Psilocybin with psychological support for treatment-resistant depression: six-month follow-up
This open-label study (n=20) expands on earlier work by Carhart-Harris and colleagues on the use of psilocybin-assisted therapy for treatment-resistant depression (TRD).
Authors
- James Rucker
- Robin Carhart-Harris
- David Nutt
Published
Abstract
Rationale
Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.
Objectives
Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.
Methods
Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.
Results
Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen’s d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen’s d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.
Conclusions
Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.
Research Summary of 'Psilocybin with psychological support for treatment-resistant depression: six-month follow-up'
βBlossom's Take
Introduction
Psilocybin, a naturally occurring serotonergic psychedelic, has been investigated for a range of psychiatric indications and prior trials have reported improvements in depressive symptoms following psilocybin‑assisted psychotherapy. Previous work has also suggested therapeutic potential for other serotonergic psychedelics in conditions such as obsessive–compulsive disorder, addiction and anxiety related to terminal illness, and mechanistic interest centres on 5‑HT2A receptor agonism. Earlier clinical and historical studies, as well as laboratory findings, indicate both promise and complexity in how 5‑HT2A signalling relates to antidepressant effects. Carhart‑Harris and colleagues present an extension of their earlier pilot study in treatment‑resistant depression, increasing the sample from 12 to 20 patients and lengthening follow‑up from 3 to 6 months. The paper reports safety and efficacy outcomes from an open‑label feasibility trial in which two oral psilocybin doses were administered with structured psychological support; the main aim was to assess symptom change over time, tolerability and relationships between acute subjective experiences and longer‑term clinical outcomes.
Methods
This was an open‑label feasibility study in 20 patients meeting criteria for treatment‑resistant, unipolar major depression. Regulatory and ethical approvals were obtained and psilocybin (formulated as 5 mg capsules) was sourced from THC Pharm and prepared by a hospital pharmacy unit. Treatment comprised two supervised oral psilocybin sessions given 7 days apart: an initial 10 mg dose followed by a 25 mg dose. Psychological support followed a three‑component model: preparation, acute/peri‑acute support and post‑session integration (acronym PSI). The primary outcome was change in self‑rated depressive symptoms measured with the 16‑item Quick Inventory of Depressive Symptoms (QIDS‑SR16). QIDS‑SR16 assessments were collected at 1–3 weeks, 5 weeks (primary endpoint), and at 3 and 6 months post‑treatment. Secondary measures included the Beck Depression Inventory (BDI), Spielberger Trait Anxiety Inventory (STAI‑T), Snaith–Hamilton Pleasure Scale (SHAPS), clinician‑rated HAM‑D and Global Assessment of Functioning (GAF); the latter two were collected at 1 week only. For the six post‑treatment QIDS contrasts a Bonferroni‑corrected α of 0.0083 was applied; the team elected not to correct other correlated clinical measures to avoid excessive type 2 error. Prospective participants underwent telephone screening and a full screening visit including MINI‑5 diagnostic interview, physical assessments, ECG and drug/pregnancy testing. Main inclusion criteria were unipolar major depression of at least moderate severity (HAM‑D ≥ 16) and failure to improve after at least two pharmacologically distinct antidepressant courses in the current episode. Main exclusions included current or first‑degree family history of psychotic disorder. Most patients on antidepressants underwent supervised taper and washout prior to dosing. Patients also attended baseline MRI and preparation visits; post‑session debriefing and MRI scans occurred the day after dosing. Subjective acute effects were measured with the 11‑dimension Altered States of Consciousness (11D‑ASC) questionnaire at the end of each dosing day with ratings referenced to the peak experience. Side effects were documented from direct patient reports at each post‑treatment visit. Statistical analysis used two‑tailed paired t tests for pre‑vs‑post contrasts with Cohen's d for dependent data reported; Bonferroni correction was applied only to the primary QIDS timepoint contrasts.
