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

NCT06624137 | Recruiting

• 1 other identifier: 2000025076
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 2

Brief Summary

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. 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. 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. 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. 4.Can changes in how the brain uses information predict who will benefit from a psychedelic and who will have side effects from psychedelics?
5. 5.Online computer assessments consisting of games and questionnaires that probe how participants think.
6. 6.Magnetoencephalography (MEG) or electroencephalography (EEG) with eyes closed and with repeated clicks, images, or sensations delivered.
7. 7.A magnetic resonance imaging (MRI) scan.
8. 8.Semi-structured qualitative interviews about their experience after taking a serotonergic psychedelic recorded via Zoom.

Conditions

OCD; Healthy Volunteer; Addiction; Tobacco Use Disorder; Major Depressive Disorder (MDD); Alcohol Use Disorder (AUD); Migraine; PTSD; PTSD - Post Traumatic Stress Disorder; Obsessive Compulsive Disorder (OCD); Opioid Use Disorder

Keywords

Psilocybin; DMT; N,N-dimethyltryptamine; Ayahuasca; Lysergic acid diethylamide; LSD; 5-MeO-DMT; O-methyl-bufotenin; eeg; meg; 5-Methoxy-N,N-Dimethyltryptamine

Outcome Measures

Primary Outcomes (9)

• Hierarchial Gaussian Filter (HGF)-estimated average precision-weighted prediction error change in the conditioned hallucinations and probabilistic reversal learning tasks

  Participants' trial-by-trial responses on auditory and visual conditioned hallucination (CH) tasks as well as a probabilistic reversal learning (PRL) task are fitted with an enhanced Hierarchial Gaussian Filter (eHGF) model of hierarchial belief updating under perceptual/informational uncertainty using eHGF package in Julia. Precision weighted prediction errors used to update the 2nd and 3rd levels are estimated for each trial for each individual. Average precision weighted prediction errors across all trials as well as trials with greatest changes (0 stimulus trials for CH tasks and the first 5 trials after reversal in PRL) will be calculated. Change relative to baseline will be calculated. Greater precision weighted prediction errors reflect a greater weighting of new compared to previously learned information and greater belief updating.

  Immediately post drug administration (when psychologically acceptable), 1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

• Auditory and visual conditioned hallucination rate change

  Participants indicate detection of an auditory tone or visual pattern within auditory or visual noise. These stimuli are paired with cross-modality cues, causing participants to subconsciously expect to detect the stimuli using pavlovian conditioning. This conditioning causes participants experience "conditioned hallucinations" where they perceive the stimuli when it is not present. Conditioned hallucination rate is calculated as number of trials in which no stimulus was present but participants indicated perceiving the stimulus divided by the total number of trials in which no stimulus was present. A greater conditioned hallucination rate indicates greater reliance on previously learned information over incoming sensory evidence and closely tracks state-level hallucination susceptibility.

  Immediately post drug administration (when psychologically acceptable), 1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

• Perseverative and jumping-to-conclusion error total change in probabilistic reversal learning task

  Participants choose one of three images over multiple trials and receive reward feedback (low vs. high) in the PRL task. Each image has different reward probabilities that are unknown to participants. Through trial and error, participants learn which image is most rewarding and aim to maximize winnings. Over time, reward probabilities reverse without warning, requiring participants to update their beliefs. Every trial is scored as a perseverative error, a jumping to conclusions error, or neither, and then total number of error types are counted. Perseverative error trials occur when participants select a high reward probability image after its reward probability switches and they receive negative feedback. Jumping to conclusions (JTC) errors occur when participants switch from the highest reward stimulus to a different stimulus when there has been no reversal.

  Immediately post drug administration (when psychologically acceptable), 1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

• Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) score change

  The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) is a 16-item self-report questionnaire that captures life satisfaction over the past week. Each question is scored on a 5-point scale from 1 (Very Poor) to 5 (Very Good) that indicates the degree of enjoyment or satisfaction achieved during the past week relative to the particular activity or feeling described in the item. Scores range from 16 to 80. Higher score indicates higher quality of life.

  1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

• Southampton Mindfulness Questionnaire (SMQ) score change

  The Southampton Mindfulness Questionnaire (SMQ) consists of 16 items, each scored on a seven-point Likert scale from 0 = "Strongly Disagree" to 6 = "Strongly Agree." It measures the degree to which individuals are able to bring mindfulness to challenging or distressing thoughts and feelings. The total score is obtained by summing all items and ranges from 0 to 96. Higher scores indicate greater mindfulness in response to distressing situations.

  1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

• HGF-estimated ratio of perceptual belief-to-sensory evidence weighting change

  In the auditory and visual conditioned hallucinations tasks, the Julia eHGF model will estimate a single parameter value "Nu" for each individual that captures the individual's ratio of perceptual belief weighting compared to sensory evidence weighting in perceptual inference. Nu is estimated, like precision errors, by inverting the model from participant choices at each stimulus strength. Higher Nu values indicate participants are more likely to rely on learned pavlovian associations rather than sensory evidence and thus report perceiving the stimulus rather than not (IE experience a conditioned hallucination).

