Clinical trial NCT02817698
Conditions: Smoking Cannabis
Keywords: smoking cannabis cocaine
Sponsor: Yale University
Start date: 2017-11-29; Completion date: 2024-06-14
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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.

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.

Arms: arm 1: 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.
Interventions: intervention 1: cannabis
Intervention descriptions: intervention 1: All cannabis dependent subjects will use cannabis cigarettes to induce elevated dopamine and beta endorphin levels in the brain.

Protocol documents:
Prot_SAP_000.pdf: 
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YALE UNIVERSITY
                                  HUMAN INVESTIGATION COMMITTEE
                                     Application to Involve Human Subjects in Biomedical Research
100 FR1 (2015-2) 
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: Imaging the neurochemistry of drug addiction with PET
Principal Investigator: Kelly Cosgrove, Ph.D.
Yale Academic Appointment: Associate Professor
Department: Psychiatry, Radiology, and Biomedical Imaging
Campus Address:  40 Temple Street, New Haven, CT 05610
Campus Phone: 203-737-
6969
Fax: 203-764-6655
Pager: 
E-mail: kelly.cosgrove@yale.edu
Protocol Correspondent Name & Address (if different than PI):  Marc Grasso
 
Campus Phone: 203-737-
7074
Fax: 203-764-
6655
E-mail: marc.grasso@yale.edu
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable):
Campus Phone: 
Fax: 
E-mail: 
Business Manager:
Campus Phone :
Fax :
E-mail
Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research. 
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)           
 NA
Yale Academic Appointment:
Campus Address: 
Campus Phone: 
Fax: 
Pager: 
E-mail: 
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See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI 
  Yes
X  No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
  Yes
X  No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as co-investigators on a protocol with a Yale 
University Principal Investigator must also have a current financial disclosure form on file with 
the University’s Conflict of Interest Office. If this has not been done, the individual(s) should 
follow this link to the COI Office Website to complete the form:  http://www.yale.edu/coi/  
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply:
 
a. Internal Location[s] of the Study:
 Magnetic Resonance Research Center 
 Yale University PET Center
     (MR-TAC)   
 YCCI/Church Street Research Unit (CSRU)
 Yale Cancer Center/Clinical Trials Office (CTO)    
 YCCI/Hospital Research Unit (HRU)
 Yale Cancer Center/Smilow
 YCCI/Keck Laboratories
 Yale-New Haven Hospital
 Yale-New Haven Hospital—Saint Raphael Campus
 Cancer Data Repository/Tumor Registry
 Specify Other Yale Location: 
b. External Location[s]:
 APT Foundation, Inc.
 Haskins Laboratories
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 Connecticut Mental Health Center
 John B. Pierce Laboratory, Inc.
 Clinical Neuroscience Research Unit (CNRU) 
Veterans Affairs Hospital, West Haven
 Other Locations, Specify: 
 International Research Site 
(Specify location(s)):
c. Additional Required Documents (check all that apply):
 N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date: 
*Pediatric Protocol Review Committee (PPRC)
Approval Date: 
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date: 
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
 YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
 Yale University RSC (YU-RSC)
Approval Date:
 Magnetic Resonance Research Center PRC (MRRC-PRC)
Approval Date:
 *Nursing Research Committee
Approval Date:
 YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
 Dept. of Lab Medicine request for services or specimens form
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found 
at  http://radiology.yale.edu/research/ClinTrials.aspx)
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities.  7 years
3. Research Type/Phase: (Check all that apply)
a. Study Type
   
 Single Center Study
   
 Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes 
No 
  
 Coordinating Center/Data Management
  
 Other: 
b. Study Phase
 N/A
    
 Pilot
 Phase I
 Phase II
 Phase III
 Phase IV
    
 Other (Specify) 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found  in the instructions section 4c:
 Clinical Research: Patient-Oriented
  
 Clinical Research: Outcomes and 
 Clinical Research: Epidemiologic and Behavioral 
                Health Services
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 Translational Research #1 (“Bench-to-Bedside”)    
 Interdisciplinary Research
 Translational Research #2 (“Bedside-to-Community”) 
 Community-Based Research
5.   Is this study a clinical trial? Yes 
No 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry 
Other (Specify) 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx 
or  contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes 
 No
 N/A
7. Will this study have a billable service? A billable service is defined as any service rendered to 
a study subject that, if he/she was not on a study, would normally generate a bill from either 
Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s insurer. The 
service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include 
x-rays, MRIs, CT scans, specimens sent to central labs, or specimens sent to pathology). Notes: 
1. There is no distinction made whether the service is paid for by the subject or their insurance 
(Standard of Care) or by the study’s funding mechanism (Research Sponsored). 2. This generally 
includes new services or orders placed in EPIC for research subjects. 
Yes 
 No
 If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research 
management system, for Epic to appropriately route research related charges. Please contact 
oncore.support@yale.edu
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8.. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes ___ No __X_  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform?
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure?
 
c. Will a novel approach using existing equipment be applied?
 
If you answered “no” to question 8a, or "yes" to question 8b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at 
the HRU, the Principal Investigator and any co-investigators who are physicians or  mid-level 
practitioners (includes PAs, APRNs, psychologists and speech pathologists) who may have direct 
patient contact with patients on YNHH premises must have medical staff appointment and 
appropriate clinical privileges at YNHH. If you are uncertain whether the study personnel meet 
the criteria, please telephone the Physician Services Department at 203-688-2615. By signing 
this protocol as a PI, you attest that you and any co-investigator who may have patient contact 
has a medical staff appointment and appropriate clinical privileges at YNHH.
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SECTION III:
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR AGREEMENT
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the
      research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects’
      rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal,
      state and local laws, as well as institutional regulations and policies regarding the protection of  
      human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating the
      study or any change and I will obtain continuing approval of this study prior to the expiration date     
      of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to
      participants.

I am in compliance with the requirements set by the University and qualify to serve as the
      principal investigator of this project or have acquired the appropriate approval from the 
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at
      Yale-New Haven Hospital, or have a faculty advisor.

I will identify a qualified successor should I cease my role as principal investigator and facilitate a
smooth transfer of investigator responsibilities.
_____
 
PI Name (PRINT) and Signature
Date
As the faculty advisor of this research project, I certify that:

The information provided in this application is complete and accurate.

This project has scientific value and merit and that the student or trainee investigator has the necessary 
resources to complete the project and achieve the aims.

I will train the student investigator in matters of appropriate research compliance, protection of human 
subjects and proper conduct of research.

The research will be performed according to ethical principles and in compliance with all federal, state 
and local laws, as well as institutional regulations and policies regarding the protection of human 
subjects.

The student investigator will obtain approval for this research study and any subsequent revisions prior 
to initiating the study or revision and will obtain continuing approval prior to the expiration of any 
approval period.

The student investigator will report to the HIC any serious injuries and/or other unanticipated       
problems involving risk to participants. 

I am in compliance with the requirements set forth by the University and qualify to serve as       the 
faculty advisor of this project. 

I assume all of the roles and responsibilities of a Principal Investigator even though the student may be 
called a PI.
___________
______
_____
    Advisor Name (PRINT) and Signature
Date
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Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a
sponsoring company, patents, licensure) associated with this research project?
 Yes (provide a description of that interest in a separate letter addressed to the HIC.)
 No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and
the sponsor of the research project, or its competitor or any interest in any intervention and/or method
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC)
No
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I assure the HIC that the principal investigator and all members of the research team are qualified by
education, training, licensure and/or experience to assume participation in the conduct of this research
trial. I also assure that the principal investigator has departmental support and sufficient resources to
conduct this trial appropriately.
   ____________________________
   Chair Name (PRINT) and Signature  
    
