The Science Behind The Psychedelics Boom

IRA FLATOW: There has been an explosion of new research into therapeutic uses for psychedelic drugs, drugs like psilocybin, the hallucinogenic chemical found in magic mushrooms; and ketamine, which was originally used as an anesthetic and then later became a popular party drug, also known as special K. Esketamine, a form of ketamine, was approved by the FDA in 2019 for use in treating resistant depression. And just last month, Colorado residents voted to legalize medicinal use of psilocybin, following on the heels of Oregon’s legalization in 2020.

A recent study published in the New England Journal of Medicine showed promising results in using psilocybin to help patients with treatment-resistant depression. That’s in patients whom other drugs have failed to help. About a third of those who received the highest dose were in remission three weeks later. This was the largest to date to look at psilocybin’s effects on depression– 233 participants over 10 countries in Europe.

To learn more about the study, I recently spoke with Dr. Steve Levene, senior vice president of Patient Access and Medical Affairs at COMPASS Pathways. That’s the company which funded this research. He joined me from Princeton, New Jersey.

So let’s talk about how big an effect did psilocybin have on the participants’ depression. It didn’t work for everyone, right?

STEVE LEVENE: That’s right. What we saw in the study is that many participants did benefit from this treatment, but also some did not.

IRA FLATOW: And is that what you expect when you’re using psychiatric drugs?

STEVE LEVENE: It’s what we expect in general with psychiatric drugs. It’s especially what we’d expect in this population that we studied. And it’s a really critical area to focus on when we interpret this data. There is a big difference between a study that looks at major depressive disorder and one that looks at a treatment-resistant depression.

Treatment-resistant depression, the regulatory definition, is a major depressive disorder that has not responded to at least two trials of an antidepressant. This wasn’t the first episode of depression for most of these participants. In fact, most have had five, six, seven prior episodes of depression. So this is a group of people who, if you were to give them another antidepressant, we would have very low expectations that they would reach remission. And in this case, despite this being just a single administration of COMP360, along with psychological support, as you said, three weeks later, we still saw about 30% of patients in remission.

IRA FLATOW: So you’re saying you saw immediate results with psilocybin as opposed to other therapies that could take days, weeks, or months to show results?

STEVE LEVENE: Exactly.

IRA FLATOW: So if this treatment gets approved, it’s something that patients would, say, take once a month, or one to four times a year, with talk therapy, and that’s how it would be administered, as opposed to this longer course of treatment with other drugs?

STEVE LEVENE: It remains to be seen, but that is the possibility. Within this study that was just published in the New England Journal, after a single administration, we followed patients out to 12 weeks. And then a subset of them continued into a longer-term extension, where we followed them out to up to 52 weeks. And we did see that most of the patients who were in remission still at that 12-week point, the sustained responders, were able to continue that out to about six months. And then the numbers get pretty small, because it’s hard to get people to stay in a long-term study like that if there is an ongoing treatment.

With our phase 3 program that we’re starting now, we will have two pivotal six-week trials. And one of them will include a second administration. And then they will feed into a longer-term extension study as well that may include components of retreatment. And that data will tell us more about what to expect about the effect of a second administration and the durability of either one or two administrations, and what we should expect in terms of the frequency of administration, should this be FDA approved and into real-world practice.

IRA FLATOW: Now, taking any drug, of course, does not come without risks. And several patients in this study reported either suicidal ideation or self-harm behaviors. Does this indicate that psilocybin is responsible?

STEVE LEVENE: That’s an important question, a really important one. So fortunately, on the whole, this was a treatment that was very well tolerated. More than 90% of any adverse events within this study were mild or moderate. The vast majority of them resolved as of the next day. And they were things like headache, nausea, fatigue, dizziness. So that was the vast majority of them.

In all three arms of the study– so we had three arms– one was a 1 milligram group, one got 10 milligrams, one got 25 milligrams– across all three groups, we did see some incidence of suicidal thinking or behavior. Looking at those on a case-by-case basis, it does not look like that was directly connected to COMP360 psilocybin itself.

And to further explain that, first, I think it’s important to understand the context of this. The population is one with treatment-resistant depression. A key symptom group within depression itself is suicidality. And 2/3 of the 233 participants in the study did have some history of suicidal thinking or behavior. Of those who had this as an adverse event during the study, all had had that at some point in their history.

