe one's experience of themselves. There's a lot of change in narrative experience too. So people will go on these journeys into themselves, into their past, all during the course of a psilocybin session and come out with a really different way of understanding, maybe a part related to the illness that they came seeking treatment for, how they moved through the world with that identity. So it is foreign and mind boggling.

And I would say that we don't really have a precedent for that in medicine so much. So it is tough to kind of think about how to convey this in a way that's accurate, precise, that can help others understand these kinds of experiences too. Terminology that I like is a non-ordinary state of consciousness, this is markedly different from the everyday sort of states that people experience.

Deboki: As a clinician David treats patients who struggle with a variety of mental health conditions, including depression, anxiety, and trauma. Right now he’s a scientific collaborator, study physician, and session therapist for multiple clinical trials of psilocybin-assisted interventions. But before that, his work mainly focused on ketamine.

David Mathai: Ketamine isn't always thought of as a psychedelic, but I think there are reasons why it's important to at least consider that it could be that it might work that way. So ketamine is a drug that originated as an anesthetic in the 1960s and was recognized really early on for its anesthetic use, but also for dreamlike and hallucinogenic kinds of effects, and what a lot of people don't know is that even in the late sixties and early seventies, people were using ketamine and thinking about its value as a medication that could facilitate psychological growth, healing, and other kinds of therapeutic processes, But these applications never really caught on and ketamine stayed out of the spotlight in psychiatry for decades. This really changed the most in the early two thousands when we had a few really rigorous randomized controlled trials looking at ketamine for depression and things began to accelerate after that.

The modern trials were really key for moving the field forward, moving the science forward. However, the approach that was taken in those trials was thinking of ketamine as a strictly biochemical intervention, where the benefits of the drug were thought to occur independently of the way it affects conscious experience or one's sense of self, but that's not something that we know to be true and there are good reasons to think otherwise, especially the more we hear from patients who undergo the treatment with ketamine. So my work has been focused on teasing this apart some more and thinking about ways to appropriately support treatment for depression with ketamine.

Deboki: And ketamine isn’t just something clinicians and researchers are considering for depression. Carolyn Rodriguez is the Director of Stanford’s Translational Therapeutics Lab and Professor in the Department of Psychiatry and Behavioral Sciences.

Sam: Carolyn’s research is focused on ketamine for treating obsessive compulsive disorder, or OCD. OCD is characterized by obsessions—which are intrusive thoughts, images, and urges that increase anxiety—and compulsions, which are repetitive behaviors that Carolyn told us are a way of decreasing that anxiety. In order to be diagnosed with OCD, people need to have these intrusive, continuous thoughts and compulsions for at least an hour a day, for at least a year. And it needs to cause significant distress and impairment in their lives that isn’t accounted for by some other disorder.

Deboki: Carolyn told us that she sees OCD misrepresented all the time, presented as just excessive hand washing or turning on and off a light switch dozens of times, and that can actually lead to misdiagnosis. But she said OCD can look like, for example, a person having intrusive thoughts of harm or even harming other people when they never have.

Carolyn Rodriguez: For example, an individual could be driving down the street and have an intrusive thought that they've run somebody over and they're worried. And so they'll go back to the site where they had that thought and check and see if there's been an accident, if there have been any problems, and they'll go home and they'll check to see if there's been a report on the news. OCD’s also called the ‘doubting disease.’ So it's hard to kind of have the full closure.

Even though obsessive compulsive disorder is treatable, it takes, on average, 14 to 17 years before somebody who first starts exhibiting symptoms to actually be diagnosed and get first line treatments. That delay is incredibly heartbreaking and leads to a lot of people's lives being derailed early on, and really significant impairment.

Deboki: First line treatment includes SSRIs and cognitive behavioral therapy with exposure and response prevention, where people are gradually exposed to situations designed to provoke their obsessions in a safe environment. The good news is that over half of people will respond to SSRIs and behavioral therapy and even more will respond when they’re used in combination. But that means people are still falling through the cracks.

