Optimizing outcomes in psilocybin therapy: Considerations in participant evaluation and preparation

Psychedelic therapies are a package of psychological interventions delivered with intermittent, supported dosing sessions with psychedelic drugs, including lysergic acid diethylamide (LSD) and phosphoryloxyN,N-dimethyltryptamine (psilocybin) (Schenberg, 2018). Previously investigated through the 1950s and 1960s, the practice was prohibited consequent to the Controlled Substances Act (CSA) (Nichols et al., 2016). After a period of quiescence through the 1970s and 1980s, contemporary re-exploration of psychedelics reemerged in the early 1990s (Carhart-Harris and Goodwin, 2017), with clinical trials exploring the mystical experience and palliative care for patients with cancer using psilocybin (Ross, 2018). While generally small in scale, current randomized control trials (RCTs) investigating psilocybin therapy (PT) provide preliminary evidence for the safety, tolerability, and efficacy of psilocybin for patients with treatment-resistant major depressive disorder (Carhart-Harris et al., 2021; Gukasyan et al., 2022). A systematic review of evidence prior to prohibition also supported the relative safety of psychedelics in medically controlled environments, no reported risk of dependence, and clinically meaningful improvements in symptoms for patients with MDD (Rucker et al., 2016).

Psilocybin is functionally a selective partial agonist of the 5-HT2A receptors (a serotonin receptor subtype) in the cortex of the human brain. The activation of the 5-HT2A receptors in both cortical and subcortical brain structures is believed to be the mechanism through which psilocybin exerts its acute behavioral and psychological effects (Vollenweider and Preller, 2020). Research further suggests that this mechanism also may lead to changes in neuroplasticity reflective of long-term improvements in symptoms (Ly et al., 2018). Although its effects are widespread, psilocybin particularly modulates the default mode network (DMN), a network of brain structures that underlie self-referential processing, including what is commonly described as a sense of self (Fox et al., 2005; Palhano-Fontes et al., 2015; Smigielski et al., 2019, Smigielski et al., 2019).

This process has been conclusively linked to the subjectively experienced altered state of consciousness (Madsen et al., 2020), alterations in auditory and visual perceptions, and positive experiences of a sense of non-dualism, oneness, or unity (Hirschfeld and Schmidt, 2021). From a psychological perspective, psilocybin is thought to introduce shifts in perspective affecting emotional, social, and self-processing, thereby leading to reductions in negative bias, rumination, and withdrawal, as well as improving relationships and reward experiences (Griffiths et al., 2011; Studerus et al., 2012).

In an RCT with 59 participants with TRD, Carhart-Harris et al. (2021) compared two sessions of 25 mg psilocybin with subsequent placebo treatment, to two sessions of 1 mg psilocybin treatment followed by escitalopram treatment. No significant difference was observed in the primary depression outcome between the two groups, but secondary analyses generally favored the group receiving 25 mg of psilocybin. A different RCT compared the safety and efficacy of a single dose of 1, 10, or 25 mg of psilocybin in 233 patients with TRD, with all groups receiving psychological support, and found that 37 % of the 25 mg group experienced a clinically significant response while 26 % of the 25 mg group met remission criteria (Goodwin et al., 2022). In a longitudinal study, 58 % of participants who received two doses (20 mg/30 mg) of psilocybin were still in remission at 12-months post-treatment (Gukasyan et al., 2022). These trials were not without adverse outcomes, with most common side effects of psilocybin administration including headaches, nausea, fatigue, and insomnia (Carhart-Harris et al., 2021; Goodwin et al., 2022; Rucker et al., 2022).

It is not yet well-understood how the milieu of psilocybin administration and the accompanying psychological-support model facilitate therapeutic change in psychedelic forms of therapy. Proposed psychological mechanisms of change include mystical experiences (Barrett and Griffiths, 2017; Griffiths et al., 2011; Johnson et al., 2019), emotional breakthroughs (Roseman et al., 2019), insightfulness (Davis et al., 2021), and altered self-perception and expanded range of affect (Breeksema et al., 2020). Patient reports further highlight themes of moving from states of ‘disconnection’ to ‘connection’, emotional ‘avoidance’ to ‘acceptance’, and increased cognitive flexibility and openness to experience (Belser et al., 2017; Doss et al., 2021; Gasser et al., 2014; Watts et al., 2017). While PT leverages both the drug administration and the context in which it takes place (i.e., setting) (Hartogsohn, 2016), PT also requires the patient to be an active agent during the course of treatment, which inherently sets in motion patient characteristics such as prior beliefs, intentions and motivations, personality traits, cultural identity, and quality of preparation (i.e., mindset). This is in direct contrast with, for example, pharmacotherapy approaches, in which the patient plays a more passive role. Therefore, it is imperative to assess patient characteristics in order to establish their eligibility and capacity (i.e., readiness) to engage in psychedelic therapy, thereby allowing for optimization and personalization of PT, and in turn, symptom and functional outcomes improvements.

In this article, we discuss the conceptualization of and rationale for assessing and estimating the extent to which patients show readiness for PT. We propose that the degree of readiness could not only predict short- and long-term outcomes but could also serve to optimize and personalize PT toward enhanced outcomes for individual patients. Specifically, we identify and focus on factors pertaining to the patient's mindset during screening and early stages of PT, that is, patient presentation, therapeutic alliance, and safety, which we believe to be relevant for successful engagement in PT. We provide a framework for the development and use of an instrument that would assess these constructs, and in turn allow clinicians and researchers to identify a patient's readiness for PT, not only to predict outcomes, but to leverage them for further adaptation and personalization of PT.

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