Clinical trial NCT01664741
Conditions: Nicotine Dependence
Keywords: Nicotine dependence cigarette smoking nicotine replacement therapy positron emission tomography
Sponsor: Johns Hopkins University
Start date: 2012-04-01; Completion date: 2018-12-01
Enrollment: 127 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The proposed research will provide significant new gender-specific information of scientific and clinical relevance on the function of the mu-opioid system in nicotine dependence and therapeutic effectiveness of nicotine replacement therapy (NRT). The studies will help to explain the differences in the prevalence of smoking in men and women, sex-specific differences in nicotine craving and withdrawal as well as the poorer therapeutic response to NRT. This work may pave the way to the design of improved pharmacotherapies that can more effectively target the endogenous opioid system in the treatment of nicotine dependence.

Detailed description:
While smoking prevalence has declined for both men and women over the last two decades, rates among women have shown a much shallower decrease and, in recent years, prevalence of cigarette initiation has been higher for girls than boys. Smoking among women of child-bearing age has significant negative health consequences for mother and child, increasing fetal and infant morbidity and mortality. Women are both less likely to initiate a quit attempt and more likely to relapse if these women do quit. Nicotine replacement therapy (NRT), still the most widely used smoking treatment intervention in the United States, is less effective for women compared with men, and women report less craving reduction on NRT. The endogenous opioid system is involved in smoking initiation, nicotine craving and reward as well as nicotine withdrawal symptoms. Interestingly, research suggests that sexual dimorphic features of the endogenous mu-opioid system may in part explain gender differences in nicotine effects. To better understand the role of the mu-opioid system in poorer NRT responses in women, this proposal will examine NRT effects on mu opioid receptor binding potential (MOR BP) in female compared to male smokers during active versus placebo NRT. Specifically, nicotine dependent women and men in active smoking status will undergo PET imaging for MOR BP measurement using 11C-carfentanil. Following baseline PET measurement in active smoking (scan 1), smokers will be randomized to active or placebo nicotine replacement therapy ((A-NRT or P-NRT); 72 hours later, a second scan will be obtained. As a reference group, demographically-matched women and men who have never smoked will undergo two scans as well. Behavioral measurements of nicotine reward, craving and withdrawal will be obtained repeatedly across the protocol. The proposed research will provide significant new, gender-specific information of scientific and clinical relevance on the function of the mu-opioid system in nicotine dependence and therapeutic effectiveness of nicotine replacement therapy.

Arms: arm 1: 21 mg nicotine patch arm 2: Matching placebo patch arm 3: Demographically-matched women and men who have never smoked
Interventions: intervention 1: Nicotine patch - transdermal intervention 2: placebo
Intervention descriptions: intervention 1: 21 mg patch intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
JHMIRB eFormA  01 
Version7.5 Dated:   04/2014 
 
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Johns Hopkins Medicine - eForm A 
 
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1. 
Abstract 
 
This protocol is an extension of previously completed studies examining the mu- and delta-opioid system in 
alcohol dependent and healthy control subjects.  The current procedures extend this work by examining 
nicotine effects on the mu-opioid system during active smoking and nicotine replacement therapy.  This work 
was previously approved in V5.0 – V5.12 of RPN 00-02-03-05.  Funding for this study is pending from the 
NIH National Institute on Drug Abuse. 
 
 
2. 
Objectives (include all primary and secondary objectives) 
 
This protocol will: 
 
1. Characterize the effects of cigarette smoking and nicotine replacement treatment (NRT) on the mu-
opioid system 
 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, drug or 
device, and any other relevant information to justify the research) 
 
The endogenous opioid system is involved in smoking initiation, nicotine craving and reward as well as 
nicotine withdrawal symptoms. Interestingly, research suggests that sexual dimorphic features of the 
endogenous mu-opioid system may in part explain gender differences in nicotine effects.  To better 
understand the role of the mu-opioid system in poorer NRT responses in women, this proposal will examine 
nicotine replacement therapy (NRT) effects on mu opioid receptor binding potential (MOR BP) in female 
compared to male smokers during active (ANRT) versus placebo (PNRT) treatment. 
 
Hypotheses: 
 
1. We predict that MOR BP will be reduced under active smoking conditions compared to nonsmokers. 
Hypotheses:  1a) We predict that female smokers will have lower MOR BP compared to male smokers 
during active smoking status. 1b) We predict that females smokers in active smoking status will have 
lower MOR BP compared with nonsmoking women. 1c) We predict that males smokers in active 
smoking status will have lower MOR BP compared with nonsmoking males. 
 
2. We predict that smokers with ANRT will have lower MOR BP compared to smokers on PNRT. 
Hypotheses:  2a) Women on A-NRT will have higher MOR BP compared with men on A-NRT.  2b) We 
predict that MOR BP in both A-NRT groups will be elevated relative to nonsmokers. 2c) Women on A- 
NRT will have higher craving and withdrawal severity than men on A-NRT. 2d) Women on placebo NRT 
will have higher MOR BP than men on placebo NRT. 2e) Men and women on placebo NRT will have 
higher MOR BP than men and women on active NRT. 2f) Women on placebo NRT will have higher 
craving and withdrawal severity than men on placebo NRT. 
 
3. We predict that smokers carrying the minor allele of the A118G polymorphism of the mu opioid receptor 
gene will have higher MOR BP and greater nicotine craving during PNRT and ANRT. 
 
