Table 4.
Prospective Clinical Trials Evaluating Antidepressant Effects of Serotonergic Psychedelics.
| Study | Design | Eligibility Criteria | Sample size | Intervention | Comparator | Antidepressant Efficacy Results | Key Limitations |
|---|---|---|---|---|---|---|---|
| Moderate to High-Dose Oral Psilocybin for Major Depressive Disorder | |||||||
| Carhart-Harris et al. (2021) | RCT | MDD | 59 | Two psilocybin doses of 25 mg separated by 3 weeks with psychological support plus 6 weeks of daily oral placebo pills | Two psilocybin doses of 1 mg separated by 3 weeks with psychological support plus 6 weeks of daily oral escitalopram | The mean (SE) changes in the QIDS total score 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 (P = 0.17). | Self-report as primary outcome; likely inadequately powered |
| Davis et al. (2021) | RCT (wait list control); blinded raters | MDD | 27 | Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) with psychotherapy (∼11 h). | Wait list control (8-week delayed start) | 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 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 (P< 0.001). | Only raters were blinded; waitlist control is a poorer comparator than placebo |
| Carhart-Harris et al. (2016) | Open label | TRD | 12 | Two psilocybin doses (10 mg and 25 mg, 7 days apart) with psychological support | None | Mean change in QIDS of −11.8 (1-week primary endpoint) partly sustained for 3 and 6 months following the high-dose session. | Open label, unblinded, no comparator arm |
| Moderate to High-Dose Oral Psilocybin for Cancer-Related Depression | |||||||
| Griffiths et al. (2016) | Cross over RCT | Cancer- related depression and anxiety | 51 | Single high-dose psilocybin 22 mg or 30 mg/70 kg with supportive psychotherapy | Single-dose psilocybin 1 mg or 3 mg/70 kg with supportive psychotherapy | 5 weeks post-dose (pre-crossover), GRID-HAMD reduced by 16 points with high dose versus seven points with low dose (P < 0.05). At 6-month follow-up, GRID-HAMD ratings showed 78% response and 65% remission rate. | For all three RCTs: Focus specific to cancer-related distress; cross-over design limits conclusions of long-term outcomes; underpowered for depression efficacy |
| Ross et al. (2016) | Cross over RCT | Cancer- related depression and anxiety | 29 | Single-dose psilocybin 0.3 mg/kg with supportive psychotherapy | Niacin with supportive psychotherapy | 7 weeks (pre-crossover) after dose 1, 83% of participants in the psilocybin first group (vs. 14% in the niacin first group) met criteria for antidepressant response (>50% reduction on BDI) with a large effect size (d = 0.82; P< 0.05). At 6.5-month follow-up, after all participants had received psilocybin, 60%–80% of participants had clinically significant sustained reductions in depression or anxiety. | |
| Grobb et al. (2011) | Cross over RCT | Cancer-related anxiety and depression | 12 | Single -dose psilocybin 0.2 mg/kg with supportive psychotherapy | Niacin with supportive psychotherapy | A trend was observed after psilocybin administration, from a mean BDI (SEM) score of 16.1 (3.6) one day before treatment to 10.0 (2.7) two weeks after treatment. Conversely, no change in BDI scores observed post-niacin dose. BDI reduction was sustained and became significant at the 6-month follow-up point (P = 0.03). | |
| Natural Oral Ayahuasca (DMT) for Major Depressive Disorder | |||||||
| Palhano-Fontes et al. (2019) | RCT | TRD (> 1 medication failure) inpatient | 29 | Ayahuasca adjusted to contain 0.36 mg/kg of DMT with inpatient support and monitoring | Oral placebo with inpatient monitoring | MADRS scores were significantly lower in the ayahuasca group compared with placebo at all time points (p < 0.001). Between-group effect sizes were large and increased from day 1 (d = 0.84) through day 7 (d = 1.5). Secondary analysis indicated significant reduction in suicidality scores. | Small sample size; minimal description of psychological support provided. |
| Sanches et al. (2016) (Including sample from Osório et al., 2015) | Open label | TRD (> 1 medication failure) inpatient | 17 | Single-dose ayahuasca (2.2 ml/kg) administered with inpatient support and monitoring | None | HAMD scores significantly decreased from 80 min to day 21 (P < 0.01 at all time points). Baseline HAMD (SD) of 19.2 (5.5) decreased to 7.6 (4.7) by day 21. Secondary analysis demonstrated large reduction in suicidal thoughts in participants with baseline suicidality. | Open label, no comparator, confounded by benefits from inpatient treatment |
Note. BDI = Beck Depression Inventory; DMT = N,N-dimethyltryptamine; HAMD = Hamilton Depression Rating Scale; MADRS = Montgomery–Åsberg Depression Rating Scale; MDD = major depressive disorder; RCT = randomized controlled trial; SE = standard error; SD = standard deviation; SEM = standard error of mean; TRD = treatment-resistant depression; QIDS = Quick Inventory of Depression Self Report.