Effects of Buprenorphine on Mood in Adults With a Range of Depressive Symptomatology
Phase: NA
Conditions: Depression
Sponsor: University of Chicago

 
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Detailed Protocol 
 
Title: Effects of buprenorphine on emotional responses to social stimuli (“Effects of drugs on 
mood and behavior” on the consent form) 
 
P.I.: Harriet de Wit 
 
Co-Investigators: Anya Bershad, Leah Mayo, Greg J. Norman, Royce Lee 
 
August 27, 2015 
 
Objectives: To study the effects of buprenorphine, a partial mu-opioid agonist, on 
emotional responses to social stimuli in healthy young adults with a range of depressed and 
anxious mood. 
 
Aim 1.  We will assess the effects of buprenorphine on subjective and psychophysiological 
responses to images and sounds with positive (rewarding), negative (aversive), social, and non-
social content. We hypothesize that buprenorphine will selectively reduce responses to negative 
social stimuli.  
 
Aim 2. We will examine the effect of buprenorphine on responses to information conveyed by 
emotional facial expressions.  We will measure automatic direction of attention towards 
emotional expressions (EOG). We hypothesize that buprenorphine will selectively reduce 
sensitivity and attention to negative emotions. 
  
Aim 3. We will examine the effect of buprenorphine on responses to simulated experiences of 
social rejection and responses to social and nonsocial touch. We hypothesize that buprenorphine 
will reduce responses to both physical and social pain. 
 
 Aim 4. We will investigate the effect of buprenorphine on motivation to socialize. During the 
sessions, participants will be given the opportunity to spend 10 minutes waiting alone or 10 
minutes waiting with another person. We hypothesize that buprenorphine will reduce the desire 
to socialize with other individuals.  
 
Background:  
 
The purpose of this study is to investigate the role of opioid signaling in mediating 
responses to social stimuli in humans. There is strong evidence in support of the role of 
endogenous opioids and opiates in mediating social behavior in humans and other animals. 
Studies in humans have shown that reduced opioid transmission underlies stronger responses to 
social rejection and social loss or “social pain”, and that the same neural systems that underlie 
perception of physical pain may underlie the perception of social pain (Eisenberger and 
Lieberman, 2004). The minor allele of the mu opioid receptor gene (OPRM1 A118G), which 
leads to reduced mu opioid transmission, is associated with increased social rejection sensitivity 
(Way, Taylor, & Eisenberger, 2009). In line with this study, PET imaging has shown that women 
recalling recent losses of relationships exhibit reduced mu opioid-mediated neurotransmission 

 
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(Zubieta et al., 2003). These studies suggest that social pain may have overlapping circuitry with 
physical pain, and that reduced opioid neurotransmission is associated with heightened responses 
to negative social stimuli such as social pain. By seeking to correlate the analgesic effects of 
buprenorphine (via the cold pressor task) with its effects on perception of social pain, we can 
better understand the relationship between these phenomena.  
In addition to the evidence implicating reduced endogenous opioid signaling in 
intensified responses to negative social input, studies in animals have shown that exogenously 
administered opiate agonists can have the opposite effect, reducing reactivity to such stimuli. It 
has been shown that opioid agonists reduce distress calls in response to social isolation in rodents 
(Panksepp, Najam, & Soares, 1979), chicks (Warnick, McCurdy, & Sufka, 2005), and non-
human primates (Kalin, Shelton, & Barksdale, 1988). The “brain opioid hypothesis of social 
attachment” suggests that reduced opioid neurotransmission increases desire for attachment 
(Fabre-Nys, Meller, & Keverne, 1982), whereas increases in opioid signaling act as a proxy for 
social reward, thereby reducing the need for social interaction (Stein, van Honk, Ipser, Solms, & 
Panksepp, 2007; Herman & Panksepp, 1978; Panksepp et al., 1979). While there is a great deal 
of evidence in the animal literature that exogenous opiates act to blunt responses to negative 
social stimuli, this question has not been fully addressed in humans. An exception to this is one 
recent study, in which the investigators administered buprenorphine to healthy volunteers and 
found that the drug reduced participants’ ability to recognize fearful facial expressions (Ipser et 
al., 2013). Additionally, a handful of small studies have shown that buprenorphine is effective in 
treating treatment-resistant depression (Bodkin et al., 1995; Emrich et al., 1982; Nyhuis et al., 
2008). In the study proposed here, we seek to determine the effect of an opioid agonist on a 
battery of tasks assessing an array of social behaviors in an effort to more thoroughly understand 
the role of opioids in mediating responses to social stimuli. Further, we plan to recruit subjects 
with a range of scores for depressed and anxious mood, in an effort to determine whether the 
drug is more effective in individuals scoring higher on this measure.  
Determining the effect of an opioid agonist on responses to social stimuli in humans is 
important for several reasons.  First, there has been a recent increase in the number of individuals 
abusing opiate drugs, particularly teenagers and young adults. It has been argued that opiate 
abusers are “self-medicating”, or using the drugs to alleviate some particularly painful 
psychological state (Khantzian, 1997), and it has been suggested that opiates may reduce 
unpleasant subjective responses to negative social stimuli. However, this idea has never been 
tested in humans in a laboratory setting. This project seeks to address these questions for the first 
time. Second, this would significantly extend our knowledge about the role of the opioid system 
in human social behavior.  This study would expand findings from the animal literature to 
humans. This is important to understanding the neurobiology underlying conditions that involve 
responses to negative social stimuli, such as social anxiety disorder and other conditions with a 
social component, such as depression.  
Based on the literature reviewed above, our central hypothesis is that buprenorphine, a 
mu partial agonist and kappa antagonist, will selectively reduce responses to negative social 
stimuli. In Aim 1 we will explore how buprenorphine affects reactions to positive (i.e., 
rewarding) vs. negative (i.e., aversive) social and nonsocial visual stimuli.  The stimuli will 
consist of pleasant pictures (e.g. of parties, pets, sunsets), neutral pictures (e.g. of household 
objects, neutral landscapes) and unpleasant pictures (e.g. medical imagery, war scenes and 
disgusting objects). We will measure subjective responses to these pictures using self-reports of 
liking and physiological hedonic responses using subtle electromyographic (EMG) 

