PsychEd Episode 43: Psychedelic-Assisted Psychotherapy with Dr. Emma Hapke and Dr. Daniel Rosenbaum

Welcome to PsychEd, the psychiatry podcast for medical learners, by medical learners. This episode covers psychedelic-assisted psychotherapy with Dr Emma Hapke and Dr Daniel Rosenbaum, both of whom are psychiatrists at the University Health Network in Toronto and co-founders of UHN’s Nikean Psychedelic Psychotherapy Research Centre (in addition to being lecturers in the Department of Psychiatry at the University of Toronto).

The learning objectives for this episode are as follows:

By the end of this episode, you should be able to…

  1. Briefly describe the history of psychedelics in psychiatry

  2. List the four classes of psychedelic drugs and their mechanism of action

  3. Summarize the evidence regarding psychedelic-assisted psychotherapy for various psychiatric disorders

  4. Discuss patient selection considerations for psychedelic-assisted psychotherapy

  5. Describe the safety, tolerability and possible side effects of psychedelic-assisted psychotherapy

  6. Understand how a psychedelic-assisted psychotherapy session is practically carried out

Guests: Dr Emma Hapke and Dr Daniel Rosenbaum

Hosts: Dr Chase Thompson (PGY4), Dr Nikhita Singhal (PGY3), Jake Johnston (CC4), and Annie Yu (CC4)

Audio editing by: Nikhita Singhal

Show notes by: Nikhita Singhal

Interview Content:

  • Introduction - 0:00

  • Learning objectives - 02:47

  • Definitions/categories of psychedelics - 03:24

    • Classic psychedelics - 04:15

    • Empathogens (e.g. MDMA) - 07:15

    • Etymology of the term “psychedelic” - 09:30

    • Ketamine - 12:24

    • Iboga - 13:28

  • Brief history of psychedelic medicine - 17:51

  • Current evidence and ongoing trials - 27:38

    • MDMA and PTSD - 29:26

    • Psilocybin and treatment-resistant depression - 32:24

    • A word of caution - 34:29

    • End-of-life care - 38:47

  • Practical aspects of psychedelic-assisted psychotherapy sessions - 45:45

  • Safety considerations - 01:04:04

  • Future directions - 01:10:33

  • Closing comments - 01:19:07

Resources:

References:

  • Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med. 2021;384(15):1402-1411. https://doi.org/10.1056/nejmoa2032994

  • Carhart-Harris R, Nutt D. Serotonin and brain function: a tale of two receptors. Journal of Psychopharmacology. 2017;31(9):1091-1120. https://doi.org/10.1177/0269881117725915

  • Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(5):481–489. https://doi.org/10.1001/jamapsychiatry.2020.3285

  • Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181-1197. dhttps://dx.doi.org/10.1177%2F0269881116675513

  • Griffiths RR, Johnson MW, Richards WA, et al. Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. J Psychopharmacol. 2018;32(1):49-69. https://doi.org/10.1177/0269881117731279

  • Johnson MW, Hendricks PS, Barrett FS, Griffiths RR. Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacol Ther. 2019;197:83-102. https://doi.org/10.1016/j.pharmthera.2018.11.010

  • Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033. https://doi.org/10.1038/s41591-021-01336-3

  • Mithoefer MC, Mithoefer AT, Feduccia AA, et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry. 2018;5(6):486-497. https://doi.org/10.1016/s2215-0366(18)30135-4

  • Nicholas CR, Henriquez KM, Gassman MC, et al. High dose psilocybin is associated with positive subjective effects in healthy volunteers. J Psychopharmacol. 2018;32(7):770-778. https://doi.org/10.1177/0269881118780713

  • Reiff CM, Richman EE, Nemeroff CB, et al. Psychedelics and Psychedelic-Assisted Psychotherapy. Am J Psychiatry. 2020;177(5):391-410. https://doi.org/10.1176/appi.ajp.2019.19010035

  • Rosenbaum D, Boyle AB, Rosenblum AM, Ziai S, Chasen MR, Med MP. Psychedelics for psychological and existential distress in palliative and cancer care. Curr Oncol. 2019;26(4):225-226. https://dx.doi.org/10.3747%2Fco.26.5009

  • Swift TC, Belser AB, Agin-Liebes G, et al. Cancer at the Dinner Table: Experiences of Psilocybin-Assisted Psychotherapy for the Treatment of Cancer-Related Distress. Journal of Humanistic Psychology. 2017;57(5):488-519. https://doi.org/10.1177/0022167817715966

CPA Note: The views expressed in this podcast do not necessarily reflect those of the Canadian Psychiatric Association.

For more PsychEd, follow us on Twitter (@psychedpodcast), Facebook (PsychEd Podcast), and Instagram (@psyched.podcast). You can provide feedback by email at psychedpodcast@gmail.com. For more information, visit our website at psychedpodcast.org.

PsychEd Episode 43: Psychedelic-Assisted Psychotherapy with Dr. Emma Hapke and Dr. Daniel Rosenbaum: Audio automatically transcribed by Sonix

PsychEd Episode 43: Psychedelic-Assisted Psychotherapy with Dr. Emma Hapke and Dr. Daniel Rosenbaum: this mp3 audio file was automatically transcribed by Sonix with the best speech-to-text algorithms. This transcript may contain errors.

Nikhita Singhal:
Welcome to PsychEd, the psychiatry podcast for medical learners, by medical learners. This episode covers an introduction to psychedelic assisted psychotherapy, an exciting and rapidly developing area in the field of psychiatry, which has been receiving growing attention in the scientific community and among the general public lately. I'm Nikhita, a third year psychiatry resident at the University of Toronto, and I'll be co-hosting this episode alongside a few of my colleagues who I'll pass it along to so that they can introduce themselves.

Chase Thompson:
Hi, I'm Chase. I'm a fourth-year resident at the University of Toronto and I'll be hosting along with Nikita.

Annie Yu:
Hi, I'm Annie. I'm a fourth-year medical student at the University of Toronto, and I'm really excited to join in on this conversation.

Jake Johnston:
And I'm Jake Johnston, a fourth year medical student at UBC. Also very happy to be here.

Nikhita Singhal:
Thanks. We also have two experts among us. Our guests for this episode are Drs. Emma Hapke and Daniel Rosenbaum. Dr. Hapke is a psychiatrist, psychotherapist and psychedelic researcher at the University Health Network in Toronto and is co-founder and associate director of the Nikean Psychedelic Psychotherapy Research Centre at UN. She's also a lecturer at the University of Toronto. Her specialty is Women's Mental Health and the treatment of developmental trauma, sexual trauma and complex PTSD. She has extensive training in multiple modalities in psychotherapy, as worked clinically with ketamine assisted psychotherapy. She also has a growing interest in psychosocial oncology. Dr. Hapke works with MAPS as the principal investigator for the Montreal site of the Phase three trial of MDMA assisted psychotherapy for PTSD, and is MAPs trained to deliver MDMA assisted psychotherapy. Dr. Rosenbaum is an attending psychiatrist at UHN, as well as the Inner City Health Associates (ICHA) in Toronto. He's also a clinical lecturer in the Department of Psychiatry at the University of Toronto. He works on an assertive community treatment team serving people with severe and persistent mental illness, as well as a palliative education and care for the homeless team through ICHA. Dr. Rosenbaum is interested in psychosocial oncology and palliative care, especially end of life issues for marginalized populations.

Nikhita Singhal:
He's a certified CALM therapist managing cancer and living meaningfully and has received training in ketamine, assisted psychotherapy and completed the MAPS MDMA therapy training program. He's also co-founder of the Canadian Climate Psychiatry Alliance. Dr. Rosenbaum has published articles in peer reviewed journals on psychedelic assisted therapy and palliative and cancer care and on psychedelic microdosing. He's also a co-founder and faculty member of Nikean Psychedelic Psychotherapy Research Centre. Now the learning objectives for this episode are as follows. By the end of the episode, the listener will be able to briefly describe the history of psychedelics and psychiatry. List the four classes of psychedelic drugs and their mechanisms of action. Summarize the evidence regarding psychedelic assisted psychotherapy for various psychiatric disorders. Discuss patient selection considerations for psychedelic assisted psychotherapy. Describe the safety, tolerability, and possible side effects of psychedelic assisted psychotherapy, and understand how psychedelic assisted psychotherapy session is practically carried out. I'll hand it over to Annie to get us started and it's great.

