Patients

One hundred and twenty people expressed an interest in the study. Seventy-four were considered appropriate for a telephone screen, from which 29 were invited for a screening visit. Twenty were ultimately recruited for the trial and 19 completed all measures. Data on 12 of the 20 have been previously reported (Carhart-Harris et al. 2016) and these 12 are included in the present analysis. Patients’ demographic and clinical characteristics are shown in Table 1. Eighteen of the 20 patients met the criteria for severe or very severe depression at baseline (QIDS-SR16 score of ≥ 16); the remaining two meeting the criteria for “moderate” depression (QIDS-SR16 score ≥ 11, < 16). The median number of (lifetime) failed previous medications was 4, the mean was 4.6 ± 2.6 and the maximum was 11. The mean duration of illness of the sample was 17.7 ± 8.4 years (range = 7–30 years), as assessed by the question: “For how long has your current depression lasted?” Note that none of the demographic variables were predictive of treatment response, including past use of psilocybin.

Data were analysed for the 19 who completed all assessment time points. Relative to baseline, QIDS-SR16 scores were significantly reduced at all six post-treatment time points (p < 0.001), with the maximum effect size at 5 weeks (− 9.2, 95% CI = − 11.8 to − 6.6, t = − 7.2, p < 0.001, Cohen’s d = 2.3) (see Fig. 1). Of the 19 patients who completed all assessments, all showed some reduction in depression severity at 1 week and these were sustained in the majority for 3–5 weeks. Changes in HAM-D ratings from baseline to 1-week post-treatment showed a reasonable correspondence with changes in QIDS-SR16 data across the same period (r = 0.61, p < 0.001) and the relationship between the QIDS-SR16 and BDI at 1 week was very strong (r = 0.81, p < 0.001).

Fig. 1 Depression severity vs time: depression severity determined by the primary outcome measure, self-rated QIDS-SR16. Mean values were calculated for the 19 completers. Data are shown for the QIDS scores of 16–20 considered to reflect severe depression. All post-treatment assessments were obtained after the high-dose session, i.e. 1-week post-treatment refers to 1 week after the 25-mg psilocybin dose. Mean values are represented by the black horizontal bars with positive standard errors also included. Cohen’s d values vs baseline are shown in red, all contrasts vs baseline yielded p values of < 0.001 with the exception of the 6 month contrast which was p = 0.0035. Patient 17’s data is not included in the chart due to absent data points at 1 week to 4 months; however, his baseline and 6-month data is included in the text contained in “Results” section and retrospective ratings for 1 and 3 weeks post-treatment were also obtained and are reported in the text only Full size image

BDI scores were significantly reduced at 1 week (mean reduction = − 22.7, 95% CI = − 17.6 to − 27.8, p < 0.001), 3 months (mean reduction = − 15.3, 95% CI = − 8.7 to − 21.9, p < 0.001) and 6 months post-treatment (mean reduction = − 14.9, 95% CI = − 8.7 to − 21.1, p < 0.001); STAI-T anxiety scores were significantly reduced at 1 week (mean reduction = − 23.8, 95% CI = − 16.5 to − 31.1, p < 0.001), 3 months (mean reduction = − 12.2, 95% CI = − 6.1 to − 18.3, p < 0.001) and 6 months post-treatment (mean reduction = − 14.8, 95% CI = − 8.1 to − 21.6, p < 0.001); SHAPS anhedonia scores were significantly reduced at 1 week (mean reduction = − 4.6, 95% CI = − 2.6 to − 6.6, p < 0.001) and 3 months post-treatment (mean reduction = − 3.3, 95% CI = − 1.1 to − 5.5, p = 0.005); HAM-D scores were significantly reduced at 1 week post-treatment (mean reduction = − 14.8, 95% CI = − 11 to − 18.6, p < 0.001); and GAF scores were significantly increased 1 week post-treatment (mean increase = + 25.3, 95% CI = 17.1 to 33.5, p < 0.001)—see Table 2.

Table 2 Individual patient clinical ratings: clinical outcomes at various time points. The clinician administered ratings were completed at baseline and 1 week post-dosing only Full size table

Treatment was generally well tolerated and there were no serious adverse events. One patient became uncommunicative during the peak of his 25-mg psilocybin experience but this normalised after the acute drug effects had abated. Follow-up discussions revealed that his experience had been “blissful” and beneficial but also overwhelming (see supplementary file). Regretfully, this patient chose not to complete further follow-up measures, with the exception of the QIDS-SR16 and BDI scores at 6 months post-treatment. Follow-up scores were 25 (QIDS) and 40 (BDI) at 6 months. See Watts et al. (2017) for more details about individual cases.

A brief note: this experience, combined with evidence supporting the importance of patient-therapist rapport in the psychedelic treatment model (e.g. Carhart-Harris et al., in review), has motivated us to revise the exclusion criteria for future psilocybin trials, i.e. with “psychiatric condition judged to be incompatible with establishment of rapport with therapy team and/or safe exposure to psilocybin, e.g. suspected borderline personality disorder” added as a criterion for exclusion.

