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1 2 PI Name: Michael E. Saladin, PhD 3 4 Study Title: Reducing Cue Reactivity and Behavior via Retrieval-Extinction Mechanism

5 A. Specific Aims 6 The goal of the study will be to adopt many of the procedures and parameters of retrieval- 7 extinction training in an attempt to demonstrate enduring reductions in craving and cue-reactivity 8 among cigarette smokers. The study will conduct an exploratory analysis of the intervention’s effects on 9 substance use (i.e., smoking behavior). This exploratory study will investigate a novel behavioral 10 strategy for altering important memory processes that underlie human smoking-related nicotine 11 . This strategy represents a paradigm shift in that it employs established cue exposure 12 procedures to putatively update1 smoking–related memory with information that will suppress 13 responding to smoking cues. The goal here is to alter existing nicotine-related memory directly rather 14 than rely exclusively on the establishment of an inhibitory extinction process2-6 via traditional cue 15 exposure therapy, which is known to be vulnerable to spontaneous recovery, renewal, and 16 reinstatement7,8. The proposed study will also be innovative and novel because, unlike the Xue et al. 17 2012 study, we will preliminarily assess, over the course of a 1-month follow-up period, the effects of 18 retrieval-extinction training on the smoking behavior of smokers who have made a cessation attempt. 19 20 B. Background and Significance 21 Smoking occurs in approximately 21% of the US population, is responsible for an annual 22 mortality rate of approximately 438,000 citizens, and has an associated healthcare economic burden of 23 $167 billion9. Although pharmacotherapies have improved cessation outcome, the vast majority of 24 individuals making quit attempts within 5-10 days of cessation10,11. The hypotheses to be 25 examined in this proposal may have potentially important implications for treatment 26 and will, therefore, target the single greatest addiction-related cause of morbidity and mortality. 27 The role of basic associative learning processes in addiction has been well established in both 28 theory and research12-23. In smoking-related nicotine dependence, numerous pairings between 29 smoking-related cues (e.g., pack of cigarettes) and the reinforcing effects of nicotine can result in cues 30 acquiring the ability to elicit a range of conditioned responses, most importantly craving and 31 physiological reactivity. Since persons trying to quit smoking commonly attribute lapse episodes to cue- 32 elicited craving24-29 and because smokers who are more vulnerable to cue-elicited craving and who are 33 more reactive to cues are less likely to quit successfully30-33, it is clear that smoking cues are a major 34 contributor to cessation failure and the deleterious effects of continued smoking. Additionally, most 35 clinical studies involving first-line cessation medications (with one exception34) have shown that they 36 have only modest effects on the craving elicited by smoking cues35-37. Thus, there is a need to develop 37 treatments that focus on reducing craving, especially cue-elicited craving. The intervention tested in this 38 study specifically targets the learning and memory processes that support cue-elicited craving to 39 smoke. 40 Cue exposure therapy is founded on the notion that the conditioned responses elicited by drug 41 cues can be extinguished by repeated exposure to the cues in the absence of drug administration. 42 While this therapy approach has intuitive appeal, efficacy studies have shown it to be of minimal utility7. 43 The modest efficacy owes, in part, to the fact that responding to drug cues often (a) spontaneously 44 recovers after the passage of sufficient time, (b) renews when the drug cues are encountered in novel 45 circumstances, or (c) reinstates following drug administration7,8,38-40. Although cue exposure therapy in 46 the has fallen out of favor, there is emerging basic and clinical neuroscience research that 47 suggests a relatively brief exposure to cues prior to conducting more protracted cue exposure can lead 48 to enduring changes in memory processes that support responding to cues. This dual element 49 approach to cue exposure, hereafter referred to as retrieval-extinction training or R-E training, is the 50 focus of this application. 51 Once new learning about the relationship between cues and outcomes has become stable in 52 memory via the process of consolidation41-45, memory for that learning can be retrieved via relatively