Annie Yu:
Thanks, Nikhita. So just to start off with some basic definitions - Dr. Hapke and Dr. Rosenbaum, can you tell us what the definition of psychedelic is and how these psychedelic drugs differ from other classes of medications that are already used in psychiatry?

Dr. Emma Hapke:
First of all, I just want to say thank you guys so much for having us. It's a real pleasure to be with you today.

Dr. Daniel Rosenbaum:
In some ways, I think it might be most helpful to start by categorising the various medicines that might be discussed at a psychedelics conference. And then I think from there, we'll be able to effectively answer the question of in what ways they're different from conventional pharmacotherapies that are used in clinical psychiatry. So I know one of the learning objectives for the episode is about the different categories of medicines, and I'll start by talking about the so called classic psychedelics, and I think that will take us towards a definition as well. Pharmacologically, the classic psychedelics are so called or defined by their action at the serotonin 2A receptor. And so some examples of the classic psychedelics include psilocybin, which is the psychoactive component found naturally derived in about 100 species of mushrooms, which can be found all over the world. In fact, there's also lysergic acid diethylamide or LSD along with mescaline, as well as dimethyltryptamine or DMT. And then there's also 5-methoxy-DMT (or 5-MeO-DMT). And together these comprise the category of classic psychedelics, the five HT2A receptor. Maybe we'll talk about this more a little bit later, but it's really key to understanding the subjective effects of the classic psychedelics. And there's plenty of evidence that points to the specificity of that receptor in particular, and serotonin 2A receptor mediated signaling in governing the profound and at times quite unusual subjective effects of psychedelics. So one piece of evidence is that the receptor occupancy after someone is administered a psychedelic at the 2A receptor has been shown to correlate with the subjective effects and then also serotonin 2A antagonists, including a medicine called ketanserin blunt or basically abort the psychedelic experience. I'll turn it over to Emma to talk about a different category of medicine.

Dr. Emma Hapke:
Sure. Maybe I'll just add a little bit about some of the subjective effects that you can experience with the classic psychedelics. In general, psychedelics induce a non ordinary state of consciousness. And so with higher doses of psilocybin and LSD, for example, you'll hear about this phenomenon called ego dissolution. So that typical sense of self starts to melt away, and parts of the brain that don't normally communicate start to communicate. So we'll probably go into the mechanism of action in more detail later on. But there's a part of the brain called the default mode network (DMN). And we think that that that's sort of the conductor of the brain. So it kind of controls which parts of the brain are communicating, and it's active when you're just at rest and letting your mind wander. And some people have wondered, is that equivalent to our sense of self or ego? I think that's an open question. But what we do know is that with these classic psychedelics, the default mode network is quieted and therefore you get these pretty profound changes in perception and emotion and thinking as a result of that and other things that are going on. Those are the classic psychedelics. I think the second big category is empathogens, of which the most well known one is MDMA, 3,4-methyl​enedioxy​methamphetamine. And this class is different in the sense that with your classic psychedelics, chemically they resemble serotonin, so they bind those serotonin receptors, whereas with MDMA, it actually causes a massive release of your own stores of serotonin.

Dr. Emma Hapke:
So it's a serotonin release, but it also releases dopamine and cortisol as well as norepinephrine in the brain and oxytocin. So it really does a number of different things in the brain. And one of the effects of it is this sort of heart opening effect, this increased sense of empathy, both for yourself and for others. It's also been called an entactogen, which means "to touch within." And part of that's getting at its ability to allow the person to become really self reflective and gain a better understanding of their own inner state in addition to sort of the empathic effects of it. One of the things that I think is interesting to note about MDMA is it's quite anxiolytic, meaning it reduces anxiety and it reduces activity in your limbic system. And the amygdala, for example, which is sort of the smoke detector of the brain and a lot of other medications in psychiatry that reduce anxiety also cloud the sensorium, so they lead to this state of greater confusion. But because MDMA also increases cortisol and dopamine, it's both anxiolytic but increases alertness. And I think that's part of what facilitates trauma processing and makes it a good catalyst for psychotherapeutic work. Dan, do you want to take it away with some of the other categories?

Dr. Daniel Rosenbaum:
Yeah, pleased to. I also wanted to come to a definition of psychedelic. It's different from the pharmacologic action of the various medicines that Emma talking about, empathogens and relating that to the nature of the effects or the experience among people who take them. The word psychedelic etymologically derives from Greek words psyche and delos, psyche, meaning "mind" and delos, meaning "to manifest." So putting them together, we get mind manifesting. And that's really what the word psychedelic means. And it comes from an exchange of letters between two quite famous figures in the world of psychedelic science and history, one of whom is Aldous Huxley, the English philosopher and writer, and the other of whom is a psychiatrist named Humphry Osmond, who was working in Weyburn, Saskatchewan and was interested in LSD and doing trials for people with alcohol use disorder, what was called alcoholism, I suppose, at the time. And Osmond was very influential as he gave Aldous Huxley mescaline for the first time. And mescaline can be found in the peyote cactus as well as the San Pedro cactus. And Huxley's experience with mescaline turned into his famous book, The Doors of Perception. And after that, these two men struck up a lifelong dialogue. But I do also want to say that before this word was created, these medicines were called and classified or understood quite differently.

Dr. Daniel Rosenbaum:
So when LSD was initially synthesised, it was distributed mostly to psychiatrists, actually. And psychiatrists were encouraged to take LSD so that they could better understand the psychotic experiences of their disturbed patients. This is quite interesting. And as a result of this understanding of what LSD was and how it might be useful, it was classified as a psychomimetic. In other words, that it mimed or brought about psychotic experiences. And it's probably not the most useful term. I think probably a lot of people are also familiar with the term hallucinogen, which is still sometimes offered as the classification of these medicines, which is to say that they bring about hallucinations. That's probably also not quite accurate. It's sort of rare for people to have frank hallucinations with these experiences. The nature of the subjective, psychedelic state or experience I think we should get into a little bit more later, but Emma's done a good job already introducing that. And then the one last term I'd offer as a potential substitute for psychedelic is this term entheogen, and entheogen refers to or means revealing the God within.

Dr. Daniel Rosenbaum:
And so entheogen is often used when referring to the use of these same medicines in their plant medicine form by indigenous cultures. And so I think maybe we'll get into some of the history of Indigenous use of psychedelics as well, but shifting to a different category of broad psychedelics or again the things you might hear discussed at the psychedelics conference, we come to ketamine and I'm aware that the podcast has covered ketamine in a different episode, but I'll just say briefly that ketamine, which acts at NMDA receptors as an antagonist, is a rapid acting antidepressant medication which can be administered either intravenously, intramuscularly, sublingually, or also orally and at high enough doses, still sub anaesthetic doses, but at high enough doses, people can have experiences on ketamine that resemble in terms of the subjective experience, a psychedelic state. And for that reason, sometimes ketamine can be paired with psychotherapy, so called ketamine assisted psychotherapy, in a similar way that the classic psychedelics or MDMA are used in conjunction with psychotherapy. But I think that's all I'd like to say about ketamine for today is I think we should leave the focus of our conversation to the classic psychedelics and MDMA.

