Shaking the kaleidoscope of the mind

The excitement around the potential of psychedelic drugs in mental health is intense. Investors are pouring money into companies developing new treatments based on psychedelics; public interest is high; and the legal restrictions on their use are gradually being rolled back. 

Early clinical trials have shown powerful anti-depressant and anti-addictive effects that can persist for up to a year, after receiving only one or two doses (Gukasyan et al., 2022), and the proponents are promising nothing less than a revolution in psychiatry, neuroscience, and psychology research. Can these well-known but uniquely powerful consciousness-altering compounds really have such an impact in clinical and research settings?

Turning points

The so-called 'classic' psychedelic drugs are psilocybin (first derived from 'magic' mushrooms), N,N-Dimethyltryptamine (DMT; found in many plant species), lysergic acid diethylamide (LSD; purely synthetic) and mescaline (derived from the peyote cactus). All these compounds can produce profound alterations in consciousness, cognition, and perception, accompanied by vivid hallucinations, and these effects are primarily due to their action at a specific brain receptor; the serotonin or 5HT 2A receptor. A number of other drugs (such as ketamine, ibogaine, and 3,4-Methylenedioxymethamphetamine or MDMA) can produce somewhat similar effects and are also being investigated therapeutically, though they have broader and more complex effects on different brain systems and receptors.

Humans have likely been using naturally-occurring psychedelics for thousands of years, and there were important early advances in the late 19th and early 20th centuries (Sessa, 2016). However, the synthesis of lysergic acid diethylamide (LSD) by the Swiss chemist Albert Hofmann in 1943 was a crucial turning point. Originally it was thought that LSD could be useful as an experimental model of schizophrenia, and it was classed as a 'psychotomimetic'. By the 1950s it was being widely used in the USA, UK, and several other countries in therapeutic settings. Between 1950 and 1966 there were over 2000 published scientific papers on the therapeutic uses of psychedelics (mostly on LSD, but some were also experimenting with mescaline and psilocybin). 

By the mid-1960s LSD had leaked from research laboratories, and was being used recreationally. Its perceived links with anti-Vietnam war protests and the general counter-culture movement led the establishment in the US to clamp down hard; it was banned in 1966. Most other countries quickly followed suit, encouraged by President Nixon's regressive 'war on drugs' in the late 1960s and early 1970s. This effectively halted almost all research on these compounds for several decades. (For a brief but comprehensive primer on the history of this area, see Ben Sessa's 2016 The History of Psychedelics in Medicine.)

Beginning again in the early 2000s, a steady trickle of research studies with psychedelics got underway, and by the 2010s this trickle had become a flood. Pioneered by two major research groups at Johns Hopkins Hospital in Baltimore (led by Roland Griffiths) and a UK group in Bristol, and later at Imperial College London (led by David Nutt), this research started to challenge the status quo and the 'war on drugs'-inspired negative rhetoric and perceptions around psychedelics. These early studies caught the mainstream media's attention, fired the public's imagination, proved that psychedelics should be a serious area of study for modern researchers, and provided the foundation for the explosion of research and investment in the field we see today.

Modern studies and clinical trial success

The very first contemporary studies of these drugs were largely focused on demonstrating tolerability, examining the effects on healthy subjects, and harnessing the power of modern neuroimaging technology to provide additional levels of measurement, analysis, and explanation of their effects. High-profile acute-challenge studies of this type were performed with psilocybin, LSD, and MDMA, all by the Bristol/Imperial College team (Carhart-Harris et al., 2012, 2015; Carhart-Harris, Muthukumaraswamy, et al., 2016).

These studies showed that tolerability of the (often very intense) drug effects is generally very good, even when subjects are in the unnatural and often anxiety-inducing confines of an MRI scanner. More importantly, these studies provided vital data on the acute brain effects of psychedelics, which have gone on to inform modern theories of both their acute and long-term effects.

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At a similar time, inspired by the positive reports from the mid-20th century work on psychedelic therapy, groups were pressing ahead with clinical trials in patient groups. The Multidisciplinary Association for Psychedelic Studies (MAPS) had been conducting clinical trials with MDMA and Post-Traumatic Stress Disorder (PTSD) patients since the mid-2000s with impressive results (Mithoefer et al., 2010). At Johns Hopkins, a pilot study using psilocybin for smoking cessation showed that 80 per cent of subjects were still abstinent at six-months follow-up; strikingly good results, which demonstrated the potential for effective treatment of addiction (Johnson et al., 2014).