Carolyn Rodriguez: My research really comes at that point, which is, I feel like the gap is for those individuals who aren't helped by first line medications. How can we innovate? How can we learn more about why the symptoms occur so that we can provide new and more targeted medications for those individuals.

My work has been centered around rapid acting therapeutics. And I was very inspired by previous work that had been done with ketamine. There had been a lot of really exciting data in the field that it could rapidly reduce depressive symptoms. I wondered whether it could be helpful for obsessive compulsive disorder for a couple different reasons.

Sam: Ketamine is known to cause the buildup of a neurotransmitter called glutamate that’s important for a bunch of things including learning and memory. And clinical trials have shown that drugs that regulate glutamate seem to be beneficial for people with OCD. A study in mice had also shown that dysregulated glutamate leads the mice to do this really repetitive, seemingly compulsive grooming behavior. So with this web of information indirectly connecting glutamate, ketamine, and OCD, Carolyn thought: hey, it’s worthwhile seeing if ketamine can improve the lives of people with OCD.

Deboki: In the first case study she did with someone with OCD, she found that when they took ketamine, there was a huge drop in their intrusive thoughts. Then she moved on to a small pilot study and found that within hours of receiving ketamine, half of the patients were no longer having intrusive thoughts, and the effect lasted for about one week.

Carolyn Rodriguez: That was incredibly exciting because nobody before then had seen such a rapid decrease in OCD symptoms, and also it was in patients that weren't taking any other medications or therapy. So the effects were due to the ketamine itself, as opposed to the interaction between ketamine and serotonin reuptake inhibitors.

Deboki: Most recently, Carolyn and her colleagues completed a study looking at a sample of 45 patients with OCD and found a similar result to the pilot study but that the effects lasted out to three weeks. Carolyn also told us that people often ask her if they should get ketamine to treat their OCD and she says, if you’re someone who has tried everything, go speak to your provider and see if they also think it could be helpful.

So now let’s talk about something very important when it comes to any drug but particularly something like a psychedelic where you may not be fully aware of your surroundings.

Sam with David Mathai: How do you think about ethics when it comes to these psychedelic experiences?

David Mathai: There are so many different dimensions of that, and I think one that has felt really important to me has been the responsibility of taking people into these kinds of states and what does that mean in terms of consent? Trying to convey to the degree possible what this kind of experience will be like to prepare someone for that. And I think also the consequences of not adequately preparing someone. I talked a little bit about ketamine and, and ketamine is sort of this interesting psychedelic-adjacent drug where it is being used widely already.

Deboki: So because ketamine is already FDA approved as an anesthetic it can be used to treat other conditions. This is generally how drugs work—once they have FDA approval if they show effectiveness in another arena they can often be used there without jumping through additional hoops. But David told us that there isn’t always attention being paid to the non-ordinary state of consciousness that people experience on ketamine.

David Mathai: And what are the ethical implications there of not providing adequate support for someone who does have, say, a really challenging “journey” on ketamine if you want to call it. I think the drugs also can turn up a lot of different processes. There are deep feelings of connection, there are deep feelings of intimacy, and that's why I think it's so important to have really responsible therapists in this space and to think a lot about appropriate boundaries, how to navigate those feelings that participants are having in a way that's firm, clear, where there isn't risk for some of the abuses that we sometimes hear about in psychotherapy that happen—sexual abuse, sexual misconduct, these things are really important to consider. I could go on and on. I think there are so many ethical areas that we really do need to focus on.

Sam with David Mathai: Thank you for sharing that. I think it’s really interesting and, like you said, this is an altered state of consciousness—how do you, for someone who has never experienced that, how do you explain that to them before they come in? It feels kind of impossible. How do you conceptualize that?

David Mathai: It's tough. Yeah. Is that a rhetorical question or…?

Sam with David Mathai: Yeah, it was, but if you have something you wanna add I would love to hear it <laugh>.

