Exploring Self-Other Processing in the Psychedelic State

Psilocybin is a psychedelic compound that naturally occurs in certain species
of fungi, and it can be artificially synthesized. At higher doses, both the
naturally occurring and synthesized psilocybin can induce mystical experiences
that are perceived as being tremendously meaningful and life-changing
(Griffiths, Richards, McCann, & Jesse, 2006). Recent clinical studies have
demonstrated the psychotherapeutic potential of psilocybin for the treatment of
conditions such as depression (Carhart-Harris et al., 2016), end-of-life
anxiety (Griffiths et al., 2016; Grob et al., 2011; Ross et al., 2016), and
substance use disorder and addiction (Bogenschutz et al., 2015; Garcia-Romeu,
Griffiths, & Johnson, 2014).

In addition to the therapeutic implications, the reemerging
neurocognitive research on psilocybin and other psychedelics using modern
neuroimaging modalities has provided us with preliminary insight into the
psychedelic state induced by psilocybin and other psychedelics such as LSD. A
set of key findings suggest that the psychedelic state is a more entropic, or
more disorganized state compared to the state of wakeful consciousness.
Consequently, these findings led to the formulation of an influential
hypothesis called the entropic brain hypothesis (Carhart-Harris et al., 2014;
Tagliazucchi et al., 2014; Carhart-Harris, 2018). In short, the entropic brain
hypothesis proposes that the psychedelic state is a high-entropy state, and
this entropic state leads to a richer repertoire of dynamical brain states that
are less predictable.

A recent proposal called the REBUS model (Relaxed beliefs under
psychedelics and the anarchic brain; Carhart-Harris & Friston, 2019) attempts
to integrate the entropic brain hypothesis within the hierarchical predictive
processing framework, and thus, provides a unified model of the brain action of
psychedelics. Predictive processing is a powerful framework for conceiving the
neural mechanisms underlying perception, cognition, and action (Rao & Ballard,
1999; Bubic et al., 2010; Friston,2010). Simply put, predictive processing
models describe counter-flowing top-down prediction/expectation signals and
bottom-up prediction error signals within the brain*s functional hierarchy.
Successful perception, cognition, and action are associated with successful
suppression (*explaining away*) of prediction error. According to the REBUS
model, via their entropic effect on neural activity, psychedelics work to relax
the influence of the highest-level predictions or beliefs in the functional
hierarchy of the brain, on lower-level beliefs and percepts. This
psychedelic-induced relaxation leads to a dramatic alteration in the dynamics
of the brain*s functional hierarchy. Therefore, besides their psychotherapeutic
potential, psychedelics are promising and exciting tools for examining the
complex neural mechanisms underlying uniquely human cognitive and affective
processes in health and disease and, for advancing our understanding of these
processes and ultimately, the nature of human consciousness.

One of the most striking and neuroscientifically interesting effects of
psychedelics are the radical disruptions of self-related processing and
self-consciousness (Huxley, 1954; Leary et al., 1964), including apparently
*selfless states* (Lebedev et al., 2015; Nour et al., 2016). These states,
instances of *Drug-Induced Ego- Dissolution* (DIED) are characterized by an
experienced loss of self and/or loss of self/world(other) boundaries (Millière,
2017; Millière et al., 2018). Furthermore, the evidence suggests that the
occurrence of DIED experiences is positively correlated with therapeutic
outcomes (Garcia-Romeu et al., 2014; Carhart-Harris and Goodwin, 2017; Roseman
et al., 2018; Yaden and Griffiths, 2020). Understanding the mechanisms and
principles underlying the DIED experiences is instrumental to understanding the
therapeutic effects of psychedelics. Accordingly, this is the aim of this
study, as we aim to investigate the effects of psilocybin truffles on
self-other processing using a trait-adjective task.


Rationale

Psilocybin is currently one of the most widely investigated substances in both
clinical trials (Horton et al., 2021) and fundamental neuroscientific and
pharmacological research (de Gregorio et al., 2021). However, nearly all
studies investigating psilocybin have done so using the synthetic version and
administering it in a controlled, lab environment. As the use of psychedelics,
especially psilocybin mushrooms and truffles, is becoming more widespread, both
globally and in the Netherlands (Winstock et al., 2022; van Laar & van
Miltenburg, 2020), the need for more ecologically valid studies, using natural
instead of synthesized products, is becoming more urgent. Furthermore, the
importance of context on the effects of psychedelics makes the need for
naturalistic study designs even more relevant and necessary (Carhart-Harris et
al., 2018). The use of truffles in psychedelic research is still largely
unexplored and of scientific and societal interest, due to its high ecological
validity and legal status in the Netherlands. So far, the research that
explored the use of truffles, did so within the context of microdosing (i.e., a
sub-hallucinogenic dose taken every third day) (Prochazkova et al., 2018;
Marschall et al., 2021; van Elk et al., 2021) or examined the sub-acute effects
of truffles administered in a field-setting (Mason et al., 2019). Accordingly,
this study builds on these previous initiatives, by implementing a naturalistic
study design and the use of psilocybin-containing truffles as the
pharmacological agent of choice instead of the synthetic preparations of
psilocybin. Lastly, we intend to increase the reliability and validity of
psychedelic research and in the spirit of open science, we will make the data
collected in this study available in online repositories for secondary analyses
by other researchers.

Accordingly, this study intends to investigate the modulation of self-other
processing in the psychedelic state. Specifically, the study has the following
key objectives:

(1) To explore the effects of psilocybin-containing truffles on self-other
processing

(2) To explore the effects of psilocybin-containing truffles on recognition
memory

The proposed study uses a within-subjects cross-over experimental design. The
study consists of a screening session, two online testing sessions that are set
at least one week apart from another, post-acute online measures on the next
day following each testing session, and one (optional) follow-up exit
interview. Subjects will self-administer/ingest the psilocybin-containing
truffles at their homes. We will not instruct the subjects on specific dosing
of the truffles and allow them to choose the dose themselves; the dosing
options will be either 5 or 10 grams of fresh truffles Subjects will also
complete the task once without using any psychoactive substances as the control
condition, a week before or after the truffle session, counterbalanced among
the subjects to avoid ordering effect. The rationale for keeping the active
dose of truffles at or under 10 grams is based on the findings that 10 grams of
fresh truffles contain approximately 10 mg of psilocybin, which can be
considered a moderate dose (Pellegrini et al., 2012; Passie et al., 2002) and
in higher doses, psilocybin has disruptive effects on attention and executive
function (Barrett et al., 2018, 2020).

The study consists of a 30-minute online screening call and survey, two
30-minute online testing sessions that are set at least one week apart from
another, two 30-minute post-acute online measures on the next day following
each testing session, and one (optional) follow-up exit interview that will
take approximately 15 minutes. During the testing sessions, subjects will
complete several questionnaires and an online cognitive task that will take
approximately 30 minutes. During the post-acute sessions, in a similar manner,
subjects will complete several questionnaires, open questionnaires, and an
online task for 30 minutes. The subjects will ingest small and small-to-medium
doses of psilocybin-containing truffles, which will induce mild cognitive and
perceptual effects. The outcomes of the study will provide important new
insight into the acute psychological effects of psilocybin-containing truffles
used in naturalistic settings.