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53 brief presentations of the cues. Following retrieval, the memories undergo a process of reconsolidation 54 in which they are gradually restabilized in long-term storage46-52. Importantly, there is a period of time 55 between retrieval and the end of reconsolidation in which retrieved memories can be altered in such a 56 way as to attenuate the conditioned behavior once supported by the memories42,50,53-58. There are two 57 methods that target the reconsolidation process as a means of attenuating conditioned behavior. The 58 first method involves pharmacological disruption via the administration of agents such as protein 59 synthesis inhibitors59 or β-adrenergic antagonists60 after cue-elicited retrieval. Incidentally, our research 60 group has published the first evidence of propranolol-induced modulation of memory reconsolidation for 61 craving in cocaine dependent humans61. 62 The second method involves R-E training in which brief cue-elicited memory retrieval is followed 63 by protracted extinction training. In this case, both animal62,63 and human laboratory1 studies have 64 shown that R-E training can produce enduring decrements in responding to conditioned fear cues that 65 are resistant to spontaneous recovery, renewal or reinstatement. Even though this relatively small 66 literature is marked by some inconsistent findings64,65 likely owing to inter-study procedural differences, 67 it broadly suggests that R-E training may represent an entirely new approach to managing clinical 68 fear/anxiety. The literature on R-E training in drug-reinforced learning is just now emerging, with only 69 two published reports, both in 2012. In one of these studies66, the authors employed a morphine 70 conditioned place preference (CPP) paradigm in rats to show that R-E training (a) facilitated extinction, 71 (b) suppressed spontaneous recovery at weekly tests, and (c) suppressed morphine-primed 72 reinstatement at 1-week post-training (but not at 4-weeks). These findings were bolstered by a Science 73 report consisting of 8 animal studies together with one translational human study (Xue et al., 201267). 74 The animal studies used cocaine-, morphine- and -reinforced CPP/self-administration paradigms 75 to show that R-E training suppresses spontaneous recovery, drug-primed reinstatement, and context- 76 induced renewal of drug-reinforced behaviors. The report culminated with the only published human 77 study to date examining the potential clinical relevance of R-E training in detoxified heroin addicts. The 78 study involved three groups. A R-E training group (n = 22) received two laboratory sessions, each of 79 which consisted of retrieval (viewing a 5-min video of people using) followed 10 min later by 1 hr of 80 extinction training (exposure to four sequences of heroin-related video, picture, and in vivo cues). Two 81 control groups (n = 22 each) received identical treatment with the following exceptions: a ‘no retrieval’ 82 control group viewed a nature video followed 10 min later by extinction training, and a ‘delay’ control 83 group viewed the heroin video followed 6 hr later by extinction training. The no retrieval control was 84 intended to show that any observed craving and cue-reactivity differences were specifically due to 85 heroin-related memory retrieval and the delay control group was designed to show that extinction 86 training performed outside the reconsolidation window will undo the effects of R-E training. All 87 participants underwent testing 24-hr, 1-month, and 6-month after the R-E training; testing involved 88 measuring craving and cardiovascular responsivity to the 5 min video with heroin-related content. The 89 results indicated that the group receiving heroin-cue elicited retrieval followed 10 min later by extinction 90 training evidenced significantly less craving and blood pressure responsivity to the video cues than 91 either control group (effect size d = 1.2). Remarkably, these differences persisted through the 6-month 92 post-treatment assessment, indicating an almost complete absence of spontaneous recovery. 93 Collectively, the findings in these two reports provide consistent and compelling initial evidence 94 that R-E training can produce enduring attenuation of drug-related conditioned responses (including 95 cue-elicited craving) that is resistant to spontaneous recovery, renewal, and reinstatement. The goal of 96 the proposed study will be to adopt many of the procedures and parameters of the R-E training 97 employed by Xue et al. in an attempt to demonstrate enduring reductions in craving and cue-reactivity 98 among cigarette smokers. Unlike the Xue et al study, the proposed study will conduct an exploratory 99 analysis of the interventions effects on substance use (i.e., smoking behavior). Positive findings would 100 represent a significant advance in exposure-based therapy for addiction and could lead to a treatment 101 that uniquely targets the problem of cue-elicited craving and reactivity, thereby addressing a major 102 obstacle to successful smoking cessation. Such therapy would likely be appealing to both clinicians and 103 consumers because it would be brief, cost-effective, and easily administered in conjunction with other 104 interventions. Furthermore, it could be potentially used in combination with nicotine patch to improve 105 overall efficacy, which in turn could serve as a therapy alternative for treating persons with a known

