Psilocybin Therapy Works… But Not Like You Think, with Compass Pathways

If one or two psychedelic sessions can produce measurable improvements in treatment-resistant depression, why does modern psychiatry still rely on daily medication?

In this episode of Divergent States, we sit down with Dr. Steve Levine, psychiatrist and Chief Patient Officer at Compass Pathways, to break down their newly released Phase 3 clinical trial results for COMP360 psilocybin therapy.

But this isn’t a hype piece.

This is a critical look at what the data actually shows—and what people might be getting wrong.

We explore:
– What Phase 3 trials really mean (and why they often fail)
– Why a “3.8 point improvement” is more significant than it sounds
– The difference between clinical psilocybin therapy and underground use
– Why one or two sessions may work—but not for everyone
– The role of neuroplasticity, subjective experience, and “set & setting”
– Why scaling psychedelic therapy is harder than it looks
– The tension between commercialization and psychedelic culture
– What FDA approval would—and wouldn’t—change

Compass Pathways has now run over 1,000 participants across Phase 2 and Phase 3 trials, showing statistically significant results in treatment-resistant depression. But translating that into real-world treatment is a completely different challenge.

This conversation pulls back the curtain on what it actually takes to turn psychedelics into medicine—and where the limitations still are.

Because this show isn’t about psychedelics being amazing.

It’s about understanding what’s true… and what holds up under scrutiny.

🎧 Subscribe to Divergent States for grounded, skeptical conversations in psychedelic science, culture, and harm reduction.

💬 Join the community Discord via r/Psychonaut (link in subreddit)

🎶 Music:
Elemental by [Drip]

 ⚠️ This podcast is for informational purposes only and does not constitute medical advice. 

Chapters:

 00:00 If Psychedelics Work, Why Daily Medication?
 01:15 Why This Isn’t a “Psychedelics Are Amazing” Episode
 04:00 From Daily Pills to 1–2 Treatments
 06:45 Why Ketamine Wasn’t the Breakthrough
 09:25 What Phase 3 Trials Actually Prove (And Don’t)
 12:50 What Regulators Are Really Looking For
 14:25 What a “3.8 Score Improvement” Actually Means
 15:55 Psychedelic Hype vs Reality
 18:30 What Actually Stood Out in the Data
 21:40 Why Psychedelics Work Faster
 24:55 Is the Experience Part of the Treatment?
 25:45 Why Set and Setting Still Matter
 30:10 Will This Ever Be At-Home?
 33:00 Why Therapists Don’t “Do Therapy” Here
 34:40 The Real Problem: Scaling Access
 39:00 Commercialization vs Psychedelic Culture
 43:00 What Are the Actual Risks?
 45:10 What Success Looks Like in 10 Years
 47:10 Why Access Matters More Than Approval
 49:50 Why This Fails in the Real World
 52:10 Outro + Patreon Integration Session 

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Transcript

speaker-0 (00:17.006)
So here's the question. If one or two psychedelic sessions can produce measurable changes and treatment resistant depression, why does the system still look like daily medication for years? And more importantly, what actually happens when you try to turn that into a real scalable treatment? Because it's one thing for something to work in a controlled trial, but it's another thing entirely to make it work in the real world. Welcome back to Divergent States. I'm Elite, founder of our Psychonaut, and back with Brian. How's it going, man? Oh, it's going great. How are you?

I'm doing good. You got that move going on, everything working out with you. Oh, it's going great, man. I'm up in Kansas City now. Finally just got settled. Just kind of doing my thing up here, made it to some auditions. So I'm having a pretty good time. Yeah. Kansas City is nice. Great area. Nice barbecue up there. Love Arthur Bryant. right. Yeah. So it'll be interesting to see how the psychedelic scene is up there.

what kind of, what they've got going on. But yeah, kind of like this show isn't about how psychedelics are just amazing, because that's honestly the easy part. This is about understanding what's actually true, what holds up under scrutiny, and what we might be getting wrong. So today we're going to be talking with Compass Pathways. They just released their phase three psilocybin trial results for treatment resistant depression.

And we're going to be joined by Dr. Steve Levine, psychiatrist, chief patient officer at Compass. We're going to walk through those results, what they actually mean and what the limitations are. So just starting out when you hear the phase three trials, like what does that mean to you, Brian? Well, to me, think it's great. We've got people out here trying to create a real medicine that actually works and helps people.