In our original study, we observed an effect of smoking status on mu-opioid binding potential (MOR BP) in 
alcohol dependent subjects maintained on nicotine replacement treatment.  Specifically, nicotine dependent 
subjects had significantly lower mu binding potential compared to subjects who were not nicotine dependent.  
Interestingly, this nicotine effect was in the opposite direction of the effect of alcohol withdrawal in alcohol 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
JHMIRB eFormA  01 
Version7.5 Dated:   04/2014 
 
Page 2 of 14 
 
dependent subjects.  That is, alcohol dependent subjects in alcohol withdrawal had significantly elevated mu 
opioid binding potential compared with healthy control subjects.  Unfortunately, in our original study sample, 
there were insufficient numbers of healthy control smokers to disentangle the effects of smoking and alcohol 
withdrawal on MOR BP. 
 
The proposed research will extend this original observation in alcohol dependent subjects through an 
investigation of mu-opioid system status in healthy nicotine-dependent social drinkers.  Smokers will be 
studied during active smoking status and then during treatment with active versus placebo nicotine 
replacement therapy.  Gender differences in mu-opioid status will be examined.  In future research, we will 
extend this research to alcohol dependent participants. 
 
We also are proposing to examine effects of a relatively common, functional polymorphism of the MOR gene 
(Exon 1 functional Asn40Asp (A118G) missense single nucleotide polymorphism) on nicotine’s modulation of 
MOR BP. Recent data support the role of A118G polymorphism in smoking initiation and nicotine craving 
and dependence (Ray, 2006; Lerman, 2004; Munafo 2007, Wang, 2008; Zhang, 2006). Notably, Ray et al 
(2006) showed a gene by gender interaction on the relative reinforcing value of nicotine (number of nicotine 
cigarette puffs); among women, only the minor allele was associated with reduced nicotine reward. Two 
studies have examined the role of the A118G polymorphism in therapeutic responses to NRT, with differing 
results.  One study showed better treatment outcomes in persons expressing the minor allele (Lerman, 2004) 
whereas the other study showed better treatment outcomes in persons expressing the major allele (Munafo, 
2007). Clearly more research is needed on the role of this genotype on smoking maintenance and NRT 
effectiveness.  While the MOR gene is our primary focus, we also will explore opportunities to study genes 
related to smoking (e.g., nicotinic acetylcholine receptor subunit genes). 
 
4. 
Study Procedures 
 
a. Study design, including the sequence and timing of study procedures (distinguish research 
procedures from those that are part of routine care). 
 
Following screening for study eligibility and informed consent, subjects will complete a detailed 
assessment of alcohol history, nicotine history, psychiatric status, medical history and physical 
examination (including standard laboratory tests) and assessment of neuroanatomy by MRI prior to the 
PET procedure. We also will obtain a breath carbon monoxide (CO) reading to confirm 
smoking/nonsmoking status and a blood spot for determination of phosphatidylethanol (PEth) to confirm 
social/heavy alcohol use status.  When available, we also review the JHH medical record to determine 
initial and ongoing study eligibility. Eligible subjects will be admitted as inpatients on the Bayview Medical 
Center CRU. 
 
Healthy Control and Nicotine Dependent Subjects Procedures: 
 
On the morning of the first scan, subjects report to the JHH research office fasting and complete a 
breathalyzer test for recent alcohol use, a urine test for recent drug use and a pregnancy test.  In 
addition, subjects complete several self-report measures on recent lifestyle and behaviors and current 
mood.  Finally, subjects eat a calorie-controlled breakfast.  
 
Nicotine dependent subjects are allowed to smoke ad lib in a specially designated area until shortly 
before PET scan 1. Several minutes prior to the scan subjects are administered a controlled dose Quest 
cigarette (0.6mg nicotine) using the CReSS device to monitor smoking characteristics.  
 
Following the first scan, subjects will be transported to the Bayview Medical Center CRU for their 3-night 
stay.  Subjects will be transported by shuttle or private care service and will be escorted by a research 
assistant. 
 
Following PET scan 1 and promptly after admission to the CRU subjects will be placed on either active 
(21 mg) or placebo transdermal nicotine patch. Nicotine craving and withdrawal severity scores will be 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
JHMIRB eFormA  01 
Version7.5 Dated:   04/2014 
 
Page 3 of 14 
 
obtained twice daily for the duration of the CRU stay.  On day 4 following the first PET scan subjects will 
undergo their second carfentanil scan.  They will be transported back to JHH from the Bayview CRU. 
 
This study uses Quest 0.6 mg nicotine cigarettes available commercially.  Quest cigarettes utilize a 
proprietary process that enables the production of nicotine-controlled tobacco that tastes and smokes 
like the tobacco in other cigarette products.  These cigarettes have comparable levels of tar and other 
cigarette constituents as regular commercially available cigarettes and differ only in nicotine level. 
 
Quest Cigarettes are smoked through sterile mouthpieces of Clinical Research Support System (CReSS) 
smoking topography machines (Plowshare, Baltimore, MD).  The duration of each puff is measured by 
the CreSS software.  Study staff will document the amount of time the participant took to smoke the 
cigarette and the time smoking was completed.  Measures of nicotine reward, craving and withdrawal will 
be obtained before and after cigarette administration as well as every fifteen minutes during the scan 
using the Nicotine Effects Scale (Hutchison, 2002). 
 