Now, entering this study, everyone had low levels of suicidality because that was one of the criteria for entering the study. So in a way, the only way to go was up. But if we actually look at Item 10 on the Madras, which is the suicide item on that scale, there was no mean change across these groups in suicidality. And also important to remember, that in this study, patients were off of antidepressants. So 2/3 of patients in the study had come in on antidepressants and they were withdrawn from them prior to the study. A third were already off.

So this is a moderate to severely depressed treatment-resistant population, off of antidepressants, in a group of non-responders, weeks after treatment. And so we think that this is likely more a reflection of the course of the illness, and to an extent that there were any differences across the three arms, likely due to chance.

IRA FLATOW: OK. So what’s next for this research? Where do you go from here?

STEVE LEVENE: Yes, we’ve had our end of phase 2 discussions with the FDA, and we are now beginning our phase 3 program. This is going to be a very large and robust program as well. It will enroll a total of about 950 participants across two pivotal trials. The first of them, we call COMP005. This will compare our 25-milligram dose of 360 to a true placebo, along with psychological support. And this will help us to really establish a true safety baseline.

And then we will look at– another study, called COMP006, that will again have three arms– so looking like our phase 2B study– looking, again, at 1 milligram versus 10 milligrams and 25 milligrams. And this will be the study that has two administrations. And this will help us to understand better whether a second administration may help a greater proportion of the participants achieve response or remission and also whether that second administration may have an impact on the durability of response.

IRA FLATOW: Dr. Levene, thank you for taking time to be with us today.

STEVE LEVENE: Oh, a pleasure. Thank you so much for having me, Ira.

IRA FLATOW: Dr. Steven Levene senior vice president of Patient Access and Medical Affairs at COMPASS Pathways, the company which funded the research we were just discussing.

Of course, this study raises many questions. What do we know about how psychedelics change the brain? What are the researchers still figuring out? And what do you want to know about psychedelics? What questions do you have about how ketamine and psilocybin are being used to treat conditions like depression, PTSD, and addiction?

You make the call, but only if you make the call. Our number is 844-724-8255, 824-SCI-TALK. Have you undergone ketamine therapy? Have you tried microdosing? Tell us about your experiences, 844-724-8255, or tweet us, @SciFri.

Just a caveat– we cannot give you personal advice. That would be unethical. But we do want to hear about your experiences and get your questions.

And joining me now to answer your questions and talk more about the latest in psychedelic research are my guests. Dr. Gerard Sanacora, professor of psychiatry and director of the Yale Depression Research Program at the Yale School of Medicine, based in New Haven, Connecticut, welcome to Science Friday.

GERARD SANACORA: It’s my pleasure to be here, Ira.

IRA FLATOW: Nice to have you.

And Dr. Alissa Bazinet, clinical psychologist, co-founder and director of research and development at the Sequoia Center; associate director of the Social Neuroscience and Psychotherapy Lab at the Oregon Health and Science University and the Portland Veterans Hospital. She joins us from Portland, Oregon. Thank you for joining us, Alissa.

ALISSA BAZINET: Thank you so much for having me.

IRA FLATOW: Let me ask you, Alissa. You’re a clinician who provides ketamine therapy and you’re advising the legalization process of medicinal psilocybin in the state of Oregon. What stands out to you from this psilocybin study?

ALISSA BAZINET: Yes. So first of all, I do believe that it’s a solid result to have such a high percentage of folks with treatment-resistant depression see remission after three weeks– or up until three weeks and beyond– is really quite amazing. But one thing that I am thinking about that does stand out to me just because I’m on the ground in Oregon where we are practically implementing this work in terms of legalizing psilocybin is the serious adverse event finding.

The COMPASS trial was really well controlled, as all clinical trials are. So it’s a little bit easier to control the environment and the variability. The folks that are accepted into the study do not necessarily– they were screened out if they had suicidality that was clinically significant. And that will not necessarily be the case for folks that are seeking treatment in Oregon.

One thing that I want to note is that we, in Oregon, did not actually legalize medicinal use of psilocybin. So psilocybin services will exist outside of the health care system. And the facilitators who become licensed will not necessarily be health care providers.

