Psilocybin administration to healthy participants: safety and feasibility W111 in a placebo-controlled study James Rucker,1 Allan Young,1 Catherine Bird,1 Aster Daniel,2 Molly Lennard-Jones,3 Lindsey Marwood,3 Kristina Grace Posadas,2 Frederick Reinholdt,1 Francesco Saldarini,3 Susan Stansfield,3 Sam Williams,3 Neil Weston,1 Hans Eriksson,3 Ekaterina Malievskaia3 1South London and Maudsley NHS Foundation Trust and Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK; 2Clinical Research Facility, King’s College Hospital, London, UK; 3COMPASS Pathways Ltd, London, UK

• Initial screening (Visit 1) took place in the 8 weeks before study drug Table 1. Participant demographics (safety population) Figure 5. Most frequent AEs: onset and duration by treatment arm administration and included an evaluation of medical and psychiatric AE onset day: 0 (day of drug administration) 1 day post-administration Background Parameter 25mg 10mg Placebo Overall history, completion of the Mini International Neuropsychiatric Interview, psilocybin psilocybin (n=29) (n=89) 2 to 7 days post-administration Ͼ1 week post-administration • Treatment-resistant depression remains a significant unmet medical need. assessment of prior/concomitant drug use, and a physical health check (n=30) (n=30) From an antidepressant drug-development perspective, interest in recent 25mg psilocybin 10510 Sex, n (%) 1 day 10mg psilocybin years has been directed at compounds with known pharmacology • Baseline assessments were completed 1 day before study drug 102 Placebo 38 administration, including assessments of emotional processing and Male 16 (53.3) 16 (53.3) 16 (55.2) 48 (53.9) • Psilocybin belongs to a class of drugs referred to as psychedelics cognitive function. During this visit, participants took part in a 2-hour Female 14 (46.7) 14 (46.7) 13 (44.8) 41 (46.1) 25mg psilocybin 9 (‘mind-manifesting’). Partial agonism of 5-HT2A receptors is a key 2 days 10mg psilocybin 11 preparatory group session with the study psychiatrist, lead therapist, and Ethnicity, n (%) mechanism contributing to its biological effects1,2 Placebo assisting therapists AE White 25 (83.3) 27 (90.0) 20 (69.0) 72 (80.9) • Psilocybin was used in psychiatric research and psychodynamic-orientated 25mg psilocybin 4 • On the day following drug administration, participants returned to the 3 to 7 days psychotherapy from the early 1960s, until it became a Schedule 1 Asian 2 (6.7) 1 (3.3) 3 (10.3) 6 (6.7) 10mg psilocybin clinic for a safety check and to discuss their experience with a therapist ation of Placebo substance in the US in 19702,3 Mixed 2 (6.7) 1 (3.3) 1 (3.4) 4 (4.5) Dur • All AEs that occurred after the signing of informed consent were recorded. 25mg psilocybin • More recently, several small studies have indicated efficacy of psilocybin Black - - 1 (3.4) 1 (1.1) All AEs occurring before the start of treatment were recorded as medical 8 to 28 days 10mg psilocybin in depressive states.4–7 Psilocybin is now in clinical development for Other 1 (3.3) 1 (3.3) 4 (13.8) 6 (6.7) history Placebo treatment-resistant depression in the US, Canada, and Europe COMP360 (psilocybin) Age at screening, years 25mg psilocybin • The safety population consisted of all randomised participants who • We present safety data from an exploratory phase I study (EudraCT Mean (SD) 36.6 (10.29) 36.1 (9.25) 35.6 (7.69) 36.1 (9.06) Ͼ28 days 10mg psilocybin received study treatment Placebo 2018-000978-30) that evaluated the feasibility and safety of simultaneous BMI, kg/m2 psilocybin administration with 1:1 psychological support in healthy • Follow-up visits were conducted via telephone on Day 7 ( 1 day), 0 10 20 30 40 50 60 70 80 90 100110 120 Mean (SD) 23.0 (3.74) 23.0 (2.89) 23.7 (3.49) 23.2 (3.37) participants Day 28 ( 7 days), and Day 84 ( 7 days) Number of events Prior psilocybin experience The most frequent AEs were (number of events in parentheses): illusion (56); mood altered (54); hallucination, visual (44); was well tolerated in Yes 11 (36.7) 15 (50.0) 7 (24.1) 33 (37.1) headache (33); fatigue (21); somatic hallucinations (19); euphoric mood (14); paraesthesia (12); tension headache (12); time perception altered (11); hallucination, auditory (9); affect lability (9) No 19 (63.3) 15 (50.0) 22 (75.9) 56 (62.9) Results AE, adverse event Methods BMI, body mass index; SD, standard deviation Participant disposition and demographics Table 2. Reported ‘mood altered’ AEs (ranked by incidence in the 25mg psilocybin group) Study