PET Procedures:  All subjects will undergo a MRI in order to obtain structural data, to align the PET 
imaging planes and to assess for behavioral tolerance of the scanning procedures.  PET data will be 
acquired on HRRT scanner.  11C-carfentanil will be used for mu-opioid receptor scans.  An IV catheter is 
placed. Prior to the scan, a blood specimen for progesterone measurement for menstrual cycle 
determination is collected using the IV line.  Subjects will be positioned in the scanner.  Images will be 
acquired over ninety minutes with an increasing duration. The patient’s position will be continuously 
monitored over the 90-minute scan and any deviation from the original line will be corrected by 
repositioning.   
Time points will be decay corrected by a calculated method and reconstructed using a 26 cm X 26 cm 
field of view and a 128 X 128 pixel matrix.  The scans will be corrected for attenuation immediately prior 
to acquisition of the emission data using an external source.  For calculation of binding potential, images 
from 35-86 minutes will be summed and smoothed using a 3 X 3 neighborhood averaging filter.  Region-
of-interest (ROI) placement will be based on the SPGR and T1 MRI images.  The MRI images will be co-
registered with the PET images in the X-Y plane by translating or rotating the MRI images until the PET 
and MRI fiducials overlap.  ROIs will then be placed on paired left and right structures in the two 
hemispheres.  The ROIs will then be transferred directly to the summed images for sampling.  Final 
values will then be given as the ratio (ROI - occipital cortex)/(occipital cortex), where occipital cortex 
represents non-specific binding. 
 
The use of the (region - occipital cortex)/(occipital cortex) ratio for quantification of 11C-carfentanil studies 
has been previously validated and used as a reliable index of mu opioid receptor binding by our group for 
many years (Frost et al, 1989; Frost et al, 1988 Mayberg et al, 1991).  This parameter is proportional to 
the Bmax/KD ratios.  It permits comparison of data from different patient groups, but does not distinguish 
Bmax (receptor number) and KD (dissociation constant).  Data from the right and left sides will be 
compared to identify right-left asymmetry if it exists.  These data will then be used in the statistical 
analyses described subsequently. 
 
Regions of interest (ROIs) for PET analyses will include: temporal, frontal, parietal, and occipital cortex; 
cingulate cortex; caudate nucleus; putamen; thalamus; amygdala; and occipital cortex as well as others 
areas that are identified as involved in nicotine reinforcement and withdrawal. Right and left ROIs will be 
placed, except in cingulate cortex. Cortical ROIs will be grouped into functional regions such as orbital 
frontal cortex, prefrontal cortex, anterior temporal neocortex, etc.  ANOVA will be used to evaluate the 
main treatment group effect in the PET data.  Relations between individual clinical measures (e.g., peak 
craving, peak withdrawal score) and the PET results will be assessed using Pearson or Spearman (as 
appropriate) correlation to assess the relationship between the set of subjective/behavioral measures 
and the set of regional PET results. We will also examine the use of classificatory methods (discriminant 
functions, cluster analysis) in analyzing the multivariate data sets, when warranted. 
 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
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Blood collection for genotype determination:  20cc of blood will be collected at the time of the 
assessment for DNA extraction and subject genotyping.  Blood will be processed into DNA in Dr. 
Wand’s laboratory. 
 
b. Study duration and number of study visits required of research participants. 
 
Healthy control smokers will have three (3) visits: assessment, MRI and CRU admission.  Total duration 
of the CRU stay will be 3 nights. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Expectations of drug effectiveness are known to influence clinical outcomes.  Subjects will be 
randomized to active versus placebo patch to control for expectancy effects. 
 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. 
 
NRT will be discontinued at the time of discharge from the CRU. 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
The PNRT group is required to determine the effects of smoking cessation on the primary outcome 
measure, MOR BP. 
 
f. 
Definition of treatment failure or participant removal criteria. 
 
Subjects may be terminated from this protocol as a result of several safety concerns.  First, if subjects do 
not comply with CRU rules or study procedures, they will first be warned of possible dismissal and, if 
noncompliance persists, will be terminated from the protocol.  Second, if subjects do not tolerate the 
NRT, we will first attempt to titrate dose induction; however, if symptoms persist, subjects will be dropped 
from the study.  . 
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
At the end of the study the nicotine patch is removed and subjects interested in smoking cessation are 
referred to their doctor. 
 
 
5. 
Inclusion/Exclusion Criteria 
 
We typically consent and screen approximately four persons for each subject who meets full study eligibility 
requirements.  This results in a total consented group of 360 persons, including nicotine-dependent and 
healthy comparison subjects.  Subjects will be recruited through the media. We will also recruit subjects 
who have participated in related studies in our group (NA_00041368; NA_00031348; 
IRB00033324; IRB00045818) and have consented to future contact for research. We will also ask 
subjects for permission to retain their information for recruitment via an IRB approved recruitment 
database for our group (IRB00029464) using the IRB-approved screening database (IRB00029464; 
Recruitment database for the Integrated Program of Substance Abuse Research [IPSAR]).   Minority 
subjects will be recruited in proportion to their representation in the Baltimore metropolitan area.  Men and 
women will be recruited in equal numbers.  To be eligible for study enrollment, nicotine-dependent subjects 
(N=60 who complete the protocols) must be 21 - 60 years old, meet DSM-5 criteria for tobacco use disorder, 
and be actively smoking 10 – 40 cigarettes daily.  Subjects are ineligible who: 1) meet DSM-5 criteria for  


