Major Depressive Disorder Podcast

Psychedelics and Major Depressive Disorder: A Lot of Promise and a Lot of Questions

Madhukar Trivedi, MD; Gregory Fonzo, PhD


September 14, 2022

This transcript has been edited for clarity.

Madhukar Trivedi, MD: Welcome to the podcast on psychedelics in major depressive disorder. We have a wonderful guest — Dr Greg Fonzo is at UT Dell in Austin, and he has been a colleague of ours and we're very excited to have you, Greg. He is also the director of one of the early psychedelic centers that has been created. So, a very timely and important topic … we'll talk about psychedelics and how to think about it. As you know, Greg, can you maybe provide a little background on why is there such a big interest in psychedelics these days?

Greg Fonzo, PhD: Thank you, Dr Trivedi. It's good to be on. There is a huge interest at the moment in psychedelics, both in terms of medical use and recreational use or spiritual use. But I think a large degree of the excitement comes from the fact that there's a lot of untreated suffering. A lot of people that are suffering from depression, anxiety, PTSD [posttraumatic stress disorder] just aren't being helped adequately by existing treatments. So, for those folks, the idea of undergoing a psychedelic-assisted therapy, where they might have a long-standing benefit from a relatively short duration treatment, seems particularly attractive. There's been a lot of buzz around that for folks that are interested in receiving the treatment and, obviously, on the scientific and medical end, there's a lot of interest in understanding why these things work.

Trivedi: Wonderful. As you rightly point out, we have had very few pharmacological advances in depression and anxiety in the past 30 years. There are some new novel approaches with the benefit of TMS [transcranial magnetic stimulation] as well as ketamine/esketamine. But I think the challenge you raised is absolutely fundamental, and that is that we have still a very large proportion of our patients who are not getting better with what we do have. Therefore, there is interest in this subject. Maybe give a little primer for the audience on when we say "psychedelics," what are the drugs we include? Can you give a little quick review of that?

Fonzo: Absolutely. The definition will depend on who you ask. Most broadly speaking, psychedelics refer to the substances that have been used since basically the early sixties and seventies that broadly act on the serotonin 2A (5-HT2A) receptor and they induce a whole range of psychological effects. These include things like psilocybin, which is the active ingredient found in magic mushrooms, LSD or lysergic acid diethylamide, and then other compounds like dimethyltryptamine or mescaline as well. But they have this characteristic effect of inducing a 6- to 8-hour state of altered consciousness that can come on with varying degrees of rapidness. Essentially [this state] induces changes in perception. It can include things like visual or auditory hallucinations and can also induce changes in one's sense of self in regard to body, state, one's relationship to the environment, and even induce some very profound, altered states of consciousness that are sometimes characterized by the term "mystical experience," where individuals have a blurring of their sense of separateness from the environment as well as from other people.

Trivedi: There is obviously a whole lot of interest in this and, therefore, more articles have been written on this topic than [there are] patients who have taken these drugs. So let's start with the basics. Can you give us a sense of what we do know about the efficacy of these psychedelic drugs in people with depression?

Fonzo: That's an interesting point there; particularly in the brain imaging area, there have been more articles published than the people that have participated in the study. It's interesting, but what we do know in terms of efficacy is that for certain individuals at least, going through a psychedelic experience in the context of a therapeutic framework: people are prepared for the experience, they ingest the psychedelic with the supervision and guidance of trained therapists or guides, and then they have a period afterward of integrative psychotherapy where they talk about their experiences and try to gain some insight from that. That will have a therapeutic benefit that lasts anywhere from about 3 to 6 months, on average, for a lot of folks. Some folks will derive a longer benefit and others will not derive as long a benefit. But the early studies, which were mostly small samples and had a lack of control or comparator condition, showed response rates of 70%-80% in some of these folks. That is quite sobering, given that a lot of our existing treatments have response rates maybe about half that size, depending on the outcome measure. But it's interesting that the newest data coming out, which hasn't yet been peer reviewed and published, which was released by COMPASS Pathways — their top-line findings for their large phase 2b trial showed a much lower rate of response. So, we're looking more at about a 30%-35% response rate about 3 weeks after receipt of a single dose of psilocybin in that therapeutic framework. That's a much larger sample. That was in about 230 people, a much broader segment of the population, with treatment-resistant depression. We're starting to see now with some of these large, more well-represented studies that that the response rates are more sobering, that they're not quite as high as we initially perhaps thought.