design • Figure 2 presents participant disposition Description of 25mg 10mg Placebo Overall • This was a phase I, randomised, double-blind, placebo-controlled study to healthy participants Adverse events ‘mood altered’ event psilocybin psilocybin (n=29) (n=89) (n=30) (n=30) evaluate the effects of 10mg and 25mg COMP360 (psilocybin) compared Figure 2. Study flow diagram • 511 AEs were reported throughout the 12-week duration of the study: with placebo in healthy participants, conducted at the Institute of Introspection 8 5 2 15 Screened 217 in the 25mg psilocybin arm (reported by 96.7% of participants); 203 in Psychiatry, Psychology & Neuroscience, London, UK n=126 the 10mg psilocybin arm (reported by 96.7% of participants); and 91 in the Reflections 4 3 2 9 Sense of oneness 2 4 0 6 • Participants, stratified by sex and age (18–35 years old; 35 years old), Excluded placebo arm (reported by 89.7% of participants) n=36 Increased empathy 2 2 0 4 were randomised in a 1:1:1 ratio to placebo, 10mg psilocybin, or Baseline and results support • Of these, 473 (92.6%) AEs were deemed by the investigators to Contemplative state 1 1 0 2 25mg psilocybin, administered orally n=90 potentially be related to study treatment, including 208 (95.9%) in the Laughter 1 1 0 2 • Figure 1 presents an overview of the scheduled study visits Excluded 25mg psilocybin arm, 188 (92.6%) in the 10mg psilocybin arm, and Clarity of thought 1 0 0 1 n=1 77 (84.6%) in the placebo arm Increased compassion 1 0 0 1 • During administration sessions, each participant received 1:1 support from Randomisation a trained assisting therapist and was supervised by a study psychiatrist n=89 • There were no SAEs, and no AEs led to withdrawal Increased creativity 1 0 0 1 Increased sense of connectedness 1 0 0 1 and a lead therapist. Each session lasted approximately 6 hours, with further investigation • Figure 4 presents the most frequently reported AEs (based on the More socially upbeat 1 0 0 1 participants encouraged to relax and engage in introspection for 25mg psilocybin arm), split by treatment arm 25mg psilocybin 10mg psilocybin Placebo Saw themselves from a new perspective 1 0 0 1 the duration. After the acute effects of the study drug had subsided, n=30 n=30 n=29 participants were discharged Non-completers Being less judgemental 0 1 0 1 n=4: Figure 4. Most frequently reported AEs (MedDRA code)a Feeling more moody/sensitive 0 1 0 1 • The study drug was administered simultaneously to groups of up to 3 lost to follow-up 1 protocol violation 25mg psilocybin 10mg psilocybin Placebo Feeling rested 0 1 0 1 6 participants Completers Completers Completers n=30 n=30 n=25 Increased wit 0 1 0 1 of simultaneous b Participants Hallucination Sense of openness 0 1 0 1 Unusual appreciation of music 0 0 1 1 Illusion • Key inclusion criteria: • Participant demographics are summarised in Table 1 Calm 0 0 1 1 —— Males or females aged between 18 and 65 years at screening Mood altered Feeling of adrenaline release 0 0 1 1 Dosing sessions • Key exclusion criteria: Headache Negative mood 0 0 1 1 • 25 dosing sessions were completed, with up to 6 participants per session 1:1 therapeutic AE, adverse event —— Current or past history of schizophrenia, psychosis, bipolar disorder, Euphoric mood (Figure 3) delusional disorder, paranoid personality disorder, schizoaffective Fatigue disorder, borderline personality disorder, major depression, panic Figure 3. Dosing sessions by group size disorder, generalised anxiety disorder, obsessive-compulsive disorder, Emotional disorder 1 Conclusions eating disorder, or body dysmorphic disorder Time perception altered • Psilocybin formulation COMP360 was well tolerated; there were no 2 —— History of the above psychiatric conditions in a first degree relative administration SAEs, and no AEs led to withdrawal Tension headache

—— Current, or history of, substance dependency or abuse code) AEs (MedDRA 3 • This study confirmed the feasibility of simultaneous psilocybin —— Current or recent (1 year) psychiatric medications Somatic hallucination 4 administration to healthy participants in a controlled setting with —— Prior psilocybin exposure within 1 year of signing of informed consent Hypoaesthesia 1:1 support from trained therapists, as demonstrated by high 5 retention rates, low levels of missing data and the willingness of Paraesthesia Assessments participants to undergo simultaneous administration and group 6 • Safety endpoints included: Affect lability preparation

