Clinical trial NCT03612713
Conditions: Prescription Drug Abuse (Not Dependent)
Sponsor: Yale University
Start date: 2018-10-30; Completion date: 2022-06-02
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will assess the effects of acute low-dose opioid administration on functional neuroimaging measures in healthy individuals

Detailed description:
This study will assess the effects of acute low-dose opioid administration on functional neuroimaging measures in healthy individuals (N=40, 20 male, 20 female). The objective of this research is to develop an understanding of factors that may influence individual variability on resting state functional connectivity in response to low-dose opioid administration with the longer term aim of understanding addictions vulnerability. Specifically, the proposed pilot research will explore the effects of single dose of oxycodone (15mg) on resting state functional connectivity and other common neuroimaging measures (e.g., diffusion MRI, structural MRI).

Arms: arm 1: one hour before fMRI scan participants will be given a single dose 15mg immediate release oxycodone arm 2: one hour before fMRI scan participants will be given a single dose placebo.
Interventions: intervention 1: Oxycodone Medication First intervention 2: Placebo First
Intervention descriptions: intervention 1: Participants will be given 15mg oxycodone one hour before fMRI scan. After at least 1 week wash out participants will be given placebo one hour before fMRI scan. intervention 2: Participants will be given placebo one hour before fMRI scan. After at least 1 week wash out participants will be given 15mg oxycodone one hour before fMRI scan.

Protocol documents:
Prot_SAP_000.pdf: 
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HRP-503B – BIOMEDICAL RESEARCH PROTOCOL 
(2016-1)
Protocol Title: Influence of medication on functional connectivity
Principal Investigator: Sarah W. Yip, MSc, PhD
Version Date: 03/04/2022
SECTION I: RESEARCH PLAN
1.
Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
This study will assess the effects of acute low-dose opioid administration on functional 
neuroimaging measures in healthy individuals (N=40, 20 male, 20 female).  The objective of this 
research is to develop an understanding of factors that may influence individual variability on resting 
state functional connectivity in response to low-dose opioid administration with the longer term aim 
of understanding addictions vulnerability.  Specifically, the proposed pilot research will explore the 
effects of single dose of oxycodone (15mg)  on resting state functional connectivity and other 
common neuroimaging measures (e.g., diffusion MRI, structural MRI).  Previous work has found 
10-20mg doses well-tolerated, but has found increased ratings of nausea following 20mg doses 
(Gorka, Fitzgerald et al. 2014, Wardle, Fitzgerald et al. 2014). Preliminary data (Gorka, Fitzgerald et 
al. 2014) suggest that 10mg and 20mg doses have similar effects on FC.  However, a 10mg dose of 
oxycodone may not be clinically sufficient for CYP3A4 fast metabolizers (Samer, Daali et al. 2010, 
Brennan 2012). To balance concerns related to excluding potential participants based on this 
relatively common genetic variation (thus potentially limiting the applicability of study findings) 
with those of a higher dose of oxycodone (e.g., 20mg), we will use a 15mg dose and test for 
genotype effects on neural responses post-hoc. Other laboratory studies in healthy controls have 
found doses between 15mg and 20mg to be well tolerated (Zacny and Lichtor 2008, Samer, Daali et 
al. 2010, Cooper, Sullivan et al. 2012).
Given the high prevalence of prescription opioid exposure in youth (McCabe, West et al. 2012), it is 
not feasible to study exclusively opioid-naïve individuals. Prior neuroimaging work using 
oxycodone has not excluded for lifetime exposure, but has excluded for abuse or dependence 
(Gorka, Fitzgerald et al. 2014). To minimize the possible influence of individual differences in prior 
exposure, we will exclude for prior 6 month use, as well for significant prior medical (>5 days of 
consecutive medical use) or nonmedical use (>5 prior uses of oxycodone). 
Peak plasma concentrations of orally administered immediate release 10mg OXY occur 
approximately 1 hour following ingestion and has a half life of 3-4 hours(Ordonez Gallego, 
Gonzalez Baron et al. 2007, Gronlund, Saari et al. 2010, Saari, Gronlund et al. 2010).  We are 
therefore confident that a 6-month washout period will be more than sufficient to ensure clearance. 
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All participants will be seen for an initial intake by a research assistant either in person or virtually via 
Zoom and who will begin the review process of eligibility, obtain medical history, provider information 
and relevant releases. Physical examination findings and laboratory tests will inform eligibility 
decisions. Potential participants will undergo medical screening to determine eligibility to receive a 
single dose of oxycodone 15mg.  Medical screening for contraindication to low-dose opioid 
administration (e.g., medication allergies, kidney or liver problems, personal or familial history of 
opioid- or alcohol-use disorders) will be conducted by a licensed physician. Lab tests will be ordered at 
the discretion of the physician to determine eligibility for study participation. Final determination of 
eligibility will be determined by the study physician and investigators. Monitoring will occur during and 
after all procedures with participants remaining in our lab for one hour post scan (3.5-4 hours after 
opioid administration). In addition, a follow up phone call will be made one day and again one month 
after scan with additional medical care, if indicated, being facilitated.
2.
Probable Duration of Project: State the expected duration of the project, including all follow-up and data 
analysis activities.  
The proposed research is a pilot project and will be complete in May 2023 (including data analysis).
3.
Background: Describe the background information that led to the plan for this project. Provide references to 
support the expectation of obtaining useful scientific data.
Resting state functional connectivity, as assessed using functional magnetic resonance imaging 
(fMRI), is a widely used method of studying in vivo spontaneous neural activity across a range of 
populations, including (though not limited to) individuals with psychiatric disorders and healthy 
controls. Prescription of low-dose opioids for symptomatic pain relief is common and most 
individuals prescribed low-dose, short-term opioids do not develop problems with opioid use.  
However, non-medical opioid use remains a major public health problem (Substance Abuse and 
Mental Health Services Administration Center for Behavioral Health Statistics and Quality 2014, 
Volkow, Frieden et al. 2014, Palamar, Shearston et al. 2016).  Very little is known about the effects 
of acute low-dose opioid administration within the brain, particularly within the context of large-
scale intrinsic brain networks. To address this gap, this pilot study will explore the effects of acute 
low-dose opioid administration on resting state functional connectivity, using a placebo-controlled, 
double-blind within-subjects design in healthy individuals. 
Approach:  This study will assess the effects of acute low-dose opioid administration using a 
within-subjects design.  Eligible participants will be asked to participate in 2 separate 90 minute 
fMRI sessions (Scan 1 and Scan 2), one of which will involve taking oxycodone (15mg) and one of 
which will involve taking a placebo pill.  Neuroimaging parameters will be the same for all scans. 
Approximately one hour prior to scanning, participants will be given either a single dose of 
oxycodone 15mg or placebo. Participants will be randomized using urn randomization, as in our 
ongoing studies to receive either oxycodone or placebo during scan 1, and will be ‘crossed-over’ to 
the other condition (oxycodone or placebo, whichever was not administered at scan 1) for scan 2. 
Participants will only participate in sessions for which they are determined eligible and for which 
they have provided written informed consent (total N=40). The order of scans (oxy/placebo) will be 
counter-balanced across participants to control for order effects.  Participants will either be 
randomized to participant in Scan A first, or will be randomized to participate in Scan B first.  
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Participants and study personnel (research assistant and PI) will be blind to which medication 
participants receive. 
Hypothesis: 
Specific decreases in functional connectivity following acute low-dose opioid administration (Oxy 
Scan < Placebo B) within cortico-limbic tracts (e.g., insular-striatal; ventrolateral PFC-amygdala 
tracts).
4.
Research Plan: Summarize the study design and research procedures using non-technical language that can 
be readily understood by someone outside the discipline. Be sure to distinguish between standard of care vs. 
research procedures when applicable, and include any flowcharts of visits specifying their individual times and 
lengths. Describe the setting in which the research will take place.
Research strategy:
Participants and recruitment: Forty healthy adults will be recruited for participation in this pilot 
study. 
Measures: All participants will also be given the Shipley Institute of Living Scale to assess general 
intellectual function (Shipley 1967), in addition to other non-fMRI measures including measures of 
depression and affective symptoms (Beck Depression Inventory-II) (Beck, Steer et al. 1996), 
Difficulties in Emotion Regulation Scale (Gratz and Roemer 2004)) and self-reported impulsivity 
(Barratt Impulsiveness Scale(Patton 1995). 
Image acquisition: fMRI data will be acquired using 3.0T scanner and multiband echo-planar 
imaging (EPI) gradient-echo sequences.  Resting state fMRI, diffusion MRI and high-resolution 
structural data will also be acquired. Total scan time will not exceed 1.5 hours.
Testing for fast metabolizers: Differences in metabolizing of opioid medications can arise from 
variations in genes encoding for the liver enzymes CPY3A4 and CPY3A5 and this can lead to 
significant variation in subjective responses (Gudin 2012).  To allow for  statistical analysis 
exploring the effects of this variable, we will collect Buccal samples to be tested for CPY450 
3A4/3A5 genotype. The procedure for collecting Buccal swabs is to have the study physician (Dr. 
Camenga) obtain attestation and patient consent, followed by sample collection, at the time of 
medical screening.  The sample will be used to test for CPY450 3A4/3A5 genotype.  The samples 
will be coded with a number directly related to that participant.  At no time will the participant’s 
identity be linked to that number.  The “key” will be kept in a locked file in the Research 
Coordinator’s office. 
Analyses: 
We will use ICD and CBF-adjusted ICD to address Specific Aims 1 & 2. As shown in Figure 5 
(below), the basic steps of ICD include, 5A, voxelwise correlation of timecourses (i.e., the 
timecourse of a given voxel is correlated with that of every other voxel in the brain; and, 5B, 
voxelwise summary of correlations with a network-theory metric (α). The network theory  metric  is 
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Figure 5 – Schematic diagram of intrinsic connectivity distribution (ICD) analysis steps (single-
subject).
Voxel →
←Voxel
Time →
e-/
A.
B.
calculated by converting the distribution of correlations for a given voxel (histogram in 5B) into a 
survival function fitted with a stretched exponential with variance α. Since α corresponds to the 
spread of the distribution of connections, high α values indicate high connectivity. Individual α 
values are computed for all grey-matter containing voxels in the brain to create parametric images of 
the α parameter, to be used for groupwise analyses. To account for physiological confounds 
associated with pharmacological FC, we will also conduct CBF-adjusted ICD. Formally, instead of 
constructing a histogram of correlations as in ICD, a weighted histogram of correlations is used for 
CBF-adjusted ICD. The weighting factor for the count of each correlation between two voxels is the 
inverse of the product of the two voxels’ CBF. After creating the weighted histogram, the same 
procedures for ICD are followed as described above. For the proposed research, two parametric 
images per participant will be created (1 OXY, 1 placebo) and entered into group-level analyses. 
Whole-brain, ANOVAs including medication (OXY/placebo) and order (OXY/placebo at Scan 1) as 
between-subjects factors and voxelwise FC (α) as a within-subjects factor will be used to identify 
OXY-associated changes. Subjective ratings of drug effects will be entered into regression analyses 
with FC indices from OXY (vs. placebo) scans to identify network-level individual difference 
factors related to subjective responses. Consistent with current recommendations, group-level 
analyses will be conducted using a cluster-forming threshold of p<.001 and a family-wise error 
(FWE) correction of p<.05. Clusters exhibiting significant main effects of medication will be entered 
into seed-based analyses to facilitate characterization of FC changes. 
FC data from placebo scans will be entered into CPM analyses to identify networks predictive of 
subjective responses to active drug (OXY). Peak DEQ responses collected during active drug 
sessions and resting state and MID task data from placebo scans will be entered into CPM analyses. 
CPM analyses will be conducted using leave-one-out cross-validation and permutation testing, as in 
our prior work.
Figure  6 – Schematic diagram of connectome-based predictive modeling (CPM; ‘neural 
fingerprinting’)
0.1
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Subject1
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A. Feature selec3on from FC data
B. Sum edge weights C. Fit brain-behavior D. Apply model to novel subject’
Opioid response
Edge weights
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novel subjects
PREDIC
OF OP
RESP
Nega3ve Σ2
Nega3ve Σ1
Posi3ve Σ2
Posi3ve Σ1
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During CPM, 6A, edges (correlations between nodes in FC matrix) and behavioral data from a 
training dataset are correlated using regression analyses to identify positive and negative predictive 
networks (networks not shown). Single-subject summary statistics, 6B, are created as the sum of the 
edge weights in each network and, 6C, used to create predictive models assuming linear 
relationships with behavioral data. Resultant polynomial coefficients are applied to novel subject’s 
FC matrices (6D, test data) to generate behavioral predictions. Performance is evaluated using mean 
squared error (MSE) or correlation between predicted and actual values. Lower MSE and higher 
correlation indicate more predictive models.
Procedures for Recruitment, Informed Consent and Initial Screening
Recruitment will be conducted using flyers distributed on the Yale campus and in New Haven, as 
well as by word of mouth.  Initial meetings will take place either in person or via Zoom in a private 
setting with a trained member of the research team. At this meeting, potential participants will be 
provided with an overview of the study protocols including a complete description of the study 
procedures, and will provide written, informed consent. This procedure will include description of 
the components described in the consent form, including: (i) voluntary nature of participation; (ii) 
participants may withdraw without consequences; (iii) study purpose and procedures; (iv) schedule 
of study visits; (v) neuroimaging procedures; (vi) risks and benefits of participation; (vii) potential 
compensation; (viii) alternatives to study participation; and (ix) confidentiality. All potential 
participants will be allowed to ask questions and given sufficient time to consider the decision to 
participate. All potential participants will be given a copy of the consent form. 
Following informed consent, potential participants will be screened for eligibility by specially 
trained members of the research team either in person or via Zoom. This will involve structured 
clinical interview and baseline self-report rating forms, including the following. 
List of assessments:
Structured Clinical Interview for DSM (SCID-5)– The SCID-5 is a reliable semi-structured 
instrument that is standard in the field for diagnosing selected current and lifetime Axis I 
disorders.  It will be used to diagnose comorbid disorders. The SCID-II, which assesses personality 
disorders, will also be used as the presence of personality disorders may bear on treatment retention 
and outcome.
Magnetic Resonance Research Center (MRRC) Safety Form – The MRRC Safety Questionnaire 
will be used to confirm eligibility for MRI scanning, consistent with the guidelines of Yale’s MRRC 
center. 
Positive and Negative Affect Scales (PANAS) – Trait and state positive and negative affect will be 
evaluated using these well-validated, brief self-report scales (Watson et al., 1998).
Shipley Institute of Living Scale (SILS) -  General intellectual functioning will be evaluated using 
the SILS (Shipley 1967), a widely-used and brief screening tool that assesses general level of 
intellectual functioning.  
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The Beck Depression Inventory (BDI) (Beck 1978) and Beck Anxiety Inventory (BAI) (Beck 
1988) are well-validated self-report measures of depression (BDI) and anxiety (BAI) symptoms. 
The Difficulties in Emotion Regulation Scale (DERS) (Gratz and Roemer 2004) is a well-
validated 36-item self-report measure assessing six domains related to emotion regulation. 
Difficulties in emotion regulation using this scale have been previously reported among newly 
abstinent cocaine users (Fox, Axelrod et al. 2007).
The Affective Reactivity Index (ARI) (Stringaris, Goodman et al. 2012) is a well-validated self-
report measure of irritability.
Barratt Impulsiveness Scale (BIS-11) (Patton, Stanford et al. 1995) - This is a 30-item, valid and 
reliable self-report scale designed to assess the personality/behavioral construct of impulsiveness.
Drug Effects Questionnaire (DEQ) (Kirk and de Wit 2000) – Subjective effects of acute opioids 
will be assessed using the DEQ, a set of four visual analogue scales assessing subjective effects (e.g., 
‘Do you feel any drug effects?’).
UPPS Impulsive Behavior Scale (Whiteside, et al. 2001) – Self report of impulse behaviors.
Screener and Opioid Assessment for Patients with Pain (Butler et al. 2008/Akbik et al. 2006)—
Screening for opioid risk related to pain.
State Trait Anxiety Inventory (STAI) (Spielberger 1991)—This is an 40 item self- report of two 
types of anxiety, anxiety about an event (state) or anxiety on a personal level (trait)
Monetary Choice Questionnaire (Kirby et al. 1999)—delay discounting measure used for testing 
impulsivity.
I. Safety and eligibility screening and baseline assessments
1. Pre-enrollment screening (by phone, Zoom or in person) - RA

