Journal of Affective Disorders 326 (2023) 18–25

Contents lists available at ScienceDirect

Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research paper

Optimizing outcomes in psilocybin therapy: Considerations in participant

evaluation and preparation
Nadav Liam Modlin a, 1, Tammy M. Miller b, 1, James J. Rucker c, d, Namik Kirlic e,
Molly Lennard-Jones e, Danielle Schlosser e, f, 2, Scott T. Aaronson b, g, *, 2
a
The Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
b
Institute for Advanced Therapeutics and Diagnostics, Sheppard Pratt, Towson, MD, United States of America
c
Department of Psychological Medicine, King's College London, Institute of Psychiatry, Psychology, and Neuroscience, London, United Kingdom
d
South London and Maudsley National Health Service Foundation Trust, Bethlem Royal Hospital, Beckenham, United Kingdom
e
Compass Pathfinder Ltd, London, United Kingdom
f
Weill Institute for Neurosciences, University of California, San Francisco, United States of America
g
University of Maryland School of Medicine, Department of Psychiatry, 701 West Pratt Street, Baltimore, MD 21201, United States of America

A R T I C L E I N F O A B S T R A C T

Keywords: Recent studies have demonstrated the promise of psilocybin therapies in creating positive changes for those with
Psychedelic therapy poor mental health across multiple diagnostic categories, including major depressive disorder (MDD), end-of-life
Psilocybin anxiety, and obsessive-compulsive disorder (OCD). While there may be a large population that is eligible to
Treatment outcomes
participate in psilocybin therapy based on psychiatric diagnosis and medical clearance, little attention has been
Optimizing psychedelics
given to intrapersonal and interpersonal factors that might influence patient's readiness (i.e., eligibility and
capacity) for psychedelic interventions. This paper proposes that readiness assessment includes both intraper­
sonal and interpersonal factors in order to improve safety, patient care, and treatment outcomes. While at the
present time a reliable and valid instrument has not been developed, we propose that three specific areas of focus
– patient presentation, therapeutic alliance, and patient safety – may be used to establish a patient's readiness for
psilocybin therapy, thus increasing therapy optimization and personalization.

1. Introduction psilocybin for patients with treatment-resistant major depressive disor­

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
der (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

* Corresponding author at: Sheppard Pratt, 6501 N. Charles Street, Baltimore, MD 21204, United States of America.
E-mail address: saaronson@sheppardpratt.org (S.T. Aaronson).
1
Co-first authors.
2
Co-senior authors.