Trivedi: That brings up the simultaneous question — what is to be still learned? If you had to develop a roadmap, what are the kinds of questions, especially about the mechanism and about reuse and duration and so on, that one would start thinking about?

Fonzo: Absolutely. One of the fundamental questions that hasn't really been adequately answered at this point is dosing … what is the adequate or the right dose for somebody? At the moment, it's based on generally uniform dosages across people, regardless of body weight or metabolism. That does seem to show benefits. But a fundamental question that we still don't really understand is what is the right dose for an individual? Beyond that, there are a lot of questions in regard to the period of time within which we would expect individuals to derive a benefit from this, if they're going to, and at what point should we re-treat them if they relapse? At the moment, most of the long-term follow-up work that has been done up to about a year afterward has been largely uncontrolled. A lot of people will seek out other treatments after the first 3 months or so during the primary follow-up period, or they might start psychotherapy. So, a lot of those effects are confounded. But ultimately, we need to better understand, in a very pure sense, how long the effects of the drug will last and what is the right time when perhaps re-treatment might be needed for those individuals that don't derive a sustained benefit. In addition to that, there are questions regarding mechanism. We really don't know how these drugs work. A lot of brain imaging studies have come out, in a relatively small number of people, but they do seem to show that, acutely, the drugs exert an effect that is characterized by a desegregation of brain networks. So, areas of the brain that typically work together or speak with one another, begin to speak with other parts of the brain or communicate with other parts of the brain that they don't normally engage in communication with. It seems to be largely a type of "unhinging" of some of the constraints that are on the normal functional repertoire of the brain. In terms of how that translates to a benefit, that's still a very much unanswered question. Initial data coming out is showing that there might be a relationship of this desegregation effect in terms of brain networks with longer-term clinical outcomes. But really, we're in the infancy in terms of understanding how that works and what is actually deriving or driving the major benefit for people.

Trivedi: Is it beginning to at least give you a little early indication of whether certain circuit dysfunctions for circuit pathologies are necessary for the treatment to work? Because it sounds like, especially with the recent data, we may not have 80% efficacy, in which case we will have to be clever about how to identify the right people. Is imaging beginning to give us some clues?

Fonzo: That's absolutely correct. At the moment, there is very little known about predictors of response. Most of the data that has come out has been looking at — across everybody — what seems to change in response to the treatment. At the moment, there's still very little known regarding the types, whether it be circuit characteristics or other kinds of neurobiological or physiological characteristics, that might predict response. That's a prime area for investigation … being able to identify who is best suited to receive this treatment and to be able to do so reliably and quickly.

Trivedi: This really brings me to what I think would be wonderful to hear about: your center that you have launched. What are you hoping to accomplish? Where are you with all the work you're doing or will be doing in the near future?

