‘Psychedelic therapy is about broadening perspective, a seed of recovery, of positive change, of something more enduring’

Dr James Rucker (MD, PhD) is an honorary consultant psychiatrist at the South London and Maudsley NHS Foundation Trust and senior clinical lecturer at the Institute of Psychiatry, Psychology, and Neuroscience (IoPPN) at King's College London. He leads the Psychoactive Trials Group (PTG) at the IoPPN's Centre for Affective Disorders.

In 2017, he received the National Institute of Health Research Clinician Scientist Fellowship to investigate the safety, feasibility, and efficacy of using psilocybin (the active ingredient in 'magic mushrooms') to treat treatment-resistant depression (TRD) in randomised placebo controlled trials. Under his leadership, the PTG has conducted phase one and two clinical trials demonstrating preliminary evidence for safety, feasibility, and efficacy [Rucker et al., 2022], and they are currently working on a large phase three clinical trial.

Jack Versace, a Psychology BSc Student at King's College London, asked the questions. References and other insertions are his.

Hello, James. To start off broadly, how would you describe psychedelics to a layperson?

Well, that's a question that would take half an hour itself!

Psychedelics are psychoactive drugs that produce an altered state of consciousness, characterised by distorted perceptions, mystical experiences, changed emotions and intensifying of sensations and feelings in general. Psychedelics occur naturally all over the world in various plant and mushroom species, and they've been used in rituals and healing ceremonies throughout geographically isolated tribes throughout antiquity [e.g. Bruhn et al., 2002; El-Seedi et al., 2005; Nichols, 2020].

What drives the unique effects psychedelics produce?

Psychedelics stimulate, in an unusual way, a subtype of serotonin receptor in the brain called 2A [Vollenweider & Kometer, 2010; Halberstadt & Geyer, 2011]. They occur particularly in the bit of the brain that makes us reason and process information, but also all over the brain, in bits that regulate mood and anxiety as well. This stimulation causes these disturbances in perception, mystical experiences, changes in mood, and often very personally meaningful experiences. So we know that the drug is doing something to the brain, and we know, roughly speaking, what.

Can you summarise the history of psychedelic research up to the point of its eventual prohibition?

Western medicine experimented with psychedelics throughout the 20th century. There were early experiments from about 1899 with mescaline.

A couple of psychiatrists, Eric Guttmann and Walter Maclay, gave mescaline to patients during psychoanalysis [Guttmann, 1936; Kempley, 2019] and observed that it disturbed the psyche in a way that, within the context of psychotherapy, helped people make progress. Some people made progress, some people didn't. They observed that it was almost like a catalyst within psychotherapy.

Things went quiet then until Hoffmann's development of LSD, and then there was a surge of interest. It initially was tried to treat schizophrenia, which didn't work at all because the drugs mimic in some ways some symptoms of schizophrenia [e.g. Liddell and Weil-Malherbe, 1953; Pennes, 1954]. It actually made a lot of them worse. But for people who are on the opposite end of the spectrum, who were not psychotic but more neurotic, these drugs seemed to help [e.g. Sandison and Whitelaw (1957); Savage et al. (1967); see Rucker et al. (2018) for full discussion of pre-prohibition clinical research with psychedelics]. But it was very context dependent, so people had to feel safe and secure within an existing therapeutic relationship for the drugs to then be used safely [Hartogsohn, 2017]. It was the first time really, that drug and context had been very specifically brought together in the pursuit of outcome.

What brought this initial period of research to an end?

Trying to fit these drugs into randomised control trials was inherently very difficult. People know whether they're on a psychedelic, and this brings in expectancy effects that are different between the placebo group and the psychedelic group. And then you can't tell what's due to drug and what's due to expectancy effect. [For a discussion of blinding and expectancy effects in clinical trials with psychedelics see Butler et al. (2022), of which Dr Rucker is a co-author.]

But at the same time, around 1970, this legal/political guillotine came down. LSD had diffused out of the clinic and into recreational use. It had become caught up in what was an escalating war on drugs in the late sixties. The research died, clinical use ceased; we entered this sort of dark period with virtually no research.

What is the motivation to re-examine psychedelics all these years later?

We've got to remember that the big advances in psychiatry have been the antidepressants and the anti-psychotics, and the last major advance in antidepressants was the introduction of fluoxetine back in the eighties. Since then we've had a lot of drugs that roughly do the same thing, but nothing really new. And they all have a sort of similarly moderate efficacy. So there is a changing sociopolitical attitude towards drugs too, I would say, but also within the context of psychiatry, we are looking for different avenues of treatment for people.

