‘What Happens Next?’: Is It Time to Join the Psychedelic Renaissance?

Dr Susan Carland:

Hi, and welcome to “What Happens Next?”. I'm Dr Susan Carland. This time we are looking at the therapeutic potential of using psychedelics to treat mental health conditions such as depression and PTSD.

Attitudes towards psychoactive drugs for the treatment of PTSD are changing. Some proponents suggest they offer a chemical safety net for patients. We speak to experts working in the field about some of the early trials using psychedelics such as MDMA and psilocybin.

Paul Liknaitzky is a joint research fellow within the Turner Institute and the Department of Psychiatry at Monash University. His work examines mechanisms of mental illness and treatment development, primarily within mood, anxiety and addiction disorders. Dr Liknaitzky is principal investigator across a number of Australia's first clinical psychedelic trials. Paul, welcome.

Dr Paul Liknaitzky:

Thank you. Thanks for having me.

Dr Susan Carland:

Tell me about your work and how you use psychedelics in your work – either in your research or even in your practise – and what are you seeing?

Dr Paul Liknaitzky:

Yeah. So it’s important to say, in Australia we're just coming through the birth canal now. We're just arriving in the space of psychedelic mental health treatment. The first trial to use a classical psychedelic was approved in 2019 and commenced seeing participants in early 2020, and then COVID put it on pause for more than a year. That trial is at St. Vincent's Hospital led by a close colleague, Marg Ross. And the other trials in Australia have all been approved or funded during the COVID lockdown. So it's been a rather strange time to see the birth of a field, but also very productive. There's been a lot happening.

And given how unique this treatment approach is, there's an enormous amount of work that we're doing on the ground in schooling up and building up the capacity and the resources to do this well. So we're about to open the gates on a number of trials, COVID permitting. We have ethics approval for four psychedelic trials in Australia, and I'm establishing two new ones at Monash University, which I'm very excited about. And they're tracking well, so we'll be submitting to ethics very soon.

Dr Susan Carland:

So what will those studies be looking at? What are you investigating? What are you hoping to see?

Dr Paul Liknaitzky:

The two new trials at Monash, one is an MDMA-assisted therapy for post-traumatic stress disorder and the other is a psilocybin-assisted therapy for generalised anxiety disorder.

I think of psychedelic treatments as experiential medicine. You need a set of ingredients to reliably produce the kinds of experiences that seem to matter. For example, you need to consume one of these substances, often it's a serotonergic agonist. You need the right kind of physical environment, the right kind of therapeutic support, the right kind of mindset going in.

But when you take care of some of these basic parameters well, the benefits are remarkably reliable. And the benefits that you see many weeks or months after this short treatment approach seem to be best predicted by certain kinds of experiences that people have while they're on the drugs.

So this is why I think of them as experiential medicines because aspects of the psychedelic experience predict outcomes better than the dose, better than almost anything else that we've been able to measure so far. And it's not just the intensity rating of the experience. It's not just that the people that were most high or most affected by the drugs do better. Even when you analyse the results and you control for that, the kind of intensity ratings of the drug, other qualities of the experience are important for clinical outcomes.

Dr Susan Carland:

Like what?

Dr Paul Liknaitzky:

So insight, what we think of as insight, is a key feature. It's not just that people are having this encounter with different perspectives. It is a sense that the different perspectives that they are up against under psychedelics are more reliable or better in some way. There's this interesting phenomenon where people really are having a far wider range of perspectives on themselves or their lives. And I think of this as the relaxation of Huxley's reducing valve. Aldous Huxley talked about the reducing valve, and that basic metaphor has been corroborated by modern neuroscience, which is that the brain primarily is an organ of inhibition, or it serves to constrain what you perceive in fundamental ways.

Most of the neurons in your brain are inhibitory neurons. They are competing with other neurons and dampening them down. And so clearly we only see and think and relate to what tends to serve our survival algorithms, if you like. And under psychedelics, it seems that that massive reducing valve, that way in which what we perceive is constrained by our survival – in the context of a modern human being or a contemporary and wealthy human being, survival is not bodily survival, it's survival of your status or something similar – under psychedelics, that relaxes. And so you get a much wider aperture, a much wider view on things. And I think that's one reason why there may be something to the feeling being more reliable, that you're getting perspectives that you don't normally see.

