The effects of psilocybin on cognitive and emotional functions in healthy participants : Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparation, James J Rucker et al., 2021

The effects of psilocybin on cognitive and emotional functions in healthy participants : Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparation

James J Rucker, Lindsey Marwood, Riikka-Liisa J Ajantaival, Catherine Bird, Hans Eriksson, John Harrison, Molly Lennard-Jones, Sunil Mistry, Francesco Saldarini, Susan Stansfield, Sara J Tai, Sam Williams, Neil Weston, Ekaterina Malievskaia and Allan H Young




Background : Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin’s effects on cognitive function have not been widely or systematically studied.

Aim : The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring.

Methods : In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants (n = 89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with oneto- one psychological support – each participant having an assigned, dedicated therapist available throughout the session.

Results : In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores.

Conclusions : These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing.

Clinical Trial Registration : EudraCT ( number: 2018-000978-30.

Keywords : Psilocybin, cognition, emotional processing, placebo-controlled, randomised clinical trial



Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a naturally occurring psychoactive alkaloid, first isolated from Psilocybe mushrooms (Passie et al., 2002). Alongside other tryptamines, including dimethyltryptamine (DMT) and ergolines such as lysergic acid diethylamide (LSD), psilocybin is a partial agonist of serotonin (5-hydroxytryptamine; 5-HT) receptors (Halberstadt and Geyer, 2011) and belongs to a class of drugs called ‘psychedelics’ (Carhart-Harris et al., 2016). Psilocybe mushrooms, and other psychedelic plants such as peyote and ayahuasca, have been used by Central and South American native groups in sacred spiritual and healing ceremonies for thousands of years (Clarke, 2007). In the West, psilocybin has been used in psychiatric research and in psychodynamic-orientated psychotherapy from the early to mid-1960s, after it was first isolated and later synthesised by Albert Hofmann in 1957 and 1958, respectively (Hofmann et al., 1958, 1959). This research on the effects of psilocybin largely halted when it became a Schedule 1 substance due to international legal controls (Rucker et al., 2020), before a resurgence in the mid-1990s (Passie, 2005; Passie et al., 2002).

Psilocybin produces a non-ordinary state of consciousness characterised by changes in emotional state and perception, including experiences of self, space and time (Hasler et al., 2004; Kraehenmann et al., 2015; Vollenweider et al., 1998, 2007). Previous reports suggest that the psychoactive effects of psilocybin are mainly attributable to partial agonism of the 5HT2A receptor subtype (Halberstadt and Geyer, 2011; Madsen et al., 2019; Passie et al., 2002; Vollenweider et al., 1998).

Pilot studies have reported on the efficacy of psilocybin in, for example, treatment-resistant depression (Carhart-Harris et al., 2016, 2018), major depressive disorder (Davis et al., 2021), terminal- cancer–related anxiety (Griffiths et al., 2016; Grob et al., 2011; Ross et al., 2016), obsessive-compulsive disorder (OCD) (Moreno et al., 2006) and alcohol and nicotine dependence (Bogenschutz et al., 2015; Johnson et al., 2014). All reported encouraging efficacy findings, with minimal adverse events (AEs), although these results should be interpreted with caution given that some studies were not specifically designed to robustly test psilocybin’s efficacy (e.g. some had open-label designs or lacked a placebo control arm) and all were limited by small sample sizes. Results from a systematic review of studies conducted prior to psilocybin prohibition in the 1970s were also encouraging (Rucker et al., 2016).

Neural correlates of cognitive and emotional processing are considered important therapeutic targets in the development of novel treatments for treatment-resistant depression and other mental disorders. Recent studies demonstrated that psilocybin and similar psychedelics modulate neural circuits implicated in affective disorders, with potential to reduce clinical symptoms of depression (Carhart-Harris et al., 2012, 2016, 2018).

Social cognitive functioning is an influential factor in the development, progression and treatment of many mental health problems. Deficits in social cognition represent key characteristics of many psychiatric and neurological disorders (Cotter et al., 2018) and may compromise real-world functioning across various settings, including work and independent living (Arioli et al., 2018; Jones et al., 2015). Current interventions for psychiatric disorders include psychosocial techniques, such as psychotherapies and occupational therapy and/or social environment and role interventions, as well as pharmacological treatments. Although these interventions are successful for some, they fail others and are only partially successful in many. Lack of an adequate breadth of interventions for mental health problems, combined with an increasingly overt impact, highlights an urgent need for alternative approaches (NHS Digital, 2014). Given this unmet need for improved treatment of social and emotional functioning deficits, a better understanding of the short- and long-term effects of psilocybin on emotional processing and social cognition is required.

The serotonin system has been reported to represent a promising target for pharmacological modulation of social and emotional functioning and has been implicated in the pathophysiology of various mental health problems (Ciranna, 2006; Švob Štrac et al., 2016). Increasing serotonin levels in healthy participants by administering a selective serotonin reuptake inhibitor promoted prosocial behaviour in one study (Crockett et al., 2010) and reduced processing of negative emotional stimuli in another (Harmer et al., 2004); however, since serotonin reuptake inhibitors block 5-HT uptake, such studies do not provide information on specific 5-HT-receptor functioning in social and emotional functioning. Since psilocybin is a preferential partial agonist of the 5-HT2A and 5-HT1A receptors, it is well-suited for investigation of the relative contributions of these subtypes to aspects of emotional processing. In healthy participants, 5-HT2A/1A-receptor stimulation following psilocybin administration acutely enhanced mood and empathy (Mason et al., 2019; Pokorny et al., 2017), prosocial behaviour (Gabay et al., 2018) and attenuated processing of negative facial expressions and social pain (Bernasconi et al., 2014; Kometer et al., 2012; Preller et al., 2016). While these acute effects of psilocybin indicate that serotonin receptor stimulation is a promising target for improvement of emotional processing, investigation of the longer-term effects is of clinical relevance, as it is unclear whether psilocybin’s prosocial effects persist post-acutely. Furthermore, it has not yet been investigated whether the beneficial effects of psilocybin may also benefit general cognitive abilities. Given the potential for psilocybin as a treatment for a range of conditions, studying its effects on cognition is important.

This study aimed to evaluate the safety and feasibility of simultaneous administration of single doses of either 10 or 25 mg doses of psilocybin compared with placebo in healthy participants, administered in a supervised setting with one-to-one psychological support, and to assess the short- and long-term effects of psilocybin on key domains of cognitive functioning. To our knowledge, this represents the largest randomised controlled trial of psilocybin to date. It is important to study the safety and feasibility of this model of simultaneous administration as it could be a more effective, time- and cost-efficient model of treatment delivery, meaning more patients could potentially benefit from this treatment, if approved. While the psychological support in psilocybin therapy delivered before and after psilocybin administration has been administered in group settings in another recent study by Anderson et al. (2020), the actual administration of psilocybin has only been given on an individual basis in modern studies, to date. Prior to the implementation of legal constraints surrounding psychedelics and subsequent assignment of psilocybin and LSD as Schedule 1 substances, several studies did administer psychedelics and/or psychedelic therapy sessions in a group setting (e.g. Harman et al., 1966; Leary et al., 1963; Pahnke, 1963). This study is the first study since the revival of psychedelic research, to our knowledge, to administer psilocybin to participants simultaneously.