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The Fever of Psychedelia

Psychedelic drugs were not mentioned to me when training as a psychiatrist, as far as I remember. Perhaps they were, in passing, but probably only in reference to the general ‘drugs of abuse’ narrative that seemed to pepper theories about why mental illnesses develop.


So, it was interesting to learn later on that both psilocybin (the active component of ‘magic’ mushrooms) and d-lysergic acid diethylamide (LSD) were synthesised by the same man (Albert Hofmann) whilst working for the pharmaceutical company Sandoz (now Novartis) during the 1940s and 1950s.


Pre 1970


LSD (and to a lesser extent psilocybin) was used quite widely in psychiatry prior to 1971. Hundreds of papers were produced. Thousands of patients treated. Whilst there were exceptions (and sometimes serious ones) the drugs were generally used safely, usually in a hospital setting and within a wider process of therapy.


Bottles of Indocybin (Psilocybin) and Delysid (LSD) Produced by Sandoz, circa 1960

These trials are summarised in various publications. The most compelling evidence was in alcoholism, where you were almost twice as likely to have reduced drinking having been given LSD when compared to a control intervention.


In problems like depression, nearly 80% of patients treated with psychedelics showed clinician-judged improvement, 65% of patients with anxiety disorders and 69% of patients with functional neurological disorders. However, many of these trials had significant design flaws. So, treat those figures with caution!


A key message from research prior to 1971 was that psychedelics seem to make people sensitive to context, so they needed to be given in a safe and supportive setting. If you didn’t do that, toxic reactions were more likely. Even so, psychedelics (not dissimilar to many drug treatments) were a bit of a gamble. It was hard to predict who would improve and who wouldn’t (or get worse). So, whether they were effective as treatments was a matter of debate up to 1970.


1971–2000


Whilst researchers were grappling with this, a legal guillotine came down. Psychedelics had diffused into recreational use and, as part of a moral panic, were swept up in the US-led ‘war on drugs’. Routine clinical use stopped and research quickly dwindled. The field entered a ‘dark age’ of prohibition, where rhetoric reigned, and stigmatised attitudes fermented for nearly 30 years. Growing up through the 1980s and 1990s, I believed firmly that psychedelic drugs were ‘bad’.


2000–2020


Since the turn of the millennium, the darkness has turned to dawn. Psychedelics are back. The reasons for this are complex and uncertain.


Perhaps societies are growing tired of a ‘war on drugs’ that hasn’t worked. Perhaps clinicians are looking to history for new ideas. Perhaps a softening of socio-political attitudes is stimulating financial interest in a commercial development process that had been cut off after 1970. Doubtless, it is all these things, and more.


Over the past twenty years, small scale trials (mostly with psilocybin) have been funded and authorised. They have established basic knowledge about how psilocybin is handled by the body in healthy volunteers. Subsequently, small scale pilot trials have taken place in patients, suggesting psilocybin (when given with psychological support) has antidepressant properties. Other small trials have investigated obsessive-compulsive disorder, tobacco addiction and the existential distress associated with life-threatening illnesses.


Small-scale trials are good, but they don’t justify psilocybin becoming a treatment. For that, we need trials costing tens to hundreds of millions of dollars, in lots of independent centres, around the world. A similar process to the covid-19 vaccine.


In 2016, a UK life sciences company called Compass Pathways announced production of psilocybin to medical standards and the intention to undertake a clinical trials program investigating psilocybin assisted therapy for difficult-to-treat (aka ‘treatment resistant’) major depression. A ‘for-profit’ entity that had previously been ‘not-for-profit’, the transition generated some tension within the psychedelic community that, long stigmatised by wider society as recreational drug users, were perhaps liable to be suspicious of the motivations of entities built on commercial principals.


Meanwhile, the Usona Institute, a not-for-profit entity in the United States, announced its own process for manufacturing psilocybin and the intent to develop psilocybin therapy for major depressive disorder (however, importantly, not for depression that was ‘difficult-to-treat’).


The process of developing a new treatment through to market usually rests on the presumption that the treatment can be patented, so allowing the developer to recuperate their costs and fund onward development. Psilocybin can’t be patented because Sandoz already did this in the late 1950s. This introduces a problem of economic sustainability. It isn’t one that I can shed much light on, as I’m not part of either Compass or Usona, but clearly, the process of getting psilocybin through to the clinic is somewhat atypical.


2021


Regardless, the development of psilocybin assisted therapy is now moving forward, apace. Compass and the Usona Institute have registered clinical trials programs for psilocybin therapy that have been given ‘Breakthrough Therapy designation’ (BTd) by the Food & Drug Administration (FDA) in the US. BTd is important because it allows speedy access to the FDA for the purposes of licensing new and promising therapies. Licensed psilocybin therapy for depression may be closer than we think.