IRA FLATOW: Dr. Sanacora, could this psilocybin study, on top of the wave of psilocybin research coming out, pave the way for similar FDA approval, do you think, that we saw for ketamine?

GERARD SANACORA: Well, I think it’s the first step in that direction, but there’s still quite a ways to go. This was a phase 2 trial. It’s nice to see more rigorous, larger studies being done, but this is really the first study. And despite having a couple of hundred people in it, it’s still a relatively small study when you’re looking at measures such as safety, and especially if you’re looking at things that could happen in a relatively small percent. But up to 5%-10% of people, if you’re treating thousands of people, are a lot of people. You really have to have these larger studies with longer exposure times to really feel much more confident about the results, especially when it comes to safety.

IRA FLATOW: How does psilocybin and ketamine compare in terms of efficacy? Do they affect the brain in similar ways?

GERARD SANACORA: So that’s a very difficult question to answer. I think there are two questions there. One is in terms of efficacy. One is the mechanism. Maybe I’ll address the mechanism question first. We don’t really or completely understand how any of these drugs– in fact, you can say that for pretty much any drug used in the treatment of psychiatric illnesses– how they work.

Ketamine was pursued largely because of increasing evidence suggesting that the glutamatergic neurotransmitter system, which is where ketamine primarily targets its effects– at the NMDA, or glutamate, receptor– glutamate had been shown to be involved in the pathophysiology of depression in several animal models and even in some human investigations. And there was increasing evidence to suggest that glutamate plays a central role in modulating neuroplasticity, the way the brain adapts to changes.

And it was thought– this was really at the turn of the millennia– that a drug that could target that system may have beneficial effects. And that was some of the studies that led to the current use of ketamine, based very much on that idea that it was targeting glutamate. Since then, we’ve learned that it’s probably much more complicated than that.

We realize there are probably many other neurotransmitter systems that are either proximally or more distally involved in the effect, but also other effects, or what we would even consider non-specific effects of the treatment, such as hope, optimism, changes in expectation, that probably all also play a large role. While the more classic psychedelics like psilocybin target primarily serotonin, there’s probably a lot of overlap in the downstream mechanisms.

IRA FLATOW: Dr. Bazinet, many patients who have done ketamine therapy talk about a profound shift in their perception and experience of the world. And as a therapist, you help guide them through this experience. Can you talk a little bit more about that process?

ALISSA BAZINET: Yes. So one thing that I like to say is ketamine, and other psychedelics as well, are really catalysts to a psychotherapeutic process. So it really is the combination of the medicine and the therapy that produces the result. And so what I’ve seen with clients with ketamine– and I’ve worked with some who I’d had in private practice regular talk therapy for years– go through a six-week protocol of ketamine and suddenly have insights about things that happened in their past or a way that they were relating to their self or someone else or the world that was completely different than anything that they had thought about or experienced before.

And so those realizations can be very profound and very acute and can cause complete shifts in the way that they are interacting, and interacting with themselves. So it’s really quite miraculous to observe when it works. It doesn’t work for everyone.

IRA FLATOW: Yeah. Let’s go to the phones, to someone, I think, who says it’s working for him, Mike. Mike, in Sioux Falls, South Dakota, hi, welcome to Science Friday.

MIKE: Hi. Thanks for having me on.

IRA FLATOW: Hi. Go ahead.

MIKE: I’m actually on the way to an appointment right now. It’s actually a few hours’ drive for me from where I’m at. But I’ve done three or four appointments so far. I’m a combat veteran.

IRA FLATOW: His car phone is– you’re breaking up. I’ll just paraphrase what he has to say on my screen. He says he’s on his way to his ketamine therapy appointment, and it has worked well for him so far. How many appointments does it take to know that it’s working, Alissa?

ALISSA BAZINET: It really varies on the individual. Sometimes you see a drastic change after the first session. I’ve had clients do one or two sessions and say they don’t feel they need anymore because the issue that they were coming to therapy for is resolved. Others, it may take multiple sessions. We do an average protocol at our clinic of six sessions– six weekly sessions. And most of the research suggests several sessions within a short period of time, with results lasting up to four weeks or so– is what the research shows.

There hasn’t been a whole lot of research on the therapeutic component added to the ketamine. So a lot of folks are going to infusion clinics and just getting the ketamine administration without the psychotherapeutic component.

