Damian Sendler: Even though an increase in mental health issues is predicted, the medium- and long-term effects of COVID-19 are not yet known. To lessen the impact of COVID-19 on one’s mental health, it may be necessary to employ a variety of approaches spanning the social, economic, and psychological spectrums. It appears that psilocybin therapy is a promising transdiagnostic treatment strategy for a range of disorders with restricted and maladaptive habitual patterns of cognition and behavior, including depression, substance abuse, and obsessive compulsive disorder. Phase 2b double-blind trial of psilocybin therapy in antidepressant-free, treatment-resistant depression (TRD) is underway to evaluate the safety, efficacy, and optimal dose of psilocybin. Imperial College London Psilodep-RCT results comparing the efficacy and mechanisms of action between psilocybin therapy and the selective serotonin reuptake inhibitor (SSRI) escitalopram are soon to be published. Efficacy and safety in treating TRD patients with a combination of psilocybin and SSRIs are still unknown. Psilocybin therapy may be affected in the future by the results of an additional COMPASS study, which will be conducted in Dublin. While still in its early stages of clinical development, psilocybin therapy has the potential to play an important therapeutic role in post-COVID-19 clinical psychiatry for a variety of mental disorders, despite the enormous challenges of COVID-19.
Damian Jacob Sendler: When faced with a crisis, people experience a wide range of emotions and exhibit varying degrees of adaptability. Anxiety, depression, and feelings of isolation are all possible outcomes of the COVID-19 pandemic because of the uncertainty it creates as well as the social isolation it causes (Holmes et al. 2020, Luykx et al. 2020, Vindegaard & Benros, 2020). A rise in psychological and psychiatric problems is expected in the medium to long term (Horesh and Brown, 2020; O’Connor and colleagues, 2020; Türközer and angullar, 2020), which will place an additional burden on those who are already at risk (Horsh and Brown, 2020; O’Connor et al., 2020; Türközer and angullar, 2020). (Kelly, 2020). COVID-19’s toll on people’s mental health may be lessened through the application of a variety of multidisciplinary strategies at the social, economic, and psychological levels.
Dr. Sendler: For a variety of disorders, including depression, OCD, and addiction, psilocybin therapy has been shown to be an effective therapeutic strategy (Carhart-Harris et al. 2016, Davis et al. 2019). (Garcia-Romeu et al. 2019, Johnson et al. 2017). In addition, psilocybin therapy for anorexia nervosa is being studied in clinical trials (NCT04052568), and psilocybin therapy may have a role in the treatment of anxiety disorders (Weston et al. 2020).
Damian Sendler
The therapeutic effects of psilocybin therapy are being gradually unraveled thanks to recent advances in psychedelic science (for example Carhart-Harris & Friston, 2019, Lord et al. 2019, Preller et al. 2020, Varley et al. 2020). Because of agonist mechanisms at the 5-HT2A receptor, psilocybin consistently alters a person’s state of consciousness, especially in the deep pyramidal cells of the cortex (Nutt et al. 2020). Transient, dose-dependent alteration of the complex interconnected neural networks of the brain (Lord et al. 2019) encompassing the self-reflecting “ego,” induced by psilocybin, can lead to profound experiences of connectivity with others and the environment, and can be harnessed by psilocybin therapy to re-conceptualise restricted and masked experiences (Erritzoe et al. 2018, Griffiths et al. 2006, 2016, Grob et al. 2011).
Since it can be used in other diagnostic contexts, the precise-personalized approach provided by psilocybin therapy allows for a translatable and transdiagnostic treatment strategy (Kelly et al. 2017, Lewis et al. 2020, Preller et al. 2016, 2020, Studerus et al. 2012). Psilocybin therapy is critical because of the wide range of responses, high relapse rates, and contraindications for people with psychosis and manic-depressive illness (Carhart-Harris et al. 2018). Psilocybin therapy may be useful in the treatment of internalizing disorders, according to some researchers (Nutt & Carhart-Harris, 2020). Psilocybin’s transdiagnostic potential could also be leveraged to enhance the targeted application of psilocybin therapy and further unravel mechanisms underpinning the acute and long-term therapeutic effects (Insel, 2014), as well as a dimensional framework (Insel, 2014). Even more research into the impact of psilocybin on neuroimmunoendocrine pathways, such as the microbiome-gut-brain-axis (Galvo, 2018; Hasler, 2004; Nau, 2013, Strajhar, 2016; Szabo, 2015), may shed light on the long-lasting therapeutic effects of the drug (Kelly et al. 2019c, Kuypers, 2019).
In spite of the limitations of animal models, preclinical data have shown that serotonergic psychedelics including psilocybin can induce hippocampal neurogenesis and promote dendritic spine growth and synapse formation in the prefrontal cortex (González-Maeso and colleagues 2007; Ly et al. 201; Catlow and colleagues 2013; Morales and colleagues 2017). 5-HT2A receptor-mediated glutamate release has been shown in preclinical studies (Ly et al., 2018), and a magnetic resonance spectroscopy study in healthy humans found that taking psilocybin led to an increase in glutamate in the medial prefrontal cortex after just one dose (Mason et al. 2020).
Damian Jacob Markiewicz Sendler: Psychedelic and consciousness researchers at Johns Hopkins University have been studying the claustrum, an area of grey matter that lies between the insular cortex and the putamen, and is thought to be involved in cognitive task switching. The claustrum contains a large number of 5-HT2A receptors and glutamatergic connections to the cerebral cortex (Barrett et al. 2020b, Krimmel et al. 2019). Using 15 healthy volunteers, psilocybin reduced the activity of the claustrum, as well as its connectivity with the default mode network and the frontoparietal task control network, indicating that this region is a key mediator in psilocybin therapy (Barrett et al. 2020b).