 
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measurements of facial muscles associated with positive and negative emotions.  We predict that 
buprenorphine will specifically reduce subjective and psychophysiological responses to negative 
social pictures. In Aim 2 we will examine attentional biases towards positive vs. negative 
expressions using eyetracking. We predict that buprenorphine selectively will blunt perception of 
attentional bias towards - negative as compared to positive facial expressions. In Aim 3 we will 
simulate experiences of social rejection and acceptance, combined with the same EMG measures 
of responses to reward used in Aims 1 and 2, in addition to testing the effects of buprenorphine 
on responses to social touch. We predict that buprenorphine will ameliorate subjective and 
psychophysiological responses to social pain (rejection) and physical pain. In Aim 4 we will 
measure participants’ desire to socialize by giving them the opportunity to spend 10 minutes with 
another person or to wait alone. We hypothesize that buprenorphine will reduce their desire to 
socialize. Finally, we hypothesize that buprenorphine will reduce negative processing biases seen 
in participants with depressed mood. 
 
Methods: 
Design: The study will use a 2-session within-subjects double-blind design in which participants 
will receive single doses of buprenorphine (0 or 0.2 mg sublingual) in randomized order. All 
screening, orientation, and study session procedures will take place in the Human Behavioral 
Pharmacology Laboratory suite in the L4 wing of 5841 S. Maryland Ave.  
 
Subjects:  86 healthy volunteers (18 male, 18 female; age range 18-35 years) will participate in 
the experiment. Based on our previous rates of participants completing two-session drug studies, 
to recruit 86 complete subjects we will need to consent 120 participants. Participants with a 
range of scores on the Beck Depression Inventory (BDI-II; Beck et al., 1996) and State-Trait 
Anxiety Inventory (STAI; Spielberger et al. 1983) will participate in the experiment. The BDI-II 
contains 21 questions, each scored from 0 to 3. Higher total scores indicate more severe 
depressive symptoms. The standardized cutoffs are: 0–13: minimal depression, 14–19: mild 
depression, 20–28: moderate depression and 29–63: severe depression.  We will aim to recruit 
approximately half the participants in the 0-13 range, and half in the 14-28 range. Candidates 
who meet criteria for Major Depressive Disorder will be excluded and referred for treatment.  All 
participants will be recruited without regard to race, religion or ethnicity through posters, 
advertisements and word-of-mouth referrals. Candidates will be screened in accordance with our 
general screening protocol, approved by the IRB under Protocol #13681B, which includes a 
physical, EKG, psychiatric screening interview and detailed drug use history questionnaire. 
Because buprenorphine will be administered as part of the study, the following populations are 
excluded for safety reasons: Individuals with a medical condition contraindicating study 
participation, as determined by our physician (e.g. liver or kidney disease), individuals regularly 
using any contraindicated medications (e.g. opioid pain-killers), individuals with current or past 
opioid abuse or dependence, individuals with past dependence on other drugs, individuals with a 
DSM-IV Axis I mood, anxiety, eating, or psychotic disorder, individuals with a previous bad 
reaction to buprenorphine, women who are pregnant, nursing, or planning to become pregnant in 
the next 3 months.  The self-report questionnaires we use require fluency in English, and have 
not been translated and validated in other languages, thus individuals with less than a high-
school education or those not fluent in English will be excluded, as lack of English familiarity at 
a high school level may compromise our ability to interpret their self-reports. Individuals with a 
BMI below 19 or above 30 will also be excluded, as this would change dosing requirements.  

