Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: a 12-month prospective follow-up.
Abstract
Bottom:
Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major depressive disorder (MDD), but little is known about long-term outcomes.
Mira:
This study sought to examine the efficacy and safety of psilocybin over 12 months in participants with moderate to severe MDD who received psilocybin.
Methods:
This randomized, controlled, waitlist study involved 27 patients aged 21 to 75 years with moderate to severe unipolar depression (GRID-Hamilton Depression Rating Scale (GRID-HAMD) ≥ 17). Participants were randomized to either an immediate or delayed treatment condition (8 weeks), in which they received two doses of psilocybin with supportive psychotherapy. Twenty-four participants completed both psilocybin sessions and were followed for 12 months after the second dose.
Results:
All 24 participants attended all follow-up visits during the 12-month period. Large reductions from baseline in GRID-HAMD scores were observed at 1, 3, 6, and 12 months of follow-up (Cohen). d = 2.3, 2.0, 2.6 and 2.4, respectively). The response to treatment (⩾50% reduction in GRID-HAMD score from baseline) and remission were 75% and 58%, respectively, at 12 months. There were no serious adverse events considered to be related to psilocybin during the long-term follow-up period, and no participant reported using psilocybin outside the context of the study. Participants' assessments of personal meaning, spiritual experience, and mystical experience after the sessions predicted increased well-being at 12 months, but did not predict improvement in depression.
Conclusions:
These findings demonstrate that the substantial antidepressant effects of psilocybin-assisted therapy can last for at least 12 months after acute intervention in some patients.
Major depressive disorder (MDD) affects more than 260 million people worldwide and is a leading cause of disability and healthcare expenditure. James et al., 2018 ). First-line treatments, including pharmacotherapy and psychotherapy, can take weeks or months to produce a clinically significant reduction in symptoms, and patients may have difficulty adhering to treatment. Cuijpers et al., 2008 ; Kolovos et al., 2017 ; Lam, 2012 ). At least 30% of patients eventually meet the criteria for treatment-resistant depressive illness after failing to respond to multiple treatment attempts. Nemeroff, 2007 ). TDM also has a highly recurrent course, with 40-60% of those diagnosed with a single episode eventually relapsing, and the relapse rate increasing with each subsequent episode. Richards, 2011 ; Solomon et al., 2000 ). New interventions are needed that can act quickly and produce sustained remission.
Several preliminary studies suggest that psilocybin-assisted treatment may have substantial antidepressant effects in patients with MDD, with treatment response occurring within a week after administration of only one or two doses in the context of psychotherapy (Carhart-Harris et al., 2018 , 2021 ; Davis et al., 2021 ). In an initial report of primary outcomes after two doses of psilocybin using a randomized waitlist-controlled study design, we reported a large effect size (Cohen d = 2.3) and high treatment response and remission rates (71% and 54%) within 1 month of intervention ( Davis et al., 2021 ). Treatment-resistant patients also appear to have a favorable response rate. Carhart-Harris et al., 2018 ). A more recent study used a sham double-blind design to compare high-dose psilocybin plus 6 weeks of placebo with very low-dose psilocybin plus 6 weeks of escitalopram (Carhart). -Harris et al., 2021 ). The authors failed to show a significant difference between the two groups at 6 weeks on their designated primary outcome measure (Rapid Inventory of Depressive Symptoms). Most results for secondary outcome measures, including other depression severity scores, favored the high-dose psilocybin group, although the analyses were not corrected for multiple comparisons.
Although psilocybin treatment for MDD appears promising, little is known about its long-term efficacy and safety. The three studies conducted so far have demonstrated effectiveness in their longer follow-up assessments of 4 weeks ( Davis et al., 2021 ), 6 weeks ( Carhart-Harris et al., 2021 ) and 6 months ( Carhart-Harris et al., 2018 ), although depression severity scores were trending upward at the 3- and 6-month follow-up time points. Carhart-Harris et al. (2018) The study with the longest follow-up period had an open-ended design. Given the chronicity and relapsing course of MDD disease ( (Richards, 2011 ), the present study represents a significant extension of these previous findings, evaluating the efficacy and safety of a psilocybin intervention during a 12-month follow-up period.