Medical history

Substance use history

Psychiatric history
2. Eligibility assessment (in person or via Zoom) - Initial assessments and screening (1-3 hours) – 
RA

Informed consent (including informed consent quiz)

Assessment of Inclusion/Exclusion criteria

Demographics

Follow-up contact form

Drug screen
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
SCID

MRRC Safety Form

BDI/BAI

DERS

BIS 11

UPPS

SOAPP-R

STAI

Delay Discounting

Schedule medical screening and start date for fMRI
Procedures for Conducting SCIDs and BDI Remotely
 Prior to beginning interview:
●      Only schedule remote when Dr. Sarah Lichenstein is available to be ‘on call’
●      When scheduling SCID with a participant, discuss where she will be and ensure she will have 
adequate privacy for the interview.
●      Before beginning the SCID, obtain the participant’s phone number and current location 
(including specific address) so that you have an alternative way to get in touch with the 
participant just in case. 
 If the participant expresses active suicidal intent during a remote/online visit:
●      Try to keep the participants on the phone, TRY NOT TO HANG UP
●      Confirm with the participant that you have the right address where she is currently located.
●      Tell the participant everything you are doing, as you do it; inform her that you are going to call a 
supervisor for some assistance. Avoid using the word ‘police’, which can be very distressing to 
some participants.
●      Text Sarah Lichenstein (clinical psychologist) without hanging up on the participant.
●      You can use the language below to assess whether this is a case of active suicide intent and 
whether the participant has access to means to execute their plan– however, you are not required 
to make a judgment call. The clinician you contact (i.e., Sarah Lichenstein) will do that.
●      Provide the participant with resources, including the National Suicide Hotline (1-800-273-8255), 
SAMHSA’s National Helpline (1-800-662-HELP (4357), United Way of Connecticut (211), and 
local Emergency Rooms (911).
●      After speaking with Sarah Lichenstein, and based on her judgment of whether this is considered a 
case of active suicidal ideation warranting immediate clinical follow-up – 
Have Sarah Lichenstein call the participant while RA is still on the line.  If warranted, then
○      Call mobile crisis and inform dispatch that a research participant expressed suicidal 
intent, and relay her contact information (name, phone number, current address). This can 
be done on a three-way call if RA is alone, otherwise RA can have someone else call 
mobile crisis while RA remains on the line with the participant. 
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●      It is not the RAs responsibility to ensure that the participant arrives at the hospital, nor to follow-
up clinically. Their responsibility is a duty to warn of the suicidal or homicidal intent, and to 
document the event in the participant’s notes/records.
3. Medical screening (in person) – approximately 1 hour
Potential participants will undergo medical screening (Dr. Deepa Camenga (FC1166683(DEA)) to 
determine eligibility to receive a single dose of oxycodone (15mg).  Medical screening for 
contraindication to low-dose opioid administration (e.g., medication allergies, kidney or liver 
problems, personal or familial history of opioid- or alcohol-use disorders) will be conducted by a 
licensed physician. Per standard clinical practice in the state of CT, Dr. Camenga will check the 
Connecticut Prescription Monitoring program to confirm participant- reported history of previous 
opioid or prescription drug prescriptions received, and to confirm that the participant does NOT have 
a significant lifetime use of prescription opioids (>7 days of consecutive medical use).  Lab tests will 
be ordered at the discretion of the physician to determine eligibility for study participation, as in our 
as in our other ongoing studies (HIC#: 1510016617).  Subjects participating in one of our other 
protocols involving a medical screening may have the results from that screening used to determine 
eligibility on this protocol if within the last 3 months.  Once determined eligible for the study, the 
study physician will access their Yale medical chart once for the purpose of attaining their medical 
record number for the prescription of oxycodone. 
Neuroimaging
Participants will be asked to abstain from drugs or alcohol for 24 hours prior to scanning. MRI data 
will be collected using a 3.0T scanner and will be stored using a numbered reference system known 
only to the Project Coordinator. All data collection and management procedures are fully compliant 
with HIPAA. Study participants will participate in two MRI scanning sessions (some subjects may 
have more than two sessions should one of the initial scans prove to be incomplete or if the data was 
found to be unusable, i.e., too much movement during the scan).  Neuroimaging will take place at 
Yale University’s Magnetic Resonance Research Center (MRRC). All MRI data will be acquired 
using a 3.0T scanner and multiband acquisition parameters. MRI scanning using a 3.0T scanner is 
non-invasive and has not been associated with any medical risks. A member of the research team 
will accompany the subjects and will stay for the MRI. 
During each scanning session, we will acquire resting state functional data and, in some cases, task-
based fMRI data using a reward task (details below).  Resting data will be acquired using up to 5 
separate acquisitions, each of approximately 6 minute duration. Between each session, participants 
will be asked to rate how they are feeling on a Likert-type scale. Diffusion-weighted data, T1-
weighted and T2-weighted images will also be obtained. In addition, a high-resolution structural 
MPRAGE scan will be obtained to aid in co-registering each subject to the template space and to 
assess gray matter volume. To allow for assessment of cerebral perfusion, arterial spin labeling 
(ASL) data will also be collected.  Scan time will not exceed 90 minutes. 
Functional MRI data will be acquired during performance of a monetary incentive delay task. 
During performance of the Monetary Incentive Delay Task, at the start of each trial, participants are 
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presented with an initial cue, indicating an amount of money to be won or lost (e.g., ‘WIN $1’), 
followed by a fixation cross (A1 phase). Participants are then presented with a target stimulus for a 
variable duration (individually calibrated). In order to win (or avoid losing) money on each trial, 
participants respond with a single button press while the target is on the screen. Following the target 
stimulus, a fixation cross is again presented (A2). Finally, participants are given feedback on the 
outcome of the trial (outcome phase). The task includes 55 trials (22 win trials, 22 loss trials, 11 
neutral trials). 
Medication administration
Approximately one hour prior to scans, participants will receive either a single oral dose of 
oxycodone (15mg) or placebo in pill form.  Medication will be prescribed by a licensed physician, 
Dr. Marc Potenza (DEA license BP5110541) or Dr. Deepa Camenga (DEA license FC1166683) and 
will be stored and dispensed by the Yale New Haven Hospital (YNHH) pharmacy. Medication will 
be collected from the YNHH by a trained member of the research team and collection and 
administration to the participant will be documented using paper and/or electronic logs, as in our 
ongoing studies (HIC#: 1510016617).  All subjects will be screened by a licensed physician for 
medication allergies and other contraindications (e.g., familial history of opioid-use disorder; details 
above). As per MRRC protocols a licensed physician will be on call during the scan.  Although the 
risk is minimal, a dose of naloxone will be on hand to counteract any effects from the opioid should 
the need arise, as determined by the study physician. 
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. 
Assessment of subjective effects 
Subjective drug effects (e.g., ‘drug liking’) will be assessed at multiple time points on each scanning 
day.  Subjective effects will be assessed using measures recommended by the PhenX Toolkit 
(Morean, de Wit et al. 2013). This will include the Drug Effects Questionnaire (DEQ )(Kirk and de 
Wit 2000), as in prior work in opioids(Comer, Collins et al. 1999, Comer, Metz et al. 2013, Gorka, 
Fitzgerald et al. 2014). The DEQ includes visual analogue scales for ‘FEEL’, ‘WANT’, ‘LIKE’ 
‘DISLIKE’, ‘HIGH’ and ‘MORE’. Physiological (pulse, blood pressure) and subjective DEQ ratings 
will be acquired at baseline. Subsequent ratings will be acquired at 30, 60, 90, 120, 180 and 
240minute timepoints. Ratings will be acquired electronically using a sliding visual analogue scale 
(VAS). Physiological measures will be acquired at baseline, 60, 120, 180 and 240min time points. In 
addition, the Addiction Research Center Inventory (ARCI) Morphine-Benzedrine Scale (McNair, 
Lorr et al. 1981) and VAS ratings of nausea, euphoria and light-headedness will be acquired at 
baseline and before and after neuroimaging.
5.
Genetic Testing   ☒
N/A 
6.
Subject Population: Provide a detailed description of the types of human subjects who will be recruited into 
this study.
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This study will include up to 40 healthy men and women between the ages of 18 and 30. We will 
recruit through the general community using established recruitment procedures such as posting flyers, 
word-of-mouth, craigslist ads, Facebook and advertisements in local papers.
7. Subject classification: Check off all classifications of subjects that will be specifically recruited for enrollment in 
the research project. Will subjects who may require additional safeguards or other considerations be enrolled 
in the study? If so, identify the population of subjects requiring special safeguards and provide a justification 
for their involvement.
☐Children
☒ Healthy 
☐Fetal material, placenta, or dead fetus
☐Non-English Speaking
☐ Prisoners
☐Economically disadvantaged persons
☐Decisionally Impaired
☐ Employees
☐Pregnant women and/or fetuses
☐Yale Students 
☐ Females of childbearing potential
We plan to recruit healthy young adults from the general community. It is therefore possible that this 
will include Yale students.
NOTE: Is this research proposal designed to enroll children who are wards of the state as potential subjects?
Yes ☐  No ☒ 
8. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or exclusion?
Inclusion criteria: 
a) males or females, ages 18-30 
b) for women of a child-bearing age, acceptable birth control methods or a negative pregnancy test 
prior to MRI scanning
c) ability to provide written, informed consent
d) eligibility and willingness to participate in fMRI scanning and to receive oxycodone
e) normal to overweight, as indicated by a body mass index (BMI) between 18.5 to 29.9
Exclusion criteria: 
a) current DSM-5 Axis I disorder 
b) any psychotropic medication or medication known to interfere with metabolism of opioids 
c) medical contraindication to participate in study activities (acute low-dose opioid admin) as 
determined by study physician
d) known family history (first-degree relative) of opioid-use disorder or alcohol-use disorder
e) not eligible for MRI scanning 
f) positive drug screen
g) recent (past 6 months) medical or non-medical opioid-use 
h) current or previous chronic pain disorder
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i) significant lifetime use of prescription opioids (>7 days of consecutive medical use or nonmedical 
use on more than 5 occasions)
j) alcohol naïve participants who may have never experienced the effects of an altering substance
k) pregnant or nursing mothers
9. How will eligibility be determined, and by whom? 
Eligibility will be determined based on the above eligibility criteria as assessed by specially trained 
medical and research staff.
10. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, or 
inconveniences associated with subjects participating in the research. 
Risks to subject privacy: There is a chance that personal information may inadvertently not be kept 
confidential. Some answers participants give during the research visits (like whether they use illegal 
drugs) may put them at risk if other people find out.
Acute low-dose opioid administration: Risks associated with oxycodone use include gastrointestinal 
upset, constipation, nausea, vomiting, somnolence, dizziness, lightheadedness, itching, headache, 
blurred vision and xerostomia. As subjects will receive only a single 15 mg oxycodone, risks are 
minimal. All subjects will be screened by a licensed physician for medication allergies and other 
contraindications (e.g., familial history of opioid-use disorder; details above).
MRI scanning: Functional MRI scanning using a 3.0T scanner is non-invasive and has not been 
associated with any medical risks. Thus, the primary anticipated complication is the experience of 
claustrophobia during scanning. All subjects will be able to terminate the MRI scan at any time for 
any reason including claustrophobia. 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.
Completing the baseline assessments has minimal potential for harm and at any time during the 
course of this study, subjects may ask us to stop.
Non-specific risks: Subjects will participate in a psychiatric evaluation, thus they will be exposed to 
undefined risks associated with these procedures.
11. Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized.
Protection of Subject Privacy and Confidentiality: All of the research and clinical staff members 
involved in both studies receive annual Good Clinical Practice, Human Subjects Protection and 
HIPAA training, and all data collection and management procedures are also fully compliant with 
HIPAA guidelines. In addition:
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1.
Study forms are specifically designed to avoid collecting identifiable information, thus no 
personal health information is collected on case report forms (CRFs). We generally 
collect only protocol session dates. 
2.
Research data are collected on CRFs, and sent to data managers in our research offices on 
a closed secure network. All computers used by research staff are password protected and 
encrypted. No identifying information is on CRFs.
3.
Limits to confidentiality include only disclosure of acute suicidality, homicidality, or 
abuse of a minor, as is standard in clinical practice.
4.
Data are stored at our secure data management center and data sets do not include 
identifying information. At the conclusion of the study, all locator data are destroyed. 
Source data are generally destroyed 3 years after completion of the study at a secure 
location (e.g., Jefferson Archives) and destroyed by Jefferson Archives or Shred-It. We 
will follow current guidelines (federal and University) at the conclusion of the study.
Protection During Neuroimaging: There are no associated medical risks of MRI scanning at 3.0T. 