Results
Recruitment began from 120 initial enquiries; 74 proceeded to telephone screening, 29 to in‑person screening and 20 were enrolled, with 19 completing all assessment time points. Eighteen of 20 patients had severe or very severe depression at baseline (QIDS‑SR16 ≥ 16). Patients reported a long illness history (mean duration 17.7 ± 8.4 years) and a high burden of prior treatment failure (median 4 failed medications, mean 4.6 ± 2.6, maximum 11). QIDS‑SR16 scores were significantly reduced relative to baseline at all six post‑treatment time points. The maximal mean change occurred at 5 weeks (mean reduction = -9.2, 95% CI = -11.8 to -6.6, t = -7.2, p < 0.001), with a large effect size (Cohen's d = 2.3). All 19 completers showed some reduction in QIDS‑SR16 at 1 week; these reductions were sustained in the majority across weeks 3–5. Other clinical measures mirrored this pattern: BDI scores fell markedly at 1 week (mean reduction = -22.7, 95% CI = -17.6 to -27.8, p < 0.001) and remained significantly lower at 3 and 6 months; STAI‑T anxiety scores and SHAPS anhedonia scores showed significant reductions at early and some later time points; HAM‑D decreased and GAF scores improved at 1 week. Safety findings indicated good tolerability and no serious adverse events. Common transient effects during or shortly after dosing included anxiety (n = 15), headaches lasting 1–2 days (n = 8), transient nausea (n = 5) and brief paranoia during the acute experience (n = 3). Fourteen patients reported autobiographical visions, which were generally experienced as insightful. One patient became uncommunicative at the peak of the 25 mg session but normalised afterwards; this individual declined most further follow‑up assessments but provided QIDS and BDI scores at 6 months (QIDS 25, BDI 40). Suicidality items on the QIDS‑SR16 were significantly reduced at weeks 1 and 2 (mean reductions -0.9 and -0.85, respectively) with trend reductions at weeks 3 and 5; HAM‑D suicide item scores were significantly decreased at 1 week with 16 of 19 patients scoring 0. Acute subjective effects measured by the 11D‑ASC were greater after 25 mg than 10 mg for experience of unity, spiritual experience, blissful state, insightfulness and complex imagery (all surviving Bonferroni correction). Because experience of unity, spiritual experience and blissful state were highly intercorrelated (r > 0.92), the investigators combined them into a USB factor and found that USB and insight scores during the 25 mg session correlated with greater reductions in QIDS‑SR16 at 5 weeks (USB r = -0.49, p = 0.03; insight r = -0.57, p = 0.01). At the 6‑month endpoint some patients had received additional treatments: six began new antidepressant courses after 3 months and five received various psychotherapies; five participants had independently obtained psilocybin outside the study between 3 and 6 months. Excluding those five did not materially alter the primary 3‑ and 6‑month results (effect sizes remained large and p values remained significant). Of the nine responders at 5 weeks, three met conservative criteria for relapse by 6 months while six maintained response.
Discussion
Carhart‑Harris and colleagues present extended data from an open‑label trial that reinforce earlier findings of rapid and substantial reductions in depressive and anxiety symptoms following two psilocybin sessions with psychological support. Many participants showed large, early improvements, with nominal peak effects at 5 weeks and durable reductions evident at 3 and 6 months for a substantial proportion of the sample. The correlation observed between acute subjective experiences labelled as insightfulness (and a composite of unity/spiritual/blissful experiences) and later symptom improvement is noted as supportive of a model in which qualities of the acute psychedelic experience relate to therapeutic benefit; the authors point to complementary fMRI data collected in the trial as relevant to refining mechanistic understanding. Importantly, the investigators emphasise limitations that constrain causal inference. The open‑label design and absence of a control condition prevent definitive efficacy claims and the sample size is small. Regulatory and logistical constraints prevented a planned placebo‑controlled RCT, leading to the present feasibility design. Generalisability is limited in part because the final eight participants were all male and because duration of the current depressive episode was based on patient estimates, introducing uncertainty. The authors also acknowledge that subsequent, non‑trial interventions among participants confounded outcomes at the 3‑ and 6‑month timepoints, although sensitivity checks excluding those who sought additional psilocybin did not substantially change results. Looking forward, the paper argues for better characterisation, measurement and control of the psychological components of the treatment model—such as expectations, interpersonal context and music—plus clearer specification or manualisation of psychotherapeutic support. The investigators caution that experiments manipulating psychological context must respect the vulnerability of individuals under psychedelics and maintain minimum standards of care. Concluding remarks frame the findings as proof‑of‑principle: psilocybin administered with psychological support appears feasible and tolerable in severe treatment‑resistant depression and warrants further investigation in larger, double‑blind, controlled trials, including studies addressing comparative and cost‑effectiveness questions.
