Biology and clinical effects

Psilocybin is a classic psychedelic drug. Other classic psychedelic drugs include lysergic acid diethylamide, mescaline and dimethyltryptamine. Psilocybin belongs to the tryptamine chemical class, with a molecular structure similar to that of serotonin. Psilocybin is orally active and rapidly absorbed. Its half-life is roughly 3 h and no detectable drug is present 24 h after a single dose.^{Reference Brown, Nicholas, Cozzi, Gassman, Cooper and Muller15,Reference Passie, Seifert, Schneider and Emrich16}

Psilocybin induces an altered state of consciousness characterised by changes in mood, thinking patterns and perceptual experience. A state of awe and other personally meaningful experiences that are often difficult to describe in words can be experienced with higher doses. Some users attribute enduring, yet generally non-specific, improvements in life satisfaction to these experiences.^{Reference Griffiths, Richards, Johnson, McCann and Jesse17,Reference Griffiths, Richards, McCann and Jesse18}

The subjective effect of psilocybin is almost entirely dependent on partial agonism at type 2A serotonin (5-HT_2a) receptors, but its activity at serotonin receptors is broad (except at 5-HT₃).^{Reference Ray19} The risk of serotonin syndrome is very low, probably because psilocybin is not a full agonist and has no significant activity at monoamine transporters.^{Reference Ray19} It is not physiologically dangerous in overdose,^{Reference Gable20} although psychological toxicity resulting in dangerous behaviour can occur rarely, probably more so in a recreational setting. Among recreational users the rate of seeking emergency medical care due to psilocybin intoxication is low.^{Reference Kopra, Ferris, Winstock, Young and Rucker21} Expert consensus concludes that psilocybin mushrooms are among the safest of recreationally used drugs.^{Reference Nutt, King and Phillips22,Reference Nichols23}

Psilocybin has little or no dependence potential and although complete tolerance rapidly develops to the subjective effect, there is no known withdrawal syndrome.^{Reference Nichols23} Large national population surveys find psychedelic use to be associated with reduced rates of suicidal thinking^{Reference Hendricks, Thorne, Clark, Coombs and Johnson24,Reference Jones and Nock25} and no association with increased psychosis rates.^{Reference Johansen and Krebs26} However, acute intoxication does bear similarity to some symptoms of psychosis, and it is reasonable to expect that psychedelics may ‘unmask’ psychotic disorders in those with pre-existing vulnerabilities or worsen symptoms in those with established psychosis. Hallucinogen persisting perception disorder is a diagnosis in the major psychiatric classification systems that refers to the persistence of perceptual psychedelic effects long after the drug has left the body. The aetiology of this is opaque and it seems likely to be rare, although some sufferers report significant distress and disability.^{Reference Halpern and Pope27}

Psychedelic therapy was used extensively in psychiatry before legal prohibition of psychedelics in 1971, when they were classed as Schedule I controlled substances by the United Nations. We have summarised pre-prohibition studies in depression in a systematic review.^{Reference Rucker, Jelen, Flynn, Frowde and Young28} Although studies of that era were generally not of good quality by modern standards, among 19 studies with 423 participants with broadly defined major depression, 79.2% of patients showed clinician-judged improvement after treatment with psychedelic therapy. The current legal classification of psychedelics prohibits their use "except for scientific and very limited medical purposes" in United Nations signatory countries. This significantly hampers research efforts,^{Reference Nutt, King and Nichols2} as it requires approval from a government agency, such as the Home Office in the United Kingdom. Nonetheless, pilot clinical studies demonstrating that psilocybin with psychological support could be safe and have enduring effects in people experiencing psychological distress paved the way for the research in MDD discussed in this article.^{Reference Moreno, Wiegand, Taitano and Delgado29,Reference Grob, Danforth, Chopra, Hagerty, McKay and Halberstadt30}

What is psilocybin therapy and what is it not?

Psilocybin therapy is a drug-assisted psychotherapeutic process. That is, intermittent day-hospital dosing sessions with psilocybin are embedded in a longer-term process of out-patient psychological support and therapy. Unlike traditional antidepressants, psilocybin can induce intense emotional and perceptual changes. Symptomatic improvement often occurs rapidly (days) after a dosing session,^{Reference Romeo, Karila, Martelli and Benyamina31} in contrast to the 1–4 weeks with traditional antidepressants.^{32,Reference Machado-Vieira, Baumann, Wheeler-Castillo, Latov, Henter and Salvadore33} Psilocybin is not given to patients to take home and there is no day-to-day requirement to take it. More than one dosing session may be required. The interval between sessions may vary from weeks to months (Fig. 1).

