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Man with depression

Difficult-to-treat, “treatment resistant depression” is clinical depression that does not respond to standard treatments.

It is a major health concern for patients, carers, society and governments, but historically has been under-researched relative to other less common conditions. It is associated with high rates of suicide and worsens outcomes in a wide variety of other health problems.

Two safe and effective treatments for depression – selective serotonergic antidepressants (e.g. Prozac (fluoxetine)) and cognitive behavioural therapy – were introduced over 30 years ago, but there have been no new breakthrough treatments since then. Up to 50% of patients find they achieve little or no benefit from established treatments, suggesting an urgent need to develop alternative paradigms of therapy.

Psilocybin is the active ingredient of so-called ‘magic’ mushrooms. Psilocybin mushrooms have a long history of use in diverse cultural settings. Psilocybin stimulates serotonin receptors in the brain. Serotonin is known to regulate mood, amongst other brain functions. Psilocybin is a classical psychedelic drug, along with d-lysergic acid diethylamide, dimethyltryptamine and mescaline. All of the classical psychedelic drugs were used as psychiatric treatments for depression prior to 1970, when the UN Convention on Drugs effectively banned all clinical use.

This decision was probably largely politically motivated, as there is little evidence that the classical psychedelics are harmful, particularly when compared to other similarly restricted drugs. Prior to the decision to ban psychedelics, numerous clinical trials had been completed however they were generally of insufficient quality to base a firm decision about safety and efficacy of the treatment today. For this reason, we need to repeat these clinical trials with the benefit of modern paradigms of trial design.

Difficult-to-treat (or ‘treatment resistant’) depression is a common, socio-economically costly health problem with few effective treatments. Those who suffer from it are at a high relative risk of completed suicide and have poorer health outcomes in a variety of other physical health problems, such as heart disease. For these reasons, developing new treatments in this area is a government priority.

Starting in 2021, this trial will recruit up to 60 participants with treatment resistant depression and randomise them to receive either a single dose of psilocybin or placebo, delivered in a safe and comfortable hospital setting. No participant will be given psilocybin to take home. We will then collect feasibility, safety, efficacy and mechanism data for 6 weeks after treatment to evaluate whether the drug is safe and effective enough to use in this population. Regardless of having received psilocybin or placebo, all participants will have the opportunity to take part in an open label extension and receive a dose of psilocybin once they have completed the main part of the study.

The PsiDeR trial protocol has been developed in liaison with service users, carers and experts in clinical trial design. The final protocol and all patient facing communications have been reviewed and authorised by the NHS Research Ethics Committee and the Medicine’s and Healthcare Products Regulatory Agency. Dr James Rucker is principal investigator of this trial. Professor Allan Young is chief investigator of this trial.

The decision to continue the trial is taken by the Sponsor, which is King’s College London and the South London and Maudsley NHS Foundation Trust. A Trial Steering Committee and Data Monitoring and Ethics Committee composed of expert and lay members who are independent of the study team and the Sponsor regularly review this trial, have access to unblinded data and can recommend to the Sponsor that it be terminated if it is not being properly executed or if significant safety concerns arise. All trial documentation is available for audit by the relevant regulatory agencies.

Yes. The PsiDeR trial is part of a wider consortium of clinical trials investigating psilocybin. The psilocybin drug substance is provided by Compass Pathways Ltd. Compass Pathways are also funding clinical trials with psilocybin, however they have no influence over the PsiDeR trial aside from providing the psilocybin drug substance.