 
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Women not on hormonal birth control will be scheduled only in the follicular phase of the 
menstrual cycle, as hormonal fluctuations may change responses to the drug (Roche, Childs, 
Epstein, & King, 2010). 
 
Drug and Doses: We will administer placebo and  0.2 mg buprenorphine (Temgesic) via 
sublingual tablet in counterbalanced order under double-blind conditions. These tablets dissolve 
within 5-8 minutes. This drug has been approved for treatment of severe pain. The onset of 
action after sublingual administration is 30 minutes, with a peak plasma concentration at 1/5-2 
hours and a half-life of 5 hours. These doses of buprenorphine is very low, and the average 
maintenance dose for opioid abusers is 8 mg. Doses will be separated by at least 72 hours. See 
“Risks” for complete safety information. 
 
Study Tasks: 
 
1. International Affective Picture System (IAPS) – (Lang, Bradley, & Cuthbert, 1999) 
Participants will view standardized positive, negative and neutral pictures from the IAPS.  
The negative and positive images will be matched on degree of valence and arousal. We will 
record psychophysiological facial EMG responses during a 1s baseline recording period 
preceding each picture, and during the 6s presentation of each (see “Psychophysiological 
Measures”). Valence-matched sounds from the Oxford Vocal Sound Database (OxVoc) will 
also be presented. An Evaluative Space Grid rating will follow each picture or sound to 
collect subjective reactions (see “Subjective Measures”).   
2. Attentional Bias Task (ABT) – In a task adapted from Garner and colleagues (Garner, Mogg, 
& Bradley, 2006) participants will be presented with pairs of faces, one on each side of a 
computer screen.  Each pair will contain one neutral face and one 100% emotional 
expression taken using the same actor.  The emotional expressions used will be from the 
standardized Karolinska set (Goeleven, De Raedt, Leyman, & Verschuere, 2008). 
Participants will be shown a central fixation cross for 1,000 ms, then the pairs of faces side 
by side for 2,000 ms. To distract participant attention from the primary purpose of the task, 
and reduce response bias, a probe (either an up arrow or a down arrow) will be presented in 
the same location as one of the previous pictures after each trial.  Participants must respond 
to the direction the arrow is pointing by pressing a key. After a response, or after 10s have 
elapsed with no response, an intertrial interval of 750 to 1,250 ms will begin, followed by the 
presentation of another trial. Electrooculograms (see “Psychophysiological Measures”) will 
be used to quantify which face is initially fixated on in each trial, and overall dwell time per 
face on each trial as indicators of attentional bias. 
3. Social Touch Task: This task, introduced as “an experimental light touch method” 
(Björnsdotter and Olausson, 2011) is designed to measure affective responses to light or 
social touch mediated via C-tactile fibers. Participants will be stroked with a painter's brush 
at varying velocities as facial EMG recordings of the corrugator and zygomatic muscles are 
obtained. Velocities will include those for which C-tactile fibers are optimally activated (i.e. 
30 cm/s) as well as non-optimal velocities (i.e. 3 cm/s). The participants will also rate the 
intensity and pleasantness of the stroking. EMG measures will also be collected during this 
task. 
4. Social Feedback Task (Hsu et al., 2013): This task will be presented to participants as a 
“hypothetical profile rating task.” During the orientation session, participants will provide 

 
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basic personal information (e.g. hobbies) and provide a digital picture of themselves.  
Participants will also log on to a web-based survey and rate profiles of other “participants,” 
which are created by the experimenter.  Subjects answer questions about each profile.  This 
survey will determine which profiles are the most likeable to each participant.  This method 
has advantages over other social feedback paradigms because the task is tailored to each 
subject. During each experimental session, subjects will be presented with their own picture, 
and a picture of the profiles that they had previously rated, and receive feedback on how that 
person rated them. Subjects will be given questionnaires before and after the task to monitor 
changes in emotion.  
 Subjective Measures: 
 