Dr Susan Carland:

Right. So it sounds like what you're saying is for someone who may be suffering, say, PTSD, the inhibitory mechanics of their brain are almost overdone and it's like they're locked into a small box and they can't have a new way of thinking. The sad reality is the terrible thing has happened to them, so they need a new way of thinking about it, because that can't be changed.

But they're locked in this loop of unhelpful ways of thinking or whatever it is, and the psychedelic opens a little window for them to say, “Here's a new way of thinking about this.” And they look out this window and go, “Actually, that looks really good.” It's not just as simple as “Live, laugh, love,” like the platitude. They're finally able to go, “Here is another way of considering this thing or understanding this thing that I've been through. This is actually helpful and good and not this small box that I've been in.”

Dr Paul Liknaitzky:

Right. And importantly, it's not just another way of thinking. It's another way of feeling and –

Dr Susan Carland:

Another way of being.

Dr Paul Liknaitzky:

... experiencing and being. Yeah, yeah. In the case of trauma, often it's very somatic. It's very much in the body. There's a trigger.

Dr Susan Carland:

Right. Like on a cellular response?

Dr Paul Liknaitzky:

Well, I think there's a – possibly an arbitrary or metaphoric distinction between body and mind. Your brain is a part of your body. But more that something very fundamental and basic is often triggered and instantiates the traumatic response.

You hear the chopper, your body just kicks in with cortisol and adrenaline and you're back at the war and you're having that reaction. And so it's not just another way of thinking about it.

Under MDMA, for example, there's the opportunity to reappraise those kinds of triggers, but again, not just in terms of the way you think about it, to go back to the things that trigger and to find a new way in which your body can respond to that. And then there's obviously a big piece in sustaining that change afterwards. In some cases, this short treatment programme leads to lasting changes. In other cases, there's, I think, a lot of work that needs to be done to scaffold that into the rest of your life.

Dr Susan Carland:

Do we have any understanding of why psychedelics might work so well for some people or not others? Do they seem to be the, "This is the classic type of person profile that this will work for"? Or is it still a mystery?

Dr Paul Liknaitzky:

No. So far we don't have any good way to predict a priori, beforehand, whether somebody is going to do well under psychedelics and benefit in the long run. As I said before, the best predictor we have is a set of experiences that people have under the acute administration, and that is reasonably reliable. So if we can get to that point where participants are having those kinds of experiences, then we can reasonably well predict their outcomes at least in the short-term.

Dr Susan Carland:

I imagine it's also similar with antidepressants, though. We don't know who will respond positively to antidepressants or not until they take them.

Dr Paul Liknaitzky:

Right, yeah. Yeah, that's right. In general, the prediction problems have not been solved in mental healthcare.

Dr Susan Carland:

If there are people that are listening to this that think, “Gee, I or someone I know, I feel like they would be the classic candidate for some assistance in this area. They struggle with PTSD or other mental health issues,” what should they do? Can the average person on the street sign up for a trial for something like this?

Dr Paul Liknaitzky:

Yes. Well, as I mentioned, the eligibility criteria are strict, but anybody who satisfies those eligibility criteria can get into these trials, subject to the numbers that we can accept into the trials. If anybody would like to be notified when trials commence recruitment, they can get in touch with my lab or a couple of other groups around the country, depending on where they're located. If you're in Melbourne, all you have to do is write to psychedelic@monash.edu and we'll put you on a notification list, and when we commence recruitment, we'll notify you. There are all kinds of requirements and it's not straightforward. And certainly, we receive many more applications than we can accommodate, unfortunately, because there's just a massive unmet need. And of course, there's an enormous interest in this treatment approach.

So people can reach out and contact us, and there are some other groups depending on where they're located. But also, we are in this research phase, so the opportunities are limited, at least for the next couple of years, as we pass through and show adequate safety and efficacy, which has not been shown to-date, it's important to say. Then we have the opportunity to move this into service delivery and register it and regulate it adequately. But it is still an experimental treatment and it's not in the bag yet.

