Imaging the Neurochemistry of Drug Addiction With PET

The investigators' project has two overarching goals. 1) The investigators will use newly developed positron emission tomography (PET) technology to investigate the dopaminergic neurochemistry of drugs of abuse including marijuana, traditional cigarettes, and cocaine, and 2) The investigators will extend PET technology to an additional neurotransmitter system - namely, the opioid-ergic system, using the same drugs of abuse.

Study Overview

• Status: Completed
• Conditions: Smoking; Cannabis
• Intervention / Treatment: Drug: cannabis

Detailed Description

Aim 1. To examine the magnitude, location and timing of drug-induced dopamine release.

1. Tobacco smokers (n=20) will be imaged with [11C]raclopride PET, after overnight abstinence from tobacco. Subjects will smoke their preferred brand of cigarette during the PET scan.
2. Marijuana smokers (n=20) will be imaged with [11C]raclopride PET, after overnight abstinence from marijuana. Subjects will smoke a marijuana cigarette during the PET scan.
3. Cocaine users (n=20) will be imaged with [11C]raclopride PET, after overnight abstinence from cocaine. Subjects will be administered cocaine during the PET scan.

Aim 2. To examine the magnitude, location and timing of drug-induced beta-endorphin release. *The Investigators will attempt to use the same subjects from Aim 1 for Aim 2.

1. Tobacco smokers (n=20) will be imaged with [11C]carfentanil PET, after overnight abstinence from tobacco. Subjects will smoke their preferred brand of cigarette during the PET scan.
2. Marijuana smokers (n=20) will be imaged with [11C]carfentanil PET, after overnight abstinence from marijuana. Subjects will smoke a marijuana cigarette during the PET scan.
3. Cocaine users (n=20) will be imaged with [11C]carfentanil PET, after overnight abstinence from cocaine. Subjects will be administered cocaine during the PET scan.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Connecticut Mental Health Center
    • New Haven, Connecticut, United States, 06519
      • Yale Magnetic Resonance Research Center
    • New Haven, Connecticut, United States, 06519
      • Yale PET Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• General Inclusion Criteria:

  1. Men and women, aged 18-55 years
  2. Able to read and write English and give voluntary written informed consent
  3. Not treatment seeking or using treatment medications

Tobacco Smokers

1. Have a Fagerström Test for Nicotine Dependence (FTND) rating of at least 3.
2. Have been using at least 7 cigarettes per day for at least 1 year
3. Carbon monoxide levels > 10 ppm during intake evaluation
4. Urine cotinine levels of > 150 ng/mL during intake evaluation
5. Are not current users of marijuana or other illicit drugs

Marijuana Smokers

1. Meet DSM-V criteria for cannabis use disorder based on the structured clinical interview diagnostic (SCID) or regular cannabis use of >5 times/week
2. Test positive for THC
3. Have been smoking cannabis on a regular basis for > 1 year

Cocaine Users

1. DSM-V criteria for Cocaine Abuse or Dependence
2. Recent street cocaine use in excess of amounts to be administered in the current study
3. Intravenous and/or smoked (crack/ freebase) use
4. Positive urine toxicology screen for cocaine

Exclusion Criteria:

• 1. Current significant medical condition such as neurological, cardiovascular, endocrine, renal, liver, or thyroid pathology.

  2. History of or current neurological or significant psychiatric disorder such as schizophrenia or bipolar disorder (DSM-IV Axis 1).

  3. History of significant head trauma. 4. Women who are pregnant or nursing, or fail to use one of the following methods of birth control unless she or partner is surgically sterile or she is postmenopausal (hormone contraceptives [oral, implant, injection, patch, or ring], contraceptive sponge, double barrier [diaphragm or condom plus spermicide], or IUD).

  5. Regular or current significant use of any prescription, herbal or illegal psychotropic medications (e.g., antidepressants, antipsychotics, anxiolytics, ecstasy) in the past 6 mo, with no current illegal drug use confirmed by urine toxicology (except for cocaine and marijuana when relevant).

  6. Significant substance misuse (including alcohol, and excluding cannabis and marijuana when relevant) that in the PI's determination interferes with the study results or safety of the subject.

  7. Have MRI-incompatible implants and other contraindications for MRI, such as a pacemaker, artificial joints, non-removable body piercings, claustrophobia, etc.

  8. Subjects with history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over FDA limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year.

  9. Subjects with current, past or anticipated exposure to radiation in the work place within one year of proposed research PET scans.

  10. Subjects with history of IV drug use which would prevent venous access for PET tracer injection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Drug of dependence; There is only one arm to the study. All subjects will receive their drug of dependence in this study. Nicotine dependent subjects will receive tobacco cigarettes, cannabis dependent subjects will receive cannabis cigarettes, and cocaine dependent subjects will receive IV cocaine.	Drug: cannabis; All cannabis dependent subjects will use cannabis cigarettes to induce elevated dopamine and beta endorphin levels in the brain.; Other Names: marijuana

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Dopamine Levels at Baseline and After Drug of Dependence Administration as Confirmed by PET Images.	PET images will be obtained in dependent subjects at baseline and after drug of dependence administration. Change in DA levels will be determined by change in binding potential of raclopride. Baseline levels will be assessed during the first scan in the morning after overnight abstinence from their drug of dependence using a 90-minute PET acquisition. Then, drug of dependence will be administered 35 minutes before a second 90-minute PET acquisition. The beginning of the second PET scan will be approximately 5 hours after the beginning of the first PET scan, however in some cases this may be longer, or the scans may take place on separate days due to scheduling constraints or scan cancellations.	90 minute PET scan acquisition. Drug of dependence will be given at -35 mins
Change in Beta Endorphin Levels at Baseline and After Drug of Dependence Administration as Confirmed by PET Images.	PET images will be obtained in dependent subjects at baseline and after drug of dependence administration. Change in beta endorphin levels will be determined by change in binding potential of carfentanil. Baseline levels will be assessed during the first scan in the morning after 12 hour abstinence from their drug of dependence using a 90-minute PET acquisition. Then, drug of dependence will be administered 35 minutes before a second 90-minute PET acquisition. The beginning of the second PET scan will be approximately 5 hours after the beginning of the first PET scan, however in some cases this may be longer, or the scans may take place on separate days due to scheduling constraints or scan cancellations.	120 minute PET scan acquisition. Drug of dependence will be given at -35 mins

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Kelly Cosgrove, PhD, Yale University

Publications and helpful links

General Publications

• Calakos KC, Liu H, Lu Y, Anderson JM, Matuskey D, Nabulsi N, Ye Y, Skosnik PD, D'Souza DC, Morris ED, Cosgrove KP, Hillmer AT. Assessment of transient dopamine responses to smoked cannabis. Drug Alcohol Depend. 2021 Oct 1;227:108920. doi: 10.1016/j.drugalcdep.2021.108920. Epub 2021 Jul 29.

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2017
• Primary Completion (Actual): January 12, 2022
• Study Completion (Actual): June 14, 2024

Study Registration Dates

• First Submitted: June 27, 2016
• First Submitted That Met QC Criteria: June 27, 2016
• First Posted (Estimated): June 29, 2016

Study Record Updates

• Last Update Posted (Actual): December 12, 2024
• Last Update Submitted That Met QC Criteria: November 18, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: smoking; cannabis; cocaine
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders
• Other Study ID Numbers: 1604017594; 1R01DA038709-01A1 (U.S. NIH Grant/Contract); 1R01DA038832-01A1 (U.S. NIH Grant/Contract); 1R03DA047588-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No