I don't think you can really ask for more than that. Right. I mean, yeah, and it's kind of cool because we're going to dig in today a little bit about what that really means and kind of like what it doesn't mean. So let's jump into that.

speaker-0 (03:59.672)
So yeah, part of what we're hoping to explore today is both the science behind these trial results and how Compass is thinking about bringing this kind of therapy into the real world. Dr. Volivian, welcome back to the show.

speaker-1 (04:10.786)
Thanks for having me back.

speaker-0 (04:12.398)
And it's great to see you as always. So for decades, psychiatry has relied mostly on medications that people tend to take, you years at a time. But psychedelic therapy seemed to be pointing towards a different model where, you know, it's one single experience has, you know, an effect on people for years to come. So from your perspective as a psychiatrist, how big of a paradigm shift is that?

speaker-1 (04:40.856)
Short answer, it's enormous. Let's first just start with the recognition that amongst the mental health crisis that we're in, there are many specific conditions for which patients really have limited options at this point. And across a range of healthcare conditions, even those that have some options to bring to bear, for a variety of reasons, whether it's efficacy or tolerability or acceptability.

the ability to continue on that treatment over a longer period of time, there are millions of people who are currently underserved. And as you said, when we focus in specifically on depression and particularly treatment resistant depression, which are folks who've been failed by multiple lines of treatment within their episode of depression, there are very, very few options. And the ones that exist are

effective for some people and acceptable to some people, but leave a lot of people wanting both in terms of efficacy, but also as you were highlighting, the actual experience of taking the treatment. Traditional antidepressants are typically picked up at a pharmacy, taken at home on a daily basis, mostly oral medications, but you need to take them for quite some time, weeks to months, before you even know if they will help you. And then if they do,

then you're likely on them for the foreseeable future. And if you are able to try to stop them at some point, they can be very difficult to come off of for some people because of withdrawal effects. What we are seeing with psychedelics and specifically right now with COMP360 psilocybin for treatment-resistant depression, and this is based on data that we announced recently from our two phase three studies, for a subset of patients, this treatment, a single treatment, one or two,

may be almost immediately effective. You will know right away if it helps you. And then one or two treatments may have a durable effect out to at least six months. And that is a scale of durability just light years beyond anything available today.

speaker-0 (06:49.806)
Right. really want to dig into those 360 results. They sound awesome. But before we really get into that, when did you start thinking psychedelics could really change the field?

speaker-1 (07:00.91)
Well, Compass has been at this since 2016 now. Me personally, I've been with Compass for about five and a half years. And the short version of the story of my path to Compass was I'm a psychiatrist by training. And I've had the very difficult experience for years of sitting across from people who have not been sufficiently helped by traditional antidepressant options.

Between 2010 and 2020, I wound up treating many of those patients first with ketamine and then once J &J's ketamine product Spravato was approved in 2019, Spravato. And that represented in some ways an iterative improvement over traditional antidepressants in the sense of being more rapidly effective for some people and not being taken every day at being a more episodic treatment. But it didn't...

it didn't solve the problem. didn't represent a magic bullet by any extent in the sense that it's not a particularly durable treatment. Patients who have ketamine or Spirvato typically have eight treatments in the first month. It's twice a week for the first four weeks. And then treatment after that is for most people weekly. And that makes it really difficult both to continue to adhere to the treatment, because that represents 25 to 50

multi-hour treatments, three-hour treatments per year. And so even if you recover and now you're able to return to work, let's say, that's not very compatible with most people's work schedules. Along with some of the access challenges, when Spravato first launched back in 2019, it was very difficult for patients to actually access that medicine for various reasons and very difficult for healthcare providers to deliver it to them.

I was on the provider side at that point and I lived through that trying to get access from my patients to these new treatments. And that's what inspired me to join Compass because I was really intrigued by the early data looking at the use of COMP360 psilocybin in treatment resistant depression, but recognize that your FDA approval wouldn't be a guarantee of patient access. And there was a lot of early work to be done to start to put things in place that would lead to

speaker-1 (09:21.998)
know, hopefully more likely this getting to the people who are waiting.

speaker-0 (09:26.732)
Yeah, and a lot of people kind of going back to easy start of dementia with the phase three trials. A lot of people here phase three trials and assume it means, you know, approval is right around the corner coming any day now. But this stage is actually one of the hardest parts of drug development. What exactly does a phase three trial test, you know, what does it test that earlier tests didn't?

speaker-1 (09:49.208)
Now that's a great question and as you said, something that's probably not widely understood. As you move through the phases of clinical trials, phase one, phase two, phase three, generally you are increasing the size of the studies, you're including more participants. And you're moving from in the earlier phases studies that are more focused just on early safety and finding the right balance of what's likely to be an efficacious dose effective as well as safe in relative to the condition you're trying to treat.