Methods
Study design
Full details of the study design and inclusion criteria were described previously ( Davis et al., 2021 ). All procedures involving individuals were approved by The Johns Hopkins Medicine Institutional Review Board. Written informed consent was obtained from all participants. The participants were between 21 and 75 years of age, clinically stable, and met the criteria for a moderate to severe episode of MDD, as defined by a score of ⩾17 on the GRID-Hamilton Depression Rating Scale (GRID-HAMD) assessed by blinded clinical assessors. Individuals with a personal or family history of first- or second-degree psychotic disorder or bipolar I or II were excluded. To avoid interactions with psychoactive drugs, including those used to treat depression, participants were required to abstain from using such medications for at least five half-lives before screening and for at least 1 month after the second psilocybin session. Following medical and psychological screening and initial assessments, participants were randomized to either an immediate or delayed treatment condition. Participants in the immediate treatment group began the intervention immediately after screening, while those in the delayed treatment group began the intervention after an 8-week interval.
After the participants entered the intervention period, they had 6 to 8 hours of preparatory meetings with two facilitators. At least one facilitator in each dyad had a master's or doctoral degree in clinical training in mental health (e.g., master's degree in social work, doctorate in clinical psychology, MD with a specialization in psychiatry). After preparation, participants received two doses of psilocybin of 20 mg/70 kg and 30 mg/70 kg approximately 2 weeks apart. Psilocybin was administered in a comfortable room under the supervision of both facilitators, following established safety guidelines. Johnson et al., 2008 ). A non-directive psychotherapeutic approach was used during the session days. Participants returned for follow-up 1 day and 1 week after each medication administration session, and then 1, 3, 6, and 12 months after the second session, during which the severity of depression was assessed using measures evaluated by participants and physicians. Each follow-up visit included a 1-2 hour meeting with at least one of the facilitating therapists. Functional magnetic resonance imaging was completed at baseline and 1 week after the second psilocybin session ( Doss et al., 2021 ).
Outcome measures
Measures of depression severity
The primary outcome measure was the GRID-HAMD ( Depression Rating Scale Standardization Team, 2003 ), which was evaluated by blinded clinical assessors by telephone, as described previously ( Davis et al., 2021 ). Inter-rater reliability at the 3, 6, and 12-month time points was 87.5% (see the Online supplement for additional information ). Depression was also assessed using two self-report questionnaires: the Rapid Inventory of Depressive Symptoms (QIDS) Rush et al., 2003 ) and the Beck Depression Inventory II (BDI-II) ( Beck et al., 1996 ). The severity of the depression was assessed at baseline and at each follow-up point.
Measures assessed by participants of the acute effects of psilocybin.
Several measures of acute psilocybin effects assessed at the end of the session or the following day have been previously reported ( Davis et al., 2021 ). The interest in this follow-up analysis was to determine whether a subset of these acute measures could predict subsequent follow-up outcomes. Based on previous studies showing associations between acute psilocybin measurements and subsequent positive effects in healthy and patient samples ( Bogenschutz et al., 2015 ; Davis et al., 2020 ; Garcia-Romeu et al., 2014 ; Griffiths et al., 2008 , 2016 , 2018 The following measures were examined: Mystic Experience Questionnaire (MEQ30) Barrett et al., 2015 ) and four single-item measures ( Carbonaro et al., 2020 ) in which participants rated the degree to which the session experience was personally significant, spiritually significant, psychologically insightful, and psychologically challenging on a scale of 1 = no more than routine, everyday experiences to 8 = the most individual (significant, spiritually significant, psychologically insightful, or psychologically challenging) experience of my life. The psychological challenge item was included for comparison because it was not expected to predict subsequent positive outcomes. The MEQ30 was completed at the conclusion of each psilocybin session, and single-item measurements were completed the day after each session.
General well-being attributed to psilocybin.