Fig. 1 Timeline for the process of psilocybin therapy. A single psilocybin administration dosing day occurs in a hospital setting, with preparatory psychological support sessions in the weeks before dosing and psychological integration sessions in the weeks after. Additional dosing days can be planned, with intervals varying from 2 weeks to 12 months.

It is hypothesised that the synergy between psilocybin and the therapeutic support provided drives therapeutic change. However, the degree of intensity of experience under psilocybin may also imply a degree of unpredictability, perhaps more so than with traditional antidepressant treatments. Informed consent is of course essential, but because the therapeutic model emphasises an engagement with difficult emotional material driving depression that may not be obvious prior to exposure to the therapy or the drug, fully informed consent is not realistic. Although this is no different, in essence, from any other treatment, psilocybin therapy brings the issue into a sharper contrast. Psilocybin therapy given without consent risks being psychologically traumatic. It may need to be specifically excluded from the compulsory treatment provisions of Mental Health Act legislation, if approved.

Over-simplifications of psilocybin therapy in mainstream media have popularised the view that it acts like a brain ‘reset’, leading to unrealistic expectations by patients of ‘quick fixes’ for depression, addictions or trauma response symptoms. This is naive. Although ‘transformative’ experiences do happen, the reality of psilocybin therapy for most is that initial improvements need to be consolidated by a longer period of positive behavioural change that is not necessarily driven by the drug itself. So, although psilocybin may be the ‘seed’ of positive change, it cannot distract from the broader psychosocial processes of recovery that may re-enforce it.

What is psilocybin therapy like in a clinical trial setting?

Within a clinical trial, the process of psilocybin therapy is divided into 3 stages: (1) preparation sessions, (2) dosing sessions and (3) integration sessions (Fig. 2). In all sessions, the primary point of therapeutic support is a psychological support practitioner. Medical assistance from a psychiatrist is available if necessary.

Fig. 2 Timeline depicting the typical process of a clinical trial of psilocybin therapy. Participants are referred from primary, secondary and private care. Informed consent is taken and eligibility is checked in a 2–3 h screening session. Once participants are enrolled, they enter a 3–8 week preparation phase which includes psychoeducation and introduction to their psychological support practitioner and withdrawal of medication such as selective serotonin reuptake inhibitors. They then proceed to a dosing day, which lasts around 8 h. Follow-up begins the day after dosing and includes mental state monitoring, discussion of the experience, psychological integration and collection of safety data. Care is handed back to referrers at the end of the trial.

Informed consent is first taken. Then, the preparation sessions begin, lasting from 3 to 8 weeks. These include eligibility assessments and psychological preparation. During these sessions, medications that may mitigate the effects of psilocybin, such as drugs active at the serotonin transporter or the 5-HT_2a receptor, are usually withdrawn under the supervision of a study psychiatrist. However, whether this is essential is an area of study, and may change in future.^{Reference Sarparast, Thomas, Malcolm and Stauffer34}

The psychological preparation includes establishment of rapport, discussion of the participant's history, focusing on material relevant to their current difficulties, expectations of treatment, including the effects of psilocybin, and intentions (or objectives) for the dosing day. Participants are familiarised with the dosing room and it is agreed what practical support they would like to receive. This may include ‘interpersonal grounding’, which may involve the therapist and participant holding each other's arms. The limitations of this are pre-agreed, defined within psilocybin therapy manuals and the contact is usually video-monitored. The aim is to provide appropriate support during what may be a highly emotive experience.

On the dosing day, participants receive a single dose of psilocybin (or comparator) in the morning, given in a calm, medically monitored setting. Eye shades and ambient music are used to encourage relaxation. Active intervention from the therapist is not emphasised, unless requested. At least one person remains with the participant throughout. The effects of psilocybin usually start at 30 min, peak at 90 min and subside after 4–6 h.^{Reference Brown, Nicholas, Cozzi, Gassman, Cooper and Muller15,Reference Passie, Seifert, Schneider and Emrich16} Dosing sessions are video-recorded to monitor for risk events or deviation from therapeutic protocols, unless participants withdraw consent for this. After the dosing session, participants are medically assessed for discharge, then accompanied home by a friend, partner or carer.

Integration sessions aim to integrate the participant's experience under psilocybin with the narrative of their depression, using any insights gained to reframe unhelpful thinking patterns and to establish the basis for changed patterns of behaviour important to longer-term improvements. Within the context of a clinical trial, the amount of psychological support is necessarily time-limited, with around 2–3 follow-up sessions. However, extra support is provided if necessary. Care is handed back to referrers at the end of the trial.

