Psilocybin in Serious Illness: James Downar, Ali John Zarrabi and Margaret Ross

Eric 00:00

Welcome to the GeriPal Podcast. This is Eric Widera.

Alex 00:03

This is Alex Smith.

Eric 00:04

And Alex, we have a great lineup today. We’re going to be talking about new research in psilocybin in serious illness. That’s a lot of S’s.

Alex 00:11

Yeah, the letters are swimming in front of me because I did my dosing in advance. Did you?

Eric 00:20

I’m doing microdosing. Alex. I’m fine. [laughter]

Alex 00:22

Our first guest today is James Downar, who is a critical care and palliative care doctor and researcher and head of palliative care at the University of Ottawa. Dr. James, welcome to the GeriPal Podcast.

James 00:32

Good afternoon.

Alex 00:33

Our next guest is Margaret Ross, who’s a clinical psychologist and researcher at St. Vincent’s Hospital in Melbourne, Australia. She’s joining us at 6am her time. Margaret, thank you so much for joining the GeriPal Podcast.

Margaret 00:45

Thank you for having me. I’m bleary eyed. Very happy to be here.

Alex 00:48

And our last guest is Ali John Zarrabi, who is an internist and palliative care doctor and researcher at Emery. Ali John, welcome to the GeriPal Podcast.

Ali John 00:58

Thank you for having me.

Alex 00:59

And I met all three of you and watched you do a presentation about psilocybin research at the Congress International Desens Palliative Miguel.

Eric 01:12

I apologize to all the Quebecois and anybody who speaks French for that pronunciation. [laughter] You can send directly to Alex any email feedback.

We got a lot to cover. We’re going to be talking about three new trials on psilocybin therapy. But before we do, we always start off with a song request. James, I think you got the song request for Alex.

James 01:34

Yeah, right on. So in our trial, because of security reasons, we are required by Health Canada to store the substance in a special secure area in my office. And one of my neighbors, my office door is green. And one of my neighbors pointed out that there’s a song called the Green Door. I’m actually going to show you a picture of the green doors just so you can see it. It’s there.

Eric 02:00

It is a green door. For all those just listening, we just saw a very green door.

James 02:05

That’s a green door. And you really probably don’t want to ask what’s going on behind the green door, but you can sing a song about it.

Eric 02:13

Who’s the song by?

James 02:14

Oh, gosh, I don’t know.

Alex 02:16

Jim Lowe.

Eric 02:17

It looks like Jim Lowe from the 50s.

James 02:20

Jim, if you’re still with us, I apologize.

Alex 02:26

(singing)

Eric 03:07

That was fabulous.

Alex 03:09

Fun choice, James. Thank you.

Eric 03:10

Let’s jump into the green door. That is psilocybin. So we’ve done a podcast. We’ve done two podcasts on psychedelic assisted therapy, not just on psilocybin, though. We did one with Ira Byock. We’ll have a link to that. We had one with – who was on that again?

Alex 03:27

We had Theora Cimino, who was a palliative care fellow at the time, Stacy.

Eric 03:31

Fisher and Brian Anderson.

Alex 03:33

Yep, there you go.

Eric 03:35

We’ll have links to both of those. So if you want to do a deeper dive into psychedelic assisted therapy, you can do there. Today, we’re going to be talking about psilocybin and specifically we did talk a little bit about what it was in the past podcast, but maybe we could just start off with a little refresher. What is psilocybin? Margaret, I’ll turn to you first.

Margaret 03:58

You turn to me. Oh, my gosh. I was like, if I go quiet, the other for sure. So psilocybin is a compound that is a psychedelic compound that is found in what is colloquially known as magic mushrooms. So in the psilocybin genre of magic mushrooms. And it has been used for many, many years in indigenous ceremony in Oaxaca to kind of occasion mystical, spiritual type experiences.

And it kind of made its way into medicine probably around, I’m going to say the 50s after there was a fairly interesting Time Life article that was published. Gordon Alwasa. Am I saying that right? I always get. Yeah. So Wasser and his wife, who was an amateur mycologist, went to Oaxaca and they experienced these magic mushrooms. And then they came back and they wrote about these experiences that they had, which were quite extraordinary. And when that article went to print, it just went ballistic. And then all of a sudden, everyone was wanting psilocybin and crowding down to this little town in Oaxaca, which actually caused a lot of problems for the indigenous there. But very long story there. But, yeah, this is how it turns out.

Eric 05:18

Psilocybin can be found in a lot of different mushrooms. Right. So it’s. Yes, it’s throughout the world in different mushrooms. I believe, like there’s questions about.

Margaret 05:29

Yes. Yeah, it’s pretty much, I think they found it on every continent and use of it in kind of sacred ceremony in a Number of indigenous societies.

Alex 05:42

And is the psilocybin used in. Oh, wait, is it psilocybin or psilocybin?