And then as you move into phase three, which is the last phase prior to submitting an application to FDA for approval, these are your largest studies. You're at this point really trying to replicate efficacy that you may have seen in phase two and answer additional questions not only for regulators, but also potentially for the clinicians who may prescribe this, for the insurance companies who will hopefully pay for it, et cetera.

As you point out, merely going into phase three doesn't mean that you're at the end of the road, particularly in psychiatry and especially in depression, and then especially, especially in treatment-resistant depression, because sadly the halls are littered with investigational compounds that looked promising in phase two and then failed in phase three. And that actually includes a lot of FDA-approved antidepressants.

that tried to prove efficacy specifically in a treatment resistant depression population and failed. In fact, even Spravato, which really is the only FDA approved medication option at this point that's marketed for treatment resistant depression, it took them five trials to get the required two positive studies to get an approval. One of the things we're really excited about is we are now three for three in our trials. If you include our large

very rigorously designed phase 2b study. And now these two phase 3s we've just reported out on, we have successfully, in a highly statistically significant way, proven efficacy at our primary endpoint in all three studies.

speaker-0 (11:54.254)
Yeah, that's a good point. I guess it kind of helps with psilocybin. We've known about the compound for centuries now. And we kind of know it works little, so that helps. You mentioned that it's a lot larger of a trial for phase three. How much larger was the sample from phase two to phase three?

speaker-1 (12:15.662)
Significant, yeah. Our 005 study, our first phase three, I believe it's 258 participants, our 006 study, which is an international study, was 500, I don't remember the exact number off the top of my head, but in the mid-500s. And so if you combine 005 and 006 and then add in...

our phase 2B study, which was 233 participants. We've now included over a thousand participants in our studies.

speaker-0 (12:50.29)
wow. Yeah, that is that's really big. What exactly are regulators really looking for by the time you get to this stage?

speaker-1 (12:58.584)
Well, one of the things while we're talking about numbers is evidence of safety in larger numbers of participants. And as you said earlier, there's some historical knowledge and experience of using at least the natural forms of psilocybin. And so we know something about how the drug affects the body. But in terms of a regulatory approval, it's really important to understand in a defined population in a specific group of people.

the safety and efficacy profile because that may look a bit different than somebody who let's say who doesn't have a diagnosed mental health condition and so what's important to regulators as I was just saying is a sufficient number of participants to demonstrate safety and Then there's the efficacy question Are you able in a statistically significant way that gives people confidence that beyond chance? It's actually a drug effect that we are seeing

that's affecting the clinical course for these patients. In our case, because it's treatment resistant depression, we use a scale called MODRIS, which is an acronym for the Montgomery-Osberg Depression Rating Scale, very commonly used clinician rated scale. And we are looking at the difference from our active arm to our control arms and the change in the MODRIS score from baseline to our primary endpoint, which was week six in both.

studies.

speaker-0 (14:24.13)
Yeah, that was, I remember seeing it was like about a 3.8 difference that just quite a big, quite a big step for, you know, especially in a treatment resistant depression, which doesn't really go anywhere. So.

speaker-1 (14:39.2)
Exactly. know, 3.8 points on Modris. That doesn't necessarily mean much to most people. That's just sort of a cold clinical number with a scale people aren't familiar with. So to really bring it home, if somebody with treatment resistant depression had a 3.8 point change relative to the comparator on their Modris, that is very likely to be somebody who would say, treatment really helped me. I want to continue on it. It is very likely life changing, if not life saving.

it's likely to translate into, you know, really impactful movement in their ability to function, to have a quality of life, to participate in life again. So that's why this is such a big deal. And then another thing to mention, and one of the things that's really remarkable about that number as a number, that reflects in the 006 study,

two treatments, two administrations, three weeks apart. In 005, it was about the same. It was a 3.6 point difference after just a single administration. So one or two treatments six weeks later, a very comparable effect size to Spravato, where at the same time point somebody would have had to have had 10 treatments.

speaker-0 (15:57.902)
Yeah, wow. So that's a big difference. It's really encouraging. So from your perspective inside the clinical development process, what do you think people really misunderstand most about these results?

speaker-1 (16:12.28)
What do they misunderstand about the results? Well, I think number one is something that I was speaking to just before, which is really contextualizing what a 3.6 or 3.8 point difference means to a patient. With some other antidepressants, typical effect sizes have been a two or three point difference, sometimes four, sometimes five.

I think because of the hype around psychedelics, some people were hoping that somehow this would be very exceptional and they would see really inflated differences. And maybe there was a little bit of a disappointment around a comparable effect size to what we saw with Spravato. But the misunderstanding that that reflects is how truly impactful that can be at the patient level and such a paradigm shifting delivery of this treatment.