 Date
   _________________________________
   Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project.
  ______________________________________
    YNHH HSPA Name (PRINT) and Signature       
Date
SECTION IV: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
Our project has two overarching goals. 1) We will use newly developed positron emission 
tomography (PET) technology to investigate the dopaminergic neurochemistry of drugs of abuse 
including marijuana, traditional cigarettes, and 2) We will extend our PET technology to an 
additional neurotransmitter system – namely, the opioid-ergic system, using the same drugs of 
abuse. 
The majority of the research investigating the neurochemical mechanisms involved in drug 
addiction has been conducted in animals. From these studies it is well known that the 
mesolimbic dopamine (DA) system drives the reinforcing effects of drugs of abuse. In particular, 
a seminal study demonstrated that DA is released (in animals) by all drugs that are abused by 
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humans1. In addition, it has been hypothesized that DA influences reward “wanting”, while the 
opioid system governs reward “liking”2, both of which are critical for understanding 
neurochemical processes underlying compulsive drug use. These findings in animals need to be 
confirmed in humans to validate the animal models, to improve our understanding of the 
neurochemistry of drug abuse, and so that we can test new medications in humans. With PET 
we can noninvasively, and now dynamically, measure neurotransmitter changes in response to 
drugs of abuse in humans. This investigation will utilize a system previously developed by our 
group for imaging and modeling DA release in humans from cigarette smoking in the PET 
scanner. Our experimental and analytical techniques are sensitive enough to detect moderate 
increases in striatal DA (in magnitude and spatial extent) that are expected with marijuana. Our 
model is also uniquely able to capture the temporal profile of brief DA responses.  The goals of 
this study are to extend our paradigm to additional drugs of abuse (marijuana) and to extend our 
technology to an additional neurotransmitter system (opioid-ergic) with the same drugs of abuse 
(tobacco, marijuana). This will allow us to determine the spatio-temporal patterns of combined 
DA and beta-endorphin fluctuations associated with drugs of abuse in the living human brain. 
Aim 1: To examine the magnitude, location and timing of drug-induced dopamine release.
a.
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.
b.
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. 
Aim 2: To examine the magnitude, location and timing of drug-induced beta-endorphin 
release. *We will attempt to use the same subjects from Aim 1 for Aim 2 (Marijuana Exposed 
Healthy Controls are the exception)  
a.
Tobacco smokers (n=20) will be imaged with [11C]carfentanil PET, after 
overnight abstinence from tobacco smoking. Subjects will smoke their 
preferred brand of cigarette before or during the drug condition PET scan.
b.
Marijuana smokers and Marijuana Exposed Healthy Controls (n=20) will be 
imaged with [11C]carfentanil PET, after overnight abstinence from marijuana 
smoking. Subjects will smoke a marijuana cigarette before or during the drug 
condition PET scan.
Aim 3: To examine the magnitude, location and timing of marijuana-induced dynorphin 
release. Cannabis has diverse effects on the endogenous opioid system. We will image 
Marijuana Smokers and Marijuana Exposed Healthy Controls (n=20) with [11C]EKAP PET, after 
overnight abstinence from marijuana smoking. Subjects will smoke a marijuana cigarette before 
or during the drug condition PET scan.
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data.
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The neurochemistry of drug addiction. Drug addiction is a widespread public health 
issue, affecting at least one quarter of the adult U.S. population. A key process of chronic 
drug use is the transition from voluntary to compulsive use in spite of adverse 
consequences. The rewarding aspects of drug abuse are known to be critical to both the 
initiation, i.e., voluntary, and maintenance of drug use4. Reward processes are primarily 
influenced by the DA and opioid neurotransmitter systems. It has been hypothesized that 
DA influences reward “wanting”, while the opioid system governs reward “liking”2, both of 
which are critical for understanding neurochemical processes underlying compulsive drug 
use. For example, initial drug seeking for the pleasurable aspects of the drug (“liking”) often 
gives way to habitual drug use (“wanting”), particularly in response to drug cues, despite 
individuals reporting little pleasure from the drug itself5. While much preclinical work has 
studied dopamine-opioid interactions in reward response6,7, extending this work to study the 
neurochemistry of reward response in clinical substance abuse disorders has been limited.  
Using PET to study to neurochemistry of drug addiction. PET neuroreceptor imaging 
has revealed a wealth of in vivo research examining basal levels of dopaminergic and opioid 
receptor availability in substance abuse disorders. In other words, these studies ask the 
question, “In the absence of drug administration, how many receptors are available for 
radioligand binding?” Using these methods, lower dopamine D2/D3 receptor availability in 
drug users compared to healthy controls has been identified as a key hallmark of substance 
abuse disorders, and this currently influences therapeutics development8,9.  In contrast, 
different substances have diverse effects on the opioid system. Reduced μ-opioid receptor 
availability in smoking10 and nicotine dependence severity11,12, while increased μ-opioid 
receptor availability was associated with chronic cocaine use13-16, heroin dependence17,18, 
alcohol dependence19-21, and alcohol craving21-23. Different drugs of abuse may thus affect 
the opioid receptors in a variety of ways, underscoring the importance of studying the opioid 
system in substance abuse disorders.  
To build on these findings, many groups have attempted to use PET neuroreceptor imaging 
to examine the acute drug response of the dopamine and opioid systems in vivo. These 
studies are designed to ask the question, “How does the number of receptors available for 
radioligand binding change after drug administration?” The common methodology for these 
experiments is to use two PET scans to measure the neurotransmitter response, inferred by 
changes in radioligand binding, following drug administration. First, a baseline PET scan is 
acquired to measure the available receptors indexed by binding potential (BP). Next, the 
drug is administered, followed by a second PET scan acquired to measure the post-drug 
BP. If the drug leads to neurotransmitter release, the additional neurotransmitter will bind to 
the receptor site, decreasing the number of available receptors for radioligand binding (and 
BP). Measured changes in BP (baseline BP minus post-drug BP) thus enable an indirect 
measure of neurotransmitter increase. This two-scan paradigm has been used to repeatedly 
demonstrate a blunted dopamine response to amphetamine administration in individuals 
chronically using drugs of abuse24-27. However, BP measures assume steady-state 
radioligand binding, and thus steady-state neurotransmitter levels, for the scan duration. 
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This assumption works well with amphetamine because this drug induces a robust and long-
lived dopamine elevation that remains steady during the entire post-drug scan, allowing for 
reliable estimates of changes in dopamine levels with the two-scan paradigm. Other drug 
stimuli, such as cigarette smoking, induce short-lived neurotransmitter release that 
dynamically changes radioligand binding throughout the post-drug scanning period. The 
classic BP paradigm can underestimate or even fail to detect such transient neurotransmitter 
responses28. Thus, alternative analysis methods are needed to identify short-lived 
neurotransmitter activation with PET imaging. 
We have developed a new imaging paradigm, known as linear parametric neurotransmitter-
PET (lpntPET), to explicitly accommodate time-varying changes in radioligand binding while 
scanning, enabling accurate detection of short-lived neurotransmitter response using PET 
imaging29-33. lpntPET identifies the spatial extent of neurotransmitter activation at the voxel 
level with improved sensitivity and specificity relative to two-scan paradigms28,34, while also 
characterizing the temporal component of endogenous neurotransmitter activation33,34. This 
approach revealed remarkable differences between men and women both in the brain areas 
and temporal dynamics of dopamine release in response to cigarette smoking35. Importantly, 
these findings were consistent with men tending to smoke for the reinforcing effects of 
nicotine than women36 (i.e., sex differences in cigarette “wanting”). However, to date 
lpntPET has only been used to image changes in the dopamine31,35 and acetylcholine37 
systems. Given the close interaction of the dopamine and opioid systems in the dynamics of 
reward processing, validating ntPET with radioligands sensitive to endorphin activation will 
provide powerful tools enhancing in vivo study of reward processes in the brain with PET 
imaging.    
PET imaging of the opioid system has primarily been conducted with the μ-selective 
[11C]carfentanil38 and non-selective [11C]diprenorphine39 radioligands. Both radioligands are 
reported to be sensitive to endorphin levels, the opioid peptides that preferentially act at μ- 
and δ-opioid receptors40. Reduced [11C]carfentanil binding, presumably due to increased β-
endorphin levels, was reported in response to acute somatic pain41-43, affective responses18, 
placebo administration44, oral amphetamine administration45,46, and cigarette smoking47. In 
particular, one study reported variation in average [11C]carfentanil BP over time following 
acute somatic pain42 suggesting time-varying β-endorphin response to pain, albeit with 
biased analysis methods. These initial reports suggest that [11C]carfentanil is a suitable 
radioligand to detect short-lived changes in β-endorphin levels.  Moreover, increasing 
interest in marijuana’s diverse effects on the endogenous opioid system have identified an 
important role for dynorphin in potentially mediating marijuana’s putative analgesic effects. 
The Yale PET center has developed the novel agonist radioligand [11C]EKAP that exhibits 
kinetic properties consistent with radiotracer sensitivity to endogenous dynorphin levels. 
Given repeated observations of short-lived opioid peptide responses to drugs of abuse with 
microdialysis techniques48,49 (see 50 for review), extension of the lpntPET paradigm to the 
opioid system could provide groundbreaking in vivo characterization of endorphin 
release following drug stimulus.    
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In the current proposal we propose to image the dopaminergic and the opioidergic 
response to drugs of abuse in the same subjects. Thus, we will be able to potentially 
visualize multiple neurotransmitter systems within the same person and we will be 
able to compare the neurotransmitter system map between drugs of abuse.   
3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and 
include any flowcharts of visits specifying their individual times and lengths. Describe 
the setting in which the research will take place.
3.1 Overall Research Design: 
This study will recruit drug users (tobacco or marijuana) to participate in one magnetic resonance 
imaging scan (MRI),one [11C]raclopride PET scan, two [11C]carfentanil PET scans, and 
two[11C]EKAP PET scans (for marijuana users/marijuana exposed) .  If subjects have never been 
in a PET scanner, they may participate in a brief “mock” PET scan session prior to their actual 
scan to familiarize them with the environment (reduce the novelty) and if they are a smoker, to 
familiarize them with the mechanics of smoking in the scanner. 
Aim 1. To examine the magnitude, location and timing of drug-induced dopamine release.
a.
Tobacco smokers (n=20) will be imaged with [11C]raclopride PET, after 
overnight abstinence  from tobacco smoking. Subjects will smoke their 
preferred brand of cigarette during the PET scan.
b.
Marijuana smokers (n=20) will be imaged with [11C]raclopride PET, after 
overnight abstinence from marijuana smoking. Subjects will smoke a 
marijuana cigarette during the PET scan.
Aim 2. To examine the magnitude, location and timing of drug-induced beta-endorphin 
release. *We will attempt to use the same subjects from Aim 1 for Aim 2. (Marijuana Exposed 
Healthy Controls are the exception)  
a.
Tobacco smokers (n=20) will be imaged with [11C]carfentanil PET, after 
overnight abstinence from tobacco smoking. Subjects will smoke their 
preferred brand of cigarette before or during the drug condition PET scan
b.
Marijuana smokers and Marijuana Exposed Healthy Controls (n=20) will be 
imaged with [11C]carfentanil PET, after overnight abstinence from marijuana 
smoking. Subjects will smoke a marijuana cigarette before or during the drug 
condition PET scan.
Aim 3: To examine the magnitude, location and timing of marijuana-induced dynorphin 
release. Cannabis has diverse effects on the endogenous opioid system. We will image 
Marijuana Smokers and Marijuana Exposed Healthy Controls (n=20) with [11C]EKAP PET, after 
overnight abstinence from marijuana smoking. Subjects will smoke a marijuana cigarette before 
or during the drug condition PET scan.
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For Aim 1 using a single scan paradigm, drugs will be administered beginning approximately 35 
minutes after the radiotracer injection, as previously validated35. For Aim 2 and 3, since this 
approach has not yet been done in people with [11C]carfentanil or [11C]EKAP, we will use a two 
scan paradigm (baseline and challenge). Drugs will be administered either before 
(approximately 15 min prior to radiotracer injection) or during (30-60 minutes after radiotracer 
injection) drug condition PET scan, which may occur after a baseline condition PET scan. The 
scans will be analyzed to produce the magnitude and temporal characteristics of the DA and 
beta-endorphin signature of drug use under each condition.
3.2 Subject Selection:
All research subjects will be recruited under guidelines of the Yale University Institutional 
Review Board (Human Investigation Committee). Subjects will be recruited from the community 
at large via IRB-approved advertising (television, newspaper, postings in community locations, 
Craigslist, Facebook).
Screening Evaluation
Potentially eligible subjects will undergo an initial screening evaluation within 6 months of PET 
scanning. The purpose of this evaluation is to ensure that subjects meet study criteria. After 
informed consent is obtained, a medical history, vital signs, physical examination, and EKG will be 
performed. Several laboratory tests will be performed at this visit, which may include a complete 
blood count (CBC), chemistry profile, thyroid function studies, serum ß-HCG (women only), 
urinalysis, and urine toxicology screen. All female subjects will undergo a pregnancy test at the 
time of screening. Additionally, urine pregnancy tests will be done on the day of each PET scan 
before radiotracer injection. Urine drug screens will be done at intake and on PET days.
3.3 Assessments:
All participants will be screened initially using a telephone screen that will include questions to 
evaluate medical history, personal and familial psychiatric and smoking history.  A wide range of 
measures, such as psychiatric and substance abuse history, medical assessments and affective 
symptoms will be measured during the intake evaluation.
3.3a. General Intake Assessments 
1.
Demographic Questionnaire This questionnaire will obtain: (1) basic demographic 
information including age, gender, marital status, employment status, occupation, (2) 
alcohol/drug history, (3) family history of alcohol/drug use, depression, anxiety, and smoking 
history.
2.
Medical History This questionnaire will obtain a basic medical history (personal and 
family) including past or current conditions such as neurological, endocrine, cardiovascular, 
renal, liver, and thyroid pathology. Current body weight and current medications will also be 
assessed. 
3.
Medical Assessments will include a physical exam by a state licensed physician, an 
EKG, and laboratory tests which may include a complete blood count, blood urea nitrogen, 
creatinine, fasting blood sugar, electrolytes, liver function tests, thyroid function tests  (including 
T3, T4, T3RU, estimated free T4), thyroid stimulating hormone levels, urine toxicology, and 
urinalysis. Female subjects will have serum pregnancy tests. 
4.
Illicit Drug/Pregnancy Screen A urine sample may be collected to determine current illicit 
drug use (for all potential subjects). In addition,  serum samples will be collected at the intake 
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visit and urine samples will be collected on each PET scan day to confirm that the subject is not 
pregnant.  
5.
Structured Clinical Interview for DSM-IV Axis I Disorders The psychotic screening and 
depression sections of the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) will 
be used to determine whether subjects meet exclusion criteria for diagnosis of significant 
psychopathology such as schizophrenia and bipolar disorder 38.
6.
Columbia Suicide Severity Rating Scale (C-SSRS).  The C-SSRS is designed to 
measure suicidal ideation (50).
7.
Multidimensional Scale of Perceived Social Support (MSPSS) is a brief research tool 
designed to measure perceptions of support from 3 sources: Family, Friends, and a Significant 
Other.
8.
Barratt Simplified Measure of Social Status (BSMSS) is a measure of socio-economic 
status.
3.3.b.  Mood Measures 
We will obtain these measures at intake and also on the PET scan day.
1. 
Center for Epidemiological Studies Depression Scale (CES-D) The CES-D39 is a 20-item 
self-report instrument, which has been extensively used in both clinical and nonclinical 
populations to measure the frequency and severity of depressive symptoms over the past week. 
The CES-D, which has been used to document the severity of depressive symptoms in adults 
and has been shown to be a sensitive measure of negative affect in smokers, will be used in the 
proposed studies to measure levels of mild depressive symptoms.
2. 
Anxiety: The State-Trait Anxiety Inventory40 is a 40-item, self-report measure, comprised 
of two subscales. The State-Anxiety scale is 20 items and assesses transitory states 
characterized by feelings of tension, apprehension, and heightened autonomic reactivity. The 
Trait-Anxiety scale is 20 items and assesses stable individual differences in anxiety proneness.
3.
Impulsivity: Barratt Impulsiveness Scale (BIS; 51) is a 30 item self-report instrument 
designed to assess the personality/behavioral construct of impulsiveness. 
4.
Beck Depression Inventory:  This widely used 21 item self-report instrument will be used 
to assess depressive symptomatology in addition to the SCID (43).
 