IRA FLATOW: Let’s go to the phones. Let’s go to Tiffany, in Kentucky. Hi, Tiffany.

TIFFANY: Hi. I would like to share my experience. I microdose with psilocybin on my own. I suffer from depression. In more than seven years, I’ve made dozens of attempts on my life. I exhibited self-harm behavior. And then I just– I microdose. The longest I did it was for eight days. I would grind up mushrooms and put them in a gel cap and swallow them. And I realized, after about day four or five, that my natural baseline was a smile.

I did figure out, though, that I go into it with intention. There is a lot of trauma in my background that I’m working through. But with therapy and periodic microdosing, this is the best I have ever been in my life.

And at the height of my illness– I say that because I’m in recovery now– I actually work as a peer support specialist– which means I’ve done the work. I’ve put in the work. I got better. I’m not saying I’m perfect. But I help people with their depression. At the height of my illness and my battle, I was taking 33 pills a day, 11 different psych meds. And that was too much. I was numb. I couldn’t feel anything.

IRA FLATOW: Well, that’s an amazing experience, Tiffany. Let me get a reaction. Thanks for calling.

Dr. Sanacora, let’s talk about microdosing. As Tiffany was saying, it’s taking smaller doses that don’t produce some of the psychoactive effects. It was working for Tiffany, when these other drugs didn’t work. Is that common?

GERARD SANACORA: Well, I think it’s very important for us to remember that these illnesses tend to have a course that waxes and wanes. So there is some natural periods of response and remission. And as I mentioned before, this idea of non-specific effects, this idea that the simple act of taking control of your treatment, or feeling that you may be getting benefit from unique treatments, is actually quite powerful– is in fact extremely powerful.

IRA FLATOW: Are you talking about the placebo effect here?

GERARD SANACORA: I’m talking about the placebo effect. But it even goes beyond placebo. It’s really the non-pharmacologic effects. But placebo is clearly part of that– which is quite powerful. And not to diminish it in any way. In fact, that’s something that I think we really need to understand much more broadly and to optimize our use of it.

But we have to be very careful from making a causative relationship between these events, where we see something changing alongside with something. We can’t really say with great confidence that it’s the drug. In fact, you’ll see in many of these studies the hard part isn’t showing a benefit from the drug. It’s showing a benefit greater than the placebo or very low dose treatment.

IRA FLATOW: Very interesting. Let’s go to Allison, in Birmingham, Alabama. Hi, Allison.

ALLISON: Hi, hi.

IRA FLATOW: Hi there. Go for it.

ALLISON: Long-term listener, first-time caller. All right. So I have a friend who is suffering from postpartum depression. She had existing depression prior. And she is– when she called me and asked, I really didn’t know. So I went to research it. And there really wasn’t that much research on postpartum depression and the effects of ketamine on what is typically a pretty stubborn, frustrating time for a woman to get any kind of treatment at all. Nothing seems to work traditionally. It’s very, very hard, I think your expert would agree.

But I guess what I want to know is what is the new research as it pertains to postpartum depression, and then, again, how does it affect breast milk and breast feeding? Should it be stopped?

IRA FLATOW: Allison, thanks for calling. Dr. Bazinet, can you answer that.

ALISSA BAZINET: Yeah. I’m not aware of any specific research on ketamine for postpartum depression, but that doesn’t mean it doesn’t exist. There are more and more studies on ketamine’s effects for all sorts of indications coming out all the time. I haven’t yet read that research specifically. But I don’t think it’s too far of a leap to suggest that it would likely be beneficial, given ketamine’s effects on treatment-resistant depression and suicidality and other mood disorders– bipolar depression as well. And I’m not sure about the breast milk question either.

IRA FLATOW: OK. Let’s go to Bob, in Upstate New York. Hi, Bob.

BOB: Yes, hi.

IRA FLATOW: Hi there.

BOB: Pleased to be on the show.

IRA FLATOW: Do you have a question?

BOB: Well, I have kind of a question and a statement. I don’t doubt that many people enjoy these medicines that are being discussed. And I’ve heard them discussed at professional conferences. But my concern is that we have testimonials– even on your show right now– we have industry people talking about these things. And you have most psychotherapists haven’t even learned scientifically validated treatments for depression yet. And they’re basically using old-fashioned psycho-dynamic therapies without adding things that have a rich and validated history.

