Computer Game, Qualitative, and MEG/EEG Assessment of Serotonergic Psychedelics

Computationally, Electrophysiologically, and Qualitatively Characterizing Serotonergic Psychedelics; Transdiagnostic Therapeutic and Pro-Psychotic Effects

This is an observational study which does NOT directly administer a psychedelic substance but rather recruits participants who are already participating in another clinical trial in which they may receive a serotonergic psychedelic. The goal of this observational study is to learn how the brain's information processing changes during and following administration of serotonergic psychedelics (psilocybin, N,N-Dimethyltryptamine/DMT, Lystergic Acid Diethylamide/LSD, etc.) for people with and without mental illness receiving serotonergic psychedelics through any clinical trial at Yale University. The main questions it aims to answer are:

1. Do serotonergic psychedelics cause the brain to rely on new information more than previously learned information while under the influence? What about 1 day, 5-14 days, and 4-6 weeks after use?
2. Do serotonergic psychedelics cause long-lasting side-effects in how people perceive (see, hear, feel, etc.) the world and how easily people change their beliefs?
3. How does the brain's electrical activity change after using serotonergic psychedelics? How does the balance between excitation and inhibition change while under their effect?
4. Can changes in how the brain uses information predict who will benefit from a psychedelic and who will have side effects from psychedelics?

Researchers will compare with people given placebos to see what changes in brain processing are unique to serotonergic psychedelics.

Participants will have the opportunity to do some combination of the following:

1. Online computer assessments consisting of games and questionnaires that probe how participants think.
2. Magnetoencephalography (MEG) or electroencephalography (EEG) with eyes closed and with repeated clicks, images, or sensations delivered.
3. A magnetic resonance imaging (MRI) scan.
4. Semi-structured qualitative interviews about their experience after taking a serotonergic psychedelic recorded via Zoom.

Mounting evidence suggests that serotonergic psychedelics (SPs; eg. psilocybin, LSD) reduce symptoms across many mental illnesses with rapid, sustained effects from single interventions. They also cause persisting, positive effects in the general population and those without mental illness. This improved wellness comes at the cost of acute psychosis-like effects, that sometimes persist in weakened forms or, rarely, as prolonged episodes of psychosis. Understanding the mechanism underlying these dual effects may help maximize therapeutic effect and minimize unwanted outcomes.

The reason SPs cause therapeutic change and also cause psychotic-like effects regardless of whether one has a mental illness may be because they alter the basic machinery that the brain uses to process all information. SPs seem to shift processing-in both how we perceive (seeing, hearing, etc.) and learn-to rely more on new, incoming information over previously learned information. Essentially, SPs shift the brain into an extreme learning mode that allows it to modify harmful thought patterns associated with many mental illnesses, but that may also be similar to the brain states of early psychosis.

Participants in this study will opt-in to complete various measures to be completed before, during, and after being administered a serotonergic psychedelic through a clinical trial at Yale University.

How participant's brains process information will be assessed by:

1. Playing 3-4 computer games that measure how people see, hear, and learn. These will be completed 1-30 days before receiving the serotonergic psychedelic, the day they receive the serotonergic psychedelic (once psychologically acceptable and permitted by relevant trial researchers), the day after, 5-14 days after, and 4-6 weeks after.
2. MEG or EEG to measure the brain activity responsible for representing new vs. old information-and structural MRI to determine where the activity is coming from. The MEG/EEG will be done the day before, day of, and day after administration of the serotonergic psychedelic. The MRI can be done before, after, or during the trial.

They behaviors that accompany these changes will be assessed by:

1. Validated, online questionnaires at the same time points as the computer games.
2. Semi-structured interviews about what participants' day-to-day experiences are like and how they have changed after taking a serotonergic psychedelic. These may be done 2-5 days after using a psychedelic, or at the same time that clinical trial staff do their interviews.

Participants participating in a trial with single-arm placebo-controlled study design that includes a placebo arm may only complete these measures around a placebo administration. Those in a trial with a crossover design may complete these measures twice (except for day 1-30 and 4-6 week time points). Those opting to complete open-label administrations after study completion may complete relevant time points.

The primary objectives are to:

1. Investigate how serotonergic psychedelics change brain reliance on new vs. old information in perception and belief-updating while under the influence.
2. Investigate how serotonergic psychedelic change brain reliance on new vs. old information in perception and belief updating at short and long-term follow-up.
3. Investigate whether serotonergic psychedelics cause side effects in people's perception, attention, and belief updating that are both healthy and psychosis-like.
4. Investigate how serotonergic psychedelics acutely alter excitation/inhibition (E/I) balance in the brain.
5. Investigate whether there are any persisting changes in resting state EEG power or E/I balance.

The secondary objectives are to:

1. Investigate whether changes in brain information processing can explain therapeutic effects of serotonergic psychedelics.
2. Investigate whether changes in brain information processing can predict who will respond positively to serotonergic psychedelics.
3. Investigate whether changes in brain information processing can explain psychotic-like side effects of serotonergic psychedelics.
4. Investigate whether changes in brain information processing can predict who will have stronger psychotic-like side effects from serotonergic psychedelics.
5. Investigate whether acute or persisting changes in E/I balance predict therapeutic or psychotic effects of serotonergic psychedelics.

Inclusion Criteria:

• Participation in approved clinical protocol at Yale University involving potential administration of serotonergic psychedelics
• Absence of pre-existing psychotic symptoms

Exclusion Criteria:

• Current intoxication based on self-report
• Any neurological, medical or developmental problem that is known to impair cognition significantly based on self-report
• History of seizures based on self-report
• Contraindications for MR scanning including metallic implants of any kind, pacemakers and history of accidents with metal, claustrophobia (specific to those who will participate in MRI)