Conditions: Cocaine Dependence
Keywords: Cocaine Dependence Cocaine Addiction
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: yes

Brief summary:
The proposed research program will investigate the changes in brain chemistry and circuitry that 're-wire' the brain during chronic cocaine use, promote relapse, and complicate treatment efforts. Currently-using and non-treatment-seeking individuals with a cocaine use disorder will undergo a cocaine self-administration paradigm 2-5 days prior to completing positron emission tomography (PET) and functional magnetic resonance imaging (fMRI).

Detailed description:
Cocaine use disorder (CUD) remains a significant public health concern that is resistant to current treatments. Challenges to treating CUD include an imbalance in neurobiological systems that 're-wire' the brain such that appetitive and habitual processes influence decision-making and behavior. This research project aims to provide insight into this reorganized circuitry in CUD by investigating neurofunctional systems related to glutamatergic plasticity and functional brain networks during initial (2-5 days) abstinence. To target this potentially critical period of recovery, currently-using and non-treatment-seeking individuals with CUD will undergo a cocaine self-administration paradigm 2-5 days prior to completing \[18F\]FPEB positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Healthy comparison (HC) subjects that have participated in \[18F\]FPEB PET as part of other Yale approved protocols will be recruited to participate in the fMRI portion of this study.

Aim 1: To determine the availability of mGluR5 using \[18F\]FPEB PET during initial abstinence in individuals with CUD. The investigators hypothesize individuals with CUD, relative to HC, will exhibit concurrently and regionally specific increases (e.g., in the striatum) and decreases (e.g., in the prefrontal cortex) in mGluR5 availability.

Aim 2: To determine patterns of resting-state, response-inhibition, an automaticity related connectivity within and between large-scale functional networks using fMRI during initial abstinence in individuals with CUD. The investigators hypothesize network-based analyses of fMRI will reveal lower frontoparietal and greater limbic network modulation in CUD as compared to HC.

Aim 3: To explore the relationships between mGluR5 availability and functional network activity during initial abstinence in individuals with CUD. The investigators will perform multi-modal analysis of PET and fMRI data to examine links between molecular and functional systems in CUD using emerging 'fusion' approaches. While exploratory in nature, the investigators expect to find links between alterations in mGluR5 systems and functional reorganization in CUD (e.g., greater dorsostriatal mGluR5 may be linked to blunted frontoparietal inhibition).

Aim 4: To explore the relationships between mGluR5 availability, functional network activity (and their linkages) with cocaine self-administration, disease severity and chronicity, and psychometric assessments of impulsivity and compulsivity. While exploratory in nature, the investigators expect more substantial neurofunctional alterations during initial abstinence will be associated with greater cocaine self-administration, disease severity, impulsivity and compulsivity in individuals with CUD.

Arms:
arm 1: All participants will complete psychiatric assessment and cognitive testing. arm 2: This arm plans to assess the subjective (e.g., euphoric) and behavioral effects (e.g., self-administration) of cocaine in experienced, non-treatment seeking users of the drug in a human laboratory study of self-regulated cocaine administration. arm 3: All participants will complete a PET scan to assess mGluR5 receptors using \[18-F\]FPEB arm 4: All participants will complete one MRI scan to assess brain structure and function.

Interventions: intervention 1: Psychiatric and Cognitive Testing intervention 2: Cocaine Self-adminstration intervention 3: Positron Emission Tomography intervention 4: Magnetic Resonance Imaging
Intervention descriptions: intervention 1: Interviews, questionnaires, and computer testing. intervention 2: The intervention will include a training and safety session that consists of physician/nurse-administered cocaine followed by a self-regulated cocaine administration period under carefully controlled and closely monitored conditions. intervention 3: PET scans will be performed on a High Resolution Research Tomograph (HRRT), the highest resolution human brain scanner available. Antecubital venous catheters will be used for IV administration of the radiotracer and for venous blood sampling. A radial artery catheter may also be inserted by an experienced physician before the PET scan. At the beginning of each scan, the participants's head will be immobilized and a 6-minute transmission scan, using an orbiting 137Cs point-source, is obtained and used for attenuation correction. PET scans will be acquired using bolus or bolus plus constant infusion administration of \[18F\]FPEB. intervention 4: Structural and functional MRI data will be acquired using a Siemens Trio TIM 3.0T system at the Yale Magnetic Resonance Research Center. High-resolution structural MRI data will be acquired to facilitate analysis of PET data and may be used in additional analysis of tissue volume and brain structure. Resting-state and task-based functional MRI data will be acquired using state-of-the-art multiband echo-planar imaging (EPI) gradient-echo sequences. Diffusion-weighted MRI data will also be acquired using multiband imaging sequences to investigate anatomical connectivity.