When you think about these medicines knocking people out of refractory depression, there are other things as well. ECT knocks people out of refractory depression. It knocks people out of a mania, which nothing else will do. If drugs have failed, ECT is the only thing. But the long, long-term effects on people’s characters, people’s personalities, their family structures, their early schema, a lot of the things that lead to depression or trigger depression later on, this really hasn’t been studied. And a lot of these things haven’t been studied one against the other. The ends are rather small.

And I’m not saying there’s nothing to this, but I am saying that, for 30 or 40 years, women were told you should take estrogen. It’s great for you. And all of a sudden there was meta-analysis of–

IRA FLATOW: Bob, let me get a reaction.

BOB: –cancer studies, and estrogen causes cancer.

IRA FLATOW: Yeah, Dr. Sanacora, valid points here that Bob’s making?

GERARD SANACORA: Yes, I think Bob is making several valid points here. You really do have to look at what the total body of data is and the rigor that was used in collecting the data and the size of the data. The best sample size we have, at least for the ketamine type drugs, is what is available for esketamine delivered intranasally that has the FDA approval. That went through the large FDA approval process. And that has data for several hundred people going out over several years. So we do have good data for that. And that’s specifically for treatment-resistant depression or, to a lesser extent, depression associated with suicidal ideation.

But the further we get away from that formulation used by that drug regimen for that duration, we get further and further away from anywhere where we’re standing on solid ground.

IRA FLATOW: Well, we’ll talk more about this. This is Science Friday, from WNYC Studios.

Dr. Bazinet, do you agree?

ALISSA BAZINET: I do agree, to some extent. Yes, I think Bob makes many valid points, and that over-generalization of research results is certainly problematic. I do think that that is what led to some of the policy changes in Oregon and Colorado, because we have these research results and now we have legalized psilocybin services. And there’s much, much more to learn about these medicines.

IRA FLATOW: Yeah. Let’s go– maybe one more call, from Tom, in Atlanta. Hi, Tom.

TOM: Hey there.

IRA FLATOW: Hey there. Go ahead.

TOM: So I actually have a question. I’m a provider. I’ve supported clients who were using ketamine. And I’m curious, as the discipline moves forward, as we see psilocybin starting to move into the field, what’s the training landscape expected to be like?

IRA FLATOW: How do you get trained for doing this is what you’re asking? Yeah.

TOM: Right. It seems like they’re different enough that maybe the training that we have for ketamine is not going to be a one-for-one likeness for psilocybin as it moves forward.

IRA FLATOW: Alissa, you’re a clinical psychologist. Can you elucidate on that?

ALISSA BAZINET: Yes. So there are several training programs that exist that train practitioners in ketamine, psilocybin, and MDMA, as those are the three that are most likely to be legally available in the near future. So you can get a certificate in psychedelic studies. I know CIS, in California, is one of those; Naropa University; I believe Berkeley as well. So there are multiple universities that have these certificates. There are also independent training programs that exist online, or a hybrid of online and in-person. And there are also ketamine-specific trainings. I really like the Polaris Insight Center’s training. They have a really comprehensive ketamine training if you’re looking to just work with ketamine.

IRA FLATOW: Dr. Bazinet, I know, in the short time we have, you are currently doing a study with veterans to take MDMA and undergo group therapy to treat PTSD. What are you hoping to come out of that?

ALISSA BAZINET: Yes. So this study will be a proof of concept, safety and feasibility study. So it is the first clinical trial to look at group psychotherapy for MDMA for PTSD at the Portland VA. So we’re hoping to assess if that is effective in that format. The thought is that having group connections, MDMA can really increase bonding and trust. And with military veterans, a lot of group psychotherapy takes place at the VA anyhow. So we’re interested to see if the MDMA protocol will adapt nicely to the group format.

IRA FLATOW: Well, we have run out of time. So much to talk about. I’m sure this is something we will have to get back to. And I thank my guests. I thank my listeners for calling in. Thank you, Dr. Gerard Sanacora, from Yale School of Medicine; Dr. Alissa Bazinet, clinical psychologist and researcher at the Oregon Health and Science University, and Portland Veterans hospital. Thank you, both. I wish we had more time.

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