Dr. Emma Hapke:
One other category of psychedelic that has its own complex pharmacology that we'll just mention very briefly is iboga. And iboga is this root bark that comes from Gabon in Africa, and it's one of the most potent psychedelics on earth. And it seems to have this possible effect around the treatment of specifically opioid use disorder. It's a molecule that can induce a rapid detoxification from opiates, which is really interesting. And then it also induces these profound mystical states, which may be linked to how it's plays a role in the healing of addiction. It's used typically in a ceremonial context. It's the tradition from Gabon that uses iboga. And I think that it's an interesting area of study. There's a higher death rate with iboga than other forms of psychedelics. So it may have some form of cardiotoxicity that we need to research. And I know there's a number of companies that are looking at extracting parts of the molecule to see what elements of it are healing.

Chase Thompson:
Thanks so much for that overview. Dan and Emma, I just had a question about a points that each of you raised. Emma, you talked about the psychedelics being causing the effect of ego dissolution. And Dan, you kind of went through the etymology of the word and how it means to manifest the mind. So I'm kind of wondering, like these might seem maybe contradictory sort of effects where you dissolve the ego or maybe the self, but also revealing the mind. I'm just wondering if you guys have any thoughts about whether that's a contradiction or how that occurs?

Dr. Emma Hapke:
When I think about psychedelics, I really think of them in some ways as like non-specific amplifiers of the psyche. And sometimes it's our ego structures and our defences that actually keep stuff from our past down. Sometimes Carl Jung would talk about the shadow - when I think of the shadow, I think it's the part of our psyche that we're not typically conscious of in our normal waking consciousness. And often things get pushed into the basement of our mind that were difficult in the past or that we were unable to process. We're still carrying them around and they're still affecting us. And so as the normal sense of self starts to dissolve away, you will often see some of that other psychic content come up for processing. And it's not always that the person's actually trying to consciously process it in the psychedelic state. It's more about experiencing it in the psychedelic state. And then after, in the integration phase, when they're no longer in the non ordinary state of consciousness, that's when we try to make meaning and interpret what came up. And I think the other piece that happens to as the ego dissolves, in addition to sort of the mind itself manifesting and coming up, is there's also these connection to these expanded states of consciousness. So people will talk about having these mystical experiences where they feel connected to everything or connected to something greater than themselves. And that also seems to be profoundly healing. Do you want to add anything, Dan?

Dr. Daniel Rosenbaum:
You've got a great answer. It's a great question too Chase. I've never really noticed actually that potential contradiction in terms. So I mentioned that the term psychedelic was coined or emerged out of this exchange between Huxley and Osmond before they arrived at Psychedelic. Huxley suggestion was a term called phanerothyme. I'm not quite sure about the etymology with phanerothyme, but it means soul revealing. So before they arrived at mind manifesting, Huxley, who was a deep mystic, thought that this word soul revealing best captured the nature of the experience, that that the mescaline or LSD was a kind of medium through which the soul was revealed to itself.

Jake Johnston:
Dr. Rosenbaum, you've sort of beautifully set us up to go into the history by talking about Huxley. You also mentioned psychedelic youth and indigenous cultures in the past. I'm wondering if you could sort of - I know it's a massive topic to go through in a short podcast - but an overarching overview of the history of psychedelics as medicines.

Dr. Daniel Rosenbaum:
Yeah, thank you for that. I'm glad you prefaced it that way because it is an enormous question that I will not be able to do justice to, nor am I an expert on this particular topic. But I do find it interesting. And I would also say - I mean, to your point, Jake, there are hundreds of ways to tell the story of psychedelics even before we come to the biomedical story in the West in the fifties and sixties. But we can say a few general things about what we know regarding indigenous use of psychedelics. And again, I'll use the term psychedelics. But in different cultures these would be understood and referred to as very different things, perhaps plant medicines, and perhaps we could apply a different term like entheogens, as I mentioned earlier. But one thing that's interesting to note is that indigenous cultures in various regions of the world for centuries or probably even millennia, have been using these plant medicines with psychoactive properties in healing and spiritual rituals and ceremonies. And I have a wonderful quote here from the Canadian ethnobotanist and anthropologist Wade Davis. And just to give a sense of the different frame or context or the kind of setting and the purpose that these medicines or plant medicines would have been used. And so he's referring here to ayahuasca and just to provide a brief orientation. Ayahuasca is an Amazonian brew, which contains a number of different psychoactive plants. One is Psychotria viridis, which is a shrub from the coffee family that contains dimethyltryptamine. Dimethyltriptamine is orally inactive, which means that it has to be combined with a different medicine, a monoamine oxidase inhibitor to inhibit the enzyme that would otherwise break down DMT.

Dr. Daniel Rosenbaum:
And somehow this occurred in a variety of different settings, in fact, which is remarkable in and of itself. People learned which combinations of plants to include in this brew to bring about these transcendent experiences. And so Davis, in describing the use of ayahuasca, says that these preparations, the ayahuasca preparations allow people to invoke some technique of ecstasy to soar away into the realms of trance, a higher state of consciousness, if you will, that allow them to achieve their medical, mystical acts of healing, but also, in the case of communities, a kind of annual or monthly reaffirmation of the connection between human beings and the natural world, a balancing of the energetic flows of the universe. And in that sense, the substances and the rituals become a prayer for the well-being of the entire Earth and the cultural continuity of the society itself. So there's obviously a lot to that quote, and I offer it only as I think a quite radical juxtaposition to some of the ways in which psychedelics are being studied and offered in a more narrow biomedical way, which I think will be the focus of our conversation. But just to kind of frame the history, I think I find that resonates so deeply. I mean, it's so powerful, right? So coming into the popularisation of psychedelics in the West, one version of the story goes that a Western banker named Gordon Wasson, who was working at J.P.

Dr. Daniel Rosenbaum:
Morgan, visited the Oaxaca region of Mexico, where a quite famous medicine woman, or Curandera named Maria Sabina, who worked with psilocybin mushrooms, welcomed Wasson and his wife and allowed them to participate in a mushroom ceremony. And upon returning to the States, Wasson wrote an article for Life magazine called, "Seeking the Magic Mushroom." And this became the most widely read edition of the magazine in its history. In parallel, a Swiss chemist named Albert Hofmann was working on the ergot fungus, which is a fungus of the rye plant, and he serendipitously discovered lysergic acid diethylamide or LSD. I say serendipitously, because he was not seeking to create or discover a psychedelic medicine, but he did, and he took some of it as a kind of test on himself. And without knowing exactly what would happen, he took a very, very low dose on the order of a couple of hundred micrograms, thinking that it might not do a lot. He didn't know that LSD is tremendously potent. And so after taking a very what he thought was a very low dose, he then bicycled home. And this was April 19, 1943, which is an infamous date now in this world, which has since become referred to as Bicycle Day, because what occurred on that bike ride home was a rather peculiar and probably disturbing experience for him. I mean, he tripped and discovered that there was something significant going on with this medication. And so the pharmaceutical company that he was working with at the time, Sandoz, began synthesising lysergic acid diethylamide.

Dr. Daniel Rosenbaum:
It was fully legal at the time, as I mentioned earlier, it was then distributed to psychiatrists, which was initially thought to be its value, helping the psychiatrist understand the experiences of their patients. And from there it it was recognised that it had potential therapeutic value. So it began to be used in some cases in conjunction with psychotherapy and in other cases more in isolation for the treatment, principally of alcoholism, as well as to help people prepare for death and dying, or to help treat anxiety and depression associated with serious illnesses like cancer or the terror associated with death and dying. And so in the fifties and sixties, there were tens of thousands of patients treated with LSD, another couple of thousand patients treated with psilocybin. Many thousand articles written. A lot of the studies did not have the same methodological rigour or ethical standards that the clinical research today does. But the results were intriguing and for the most part, research participants that the treatments were safe. Unfortunately, there was a large political backlash that occurred, which led to the scheduling of these medicines and the almost total banning of research involving psychedelics by the 1970s. And the political backlash followed basically from the associations between psychedelics and the counterculture movement of the sixties. So that infamous figures like Timothy Leary, who then President Richard Nixon called the most dangerous man in America because of his psychedelic evangelism, the famous phrase "Turn on, tune in, drop out." The use of these medicines outside the lab and I guess even inside the lab was thought to be too terrifying for the establishment, essentially.