Starting in the mid-2010s the Imperial group conducted two clinical trials with psilocybin and depression patients, also incorporating a battery of neuroimaging measures to examine the brain effects of the treatment. The first (open-label) study showed powerful anti-depressant effects of the therapy in a treatment-resistant depression group, with strong responses in most patients, and a number of patients still in complete remission at a three-month follow-up (Carhart-Harris, Bolstridge, et al., 2016). 

The second (double-blind) study compared psilocybin therapy with a standard first-line depression treatment; the selective serotonin reuptake inhibitor (SSRI) escitalopram. Psilocybin therapy compared favourably to escitalopram on all the clinical measures used in the study, with remission rates of 57 per cent and 28 per cent, respectively (Carhart-Harris et al., 2021). All the studies so far have essentially been small-scale, proof-of-concept investigations; but the results are generally very promising.

The psychology of psychedelic therapy

These clinical studies have generated a great deal of excitement and hope around psychedelic-based therapies as new treatments in psychiatry. However, the treatment paradigm is quite different to standard psychiatric pharmacotherapy. Psychedelic therapy is 'psychopharmacological' in a genuine sense, in that it incorporates psychological therapy with a drug component, and the two are thought to act in a synergistic manner to produce the clinical effects.

Current theories as to how these two factors interact are informed by fMRI results of both acute drug and therapy-related effects and suggest that the radical breakdown of the standard mode of brain function (see figure 1) produced by the drug allows the brain to enter a more flexible, plastic state. 
This state provides the opportunity for pathological beliefs, cognitions, and responses to be revised into healthier ones (Carhart-Harris, 2019). As a simple metaphor, psychedelics shake the kaleidoscope of the mind, and allow the patient to form a new view on their trauma, addiction, or other psychopathologies.

This view of how psychedelic therapy works has two important implications. Firstly, it suggests they have transdiagnostic potential and may be applicable to a wide range of disorders where dysfunctional beliefs and cognitions are an important factor. This clearly contrasts with standard psychiatric pharmacotherapy which tends to use specific drugs, which target specific brain receptors, thought to be dysfunctional in specific disorders. Secondly, it implies that the psychological therapy is, in a sense, the primary treatment; the drug just enables the therapy to take place.

As such, a great deal of attention needs to be given to psychological factors when conducting psychedelic therapy, and clinical psychologists are at the forefront of this field. The standard modern approach developed over the last ten years or so (as outlined in Watts & Luoma, 2020) uses quite extensive preparation sessions, where the patient is able to get to know the therapists, any concerns are addressed, and the patient is encouraged to approach the therapy with as little resistance as possible. During the dosing sessions, two therapists (sometimes termed 'guides'; often one psychiatrist, and one clinical psychologist) are always present for the duration of the session, which can be up to six hours.

The main role of the therapists during the sessions is to provide support, encouragement, and reassurance during what can be a profoundly challenging and intense experience, often involving past trauma or other painful emotional issues. The therapists act as facilitators, but are essentially non-directive, with the only explicit instructions being to accept the difficult aspects of the experience rather than avoid them, and to 'go wherever you need to go'. Finally, post-dosing integration sessions help patients process what happened during the dosing sessions, consolidate any insights gained, and may aim to incorporate key lessons into their ongoing life and any subsequent therapy.

Dr Ros Watts (pictured, above) was a guide in both of the Imperial psilocybin/depression trials, and a clinical lead in the second trial. In the process of that work, she has developed a new therapy model for use with psychedelic therapy, called ACE (Accept, Connect, Embody). She describes it in this way:

'Accept, Connect, Embody is a flexible protocol which provides a framework to support the psychedelic therapy journey. Guided imagery exercises are the principal components, they form the basis of the preparation and integration sessions (that happen before and after the psychedelic sessions themselves). The psychedelic session is conceptualised as a "deep sea dive"; they will be invited to swim down beneath the waves of the busy mind, fully accept and feel any sensations and emotions arising, and then swim back up to the big sky to see themselves, their relationships, and the world around them in the light of any insights experienced.'

Other psychological factors are also extremely important, particularly 'set' (i.e. the patients' mindset, or their approach to the experience) and 'setting' (i.e. the environment in which the experience occurs). The context of drug experiences has long been known to have important effects, with traditional (e.g. ayahuasca ceremonies) and recreational (e.g. the acid-house/rave scene in the 1980s and 1990s) uses incorporating music as a key part of the experience. Modern studies have shown that LSD can enhance a specific emotional response to music (Kaelen et al., 2015), and also that music may in turn enhance specific aspects of the drug experience, including visual hallucinations (Kaelen et al., 2016). This synergism between music and drug effects will perhaps be familiar to anyone with relevant experiences in nightclubs or raves.