All MRI scanning will be conducted in the presence of experienced research and technical staff. As 
indicated above, all participants will be thoroughly screened for any contraindication to MRI 
scanning (e.g., metal implants, claustrophobia) using the Yale MRI Safety Sheet and potential 
participants not meeting safety requirements will be excluded. In addition, subjects will walk 
through a ferromagnetic detector to minimize the risk of projectile injury. In addition to the MRI 
operator, a member of the research team will accompany the study subject and will stay for the MRI. 
Women of child-bearing age will be given a pregnancy test prior to scanning to rule out pregnancy.
All participants may terminate imaging at any time for any reason. In rare cases, participants may 
report minor dizziness or nausea. Should this or any other unanticipated event occur, appropriate 
treatment will be immediately initiated for symptomatic relief.
Risks associated with use of 15 mg oxycodone: As subjects will be given a small dose the risks are 
minimal. All subjects will be screened by a licensed physician for medication allergies and other 
contraindications (e.g., familial history of opioid-use disorder; details above).This is an additional 
safeguard as per MRRC protocols a licensed physician will be on call during the scan. Subjects will 
be required to have transportation home from the study and if they cannot get a ride from someone 
else (friend, family, bus) we will arrange for a taxi to pick up and drop off the subjects on testing 
days. 
To further minimize risks, we will exclude participants with family histories of alcohol or opioid 
addiction (exclusion criteria, above) or with any past or current substance-use disorder. In addition, 
all potential participants will be given a copy of the SAMHSA Opioid Overdose Prevention toolkit 
to read through so they are aware of the signs and symptoms of opioid overdose/dependence8. We 
will also have a list of addiction recovery centers and helplines available in the area that we will 
provide to every participant. Every effort will be made to ensure subjects understand the issues 
surrounding opioid abuse and what to look for in the first few hours of taking the 15 mg oxycodone 
as well as signs and symptoms that they may be developing an addiction to opioid medications. We 
will ensure participants understand the risk and are aware they can reach out to us or to the list of 
recovery centers/helplines should they (or someone they know) develop a problem. 
All participants will be given a wallet card with contact details for the study physician. In 
addition to close monitoring during study visits involving oxycodone, participants will be contacted 
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via phone following each study visit (OXY and placebo) and at one-month follow-up by a trained 
member of the research staff to check for any possible any adverse effects and will be referred to the 
study physician if necessary. The study physician, Dr. Camenga has significant expertise in 
adolescent and young adult substance use and addiction and emergency medicine.  She is also a 
licensed buprenorphine provider (FC1166683(DEA)/XC1166693(X-waiver))  and runs an outpatient 
treatment program for adolescents and young adults with opioid use disorders in New Haven.  She is 
therefore extremely well qualified to deal with possible oxycodone-associated risks, in the unlikely 
event that they arise.  If at any time during the study participants are found to be at risk for hurting 
themselves they may be hospitalized as a safety measure.
12. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan (DSMP) based on 
the investigator’s risk assessment stated below. (Note: the HIC will make the final determination of the risk to 
subjects.)
a. 
What is the investigator’s assessment of the overall risk level for subjects participating in this 
study? Greater than Minimal Risk
b.
If children are involved, what is the investigator’s assessment of the overall risk level for the 
children participating in this study?   N/A
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are  
available here http://your.yale.edu/policies-procedures/forms/420-fr-01-data-and-safety-
monitoring-plans-templates for
i.
Minimal risk
ii.
Greater than minimal
d. For multi-site studies for which the Yale PI serves as the lead investigator:  N/A
DATA AND SAFETY MONITORING PLAN (DSMP)
Personnel responsible for the safety review and its frequency:
This project will be monitored by a Data and Safety Monitoring Board (DSMB), because the study 
involves administration of oxycodone. Specifically, this study will assess the effects of acute low-dose 
opioid administration on functional neuroimaging measures in healthy individuals (N=40, 20 male, 20 
female).  The objective of this research is to develop an understanding of factors that may influence 
individual variability on resting state functional connectivity in response to low-dose opioid 
administration with the longer term aim of understanding addictions vulnerability.  Specifically, the 
proposed pilot research will explore the effects of single dose of oxycodone (15mg)  on resting state 
functional connectivity and other common neuroimaging measures (e.g., diffusion MRI, structural 
MRI).  Previous work has found 10-20mg doses well-tolerated, but has found increased ratings of 
nausea following 20mg doses (Gorka, Fitzgerald et al. 2014, Wardle, Fitzgerald et al. 2014). 
Preliminary data (Gorka, Fitzgerald et al. 2014) suggest that 10mg and 20mg doses have similar 
effects on FC.  However, a 10mg dose of oxycodone may not be clinically sufficient for CYP3A4 fast 
metabolizers (Samer, Daali et al. 2010, Brennan 2012). To balance concerns related to excluding 
potential participants based on this relatively common genetic variation (thus potentially limiting the 
applicability of study findings) with those of a higher dose of oxycodone (e.g., 20mg), we will use a 
15mg dose. Other laboratory studies in healthy controls have found doses between 15mg and 20mg to 
be well tolerated (Zacny and Lichtor 2008, Samer, Daali et al. 2010, Cooper, Sullivan et al. 2012).
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Given the high prevalence of prescription opioid exposure in youth (McCabe, West et al. 2012), it is 
not feasible to study exclusively opioid-naïve individuals. Prior neuroimaging work using oxycodone 
has not excluded for lifetime exposure, but has excluded for abuse or dependence (Gorka, Fitzgerald et 
al. 2014). To minimize the possible influence of individual differences in prior exposure, we will 
exclude for prior 6 month use, as well for significant prior medical (>5 days of consecutive medical 
use) or nonmedical use (>5 prior uses of oxycodone). 
Peak plasma concentrations of orally administered immediate release 10mg OXY occur approximately 
1 hour following ingestion and has a half life of 3-4 hours (Ordonez Gallego, Gonzalez Baron et al. 
2007, Gronlund, Saari et al. 2010, Saari, Gronlund et al. 2010).  We are therefore confident that a 6-
month washout period will be more than sufficient to ensure clearance. 
All participants will be seen for an initial intake by a research assistant either in person or virtually via 
Zoom and who will begin the review process of eligibility, obtain medical history, provider 
information and relevant releases. Physical examination findings and laboratory tests will inform 
eligibility decisions. Potential participants will undergo medical screening to determine eligibility to 
receive a single dose of oxycodone 15mg.  Medical screening for contraindication to low-dose opioid 
administration (e.g., medication allergies, kidney or liver problems, personal or familial history of 
opioid- or alcohol-use disorders) will be conducted by a licensed physician. Lab tests will be ordered 
at the discretion of the physician to determine eligibility for study participation. Final determination of 
eligibility will be determined by the study physician and investigators. Monitoring will occur during 
and after all procedures with participants remaining in our lab for one hour post scan (3.5-4 hours after 
opioid administration). In addition, a follow up phone call will be made one day and again one month 
after scan with additional medical care, if indicated, being facilitated.
The Principal Investigator (PI) will be responsible for monitoring the data, assuring protocol 
compliance, and ensuring safety reviews are conducted every 6 months (including when reapproval of 
the protocol is sought). During the review process, the PI (monitor) will evaluate whether the study 
should continue unchanged, require modification/amendment, or close to enrollment. Either the PI, the 
IRB, or the DSMB will have the authority to stop or suspend the study or require modifications.
The DSMB is composed of persons not otherwise affiliated with the trial who are experienced in 
various aspects of the conduct of trials. We propose four who are not directly involved in this trial but 
who serve are members of the Departments of Psychiatry and Child Study—Declan Barry, PhD, 
Stephanie O’Malley, PhD, Godfrey Pearlson, MA, MBBS and Linda Mayes, MD—as the membership 
of the DSMB. These four individuals have appropriate expertise in drug challenge studies, clinical 
trials, research in young adults and/or opioid use disorder. None of these three are directly involved 
with this proposed trial and consequently should not pose a conflict of interest. The members of the 
DSMB and all study Investigators will complete Conflict of Interest forms created by Yale’s IRB in 
accordance with NIH guidelines. 
For the DSMB to fulfill its mission of assuring the safety of human subjects and the scientific integrity 
of the studies conducted, the Board will have access to accumulating study outcome data in a manner 
that will protect its confidentiality and preserve its statistical integrity. The Board will examine 
accumulating data to assure that the risks and benefits of participation remain acceptable and that the 
results of the trial will be considered scientifically reliable. The conditions under which the Board will 
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examine this data are described below. This monitoring will be consistent with NIH policy regarding 
the protection of human subjects in research, and FDA guidance on statistical practices for clinical 
trials (ICH E9) and good clinical practices (ICH E6). In general, the data to be reviewed will include 
the following.
1. Recruitment, retention, and follow-up rates for the study for comparison to target rates
2. Rates of data completeness and availability of primary outcome data
3. Occurrence of adverse events (AEs) and serious adverse events (SAEs; see below for 
definition)
4. Report of study progress since the last report
5. Rates of recruitment of women and minorities with respect to targeted rates
This will allow board members to ensure that the risks and benefits of participation remain acceptable 
and that the results of the research will be considered scientifically reliable, in accordance with NIH 
policies on the protection of human subjects in research. Following each report, each DSMB member 
will complete a form making one of two recommendations:
1. Continuation of recruitment as planned
2. Immediate scheduling of a formal DSMB meeting
In the event of option #2 (recommendation of an immediate meeting), this will be scheduled within one 
week, minutes will be kept, the report will be reviewed with the PI (Dr. Yip), the study physician (Dr. 
Camenga) and both of the PI’s primary K01 mentor (Dr. Potenza), and the committee will vote on 
whether the study should:
1. Continue recruitment without any changes
2. Continue recruitment following protocol amendment
3. Stop recruitment pending further investigation
In the event of option #3 (cessation of recruitment), the Yale School of Medicine Human Investigation 
Committee will be informed.
Adverse event data and other data intended for the monitoring of safety will be presented to the 
DSMB. Within the scope of the proposed study, an adverse effect is defined as any reaction, side 
effect, or untoward event that occurs during the course of the study, whether or not the event is 
considered medication-related or clinically significant. A side effects scale will be used that enquires 
regarding physical or health problems since the last visit, including changes in physical appearance 
and changes in functioning due to physical condition. This will be followed by an assessment of 
whether the patient experienced specific problems such as nausea/vomiting, diarrhea, abdominal pain, 
change in appetite, headaches, dizziness, fatigue, nervousness/anxiety. If the patient answers 'yes' to 
any of the above questions, date of onset and duration, and pattern of symptom will be documented, 
and a severity rating will be elicited.
Attribution of Adverse Events:
We will use the Yale University School of Medicine – Human Investigation Committee (HIC) 
recommended 
guidelines for assessing the attribution of adverse events. The PI will conduct a review of all adverse 
events
and determine the attribution of the adverse event by using the following categories:
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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).
Plan for Grading Adverse Events:
We will use the following scale in grading the severity of adverse events noted during the study: 
0: No adverse event or within normal limits
1: Mild adverse event- discomfort noticed, but no disruption of normal daily activity
2: Moderate adverse event- discomfort sufficient to reduce or affect normal daily activity
3: Severe adverse event resulting in hospitalization or prolongation of existing hospitalization, a 
persistent or   significant disability/incapacity, or a congenital anomaly/birth defect
4: Life-threatening or disabling adverse event
5: Fatal adverse event
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; 
3. In-patient hospitalization or prolongation of existing hospitalization; 
4. A persistent or significant disability or incapacity; 
5. A congenital anomaly or birth defect; OR
6. 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. The PI 
will consider the grade of the event as well as its “seriousness” when determining whether reporting to 
the IRB is necessary.
The PI (Sarah Yip, Ph.D.) will assume full responsibility for reporting serious adverse events and will 
consult with the study nurse and/or physician in making attribution of risk and relatedness. Subjects 
will be terminated from participation if the investigator feels that subjects' health or well-being may be 
threatened by continuation in the study.
Plan for reporting UPIRSOs (including Adverse Events) to the IRB
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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 possibly, probably or definitely 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.
UPIRSOs meeting these criteria will be reported to the Yale IRB in accordance with the timeline(s) 
detailed within IRB Policy 710, specifically: 