https://doi.org/10.1016/j.jad.2023.01.077
Received 31 July 2022; Received in revised form 11 January 2023; Accepted 21 January 2023
Available online 25 January 2023
0165-0327/© 2023 Elsevier B.V. All rights reserved.
N.L. Modlin et al.
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., 2019a, 2019b).
This process has been conclusively linked to the subjectively expe­
rienced 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 out­
comes, 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 adminis­
tration and the accompanying psychological-support model facilitate
therapeutic change in psychedelic forms of therapy. Proposed psycho­
logical 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, per­
sonality traits, cultural identity, and quality of preparation (i.e., mind­
set). 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 ther­
apy, 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, thera­
peutic 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.
19
Journal of Affective Disorders 326 (2023) 18–25
2. Psilocybin therapy
PT integrates the administration of psilocybin with structured psy­
chological support across three unique phases: (1) preparation, (2) psi­
locybin dosing, and (3) integration (Fig. 1: Tai et al., 2021). Within this
milieu, the mindset of the individual, the physical setting in which the
treatment is administered, and the drug administration are distinct, yet
equally important components of intervention that may influence
overall experience and outcomes (Fig. 2; Carhart-Harris et al., 2018;
Gukasyan and Nayak, 2021; Johnson et al., 2008). Mindset refers to the
intentions, expectations, motivations and overall mental state of the
participant, whereas setting refers to the physical environment and
wider socio-cultural setting in which the treatment is delivered and the
interpersonal elements of the treatment (Hartogsohn, 2016).
During the preparation phase occurring over a number of weeks, the
patient meets with a licensed clinician trained in the psychological
support model with a goal of a) establishing a strong therapeutic alliance
and the framework of the therapeutic support, b) gaining the relevant
psychoeducation, c) exploring intentions and expectations, and d)
assessing safety and readiness to proceed to dosing. Therapists work to
create a non-judgmental, affirming and supportive therapeutic rela­
tionship by maintaining a ‘warm’, ‘accepting’ and ‘curious’ stance.
Further, therapists provide rationale for the various support methods
and work collaboratively with the patient to agree upon preferred
methods and procedures ahead of the psilocybin dosing session.
The psilocybin dosing session occurs over a single day, lasting
approximately 6 h in a clinical setting. First and foremost, the therapist
engenders feelings of safety and trustworthiness by maintaining
attunement to the patient's needs and experience. Correspondingly,
therapists support the patient in ensuring that psychological distress is
not overwhelming. Furthermore, the therapist encourages the patient to
maintain a focus on internal states with a goal of facilitating a mean­
ingful experience. Finally, the therapist models a similar stance that is
encouraged in the patient, including maintaining awareness of their own
states and maintaining openness, interest, and compassion toward the
patient.
Finally, during the subsequent integration sessions patients and the
therapists explore ways in which the psilocybin dosing session informs a
process of recovery. The patient is supported toward describing and
connecting with their internal states that took place during the psilo­
cybin administration phase, as well relating it to their past, present, and
future. This is believed to support patients to create meaning of their
experiences, increase insight, and facilitate ongoing behavioral change
and emotional processing. Therapists work to enhance psychological
safety and reduce negative feelings or perceptions following a chal­
lenging experience.
3. Conceptualizing readiness for psilocybin therapy
The novel paradigm of care that PT introduces (psilocybin + psy­
chological support + mindset & setting elements) requires a shift in how
we understand patient readiness to encourage durable positive out­
comes. While there may be a large population that is eligible based on
their psychiatric diagnosis and medical clearance, it does not directly
indicate that they are sufficiently positioned to engage in and benefit
from PT. Consequently, we consider readiness for PT to include both the
medical and psychological eligibility, as well as patient-centered factors
influencing their capacity to engage in treatment.
To optimally select and prepare patients for PT, the eligibility pro­
cess and the preparation phase may need to take into consideration
important extra-diagnostic factors that relate to patients' response to PT.
Research exploring predictors of response to recreational use of psy­
chedelics have highlighted that having a positive mindset and clear in­
tentions is associated with a decreased likelihood of a challenging
psychedelic experience (Haijen et al., 2018). Similarly, mental states
such as ‘surrender’, ‘preoccupation’ and ‘absorption’ mediate the quality
N.L. Modlin et al. Journal of Affective Disorders 326 (2023) 18–25

Fig. 1. Primary therapeutic aims and tasks in psilocybin therapy within clinical trials.

Fig. 2. ‘Set’ refers to intrapersonal elements impacting the patient's presentation and experience of self during the course of PT. ‘Setting’ refers to the physical
environment in which PT is delivered, including treatment room aesthetics, interpersonal interactions with staff, and wider socio-cultural factors.

of the psychedelic experience and therefore its self-reported impact on of the therapeutic alliance between patient and therapist predicted
wellbeing (Russ et al., 2019a). Conversely, ‘confusion’ and ‘preoccupa­ positive outcomes in PT for depression (Murphy et al., 2022). This
tion’ predict adverse reactions to psilocybin. In clinical trials, the quality suggests that both intrapsychic and clinical-relational factors may

Fig. 3. Schematic representation of the model of readiness for psilocybin therapy. Patient presentation refers to patient's capacity for openness, motivation to engage
in and expect positive outcomes from treatment, and affective tolerance. Therapeutic alliance refers to a safe and effective working relationship between the therapist
and the patient. Safety refers to psychological factors related to patient's state and well-being.