Protocol document:
Prot_SAP_000.pdf: 
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HRP-503B – BIOMEDICAL RESEARCH PROTOCOL 
(2016-1)
Protocol Title: Investigation of cocaine addiction using mGluR5 PET and fMRI
Principal Investigator: Patrick D. Worhunsky, Ph.D.
Version Date:       MAR 28 2022
Clinicaltrials.gov Registration #: NCT03471182
SECTION I: RESEARCH PLAN
1.
Statement of Purpose: 
Cocaine use disorder (CUD) remains a significant public health concern that is resistant to current 
treatments. Challenges to treating CUD include an imbalance in neurobiological systems that ‘re-wire’ the 
brain such that appetitive and habitual processes influence maladaptive decision-making and behavior. This 
research project aims to provide insight into this reorganized circuitry in CUD by investigating neurofunctional 
systems related to glutamatergic plasticity and functional brain networks during initial (2-5 days) abstinence. 
To target this potentially critical period of recovery, currently-using and non-treatment-seeking individuals 
with CUD will complete [18F]FPEB positron emission tomography (PET) and functional magnetic resonance 
imaging (fMRI) within days of admission to an inpatient research facility. Healthy comparison (HC) subjects 
from the community or that have participated in [18F]FPEB PET as part of other Yale approved protocols 
(HIC#1101007933, HIC#1111009365, HIC#2000027842/2000020186) will be recruited to participate in the 
fMRI portion of this study.
Aim 1: To determine the availability of mGluR5 using [18F]FPEB PET during initial abstinence in individuals 
with CUD. We hypothesize individuals with CUD, relative to HC, will exhibit concurrently and regionally 
specific increases (e.g., in the striatum) and decreases (e.g., in the prefrontal cortex) in mGluR5 availability.
Aim 2: To determine patterns of resting-state, response-inhibition, an automaticity related connectivity 
within and between large-scale functional networks using fMRI during initial abstinence in individuals with 
CUD. We hypothesize network-based analyses of fMRI will reveal lower frontoparietal and greater limbic 
network modulation in CUD as compared to HC. 
Aim 3: To explore the relationships between mGluR5 availability and functional network activity during 
initial abstinence in individuals with CUD. We will perform multi-modal analysis of PET and fMRI data to 
examine links between molecular and functional systems in CUD using emerging ‘fusion’ approaches. While 
exploratory in nature, we expect to find links between alterations in mGluR5 systems and functional 
reorganization in CUD (e.g., greater dorsostriatal mGluR5 may be linked to blunted frontoparietal inhibition).
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Aim 4: To explore the relationships between mGluR5 availability, functional network activity (and their 
linkages) with cocaine self-administration (collected in some subjects during a prior version of this protocol), 
disease severity and chronicity, and psychometric assessments of impulsivity and compulsivity. While 
exploratory in nature, we expect more substantial neurofunctional alterations during initial abstinence will be 
associated with greater cocaine self-administration, disease severity, impulsivity and compulsivity in 
individuals with CUD.
Aim 5 (pilot): To assess the degree to which mGluR5 availability and functional network activity may 
change during early abstinence in CUD.  A pilot sample of CUD participants (up to 10) will be invited to repeat 
[18F]FPEB PET and fMRI procedures within three weeks of initial scans (typically 5-14 days). A pilot sample of 
HC individuals (up to 10) will also be recruited to complete longitudinal MRI scanning procedures (i.e., two 
MRI scans up to 30 days apart) for test-retest comparison purposes. We hypothesize that individuals with 
CUD will exhibit widespread decreases in mGluR5 availability from levels measured during initial abstinence, 
and that decreases in mGluR5 will be related to blunted activity of cognitive flexibility-related networks and 
stable or increased activity within automaticity-related networks. 
2.
Probable Duration of Project:  
5 years. 
3.
Background:
Illicit-substance-use disorders affect over 8% of individuals in the US (1), leading to negative health 
outcomes and a substantial impact on society (2). Despite decades of research, cocaine use disorder (CUD) 
remains one of the most treatment-resistant addictions; there is currently no FDA-approved medication with 
an indication for the treatment of CUD (3), and behavioral interventions for CUD remain suboptimal with high 
rates of relapse (4). 
CUD-related reorganization of brain circuitry. CUD is associated with a complex set of neurobiological 
alterations that impact a range of cognitive functions including attentional, emotional, inhibitory and 
consummatory processes (5, 6). Current models of CUD, and addictions more broadly, implicate a dysfunction 
in the balance of cognitive systems such that appetitive and habitual processes drive maladaptive decision-
making and behavior (7, 8). This imbalance in brain systems develops through neuroplastic adaptations 
similar to the neural mechanisms underlying learning and memory (9, 10). Furthermore, the maintenance and 
persistence of chronic drug-use behavior in CUD is supported by ‘metaplastic’ alterations, or changes in the 
plasticity of neuroplasticity (11, 12). That is, molecular changes occurring with chronic cocaine exposure 
enhance learning and memory processes associated with drug use while impairing the potential for learning 
and memory associated with non-drug-related stimuli (13, 14).
mGluR5 and neuroplasticity in CUD. The metabotropic glutamate 5 receptor (mGluR5) is primarily a 
postsynaptic receptor located in perisynaptic and extrasynaptic regions (15), and is associated with 
modulating plasticity through multiple signaling pathways (16). mGluR5 has been linked to key neuroplastic 
processes in chronic CUD, and during early abstinence  (10-14, 17-22). mGluR5-related mechanisms are also 
critical to ‘metaplasticity’, or the functioning of neuroadaptive mechanisms in CUD (23). Blocking mGluR5 
activity (through deletion or antagonism) interferes with neuroadaptive processes linked to CUD including 
learning of self-administration behavior (21, 22), cue-induced reinstatement (24, 25), and extinction of 
cocaine-seeking behavior (20, 26) in animal models. Thus, mGluR5 availability, as an indicator of neuroplastic 
activity, may lend insight into the functional reorganization in CUD. 
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mGluR5 research in CUD. To date, three human studies have examined mGluR5 in CUD. During early 
abstinence (i.e., 10-14 day from last use), mGluR5 availability was globally reduced in CUD (27). A subsequent 
study examining a wider range of abstinence in CUD (2-14 days) also observed reductions in mGluR5 
availability; and importantly, lower mGluR5 availability was associated with longer abstinence, with an 
approximate 60-80% reduction in receptor availability after two weeks (28). This finding suggests that the 
lowered mGluR5 availability in CUD may be the net result of molecular changes that occur through early 
abstinence (10, 13, 27, 29); however, this has not been directly examined within individuals. These reports 
are in conflict with an initial study reporting no cocaine-related changes in mGluR5 (30). However, limitations 
caution against firm conclusions of this study: (i) only half of the cocaine-using sample met criteria for CUD, 
perhaps indicating an absence of CUD-related functional reorganization; and (ii) nearly half of cocaine-users 
tested positive for cocaine-metabolites, suggesting data were from a mixture of current users and early-
abstinent individuals. 
Functional circuitry in CUD. A substantial body of research demonstrates regional alterations in brain 
activity in individuals with CUD across a range of cognitive tasks, implicating a reorganization in functional 
circuitry (6, 8). CUD-related impairments are frequently reported in striatal and prefrontal regions that are 
consistent with models of altered reward-sensitivity, impulsivity, and compulsivity (5, 6, 31). However, these 
regions are anatomically connected to diverse sets of brain regions (32), and less is known how regional 
impairments integrate into, and influence functionally distinct brain circuits. Independent component analysis 
(ICA) is a computational technique that evaluates higher-order data structures, and when applied to fMRI 
data, identifies networks of brain regions showing coherent patterns of brain activity, forming ‘functional 
brain networks’ (33). Several distinct functional brain networks (e.g., fronto-parietal, cingulo-insular, and 
default-mode) are reliably identified in resting-state and task-based fMRI (34, 35), and exhibit particular 
functional roles (36). Several functional networks have been implicated in successful and erroneous response 
inhibition processing (37-39), an executive function central to models of addictive behavior (8, 40). Individuals 
with CUD exhibit regional alterations in brain activity during response inhibition processing (41, 42); however, 
activity of functional networks in CUD during response inhibition and automatic/habitual behavior remains 
largely unexplored. Examining the activity of functional networks at rest, during automatic responding, and 
response inhibition will lend insight into the nature of brain reorganization in CUD (e.g., altered functional 
roles, regional integration, or inter-network dynamics).
Multi-modal imaging in CUD. Resting-state connectivity and inhibitory processing have been linked to 
glutamatergic processes (43-46). Sophisticated analytical techniques that investigate shared higher-order 
data structures within and across imaging modalities (such as using parallel-ICA to combine PET and fMRI 
data), will allow greater understanding of the relationships between these neurofunctional systems than 
simple correlational procedures (47). Links between mGluR5 and functional network activity during resting-
state, automatic responding, and response inhibition will provide unique insight into the reorganization of 
neurocircuitry in CUD. 
Summary. CUD is one of the most treatment-resistant addictions, and greater understanding of the 
functional reorganization and neurobiological risk factors of relapse may improve long-term outcomes. We 
propose to study mGluR5 (a glutamate receptor linked to neuroplasticity) during initial (2-5 days) abstinence 
in individuals with CUD to examine brain regions and networks of altered neuroplastic capacity. In addition, 
investigation of resting-state and task-based functional connectivity using fMRI will help clarify the 
reorganization of brain circuitry that occurs in CUD. Finally, integration of the two modalities using novel 
analytic methods will lend unique insight into the relationships between these neurofunctional systems.
4.
Research Plan:
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a.
General design and overview
Twenty experienced, currently-using, non-treatment-seeking and medically healthy individuals with 
cocaine-use disorder (CUD) will participate in a multi-modal imaging investigation of neurofunctional systems 
during initial (2-5 days) abstinence. Subjects determined to meet eligibility criteria through phone and in-
person screening will be scheduled for admission to the Clinical Neuroscience Research Unit (CNRU), 
Connecticut Mental Health Center (CMHC) for the duration of their study participation (up to 10 days). 
Following admission (approximately 2-5 days), subjects will undergo a single [18F]FPEB PET scan at the Yale 
PET Center and complete an fMRI scanning session at the Yale Magnetic Resonance Research Center (MRRC). 
Primary outcome measures will include mGluR5 distribution/availability and activity of functional brain 
networks. Secondary outcomes will include cocaine administration measures (e.g., amount consumed, inter-
response intervals, etc.), cocaine-induced subjective effects (e.g., self-ratings of euphoria, ‘high’, etc.) for 
subjects having completed the prior study protocol, and psychometric assessments of impulsivity and 
compulsivity.
Data from age- and gender-matched healthy comparison (HC) subjects that have participated in [18F]FPEB 
PET as part of other Yale approved protocols (HIC#1101007933, HIC#1111009365, 
HIC#2000027842/2000020186) will be recruited to participate in the fMRI portion of this study. These 
protocols currently obtain written consent from subjects to allow sharing of their information to other Yale 
research groups for recruitment purposes, along with use of their PET data for research purposes among 
collaborating groups. Thus, HC participants will not need to undergo an additional [18F]FPEB PET scanning, but 
may be asked to complete additional screening (e.g., structured interviews), and will be asked to complete 
appropriate assessments and an fMRI session. Additional community-recruited HC individuals may be 
enrolled (i.e., those that have not completed [18F]FPEB PET scanning) to participate in longitudinal MRI 
procedures consistent with Aim 5. These participants will undergo appropriate screening procedures to 
determine eligibility, may complete self-assessments and complete MRI scanning up to 30 days apart. 
b.
Subject screening, admission, and assessment
CUD subjects:
Recruitment of CUD subjects will include experienced, currently-using, non-treatment-seeking, 
medically-healthy, adult volunteers meeting criteria for cocaine-use disorder.  CUD subjects that have 
agreed to participate in similar research at the Cocaine Research Clinic as part of another Yale approved 
protocol (e.g., HIC#2000029552) may be invited to participate. When possible, these individuals will be 
recruited to participate in the PET and fMRI portions of this study concurrently with their participation in 
the other protocols. Simultaneous participation in multiple studies will be permitted at the discretion of 
the Investigators only if it would lessen subject burden (i.e., minimizing inpatient residencies and 
repeated assessments) without impacting the integrity of either study. Additional CUD subjects may be 
recruited through community advertising (e.g., flyers), screened, consented, evaluated, admitted to the 
CNRU. 
Telephone screening. Study staff will initially screen subjects by telephone. During initial telephone 
screening, study staff will offer a brief explanation of the study, its purpose, duration, risks, and 
compensation. If the subject is willing to proceed, the study staff will ask a set of questions that will allow 
for an early exclusion of subjects who do not qualify (e.g., individuals with a major psychiatric disorder, 
individuals with exclusionary medical conditions or medications, individuals meeting criteria for other 
drugs/alcohol use disorders, individuals not using smoked/IV cocaine, etc.; see inclusion/exclusion criteria 
below for specifics). If subjects do not meet criteria and are excluded, or if they are not interested in 
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participating, telephone screening information will be discarded in accordance with Yale established 
procedures.
In-person screening. After telephone screening, potentially eligible subjects will be invited to an in-
person screening visit on the Clinical Neuroscience Research Unit (CNRU). The screening visit will last 
approximately 2 hours. Subjects will first undergo a process of informed consent, during which they will 
first read the consent form and meet with a study physician and/or trained research staff member. 
Subjects will receive an explanation of the study’s purpose, procedures, benefits, risks, compensation, 
and alternatives. They will have time to ask any questions and, if interested in participating, will be asked 
to sign a current, HIC-approved consent form.
Remote screening option. Potential subjects who pass the phone screen portion will have the option 
to do the consenting screening portion remotely. They will be sent two copies of the consent form and a 
release of information to review at their leisure through a method that is most convenient for them (i.e., 
email, fax, or mail). This way subjects have time to review the consent prior to signing and they have their 
own copy to follow along and ask questions during the consenting phone call. If they agree to participate, 
subjects can keep one copy of the consent and sign, date, and return the other copy along with a signed 
released of information back to our research office either by fax, email, or mail in a prepaid envelope. 
When the consent is also signed by a member of the research team, it will be filed in the subject’s 
research record. Using tele-health platforms (i.e., Zoom) the researcher and subject will thoroughly 
review and sign the consent form, complete a structured clinical interview (SCID) by a member of the 
research team, and a medical history and psychiatric interview by a study physician. This will take up to 
two hours to complete in total. If deemed eligible by initial Zoom call and interviews, potential subjects 
will be asked to complete the rest of the study procedures as detailed in the protocol.
Consenting individuals will then undergo additional  screening evaluation, including a clinical 
psychiatric interview (including questions regarding patterns/routes of cocaine use) and the collection of 
other clinical phenotypic information (e.g., body mass index, frequency and amount of cocaine use, 
comorbid nicotine and alcohol use, etc.) that may be completed in-person or remotely, and an in-person 
physical examination, including  a blood draw for CBC and basic metabolic panel, a pregnancy test if 
needed, an electrocardiogram, and a urine sample for urinalysis and toxicology tests. Results of these 
tests are confidential. A qualified physician will inform the subjects of any clinically significant results. 
Subjects will be asked to complete a release of information form allowing study staff to contact the 
subject’s primary care physician to corroborate aspects of the patient’s medical history. If the participant 
does not have a primary care physician, the release will be completed with another alternative source of 
collateral information (i.e., parent, relative, or significant other). 
Once subjects finish the screening visit, lab results are reviewed, collateral information is verified, and 
screening interviews are reviewed, the subject’s eligibility is confirmed. Up to one month may elapse 
between the screening and the study visits, although in most instances we anticipate that such visits will 
be a week apart.
Admission to the CNRU. Once eligibility is confirmed, subjects will be contacted and scheduled for 
inpatient admission to the CNRU. Subjects will reside on the CNRU for the duration of their study 
(typically 5-8 days, possibly up to 10 days) to ensure abstinence from non-laboratory cocaine, participate 
in experimental procedures, and facilitate monitoring. The CNRU is an elective 13-bed, locked inpatient 
clinical research unit where visitors are restricted, access to drugs prevented (except for nicotine which is 
restricted to scheduled daily smoking breaks), and drug abstinence confirmed by regular (3x per week) 
urine toxicology testing. As inpatients, subjects will be required to participate in non-treatment related 
aspects of a structured program of inpatient activities that may include individual (daily with psychiatry 
resident) and group modalities (e.g., life skills, occupational therapy, etc.).
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Subject assessments and ratings. Subjects will participate in a variety of structured clinical, 
psychometric, and behavioral assessments as part of their screening and/or research participation:
i. Structured Clinical Interview for DSM-V (SCID). The SCID is a semi-structured, clinician-administered 
interview for making major DSM-V psychiatric diagnoses and will be used during screening to confirm 
inclusion criteria such as cocaine use disorder and to identify psychiatric exclusion criteria (48).
ii. Semi-Structured Assessment of Drug Dependence and Alcoholism (SSADDA). Subjects will be assessed 
with substance-use (e.g., cocaine and alcohol) and psychiatric (e.g., ADHD) sections of the SSADDA 
during screening as well (49). CUD subjects recruited through similar ongoing  studies (e.g., 
HIC#2000029552) may have completed this interview as part of the other research program. CUD 
subjects recruited through the community will complete this interview as part of their participation in 
this protocol. 
iii. The Substance Use Calendar. The Substance Use Calendar uses the Time-Line Follow-Back Method to 
assess day-to-day use of cocaine and other drugs during the last 90 days and will be administered 
during screening and updated at admission (50). CUD subjects recruited through similar ongoing 
studies (e.g., HIC#2000029552) may have completed this assessment as part of the other research 
program. CUD subjects recruited through the community will complete this assessment as part of their 
participation in this protocol.
iv. Visual Analog Scale (VAS) Ratings of Cocaine-Related Subjective Effects. During cocaine administration 
procedures, subject will complete 14 self-rated subjective effects measures according to a graduated 
scale (0 = not at all; 10 = most ever). VAS ratings are designed to assess several dimensions of 
stimulant-induced subjective effects, including positive (“high”, “rush”, “good”), negative (“bad”, 
“anxious”, “paranoid”), psychomotor (“stimulated”, “restless”, “talkative”, “tongue-tied”), 
appetitive/craving (“want drug”) and drug-valuing effects (“drug liking”, “drug potency”, “drug 
quality”). Ratings are recorded using a touch-screen laptop computer and will be administered every 5 
minutes throughout cocaine sessions (51).
v. Hedonic Response Questionnaire (HRQ); (admission and after each cocaine session): The HRQ is a 13-
item questionnaire used to assess pleasure derived from a range of activities (e.g., watching sports, 
exercising, reading, etc.) from “not at all” to “very much so.” The HRQ will administered at admission 
and following self-administration sessions, to explore general hedonic responses (52).
vi. Cocaine Selective Severity Assessment (CSSA). The CSSA will also be administered daily to assess 
symptoms of acute withdrawal following self-administration until symptoms are no longer reported or 
study procedures are completed (53). For CUD subject not completing self-administration procedures, 
the CCSA may be administered daily following admission until no symptoms of withdrawal are 
reported.
vii. Assessments of impulsivity and compulsivity. Subjects will complete a series of standard self-report 
questionnaires of impulsivity and compulsivity at admission: Barratt Impulsivity Scale (54); Padua 
Inventory (55); Sensitivity to Reward/Punishment Questionnaire (56), and the UPPS Impulsivity Scale 
(57). It is expected that these assessments will take approximately one hour to complete in total.
viii. Additional questionnaires and cognitive testing. Prior to scanning procedures, subjects will complete 
additional, standard assessments of depression and anxiety (e.g., Hamilton Rating Scale for Depression 
(HAM-D) and Hamilton Rating Scale or Anxiety (HAM-A)), as well as a brief series of computerized 
neurocognitive tests (CogState) in line with on-going research (HIC#1101007933, HIC#1111009365, 
HIC#2000027842/2000020186) examining relationships between these cognitive and psychological 
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factors and mGluR5 availability. It is expected that these additional assessments will take 
approximately one hour to complete in total.
CUD subjects recruited through similar Yale-approved studies being conducted by the Cocaine 
Research Clinic (e.g., HIC#2000029552) will have completed assessment items i.-v. as part of the other 
research program, and will complete assessment items vi.-vii. as part of their participation in this 
protocol. CUD subjects recruited through the community will complete all assessment items as part of 
their participation in this protocol, with the exception of items iv. and v. that are not applicable for future 
CUD subjects (as they will not complete the self-administration procedure). However, existing data 
collected using these items may be included in future analyses.
HC subjects.
HC subjects that have completed [18F]FPEB PET scanning as part of other Yale approved protocols 
(HIC#1101007933, HIC#1111009365, HIC#2000027842/2000020186) and have provided written consent 
to permit sharing of their data from these studies with other Yale approved research programs, and have 
consented to receive information regarding other research opportunities at Yale, will be contacted to 
participate in the fMRI portion of this study. Consenting volunteers will have completed the SCID 
interview (item i. above) as part of the PET research study. Only HC subjects reporting a history of 
substance use on the SCID will be asked to complete the SSADDA interview (item ii. above). Eligible HC 
subjects will be asked to complete assessments of impulsivity and compulsivity (item vii. above). 
Additional HC individuals who have not completed [18F]FPEB PET scanning may be recruited from the 
community to participate in longitudinal MRI scanning consistent with the goals of Aim 5. These 
individuals will undergo appropriate screening procedures (that may include remote screening and 
consenting), self-assessments, and MRI scanning procedures up to 30 days apart.
c.
PET imaging of mGluR5 with [18F]FPEB (CUD and HC subjects)
PET scanning sessions will take place at the Yale University PET Center. Subjects will participate in one 
[18F]FPEB scan. However, in situations where a PET scan is not successful following [18F]FPEB injection (e.g., 
problems with the PET camera), CUD subjects may be rescheduled to complete an additional PET scan, if 
possible within the 2-5 day window following inpatient adminission. HC subjects will complete [18F]FPEB PET 
as part of other Yale approved protocols (HIC#1101007933, HIC#1111009365, 
HIC#2000027842/2000020186).
The PET scan will be acquired as the subject lies supine on the scanner bed. Venous catheters will be used 
for intravenous administration of the radiotracer and possibly for additional venous blood sampling. A radial 
artery catheter may be inserted by an experienced physician before the PET scan to draw arterial blood 
samples for metabolite analysis and for determination of the fraction of plasma radioactivity unbound to 
protein. Prior to arterial line placement, the skin will be numbed with a local anesthetic so participants will 
feel less pain when the catheter is inserted. The goal of the arterial line is to be able to measure absolute 
physiological functions by mathematically relating the signal (from the PET scanner) to the tracer availability 
(from the blood). This approach is the gold standard for obtaining quantitative PET data. In some cases, for 
well-established tracers, methods have been developed and validated that provide comparable results to the 
gold standard. In those cases, the arterial samples may not be necessary. However, validation of such an 
approach must be performed in each subject group and for each unique experimental design. In this study, if 
an arterial line cannot be placed, a second intravenous line may be placed for venous blood sampling.
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PET scans will be performed with the Siemens HRRT. An attenuation correction scan is obtained 
immediately before or after each emission scan. The PET scan will be acquired using bolus or bolus plus 
constant infusion administration of up to 5 mCi of [18F]FPEB, followed by up to 120 minutes of dynamic PET 
data acquisition. 
Subjects may be asked to fast (except for water) from midnight until the completion of the test. Vital 
signs (blood pressure, pulse and respiration) are collected prior to and during the PET scan. Any adverse 
events will be evaluated and recorded continuously through the PET imaging day. Subjects will be asked to 
void immediately after each scan is completed to reduce radiation exposure to the bladder.
All scans will be done in the presence of medical supervision and trained staff in an institution specifically 
designed to support imaging studies in different patient populations.
d.
fMRI of resting-state, automatic behavior and response-inhibition (CUD and HC subjects)
Functional and structural MRI data will be acquired using a Siemens Trio TIM 3.0T system at the Yale 
Magnetic Resonance Research Center. High-resolution structural data will be acquired to facilitate analysis of 
PET data and may be used in additional analysis of tissue volume and brain structure. Resting-state and task-
based functional data will be acquired using multiband echo-planar imaging (EPI) gradient-echo sequences.  
Diffusion-weighted MRI data will also be acquired using multiband imaging sequences to investigate 
anatomical connectivity and to inform connectivity-based analyses of functional data. Total scan time will not 
exceed 1.5 hours. 
Resting-state fMRI. Participants will complete up to three 6-min resting-state scans. During this time, they 
will be presented with a fixation cross to enhance reliability of resting-state network activity (58).
The Habitual and Automatic Behavior and Inhibition Task (HABIT). The HABIT is a modification of the 
standard Go/NoGo task of response inhibition (39, 59). The modifications include adjustments to the 
frequency of stimulus presentation, incentivizing performance at times during the task, and switching target 
stimulus at times during the task in order to examine the neural correlates of automatic responding, and 
inhibition of automatic, and non-automatic behavior (60-63).
During HABIT performance, participants are instructed to press a button in response to all Go stimuli 
(e.g., ‘X’) and withhold responses to NoGo stimuli (e.g., ‘K’). Stimuli are presented onscreen for 250-500ms 
with random inter-trial intervals in order to optimize the analysis of both Go and NoGo events. Task 
instructions emphasize speed and accuracy equally. At times during the HABIT, participants will be 
incentivized for their performance (e.g., $0.10 for correct Go responses, and/or $0.25c for successful NoGo 
inhibition, and/or $-0.10 for failed NoGo inhibition). Task instructions emphasize speed and accuracy equally. 
Participants will complete up to six runs of up to 6 minutes each, and may earn up to $20 for their 
performance. Actual achieved earnings during the task are expected to be between $10-20, and no 
participant will receive less than $5 for task completion, independent of performance (i.e., for subjects 
earning less than $5 on the task, they will receive the $5 minimum additional compensation).
All scans will be conducted by an MRI technologist, and a member of the research team will accompany 
the study subject and will stay for the MRI session.
As the PI of this protocol has multiple other HIC approved studies involving neuroimaging, the data from 
this study may be shared across those protocols. Subjects from this protocol may be recruited for the other 
protocols run under the PI so their data can be analyzed across studies.
e.
Participation timeline
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Eligible CUD subjects recruited through the community will complete the study procedures according to 
the described timeline, including interviews (day 0 and possibly day 1), self-assessments (possibly day 0 and 
day 1), and PET and MRI scanning (between day 3 and day 10; depending on scanner availability) (with day 0 
indicating a non-consecutive screening appointment to occur at some time prior to CNRU admission on day 
1). For CUD participants, CNRU admission will be scheduled at least 1 day (and no more than 5 days) prior to 
PET/MRI scanning. While community-recruited participants are expected to remain on the unit 5-8 days total, 
rare occurrences in scheduling may require more flexibility and inpatient stays up to 14 days. 
CUD subjects recruited through similar ongoing cocaine studies (e.g., HIC#2000029552) will complete 
study procedures according to the same timeline. Research-recruited CUD subjects may be discharged from 
the CNRU according to the procedures and timeline of the referring protocol if additional procedures are to 
be completed for that study after PET/MRI scanning.
HC subjects recruited through the ongoing [18F]FPEB PET studies (HIC#1101007933, HIC#1111009365, 
HIC#2000027842/2000020186) will complete interviews and PET scanning as part of participation in those 
studies. Any additional interviews (e.g. SSADDA) and all self-assessments will be administered following 
successful PET scanning. HC subjects will complete MRI procedures within a week of PET scanning, or as near 
the date of PET scanning as equipment availability allows. 
f.
Pilot addendum: Second PET and fMRI in early abstinence 
A pilot sample of CUD participants (up to 10) will be invited to repeat [18F]FPEB PET and fMRI procedures 
within one month of initial scans (typically 10-20 days). Following completion of primary study procedures 
described above, CUD participants agreeing to complete the optional scanning procedures will remain on the 
CNRU until the second PET and fMRI procedures can be successfully completed. Participants may also be 
asked to repeat additional questionnaires and cognitive testing around the time of scanning procedures. 
While participants are expected to remain on the unit an additional  10-20 days total, rare occurrences in 
scheduling may require more flexibility and inpatient stays extended up to approximately one month. Given 
the current scheduling practices at the Yale PET Center and MRRC, participants will likely be provided 
information regarding the likely dates of additional scans and thus the approximate duration of the extended 
stay required to complete the pilot study during the consenting processes. HC subjects (up to 10) will be 
recruited to participate in the fMRI portion of Aim 5. These community-recruited HC individuals will complete 
screening procedures (that may include remote interviews and consenting), self-assessments and participate 
in two MRI scanning session up to 30 days apart as scheduling allows.
5.
Genetic Testing:   
☒ N/A 
6.
Subject Population:
CUD subjects. CUD subjects will be 20 experienced, currently-using, non-treatment-seeking, medically-
healthy, adult volunteers meeting criteria for cocaine-use disorder (see inclusion/exclusion criteria below; 
Section I, item 8).
HC subjects.  HC subjects will be 20 medically-healthy, adult volunteers that have participated in an 
[18F]FPEB scan as part of another Yale approved protocol (HIC#1101007933, HIC#1111009365, 
HIC#2000027842/2000020186), or that are recruited from the community (Aim 5). Subjects will be contacted 
to participate in the fMRI portion of this study, and may be asked to completed additional assessments and 
screening procedures (see inclusion/exclusion criteria below; Section I, item 8).
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7. Subject Classification:
☐ 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 
Since cocaine dependence often involves serious financial difficulties, it is also possible that some of our 
subjects may be economically disadvantaged persons. We will carefully screen all participants to make sure 
that the potential for improvement in their cocaine addiction is the primary motivation for participation. We 
may enroll females of childbearing potential. All females will be carefully assessed to ensure the absence of 
pregnancy both before and during study participation.
8. Inclusion/Exclusion Criteria:
Inclusion criteria:
HC and CUD subjects:
Age 21 - 60 years
Provide voluntary, written, informed consent
Physically healthy by medical history, physical, neurological, ECG, and laboratory examinations
For females: non-lactating, no longer of child-bearing potential or agreeing to practice effective 
contraception during the study (e.g., established use of oral, injected or implanted hormonal methods 
of contraception; placement of an intrauterine device [IUD] or intrauterine system [IUS]; barrier 
methods: condom or occlusive cap [diaphragm or cervical/vault caps] with spermicidal 
foam/gel/film/cream/suppository; male partner sterilization; true abstinence when this is in line with 
the preferred and usual lifestyle of the subject), and a negative serum pregnancy (-HCG) test
CUD subjects:
DSM-5 criteria for moderate or severe cocaine-use disorder
Positive urine toxicology screen for cocaine
CUD subjects (Pilot addendum):
Successful completion of primary study procedures
Provide voluntary, written, informed consent to participate in additional procedures
Exclusion criteria:
HC and CUD subjects:

Any condition that, in the opinion of investigators, would prevent compliance with the study 
protocol

A history of significant medical or neurological illness (e.g., coronary artery disease, significant 
anemia, seizures)
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
Current use of psychotropic and/or potentially psychoactive medications

Physical or laboratory (-HCG) evidence of pregnancy

Meet any additional PET/MR imaging-related exclusion criteria, including:
o
Presence of MRI incompatible implants and other contraindications for MRI (e.g., pacemaker, 
artificial joints, non-removable body piercings, etc.)
o
Participation in other research studies involving ionizing radiation within one year of the PET 
scans that would cause the subject to exceed the yearly dose limits for healthy volunteers
o
History of a bleeding disorder or are currently taking anticoagulants (such as Coumadin, 
Heparin, Pradaxa, Xarelto).
o
Claustrophobia
o
Severe motor problems that prevent the subject from lying still for PET/MR imaging
o
Complaints of chronic pain (e.g., as the result of rheumatoid arthritis)
o
Current, past or anticipated exposure to radiation in the work place
CUD subjects:
Other moderate or severe drug use disorder (except for tobacco-use disorder)
< 1 year of cocaine use disorder
A DSM-5 major psychiatric diagnosis (schizophrenia, bipolar disorder, etc.) unrelated to cocaine
HC subjects:
Any DSM-5 major psychiatric diagnosis (schizophrenia, bipolar disorder, etc.), except tobacco-use 
disorder
Positive drug screen
9. How will eligibility be determined, and by whom? 
CUD subjects. Potential community-recruited CUD subjects will be initially phone screened by research 
staff. As part of this screen, subjects will be asked to provide information on medical and psychiatric history, 
substance use/abuse history, patterns/routes of cocaine use, and whether they are seeking treatment for 
their cocaine use or not. Potential subjects who pass this phone screening will be scheduled for an in-person 
screening, which will be done by the study physician, research nurse and/or research coordinator. As part of 
this screening, subjects will undergo a process of informed consent, including reading the consent form and 
reviewing it with a study physician and/or trained research staff member. Subjects will receive an explanation 
of purpose, procedures, benefits, risks, compensation, and alternatives to the study. They will have time to 
ask any questions and, if interested in participating, will be asked to sign an approved consent form. After 
providing informed consent for the study, subjects will undergo a physical exam and an informal interview to 
assess medical, psychiatric, and substance abuse problems, medications, allergies, patterns/routes of cocaine 
use, and whether they are actively seeking treatment for their cocaine use. They will also undergo a clinician-
administered structured interview (i.e., SCID), blood drawing for basic hematologic, chemistry and liver 
panels, a urine test to detect cocaine and its metabolites, a serum (-HCG ) pregnancy test (if needed) and an 
electrocardiogram. Information collected during in person screening visits will be discussed by the study 
physicians, study nurse, research coordinator, and Principal Investigator (who meet on a weekly basis) in 
order to determine eligibility. CUD subjects recruited through ongoing Cocaine Research Clinic studies (e.g., 
HIC#2000029552) will have completed this screening process as part of that study, and be invited by study 
staff to participate in this study. 
HC subjects. Subjects that have participated in [18F]FPEB PET as part of other Yale approved protocols 
(HIC#1101007933, HIC#1111009365, HIC#2000027842/2000020186) will be contacted by research staff to 
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participate in the fMRI portion of this study.  Additional HC subjects will be recruited through the community. 
Subjects will undergo a process of informed consent in person or remotely, including reading the consent 
form and reviewing it with a research staff member. Subjects will receive an explanation of purpose, 
procedures, benefits, risks, compensation, and alternatives to the study. They will have time to ask any 
questions and, if interested in participating, will be asked to sign an approved consent form. Subjects from 
other [18F]FPEB PET studies may be asked to undergo a structured interview (i.e., SCID) to confirm eligibility if 
this or a comparable assessment was not completed by the referring study.
10. Risks: 
a.
Risks associated with interviews, questionnaires and neurocognitive testing
The medical and psychiatric interviews, self-report questionnaires, and computerized neurocognitive 
tests may be stressful, uncomfortable, or tiring for subjects. Unanticipated psychiatric and medical 
information may be uncovered during evaluation.
b.
Risks associated with phlebotomy/intravenous lines
Drawing blood and inserting an intravenous line (IV) are safe and standard medical procedures. Venous 
sampling may be associated with mild-to-moderate pain or bruising at the puncture site. Bruising and 
thrombosis can occur during phlebotomy and the placement of the intravenous line. In rare instances poor 
healing, or infection at the catheter insertion site may occur. Certain individuals may feel light-headed during 
venipuncture; to avoid injury due to fainting, procedures will be performed when the subjects are 
seated/recumbent. Blood samples will be drawn for routine labs (up to 60mL) and blood will be taken during 
each PET scan (up to 120mL).
c.
Risks associated with use of an arterial catheter
On the PET scanning days a radial arterial catheter may be inserted. Certain individuals may feel light-
headed during arterial catheter placement. Arterial catheter placement may be associated with mild-to-
moderate pain, hematoma, inflammation, bleeding, or bruising at the puncture site. If any of these, or other, 
symptoms occur and do not diminish within 24 to 72 hours after the arterial line removal, or in the event that 
they worsen, subjects will be advised to call the on-call doctor listed on the PET discharge instructions. In rare 
instances blocking of the artery, tearing of the artery, arterial leakage, poor healing, or infection at the 
catheter insertion site may occur.
d.
Risks associated with MRI
Functional MRI scanning using a 3.0T scanner is non-invasive and has not been associated with any 
medical risks. However, MRI scanning carries a risk for subjects who are claustrophobic or have pacemakers, 
metal pieces, aneurysm clips, or any other contraindications for MR. As individuals with contraindications for 
MR will be excluded, the primary anticipated complication is the experience of claustrophobia during 
scanning. On rare occasions, some people might feel dizzy, get an upset stomach, have a metallic taste or feel 
tingling sensations or muscle twitches. Another risk is the possibility of metal objects being pulled into the 
magnet and striking the subject or heating up during scanning. While the scans performed in this study are 
not designed for diagnostic purposes, potential abnormalities may be detected by the MR technologist during 
acquisition, or members of the research team during image analysis.
e.
Risks associated with radiation
This research study involves exposure to radiation from [18F]FPEB PET scanning. This radiation exposure is 
not necessary for medical care and is for research purposes only. The targeted amount of radiation an 
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individual subject will receive from participating in Aim 1 of this study is from one injection of ≤ 5mCi (0.57 
rem) of [18F]FPEB, plus attenuation correction (i.e., transmission) scans of the brain. Participants that return 
to complete a second PET scan as part of Aim 5 will receive a second injection of ≤ 5mCi (0.57 rem) of 
[18F]FPEB, for a total of 1.14 rem.  
However, in situations where the PET scan is not successful following injection (e.g., problems with the 
PET camera) subjects may receive an additional [18F]FPEB injection, if deemed appropriate, for a total of 2 
[18F]FPEB injections for those completing Aim 1, and up to 3 [18F]FPEB injections for those subjects also 
participating in Aim 5.  
Although each organ will receive a different dose, the maximum amount of radiation exposure subjects 
will receive from one scan in this study is equal to an effective dose equivalent of 0.57 rem, for a total of up to 
5 mCi of [18F] FPEB in 1 injection, and 1.14 rem from two injections, or two 5 mCi doses (10 mCi total) of [18F] 
FPEB. This calculated value is used to relate the dose received by each organ to a single value. 
In the unexpected case where participants may be asked to undergo an additional  PET scan (i.e., if the 
first or second is not successful), the maximum amount of radiation received from participating in Aim 1 
would be 1.14 rem from up to 2 scans (10 mCi of [18F]FPEB total). The maximum amount of radiation for 
those returning to complete Aim 5 would be 1.71 rem, from up to 3 scans (15 mCi of [18F]FPEB total).
The amount of radiation that subjects will receive in this study is below the dose limit guidelines 
established by the FDA and monitored by the Yale University Radioactive Drug Research Committee for 
research subjects.
f.
Risks associated with privacy/loss of confidentiality
Since some of the data collected (e.g., history of substance use behavior) is private in nature and may 
have legal implications, risks related to loss of confidentiality also exist.
g.
Risks associated with unanticipated events
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 unanticipated event, all necessary medical action will be taken.
i. 
X-ray to rule out metal
The risk of undergoing an X-ray are minimal as the radiation exposure is low and is no different than an X-
ray done as part of routine dentistry or medical screenings.
11. Minimizing Risks:
a.
Minimizing risks from interviews, questionnaires, and neurocognitive testing 
Subjects will be offered short breaks during and in between interviews, questionnaires, and computerized 
neurocognitive testing. The staff responsible for the data collection has received training in empathetic/non-
judgmental techniques for interviewing, and subjects may discontinue at any time. 
 