Margaret 05:49

Oh, you know what? I’m going to throw this to the lads.

Alex 05:53

It doesn’t depend on your accent. Canadian, Australian, tomato, Tomato, it doesn’t matter.

Eric 05:59

Oh, good. So I can say anything I want. I am not sticking my foot in my mouth.

Alex 06:03

Is psilocybin that’s used for medicinal purposes in your studies, for example, is that manufactured or is it derived directly from mushrooms?

James 06:13

So I think in most cases. So some people are using actual dried mushrooms and you test portions of it to make sure that you have a rough idea of what you’re giving. In our. It can also be purified from mushrooms and given in a very measured quantity for quality purposes. Psilocybin itself is a prodrug and it gets activated by just simple. I think it’s phosphorylation or something or I forget which. By an enzyme that is ubiquitous before it becomes psilocin, which is the active form. So some people actually just take straight psilocin, but it’s much cheaper and easier to use psilocybin.

Eric 06:47

And how does it work? What receptors are we activating or deactivating or.

James 06:54

So it’s an agonist at this 5ht2 receptor. Serotonin 2 receptor, which is. There’s a whole big class of different serotonin receptors. And those of us who work in palliative care are more familiar with the 5ht3 receptor, which we use for nausea management. But there’s a whole bunch that seem to have very varied roles and not all of them are understood. So 5ht2 was. I don’t think anyone really quite understands how it works, but agonism at that site seems to be the mechanism of this particular psychedelic.

Eric 07:26

And why use it in palliative care? Ali John, I actually had the chance to watch your talk at ahpm, and what I remember from that talk is that you were talking about how demoralization was like the central hub for total pain. And then the last couple slides you talked about the potential role for psilocybin and psychedelic assisted therapy. Tell me what you meant by it’s the central hub. Demoralization.

Ali John 07:59

Oh, yeah. So, just going a step back, I do mostly outpatient work and I see a lot of chronic pain, existential distress, anxiety, depression, opioid dependence, et cetera. And I spent the past couple years just collecting data from several hundred early palliative care patients and did a network analysis, which basically just looks at the Correlations between different constructs, whether they’re physical, emotional, social or spiritual. Demoralization had the highest strength centrality, which means it had the greatest effect on other constructs within total pain, depression, ptsd. It was connected death anxiety, and it was connected to chronic pain through pain catastrophizing or pain related helplessness. What I was interested in. And this work ran parallel to the psilocybin work. Should I just start talking about my study?

Eric 08:56

Yeah, let’s hear it.

Alex 08:57

Segue.

Eric 08:58

And we’re gonna have a whole podcast coming up on death anxiety probably in like a month from now.

Alex 09:07

And we wanna have a podcast with, I think it’s David Kissane, who’s like the major researcher who studies demoralization.

Margaret 09:17

Yeah, yeah.

Alex 09:18

And Margaret, if you could bug him because he agreed to be on the podcast and then ghosted us, tell him to get back to us with some dates. Thank you. Okay. Ali John, thank you.

Ali John 09:28

And I use David Kissane’s demoralization scale too.

Margaret 09:33

He will be thrilled with that, actually.

Eric 09:36

So what’d you do in your study?

Ali John 09:38

Yeah, so on a hunch, I had to basically select a patient population, right? So for me, it was outpatient palliative care patients. And even though this is a pilot, the eye was. My eyes were really focused on dissemination and implementation. How do we potentially include an interdisciplinary palliative care team in rolling out psychedelic assisted therapies? So I went ahead and just chose demoralization and chronic pain because I felt that those were the two most salient constructs in outpatient palliative.

Eric 10:10

So people had to have demoralization or chronic pain. What definition of demoralization are you they?

Ali John 10:16

Well, using David Kissane’s scale, they had to meet a certain threshold, a score of 10. And demoralization is a construct of helplessness, hopelessness, and this quote, unquote failure to cope or an inability to quote to cope. Sorry. Due to this sense of allostatic overload, like you’re just overwhelmed and you don’t have the resources, the self efficacy or the self esteem to manage it. It’s similar to depression, but you don’t really have to have anhedonia or neuro vegetative symptoms to have demoralization. Patients in this pilot had to have both pain and demoralization together. Then fast forward a year. What I presented at HPM was findings of several hundred outpatients and the two most salient constructs were depression. Sorry, Demoralization and chronic pain. This hypothesis Played itself out in an interesting way,

Ali John 11:15

Thinking about total pain and addressing physical, emotional, social, and spiritual issues. We had an interdisciplinary team of physicians, nurses, social workers, and chaplains supporting patients through their psychedelic journey.

Eric 11:31

And they were getting psilocybin.

Ali John 11:34

Yep.

Eric 11:35

A large dose, small dose, microdose, A large dose.