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
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Page 5 of 14 
 
current  alcohol or drug use disorder  (excluding nicotine, marijuana and caffeine); 2) meet DSM-5 criteria for 
life psychotic disorder, current mood or anxiety disorders and are in need of or currently undergoing 
pharmacotherapy.  Participants who are current taking a SSRI or SNRI medication but do not meet current 
diagnostic criteria for a mood or anxiety disorder will be included; 3) are pregnant or lactating; 4) are 
currently experiencing a serious medical condition that would place them at risk or interfere with study 
participation; 5) have a history of severe allergies, multiple adverse drug reactions or known allergy to NRT; 
8) have a Shipley vocabulary score below the 5th grade reading level; 9) abnormal MRI scan; 10) are HIV 
positive (to rule out potential neurological sequalae); 11) significant CNS disease; 12) significant history of 
seizure disorder or closed head trauma; 13) neuroendocrine disorder; or 14) treatment with opioid agonists 
or antagonists within the last six months. 
 
In addition to recruitment of nicotine-dependent subjects, age- and race-matched nonsmokers (N=30 who 
complete the protocols) will be recruited as a comparison sample.   This comparison sample is needed to 
determine magnitude and direction of opioid system derangements in nicotine-dependent subjects relative to 
age-matched controls.  These subjects will be recruited through the media and will include equal numbers of 
men and women.   
 
Table 1:  Inclusion Criteria 
Nicotine- 
Dependent 
Subjects 
Healthy 
Nonsmokers 
Males and females 
X 
X 
Age 21 - 60 (inclusive) 
X 
X 
Meet DSM-5 criteria for tobacco use disorder 
X 
 
Actively smoking 10 – 40 cigs/day 
X 
 
 
Table 2:  Exclusion Criteria 
Nicotine- 
Dependent 
Subjects 
Healthy 
Control 
Nonsmokers 
Abnormal MRI scan 
X 
X 
Weight > 350 lbs 
X 
X 
Currently experiencing serious medical condition that would place 
subject at risk or interfere with study participation 
X 
X 
Meet DSM-5 criteria for life psychotic disorder, current mood 
or anxiety disorders and are in need of or currently undergoing 
pharmacotherapy.  Participants who are current taking a SSRI 
or SNRI medication but do not meet current diagnostic criteria 
for a mood or anxiety disorder will be included; 
X 
X 
DSM-5 criteria for current alcohol use disorder 
X 
X 
DSM-5 criteria for current substance use disorder (non-alcohol) 
(excluding caffeine, marijuana and nicotine); with the exception of 
marijuana, subjects who report drug use in last 30 days or have a 
positive urine toxicology screen at initial assessment will be given 
additional opportunities to qualify for the study. 
X 
X 
For women, amenorrhea; pregnancy, planned pregnancy or lactation; 
postmenopausal women are eligible 
X 
X 
Hx of any central nervous system disorder; or presence of a 
seizure disorder or closed head trauma 
X 
X 
Hx of severe allergies, multiple adverse drug reactions or known 
allergy to NRT 
X 
X 
HIV positive 
X 
X 
Neuroendocrine disorder 
X 
X 
Shipley vocabulary score < 18, corresponding  to a 5th grade 
reading level 
X 
X 
Treatment with antidepressants, neuroleptics, sedative hypnotics, 
glucocorticoids, appetite suppressants, opiates, or dopamine 
X 
X 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
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Version7.5 Dated:   04/2014 
 
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medications within the last 6 months 
Smoking cessation treatment within last 6 months 
X 
X 
 
We exclude potential subjects with a Shipley score below the 5th grade reading level because of concerns 
about their ability to adequately participate in the study procedures.  Many of our behavioral/subjective 
measures are self-administered and require basic literacy skills of the subjects.  If subjects are not at a 5th 
grade level, they have difficulty responding accurately to the study questionnaires. 
 
Historically, we have not had language/hearing-impaired individuals apply for study participation.  If a 
language or hearing impaired individual did apply, s/he would be ruled out on this basis. 
 
Consent Issues: 
 
Consent is obtained at the initial face-to-face interview in the research office by the IRB-approved research 
staff.  Subjects are familiarized with the scope of study procedures and time commitment during the initial 
telephone contact with research staff.  They read and are asked to sign the consent document at the start of 
the face-to-face assessment session. If subjects have questions or concerns, they are free to reschedule the 
assessment and delay signing the consent document. 
 
We take several precautions to ensure that subjects are fully informed and understand the risks of our 
research protocols.  When individuals first call in response to our advertisements, we provide a brief 
overview of the study to acquaint them with the nature and primary requirements of the study.   If the 
individual remains interested and reports for the in-person interview, we obtain a breath alcohol level to 
determine that the potential subject is alcohol-free at the time we obtain informed consent.   
 
 
6. 
Drugs/ Substances/ Devices 
 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Active nicotine patch (21 mg) is the standard of care for management of nicotine withdrawal. 
 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. 
 
Not Applicable. 
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered. 
 
Quest 0.6 mg nicotine and 0.05 mg nicotine ("denicotinized") cigarettes are available commercially. 
These are not regulated by the FDA. 
 