b.
Minimizing risks from phlebotomy/intravenous lines
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 intravenous 
catheters will be inserted when the subjects are recumbent. Subjects completing study procedures will have 
no more than 240mL of blood drawn across study participation (including screening, admission and PET scan), 
which is less than a standard blood donation (450 mL or roughly a pint). To minimize the risks of blood draws 
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and the discomfort associated with it, there will only be one blood draw on the screening visit and blood 
draws during PET scanning sessions will be obtained from an inserted catheter. Subjects with history of 
significant anemia will be excluded, and subjects will be asked to abstain from using aspirin, NSAIDS or 
anticoagulants unless medically necessary (at which point they will be re-assessed for eligibility). Bleeding is 
minimized by local pressure applied for 5 minutes after the procedure. Infection is avoided by adequate 
cleansing of the skin prior to venipuncture and by the exclusion of immunocompromised subjects.
c.
Minimizing risks from an arterial catheter
Risks of radial artery cannulation are minimized by having the procedure performed by an experienced 
health care provider. The health care provider would be either a physician or an advanced practice registered 
nurse (APRN) with experience in critical care and placement of arterial catheters, as is the practice at Yale-
New Haven Hospital. For an APRN to place the arterial line at the Yale PET Center, they must meet the 
following criteria:
1.) Be currently credentialed at Yale-New Haven Hospital or similar institute and
2.) Perform 3 arterial line procedures supervised by a currently privileged PET Center physician
The 3 supervised arterial line placements will be documented and signed off by both the APRN and 
supervising physician. The completed document must be on file at the Yale PET Center prior to an APRN 
performing any arterial line catherizations independently. Pain is minimized by using local anesthesia. 
Infection is avoided by adequate cleansing of the skin prior to intravascular line insertion. After arterial 
catheter removal, bleeding is minimized by direct pressure applied to the site for a minimum of 15 minutes 
followed by a pressure dressing (coban) that should be kept clean and dry until evening or 10 hours post PET 
scan. Subjects will have their hand and finger blood supply examined after arterial cannulation, throughout 
the study and again following catheter removal. Also, subjects will be asked to abstain from using aspirin and 
other NSAIDS for 7-10 days prior to arterial line insertion and 7-10 days following arterial line removal unless 
medically necessary. Subjects will be provided a 24 hour emergency physician contact 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. A nurse will provide 
discharge instructions outlining general instructions in addition to post-arterial catheter precautions, 
problems to watch for, and procedures to follow should such problems occur.
d.
Minimizing risks of MRI
All MRI scanning will be conducted in the presence of experienced research and technical staff. All 
subjects will be able to terminate the MRI scan at any time for any reason including claustrophobia or 
discomfort. All subjects will be screened using the Yale MRI Safety Sheet for any metallic objects that they 
may be holding or have implanted in their bodies and all potential subjects with metallic implants will be 
excluded. This questionnaire will be repeated prior to imaging to ensure that they are not bringing any 
metallic materials into close proximity of the magnet, where they might be pulled toward the magnet or 
heated by the magnet. For additional safety, subjects will be taken through a ferromagnetic metal detector 
immediately before going to the scan room, and once subjects are in the scanner, the door to the room will 
be closed. In addition to the MRI operator, a member of the research team will accompany the study subject 
and will stay for the MRI. All participants may terminate imaging at any time for any reason.
In cases of a possible incidental medical finding, a radiologist will be asked to review the relevant images. 
Based on his or her recommendation (if any), the principle investigator or consulting physician will contact 
the subject, inform them of the finding, and recommend that they seek medical advice as a precautionary 
measure.
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e.
Minimizing risks from radiation
The Yale-New Haven Hospital Radiation Safety Committee (Y-NHH RSC) and the Yale University Radiation 
Safety Committee (YU RSC), will review the use of radiation in this research study, and no subjects will be 
scanned until approval is obtained. All scans will be done in the presence of medical supervision and nursing 
staff in an institution specifically designed to support imaging studies. In the event of serious medical 
complications, the Yale University PET Center facilities have immediate access to, or consultation with, 
specialized medical units at the Yale-New Haven Hospital. Preparation of radiopharmaceuticals and execution 
of PET scans will be performed by radiochemists, physicians, and technologists of the Department of 
Radiology and Biomedical Imaging, Yale University School of Medicine. These professionals are qualified by 
training and experience in the safe use and handling of radionuclides. 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.
No PET studies will be performed on pregnant or potentially pregnant women, as confirmed by pregnancy 
testing during evaluation and on scan days before initiation of any procedures. If subjects are breastfeeding 
they will not be able to participate in this research study.
f.
Minimizing risks related to privacy/loss of confidentiality
Security of subject information is of paramount importance to us. Research personnel will not contact any 
person or agency without appropriate written release of information. All information collected will be kept in 
password-protected, HIPAA-compliant computers, secured using the best available methods. Research 
records will be kept as confidential as possible. Only a code number will identify subject research records. The 
code number will not be based on any information that could be used to identify subjects (e.g., social security 
number, initials, birth date, etc.). The master list linking names to code numbers will be kept separately from 
the research data. This master list, as well as all the other research information, will be kept in locked files at 
all times. Subjects’ identity will not be revealed in any reports or publications resulting from this study. Only 
authorized persons will have access to the information gathered in this study. As part of the study 
procedures, some information about subject’s participation will become part of their CMHC medical record. If 
a subject does not already have a medical record at CMHC, one will be made for their visit. Moreover, if a 
subject has been a patient at CMHC at any time, his or her previous medical records of other visits or 
admissions will become available to the researchers and to the staff of the CMHC, as part of the screening, or 
when the information collected for this research is added into their medical record. Information will be stored 
as per HIPAA guidelines. All staff has been trained in accordance with HIPAA regulations. Information will not 
be dispensed to anyone outside of this research project, Yale HIC, CMHC, or YNHH HRU without prior written 
authorization from the subject. If we see or are told that a child is being abused or neglected or that there is a 
risk of harm to subject or others, we will disclose this information to the proper authorities.
g.
Minimizing risks from unanticipated events
Medication might be administered as needed, per the CNRU and Yale PET Center standard operating 
procedure for medical emergencies, in order to treat any unanticipated events/complications.
12. Data and Safety Monitoring Plan:
a.
What is the investigator’s assessment of the overall risk level for subjects participating in this study? 
The overall risk level associated with participating in this protocol is greater than minimal. 
b.
If children are involved, what is the investigator’s assessment of the overall risk level for the children 
participating in this study? 
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Not Applicable.
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are available here .
1.
Personnel responsible for the safety review and its frequency
The principal investigator 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 and monitors will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment. The principal investigator, IRB/HIC, Y-NHH RSC, and MRRC 
have the authority to stop or suspend the study or require modifications.
2.
The risks associated with the current study are deemed greater than minimal for the following reasons 
We do not view the risks associated with the radiotracer imaging procedure as minimal risks. 
Given the now established safety and validity of the current methods in our prior work, we do not view 
the proposed studies as high risk.
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 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 Patrick Worhunsky Ph.D. and Drs. Potenza, Chen or Angarita 
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 
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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/HIC 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: 
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).
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7.
Plan for reporting adverse events to co-investigators on the study as appropriate, the protocol’s research 
monitor(s)
For the current study, the following individuals, funding and/or regulatory agencies will be notified:

All Co-Investigators listed on the protocol.

Yale Human Investigations Committee (HIC)

Yale-New Haven Hospital Radiation Safety Committee (Y-NHH RSC) 