Ali John 11:39

So how these trials with the large doses usually go is there’s preparation, dosing, and then integration. So classically with preparation, in individual settings or even in group settings, you have one or two people supporting people through psychoeducation, what to expect, life review. A lot of constructs similar to what we know about in palliative care, like dignity therapy, meaning centered psychotherapy, et cetera. Then the flight instructions, as we call them, the strength, the courage to trust and to let go into the experience, which Margaret will share more about.

Then you have dosing day. We give 25 milligrams of psilocybin, which is the equivalent of anywhere between three and a half to five grams, depending on the potency of your mushroom. Then we have integration. What made this trial, I would say, unique, is that you have a palliative care physician and nurse following people with medication tapering in order to be dosed. Some patients came off of opioids entirely, and now, a year later, have stayed off of opioids, and they’re still alive. So medication adjustments. We had a social worker addressing social issues. One of our patients was temporarily homeless during the trial and really supported the patient with that. Then, really importantly, the chaplain served a really important role in this trial. The chaplain was the person in the room during dosing. And we have a qualitative paper out published in Psychotherapy. Our dyad is a trained psychotherapist and a palliative care trained chaplain or exposed chaplain, someone who works in the palliative care system.

Eric 13:16

Those are the two people in the room.

Ali John 13:17

Two people in the room, and all of the patients, their caregivers, and the treatment team really found this dyad to be really useful. It opened up spaces for people to address spiritual, existential, religious, and theological concern concerns. And just to summarize the results, it was a pilot study, so it was highly acceptable. 7 out of 10 of these patients said it was one of the top five most educational and meaningful experiences of their entire lives. And six out of 10 said it was among the top five most spiritually significant experiences of their lives. Just to wrap up my portion of telling about the trial, these medications are amplifiers of consciousness, and they can worsen pain.

Some of our patients have dramatic worsening of their pain during the experience, even though catastrophizing and the median scores dropped by 50% for pain intensity, impact on mood and catastrophizing, the experience can be really intense. And our palliative care patients really want some sort of way to tap out or to even be able to be medicated with opioids during their experience, which really isn’t part of the, the language of psychiatry that really leads most of these trials. They really wanted palliative care teams to connect them with spiritual and religious organizations to help process these experiences. We’ve had atheists enroll in seminary from this experience. We’ve had people reconnect to their synagogues, to their mosques. So to what degree is a palliative care team kind of hand holding someone into a religious order, though? This is what they wanted. And the last thing is they really wanted support after the trial.

So we created a spiritual health or spiritually integrated acceptance and commitment therapy group model for our patients to meet weekly after the trial. And this was not part of the original protocol so they could get to know each other and process this together. So it really helped form community between patients and helped build community with the palliative team that was involved. It took a whole order of us to pull this off.

Eric 15:28

So it sounded like during the dosing part pain worsened for some people. What happened after?

Ali John 15:37

Not just pain, depression worsened. One of her patients said she felt more depressed afterwards. And then, you know, weeks later she’s listening to spiritual podcasts and, you know, was gardening and, you know, has had, has had her transformation. I think for people approaching the end of life, these, these medications can cause this kind of ontological shock. Like all of. And for those who are, are just listening, Margaret’s really emphatically nodding because, because they can change the way you view the world, especially the ways in which we use them.

Right. This is not. Although you can change the way you view the world, taking some mushrooms and going on a hike or going to a concert, we are putting a blindfold on you or a mask on you to go look inwards and, and giving you 20 plus hours of psychotherapy, trying to look at all the different things that you’ve kind of hid behind shelves or packed away that might bubble up in the form of terminal delirium at the very end of life. And they’re going to potentially explode on you during your peak experience. So for patients who might be listening to this and you are 100% craving and desiring and feel deserving of a mystical type, awe inspiring experience without the potential pain, you Know, odd doesn’t always mean good. Sublime doesn’t mean happy. There is pain with that, with going to the mountaintop and coming back. I am preaching now, but it’s important.

Eric 17:02

To share this, you know, and Margaret, I remember I watched one of your videos and you talked about that this is not a panacea, this is, this is like there’s this idea like, oh, like I want only the good stuff. Can you just medicate the bad stuff away so I don’t have to feel it during the therapy?

Margaret 17:19

100%. And I think, and I, I have been nodding like I’m going to give myself whiplash here. Ali. Everything he’s saying is everything that we have experienced and seen and I’m so excited to see your results. Ali. But the, yeah, I think people were coming along with this idea that was just going to reset my brain. There’s this unfortunately wrong headed idea about psychedelics. I think in the media that if I just lay back, if I just take the pill, everything will vanish, it will reset my brain. I don’t have to do anything.

