Ann Mossop: In a world of global pandemics, climate emergencies, and ever-increasing costs of living, it's understandable that we might feel fearful about what the future holds. But as we make our way through the 21st century, there are, in fact, many new and exciting discoveries which can improve our lives. I'm Ann Mossop, director of the UNSW Centre for Ideas. Welcome to What comes next? From the potential healing powers of magic mushrooms in mental health, to how x-ray vision might help us transition to a renewable economy. In this 10-part series, we'll hear from UNSW Sydney’s brightest minds, unpacking some of the big ideas, which are integral to our 21st century challenges.
 
More than 264 million people worldwide suffer from depression, but for many people struggling with severe or treatment resistant depression, standard therapies may not work. Psychiatrist Adam Bayes asks; can psychedelics like ‘magic’ mushrooms play a role in managing mental health?
 
Adam Bayes: I want to share with you a story explaining what motivates me to work as a psychiatrist and researcher in the area of novel treatments for depression. Catherine is a 36-year-old single mother with three young children. She was referred to the Black Dog Institute clinic with severe depression and suicidal thinking. When her psychiatrists phoned me, there was desperation in his voice as he was running out of treatment options for Catherine. When I first met Catherine, she was moving slowly, and she struggled to gather her thoughts. She had few facial expressions and had lost the light in her eyes. She told me about all of the failed trials of antidepressant medications and other treatments. I could really feel her struggle. Her children miss their mum as she went back and forth in and out of hospital. I assess Catherine is suitable for the ketamine program, a long-used anesthetic. There was a growing body of trial evidence for ketamine in depression, where other treatments had failed. The team objectively measured Catherine's depression scores at the start of treatment, and with every ketamine session. Now, I want you to imagine Catherine begins at the foot of a giant mountain. That's where her depression score was, rock bottom, way down in the severe range and after just a few treatments, she began to climb that mountain. Soon she reached the halfway point and started to feel some real relief, and the glimpse of a smile crept in. Now given how unwell she had been, I thought, well, maybe this is as good as it gets. However, she kept on with her ascent, and after treatment seven, Catherine reached the summit, or to use medical jargon, she went into remission, no longer meeting criteria for clinical depression. At the two month follow up, she remained on top of the world, still in remission, while continuing on an oral antidepressant. Catherine told me that she had got her life back. She used the term resilience. She could take care of her kids, she could do things like go to the supermarket and importantly, suicidal thoughts had markedly reduced.
 
This is an example of a novel treatment changing Catherine's life. Depression is a common mental illness, globally, more than 264 million people have depression. It affects more women than men and among you here today, one in seven will experience depression in your lifetime, and one in 16 are currently affected by depression. Depression can vary in different people from more mild forms where lifestyle changes and psychological help can make a big difference. Through to more severe biological forms where, like Catherine, someone can't get out of bed in the morning. They have slowed down mentally and physically, and they may be suicidal. At this severe end of the spectrum, medications, going into hospital and treatments like electroconvulsive therapy or ECT can be lifesaving. The research team I'm a part of is interested in this more severe end, which includes treatment resistant depression. This is the one in three patients who, like Catherine, have failed to respond due to multiple trials of antidepressants and psychological therapies.
 
So, what can we do for patients with treatment resistant depression? I've shared with you a success story involving ketamine, an anesthetic also used recreationally because of its mind altering properties. But when we use it in a controlled medical setting, we have found it safe and effective for depression. In fact, last year, a ketamine drug was approved in Australia for depression by the TGA. You have no doubt heard about the renaissance of interest in psychedelics as possible treatments for mental health conditions. LSD, MDMA, ayahuasca, psilocybin. Psychedelic research here in Australia has only recently started up. Now, I've been curious as to whether psychedelics have potential, like ketamine, to tackle treatment resistant depression. One psychedelic which is showing promise is psilocybin, the active ingredient in so-called ‘magic’ mushrooms.
 
Now, use of psilocybin is not new; prehistoric rock murals in places like Spain and Algeria suggest that psilocybin mushrooms have been used for thousands of years, with indigenous tribes consuming them in spiritual ceremonies. So why would we want to give psilocybin to a patient with severe depression? Well, we know that in clinical depression, there is reduced connectivity in the brain, and that brain cells, or neurons, actually atrophy. Animal studies show that psychedelics like psilocybin, stimulate the growth of neurons, increase the number of connections between them, and overall promote neuroplasticity, potentially reversing the effects of depression. Now, in humans given psychedelics, they report to us subjective things like changes in colors and sounds, mystical experiences, a greater sense of meaning in life, increased empathy, and connectedness with others, and a deeply felt positive mood. These effects likely result from stimulating the neurotransmitter serotonin, as well as changing the brain's activity at rest. When we look at brain activity with psilocybin treatment in healthy individuals, what we see is an increase in different brain regions talking to each other. Functional MRI shows that the whole brain seems to live up.
 