National Institutes of Health
The principal investigator Patrick Worhunsky Ph.D. and Drs. Potenza, Chen or Angarita 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: 
Not Applicable
13. Statistical Considerations:
Standard neuroimaging analysis. Analysis of PET and fMRI data will be performed using standard general 
linear modeling approaches using regions-of-interest (ROIs) and whole-brain analyses of variance (ANOVAs) in 
SPM12. ROIs will be defined using the Neuromorphometrics atlas (neuromorphometrics.com) and include 
basal ganglia structures, subdivisions of the cingulate and other prefrontal and parietal regions that exhibit 
high [18F]FPEB uptake (64) and are implicated in response inhibition (65). Standard analyses will be performed 
as the primary investigation of mGluR5 availability in CUD relative to HC, and will support findings from 
network-based analyses of fMRI and multi-modal fusion techniques. 
Network-based analysis. Independent component analyses (ICA) of PET and fMRI data will be performed 
using the Group ICA of fMRI Toolbox (GIFT; icatb.sourceforge.net). This software package was designed by Dr. 
Calhoun (co-investigator) and colleagues for functional network analysis of fMRI data, and includes a source-
based morphometry (SBM) toolkit for analysis of structural/static biomedical images (66). The principles of 
ICA for fMRI and PET are largely consistent and have been previously performed in parallel (67, 68) 
Multi-modal data fusion. Joint-ICA (jICA), parallel-ICA (pICA) and linked-ICA (lICA) are implementations of 
the ICA principles to fully integrate, or ‘fuse’, multiple datasets into a single coherent analysis (69-71). jICA 
identifies a single set of independent sources (e.g., the same functional brain networks) present in datasets 
collected in the same individuals under multiple conditions. Thus, jICA is suited to examine activity of 
functional networks active during both resting-state and HABIT performance, and examine changes in 
network dynamics (i.e., ‘connectivity’-like patterns of network-to-network interactions) between conditions, 
providing advanced insight into the organization of functional systems. By comparison, pICA combines multi-
modal data collected in the same individuals, identifying a shared higher-order data structure present in 
datasets, but that originate from separate sources in respective modalities (e.g., receptor-availability 
networks and functional brain networks. Similar to pICA, lICA combines multiple outcomes from within 
modality groups (e.g.fMRI group: resting-state and HABIT activity, PET group: VT and k1 parameters) toward a 
more fully integrated fusion analysis. 
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Relationships with self-administration and impulsivity. Standard analysis of variance (ANOVA) and linear 
regression models will be used to examine potential associations between the neuroimaging measures with 
subjective effects and behavior during cocaine self-administration (e.g., ‘high’, infusion intervals, doses) 
collected under and earlier versions of this protocol, and scores on self-report assessments of impulsivity and 
compulsivity. Additional analysis will explore relationships between neuroimaging measures and self-
administration behavior with additional psychological and cognitive factors (e.g., depression, anxiety, 
neurocognitive performance), which may indicate use of these measures as covariates for primary analyses.
Power considerations. The proposed project will include 20 CUD and 20 HC participants. Prior research of 
mGluR5 differences in CUD (27), and our work of functional-network differences in addiction-vulnerable 
populations using the Go/NoGo task (39) indicate this sample will be sufficiently powered (d’s>.95) for 
analysis at a threshold of α=.05  (PET: non-centrality parameter (δ)= 3.60, critical t38=1.81, power (1-β)=0.96; 
fMRI:  δ= 3.06, critical t38=1.54, power (1-β)=0.93). The modified HABIT task is expected to be similarly 
powered to the Go/NoGo.
Pilot addendum. Standard within-subjects repeated-measures analysis will be conducted to investigate 
changes in mGluR5 availability and functional network parameters between time points. Mixed effects 
models will be performed to examine differences in functional brain activity (i.e., fMRI data) and task-
performance in CUD relative to HC. While this has not been directly explored previously, prior research 
examining differences between-subjects suggests a robust change in mGluR5 during the first few weeks of 
cocaine abstinence [28]. For the current purposes, if hypothesized changes are observed, results will serve as 
pilot data to estimate effect sizes toward obtaining additional funding.
SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
A.  RADIOTRACERS
☐ N/A
1.
Name of the radiotracer: [18F]FPEB
2.
Is the radiotracer FDA approved?    ☐ YES
☒ NO
If NO, an FDA issued IND is required for the investigational use unless RDRC assumes oversight
3.
Check one:    ☒ IND#59,121           or            ☐ RDRC oversight (RDRC approval will be required prior to use)
This study was previously approved by the YU RDRC (initial approval date: 10/11/17; Aim 5 amendment 
approval date: 3/1/19). In April 2019 the FDA requested complete [18F]FPEB Chemistry Manufacturing and 
Controls documentation be submitted for review to support use of [18F]FPEB PET in this study under IND# 
59,121. The FDA has reviewed and accepted all documentation (email communication uploaded in IRES IRB) 
which was subsequently submitted as an amendment to the IND (cover letter uploaded in IRES IRB).. Going 
forward, FPEB administration is now covered under IND# 59,121.
B.  DRUGS/BIOLOGICS    ☐ N/A
Cocaine (cocaine hydrochloride), intravenous (IND #59,121; held by: Gustavo A. Angarita , co-investigator)
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1.
If an exemption from IND filing requirements is sought for a clinical investigation of a drug product that is 
lawfully marketed in the United States, review the following categories and complete the applicable category 
that applies.  
No exemption from IND filing requirements is being requested.
2.
Background Information:
[18F]FPEB:
The radiotracer [18F]FPEB has previously been used in human subjects; 5 individuals at the Institute for 
Neurodegenerative Disorders (IND) in New Haven CT, and over 150 individuals and over 200 injections at Yale 
University. No subjects have reported any adverse event with this radiotracer. However, subjects will be 
monitored carefully during and after the PET scan for any potential side effects.
The radiation dose estimates are based on the biodistribution data for [18F]FPEB in 6 healthy adults (3 
men and 3 women) and calculated using OLINDA/EXM software (72). Based on these numbers, the critical 
organ is the gallbladder wall (0.191 mGy/MBq, i.e., 0.708 rad/mCi). Another radiation dose study (73) also 
reported the gallbladder wall (0.193 mGy/MBq, 0.714 rad/mCi) as the critical organ based on the 
biodistribution data in 9 healthy adults (5 men and 4 women).
However, (73) reported the urinary bladder wall as the critical organ (0.258 mGy/MBq, 0.955 rad/mCi) 
when no voiding takes place prior to a 3.5 h period. Thus, the maximum allowable injection doses for 
[18F]FPEB to remain below the 21 CFR 361.1 dose limits for research subjects are 5.2 mCi per single injection 
(calculations based upon the urinary bladder wall for a 3.5 h voiding), and 7 mCi per single injection 
(calculations based upon the gallbladder wall as the critical organs); 3 rads per single study for whole body, 
active blood forming organs, lens of the eyes and gonads; 5 rads for other organs per single study limit. 
Additional risks and procedures toward their minimization are detailed above (see Section I, items 10-11).
.
3. Source:  Identify the source of the drug or biologic to be used.
 
[18F]FPEB: Will be synthesized at the Yale University PET Center radiochemistry Laboratory under the 
supervision of Dr. Henry Huang and Dr. Nabeel Nabulsi.
a.
Is the drug provided free of charge to subjects?   ☒YES   ☐ NO 
If yes, by whom?  Supporting research grant(s) (e.g., NIDA) will cover costs of the radiotracer).
4.
Storage, Preparation and Use: 
[18F]FPEB:
Due to the short half-life, PET drugs are prepared ex tempore 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 8 hours after preparation. 
[18F]FPEB will be prepared at the Yale PET Center in accordance with procedures and quality 
specifications described in local Drug Master File (DMF) submitted to the FDA (IND# 59121) which was 
previously approved by the Yale University Radioactive Drug Research Committee (YU RDRC). 
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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 ex post facto for further confirmation. 
Investigational Drug Service utilized: 
    ☐  YNHH IDS
☐  CMHC Pharmacy
☐ West Haven VA
    ☒  PET Center
☐    None      
    ☐  Other: 
5.
Use of Placebo:     ☒ N/A
6.
Continuation of Drug Therapy After Study Closure:     ☒ N/A
 C.  DEVICES:
☒ N/A
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects: 40 completers (20 CUD and 20 HC)
a.
Targeted for enrollment at Yale for this protocol: 
Approximately 40 potential CUD subjects will be enrolled (i.e., sign consent forms) to achieve a target of 
20 CUD completers. Up to 25 potential HC subjects will be enrolled (i.e., sign consent forms) to achieve a 
target of 20 HC completers. 
Up to 10 CUD and 10 HC subjects may be invited to complete the pilot addendum procedures. 
Preliminary analyses will be conducted on an ongoing basis to determine if evidence supports continued 
data collection or if sufficient data has been collected to support a grant application to continue 
investigation in a larger sample. 
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
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☐ Posters
☐ Mass email solicitation
☐ Telephone
☐ Letter
☐ Departmental/Center website
☐ Television
☐ Medical record review* 
☐ Departmental/Center research boards
☐ Newspaper
☐ Departmental/Center newsletters
☐ Web-based clinical trial registries
☐ Clinicaltrials.gov 
☒ YCCI Recruitment database
☒ Social Media (Twitter/Facebook): 
☐ Other: 
* Requests for medical records should be made through JDAT as described here. 
3.
 Recruitment Procedures: 
a.
Describe how potential subjects will be identified. 
Community-recruited CUD and HC subjects will be recruited through the methods listed above (see 
written material attached to protocol) as well as through word of mouth referrals from other research 
groups/clinicians at CMHC and/or prior study participants. HIC approved study announcements providing 
individuals with study contact information may be posted to internet-based community resources (e.g., 
craigslist.org), on social media (e.g., Facebook), the YCCI recruitment database, and flyers will be posted 
in the local community.  Research-recruited CUD subjects (e.g., from HIC#2000029552) may be invited by 
study staff or provided contact details in order to inquire about potential participation in this study. 
Research-recruited HC subjects will have provided consent to be contacted regarding additional research 
opportunities and will be contacted by study staff to provide information regarding potential participation 
in this study. 
b.
Describe how potential subjects are contacted.
Potential community-recruited CUD and HC subjects will be encouraged to contact our study 
recruitment line for inclusion in our study. Potential research-recruited CUD subjects may be invited to 
participate by shared research staff or will be given direct phone contact information for study staff. 
Potential HC subjects will have consented to being contacted by the study staff regarding potential 
participation.
c.
Who is recruiting potential subjects?
 A member of our research staff will describe the study to participants who call the recruitment 
phone line (community-recruited CUD and HC subjects), contact them directly (research-recruited CUD 
subjects), or are contacted by research staff (research-recruited CUD and HC subjects), answer any 
questions the potential subjects have and then complete any appropriate phone screening questionnaire 
to determine the subject’s eligibility for an in-person screening visit.
4. 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
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5. Request for waiver of HIPAA authorization:
Choose one: 
☐ For entire study 
☒ For recruitment/screening purposes only
☐ For inclusion of non-English speaking subject if short form is being used and there is no translated 
HIPAA research authorization form available on the University’s HIPAA website at hipaa.yale.edu.
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: 
The initial screening/recruitment information will be collected over the phone and is required prior to 
the subject being considered for an in-person screening and evaluation appointment. As this screening is 
done over the phone rather than in person, obtaining signed authorization would be impractical.
6.
Process of Consent/Assent: 
All subjects will be consented through a multi-step consent process. Subjects are first described the study 
in detail over the phone during the phone screen. They are then invited to come to the in-person screening 
appointment or provided the option to complete additional screening and consenting procedures remotely. A 
trained research staff member will conduct the informed consent process in a private, quiet setting.  The 
research team member and the participant will discuss the basic components described in the consent form.  
These include: participation is voluntary and participants may withdraw at any time, procedures, visit 
schedule, risks and benefits, potential compensation, alternatives to study participation, and confidentiality.  
Potential participants will be provided an opportunity to ask questions and time to consider his/her decision 
to participate.  Anyone who cannot demonstrate appropriate understanding of the study will not be eligible 
to participate. Those who demonstrate understanding of the study and voluntarily agree to participate will be 
asked to sign the informed consent form and proceed with the screening assessments. As part of the 
informed consent procedures, participants will be asked to provide or decline consent to be contacted for 
future studies. A copy of the signed study consent form will be given to the participant.
7.
Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: 
Study staff are trained to assess the subject’s understanding of pertinent information given to them and 
whether or not subjects can appreciate the implications of their decision. Study staff will ask the subject to 
reiterate the study procedures back to them and will ensure that the subject has had substantial time to ask 
questions about any/all study procedures. Study staff will also assess the subject’s understanding of the study 
with a 5-item written quiz. Subjects who answer all the questions in the correct way will be able to sign the 
consent form.
8.
Non-English Speaking Subjects: 
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There are no plans to recruit or enroll non-English speaking subjects. There are no provisions in the 
current protocol to accommodate non-English speaking participants (to translate study documents, 
assessment battery, informed consent form, or other study material into other languages).
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
9.
Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or a full waiver of 
consent, depending on the study.  
☐  Not Requesting any consent waivers 
☒  Requesting a waiver of signed consent:
☒  Recruitment/Screening only (if for recruitment, the questions in the box below will apply to 
recruitment activities only)
☐  Entire Study (Note that an information sheet may be required.)
 For a waiver of signed consent, address the following:
Would the signed consent form be the only record linking the subject and the research?  
☐ YES   ☐ NO    
Does a breach of confidentiality constitute the principal risk to subjects? 
☐ YES   ☐ NO    
OR
Does the research pose greater than minimal risk? 
☐ YES   ☒ NO    
Does the research include any activities that would require signed consent in a non-research context? 
☐ YES   ☒ NO    
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SECTION IV: PROTECTION OF RESEARCH SUBJECTS
Confidentiality & Security of Data:
1.
What protected health information (medical information along with the HIPAA identifiers) about subjects will 
be collected and used for the research? 
CUD subjects who decide to participate in the study will have a medical record at the Connecticut Mental 
Health Center (CMHC) and at Yale New Haven Hospital (YNHH). If subjects already have a medical record at 
CMHC or YNHH, some information about their participation in the study will be included here. If they do not 
have a medical record at CMHC or YNHH, 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 experiments 
at the YNHH HRU, date of discharge from the CNRU, X-ray results if required for MRI eligibility, phone 
number, address, medical history, individual and family history of psychiatric problems, and substance abuse 
history. One of the instruments used to assess substance abuse history will include questions pertinent to 
legal problems. 
All subjects will be asked to provide their name, date of birth, address, and phone number which will not 
be used in analyses or presentation of the results. The exact dates of CNRU admission and discharge (CUD 
subjects only) and exact dates of experiments and procedures will not be used in presentations; however, 
these dates may be de-identified data (i.e., using coded, subject-specific random identifiers) and used to 
calculate the time between procedures for use in analyses. All data from medical/psychiatric interviews, urine 
drug screen results, blood-draws, self-assessments, PET and MRI scans will be collected in the form of de-
identified data (i.e., using coded, subject-specific random identifiers) and will be used in analyses and 
presentations.
2.
How will the research data be collected, recorded and stored?
Research data will be collected over the phone, by paper-pencil and/or electronic self-questionnaires, 
computerized testing, by interviews, by use of the self-administration paradigm, physical examination, and 
laboratory work. This information will be recorded/transferred in each subject’s Case Report Form and on 
password protected University computer servers that are kept in locked offices. However, coded data lacking 
personal identifiers (name, social security #, address, phone, medical record number, etc.) will be kept on 
other research desktop and/or laptop computers. Imaging data is collected during the PET/fMRI scans by 
trained technologists and is stored on password-protected and encrypted computers with identifying 
information carefully in compliance with HIPAA regulations.
3.
How will the digital data be stored? 
☐CD 
 ☒DVD 
☒Flash Drive
☒Portable Hard Drive ☒Secured Server
☒Laptop Computer
☒Desktop Computer 
☐Other
4.
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?
All staff members that come into contact with the data are fully trained to the current HIPAA regulations 
and are informed as to the proper use of all data. The only ones who have access to this information are the 
medical personnel and the research staff at the CNRU or at the YNHH HRU. CUD subjects participating in 
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research at the CHMC and YHNN HRU will have medical records created for them, if they do not already have 
such records. The researchers and staff at the CMHC and YHNN/HRU will have access to records of any prior 
admissions, including the details of those admissions, and some information regarding their participation in 
this study will be included in those records (e.g., dates of admission/discharge, dates of procedures). All 
information obtained in this study will be stored in locked cabinets or password protected and encrypted 
computers and hard drives. 
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. Direct identifiers belonging to subjects who withdraw from the study will be stripped 
from 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. 
PET, MRI and assessment data are identified by subject code number rather than name. Users always 
access research data through the random identifier only. Screening information will remain identified by 
name. Procedures to protect this PHI have been described above (see Section I, item 11, Section IV, items 2 
and 4). After termination of this 5-year study all identifying information will be discarded, but other research 
data is kept indefinitely. Paper and electronic data will be destroyed by research assistants and study 
personnel at Yale University following current procedures from the HIC regarding the de-identification, 
storage, and destruction of records. Private identifiable information will not appear in any publication or be 
released to anyone without the individual’s written consent.
5.
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. 
In accordance with institutional standards and guidelines, after termination of this study and completion 
of all analysis and publications, all data and screening information will be anonymized and kept in a secure 
fashion for the purpose of further analyses indefinitely unless prevailing University or Federal guidelines at the 
time require a change.
6.
If appropriate, has a Certificate of Confidentiality been obtained? 
We have obtained a Certificate of Confidentiality.
SECTION V: 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.) 
Subjects will receive a thorough medical and psychiatric evaluation at no cost to themselves, as well as 
benefit from the knowledge that their participation in such studies may help individuals with cocaine use 
disorders in the future. It is possible that CUD subjects will experience less cocaine use during the experimental 
phase of the study. However, it is made clear to subjects that this potential reduction in drug use is not a desired 
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outcome for this study. Otherwise, there are no direct benefits to individuals participating in this research. 
Expanding the current understanding on physiological and biological effects of cocaine use could benefit society 
in as much as better methods of treatment could be designed.
         SECTION VI: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.
Alternatives: What other alternatives are available to the study subjects outside of the research? 
As this is not a treatment study, the only alternative is to not participate.
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.
Subjects will be compensated for their time commitment and inconveniences for completing the study at 
standard rates offered by researchers in the Yale community:
Procedure
Group 1
Amount
Screening interviews/exams (i.e., to determine eligibility)
B, C
$25
Baseline self-reports and cognitive tests
C
$20
Baseline self-reports, cognitive tests, and any repeat exams
B
$25
Additional self-reports,  cognitive testing, and exams (pilot addendum) 
B
$25
PET scanning
Arrival and setup (including IV and/or arterial line placement)
B
$50
Injection of radiotracer and/or scan completion 2
B
$350
MRI scanning
Arrival and setup
B, C
$15
Scan completion (part or whole) 2
B, C
$65
Task-performance earnings
B, C
up to $20
Inpatient stay
Duration of primary study procedures (up to 10 days)
B
$100
Extended duration for pilot addendum (up to 30 days)
B
$200
Travel reimbursement 3
B, C
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1 References corresponding Consent version: B) community-recruited CUD subjects; C) HC subjects.
2 In cases of technical failures or early termination (either voluntarily or at the discretion of study staff) once 
procedures have been initiated, subjects will receive full compensation for that procedure
3 Subjects may be required to provide proof of travel costs to receive reimbursement for travel expenses.
Thus, the total amount of subjects could receive for participating in all relevant study procedures (not 
including possible travel reimbursements) are:

Consent B. Community- and research- recruited CUD subjects: $650 + $725; up to $1375

Consent C. HC subjects: $245
* NOTE: Consent Forms A and D were related to prior protocol versions and will no longer be used.
Payments will typically be made via a pre-paid debit card in loadable increments after completing 
individual study procedures using ePayments via Oncore. The debit cards will be provided by the Bank of 
America and participants will be informed that their name, address, and telephone number will be shared 
with the bank to order their debit card. Cards may be mailed to subjects or provided in person. 
Reimbursements may also be made in the form of small cash payments (i.e., for the outpatient appointments) 
or checks.
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 have no financial responsibilities for any portion of the study.
4.
In Case of Injury: This section is required for any research involving more than minimal risk, and for minimal 
risk research that presents the potential for physical harm (e.g., research involving blood draws).
a.
Will medical treatment be available if research-related injury occurs? 
In the event that a participant develops any mental or physical problems as a direct result of being in 
this study, our staff will be available to help evaluate the problem
b.
Where and from whom may treatment be obtained? 
As noted above (see Section I, item 11) trained medical and research staff will be present or available 
to provide assistance during study procedures. Medical treatment, or assistance in obtaining medical care 
through information and referral, will be offered to the subjects for any physical injuries that they receive 
as a result of participating in this research.
c.
Are there any limits to the treatment being provided? 
For most of the study related sessions there will be trained research staff on hand who have been 
trained in recognizing medical emergencies and how to activate an emergency response. However, in 
case of injury, only evaluation and referral to trained medical staff will be provided. 
d.
Who will pay for this treatment? 
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The participant or his/her insurance carrier will be expected to pay the costs of this treatment. The 
study will not cover treatment expenses. No additional financial compensation for injury or lost wages is 
available; however the subject does not waive any of their legal rights.
e.
How will the medical treatment be accessed by subjects? 
The study will only refer subjects for appropriate treatment. It is the subject's responsibility to access 
treatment themselves. A follow-up will be completed to ensure the subject sought treatment and if not, 
why.
IMPORTANT REMINDERS
1.
Will this study have a billable service?
☐ YES 
☒ NO  
2.
Are there any procedures involved in this protocol that will be performed at YNHH or one of its affiliated 
entities?
 ☐ YES 
☒ NO  
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ICF_001.pdf: 
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IRB#2000021196
Page 1 of 17                                                                                                   Consent Form B: Mar 28 2022
                                                                                                                                             
COMPOUND AUTHORIZATION/CONSENT FOR PARTICIPATION
IN A RESEARCH PROJECT
YALE UNIVERSITY SCHOOL OF MEDICINE
YALE NEW HAVEN HOSPITAL
YALE UNIVERSITY SCHOOL OF MEDICINE
CONNECTICUT MENTAL HEALTH CENTER
YALE UNIVERSITY SCHOOL OF MEDICINE
YALE POSITRON EMISSON TOMOGRAPHY CENTER
YALE UNIVERSITY SCHOOL OF MEDICINE
YALE MAGNETIC RESONANCE RESEARCH CENTER
Study Title: Investigation of cocaine addiction using mGluR5 PET and fMRI
Principal Investigator:  Patrick D. Worhunsky, Ph.D.
Funding Source: National Institute on Drug Abuse (NIDA)
Consent for non-treatment seeking individuals with recent cocaine use
Invitation to Participate and Description of Project
You are invited to participate in a research study designed to look at the brain chemical 
glutamate and how it may be related to the way the brain processes information in people with 
cocaine use disorder. You have been asked to participate because you regularly use cocaine, are 
not currently seeking treatment for your cocaine use, you are in good physical and psychiatric 
health, and you are not having problems with other drugs. If you are eligible, you will be one of 
approximately 20 individuals with a cocaine use disorder participating in this study.
To decide if you wish to be a part of this research study you should know enough about its risks 
and benefits to make an informed decision. This consent form gives you detailed information 
about the study, which a member of the research team will discuss with you.  This discussion 
should go over all aspects of this research: its purpose, the procedures that will be performed, 
any risks of the procedures, and possible benefits. Once you understand the study, you will be 
asked if you wish to participate; if so, you will be asked to sign this form.
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Page 2 of 17                                                                                                   Consent Form B: Mar 28 2022
                                                                                                                                             
Description of Procedures
If you agree to participate in this research, you will be asked to undergo a series of procedures 
that will allow us to 1) measure chemicals in your brain that are related to glutamate and 2) 
examine your brain activity. You will be asked to undergo medical and psychiatric exams that 
include blood and urine testing and tests of your cognitive performance. You will also be asked 
to spend approximately one week at our inpatient research unit while participating in this study. 
You may also be invited to remain on the unit for approximately one month to repeat brain scans 
and cognitive testing.
This study takes place at several locations at Yale University. The Clinical Neuroscience 
Research Unit (CNRU) is located on the 3rd floor of the Connecticut Mental Health Center 
(CMHC) and is a 13-bed, full-service inpatient psychiatric research unit where visitors are 
restricted and access to drugs is prevented. The Hospital Research Unit (HRU) is located on the 
10th floor of the Yale New Haven Hospital (YNHH) and is equipped with medical, nursing, and 
laboratory services and suites for outpatient research studies. The Yale PET Center and Magnetic 
Resonance Research Center (MRRC) are located at the Yale School of Medicine and host state-
of-the-art molecular and magnetic imaging facilities.
Screening and Evaluation:
If you received this consent form, it is because you already completed initial screening by 
telephone, or because you are participating in a similar study being conducted by the research 
team and are likely eligible to participate in this study. Before being admitted to participate in the 
study, you may be asked take part in an additional screening phase that will include an in person 
visit at the CNRU in order to determine your eligibility.
The screening phase will take approximately 2 hours and will include medical and psychiatric 
history, specialized diagnostic interviews to help us better understand your cocaine use patterns, 
how you use cocaine (e.g., snorting, smoking, IV), and other drug use history, physical and 
neurological exams, a study of the electrical activity in your heart (i.e., electrocardiogram or 
ECG), routine laboratory studies of blood (less than 4 tablespoons) and urine, including a 
toxicology screening. Portions of the screening (i.e., psychiatric interview and related 
questioning) may be conducted remotely over the phone or using tele-health platforms (e.g. 
video chat). The medical exam will be conducted at the CNRU.  If you test positive for drug use 
other than cocaine, you may not be allowed to participate in the study. Women of childbearing 
age will also have a blood pregnancy test. If your pregnancy test result is positive, you may not 
participate in this study. The results of these tests will be discussed with you.
There will be no charge for these tests or interviews. If you qualify for the study and if you 
decide (i.e., consent) to participate, you will then be asked to participate further in the study. 
Lastly, we will ask you for a release of information so that study staff may contact your primary 
care doctor. If you do not have a primary care doctor, we will ask you for the name of a family 
member or close friend. The purpose of this release of information is to help confirm study 
eligibility and ensure it’s safe for you to participate. Under no circumstances will the specifics of 
your study participation be revealed to your primary care doctor or your family member (e.g., 
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Page 3 of 17                                                                                                   Consent Form B: Mar 28 2022
                                                                                                                                             
they will not be informed that you’re participating in a study for individuals who have a cocaine 
use disorder).
If you are participating in a similar study being conducted by the research team, you will already 
have completed this evaluation. By agreeing to participate in this study, you are authorizing the 
research team to share the data collected during that evaluation for use in this study as well.            
You may also be asked to repeat some of these procedures (e.g., urine drug screening). 
Admission to the Clinical Neuroscience Research Unit (CNRU):
If you are eligible and would like to participate, you will be admitted to the CNRU. During Day 
1 of your admission, you will meet with the medical and nursing staff who will complete 
additional interviews and a physical exam. If your screening visit was conducted more than 7 
days prior to admission, staff will repeat your laboratory work (i.e. blood and urine tests). A few 
days (usually 2-4 days) after your admission, you will complete a PET scan and MRI scan 
(described below). You will return to the CNRU following each procedure.
You will be discharged from the CNRU upon completion of study procedures (unless your 
participation in another study has not been completed). If you agree to complete the initial set of 
study procedures, your stay at the CNRU may be up to 10 days (typically 5-8). If you are invited 
and agree to repeat the study procedures approximately 1-4 weeks later, you will stay at the 
CNRU until those procedures are completed (typically an additional 10-20 days).
Interviews, Questionnaires, and Cognitive Testing:
We will ask you questions about several topics including your cocaine use, how strong your 
desire for it is, your general functioning, history of medical problems, history of psychiatric 
problems, history of other drug use, and social aspects of your life such as years of education 
completed, whether you have legal problems or not, presence of supportive persons in your life, 
etc. Most of the questionnaires on cocaine use, medical problems, psychiatric/drug use, and 
social aspects of your life will be completed during the screening visit and could be repeated 
during the admission. Also at admission, we will also ask you to complete a brief series of 
questionnaires about your behavior, thoughts, and tendencies in general and as related to your 
drug use. You will also be asked to complete a brief series of cognitive tasks (e.g., to assess your 
memory and reasoning abilities) on a computer. We expect it may take about two hours to 
complete these questionnaires and computer tasks.
Positron Emission Tomography (PET) scan:
You will be asked to participate in a PET scanning session that will be conducted at the Yale 
PET Center in New Haven. PET scanning involves the use of a ‘radiotracer’, which is a small 
amount of a drug that is labeled with a very small amount of a radioactive substance. The 
radiotracer drug binds to the receptors in the brain and the radioactivity can be detected by a 
special camera in the PET scanner. In this study, you will receive the radiotracer [fluorine-18]F-
PEB, a drug which is limited by Federal Law for research use only. This radiotracer binds to a 
receptor called the metabotropic glutamate receptor type-5 (mGluR5), and we will use the 
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Page 4 of 17                                                                                                   Consent Form B: Mar 28 2022
                                                                                                                                             
information from the PET scan to measure the location and concentration of these receptors in 
your brain.
You may be asked to fast prior to the PET scan. On the day of your PET scan, a trained nurse or 
Certified Nuclear Medicine Technologist will place one or two plastic catheters (tubes) in your 
arms (one for the radiotracer injection and one to take venous blood samples, if necessary). 
An experienced health care provider may insert an arterial catheter in your wrist area. The arterial 
catheter is about 2 inches long and looks like a regular IV tube, but it is inserted into an artery, not a 
vein. The blood flow in the arteries can tell us about your blood pressure. If an arterial catheter is in 
place, we can measure your blood pressure continuously. Thanks to an arterial catheter, we can draw 
blood quickly, more than once, and without causing you pain.  Here is what happens when an arterial 
line is placed: 
 • We will clean the skin with betadine solution (contains iodine). It will reduce the risk of an 
infection.  
• We will numb your skin with a local anesthetic so that you feel less pain when the catheter is 
inserted. You will probably just feel pressure but may also feel pain. It would be similar to the pain 
you feel with an IV. 
• We will flush the catheter often during your scan with saline (a salt solution) to make sure it does 
not clog.   
• After we remove the catheter, we will apply pressure to your skin for a minimum of 15 minutes to 
prevent bleeding under the skin.  
• We will apply a pressure dressing (coban) and clear dressing (tegaderm). You will need to keep it 
clean and dry. Do not exercise too much and do not lift heavy objects weighing more than 5 
pounds. Avoid making the same movements for 48 hours.  
• You may remove the pressure dressing at bedtime and the clear dressing after 48 hours, but do not 
put your hand and wrist in water for a full 72 hours. Since the catheter is in for a minimal period, 
there is a low risk of infection.
During the PET scanning session, the radiotracer will be injected into the tube in your vein. You may 
not feel anything as a result the drug; however, you may briefly experience nausea shortly after it 
is administered. You will then be asked to lie very still on a table for up to 2 hours while the scanner 
camera collects information. 
After the PET scan, you will be asked to drink several glasses of water to help wash out the 
radiotracer, and a light meal may also be provided. You may be asked to return to the CNRU 
following the PET scan if you have not completed all other study procedures. You will also be 
provided with a telephone number you can call any time after the study if you need assistance for 
problems related to the study procedures.
Occasionally there may be problems making the radiotracer, such that there is not enough to 
perform the PET scan. If this happens, a member of the research team will discuss with you the 
options for participating in the study again within a few days or weeks.
Magnetic Resonance Imaging (MRI) scan:
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Page 5 of 17                                                                                                   Consent Form B: Mar 28 2022
                                                                                                                                             