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INTRODUCTION
Psilocybin is a naturally occurring plant alkaloid that is being increasingly researched as treatment for a range of different psychiatric disorders. Four separate trials have reported improvements in depressive symptoms after psilocybin-assisted psychotherapy, including one in which 'treatment-resistant depression' was the primary criterion for inclusion. Psilocybin has shown promise in the treatment of obsessive compulsive disorder, alcoholand tobacco addiction) and anxiety related to terminal diagnoses. Treatment procedures typically involve psychological preparation prior to one or two therapist-supported drug sessions followed by psychological integration. Using a consistent model (i.e. involving appropriate psychological support), sustained improvements in well-being in healthy individuals were observed after a single dose of psilocybin in a doubleblind design incorporating an active placebo. Studies involving other serotonergic psychedelics combined with psychological support have found similarly promising outcomes: Sustained reductions in end-of-life anxiety were observed after LSD-assisted psychotherapy, and reduced depressive symptoms were seen after ayahuasca in patients with 'recurrent depression'. Naturalistic, observational studies of ayahuasca support its long-term well-being promoting and anti-addiction propertiesand a recent population survey found lower rates of suicidality and psychological distress in association with psychedelic drug use)-an anomalous association for a drug of potential misuse. Drug experts and users have consistently rated psilocybin as the least harmful and potentially 'most beneficial' drug of potential misuse-although the influence of context (e.g. expectations and environmental factors) on potential harms and benefits has been much emphasised. Further evidence favouring the therapeutic potential of psychedelics can be found in literature documenting the extensive research carried out with these compounds in the mid-twentieth century, e.g. two relevant meta-analyses have found positive safety and efficacy data for LSD for alcohol dependenceand mood disorders. See Carhart-Harris andfor a review of historical and recent trials with psychedelics. Like all serotonergic psychedelics, psilocybin initiates its characteristic effects via serotonin 2A receptor (5-HT2AR) agonism. 5-HT2AR signalling has been associated with better responses to conventional antidepressants, and preclinical work indicates that 5-HT2AR signalling may mediate (at least some of) the therapeutic effects of SSRIs. Paradoxically, 5-HT2AR antagonists have been found to augment the antidepressant effects of SSRIsand many effective antidepressant augmentation medications have 5-HT2AR antagonist properties. This paradox implies that 5-HT2AR agonism and antagonism can achieve consistent ends, in terms of alleviating depressive symptoms, but via different mechanisms (seeand Carhart-Harris and Nutt (2017) for a relevant discussion). The present report documents an extension to our recently published pilot study assessing psilocybin with psychological support for treatment-resistant depression. The number of patients treated was increased from 12 to 20 and the follow-up period extended from 3 to 6 months.
APPROVALS AND DRUG SOURCE
This clinical trial received a favourable opinion from the National Research Ethics Service (NRES) London-West London, was sponsored and approved by Imperial College London's Joint Research and Complication Organisation (JRCO), was adopted by the National Institute of Health Research (NIHR) Clinical Research Network (CRN) and was reviewed and approved by the Medicines and Healthcare products Regulatory Agency (MHRA). A Home Office Licence for storage and dispensing of Schedule One drugs was obtained. Psilocybin was obtained from THC Pharm (Frankfurt) and formulated into the investigational medicinal product (5 mg psilocybin in size 0 capsules) by Guy's and St Thomas' Hospital's Pharmacy Manufacturing Unit (London, UK).
STUDY DESIGN
This was an open-label feasibility study in 20 patients with treatment-resistant depression. Treatment involved two oral doses of psilocybin (10 and 25 mg), 7 days apart. The primary outcome was mean change in the severity of self-reported (SR) depressive symptoms (measured primarily with the 16-item Quick Inventory of Depressive Symptoms, QIDS-SR16) from baseline to specific time points after the high-dose psilocybin session (henceforth referred to as 'post-treatment'). QIDS-SR16 ratings were collected 1-3 and 5 weeks and 3 and 6 months post-treatment, with 5 weeks post-treatment regarded as the primary endpoint. BDI (depression) and STAI (anxiety) ratings were collected at 1 week and 3 and 6 months. SHAPS (anhedonia) was collected at 1 week and 3 months and HAM-D (depression, clinician-administered) and GAF (global functioning, clinician administered) ratings were collected at 1 week only. These secondary measures were collected to enable comparisons to be made with other studies that use the same measures. For this reason and since they were highly correlated with the primary outcome measure, we chose not to correct for their use. A revised α of 0.05/ 6 = 0.0083 for the six post-treatment QIDS-SR16 contrasts vs baseline was used however.