Now, you might think that this medicine is simply stimulating brain networks, but in fact, psilocybin actually quietens default mode network activity in the brain. Default mode network activity is what the brain is doing when we are not focusing on anything in particular, the opposite of when we are paying attention, and by quieting resting activity, this allows other brain networks to communicate. Now, while the science is not yet certain, our best guess is that in those with depression, the default mode network locks individuals into rigid negative ways of thinking about themselves, the world, and the future, and by temporarily reducing default mode network activity, this allows greater whole brain connectivity, and for depressed patients trapped in repetitive cycles of thinking, feeling and behaving, a reset in formation of new brain connections, which may assist with depression recovery. Two main studies to date have looked at psilocybin for depression, with promising results. Though, these studies haven't been done in treatment resistant depression and we already have very effective therapies for mild depression, it's those with treatment resistant depression that are in need of new therapies, and this is where the research gap lies.
 
You may be curious about how psilocybin treatment works in practice. So, let's go back to Catherine and imagine that she didn't respond to ketamine. Would we give her a magic mushroom and send to the forest to have a psychedelic experience? For a start psilocybin is a Schedule 9 illegal drug in Australia, and it cannot be prescribed in a clinical setting by a doctor. However, special government permits can be sought to administer the drug as a part of a clinical trial, approved by a research ethics committee, with trials seeking to evaluate safety, and if psilocybin could be an effective treatment for depression. As part of entry into a clinical trial, Catherine will undergo a full medical and psychiatric assessment to determine her suitability. For example, excluding a personal or family history of psychosis would be important, where giving her psilocybin could cause harm. For safety purposes, she would not be given actual mushrooms, but instead 100% pure psilocybin, made in a lab.
 
Now to the process itself, there would be two therapists present, for example, me and a co-therapist, who would work with Catherine. Preparing her mindset would be important. Psychedelics act as amplifiers and negative headspace before treatment would be magnified, and vice-versa. That's why in the days before the treatment session, we would build rapport and ensure Catherine felt safe and secure about the process. The setting also impacts the outcome, and that's why we have carefully designed our therapy rooms. While they are located in a hospital, they do not look like hospital rooms. Imagine Catherine enters a quiet and tranquil room where she sits on a cozy and comfortable couch with warm lighting and contemplative artwork. She would be given a psilocybin capsule with careful monitoring of physical and mental states, and full medical backup, the whole psychedelic experience taking over eight hours. In the days following, we would work with Catherine to understand the insights she has gained during the small number of psilocybin treatments, helping her to integrate them into lasting changes.
 
So what happens to the next patient I see in my clinic like Catherine? They are running out of treatment options, and perhaps don't respond to ketamine. Could psilocybin combined with psychotherapy be a new magic treatment that resets their default mode network and allows new brain connections to perform? There is great hope from patients and clinicians that psilocybin might provide an answer. But before psilocybin can be considered therapy for treatment resistant depression, we first need to undertake carefully designed research trials, with my team embarking on one such study. How we answer the questions of safety, and if psilocybin works for treatment resistant depression, is not a matter of magic, but of science.
 
Ann Mossop: Adam, thanks for coming to talk to us.
 
Adam Bayes: Thanks for having me.
 
Ann Mossop: Before we come to talking more about psychedelics and how you see their use evolving in the future, can we go back to what drew you into psychiatry in the first place?
 
Adam Bayes: Sure. So, I was a junior doctor, and I knew that I wanted to do something to do with the brain. So it was a toss up between neurosurgery, neurology and psychiatry. Neurosurgery, I realised, surgery, just wasn't, didn't have the temperament for surgery. Having done some sort of really basic surgery, I realised, no, that wasn't going to be for me. Neurology I found fascinating, but then it wasn't until I did a rotation in psychiatry on the first day, on the acute ward, I realised that was definitely what I wanted to do.
 
Ann Mossop: And what was it about that experience? Because I don't imagine an acute ward is a walk in the park.
 