Events that may require a temporary or permanent interruption of study activities by the 
Principal Investigator (PI) or sponsor to avoid potential harm to subjects will be reported to 
the IRB immediately (if possible), followed by a written report to the IRB using the 
UPIRSO Reporting Form (710 FR 4) no more than 5 calendar days after the Yale PI 
becomes aware of the event.

Internal Events meeting the criteria above will be reported to the IRB using the UPIRSO 
Reporting Form (710 FR 4) within 5 calendar days of the PI becoming aware of the event.
All related events involving risk but not meeting the prompt reporting requirements described above 
will be reported to the IRB in summary form at the time of continuing review. If appropriate, such a 
summary may be a simple brief statement that events have occurred at the expected frequency and 
level of severity as previously documented. A current DSMB report may be submitted in lieu of a 
summary of external events. 
Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s 
research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and Safety Monitoring 
Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study sponsors, funding and 
regulatory agencies, and regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory agencies will be notified 
(choose those that apply):
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x All Co-Investigators listed on the protocol.
□ Yale Cancer Center Data and Safety Monitoring Committee (DSMC)
x National Institutes of Health
□ Food and Drug Administration (Physician-Sponsored IND #_______)
□ Medical Research Foundation (Grant______)
□ Study Sponsor
x Other Data Safety Monitoring Board (DSMB) or Committee (DSMC)
UPIRSOs will be reported to the IRB in accordance with IRB Policy 710 (detailed above in Section 6. 
Plan for reporting UPIRSOs (including Adverse Events) to the IRB). In addition, serious 
anticipated adverse events (SAE) that occur with a greater frequency than expected, and unanticipated 
adverse events that are possibly, probably, or definitely related to study procedures will be reported in 
writing to the Data Safety Monitoring Board (DSMB) constituted for this study according to the 
timeline outlined above in Section 6, and will be reported to NIDA according to NIDA’s reporting 
guidelines (e.g., within 48 hours of the event becoming known). The study team, in consultation with 
the DSMB, will evaluate the adverse event and determine whether the adverse event affects the 
Risk/Benefit ratio of the study and whether modifications to the protocol or consent form are required. 
In addition, they will conduct a review of all adverse events at least semi-annually, and they will 
evaluate the frequency and severity of the adverse events and determine if modifications to the 
protocol or consent form are required. The sequence of events that will determine if this clinical trial is 
to be terminated are: a) evaluation of individual stopping rules; b) evaluations of several individuals as 
aggregate data; c) determination of the likelihood that the adverse events are study-related; d) if the 
severity of study-related adverse experience(s) is judged extreme, then the study will be terminated; 
and e) emergence of unexpected serious adverse experience(s). 
Following each DSMB meeting written minutes will be prepared and distributed to the PI 
summarizing any recommendations including any recommendations for interim analyses. These 
written reports will ensure timely communication with the study PI with preparation of any protocol 
amendments necessary. After each DSMB meeting, this written report will describe all 
recommendations including additional safety steps. The FDA adverse drug experience reporting 
timelines will be utilized as timelines to disseminate feedback from the DSMB to the PI and co-
investigators. That is, three days for acute circumstances and ten days for nonacute circumstances. We 
will report substantial protocol amendments or changes in the informed consent to NIDA as well as 
any temporary or permanent suspension of patient accrual.
13. Statistical Considerations: Describe the statistical analyses that support the study design. 
Based on findings reported by Gorka and colleagues3, we anticipate that a sample size of 30 
individuals will be sufficiently powered (>.90) to detect changes in FC following OXY versus 
placebo (noncentrality parameter (δ)=7.26, critical t-value=2.05, df=29, power (1-β)=0.99). We are 
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therefore confident that our recruitment aim of N=40 will be sufficiently powered, even after 
accounting for possible subject drop-out and/or data exclusion due to excessive motion 
(approximately 20% in prior studies).
SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
If this section (or one of its parts, A or B) is not applicable, check off N/A and delete the rest of the section.
A.  RADIOTRACERS
☒N/A
B.  DRUGS/BIOLOGICS    ☐N/A
Generic name: oxycodone
Chemical name: 14-hydroxydihydrocodeinone
FDA approved? Yes, by prescription only
Indications: This is a medicine used to relieve moderate to severe pain
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 category that 
applies (and delete the inapplicable categories):
Exempt Category 1: The clinical investigation of a drug product that is lawfully marketed in the United States 
can be exempt from IND regulations if all of the following are yes: 
1.
The intention of the investigation is NOT to report to the FDA as a well-controlled study in support 
of a new indication for use or to be used to support any other significant change in the labeling for 
the drug.
☒
2.
The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and 
the intention of the investigation is NOT to support a significant change in the advertising for the 
product.
☒
3.
The investigation does NOT involve a route of administration or dosage level or use in populations 
or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product
☒
4.
The investigation will be conducted in compliance with the requirements for institutional (HIC) 
review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50 and 
21 CFR Part 56).
☒
5.
The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs.
☒
2. 
Background Information: Provide a description of previous human use, known risks, and data addressing 
dosage(s), interval(s), route(s) of administration, and any other factors that might influence risks. If this is the first 
time this drug is being administered to humans, include relevant data on animal models. 
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Peak plasma concentrations of orally administered immediate release 10mg OXY occur 
approximately 1 hour following ingestion (Gronlund et al., 2010; Saari et al., 2010), as do peak 
ratings of subjective ‘high’(Wardle et al., 2014). Oxycodone (or generic equivalent) will be 
administered orally in a private medical room at Yale University’s Magnetic Resonance Research 
Center (MRRC) 1 hour prior to scanning by a trained member of the research team. The study 
physician will be available via pager (and in close proximity to the MRRC) during medication 
administration and scanning, consistent with Yale safety policies. All participants will be closely 
monitored for any possible adverse side effects. As subjects will receive only a single oral dose of 15 
mg oxycodone, risks are minimal. The most common risks associated with oxycodone include 
constipation (in 25-30% of individuals), nausea (25%), drowsiness (25%), dizziness (15%), vomiting 
(10-15%) and pruritis (10-15%) (Ordonez Gallego, Gonzalez Baron, & Espinosa Arranz, 2007). 
Should these side effects occur, participants will be offered symptomatic relief by the study 
physician (Dr. Camenga) as appropriate based on her clinical judgement.  Participants will be 
monitored closely until side effects have subsided. The study physician, Dr. Camenga has significant 
expertise in adolescent and young adult substance use and addiction and emergency medicine.  She 
is also a licensed buprenorphine provider (FC1166683(DEA)/XC1166693(X-waiver))  and runs an 
outpatient treatment program for adolescents and young adults with opioid use disorders in New 
Haven.  She is therefore extremely well qualified to deal with possible oxycodone-associated side 
effects, in the unlikely event that they arise.
Although the risks are minimal, a dose of naloxone will be on hand to counteract any effects from the 
opioid should the need arise (as determined based on the discretion of the study physician). Previous 
experimental work using up to 20mg of OXY found both 10mg and 20mg doses to be well-tolerated, but 
found increased ratings of nausea following 20mg doses (Gorka, Fitzgerald, de Wit, Angstadt, & Phan, 
2014; Wardle et al., 2014). As preliminary data (Gorka et al., 2014) suggest that 10mg and 20mg doses 
have similar effects on FC, we chose to use 15mg to further minimize possible risk to participants. The 
starting initial dose for oxycodone in healthy adults is between 5 and 15mg, thus 15mg should be well 
tolerated
3. 
Source:  Identify the source of the drug or biologic to be used. 
The YNHH pharmacy will be ordering the medications from their established vendors.
a)
Is the drug provided free of charge to subjects? ☒YES 
☐NO 
If yes, by whom?  
The study investigator will be responsible for purchasing the drug in order to provide it free of 
charge to participants.
1.
Storage, Preparation and Use: Describe the method of storage, preparation, stability information, and for 
parenteral products, method of sterilization and method of testing sterility and pyrogenicity.
 