At the 1, 3, 6, and 12-month follow-up points, participants completed the Persistent Effects Questionnaire ( Griffiths et al., 2018 ), which involved rating on a 6-point scale the current persistent effects they attributed to their experiences with psilocybin (see The online supplement provides more information. ). For this study, an overall well-being score was calculated as the grand average of the five positive change subscales: attitudes about life, attitudes about oneself, mood, relationships, and behavior, with each expressed as a percentage of the maximum possible score.
Safety measures
At each follow-up point, adverse events were recorded, and suicidal ideation was assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). Posner et al., 2008 ) and symptoms indicative of hallucinogen persistent perception disorder (HPPD) were elicited (e.g., “Since your drug session, have you experienced any uncontrolled or disturbing return of drug-like effects?”).
statistical analysis
A repeated measures analysis of variance was performed with time (baseline, 1 week post-treatment, and 1, 3, 6, and 12 months post-treatment) and condition (immediate and delayed treatment) as factors in the primary depression outcome (GRID-HAMD score), with effect sizes calculated using partial eta-squared ( the � 2 ). This analysis showed a significant effect of time, but no significant effect of condition or a time-by-condition interaction. Therefore, the data were grouped according to the conditions and a series of tests. t Paired studies compared baseline scores with scores at each of the follow-up time points, adjusting for Bonferroni for multiple comparisons. The effect sizes of the t-test paired were calculated using Cohen d . Descriptive statistics of follow-up measures were calculated, including treatment response (≥50% reduction in depression scores from baseline) and remission (GRID-HAMD ≥7, QIDS ≥5, BDI-II ≥9) for depression measures (Beck et al., 1996 ; Rush et al., 2003 ; Zimmerman et al., 2013 ). The relationship between acute measures of session experiences and follow-up measures of acute psilocybin effects (MEQ30 and ratings of meaning, insight, spiritual significance, and psychological challenge) were examined using Spearman correlations (r). s ) . For these calculations, the highest scores or ratings from Session 1 and Session 2 were used for each participant. For the follow-up measures, the overall well-being score was expressed as a percentage of the maximum possible score, and the depression measures were expressed as a percentage change from the baseline score for each participant. Analyses of multiple group-based comparisons were conducted using χ². 2 for categorical variables and t- test for continuous variables. A two-tailed significance level of p A value < 0.05 was used for comparisons and correlations between groups. The analyses were completed using SPSS 26 and 27.
Results
participants
As described in more detail earlier ( Davis et al., 2021 ), 27 participants were randomized and 24 completed both psilocybin sessions, with 13 and 11 assigned to the immediate and delayed treatment groups, respectively. All 24 participants completed all long-term follow-up assessment visits (see online supplement, CONSORT diagram ). The group was 67% female and 92% Caucasian. One participant identified as Black and another as Asian; None identified as Hispanic. The participants had a mean age (SD) of 39.8 (12.2) years. The average duration of illness (years since MDD diagnosis) was 21.5 (12.2) years, and the average time in the current major depressive episode was 24.4 (22.0) months. Of the participants, 88% had previously tried treatment with an antidepressant (e.g., a selective serotonin, norepinephrine, or dopamine reuptake inhibitor, etc.) and 58% reported prior use of such medication during the current depressive episode. Twenty-five percent had used a psychedelic drug previously, with an average of 3.3 previous uses and an average time of 9.2 years since the last use.
Changes in depressive symptoms
As previously reported ( Davis et al., 2021 ), GRID-HAMD scores were significantly lower in the immediate treatment group at 1 and 4 weeks post-treatment when compared to the corresponding time points after randomization in the delayed treatment group. After completing the delay period, participants in the delayed treatment group finished the psilocybin intervention and follow-up assessments. In this follow-up study, analysis of variance with GRID-HAMD scores showed a significant effect of time (baseline and 5-point post-treatment time) F (4.4, 96.3) = 34.9, p < 0.001; the � 2 = 0.61), but without a significant effect of the condition (immediate versus late treatment) or a time-by-condition interaction. Therefore, the following results are from data collected between the conditions.
