Psychedelic science in post-COVID-19 psychiatry

J. R. Kelly, M. T. Crockett, L. Alexander, M. Haran, A. Baker, L. Burke, C. Brennan and V. O’Keane

Key words : Coronavirus, COVID-19, depression, psilocybin, psychedelics, selective serotonin reuptake inhibitors, treatment- resistant depression.

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. 2020, Luykx et al. 2020, Vindegaard & Benros,2020). While the medium- to long-term mental health consequences are not yet known, an increase in psychological and psychiatric problems are predicted (Horesh & Brown, 2020, O’Connor et al. 2020, Türközer & Öngür, 2020), with an excess burden on vulnerable groups (Kelly, 2020). 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. 2016, Davis et al. 2019), obsessive compulsive disorder (Moreno et al. 2006) and addiction disorders (Garcia-Romeu et al. 2019, Johnson et al. 2017). In addition, clinical trials are under- way to investigate psilocybin therapy in anorexia nerv- osa (NCT04052568) and there may be a role for psilocybin therapy in the treatment of anxiety disorders (Weston et al. 2020).

Recent advances in psychedelic science are gradu- ally unravelling the multimodal mechanisms underly- ing the therapeutic effect of psilocybin therapy (for example Carhart-Harris & Friston, 2019, Lord et al. 2019, Preller et al. 2020, Varley et al. 2020). 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. 2020). The transient, dose-dependent alteration of the complex interconnected neural net- works of the brain (Lord et al. 2019, Varley et al. 2020) encompassing the self-reflecting ‘ego’, induced by psilocybin, can lead to profound experiences of connec- tivity to others and the environment (Erritzoe et al. 2018, Griffiths et al. 2006, 2016, Grob et al. 2011, Kettner et al. 2019, Smigielski et al. 2019) 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. 2017, Lewis et al. 2020, Preller et al. 2016, 2020, Studerus et al. 2012). 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. 2018). It has been suggested that internalising dis- orders may be a useful broad construct for the thera- peutic application of psilocybin therapy (Nutt & Carhart-Harris, 2020). Moreover, given the transdiag- nostic potential, a dimensional framework (Insel, 2014) 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. 2018, Hasler et al. 2004, Nau et al. 2013, Strajharet al. 2016, Szabo, 2015), including the microbiome– gut–brain axis, may provide additional insights into the persisting therapeutic effects (Kelly et al. 2019c, Kuypers, 2019).

Notwithstanding the limitations of animal models in fully capturing the different aspects of psilocybin therapy (Jefsen et al. 2019, Meinhardt et al. 2020), pre- clinical data have shown that serotonergic psyche- delics, including psilocybin, can induce hippocampal neurogenesis (Catlow et al. 2013, Morales-Garcia et al.2017, Vaidya et al. 1997), promote dendritic spine growth and stimulate synapse formation in the prefron- tal cortex (González-Maeso et al. 2007, Ly et al. 2018). Preclinical data also suggest that psychedelics lead to 5-HT2A receptor-mediated glutamate release (Ly et al. 2018), and a recent magnetic resonance spectroscopy study in healthy humans found that psilocybin admin- istration was associated with increased glutamate in the medial prefrontal cortex (Mason et al. 2020).

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 recep- tors and glutamatergic connectivity to the cerebral cor- tex, and thought to be associated with cognitive task switching (Barrett et al. 2020b, Krimmel et al. 2019). 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. 2020b).

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. 2020a). At both 1 week and 1 month after psilocybin, there were global increases in brain functional connectivity (Barrett et al. 2020a). 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. 2015). 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. 2018) and decreased functional connectivity between the ven- tromedial prefrontal cortex and the right amygdala 1 day after psilocybin (Mertens et al. 2020). Larger stud- ies may be needed to resolve the complexities.

In the midst of this evolving ‘Psychedelic Revolution in Psychiatry’ (Nutt et al. 2020) 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. 2020), 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 poten- tial 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, 2019). The reported fears related to ‘brain damage and bad trips’ (Winstock & Johnson, 2019). Psilocybin therapy data from John Hopkins University, over a 16-year period, encompassing 250 volunteers and 380 sessions, reported no major psycho- logical issues, with 0.9% of volunteers experiencing minor and transient psychological issues (Carbonaro et al. 2016). However, high-quality clinical data on the long-term effects of psychedelics are lacking. For exam- ple, there is very limited data on hallucinogen-persist- ing perception disorder (HPPD), a rare condition that involves the continued presence of sensory disturb- ances (Halpern et al. 2018; Martinotti et al. 2018; Orsolini et al. 2017). A review by Halpern and col- leagues 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. 2018). 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. 2018). Similarly, the impact of regular psychedelic use on the brain is limited (Bouso et al. 2015; Halpern et al. 2005). 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. 2019a). 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 poten- tially 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, 2020) and acknowledge that for some people with depression, SSRIs and psilocybin may become ‘com- petitive options’ despite postulated mechanistic complementarity, with SSRIs enhancing 5-HT1AR pathway and psilocybin enhancing the 5-HT2AR path- way (Carhart-Harris & Nutt, 2017). However, many people with depression may choose to remain on anti- depressants (Kelly et al. 2019b) 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. 2017), whereas the partial 5-HT1A agonist buspirone may exert inhibitory effects (Pokorny et al. 2016). However, apart from anecdotal evidence suggesting a blunted effect (Bonson et al. 1996; Bonson & Murphy, 1996), 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 explor- atory 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 dura- tion 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 admin- istered 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, 2020; Türközer & Öngür, 2020). To mitigate the spread of COVID-19 and facili- tate the safe reopening and progress of ongoing psilo- cybin trials, in line with local and national guidelines, a number of measures will be implemented. These include, for example, participant and researcher respi- ratory symptom checklists, regular temperature checks, access to COVID-19 testing (if indicated), meticulous attention to extra hygiene measures, personal protec- tive 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 fore- front of translational neuroscience and psychiatry, is likely to play an important therapeutic role for certain conditions in post-COVID-19 clinical psychiatry.

(…)