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:
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.
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:
Validated, online questionnaires at the same time points as the computer games.
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:
Investigate how serotonergic psychedelics change brain reliance on new vs. old
information in perception and belief-updating while under the influence.
Investigate how serotonergic psychedelic change brain reliance on new vs. old
information in perception and belief updating at short and long-term follow-up.
Investigate whether serotonergic psychedelics cause side effects in people's
perception, attention, and belief updating that are both healthy and psychosis-like.
Investigate how serotonergic psychedelics acutely alter excitation/inhibition (E/I)
balance in the brain.
Investigate whether there are any persisting changes in resting state EEG power or
E/I balance.
The secondary objectives are to:
Investigate whether changes in brain information processing can explain therapeutic
effects of serotonergic psychedelics.
Investigate whether changes in brain information processing can predict who will
respond positively to serotonergic psychedelics.
Investigate whether changes in brain information processing can explain
psychotic-like side effects of serotonergic psychedelics.
Investigate whether changes in brain information processing can predict who will
have stronger psychotic-like side effects from serotonergic psychedelics.
Investigate whether acute or persisting changes in E/I balance predict therapeutic
or psychotic effects of serotonergic psychedelics.