3.3.c. Smoking and other Drug Measures
We may obtain these measures at intake and also on the PET scan day. 
1.Fagerstrom Test for Nicotine Dependence (FTND). This will be used to measure the severity 
of nicotine dependence.  It is a 6-item scale with an internal consistency of .61 and its total 
score is closely related to biochemical measures of intensity of smoking.  A score of at least 3 is 
necessary for inclusion in the study. 
2. Smoking History. This questionnaire will assess basic smoking status and history such as 
number of years smoked, number and length of quit attempts, reasons for quitting, and second 
hand smoke exposure.  
3. Nicotine Withdrawal Checklist. This measures the severity of eight withdrawal symptoms on 
5-point Likert scales.  
4. Tiffany Questionnaire of Smoking Urges (QSU). The QSU-brief is a 10-item questionnaire 
that evaluates the structure and function of smoking urges.  Subjects indicate on a likert-type 
scale how strongly they agree or disagree with each statement with a score of 1 (strongly agree) 
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to 7 (strongly disagree).  This characterizes ‘urges to smoke’ into a negative affect related to 
relief of withdrawal symptoms and positive affect related to expectancy of reinforcement.   
5. Wisconsin Predicting Patients' Relapse Questionnaire (WI-PREPARE).  A brief, 7-item 
questionnaire that predicts relapse rate (49).
6.  Timeline Followback for alcohol, tobacco, and illicit drugs.  Questionnaire to measure the 
amount of alcohol, tobacco, and other drugs that have been used in the past 30 days.
7.   Visual Analog Scale (VAS) self ratings for drug effects.  Subjects will answer questions to 
assess behavioral changes induced by substance use.
8. Cannabis Problems Questionnaire is a 22 item self-report instrument to document cannabis-
related problems. 
9.
Marijuana Motives Questionnaire is a 25 item self-report instrument to characterize 
individual’s motivations for using marijuana. 
10.
Marijuana Smoking History Questionnaire is a 23 item self-report instrument to 
characterize the dose and frequency of marijuana use and quit attempts, both over lifetime and 
the past 30 days. 
11.
Marijuana Craving Questionnaire is a 12 item self-report instrument to document 
marijuana craving. 
12.
Cannabis Withdrawal Scale is a 19 item self-report questionnaire to document symptoms 
of cannabis withdrawal. 
13.
Clinician Administered Dissociative Symptoms Scale is a 27 item instrument 
administered by trained research staff to characterize present-state dissociative symptoms. 
3.3.d. Cognitive Measures
We may obtain these measures at baseline and up to two times on the PET day.
1. Cogstate Battery (30 minutes) – This computerized test battery will assess memory and 
cognition.  The tasks may include:
a. International Shopping List Task – a computerized task to assess verbal learning and 
memory.
b.  Groton Maze Learning Task – a computerized task to assess executive function and spatial 
problem solving.
c.  Detection Task – a computerized task to assess psychomotor function and speed of 
processing.
d.  Identification Task – a computerized task to assess visual attention and vigilance.
e.  One Card Learning Task – a computerized task to assess visual learning and memory.
f.  One Back Task and Two Back Task – computerized tasks to assess attention and working 
memory.
Probabilistic Reward Task (PRT) – The PRT has been successfully used to assess reward 
responsiveness (51-53). In each trial, subjects choose which of two difficult-to-differentiate stimuli 
was presented. Stimuli consist of simple cartoon faces (diameter: 25 mm; eyes: 7 mm) presented 
in the center of the monitor. At the beginning of the trial, the face has no mouth. After a given 
delay, either a straight mouth of 11.5 mm (“short mouth”) or 13 mm (“long mouth”) is presented 
for 100 ms. Subjects are instructed to press an appropriate button to decide whether a long or 
small mouth had been presented.  Unbeknownst to subjects, correct identification of one stimulus 
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(“rich stimulus”) is rewarded three times more frequently (“Correct! You won 20 cents”) than the 
other (“lean”) stimulus. In healthy controls, this reinforcement schedule leads to a response bias 
(i.e., a preference for the more frequently rewarded stimulus). The degree of response bias toward 
the more frequently reinforced alternative will be used for operationalizing sensitivity to reward.
Cold Pressor Task
Subjects may be asked to participate in the Cold Pressor Task.  The cold pressor task (CPT) is a 
stress task used to measure pain sensitivity and pain tolerance.  This task will be used to 
determine alterations in pain thresholds as a result of substance use.  Participants will immerse 
their hand (up to the wrist) for up to 5 minutes in the experimental (ice-cold temperature 0-4°C)) 
and control (room temperature (20°C)) conditions.  Physiological measure (heart rate, blood 
pressure and subject responses (stress, mood) will be collected 5 minutes before, 1 minute into, 
and immediately after the CPT.
3.4 Procedures
Screening, Evaluation and Clinical Ratings
Screening, evaluation and clinical ratings (as described above) are obtained during the 
screening process.
Magnetic Resonance Imaging (up to 1 hour)
Magnetic resonance imaging (MRI) scans (3T) will be collected in each subject to co-register 
PET and MRI for image analysis as well as collect resting state data. MRI is without contrast. 
Within approximately two weeks of the PET study, an MRI will be acquired at the Yale 
University MRI Center. Subjects will be taken through a ferromagnetic metal detector before 
entering the scan room. 
3T Scan sequence: 
Series 1: 3 plane localize 
Series 2: Sag 3d tfl; 256fov; 1mm thick slices; 176 slices total; TE 2.77; TR 2530; TI 1100; FA 7; 
256X256 1 average. 
Series 3 – Resting state: Ep2d bold; 210fov; 2.5mm thick slices; TE 30; TR 3400; FA 85; 84x84 
(Run twice).
MR images provide a matching anatomical atlas for creating individualized region-of-interest 
templates for each subject. We will also examine functional connectivity at rest.
If an MR image is already on file at the PET Center, and has been collected within a reasonable 
time period, a new MRI may not need to be collected.
A member of the research staff will accompany the subject and stay for the duration of the mri. 
PET Scans
PET experiments will be conducted at the Yale University PET Center. Subjects will have one 
[11C]raclopride PET scan, two [11C]carfentanil PET scans, and/or two [11C]EKAP PET scans with 
different radiotracer studies on separate days.  If technical difficulties arise, additional PET scans 
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may be scheduled at a later date, for a total of up to 8 PET scans. We may ask subjects to refrain 
from eating 4-6 hours prior to injection and remain fasting until the study is over.  Subjects may 
also be asked to refrain from drinking caffeinated beverages that day, and from drinking alcoholic 
beverages the week prior to the scan.  
All participating subjects will be asked to abstain from smoking or drug use for approximately 12 
hrs before each scan (e.g., overnight abstinence) to maximize craving). Upon arrival at the PET 
center, subjects will complete questionnaires on drug urges, withdrawal symptoms, and mood.  
Plasma will be drawn before scans to measure drug levels in the blood.  CO levels will also be 
measured (MicroDirect CO Monitor) upon arrival for scan.  CO < 11ppm indicates that subjects 
were abstinent as requested prior to tobacco and marijuana sessions. If the CO level is positive, 
subject participation will be up to the discretion of the PI. .Urine drug tests may be performed 
before all PET scansSubjects’ vitals will be monitored throughout the scans up until at least an 
hour before discharge. 
For all women, a urine pregnancy test will be performed at the beginning of the imaging day, 
prior to radiotracer injection, at the Yale University PET Center.
PET Data Acquisition and Analysis
Subject preparation consists of intravenous (IV) catheterizations and immobilization of the head. 
Venous catheters will be used for IV administration of the radiotracer and blood sampling. For 
[11C]EKAP scans, a radial artery catheter will be inserted by an experienced physician in the 
morning before the PET scan. The site will be anesthetized with lidocaine prior to arterial line 
insertion. The arterial line will remain in place for the whole day of scanning, after which it will be 
removed. PET scans are acquired as subjects rest using an HRRT, PET-CT, or NX-CT scanner 
. For HRRT scans, a transmission scan using an orbiting 137Cs point-source is obtained for each 
emission scan. Motion correction will be performed dynamically with measurements from the 
Vicra (NDI Systems, Waterloo, Ontario) used by a dedicated list-mode reconstruction algorithm 
52.
The PET scans will be acquired using IV bolus or bolus plus constant infusion administration of 
up to 20 mCi or less of high-specific activity [11C]raclopride, and/or[11C]carfentanil, and /or 
[11C]EKAP using a dynamic PET scan of up to 120 min. 
For NX scans, a stereovision motion tracking system will be used. This markerless (no head 
attachment) monitoring system uses 3D cameras mounted to the PET camera that will track 
head motion using optical measurement of facial features (face detection). No recognizable 
images of the subject’s face will be recorded. Data about the subject’s facial features will be 
captured in order to detect movement of the head while on the scanner bed. A computer-
generated grid that detects movement will generate the motion data.  Data may be shared with 
the manufacturer, United Imaging Healthcare America (UIHA). Data will be coded, and though 
images of the head will be captured, no other identifying information will be attached to the data 
acquired and shared with UIHA. A low-dose head CT scan will be acquired before or after each 
NX-CT and PET-CT scan to be used for attenuation correction.
 For HRRT scans, a transmission scan of approximately 6 minutes will be acquired for each 
emission scan to be used for attenuation correction.  Acquisition of HRRT list-mode data will 
begin shortly before radiotracer injection and will continue for up to 120 minutes post-injection. 
Dynamic images of radioactivity concentration are reconstructed with corrections for measured 
attenuation, normalization, random events, scatter, and deadtime. Subject motion is also 
corrected automatically on an event-by-event basis with the Vicra. The resolution (full width at 
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half maximum) of the HRRT is 2-3 mm. The extended scanning time will reduce the noise in 
data acquisition, and thus, improve the binding potential (BP) estimates. This will be more 
important if we want to quantitate in small regions with the HRRT, specifically the 
ventromedial/dorsomedial PFC, NAc, amygdala, ventral/dorsal striatum, GP, and SN. Individual 
IV blood samples may be taken IV prior to radiotracer injection and during the scan for analysis 
of the fraction of plasma radioactivity unbound to protein and for metabolite analyses. For 
[11C]EKAP scans, after arterial cannulation has been performed by a qualified physician, 
individual blood samples are manually taken at various time points and counted in a gamma 
counter. Samples are centrifuged to obtain plasma, which will be counted, and selected 
samples will be assayed for the presence of the parent radiotracer compound that has not been 
metabolized. These measurements will be performed by HPLC. In addition, the fraction of 
plasma radioactivity unbound to protein will also be determined. Subjects will be asked to void 
after the scan is completed to reduce radiation exposure to the bladder.
Tobacco Smoking in the Scanner 
All subjects may initially participate in mock PET session during which they will lie in a replica of 
the PET scanner and be told when the scanner is being “turned on”. In addition, the subjects will 
be instructed to smoke with minimal to no head movement and to avoid bringing their smoking 
hand into the field of view of the scanner. They will practice being guided to flick their ashes into 
a large ashtray held at their side during the smoking epochs. These procedures will minimize 
the potential for motion during scanning. They will also help reduce order effects in the current 
design that might otherwise be caused by anxiety or expectation since it has been shown that 
even a scan of the rest condition can be affected by expectation. 
On the scan day(s), subjects will smoke 1 cigarette at a pre-determined time in the scanner 
(approximately 35 minutes following radiotracer injection for [11C]raclopride; from approximately 
15 min before radiotracer injection to 60 min afterwards for [11C]carfentanil). Subjects will 
understand from the preceding training session how to bring the lit cigarette to their mouths, 
roughly how many puffs to take (~10), at what speed, and where to deposit their ashes.  
Subjects positioned normally in the HRRT will still have enough clearance to smoke comfortably 
(based on dry runs).
Prior to scanning, subjects will be asked to rate their craving immediately before their drug, and 
their satisfaction from craving, feeling of reward, and drug “liking” periodically thereafter. They 
will also be asked about unpleasantness, and perceived high pre- and post-scan.  
To assess the specific reinforcement from smoking the cigarette in the scanner, the Cigarette 
Evaluation Scale will be administered immediately after the PET scan. The questions (see 
below) are answered with reference to the immediate past cigarette (on a scale from 1 = “not at 
all”, to 7 = “extremely”)
1. Was smoking satisfying?
2. Did cigarettes taste good?
3. Did you enjoy the sensations in your throat 
and chest?
4. Did smoking calm you down?
5. Did smoking make you feel more awake?
6. Did smoking make you feel less irritable?
7. Did smoking help you concentrate?
8. Did smoking reduce your hunger for food?
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9. Did smoking make you dizzy?
10. Did smoking make you nauseous?
11. Did smoking immediately relieve your 
craving for a cigarette?
12. Did you enjoy smoking?
Marijuana Smoking in the Scanner 
All subjects may initially participate in mock PET session during which they will lie in a replica of 
the PET scanner and be told when the scanner is being “turned on”. They will practice taking 
deep breaths. These procedures will minimize the potential for motion during scanning. They 
will also help reduce order effects in the current design that might otherwise be caused by 
anxiety or expectation since it has been shown that even a scan of the rest condition can be 
affected by expectation. 
Subjects will have abstained from cannabis use overnight and at least for 12 hours (verified by 
carbon monoxide levels < 11 ppm). At the pre-determined time (approximately 35 minutes 
following radiotracer injection for [11C]raclopride; from approximately 15 min before radiotracer 
injection to 60 min afterwards for [11C]carfentanil), subjects will smoke up to the entirety of a 
standardized cannabis cigarette (Between 3.5% and 10% THC) obtained from NIDA. We will 
use a protocol similar to other studies in which subjects inhale for 3 sec, hold the smoke in their 
lungs for 5 sec and exhale. They will smoke up to the entirety of the cigarette at approximately 
