Elucidating the Relevance of the Psychedelic Experience to Psilocybin's Anti-Anhedonic Effects

This task is designed to evoke and probe the nature and extent of the aesthetic experience. Two sets of stimuli will be presented. Each set consists of 20 pieces of self-selected music with 10 pieces inducing highly hedonic experiences and 10 neutral pieces. After stimulus presentation, subjects will rate how aesthetically moving the experience was, whether they experienced chills, and what the valence of the experience was on a Likert scale.

The MID task is established to evoke and assess reward and punishment, which are centrally involved in anhedonia. The task observes several stages of reward processing, i.e., reward prediction, anticipation and reward consumption. The aim of the paradigm is to maximize gain and avoid loss by fast reaction upon presentation of a target stimulus.

A trial starts with the presentation of a cue, indicating the potential gain or loss (e.g., -1€, +3€). After a variable delay of for instance 3-5 seconds the target stimulus is shown, and subjects press a button as fast as possible. If the reaction is within a given time limit the amount is gained or loss avoided. Otherwise, the amount is not gained or lost. Each button press is followed by immediate feedback, showing the outcome and the accumulated amount of money.

This task has been implemented by our group to assess changes to sexual arousal, a central and burdensome, yet often understudied, component of anhedonia.

During this task, subjects are presented images intended to be sexually arousing and are instructed to denote the extent to which they find the image arousing.

The CFI is a 20-item self-report measure to assess two aspects of cognitive flexibility:

the adaptive ability to perceive multiple alternative explanations for life occurrences and the ability to generate multiple alternative solutions to difficult situations, as well as having an internal locus of control, or the tendency to perceive difficult situations as somewhat controllable.

A self-reported rating of the subjective intensity of the acute psychedelic experience will be collected after each medication session on a scale from 0 (not at all) to 4 (extreme).

The WEMWBS is a self-report scale which will be used to assess mental well-being over the course of study participation.

The BDI is a self-rated scale which is used to assess symptoms of depression.

The MADRS is a observer-rated scale which is used to assess symptoms of depression.

The DARS is a self-report scale that measures anhedonia across four domains on a five-point-likert scale.

The AES is a self-report scale which is used to assess aesthetic experiences in the form of 'aesthetic chills', the response of goose bumps and shivers in response to the arts.

The TEPS is a self-rating scale which is used to assess the experience of anticipatory and consummatory experiences of pleasure.

The BMRQ is a psychometric scale designed to assess different factors underlying the experience of music reward, as measured through 20 items on a 5-point Likert scale.

Properties of the psychedelic experience as assessed via the 5D-ASC, a a 94-item self-report scale that assesses the participants' alterations from normal waking Consciousness.

Properties of the psychedelic experience as assessed via the MEQ30, a 30 point self-rated scale, which is used to measure the intensity of common aspects of a psychedelic experience (divided into mystical, positive mood, transendence of time and space, and ineffability).

Properties of the psychedelic experience as assessed via the Challenging Experience Questionnaire (CEQ), an instrument designed to measure challenging psychological experiences associated with the acute effects of psychedelics.

The CD-RISC is a self-rating scale which is used to assess changes in study participants' resilience over the course of their participation.

Changes in proinflammaotry cytokines, suchz as interleukin 6 and tumor necrosis factor alpha, which have been associated with depression and anhedonia, assessed via Legendplex cytokine panel

Changes in blood markers which have been associated with depression and anhedonia, assessed via BDNF concentration.

Neural activity during MID and sexual arousal task, assessed via fMRI measurement.

Brain complexity measures during the hedonic experience assessed with fMRI, as assesed via integrated information decomposition and BOLD variability

Prior to discharge at each session, subjects will be asked to report any and all adverse events they experienced and common side effects will explicitly be asked about.

The most common side effects include anxiety, nausea, headache, and fatigue which are highly likely to be self-limiting or can be easily treated if necessary.