Crises induce a wide range of psychological reactions, with varying degrees of adaptability. The combination of uncertainty and social distancing induced by the COVID-19 pandemic can lead to excessive fear/anxiety, loneliness and depressive thoughts (Holmes et al. Reference Holmes, O’Connor, Perry, Tracey, Wessely, Arseneault, Ballard, Christensen, Cohen Silver, Everall, Ford, John, Kabir, King, Madan, Michie, Przybylski, Shafran, Sweeney, Worthman, Yardley, Cowan, Cope, Hotopf and Bullmore2020, Luykx et al. Reference Luykx, Vinkers and Tijdink2020, Vindegaard & Benros, Reference Vindegaard and Benros2020). While the medium- to long-term mental health consequences are not yet known, an increase in psychological and psychiatric problems are predicted (Horesh & Brown, Reference Horesh and Brown2020, O’Connor et al. Reference O’Connor, Wrigley, Jennings, Hill and Niazi2020, Türközer & Öngür, Reference Türközer and Öngür2020), with an excess burden on vulnerable groups (Kelly, Reference Kelly2020). The implementation of a range of multidisciplinary strategies across socio-economic and psychological levels may be needed to mitigate the mental health burden of COVID-19.
Accumulating clinical data shows that psilocybin therapy may be an effective therapeutic strategy across a range of disorders, including depression (Carhart-Harris et al. Reference Carhart-Harris, Bolstridge, Rucker, Day, Erritzoe, Kaelen, Bloomfield, Rickard, Forbes, Feilding, Taylor, Pilling, Curran and Nutt2016, Davis et al. Reference Davis, May, Cosimano, Johnson, Barrett and Griffiths2019), obsessive compulsive disorder (Moreno et al. Reference Moreno, Wiegand, Taitano and Delgado2006) and addiction disorders (Garcia-Romeu et al. Reference Garcia-Romeu, Davis, Erowid, Erowid, Griffiths and Johnson2019, Johnson et al. Reference Johnson, Garcia-Romeu and Griffiths2017). In addition, clinical trials are underway to investigate psilocybin therapy in anorexia nervosa (NCT04052568) and there may be a role for psilocybin therapy in the treatment of anxiety disorders (Weston et al. Reference Weston, Gibbs, Bird, Daniel, Jelen, Knight, Goldsmith, Young and Rucker2020).
Recent advances in psychedelic science are gradually unravelling the multimodal mechanisms underlying the therapeutic effect of psilocybin therapy (for example Carhart-Harris & Friston, Reference Carhart-Harris and Friston2019, Lord et al. Reference Lord, Expert, Atasoy, Roseman, Rapuano, Lambiotte, Nutt, Deco, Carhart-Harris, Kringelbach and Cabral2019, Preller et al. Reference Preller, Duerler, Burt, Ji, Adkinson, Stämpfli, Seifritz, Repovš, Krystal, Murray, Anticevic and Vollenweider2020, Varley et al. Reference Varley, Carhart-Harris, Roseman, Menon and Stamatakis2020). Psilocybin reliably alters an individual’s state of consciousness, probably through agonist mechanisms at the 5-HT2A receptor, especially in the deep pyramidal cells in the cortex (Nutt et al. Reference Nutt, Erritzoe and Carhart-Harris2020). The transient, dose-dependent alteration of the complex interconnected neural networks of the brain (Lord et al. Reference Lord, Expert, Atasoy, Roseman, Rapuano, Lambiotte, Nutt, Deco, Carhart-Harris, Kringelbach and Cabral2019, Varley et al. Reference Varley, Carhart-Harris, Roseman, Menon and Stamatakis2020) encompassing the self-reflecting ‘ego’, induced by psilocybin, can lead to profound experiences of connectivity to others and the environment (Erritzoe et al. Reference Erritzoe, Roseman, Nour, MacLean, Kaelen, Nutt and Carhart-Harris2018, Griffiths et al. 2006, Reference Griffiths, Johnson, Carducci, Umbricht, Richards, Richards, Cosimano and Klinedinst2016, Grob et al. Reference Grob, Danforth, Chopra, Hagerty, McKay, Halberstadt and Greer2011, Kettner et al. Reference Kettner, Gandy, Haijen and Carhart-Harris2019, Smigielski et al. Reference Smigielski, Scheidegger, Kometer and Vollenweider2019) and can be harnessed by psilocybin therapy to re-conceptualise restricted and maladaptive habitual patterns of cognition and behaviour.