As shown in Figure 1 , the mean GRID-HAMD scores for the overall treatment sample decreased from a mean (SD) of 22.8 (3.9) at baseline pre-treatment to 8.7 (7.6) at 1 week, 8.9 (7.4) at 4 weeks, 9.3 (8.8) at 3 months, 7.0 (7.7) at 6 months, and 7.7 (7.9) at 12 months post-treatment ( p > 0.001 at all times, tests t paired with Bonferroni correction). The effect sizes for these differences were large, according to Cohen. d (95% CI) being 2.3 (1.5, 3.1) at 1 week, 2.3 (1.5, 3.1) at 4 weeks, 2.0 (1.3, 2.7) at 3 months, 2.6 (1.7, 3.4) at 6 months and 2.4 (1.6, 3.2) at 12 months. Similar significant, large-magnitude, and sustained reductions in depression from pre-treatment in the five follow-up assessments occurred with both patient-administered depression assessment questionnaires (QIDS and BDI-II, online supplement Table S1). Figures S1 and S2 ) .
Figure 1 . Decrease in GRID-HAMD depression scores over time from baseline to 12-month follow-up ( N = 24).
The data points are averages and the brackets are ±1 SD; The lower brackets are truncated at GRID-HAMD scores of 0. The mean GRID-HAMD was 22.8 (3.9) at baseline, 8.7 (7.6) at 1 week, 8.9 (7.4) at 4 weeks, 9.3 (8.8) at 3 months, 7.0 (7.7) at 6 months, and 7.7 (7.9) at 12 months post-treatment. All time points were significantly different from the baseline ( p < 0.001). The magnitude of the Cohen effect d It is shown for each point in time. Cohen d (95% CI) was 2.3 (1.5–3.1) at 1 week, 2.3 (1.5–3.1) at 4 weeks, 2.0 (1.3–2.7) at 3 months, 2.6 (1.7–3.4) at 6 months and 2.4 (1.6–3.2) at 12 months.
As previously reported ( Davis et al., 2021 ), 1 week after treatment, 17 of the 24 participants (71%) showed a clinical response rate on the GRID-HAMD (≥50% reduction from pre-treatment) and 14 (58%) were in remission (GRID-HAMD score ≥7) Zimmerman et al., 2013 ). As shown in Table 1 Response and remission rates were generally maintained during the 12-month follow-up assessment, with final response and remission rates of 75% and 58%, respectively. Table 1 shows similar or greater responses and remission rates with both patient-assessed depression measures (QIDS and BDI-II).
| Post-treatment follow-up time | |||||
|---|---|---|---|---|---|
| 1 week | 4 weeks | 3 months | 6 months | 12 months | |
| GRID-HAM | |||||
| Response rate | 71% | 71% | 67% | 79% | 75% |
| remission rate the | 58% | 54% | 54% | 71% | 58% |
| QIDS | |||||
| Response rate | 79% | 71% | 79% | 79% | 79% |
| remission rate b | 54% | 54% | 58% | 67% | 67% |
| BDI-II | |||||
| Response rate | 79% | 79% | 79% | 88% | 83% |
| remission rate w | 67% | 63% | 58% | 75% | 75% |
GRID-HAMD: Hamilton Depression Rating Scale; QIDS: Rapid Inventory of Depressive Symptoms; BDI-II: Beck Depression Inventory II.
the
b
w
Figure 2 This shows the GRID-HAMD depression scores for each of the 24 study participants from pre-treatment to the 12-month follow-up assessment. Most participants showed significant reductions in their depression score at the first follow-up interval 1 week after treatment, consistent with the 71% response rate and 58% remission rate shown in the Table. 1 . The figure shows that psilocybin did not exacerbate depression in any participant and that 3 of the 24 participants (13%) did not meet the criteria for a treatment response at any time post-treatment.
Figure 2 . Depression scores (GRID-HAMD) for each of the 24 study participants at baseline and each of the 5 follow-up assessment time points.