David Mathai: You know I think you'd be surprised that how many people have some way of thinking about these kinds of states and whether that was getting pain medicines or anesthesia, and remembering what that kind of experience was like. Other people have experienced meditation or different sort of non-ordinary states that they can maybe draw from or use to relate to the experience. But for many people, especially with the doses that are used in most of the trials, you're stepping into an experience that doesn't really have precedent. So I think a lot of that comes with as much education upfront, you know, mutual conversations about what the experience will be like. And I think the importance of just trust for everyone involved.

Sam with David Mathai: I think sometimes when people think about using psychedelics in medicine, it's not like they're just gonna show up at CVS and CVS is gonna be like, “here's your magic mushrooms have a good day.” This is a guided experience. Tell me a little bit about what you see for the future of psychedelics in medicine as a treatment and what that would look like.

David Mathai: I think we're really close actually. And maybe much closer than people even recognize. MDMA assisted therapy for PTSD is projected to be approved by the FDA in 2024, so next year. And psilocybin for treatment-resistant depression is also in advanced phases of the clinical trial process. So all of this is a really important step. Taking in the risk-benefit analysis, making sure that the data says what the researchers are claiming that it says. There is something here to show that we have a really helpful intervention, and that we can manage whatever the risks are in ways that will ensure safety for patients. After that, I think there will be different kinds of complexity. A big one that I can anticipate is just thinking about how these treatments will fit in with existing treatment infrastructures.

Like you said, you're not going to go to CVS for psychedelic assisted therapy, at least not yet. And I think there are gonna be lots of regulations in place thinking about what is a safe way to roll these drugs out in ways that are going to be helpful for people. I personally am in favor of a lot more support early on and kind of coming in more cautiously when we think about the amount of preparation that individuals should have going into these kinds of experiences,  making sure that we're in settings that promote more positive experiences as opposed to, say, in a hospital ER where things can get really chaotic.

Deboki: David also said it’s important for people to have time after sessions to integrate what just happened. These can be really dramatic, intense experiences, so he says it’s important to have support provided by staff to be able to make sense of these experiences and integrate any benefits into everyday life. And so there needs to be staff trained to do that.

David Mathai: From my psychiatry training, I think I did get a lot of really important training just in terms of being with people, supporting them through difficult experiences and states, but something that didn't really prepare me for the kinds of experiences that we're supporting here. In some ways it did, but in other ways, this is unlike treatments that we give and very unlike what the current training is equipped to address. So I think about what does adequate training look like? How can we build these in with different organizations, different educational programs, and prepare folks to have as positive an experience as possible?

Sam: It's Tiny Show & Tell time. I am happy to kick things off. I think you kicked things off last time Deboki.

Deboki: That sounds believable. I believe that.

Sam: All right, so mine is a space one.

Deboki: Ooh, I hope you're here to talk about Stars on Mars.

Sam: I'm not here to talk about... Oh my gosh. Stars on Mars. All right. So back in 2020, researchers were going through data from the Palomar Observatory in California to look for spots in the sky that show rapid increases in brightness. Which I did not realize, but that can actually be a sign that stars are coming close enough together that one can actually suck matter from the other one. There was some particular data from 2020 that was kind of interesting. So the researchers saw that there was a spot of light that was about 12,000 light years away. And really, really quickly, it became about a hundred times as bright as it had been. Which they thought, "Oh my gosh, maybe two stars merged."

But then using an infrared space telescope from NASA, they were able to see that the total amount of energy released in that flash was around a thousandth of what they would expect if two stars had actually merged. And also you would expect some hot plasma that would indicate a merger, but all they were seeing was this chilly dust. So, what could have happened? So what they were able to figure out is that the low energy actually suggested that this wasn't two stars merging, but a star and a giant planet.

Deboki: Oh, that's cool.

Sam: And as the star ate the planet, that cold dust that they were seeing, in the story that I was reading, they refer to it as "the cosmic breadcrumbs from the stellar snack". Which I love that. I love that line. So good. So good. Planetary engulfment is what this is called. And I guess that scientists have predicted that this exists for a long time, but this is the first time that anyone has actually seen a star eat a planet. And I guess you could say this hits a little close to home, because eventually our sun is expected to consume Earth. But we have 5 billion years. But this is always, it's a good opportunity to really just ponder our collective mortality as a species. And I guess, as a planet.