20
N.L. Modlin et al.
influence response to PT and psychedelic forms of therapy. Therefore,
we propose that the readiness for PT includes the following patient-
centered factors: patient presentation, therapeutic alliance, and safety
(Fig. 3). We now discuss our rationale for selecting these factors.
4. Patient presentation
Patient presentation refers to potentially malleable traits and char­
acteristics of the patient, stemming from past experiences, currently
held beliefs, future-oriented outlooks, and previously learned psycho­
logical skills. These include ‘openness’, ‘motivation’, and ‘affective
tolerance’. Importantly, these patient traits and characteristics might
inform the duration and clinical focus of the preparation phase to
optimize outcomes in PT. While difficult to operationalize in random­
ized trials, consideration of optimizing length and character of prepa­
ratory sessions for each patient is likely to be critical within a post-
approval clinical framework to improve outcomes.
5. Openness
The ability and willingness of a patient to be open to the potentially
intense psilocybin experience is thought to be a critical element of PT
and may directly impact outcomes (Aday et al., 2021). Openness is
defined as attentiveness to inner feelings, toleration of novel experi­
ences, and intellectual curiosity for the present-moment states (Costa
and McCrae, 1992; McCrae and Costa, 2008; Ehrler et al., 1999). The
opposite to a state of openness here is experiential avoidance, that is,
attempts to avoid or suppress uncomfortable thoughts, feelings, and
memories. Experiential avoidance may stem from past experiences and
previously learned behavior, such that engaging in it has served to
reduce emotional discomfort and its impact on functioning. In general,
patients' openness has been shown to have a positive impact on out­
comes in Cognitive Behavioral Treatment (Keijsers et al., 2000). Open­
ness at the beginning of treatment relates to lower depression severity at
the end of treatment (Bagby et al., 2008). Patient openness has also been
shown to moderate outcomes in Methylenedioxymethamphetamine
(MDMA) therapy for posttraumatic stress disorder (PTSD) (Wagner
et al., 2017). Openness to experience also predicted higher scores on the
5-Dimensional Altered State of Consciousness Rating Scale (5D-ASC),
and was associated with mystical experiences (ME) and oceanic
boundlessness (OB; i.e., loosening or loss of self/ego boundaries), which
was, in turn, was related to symptom reduction (Barrett et al., 2015;
Roseman et al., 2018; Smigielski et al., 2019a, 2019b; Studerus et al.,
2012; Yaden and Griffiths, 2020). Conversely, plethora of research ev­
idences experiential avoidance as a predictor of psychopathology and
poorer treatment outcomes (Chawla and Ostafin, 2007; Hayes et al.,
2004). In PT, openness may lead the patient to fully welcome the psi­
locybin experience, derive insight and meaning from it, and integrate it
with their personal narrative to effect change in symptom and functional
outcomes.
6. Motivation
Motivation consists of patient's a) behavioral engagement, and b)
expectation of treatment outcomes. The behavioral component of
motivation refers to the participant's willingness to engage with the
various tasks of the treatment. This may include setting intentions,
creating a therapeutic alliance with the therapist, and exploring new
behaviors in light of the psychedelic experience (Horton et al., 2021).
Patient's expectation of treatment outcomes refers to the belief that the
patient can leverage the therapeutic effects of the psilocybin experience
toward improving symptoms and quality of life. Research shows that
behavioral engagement and expectation of treatment outcomes have a
positive impact on clinical outcomes (Constantino et al., 2018), and that
the two are closely related. Interestingly, patient's level of behavioral
motivation may be influenced by their belief in their capacity to create
21
Journal of Affective Disorders 326 (2023) 18–25
change (autonomous motivation) (Hagger et al., 2014). This belief has
been found to be a factor in positively influencing psychological treat­
ment outcomes (Ibanez et al., 2016; McBride et al., 2010; Ntoumanis
et al., 2020; Zuroff et al., 2007). Therefore, patient's continuous
engagement with PT phases and belief in their capacity to participate
may result in similar positive outcomes. Understanding and capitalizing
on patients' motivation in PT will be instrumental in predicting and
modifying outcomes.
7. Affective tolerance
PT may require the patient to tolerate and engage in potentially
challenging or uncomfortable transient experiences in aid of healing
(Johnson et al., 2008). Therefore, understanding the rationale for