Individual participants are represented with different colors. The dashed lines indicate three participants who did not meet the criteria for a treatment response at any post-treatment time point. The enlarged data points indicate participants who reported treatment with antidepressant medication, with the leftmost enlarged data points showing the first follow-up point at which medication use was reported.
Figure 2 It also provides detailed information about participants who started or resumed daily use of an antidepressant medication for depression (i.e., a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a norepinephrine-dopamine reuptake inhibitor) after treatment with psilocybin. Of the 24 participants, 0 (0%), 3 (12.5%), 5 (20.8%), 8 (33.3%), and 8 (33.3%), respectively, reported daily use of antidepressants in the 4th and 3rd weeks, according to 6- and 12-month follow-up assessments. The 8 participants who started antidepressant treatment within the 12-month period had higher baseline GRID-HAMD scores (mean of 25.3 vs 21.5). p = 0.02) compared to those who did not report using antidepressants; However, they were not statistically different in terms of age, sex, years with depression, duration of the current depressive episode, or history of medication use during the current depressive episode. Mean GRID-HAMD scores and 12-month overall well-being scores did not differ significantly between those who started and those who did not start antidepressant treatment.
Overall well-being attributed to psilocybin at the 1, 3, 6, and 12-month follow-up time points was intermediate and stable. The overall mean (SD) well-being score, expressed as a percentage of the maximum possible score, was 63.9 (22.6), 60.0 (21.3), 59.0 (24.0) and 65.0 (20.0), respectively.
Measures assessed by participants in the session experiences as predictors of subsequent overall well-being and changes in depression severity.
The correlations between the measures assessed by participants in psilocybin experiments at the time of the session and subsequent measures of well-being and depression were examined. In the first long-term follow-up assessment ( Table 2 In Week 4, the ratings of personal significance, psychological perception, spiritual significance, and mystical experience (MEQ30) correlated significantly with well-being, and the ratings of personal and spiritual significance correlated significantly with improvement in depression (GRID-HAMD). However, at subsequent follow-up time points, none of these session experience measures were significantly correlated with improvements in depression ( Table 2 ). The MEQ30 correlated significantly with well-being at all four follow-up points, and assessments of personal meaning and spiritual meaning were significantly correlated at three of the four time points. Assessments of psychological challenge during the session were not significantly correlated with subsequent measures of well-being or depression at any follow-up point.
| Session measures b | 4 weeks | Follow | 3 months | Follow | 6 months | Follow | 12 months | Follow |
|---|---|---|---|---|---|---|---|---|
| well-being w | GRID-HAM d | well-being w | GRID-HAM d | well-being w | GRID-HAM d | well-being w | GRID-HAM d | |
| Personal meaning and | 0.70* | 0.67* | 0.43 | 0.34 | 0.51 | 0.44 | 0.45 | 0.43 |
| Psychological Perception and | 0.49 | 0.36 | 0.35 | 0.04 | 0.27 | 0.34 | 0.39 | 0.25 |
| Spiritual meaning and | 0.67* | 0.56* | 0.54 | 0.16 | 0.44 | 0.28 | 0.60* | 0.40 |
| Psychological challenge and | 0.12 | 0.32 | 0.09 | 0.18 | 0.13 | 0.31 | 0.06 | 0.13 |
| Mystic Experience MEQ30 | 0.71* | 0.38 | 0.43 | 0.17 | 0.50 | 0.05 | 0.50 | 0.19 |
HAMD: Hamilton Depression Rating Scale; MEQ30: Mystical Experience Questionnaire.
the
The data show Spearman correlations ( r s ); bold font indicates p < 0.05 and asterisks indicate p < 0.01.
b
The ratings shown in this column are the highest rating or score from Sessions 1 and 2 for each participant.
w
Well-being scores were expressed as a percentage of the maximum possible score.
d
GRID-HAMD depression scores were expressed as a percentage change from baseline for each participant.
and
Only 20 of the 24 participants completed these measurements due to an error in the research scheduling.