As such, psilocybin therapy provides a translatable, transdiagnostic treatment strategy that can be further refined by a precise-personalised approach (Kelly et al. Reference Kelly, Clarke, Cryan and Dinan2017, Lewis et al. Reference Lewis, Preller, Braden, Riecken and Vollenweider2020, Preller et al. 2016, Reference Preller, Duerler, Burt, Ji, Adkinson, Stämpfli, Seifritz, Repovš, Krystal, Murray, Anticevic and Vollenweider2020, Studerus et al. Reference Studerus, Gamma, Kometer and Vollenweider2012). Advancing precise-personalised psilocybin therapy is of particular importance given the individual variation in responses, high rates of relapse in psychiatric disorders and contraindication in psychotic and manic conditions (Carhart-Harris et al. Reference Carhart-Harris, Bolstridge, Day, Rucker, Watts, Erritzoe, Kaelen, Giribaldi, Bloomfield, Pilling, Rickard, Forbes, Feilding, Taylor, Curran and Nutt2018). It has been suggested that internalising disorders may be a useful broad construct for the therapeutic application of psilocybin therapy (Nutt & Carhart-Harris, Reference Nutt and Carhart-Harris2020). Moreover, given the transdiagnostic potential, a dimensional framework (Insel, Reference Insel2014) that aligns with bio-psycho signatures could also be leveraged to enhance the targeted application of psilocybin therapy and further unravel the mechanisms underpinning the acute and persistent therapeutic effects. Indeed, further exploration of psilocybin’s impact on neuroimmunoendocrine pathways (Galvão et al. Reference Galvão, de Almeida, Silva, Freire, Palhano-Fontes, Onias, Arcoverde, Maia-de-Oliveira, de Araújo, Lobão-Soares and Galvão-Coelho2018, Hasler et al. Reference Hasler, Grimberg, Benz, Huber and Vollenweider2004, Nau et al. Reference Nau, Yu, Martin and Nichols2013, Strajhar et al. Reference Strajhar, Schmid, Liakoni, Dolder, Rentsch, Kratschmar, Odermatt and Liechti2016, Szabo, Reference Szabo2015), including the microbiome–gut–brain axis, may provide additional insights into the persisting therapeutic effects (Kelly et al. Reference Kelly, Keane, Cryan, Clarke and Dinan2019c, Kuypers, Reference Kuypers2019).
Notwithstanding the limitations of animal models in fully capturing the different aspects of psilocybin therapy (Jefsen et al. Reference Jefsen, Højgaard, Christiansen, Elfving, Nutt, Wegener and Müller2019, Meinhardt et al. Reference Meinhardt, Güngör, Skorodumov, Mertens and Spanagel2020), preclinical data have shown that serotonergic psychedelics, including psilocybin, can induce hippocampal neurogenesis (Catlow et al. Reference Catlow, Song, Paredes, Kirstein and Sanchez-Ramos2013, Morales-Garcia et al. Reference Morales-Garcia, de la Fuente Revenga, Alonso-Gil, Rodriguez-Franco, Feilding, Perez-Castillo and Riba2017, Vaidya et al. Reference Vaidya, Marek, Aghajanian and Duman1997), promote dendritic spine growth and stimulate synapse formation in the prefrontal cortex (González-Maeso et al. Reference González-Maeso, Weisstaub, Zhou, Chan, Ivic, Ang, Lira, Bradley-Moore, Ge, Zhou, Sealfon and Gingrich2007, Ly et al. Reference Ly, Greb, Cameron, Wong, Barragan, Wilson, Burbach, Soltanzadeh Zarandi, Sood, Paddy, Duim, Dennis, McAllister, Ori-McKenney, Gray and Olson2018). Preclinical data also suggest that psychedelics lead to 5-HT2A receptor-mediated glutamate release (Ly et al. Reference Ly, Greb, Cameron, Wong, Barragan, Wilson, Burbach, Soltanzadeh Zarandi, Sood, Paddy, Duim, Dennis, McAllister, Ori-McKenney, Gray and Olson2018), and a recent magnetic resonance spectroscopy study in healthy humans found that psilocybin administration was associated with increased glutamate in the medial prefrontal cortex (Mason et al. Reference Mason, Kuypers, Müller, Reckweg, Tse, Toennes, Hutten, Jansen, Stiers, Feilding and Ramaekers2020).