30 sec intervals per puff, subjects will not be asked to smoke more than they are accustomed 
to. Subjects will rate their craving immediately before smoking, and their satisfaction from 
craving, feeling of reward, and drug “liking” periodically thereafter. Subjects will be asked about 
unpleasantness and perceived “high” pre- and post-scan.  
Data Processing
All PET data will be reconstructed with an iterative reconstruction algorithm, MOLAR, designed 
specifically for the HRRT. MOLAR incorporates attenuation, scatter and deadtime, and subject-
motion (detected by the Vicra system), into the forward projection model for the scanner.  
Emission images are binned into equal frame times (typically 3 minutes).  Following image 
reconstruction, an early summed image (0-12 min) will be registered to the subject's MR image, 
which will be registered to an MR template so PET can be transformed to a standard (MNI) 
space. HYPR filtering will be applied to all emission data before analysis. lp-ntPET and 
voxelwise analysis will be conducted.
4. Genetic Testing   N/A 
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
- One 10 mL tube of blood will be collected for DNA for testing of 
polymorphisms in genes of interest to drug addiction. This sample may be 
collected during the screening appointment or on one of the PET scan days.
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ii. the plan for the collection of material or the conditions under which material will 
be received
-as above, a blood sample will be collected at intake to test polymorphisms of 
interest for drug dependence. 
iii. the types of information about the donor/individual contributors that will be 
entered into a database
- the genetic polymorphism results will be entered. The results of this testing will 
be confidential, will not be entered into the subject’s medical record, and will not 
be made available to the subject.
iv. the methods to uphold confidentiality
- The results of genetic testing will be kept on a University encrypted computer or 
secure server.  We will separate the personal identifying information of the subjects 
from the genetic information.
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects?
Some samples and related information may be stored (banked) for future research.  The 
specimens will be stored for an unlimited time and may be used to make a cell line that 
will live indefinitely. When specimens and information are stored, we are careful to try to 
protect subject identity.  Samples and information will receive a unique code.  Other 
researchers will only receive coded samples and information.  
C. Is widespread sharing of materials planned?
Yes
D. When and under what conditions will materials be stripped of all identifiers?
It will not.
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials?  Yes.
i.
How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)?
Subjects will be informed that their material has been destroyed.
F. Describe the provisions for protection of participant privacy
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Risks associated with genetic testing will be minimized by keeping the results of genetic 
testing on encrypted computers or a secure server, and by separating the personal 
identifying information of the subjects from the genetic information.
G. Describe the methods for the security of storage and sharing of materials 
The results of genetic testing will be kept on an encrypted computer or secure server and 
personal identifying information of the subjects will be separated from the genetic 
information.  Materials will not be shared.
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
Up to 110 subjects (55 men, 55 women) will participate in the study. According to census 
figures, minority groups comprise approximately 50% of the population of New Haven (36.1% 
African-American, 13.2% Hispanic, 0.3% Native American, 2.4% Asian, and 4.1% other). While 
we prefer to have 60 subjects complete both Aim 1 and Aim 2, we anticipate up to a 50% drop 
out rate between scans so we are allowing for the possibility having 110 subjects participate.
All subjects will be 18-55 years of age and physically healthy. All research subjects will be 
recruited under guidelines of the Yale University Institutional Review Board (Human 
Investigation Committee). Subjects will be recruited from the community at large via IRB-
approved advertising (television, newspaper, postings in community locations, Craigslist, 
Facebook). All participants will be screened initially on the telephone by a research assistant 
who will schedule the initial intake assessment. The screening and scanning sessions will 
involve psychological tests in the form of rating scales and questionnaires. These are all 
noninvasive questionnaires, e.g., to assess mood and craving, and should add no risk.
6. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement.
 Children
 Healthy 
Fetal material, placenta, or dead fetus
 Non-English Speaking
 Prisoners
 Economically disadvantaged persons
 Decisionally Impaired
 Employees
 Pregnant women and/or fetuses
 Yale Students 
Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects? 
 Yes  
 No (If yes, see Instructions section VII #4 for further 
requirements)
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion?
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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
Marijuana Exposed Health Controls
1. Do not meet DSM-V criteria for cannabis use disorder based on the structural clinical 
interview diagnostic (SCID)
2. Have used cannabis in the past recreationally
General 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 (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.
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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.
8. How will eligibility be determined, and by whom? 
Eligibility to participate in screening session will be determined by the research staff under the 
guidance of Dr. Kelly Cosgrove. Study participation will be determined after the screening 
session by the study physician and Dr. Cosgrove.
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research. 
Risks Associated with Unknowns
The subject’s health and safety will always be the primary concern of the doctors and staff 
performing the study. In the event of an unexpected outcome, all necessary medical action will 
be taken.
Medication might be administered as needed, per the Yale University PET Center standard 
operating   procedure for medical emergencies, in order to treat complications.
Risks Associated with Blood Drawing and IV Line Insertion
At the screening visit, a routine venipuncture will be performed for screening laboratory studies. 
On the PET scan day(s), up to two venous catheters will be inserted for bolus injection and/or 
constant infusion of the radiotracer, and for blood draws. 
Drawing blood and inserting an intravenous line (IV) into an arm vein are safe and standard 
medical procedures. Sometimes a bruise will occur at the puncture site and rarely a blood clot 
or infection will occur in the vein. Certain individuals may feel light-headed during venipuncture. 
The volume of blood collected during this study will be up to 32 tablespoons. Blood samples 
may be drawn for routine labs and drug screening; measurement of radiopharmaceutical parent 
and metabolites, for analysis of plasma drug levels, serum estrogen, progesterone, and follicle 
stimulating hormone levels. This is not expected to have any serious negative effects on a study 
participant.
Risks Associated with Arterial Line
On the PET scan day, a radial arterial catheter will be inserted. Arterial sampling may be 
associated with mild-to-moderate pain, hematoma, inflammation, bleeding, or bruising at the 
puncture site. If this occurs, signs and symptoms will dissipate over time, usually 24 to 72 hours 
after the event. In rare instances blocking of the artery, tearing of the artery, arterial leakage, 
poor healing, or infection at the catheter insertion site may occur. Certain individuals may feel 
light-headed during arterial catheter placement.
Risks Associated with Radiation
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The Yale University Radioactive Investigational Drug Committee (Yale RIDC) will review the use 
of radiation in this research study, and no subjects will be scanned until RSC approval is 
obtained. This research study involves exposure to radiation from [11C]raclopride, 
[11C]carfentanil PET, and [11C]EKAP scanning, all of which will be under IND #132971 . This 
radiation exposure is not necessary for medical care and is for research purposes only. 
The maximum amount of radiation an individual subject will receive in this study is from one 
injection of ≤ 20 mCi of [11C]raclopride (0.46rem), two injections of < 20 mCi of [11C]carfentanil 
(0.68rem total), two injections of < 20 mCi of [11C]EKAP (0.64 rem total) (plus a small amount 
of radiation from the transmission scans of the brain).  However, in situations where a PET scan 
is not successful following a radiotracer injection (e.g., problems with the PET camera), the 
subject may receive an additional [11C]raclopride, [11C]carfentanil, and [11C]EKAP injection, 
for up to 8 total radiotracer injections during the study, if deemed appropriate.
Although each organ will receive a different dose, the targeted amount of radiation exposure 
subjects will receive from this study is equal to an effective dose of 2.01 rem for a total of up to 
20 mCi of [11C]raclopride in one injection, up to 40 mCi of [11C]carfentanil in two injections, and 
up to 40mCi of [11C]EKAP. This calculated value is used to relate the dose received by each 
organ to a single value.
In the event that a scan fails after radiotracer injection and the subject is scheduled for a second 
injection of [11C]raclopride, a third injection of [11C]carfentanil, each subject would also receive 
an additional effective dose of 1.26rem, for a total of up to 40 mCi of [11C]raclopride in two 
injections, up to 60 mCi of [11C]carfentanil in three injections, and up to 60 mCi of [11C]EKAP in 
three injections. Therefore, the maximum possible radiation exposure for this study, 
taking additional injections due to cancellation into account, would be an effective dose 
of up to approximately 3.26rem.  
This amount of radiation exposure is below the annual limit of 5 rem, followed by the Yale 
University PET Center, which is also the occupational exposure limit.
Studies of occupational workers who are chronically exposed to low levels of radiation above 
normal background have shown no adverse biological effects. However, to be conservative, we 
assume that any amount of radiation may pose some risk for causing cancer and hereditary 
effect, and that the risk is higher for higher radiation exposures.  This means that any increase 
in radiation dose, no matter how small, results in an increase in risk. The U.S. Nuclear 
Regulatory Commission (NRC) accepts this model, referred to as the “linear no-threshold (LNT) 
dose-response relationship”, for estimating radiation risk. Monitoring of radiation exposure is 
done by Yale University Radioactive Investigational Drug Committee for research subjects. 
Adverse effects of the radiopharmaceuticals in this study have not been reported. However, the 
possibility exists for a rare reaction to any of the substances or procedures to which a subject is 
exposed.
Risks Associated with MRI
MR carries a risk for subjects who are claustrophobic or have pacemakers, metal pieces, 
aneurysm clips, large colored tattoos, or any other contraindications for MR.
Magnetic resonance imaging (MRI) is a technique that uses magnetism and radio waves, not x- 
rays, to take pictures and measure chemicals of various parts of the body. The United States 
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Food and Drug Administration (FDA) has set guidelines for magnet strength and exposure to 
radio waves, and we carefully observe those guidelines.
Subjects will be watched closely throughout the MR study. Some people may feel 
uncomfortable or anxious.  If this happens, the subject may ask to stop the study at any time 
and we will take them out of the MRI scanner. On rare occasions, some people might feel dizzy, 
get an upset stomach, have a metallic taste or feel tingling sensations or muscle twitches. 
These sensations usually go away quickly but we will ask subjects to tell the research staff if 
they have any of these symptoms.
There are some risks with an MRI study for certain people.  If subjects have a pacemaker or 
some metal objects inside their body, they may not be in this study because the strong magnets 
in the MRI scanner might harm them.  Another risk is the possibility of metal objects being 
pulled into the magnet and hitting a subject. To reduce this risk we require that all people 
involved with the study remove all metal from their clothing and all metal objects from their 
pockets. We also ask all people involved with the study to walk through a detector designed to 
detect metal objects.  It is important to know that no metal can be brought into the magnet room 
at any time. Also, once subjects are in the magnet, the door to the room will be closed so that 
no one from outside accidentally goes near the magnet.
We want subjects read and answer very carefully the questions on the MRI Safety 
Questionnaire related to your personal safety. We will be sure that subjects have read the MRI 
Safety Questionnaire and tell us any information they think might be important.
This MRI study is for research purposes only and is not in any way a clinical examination.
The scans performed in this study are not designed to find abnormalities. The primary 
investigator, the lab, the MRI technologist, and the Magnetic Resonance Research Center 
are not qualified to interpret the MR scans and are not responsible for providing a 
diagnostic evaluation of the images.  If a worrisome finding is seen on a subject’s scan, a 
radiologist will be asked to review the relevant images.  Based on his or her recommendation (if 
any), the primary investigator or consulting physician will contact the subject, inform them of the 
finding, and recommend that they seek medical advice as a precautionary measure.  The 
decision for additional examination or treatment would lie solely with the subject and your 
physician. The investigators, the consulting physician, the Magnetic Resonance Research 
Center, and Yale University are not responsible for any examination or treatment that a 
subject receives based on these findings. The images collected in this study are not a 
clinical MRI exam and for that reason, they will not be made available for diagnostic 
purposes.
Risks Associated with Drug Use and Suicidal/Homicidal Behavior
Participants will be asked about current or past use of illicit "street" drugs and urine drug 
screens will be performed at the initial intake appointment to rule out substance abuse that is 
not relevant to the study. Participants currently using drugs or who have a history of using drugs 
may not be eligible to participate. Suicidal thoughts and behaviors will also be assessed.  Any 
reports of homicidal or suicidal tendencies will be immediately directed to treatment for this 
condition; and appropriate authorities will be notified.
Risks Associated with Marijuana Smoking
THC Effects: Δ9-THC is the primary active component in cannabis/marijuana and has been 