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106 sensitivity to the first-line medication, varenicline. Lastly, it could be easily adapted for use with other 107 addicted populations. 108 109 C. Research Design and Methods 110 i. Overview: Following initial contact with study staff, participants will be scheduled for a general 111 clinical assessment and laboratory session in which baseline levels of craving and cue reactivity will be 112 assessed. Participants will be required to remain overnight abstinent from smoking prior to this visit so 113 that the baseline cue reactivity assessment will be performed under the same conditions of abstinence 114 as will prevail for the subsequent three laboratory assessments. Monetary incentives will reinforce 115 compliance with session attendance and overnight abstinence. Following this laboratory assessment, 116 participants will be randomized to one of two groups (R-E vs. NR-E) and then will plan their cessation 117 attempt to begin the night before the first of three consecutive daily laboratory sessions. Participants 118 will receive monetary incentives to remain abstinent as well as compliant with session attendance for 119 these three laboratory sessions. The first two sessions will involve R-E training. During these sessions, 120 R-E group members will first view a 5-min ‘retrieval’ video containing smoking content and then, 10 121 minutes later, receive 1-hour of ‘extinction’ training in which they will be administered four sequences of 122 video, picture and in vivo smoking cues (described below). Members of group NR-E will be treated the 123 same as group R-E except that they will view a ‘no retrieval’ video that has non-smoking, neutral 124 content. The two groups will be treated identically on all remaining sessions. The third session, 125 performed 1-day later, will be a test session that will involve exposure to the smoking video cues (same 126 as baseline assessment) and to a series of novel smoking picture cues, the latter of which will assess 127 generalization of R-E training effects. The remaining two test sessions, performed 2- and 4-weeks after 128 R-E training, will be identical to the first test session except (a) there will be no compensation for 129 abstinence, (b) participants will use diaries to collect daily information about smoking and craving, and 130 (c) urine will be collected to permit biochemical verification (via urine cotinine level) of self-report 131 smoking/abstinence. 132 To increase the likelihood that R-E training will produce the desired response-dampening effect 133 on smoking-related behaviors, the proposed study will draw heavily from the design, procedures and 134 training parameters employed by Xue et al. There are notable exceptions. First, this study targets 135 treatment-seeking smokers rather than detoxed heroin addicts because, from a public health impact 136 perspective, cigarette smoking is the most costly addiction. Second, the follow-up period in this study 137 will be one month (vs. 6 mo. in the Xue et al) because, as noted above, most occur within the 138 first 10 days of cessation10,11 and so a 30-day window will allow ample opportunity for variation in 139 smoking behavior to naturally recur. Longer follow-up would also be difficult to achieve within the time 140 constraints of an R21 project period. Third, a limitation of the Xue et al study was that it did not report 141 on substance use during follow-up. This limitation will be addressed in the proposed study by having 142 participants monitor their smoking behavior over follow-up (this will permit preliminary analysis of 143 treatment impact on indices of smoking behavior/cessation) and by obtaining breath CO and performing 144 urine cotinine to objectively corroborate the self-report smoking data. Fourth, we will not include a 145 control in which the extinction training occurs 6 hr. after retrieval because demonstrating that 146 reconsolidation is time limited is not essential/relevant to the primary clinical focus of this proof-of- 147 concept study. Finally, Xue et al administered four, 15-minute sequences of cue exposure during the 148 extinction component of each retrieval-extinction session whereas we plan to administer three. We 149 have elected to modestly reduce the cue exposure in favor of allowing time to collect outcome data to 150 assess the effects of training. This may prove invaluable in gaining some insight into the cumulative 151 effects of retrieval-extinction training (i.e., between group differences in cue reactivity across the two 152 retrieval-extinction sessions). 153 154 ii. Participants: A total of 88 treatment-seeking men and women smokers (44 per group), aged 155 18 to 65, will be enrolled in the study. Participants must smoke 10+ cigarettes/day for three or more 156 years and be willing to make a cessation attempt and comply, at minimum, with the (a) overnight 157 abstinence required prior to the baseline smoking cue-reactivity assessment, and (b) reinforced