Fonzo: We launched in December 2021, so we've been open now for about 9 months, which is very exciting. We were working behind the scenes prior to the official launch, and at the moment we're getting ramped up to begin studies. As you probably know, Dr Trivedi, a lot of the work in this area has not been funded by traditional funding mechanisms such as NIH [National Institutes of Health], DOD [Department of Defense], or the VA [Veterans Affairs]. A lot of the funding for these studies has come from philanthropy or commercial alignments. We've been working hard to accumulate both commercial alignments and philanthropic funding to begin research and are fortunately now at the point to begin that process. Our center is really focused on a few key questions, one of which you mentioned before: how do we identify who is most likely to respond well to this treatment? That will help us to inform the clinical approach here, in terms of if and when do these become FDA-approved treatments. We're particularly interested in using in noninvasive brain measures like functional magnetic resonance imaging and electroencephalography recordings to be able to characterize brain function at baseline or before individuals take the drug and hopefully be able to derive a biomarker that will tell us who's likely to respond well. Another key area that we're very interested in is how do we optimize the delivery of psychedelics? At the moment, the framework is in its early stages, so it's not extremely well developed in terms of [determining] the right psychotherapeutic approach to pair with the delivery of the drug. How long should that psychotherapy be delivered? Are there specific types of intervention approaches that we should be utilizing that aren't utilized at the moment? It's interesting to note that the therapeutic framework around these substances is very different than what somebody would get if they went into a mental health clinic to receive treatment for depression or anxiety, where they might get cognitive behavioral therapy or behavioral activation or some other form of empirically supported treatment. At the moment, it's really more of a supportive framework in terms of helping the individual navigate the experience and be able to come through that, while hopefully deriving some benefit. But it's an open question about what those therapeutic interventions should be or what the proper type of aftercare is. One of the initial studies that we're going to be pursuing is looking at neuromodulation as a form of aftercare following a psychedelic experience. For those that don't know, neuromodulation is using things like repetitive transcranial magnetic stimulation or other forms of fundamental physical energy that are deposited into the brain to try to causally modulate brain function. We have the hypothesis that if we're able to — well, this might be a long explanation — but essentially in short, the idea that we're pursuing is that psychedelics might increase plasticity or allow the brain's ability to restructure … to rewire itself. If we intervene with a more direct approach to modulating brain function afterward, that might be a particularly powerful combination.

Trivedi: Thank you. One more thing related to your work. I know you have an interest in MDMA (methylenedioxymethamphetamine or ecstasy), so maybe give us some idea about where that stands for mood disorders and anxiety disorders.

Fonzo: That's a great question. So that's one of these drugs that some people will include under the term "psychedelic" and others will not, depending on who you talk to. MDMA operates, as far as we know, via a slightly different mechanism. It seems to be more involved in the release of endogenous neurotransmitters like dopamine and serotonin, norepinephrine as well. It's shown a lot of initial signs of efficacy and in some very impressive trials that have been run by the Multidisciplinary Association for Psychedelic Studies, specifically for the treatment of post-traumatic stress disorder. It has a qualitatively different effect than a psychedelic. At the current time, the evidence base for MDMA is really just in PTSD. There have been a handful of studies here and there looking at other conditions, but that's where the broad evidence base lies. It is an interesting question, right … whether MDMA would be particularly beneficial for somebody with depression. There really hasn't been much work done in that area at the moment. We're going to be starting with some of the more classic psychedelics like psilocybin, but we will eventually move into looking at MDMA as a treatment modality as well.

Trivedi: You mentioned dosing issues. There is also some interest and some publications coming out on this whole idea of microdosing. Just give a little bit of background on that.

Fonzo: "Microdosing" is a term that's been around for a while and it's also ill defined. The idea behind it is that you take a very low sub-psychedelic dose of a classic psychedelic compound chronically. So, it's more akin to a typical pharmacological approach that we use for depression where somebody takes a pill every day, for example. Some people say, if you can feel it, then you've taken too much, in which case it's not really a microdose. If we go based on that criterion, then these would be very low doses of things like psilocybin or LSD that you would take either every day or some people take them for 3 days at a time and then take a week off, or they might take it every other day. It's an all-over-the-place dosing regimen. There's been very little controlled research done on microdosing, but it does have some distinct advantages if it does work. Because, on the one hand, for people who are perhaps a bit ambivalent or afraid to wildly alter their state of consciousness with a macrodose of a psychedelic, this might be a really good option for them if it does have efficacy.

Trivedi: A couple of final questions. You obviously also have expertise in psychotherapy so maybe give a little bit of a description on what happens. There is supportive care, but then there is an additional psychotherapeutic intervention happening. Describe that for the audience.