Adam Bayes: Yeah, I think it was just the whole mixture of different presentations I found fascinating, in terms of the disorders and then combining that with the different stories that each patient had. And there's this mixture which I just found incredibly fascinating, and also patients did get better. And that was, sometimes I think people think in psychiatry, mental health patients may not get better, but certainly you could see someone come in being very unwell, and then with the right treatment, a few weeks later, they could be discharged and I think that just really fascinated me. They could start off, say, with a manic psychosis, and then a few weeks later, you know just walk out of the door of the unit and be completely back to their usual selves so that just hooked me.
 
Ann Mossop: The whole thing about feeling like what you were doing could really make a difference and help people in this very direct way.
 
Adam Bayes: Yeah, absolutely.
 
Ann Mossop: Yeah, I was really interested in what you said about what the temperament is for surgery, because anybody who's ever been anywhere near surgery, you think, how can people do that all day? But also, that temperament for psychiatry, where you see people in these very desperate states, I was quite intrigued why you said after day one, you were hooked because, you know, I imagine that what you're seeing is quite challenging, quite confronting, quite difficult?
 
Adam Bayes: Yeah, look, I think certainly there are some confronting stories. Uh, you know, hearing people's trauma histories, seeing people, you know, go through desperate situations, or their illness has led them into a desperate situation. But I think taking care of yourself is important, making sure that you stay on top of things yourself, otherwise, you can't really help others. But no, I never found it sort of got me down or anything like that, I've never had a boring day at work. I've had challenging days, but never had a boring day.
 
Ann Mossop: Yeah, and how did you move into thinking more about depression and in particular, treatment resistant depression?
 
Adam Bayes: Yeah. So, I've found mood disorders, which broadly comprises bipolar disorder and depression, particularly interesting. Something about the presentations of those disorders, mania, for example, bipolar mania, patients may come in having not slept for weeks on end. They're talking very rapidly, moving very quickly, and they may have some delusions. They think that, you know, they've been Napoleon or something like that, fascinating to see how the mind works. And likewise, with depression, it's almost the opposite, where the patient is really slowed down, can't move, can't get out of bed. But just seeing that there are treatments that can help patients get back on track, and then to see them return back to their usual selves, to me is what was just really fascinating. Yeah, and that there was the potential to really help people, yeah.
 
Ann Mossop: Now, what we've seen in recent decades is a completely different approach to treating things like depression, and the kinds of things that you're talking about, novel treatments, there's been a really big change in the way we think about depression, the way the community thinks about mood disorders, trying to reduce stigma, but also in the treatments that are available. How different is this world that we live in now and that you're working in now to what you learnt when you were training as a psychiatrist?
 
Adam Bayes: Yeah, look there have been a lot of developments in psychiatry, which is very exciting. I must say, when I was doing my registrar training, which wasn't that long ago, in the late 2000s. There had not been a lot of advances in psychiatry. And when I first started my training, some of my senior colleagues, you know, said really, you know, ECT, it's still used, has been around for a long time, there haven't been many advances, there have been some improvements around the edges, but nothing breakthrough. And a lot of the drug treatments, antidepressants, they've been tinkered around, some different classes, but nothing really stands out, which is a bit disappointing. But then, you know, actually, during my training for example, neurostimulators started to take off. So things like transcranial magnetic stimulation, or TMS, which is where powerful magnets are placed close to the skull, it's a non invasive procedure, and by aiming these magnetic fields in particular brain regions can either upregulate or downregulate different parts of the brain, which we know are related to depression. So that was more in a research setting when I was doing my training. And now, you know, you can go and have TMS. We do it over at Black Dog Institute, and it's now a treatment for depression.
 
And there's been a whole other raft of different neurostimulation treatments so that's very exciting. So there's options other than ECT, which is still a good treatment, but there's other options for less severe depression. And then in terms of antidepressants, there hadn't really been any breakthroughs. And then again, ketamine, some early studies back in 2000, showed that it may actually have these powerful antidepressant properties, fast forward, and there's now a ketamine drug which is approved in Australia by the TGA. So there's been sort of leaps and bounds and these new paradigms if you like, and then psychedelics is another potential area.
 
Ann Mossop: We've been talking specifically about ‘magic’ mushrooms, let's go back a step. What are psychedelics as substances?
 
Adam Bayes: Yeah, so psychedelics is really a general term, which means mind manifesting. And it's a general term for a group of substances where there's these profound changes in a person's subjective experience, or cognitions. The technical classification often involves stimulation of the serotonin to a receptor, but there are substances such as ketamine, for example, that don't neatly fall into the category of psychedelics. So it's sort of a broad term.
 
