Psychopharmacology https://doi.org/10.1007/s00213-017-4771-x ORIGINAL INVESTIGATION Psilocybin with psychological support for treatment-resistant depression: six-month follow-up R. L. Carhart-Harris1 & M. Bolstridge1,2 & C. M. J. Day1,2 & J. Rucker 1,3,4 & R. Watts1 & D. E. Erritzoe1 & M. Kaelen1 & B. Giribaldi1 & M. Bloomfield5 & S. Pilling6 & J. A. Rickard7 & B. Forbes8 & A. Feilding9 & D. Taylor10 & H. V. Curran6,11 & D. J. Nutt1 Received: 13 July 2017 /Accepted: 19 October 2017 # The Author(s) 2017. This article is an open access publication Abstract for the first 5 weeks post-treatment (Cohen’s d = 2.2 at week 1 Rationale Recent clinical trials are reporting marked improve- and 2.3 at week 5, both p < 0.001); nine and four patients met the ments in mental health outcomes with psychedelic drug-assisted criteria for response and remission at week 5. Results remained psychotherapy. positive at 3 and 6 months (Cohen’s d = 1.5 and 1.4, respectively, Objectives Here, we report on safety and efficacy outcomes for both p < 0.001). No patients sought conventional antidepressant up to 6 months in an open-label trial of psilocybin for treatment- treatment within 5 weeks of psilocybin. Reductions in depressive resistant depression. symptoms at 5 weeks were predicted by the quality of the acute Methods Twenty patients (six females) with (mostly) se- psychedelic experience. vere, unipolar, treatment-resistant major depression re- Conclusions Although limited conclusions can be drawn ceived two oral doses of psilocybin (10 and 25 mg, 7 days about treatment efficacy from open-label trials, tolerability apart) in a supportive setting. Depressive symptoms were was good, effect sizes large and symptom improvements ap- assessed from 1 week to 6 months post-treatment, with peared rapidly after just two psilocybin treatment sessions and the self-rated QIDS-SR16 as the primary outcome remained significant 6 months post-treatment in a treatment- measure. resistant cohort. Psilocybin represents a promising paradigm Results Treatment was generally well tolerated. Relative to base- for unresponsive depression that warrants further research in line, marked reductions in depressive symptoms were observed double-blind randomised control trials. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00213-017-4771-x) contains supplementary material, which is available to authorized users. * R. L. Carhart-Harris 6 Clinical Psychology and Clinical Effectiveness, University College [email protected] London, London, UK 7 Barts Health Pharmaceuticals, Barts Health NHS Trust, the Royal 1 Psychedelic Research Group, Centre for Neuropsychopharmacology, London Hospital, London, UK Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK 8 Institute of Pharmaceutical Science, King’s College London, 2 South London and Maudsley NHS Foundation Trust, London, UK London, UK 3 The Institute of Psychiatry, Psychology and Neuroscience, King’s 9 The Beckley Foundation, Beckley Park, Oxford, UK College London, London, UK 4 ’ South West London and St George s Mental Health NHS Trust, 10 Pharmacy and Pathology, South London and Maudsley NHS London, UK Foundation Trust, London, UK 5 Division of Psychiatry, University College London and Clinical Psychopharmacology Unit, University College London, 11 Clinical Psychopharmacology Unit, University College London, London, UK London, UK Psychopharmacology Keywords Serotonin . 5-HT2AR . Depression . and mood disorders (Rucker et al. 2016). See Carhart-Harris Treatment-resistant depression . Psilocybin . Psychedelic . and Goodwin (2017) for a review of historical and recent trials Mood . Hallucinogen . Psychotherapy with psychedelics. Like all serotonergic psychedelics, psilocybin initiates its characteristic effects via serotonin 2A receptor (5-HT2AR) Introduction agonism (Vollenweider et al. 1998). 5-HT2AR signalling has been associated with better responses to conventional antide- Psilocybin is a naturally occurring plant alkaloid that is being pressants (Qesseveur et al. 2016; Petit et al. 2014), and pre- increasingly researched as treatment for a range of different clinical work indicates that 5-HT2AR signalling may mediate psychiatric disorders (Carhart-Harris and Goodwin 2017). (at least some of) the therapeutic effects of SSRIs (Nic Four separate trials have reported improvements in depressive Dhonnchadha et al. 2005; Buchborn et al. 2014). symptoms after psilocybin-assisted psychotherapy (Griffiths Paradoxically, 5-HT2AR antagonists have been found to aug- et al. 2016;Rossetal.2016;Grobetal.2011;Carhart- ment the antidepressant effects of SSRIs (Ostroff and Nelson Harris et al. 2016), including one in which ‘treatment-resistant 1999) and many effective antidepressant