Safety results
During the follow-up period, there were no serious adverse events, suicidal ideation remained low, there were no cases of self-harming behavior, no reported use of psilocybin or other psychedelics, and no participant met the criteria for HPPD. More details about adverse events are available at online supplement .
Discussion
This study suggests that two doses of psilocybin administered in the context of supportive therapy for MDD produced large and stable antidepressant effects over a 12-month follow-up period. More specifically, depression, as measured by blinded physician-rated assessments (GRID-HAMD), decreased substantially after treatment and remained low at 1, 3, 6, and 12 months post-treatment. The effect size at 12 months was very large (Cohen d = 2.4). Similarly, high and stable response and remission rates occurred throughout the follow-up period (75% response and 58% remission at 12 months). Two patient-assessed measures of depression (QIDS and BDI-II) showed similar stable and large-magnitude antidepressant effects in mean scores and response and remission rates. These findings suggesting long-lasting antidepressant effects of psilocybin 1 year after treatment significantly extend previous results from this and two other trials that showed antidepressant effects for 4 weeks ( Davis et al., 2021 ), 6 weeks ( Carhart-Harris et al., 2021 ) and 6 months ( Carhart-Harris et al., 2018 ). Notably, the remission rate and magnitude of the effect in the current study at 6 and 12 months were substantially higher than in a previous study at 6 months (QIDS, remission rate of 67% and 67% vs 32%, Cohen d 2.2 and 2.3 vs 1.6, respectively) Carhart-Harris et al., 2018 ). It is unknown whether this difference reflects population differences in disease severity or procedural differences. Further research is needed to explore the possibility that the effectiveness of psilocybin treatment in MDD may be substantially longer than the 12 months observed in the present study, as suggested in a study that documented reductions in depressive symptoms up to 4.5 years after psilocybin treatment in patients with cancer-related distress ( Agin-Liebes et al., 2020 ).
It is noteworthy that eight patients (33%) reported starting a new course of treatment with a daily antidepressant medication at some point during the 12-month follow-up period, which is similar to the 32% of patients in a previous study who did so at 6 months ( Carhart-Harris et al., 2018 ). Although patients who used antidepressants during the follow-up period had higher GRID-HAMD scores at baseline, at 12 months they did not differ significantly from those who did not start medication. It is not possible to determine the extent of the contribution of psilocybin versus other medications to clinical improvement in those who resumed the use of antidepressants. However, participants' assessments of persistent well-being attributed to psilocybin sessions were not significantly different from those who did not use antidepressant medication, suggesting that psilocybin treatment resulted in some independent benefit.
Although relapse and remission rates at 12 months were favorable, the ability to accurately compare the long-term effectiveness of psilocybin-assisted treatment with that of standard antidepressant treatment is limited. Most recent studies of long-term antidepressant efficacy exclude non-responders from follow-up and focus on the relapse rate among those who respond to a given medication, which is usually a minority of the intention-to-treat sample (Mcgrath). et al., 2006 ; Trivedi et al., 2006 ). In our sample, of the 17 participants who met the treatment response criteria at 1 month of follow-up, 12 (71%) continued to meet the treatment response criteria at all subsequent time points. Three other participants who responded within 1 month also met the criteria for treatment response at 12 months, but had one or more interim assessments during which their GRID-HAMD score was elevated outside the treatment response range. The 71% response rate to continuous treatment at 12 months is slightly higher than the 54% rate reported in a study of fluoxetine responders who were maintained on fluoxetine, and much higher than those who switched to placebo (28%) (Mcgrath et al., 2006). ) . .