I think another thing that people often misunderstand is the length, the complexity, the difficulty, the costliness of running this type of research. I think we all feel the pressure of getting new treatments to these patients as quickly as possible, and it can feel frustrating, especially in the case of psilocybin, where we've been using psilocybin in a variety of contexts for eons. There can be that frustration of why do we have to go through this process?

But it comes back to, think, what I was saying earlier, that there can be a big difference between somebody taking a natural mushroom product for any kind of reason in a different context, whether it's a retreat or ceremonial or whatever it might be, and somebody living with a severe mental illness who is very vulnerable, who may be taking other medications, who may have other either psychiatric or medical comorbidities.

And it's really important that we don't cut corners, that we really lead with science and that we run rigorous trials. Unfortunately, it does mean that that takes some time and we can't just go directly to patients, but hopefully it's in the service of if we do have an approved product, we can have some confidence that this will be safe for patients and we understand the right way to deliver it.

speaker-0 (18:27.458)
That's, yeah, it's really surprising. What do you think stood out most to you? Stood out most to you about that data.

speaker-1 (18:35.552)
A few things really jumped out to me. First and foremost, as I've said a couple of times already, the fact that we saw that for some patients after just one or two administrations, there could be an almost immediate benefit that could be durable out to at least six months is really, really exciting. Number two, the safety profile.

We saw in these studies that COM360 was generally safe and well tolerated, and that's really, really reassuring. You could have the most efficacious drug in the world, but if it's going on the other side to come with it, significant risks, significant side effects that people may need to tolerate or even risk to life, then that really impacts the practicality of the treatment and whether people would accept it.

seeing a very clean safety profile was extremely reassuring. Another thing that jumps out is in a presentation, we showed an overlay of the primary endpoints, the first six weeks of both phase three studies. And what you see is that in the first three weeks, there is almost a direct superimposition of the 25 milligram arms from both studies.

They are directly on top of each other, which is something you almost never see, such consistency in the results across multiple trials. Like I mentioned earlier, sometimes you get contradictory results in these studies. You run five and you only get two that work. Or even if you have multiple positive studies, the shapes of those curves may look very different. In this case, again, we see almost a direct overlay in those first few weeks, which really speaks to the quality of the design and execution of the trials.

And then at week three, where in the O06 study, people then got a second administration of COMP360, you then see a drop off the line showing that there is an impact of a second dose. And so it'd be really interesting when we get the second part of the O06 study, the longer term 26 week data to see the impact of longer term if people get a potential third dose. Because another thing that we saw

speaker-1 (20:59.232)
in the 005 study, and I know this starts to get a little bit convoluted, but as a reminder, the 005 study was just a single administration before the primary endpoint. But there's a part B that runs out to 26 weeks, six months, where people are potentially eligible to have another treatment. And what we saw there was that for the group that had at least a clinically meaningful benefit after the first treatment,

For those that received a second treatment, 40 % of them went into remission.

speaker-0 (21:33.516)
Bye.

speaker-2 (21:33.592)
Wow. Which is a big, deal.

speaker-1 (21:34.71)
especially in this population.

speaker-0 (21:38.264)
Yeah, that seems really surprising, not so at the same time, I guess. So one thing that really stands out with psychedelic therapies is, as you're talking, how quickly they seem to work. And traditional antidepressants can sometimes take weeks or months to even really kick in. But treatments like ketamine and psilocybin sometimes they produce improvement within days. What do we think is happening there biologically?

speaker-1 (22:08.13)
That's a great question. It's one that we don't fully have an answer to at this point, but we have some information, we have some hints that can allow us to form some theories around that. And let's start with the distinction that you drew between the onset of effect for traditional antidepressants like SSRIs versus what we're seeing with more rapid acting treatments like COM360 or ketamine. Ultimately, they may work somewhat similarly.

in the sense of they both have the potential to increase the plasticity of the brain, that capacity the brain has to grow and heal and change over time. With SSRIs, the mechanism may be a very indirect one, where a number of steps have to happen between first ingesting that drug and then taking it every day and actually seeing the positive result, which is that enhancement of plasticity.