And I think unfortunately, when anything kind of is moved into the clinical arena, similar to mindfulness in that way, where all of a sudden people became passive recipients, like they went and they got mindfulness in a consulting office. Now they’re getting psychedelic experiences, you know, and transformation in a consulting office. It’s, it’s kind of a strange thing. It moves people into this very passive role. But actually they’ve got to work really hard. They have to face very painful ideas that, as Ali said, you know, have been cordoned off for a long time. And, but if they can do that, you know, there’s some extraordinary transformation that can take place.

Eric 18:34

Is there such a thing as a bad trip then? Or is that just like you working through your.

Margaret 18:41

Your stuff?

Eric 18:42

I was trying to find the non.

Alex 18:45

Talking to a psychologist.

Eric 18:48

Is it just you working through your stuff and you need to go through the bad stuff?

Margaret 18:52

Some of the, you know, when people have these really kind of bad experiences, they’re often ill prepared and it kind of just comes out of nowhere and just kicks them in the butt, you know. But one of the things that, you know, as Ali mentioned, when we do preparation, we do a lot of psychotherapy, we do a lot, you know, developmental history and get a good picture of who they are, their life story, the story of their illness and things that may not want to come up for them. One of the questions that we ask is, is there anything that you don’t want to come up in these Sessions, because that’s the stuff we have to talk about now.

Because if it does come up in the, it’s going to be augmented and very difficult to pull yourself into your kind of rational thinking, you know, daily waking state to kind of zip that back up. So we really want to get a good sense of what the landmines might be and, and go, okay, well, you know what? You’ve now got this opportunity to meet in a whole other way. So we kind of prepare them for that. The flight instructions. I love that. Ali, I’m going to totally plagiarize that. So when they do meet it, how are you going to be in relationship to it? How are you going to ask it? What are you here to teach me? That kind of thing? So we kind of gear them towards. If you do have this challenging or really frightening thing come up for you, we’re going to be right beside you. We’re not leaving you aside. How can we meet this, how can we work with this and how can we interview it, if you like. And the curiosity that you can generate is a really important component of that because the curiosity then helps that anxiety really dissipate.

Eric 20:30

And Margaret, in your study, did you do kind of the same framework as Ali, John, where you, you focused on the, the, the pre. Part. Was it the integration and the.

Margaret 20:43

Yeah, preparation and then integration. I, I wish we had looked at the pain concept a little bit more. We had some interesting experiences. Ali, you’d be interested in this. We had one gentleman who sat up during his experience and said, what have you done with my cancer? Where is it? Where is it? I can’t feel it. And he had extraordinary pain prior to coming in and then had the experience and could not feel pain at all. We had a number of people who had that experience. I don’t know if that was common.

Eric 21:15

Even afterwards, like weeks afterwards, for a.

Margaret 21:18

Couple of days, they had said, I can’t actually feel anything. It’s is remarkable. And you know, can we do this again? And so, but, but then there were also experiences of, of augmented pain as well. But, you know, yes, we did, we did the same kind of setup, which is what they call the Set and Setting protocol, which is, if you’re interested, it’s a 2008 reference by, I think, Mattie Johnson, Roland Griffiths and, and Bill Richards about the safety guidelines around hallucinogenic use, which really details how you’ve got to really thoroughly screen people and prepare them to go on these experiences and then you don’t just leave them hanging, you know, instructions on how to be with them during dose day and how they can make use of you, who.

Eric 22:02

Was with in your study, who was with them during dose day.

Margaret 22:04

So we had dyads that were psychiatrists, psychologists who were palliative care trained. I’m very fortunate to be part of a team that is psychosocial cancer care. We dedicated team working with cancer and palliative medicine in our hospital. So we did the study and it was, I think completely mind blowing in a parallel process for us as well as well we should say.

Alex 22:33

Just sorry, Margaret, for a sec, just to interrupt. How many patients were in the study?

Margaret 22:38

Oh, so we had 35 participants and.

Alex 22:40

They were people seen by palliative care or what was the eligibility?

Margaret 22:45

So the eligibility was that they had to have a life threatening illness. So all of the malignancies were stage four. We also wanted to expand on previous studies that had looked at cancer patients because we were seeing non malignant diseases that in some cases had even more distress because of an uncertain trajectory. So things like COPD and end stage cardiac failure, als, which we know is motor neurone disease in Australia. So we kind of expanded that to people who were receiving palliative care. If they were not receiving palliative care, it wouldn’t be unreasonable that they would receive palliative care. So we did a. Yeah.

Eric 23:26

And did you use the dried mushroom or psilocybin itself?

Margaret 23:30

No, we used psilocybin that was synthetically derived. Because it was. Well, we used 25 milligrams.

Alex 23:37

Remind me, is that the same as Ollie John’s?

Eric 23:39

Ollie’s was more right.

Margaret 23:41

I.

