Genetics of Cannabis Use Disorder and Cannabinoid Response in Humans

Cannabis is widely used worldwide and is associated with negative outcomes including cannabis use disorder (CanUD), psychosis, and cognitive impairment amongst others. Given the legalization of "recreational" and "medical" cannabis globally, the increasing availability of cannabis, the higher potency of cannabis, the availability of highly potent cannabinoid products, the commercialization of cannabis, and the rising rates of cannabis use, it is critical to understand how genetic factors influence 1) an individual's vulnerability for addiction and psychosis, 2) the response to cannabinoids, 3) the response to novel treatments for CanUD. CanUD is strongly genetically influenced; the investigators published the first CanUD genomewide association study (GWAS) with genomewide-significant results; however, the precise nature of the contribution of genetic factors in the development of CanUD is still not clear. Cannabis exposure has also been linked to a number of psychosis outcomes including schizophrenia (SCZ). SCZ is highly heritable and population-based and genetics studies both support a bidirectional genetic relationship between SCZ and CanUD. However, the precise contribution of genetic factors in the development of psychosis outcomes related to cannabis are not clear.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia; Cannabis Use Disorder
• Intervention / Treatment: Drug: Placebo; Drug: Delta-9-THC Very Low Dose; Drug: Delta-9-THC Medium Dose

• Study Type: Interventional
• Enrollment (Estimated): 215
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Deepak D'Souza, MD; Phone Number: 12594 203-932-5711; Email: deepak.douza@yale.edu

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • Recruiting
      • West Haven Veterans Affairs Medical Center
      • Contact: Deepak C D'Souza, MD; Phone Number: 12594 203-932-5711; Email: deepak.dsouza@yale.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

-Ages 21-60 years old

Exclusion Criteria:

• Major or unstable medical conditions based on history, the Structured Clinical Interview for DSM-5, collateral information, physical and laboratory examinations, ECG, and vital signs.
• Cannabis naïve individuals
• Positive pregnancy test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Control: small amount of alcohol administered intravenously (quarter teaspoon), with no delta-9-THC, over 20 minutes.	Drug: Placebo; Control: Small amount of sterile 190 proof USP ethanol (1-2 mLs), with no THC, administered intravenously over 20 minutes.
Active Comparator: Delta-9-THC Very Low Dose; Active delta-9-THC administered intravenously over 20 minutes.	Drug: Delta-9-THC Very Low Dose; Active Delta-9-THC administered intravenously over 20 minutes.
Active Comparator: Delta-9-THC Medium Dose; Active delta-9-THC administered intravenously over 20 minutes.	Drug: Delta-9-THC Medium Dose; Active Delta-9-THC administered intravenously over 20 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analog Scale (VAS)	The VAS is a scale to document perceived reward. A higher score reflects a positive response.	Measured at baseline, 20 minutes, 45 minutes, 90 minutes, 140 minutes, 165 minutes, 210 minutes, 270 minutes, and 360 minutes after the start of the initial THC/placebo drug infusion.
Positive and Negative Symptom Scale (PANSS)	The Positive and Negative Syndrome Scale is a 30-item scale to assess both the positive and negative symptom symptoms of schizophrenia. The range total score is 30-210. An improvement in symptoms is reflected by a lower score.	Measured at baseline, 45 minutes, 90 minutes, 165 minutes, 210 minutes, and 360 minutes after the start of the initial THC/placebo drug infusion.
Clinician Administered Dissociative Symptoms Scale (CADSS),	Perceptual alterations will be measured using scales such as the Clinician Administered Dissociative Symptoms Scale (CADSS), a scale consisting of 19 self-report items and 8 clinician-rated items (0 = not at all, 4 = extremely) that we have shown to be sensitive to THC effects. The scale captures alterations in environmental/time/body perception, feelings of unreality, and memory impairment.	Measured at baseline, 45 minutes, 90 minutes, 165 minutes, 210 minutes, and 360 minutes after the start of the initial THC/placebo drug infusion.
CogState Battery	The CogState Battery measures cognition including verbal learning and recall and episodic memory.	Measured at baseline, 45 minutes, and 165 minutes after the start of the initial THC/placebo drug infusion.

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Deepak D'Souza, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2024
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: September 15, 2023
• First Submitted That Met QC Criteria: September 21, 2023
• First Posted (Actual): September 28, 2023

Study Record Updates

• Last Update Posted (Estimated): July 8, 2025
• Last Update Submitted That Met QC Criteria: July 1, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Schizophrenia; Marijuana Abuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Neurotransmitter Agents; Psychotropic Drugs; Hallucinogens; Cannabinoid Receptor Agonists; Cannabinoid Receptor Modulators; Dronabinol
• Other Study ID Numbers: 2000036194; RO1 (Other Identifier: National Institute on Drug Abuse)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No