engaging in challenging experiences and establishing this capacity for
the patient is an essential part of the preparation process. Patients with
mental health conditions, such as MDD, often exhibit elevations in
negative affectivity. Negative affectivity describes propensity to expe­
rience distress, excessive vigilance, perception of uncontrollability and
uncertainty, and elevated physiological arousal, particularly in response
to challenging environmental and physiological stressors (Barlow, 2004;
Brown and Barlow, 2009; Clark and Watson, 1991; Ormel et al., 2013).
Importantly, this propensity is accompanied by low self-efficacy
regarding one's ability to cope with or regulate negative affectivity.
Because negative affectivity related distress is not well tolerated for
these individuals, they are prone to engaging in what are often consid­
ered maladaptive regulation strategies, such as avoidance, suppression,
and withdrawal (Ehring et al., 2008). Consequently, this could lead to
less engagement with PT during the expected emotionally salient pe­
riods. Further, studies exploring predictors of response to psychedelics
suggest that trait negative affectivity mediates the acuteness of the
psychedelic experience (Barrett et al., 2017). Specifically, elevated
levels of trait neuroticism predict challenging psychedelic experiences
(Barrett and Griffiths, 2017). Correspondingly, psychedelic-induced
emotional breakthrough experiences, often accompanied by a sense of
relief or resolution, predict positive changes in well-being after psy­
chedelic experiences (Roseman et al., 2019). The ‘emotional break­
through’ construct suggests that engaging with challenging affective
states in PT may yield greater therapeutic effects. Taken together,
identifying patients' regulation strategies and assessing their capacity to
tolerate challenging affective states may support positive outcomes by
optimizing and personalizing care. In conclusion, we propose that if
openness, motivation and affective tolerance are low or absent for a
patient, then the patient may struggle to engage in PT and receive the
full potential of its benefits. Since the preparation period ahead of the
psilocybin dosing session is time limited, identifying these attributes
may allow the therapist to focus the psychological support to increase
the participant readiness during the preparation phase to further treat­
ment outcomes.
8. Therapeutic alliance
Therapeutic alliance refers to a working relationship between the
therapist and the patient, representing the pillar of the process that takes
place between the two to effect positive outcomes for the patient.
Fundamental elements of the alliance include an agreement on the goals
and tasks of the treatment, and the development of a positive working
relationship based on mutual respect, interpersonal safety and positive
feelings between patient and therapist (Ardito and Rabellino, 2011;
Bordin, 1979). Meta-analyses of studies examining the relationship be­
tween the therapeutic alliance and outcomes in adult and youth psy­
chotherapy suggest that the quality of the alliance is more predictive of
positive outcome than the type or length of intervention (Flückiger et al.,
2019; Horvath and Symonds, 1991; Karver et al., 2006; Laws et al.,
2016; Martin et al., 2000; Prusiński, 2022; Shirk and Karver, 2003).
In PT, participants may be more vulnerable during the psilocybin
N.L. Modlin et al.
dosing session due to the expected effects of the drug, the relatively
limited time of preparation ahead of the psychedelic session, and the
practice of reclining and wearing eye shades. Furthermore, participants
may be highly sensitive to external stimuli, including their experience of
psychological safety and trust in their therapist. Therefore, it is para­
mount that a sense of interpersonal safety and trust, that is therapeutic
alliance, is established between the therapist and the patient before
proceeding with PT. Indeed, preliminary research suggests that the
quality of the therapeutic alliance predicts emotional breakthroughs and
mystical experiences, which in turn contributes toward positive treat­
ment outcomes in PT (Murphy et al., 2022). Correspondingly, a weaker
therapeutic alliance is associated with higher depression scores and
poorer treatment outcomes. It is believed that the patient's feelings of
safety and trust in their therapist's competence and intentions impacts
their ability to not only navigate potentially challenging experiences,
but also make meaning of their experience (Brennan and Belser, 2022;
Johnson et al., 2008; Tai et al., 2021; Wagner et al., 2017). Therefore,
the patient's capacity and willingness to develop rapid rapport and make