1. Beck Depression Inventory (BDI-II: Beck et al., 1996) The BDI-II is a validated 
questionnaire to assess depressed mood.  
2. The State-Trait Anxiety Inventory (STAI; Speilberger et al. 1983) is a validated 
questionnaire consisting of 40 questions assessing anxiety levels.  
3. Profile of Mood States – (POMS:McNair, Lorr, & Droppleman, 1971) The POMS is a 
validated measure consisting of 72 adjectives commonly used to describe momentary mood 
states. The POMS is highly sensitive to the effects of drugs in similar samples of healthy 
volunteers (de Wit & Griffiths, 1991;Johanson & Uhlenhuth, 1980), and will be used to 
assess mood effects of the drug during the study sessions. 
4. Drug Effects Questionnaire - (DEQ:Fischman & Foltin, 1991) The DEQ is a validated 
measure consisting of questions on a visual analog scale about the subjective effects of drugs. 
Subjects are asked to rate the extent they feel a drug effect, whether they like or dislike the 
drug effect, and if given a choice would they want to take more of the drug.  This will also be 
used to assess the pharmacodynamics of the drug effect during the study. 
5. Visual Analogue Scale (VAS) – This includes adjectives assessing common side effects of 
buprenorphine, such as dizziness and nausea. During the cold pressor task, a VAS including 
adjectives such as pain intensity and unpleasantness will be presented. 
6. The Addiction Centre Research Inventory (ARCI: Haertzen,1970) is a true-false 
questionnaire that consists of empirically derived scales sensitive to the effects of a variety of 
classes of psychoactive drugs. We used a 53-item version, which yields scores for six scales 
that include: sedation (Pentobarbital-Chlorpromazine Group; PCAG), stimulant-like effects 
(Amphetamine; A, and Benzedrine Group; BG), somatic and dysphoric effects (Lysergic 
Acid; LSD), and euphoria (Morphine-Benzedrine Group; MBG). 
7. The Evaluative Space Grid - (ESG:Larsen, Norris, McGraw, Hawkley, & Cacioppo, 2009) 
The Evaluative Space Grid is validated measure consisting of a two dimensional grid that 
provides a single item measure of positivity and negativity.  This will be used to measure 
subjective reactions to the IAPS pictures and OxVoc sounds. 
8. Motivation to socialize – Drug effects on the motivation to socialize will be measured by 
giving the participants the opportunity to wait alone for 10 minutes, or with another person (a 
trained experimenter).  
 
Psychophysiological Measures: 
 
1. Cardiovascular measures – Blood pressure and heart rate will be periodically monitored 
using portable blood pressure cuffs, to track the cardiovascular effects of the drug, and ensure 

 
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participant safety. Additional cardiovascular effects will be measured using EKG electrodes 
during the Cyberball task and cold pressor task to provide information about autonomic 
reactivity to physical and social pain. We will use disposable self-adhesive electrodes 
arranged in the standard Lead II configuration. These signals will be amplified and processed 
by an integrated Mindware Bionex system (Mindware Technologies, Gahanna, OH). We will 
analyze the ECG waveform with Heart Rate Variability Analysis Software 2.51, also by 
Mindware Technologies. The software will prepare the interbeat interval (IBI) series for 
spectral analysis as follows: each IBI series will be interpolated and sampled at 4 Hz to 
ensure adequate resolution of the appropriate frequencies and equal intervals between 
samples, and then de-trended with a quadratic function to ensure stationarity (full details of 
this procedure in (Berntson, Hart, & Sarter, 1997). This signal will be brought into the 
frequency domain using a fast Fourier transform, and integrating the power over the 
respiratory frequency band (0.12 to 0.40 Hz) will give us the measurement we will report as 
RSA. Values will be obtained at baseline and at peak drug effect for each sixty-second 
segment of a five-minute recording period, and for each sixty-second segment of a three-
minute recording period during the Cyberball games and then ensemble averaged. To ensure 
that participants were aware of their social condition before we measure RSA, we will allow 
90 s game time to elapse before taking 3 min of cardiovascular data. 
 
2. Corrugator supercilii and zygomaticus major electromyography (EMG) – Muscle activity in 
the corrugator (frown) and zygomatic (smile) muscles is sensitive to the presentation of 
pleasant and unpleasant images and faces (Larsen, Norris, & Cacioppo, 2003).  Corrugator 
activity is potentiated by negative images and reduced by positive images, while zygomatic 
activity is potentiated by positive images. This activity is measurable using 
psychophysiological recording techniques even when it is not large enough to produce a 
visible facial expression. There is some evidence that EMG may be sensitive even to 
emotional impulses that do not reach the level of conscious expression (Dimberg, Thunberg, 
& Elmehed, 2000).  We have previously demonstrated that facial EMG activity to similar 
stimuli can be altered by pharamacological manipulations (Wardle & de Wit, 2012).  EMG 
will be recorded using 4 standard 4mm silver/silver chloride electrodes (2 at each site on the 
right side of the face), plus one ground electrode.  Data will be relayed to a Biopac (Biopac 
Systems, Inc, Santa Barbara CA) EMG100C amplifier, which will amplify signals 5,000x, 
and band pass filter signals below 10 Hz and above 500 Hz.  Signals will be digitized at 5000 
Hz by a Biopac MP150 system and recorded using Acqknowledge, Biopac’s recording and 
analysis software.  If needed, data will be submitted offline to a 15-Hz high pass filter to 
reduce movement and blink artifact, and a 50/60 Hz notch filter to reduce line noise, the need 
for which will be decided during the pilot test period.  EMG in each case will be quantified 
as the difference between mean activity during a 1,000 ms period before the onset of the 
stimuli, compared to mean activity during the presentation of the stimulus.  
 