Dr Susan Carland:

Let's assume everything goes really well. The clinical trials go well. You get phenomenal results. You're the hero of nature. What kind of timeframe can people think, “Look, maybe, in this year, year dot, I might be able to go to my GP and request something like this”?

Dr Paul Liknaitzky:

The earliest that that would happen would be 2023 –

Dr Susan Carland:

Which is soon.

Dr Paul Liknaitzky:

... which is soon, for MDMA in the treatment of post-traumatic stress disorder specifically. And that would be through the organisation MAPS that I mentioned before, because they've taken it through the drug development pathway and they've done very well in the trials to-date and they're nearly at the finish line. There are another couple of organisations in the US and Europe that are looking at psilocybin for depression. And those programmes, if they're successful, will probably be a couple of years at least behind MDMA for PTSD.

So it's still a few years away for most indications. And there is already a proliferation of research trials looking at the application of psychedelics for a range of different conditions and issues and also a whole set of innovations. I mean, while this is both an old and a new treatment approach, in a strange way, and there are so many ways in which we can still innovate and develop this treatment approach, currently there are a number of trials looking at combining psychedelics with various evidence-based psychotherapies and other practises. So that's happening all over the world and we're doing some of that here at Monash as well, which is very exciting.

Dr Susan Carland:

Paul, thank you so much for joining us.

Dr Paul Liknaitzky:

Thanks for having me.

Dr Meaghan O'Donnell:

Part of the reason that psychedelic research is hard to do is because it's illegal. It's an illegal drug.

Dr Susan Carland:

Dr Meaghan O'Donnell is the head of research at Phoenix Australia, the Centre for Posttraumatic Mental Health, and professor in the Department of Psychiatry at the University of Melbourne. She discusses the potential for psychedelics such as MDMA to be used in the treatments of PTSD and some of the barriers to enabling the use of these drugs. Dr Meaghan O'Donnell, thank you so much for joining us.

Dr Meaghan O'Donnell:

It's a pleasure.

Dr Susan Carland:

What are you finding in your research about the use of MDMA in being an effective treatment, at least in some cases, for people with things like PTSD?

Dr Meaghan O'Donnell:

The MDMA research is in its early days. There have been about six or seven trials that have been conducted in the US, and these are what we call phase two studies. So they are small studies just to look at if this particular medication looks like it's going to be effective in the treatment of PTSD, in this case, and that it's safe. And what we've seen with these small studies is that it does look like MDMA is effective.

And so now we've just had our first phase three study come out of the US. Same research group are doing this research. They have the expertise. And phase three means that it's a much larger study, they're able to look at safety more broadly, and we're able to look at efficacy. And what we are seeing is that in people who have been treatment resistant in the past, we do see this effect for MDMA.

So the question that's really interesting for me is, what is it about MDMA that makes us think that it could actually be a useful treatment for PTSD? And that is that what happens when someone takes MDMA, they have an effect where they start feeling euphoric. There's a sense of wellbeing. There's a prosocial effect in that way, that there's a connection to other people. And what we feel is that those positive effects and those positive experiences really help a person. If they recall a traumatic event, they are recalling this really difficult, painful thing that's happened to them, but they're feeling in a very positive mood-state. And that discordance between this really distressing memory and their positive mood-state helps change the memory. So it's kind of like we reprogram that memory and take out some of the distress and put in some of that positive feeling. And we think that that's what's happening and why MDMA might be useful for PTSD.

Dr Susan Carland:

That's actually fascinating. So it's like you're taking two separate issues within the brain and getting them to join hands. So when previously traumatic memory was joining hands with negative feeling, now you're getting the traumatic memory to join hands with positive feeling and create a new pathway.

Dr Meaghan O'Donnell:

Yeah, that's right. So it's kind of reprogramming the memory. What happens when someone has a trauma memory is that, and they have PTSD, when they experience that trauma memory, it takes them right back to when they first had the trauma. And often the pain, the distress, the fear and sensory experiences, it takes a person right back to that original event.