Ali John 23:43

We use 25 milligrams of psilocybin. I think across the board we’re all using synthetic psilocybin because all that’s approved just. I don’t know when this will be aired, but in early April, Sue Sicily in Arizona just got fda, I believe, IND to study the actual mushroom itself. Wow, very funny name. Anyone who wants to Google it that involves an expletive that I can’t say on here that she specifically named.

Alex 24:12

You could say it. We’re not a PG podcast.

Eric 24:15

Say it.

Alex 24:15

What is it now? I’m curious.

Ali John 24:18

Yeah, yeah, it’s called Jedi Mind F*ck. [laughter]

Eric 24:23

That’s the mushroom name?

Ali John 24:25

Yeah. And that’s what the FDA approved.

Alex 24:27

So that’s what the FDA approved. They’re FDA documents say we approve Jedi Mind F*ck for use in clinical trials.

Ali John 24:35

In clinical trials. And she’ll be the true pioneer.

Eric 24:39

True pioneer.

Alex 24:40

That’s all the places this podcast is taking us. [laughter]

Eric 24:44

And so, Margaret, what were your two outcomes and did it show? What do we know about the outcome itself?

Margaret 24:50

I think, you know, one of the things that it was. It was significant. I’m just about to submit the manuscripts, as in this week, so you don’t.

Eric 24:59

Have to release any embargoed information with us.

Margaret 25:02

No, look, except to say we were extremely pleased with the results and we saw really wonderful reductions. Depression, anxiety, demoralization. But not just that, because, you know, and I often say this, you know, psychedelics are not just about symptom reduction. We can do that now. We can give people a sedative and new symptoms. This is about transformation. And I think that that was the beauty of it. The spiritual wellbeing just went through the roof. Ali talked about, you know, ontological shock. We saw that in spades. I think we probably, out of 35, had four non responders. People worked very, very hard.

They were very, you know, extraordinarily touched. I think, you know, these experiences are so non linear. They. They really reached into parts of human experience that, to be honest, I don’t think that as psychologists, psychiatrists, we have good language for. So seeing it implemented in the, the hospice model the way that Ali’s group has done. And also Yvonne Bessant, who is a good friend of ours, is a very important way to encourage community help with integration, but also to kind of nourish the spiritual transformation that goes on here. Because we don’t. We need language and we need systems that really honor that. And I don’t think that we have that in the current Western model.

Alex 26:27

That’s beautifully said. And we have to keep in mind these are uncontrolled pilot studies before, after.

Margaret 26:33

Studies, very small, as was randomized control. Oh, you had randomized with 35. It was small, but we, you know, we had. But it was.

Eric 26:43

That’s why you use niacin, Right, Right, correct.

Alex 26:46

Niacin.

Eric 26:46

Niacin. So what happens when you give people niacin? They get like flushing and they get flushing.

Margaret 26:51

And they got disappointed because they could tell, right?

Alex 26:55

You could tell.

Margaret 26:58

They thought for maybe a few hours that something might be coming on. But it’s one of the. It’s the old chest.

Eric 27:04

How long does it take to come on? Like a half an hour, hour. Is that the onset?

Margaret 27:09

Oh, you know, what we had. I’m really interested to hear what James and Ali have got to say about this. We had such a range in how quickly it came on, from 15 minutes to three hours. Like we had. One gentleman particularly, I think with cardiac failure, it seemed to be a lot slower to come on. We had a gentleman who was ready to go home. We were about to call his support person and he asked for a sandwich, which I think probably stimulated the thing to come on. All of a sudden, this is the.

Alex 27:43

Time it takes for the psychoactive components.

Margaret 27:46

Going to do this.

Alex 27:49

So we have two resource intensive interventions.

Eric 27:52

Yeah. And Margaret said, you know, we’re society right now. We just want that reset that pill that we can take every single day and like not have to do this hard stuff. What if we just micro dose it, take it every day? James, what did you do in your study?

James 28:14

And that’s, I think that’s really a great segue into why. Why these two things that we’re talking about are actually fundamentally different things. And I think they fundamentally are aimed at different populations and both could have a really important role. So take a step back. Right. Why are we, you asked why are we doing this in the first place? Right. The challenge is that people with advanced illness, people who see in palliative care, they have a lot of psychological distress. Existential distress in many studies is the most common and most burdensome problem that anyone will report. And unfortunately, our treatments for this really stink. You know, there have been a number of reviews, systematic reviews on this that just show, like medications, nothing really seems to work well.

Even when you look at the more advanced psychotherapies that have been studied, meta analysis, you know, where there is an effect, it tends to be of modest magnitude and duration. And it just, it’s a big therapeutic gap for us. So, you know, naturally, if you’re distressed about the world and about what your illness is causing you, you should just go and grab a bunch of mushrooms and stuff them in your face. Why does this work? It’s amazing that it works. There’s actually a really interesting study that was just in nature last year that did functional MRI studies on people while they were taking macro doses of psilocybin. And afterwards, which has to be the most amazing. Could you imagine taking a hallucinogen and then having an MRI while you’re on the hallucinogen?

