Psilocybin therapy for depression. A good trip?

It comes as a surprise to many to learn that psilocybin, the active component of magic mushrooms, has been the subject of modern in-vivo human research for 25 years. Starting with tentative phase 1 work in the late 1990s (Hasler et al., 1997), psilocybin therapy is now on the threshold of phase 3 trials for Treatment Resistant Depression (TRD). Combined with a standardised form of psychological support, there are promising signs that it may serve as a sort of cross-cutting 'catalyst' of mentally salutary change in a broad range of non-psychotic mental health problems that are otherwise resistant to more standard forms of psychotherapy or pharmacotherapy. That is, if it is given in a safe, supportive and therapeutic context.

How did we get here? Psychedelics are heavily criminalised in countries around the world. They are not prescribable, unless the prescriber does so under a special license and within a clinical trial (this is changing in some countries). They remain highly stigmatised, with the media disproportionately focussing on the rare and tragic cases of recreational use gone terribly wrong.

There are many factors. Shifts in societal attitudes towards drugs in general have been reflected in changes in legislature in many countries towards the use of cannabis, as well as the granting of licenses to start clinical trials with MDMA (“Ecstasy”) and psilocybin. This has brought investor confidence to fund clinical trials with the power to inform licensing. Post Prozac, there has not been much of note in the more classic pharmacological pipeline; lots of “me too” type drugs, but nothing fundamentally different. The one exception is ketamine, and this is also a “drug from the past”, repurposed.

Intriguingly, psilocybin and ketamine exert similar influences by an allied mechanism that converges on a large a surge of glutamate in the prefrontal cortex, and various downstream BDNF dependent changes to neural growth and synapse formation (Vollenweider & Kometer, 2010; Ly et al., 2020). Changes in neuronal architecture and dendritic complexity are phenomena seen also with antidepressants, however such changes take weeks to manifest. Here, the change is rather more rapid. This is accompanied by a much more rapid clinical response, with benefit reported in days (sometimes hours). So, perhaps, ketamine and psychedelics are targeting a biochemical process closer to the biological “source” of depression (if there is such a thing). The biology serves as an inspiration for clinical researchers to pick up the baton of history. And here there is, in any case, precedent. Psychedelic assisted therapy (generally with LSD) was not uncommon prior to politically motivated prohibition around 1970 (Rucker et al., 2016). If such prohibition hadn’t happened, one wonders where we would be today with this research? Doubtless a lot further forward.

The most recent multicentre RCT of psilocybin therapy in 233 patients with TRD showed a statistically and clinically significant separation on the MADRS score for up to six weeks from a single dose of 25 mg of psilocybin, when compared to 1 mg (Goodwin et al., 2022). A 10 mg dose fell in-between the two. Such a “dose dependent” effect seems reassuring to those who might tend to favour drugs as both causes and treatments of mental disorder.

But it is not so simple. Trials with psilocybin (and ketamine) are, by definition, almost impossible to blind. In a recent trial of psilocybin therapy in alcoholism around 95% of participants and their therapists correctly guessed their allocation, despite a form of “active placebo” (diphenhydramine) being used (Bogenschutz et al., 2022). If blinding fails so spectacularly, then expectancy effects will inevitably colour the outcomes. Could the results we are seeing be a form of mirage?

Probably not, but it’s hard to say for sure, and here is the rub. Even if you measure blinding adequacy successfully, one is then faced with the problem of how to capture reliably the nature and extent of people’s expectancies about the different treatment conditions in a trial. Such patterns of belief will vary through a trial, and it may also be the case that the drug treatment itself is a direct pharmacological moderator of such expectancy. Within a trial design in which psychological support needs to be provided, and therapists are also liable to become unblinded, a whole world of complexity emerges. There may be a good reason why blinding and expectancy have been side stepped by commercial pharmaceutical companies thus far. But trials with psychedelics seem to make the issue unavoidable.

Could this be an opportunity? If blinding fails so comprehensively, can we use that as a route to capturing and analysing the moderating role of context; of “set” and “setting” on outcome? Might this inform us in a more general sense about treatment development in psychiatry, where many clinicians instinctively know that the psychosocial contexts of treatment delivery are far more powerful mediators of outcome than the treatments themselves? The opportunity is there, but understandably there is little commercial incentive to research it lest it threaten to confuse a regulatory process that is focussed on the drug itself. So such research is likely to need public and charitable forms of funding.

The mystique and cultural repression that comes along with psychedelics in Western societies has driven an unhelpful form of polarisation. Evangelists evangelise. Demonisers demonise. Both are off-putting to the moderate majority. The reality is that psilocybin therapy, whilst showing much promise, is not a panacea. Like any intervention, there are risks.

After delivering thousands of LSD assisted psychotherapy sessions, the psychiatrist Stanislav Grof commented that psychedelics “activate the psyche and mediate emergence of the unconscious and superconscious contents into consciousness” (Grof, 1988). If this is true, if psilocybin “opens the doors” to those elements the psyche normally inaccessible to us, then the effects are inherently unknowable. It is hard to consent patients on this basis. It will be even harder to describe the likely side effects (and such descriptions may be inherently leading). Ultimately, the potential for tragedy is always on the table, as is the potential for transformation. Or, more likely, something in-between. But it is inherently a form of gamble. For some this will be one they want to take. Psilocybin has an inherently “natural” quality to it that appeals to those who tend to be suspicious of the “synthetic” nature of most other prescribed drugs.

There will always be an unknowable element to psilocybin. It elicits changes that are ineffable (hard to describe in words). Should we attempt to interrogate the ineffable? Opinions vary. I think so, but science tends to shy away from the immeasurable. But here in the ineffable lie some of the most fundamental experiences of mental ill-health – the loss of “connection”, of “love”, of “faith”, of “self”, of “meaning”, even of the “divine”. All ineffable to varying degrees, yet instinctively so important to our day-to-day mental health. So, perhaps, here, hidden in the mists where psychiatric science has historically feared to tread, lie gems of insight waiting to be discovered.

Disclosure statement

James Rucker leads the Psychoactive Trials Group at Kings College London, undertaking clinical trials with psilocybin and related compounds. Kings College London receives grant funding from Compass Pathways and Beckely PsyTech for clinical trials with psychedelics. James Rucker has no shareholdings in any pharmaceutical company.

Additional information

Funding

JR acknowledges funding (CS- 2017-17-007) from the National Institute for Health Research (NIHR) from 2018-2023. This work presents independent research part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. No award/grant number is applicable.