This double-blind placebo-controlled study (n=59) compared psilocybin (2x25mg; 3 weeks apart) to escitalopram (SSRI) over a six-week period and found large improvements in depression scores for those suffering from depression (MDD) in both groups. On the main measure of depression, the QIDS-SR-16, there was no significant difference between both groups. The study did find significant differences, favouring psilocybin, on the HAM-D-17, MADRS, avoidance, flourishing, wellbeing, and suicidality.
Abstract of Trial of Psilocybin versus Escitalopram for Depression
“Background Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking.
Methods In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. 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, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.
Results A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups.
Conclusions On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants.”
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Summary of Trial of Psilocybin versus Escitalopram for Depression
Major depressive disorder affects 10% of the general popu-lation and is costly to society. Selective serotonin-reuptake inhibitors are first-line treatments, but take several weeks to work.
Psilocybin is a psychedelic compound that occurs naturally in the psychoactive psilocybe genus of mushrooms. It has been shown to reduce depressive symptoms in several clinical trials, including a small open-label trial involving patients with treatment-resistant depression.
This paper was also featured on the podcast (at 39:00min) by Drug Science with Robin Carhart-Harris and David Nutt. And an interview with Matthew Johnson (not part of the study) for HealthDay. And commentary in The Guardian by Robin Carhart-Harris. And an excellent breakdown in The Trip Report. And (last but not least) on The Tab.
This study is investigating the effects of psilocybin versus escitalopram (brand names: Cipralex/Lexapro), a commonly prescribed antidepressant (SSRI) for the treatment of major depressive disorder (MDD).
Depression affects between 2% to 6% of the world population (Our World in Data, 2017). As a cause of burden of disease, the WHO ranked it as the third-highest, and projected it to rise to the number one spot by 2030. The paper approximates that MDD affects 10% of the population, but this is not found in the linked source (Malhi & Mann, 2018), and might be referring to lifetime prevalence (although that is estimated at 15-18%).
Escitalopram is an antidepressant that works by selectively inhibiting the reuptake of serotonin. As with many other antidepressants, it is generally believed that it works by dampening or blunting of emotions/affect and via that route also lessening depressive symptoms. This is very much a simplification, but also something where it’s very much in contrast to how psilocybin is thought to work.
The most common side-effects of Escitalopram are headaches (24%), nausea (18%), ejaculation disorder (9-14%), drowsiness (4-13%) and insomnia/trouble sleeping (7-12%).
A review (Waugh & Goa, 2012) of escitalopram usage for depression and anxiety disorders showed that it was effective as measured on the MADRS, CGI-I, CGI-S, and HAM-D depression scales. The review notes that the recommended dose is 10mg/day with the possibility of increasing it to 20mg/day. In the current study, this increase in dose was done for all patients for the last three weeks. Scores on the MADRS in several double-blind studies decreased from a baseline of 28.5 (average) by 12 points to 16.5 after four weeks, and by 14.7 points to 13.8 after eight weeks. (see table II, n=587)
Regarding this review, and also the current study, it should be noted that the placebo group (usually also receiving therapy) also improved by quite a lot. On average their scores were 10 points lower after four weeks, and 12 points lower at eight weeks.
The cost of escitalopram ranges widely, but has not been sold as a generic medicine (without the brand name) and can be found as low as $0.23 per 10mg tablet.
The psilocybin (COMP360) used in the trial was provided by Compass Pathways. The company, nor any other company, had any involvement in this study.
The participants in the study were recruited informally via social media and other sources. As is noted in the discussion, the patient group of white and highly educated men is not representative of the wider population. Studies with a higher percentage of women (who are disproportionally affected with depression) and those with other relationships to mental health care and socioeconomic backgrounds should be evaluated in future trials.
The total number of participants was 59, of which 30 received psilocybin. If patients were using antidepressants before the trial (39%), they were completely discontinued at least two weeks before the study. Any psychotherapy they were engaged in (7%) was also stopped at least three weeks before the trial start.
Patients visited the study site a total of six times. At the first visit, they underwent fMRI scans, cognitive tests, affective processing tasks, and a preparatory therapeutic session. One day later, they received either 25mg of psilocybin or 1mg (as a placebo) of psilocybin. The next day, visit three, consisted of a debrief of the second day.
After that, patients took one pill (placebo or 10mg of escitalopram) for the next 21 days.