And what we're doing is we want to bring memory into the current reality, which is, “You're now safe. That thing happened in the past. It's not happening to you now, and you're safe.” And so it's that – this positive euphoria that someone's experiencing, we do think that it does help to reprogram that memory.

Now, I must say that we need more brain studies to actually show... There's been very few scanning studies where we can see brain changes while someone's taking MDMA with PTSD. So a lot of what we think happens is either through rodent studies. So we have to work out what's happening in rats and work out what's happening in humans. But there's lots of opportunity. So the mechanism that we're a bit unsure about, we think that's what's happening, but we need, obviously, the brain studies to confirm that that's the case.

Dr Susan Carland:

Of course. Well, it's hard to get a rat to tell you exactly how they're feeling at the time. Is one experience with a psychedelic enough to create that new handholding situation between the traumatic memory and the positive feeling? Does it only require one time and that positive feeling will override the old negative feeling? Or do you need a few goes?

Dr Meaghan O'Donnell:

So there's a protocol. It's not that someone's just given MDMA and then they lose their PTSD diagnosis. There is a protocol. And what happens is, first of all, the person with PTSD sits down with two therapists. So the protocol involves two therapists of different genders. So there's a male and a female therapist. And there's two introductory sessions where the individual is orientated to what's going to happen with the MDMA session. They talk about their trauma, and there's these preparatory sessions. So they're feeling very, very safe and secure when they go into the MDMA session. They go into an MDMA session that lasts up to eight hours. So it's a very long, intensive experience. And the two therapists are really supporting the person. They're not directing the experience at all.

But usually what happens is the person talks about their trauma and talks about... just, it's very supportive. So it's not directive at all. And the individual just talks about new awareness and new information that they're getting about their traumatic event. Then there's three sessions after that called integrative therapy, where the two therapists and the patient talk about the experience and then new learnings from that. And then the trials are showing between two or three doses of MDMA, sessions of MDMA, plus then the integrative sessions, so it happens over about a 10 to 12 week course of treatment, but usually it's two to three doses of MDMA.

Dr Susan Carland:

Do you think use of things like MDMA or psychedelics to treat mental health conditions, does it have a bit of a bad reputation, or does it have bad PR?

Dr Meaghan O'Donnell:

These illicit substances have been made illicit for a reason and that's because they can be dangerous. And certainly, in terms of using it therapeutically, we are still learning the best way of doing that. So I certainly would say to people, if they're interested in using psychedelics in terms of improving their mental health, to only ever do that in Australia in a research setting so that we can make sure that safety and their best possible outcomes will be assured.

Dr Susan Carland:

Right. So not with their dealer in a tent somewhere.

Dr Meaghan O'Donnell:

No. And it really speaks to how we make the substances to make sure that they don't have any... The illicit substances, often you don't know what you're going to take. So one thing about doing it within the structure of a research trial means that you're guaranteed to get a certain dose of the drug, which is very, very important.

Dr Susan Carland:

Do you feel positive when you look to the future and think about what things like psychedelics could mean for the future of treating mental illness?

Dr Meaghan O'Donnell:

I'm very excited about how a whole range of new interventions will improve outcomes for trauma survivors. I think that the more we can move to a personalised medicine approach, the more useful our treatments will be. And I do think our existing treatments work very well for some people. What we need to learn is which people do they work better for? And so there might be some people who just need our current treatments, and then there's a group of people who need something else.

At the moment, we are not very good at working out which treatment for which patient, mainly because we just have either they are talking, trauma-focused treatments. We do use antidepressants, too. They have some effect, not as good as our trauma focused treatments.

But at the moment, everyone just gets the current stock standard, “If you do this, we'll see how well you respond to that before we think of something else.” I'd love to see the day, like cancer, where we can do some kind of testing and we can say, “Well, actually the kind of PTSD you have will respond better to this treatment, so we're going to do this treatment first.” We're not there yet, but that's what I feel very excited about moving into the future.

Dr Susan Carland:

Dr Meaghan O'Donnell, thank you so much for your time today.

Dr Meaghan O'Donnell:

Thank you. It was fun.

Dr Susan Carland:

That's it for this episode and for this topic. A big thank you to all our guests. And as always, more information on what we talked about today can be found in the show notes.