Yeah, exactly. Now, what they find, it’s really interesting because there’s, you know, we’re understanding more and more about brain circuitry and how it relates to psychological distress. There is something known as the default mode network. Unsurprisingly, it’s the network that’s most active when you’re not doing other things. Default mode. When your brain’s default mode network is active, you Tend to be more like you have more anhedonia, pain sensations are increased.

Ali John 30:00

Right.

James 30:00

So when you’re sort of. I would, you know, I’m not a psychiatrist. I would think of this as like a ruminant kind of circuit that just kind of makes you stew on stuff and makes you unable to get out of your rut. And so you’re stewing on things that are bugging you and the pain is twice as bad. And if you can get out of that rut, then maybe things will get a little bit better. And that’s kind of what seems to happen when they give psilocybin to people, is that there’s what’s known as functional connectivity between the anterior hippocampus, which is partly memory, partly anticipation, and this default mode network.

The two are closely connected in baseline, but when you take psilocybin and it works, the two become disconnected. So this kind of the anticipation, the freakout that you have about what’s going on in your life and all the horrible things that are happening and could happen to you, it doesn’t tend to link you too much to this default mode network state where you seem to be more bothered by everything. And that could be a common pathway because that obviously it doesn’t have to me any obvious link to the hallucinatory effects of these medications, but it seems to be this residual thing that just lasts for weeks and weeks and weeks. So.

Eric 31:08

So maybe you don’t need to go through the trip part, if you can just. Or this. This very research. How many hours did you say this? This lasted with the. 20 hours.

Ali John 31:22

20 plus. And patients wanted more patient.

Alex 31:25

And Margaret, yours?

Margaret 31:27

Yeah, it looks similarly with 6. 6 hours prep, 8 hours on dose day, another 6 hours of integration per dose.

Eric 31:35

And James, how many psychiatrists, psychotherapists?

James 31:39

Zero. Zero plus or minus zero as part. Yeah, so, like, I mean, just to be clear, the patients that we saw again, were generally, I think, much more advanced in their illness course. So these were people who are felt to have like, all you had to do is basically have more than a month to live just so we could get through the protocol in order to be included in the study and followed by a palliative care provider. Some of them also had psychiatric or psychosocial oncology providers as well.

But these were people who were. We didn’t want people with very severe physical symptoms as we worried that might sort of lose our signal a little bit. We wanted to really focus on people who are having more of the psychological distress and the existential distress. So it was essentially anybody with an ESAS, depression, anxiety or well, being above 7. And if you had between a month to a year to live and were followed by a palliative care provider, many of these people had quite advanced illness. And so I don’t think would have been able to get through the psychotherapy that would be involved in doing a macrodose experience. So that’s an important difference there.

Eric 32:42

All right, Margaret Ali, I got a question for you. Like, would you put people with very, very advanced serious illness through this protocol that you’re using?

Margaret 32:50

It depends. I mean, we were lucky enough that many of our participants were not that, you know, they weren’t. We actually know we did have a couple of people who were bedbound. But in terms of our protocol, we were looking at people who had a six month prognosis because we had quite a bit of follow up. But I think that if people are very, very sick, you know, as James said, you lose your signal. But also, you know, we’re mindful of, of, you know, it’s exhausting.

It’s a really exhausting experience for people. And 25 milligrams is a whacking dose. Like it’s not underwhelming at all. So I know Yvonne had people who were much sicker and they seem to tolerate it quite beautifully. I think, you know, things like, you know, they’ve already got such a symptom burden of nausea and, and fatigue and things like that. So when we did have.

Eric 33:40

It may make things worse for during the.

Margaret 33:42

Well, it can, you know. Yeah.

Alex 33:44

Yvonne was a fourth presenter at the Congress International. I’ll stop there. We figured we could only have three guests. Apologies, Yvonne, we’ll have you on in another podcast.

Eric 33:55

Okay, James, what outcome did you look at?

James 33:58

So we were looking at something called the PGIC or Global Impression Patient Global Impression of Change Scale. So it’s a seven point validated scale scale where the patient themselves just evaluates how they feel compared to their baseline on A scale of 7, 5 and above is generally considered to be a significant response.

Eric 34:14

Is it quality of life symptoms? What’s the scale?

James 34:16

Whatever they want it to mean. That’s one of the challenges. It’s commonly used in the chronic pain field and it’s quite a commonly used endpoint. But it’s meant to be a very patient centered, whatever is most bugging you or whatever. And then also you’re integrating the burdens and the side effects of the therapy as well to decide like, do you want this or not and how impactful, how beneficial did you Find this. And so that was our primary endpoint, primary efficacy endpoint. It was a feasibility study and we were also doing dose findings. So we gave a week at 1 milligram, week at 2 milligrams, week at 3 milligrams compared to the 25 industrial strength doses that Ali, John and Margaret were using.