This study provides new information on qualitative characteristics of acute psilocybin experience that predict subsequent lasting effects. Patients' assessments of personal meaning, spiritual significance, and MEQ30 scores after psilocybin sessions correlated significantly with a measure of overall well-being at most follow-up points. However, except for ratings of personal significance and spiritual significance in the first long-term follow-up assessment at 4 weeks, none of the patient's assessments of the psilocybin experience at the time of the session were predictive of improvements in depression. Notably, two previous studies in individuals with cancer-related depression and anxiety ( Griffiths et al., 2016 ; Ross et al. (2016 ) showed positive associations between MEQ30 session experiences and improvements in depression symptoms within 5 or 6 weeks. Considering that the direction of the correlation in 4 weeks was in the predicted direction ( r s = 0.38 p = 0.066), it is possible that the present study has insufficient power to detect such an effect with MEQ30 or other measures of psilocybin experience. Alternatively, this difference may reflect the lack of such a relationship in a sample of individuals with MDD as opposed to depressive symptoms secondary to a cancer diagnosis.
There were no serious adverse events, depressive symptoms were not significantly exacerbated in any participant, and there were no reports of psilocybin or other psychedelic drug use during the follow-up period. This last observation contrasts with a previous study in which 5 of 19 participants reported using psilocybin outside the research setting until the end of the 6-month follow-up period ( Carhart-Harris et al., 2018 ). The reasons for this difference are unknown, but the observation indicates the importance of evaluating the use of psychedelics outside of a clinical trial. Although the safety results presented here are favorable, larger phase 3 and 4 studies will be needed to more fully assess safety.
Strengths and limitations
The strengths of this study of psilocybin-enhanced depression treatment include a primary outcome measure that was assessed by blinded clinical assessors, the longest post-treatment follow-up interval to date, and excellent participant retention. Although no participant reported any unusual use of psilocybin, 33% reported using antidepressants during the follow-up period, which prevents the determination of the effects of psilocybin alone in these patients. Although the randomized waitlist control design of the study allowed for comparison of the effects of short-term treatment with the control group, as described earlier ( Davis et al., 2021 ), the design did not allow for a comparison group in the long-term follow-up. A recent study suggests that the effects of expectation and psychotherapy may be responsible for some of the clinical benefits of psychedelic-assisted therapy ( Carhart-Harris et al., 2021 ). In this study, which used a double-blind, double-sham design, both the high-dose and very low-dose psilocybin groups showed significant immediate reductions in depression, suggesting that daily medication preparation and administration procedures can reduce depressive symptoms even in the absence of high doses of psilocybin. Studies of other types of interventions for patients with MDD have shown that placebo effects can last for weeks or months after the intervention, and the lack of a comparison group makes it difficult to explain these effects in our study ( Khan et al., 2008). ). Other limitations include the small sample size, the predominantly Caucasian rather than Hispanic study sample, and the exclusion of those considered at high risk of suicide.
Clinical implications
Like newer antidepressants, classic psychedelics are commonly compared to ketamine and its analogues. Despite their distinct pharmacological mechanisms of action, both have rapid antidepressant effects and both have generated concern about their potential for non-medical use. Schak et al., 2016 ; Shalit et al., 2019 ). Ketamine has non-trivial abuse potential, and there may be overlap between the mechanisms underlying its antidepressant effects and abuse potential, which may be exacerbated by the need for repeated administration to maintain therapeutic efficacy (Kokane et al., 2020; Liu et al.). , 2016 ) . Although the evidence to date suggests that psilocybin has a relatively low potential for abuse ( Johnson et al., 2018 ), there is still concern about its potential to cause harm or encourage substance misuse in vulnerable populations ( Reiff et al., 2020 ; Schatzberg, 2020 ). This study highlights an important potential advantage of psilocybin treatment over ketamine, as the antidepressant effects after just two administrations of psilocybin paired with psychological support appear to be sustained for 12 months, which is well beyond the duration of effects reported with ketamine (McIntyre et al.). al., 2021 ; Salloum et al., 2020 ). Future research will be important to determine the risks and benefits of administering additional psilocybin to those who did not respond or had an early relapse.
Conclusions
The results of this long-term follow-up of participants who were not blinded to the drug condition suggest that psilocybin-assisted treatment for MDD produces large and stable antidepressant effects for at least 12 months after treatment. These data document greater and longer-lasting effects than previous studies of psilocybin in depressed patients. Further studies are needed with active treatment or placebo-controlled comparisons in larger and more diverse populations.