3. Eyetracking – To examine attentional biases for one type of emotional expression over 
another, electrooculogram (EOG) eyetracking equipment will be used to measure horizontal 
eye movement during the attentional bias task, during which two pictures are presented side 
by side. A 4mm Ag/AgCl electrode filled with electrolyte (Biopac System Inc.) will be 
attached 1.5 cm from the outer canthus of each eye, using the same ground as the EMG 
signal. The EOG signal will be amplified using an EOG100C (Biopac Sysems, Goleta.CA), 

 
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digitized using a Biopac MP150 system and sampled at 1000 Hz throughout the task using 
AcqKnowledge software. Picture stimuli will be presented using E-Prime and a 17" VGA 
monitor. The EOG signal will be filtered using a low pass filter 20 Hz. Fixations to each 
picture will be identified as changes in EOG trace reflecting a shift in gaze towards one of 
the pictures. Criteria for identifying an initial shift in gaze on each trial will be as follows: (a) 
participants are fixated in the central region before picture onset, (b) eye movements occur at 
least 100 ms after picture onset and before picture offset, (c) gaze is directed to either picture 
(left or right) rather than remaining at the central position during the picture presentation. 
 
Procedure:  
 
Orientation: Participants who meet criteria will first be scheduled for an orientation session.  
During this session, subjects will be informed that the capsules used in the study may contain a 
placebo, a stimulant drug used to treat ADHD (e.g. methylphenidate), a sedative drug used to 
treat sleep disorders (e.g. diazepam), or an opiate drug used to treat drug used to treat pain (e.g., 
buprenorphine).  In previous studies we have found this procedure reduces expectancy effects. 
Participants will be given an oral description of the study procedures and the written consent 
form. After the experimenter reviews this information and the consent form with the subject, and 
answers any questions he/she may have, subjects will answer questions confirming their 
understanding of the study, and sign the informed consent document.  The subject will then 
practice completing the tasks and questionnaires to be used in the study, including providing a 
photo for their profile for the social feedback task and rating of other profiles.  This will help 
reduce practice effects across the study sessions. Abstention from recent drug and alcohol use 
will verified by breathalyzer and urine drug tests.  Women will also be urine tested for 
pregnancy.  
 
Study Session: Please see below for a full timeline of the study session. On study session days, 
participants will arrive at 1pmm, and consume a standardized snack.  Participants will then 
complete a urine and breath screening for recent alcohol and drug use, and a pregnancy test (for 
women).  We will then take Time 1 measures of subjective mood, drug effects and 
cardiovascular variables. We will continue to take these same measures periodically throughout 
the study (see below).  Participants will be administered the drug or placebo at 1:30pm.  While 
waiting for the drug effect to reach peak, participants will be allowed to relax and watch a movie 
or read a book, but will not be allowed to do work. At 2:pm and 2:30pm we will reassess mood. 
The task portion of the study will begin 1.5 hrs after administration of the drug, and will last for 
approximately 1.5 hours, to coincide with the peak effect of the drug. Participants will first have 
the areas for the psychophysiological electrodes for EMG and EOG prepped by cleaning with a 
rubbing alcohol and an exfoliant. Psychophysiological electrodes will be attached, and 
impedance checks will be done on the EMG pairs.  If impedance across each EMG pair is not 
below 5 K, the cleaning and application procedure for that pair will be repeated. EkG 
electrodes will also be placed. All tasks involving psychophysiology will take place with the 
participant seated in a comfortable chair with a headrest, placed a pre-determined distance from 
the computer monitor. The IAPS, DEIT, ABT, social touch, and social feedback tasks will be 
presented in a counterbalanced order. The psychophysiological equipment will then be 
disconnected. Participants will remain in the lab completing subjective measures of the drug 
effect every half-hour until at least 5:15pm (when we expect drug effects will end), or until 

 
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effects of the drug return to baseline (as measured by both subjective report and cardiovascular 
variables).  Sessions will be separated by at least 72 hours. 
 