Quest cigarettes utilize a proprietary process that enables the production of nicotine-free tobacco that 
tastes and smokes like the tobacco in other cigarette products. These cigarettes have comparable levels 
of tar and other cigarette constituents as regular commercially available cigarettes and differ only in 
nicotine level. 
 
7. 
Study Statistics 
 
a. Primary outcome variable. 
 
Part I.  CRU Stay: 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
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Version7.5 Dated:   04/2014 
 
Page 7 of 14 
 
 
PET-derived regional mu opioid receptor binding by ROI and SPM 
 
Presence or absence of NRT 
 
Subjective/behavioral measures on the CRU: 
• 
peak analog craving 
• 
peak nicotine withdrawal score 
 
 
b. Secondary outcome variables. 
 
Not Applicable. 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
The proposed sample sizes of 60 nicotine-dependent subjects and 30 non-smoking control subjects 
provide power in excess of .80 to detect a medium effect size in ANOVA analyses of group differences 
and a correlation of .25 at the 95% confidence level. 
 
Analysis of Variance (or, if necessary, Covariance to adjust for baseline group differences) will be used 
to examine differences between nicotine dependent and nonsmoking subjects on PET, neuroendocrine 
and subjective measures. 
 
 
Multiple regression analysis will be the primary data analytic method to examine the relationships 
between the predictor measures (gender, NRT (active vs placebo), nicotine withdrawal severity and 
craving) and opioid receptor binding potential. 
 
Assessment Measures for Statistical Analysis: 
 
This study will not involve the use of a data monitoring board since the therapy to be studied is the 
current FDA approved standard of care. Should a subject experience a serious adverse event, this will 
be immediately reported to the JCCI and to our NIDA project officer.  Also, should we observe a trend in 
the occurrence of adverse events related to one or more study procedures, we will examine the need to 
modify the study protocol to further enhance subject safety.  Finally, in the annual renewal report for this 
project, adverse events will be summarized. 
 
There are no plans for interim data analyses. 
 
d. Early stopping rules. 
 
Pharmacotherapy will be discontinued based on adverse drug reactions. 
 
 
8. 
Risks 
 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
 
This study involves several separate procedures, each of which entails some risk of discomfort or 
medication side-effects.  First, PET risks include a risk of bleeding or infection from the venous catheter, 
which is placed.  The effective radiation dose to the whole body for two studies is below the yearly 
occupational limit for a radiation worker.  Fourth, the nicotine patch dose selected for study in this 
protocol is FDA-approved and has been shown to have a low incidence rate of serious side-effects or 
adverse events in clinical trials with nicotine-dependent patients. Less than 5% of smokers have to stop 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
JHMIRB eFormA  01 
Version7.5 Dated:   04/2014 
 
Page 8 of 14 
 
using a nicotine replacement product because of side effects. Side effects of nicotine patches may 
include: skin rash at the location of the patch; sleep problems when using a 24-hour patch, such as 
having trouble sleeping or having especially vivid dreams. On rare occasions, there have been reports of 
severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the 
mouth, face, lips, or tongue); fast or irregular heartbeat; mouth, teeth, or jaw problems; pounding in the 
chest; severe diarrhea, dizziness, nausea, vomiting, or weakness. The relatively brief period of NRT 
administration in this study (4 days) should minimize the likelihood of any serious problems developing.   
 
Several additional risks occur throughout the course of the study. There is a slight risk of bruising and 
irritation at the site of blood draws.  This risk is minimized through the use of sterile equipment and well-
trained medical personnel.  There is a risk of distress or personal discomfort elicited during assessment 
or psychosocial treatment sessions.  This risk is minimized by the use of standardized assessment and 
treatment procedures that are widely and successfully used in clinical settings. Also, all study staff are 
trained in nonjudgmental interview techniques and crisis intervention procedures.  If serious 
psychological concerns (e.g., suicide risk) arise, staff are trained to refer these to Dr. McCaul, a licensed 
psychologist. 
 
If subjects are required to have an x-ray examination of the head/eyes because of a history of working 
with metal or a history of metal in the subject’s head/eyes, the subject will be exposed to additional 
radiation.  The total additional amount of radiation subjects will receive from the x-ray examination is 0.01 
rem.  Naturally occurring radiation (cosmic radiation, radon, etc) produces whole body radiation 
exposures of about 0.3 rem per year.  Occupationally exposed individuals are permitted to receive whole 
body exposure of 5 rem per year. 
 
11C-Carfentanil:  11C-Carfentanil is a carbon 11 labeled opioid agonist radiopharmaceutical used for 
imaging the mu subtype opioid receptor.  11C-Carfentanil is currently the only validated PET ligand for 
studying in vivo the mu-opioid receptors in humans (Henriksen et al, 2005) and has been used safely in 
numerous recent studies (Bencherif et al, 2002; Bencherif et al, 2004b; Liberzon et al, 2002; Liberzon et 
al, 2007; Weerts et al, 2008; Weerts et al, 2011; Zubieta et al, 2001; Zubieta et al, 2002; Zubieta et al, 
2003; Zubieta et al, 2005).  There is a single report of an adverse event; one subject experienced an 
idiosyncratic allergic reaction which may have been to carfentanil or Hydromorphone, but the source 
could not be confirmed (Greenwald et al. 2003).  
 