Consistent with our earlier report on the initial 12 patients from this trial (Carhart-Harris et al. 2016), transient anxiety lasting for minutes (n = 15) and headaches lasting no more than 1–2 days (n = 8) were the most common side effects. Five reported transient nausea but there were no cases of vomiting. Three reported transient paranoia within the duration of the acute drug experience but this was short-lived in every case. As with all our previous work with this compound, there were no reported cases of so-called flashbacks or persisting perceptual changes.

Fourteen patients reported visions of an autobiographical nature. In most cases, such visions were regarded as insightful and informative. One patient reported a vision of his father attempting to physically harm him when he was child, something he claimed not to have been previously conscious of. This patient subsequently felt confused about the authenticity of this putative memory and this was associated with a transient worsening of symptoms (see weeks 2 and 3 in fig. S1). Appealing to clinical equipoise, the study team felt it best practice not to make a judgement on the veridicality of this alleged memory but open and compassionate listening was maintained and the patient subsequently improved.

Suicidality scores on the QIDS-SR16 were significantly reduced 1 and 2 weeks post-treatment (mean reductions at week 1 = − 0.9, 95% CI = − 0.4 to − 1.4, p < 0.002; mean reduction at week 2 = − 0.85, 95% CI = − 0.4 to − 1.3, p = 0.004), with trend decreases at 3 (mean reduction = − 0.8, 95% CI = − 0.25 to − 1.3, p = 0.01) and 5 weeks (mean reduction = − 0.7, 95% CI = − 0.22 to − 1.2, p = 0.01). Scores on the suicide item of the HAM-D were significantly decreased 1-week post-treatment (mean reduction = − 0.95, 95% CI = − 0.58 to − 1.3, p < 0.001), with 16 of 19 patients scoring 0 at this time point and none showing an increase from baseline nor scoring the maximum on this measure. Scores on the genital/sexual dysfunction item of the HAM-D were also significantly reduced 1-week post-treatment (mean reduction = − 0.58, 95% CI = − 0.18 to − 0.98, p = 0.002) and no one scored the maximum nor showed an increase in sexual dysfunction from baseline.

The complete 11D-ASC scores can be found in the supplementary file. After Bonferroni correction (0.05/11 = 0.004), values for experience of unity (mean difference = 0.26, 95% CI = 0.12 to 0.41, p = 0.001), spiritual experience (mean difference = 0.28, 95% CI = 0.11 to 0.41, p < 0.001), blissful state (mean difference = 0.3, 95% CI = 0.16 to 0.44, p < 0.001), insightfulness (mean difference = 0.26, 95% CI = 0.11 to 0.41, p < 0.001) and complex imagery (mean difference = 0.18, 95% CI = 0.08 to 0.28, p < 0.001) were found to be significantly higher after 25 mg psilocybin than the 10-mg dose.

Previous work has indicated a strong relationship between the following 11D-ASC factors: experience of unity, spiritual experience and blissful state (Studerus et al. 2010); and a multiple correlation analysis confirmed their inter-relatedness here (r > 0.92 for all permutations). We therefore decided to treat them as one factor (assigned the acronym ‘USB’), taking mean values for each patient. Testing the hypothesis that this USB factor and insight would predict better clinical outcomes, we found significant relationships between mean scores of USB and insight (Fig. 2) during the 25-mg psilocybin experience and changes in QIDS-SR16 scores at 5 weeks (r = − 0.49, p = 0.03 and r = − 0.57, p = 0.01, respectively).

Fig. 2 Acute ‘insight’ measured by the ‘insightfulness’ factor of the 11D-ASC rated in the evening after the 25-mg psilocybin experience correlated significantly with reductions in depressive symptoms 5 weeks later (r = − 0.57, p = 0.01, two-tailed) Full size image

After the 6-month endpoint, information was collected on other treatments received by the patients (Watts et al. 2017). With the exception of patient 2 (who remained on venlafaxine throughout the trial and also received CBT shortly afterwards), no patients received additional treatments within 5 weeks of the 25-mg psilocybin dose. Six began new courses of antidepressant medication after the 3-month time point. Five received psychotherapy (CBT, psychodynamic, counselling and group therapy × 2) shortly before or after the 3-month period and five sought and successfully obtained psilocybin (without sanction from the study team) between 3 and 6 months. Removing the five that obtained psilocybin from the 3- and 6-month analyses did not substantially alter the main results: at 3 months, the effect size increased to 1.6 and the p value remained < 0.001; and at 6 months, the effect size increased to 1.7 and the p value became 0.018.

Assessing relapse at 6 months in responders (at 5 weeks) revealed only three of nine cases—with the remaining six maintaining response—even when using conservative criteria for relapse of QIDS score of 6+ or above at 6 months. These data tentatively imply that psilocybin may protect against relapse to an equivalent extent to daily use of an established antidepressant—as seen in discontinuation trials where responders either continue on medication (33% relapse) or transfer to placebo (46% relapse) for 6 months (Gueorguieva et al. 2017). Two major caveats here, however, are that one cannot reliably extrapolate from a sample of nine, and whereas patients in our trial received no interventions from us beyond the integration work done 1 week after their 25-mg psilocybin session, patients in clinical trials typically ingest a potentially active antidepressant daily for 6 months.