Alex 34:56

And that’s daily, 1 milligram daily.

James 34:59

So Monday to Friday, you take the weekend off. One of the key things they find with microdosing and psychedelics in general is you have to take breaks because they tend to get a sort of tachyphylaxis type effect very quickly where you get no response. They seem to be related to receptor modifications when they’re constitutively active.

Eric 35:17

You don’t have any hallucinations or do you know, you’re like, do you feel different?

James 35:21

So that’s the difference between us. And again, this sort of functionality unblinding that the FDA gets very upset about for the controls. Like, you know, everyone seems to know what group they’re in. And I have to say, man, if you have a psychedelic experience and you’re not sure whether you’ve had a psychedelic experience, you must be a very, very interesting person.

Eric 35:38

In terms, even at 1mg, our patients.

James 35:41

Are not getting that. They’re not getting that at the higher doses. So it seems to be weight based. So we had a couple of people that above, once they got above like 0.05 per kilo, I don’t know, don’t make me do math right now. But for people who were very small, like physically very frail and got to our higher doses, they started to have like, you know, they would feel like their arms would become numb and they’d feel funny and dizzy and then they’d have to lie down for an hour. So we bring them back down to a lower dose.

There was, you know, one person that started to have what I think were maybe more dissociative symptoms where they, you know, were sort of like, is that chair? Was that chair there before? Hang on, what happened? So no actual frank hallucinations, but some people do describe their visual changes. Like we had somebody with ALS who responded extremely well, who had a. They communicated by looking at a letter screen and it would track his eye movements. And it was funny because, of course, he needed to be able to look at the letters. But he said the letters were kind of melting a bit and while he was using them. And we said, oh, we should cut back the dose. Like, no, no, no, no, no, no. I want keep it. Keep it. Because he was getting a really good response. And sure enough, those sort of visual hallucinations went away after.

Eric 36:51

And how long were they on it for?

James 36:53

So we just did a dose fighting up to a week. And again, we would find most people would get the response at the dose they got. It was usually at 3 milligrams. Some people benefited at 2. We had a small number that didn’t benefit at all and of course a few that because of their illness, they just couldn’t even complete.

Alex 37:07

How many people people were in the study?

James 37:09

20. We just enrolled our 20th. So the 20th and 19th and 20th are just going through it now.

Alex 37:14

And it’s before after.

James 37:16

Yeah, it’s a before after. We’re asking them to just rate their own benefit. We’ve already actually got funding for an RCT using placebo control, which we’re hoping to get off the ground in the next couple of months.

Eric 37:28

How many people for that one?

James 37:30

We’re aiming for, I think 120. We’ve got about nine. Like, we’ve had a lot of interest from other sites in Ontario and same outcome. Sight of that of the Montreal Congre.

Eric 37:41

As Same primary outcome.

James 37:43

Exactly. Same primary outcome of pjec. We’re having a bit of an arm wrestle with Health Canada about that now, just. But I think we like the outcome. We think, again, we’re looking. And I think it’s important to distinguish that we are actually not all looking at precisely the same construct here, which again, similar, like pulling in, like cannabis research. Like similar problems with cannabis research, where everybody would sort of argue about whether you were looking at the right thing or not.

Eric 38:05

Yeah, well, I guess this. How long would they havehow long would they be on the microdose? The one to.

Alex 38:12

So that’s it.

James 38:12

So when we stopped after 3 milligrams a week, we found that many people, you know, their benefit would last at least a couple of weeks. We left them off for four weeks and then we gave them the opportunity of doing an Opal label extension for infrastructure Infinity, which many people have kind of taken us. Those who survived have taken us up on and want to continue. So we’ve had a number of people go on now for many months with the same medication. And they drive.

Eric 38:37

Like. Do you educate them not to drive?

James 38:39

Yeah, most of them are not really in a point of driving, but some of them have been. What we’ve done is we said, do your driving in the morning, get your driving done, then when you’re done driving, take the medication then.

Ali John 38:49

So that.

James 38:49

That doesn’t come up.

Eric 38:51

Oh, wow. And then side effects from all of your studies. Are you seeing much in the way? I mean, hearing some of the things, like amplifying a lot of potential symptoms or not amplifying other. Like, are you seeing like the higher heart rates or nausea or anything like that?

James 39:08

Not in microdosing, but in the macro dosing. Yeah, I think you guys are seeing it pretty common.

Eric 39:13

Like, what are the common symptoms that you’re seeing, Margaret?

Margaret 39:16

Look, usually nausea, headache, fairly transient elevations in heart rate, blood pressure can get anxiety. Often anticipatory, though, but then, yeah, anxiety during the experience, which is often easily sort of managed with supportive interventions, you can get some paranoia. We had one or two instances where people got transiently paranoid. And again, with supportive intervention, that was, that was worked through.