The fourth and fifth visits mirrored that of the second and third days. For the next 21 days, participants took two pills per day (placebo or 20mg of escitalopram in total).
Then on the final day, the same tests as on the first day were repeated. The study also investigated adverse events, and two measures of acute subjective experience after the dosing days.
In the escitalopram group, five patients didn’t complete the protocol. In the psilocybin group, three didn’t complete the protocol with two not being able to do the second dosing day due to Covid-19 restrictions.
The primary outcome, the QIDS-SR-16, significantly decreased for both groups.
For the psilocybin group, it decreased from 14.5, by 8 points, to 6.5 on average. For the escitalopram group, it decreased from 16.4, by 6 points, to 10.4 on average. The difference between both groups, at the six-week point, was not statistically significant. This means that this study can’t say that psilocybin was more effective than escitalopram on this measure.
Many of the secondary measures did show that psilocybin was significantly more effective. Somewhat conservatively, the authors do note: “Secondary outcomes generally favored psilocybin over escitalopram; however, the confidence intervals for the between-group differences were not adjusted for multiple comparisons, and no conclusions can be drawn from these data.”
There were about the same amount of adverse events in both groups, with headaches the day after dosing being the most common for the psilocybin group.
As noted above, most patients referred themselves to this study. Many of them expressed a preference for psilocybin, indicating a certain (but not measured) level of expectancy effects. One could also interpret this as a possible indication for ‘disappointment effects when patients found out (guessed) that they were in the escitalopram group. For much more on expectancy and blinding see Muthukumaraswamy and colleagues (2021).
The average depression scores for the patient group was moderate. Other effects might be found for those with severe or treatment resistant depression (TRD).
Although there was no correction for multiple comparisons, in the current format (figure S4), psilocybin compared favorably to escitalopram on all other scales. The measures taken were the following: QIDS-SR-16, HAM-D-17, MADRS, BDI-1A, Avoidance, Anhedonia (inability to feel pleasure), Work and social functioning, flourishing, State-Trait Anxiety Inventory (STAI), Wellbeing, and Suicidality.
The MARDS scores were, on average, 14.4 points lower in the psilocybin group, and 7.2 points lower in the escitalopram group, at the six-week measure. Although there is no direct comparison to be made, the decrease is scores of the psilocybin group is quite similar to that of the earlier studies with escitalopram (12 points drop) mentioned above. (note: we couldn’t immediately find the baseline MARDS scores, which if they are lower than in the other studies could explain this in part)
Questions and Follow-up
This study provides evidence for parity between a very good antidepressant and psilocybin. A phase 3 trial can be informed by the data here and could possibly show that psilocybin is more effective than antidepressants.
The study does leave one with several questions, of which we hope to have some answered:
- Why did they switch from 10mg to 20mg escitalopram after the first three weeks? The scores, which of course we know now in retrospect, don’t show much improvement at the higher dose, and a quick look at the literature doesn’t suggest that a higher dose is needed/better.
- It would be very interesting, and a study on this is planned, to see the long-term follow-up of both groups. It would probably matter a lot if escitalopram was continued (which the meta-analysis above showed to increase its efficacy further) or if after the study, both groups received no medication or support.
- The study did provide some support for participants, but it does seem that no extensive psychotherapy was provided. Other studies with MDMA (e.g. Mithoefer et al, 2020), but not those with psilocybin (e.g. Carhart-Harris et al., 2017), provided much more therapy. A meta-analysis of studies with and without therapy could possibly hint at the need or effectiveness of this (although probably there are too few data points at this time)
- And how does this trial compare to Davis and colleagues (2020) which found psilocybin-assisted therapy to be effective for depression (MDD) when compared to placebo.
- Why do two sessions with psilocybin? And why the high dose? Other studies use about half the dose, but as a friend pointed out, many of the therapeutic studies were done with this high dose. Also, Johnson (2021) recommends 25mg, so that is exactly what was used here.
- Finding out more about the needed dose, but especially the need for two sessions (and the need for therapy around it) could add more information on calculating costs for treatments.
- Should we do away with the QIDS-SR-16? See for some notes this tweet by Carhart-Harris. It would be interesting to further investigate the different measures of depression and their pros and cons.
- How do studies like this better recruit participants? How can the better represent the average (depressed) population that will (hopefully) be able to receive this type of treatment in the future?