Deboki: For some reason in my head, I know that it doesn't look like this at all, but it just feels very Pac-Man. That star opened its mouth wide and it just gobbled that planet right up.

Sam: Yep. Yeah. It definitely has a Pac-Man feel to it.

Deboki: And I love that phrase, "the cosmic breadcrumbs".

Sam: Yeah. And of course, we always link to the stories in the description. We've got to give credit where credit is due for a line like "cosmic breadcrumbs from a stellar snack".

Deboki: I'm here for a slightly more recent mystery, which is, what did the first animal look like? I think collectively it makes sense, our intuition says that probably the first animal was pretty simple, right? It's something that probably didn't really have much of a nervous system. Maybe something like a sponge, which is very simple. They don't have a nervous system like I just said. And they get their food by just filtering water through their bodies and kind of absorbing whatever nutrition gets through it. Something like a sponge is something that a lot of people have imagined as being what the first animal could look like. And there are scientists who do think that the DNA evidence suggests that sponges are one of the deepest branches in the animal family tree. But there's another animal that, I didn't know this, but that people have thought might also actually go back further than sponges.

And it is a comb jelly. They're oval. They live in the deep ocean. They've got these gorgeous iridescent bands that just kind of flicker. And so they're really beautiful to look at, but it's sort of weird to think of them as being an earlier animal than a sponge. Because they're a little more complicated. They have a nervous system, for example. And so that's a big one. Just the idea that they would have some kind of system in place that makes them feel just inherently more complex than a sponge. So this has been really contentious. There are scientists who think the DNA points towards sponge. There are other scientists who think that the DNA evidence points towards the comb jelly. But now there's a question of like, "Well, how should we be looking at the DNA?" One of the common techniques is to look at mutations to draw out these family trees to see how we've gone from one organism to the other.

And mutations are really useful at showing how genetic sequences have changed over time, but they're not the only kind of genetic change that can be made. And they're also sometimes misleading, because you can have something mutate one way and then mutate back. So you don't always know if the change you're seeing is indicative of a direct path through our evolutionary history. So there's a team of scientists who decided to use this other method, where instead of looking at specific mutations, they looked at basically bigger sequences of DNA that move from one chromosome to another chromosome. Kind of just like on accident. That's a thing that can happen with DNA. And basically by following this method instead, their conclusion is that comb jellies are deeper in the family tree.

So this is the newest piece of evidence for comb jellies being older. And if that's true, it's weird. Because it means the earliest animals maybe weren't as simple as we think they are. Also, that means that sponges came later, and that somehow they were like, "Well, it's great that you guys have a nervous system, but we just don't want it. We're just going to be simple here." And I did not know that this debate existed, so now I'm really invested in its outcome.

Sam: That's really interesting. This kind of reminds me a bit of the algae episode we did and thinking about photosynthesis. And did photosynthesis that produces oxygen versus photosynthesis that didn't, which one came first? And sort of the debate about that. It even makes me think about that episode and one of the researchers we talked to who said, "The further back you go, you will never know 100%." Even though you have different genetic techniques or ways of analyzing genomes of sea jellies and sponges, we are coming up with ways of trying to figure a thing out. And we will never know because we can't go back millions and millions of years. So almost nothing is ever solved. But it's cool that we get to continue to have conversations and refine what we think is true.

Deboki: Thanks for tuning in to this week’s episode of Tiny Matters, a production of the American Chemical Society. This week’s script was written by Sam, who is also our executive producer, and was edited by me and by Michael David. It was fact-checked by Michelle Boucher. The Tiny Matters theme and episode sound design are by Michael Simonelli and the Charts & Leisure team. Our artwork was created by Derek Bressler.

Sam: Thanks so much to David Mathai and Carolyn Rodriguez for joining us. If you have thoughts, questions, ideas about future Tiny Matters episodes, send us an email at tinymatters@acs.org. You can find me on social at samjscience.

Deboki: And you can find me at okidoki_boki. See you next time.