You will be asked to participate in a MRI scanning session that will be conducted at the Yale 
Magnetic Resonance Research Center in New Haven. MRI scans are painless, do not involve the 
use of radiation, and are used routinely to diagnose neurological problems. You must inform the 
research staff if you have any metal (for example, shrapnel or surgical prostheses) in your body 
because having an MRI could be harmful. Some people feel mildly anxious in the scanner, and if 
it is too difficult for you to be in it, you may withdraw at any time. The scans will take place in 
New Haven, at the Yale MRI Research Center. The scan will be conducted by an MRI 
technologist, and a member of the research team will accompany you and stay for the MRI 
session.
During the MRI session, you will lie on your back on a comfortable mattress, which is then slid 
into a large tube until your head and the upper part of your body are inside the tube. Your head 
will be held still in a cushioned head rest, and you will wear earplugs to reduce the level of noise. 
You will also be wearing headphones to help communicate with the research staff and possibly 
additional devices to measure things such as your breathing and heart rate.
The MRI session may last up to 2 hours, during which you will be asked to lie very still. We will 
tell you when we begin taking pictures of your brain and you will notice a series of knocking 
noises made by the machine when the pictures start. Each series of pictures may last up to 10 
minutes, and we may ask you some questions about how you are feeling in between series. 
We will take some pictures while you are simply resting with your eyes open, and some pictures 
while you are performing a simple computer task. The computer task will be used to examine 
your brain activity while you push a button in response to letters or shapes displayed on a 
projection screen that you will be able to see in the MRI scanner using mirrors. For example, the 
letters ‘X’ and ‘K’ will be quickly presented one at a time, and you will be asked to push a 
button only when you see an X; and try not to push the button when you see a K. At times during 
the task, you may earn money depending on how well you perform the task (i.e., pushing and/or 
not pushing the button at the right times). We will give you the opportunity to practice this task 
outside the scanner before the MRI session. Following the MRI scan you may be asked to return 
to the CNRU if you have not completed all other study procedures.
Study timeline and duration
This study will take place over approximately one week. Following admission to the CNRU, you 
will complete the interviews, questionnaires, and cognitive testing at the CNRU and/or at the 
PET/MRI centers. A few days later you will complete the PET and MRI scans. When possible, 
we will schedule your PET and MRI scans on the same day, but they may also take place on 
separate days. In these instances, the scans will not be more than a few days apart. When you are 
not participating in the PET and MRI scans you will be asked to remain at the CNRU. Once you 
complete all the procedures for this study, you will be discharged from the CNRU.
Optional extended study:
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You may be invited to participate in an optional extension of this study that would occur after 
you have successfully completed the procedures of the main study described above. The study 
involves remaining on the CNRU for an additional month (typically 10-20 days) before 
completing a second set of PET and MRI scans and cognitive tests. Your participation in the 
study extension is optional and you may participate in the main study without participating in the 
longer study. 
Risks and Inconveniences
There are some risks associated with the procedures you will be asked to complete during this 
research study. It is important you fully understand these risks before you decide to take part in 
this study. A member of the research staff will discuss these risks with you, including the 
measures we will take to reduce these risks. You are encouraged to ask them any questions you 
may have regarding the procedures and their risks to help you decide whether to take part in this 
study. Please note that even if you do decide to participate, you may change your mind at any 
time during the study.
Risks Associated with Interviews, Questionnaires, and Cognitive Testing:
There are no significant risks known to be associated with the completion of the interviews, 
questionnaires, and cognitive testing. However, you may become tired and may feel 
uncomfortable/ashamed disclosing some of this information. The staff who will conduct the 
interviews have received training in empathetic/non-judgmental techniques, and you will be 
allowed to take a break for as long as is necessary before proceeding if you become tired or 
uncomfortable. 
Since some of the data collected (e.g., history of drug use behavior) is private in nature and may 
have legal implications, risks related to loss of confidentiality also exist. The staff responsible for 
the data collection will explain to you how we handle confidential information. Any identifiable 
information that is obtained during this study will remain confidential and will be disclosed only 
with your permission or in specific cases. Examples of information that we would involuntarily 
disclose include abuse of a child or elderly person, or certain reportable diseases. All the 
information obtained in this study is stored in locked cabinets or on password protected 
computers. Only the medical personnel and the research staff involved in this study will have 
access to this information. When the results of the research are published or discussed in 
conferences, no information will be included that would reveal your identity.
Risks Associated with Blood Draws and Intravenous Lines:
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. Blood draws are done by expert personnel who will follow 
aseptic/antiseptic standards and who will stop the procedure after two failed attempts.
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Blood draws have also been associated with feeling lightheaded or fainting in some people. You 
will be excluded from this study if you have a history of fainting during blood draws. Including 
screening, any possible admission laboratories and the PET scan, the total volume of blood 
collected during this study will be up to 16 tablespoons, which is half of the amount taken in a 
standard 1-pint blood donation. You should not donate blood for at least 8 weeks after the study. 
Risks Associated with Arterial Lines:
Important: You cannot take part in the study if you have ever had a bleeding disorder or 
are taking medication to thin your blood.  
 
The insertion of the arterial line may be painful and you can get bruises. The arterial puncture 
may cause a spasm, a temporary tightening (constriction) of the muscles in the wall of the artery. 
You may get a clot and your blood flow will slow down for a little while. You can get a 
hematoma (swelling of blood within the tissues). The site can bleed or get inflamed (become red, 
swollen, hot, and painful). These feelings will go away after some time, usually 24 to 72 hours 
after the procedure. Rarely, you may experience blocking of the artery or nerve damage to the 
insertion site. The insertion site may not heal as fast or you may get infection. This is why an 
experienced health care provider will insert the arterial line and a trained nurse will look after for 
you. 
 
Check your wrist and arm every day for two days after the study visit with the arterial line. Call 
right away your study team or the PET Center Physicians, Dr. David Matuskey at 203-370-1403 
(voice mail pager) or Dr. Ming-Kai Chen 203-675-0120 (cell), if you notice any of the 
following:
 
• You feel a lot of pain  
• Your wrist or arm is tender, swollen, or red 
• You see some blood or other fluids coming out of the injection site
• The color of your skin changes 
• Your arms feel numb
• You feel pins and needles in your arm 
• Your arm that had the catheter does not feel as strong
 
Tell us if you have had a bad reaction to lidocaine, novocain, or other drugs used to numb the 
skin in the past. You may experience a rare allergic reaction to the medicine used to numb your 
skin prior to placement of the arterial catheter. Severe allergic reactions can be life threatening. 
Some things that happen during an allergic reaction are:  
•  rash  
•  hives  
•  having a hard time breathing  
•  wheezing when you breathe  
•  sudden drop in blood pressure 
•  swelling around the face, mouth, lips, tongue, throat, or eyes  
•  fast pulse  
•  sweating 
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If you have any of the above allergy related side effects or symptoms, your study doctor will 
assess you and treat these symptoms. 
  