administered in very large oral doses (50-712 mg)53 and modest intravenous doses (1-10 mg) to 
cannabis users and abusers without any serious adverse events53. Cannabis cigarettes have 
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been used in research studies in cannabis users and abusers without any serious adverse 
effects52,66 
The unpleasant behavioral effects of Δ9-THC include anxiety, panic, paranoia and rarely 
psychosis; all of these may be extremely distressing. However, the extent to which Δ9-THC 
effects are perceived as unpleasant is context dependent. These effects are rare in our 
experience. Precautions will be taken to minimize the risk of discomfort to subjects.
The acute physical effects of Δ9-THC include motor incoordination, tremulousness, muscle 
weakness, hypo or hypertension, tachycardia, conjunctival injection, dry mouth, and increased 
appetite, which generally resolve spontaneously. The estimated lethal dose of Δ9-THC (30 
mg/kg) is nearly 1000-fold higher than the dose proposed in this study (up to one ~3.5%-10% 
THC cannabis cigarette).  Regular cannabis users recruited from this study are unlikely to report 
any adverse effects in response to the cannabis cigarette. 
An air purifier approved by Yale Environmental Health and Safety will be used to filter cigarette 
and cannabis smoke from the air during all smoking challenges to minimize exposure to study 
personnel.
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
Risks Associated with Blood Drawing & IV Line Insertion:
The risks of bruising, clotting, and infection will be minimized by having venipuncture performed 
by trained and experienced personnel using aseptic technique. To avoid injury due to fainting, the 
catheter will be inserted when the subjects are in a recumbent position. The blood draws during 
PET scanning sessions will be obtained from the already inserted catheter, to minimize 
discomfort.
Risks Associated with Arterial line: 
Risks of radial artery cannulation are minimized by having the procedure performed by an 
experienced physician. Pain is minimized by local anesthesia. Bleeding is prevented by local 
pressure applied for a minimum of 15 minutes after catheter removal. Subjects will have their 
hand and finger blood supply examined after arterial cannulation and again following catheter 
removal. Also, subjects will be asked to abstain from anticoagulants for 7-10 days prior to 
arterial line insertion and 7-10 days following arterial line removal. Subjects will be provided a 24 
hour emergency physician telephone number to call if they encounter pain, discoloration, 
numbness, tingling, coolness, hematoma, inflammation, or any other unusual symptoms in the 
wrist or hand, or fever, chills or drainage from the vascular puncture sites, following the 
procedure. In addition, if an emergency arises at the time of cannulation or scanning, 911 will be 
called, and the subject will be sent to the Emergency Department for evaluation and treatment. 
Nurses will provide the subjects an instruction sheet documenting problems to watch for and 
procedures to follow should such problems occur. Infection is avoided by adequate cleansing of 
the skin prior to intravascular line insertion.
Risks Associated with Radiation: 
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The dose of radiation will be submitted for approval to the Yale University Radioactive 
Investigational Drug Committee All scans will be done in the presence of medical supervision 
and trained staff in an institution specifically designed to support imaging studies. In the event of 
serious medical complications, the PET scan facilities have immediate access to or consultation 
with specialized medical units at the Yale-New Haven Hospital. Preparation of 
radiopharmaceuticals and performance of PET scans will be by radiochemists, physicians, and 
technologists of the Department of Diagnostic Radiology, Yale University School of Medicine. 
These professionals are qualified by training and experience in the safe use and handling of 
radiopharmaceuticals. Subjects will be asked about their previous radiation exposure and those 
who have had research exposure within the past year will be excluded if their cumulative annual 
exposure (including the present study) exceeds FDA limits. The information on the previous 
radiation exposure of study subjects will be notified to the study doctor. 
No PET studies will be performed on pregnant or potentially pregnant women, as confirmed by 
pregnancy testing during evaluation and on each scan day before initiation of any scan 
procedures. If subjects are breastfeeding they will not be able to participate in this research 
study. 
Risks Associated with MRI Scanning. 
To minimize risks, each subject will fill out the Yale Magnetic Resonance Research Center MRI 
Safety Questionnaire before the study. Only subjects who fulfill the criteria by this questionnaire 
will be eligible for the study. In addition, subjects will remove all metal (watch, hair pins, jewelry) 
and walk through the metal detector in the MRRC before entering the MRI room. If the subject 
has any metallic prostheses/implants they will be excluded from the study. If a subject becomes 
anxious during the scan they can request that the MRI scan be stopped.
Risks Associated with Drug Use and Suicidal/Homicidal Behavior
Effective screening will exclude all subjects who would be at greater risk for complications 
because of medical or psychiatric illnesses. Any subject with a prior suicide attempt or with 
active suicidal ideation at baseline as determined by psychiatric evaluation and C-SSRS, will be 
excluded from this study.
The subject’s health and safety will always be the primary concern of the doctors and staff 
performing the study. In the event of an unexpected outcome, all necessary medical action will 
be taken.
Risks associated with marijuana smoking
3.5%-10% THC is considered a moderate dose that should not lead to any adverse effects in 
regular cannabis users.  Minimization of the risk entailed by cannabis smoking will be 
accomplished by (a) criteria for a history of recent, regular use of cannabis >5 times/week (b) 
test positive for THC at screening (c) have been smoking cannabis on a regular basis for > 1 
year and (d) stringent criteria for the absence of clinically significant medical or primary 
psychiatric disorders.  
Measures of heart rate, systolic blood pressure, and diastolic blood pressure will be obtained at 
baseline and every 15 minutes after cannabis administration.  In the event of psychiatric 
complications such as psychosis or anxiety, and appropriately trained psychiatric support staff 
involved in the study will be available and medications to alleviate such conditions (e.g., 
benzodiazepines) will be on hand.
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Risks Associated with Carfentanil
Although Carfentanil can be considered a potent analgesic, side effects from the amount of 
carfentanil in the tracer dose should be minimal to non-existent. Monitoring of oxygen 
saturation, blood pressure, pulse, and other vitals are done before, during and for minimum of 
30 minutes post scan (2.5hrs post carfentanil). Should the need arise oxygen and naloxone are 
on hand to reverse any negative side effects that may occur. MD will decide if subject is ready 
for discharge should there be any clinically significant changes from baseline vitals. Should 
vitals not return to baseline after additional monitoring and treatment, MD may decide to have 
subject sent to the ER. In this case a SAE will be filed. 
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24.
a.
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? 
This study represents a greater than minimal risk to the participants.
b.
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study?  N/A
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are  
 available here http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk
ii. Greater than minimal
1.  Personnel responsible for safety review and its frequency:
The principal investigator, in collaboration with David Matuskey, MD, will be responsible for 
monitoring the data, assuring protocol compliance, and conducting the safety reviews at the 
specified frequency, which must be conducted at a minimum of every 6 months (including when 
reapproval of the protocol is sought).  During the review process, the principal investigator 
(monitor) will evaluate whether the study should continue unchanged, require 
modification/amendment, continue or close to enrollment. The principal investigator, the HIC, 
the FDA, or the RSC, have the authority to stop or suspend the study or require modifications.
2. The risks associated with the current study are deemed moderate for the following 
reasons:
We view the risks associated with radiation exposure as greater than minimal.
Although we have assessed the proposed study as one of greater than minimal risk, the 
potential exists for anticipated and/or unanticipated adverse events, serious or otherwise, to 
occur since it is not possible to predict with certainty the absolute risk in any given individual or 
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in advance of first-hand experience with the proposed study methods.  Therefore, we provide a 
plan for monitoring the data and safety of the proposed study as follows:
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the 
study procedures / design by the principal investigator Kelly Cosgrove, PhD. according to the 
following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s).
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s).
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the 
study:
1.
Mild adverse event
2.
Moderate adverse event
3.
Severe 
5. Plan for Determining Seriousness of Adverse Events:
Serious Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse event meets 
the criteria for a Serious Adverse Event (SAE).  An adverse event is considered serious if it 
results in any of the following outcomes:
1.
Death;
2.
A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization; 
3.
A persistent or significant disability or incapacity; 
4.
A congenital anomaly or birth defect; OR
5.
Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the other outcomes listed in this definition. 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event.  Similarly, an adverse event may be graded as moderate but still meet the criteria for an 
SAE.  It is important for the PI to consider the grade of the event as well as its “seriousness” 
when determining whether reporting to the IRB is necessary.
6. Plan for reporting UPIRSOs (including Adverse Events) to the IRB
The principal investigator will report the following types of events to the IRB: 
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Any incident, experience or outcome that meets ALL 3 of the following criteria:
1.
Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the 
research procedures described in the protocol-related documents, such as the IRB-
approved protocol and informed consent document and (b) the characteristics of the 
subject population being studied; AND 
2.
Is related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); AND
3.
Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, legal, or social harm) than was 
previously known or recognized.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical 
or non-medical in nature, and include – but are not limited to – serious, unexpected, and 
related adverse events and unanticipated adverse device effects.  Please note that adverse 
events are reportable to the IRB as UPIRSOs only if they meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the 
appropriate forms found on the website. All related events involving risk but not meeting the 
prompt reporting requirements described in IRB Policy 710 should be reported to the IRB in 
summary form at the time of continuing review. If appropriate, such summary may be a simple 
brief statement that events have occurred at the expected frequency and level of severity as 
previously documented.  In lieu of a summary of external events, a current DSMB report can be 
submitted for research studies that are subject to oversight by a DSMB (or other monitoring 
entity that is monitoring the study on behalf of an industry sponsor).
7. Plan for reporting adverse events:
For the current study, the following individuals, funding, and/or regulatory agencies will be 
notified (choose those that apply):
  All Co-Investigators listed on the protocol.
  National Institutes of Health
  Yale University Radioactive Drug Research Committee (if applicable)
  Yale University Radiation Safety Committee (if applicable)
The principal investigator, Kelly Cosgrove, PhD, in collaboration with David Matuskey, MD, 
will conduct a review of all adverse events upon completion of every study subject. The principal 
investigator will evaluate the frequency and severity of the adverse events and determine if 
modifications to the protocol or consent form are required.
d. For multi-site studies for which the Yale PI serves as the lead investigator:
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed?
ii. What provisions are in place for management of interim results?
iii. What will the multi-site process be for protocol modifications?
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12. Statistical Considerations: Describe the statistical analyses that support the study design. 
a. The presence of neurotransmitter activation is determined, statistically, by comparing the best 
lp-ntPET fit to MRTM. The F-statistic is used to compare formally the residual sum of squares 
for each model taking into account differences in degrees of freedom.  MRTM has 3 
parameters. lpntPET has 7 (4 explicit, 3 implicit).  Only those voxels for which the F-test 
indicates an improved fit (p<0.01) are retained for the neurotransmitter movie. The map of all 
retained voxels is a “Significance Mask”.  
b. To correct for multiple comparisons (~1000 voxels in our striatal mask) we apply a cluster-
size threshold to the Significance Mask.  For a scan on the HRRT, 15-20mCi dose of 
radiotracer, and approximately 3 minute time-frames, we have determined that a cluster-size 
threshold of 17 contiguous voxels is the minimum size activation cluster to retain so that we 
achieve a global incidence of less than 1/10 subjects with any false positive clusters.
SECTION V: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND 
DEVICES
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section.
A.  DRUGS, BIOLOGICS and RADIOTRACERS
1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the drug(s) 
biologic(s)  or radiotracer(s) being used? Identify whether FDA approval has been granted and for 
what indication(s). 
1.  [
11C]Raclopride (radiotracer for PET studies), IV
     [
11C]Raclopride is the most commonly used D2/3 radioligand for PET studies in humans. It has been  
     used in many PET centers through out the world and its dosimetry has been well characterized and 
     published. Studies contained in this protocol will not commence until the Yale New Haven Hospital 
RSC grants approval for this protocol.
     An application will be submitted to the Yale New Haven Hospital RSC for use of [11C]raclopride in 
this protocol as it is covered under IND# 132971. No subjects will be scanned until approval is 
obtained fro YNHH RSC.
2. [
11C]Carfentanil (radiotracer for PET studies), IV
    