Music also forms a crucial part of both the mid-20th century and the modern incarnations of psychedelic therapy. In contrast to popular recreational uses, a calm, quiet, comfortable environment is used, with relatively dim lighting and soft music. Great attention has been given to the appropriate selection of music to form a useful soundtrack for the psychedelic dosing sessions. In 'The hidden therapist: evidence for a central role of music in psychedelic therapy', Mendel Kaelen (both a psychedelic researcher and accomplished musician/composer) and colleagues (Kaelen et al., 2018) conducted semi-structured interviews with patients about their experiences with music during the dosing sessions.

They found that music had both 'welcome' and 'unwelcome' influences during the sessions, with positive influences promoting calm, guidance, openness, and safety, and negative ones including feeling misguided, resistance, and the evocation of negative emotions. Crucially, they also found that the nature of the patients' response to music predicted reduced depression scores one week after dosing, whereas the more general intensity of the drug experience did not. Recent fMRI data have identified significantly higher responses to a music stimulus in patients' brains after therapy, and that this greater response is related to particular qualities of the drug experience during the dosing sessions (Wall et al., 2022).

In terms of the psychological effects of the therapy, several important themes have emerged. In a qualitative study using semi-structured interviews six months after treatment (Watts et al., 2017), patients reported an increased feeling of connectedness (to others, to the natural world, to their own emotions) as a result of the therapy. A second theme that emerged was specifically around emotions and a change from avoidance to acceptance of their own feelings. 

Neuroimaging studies have shown increased brain responses to emotional faces following psilocybin therapy (Roseman et al., 2018); an important contrast with the 'emotional blunting' and reduced responses to emotional stimuli often seen with standard depression treatments such as SSRIs. Other studies have documented long-term changes in personality, particularly in the trait 'openness to experience' (one of the Big Five personality factors) as a result of MDMA therapy (Wagner et al., 2017). 

Similar associations between openness and psychedelic use are also present in recreational users (Erritzoe et al., 2019) with other studies even suggesting that lifetime psychedelic use is predictive of progressive political (Nour et al., 2017) and environmental views (Forstmann & Sagioglou, 2017). These early findings on the effects of psychedelics on the structure of personality are intriguing, especially given the general view that personality traits like openness to experience generally remain relatively fixed in adulthood.

Psychedelics as research tools

There has been a strong focus in the current 'psychedelic renaissance' on translation to clinical uses. This is positive in many ways; new treatments for psychopathology are badly needed, and psychedelics are a promising option for a number of common and debilitating disorders. However, in the rush to prove the viability of these new therapeutic models, there are perhaps opportunities in basic research that are being neglected. The early studies at Bristol and Imperial (e.g. Carhart-Harris et al., 2012) used healthy subjects and were focused on the acute psychological and neurological effects of psilocybin and LSD. 

These provided valuable and highly novel insights, but there is a great deal more 'low-hanging fruit' in the research sphere. One tried-and-tested approach to studying a complex system (like the human mind) is to perturb the system in some way and document the effects. Psychedelics are the most powerful modulators of consciousness that we know of, with obvious potential in the scientific study of consciousness, personality, perception, addiction, and other fields.

Currently, work like this is impeded by the tight legal restrictions on the use of these drugs. Research with psychedelics in the UK requires a Schedule 1 licence from the Home Office, which can be difficult and expensive to obtain. Given successive UK government's unwillingness to revisit our generally regressive drug laws, it seems unlikely this will change anytime soon, despite increasing public interest and pressure. As seen previously with the medical use of cannabis, some US states are leading the way, with Oregon recently being the first to widely relax prohibitions to allow the therapeutic use of psilocybin, and others of the more liberal states expected to follow. 

Availability of the drugs themselves has also been a severe constraint, with only a few laboratories in the world licensed to manufacture them, though as part of the current psychedelics 'gold rush' many specialist production companies are being founded, so this may be less of a problem in the future. Hopefully, the relaxation of legal restrictions and wider availability in the future will mean that more basic research can be done using these uniquely powerful drugs.

The future of psychedelics

The current status of the psychedelic revolution might be described as 'febrile'. There are new active research groups dedicated to psychedelics at many major research institutions around the world, and (at the time of writing) around 50 publicly-listed pharmaceutical or biotech companies seeking to develop them as therapeutics, plus a great many more privately-owned companies. With only a few exceptions, these companies have all been founded in the last three years. Enthusiasm and investment are everywhere, but true expertise is somewhat lacking, with relationships between expert academics and those wanting to rapidly commercialise treatments often being somewhat prickly and suspicious.