Timeline 
9:00am – Arrival, snack, breath and urine tests 
9:15am – Mood (POMS), drug effect (DEQ) and cardiovascular measures 
9:30am – Tablet administered 
10:00am - Mood (POMS), drug effect (DEQ) and cardiovascular measures 
10:30am - Mood (POMS), drug effect (DEQ) and cardiovascular measures 
10:45am – Social Choice Task, Psychophysiology sensors applied 
11:00am – IAPS, ABT, social feedback, social touch task counterbalanced 
12:30pm –Mood (POMS), drug effect (DEQ) and cardiovascular measures 
1:00pm - Mood (POMS), drug effect (DEQ) and cardiovascular measures 
1:15pm – Leave Laboratory 
 
Debriefing: Participants will be emailed a final DEQ rating of how much they liked each study 
drug and how much they would want to take each study session drug again.  Participants will 
also be asked to report which type or types of drugs they think they received at each session.  
Finally, participants will be fully debriefed with regard to the study hypotheses, methods and the 
types of drugs that they received, and will be given a chance to ask any final questions in person, 
via phone, or via email. 
 
Data Analysis 
 
 
The subjective effects of the drug will be assessed using three-way repeated measures analysis of 
variance (ANOVA), with group (high vs. low BDI scores) as the between-group factor and dose 
and time as within-subjects factors. We hypothesize buprenorphine will dose-dependently reduce 
depressed mood in those individuals with high scores on the BDI. Our primary mood measure 
will be scores on the Depression scale of the POMS.   
 
Behavioral Tasks:  
 
IAPS: We hypothesize that participants will react less negatively to unpleasant social pictures 
while taking buprenorphine, while reactions to positive and neutral slides will be unchanged. We 
will conduct a Mixed Linear Model analysis in R using lme4 on each dependent variable 
(subjective ratings, corrugator and zygomatic responses) using Drug (0, .2mg) and picture type 
(positive, neutral, negative) as independent variables, and including random variables for Subject 
and Drug. 
 
ABT: We hypothesize that participants will show reduced attentional bias to negative facial 
expressions on buprenorphine, as measured by reduced initial fixations and overall dwell times 
on happy faces. We will conduct a Generalized Mixed Linear Model analysis in R using lme4 on 
the binomial variable of initial gaze direction with Drug (0, .2mg) and expression type (happy, 
angry, fearful, sad) as independent variables, and including random variables for Subject and 
Drug (per Wardle et al.).  We will conduct a Mixed Linear Model analysis in R using lme4 on 
total dwell time on each face, using Drug (0, .2mg) and expression type (happy, angry, fearful, 

 
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sad) as independent variables, and including random variables for Subject and Drug (per Wardle 
et al.). 
 
Social feedback and social touch tasks: We hypothesize that participants will be less sensitive 
to both social rejection and the positive effects of social touch. We will conduct a Generalized 
Mixed Linear Model analysis in R using lme4 on each dependent variable (ratings of rejection 
and pleasantness) using drug as the independent variable (0, .2mg), and including random 
variables for Subject and Drug (per (Wardle et al.)). 
 
Human Subjects Information 
 
Recruiting methods: We will place print ads in newspapers and on online job search sites such 
as craigslist.org, and flyer in the Chicago area.  Healthy volunteers who respond to our ads are 
screened using our standard screening protocol for all studies in the Human Behavioral 
Psychopharmacology Laboratory, which is separately approved by the IRB under Protocol 
#13681B 
 
Obtaining consent: Written informed consent for the screening session only is obtained at the 
screening according to procedures outlined in Protocol #13681B.  Written informed consent for 
the study procedures is obtained at the orientation session, after a verbal explanation of study 
procedures, check of comprehension, and an opportunity for the participant to ask any questions 
they may have.  Consent is verbally re-verified at the beginning of each study session.   
   
Risk to subjects: 
 
1. Diagnostic procedures and questionnaires: Some of the questions asked during the screening 
may be considered sensitive information, including drug use history and psychiatric history. We 
have rigorous procedures in place to ensure confidentiality of data, including locked cabinets for 
confidential files, subject coding, secure computer systems, and rigorous training of personnel. 
Please see screening protocol #13681B for full information on steps taken to protect information 
gathered as part of the screening.   
 
2. Study drug:  
The possible side effects of buprenorphine include: fatigue, nausea, vomiting, sweating, 
lightheadedness, miosis, orthostatic hypotension, respiratory depression, and a sensation of 
heat. However, the risk of these effects is low at the doses used in this study. The risk of nausea 
is reduced by asking participants to each breakfast before the sessions. In addition, to protect 
against, or minimize any possible risks with buprenorphine, subjects are carefully screened to 
exclude those who are physically or psychiatrically at risk (e.g., any history of AXIS I disorders 
or history of psychosis). The studies are conducted in a hospital, where emergency assistance, 
including the psychiatry resident on-call, and the psychiatrist connected with the study are close 
at hand. A research assistant will be present throughout the procedures and will monitor heart 
rate, blood pressure, and respiratory rate throughout the sessions. In addition, on-call physicians 
will be available in the case of medical emergencies. Subjects will be told not to drive following 
the sessions and, if necessary, will be reimbursed for public transportation costs. Subjects will 
be told that small amounts of the drugs or their metabolites will be detectable in the body for 

 
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several weeks and to advise the experimenter if they intend to undergo a drug screening within 
one month of participating in the study. 
 