augmentation medi- depression’ was the primary criterion for inclusion (Carhart- cations have 5-HT2AR antagonist properties (Carpenter et al. Harris et al. 2016). Psilocybin has shown promise in the treat- 1999). This paradox implies that 5-HT2AR agonism and an- ment of obsessive compulsive disorder (Moreno et al. 2006), tagonism can achieve consistent ends, in terms of alleviating alcohol (Bogenschutz et al. 2015) and tobacco addiction depressive symptoms, but via different mechanisms (see (Johnson et al. 2014) and anxiety related to terminal diagnoses Carhart-Harris et al. (2017) and Carhart-Harris and Nutt (Griffiths et al. 2016; Ross et al. 2016; Grob et al. 2011). (2017)forarelevantdiscussion). Treatment procedures typically involve psychological prepa- The present report documents an extension to our recently ration prior to one or two therapist-supported drug sessions published pilot study assessing psilocybin with psychological followed by psychological integration. Using a consistent support for treatment-resistant depression. The number of pa- model (i.e. involving appropriate psychological support), tients treated was increased from 12 to 20 and the follow-up sustained improvements in well-being in healthy individuals period extended from 3 to 6 months. were observed after a single dose of psilocybin in a double- blind design incorporating an active placebo (Griffiths et al. 2008). Methods Studies involving other serotonergic psychedelics com- bined with psychological support have found similarly prom- Approvals and drug source ising outcomes: Sustained reductions in end-of-life anxiety were observed after LSD-assisted psychotherapy (Gasser This clinical trial received a favourable opinion from the et al. 2014), and reduced depressive symptoms were seen after National Research Ethics Service (NRES) London-West ayahuasca in patients with ‘recurrent depression’ (Osorio Fde London, was sponsored and approved by Imperial College et al. 2015; Sanches et al. 2016). Naturalistic, observational London’s Joint Research and Complication Organisation studies of ayahuasca support its long-term well-being promot- (JRCO), was adopted by the National Institute of Health ing and anti-addiction properties (Thomas et al. 2013; Bouso Research (NIHR) Clinical Research Network (CRN) and et al. 2012) and a recent population survey found lower rates was reviewed and approved by the Medicines and of suicidality and psychological distress in association with Healthcare products Regulatory Agency (MHRA). A Home psychedelic drug use (Hendricks et al. 2015)—an anomalous Office Licence for storage and dispensing of Schedule One association for a drug of potential misuse. Drug experts and drugs was obtained. Psilocybin was obtained from THC users have consistently rated psilocybin as the least harmful Pharm (Frankfurt) and formulated into the investigational me- and potentially ‘most beneficial’ drug of potential misuse dicinal product (5 mg psilocybin in size 0 capsules) by Guy’s (Carhart-Harris and Nutt 2013; van Amsterdam et al. and St Thomas’ Hospital’s Pharmacy Manufacturing Unit 2015)—although the influence of context (e.g. expectations (London, UK). and environmental factors) on potential harms and benefits has been much emphasised (Hartogsohn 2016;Carhart- Study design Harris et al., in review). Further evidence favouring the ther- apeutic potential of psychedelics can be found in literature This was an open-label feasibility study in 20 patients with documenting the extensive research carried out with these treatment-resistant depression. Treatment involved two oral compounds in the mid-twentieth century, e.g. two relevant doses of psilocybin (10 and 25 mg), 7 days apart. The primary meta-analyses have found positive safety and efficacy data outcome was mean change in the severity of self-reported for LSD for alcohol dependence (Krebs and Johansen 2012) (SR) depressive symptoms (measured primarily with the 16- Psychopharmacology item Quick Inventory of Depressive Symptoms, QIDS-SR16) received 10 mg psilocybin and in the second, 25 mg. from baseline to specific time points after the high-dose psi- Patients were seen the following day for debriefing and a locybin session (henceforth referred to as ‘post-treatment’). post-treatment MRI scan, and for one final time 1 week after QIDS-SR16 ratings were collected 1–3and5weeksand3 the 25-mg session. Subsequent follow-up measures were col- and 6 months post-treatment, with 5 weeks post-treatment lected remotely. Patients emailed their completed question- regarded as the primary endpoint. BDI (depression) and naires to the study team. Six-month follow-up interviews were STAI (anxiety) ratings were collected at 1 week and 3 and carried out by