  Immediately post drug administration (when psychologically acceptable), 1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

• Aberrant Salience Inventory (ASI) score change

  The Aberrant Salience Inventory (ASI) consists of 29 items, each scored on a dichotomous scale: 0 = "No" and 1 = "Yes." It measures a variety of experiences related to aberrant salience, which refers to the inappropriate assignment of importance or significance to irrelevant, everyday, incoming stimuli/noise. The total score is calculated by summing all 29 items (0-29 range). Higher scores indicating higher levels of aberrant salience.

  1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

• Change in the exponent of the 1/f power spectrum law from resting state EEG

  Excitation/Inhibition (E/I) balance will be approximated by calculating the exponent of the 1/f power spectrum law from participants' processed EEG power spectra using the Fitting Oscillations and One-Over-F (FOOOF) package in python. Lower exponents indicate a shift towards excitation in E/I balance - hypothesized to reflect bottom-up noise.

  Period of peak drug effect and 1 day after drug administration

• Change in resting state delta, alpha, theta, low gamma, medium gamma, and high gamma bands

  At least 10 minutes of resting state M/EEG with eyes closed will be recorded at each time point. For recording during acute drug administration, a 10 minute epoch of highest data quality around peak drug effect will be selected. After preprocessing to remove common artifacts and/or non-resting segments (eg. when participant opened eyes, moved around, or talked with study monitors), data will be filtered via fast fourier transformation (FFT) into canonical delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), low gamma (25 to 40 Hz), medium gamma (40 to 65 Hz), and high gamma (65 to 85 Hz) bands, and then average power (amplitude2) will be calculated. Change from baseline will be calculated for each participant in each band.

  Period of peak drug effect and 1 day after drug administration

Secondary Outcomes (5)

• Patient Health Questionnaire-9 (PHQ-9) score change

  5-14 days post drug administration and 4-6 weeks post drug administration

• Change in learning rate difference between noisy and volatile learning conditions in a probabilistic learning game

  Immediately post drug administration (when psychologically acceptable), 1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

• Change in jumping to conclusion and perseverative errors in a feedback-free probabilistic learning game

  Immediately post drug administration (when psychologically acceptable), 1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

• Reward and punishment learning rate changes in probabilistic reversal learning task

  Immediately post drug administration (when psychologically acceptable), 1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

• Psychedelic Change Questionnaire (PCQ-26) score change

  1 day post drug administration, 5-14 days post drug administration, and 4-6 weeks post drug administration

Study Arms (2)

Serotonergic Psychedelic Arm

Group (healthy or with psychological or neurological disorder) administered serotonergic psychedelic (psilocybin, DMT, LSD, 5-MeO-DMT, Ayahuasca, etc.) regardless of administration route.

Drug: Serotonergic Psychedelic

Placebo Arm

Group (healthy or with psychological or neurological disorder) administered placebo (diphenydramine, saline, niacin, etc.) regardless of administration route.

Drug: Placebo

Interventions

Serotonergic Psychedelic DRUG

Any serotonergic or "classic" psychedelic that exhibits mainly Serotonin 2A receptor (5-HT2AR) agonism and is judged to produce subjectively similar effects.

Serotonergic Psychedelic Arm

Placebo DRUG

Matched Placebo

Placebo Arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

200 individuals who have consented to be administered serotonergic psychedelics through a clinical trial at Yale University.

You may qualify if:

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

You may not qualify if:

• 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)

Sponsors & Collaborators

• National Institutes of Health (NIH): collaborator
• Yale University: lead
• Burroughs Wellcome: collaborator

Study Sites (2)

Connecticut Mental Health Center

Hamden, Connecticut, 06517, United States

RECRUITING

West Haven VA Medical Center

West Haven, Connecticut, 06516, United States

RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Major; Alcoholism; Migraine Disorders; Stress Disorders, Post-Traumatic; Combat Disorders; Behavior, Addictive; Tobacco Use Disorder; Obsessive-Compulsive Disorder; Opioid-Related Disorders

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Compulsive Behavior; Impulsive Behavior; Behavior; Anxiety Disorders; Narcotic-Related Disorders

Study Officials

• Maximillian S Greenwald, BA

  Yale University

  STUDY DIRECTOR

• Albert R Powers, MD, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maximillian S Greenwald, BA

CONTACT

4254959793; maximillian.greenwald@yale.edu

Albert R Powers, MD,PhD

CONTACT

2039010290; albert.powers@yale.edu

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2024
• First Posted: October 2, 2024
• Study Start: December 12, 2024
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2028
• Last Updated: May 1, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)