Dr. Daniel Rosenbaum:
And so all research was halted. I'll just mention briefly, there is a dark side, if you will, to the psychedelic history that I think it's important that we don't gloss over and people may be familiar with or have heard at least something about the CIA's use of an investigation into LSD. And this was part of the MK-ULTRA program. Canada also has a dark history to play here. There was a psychiatrist at McGill, in fact, named Ewen Cameron, who was part of the LSD experiments involving LSD. And in general, in a number of different places, people were frankly tortured in conjunction with the use of LSD. So people were put together in groups forced to take very high doses of LSD repeatedly. They were naked. They were fed through straws from a hole in the wall. I mean, really, really horrific kind of stuff. And for people who are interested, there's a great CBC podcast series called Brainwashed, which covers this history. And skipping ahead a few decades, there was the beginning of the so-called psychedelic renaissance, or the resurgent interest in psychedelic research, at least in the States, began in the nineties and into the early 2000s. And some of that work was done in California with Charlie Grob, a psychiatrist at UCLA, but also at Johns Hopkins, Roland Griffiths and his group. And maybe I'll leave it there because I feel like I've been talking for a while.

Jake Johnston:
That was a terrific answer. And you've really sort of synthesised a complex, broad history down into a very nice narrative for us.

Nikhita Singhal:
Yeah, it's certainly had a very turbulent course, both in medicine and in politics. And it seems like we're arriving now at an era where things may be showing promise and improvements in terms of a lot of the errors and things that happened in the past. You mentioned there's many exciting ongoing trials within the field of psychedelics. Now, what do we kind of know about psychedelics so far in terms of their efficacy and clinical potential for various psychiatric disorders?

Dr. Emma Hapke:
So I think in terms of psychedelics moving through the drug development process, mostly in the United States, the one that's furthest along is MDMA assisted psychotherapy for the indication of post-traumatic stress disorder. And so that's in the second half of the phase three trial. So that trial has 16 sites, 12 in North America, there's two in Canada and one in Israel. And so they've published the first half of that in Nature Medicine, and the second half is recruiting and underway right now. Psilocybin is the next furthest along. So there's sort of two main groups that are moving it through the drug development process. So we have Compass Pathways, which is a for profit company that's moving psilocybin assisted psychotherapy through the drug development process for the indication of treatment resistant depression. And they've recently published their Phase two data. And I believe they'll be moving on to conversations with the FDA to start phase three trials next and then Usona Institute, which is a non-profit player, is also moving their formulation of psilocybin through the drug development process for the indication of major depression. And they have yet to publish their phase two results, but those should be coming soon. So that's sort of those two are the furthest along. And there's an emerging and fairly strong evidence base for psilocybin assisted psychotherapy at the end of life, which maybe I'll let Dan talk about in a moment, I'll tackle MDMA first, because that's sort of the literature that I'm most familiar with. So I think what we're seeing with MDMA assisted psychotherapy is at least for a significant portion of patients that take this treatment, that it is both a safe and effective treatment.

Annie Yu:
So if you look at our phase three results, 88% had a clinically meaningful response to the treatment and 67% lost their diagnosis of PTSD by the end of the trial, and 33% went into complete remission, which means they lost their diagnosis of PTSD and they had something called a Caps five score under ten, which means very, very low symptomology for PTSD. And so that's at the end of an 18 week protocol, which includes three MDMA sessions. And what I think is important to note that these are people with severe and treatment resistant PTSD. So the average number of years that they had suffered in the trial was 15 years. They had high degrees of comorbidity, so comorbid childhood trauma, dissociation, history of substance use disorder. So this is a difficult to treat population that had failed other treatments. So failed pharmacotherapy that has been unable to gain benefit from some of the other evidence based psychotherapies for PTSD. So that's one thing. And what's also interesting is that we saw good results as well in people with those comorbidities. So they're also responding to the treatment. And in addition to the reduction of PTSD symptomology, we also saw reduced incidence of depression in the MDMA group and improvements on something called the Sheehan Disability Scale, which looks at sort of people's functional abilities and sort of domains of work in general life.

Dr. Emma Hapke:
So it's interesting it seems to work in a significant proportion of patients that take the treatment. There's definitely still a group that don't respond that I think we need to study better and understand. And then the next question is, do these results last is are they durable? We don't have the long term follow up data yet from the Phase three study. But what we do know from Phase two is it does seem that the results are durable. So the phase two data, if you look at it a year later, again, 67 or 68% of people are showing that response. So it seems that with MDMA anyways for PTSD that what we're seeing is the results seem to be durable for the vast majority of patients. So it seems that it catalyses this process of healing and resilience that then allows people this ability to perhaps have greater resilience in the face of future stress or continue to their own self healing journey that's catalysed by the MDMA therapy. Things are less clear with the treatment of psilocybin assisted psychotherapy for depression, especially treatment resistant depression. So the Compass Phase two results were recently published, and what we're seeing is about 25% response at the 12 week mark, which is not insignificant for a population with treatment resistant depression. But there's still a significant subset that are not responding at 12 weeks. Now, in that trial, they just did one high dose session in one low dose session.

Dr. Emma Hapke:
So I think one of the unanswered questions is, is do people actually need more sessions with psilocybin assisted therapy to get a more prolonged and endurable response? Also, I think what's important to note in the Compass trial is there was a higher incidence of serious adverse events around suicidality in the group that got the high dose psilocybin. Not statistically significant, but more than in the group that got the low dose. And so I think that's important to note because it brings up a lot of questions around the safety of this, especially since in most cases people have to be taken off their SSRI to participate in these trials. And that's another unanswered question is can people stay on their SSRIs and take psilocybin? And I think the jury's still out on that one. So we're taking people off of their treatments in order to participate. And is there a risk involved there? And I think that, again, getting into that sort of hype disappointment cycle in the Compass results, it's the people that had those adverse effects were typically the non responders to this treatment and so going off of their typical treatments to participate in this and then not getting a response I think has a potential to be harmful for people or at least there's some risk involved that people really need to consent to and to understand before they participate.

Dr. Daniel Rosenbaum:
I wanted to make a comment or, you know, a plea for restraint is maybe one way to put it, just to call attention to the tremendous amount of hype that exists around psychedelics, a lot of which is driven from the commercial, corporate, for profit sector. And we've come to a place where it could be fairly argued, I think, that the hype has outpaced the state of the clinical research. So in terms of what we know for sure, what I feel most comfortable hanging my hat on is that results from the preliminary research in the contemporary clinical trials are promising enough clearly to warrant greater study. Again, well designed, methodologically rigorous study with a greater number of patients proceeding into phase three trials and so on and so forth. But I think we want to be careful not to say at this point, psychedelics are going to be the next breakthrough, revolutionary treatment, silver bullet, panacea that's going to fix mental illness.

Dr. Emma Hapke:
Just add to that. I think that the hype is actually a really big challenge for researchers because there's so much coverage in the lay press about psychedelics and it's often not factual and the effects can be exaggerated. So people come in with these very high expectations that this treatment is going to work. And these people often feel very desperate because they've failed many other treatments. So they can be really set up for significant disappointment if it doesn't work. And that can actually present a number of really challenging ethical dilemmas for the field. And the other big challenge is - gets into some of the challenges in the field - is I think we clearly have enough of a signal that this is worth continuing investigating, but it's also a treatment that's very hard to study with our traditional methods of double blind RCTs because of this big problem in psychedelic research of blinding. So it's usually pretty obvious to the patient for the most part, whether they've received a psychedelic or not. And so that creates a whole host of methodological issues that the field is grappling with. And I think some people are even questioning, like, can we even conclude that this works when with some of these methodological challenges? So we need to be very cautious as we proceed. And I think we need to really educate our patients that this remains an experimental treatment, that it's not for everybody.