The YNHH pharmacy will be in charge of the necessary storage, stability, testing, etc. The research 
pharmacist and his staff will prepare the prescribed drugs. Once prepared, the study staff will pick it 
up, bring it to the appropriate study location and hand it over directly to the subject. The study staff 
will also collect from the subject any unused drugs and return it to the pharmacy. Drug delivery and 
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distribution will be tracked via a drug accountability form and other pharmacy or sponsor-required 
paperwork.
Check applicable Investigational Drug Service utilized:
    ☒  YNHH IDS                                                        ☐  CMHC Pharmacy                                           ☐ West Haven VA
    ☐  PET Center                                                      ☐    None      
    ☐  Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in detail how the PI 
will oversee these aspects of drug accountability, storage, and preparation.  
2.
Use of Placebo: 
Yes - applicable to this research project
This protocol is being conducted to determine if oxycodone influences neural functional responses in healthy 
young adults. To control for possible ‘placebo effects’ – i.e., neural responses related to the expectation of 
receiving an active drug - we have added a placebo condition.  Note that this randomized, counter-balanced, 
within-subject, cross-over design is considered the ‘gold standard’ for pharmacotherapy research.  As this is 
not a treatment trial, administration of placebo will not involve any additional risks in comparison to 
administration of oxycodone. All participants will be closely monitored for any possible adverse side effects by 
the study physician researchers. Placebo medications will be prepared by IDS, YNHH or APT pharmacy staff, as 
in our other ongoing protocols (HIC# 1510016617).  Placebo and active drug (15mg OXY) will be encapsulated 
in identical capsules and administration will be documented by research and pharmacy staff, as in our other 
studies. 
3.
Continuation of Drug Therapy After Study Closure   ☒Not applicable to this project
 