3. Tasks: Some of the tasks (emotional pictures, pictures of facial expressions) employ stimuli 
that are designed to elicit short-term positive and negative emotional reactions. Although the 
pictures used are designed to elicit emotional reactions, these reactions are typically brief, and 
similar methods to have previously been used in a wide range of studies without evidence of any 
long-term adverse reactions.  Further, participants are screened for any psychiatric conditions 
that might make them vulnerable to experiencing adverse reactions to brief alterations in mood.  
Any participants who are unduly distressed will be counseled by a trained staff member. 
 
4.  Electrical equipment: We will monitor cardiovascular and psychophysiological responses to 
the drug and tasks using conductive electrodes attached to the skin of participants using an 
adhesive.  There may be mild discomfort or irritation to the participant’s skin as a result of 
cleaning the sites to apply the sensors, but this should be transient. All equipment will be 
appropriately grounded and shielded, and stimulus equipment will be optically isolated from the 
participant making any electrical hazard to the participant extremely unlikely. 
 
Benefits to subjects: There is no direct benefit to the participants, although we hope that the 
information learned from this study will contribute to our knowledge of factors influencing drug 
use.  Additionally, participating in research may be an educational experience for participants, 
and we attempt to facilitate this by providing a thorough debriefing including an explanation of 
study hypotheses and procedures at the conclusion of participation. 
 
Subject time commitment and compensation: The orientation typically takes approximately 
one hour.  The study sessions are estimated to last 4.25hrs each, for a total of 9.5 hours spent in 
study sessions. Participants are compensated $10 for the orientation, $30 for each study session, 
with a bonus of $80 for completion of all study sessions, giving a total of $150.  
 
Data and Safety Monitoring: The PI will monitor data collection and safety at weekly staff 
meetings.  During these meetings, the PI will review and respond appropriately to (1) data 
collection and storage practices and (2) any adverse or unexpected effects from the study drugs.  
Both the study physician and PI will monitor the safety of study participants on an ongoing basis. 
The physician connected with this study will be on call during the experimental sessions and for 
24 hours after sessions.  Subjects will be given telephone numbers for the study physician and 
investigators in case they experience unpleasant effects after leaving the laboratory. If a serious 
or unexpected adverse event were to occur, the staff member most closely involved with the 
subject at that time or the physician would notify the PI immediately. The PI would then take 
appropriate action and communicate with all necessary offices within the University and the 
FDA. 
 
 
References 
 
Berntson, G. G., Hart, S., & Sarter, M. (1997). The cardiovascular startle response: anxiety and 
the benzodiazepine receptor complex. Psychophysiology, 34(3), 348-357. 

 
11
Bodkin, J.A., Zornberg, G.L., Lukas, S.E., Cole, J.O., 1995. Buprenorphine treatment of 
refractory depression. Journal of clinical psychopharmacology 15, 49-57. 
de Wit, H., & Griffiths, R. R. (1991). Testing the abuse liability of anxiolytic and hypnotic drugs 
in humans. Drug and alcohol dependence, 28(1), 83-111. 
Dimberg, U., Thunberg, M., & Elmehed, K. (2000). Unconscious facial reactions to emotional 
facial expressions. Psychological science, 11(1), 86-89. 
Edes, B., & Dallenbach, K. M. (1936). The adaptation of pain aroused by cold. The American 
Journal of Psychology, 307-315. 
Emrich, H., Vogt, P., Herz, A., 1982. Possible antidepressive effects of opioids: action of 
buprenorphine. Annals of the new York Academy of Sciences 398, 108-112. 
Fabre-Nys, C., Meller, R. E., & Keverne, E. (1982). Opiate antagonists stimulate affiliative 
behaviour in monkeys. Pharmacology Biochemistry and Behavior, 16(4), 653-659. 
Fischman, M. W., & Foltin, R. W. (1991). Utility of subjective‚Äêeffects measurements in 
assessing abuse liability of drugs in humans. British journal of addiction, 86(12), 1563-
1570. 
Garner, M., Mogg, K., & Bradley, B. P. (2006). Orienting and maintenance of gaze to facial 
expressions in social anxiety. Journal of Abnormal Psychology, 115(4), 760. 
Goeleven, E., De Raedt, R., Leyman, L., & Verschuere, B. (2008). The Karolinska Directed 
Emotional Faces: A validation study. Cognition and Emotion, 22(6), 1094-1118. 
Haertzen, C. A. (1970). Subjective effects of narcotic antagonists cyclazocine and nalorphine on 
the Addiction Research Center Inventory (ARCI). Psychopharmacologia, 18(4), 366-377. 
Herman, B. H., & Panksepp, J. (1978). Effects of morphine and naloxone on separation distress 
and approach attachment: Evidence for opiate mediation of social affect. Pharmacology 
Biochemistry and Behavior, 9(2), 213-220. 
Ipser, J. C., Terburg, D., Syal, S., Phillips, N., Solms, M., Panksepp, J., et al. (2013). Reduced 
fear-recognition sensitivity following acute buprenorphine administration in healthy 
volunteers. Psychoneuroendocrinology, 38(1), 166-170. 
Johanson, C., & Uhlenhuth, E. (1980). Drug preference and mood in humans: diazepam. 
Psychopharmacology, 71(3), 269-273. 
Jones, S., McQuay, H., Moore, R., & Hand, C. (1988). Morphine and ibuprofen compared using 
the cold pressor test. Pain, 34(2), 117-122. 
Kalin, N. H., Shelton, S. E., & Barksdale, C. M. (1988). Opiate modulation of separation-
induced distress in non-human primates. Brain research, 440(2), 285-292. 
Khantzian, E. J. (1997). The self-medication hypothesis of substance use disorders: a 
reconsideration and recent applications. Harvard review of psychiatry, 4(5), 231-244. 
Koltzenburg, M., Pokorny, R., Gasser, U. E., & Richarz, U. (2006). Differential sensitivity of 
three experimental pain models in detecting the analgesic effects of transdermal fentanyl 
and buprenorphine. Pain, 126(1–3), 165-174. 
Lang, P. J., Bradley, M. M., & Cuthbert, B. N. (1999). International affective picture system 
(IAPS): Technical manual and affective ratings: Gainesville, FL: The Center for Research 
in Psychophysiology, University of Florida. 
Larsen, J. T., Norris, C. J., & Cacioppo, J. T. (2003). Effects of positive and negative affect on 
electromyographic activity over zygomaticus major and corrugator supercilii. 
Psychophysiology, 40(5), 776-785. 