—— Vital signs Mental fatigue • Psychedelic effects associated with psilocybin administration were Effects on cognition and emotional function transient and consistent with previous studies —— Suicidality, measured using the Sheehan Suicidality Tracking Scale Nausea • Extensive assessments of cognitive and emotional functions showed no —— Adverse events (AEs) and serious AEs (SAEs) negative impact of psilocybin. The results of these assessments will be —— Clinical laboratory tests 0 5 10 15 20 25 30 35 presented in future publications Number of events reported References 1. Halberstadt AL, Geyer MA. Neuropharmacology 2011; 61(3): 364–381

a Figure 1. Schedule of visits Ranked by incidence in the 25mg psilocybin group 2. Passie T et al. Addict Biol 2002; 7(4): 357–364 bIncludes auditory, gustatory, olfactory, tactile, and visual hallucinations 3. Passie T. A History of the Use of Psilocybin in Psychotherapy. In: Metzner R, ed. Sacred mushroom of visions: Teonanacatl: Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities A sourcebook on the psilocybin mushroom. Simon and Schuster; 2005: 113–138 (Day –56 to –2) (Day –1) (Day 0) (Day 1) (Day 7) (Day 28) (Day 84) 4. Griffiths RR et al. J Psychopharmacol 2016; 30(12): 1181–1197 5. Carhart-Harris RL et al. Psychopharmacology (Berl) 2018; 235(2): 399–408 • The median duration of AEs in all treatment arms across the 12-week trial 6. Grob CS et al. Arch Gen Psychiatry 2011; 68(1): 71–78 7. Ross S et al. J Psychopharmacol 2016; 30(12): 1165–1180 Eligibility Baseline Randomisation Follow-up Follow-up Follow-up Follow-up was 1 day screening assessments and dosing at clinic by telephone by telephone by telephone • Onset and duration of AEs by treatment arm are summarised in Figure 5 Informed consent form 3 Disclosures —— 67% of all AEs appeared and resolved on Day 0 (day of dosing) James Rucker has received grant and congress funding from COMPASS Pathways Ltd. Medical and psychiatric history 3 Allan Young has received honoraria for attending advisory boards and presenting lectures for Allergan, AstraZeneca, Bionomics, —— 92% of AEs likely to be psychedelic in nature were resolved by Day 1 Eli Lilly, Janssen, LivaNova, Lundbeck, Servier, Sumitomo Dainippon Pharma, and Sunovion; and has received consulting fees from Preparatory session 3 Johnson & Johnson and LivaNova. • Mood alteration was one of the most frequently reported AEs; 57 AEs Catherine Bird has received research funding from COMPASS Pathways Ltd. Dosing 3 of ‘mood altered’ were reported (grouped according to regulatory Aster Daniel receives salary support from COMPASS Pathways Ltd. Integration session 3 requirements in MedDRA terms), of which 2 were negative alterations in Molly Lennard-Jones, Lindsey Marwood, Frederick Reinholdt, Francesco Saldarini, Susan Stansfield, Sam Williams, Hans Eriksson, mood: 1 in the placebo arm (‘negative mood’, which started and resolved and Ekaterina Malievskaia are employees of COMPASS Pathways Ltd. Vital signs 3 3 3 Kristina Grace Posadas and Neil Weston have no conflicts of interest. on Day 0) and 1 in the 10mg psilocybin arm (‘feeling moody or sensitive’, Clinical laboratory tests 3 3 which appeared on Day 2 and lasted 8 days) Acknowledgements Recording of adverse events 3 3 3 3 3 3 3 • Table 2 shows the frequency of specific ‘mood altered’ AEs. Most ‘mood altered’ Medical writing support, under the direction of the authors, was provided by Paul O’Neill, PhD, of CMC AFFINITY, a division of McCann Health Medical Communications Ltd, Glasgow, Cognitive function 3 3 3 AEs were positive or neutral in nature (96%), by a post-hoc adjudication UK, in accordance with Good Publication Practice (GPP3) guidelines. 3 3 3 3 This assistance was funded by COMPASS Pathways Ltd, London, UK. Emotional processing • No clinically relevant changes in vital signs were observed

COMPASS Pathways Ltd is a UK private limited (by shares) company registered in England and Wales Poster presented at the 58th Annual Meeting of The American College of Neuropsychopharmacology, Orlando, FL, USA, 8–11 December 2019 with company #10229259 and its registered office at 16 Old Bailey, London EC4M 7EG