C.  DEVICES
 ☒N/A
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects: 
a.
Targeted for enrollment at Yale for this protocol: 40 (may screen up to 100 individuals)
b.
If this is a multi-site study, give the total number of subjects targeted across all sites: N/A
2.
Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
☒Flyers
☒ Internet/web postings
☐ Radio
☐ Posters
☐ Mass email solicitation
☐ Telephone
☐ Letter
☐ Departmental/Center website
☐ Television
☐ Medical record review* 
☐ Departmental/Center research boards
☐ Newspaper
☐ Departmental/Center newsletters
☐ Web-based clinical trial registries
☐ Clinicaltrails.gov 
☒ YCCI Recruitment database
☒ Social Media (Twitter/Facebook): 
☐ Other: 
3.  Recruitment Procedures: 
a. Describe how potential subjects will be identified. 
b. Describe how potential subjects are contacted. 
c. Who is recruiting potential subjects? 
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Healthy individuals will be recruited by community advertisement (all announcements have been 
approved by the HIC) through print or internet media. In addition, subjects may learn about our study 
and be given contact info through research staff of other IRB-approved studies. We will provide 
research staff of other research groups with a letter explaining our study procedures, need for 
subjects, and eligibility criteria. They will be asked to tell their subjects about the possibility of 
participating in our study and how to contact us for more info. Through this process of collaboration, 
our ‘collaborators’ will not be screening our subjects, they will only be telling them about an 
additional research opportunity that may or may not be available to the subject.  Study personnel 
listed on this protocol may also inform subjects with whom they have contact about other research 
opportunities regarding other studies for which they are also listed as study personnel. In this case, 
they may provide contact information to the subject. All recruitment will be conducted by Local HIC-
approved study personnel who completed HIC training requirements.
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
5. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization for either the 
entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of a phone or email 
screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: 
☐ For entire study 
☒ For recruitment/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: 
Subjects are, in most cases, screened by phone, Zoom or are screened off-site. Both situations are 
not suitable or practical for obtaining signed authorization.
The investigator assures that the protected health information for which a Waiver of Authorization has been 
requested will not be reused or disclosed to any person or entity other than those listed in this application, except 
as required by law, for authorized oversight of this research study, or as specifically approved for use in another 
study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale HIPAA-Covered 
entity must be accounted for in the “accounting for disclosures log”, by subject name, purpose, date, recipients, 
and a description of information provided.  Logs are to be forwarded to the Deputy HIPAA Privacy Officer.
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6.
Process of Consent/Assent: Describe the setting and conditions under which consent/assent will be obtained, 
including parental permission or surrogate permission and the steps taken to ensure subjects’ independent 
decision-making. 
A trained research staff member at the performance site will obtain written informed consent prior to 
any study related procedures either in person or via Zoom.  For those consents conducted via Zoom a 
photo will be taken of the consent form including signature page for verification per Yale’s 
guidelines..  The informed consent process will be conducted 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: Indicate how the personnel obtaining 
consent will assess the potential subject’s ability and capacity to consent to the research being proposed. 
Comprehension will be assessed during the informed consent process through a verbal interaction 
between the prospective subject and study personnel obtaining informed consent.
8.
Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for research involving 
non-English speaking subjects. If enrollment of these subjects is anticipated, translated copies of all consent 
materials must be submitted for approval prior to use. 
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. If you will request either a waiver of consent, or a waiver of signed consent 
for this study, complete the appropriate section below.
☐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.)
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 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 ☒
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?   
Medical/psychiatric history, urine drug screen results, psychological assessments, MRI data, email 
addresses, phone numbers, all geographic subdivisions smaller than a State, including: street address, 
city, county, precinct, zip codes, all elements of dates related to an individual, including: birth date, 
admission date, discharge date, date of death, and all elements of dates (including year) indicative of 
such age, except that such ages and elements may be aggregated into a single category of age 18 or 
older. 
2.
How will the research data be collected, recorded and stored? 
Assessment, screening, and interview data will be recorded on paper, and in Qualtrics on password-
protected computers, and on Yale ITS shared server with limited access to approved research staff. 
Data from scans and assessments will be labeled with a corresponding subject identification number 
and stored as described above. A ‘master file’ will record the identity of the subject numbers and be 
kept in a secure fashion either in a locked cabinet or an encrypted password-protected file stored on a 
password-protected computer. Access to data and PHI will be strictly limited to approved study 
personnel and others allowed through disclosure policies.
De-identified MRI data will be stored on a secure server and may be archived and/or backed-up to a 
portable hard drive/flash drive, CD or DVD.
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? 
MRI data and assessment data will be identified by subject number rather than name. Screening 
information will remain identified by name. Procedures to protect this PHI have been described above. 
After termination of this study and completion of all analysis and publications,, we will follow current 
procedures from the HIC when de-identifying and storing/destroying records. Private identifiable 
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information will not appear in any publication or be released to anyone without the individual’s written 
consent. 
Human subjects enrolled in the study are assigned a subject-specific random identifier. Subject 
identifiers and the means to link the subject names and codes with the research data are stored in 
separate locations within the database. The software of the database limits the ability to connect the 
random identifier to the actual subject identification information to research team members only. 
Access to the database is password protected and each research team member is required to have a 
unique ID and password to gain access to the database. Authorized users employ their netid and 
authentication is performed using Yale’s central authentication server. Users always access research 
data through the random identifier only. Direct identifiers belonging to subjects who withdraw from 
the study, will be stripped from the key. 
Data is protected by storage in locked file cabinets, password protected computers, and shared limited 
access server. Please refer to section IV question 2 above for more details.
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 de-identified 
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? 
Coverage defined by the COC regulation is automatic and in compliance with the requirements of the law and 
is a term and condition of award for grant recipients who are collecting identifiable, sensitive information as 
part of their NIH funded research.
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.) 
There are no direct benefits from participation in this research protocol. However, knowledge gained 
may help us to better understand how individual difference factors that contribute to variation in 
neuroimaging studies, which may be used to design more effective research protocols for use in 
psychiatric populations.
         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.
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2.
Payments for Participation (Economic Considerations): Describe any payments that will be made to subjects, 
the amount and schedule of payments, and the conditions for receiving this compensation.
Potential participants will be paid $25 to participate in a baseline screening session and $10 for a 
medical screening session. Eligible participants will be paid $145 for participation in each fMRI 
session, with a bonus of $75 for completing both sessions. The total possible compensation for 
participants is therefore $400.
In addition, subjects may be paid a referral payment up to $25 for each eligible participant they refer 
to this study.
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. 
There are no costs to the subject for participation. 
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? 
When appropriate, the subject may be referred to a suitable treatment program.
c.
Are there any limits to the treatment being provided? 
The study staff will not provide treatment. In case of injury, only evaluation and referral 
will be provided. A follow-up will be completed to ensure the subject sought treatment 
and if not, why.
d.
Who will pay for this treatment? 
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.
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IMPORTANT REMINDERS
Will this study have a billable service?  Yes ☐
 No ☒ 
Are there any procedures involved in this protocol that will be performed at YNHH or one of its affiliated entities?  
Yes ☐  No ☒ 
References
References
Beck, A. (1978). Depression Inventory, Center for cognitive therapy.
Beck, A., Epstein N, Brown G, Steer RA (1988). "An inventory for measuring clinical anxiety: 
psychometric properties." J Clin Consult Psychology 56: 893-897.
Brennan, M. J. (2012). "The Clinical Implications of Cytochrome P450 Interactions With Opioids and 
Strategies for Pain Management." Journal of Pain and Symptom Management 44(6, Supplement): S15-
S22.
Comer, S. D., E. D. Collins, R. B. MacArthur and M. W. Fischman (1999). "Comparison of intravenous 
and intranasal heroin self-administration by morphine-maintained humans." Psychopharmacology (Berl) 
143(4): 327-338.
Comer, S. D., V. E. Metz, Z. D. Cooper, W. J. Kowalczyk, J. D. Jones, M. A. Sullivan, J. M. Manubay, 
S. K. Vosburg, M. E. Smith, D. Peyser and P. A. Saccone (2013). "Comparison of a drug versus money 
and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid 
addicts." Behavioural pharmacology 24(0): 504-516.
Cooper, Z. D., M. A. Sullivan, S. K. Vosburg, J. M. Manubay, M. Haney, R. W. Foltin, S. M. Evans, W. 
J. Kowalczyk, P. A. Saccone and S. D. Comer (2012). "Effects of repeated oxycodone administration on 
its analgesic and subjective effects in normal, healthy volunteers." Behav Pharmacol 23(3): 271-279.
Fox, H. C., S. R. Axelrod, P. Paliwal, J. Sleeper and R. Sinha (2007). "Difficulties in emotion regulation 
and impulse control during cocaine abstinence " Drug Alc Dep.
Gorka, S. M., D. A. Fitzgerald, H. de Wit, M. Angstadt and K. L. Phan (2014). "Opioid modulation of 
resting-state anterior cingulate cortex functional connectivity." J Psychopharmacol 28(12): 1115-1124.
Gratz, K. L. and L. Roemer (2004). "Multidimensional assessment of emotion regulation and 
dysregulation: Development, factor structure, and initial validation of the difficulties in emotions 
regulation scale." Journal of Psychopathology and Behavioral Assessment 26: 41-54.
Gronlund, J., T. Saari, N. Hagelberg, I. K. Martikainen, P. J. Neuvonen, K. T. Olkkola and K. Laine 
(2010). "Effect of telithromycin on the pharmacokinetics and pharmacodynamics of oral oxycodone." J 
Clin Pharmacol 50(1): 101-108.
Gudin, J. (2012). "Opioid therapies and cytochrome p450 interactions." J Pain Symptom Manage 44(6 
Suppl): S4-14.
Kirk, J. M. and H. de Wit (2000). "Individual differences in the priming effect of ethanol in social 
drinkers." Journal of Studies on Alcohol 61(1): 64-71.
McCabe, S., B. T. West, C. J. Teter and C. J. Boyd (2012). "Medical and nonmedical use of prescription 
opioids among high school seniors in the united states." Archives of Pediatrics & Adolescent Medicine 
166(9): 797-802.
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McNair, D., M. Lorr and L. Droppleman (1981). Manual of the profile of mood states. San Diego, 
California.
Morean, M. E., H. de Wit, A. C. King, M. Sofuoglu, S. Y. Rueger and S. S. O’Malley (2013). "The 
Drug Effects Questionnaire: Psychometric Support across Three Drug Types." Psychopharmacology 
227(1): 177-192.
Ordonez Gallego, A., M. Gonzalez Baron and E. Espinosa Arranz (2007). "Oxycodone: a 
pharmacological and clinical review." Clin Transl Oncol 9(5): 298-307.
Patton, J. H., M. S. Stanford and E. S. Barratt (1995). "Factor structure of the barratt impulsiveness 
scale." Journal of Clinical Psychology 51(6): 768-774.
Saari, T. I., J. Gronlund, N. M. Hagelberg, M. Neuvonen, K. Laine, P. J. Neuvonen and K. T. Olkkola 
(2010). "Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and 
orally administered oxycodone." Eur J Clin Pharmacol 66(4): 387-397.
Samer, C. F., Y. Daali, M. Wagner, G. Hopfgartner, C. B. Eap, M. C. Rebsamen, M. F. Rossier, D. 
Hochstrasser, P. Dayer and J. A. Desmeules (2010). "Genetic polymorphisms and drug interactions 
modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and 
safety." Br J Pharmacol 160(4): 919-930.
Shipley, W. (1967). Shipley Institute of Living Scale. Los Angeles, CA, Western Psychological Services 
Stringaris, A., R. Goodman, S. Ferdinando, V. Razdan, E. Muhrer, E. Leibenluft and M. A. Brotman 
(2012). "The Affective Reactivity Index: a concise irritability scale for clinical and research settings." 
Journal of Child Psychology and Psychiatry, and Allied Disciplines 53(11): 1109-1117.
Wardle, M. C., D. A. Fitzgerald, M. Angstadt, C. A. Rabinak, H. de Wit and K. L. Phan (2014). "Effects 
of oxycodone on brain responses to emotional images." Psychopharmacology 231(22): 4403-4415.
Zacny, J. P. and S. A. Lichtor (2008). "Within-subject comparison of the psychopharmacological 
profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers." Psychopharmacology 
196(1): 105-116.
Gorka, S. M., Fitzgerald, D. A., de Wit, H., Angstadt, M., & Phan, K. L. (2014). Opioid modulation of 
resting-state anterior cingulate cortex functional connectivity. J Psychopharmacol, 28(12), 1115-1124. 
doi:10.1177/0269881114548436
Gronlund, J., Saari, T., Hagelberg, N., Martikainen, I. K., Neuvonen, P. J., Olkkola, K. T., & Laine, K. 
(2010). Effect of telithromycin on the pharmacokinetics and pharmacodynamics of oral oxycodone. J 
Clin Pharmacol, 50(1), 101-108. doi:10.1177/0091270009336444
Ordonez Gallego, A., Gonzalez Baron, M., & Espinosa Arranz, E. (2007). Oxycodone: a 
pharmacological and clinical review. Clin Transl Oncol, 9(5), 298-307. 
Saari, T. I., Gronlund, J., Hagelberg, N. M., Neuvonen, M., Laine, K., Neuvonen, P. J., & Olkkola, K. T. 
(2010). Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and 
