Psilocybin versus Escitalopram, Phase 2 Trial

Trial of Psilocybin versus Escitalopram for Depression.

Carhart-Harris R, Giribaldi B, Watts R, et al.

N Engl J Med. 2021 Apr 15;384(15):1402-1411. [Full text]

The psychedelic compound psilocybin is the phosphorylated ester of its metabolite, psilocin, both of which are naturally occurring substances (from the psilocybe genus of mushrooms). Psilocin has multiple effects, including acting as a partial agonist of serotonin 5-hydroxytryptamine type 2A (5-HT2A) receptors. Mechanistically this could explain its purported anti-depressant activities [1].

This phase II, randomized, double blind study of psilocybin versus escitalopram was just published in 2021. However, psychadelics had previously been a hot area of inquiry, with, for example, up to 40,000 patients having them prescribed and >1000 scientific papers by the 1960s. When they became schedule 1 controlled substances in 1973 the scientific inquiry nearly ceased [1]. There is renewed interest in these substances and this study represents one of the few with a study design of high rigor. As this is only a phase II study, general applicability cannot be established, but at least safety can with enough efficacy to justify continuing to phase III.


Adults aged 18 to 80 years with 17-item Hamilton Depression Scale score of at least 17 (indicating moderate-to-severe major depressive disorder, MDD) were recruited. Exclusion criteria included an immediate family or personal history of psychosis, a history of serious suicide attempts, pregnancy, contraindications to SSRIs, prior escitalopram us (prior psilocybin was allowed).

The patients discontinued all psychiatric medication by at least 2 weeks before starting a trial medication. Also, ; any psychotherapy was stopped at least 3 weeks before starting.

Design and Outcomes

Patients were assigned in a 1:1 ratio to receive in the psilocybin group – two separate doses of 25 mg of psilocybin Q 3 weeks with 6 weeks of daily placebo or for the escitalopram group – two separate doses of 1 mg of psilocybin Q 3 weeks plus 6 weeks of daily escitalopram, titrated up to 20 mg in that time.

The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16; scores range from 0 to 27, higher scores indicate greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (reduction in score of >50%) and QIDS-SR-16 remission (score of ≤5) at week 6.


A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean age was 40 yrs, and most were white (~85%) and male (~65%) with a university level education (~75%). A fair amount of patients had used psilocybin previously (~21%). Most actually did not stop other psychiatric medications (~38% stopped). Mean scores on the QIDS-SR-16 at baseline were similar

Mean changes in the scores from baseline to week 6 (the primary outcome) equivalent between groups: −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9, P=0.17).

The psilocybin group more often had a QIDS-SR-16 “response” – 70% psilocybin vs. 48% escitalopram, a between-group difference of 22 percentage points (95% CI, −3 to 48); and a QIDS-SR-16 “remission” – 57% and 28%, respectively, between-group difference of 28 percentage points (95% CI, 2 to 54).

No serious adverse events were observed in either trial group and the frequency of reporting adverse events was similar in the two groups, but that frequency was high, >80%.


A phase II trial is to establish some degree of efficacy and monitor safety. In this phase II trial, psilocybin was non-inferior to 20 mg daily of escitalopram given over 6 weeks, with a measurable response on a validated depression instrument (QIDS-SR-16 score). Additionally, psilocybin was as safe as escitalopram over the 6 month monitoring period. One major note is that most patient continued their existing psychiatric medication, but this was equivalent across groups.

This April 2021 publication which included only 59 patient is essentially the ‘state of the art’ evidence supporting psilocybin for the management of MDD. While the objective was met and further study of psilocybin should be pursued, any claim of established efficacy is not supported at this time. Psychedelics as therapy remains in its exploratory phase.

As the field matures there will remain the open question, should one prescribe psilocybin, how to address reported patient experiences of “losing self-importance, ineffable knowledge, feelings of unity and connection with others and encountering ‘deep’ reality or God.”? Balancing any therapeutic benefit with the potential change to a patient’s personality and worldview is a discussion we as providers may not yet be equipped for [2].

F: Follow up6 mo, with 6 visits within 1st 6 weeks
R: RandomizationYes
I: Intention to treatYes
S: Similar at baselineYes
B: BlindingYes
E: Equal treatmentYes, all patients received some Psilocybin
S: Source (funding)Alexander Mosley Charitable Trust and Imperial College London’s Centre for Psychedelic Research

  1. Lieberman JA. Back to the Future – The Therapeutic Potential of Psychedelic Drugs. N Engl J Med. 2021 Apr 15;384(15):1460-1461.
  2. Smith WR, Sisti D. Ethics and ego dissolution: the case of psilocybin. J Med Ethics. 2020 May 27:medethics-2020-106070.