Researchers from the Center for Psychedelic and Consciousness Research at Johns Hopkins University recently focussed on the claustrum, a thin sheet of grey matter, embedded in the white matter of the cerebral hemispheres and situated between the putamen and the insular cortex, with a rich supply of 5-HT2A receptors and glutamatergic connectivity to the cerebral cortex, and thought to be associated with cognitive task switching (Barrett et al. Reference Barrett, Krimmel, Griffiths, Seminowicz and Mathur2020b, Krimmel et al. Reference Krimmel, White, Panicker, Barrett, Mathur and Seminowicz2019). Psilocybin acutely reduced claustrum activity and altered its connectivity with the default mode network and frontoparietal task control network, in a study involving 15 healthy volunteers, thus implicating this region as a key mediator in psilocybin therapy (Barrett et al. Reference Barrett, Krimmel, Griffiths, Seminowicz and Mathur2020b).
The same research group, in an open-label pilot study of 12 healthy volunteers, showed that psilocybin reduced both negative affect and amygdala responses to emotional stimuli 1 week after psilocybin, whereas by 1 month after psilocybin the responses returned to baseline (Barrett et al. Reference Barrett, Doss, Sepeda, Pekar and Griffiths2020a). At both 1 week and 1 month after psilocybin, there were global increases in brain functional connectivity (Barrett et al. Reference Barrett, Doss, Sepeda, Pekar and Griffiths2020a). A previous study in healthy controls also showed reduced amygdala reactivity, particularly on the right side, to negative and neutral stimuli due to psilocybin (Kraehenmann et al. Reference Kraehenmann, Preller, Scheidegger, Pokorny, Bosch, Seifritz and Vollenweider2015). In contrast, an open-label study of 19 subjects with treatment-resistant depression (TRD) showed that psilocybin increased amygdala responses to emotional faces (Roseman et al. Reference Roseman, Demetriou, Wall, Nutt and Carhart-Harris2018) and decreased functional connectivity between the ventromedial prefrontal cortex and the right amygdala 1 day after psilocybin (Mertens et al. Reference Mertens, Wall, Roseman, Demetriou, Nutt and Carhart-Harris2020). Larger studies may be needed to resolve the complexities.
In the midst of this evolving ‘Psychedelic Revolution in Psychiatry’ (Nutt et al. Reference Nutt, Erritzoe and Carhart-Harris2020) and potential increasing recreational psychedelic use, albeit from 0.55% in 2015 to 0.86% in 2018, in a sample of 168,000 members of the public (Yockey et al. Reference Yockey, Vidourek and King2020), the Royal Australian and New Zealand College of Psychiatrists (RANZCP) recently published a clinical memorandum on the ‘Therapeutic use of psychedelic substances’ (RANZCP, 2020). This memorandum acknowledges not only the emerging therapeutic potential of psychedelics but also the need for more efficacy and safety data, particularly on potential long-term effects, to inform future potential use in psychiatric practice.
In terms of acceptability and tolerability, results from the Global Drug Survey (2019) of 85,000 people showed only 18% of those surveyed, who have never used psychedelics, said they would accept psilocybin therapy for depression or PTSD, increasing to 59% in those who had previously tried psychedelics (Winstock & Johnson, Reference Winstock and Johnson2019). The reported fears related to ‘brain damage and bad trips’ (Winstock & Johnson, Reference Winstock and Johnson2019). Psilocybin therapy data from John Hopkins University, over a 16-year period, encompassing 250 volunteers and 380 sessions, reported no major psychological issues, with 0.9% of volunteers experiencing minor and transient psychological issues (Carbonaro et al. Reference Carbonaro, Bradstreet, Barrett, MacLean, Jesse, Johnson and Griffiths2016). However, high-quality clinical data on the long-term effects of psychedelics are lacking. For example, there is very limited data on hallucinogen-persisting perception disorder (HPPD), a rare condition that involves the continued presence of sensory disturbances (Halpern et al. Reference Halpern, Lerner and Passie2018; Martinotti et al. Reference Martinotti, Santacroce, Pettorruso, Montemitro, Spano, Lorusso, di Giannantonio and Lerner2018; Orsolini et al. Reference Orsolini, Papanti, De Berardis, Guirguis, Corkery and Schifano2017). A review by Halpern and colleagues suggests that HPPD is, in most cases, due to a ‘subtle over-activation of predominantly neural visual pathways that worsens anxiety after ingestion of arousal-altering drugs, including non-hallucinogenic substances’ (Halpern et al. Reference Halpern, Lerner and Passie2018). The authors note that a personal or family history of anxiety and pre-drug use complaints of tinnitus, eye floaters and concentration problems may predict vulnerability for HPPD (Halpern et al. Reference Halpern, Lerner and Passie2018). Similarly, the impact of regular psychedelic use on the brain is limited (Bouso et al. Reference Bouso, Palhano-Fontes, Rodríguez-Fornells, Ribeiro, Sanches, Crippa, Hallak, de Araujo and Riba2015; Halpern et al. Reference Halpern, Sherwood, Hudson, Yurgelun-Todd and Pope2005). Although, it is important to note that psilocybin therapy studies do not use regular dosing, using between 1 and at most 3 doses of psilocybin.