In late 2020, Compass went through a process of offering shares in the company to the public, generating very significant capital value. Meanwhile, ‘pop up’ psychedelic investment companies and paid psilocybin retreat centres (in countries where laws are less stringent) have appeared with almost magical speed. As investors have piled in to take advantage of the optimism, the field has the feel of something like Bitcoin. What is it exactly? Not quite sure yet. Where is it going? Uncertain, but it looks promising.


A Psychedelic Future?


In this heady mix of investor fever, therapeutic optimism and counter-cultural suspicion, we’d be wise to be cautious.


I’ve argued recently that psychedelics need to be tested in a way that governments and wider society understand, or we may risk another legal crackdown.

On the other hand, this is now a process with its own momentum. Not just clinical trials, but the emergence of paid retreat centres, activist organisations calling for liberalisation and speculating venture capitalists.


In some senses, it feels like the unbridled, unregulated optimism of the pre-prohibition era. That ended in darkness. Can this be avoided today? This boils down to whether modern society and psychedelia can be reconciled. Opinion varies. I am, in general, optimistic.


From a medical perspective, psychedelics seem very safe in terms of toxicity to the body. On the other hand, the subjective effects can be unpredictable, although it seems that we can manage this safely in a medically controlled environment. The effects are hard to measure and there are inherent problems with designing unbiased trials with psychedelics. This can make the evidence base harder to interpret. However, as more studies accumulate, a general theme is likely to emerge. The evidence base is growing (and largely encouraging).


Meanwhile, the long history of human use of psychedelics and the legal crackdown on recreational use 50 years ago hint at the complex and deep-rooted cultural interplays that surround the use of psychedelics. Here, emotions run high (and deep). Whilst many are deeply opposed to the restrictive laws that surround psychedelics, the silver lining may be that those laws enable science and medicine to rediscover psychedelics in a way that governments and wider society can engage with. Few could argue with a reorientation of society’s relationship with psychedelics if they were found to have a confirmed use in healthcare. But, that is still an ‘if’. The jury will be out on this for a few years yet.


My feeling is that both science and medicine have much to learn by studying psychedelics, regardless of their potential use in healthcare. They stimulate brain cells through chemical mechanisms (serotonin receptors) in unusual ways, modulate our immune systems, cause brain cells to form new connections, and change patterns of electrical activity and connectivity between different brain regions. The result of this is an altered state of consciousness that poets, mystics and artists through history have attempted to capture, yet inevitably with only partial success. No one medium, it seems, can ever really describe it.


Whatever ‘it’ is, the creator of the term ‘psychedelic’ (a British psychiatrist called Humphrey Osmond) tried to capture it in a single word. A concatenation of two Greek words, ‘psychedelic’ literally means ‘mind manifesting’ or ‘soul revealing’. It’s a term that has spread all over the world, so perhaps it does mean something to many people. Perhaps, Osmond was on to something.


What’s in the future? The clinical trials and wider research continues. The data from this will speak for itself. But if it is good, what then? Psilocybin is not like Prozac. Delivering psilocybin assisted therapy will be met with the logistical problem of adapting health care systems that left psychedelic therapy behind in 1970, and the practical problem of who pays. These are surmountable.


What’s trickier, perhaps, is how to manage that within the context of what may be ongoing psychedelic stigma. I know now that psychedelics aren’t ‘bad’. But how many others do? Ideological change takes generations. Whilst we will come and go, psychedelics are here to stay.



 

Declarations and Conflicts of Interest


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.


James Rucker is an honorary consultant psychiatrist at The South London & Maudsley NHS Foundation Trust, a consultant psychiatrist at Sapphire Medical Clinics and an NIHR Clinician Scientist Fellow at the Centre for Affective Disorders at King’s College London. James Rucker’s salary is funded by a fellowship (CS-2017–17–007) from the National Institute for Health Research (NIHR). James Rucker leads the Psychedelic Trials Group with Professor Allan Young at King’s College London. King’s College London receives grant funding from COMPASS Pathways PLC and Beckley PsyTech to undertake phase 1 and phase 2 trials. COMPASS Pathways PLC has paid for James Rucker to attend trial related meetings and conferences to present the results of research using psilocybin. James Rucker asserts that COMPASS Pathways & Beckley PsyTech had no influence over the content of this article. James Rucker has undertaken paid consultancy work for Beckley PsyTech and Clerkenwell Health. Payments for consultancy work are received and managed by King’s College London. James Rucker does not benefit personally. James Rucker has no shareholdings in pharmaceutical companies.

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