Dr. Emma Hapke:
And the other thing that I say is that know what I was when I'm coaching people who are considering being in a clinical trial for PTSD with MDMA, it's a piece of work. I think it's harmful when people think that they're going to go into this trial and aim for a complete cure. I really think of the MDMA as a catalyst for your own psychotherapeutic process, and it's for people who are ready to go in and go deeper because we're starting to see the medicine and the container can start to strip away some of your defensive mechanisms like dissociation and numbing, for example. And if you're not ready to start facing what's coming up and you don't have adequate support internally and externally, that can be really challenging. And especially in a clinical trial which is not flexible, you can only have three treatments and then it's illegal. So you can't actually access it legally. So what if you find that you're starting, but then there's more work to do. That can be a real challenge for people. And we've noticed that at the termination phase of the study that some people feel there's more work to do. So these are things that I think we're all grappling with and there's no easy answers to them.

Nikhita Singhal:
Thank you so much for mentioning those really important considerations. I think being cautious and aware of some of the risks is really key. And you've mentioned that another of the indications is end of life care. Could you tell us more about that?

Dr. Daniel Rosenbaum:
The greatest area of clinical interest for me personally in this field is the application of psychedelic assisted psychotherapy in palliative and cancer care to help people prepare for death and dying, to help mitigate some of the distress associated with life threatening illness. And there's an interesting history to these research programs, again, at least as far as the US based research is concerned. At Spring Grove, the Maryland Psychiatric Research Institute in Maryland, of course, there was a program of LSD assisted therapy research for the treatment of alcoholism in the sixties, and one of the nurses involved with that was diagnosed with cancer. And I believe the story goes that she asked her fellow researchers to receive LSD to help her manage the distress associated with her condition. And from that emerged a series of research trials and a whole research program, including luminary psychiatrist Stanislav Grof, who initially did a lot of his work and Czech Republic before coming to the states, but also people like Bill Richards. And there's a wonderful book about this research program for people who are especially interested called The Human Encounter with Death, which Stan Grof wrote with his then wife, Joan Halifax. But what I can say is that between the mid sixties and up to about 1980, there were six open label trials of psychedelic assisted psychotherapy for end of life distress, existential distress, that sort of thing. Most of the participants had advanced cancer or terminal cancer. More recently in terms of the contemporary clinical trials, there have been four randomised controlled trials done since 2011, one of which included LSD and three of which used psilocybin. All of the psilocybin randomised controlled trials were done in the States and they were all based on the Spring Grove program developed by Grof and colleagues.

Dr. Daniel Rosenbaum:
In all of the contemporary clinical trials, what we see is rapid, robust and sustained improvements in cancer related psychological and existential distress. Then in terms of the robustness, the effect sizes, these are relatively small studies, so the biggest of which was done at Johns Hopkins. A landmark paper published in 2016 by Roland Griffiths and colleagues had 51 patients, so not huge. But in terms of psychedelic clinical trials, this is quite a large study and the effect size in terms of reductions in cancer associated depression and anxiety are massive like really blows something like an SSRI or more conventional pharmacologic treatment for depression among cancer patients really out of the water. Again just highlight as a point of caution. This was not a head to head trial. It was not comparing a psychedelic to an SSRI, but just to highlight the really robust effect sizes associated with this intervention in these patients. Importantly, the intervention has been shown to be safe for people even with serious illness, which is very important because we're talking about people with potentially significant medical issues approaching end of life and so forth. So the two most important studies that have been done in this area thus far, both published in 2016, in the Journal, the same edition of the Journal of Psychopharmacology, one was the Johns Hopkins study that I mentioned. The other was conducted at New York University. The lead author is Stephen Ross. They're quite similar in terms of the study design, the patient population, the results, the NYU study.

Dr. Daniel Rosenbaum:
It was really useful because it came along with a couple of qualitative research papers, one of which I always recommend to people who are interested in this area. It's called Cancer at the Dinner Table. It's a 2017 paper published in the Journal of Humanistic Psychology and the lead author there is Thomas Swift. And so in this paper, transcripts of participant interviews, which were done with the researchers using a semi-structured interview kind of questionnaire, were coded and distilled into themes. So this was a kind of interpretive, phenomenological analysis, and I'll just say, just will highlight the ten themes that emerged from participant reports about their experiences in the trial. Because this is I find always I find so moving and the language is so evocative. So first of all, participants experience the psilocybin session as very distressing. This is an immersive experience. It's not always ecstatic or it's not the same kind of use that you might that people might use recreationally for fun. I mean, Emma's already spoken about the fact that high dose psychedelic therapy is work and it can be really, really distressing. And so this emerged from the participant reports in this trial. Participants also reported that the psilocybin helped them reconcile with death. It helped them acknowledge the place of cancer in life. Uncouple emotionally from the cancer and to reconnect to life or to reclaim presence in the face of cancer or possible cancer recurrence. And one last thing I'll mention about this is that there is a lot of the participants had a spiritual or religious interpretation of the experience, and I think that opens a whole other door of conversation potentially.

Dr. Emma Hapke:
I would just add that what we're seeing in the psilocybin literature, especially for the treatment of end of life distress, but also for depression, is that having a mystical experience which is measured on something called the MEQ, the mystical experience questionnaire, seems to mediate positive therapeutic benefit in the psilocybin literature. And so I believe it's approximately 70% are having a complete mystical experience in those end of life population using psilocybin. What's interesting in MDMA, it's closer to 40% are having a mystical experience. So it's lower and it doesn't seem to connect to positive therapeutic outcomes. So we think that the MDMA may facilitate more an ability to process trauma as opposed to connect to the mystical, although that element and the transpersonal element is very much still present with MDMA.

Nikhita Singhal:
Thank you both so much for that. I think we've kind of covered some of the what the evidence has shown so far. Maybe to give our listeners a better idea, maybe hand it over to Annie for our next question, what this actually looks like for sure.

Annie Yu:
So in our discussion around some of the evidence and literature around psychedelics, the term that popped up was psychedelic assisted psychotherapy. So it sounds like aside from just the psychedelic treatment itself, it's generally paired in both clinical and research settings with more guidance using psychotherapy. So can you maybe walk listeners through what the components of psychedelic assisted psychotherapy looks like and what a typical session session looks like in your respective practices?

Dr. Emma Hapke:
Sure. So when I think about psychedelic assisted psychotherapy, I like to think of a triangle. So at the top we have the therapeutic modality and there's research going on into like what is the best type of therapies to pair with different psychedelics for different indications, but you have the actual therapy itself. Another point on the triangle would be the therapeutic relationship, which we know for any psychotherapeutic process, that is a really important mediator of a successful outcome. And then on the third point of that triangle, we have the drug effects, which I really see as a catalyst, catalysing the psychotherapeutic process, and then inside the triangle, I imagine the patient's own inner healer. So in some of the models that I've been trained in that come from Stan Grof and other sort of pioneers in the field, they talk about this idea of the inner healing intelligence. And you think about it just as the body moves towards healing. For example, let's say you cut your arm, you go to the emerg. The Emerg doc might clean it out, even suture it. But it's your body that heals that from the inside out. And similarly, your psyche wants to move towards wholeness. And sometimes what we're doing in the psychedelic state is we're removing some of those blockages to allow your own natural inner healing intelligence to work. And so really in this model, we're really trusting the patient's inner healer and the patient to allow up the thoughts, feelings, memories, sensations that are most in service of their healing. And especially in the integration phase. It's the patient's inner healer that's the has the ultimate authority on interpretation and meaning making, and we're really following that.