Fonzo: Sure. This will vary a bit depending on the protocol in the modality but, in general, the approach is one of three phases. You have preparation, you have dosing, and then you have what we call integration or follow-up. Preparation is really about forming a therapeutic alliance between the therapist and the patient. A lot of times, more than one therapist might be present for that. Sometimes only one, though there's usually psychoeducation in terms of the therapists educating the individual about their particular clinical condition and some of the mechanisms perhaps that underlie that. Then there is also a pretty lengthy assessment process to make sure that the person is well suited for the treatment and then some discussion of what to expect with the psychedelic experience for those who maybe have never gone through it. That can be one session, it can be three sessions, or sometimes even more than that, depending on the particular protocol. Then you have the dosing session in which the individual comes in in the morning, usually after a light meal, and will receive the psychedelic drug, and they take that drug in a very comfortable living room-type setting typically. So, there'll be couches and furniture and artwork, and the idea is to really develop an environment that's very conducive to the individual feeling relaxed, calm, and at peace, so that they are best able to navigate the altered state of consciousness without anxiety and that kind of thing. That lasts typically anywhere from 6 to 8 hours. It's usually a full day experience. Sometimes people will stay overnight afterward, or they might have a night monitor to watch them. Other times, individuals are released to the care of a close family member or friend, and then usually individuals will come the next day to do their first integration session, and that's first checking in on them to make sure that they're doing okay and that there are no adverse events or serious side effects they're experiencing. It's really, at that point from my understanding, more open ended, where people will talk about what they experienced with their therapists. Therapists might offer interpretations for the participant about what some of the experience might mean for them. Essentially, the goal is to help the person derive some kind of deep insight in regard to themselves or their disease or their life in general, that they can then carry forward as a way to help bring the information that they garnered in the psychedelic experience to bear on their day-to-day life. That can usually last for one to three sessions as well.

Trivedi: One final question. The train seems to be moving much faster than the science in this area. So, I would love to hear your thoughts on this whole experiment that Oregon is going to undertake by allowing its use. It's unclear but it obviously sounds like you don't need a prescription. What are your thoughts or what do we know about their journey?

Fonzo: That is an area of concern because the way it's evolving is they are specifically trying to get away from viewing this as a medical model of psilocybin administration. So, for those who don't know, Oregon passed a bill to mandate the legal distribution of psilocybin to individuals that are eligible, which I'm assuming means of a certain age and that kind of thing. They're currently planning to set up and implement this framework, but at the moment, they're veering away from this as a medical model and viewing it more as what they call "psilocybin services," where it's more of a personal development or recreational type of approach. So, there are a lot of concerns with that because first, we know that certain individuals probably should not be receiving a psychedelic. For example, those with a history of psychosis or other types of conditions that might render them not well suited for the experience … heart conditions, for example, or uncontrolled blood pressure. It remains to be seen if people are actually going to be screened well for that. There's a lot of concern regarding the potential for adverse events to come up in regard to this. Then, the degree to which participants need to be trained to guide people through this experience has not been well established. Whether or not Oregon is going to enforce certain training guidelines has not been clearly established. There are just a lot of areas where things could go wrong here, and I wouldn't recommend to any of my clients or patients to go to Oregon and pursue this. We still have a lot of work to do to really work out these questions.

Trivedi: I would totally agree, but it is likely that we will interact with people who have attempted so.

Fonzo: Absolutely.

Trivedi: It's best to keep track. So, thank you very much. Any final thoughts on this whole area of the study of psychedelics?

Fonzo: It's an exciting area. As you mentioned earlier, there's a lot of promise here but we have to proceed cautiously. We have to use the best science available. We have to try to guide our decisions and we have to try to not be overwhelmed with enthusiasm before we have hard evidence to feel that way. I'm very excited to be participating in this, and I'm really looking forward to the future but also trying to maintain some of that healthy scientific skepticism in the path.

Trivedi: Thank you so very much. Thank you for joining, Greg — I appreciate your thoughts on this.

Fonzo: Thank you. I appreciate you having me.



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