Modern clinical trials of psilocybin therapy in depression

In total, 388 participants with MDD have participated in five clinical trials of psilocybin therapy for depression from 2016 to the time of writing.^{Reference Davis, Barrett, May, Cosimano, Sepeda and Johnson10–Reference von Rotz, Schindowski, Jungwirth, Schuldt, Rieser and Zahoranszky12} Of these, 253 met criteria for TRD.^{Reference Carhart-Harris, Bolstridge, Rucker, Day, Erritzoe and Kaelen13,Reference Goodwin, Aaronson, Alvarez, Arden, Baker and Bennett14,Reference Carhart-Harris, Bolstridge, Day, Rucker, Watts and Erritzoe35}

Published in 2016, the first study was an open-label trial conducted in London, UK, involving 20 participants with moderate to severe TRD.^{Reference Carhart-Harris, Bolstridge, Rucker, Day, Erritzoe and Kaelen13} They had a mean 17.7 years (range 7–30 years) of illness duration, had tried a mean 4.6 (range 2–11) previous medications and 17/20 had previously had psychotherapy. Lifetime exposure to psilocybin was 35%. Participants received a 10 mg psilocybin session, with 25 mg 2 weeks later. At 1 week after treatment, 19 participants had some reduction in depression severity (Cohen's d = 2.2 compared with baseline) and 45% were responders at 5 weeks.^{Reference Carhart-Harris, Bolstridge, Day, Rucker, Watts and Erritzoe35} There were no serious adverse events reported.

A subsequent study, published in 2021, included 24 participants with moderate to severe MDD in a double-blind randomised waiting-list controlled trial.^{Reference Davis, Barrett, May, Cosimano, Sepeda and Johnson10} Participants had experienced the current depressive episode for a mean 24.4 months; 58% had trialled medication. Lifetime exposure to psychedelics was 25%.^{Reference Gukasyan, Davis, Barrett, Cosimano, Sepeda and Johnson36} Participants received two weight-adjusted doses of psilocybin (20 mg/70 kg, followed by 30 mg/70 kg 1.6 weeks later) with psychological support. In total, 71% of participants were responders at 1 week post-dose^{Reference Davis, Barrett, May, Cosimano, Sepeda and Johnson10} and 67% at 3 months.^{Reference Gukasyan, Davis, Barrett, Cosimano, Sepeda and Johnson36}

A third study, published in early 2022, included 59 participants with moderate MDD.^{Reference Carhart-Harris, Giribaldi, Watts, Baker-Jones, Murphy-Beiner and Murphy11} They had a duration of 2–46 years’ depression (escitalopram group mean: 15 years; psilocybin group mean: 22 years), had trialled 0–6 medications and 90% had had psychotherapy. Lifetime psychedelic exposure was 27%. This was a double-blind RCT. Half the participants received daily escitalopram tablets and two 1 mg psilocybin therapy sessions. The other half received daily placebo tablets and two 25 mg psilocybin therapy sessions. No significant difference was found between the treatment groups on the primary outcome for depression at 6 weeks, although the primary aim of this trial was to study comparative neuroimaging mechanisms, not efficacy.

Published in late 2022, the first large, multi-centre trial recruited 233 participants with moderate to severe TRD, representing 54% of those assessed for eligibility.^{Reference Goodwin, Aaronson, Alvarez, Arden, Baker and Bennett14} Lifetime exposure to psilocybin was lower than in general population estimates,^{37,Reference Yockey and King38} at 6%. Eighty-two per cent had not responded to two previous antidepressants; the remainder had trialled three or four. This was a double-blind randomised single-dose trial: 79 participants received a dosing session with active placebo (1 mg of psilocybin), 75 received 10 mg of psilocybin and 79 received 25 mg. All participants received psychological support. At the 3-week primary end-point, 37% of participants had responded in the 25 mg group, 19% in the 10 mg group and 18% in the 1 mg group. Around 20% of participants experienced a remission above the placebo rate at the 3-week primary end-point (29% remission rate at 25 mg, 9% at 10 mg, 8% at 1 mg). At 12 weeks, 20% of participants who had received 25 mg had sustained their response, compared with 10% in the 1 mg group. It is important to note that this represents the difference between 1 mg and 25 mg of psilocybin, since all participants in this trial received the same psychological support. This trial demonstrated that a 25 mg dose was superior to a 1 mg dose.

Most recently published (in early 2023), a Swiss group conducted a double-blind RCT with 52 participants with MDD.^{Reference von Rotz, Schindowski, Jungwirth, Schuldt, Rieser and Zahoranszky12} This assessed the effects of a 0.215 mg/kg psilocybin dose (corresponding to a moderate dose of 16 mg for a 70 kg participant) versus placebo, with both groups receiving psychological support. Thirty-one per cent had prior experience of psychedelics. At the primary end-point of 2 weeks after drug administration, there was a significant improvement in both clinician-rated Montgomery–Åsberg Depression Rating Scale (MADRS) and self-reported Beck Depression Inventory (BDI) scores, with response and remission rates significantly higher in participants receiving psilocybin (MADRS: psilocybin 58% v. 16% placebo; BDI: 54% v. 12%) at the 2-week end-point.