Dr. Emma Hapke:
So as a therapist, you're following the patient's lead. A typical course of psychedelic psychotherapy would typically have two therapists and involves three main phases. There's a preparatory phase, there's the dosing or the medicines administered, and then there's an integration phase, and you'll hear these terms set and setting. And I think they're really important to be aware of when we're understanding psychedelics. So the setting is the physical environment in which the person takes a psychedelic, but it also includes the psychotherapeutic environment that's created by the therapeutic relationship and the entire container in which the experience is going to unfold. And we pay a lot of attention to that. In psychedelic therapy, we want people to feel at ease so that they can trust the process, trust the therapist, trust themselves. And so you'll often see psychedelic therapy rooms look less clinical. There's dim lights, there's art, there's plants, and there's a bed. The patient in the dosing session will lie down. They'll typically have eye shades on. There's music played throughout, which also supports that setting for the person. And part of why the setting is so important is because psychedelics induce a greater state of neuroplasticity. So we're really seeing this especially in the psilocybin literature, but also for MDMA. So it's inducing these states of neuroplasticity, which is why the setting in which you take it is so important. And that's happening both while you're being dosed with the medicine, but also in the time that follows. And that's when the integration phase is also really important because the brain is more changeable.

Dr. Emma Hapke:
And so what you do in that time after really matters in terms of set. What that refers to is sort of the mindset of the person going into the experience. And so it includes things like their intention, how they're feeling that day and what work they've done to prepare. And so the preparation phase, it varies, but typically would be at least three sessions that are 60 to 60 minutes to 2 hours long, where the therapists are really getting to know this patient, they're getting to understand their life history to connect with them. You're beginning that process of trust building and you're providing a lot of psychoeducation on the effects and what they might what they might experience in the psychedelic state. And one of the things that we really encourage people in the preparation phase is to trust and surrender to the experience as much as possible. So the more that you're able to surrender and open up in the psychedelic state, they're more able to access these expanded states of consciousness that can be really healing. And so we also encourage people to move towards things that are difficult and to adopt the stance of curiosity towards the darker elements that might come up. And there's something very transformational that comes from moving towards something that's difficult and working through that and coming through the other side of it. And that's one of the mechanisms that we're learning seems to be facilitated by psychedelic therapy, is overcoming experiential avoidance, which can often maintain a lot of psychiatric disorders. The integration phase then is a, I think, there's two main things that are happening in integration.

Dr. Emma Hapke:
One is meaning making. So the person is continuing to process what came up and connect the dots and understand how might this apply to my life. And often some lessons will emerge that then they want to then try to implement to make change in their life. And then the second part of integration I think of as practices to maintain that sense of connection that they felt in the psychedelic state. So really encouraging people, especially in the days and weeks that follow, to take time to go inward, be it journaling or art or time in nature, meditation, whatever works for them to reconnect to themselves and to try to continue to maintain that sense of connection. And I think the sense of connection is, again, one of these what we're learning is sort of one of the mechanisms of action when I think about trauma in particular, but really a lot of psychiatric illness, a state of disconnection from yourself, from others, and then from something bigger than yourself are really, I think, predominant themes that we see in a lot of psychiatric illness. And I think the psychedelic state has the potential to help people feel more connected. But then in the integration phase, it's like, how do you maintain that? I think communities of practice and communities of patients who have received this kind of treatment that can connect to each other in an ongoing fashion after is going to be part of what really increases the chance that people can maintain the gains that they're seeing in the immediate post session phase.

Dr. Daniel Rosenbaum:
Emma mentioned set and setting. Set as having to do with someone's degree of preparedness heading into the experience, the intention they bring to it and so forth, and setting being for the most part synonymous with environment or the surrounding influence of the environment. So you can imagine if someone takes a handful of mushrooms at a music festival and they're surrounded by thousands of screaming people, and there's lots of stimulation in the form of loud noises and flashing lights and so forth that they might be more likely to have a challenging experience, to have a bad trip, so to speak, even if their intention is to have a good time with others. On the other hand, if someone takes the same dose of mushrooms with a loved one who they trust very much and who will be taking care of them in an idyllic setting like a meadow, and their intention is to connect with nature and have a peaceful experience then the kind of experience they have will likely be quite different even though it's the same medicine at the same dose that they're taking. So I think that's a helpful illustration of the importance of setting in terms of set, the mindset, the preparation. Think about the same meadow, the same couple, let's say, and someone comes across some mushrooms in the meadow and they decide to take the mushrooms because they figure they're edible mushrooms. If they don't know that they're psychedelic mushrooms and within an hour they start to trip out, they're liable to go to the emergency department because they're not prepared, they're not expecting, they don't have the intention to take a powerful psychedelic, to have an experience of connection with nature or whatever. And so I think that's been a helpful way for me regarding the importance of those factors.

Dr. Daniel Rosenbaum:
And why that's important is that the quality of the acute drug experience has been shown across human studies in various indications to predict, be correlated with or mediating the long term outcomes. So the acute drug experience is key. And one of my favourite findings in the field of psychedelic science comes from regarding the nature of the acute drug experience and how it leaves people afterwards is a healthy volunteer study from Johns Hopkins. So this was one of the early studies that constituted the psychedelic renaissance and really, I think, kindled people's interest in this. So researchers at Johns Hopkins offered people synthetic psilocybin under blinded conditions. So they told people that they might get a variety of drugs. And under blinded conditions in a hospital room with guides and in the same kind of setting that I described with eyeshades and the headphones, and in a comfortable living room like environment, people who took a high dose of psilocybin reliably reported that it was either the most or among the top five most personally meaningful experiences of their lives. If you stop and consider that for a moment, I think you'll find that it's remarkable. It's incredible. The same is true that the researchers always used readings of spiritual significance, and people also reported these experiences were among the most spiritually significant of their lives. And so both in terms of personal meaning, meaningfulness and spiritual significance, people talked about them as being akin to the birth of a child or the death of a parent. So clearly something profoundly moving is happening for people in relation to these experiences of taking a high dose psychedelic under the appropriate set and setting.

Dr. Daniel Rosenbaum:
The only other thing I'd add to that is, you know, in a clinical context, it's still common for parts of the experience to be quite distressing or challenging. And it's just that I think one of the differences in a clinical setting is that the person has support and feel safe to actually work through those challenging experiences, which can then lead to this feeling of resolution, which can then often lead into these transcendent and ecstatic states. And so people will also describe them as some of the most challenging experiences of their lives. But it's the resolution of that that also seems to be healing.

Chase Thompson:
I think that leads to an important question that I have, which is, you know, in that study that you mentioned, and it sounds like people are describing some of their experiences with psychedelic psychotherapy experiences, some of the most important in their lives. I think some people might hear that and think about ethics. Whether that's something that should be happening in a medicalized setting with patients, doctors versus friends and colleagues. And I think from the psychedelic community, there's been some pushback that psychedelics should not be administered in a medical setting and should be kind of more available in the community for people to just do given that they're very physiologically safe and that there's a low risk of harm from medical causes. I'm just wondering if you have any thoughts on kind of the movement of psychedelics into a more clinical setting? And what are the ethical implications of having this really significant or profound experience with your doctor, say, versus your friend or partner?

Dr. Emma Hapke:
Yeah, I mean, I think one thing that comes to mind there is that for people with psychiatric distress and psychiatric illness, such as trauma, having somebody who's trained in trauma informed psychotherapy, who's bound by a regulatory college, who has training in psychedelic assisted psychotherapy, I think can increase the chance that this is a healing experience and it can increase the safety of the experience. So for people that are really suffering with these treatment resistant conditions, I think there are certain risks when taking them outside of a clinical setting. So I think that's one thing. I think that you bring up an interesting question, which is sort of what is the role of spirituality in modern medicine? It's been largely divorced from and when we're taught to formulate us in psychiatry, we're taught the biopsychosocial model. But I've also wondered what about the biopsychosocial spiritual model? Because it's often those things that are greater than ourselves and doesn't necessarily need to be a specific religion, but it could be meaning and purpose or a sense of connection to nature. Or just connecting to something that's bigger than you is fundamentally really healing. And I think thinking about that in the context of healing as psychiatrists is actually important, but it brings up a question of training and exposure. And I think that there's a real role in psychedelic medicine for interdisciplinary teams. Like on one of our teams, we're bringing on spiritual care providers, for example, who can really help us in the preparation integration phase with patients who've had these complete mystical experiences, which can be paradigm shifting for people who have previously had no sense of that kind of connection. So I think training and interdisciplinary teams in our ways to address some of these ethical issues and I think it's also a really important area of study. So those would be some of my initial thoughts. Dan, do you want to add anything?

