Ongoing Research

Researchers at Yale have been studying the psychological, neurobiological, and therapeutic effects of psychedelic substances and other mind-altering drugs for decades. The Yale Program for Psychedelic Science supports this broad, multidisciplinary community. Active studies in psychedelic science include:

Efficacy of Psilocybin in OCD: A Double-Blind, Placebo-Controlled Study

Principal Investigators: Benjamin Kelmendi, MD; Christopher Pittenger, MD, PhD

This study is investigating the effects of psilocybin on obsessive-compulsive disorder symptomatology, and corresponding neural changes. We hypothesize that psilocybin will lead to greater symptom improvement at all assessment points. This study includes functional magnetic resonance imaging (fMRI) prior to and following the drug administration. If successful, this study will provide the first controlled evidence for the effect of psychedelic treatment on OCD, and the first data on accompanying neural mechanisms.

The Effects of MDMA on Prefrontal and Amygdala Activation in PTSD

Principal Investigator: Benjamin Kelmendi, MD

MDMA is in phase 3 trials for the treatment of post-traumatic stress disorder (PTSD). Here, we are studying the effects of MDMA on brain activation – specifically in the prefrontal cortex and amygdala – in PTSD, to explore the relationship between MDMA-induced neural plasticity and the behavioral effects, We hypothesize that MDMA will increase prefrontal activity, but decrease amygdala activation in response to negative stimuli. This study includes a functional magnetic resonance imaging (fMRI) session during drug administration.

Psilocybin-Induced Neuroplasticity in the Treatment of Major Depressive Disorder

Principal Investigators: Deepak C. D’Souza, MBBS, Jordan Sloshower, MD, MSC, Patrick Skosnik, Ph.D.

This study aims to understand how psilocybin alters neural plasticity and behavior in those with major depressive disorder (MDD). We hypothesize that psilocybin will result in neuroplastic changes that parallel improvements in symptomatology. Changes in electrical brain activity associated with neuroplasticity are measured using electroencephalography (EEG).

Effects of Psilocybin in Cluster Headache

Principal Investigators: Emmanuelle Schindler, MD, PhD; Deepak D’Souza, MD

The purpose of this study is to investigate the effects of an oral psilocybin regimen in those who suffer from cluster headache. Subjects are randomized to receive placebo, low dose psilocybin, or high dose psilocybin in three experimental session. Sessions are separated by five days. Subjects will maintain a headache prior to, during, or after the pulse regimen in order to document headache frequency and intensity before, during, and after the pulse regimen. Six months after the last experimental session, subjects may be invited for a second round, in which they will be randomized to receive either low dose or high dose psilocybin.

Effects of Psilocybin on Post-Traumatic Headache

Principal Investigators: Emmanuelle Schindler, MD, PhD; Deepak D’Souza, MD

The purpose of this study is to investigate the effects of psilocybin in post-traumatic headache, also known as post-concussion headache. Subjects will be randomized to receive placebo, low dose psilocybin, or high dose psilocybin on two test days approximately two weeks apart. Subjects will maintain a headache diary prior, during, and after the treatments to assess frequency and intensity and any other associated symptoms. Inflammatory peptides will also be assessed via blood draw at various time points throughout the study.

Repeat Dosing of Psilocybin in Migraine

Principal Investigators: Emmanuelle Schindler, MD, PhD; Deepak D’Souza, MD

The purpose of this study is to compare the preventive effects of a single vs. two administrations of psilocybin in migraine headache. Patients are randomized to receive zero, one, or two doses of psilocybin (10mg/70kg) one week apart. Subjects will maintain a headache diary out to two months in order to measure the lasting effects on headache burden. Subjects may also elect to wear an actigraphy and/or headband electroencephalography device during the study in order to measure circadian and sleep rhythms. These additional measures will provide preliminary data on the effects of psilocybin on these biological functions that are so relevant to headache disorders.

Mechanisms of Psilocybin’s Effects on the Prefrontal Cortex

Principal Investigator: Alex Kwan, PhD

The goal of this project is to determine the long-lasting impact of psilocybin on dendritic architecture in the mouse frontal cortex. We propose to first characterize the dose-response curve for psilocybin in mice, focusing on drug concentrations that lie below the threshold for motor responses. Next, we will determine the effects of administering a single dose of psilocybin on the density and turnover of dendritic spines over a two-week period.

A Comparative Study of Rapid-Acting Psychedelic Substances in Mice

Principal Investigators: Alfred Kaye, MD, PhD; Christopher Pittenger, MD, PhD

The goal of this project is to compare effects of multiple psychedelic compounds. We will test 5 conditions, including several psychedelic compounds of main interest, and a vehicle control (saline). We propose to first characterize the dose-response curves for the psychedelic compounds by measuring head-twitch response in mice. Next, we will determine plasticity-enhancing effects of administering a single dose of each compound on fear extinction behavior.

Functional Neuroimaging Correlates of Psychedelic Effects

Principal Investigator: Alan Anticivic, PhD

The current study aims to comprehensively map time-dependent pharmacological effects of psychedelic compounds on neural functional connectivity in healthy human adults and compare them to the spatial expression profile of genes coding for receptors interacting with psychedelic compounds.

Effects of Dimethyl Tryptamine in Humans

Principal Investigator: Deepak D'Souza, MD

The goal of this fixed order, open-label, dose-escalation study is to investigate the safety and efficacy of specific doses of dimethyltryptamine (DMT) in humans. We hypothesize that DMT will induce neuroplastic changes in the brain as well ameliorate depressed mood. Electroencepholographic (EEG) and psychometric data will be collected from healthy subjects as well as those with major depressive disorder. The results of this study will inform the doses of larger, placebo-controlled studies of DMT in the future.

A Multi-Center Study of Psilocybin in the Treatment of Major Depressive Disorder

Principal Investigators: Gerard Sanacora, MD, PhD; Benjamin Kelmendi, MD

This study is investigating the effects of psilocybin on major depressive disorder symptomatology, and corresponding neural changes. Subjects will be randomized to a niacin placbo or a single 25mg dose of psilocybin. Psilocybin dosing will be accompanied by a Set and Setting (SaS) protocol to ensure patient safety and maximize the effectiveness of the experience. We hypothesize that psilocybin will lead to greater symptom improvement across multiple psychometric data collection points, pre and post dosing.

Dose-Response Relationships in Psilocybin Treatment of Obsessive-Compulsive Disorder

Principal Investigators: Benjamin Kelmendi, MD; Christopher Pittenger, MD, PhD

The purpose of this study is to investigate the effects of repeated dosing of oral psilocybin on obsessive-compulsive disorder (OCD) symptomatology and assess psychological mechanisms that may mediate psilocybin’s therapeutic effects on OCD. We will employ a randomized, waitlist-controlled design with blinded ratings, with participants randomized to receive either immediate treatment (two doses oral psilocybin separated by one week) or delayed treatment (7 weeks post-randomization). An adaptive dose selection strategy will be implemented, with the first dose being fixed at 25 mg of psilocybin, and the second dose being either the same or a higher dosage (i.e., 30 mg), determined on the basis of a clinically significant response.