Adverse effects and risks

Common immediate physical adverse effects are nausea (4%^{Reference von Rotz, Schindowski, Jungwirth, Schuldt, Rieser and Zahoranszky12} to 22%^{Reference Goodwin, Aaronson, Alvarez, Arden, Baker and Bennett14}) and headache (15%^{Reference von Rotz, Schindowski, Jungwirth, Schuldt, Rieser and Zahoranszky12} to 50%^{Reference Rucker, Marwood, Ajantaival, Bird, Eriksson and Harrison39}). Psychological adverse effects during dosing include anxiety or other emotional distress. These are managed with reassurance, although a rescue medication (usually a short-acting benzodiazepine) may be given (to <1% in Goodwin et al^{Reference Goodwin, Aaronson, Alvarez, Arden, Baker and Bennett14}). Expected effects (such as misperceptions or hallucinations) are not recorded as adverse events unless associated with clinically significant distress. Acute substance-induced psychotic disorder appears to be rare. In a trial involving 89 healthy volunteers, one case was reported.^{Reference Rucker, Marwood, Ajantaival, Bird, Eriksson and Harrison39} This had mostly resolved within hours and completely resolved by the next day. Long-lasting adverse events have not generally been identified.^{Reference Rucker, Iliff and Nutt3,Reference Rucker, Marwood, Ajantaival, Bird, Eriksson and Harrison39,Reference Roscoe and Lozy40} No evidence for hallucinogen persisting perception disorder has been reported in the clinical trials above or in healthy volunteers.^{Reference Roscoe and Lozy40} Serious adverse events such as suicidality and suicidal behaviour have been rarely reported.^{Reference Roscoe and Lozy40} In the largest clinical trial to date,^{Reference Goodwin, Aaronson, Alvarez, Arden, Baker and Bennett14} within 3 weeks of treatment, five participants reported suicidal ideation in the 25 mg group, compared with four participants in the 10 mg and two in the 1 mg groups. Intentional self-injury occurred in two participants in the 25 mg group and one in the 10 mg group. Although rates of these adverse events were not statistically significant between groups, it will be an area of careful monitoring in future trials.

Concerning allegations, substantiated by video evidence,^{41, 42} have been made against two practitioners providing psychological support to a participant in a trial of 3,4-methylenedioxymethamphetamine (MDMA) therapy for severe post-traumatic stress disorder. Although there have been no reports of similar events in psilocybin therapy trials, the risk of inappropriate behaviour by therapists is highlighted. This is a risk in all forms of therapy; however, it is more of a concern where the drug induces a state in which users may become more suggestible and psychologically vulnerable. Therapist training and manuals define the scope of psychological support to be provided. Within larger trials, fidelity to the therapeutic manual is also assessed by a third party reviewing the video recording of dosing sessions. The same provisions may be required if psilocybin therapy is licensed.

Psychedelics are prone to attract social narratives of hyperbole, which fuel patient expectations of transformational change.^{Reference Young43} This is unrealistic and comes with risks of its own. Lack of recovery in the presence of high expectations has the potential to worsen depression through disappointment. The preparation for clinical trials includes the moderation of expectations of treatment.

What is still unknown

Where do we go from here?

Psilocybin therapy has been shown to have potential as a treatment for depression in almost 400 participants. Phase 3 trials starting in 2023 will further probe efficacy against placebo. Longer-term follow-up data are being collected to examine crucial questions regarding long-term efficacy. Ongoing studies will address whether repeated doses may have a consolidating effect on outcome. Health economic analyses are ongoing. If approved, the target clinical population is likely to be TRD, but since this encompasses a heterogeneous group, the scope of delivery may be wide. If approved, psilocybin therapy will likely require oversight to maintain safety and quality of treatment provisions, which may look a bit like the acceditation service currently used for electroconvulsive therapy in the UK. Such regulation may represent a new, and very different, treatment option for the significant proportion of people with major depressive disorder who have not responded to initial treatment trials.

About the authors

Anya Borissova, MBBS, MRCPsych, is a National Institute for Health and Care Research (NIHR) Academic Clinical Fellow in the Centre for Neuroimaging Sciences at King's College London, UK. James J. Rucker, MBBS, MRCPsych, PhD, is a consultant psychiatrist and senior clinical lecturer in psychopharmacology in the Department of Psychological Medicine at the Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.