Dr. Daniel Rosenbaum:
Yeah, I'll add a couple of things and I'll just say it. It's a great question and it brings to mind quite a lot of considerations, a few of which Emma's already touched on the study that I was referring to with the healthy volunteers at Hopkins and the personal meaning and spiritual significance that people derive from the psychedelic state. I think there's a way to take those results and come away with the view that the psychedelic experience is itself intrinsically healing. And I think that's a partial misread because again, talking about the critical importance of context, the people in the study were offered a high dose psychedelic in the presence of trained guides and therapists. They had been prepared for the experience extensively, and in the end, following the experience, they had opportunities to process challenging material and to. There was a clear and explicit invitation of frame to make meaning from the experience. So I think it's probably more helpful to think of the psychedelic experience. I mean, setting aside for a moment the awesome, literally awesome and profound kinds of subjective things that might go on for someone but the experience opens a window of change. And this is the sort of recently proposed terminology about psychedelics as psychoplastic, meaning that you're opening up a critical window for change and that that window itself is outcome agnostic and that we can expect a greater potential for healing.

Dr. Daniel Rosenbaum:
And I'm not saying that that has to be done in a hospital with a psychiatrist per se, but with people who are trained to work with the medicines, who are trained psychotherapist, as Emma was alluding to, that that's where a greater potential for healing can come and where harm can be reduced, I think to a greater extent. I don't know that bio psychiatry has yet to come to a good, doesn't know exactly where to place this treatment paradigm. It's a complex intervention and clearly it kind of straddles a number of perspectives. It's not a pure pharmacology. It's not pure psychotherapy. It seems to invite this this marriage of the two: the psychological, the biological. It invokes the spiritual. I mean, words like mystical experience appear in the German Journal of Psychopharmacology, and it rests on a great deal of indigenous traditions and wisdom. So there's really a lot of paradigm and perspective straddling going on that it's just key that we recognise all these perspectives being brought to bear and that we're thoughtful about offering these treatments to people. And that sets aside altogether the question of decriminalisation, legalisation, recreational use and so on, which I hesitate to get into too much at the moment.

Chase Thompson:
I think one of the things that you've also mentioned is having a challenging experience and and that's the so called "bad trip" can sometimes arise and whether that occurs can be influenced by the setting that one uses psychedelics in. And so I'm wondering, in a more clinical setting, how common is it for people to have challenging or bad trips and and does that lead to a poor outcome for people? I think many in the general population may have a notion that's having a bad trip, for example, could produce lasting psychological damage or even trauma.

Dr. Emma Hapke:
So I think that in some of the trials, they see something called anxious ego dissolution, which is when as the psilocybin is coming on and the sense of self is starting to soften, that can be really terrifying for some people and can induce this these states of terror and panic. And I've seen rates around 30% in some of the trials. So it's not insignificant, but that doesn't necessarily mean that it's going to negatively impact the outcome. And it's very often that as people work through those really intense, challenging moments of a trip, that that in of itself is actually healing. And so, one, I could draw your attention to the Zendo Project because they have these principles of harm reduction that they use at festivals for people. And this idea that there's no bad trip, that no matter what happens, this is data that's coming up. And if the person is able to work through it in the integration process, though, it can be challenging. It still has the potential to be healing. And so I think that's something that's really important for people to keep in mind, especially if they've had their own difficult psychedelic experience and they're not knowing what to do with it. Finding an integration coach or somebody that's experienced with psychedelic integration can be really helpful because even if you're still feeling like something's opened and it hasn't closed or I have so many questions or I'm feeling really unstable, there's work that can be done and integration can go on for months or even years after a psychedelic experience for people.

Dr. Daniel Rosenbaum:
The qualitative study that I mentioned out of NYU, in their cancer psilocybin trial, they said almost everyone referred to the immersive and distressing nature of the psilocybin experience. There are a few quotes from that cancer at the dinner table paper about people being being brought right to the brink of what they can tolerate. And what I think what that experience is like is, as I mentioned, sometimes terror, anxiety. People can even have transient experiences of paranoia during the psychedelic session. This again speaks to the trust and presence of trained guides so that during the experience the participant can seek support if needed, whether that's gentle touch in the form of hand-holding or to say, I'm really scared, I'm having a hard time. And the response that they would typically be met with is, You're safe, we're here with you. Everything's unfolding the way it should be. And people are encouraged to go into that experience and to be curious about it. There's a story which I hope I won't misrepresent too much in Buddhist psychology about encountering one's demon and one's demons and inviting them, welcoming them. And to the extent that you can tolerate it, being curious about it. And I think that's where, as Emma was alluding to, a lot of the healing can happen, going through the challenging material and going all the way back to one of the initial questions about the ways in which psychedelics may be different from conventional pharmacotherapy is a lot. In a lot of ways, pharmacotherapy is like SSRIs for the treatment of, say, depression or anxiety disorders can be understood as suppressive, which means that they suppress some of the distressing symptoms of those illnesses. And there's a great paper from Robin Carhart-harris and David Nutt about it's called A Tale of Two Receptors, and it examines the differences between SSRI mediated serotonin 1A receptor signalling which governs this sort of suppressive response compared with the psychedelic mediated, serotonin 2A receptor signalling, which has to do with working through. That distinction, is maybe helpful.

Chase Thompson:
Yeah. Just to note, I would direct our listeners just to our previous episode with Dr. Carhart-harris. We actually talked about some of those differences with him for overview. If you're interested on the differences between the more suppressive effects of SSRIs and the activating effects of psychedelics, and it's episode 27, just for reference.

Dr. Emma Hapke:
I think the other thing that this brings up is the question of how to train therapists to hold space for people in psychedelic states. So I think an unanswered empirical question is whether having your own psychedelic experience as the therapist gives you a greater competence or confidence or ability to hold space for people. And that's a question we hope to maybe start to address empirically at the Nikean Centre that we're developing. And, you know, as as I said, it's an unknown question. But what I will say is that things can look really rough from the outside of when you're watching somebody on a psychedelic, it can look terrifying. It can look like they are in so, so much distress. And there can be a very strong urge to want to help and try to get them through that and try to stop what's going on. Or a guide who's not experienced with, you know, not necessarily psychedelics themselves, but just psychedelics in general could really think there's a problem here when actually everything is unfolding just as it's meant to. And when the guide trusts the psychedelic state and the person and the medicine and the container and doesn't get too worked up about what they're witnessing, I think that really creates a greater state of trust in the patient. And so that's one possible reason why having your own experience may allow you to better hold space. But like I said, we need more research on that.

Nikhita Singhal:
Thank you both so much for for walking us through that. And I think we've touched on a lot of the challenges, the risks and and you mentioned some of the upcoming work. So I guess I'm curious to hear what what do you see as kind of the future of this field moving forward? What are you most excited about investigating and what are what are you working on now?

Annie Yu:
So I think, you know, one of the things that I'm really curious about is how is this how are these treatments going to be integrated into the public health care system in Canada and down in the States, of course, into their more complex health care system with all the different insurers? The last I heard, MDMA could be regulated by the FDA in Q4 of 2023. So this treatment is coming down the pipeline very soon. And in Canada, we recently had the government open up something called the Special Access Program, which potentially creates a route for a physician to prescribe MDMA for a patient with severe and life threatening PTSD. And I think we're going to see in Canada a lot of for profit clinics potentially trying to provide these treatments. And I think one of the things that really concerns me is how are we going to create equitable access? I would hate to see this treatment only be available to the elites and those who can afford it. And I think in Canada we really need to watch this creep of privatisation in our health care system where we have a universal health care system. So I think some of the work that we hope to do at the Nikean Centre over time is collect data both on patient safety and quality improvement, but also to create a cost benefit analysis for OHIP, which is our provincial insurer here in Ontario, really create the business case of why the government insurer should cover these treatments. That's a stage once we really are confident that the treatment works. So that's one piece that I've been thinking about.

