Psilocybin is being studied for use in treatment-resistant depression.

Materials and Methods:

In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery–Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits).

Results:

A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were −12.0 for 25 mg, −7.9 for 10 mg, and −5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was −6.6 (95% confidence interval [CI], −10.2 to −2.9; P<0.001) and between the 10-mg group and 1-mg group was −2.5 (95% CI, −6.2 to 1.2; P=0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups.

Conclusion:

In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder.

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. This study sought to examine the efficacy and safety of psilocybin through 12 months in participants with moderate to severe MDD who received psilocybin.

Materials and Methods:

This randomized, waiting-list controlled study enrolled 27 patients aged 21-75 with moderate to severe unipolar depression (GRID-Hamilton Depression Rating Scale (GRID-HAMD) ⩾ 17). Participants were randomized to an immediate or delayed (8 weeks) treatment condition in which they received two doses of psilocybin with supportive psychotherapy. Twenty-four participants completed both psilocybin sessions and were followed through 12 months following their second dose.

Results:

All 24 participants attended all follow-up visits through the 12-month timepoint. Large decreases from baseline in GRID-HAMD scores were observed at 1-, 3-, 6-, and 12-month follow-up (Cohen d = 2.3, 2.0, 2.6, and 2.4, respectively). Treatment response (⩾50% reduction in GRID-HAMD score from baseline) and remission were 75% and 58%, respectively, at 12 months. There were no serious adverse events judged to be related to psilocybin in the long-term follow-up period, and no participants reported psilocybin use outside of the context of the study. Participant ratings of personal meaning, spiritual experience, and mystical experience after sessions predicted increased well-being at 12 months, but did not predict improvement in depression.

Conclusion:

These findings demonstrate that the substantial antidepressant effects of psilocybin-assisted therapy may be durable at least through 12 months following acute intervention in some patients.

Background:

Psilocybin shows promise as a treatment for major depressive disorder (MDD).

Materials and Methods:

In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days’ duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing.

Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support.

The primary outcome was change in central rater–assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment.

Results:

A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,−12.3 [95% CI, −17.5 to −7.2]; P <.001) and from baseline to day 8 (mean difference, −12.0 [95% CI, −16.6 to −7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, −2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs.

Conclusion:

Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin—when administered with psychological support—may hold promise as a novel intervention for MDD.

Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression.

Materials and Methods:

This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population).

Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay.

The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR).

Results:

Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 2.6; 95% CI, 1.8-3.5; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 2.3; 95% CI, 1.5-3.0; P < .001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score).

Conclusion:

Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.

Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression.

Methods:

In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks.

Results:

Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60–80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.

Conclusions:

In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress.

(# of subjects/ studies, cohort definition etc. )

-79 participants in 25 mg group

-75 participants in 10 mg group

-79 participants in 1 mg group

-Participants were randomly assigned to receive a single dose of psilocybin and psychological support

-The Montgomery-Asberg depression rating scale was used to assess depression severity at baseline and in response to treatment

-Secondary: response at week 3 (>50% decrease from baseline), remisson at week 3 (MADRS score < 10), sustained response at 12 weeks

-25 mg group showed response and remission at 3 weeks but not sustained response at 12 weeks

-Adverse events were more significantly associated with the 25 mg group

-Lacks ethnically diverse participants

-People judged to be at a clinically significant risk for suicide were excluded

-Follow up period was limited to 12 weeks

-24 patients completed full follow up period

-Participants received immediate or delayed (8 weeks) psilocybin treatment

-Follow up periods were at 1, 3, 6 and 12 months.

-Treatment response was measured using GRID-HAMD scores

-Secondary: adverse effects, suicidal ideation, overall well-being score via patient questionnaires

-Treatment response and remission were 75% and 58% at 12 months

-No serious adverse events

-Overall patient judged wellbeing via questionnaire was increased at 12 months

-Predominately Caucasian study sample

-Excluded those judged to be at high risk of suicide

-Lack of comparator group

-51 received psilocybin (25mg)  and 53 received niacin (100 mg) along with both groups getting psychological support

-Primary and secondary outcomes were measured at 2 days, 8 days, 15 days, 29 days and 43 days.

-Secondary outcomes = change in Sheehan disability score; adverse effects

-Psilocybin associated with reduced Sheehan Disability Scale scores compared with niacin

-Participants receiving psilocybin had sustained response compared to those receiving niacin

-Psilocybin was associated with a higher rate of overall adverse effects

-Use of niacin as an active placebo may contribute to enhanced placebo response

-Duration of treatment follow up was limited to 43 days

-Psychologic support offered to both groups was not assessed

-Lack of ethnic and racial diversity

-Two psilocybin sessions were given

-Participants were randomized to begin treatment immediately or after an 8 week delay

-Participants received 2 sessions of psilocybin

-GRID-HAMD scores in the group who received immediate treatment were significantly lower than the group who did not receive immediate treatment at that same time

-Secondary outcome = quick inventory of depressive symptomatology self rated score (QIDS-SR)

-About 71% of patients had a clinically significant response to intervention (GRID-HAMD score reduction of >50%)

-Greater than 50% of participants were in remission at the end of follow up period

-Small sample size

-Participant sample mainly composed of white non-hispanic participants

-Patients either received single dose psilocybin or niacin, both in conjunction with psychotherapy

-The intervention was then crossed over at 7 weeks after administration of dose 1 and participants received the other treatment option

-Follow up assessments at baseline, 1 day before dose, day of dose. 1 day after dose. 2 weeks after dose. 6 weeks after dose

-Total duration of srudy = 9 months

-Secondary outcomes = existential distress, quality of life, spirituality, adverse effects

-Psilocybin decreased cancer related demoralization (loss of meaning/hope)

-Psilocybin improved spiritual well-being, life satisfaction and quality of life

-No serious adverse effects observed

-Population specifically cancer patients

-Non-nationally representative of cancer patients (majority Caucasian women)

-Control with limited blinding

-Excluded studies that focused on spiritual effects

-Included studies in English and Spanish

-5 RCTs and 3 open label trials

-Sample size = 12 – 59 participants

-Age range = 39 – 56 years

-Duration of study ranged from 6-8 weeks t months

-Most commonly used dose of psilocybin was 25 mg

-Using beck depression inventory, quick inventory of depressive symptoms, GRID-HAMD or MADRS scales

-Significant results were observed as early as 1 day, results immediate

-Improvement was long-lasting (maintained reduction up to 6, 8 and 12 months)

-Unable to include effect on other psychiatric disorders

-Population not generalizable to world as most of studies were conducted in US or UK

-Sample population imbalances (sex, age, etc)