TRIAL PROCEDURES
Full details of trial procedures can be found in. Briefly, patients contacted the study team after which a telephone screen was organised with the main study psychiatrist. After checking eligibility criteria, candidates were invited for a screening visit at the Imperial Clinical Research Facility (ICRF) at the Hammersmith Hospital. This comprised of informed consent, documenting mental and physical health backgrounds, a psychiatric interview (MINI-5) to confirm diagnosis, physical examination, routine blood tests, ECG, urine test for drugs of abuse and pregnancy where relevant, a breathalyser and the completion of baseline assessments. The main inclusion criteria were as follows: unipolar major depression of at least moderate severity (16+ on the 21-item HAM-D) and no improvement despite two courses of pharmacologically distinct antidepressant medications for an adequate duration (6 weeks minimum) within the current episode. Main exclusion criteria were as follows: a current or previously diagnosed psychotic disorder or an immediate family member with a diagnosed psychotic disorder. Patients' mental health histories were confirmed with their GP or psychiatrist prior to study entry. With the exception of patient 2 (Table), eligible patients medicated with an antidepressant were advised to stop this for the trial, to avoid suspected attenuation of psilocybin's effects. This was done in a tapered manner under careful supervision from the study psychiatrist. Washout occurred over at least 2 weeks prior to study entry, with the exception of patient 6, who stopped tramadol use only after the first psilocybin session (when the tramadol use was discovered). Eligible patients attended a pretreatment MRI scan and psychological preparation visit, followed by two dosing sessions, separated by 1 week. In the first session, patients received 10 mg psilocybin and in the second, 25 mg. Patients were seen the following day for debriefing and a post-treatment MRI scan, and for one final time 1 week after the 25-mg session. Subsequent follow-up measures were collected remotely. Patients emailed their completed questionnaires to the study team. Six-month follow-up interviews were carried out by RW with all 20 patients and the relevant qualitative data are reported elsewhere.
REPORTING SIDE EFFECTS
Side effects were documented based on patient reports in response to the question: BHave you experienced any side effects in relation to the treatment?^This was asked at all posttreatment visits and any spontaneously reported or observed side effects were also documented.
PSYCHOLOGICAL SUPPORT
Psychological support comprised of three components: (1) preparation (P), () acute and peri-acute support (S) and () integration (I). () Preparation (P) involves getting to know the patient and his/her background, building a relationship of trust and providing some information on what can be expected from psilocybin and how best to navigate its effects. () Support (S) involves being physically and emotionally present for the patient before, during and after the acute drug session. It may incorporate empathetic listening and reassurance, for example. (3) Integration (I) involves non-judgmental listening to the patient's testimony after his/her experience and may occasionally feature some interpretation regarding the content of the experience and its potential meaning, as well as advice regarding maintaining and cultivating positive changes in outlook and lifestyle. We assign the acronym PSI to these core components of psychological support.
-DIMENSION ALTERED STATES OF CONSCIOUSNESS (11D-ASC) QUESTIONNAIRE
This is a 94-item questionnaire, of which 44 items are scored. The 44 items are factorised according to a previous validation paper. Each item is scored as in a visual analogue scale with the upper anchor reading Bmuch more than usual^and the bottom one reading Bno more than usual^. Patients performed the 11D-ASC at the end of each dosing day when the subjective effects of psilocybin had subsided to a negligible level; however, ratings were done with reference to the period when effects were most intense. t tests with Bonferroni correction (revised α = 0.05/11 = 0.0045) contrasted scores for the 10-and 25-mg dose sessions.
DATA ANALYSIS
Two-tailed paired t tests were performed for all pre-vs posttreatment QIDS-S16 contrasts, with Bonferroni corrected α of 0.05/6 = 0.0083 for the six post-treatment time intervals. 95% confidence intervals (CI) are provided. Effect sizes were calculated using Cohen's d values for dependent data. We chose not to correct for additional clinical measures beyond correcting for QIDS-SR16 changes at multiple time points. This decision was made so as to avoid introducing type 2 errors through overly conservative correction and because of the high covariance between clinical measures (see BResultsŝ ection). For transparency, we provide all relevant p values and effect sizes.
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) and these 12 are included in the present analysis. Patients' demographic and clinical characteristics are shown in Table. 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 Bmoderate^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: BFor 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.). 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 posttreatment 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). 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 posttreatment (mean increase = + 25.3, 95% CI = 17.1 to 33.5, p < 0.001)-see 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 Bblissfulâ nd 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. Seefor 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., has motivated us to revise the exclusion criteria for future psilocybin trials, i.e. with Bpsychiatric 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, 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 about the authenticity of this putative memory and this was associated with a transient worsening of symptoms (see weeks 2 and 3 in fig.). 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; and a multiple correlation analysis confirmed their interrelatedness 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.) 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). After the 6-month endpoint, information was collected on other treatments received by the patients. 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 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 BResultsŝ ection and retrospective ratings for 1 and 3 weeks post-treatment were also obtained and are reported in the text only period and five sought and successfully obtained psilocybin (without sanction from the study team) 3 and 6 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. 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.