In the case of COMP360, it is acting at serotonin receptors on glutamate neurons in the brain that very quickly lead to a shifting in the pattern of connectivity of different regions of the brain. It's kind of taken offline in a way immediately and then is able to kind of reconnect. It's almost like a reboot in a way that may enable the shifting of patterns of thinking from those that are characteristic of depression.

negative thinking about yourself, about the world, about yourself and the world, to enable shifts of that to less depressive, less ruminative ways of framing your experience.

speaker-0 (23:50.306)
Yeah, how much would you say that the subjective experience itself contribute to that?

speaker-1 (23:57.806)
It'll be interesting to see what we see about that in phase three, because we do measure that experience. We primarily use a scale called the 5D ASC, five dimensions of altered states of consciousness. And in phase two, in that 233 patient phase two study, we did see that some elements of that scale correlated with the therapeutic benefit. In particular, and I know this is a squishy kind of term, but oceanic boundlessness.

which I suppose in some ways describes a sense of unity, of oneness with the universe, kind of like if you were out in the middle of the ocean and you could see all the way out to the horizon. That did seem to have a moderate correlation with the therapeutic benefits. So now, with about 800 some odd more patients and measuring that in the phase three studies, we'll look to see if there are kind of a replication of that correlation.

speaker-0 (24:55.79)
Yeah, it reminds me there was a study that just came out recently about high effects of psilocybin on neuroplasticity. But I want to say in that instance, it would have had to have been something like 10 grams for a normal human to have the same kind of effect on that massive neuroplasticity considering. But it's really interesting to see how COM 360 is doing the same thing, kind of on a smaller scale.

So again, psychedelic therapy really just isn't about taking the pill. involves preparation sessions, guided experiences, integration, journaling. How important is that therapeutic context instead of just going out and taking shrooms on your own like we're talking?

speaker-1 (25:45.378)
That's a really important question and I can approach it in a couple of ways. First, there's a safety consideration. There certainly are some people, maybe, maybe not those who might have a diagnosis, not the health condition, who might feel safe and comfortable having that experience on the road, but that is very different than what we're doing. And really probably the more significant risks of taking any kind of a psychedelic.

are more around that context of making sure that you feel some psychological safety, that you have trust in the people that are around you, that you, because you are in a more vulnerable state, that you, that that vulnerability may not be exploited in some way. And so, you know, that's why we think that the context in which we're delivering our Comp360 and our trials and, you know, hopefully in the real world, if approved, is really critical and is so different than just the

you know, more kind of informal taking of a natural product. And so with that and going through some of the steps that you named just a moment ago, we do take some care in our trials to prepare people for the experience. Particularly since the overwhelming majority of people in our trials have not previously had psychedelic experiences or psilocybin. In fact, in phase three only

around five to 7 % across the arms of people had that prior experience. So given that they're naive to the experience, but also given the very powerful nature of that experience, and so they're prepared and feel safe, we have a model that's really guided by the principles of trust and psychological safety that ultimately kind of teaches the participant how to be a COM 360 patient, if you will.

Right? How to self-navigate that experience. Because I think that is something that's commonly misunderstood. Many people here commonly use language like psychedelic assisted psychotherapy. And they picture psychotherapy that they've had in the past and would imagine that there is an active dialogue with a therapist during these sessions. But it's actually the opposite of that. You know, partly derived from the fact that the typical experience of psilocybin is a very inwardly directed one.

speaker-1 (28:09.39)
and facilitated by people wearing an eye shade and listening to music and lying down during these sessions, there tends to be very little interaction with the support person in the room. And so going back to where I was before, all the more reason why it's important to prepare people ahead of time, to equip them with some basic skills and principles that they can use to self-navigate that experience on that administration day. And that would be things like

you know, the inner directed experience to really trust the process, to be able to focus internally and not to try to move away from that. You know, if somebody gets a bit anxious, if they're having a challenging experience, what we'd like them to be able to do is to go in and through that. And that's the primary role of the person sitting with them is if they are having a more difficult time to try to help them refocus on the experience and stay with

speaker-0 (29:05.762)
So kind of integrating somatic therapies and with the psychedelic therapies sounds and it's, I mean, it's very similar to what, you know, people have been doing for years with set and setting. You know, we always preach that, especially like on Psychonaut and everywhere else where, you know, you have the proper mindset, you're in the proper place where people won't take advantage of you, et cetera. But yeah, you bring it up, you know,

kind of doing it in isolation and doing it by yourself, I can see why it's really good to have that, you know, the therapist there or whatever to help with that, you know, kind of somatic healing of, you know, you feel something in your body will feel that, go further into that, see where that comes from. And so, yeah, it sounds very similar, you know, kind of to the underground or the, you know, the rest of the world. It's good to see you guys using those same kind of, you know, techniques.

Could psilocybin ever function like a traditional medicine or is it something the environment inseparable from the treatment in that sense?

speaker-1 (30:08.878)
traditional with sense of people taking it at home.

speaker-0 (30:12.738)
Yeah, yeah, somebody gives you, know, you get your prescription, you know, and you bring it home. And as you were saying, is that environment with the therapist, is that inseparable from the actual treatment or is it something that could possibly, as you're saying, you're kind of training people to become 360 patients.