[11C]Carfentanil is a mu opioid receptor agonist. Its primary actions of therapeutic value are analgesia 
and sedation. It has been used in many PET centers throughout the world and its dosimetry has been 
well characterized and published. An application will be submitted to the Yale New Haven Hospital 
RSC for use of [11C]Carfentanil in this protocol as it is covered under IND# 13297. No subjects will be 
scanned until approval is obtained from YNHH RSC. 
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3. Cannabis cigarettes: standardized cannabis cigarette (approximately 3.5%-10% THC) obtained 
from NIDA.
4. [11C]EKAP(radiotracer for PET studies), IV: is a kappa opioid receptor agonist. The tracer has been 
used at the Yale PET Center under an eIND and will be submitted to IND #13297 for use in this study. 
All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, the FDA, 
or a radiotracer regulated by the RDRC, must provide the following information:  
a. What is the Investigational New Drug (IND) number assigned by the FDA?
Cannabis cigarettes – (IND #132971; Kelly Cosgrove PhD
b. Who holds the IND? 
Cannabis cigarettes – Kelly Cosgrove PhD 
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA must 
provide the IND number: __132971_____________
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)_____
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission.     
Alternatively, an exemption from IND filing requirements may be sought for a clinical
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND and
 an exemption is being sought, review the following categories and complete the category that applies
 (and delete the inapplicable categories):
Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can be
exempt from IND regulations if all of the following are yes:
i.   The intention of the investigation is NOT to report to the FDA as a well-controlled study in support
     of a new indication for use or to be used to support any other significant change in the labeling for
     the drug.  
 Yes  
 No
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and
      the intention of the investigation is NOT to support a significant change in the advertising for the
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      product. 
 Yes  
 No
iii.  The investigation does NOT involve a route of administration or dosage level or use in populations
      or other factor that significantly increases the risks (or decreases the acceptability of the risks)   
      associated with the use of the drug product. 
 Yes  
 No
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC)   
      review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50 
and 21 CFR Part 56). 
 Yes  
 No
v.   The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs. 
 Yes  
 No
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption)
 i. The clinical investigation is for an in vitro diagnostic biological product that involves one or
more of the following (check all that apply):
 Blood grouping serum
 Reagent red blood cells 
 Anti-human globulin
 ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the
diagnosis made by another, medically established, diagnostic product or procedure; and
 iii. The diagnostic test is shipped in compliance with 21 CFR §312.160.
Exempt Category 3
 The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60
Exempt Category 4
 A clinical investigation involving use of a placebo if the investigation does not otherwise 
require submission of an IND.
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models. 
Preclinical Characterization of [11C] raclopride: in vitro assays
Using the Cheng-Prusof Method 60, the affinity, KD, of [11C]RAC for the D2 receptor ranges from 
1.6 nM 61 to 3.4 nM.62. The raclopride affinities for D2 and D3 are approximately the same, ~1.5 
nM and 1.2-2.1 nM, respectively 63 64 65. 
Clinical Application of [11C]raclopride 
[11C]raclopride is the most commonly used D2 radioligand for PET studies in humans.  It has been 
used in many PET centers throughout the world and its dosimetry has been well characterized and 
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published.  This tracer has been synthesized at the Yale PET Center radiochemistry lab using an 
automated module, GE FXc, according to a known procedure and three validation studies have 
been conducted.  This tracer is already used in human studies at the Yale PET center so will be 
ready for human studies upon HIC/YNHH RSC approval of this protocol.
[11C]carfentanil will be administered at tracer doses of  ≤0.03μg/kg, at which significant side-
effects of the radiotracer are not expected.  In over 20 PET imaging studies of [11C]Carfentanil 
involving over 270 human volunteers with a range of diagnoses, no clinically-significant side-
effects have been observed; mild drowsiness has been reported in some studies 66.
Cannabis cigarettes with a potency of ~3.5%-10% THC will be administered to research 
subjects.  3.5%-10% THC is considered a medium dose and should be well tolerated in regular 
cannabis users and cannabis exposed users.  
3. Source: a) Identify the source of the drug or biologic to be used. 
PET drugs (radiotracers), [11C]raclopride and [11C]carfentanil are supplied by the Yale University 
PET Center.
Cannabis:  Will be obtained as cannabis cigarettes from the National Institute on Drug Abuse 
b) Is the drug provided free of charge to subjects? 
 Yes  
 No
    If yes, by whom?  
NIDA
The Yale University PET Center. The Yale PET Center has an in-house chemistry  
                         