Research conducted by the same team found that psilocybin reduced negative affect and amygdala responses to emotional stimuli one week after psilocybin, but that the responses returned to baseline one month after psilocybin use (Barrett et al. 2020a). After psilocybin, there was a global increase in brain functional connectivity one week and one month later (Barrett et al. 2020a). Psilocybin reduced amygdala reactivity to negative and neutral stimuli in healthy controls, according to a previous study (Kraehenmann et al. 2015). One study of 19 people with TRD found that psilocybin decreased functional connectivity between the ventromedial prefrontal cortex and the right amygdala one day after psilocybin treatment (Roseman et al., 2018) but increased amygdala responses to emotional faces (Mertens et al. 2020). The complexities may necessitate additional research.
Damian Jacob Sendler
To address the ‘Psychedelic Revolution in Psychiatry’ (Nutt et al., 2020) and possible increases in recreational psychedelic use (from 0.55 percent to 0.86 percent, respectively, in 2015 and 2018), the Royal Australian and New Zealand College of Psychiatrists (RANZCP), published a clinical memorandum on ‘Therapeutic use of psychedelic substances’ (Yockey et al., 2020). (RANZCP, 2020). This memorandum acknowledges the therapeutic potential of psychedelics, but also the need for more efficacy and safety data, particularly on the potential long-term effects, to inform future use in psychiatric practice.
Acceptability and tolerance were measured by the Global Drug Survey (2019), which polled 85,000 people. The results showed that only 18% of those who had not previously used psychedelics said they would accept psilocybin therapy for depression or PTSD, rising to 59% among those who had (Winstock & Johnson, 2019). There were concerns about “brain damage and bad trips,” according to the information available (Winstock & Johnson, 2019). No significant psychological problems were found in the 16-year study by John Hopkins University’s psilocybin therapy team, which involved 250 volunteers and 380 sessions. Of those, only 0.9% of volunteers experienced minor or transient psychological problems (Carbonaro et al. 2016). Many studies have examined the long-term effects of psychedelics, but there are not enough high-quality clinical studies to draw conclusions. In the case of hallucinogen-persisting perception disorder (HPPD), for example, there is a dearth of information on the condition (Halpern et al. 2018; Martinotti et al. 2018; Orsolini et al. 2017). Most of the time, a review by Halpern and colleagues suggests that HPPD is caused by over-activation of neural visual pathways that worsens anxiety following the ingestion of arousal-altering drugs, including non-hallucinogenic ones (Halpern et al. 2018). Pre-drug use complaints of tinnitus, eye floaters, and concentration problems, as well as a personal or family history of anxiety, may indicate vulnerability to HPPD, according to the authors (Halpern et al. 2018). Regular psychedelic use, on the other hand, has a limited effect on the brain (Bouso et al. 2015; Halpern et al. 2005). To be clear, in the majority of clinical trials involving psilocybin, the drug is administered in doses ranging from one to three times the usual therapeutic dose.
A double-blind, randomised, controlled phase 2b COMPASS trial of psilocybin therapy in TRD (COMP001) is taking place at the Dublin clinical trial center (Kelly et al. 2019a). The results of this large-scale study and others will address concerns about psilocybin safety, efficacy, and dose optimisation.. In addition, we eagerly await the results of the potentially paradigm-shifting double-blind trial of psilocybin therapy versus SSRI escitalopram at Imperial College London’s Centre for Psychedelic Research (Psilodep-RCT, NCT03429075) in depression (Nutt & Carhart-Harris, 2020) and acknowledge that for some people with depression, SSRIs and psilocybin may become (Carhart-Harris & Nutt, 2017). It is important to determine the safety and efficacy of antidepressants for people with depression, as many choose to continue taking them (Kelly et al. 2019b). In contrast to 5-HT2AR antagonists, such as ketanserin, 5-HT1A partial agonist buspirone may have inhibitory effects on the therapeutic effects of psilocybin (Preller et al. 2017). (Pokorny et al. 2016). However, psilocybin therapy in combination with SSRIs has never been investigated in TRD aside from anecdotal evidence suggesting a blunted effect (Bonson et al. 1996; Bonson & Murphy, 1996).
Damien Sendler: To determine the antidepressant effects of psilocybin therapy in people with TRD who are still taking SSRIs, a new COMPASS clinical study (COMP003) will be launched in Dublin and San Diego. Open-label study: 20 participants with at least a 3-month or 2-year history of clinical depression that has not responded to at least two pharmacological treatments will be recruited for this exploratory open-label study. Participants who have been taking an SSRI for at least six weeks will be given a single 25mg dose of oral psilocybin with psychological support. For future phase 3 trials in TRD, which could pave the way for psilocybin therapy to be integrated into clinical psychiatry based on these results, the findings of this study could have significant practical implications.
Clinical and research psychiatry have been transformed by COVID-19, requiring additional strategies to overcome the significant challenges (O’Brien & McNicholas, 2020; Türközer & ngür, 2020). Several measures will be implemented in accordance with local and national guidelines in order to reduce the spread of COVID-19 and facilitate the safe reopening and progress of ongoing psilocybin trials. For example, participants and researchers can use respiratory symptom checklists, temperature checks, access to COVID-19 testing, extra hygiene measures, personal protective equipment, and even remote study visits if it is not expected to have a negative impact on the participant’s experiences (where possible by the protocol). Psilocybin therapy, at the forefront of translational neuroscience and psychiatry, is likely to play an important role in post-COVID-19 clinical psychiatry, despite the challenges and early stage of clinical development.