So people have looked to history for inspiration, and there we found ketamine to start off with. Esketamine is now a licensed treatment for depression [Newberry, 2023]. And ketamine and psychedelics converge on similar brain mechanisms, albeit by different routes. So in some ways, now concentrating on psychedelics makes a lot of molecular and pharmacological sense. But it also just represents picking up the baton of history, trying to progress this research using the established paradigms of drug development that that we all know and love.

However, we come up against the same problems, which are how to disambiguate placebo and expectancy effects from the effects of the drug itself. Blinding fails in 95 per cent of participants, so expectancy effects are the norm, not some nuisance effect that we want to get rid of. That's very new and it's something I think that the scientific community and the medical community have a lot of problems accepting.

We've had one really good trial now in treatment resistant depression that shows safety and preliminary efficacy for psilocybin. And we're moving into phase three work. If the phase three work is positive, you might get a clinical license, and if you get a license, a whole new world of opportunity opens up. But that's where we are now.

You volunteered as a psychiatrist overseeing open-label clinical trials with psychedelics at Imperial College London throughout the 2010s. When you were working with the Imperial group, it was solely in a psychiatric capacity. How has doing clinical work with psychedelics varied from your work with traditional methods?

When I volunteered to help at Imperial, it was new and exciting. There was a lot of passion and drive and a lot of that fed into the trial, which was an open-label pilot trial, and it was published to great fanfare in a high impact journal.

But that was just a pilot trial, everyone knew what they were getting. The researchers collected the outcomes and knew what the patients were getting, patients knew what they were getting. So it wasn't surprising that you saw this huge effect size. And that's a known phenomenon in clinical trials: the early phase research often shows effect sizes far greater than what happens in the real world.
I just worked there as a clinician. I didn't design the trial, but I sat with the patients, I prescribed the drug. I got my first experience of how these drugs work at an experiential level, and the processes of change, I would say, in people with mental health difficulties, and the dangers, also, in people with mental health difficulties. I'm used to prescribing drugs and doing therapy separately. This was something very, very different.

Imperial focus more on brain mechanisms, but my real interest is 'do they work? Is this safe and feasible? If so, how do you deliver a new paradigm of care, of treatment, like this in a mental health system that is underfunded and often quite resistant to change?'

Psychedelic research also enables a very interesting exploration of conscious processes. You know, people can take the drugs and then tell you what's going on. And then us knowing about the mechanism of action of psychedelics molecularly, well you can start to put the pieces together. Tiny pieces, but pieces, nonetheless. So as well as being a fascinating therapeutic paradigm, it is also a fascinating academic paradigm – and that's what I was looking for as a clinical academic.

You coauthored a paper called 'On redescribing the indescribable: trauma, psychoanalysis and psychedelic therapy' [Modlin et al., 2023]. Robin Carhart-Harris at Imperial also references Carl Jung and talks about the merits of a psychodynamic perspective. How do you characterise the relationship of psychodynamic thought to psychedelics?

I think that with all of these, the word that's in common for me is depth.

Psychodynamic and psychoanalytic therapies are often referred to as depth psychotherapies, insofar as they are trying to access ineffable, pre-conscious and subconscious elements of experience that might be driving people's behavior, feelings, mental health problems, etcetera. Psychedelics are, in the way they disturb our conscious mechanisms of repression of subconscious material, also, in theory, a form of depth psychotherapy.

That's why I think the language of Jung and the language of Freud and others is helpful in starting to put together this jigsaw puzzle, really, of how the human brain works and trying to scratch the surface of what we are not aware of that is going on. It's what psychotherapy in general tries to get at, to catalyse awareness of the deeper driving processes. Because if you have awareness, then that raises the possibility of agency, of having control, and then of change.

And this is what psychedelic therapy is about as well. It's about using this experience to try and raise awareness, to get insights, to broaden perspective, and from there sow a seed of recovery, of positive change, of something more enduring. That's what Jung and Freud were trying to get at.

If you have awareness of the processes that are driving your depression, you have the possibility of change. That doesn't mean change is going to happen, but there is the possibility of change. That then brings in the whole context of the delivery of psychedelic therapy, which is a whole other subject and explains why it's never just the drug, it's the things that surround it as well: the mechanisms of support, the psychotherapy, the social situation of the patient, and all of the history that they bring to that experience in their life so far. Very, very complex.

Within experimental psychology, the psychodynamic view of the unconscious has been treated very skeptically. Do you think that psychedelics and psychedelic research have the power to change this perspective?

Scientists are very empirical people, you know, they like the measurable. And, I think, behaviorism and cognitive neuroscience have necessarily focused on the measurable, and that's fine. That's fine, but from my perspective it doesn't get us far enough when it comes to the problems that people with mental health difficulties present to us. These problems are often emotional, existential, or spiritual more than they are practical.

The reason why it is seen with such skepticism is it's inherently subjective and inherently very difficult to measure. My argument is that given where we are in understanding the human mind and psychiatric problems and psychological problems and all the rest of it, we should be using all the tools at our disposal.