Radioactive Drug and Radiation Exposure:  The radioligand 11C-carfentanil was developed at Johns 
Hopkins by Dr. James Frost in the 1980s.  11C-carfentanil has been administered to numerous human 
subjects over the years without any known incident of a subject experiencing an adverse effect.  Based 
on other 11C-carfentanil studies (Weerts et al, 2008; Weerts et al, 2011; Zubieta et al, 2000; Zubieta et al, 
2003; Greenwald et al, 2003) and personal communication with Drs. Frost and Zubieta, the dose of 
carfentanil that will be administered in this study is 0.05 µg/kg.  At this dose, we have not observed any 
adverse effects.  At larger doses of 11C-carfentanil, opiate-like effects such as drowsiness, a good or bad 
change in mood state, nausea, vomiting, itching or a mild headache could occur.  However, at the mass 
dose being administered, subjects may possibly experience lightheadedness (J. Frost, personal 
communication). 
 
Participants are exposed to 0.644 rem in this study, less than 5 rem effective dose per year currently 
approved occupational limit.  The Clinical Radiation Research Committee of Johns Hopkins University 
has increasingly employed the ICRP method of effective dose calculation (Annals ICRP 1987).  This 
method consists of weighing various organs by dosimetry relative to their radiosensitivity to provide a 
single effective dose for the total body.  Johns Hopkins University has taken the position that effective 
total body dose should typically remain below 5 rem to remain within the occupational limit per year.  For 
11C-carfentanil, the effective dose equivalent is 16 mrem/mCi; so for two 20 mCi intravenous injections, 
the total radiation exposure is 639 mrem or 0.639 rem.  All subjects will undergo a brain transmission 
scan after each PET scan and will receive an additional 2.6 mrem of radiation exposure from each 
transmission scan.  Thus the total radiation dose (effective dose) from PET scanning procedures will be 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
JHMIRB eFormA  01 
Version7.5 Dated:   04/2014 
 
Page 9 of 14 
 
644 mrem or 0.644 rem.  If participants are required to have the skull x-rays performed, the radiation 
exposure will increase by 0.01 rem.  Thus the total radiation exposure for both procedures will be 0.654 
rem.  The specific radiation absorbed doses to individual organs, provided by Dr. James Frost from his 
IND (#IND 24,068) for 11C-carfentanil, are listed in the accompanying radiation form. 
 
The maximum radiation exposure subjects will receive from this research study is approximately 0.654 
rem.  This is more than the 0.3 rem that the average person in the United States gets each year from 
natural sources like the sun, outer space, air, food and soil.  It is less than the 5 rem of radiation that is 
allowed each year for people who are exposed to radiation in their jobs.  This research study includes 
exposure to radiation from x-rays or gamma rays.  This radiation exposure is for research purposes only 
and is not part of the subject’s medical care.  X-rays and gamma rays from natural or medical sources 
can damage the genetic material (DNA) in the subject’s cells. At low doses, the body is usually able to 
repair the damage. 
 
Dean Wong, MD PhD is a Professor of Radiology, Psychiatry and Environmental Health Sciences at 
Johns Hopkins University and a Board-Certified Nuclear Medicine Physician. He will have overall 
responsibility of the PET scanning component of the project.  He will supervise all Hopkins staff and the 
PET technologist who will acquire the PET scans.  Dr. Wong will supervise all PET scan acquisitions.  
Dr. Wong’s faculty and staff will analyze the PET data. 
 
Blood draws and urine collection: We will collect blood for nicotine-related genetic analyses. Blood 
chemistries and urinalysis are performed at assessment. We also collect a blood specimen for 
progesterone measurement for menstrual cycle determination. Urinalysis for drug toxicology assessment 
is performed to identify illicit drug use. These procedures involve minimal risks, such a slight risk of 
discomfort at the intravenous site. A small amount of bleeding under the skin will produce a bruise in 
about 5% of cases. The risk of temporary clotting of the vein is about 1%. The risk of infection or 
significant blood loss is less than 1 in 1000. In rare cases, fainting could occur. 
 
Genetic information: The genetic SNP variants to be studied are not currently known to cause any 
medical conditions and are being examined for the purposes of this experiment only. Thus, the risks, 
such as loss of privacy, resulting from our ascertainment of genetic information are extremely low. DNA 
will be banked for future analyses based on new research findings; samples are stored using subject ID 
only.  
 
Risk/Benefit Ratio:  The primary risk to participants is the radiation exposure.  The effective dose of two 
20 mCi injections of 11C-carfentanil and two transmission scans is 0.644 rem.  This radiation exposure is 
4.356 rem or 87% less than the annual radiation exposure limit of 5 rem for occupationally exposed 
persons.  Given the percentage of exposure is significantly lower than the annual limit and participants 
will be excluded from the study if they have had previous radiation exposures that in addition this study 
would place above the annual limit, the risks are perceived to within acceptable limits. 
 
b. Steps taken to minimize the risks. 
 
Some subjects may develop a skin rash at the location of the nicotine patch. This may be a reaction 
either to the sticky backing on the patch or to the nicotine. People who experience significant allergic 
reaction to the patch will be discontinued and will be provided with medical care to reverse symptoms. 
Moving the patch to a different part of your body or using a nonprescription antihistamine cream, 
ointment, or gel (such as Benadryl) may relieve some of the discomfort.  
 
c. Plan for reporting unanticipated problems or study deviations. 
 