Would that be something that could eventually go into your own home or is it always going to be, I guess, therapist dependent?

speaker-1 (30:44.736)
It's a great question. For a number of reasons, it's unlikely that this treatment would go home anytime soon. I number one, there are some people who are fortunate enough to have a calm and controllable home environment. Sadly, that's not everyone. And even those who do have a calm, controllable home environment, generally, things happen, and that could potentially be dangerous. But also because, of course, currently,

psilocybin is schedule one, it's considered an illegal substance. If FDA approved, then DEA would have to reschedule that so that it can be legally prescribed by physicians and other prescribers. But it will likely come with relatively clear and strict guidelines for how the medication may be prescribed. And that program is one called a REMS.

which is not unusual. Spravato has a Rams. There are other psychiatric treatments that have Rams. But it's essentially a framework for the longer term tracking of potential adverse events and ensuring that there isn't misuse or diversion of the product. So yeah, if we have an FDA approval and COM 360 is rescheduled, then when prescribed, this would be shipped to the setting of care and it would be supervised in that setting.

One other thing to mention, just as a point of clarification, you talked about the therapist who's supporting the treatment. Going back to the distinction between how people are supported in our trials while having this experience and how they're providing that support versus what people traditionally think of as psychotherapy, in our trials, in most cases, the person in the room has been a therapist.

But their training, and this is kind of funny, their training is mostly to talk them out of their training, to teach them not to lean on the usual psychotherapy principles that they would use and engage with people in that way, because it's actually contraindicated. Therapists should not be proactively inserting themselves into that process, but rather they're just there to support, to monitor, and to redirect people back into the experience.

speaker-1 (33:05.26)
And so why do we include therapists in our studies if actually therapy shouldn't be done? And it typically leads to the question, could it be a non-therapist who is supporting patients? And that's often a question raised around broader access because there's a limited number of therapists. And the answer to that is, it's very important that there is an appropriately trained mental health care professional available, a licensed health care provider.

the way that this treatment will likely be delivered in the real world if approved is somewhat similar to Spirato in the sense that it's a team-based model of care delivery. And that team will likely include the person prescribing the drug, probably a physician. There may be a therapist available. And then, you know, a team of other healthcare professionals that may include nurses and medical assistants and technicians and so forth that

that collaborate on the care of probably multiple patients having treatment in their center, whether it's Spravato or Comp360 or other psychedelics once they're approved. And so I mentioned it just because, again, we're interested not only in an approved product, we're interested in actually getting to patients in a way that reaches those who maybe historically haven't had access to care.

And that means we also need to have an eye towards what are the potential barriers to access and what does that mean in terms of workforce and training, et cetera.

speaker-0 (34:40.174)
Yeah, as you brought up accessibility, psilocybin therapy, if it eventually receives regulatory approval, that really becomes one of the big questions. And the trade and facilitators, hours of supervision, how do we scale that, something like that anyway, so that patients can eventually access it?

speaker-1 (35:03.224)
That is where I spend most of my time. So several things in no particular order. First, we can take some lessons, some notes from some of the early challenges with trying to commercialize Provado and get that to patients. One of the difficulties they had earlier on was the reimbursement framework for health care providers. Because if they can't get paid to deliver the treatment, then of course they're going to be less likely to prescribe it.

One of the challenges they faced was that there weren't codes in place, the codes that providers use to submit to insurance companies to get reimbursed. There weren't codes in place for the required hours of monitoring after a patient self-administers the spirolata spray. So that led to a lot of confusion of how these providers should code. It led to them having delays in the payment of their claims. In many cases, care being denied, et cetera.

So we did apply for and were granted new codes, they're called CPT codes, that are specific to the administration day of not just COM 360, but any psychedelic treatment. So that's one step and that's one important thing. Other things include, along the lines of what I was saying about who may be involved in the care of these patients, really getting a good understanding of

what treatment models look like in various settings of care today, and how they may be adapted to be able to deliver a treatment like this without adding additional resources into the system, along with how those workforces are currently trained and what it may take to train them specifically in delivering treatments like this. And so to answer some of those important questions, we, and I think we've maybe discussed this previously, we've assembled a network

of what we call strategic collaborations. This is a broad range of different phenotypes, to use a fancy word, of different sites of mental health care delivery that cover interventional psychiatry clinics, which are those that deliver in-office treatments like Spravato or transcranial magnetic stimulation, other things, hospital systems, integrated behavioral health care, primary care.

speaker-1 (37:29.388)
settings, community behavioral health, really importantly, specifically certified community behavioral health clinics, and other types. And that allows us to really understand by exchanging information with them, by us teaching them about how we're delivering this in our trials right now, them teaching us about how they're delivering other treatments today that are already available, what any gaps might be in terms of the personnel they'll need.