orally administered oxycodone. Eur J Clin Pharmacol, 66(4), 387-397. doi:10.1007/s00228-009-0775-8
Wardle, M. C., Fitzgerald, D. A., Angstadt, M., Rabinak, C. A., de Wit, H., & Phan, K. L. (2014). 
Effects of oxycodone on brain responses to emotional images. Psychopharmacology (Berl), 231(22), 
4403-4415. doi:10.1007/s00213-014-3592-4
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ICF_001.pdf: 
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HIC#:2000020857
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Opioid consent
Version 11
COMPOUND AUTHORIZATION/CONSENT FOR 
PARTICIPATION IN A RESEARCH PROJECT
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE MAGNETIC RESONANCE 
RESEARCH CENTER
Study Title: Influence of medication on functional connectivity
Principal Investigator:  Sarah W. Yip, PhD
Funding Source: National Institute on Drug Abuse & departmental account
Invitation to Participate and Description of Project
You are invited to participate in a research study designed to assess potential sources of variance 
for neuroimaging studies. This research study will use functional magnetic resonance imaging 
(fMRI) to measure changes in the flow of blood through the brain during periods of rest.  The 
proposed research will explore the effects of a single dose of oxycodone (15mg) on brain activity 
during neuroimaging measures (fMRI). You are invited to participate in this study because you 
are a medically healthy adult. If you are eligible, you will be one of approximately 40 individuals 
participating in this study.
In order to decide whether or not you wish to be a part of this research study you should know 
enough about its risks and benefits to make an informed judgment. This consent form gives you 
detailed information about the research 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, possible benefits and possible alternative 
treatments. Once you understand the study, you will be asked if you wish to participate; if so, 
you will be asked to sign this form.
Description of Procedures
Screening: 
The total time of this process is estimated to be from 3-4 hours and may take more than 1 visit to 
complete either in person or virtually via Zoom. To determine if you are eligible for this study, we 
will ask you questions about different aspects of your life including your health, smoking, sexual 
behaviors, substance use behaviors and attitudes, and the ways in which you view yourself.  If you 
are determined to be eligible we may ask you to complete additional interviews and questionnaires. 
You may also be asked for a urine drug test. If the drug test is positive then this would exclude 
you from participation in this study and these results would be destroyed to maintain your privacy. 
If you have recently (within the past 6 months) participated in another study under Dr. Yip 
involving an intake/medical screening, you will not need to complete a second screening.  
Baseline assessments:
If you are determined to be eligible for study participation we will ask you to complete a few more 
assessment measures involving interviews and questionnaires. This also may be conducted either 
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Opioid consent
Version 11
in person or virtually via Zoom. This will take about 1½ hours.  During this visit we will also 
schedule your first MRI appointment. 
The researcher will also interview you to determine if it is safe for you to participate in MRI 
scanning. To be sure that you are free of major medical illnesses and that it is safe for you to 
receive the medication, you will also receive a medical evaluation by a study physician. This 
examination will be in person and include a medical history and physical examination and may 
also involve routine cheek swab tests, urine analysis, and urine toxicology to test your urine for 
drugs of abuse such as heroin, cocaine, marijuana, and benzodiazepines, as deemed necessary by 
the study physician.  This will take about 1 hour. Results of the medical evaluation will be made 
available to you or your personal physician upon your written request.  Before admission into the 
study, a study physician reviews all results. Once admitted into the study, the study physician 
will access your Yale medical chart once for the purpose of attaining your medical record 
number for the prescription of oxycodone.  We will also ask you for a small cheek swab sample, 
to be taken by the study physician during your medical screening session.  The cheek swab in 
this sample will be used to test for a common genetic variation that can influence how fast your 
body metabolizes medications such as oxycodone. Your sample will only be used to test for this 
variation and will not be saved for other purposes.
This research study will use functional magnetic resonance imaging (fMRI) to measure changes 
in the flow of blood through the brain during resting states or performance of a behavioral task. If 
you have significant metal implants in your body (for example, a metal skull plate), you will be 
excluded from the study. We are also excluding from this study women who are pregnant or 
nursing because oxycodone could be harmful to an unborn baby and because oxycodone does enter 
breast milk. If you become pregnant while you are in the study, please let us know as soon as 
possible. Women of child-bearing age will be given a pregnancy test prior to scanning to rule out 
pregnancy. You will be required to abstain from the use of any alcohol or drugs (other than 
prescription) 24 hours prior to your scan. If at any time during the study you are found to be at risk 
for hurting yourself you may be hospitalized as a safety measure.
MRI scanning:
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. 
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, as well as 
devices to measure things such as your heart rate.
You will be asked to participate in up to two 90 minute fMRI sessions. For one of the sessions we 
will require you take a single dose of oxycodone (15mg) just prior to the scan. For one of the 
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session we will require you to take a placebo pill just prior to the scan.  The order in which you 
receive oxycodone or placebo pills will be randomized and will not be known to you or the primary 
researcher. A licensed physician will be on-call for both scans.
During the MRI session, you will be able to communicate with the research staff with 
headphones and a microphone. We may 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. We will 
take a series of pictures while you are simply resting with your eyes open and laying still. In 
between each series of resting pictures (approximately 6 minutes each), we will ask you to 
answer some questions about how you are feeling and you will indicate your responses using a 
simple button or lever press. We will also take another series of pictures will be taken for a more 
detailed image of your brain. During this time you will be asked to simply lie still. You may 
close your eyes during this time. We may also take pictures of your brain while you are 
performing a simple emotion regulation task (described below).  The entire imaging procedure 
may last between 60 and 90 minutes. In addition to the MRI operator, a member of the research 
team will accompany you and will stay for the MRI. For all scans a trained medical professional 
will also be on hand in addition to a licensed medical doctor being available by pager. 
During fMRI scanning, you may be participating in a task called the Monetary Incentive Delay 
Task (MID).  The basic goal of the task is to press a button as quickly as possible when you see a 
target, in order to win or avoid losing money.  At the start of each trial, you will see a screen 
indicating the amount of money that can be won or lost ($0, $1, or $5).  Then there will be a 
short delay and a box will flash on the screen.  Your job is to press the button as soon as you see 
the target – in other words ‘hit the box’.  After each trial, you will receive feedback indicating 
whether or not you hit the target and also telling you how much money you have won so far. 
Some of the trials will be trials for which you may win money, as indicated via a cue (for 
example, ‘WIN $1’).  Other trials will be trials for which you may lose money, as indicated via a 
cue (for example ‘LOSE $1’).  For both trial types, your goal is to press the button as quickly as 
possible in response to the target.  The task takes about 12 minutes.  In order to help you to 
perform your best during task performance we will give you the opportunity to practice the task 
before the MRI scan.
Risks and Inconveniences
During the study you will be asked questions related to your mental health and drug use history 
that may make you feel uncomfortable or sad. If this happens, you will be allowed to take a 
break for as long as is necessary before proceeding. We would like you to tell us about any times 
you use cannabis or any other drugs while you are in the study.  It is not illegal to report past 
substance use and we will make every effort to insure your confidentiality. However, you should 
understand that there is a risk that you may be recognized by other participants or staff involved 
in the study, but this is no greater than the usual risk of identification that occurs in our usual 
treatment in this clinic.
Magnetic Resonance Imaging: 
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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, all people involved with the study must 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 health care 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 health care 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 health care MR exam and for that reason, they will not be 
made available for health care purposes. 
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. 
Oxycodone 
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Risks associated with oxycodone use include gastrointestinal upset, constipation, nausea, 
vomiting, tiredness, dizziness, light-headedness, itching, headache, blurred vision and dry mouth. 
Among these, the most common risks include constipation (in 25-30% of individuals), nausea 
(25%), drowsiness (25%), dizziness (15%) and vomiting (10-15%). It is possible that serious, 
life-threatening or fatal respiratory depression may occur. As you will only be taking a single 15 
mg oxycodone pill, risks are minimal and trained staff will be on hand to monitor you. 
Should these side effects occur, you will be offered symptomatic relief by the study physician 
(Dr. Camenga or her designee) as appropriate based on her clinical judgement.  You will be 
monitored closely until side effects have subsided. The study physician, Dr. Camenga has 
significant expertise in adolescent and young adult substance use and addiction and adolescent  
medicine. She is therefore extremely well qualified to deal with possible oxycodone-associated 
side effects, in the unlikely event that they arise.
A dose of naloxone will be on hand to counteract any effects from the opioid should the need 
arise (as determined based on the discretion of the study physician), although this is highly 
unlikely to be necessary given the low dose of oxycodone. Other risks associated with 
oxycodone include the risk of possible interactions with other opioids, alcohol, benzodiazepines 
and other medications.  For this reason, participants taking medications that could interact with 
oxycodone are not eligible for this study, and we will ask you to abstain from drugs or alcohol 
for 24 hours prior to each study visit.
You will not be allowed to drive after the scan on the day when you take the medication. As 
such, you will need to arrange for transportation home following the scan. 
As with most opioid medications, oxycodone has abuse liability and its prolonged use may lead 
to addiction and drug seeking behavior. These adverse events are unlikely to develop when 
oxycodone is used at approved doses and for a short time (single administration) as in this study. 
In addition to being closely monitored during study visits, you will be contacted via phone 
following each study visit and at one-month follow-up by a trained member of the research staff 
to check for any possible any adverse effects and will be referred to the study physician if 
necessary. You will also be given a card to keep in your wallet with the contact information for 
the study physician.  The study physician, Dr. Camenga, has significant expertise in adolescent 
and young adult substance use and addiction and adolescent medicine.  She is therefore 
extremely well qualified to deal with possible oxycodone-associated risks, in the unlikely event 
that they arise.
Baseline assessments
Completing the baseline assessments has minimal potential for harm. We will do everything in 
our power to minimize any risks or inconveniences. We would like you to feel comfortable in 
our testing environment. Also, please note that at any time during the course of this study, you 
may ask us to stop.
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Benefits
The study will be of no direct benefit to you. It will provide us with information on the possible 
influence of acute opioid use on parts of the brain. We hope and believe this information will 
prove useful in the future ultimately with respect to determining if these conditions affect 
neuroimaging results.  
Economic Considerations
There are no additional costs to you for participation in this study except for transportation to the 
study visits and your time.  You will be paid $25 to participate in an initial screening session and 
$10 in a medical screening session.  Eligible participants will be paid $145 for participation in 
each of the fMRI sessions, with a bonus of $75 for completing both sessions. The total possible 
compensation is therefore up to $400. If you leave the study prior to completing it, you will be 
paid only for those parts you have completed.
In addition, you may be eligible for a referral payment up to $25 for each eligible participant you 
refer to this study.
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
This is not a treatment study. The only alternative in this study is simply to not participate. You 
are free to choose not to participate and if you do become a subject, you are free to withdraw 
from the study at any time. If you withdraw it will not adversely affect your relationship with this 
clinic or the clinicians or doctors here. 
Confidentiality and Privacy
If you decide to be in this study, the researchers will get information that identifies you and your 
personal health information. This may include information that might directly identify you, such 
as your name and address. All personal information will be coded and stored in a locked cabinet 
to protect your confidentiality.  
We will replace your identifying information with a code that does not directly identify you. The 
principal investigator will keep a link that identifies you to your coded information until all 
analyses and publications arising from this research are complete, but 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. The research team will only give this coded 
information to others to carry out this research study. After termination of this study and 
completion of all analysis and publications, all data and screening information will be de-
identified, thereby making the data anonymous, 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.  
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The information about your health that will be collected in this study includes:

Past and present medical records

Research records

Records about phone calls made as part of this research

Records about your study visits

Information obtained during this research about:

Laboratory test results

The diagnosis and treatment of a mental health condition
Information about you and your health, which might identify you, may be given to

Yale University School of Medicine personnel involved in the study on a need to know 
basis

Members of the Human Investigations Committee or ethics Committee(s)

Key Investigators: Sarah Yip, PhD; Dustin Scheinost, PhD; Deepa Camenga, MD

Key Study Personnel

The Secretary of the Department of Health and Human Services, if needed for an audit of 
the study

The National Institutes of Health, study funding source

The Food and Drug Administration (FDA)

Those individuals at Yale who are responsible for the financial oversight of research 
including billings and payments
The research team can only give information about you to others for research with your 
permission. We will make every effort to insure your confidentiality. In all records of the study 
you will be identified only by a number. Your name will not appear in any publication or be 
released to anyone without your written consent. However, you should understand that there is a 
risk that you will be recognized by other participants or staff involved in the study, but this is no 
greater than the usual risk of identification that occurs in our usual treatment in this clinic. If you 
find this risk unacceptable you should not sign this consent form.
The data we collect from you may be shared across other protocols the Principal Investigator is 
running. 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 and APT Foundation 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 
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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. 
If you decide to take part in this research study, you will be required to give us information about 
your substance use (e.g., past or current opioid use). To protect this information, this research is 
covered by a Certificate of Confidentiality from the National Institutes of Health. The 
researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other 
scientific research, as allowed by federal regulations protecting research subjects. 
 The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the Department of Health and Human Services through NIDA which is 
funding this project or for information that must be disclosed in order to meet the requirements 
of the federal Food and Drug Administration (FDA).  You should understand that a Certificate of 
Confidentiality does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. If you want your research information released to an insurer, 
medical care provider, or any other person not connected with the research, you must provide 
consent to allow the researchers to release it.
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, 
state, or local law such as child abuse and neglect, or harm to self or others]. 
You have the right to review and copy your health information in your medical record in 
accordance with institutional medical records policies.  However, by deciding to take part in a 
single or double blinded treatment study and sign this permission form, you will not be allowed 
to look at or copy your study related information until after the research is completed.  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 while on study, seek treatment and contact the study doctor as soon as you are 
able, (203) 737-4358. Yale School of Medicine and [Specify health care facility, e.g., Yale-New 
Haven Hospital, 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.
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Voluntary Participation and Withdrawal
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 (the person who has 
been scheduling your appointments) 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.
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 or with Yale-New Haven 
Hospital
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, Sarah Yip, PhD; 1 Church Street, 7th Floor, New Haven, CT, 06510-0333.
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 to consider this research and the consent form carefully – as long as you feel is 
necessary – before you make a decision.
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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 Person Obtaining Consent or PI
Date
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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.
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. Sarah W. Yip at (203) 737-4358. 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.
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