department capable of producing the radiotracer (PET drug) necessary for the 
research study. All fees charged by the PET Center for services rendered are 
covered by the study funding.
4. Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity. 
Check applicable Investigational Drug Service utilized:
     
   YNHH IDS                                                                      
   Yale Cancer Center 
     
   CMHC Pharmacy                                                          
  West Haven VA
     
   PET Center                                                     
    None      
     
    Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.  
Preparation of radiotracers: 
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[11C]Raclopride, [11C]Carfentanil, and [11C]EKAP will be manufactured by experienced 
radiochemists at the Radiochemistry Laboratory of the Yale University PET Center in accordance 
with our local Chemistry Manufacturing & Control (CMC) procedures and quality specifications 
described in local Drug Master File (DMF) that have been approved by the Yale University  RDRC 
(YURDRC). 
Due to the short half-life, PET drugs are prepared and formulated immediately before 
administration, and therefore there are no issues with storage or stability. PET drug products are 
stored at room temperature and are stable for at least 60 min after preparation. 
The preparation of sterile PET drug products is validated prior to human use. Sterility is achieved 
by passing the PET drug product through a 0.22 micron membrane filter during the last step of 
the formulation process. Prior to release for administration, a bubble point test is performed on 
the membrane filter used for terminal sterilization in order to validate and verify its integrity 
during the filtration process. Due to the short half-life, a sample of the PET drug product is tested 
for sterility after administration for further confirmation. 
The level of endotoxin in each batch of the final PET drug product is determined quantitatively 
prior to release for administration using the FDA approved Charles River Laboratory’s Portable 
Testing System (Endosafe®-PTS).
[11C]raclopride ([11C]RAC): Briefly, [11C]RAC is synthesized by 11C-methylation of the 
desmethyl phenolate precursor with [11C]methyl triflate according to known literature methods. 
The resulting PET drug is purified first by semi-preparative HPLC, followed by solid-phase 
extraction to remove the HPLC buffer mixture. Finally [11C]RAC is formulated in <10% 
ethanolic saline solution (USP), and the resulting PET drug product is then passed through a 0.22 
micron sterile membrane filter for terminal sterilization and collected in a sterile pyrogen free 
collection vial to afford a formulated I.V. solution ready for dispensing and administration.
 
[11C]carfentanil ([11C]CFN): Briefly, [11C]CFN is synthesized by 11C-methylation of the 
carboxylate oxygen of the desmethyl precursor with [11C]methyl iodide according to known 
literature methods. The resulting PET drug is purified first by semi-preparative HPLC, followed 
by solid-phase extraction to remove the HPLC buffer mixture. Finally [11C]CFN is formulated in 
<10% ethanolic saline solution (USP), and the resulting PET drug product is then passed through 
a 0.22 micron sterile membrane filter for terminal sterilization and collected in a sterile pyrogen 
free collection vial to afford a formulated I.V. solution ready for dispensing and administration.
Preparation of [ 11C]EKAP: Cyclotron produced [ 11C]CO2 is transferred into the GE 
FxC/FxC-pro, Fx-MeI module and trapped in a mixture of nickel and molecular sieve. Hydrogen 
is then passed through the catalyst and reacted with [ 11C]CO2 to afford [ 11C]methane, which 
is converted to [ 11C]methyl iodide by reaction with iodine at high temperature (720 °C). 
Conversion to [ 11C]methyl triflate is effected by passing [ 11C]methyl iodide in a stream of 
inert gas through a silver triflate/graphite column heated at 190 °C. Radiolabeling is performed 
by trapping the reagent [ 11C]methyl triflate in a solution of descarboxymethyl-EKAP and DBU-
CO2 (1.2 equivalents), in the presence of tetrabutylammonium triflate (TBATf) and cesium 
carbonate (Cs2CO3), in the solvent N,N-dimethylformamide (DMF, 0.3 mL), at 0 °C, and then 
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reacting at 25 °C for 5 min. Purification of the labeled product [ 11C]EKAP is achieved by semi-
preparative HPLC. The desired product fraction from the HPLC is collected, diluted with 0.1% 
ascorbic acid in water (50 mL), and passed through a C-18 SepPak cartridge. The SepPak is then 
rinsed with 10 mL of 0.1% aqueous ascorbic acid solution. The radioactive product, trapped on 
the SepPak, is recovered by eluting the SepPak with 1 mL of USP absolute ethanol, followed by 
3 mL of 0.1% ascorbic acid in USP saline, into a product vial containing 7 mL of 0.1% ascorbic 
acid in USP saline and 200 µL of 4.2% sodium bicarbonate solution, USP. This mixture is then 
passed through a sterile membrane filter (0.22 m) for terminal sterilization and collected in a 
sterile empty vial to afford a formulated solution ready for dispensing and intravenous injection. 
The radioactive product is stored at room temperature and is stable for at least 60 min after 
preparation. Pyrogen test is performed for each batch of product. Sterility is achieved by passing 
product through a membrane filter for terminal sterilization as the last step in the formulation 
process, and confirmed by sterility test performed after administration.
 Cannabis: Will be obtained from NIDA as prepared cannabis cigarettes. Cannabis will be kept 
in the PET Center located at 801 Howard Ave, New Haven, CT which is a key card only access 
floor, in room 203A closet which is kept locked at all times. It will be locked in an approved 
Gardall Light Duty Commercial Utility/Under Counter Safe.
Dimensions: 14"H X 14"W X 14"D
Overall Product Weight: 61 lbs
It is bolted permanently to the concrete floor. Only individuals with Power of Attorney as listed 
above will have the combination.
5. Use of Placebo: 
 Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
1. Describe the safety and efficacy of other available therapies. If there are no other
available therapies, state this.
b.   State the maximum total length of time a participant may receive placebo while on the study. 
c.   Address the greatest potential harm that may come to a participant as a result of  receiving    
  
   placebo. 
d.   Describe the procedures that are in place to safeguard participants receiving placebo. 
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
 Yes  
 No See HIC Application Instructions to view controlled substance listings. 
If yes, is the use of the controlled substance considered:
 Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant.
 Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical 
studies or other non-therapeutic purposes. See Instructions for further information.
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7. Continuation of Drug Therapy After Study Closure   
 Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?
 
 Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access. 
 
 No    If no, explain why this is acceptable.
SECTION VI: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects:
a.
  targeted for enrollment at Yale for this protocol__250 subjects will be screened to 
have 110 subjects participate._
b.    If this is a multi-site study, give the total number of subjects targeted across all 
sites__N/A_ 
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
 Flyers
 Internet/Web Postings
 Radio
 Posters
 Mass E-mail Solicitation
 Telephone
 Letter
 
 Departmental/Center Website
 Television
 Medical Record Review
 Departmental/Center Research Boards
 Newspaper
 Departmental/Center Newsletters
 Web-Based Clinical Trial Registries
  YCCI Recruitment database
 Clinicaltrials.gov Registry (do not send materials to HIC)
 Other (describe):
3.  Recruitment Procedures: 
a.
Describe how potential subjects will be identified.
All subjects will be 18-55 years of age and physically healthy. All research subjects will be 
recruited under guidelines of the Yale University Institutional Review Board (Human 
Investigation Committee). Subjects will be recruited from the community at large via 
IRB-approved advertising (newspaper, postings in community locations, Craigslist, 
Facebook).
b.
Describe how potential subjects are contacted. 
The subjects will be asked to call us if they are interested in participating in the research 
study. Interested individuals contacting the clinic by phone in response to advertisements 
are told that the information they give over the phone is written down and discussed by 
the research team.  They are advised that if they do not enroll in research with the clinic 
the information is destroyed, and that if they do, it becomes part of their research chart.    
If an individual appears to meet enrollment criteria and is interested in participating, a 
face-to-face interview is conducted by one of the project investigators. A release of 
information is obtained for review of any available historical and clinical data. A written 
authorization form is also obtained from each subject, permitting the research team to 
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use, create, or disclose the subject's PHI for research purposes.  The nature of the project, 
procedures, relative risks and benefits, and alternatives to participation in the project are 
discussed with the individual.  Following this discussion, the individual is given a copy of 
the consent form to review, and any questions are answered. The PI of the protocol will 
seek written consent from all participants.
c.
Who is recruiting potential subjects? 
Members of the research team, as identified under consent personnel below.
4. Screening Procedures
a.
Will email or telephone correspondence be used to screen potential subjects for 
eligibility prior to the potential subject coming to the research office? 
 Yes  
 No
b.
 If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process. 
HEALTH INFORMATION TO BE COLLECTED: 
personal and family psychiatric, medical, and substance use history.
 