All unanticipated problems or study deviations will be reported promptly to the IRB. 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
JHMIRB eFormA  01 
Version7.5 Dated:   04/2014 
 
Page 10 of 14 
 
Subjects will be assigned a code number and all blood samples will be analyzed using code numbers 
and not names.  However, a master list of names and code numbers will be retained by the Investigators 
and will be stored separately from the study data. 
 
In any study that involves questions about hazardous or possibly illegal behaviors, there is a risk of 
breach of confidentiality by study staff.  This risk is minimized by all staff being carefully trained in the 
protection of confidentiality and their participation in regular updates of patient/subject confidentiality.  
Further protections include the use of subject numbers to code all data forms for computer entry and 
storage, and reporting of study findings using group data only.  All data are stored with code numbers 
only; the master list of names and associated code numbers is maintained by the Investigators 
separately from the data files.   
 
e. Financial risks to the participants. 
 
All costs will be covered by NIH grants. 
 
 
9. 
Benefits 
 
a. Description of the probable benefits for the participant and for society. 
 
This study is conducted for the advancement of science.  It is clinically and scientifically important to 
understand perturbations of the opioid system associated with tobacco use disorder and to identify 
predictors of clinical effectiveness of nicotine replacement therapy.  
 
 
10. 
Payment and Remuneration 
 
a. Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. 
 
Possible Total Compensation: 
 
All enrolled subjects will receive $25/day as their earnings for each CRU day.  While the duration of the 
CRU stay may vary slightly across subjects (e.g., based on availability of the PET imaging Center), we 
expect subjects to average 4 days (3 nights) on the unit.  Subjects who complete all study procedures 
will receive a $100 bonus. Total compensation for study participation includes: 
 
Payments for study completers: 
 
Assessment 
$ 75.00 
MRI 
$ 50.00 
PET scan(s) - $125/scan X 2 scans 
$250.00 
3 CRU nights X $25/night 
$ 75.00 
2 additional CRU nights X $25/night 
$ 50.00 
(if needed) 
Completion Bonus 
$100.00 
Maximum total subject payment 
$600.00 
 
Reductions or Penalties for Not Completing: 
 
Subjects who are terminated for noncompliance or who drop out of the study will be paid only the amount 
earned to date for completed procedures, CRU stay or outpatient visits.  They will forfeit future possible 
earnings and bonus payments. To eliminate any financial incentive for early termination, subjects who 
are noncompliant or drop out will not receive payment until the day when they were scheduled to 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
JHMIRB eFormA  01 
Version7.5 Dated:   04/2014 
 
Page 11 of 14 
 
complete their study procedures. If subjects are terminated by the Investigators for safety reasons, they 
will paid the amount earned to date for completed procedures, CRU stay or outpatient visits. Additionally, 
they will still be eligible for bonus payments prorated for length of study participation. 
 
 
11. 
Costs 
 
a. Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify who will 
pay for them. 
 
Not Applicable. 
 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
JHMIRB eFormA  01 
Version7.5 Dated:   04/2014 
 
Page 12 of 14 
 
12. 
References 
 
 
1. Bencherif B, Fuchs PN, Sheth R, et al:  Pain activation of human supraspinal opioid pathways as 
demonstrated by [11C]-carfentanil and positron emission tomography (PET).  Pain 2002; 99 (3): 589-598. 
 
2. Bencherif B, Wand GS, McCaul ME, et al:  Mu-opioid receptor binding measured by [11C]carfentanil positron 
emission tomography is related to craving and mood in alcohol dependence. Biol Psychiatry 2004b; 55 (3): 
255-62. 
 
3. Cohen MR, Cohen RM, Pickar D, et al:  High-dose naloxone infusions in normals. Dose-dependent 
behavioral, hormonal, and physiological responses.  Arch Gen Psychiatry 1983; 40 (6): 613-619. 
 
4. Frost JJ, Douglass KH, Mayberg HS, et al:  Multicompartmental analysis of [11C]-carfentanil binding to 
opiate receptors in humans measured by positron emission tomography.  J Cereb Blood Flow Metab 1989; 9 
(3): 398-409. 
 
5. Frost JJ, Mayberg HS, Fisher RS, et al:  Mu-opiate receptors measured by positron emission tomography 
are increased in temporal lobe epilepsy.  Ann Neurol 1988; 23 (3): 231-237. 
 
6. Frost JJ:  Personal communication on the adverse effects of  11C-carfentanil. 2006. 
 
7. Greenwald MK, Johanson CE, Moody DE, et al:  Effects of Buprenorphine Maintenance Dose on mu-Opioid 
Receptor Availability, Plasma Concentrations, and Antagonist Blockade in Heroin-Dependent Volunteers.   
Neuropsychopharmacol 2003; 28: 2000–2009. 
 
8. Henriksen G, Platzer S, Marton J, et al:  Syntheses, biological evaluation, and molecular modeling of 18F-
labeled 4-anilidopiperidines as mu-opioid receptor imaging agents.  J Med Chem 2005; 48 (24): 7720-7732. 
 
9. Hutchison KE, LaChance Niaura HR, et al:  The DRD4 VNTR influences reactivity to smoking cues.  J 
Abnorm Psychol 2002; 111 (1): 134–143. 
 