Ann Mossop: So, psychedelics are not substances that are similar in any way necessarily. They're things that have a particular effect, although obviously some of them…
 
Adam Bayes: There are some structures that are similar, there's some different classes and they tend to act on this serotonin to a receptor. But as I said, things like ketamine have a different mechanism. But some would say it's a quasi-psychedelic, because it does produce these subjective changes. This is different to say standard antidepressants, for example, they do also act on serotonin, but they don't tend to cause profound subjective changes, you know, immediately after ingestion.
 
Ann Mossop: So, somebody taking a type of antidepressant that acts in some way on serotonin, it's much more like an ordinary, taking experience, they may experience improvement, they may have some side effects of greater or lesser degree. And it may or may not work, in that sense.
 
Adam Bayes: Exactly. So standard, antidepressants usually take several weeks to take effect. So they have sort of slower impact on neurotransmitters, and overall can produce improved mood, that's the idea. But a psychedelic, if it’s a therapeutic dose, will have a profound effect within, you know, 10 minutes or half an hour. Then going up to a peak experience, which is a maximal effect, and then it will taper off.
 
Ann Mossop: And the kind of thing that we're talking about with a therapeutic use of psilocybin, the active substance from ‘magic’ mushrooms, is something like eight hours.
 
Adam Bayes: Yeah, yeah, the full experience is about eight hours. So in the studies that we will be doing, it's a full day for the participant, [and then] the patient's able to leave the therapy room and function normally, again.
 
Ann Mossop: Where do you see the real potential for psychedelics?
 
Adam Bayes: There are other trials outside of depression as well. So I'm aware, you know, for example, anorexia nervosa, also in anxiety disorders, so it's not just necessarily for depression, severe depression.
 
Ann Mossop: You know, I realised that that's not, you know, that's not the trial you're running. But what is it about something like psilocybin that would make it work for things like anorexia and anxiety? Can you see that there are common potential mechanisms in people?
 
Adam Bayes: Potentially, look, I think that the science is a bit unclear, but certainly this concept of the default mode network, which is what the brain is doing when we're not paying attention and focused on external things. And it's possible, I mean, it's all very speculative, but there could be some overlap between disorders like depression and say anorexia nervosa, where someone is very stuck. And what the psilocybin may do is kind of loosen up that framework. And we know that if we look at fMRI, that does seem to happen. So we actually see this happening on brain scans, and again, we couldn't do that back in the 60s and 70s and I think that makes it also interesting to revisit psychedelics now with the technology that we have. And you can actually see, you know, what is going on with brain networks. So that might be very speculative, but there's potential that you can imagine in anorexia nervosa, someone's very stuck, and they they're stuck in a pattern of thinking, and they can't break out of it, and it will be interesting to see if psilocybin can alter that.
 
Ann Mossop: Obviously, you're just at the beginning of this potential trial with psilocybin, so I'm not expecting you to be personally responsible for all psychedelic drugs, but what else is there that's interesting in the field of psychedelics that you are observing, that people are thinking about, or people are starting to do some trials with?
 
Adam Bayes: Yeah, look, I think there's, there's obviously other psychedelics out there. You know, LSD, ayahuasca, MDMA is one, so that's commonly called ecstasy that people use recreationally at dance parties and things like that. There is a lot of interest in MDMA for treatment resistant PTSD, there's been a large trial in the US, so that's potentially very interesting. So again, the idea with MDMA, which is quite a different subjective experience to psilocybin. And again, it's sort of, you know, maybe quasi psychedelic, it has sort of pro- social effects, it's got an empathogen so people become more empathic. So you can imagine in the context of a patient that has PTSD, perhaps they're a veteran or something like that, that unable to go back to the trauma, perhaps there was a sentinel event, or it's a chronic trauma from, you know, multiple tours of duty. What MDMA can do is, so it's done in conjunction with a therapist, to sort of have greater trust in the room with the therapist and actually to face that fear. So there's a lot of interest in MDMA for that area. But again, it's not my area of expertise, but why I kind of conceive it, as different psychedelics have differing effects, it's then about combining that with some sort of a therapy. And again, there's different kinds of therapies, then applying it to the individual patient with a disorder. So it might be depression, PTSD. And so there's a lot of, there really needs to be a lot of trials done to kind of marry all those up and see which combinations actually work, and what might not work. You know, for example, could be certain psychedelic drugs are not great for certain disorders. So I think it's working all that out. And as you say, we’re sort of at the beginning, there was a lot of research done in the 60s and 70s. But look, I think that was a different time, there was different research, rigor, you know, and there weren't sort of the ethical parameters etc. that are more in place now, it was sort of going back to the future. But I think we're going with greater technology in the sense of brain scans etc., more rigorous protocols, and or thought, I guess, given the sort of ethical frameworks.
 