DISCUSSION
This paper presents updated and extended data from an openlabel clinical trial assessing psilocybin with psychological support for treatment-resistant depression. Findings corroborate our) and others' previous resultssupporting the safety and efficacy of psilocybin for depressive and anxiety symptoms. A fast and sustained response exceeding what might be expected from a placebo response was observed in many of the patients (see Carhart-Harris and Nutt (2016) for a relevant discussion). Notably, all 19 completers showed some reductions in the QIDS-SR16 scores at 1-week post-treatment and (nominally) maximal effects were seen at 5 weeks. Other interventions, not formally part of the present trial, confounded outcomes at 3 and 6 months, although safety was maintained and a sizeable proportion of the sample continued to demonstrate benefit (seefor more details). Conclusions on efficacy are limited by the absence of a control condition in this trial, however. Recent studies, including the present one, help demonstrate the feasibility of treating patients with major depressive disorder with psilocybin plus psychological support. Two recent double-blind randomised control trials (RCTs) of psilocybin for depression and anxiety symptoms in a combined sample of 80 patients with life-threatening cancer found consistent safety and efficacy outcomes with those reported here. Only a subset of. The abovereported correlation between acute 'insightfulness' and enduring reductions in depressive symptoms may be viewed as broadly supportive of this model. Moreover, recently published fMRI data collected as part of the present trial may help to develop and refine this model. Future research should endeavour to better characterise, control and measure the various psychological components contained within the current psychedelic treatment model. There is an assumption that individuals under the influence of a psychedelic are especially sensitive to the context in which the experience occurs, both in terms of (1) prior expectations and other relevant state and trait factors and (2) environmental factors, e.g. the quality of the relationships with persons attending to them before, during and after the experience and patients' relationship to the music listened to during the sessions-and this matter has recently been discussed in length. In order to properly assess the relative contribution of these variables and their assumed interactions with psilocybin, it will be necessary to properly control and measure them, and this has presently not yet been done to a satisfactory level (seefor suggestions on how this might be done). Relatedly, psychotherapeutic models used to support and mediate the psilocybin experience need to be better defined, tested and potentially manualised. Basic principles for safe therapeutic work with psychedelics can be found in guidelines) and books) but more systematic verification, refinement and (eventual) manualisation of treatment approaches are needed for subsequent roll-out (Carhart-Harris and Goodwin 2017). Moreover, cost-effectiveness will become increasingly salient as the development of psilocybin as a treatment model progresses. The major qualifier here is that experiments intended to evaluate the contribution of psychological variables to the psychedelic experience need to be conceived and conducted with an appreciation of the special vulnerability of individuals under the influence of psychedelics (again, see. Thus, certain standards of care, including a certain level of psychological support, may be non-negotiable if safety is to be maintained. An obvious limitation of the present study is its open-label design and absence of a control condition. The initial plan was to conduct a placebo-controlled RCT but regulatory and drug procurement challenges meant that available resources could only support a smaller trial. The present results may be viewed as a successful demonstration of proof-of-principle, however, supporting the view that psilocybin can be given safely, even in severe cases of depression, with the caveat that appropriate control of context (e.g. the provision of psychological support and a comfortable environment) is essential for positive outcomes. Impressions of efficacy gleaned from the present study's findings may be cautiously described as 'promising'-and if supported by larger and better controlled trials, psilocybin's low toxicity, favourable side effect profile and putative and enduring action could render it at least competitive with currently available treatments for major depression, whose therapeutic actions may be delayed, e.g. in the cases of SSRIs and psychotherapy, or short-lived, e.g. in the case of ketamine. Comparative efficacy trials may therefore be an interesting next step. Such designs may also have merit in terms of addressing the challenge of maintaining the study blind in trials with psychedelics. Another limitation of the present trial is that the final eight patients were all male. This is regretful as it limits extrapolation to the general population, where rates of treatmentresistant depression may be marginally higher in women than in men. Greater effort will be made in future trials to recruit more representative samples of the target population. Another limitation deserving of mention is the issue of assessing duration of current depressive episode. Patients gave estimates based on the question BFor how long has your current depression lasted?^but some chose to estimate based on the duration of their chronic illness, believing they had not experienced a discernable remission for yearsdecades, even during periods when their symptoms were relatively less severe. In summary, we have presented updated and extended data from a feasibility trial assessing psilocybin with psychological support for treatment-resistant depression. With the caveat that this was an open-label trial with no control condition, safety and efficacy outcomes continue to support the case for further research (Carhart-Harris and Goodwin 2017). Identifying key psychological and pharmacological variables comprising the treatment model, and testing their assumed interactions, is one of a number of important next steps. Open Access This article is distributed under the terms of the Creative Comm ons Attribution 4.0 International License (), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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