Find this paper
Authors associated with this publication with profiles on BlossomRobin Carhart-Harris
Dr. Robin Carhart-Harris is the Founding Director of the Neuroscape Psychedelics Division at UCSF. Previously he led the Psychedelic group at Imperial College London.
Rosalind Watts is a clinical psychologist and clinical lead at the Psychedelics Research Group at Imperial College London. She is also known for developing the 'Accept, Connect, Embody' psychedelic therapy model.
David John Nutt is a great advocate for looking at drugs and their harm objectively and scientifically. This got him dismissed as ACMD (Advisory Council on the Misuse of Drugs) chairman.
David Erritzoe is the clinical director of the Centre for Psychedelic Research at Imperial College London. His work focuses on brain imaging (PET/(f)MRI).
Institutes associated with this publicationImperial College London
The Centre for Psychedelic Research studies the action (in the brain) and clinical use of psychedelics, with a focus on depression.
The psychedelics given at which dose and how many timesPsilocybin 25 mg | 2x
Linked Research Papers
Notable research papers that build on or are influenced by this paperAssessing expectancy and suggestibility in a trial of escitalopram v. psilocybin for depression
This reanalysis of an RCT (n=55) compared escitalopram and psilocybin (COMP360) for treating depression (MDD). Patients had higher expectancy for psilocybin, but only expectancy for escitalopram predicted therapeutic outcomes. Additionally, pre-treatment trait suggestibility was associated with therapeutic response in the psilocybin arm, suggesting psychedelic therapy may be less vulnerable to expectancy biases, and highly suggestible individuals may be primed for response to psilocybin treatment.
Reduced brain responsiveness to emotional stimuli with escitalopram but not psilocybin therapy for depression
This pre-print analysis of an RCT (n=59) investigates the impact of psilocybin-assisted therapy (PAT) and escitalopram (SSRI) on responsiveness to emotional stimuli in patients with moderate-to-severe major depressive disorder over a 6-week trial period. Responses to emotional faces were reduced in the SSRI group, not the psilocybin group at the follow-up.
Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression
This analysis of an RCT (n=59) investigates the impact of psilocybin-assisted therapy (PAT) and escitalopram on personality traits in patients with moderate-to-severe major depressive disorder over a 6-week trial period. Significant decreases in neuroticism, introversion, disagreeableness, and impulsivity, and increases in absorption, conscientiousness, and openness were observed in the PAT group, while similar changes were seen in the escitalopram group.
Effects of psilocybin versus escitalopram on rumination and thought suppression in depression
This analysis (n=59) of the psilocybin vs escitalopram for depression study finds that those in the psilocybin arm of the study significantly decreased rumination. Only those who were in the psilocybin arm and responded (>50% symptom reduction) had reduced thought suppression (rumination was lower in both responder groups). Ego dissolution and psychological insight, for the psilocybin group, correlated with decreases in rumination and thought suppression.
A Bayesian Reanalysis of a Trial of Psilocybin versus Escitalopram for Depression
This preprint (2022) reanalyses the data of a clinical trial in which the effects of psilocybin were compared to that of the SSRI escitalopram for major depressive disorder. Bayesian reanalysis found indeterminate evidence that psilocybin is superior that escitalopram using the QIDS SR-16 while strong evidence favoured psilocybin when using the BDI-1D and MADRS and extremely strong evidence when using the HAMD-17. The results support the idea that psilocybin outperformed escitalopram but was not clinically meaningful and, psilocybin is almost certainly non-inferior to escitalopram.
Therapeutic Alliance and Rapport Modulate Responses to Psilocybin Assisted Therapy for Depression
This trial (n=59) assessed the relationships between therapeutic alliance and rapport, the quality of the acute psychedelic experience and treatment outcomes. Following psilocybin administration at a second session, the therapeutic alliance had a direct impact on final depression scores, not mediated by the acute experience, with a weaker alliance ahead of the second psilocybin session predicting higher absolute depression scores at the endpoint.
PDF of Trial of Psilocybin versus Escitalopram for Depression
Linked Clinical TrialPsilocybin vs Escitalopram for Major Depressive Disorder: Comparative Mechanisms
This is a randomised double-blind clinical trial. The aim is to compare the efficacy and mechanisms of action of psilocybin, the primary psychoactive substance in 'magic mushrooms', with the SSRI (selective serotonin reuptake inhibitor) escitalopram for major depressive disorder (MDD).