Many of these companies are seeking to differentiate themselves by expanding the remit of psychedelic therapeutics to different indications or conditions. Chronic pain is a particular area of interest, and small (academic) clinical trials are underway in the US and UK, with some commercial players also focusing on pain. Addiction is also a strong focus, with some companies currently developing treatments based on ibogaine for opiate addiction, and others focusing on smoking or behavioural addictions such as gambling.

Encouraged by some positive reports from the first wave of psychedelic research in the 1950s/60s, eating disorders are also a potential area of opportunity. Hannah Douglass is the lead researcher in a current trial of psilocybin therapy for anorexia nervosa (AN), sponsored by Imperial College:

'There is a substantial unmet need for effective treatment options for eating disorders, with high relapse rates seen in these patients. Psychedelics can potentially help with a number of pathological features associated with AN, including cognitive inflexibility, emotional or experiential avoidance, and neurobiological factors such as serotonergic dysfunction and reduced neuroplasticity. The ability of psychedelics to potentially enhance self-love, self-compassion, and self-acceptance could also be of particular value in the treatment of AN and other eating disorders given the highly critical view these individuals tend to hold of themselves. All these effects clearly warrant the investigation of psilocybin-assisted therapy as a new treatment for AN.'

Despite all the promise and excitement, there are significant hurdles to clear before we see psychedelic treatment rooms as a standard feature in psychiatric clinics. Most clinical studies have so far been quite small (in the range of 20-30 subjects), but much larger studies will be needed to definitively prove clinical efficacy and better understand the true variability in the response to treatment. Another big issue is about how to extend psychedelic treatments over the long term. 

While some recent studies have shown anti-depressant effects of treatment can extend for up to a year (Gukasyan et al., 2022), this is not the case for all patients, and the longer-term effects are generally unclear. A therapy model consisting of six-monthly or annual 'booster' dosing sessions in order to maintain clinical effects is one possibility, though this remains to be tested, and will need long-term commitments both in researcher time and funding to figure out.

There are also questions about the broad applicability of psychedelic therapy. Most studies so far have used carefully selected patient groups, with particular care taken to exclude patients who may be vulnerable to psychosis. The link between (recreational) psychedelic use and psychosis is currently unclear, and controversial, but even the possibility that a psychotic episode could be induced means that any attempt at broadening the use of psychedelics beyond carefully selected patients needs to proceed with extreme caution. A similar issue surfaces around drug-drug interactions in patients who may be taking other psychiatric medication, particularly 5HT-active drugs like SSRIs (Sarparast et al., 2022). There are currently only a few studies in this area, but this is an obvious issue in broadening the scope of psychedelic therapy. 

Despite these issues, and the current legal restrictions on research, it's fair to say that psychedelics represent a potentially breakthrough new treatment for a range of psychopathologies, and the possibilities for their applications in both therapy and research are exciting. Novel treatments are badly needed in psychiatry, and psychedelic therapy is perhaps the most promising new option to come along for decades. 

There are enormous challenges ahead, and big questions remain over how truly effective these treatments will be in larger and more diverse patient groups, their application to different disorders, and whether they can be reliably deployed at scale. But the research is moving fast, and the legal restrictions will likely be ameliorated by the combination of more positive clinical trial results, and public pressure for the availability of treatments. The true impact of these uniquely powerful compounds, first discovered in the depths of the Second World War, might be to change the way we study and treat the human mind in the 21st Century.

Matt Wall, PhD., is Head of MRI Applications Invicro London; Honorary Senior Lecturer, Faculty of Medicine, Imperial College, London, and Clinical Psychopharmacology Unit, University College London. [email protected]

Key sources

Carhart-Harris, R., Giribaldi, B., Watts, R., et al. (2021). Trial of Psilocybin versus Escitalopram for Depression. New England Journal of Medicine, 384(15), 1402–1411. 
Kaelen, Mendel, Giribaldi, B., Raine, J., et al. (2018). The hidden therapist: evidence for a central role of music in psychedelic therapy. Psychopharmacology, 235(2), 505–519. 
Sessa, B. (2016). The History of Psychedelics in Medicine. Handbuch Psychoaktive Substanzen, 1–26. 
Watts, R., Day, C., Krzanowski, J., Nutt, D., & Carhart-Harris, R. (2017). Patients' Accounts of Increased "Connectedness" and "Acceptance" After Psilocybin for Treatment-Resistant Depression. Journal of Humanistic Psychology, 57(5), 520–564. 
Watts, R. & Luoma, J. B. (2020). The use of the psychological flexibility model to support psychedelic-assisted therapy. Journal of Contextual Behavioral Science, 15(April 2019), 92–102.

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