Ann Mossop: And also obviously you know, between the 60s and now, the state of knowledge about so many other aspects that connect with that has changed as well, absolutely. Thinking about the potential of the kind of psilocybin treatment that you're looking at trialing. It's a treatment that takes multiple sessions with two therapists in a comfortable and non-medical space. And the treatments take around eight hours, what you're obviously thinking is there's the potential to be really effective and make a tremendous difference to people's lives. But when we think about the realities of the health system, and the fact that for many people, it's quite difficult to think about one hour with a psychiatrist or qualified therapist, how do you see the possibility of that rolling out practically in the future?
 
Adam Bayes: Yeah, that's an excellent question. Look, you're right. The treatment course, again, is in a research setting, but many, many hours, yes, as you say, in a full day with a psychiatrist, and that does raise issues in terms of, you know, how practical is this treatment, I think that's why we are investigating treatment resistant depression. So these are patients that, you know, they've tried standard treatments, and they haven't worked, non-treatment resistant depression, we do have a lot of effective medications, talking therapies out there that do work. So this is for the more of the pointy end, because it would be such an investment, it would be an expensive treatment. I think if the science does say this treatment works, there would be potentially some equity issues, though, because I would imagine it wouldn't initially be paid for by the Government. And so, you know, I imagine it would be the type of thing that would be available in a private setting. But one would hope that it was open to everybody. Particularly we know that, you know, so many people with severe depression, also may not have the funds. So I think they're important issues to be thought through. If the trials show that this works, and there's an evidence base there, I think, yeah, all those issues do need to be thought through.
 
Ann Mossop: And it's really interesting, when we think about the story that you told us in your talk about somebody who is suffering from tragic treatment resistant depression, you can see that in any health system, a treatment that cures that patient would be worth a very significant investment, because it's a life and a person really coming back.

Adam Bayes: Absolutely. And if the treatment was able to get that particular individual functioning, again, to get them back into the workforce, you know, you have to think of all those costs as well. A lot of having multiple hospitalisations per year. We have to sort of also balance it out with all those costs, yeah.
 
Ann Mossop: In terms of the work that you do you combine research with clinical work. And this is a pattern, you know, among your medical colleagues, there are people who are clinicians only, there are people who are researchers only, what's that like to try and do?
 
Adam Bayes: Look, I think it's really enriching to be able to combine the two, it's not necessarily a straightforward process though, in terms of how you do that, I kind of had to work it out for myself in a way, partially because being a clinician, there's a lot of clinical training. And so then doing a PhD and amongst all that, is a little tricky and when you do it.
 
Ann Mossop: That’s safely in the past, so you've navigated your way through that!
 
Adam Bayes: Navigated that, and what got me into the clinical academic or clinician scientist realm, I guess I saw certain clinicians that were also academics, I just saw that they had an ability to step back from the framework that they were working in and consider other frameworks. So that, to me, was really interesting. So I got a meta view, and, also, I think the two worked very nicely together. So, you know, you get ideas, when you see patients, you know, you get ideas about, well, what about this? So could we investigate that, etc. And vice versa? You know, in the research world, you think, you know, this might apply to dissipation, and you can develop things and answer questions. So the two work very nicely together. I think for me, not being a pure researcher, keeps me connected to patients and what's actually happening at the coalface, which I think is very important. And likewise, I’d probably get burnt out if I saw patients full time and kudos to my colleagues that do that. So for me having that balance works very well.
 
Ann Mossop: Well, the best of luck with the trial, I think it's going to be really interesting to keep an eye on this field in the future and see what happens and how that rolls out into treatment. I thank you so much for coming to talk to us.
 
Adam Bayes: Thanks Ann, thank you very much.
 
Ann Mossop: What comes next? is produced by the UNSW Center for Ideas. With music composition by Lana Zacharia and editing by Bryce Halladay. For more information, visit centreideas.com, and don't forget to subscribe wherever you get your podcasts.