HIPAA identifiers: 
 Names 
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits contains 
more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 20,000 or fewer 
people is changed to 000. 
  Telephone numbers
 Fax numbers 
 E-mail addresses
 Social Security numbers 
 Medical record numbers
 Health plan beneficiary numbers 
 Account numbers 
  All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older 
 Certificate/license numbers 
 Vehicle identifiers and serial numbers, including license plate numbers 
 Device identifiers and serial numbers 
 Web Universal Resource Locators (URLs) 
 Internet Protocol (IP) address numbers 
 Biometric identifiers, including finger and voice prints 
 Full face photographic images and any comparable images 
 Any other unique identifying numbers, characteristics, or codes 
In addition, if a subject agrees to participate in this study, and will be visiting the Connecticut Mental Health Center 
(CMHC) as part of study procedures, some information about participation in this research study will become part of 
CMHC medical record that identifies the subject. If they do not already have a medical record at CMHC, one will be 
made for their visit. The information that will be entered into their medical record may include the HIPAA identifiers 
mentioned above.
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5. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject? 
 Yes, all subjects
 Yes, some of the subjects
 No
If yes, describe the nature of this relationship.
6. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: 
☐ For entire study 
☒ For recruitment purposes only
☐ For inclusion of non-English speaking subject if short form is being used
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data;
As the initial subject screening will be done by telephone, it will not be possible to 
obtain the subject’s signature.
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer.
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7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided:
 Compound Consent and Authorization form
 HIPAA Research Authorization Form
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent. 
This list is maintained in the IRES database application
9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making. 
Subjects will be given verbal and written information describing the study under conditions in 
which they have adequate time to consider the risks of participation. Each study subject will be 
given a copy of the Consent Form/Compound Authorization Form enclosed with this protocol 
outlining the risks and benefits of participation in this study.  
Prior to signing the Compound Authorization Form, the principal investigator or her designee 
(Sub-Investigator/Coordinator, Key Personnel) will discuss the Compound Authorization Form 
with each subject. The prospective subject will be given verbal and written information (the 
Compound Authorization Form) describing Protected Health Information (PHI) and why and to 
whom it will be distributed. The subject will have adequate time to consider this information 
before signing. If the subject decides not to sign the Compound Authorization Form, he/she will 
not be able to participate in the study. A copy of the signed and dated Compound Authorization 
form will be given to each subject and informant.
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed. 
We will not recruit subjects with limited decision-making capacity. All of the subjects who sign 
the consent to participate in the protocol will have completed and met medical (urine and blood 
tests, EKG, and physical) and psychological (SCID and clinical interview) criteria. As part of the 
consent process, prospective subjects are asked open-ended questions about the research in order 
to determine whether the subject recalls and understand the process of the study. If an individual 
shows poor comprehension of the consent form and study, we will not enroll them. A study 
doctor supervises the screening and enrollment process.
11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects. 
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The following consent forms will be used:
1. Aim 1 and 2 Compound Authorization Form
2. Aim 3 Compound Authorization Form
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. If enrollment of these subjects is anticipated, 
translated copies of all consent materials must be submitted for approval prior to use. 
Non-English speaking subjects will not be recruited for this study.
12(a) As a limited alternative to the above requirement, will you use the short form* for 
consenting process if you unexpectedly encounter a non-English speaking individual interested 
in study participation and the translation of the long form is not possible prior to intended 
enrollment? 
YES ☐  NO ☐
Note* If more than 2 study participants are enrolled using a short form translated into the same 
language, then the full consent form should be translated into that language for use the next time 
a subject speaking that language is to be enrolled.
Several translated short form templates are found on our website 
at:  http://www.yale.edu/hrpp/forms-templates/biomedical.html. If the translation of the short 
form is not available on our website, then the translated short form needs to be submitted to the 
IRB office for approval via amendment prior to enrolling the subject. Please review the 
guidance and presentation on use of the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please 
request a HIPAA waiver in the section above. 
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.  
 
 Not Requesting a consent waiver 
 
 Requesting a waiver of signed consent
       
 Requesting a full waiver of consent
   
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
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 Requesting a waiver of signed consent for Recruitment/Screening only 
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research activity pose greater than minimal risk? 
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity  
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No
 Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research pose greater than minimal risk? 
 Yes If you answered yes, stop. A 
waiver cannot be granted.    
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No
B. Full waiver of consent: (No consent from subjects will be obtained for the activity.) 
 Requesting a waiver of consent for Recruitment/Screening only 
a. Does the research activity pose greater than minimal risk to subjects?  
 Yes  If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity 
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
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 Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.)
If requesting a full waiver of consent, please address the following:
a. Does the research pose greater than minimal risk to subjects?  
 Yes  If you answered yes, stop. A waiver cannot be granted.  
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
SECTION VII: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
a.    What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?   
Required private identifiable information about individuals, such as their medical history, 
current medications, psychiatric problems, and family history, will be collected by research staff and 
be used for research purposes and charting after consent is obtained.
Subjects will also provide information about their smoking history, their family smoking and 
psychiatric history, drinking and drug use history, mood, cardiovascular health, and other 
demographic variables. Biological specimens to be taken from subjects include urine samples to 
rule out or confirm drugs of abuse prior to imaging, and blood samples (during imaging) to 
measure plasma concentration of tracer and other times as well as to measure blood drug levels.
Subjects who decide to participate in the study will have a medical record at the Connecticut 
Mental Health Center (CMHC).  If subjects already have a medical record at CMHC, some 
information about their participation in the study will be included here.  If they do not have a 
medical record at CMHC, one will be made for their visit.  The information that will be entered 
into this medical record will include: name, date of birth, date of admission to the CNRU, date of 
discharge from the CNRU, phone number, address, medical history, individual and family 
history of psychiatric problems, and substance abuse history.  Subjects will also sign a separate 
Notice of Privacy Practices specific to CMHC.
       
b.    How will the research data be collected, recorded and stored? 
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard   
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other
d.    What methods and procedures will be used to safeguard the confidentiality and security of    
the identifiable study data and the storage media indicated above during and after the subject’s 
participation in the study?
Do all portable devices contain encryption software? 
 Yes   
 No
         If no, see http://hipaa.yale.edu/guidance/policy.html
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Identifiable paper information is kept in locked file drawers and password protected computer files 
on University encrypted computers. Results are published as group data without the use of 
characteristics that would identify individual subjects. We quote information only by number in 
conference discussions, scientific reports, or publications, in order to maintain anonymity. 
Identifiable brain research data are stored on a secure database located on the internal PET 
Center Network. The PET network is protected by a Cisco PIX firewall operated by ITS. All 
research data are backed up nightly to a Dell PV-136T library wit 4 IBM Ultrium-TD2 tape 
drives using the backup software Legato Networker 7.3 from EMC. Human subjects enrolled in 
the study are assigned a subject-specific random identifier. Subject identifiers and the means to 
link the subject names and codes with the research data are stored in separate locations within the 
database. The software of the database limits the ability to connect the random identifier to the 
actual subject identification information to research team members only. Access to the database 
is password protected and each research team member is required to have a unique ID and 
password to gain access to the database. Authorized users employ their netid and authentication 
is performed using Yale’s central authentication server. Users always access research data 
through the random identifier only.
e.
What will be done with the data when the research is completed? Are there plans to destroy     
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If 
no, describe how the data and/or identifiers will be secured.
The data will be stored in locked filing cabinets and on the password-protected secure database on the 
internal Yale University PET Center Network for at least 7 years, accessed only by study personnel.
f.   Who will have access to the protected health information (such as the research sponsor, the  
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified 
data) 
Only very select, authorized individuals in the PET center (appointment scheduler, nurse, nuclear 
medicine technician, administrator in charge of billing and patient reimbursement) and the PI 
will have access to the key that identifies patient codes.  Relevant research staff at CMHC will 
also have access to the information entered into the participant’s CMHC medical record.
No external agency (other than the FDA) will have access to the data.
g.   If appropriate, has a Certificate of Confidentiality been obtained?
A Certificate of Confidentiality from NIH will be obtained prior to study enrollment. With this 
Certificate, the researchers cannot be forced to disclose information that may identify subjects, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings. The Certificate does not imply approval or disapproval of the project by the Secretary of 
DHHS. It adds special protection for the research information about subjects. The researchers will use 
the Certificate to resist any demands for information that would identify subjects, except as explained 
below.  The Certificate cannot be used to resist a demand for information from personnel of the United 
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States Government that is used for auditing or evaluation of federally funded projects or for 
information that must be disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA).  A Certificate of Confidentiality does not prevent subjects or subject family 
members from voluntarily releasing information about the subject or their involvement in this 
research.  If an insurer, employer, or other person obtains written consent from the subject to receive 
research information, then the researchers may not use the Certificate to withhold that information.
h.   Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents 
of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported. 
The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, 
without subject consent, information that would identify the subject as a participant in the research 
project under the following circumstances:  In the event of relevant discovery related to events of 
abuse, identified health risks, or threats to self or others, as related to the health and safety of the public 
and/or individual study participants, a report will be made to the relevant agencies and authorities to 
be conducted as outlined and mandated by HIC guidelines, and Federal, State, and Local Statutes.
SECTION VIII: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.) 
These studies are not of direct benefit to subjects. This study will help advance 
knowledge regarding the brain’s dopamine and beta-endorphin response to drug addiction.  
In the long term, the knowledge mentioned above can guide scientists in their efforts to 
develop new treatments for drug addiction. There is no direct benefit to these subjects. They will 
be able to withdraw from the study at any time.
         SECTION IX: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.     Alternatives: What other alternatives are available to the study subjects outside of the research?
The alternative to participation in this research protocol is to not participate. Subjects will be 
informed that they are free to choose not to participate and, if they do agree to become a subject, 
they will be free to withdraw from the study at any time during its course. They will also be 
informed that if they choose not to participate or if they withdraw, it will not adversely affect 
their relationship with their doctors or the hospital (per the consent form).
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2. 
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation. 
The subjects will be compensated for their time commitment and inconveniences necessary for 
completing the study. Subjects will have no financial responsibilities for any portion of the study.
For all aims, compensation will be the following:

$400 for each PET scan (i.e., up to $800 if participating in both scans)

$50 for the MRI scan. 

$50 for an arterial line (aim 3)

$100 bonus upon completion of all study procedures
Subjects participating will receive a total of up to $950 for Aim 1, and up to $1000 for Aim 3 . This 
includes a $100 completion bonus after finishing their participation in each aim (1 MRI and up to 3 
PET scans).  Subjects who participate in the Probabilistic Reward Task may also be compensated 
for the amount that they “win” during the task up to 50$.  Subjects who complete cogstate will 
received 40$. may also receive $10 each time they participate in the Cold Pressor Task
Subjects will be paid either by check, and are advised to allow 4-6 weeks for receipt of payment, or 
they will be given a credit card or cash. In addition, subjects will be provided with a light lunch, 
valued at no more than $10. They will also be reimbursed for parking on their PET scan days, or they 
may be compensated for reasonable transportation costs, including taxi fees to and from scans.  
         Cancellations: If a PET scan should be cancelled by the PET Center for a reason outside of the 
subject's control (i.e. radiotracer synthesis failure) the subject will be paid $50 minimum, or a higher 
amount not to exceed the payment for a full scan day. The amount of the payment for cancellation 
will be based on the subject's length of participation on that scan day prior to the cancellation, and 
will be up to the discretion of the PI.
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.     
Subjects will not be financially responsible for tests, examinations, and medical care provided to 
them during their participation in this study.
4.
In Case of Injury: This section is required for any research involving more than minimal risk.
a.     Will medical treatment be available if research-related injury occurs? 
b.     Where and from whom may treatment be obtained? 
c.     Are there any limits to the treatment being provided? 
d.     Who will pay for this treatment? 
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e.     How will the medical treatment be accessed by subjects? 
Medical treatment will be offered to the subjects for any physical injuries that they receive as a result 
of participating in this research. However, the subject or his/her insurance company is responsible for 
the cost. Federal regulations require that subjects be told that if they are physically injured, no 
additional financial compensation is available.
Treatment may be provided by Yale-New Haven Hospital or any health care provider chosen by 
the study subjects.  The study team will provide assistance to the study subjects in accessing 
medical treatment through referrals, or the study subjects may choose to access treatment on 
their own.
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Page 48 of 51
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