Do not take aspirin and other anti-inflammatory drugs (such as Motrin or Aleve) for 7-10 days 
before arterial line placement and 7-10 days after the study visit.
Risks associated with cocaine withdrawal:
Upon admission to the CNRU, it is possible you may experience withdrawal. Unlike some 
substances of abuse (e.g. alcohol, benzodiazepines), cocaine withdrawal does not typically cause 
physiological changes that are life threatening. Cocaine-withdrawal symptoms may include 
depressed mood, lack of motivation, fatigue, sleep changes, increased appetite, and suicidal 
ideation.  The medical and nursing staff on the inpatient unit is trained to assess for withdrawal 
symptoms and will be available 24 hours a day should you experience any symptoms of 
withdrawal. Depending on the severity of any potential symptoms, you will have the opportunity 
of receiving any appropriate treatment. If you are still experiencing withdrawal-related distress at 
the time of study completion, you will have the option of remaining on the inpatient unit to 
receive appropriate monitoring and treatment.
Although we are unaware of research situations where this has happened, if your emotional 
reaction to cocaine withdrawal puts your or other individuals' lives at risk, a physician would be 
obligated by law to keep you in the hospital until yours and others' safety could be assured. 
Even if you are not currently interested in drug treatment, if you decide during the study to 
request treatment for your drug use, we are prepared and ready to refer you for treatment the 
moment you request it. The staff will give you information about drug treatment opportunities if 
you wish to take advantage of these in the future.
Risk Associated with Radiation
This research study involves exposure to radiation. The radiation you will receive in this study 
is from an injection of the radiotracer [fluorine-18]FPEB and transmission scans that will be 
used during PET imaging. This radiation exposure is not necessary for your medical care and 
is for research purposes only. Although each organ will receive a different dose, the amount of 
radiation exposure you will receive from one scan in this study is equal to a uniform whole-
body exposure of 0.57 rem. If you agree to participate in the extended study or are asked to 
complete a second PET scan for technical problems, the total amount of exposure would be 
1.14 rem for the two scans. In the unexpected case where you may be asked to undergo third 
PET scan, you would be exposed to an additional dose of radiation, totaling 1.71 rem for three 
injections. This calculated value is known as the “effective dose” and is used to relate the dose 
received by each organ to a single value. This amount of radiation is well below the dose 
guidelines established by the federal government (i.e., not more than 5 rem per year) and 
adhered to by the Yale-New Haven Hospital Radiation Safety Committee for research 
subjects. To give you an idea about how much radiation you will get, we will make a 
comparison with an every-day situation. Everyone receives a small amount of unavoidable 
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radiation each year. Some of this radiation comes from space and some from naturally-
occurring radioactive forms of water and minerals. Each PET scan as part of this research 
gives your body the equivalent of about 2 extra years' worth of this natural radiation. That 
means two scans will be equivalent to 4 years, and three scans would be equivalent to 6 years’ 
worth of this natural radiation. 
Risks Associated with Magnetic Resonance Imaging (MRI): 
Magnetic resonance (MR) is a technique that uses magnetism and radio waves, not x-rays, to 
take pictures and measure chemicals of different parts of the body.  The United States Food and 
Drug Administration (FDA) has set guidelines for magnet strength and exposure to radio waves, 
and we carefully observe those guidelines.  
You will be watched closely throughout the MR study.  Some people may feel uncomfortable or 
anxious.  If this happens to you, you may ask to stop the study at any time and we will take you 
out of the MR 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 please tell the research staff if you have them.  
There are some risks with an MR study for certain people.  If you have a pacemaker or some 
metal objects inside your body, you may not be in this study because the strong magnets in the 
MR scanner might harm you.  Another risk is the possibility of metal objects being pulled into 
the magnet and hitting you.  To lower 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 
you 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 you to read and answer very carefully the questions on the MR Safety Questionnaire 
related to your personal safety.  Take a moment now to be sure that you have read the MR Safety 
Questionnaire and be sure to tell us any information you think might be important.  
This MR study is for research purposes only and is not in any way a healthcare examination of 
the brain.  The scans performed in this study are not designed to find abnormalities.  The 
principal investigator, the lab, the MR technologist, and the Magnetic Resonance Research 
Center are not qualified to interpret the MR scans and are not responsible for providing a 
healthcare evaluation of the images.  If a worrisome finding is seen on your scan, a radiologist or 
another physician will be asked to review the relevant images.  Based on his or her 
recommendation (if any), the principal investigator or consulting physician will contact you, 
inform you of the finding, and recommend that you seek medical advice as a precautionary 
measure.  The decision for additional examination or treatment would lie only with you 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 you 
receive based on these findings.  The images collected in this study are not a healthcare MR 
exam and for that reason, they will not be made available for healthcare purposes.  
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If, during the screening for MRI, it is determined you may have metal in your body, we may 
require an X-ray to rule this out. If so, the risk of undergoing an X-ray are minimal as the 
radiation exposure is low and is no different than an X-ray you would receive from your dentist 
or doctor.
There are no additional risks associated with completing more than one MRI scan should you be 
asked to complete additional scans because of technical problems or if you agree to participate in 
the extended study.
There may be additional risks related to this study that are not yet known. You will be told of any 
new findings that may affect your decision to participate in the research.
Benefits
This research is not intended to benefit you directly. However, you will receive a thorough 
medical and psychiatric evaluation at no cost to you. The results obtained from this study will 
contribute to the knowledge of the medical and scientific community. This study may help 
inform future research toward better treatments to help people with addictive disorders.
Economic Considerations
You will not be responsible for payment of any study related procedures. You will be 
compensated for your participation for each procedure as follows: 
Procedure
Amount
Screening interviews/exams (i.e., to determine eligibility)
$25
Baseline questionnaires, cognitive testing, and exams
$25
PET scanning
Arrival and setup (including IV and/or arterial line placement)
$50
Administration of radiotracer and PET scan*
$350
MRI scanning
Arrival and setup
$15
MRI scan*
$65
Task-performance earnings
up to $20
Inpatient stay (up to 10 days)
$100
Extended-study questionnaires, cognitive testing, and exams
$25
Extended-study inpatient stay (up to one additional month)
$200
* In rare cases of technical problems or early termination (either voluntarily or at the discretion of study staff) 
once procedures have been initiated, you will receive full compensation for that procedure.
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Thus, the total possible compensation for participating in the initial study is $650. If you are 
invited and complete the extended study, repeating questionnaires, cognitive testing, PET and 
MRI scans, and remain on the unit for up to an additional month, you would be compensated an 
additional $725 (for a total of $1375). You may also be reimbursed for travel expenses (please 
provide receipts for trains, buses, taxis, parking, etc.). You are free to stop the study at any time; 
however, if you choose to withdraw, you will be paid only for the parts of the study that you 
completed. 
Payments will typically be made via a pre-paid debit card in loadable increments after 
completing individual study procedures. These pre-paid debit cards are provided by the Bank of 
America, and we will need to share with them with your name, address, and telephone number to 
order your debit card. The card may be mailed to you or provided in person. Reimbursements 
may also be made in the form of small cash payments (i.e., for the outpatient appointments) or 
checks.
According to the rules of the Internal Revenue Service (IRS), payments that are made to you as a 
result of your participation in a study may be considered taxable income. You are responsible for 
paying state, federal, or other taxes for the payments you receive for being in this study. Taxes 
are not withheld from your payments.
Alternatives
The purpose of this study is not diagnosing, preventing, or providing a treatment for cocaine use 
disorders. You have the alternative to decline participation in the study. Declining to participate 
has no effect on any relationship that you may have with your healthcare providers, the 
Connecticut Mental Health Center or the Yale New Haven Hospital. You should not feel 
pressured to participate in this. If you want formal treatment for cocaine dependence, please let 
us know and we may be able to help with the referral.
Confidentiality and Privacy
If you decide to take part in this research study, you will be required to give us information about 
your substance use. We have obtained a Certificate of Confidentiality (CoC) issued by the 
National Institutes of Health (NIH). The researchers can use this Certificate to legally refuse to 
disclose information that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings, for example, if there is a court subpoena. The 
researchers will use the Certificate to resist any demands for information that would identify you, 
except as explained below.
The protection offered by the CoC does not stop us from voluntarily reporting information about 
suspected or known sexual, physical, or other abuse of a child or older person, or a participant’s 
threats of violence to self or others. If any member of the research team is given such 
information, he or she will make a report to the appropriate authorities. When the CoC is 
obtained, we will inform all active study participants.
Because this research is sponsored by the Department of Health and Human Services through the 
National Institute on Drug Abuse (NIDA), staff from that and other DHHS agencies may review 
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records that identify you only for audit or program evaluation. They cannot report anything that 
would harm you or other research subjects.
Even when a CoC is in place, you and your family members must still continue to actively protect 
your own privacy. If you voluntarily give your written consent for anyone to receive information 
about your participation in the research, then we may not use the CoC to withhold this information.
Any identifiable information that is obtained in connection with this study will remain 
confidential and will be disclosed only with your permission or as permitted by U.S. or State 
law. Any identifying information will be stored in a locked cabinet. All research data will be 
coded with a participant number in place of any identifying information, and stored separately in 
locked cabinets or on password protected computers. When the results of the research are 
published or discussed in conferences, no information will be included that would reveal your 
identity unless your specific consent for this activity is obtained.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
If you decide to be in this study, you will be visiting the Connecticut Mental Health Center 
(CMHC) as part of your study procedures. Some information about your participation in this 
research study will become part of your CMHC medical record that identifies you.  If you do not 
already have a medical record at CMHC, one will be made for your visit.  The information that 
will be entered into your medical record may include the following: name, date of birth, date of 
admission to the CNRU, date of experiments at the YNHH HRU, date of discharge from the 
CNRU, phone number, address, medical history, individual and family history of psychiatric 
problems, and substance abuse history. One of the instruments used to assess substance abuse 
history will include questions related to legal problems. 
As a participant in a clinical research study involving the Yale-New Haven Hospital (YNHH) 
Research Unit (HRU), it is important for you to know that if you do not already have a medical 
record at YNHH, one will be made for your admission.  In addition, you need to know that if you 
have ever been a patient at YNHH at any time, your previous medical records of other visits or 
admissions will become available to the researchers and to the staff of the HRU when 
information regarding your participation in this study is added into the medical record.
These medical records, while not protected by the Certificate of Confidentiality issued by the 
NIH, are covered under federal HIPAA laws described further below.
We understand that information about you obtained in connection with your health is personal, 
and we are committed to protecting the privacy of that information.  If you decide to be in this 
study, the researcher will get information that identifies you and your personal health 
information.  This may include information that might directly identify you, such as your name, 
birthday and address.  This information will be de-identified at the earliest reasonable time after 
we receive it, meaning we will replace your identifying information with a code that does not 
directly identify you. The principal investigator (PI) will keep a link that identifies you to your 
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coded information, and this link will be kept secure and available only to the PI or selected 
members of the research team. Any information that can identify you will remain confidential.   
All your information will be kept on a study record in a locked filing cabinet, in a locked office. 
Any electronic data is stored on a secure server or in password protected computer files. The 
research team will only give this coded information to others to carry out this research study. The 
link to your personal information will be kept for up to five years, after which time the link will 
be destroyed and the data will become anonymous. The data will be kept in this anonymous form 
indefinitely.  
The information about your health that will be collected in this study includes:
Research study records 
Medical and laboratory records of only those services provided in connection with this study
The entire research record and any medical records held by Connecticut Mental Health Center 
and the Yale New Haven Hospital created from the date signed below to completion of all 
research procedures included in this form. 
The following information: 
Records about phone calls made as part of this research 
Records about your study visits 
Information obtained during this research regarding: 
Hepatitis infection 
Other reportable infectious diseases 
Physical exams 
Laboratory, x-ray, and other test results 
Diaries and questionnaires 
The diagnosis and treatment of a mental health condition 
Use of illegal drugs or the study of illegal behavior 
Records about any study drug you received
Information about you and your health which might identify you may be used by or given to:
The U.S. Department of Health and Human Services (DHHS) agencies 
Representatives from Yale University, the Human Investigation Committee (the committee that 
reviews, approves, and monitors research on human subjects), who are responsible for ensuring 
research compliance. These individuals are required to keep all information confidential. 
Those individuals at Yale who are responsible for the financial oversight of research including 
billings and payments 
The Principal Investigator, Patrick D. Worhunsky Ph.D.
The U.S. Food and Drug Administration (FDA). This is done so that the FDA can review 
information about the drug product involved in this research. The information may also be used 
to meet the reporting requirements of drug regulatory agencies. 
The study sponsor 
Governmental agencies to whom certain diseases (reportable diseases) must be reported 
Health care providers who provide services to you in connection with this study. 
Laboratories and other individuals and organizations that analyze your health information in 
connection with this study, according to the study plan. 
Co-Investigators and other investigators 
Study Coordinator and Members of the Research Team 
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Data and Safety Monitoring Boards and others authorized to monitor the conduct of the study 
The data we collect from you may be shared across other protocols the Principal Investigator 
is running. Similarly, if you are participating in another study being conducted by the research 
team, any data collected may be shared between studies. The data will be coded so your 
personal information cannot be determined.
By signing this form, you authorize the use and/or disclosure of the information described 
above for this research study.  The purpose for the uses and disclosures you are authorizing is 
to ensure that the information relating to this research is available to all parties who may need 
it for research purposes.
All health care providers subject to HIPAA (Health Insurance Portability and Accountability 
Act) are required to protect the privacy of your information.  The research staff at the Yale 
School of Medicine, Yale-New Haven Hospital, and the Connecticut Mental Health Center are 
required to comply with HIPAA and to ensure the confidentiality of your information. Some 
of the individuals or agencies listed above may not be subject to HIPAA and therefore may not 
be required to provide the same type of confidentiality protection. They could use or disclose 
your information in ways not mentioned in this form.  However, to better protect your health 
information, agreements are in place with these individuals and/or companies that require that 
they keep your information confidential. 
You have the right to review and copy your health information in your medical record in 
accordance with institutional medical records policies.
This authorization to use and disclose your health information collected during your participation 
in this study will never expire.
In Case of Injury
If you are injured as a result of your participation in this study, seek treatment and contact the 
study doctor as soon as you are able.  
Yale School of Medicine, Yale-New Haven Hospital, and the Connecticut Mental Health Center 
do not provide funds for the treatment of research-related injury.  If you are injured as a result of 
your participation in this study, treatment will be provided. You or your insurance carrier will be 
expected to pay the costs of this treatment. No additional financial compensation for injury or 
lost wages is available.
You do not give up any of your legal rights by signing this form.
Voluntary Participation and Withdrawal
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Participating in this study is voluntary. You are free to choose not to take part in this study.   
Refusing to participate will involve no penalty or loss of benefits to which you are otherwise 
entitled (such as your health care outside the study, the payment for your health care, and your 
health care benefits).  However, you will not be able to enroll in this research study and will not 
receive study procedures as a study participant if you do not allow use of your information as 
part of this study.
Withdrawing From the Study
If you do become a subject, you are free to stop and withdraw from this study at any time during 
its course. 
To withdraw from the study, you can call a member of the research team at any time and tell 
them that you no longer want to take part. This will cancel any future appointments.
 
The researchers may withdraw you from participating in the research if necessary. Reasons why 
you could be withdrawn from the study include non-compliance with study procedures or if the 
medical/nursing or research staff determine it would be in your best interest to cease study 
procedures.
Withdrawing from the study will involve no penalty or loss of benefits to which you are 
otherwise entitled. It will not harm your relationship with your own doctors, Yale-New Haven 
Hospital, the Connecticut Mental Health Center.
Withdrawing Your Authorization to Use and Disclose Your Health Information
You may withdraw or take away your permission to use and disclose your health information at 
any time. You may withdraw your permission by telling the study staff or by writing to the 
principal investigator: Patrick D. Worhunsky Ph.D.; Yale University Department of Psychiatry; 1 
Church Street, Room 730, New Haven, CT, 06510.
If you withdraw your permission, you will not be able to stay in this study.
When you withdraw your permission, no new health information identifying you will be 
gathered after that date. Information that has already been gathered may still be used and given to 
others until the end of the research study, as necessary to ensure the integrity of the study and/or 
study oversight.  
Questions
We have used some technical terms in this form. Please feel free to ask about anything you don't 
understand, and please consider this research and the consent form carefully – for as long as you 
feel is necessary – before you make a decision.
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Authorization and Permission
I have read (or someone has read to me) this form and have decided to participate in the project 
described above.  Its general purposes, the particulars of my involvement and possible hazards 
and inconveniences have been explained to my satisfaction.  My signature also indicates that I 
have received a copy of this consent form.
Please initial below if applicable:
__________
I agree to participate in the extended study that involves remaining on the 
research unit for up an additional month to repeat study procedures. 
__________
I am participating in other research being conducted by the study team and 
authorize the release of data collected during that research for use in this study.
By signing this form, I give permission to the researchers to use and give out information about 
me for the purposes described in this form. By refusing to give permission, I understand that I 
will not be able to be in this research. 
__________________________________________
Name of Subject
            
___________________________________________
___________________
Signature
Date
___________________________________________
___________________
Signature of Principal Investigator
Date
                                      or
___________________________________________
___________________
Signature of Person Obtaining Consent
Date
If after you have signed this form you have any questions about your privacy rights, please 
contact the Yale Privacy Officer at (203) 432-5919.
If you have further questions about this project or if you have a research-related problem, you 
may contact the Principal Investigator, Dr. Patrick D. Worhunsky at (203) 737-2668. If you 
would like to talk with someone other than the researchers to discuss problems, concerns, and 
questions you may have concerning this research, or to discuss your rights as a research subject, 
you may contact the Yale Human Investigation Committee at (203) 785-4688.
APPROVED BY THE YALE UNIVERSITY IRB 3/29/2022


APPROVED BY THE YALE UNIVERSITY IRB 3/29/2022
 
IRB#2000021196
Page 17 of 17                                                                                                   Consent Form B: Mar 28 2022
                                                                                                                                             
Research Authorization/Permission to Contact for Future Research
I give permission for Yale research staff to approach me or to contact me in the future regarding 
other research studies I may be eligible for.  (Please initial below your preference).
 Yes
 No
I understand that by agreeing to or declining this option in no way affects my eligibility for the 
present study.
__________________________________________
Name of Subject
            
___________________________________________
___________________
Signature
Date
___________________________________________
___________________
Signature of PI or Person Obtaining Consent
Date
APPROVED BY THE YALE UNIVERSITY IRB 3/29/2022