use of the therapist's support is crucial. Conversely, the therapist's
conduct, characteristics, and values equally influence the quality of the
therapeutic alliance (Ackerman and Hilsenroth, 2003; Arnow and
Steidtmann, 2014).
In this context, PT builds on a relational process that is a) intrapsy­
chic, such that it relies on quality of the relationship with all facets of
self, and the subjective response to psilocybin, and b) interpersonal, such
that it relies on the quality of the relationship with the treatment team,
the social support system, and intersecting cultural identities. Accord­
ingly, it is important to consider various mediating factors influencing
participants ability to trust themselves and the treatment team. For
example, a participant's willingness and capacity to trust the treatment
team may be influenced by past traumatic experiences and failed
treatment, as well as feelings of invalidation due to the potential lack of
cultural competency by treatment providers (Michaels et al., 2018;
Smith et al., 2022). Consequently, the rapid development of an effective
therapeutic alliance with accompanying feelings of interpersonal safety
may be challenging. Further, trait agreeableness has been positively
associated with therapeutic alliance (Bucher et al., 2019). Patients with
high agreeableness tend to possess higher levels of trust in others and a
willingness to cooperate (McAdams, 2015; Bartosik et al., 2021).
Therefore, PT readiness needs to capture patients' attitudes toward trust
in self and others, and the factors influencing their capacity and will­
ingness to build an alliance with their therapist. This would help
personalize care by attending to the participant's unique relational
needs.
9. Patient safety
Our clinical observations during PT indicate that there are other
psychological factors related to patient's safety and well-being that in
turn may influence outcomes. Specifically, the extent to which the pa­
tient engages in rumination and experiences despair during PT may have
undesirable results for symptom improvement. Rumination refers to
repetitive negative thinking focused on the past or present circum­
stances related to self, can be in response to a stressful event, and often
results in sustained emotional distress (Nolen-Hoeksema et al., 2008).
Despair, a related state, is a feeling of hopelessness and helplessness, in
which there is a profound sense of things having gone wrong and not
likely to improve. In general practice, rumination negatively influences
treatment outcomes and is a risk factor for MDD and anxiety symptoms
(Breeksema et al., 2020; Ehring, 2021; Michl et al., 2013; Watkins and
Roberts, 2020) For example, it is not uncommon for patients with TRD to
exhibit a strong sense of ‘being beyond repair’ and excessively ruminate
on “what is wrong with me”.
These rigid ruminations may lead to increased feelings of incompe­
tence and associated feelings of despair when entering psychedelic
therapy. Further, mental states such as preoccupation and confusion
22
Journal of Affective Disorders 326 (2023) 18–25
may be associated with adverse reactions (Russ et al., 2019b). Should
these aspects not be addressed during the preparation phase of PT, the
patient may struggle to feel sufficiently capable and hopeful in their
ability to engage in and benefit from the overall treatment and specif­
ically the psilocybin experience to leverage its potential benefits.
The subsequent lack of perceived benefit from PT may confirm
previously held beliefs about treatment and self, further perpetuating
feelings of disappointment, disillusionment, and despair. In rare cases,
this may result in increased safety concerns, such as emotional dysre­
gulation and suicidal ideation. To that end, the presence of the rumi­
native process characterized by despair, shame, and hopelessness would
require intentional focus and interventional targeting by the treatment
team to optimize PT.
10. Development of the Psilocybin Therapy Readiness Scale
In evidence-based medicine (EBM) and psychopharmacology, the
intention and design of RCTs are broadly concerned with isolating the
biological effects from non-pharmacological factors such as the thera­
peutic alliance and patient characteristics (Armitage, 1982). Tradition­
ally, non-pharmacologic components have been viewed as confounding
factors, potentially undermining the generalisability and reliability of
the investigation by creating conscious and subconscious biases in study
participants and researchers (Spieth et al., 2016). Psychedelic therapy
relies on the integration of pharmacotherapy and psychotherapy. It has
been proposed that RCTs are less suitable to investigate psychological