Do you think that the potential benefits of psychedelics are best understood primarily as a result of a transformative subjective experience, or as a result of neuroplasticity and relearning? Is this a false distinction?

It depends on who you are. If you're a neuroscientist, you're going to be interested in plasticity. If you're a psychologist, you're going to be interested in cognitive changes. If you're a therapist, you're probably going to be interested in subjective narrative.

I would say that with all of these ways of looking at it, it's a bit like having three people talking about how to describe an elephant, where one of them is underneath it, one's on top of it, and one's in front of it. They all give completely different descriptions because they're constrained by their own paradigm or the limits of their own perspective.

So all of them have something to say, but it ultimately it can't be 'either/or'; it has to be 'both/and'. That's the issue, isn't it?

During psychedelic therapy, a person may have the opportunity to gain a new perspective or new insights with potentially very significant implications for how they view themselves. For example, if someone has the mystical experience of feeling a direct union with nature, they may begin to think or feel that the bounds of who/what they are extend beyond the merely personal and include nature.

Do you have any thoughts as to how psychedelics influence people's self-concepts, both positive and negatively, and what is the role of integration in bringing this about?

I think of psychedelics as broadly allowing a process of change to happen, but what that process is, is not definable by the psychedelic. Really, it's definable by the person, their intention, and their surroundings. So, when we work in our trials we work quite carefully with people around their intention. 'What is it that they want to change? How do they see themselves improving? What is that mechanism? What is that process and what does it look like?' And if that means a connection to nature, well fine, you know. It would be ideal, then, to experience psychedelics as Aldous Huxley did: obsess over a rose petal for ages maybe. ['… a bunch of flowers shining with their own inner light and all but quivering under the pressure of the significance with which they were charged…']

But if it's something else, if it's your relationship with your partner or your friend or whatever, really, maybe you need some sort of prompt for that. So I think it's about getting to know people and helping them to understand what their own narrative process of positive change is and enabling that.

That is the point of preparation and dosing support, and then integration is about nurturing that. I often use the analogy that preparation is about preparing the soil, the dosing session is about planting a seed, and integration is about nurturing the seed. But what that seed is, is very different to everyone. It speaks to the role of the preparation, the psychological support and the integration. But it also speaks to the role of the drug as well, and you can't easily disambiguate.

You wrote an editorial in the British Medical Journal in 2015 arguing that the legal status of psychedelics should be changed, not to allow for recreational use, but to make medical research easier and less expensive. What drove you to take this stance?

Generally speaking, we live in a society in which ministers tend to ignore the advice of advisory councils on drugs, if it conflicts with the narrative of 'tough on drugs'. And that's essentially why there is this resistance to change the Schedule 1 status of psychedelics.

I wrote the article because Schedule 1 imposes huge amounts of security and safe custody restrictions on these drugs, and it means that even getting the research started is so expensive that it kind of never happens. It is happening now and in the sense that's part of the problem, because the government just says, 'well, you're doing it. So what's the problem?'

The answer is you're making it so expensive. And it's not providing any advantage, no one's being protected by the drug being in Schedule 1. The safe custody and security requirements of Schedule 2 would be absolutely fine, and all you need to do is define the drug as being restricted to authorised research studies.
We've had something in Australia which some might think is what I wanted to happen in the UK, but it isn't. I think actually the Australian Therapeutic Goods Administration has gone too far and they're putting people at unnecessary risk. [Since new regulation which came into effect 1 July 2023, doctors in Australia are allowed to prescribe MDMA and psilocybin to treat post-traumatic stress disorder and depression respectively (Wertheimer, 2023).] So it's a balance between keeping the drug on the short enough leash, but not so short that you can't even investigate the benefits and the harms.

Finally, what do you think is the most interesting frontier in psychedelic research right now?

The lowest hanging fruit are depression and anxiety because so many people suffer with them. That's the low hanging fruit, and it's the big frontier, really.

In terms of academia, for me it's the exploration of mysticism as a function of pharmacology and brain mechanisms. [For example, see Garcia-Romeau et al. (2014). Preliminary results from their study testing the effect of high doses of psilocybin on smoking cessation suggested that mystical experiences may be a mediating factor in how psychedelics help to treat addiction.] And how that relates to the mechanisms we already know about what might drive what we call mental illness. The medical model has a tendency to view disease as abnormal and something to be removed or expunged in some way. It's more complicated than that. It's been said that psychiatric diseases are social phenomena, and I think that's true to an extent. But it would be interesting to know the molecular underpinnings of different facets of experience, which we could then compare to the facets of experience that go on in people with mental health problems. Psychedelics help us do that.

Thank you very much for your time.

Of course, good to see you Jack.

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