the physical infrastructure they'll need, the training requirements and so on. Now the good news is that it seems pretty clear that in the 7,000 plus centers delivering Spravato right now, there's little to nothing they need to do. Because a Spravato room is a Comp360 room, the workforce that supports delivering Spravato is the same workforce we'll need for Comp360. The workflows are very similar.

they're already familiar with complying with the REMs like we were talking about before, et cetera. So COM360 drops very neatly into that existing infrastructure. For some of the other site types, it gives us a chance to really kind of build a playbook for how COM360 might be implemented in their setting of care. And then because typically they're not unique, but they're just representative of a type, we can build templates that help us understand how we'll need to support those sites.

speaker-2 (38:34.574)
sure.

speaker-1 (38:54.978)
with a range of services at the time of launch to ensure that they're able to onboard this treatment too.

speaker-0 (39:02.126)
Yeah, that sounds good. sounds, you know, that it keeps everybody, you know, everybody's ready for it for if it eventually comes. Excuse me. But it also comes up, it brings up, you know, the question as you're talking about insurance agencies and all this, you know, the commercialization. One of the biggest tensions in psychedelic medicine right now is commercialization. Companies are developing patents, clinical procedures, you know, around substances that have been long existed underground or even in traditional contexts.

How do you personally think about that tension between medical development and the culture history of psychedelics?

speaker-1 (39:38.19)
There's a rich cultural history of using psychedelics in a variety of contexts. Developing psychedelics in a medical context as an FDA approved medicine for people living with severe mental health conditions is a new and different context. So I think in some ways they can be treated separately because there's nothing about the path that Compass Pathways is taking, which is the FDA medical route that in any way says that

you know, depending upon existing laws that people shouldn't be able to use psychedelics in different ways. We are just trying to address the mental health crisis and the fact that there aren't options right now for people, for example, living with treatment resistant depression or PTSD, is our other program, which is advancing. And to the extent that some of the concern with a medical model may be that

it's being stripped of some of those contextual elements that people find important. Certainly, the steps after an FDA approval and us shipping our product to health care sites are not dictated by us. That then becomes the practice of medicine. And medicine is practiced and delivered in a variety of ways. And every day, people are choosing their health care providers if they're fortunate enough to have some choice.

based upon, which I know is a big F, but based upon the fit for their values and how they want to receive their healthcare. What I will say is that those sites of care are going to have some latitude in those real-world care settings to decide what they deliver around this treatment. Many of these sites may decide to add psychotherapy to this before or afterwards.

And there's nothing about the path we're taking that will prohibit that. Many of those sites may decide that they want to furnish or decorate their rooms or offices in a certain way, or building community elements as far as peer support or group settings or anything like that. Nothing about the route we're taking will prohibit that either. So I think we are trying to stay within our lane in a sense of

speaker-1 (41:58.926)
trying to address unmet needs for specific conditions, going through a very specific process that is required to appropriately demonstrate to a regulatory body the safety, efficacy, and quality of the drug product that then potentially is the opportunity to go out in the world for people to deliver in the ways that they see best fit for their patients.

speaker-0 (42:25.33)
Yeah, that's a good point. I think a lot of the tension comes from people seeing these as ancient medicines, they're having that context, and they lose sight of you're trying to bring this to a mass market to bring this healing to everyone. And so to do that, you have to take specific steps. Another important part, you know, we talk about a lot of safety around it. Psilocybin, as you mentioned earlier, appears pretty safe in these controlled environments.

but it's still a very powerful psychedelic experience or psychological experience. What are the biggest risks researchers are watching for right now?

speaker-1 (43:03.906)
Yeah, as you say, unfortunately, the research so far has demonstrated these compounds can be generally safe and well tolerated, but that doesn't mean we should ever take powerful drugs lightly. And what we've seen in our, at least our phase three studies, is that the vast majority of adverse events have been mild to moderate and have been things you would expect, headache, fatigue, nausea.

visual illusions or hallucinations, they tend to occur.

speaker-0 (43:37.726)
I see that as a feature, not a bug.

speaker-1 (43:40.238)
They tend to occur on the day of administration and in most cases resolved by the next day. And so those aren't necessarily things people are concerned about so much as being either features, as you say, or just very expectable and tolerable short-term effects. Something that people have been concerned about longer term in a vulnerable population, especially with TRD, has been suicidality.

speaker-2 (43:40.802)
Thank you.

speaker-1 (44:08.012)
That is something that is always a risk in this population and so something we take very seriously and watch carefully and one of the reasons for all the elements of support in these trials. What we saw in phase three is that it was a very low rate of suicidal thinking. It was balanced across the arms and so it doesn't seem specific to 25 milligrams of COMP360. Fortunately, we didn't see any suicide attempts or completed suicides.