10. Lerman C, Wileyto EP, Patterson F, Rukstalis M, Audrain-McGovern J, Restine S, Shields PG, Kaufmann V, 
Redden D, Benowitz N, Berrettini WH:  The functional mu opioid receptor (OPRM1) Asn40Asp variant 
predicts short-term response to nicotine replacement therapy in a clinical trial.  Pharmacogenomics J 2004; 4 
(3):184-192. 
11. Liberzon I, Taylor SF, Phan KL, et al:  Altered Central mu-Opioid Receptor Binding After Psychological 
Trauma. Biol Psychiatry 2007; 61 (9): 1030-1038. 
 
12. Liberzon I, Zubieta JK, Fig LM, et al:  mu-Opioid receptors and limbic responses to aversive emotional 
stimuli.  Proc Natl Acad Sci USA 2002; 99 (10): 7084-7089. 
 
13. Mayberg HS, Sadzot B, Meltzer CC, et al:  Quantification of mu and non-mu opiate receptors in temporal 
lobe epilepsy using positron emission tomography.  Ann Neurol 1991; 30 (1): 3-11. 
 
14. Munafò MR, Elliot KM, Murphy MF, Walton RT, Johnstone EC:  Association of the mu-opioid receptor gene 
with smoking cessation.  Pharmacogenomics J 2007; 7 (5): 353-361. 
 
15. Ray R, Jepson C, Patterson F, Strasser A, Rukstalis M, Perkins K, Lynch KG, O'Malley S, Berrettini WH, 
Lerman C:  Association of OPRM1 A118G variant with the relative reinforcing value of nicotine.  
Psychopharmacology (Berl) 2006; 188 (3): 355-363. 
 
16. Task Group of Committee 2:  Radiation Dose to Patients from Radiopharmaceuticals.  Annals ICRP 1987; 18 
(1-4): 1-29. 
 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
JHMIRB eFormA  01 
Version7.5 Dated:   04/2014 
 
Page 13 of 14 
 
17. Wang Z, Ray R, Faith M, Tang K, Wileyto EP, Detre JA, Lerman C:  Nicotine abstinence-induced cerebral 
blood flow changes by genotype.  Neurosci Lett 2008; 438 (3): 275-280. 
 
18. Weerts EM, Kim YK, Wand GS, et al:  Differences in delta- and mu-Opioid Receptor Blockade Measured by 
Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects.  
Neuropsychopharmacol 2008 33: 653-665. 
 
19. Weerts EM, Wand GS, Kuwabara H, et al:  PET imaging of mu- and delta-opioid receptor binding in alcohol 
dependent and healthy subjects.  Alcohol Exp Clin Res 2011.  In Press. 
 
20. Zhang L, Kendler KS, Chen X:  The mu-opioid receptor gene and smoking initiation and nicotine 
dependence.  Behav Brain Funct 2006; Aug 4; 2: 28. 
 
21. Zubieta J, Greenwald MK, Lombardi U, et al:   Buprenorphine-induced changes in mu-opioid receptor 
availability in male heroin-dependent volunteers: a preliminary study.  Neuropsychopharmacol 2000; 23 (3): 
326-334. 
 
22. Zubieta JK, Bueller JA, Jackson LR, et al:  Placebo Effects Mediated by Endogenous Opioid Activity on µ-
Opioid Receptors.  J Neurosci 2005; 25 (34): 7754 –7762. 
 
23. Zubieta JK, Ketter TA, Bueller JA, et al:  Regulation of human affective responses by anterior cingulate and 
limbic mu-opioid neurotransmission.  Arch Gen Psychiatry 2003; 60 (11): 1145-1153. 
 
24. Zubieta JK, Smith YR, Bueller JA, et al:   Regional mu opioid receptor regulation of sensory and affective 
dimensions of pain.  Sci 2001; 293 (5528): 311-315.  
 
25. Zubieta JK, Smith YR, Bueller JA, et al:  Mu-Opioid Receptor-Mediated Antinociceptive Responses Differ in 
Men and Women.  J Neurosci 2002; 22 (12): 5100–5107. 
 
 
 
 
 


Date: 
October 19, 2017 
Protocol Title: 
Nicotine Dependence, Withdrawal and Replacement Therapy Assessed by PET Imaging 
Principal Investigator: 
Mary E. McCaul, PhD 
NCT 
01664741 
Application Number: 
00-02-03-05 / NA_00036996 
 
JHMIRB eFormA  01 
Version7.5 Dated:   04/2014 
 
Page 14 of 14 
 
 
APPENDIX 1:  List of Current Study Instruments 
 
• 
90-day Time Line Follow Back Assessment 
• 
Alcohol Use Disorders Identification Test (AUDIT) 
• 
Analog craving scales 
• 
Beck Depression Scale 
• 
Breath Alcohol Concentration (BAC) 
• 
Fagerstrom Test for Nicotine Dependence (FTND) 
• 
Minnesota Nicotine Withdrawal Scale (MNWS) 
• 
Nicotine Effects Scale 
• 
Questionnaire of Smoking Urges (QSU-Brief) 
• 
Alcohol and Nicotine sections of the Semi-structured Assessment for the Genetics of Alcoholism 
• 
Shipley Vocabulary Questionnaire 
• 
Michigan Nicotine Reinforcement Questionnaire  
• 
Health Checklist 
• 
Registration Sheet 
• 
Menstrual Cycle Questionnaire 
• 
M.I.N.I. International Neuropsychiatric Interview 7.0 (01/01/14 version) – IPSAR version 2014.04.16 
• 
Life Events Checklist for DSM 5 (LEC-5) 
 
 
 
Race and ethnicity will be determined by self-report using NIH categories.