 
12
Larsen, J. T., Norris, C. J., McGraw, A. P., Hawkley, L. C., & Cacioppo, J. T. (2009). The 
evaluative space grid: A single-item measure of positivity and negativity. Cognition and 
Emotion, 23(3), 453-480. 
McNair, D., Lorr, M., & Droppleman, L. (1971). POMS, Profile of mood states. San Diego, CA: 
Educational and Industrial Testing Services. 
Naef, M., Curatolo, M., Petersen-Felix, S., Arendt-Nielsen, L., Zbinden, A., & Brenneisen, R. 
(2003). The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a 
THC-morphine combination in healthy subjects under experimental pain conditions. 
Pain, 105(1–2), 79-88. 
Nyhuis, P.W., Gastpar, M., Scherbaum, N., 2008. Opiate treatment in depression refractory to 
antidepressants and electroconvulsive therapy. Journal of clinical psychopharmacology 
28, 593-595. 
Panksepp, J., Najam, N., & Soares, F. (1979). Morphine reduces social cohesion in rats. 
Pharmacology Biochemistry and Behavior, 11(2), 131-134. 
Roche, D. J. O., Childs, E., Epstein, A. M., & King, A. C. (2010). Acute HPA axis response to 
naltrexone differs in female vs. male smokers. Psychoneuroendocrinology, 35(4), 596-
606. 
Stein, D. J., van Honk, J., Ipser, J., Solms, M., & Panksepp, J. (2007). Opioids: from physical 
pain to the pain of social isolation. CNS spectrums, 12(9), 669. 
Wardle, M., & de Wit, H. (2012). Effects of amphetamine on reactivity to emotional stimuli. 
Psychopharmacology, 220(1), 143-153. 
Wardle, M., Garner, M., Munafò, M., & de Wit, H (2012). Amphetamine as a social drug: effects 
of d-amphetamine on social processing and behavior. Psychopharmacology, 1-12. 
Warnick, J. E., McCurdy, C. R., & Sufka, K. J. (2005). Opioid receptor function in social 
attachment in young domestic fowl. Behavioural brain research, 160(2), 277-285. 
Way, B. M., Taylor, S. E., & Eisenberger, N. I. (2009). Variation in the μ-opioid receptor gene 
(OPRM1) is associated with dispositional and neural sensitivity to social rejection. 
Proceedings of the National Academy of Sciences, 106(35), 15079-15084. 
Williams, K. D., & Jarvis, B. (2006). Cyberball: A program for use in research on interpersonal 
ostracism and acceptance. Behavior research methods, 38(1), 174-180. 
Zubieta, J.-K., Ketter, T. A., Bueller, J. A., Xu, Y., Kilbourn, M. R., Young, E. A., et al. (2003). 
Regulation of human affective responses by anterior cingulate and limbic {micro}-opioid 
neurotransmission. Archives of General Psychiatry, 60(11), 1145. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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