And so to the extent that people within watchful for that as a potential adverse event, this data was reassuring.

speaker-0 (44:50.434)
Yeah, that's good to hear that it didn't increase anything. And that's a very important milestone in that. So kind of looking forward, say, 10 years, what would success actually look like for psychedelic medicine? Not just Compass, but for the field overall.

speaker-1 (45:10.81)
That's a big question. 10 years, think, first of all, we will hopefully have multiple approved products across a range of indications. To belabor this, because it's maybe worth belaboring, we need new options. Millions and millions of people are not well served by the options that exist today. And when you look at the development pipeline, trial after trial,

of a psychedelic compound, not just COM360, but across a range of them has been very positive and positive in ways that we're just not used to seeing, particularly with this kind of consistency. More traditional mechanisms, many of them have failed in the recent past. And so the current development pipeline is very psychedelic heavy. And I think that's promising. I think it means that there's a good chance that multiple of these products may receive an approval.

And so then that moves to the next step, which is I think success is not just approved products, but it's access in a way that helps to start to close some of the gaps we have, some of the disparities in healthcare access, rather than widening them. Sadly, historically, when innovation has come, it has tended to go first to those who already have access and it has exacerbated these disparities.

My hope is that the attention that we're paying early to broad and equitable access, the time, the attention, the priority that we're placing on access insights of care that reach those who historically have been underserved will bear fruit in the sense of we are ensuring that we're able to reach people in underserved urban settings, reaching people in underserved rural settings, et cetera.

speaker-0 (47:08.082)
Yeah, those are that I mean, that's sounds like a great future, honestly, where hopefully we can't have more of these healings and more of the, just the whole ecosystem coming together to to kind of heal each other. And, know, this is, you know, something we've talked about for years is, I guess, psychedelics helping everyone and that we actually have the chance to do that now. So we're going to wrap the public portion of the episode right here. We're continuing the conversation on the Patreon integration section.

We'll go deeper into topics like ketamine versus psilocybin, commercialization versus patents, and where psychedelic research might really go next. If you'd like to hear the extended conversation, support the show. Join Patreon at patreon.com slash Diversion States. Your support helps keep the show independent and allows us to keep bringing these conversations like this to the public. Before we jump into the integration session, I want to give a quick shout out to the Zendo Project. Zendo provides peer support services at festivals and events.

to help people navigate difficult psychedelic experiences. Harm reduction is one of the most important parts of psychedelic culture. So if you want to support the work they're doing, go check them out at zendoproject.org. And if you want to sign up for their SIT class, use our affiliate code Divergent as TIN, and it also helps support the show. So we're going to head over to the Patreon section and kind of integrate everything together on this. And we'll see you guys there.

speaker-0 (49:50.776)
So zooming out for a sec, the results here are promising. But that's not really the hard part. The hard part is everything that comes after, getting this out of the trials into the real world systems, actually working in people's lives without breaking what makes it work. And I think that's where most of the tension in this space comes from. You've got something clearly that does something, but we're still figuring out how to deliver it responsibly at scale and without losing the context of what makes that effective.

So a few parts I want to I don't want to before I push a little further some of the assumptions some of these trade-offs and Where this really realistically goes from here? That's what we do in the integration session over on patreon. We slow it down and actually unpack it If you want to have these conversations in real time our discourse been growing. We've got over 300 people there now Still kind of quiet, but if you guys want to come chat talk it up join us the

invite page is over on the subreddit and I'll try and throw out the show notes of this episode. One final thing, if you're interested in doing this responsibly, the Zendo Project offers sit training on how to actually support people through difficult psychedelic experiences, real-world harm reduction, not just theory. They've got a four-week cohort starting in May, this upcoming May, May 4th and a weekend intensive in June 6th and 7th. They've also got scholarship applications open.

and an early bird rate available through April 15th, you can still use our code there, get 10 % off of that early bird rate. You can check it out, go to zendoproject.org and use our code divergentS10 for 10 % off. But for now, I think that's for the public episode. Unless you've got anything, Brian, you'd like to add to any of that? No, no, I think it's great that we're starting to find

You know, realistic solutions for serious depression. And I really hope that this helps people. Yeah, really, I think so. And I think it's moving in the right direction. It's it's really cool to be in this kind of brave new world of, you know, legal psilocybin out on the market, you know, by pharmaceutical companies. So it's a cool direction that we're going in. So that's it for the public episode. If you guys want more, you know, integrate on Patreon otherwise.

speaker-0 (52:12.214)
Enjoy this episode and we'll see you next time.