Dr. Daniel Rosenbaum:
As I said earlier, the area of interest that most excites me in this field is the potential application of psychedelic therapy and palliative and cancer care. And in that regard, actually, maybe first I'll mention that a great paper that was published in 2021 by Yvonne, a palliative care physician in the States, who, with his colleagues and after convening a conference of experts and soliciting opinions and so forth, set out a research agenda for psychedelic assisted therapy among patients with serious illness. And they highlighted it as actually four areas of opportunity. And I think our research group here at UHN, which has developed a psychotherapy intervention called Pearl, which stands for Psilocybin, Assisted Existential Attachment and Relational Therapy. Which I can say more about in a moment. But we're trying to operationalise these four opportunities in terms of advancing research in this area. So one of which is clarifying indications. Is it important, for example, that someone carries a diagnosis of major depressive disorder in addition to their advanced cancer in order to qualify for or benefit from a course of psilocybin assisted therapy, these researchers identified the development of clear therapeutic protocols as important. So in response to that, that's part of how we and why we developed Pearl therapy. Investigating the impact of set and setting.

Dr. Daniel Rosenbaum:
This is key. One major element of set and setting, which we haven't talked about and which I think again is a big open door that we can spend a long, long time on is the role of music in psychedelic therapy. And so we have a wonderful PhD music therapist on our team, and we might begin to pose some questions about the role of music and psychedelic therapy for people at end of life. And then finally continuing to further the understanding about mechanisms of action. So thinking about at the biological level, the psychological level, so what kinds of psychotherapeutic processes are at play over the course of psychotherapy, not just in the psychedelic session? And then of course however you might characterise or whatever language you might bring to bear on the psychedelic experience itself, which often leads into the terrain of the spiritual. And so in this regard, we're also planning collaborations with spiritual care providers and chaplains, both to help in the spirit of training and making sure that our therapists are most well equipped to work with people who are experiencing these profound states. Also thinking about in terms of the mechanism of action, what is going on? How can we best understand this so that we can best help people in the future?

Dr. Emma Hapke:
I think a lot of those questions also apply just more broadly in the field. So figuring out what indications are best treated with which psychedelics in combination with which types of psychotherapy. So for example, people have combined access ACT, which is Acceptance and Commitment Therapy with psilocybin for depression. There are studies that are going to be happening in Toronto that combine cognitive processing therapy with MDMA for the treatment of PTSD. So what existing psychotherapy is best combined with which molecules for which indications I think is going to be really interesting work. And then, as Dan said, a greater understanding of the mechanism of action and biomarkers both biologically, also psychologically and also spiritually, and really trying to understand how this treatment works. And I think moving eventually to personalised medicine, which I think the entire field is going to hopefully move in that direction. So can we actually scan somebody and interview them and figure out where what type of psychedelic is best? Where do we start? I think down the line you may actually see like a menu of psychedelics. Maybe you start someone, for example, with PTSD, with some ketamine, which can allow them to feel good in their body again, which can help them get used to being in a non ordinary state of consciousness. Then they might move on to processing with MDMA or psilocybin. So I think really understanding the person's unique makeup, both genetically and psychologically, will help us better figure out which psychedelic in which treatment is going to help them the most. So just a couple other things that I think we're really interested in at the Nikean Centre. One is this question that I mentioned earlier of how do we train therapists and studying experiential training through things such as whole entropic breathwork, which is a form of breathing that can induce a non ordinary state of consciousness and may provide a way for therapists to have some experience of both holding space and being in a non ordinary state without having to take a psychedelic.

Dr. Emma Hapke:
And then also potentially what is the role of having an actual psychedelic as part of your training? And that's being used in the ketamine model of training pretty commonly is therapists will receive their own dose of ketamine when they're training for that, but hasn't been studied. So that's, I think, something that's really interesting to us. I think another question that the field is grappling with that I think is really important to keep on the forefront, is remembering that using substances to induce a non ordinary state of consciousness comes from indigenous cultures around the world. And this question of how do we incorporate indigenous worldviews into the training of therapists without appropriating their cultural practices and with making it suitable to our own setting and culture while also honouring what they've learned, including their their knowledge and working in the unseen and working with spirit. So these are really important questions to grapple with in this. You have indigenous reciprocity that we're not just taking something and potentially capitalising on it in a for profit model, but actually giving back and working with Indigenous healers and indigenous teachers. When we think about the design of curriculum and also when we think about the actual treatments and especially when we're treating patients from an indigenous background. So that's just something I wanted to mention as well.

Nikhita Singhal:
Thank you both so much. It's been an incredible episode and I think our listeners have learned so much and we have as well, I guess, tying things up. Do you have any recommendations for people in terms of learning more like a favourite book, podcast movie in this field? And are there any last thoughts that you want to leave our listeners with?

Annie Yu:
I'll do a little plug for our research centre. So we've co-founded the Nikean Psychedelic Psychotherapy Research Centre at the University Health Network in Toronto, and so we're Canada's first non-profit academic research centre, and we're really hoping to develop an academic and innovation hub for psychedelic assisted psychotherapy in Canada and abroad. So you can check out our website. Nikean is spelled "N I K E A N," and you'll find us and you can learn more about the work that we're doing and we're always accepting donations as well. So if you're looking to donate to psychedelic research in Canada, we of course would welcome that. In terms of training, we are going to be developing a training program through the Nikean Centre that will launch in the fall. I think you're going to see a number of trainings popping up all over. So I think it's really important that you do research on the training program that you're considering, too. If you're really keen on being a psychedelic therapist and you're already part of a regulated health profession or in training to do so to programs that have a really good reputation would be the certificate in Psychedelic Therapy and research at the California Institute of Integral Studies. So I'd recommend checking them out. And then MAPS is also doing a lot of training, specifically around MDMA assisted psychotherapy. And both Dan and I have done their training program and it's really good. So those are a couple really reputable ones. There's going to be a lot popping up, so make sure you do your due diligence and ask questions about what they're offering and who's teaching.

Dr. Daniel Rosenbaum:
Yeah, and I'd just like to add, I'd like to start by expressing my gratitude for the invitation to be here and to participate in this podcast series. I think it's wonderful that you're covering this area, of course, being a researcher and someone interested in the field. Nikhita, you talked about a favourite podcast. I mean, if I'm right, this is one of what will become a series around psychedelics, and I look forward to listening to future episodes of this podcast around psychedelics. And I would also direct listeners, as has been done already today, to the episode with Dr. Robin Carhart-harris. But thank you so much for being here and directing the conversation.

Annie Yu:
Yeah, thank you guys so much for your interest in this area. You know, it's exciting in mental health to have a new treatment and really a new treatment paradigm on the horizon. And so I think we all owe it to ourselves and our patients to learn more about this area. So thank you so much.

Nikhita Singhal:
This concludes our episode on Psychedelic Assisted Psychotherapy with Dr. Mahaffey and Dr. Dan Rosenbaum. And we hope it may be the first, as mentioned, of a series of episodes that focus on this topic. Psyched is a resident driven initiative led by residents at the University of Toronto. We're affiliated with the Department of Psychiatry at the University of Toronto, as well as the Canadian Psychiatric Association. The views endorsed in this episode are not intended to represent the views of either organisation. This episode was produced and hosted by Chase Thompson, Jake Johnston and you and Nikhita Singhal. The audio editing was done by Nikita Singhal. Our theme song is "Working Solutions" by All of These Things. Special thanks to our incredible guests, Dr. Emma Hapke and Dr. Daniel Rosenbaum, for serving as our experts for this episode. You can contact us at psychedpodcast@gmail.com Or visit us at psychedpodcast.org. Thank you so much for listening.

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