Dublin is one of the clinical trial centres participating in a double-blind randomised controlled phase 2b COMPASS trial of psilocybin therapy in TRD (COMP001) (Kelly et al. Reference Kelly, Baker, Babiker, Burke, Brennan and O’Keane2019a). Results from this large scale trial, and others, will address concerns regarding psilocybin safety, efficacy and dose optimisation. Moreover, we eagerly await the results from the potentially paradigm shifting, double-blind trial of psilocybin therapy versus the selective serotonin reuptake inhibitor (SSRI) escitalopram in depression from the Centre for Psychedelic Research at Imperial College London (Psilodep-RCT, NCT03429075) (Nutt & Carhart-Harris, Reference Nutt and Carhart-Harris2020) and acknowledge that for some people with depression, SSRIs and psilocybin may become ‘competitive options’ despite postulated mechanistic complementarity, with SSRIs enhancing 5-HT1AR pathway and psilocybin enhancing the 5-HT2AR pathway (Carhart-Harris & Nutt, Reference Carhart-Harris and Nutt2017). However, many people with depression may choose to remain on antidepressants (Kelly et al. Reference Kelly, Cosgrove, Judd, Scott, Loughlin and O’Keane2019b) and it is important to determine the safety and efficacy of this approach. 5-HT2AR antagonists, such as ketanserin, block the therapeutic effect of psilocybin (Preller et al. Reference Preller, Herdener, Pokorny, Planzer, Kraehenmann, Stämpfli, Liechti, Seifritz and Vollenweider2017), whereas the partial 5-HT1A agonist buspirone may exert inhibitory effects (Pokorny et al. Reference Pokorny, Preller, Kraehenmann and Vollenweider2016). However, apart from anecdotal evidence suggesting a blunted effect (Bonson et al. Reference Bonson, Buckholtz and Murphy1996; Bonson & Murphy, Reference Bonson and Murphy1996), psilocybin therapy in conjunction with SSRI’s has never been investigated in TRD.
The gradual emergence from COVID-19 lockdown will see the launch of a new COMPASS clinical study (COMP003) in Dublin and San Diego to determine the antidepressant effect of psilocybin therapy in people with TRD who continue SSRI medication. This exploratory open-label trial will aim to recruit 20 participants with a single or recurrent episode of at least moderate clinical depression between 3 months and 2 years duration that has not responded to an adequate dose and duration of at least two pharmacological treatments. A single dose of oral psilocybin of 25mg will be administered with psychological support to participants who have been taking an SSRI’s for at least 6 weeks. The results of this study could have important practical implications for the future of psilocybin therapy and may have implications for future phase 3 trials in TRD, which could pave the way for the integration of psilocybin therapy into clinical psychiatry.
However, both clinical and research psychiatry have been transformed by COVID-19, demanding additional strategies to overcome the considerable challenges (O’Brien & McNicholas, Reference O’Brien and McNicholas2020; Türközer & Öngür, Reference Türközer and Öngür2020). To mitigate the spread of COVID-19 and facilitate the safe reopening and progress of ongoing psilocybin trials, in line with local and national guidelines, a number of measures will be implemented. These include, for example, participant and researcher respiratory symptom checklists, regular temperature checks, access to COVID-19 testing (if indicated), meticulous attention to extra hygiene measures, personal protective equipment (where not expected to negatively impact the participant’s experience), and the option of remote study visits (where possible by the protocol). Notwithstanding the challenges and the early stage of clinical development, psilocybin therapy, at the forefront of translational neuroscience and psychiatry, is likely to play an important therapeutic role for certain conditions in post-COVID-19 clinical psychiatry.
COMP001 and COMP003 are funded by COMPASS Pathways.
Conflict of interest
Authors have no conflicts of interest to disclose.
The Cork Clinical Research Ethics Committee approved COMP001 and COMP003. The authors assert that all procedures contributing to this work comply with the ethical standards of the Cork Clinical Research Ethics Committee and with the Helsinki Declaration of 1975, as revised in 2008.