Eric 39:47

And you’re excluding high risk patients for, for paranoia people?

Margaret 39:51

Yeah, yeah.

Alex 39:52

Schizophrenia.

Margaret 39:53

Schizophrenia, first degree relatives with, you know, any kind of psychosis or bipolar spectrum disorder.

Eric 39:59

What’s next for you, Margaret?

Margaret 40:01

Oh, gosh, I don’t know. I was gonna say, is that a bigger trial? We just need money. The thing that’s happened in Australia is that we had a relaxing of legislation, so we have now got expanded access. So for people who have depression, treatment resistant depression, you can access psilocybin with an authorized prescriber in Australia, outside the.

Eric 40:23

Clinical trial, do you get the same two person, like the. I mean, it sounds like. Yeah, you have to go through that part.

Margaret 40:30

Yeah, yeah.

Eric 40:31

Or is it like my high school friends who just.

Margaret 40:35

I have to say, the underground is booming here. Yeah, it’s, you know, the genie’s out of the bottle. So there’s a lot of off campus activity. Well, I say, I think, look, I would love to see more of the work of James and Ali in terms of. And also some colleagues in Baltimore, you know, Manish Agrawal and Brian Richards and Bill Richards, who did groups of cancer patients with psychotherapy. It’s a much more accessible from a. From a cost point of view, from a time point of view. But also it brings community. Ali, you know, his group that were like, hey, we really need to kind of get together and talk about our experiences.

It was such an important learning for us because people came out and went, I just saw the cosmos. Who do I tell about this without sounding like I’m absolutely, you know, batshit? And they did. We were like, you know, who do I talk to about this? I can only talk to you two as my therapist. So they needed community to be able to talk about this and feel understood. And that’s the biggest regret that I had for my study and really strong.

Alex 41:49

Anecdotal evidence, some early empirical evidence from these really small studies. But I would be remiss if I didn’t channel Stacy Fisher and say the hype machine has gone far and away ahead of where the evidence is on psychedelics in general, including psilocybin. Ali John, what’s next for you and what do you think the field needs in order to advance here?

Ali John 42:18

I think we need to study adverse effects a lot more, especially among older adults who are using this more and more frequently in clinical trials. 4% of people across the board have persisting adverse effects. And that’s not a tiny number. Meditation is like 9%, by the way. So meditation is not innocuous either.

Eric 42:39

Are you doing a bigger trial?

Ali John 42:41

Yeah. So I want to do a. I want to use the spiritually integrated palliative care model, looking at total pain as the outcome. So, I mean, I’m not bound by the FDA for drug approval, so I can do what I think matters most. I just need a funder. So that would be great. And including groups afterwards for integration, which I think is really, really critical.

Eric 43:05

That’s great. Lightning round, real quick. Super lightning round. Because we got to get back to the green door. One main hope that you have for psilocybin therapy, when we’re thinking about it for people with serious illness, James?

James 43:22

Yeah, I mean, I’m very interested in anything that’s really scalable. The things that we’re looking to study here are really just things we could do for a lot of people easily. And that’s why, again, I think the psychotherapy and the psychedelic assisted macrodosing psychotherapy is super important. And I’m hoping that these things can all be like, can we get something for the masses? Because this stuff may be something that could work really well for those few.

Eric 43:50

Who don’t for a select group. Wonderful, Margaret.

Margaret 43:54

I would probably echo James in that way. I think that there’s room for all of that in terms of the microdosing and macro dosing. I’m so keen to hear more about your work too, James. But I think, yeah, having. Having systems that, that allow for accessibility. The biggest problem at the moment is that it is prohibitively expensive.

Eric 44:14

Is the psilocybin expensive or is it the two therapists and everything else?

Margaret 44:17

It’s the, it’s the way that it’s delivered. You know, we, we need better. We need a better model. And I don’t think that our current system is holding that very well. I love the idea of the hospice community and doing community, community, community. I can’t stress that enough. I think that it will allow for accessibility, allow for scalability as well. Yeah.

Ali John 44:37

And all federal and foundation funding, almost all in the United States are funded. Almost all. Not Stacy’s, but everyone else is funded by individual billionaires, millionaires and billionaires. So we really need more NIH funds in America.

Alex 44:55

And yeah, I think VA is.

Eric 44:58

Well, I want to thank all three of you, but I think we’re going to end by going back through James’s green door. Alex.

Alex 45:10

(singing)

Eric 45:49

Ali John, James, Margaret, thanks for joining us on this GeriPal podcast.

James 45:54

Thank you so much, guys.

Margaret 45:55

Thank you.

Eric 45:57

And to all of our listeners, thank you for your continued support.

This episode is not CME eligible.