interventions (Philips and Falkenström, 2021). For example, double
blinding is difficult if not impossible to achieve (e.g., psychological
therapists are inevitably unblinded to the intervention they are deliv­
ering (Deaton and Cartwright, 2018; Enck and Zipfel, 2019)). Accord­
ingly, expectancy effects are impossible to eliminate in psychotherapy
research (Dozois, 2019).
As such, psychedelic researchers must contend with and account for
a complex interaction between dynamic drug effects, non-liner psy­
chotherapy processes and enhanced placebo/nocebo effects (Aday et al.,
2022). Addressing these conditions, psychedelic researchers are
encouraged to adhere to and maintain a high degree of clinical equipoise
and research rigour (Butler et al., 2022). More recently, calls have been
made to view extra pharmacologic factors in psychedelic research such
as the therapeutic alliance, patient characteristics, the socio-cultural
environment and patient expectations as essential contextual factors
inextricable from treatment outcomes (Okano et al., 2022; Butler et al.,
2022). Accordingly, if validated, the impact of the readiness assessment
and its potential for eliciting an optimized preparation procedure will
require careful investigation. This is likely to be challenging given that a
psychological support model optimized to account for a participants'
therapeutic weaknesses, if effective, may provide sufficient support as to
mitigate some of the differences between psychedelic and placebo dosed
subjects.
11. Conclusion
Psychedelic-assisted therapies is an emerging field in mental health
that is showing preliminary evidence as a safe and effective treatment
for a range of mental health conditions, although further definitive trials
are awaited. Simply, personalized approaches to treatment may result in
more improved and sustained outcomes. Here, we discussed the
importance of identifying the ‘readiness’ (e.g., eligibility + capacity) of
patients for psilocybin therapy, as well as how these factors may be
leveraged to optimize the therapy protocol.
We identified patient presentation, therapeutic alliance, and safety
factors as relevant patient-centered factors for successful engagement
with and potential benefit from PT. A patient showing high levels of
readiness is therefore expected to have favorable patient presentation,
therapeutic alliance, and safety. Conversely, a patient that would be a
less ideal candidate for PT may exhibit marked rumination and despair,
N.L. Modlin et al.
evidence of low openness and motivation, and show low therapeutic
alliance. Nevertheless, variability across these domains may suggest that
the participant with personalized preparation may increase readiness
and, thus, optimize treatment outcomes.
Therefore, we suggest that the trajectory of PT can be improved by
identifying and tailoring the treatment experience based on these
readiness indicators (i.e., Participant Presentation, Therapeutic Alli­
ance, and Safety), including with a use of a formalized assessment tool.
Understanding and targeting these phenomena within PT may allow for
optimization of the psychological support model and thus enhancement
of the effect of psilocybin and subsequent short- and long-term out­
comes. Potential treatment failures may be thus mitigated through
establishing the compatibility between patient and the treatment
approach, as well as the greater personalization of the treatment plan
(Huibers et al., 2015; Norcross and Wampold, 2011). Although care will
need to be taken in the interpretation of results in a placebo/psychedelic
RCTs (Butler et al., 2022). Finally, this may improve our mechanistic
understanding on how psychedelics effect change for patients and in­
fluence outcomes.
Support
No support was received for the creation of this paper.
CRediT authorship contribution statement
The manuscript data presented is original, not published or submit­
ted elsewhere, and abides by all ethical and legal standards required. We
confirm the authorship criteria has been met and is in accord with
ICMJE guidelines.
No funding was supplied for this manuscript.
Conflict of interest
NLM has received consulting fees from Compass Pathways PLC,
Small Pharma Ltd. and Beckley Psytech Ltd., TMM has received research
support from Compass Pathways, PLC, JRR receives grant funding from
COMPASS Pathways PLC and consulting fees from Beckley PsyTech and
Clerkenwell Health. NK, ML-J and DS are employees of Compass Path­
ways. STA has received research support from Compass Pathways and
Neuronetics and consulting fees from Janssen, Compass Pathways,
LivaNova, Neuronetics, Genomind and Sage Therapeutics.
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