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158 abstinence requirements for the three laboratory sessions described below. Inclusion and exclusion 159 criteria are detailed in the Protection of Human Subjects section of this application. 160 Sample Size Estimation. This study is powered to detect clinically relevant effects on a sample 161 size of 44 participants per treatment group (randomized) and is optimized to provide adequate power to 162 detect meaningful effects across both primary hypotheses in the study. Among heroin addicts, Xue et al. 163 (2012) reported a significantly attenuated cue-elicited craving response in participants who received 164 heroin-relevant retrieval (prior to extinction) as compared to those that did not. The study showed a 165 similarly large effect at both 24-hr and 1-month follow-up sessions with an approximate effect size of d 166 = 1.2 at both time points. Operating on the conservative assumption that the proposed study will yield a 167 smaller effect size, we anticipate that the between group effect size will be d = 0.8. Accordingly, we will 168 have at least 80% power, with α = .05, to detect the stated group difference (d = 0.8) with 25 169 participants randomized to each group (n = 50 total participants). Assuming a rate of attrition of 10% 170 between the baseline assessment and the R-E training sessions and 20% at the 1-month follow-up, the 171 sample size is inflated to 44 participants per group (n per group / (1-drop out rate) = 25 / (1-0.20). Thus, 172 88 total participants randomized to either group will provide 80% power to detect an effect size of 0.66 173 at all pre-specified time points. For secondary Aim 2, the study proposes to estimate smoking behavior 174 outcomes between the R-E and NR-E groups. The sample size of 88 participants will provide 80% 175 power to detect a minimum effect size of d = 0.66 for the continuous outcomes of cigarettes/day 176 smoked, days to first cigarette, and percent of smoke free days at each follow-up time point. 177 Recruitment. Participants will be primarily recruited using local media (e.g., print, online, radio), 178 a recruitment strategy that has been very successful in our previous and ongoing studies with smokers. 179 We may also elect to recruit participants from several outpatient services at the Medical University of 180 South Carolina (MUSC) including Family Medicine, Weight Management Services and also the Ralph H. 181 Johnson VA Medical Center (where Dr. LaRowe, Co-I, is a staff psychologist and Health Behavior 182 Coordinator). 183 184 iii. Cue-Reactivity Measures: All of the following measures have strong psychometric 185 properties and have been routinely employed in laboratory studies performed by our research group. 186 Craving Questionnaire (CQ) is a brief, 4-item self-report questionnaire68 that assesses urges to 187 smoke. It has the benefits of multi-item craving assessment without being intrusive or time consuming. 188 Mood Form (MF) is a 9-item form69 that will provide an immediate, corroborative assessment of 189 current positive and negative mood states. Our modified MF contains an item to assess subjective 190 stress. 191 Heart rate (HR), skin conductance (SC), and blood pressure (BP) will be measured repeatedly 192 over the course of the laboratory sessions. HR will be collected via two electrodes along the bottom of 193 the participant’s ribcage, rather than on the participant’s forearm, to minimize movement artifacts while 194 SC will be recorded using Ag/AgCl electrodes attached to the second phalanx of the first and third 195 fingers of the non-dominant hand (HR and SC signals will be amplified using the ECG 100c and GSR 196 100c Modules of the Biopac MP100 data acquisition system). BP will be measured via a non-invasive, 197 inflatable arm cuff. 198 199 iv. Experimental Stimuli: Consistent with Xue et al. 2012, we will use three formats of smoking 200 cues: video, picture, and in vivo. The baseline and the test sessions (i.e.,24 hr, 2-weeks, and 1 month 201 post R-E training) will involve exposure to the video smoking cues and a set of novel picture cues as 202 described below. For Group R-E, each of the two R-E training sessions will involve exposure to the 203 smoking video cues followed 10 min later by four sequences of cues, with each sequence consisting of 204 video, picture, and in vivo cues (as described below). Within a stimulus sequence, each of the three 205 formats will be presented only once and the order of presentation of the first two formats will be 206 randomly determined (the third is fixed). 207 Video cues. The video cues (acquired from Dr. Joel Erblich’s research group at Mount Sinai 208 School of Medicine) consist of 12, 30-s high-resolution video segments of individuals of both sexes 209 engaging in smoking related behaviors (e.g., lighting up a cigarette and smoking). A selection of 10 of 210 the 12 video segments will be assembled into a continuous 5-min smoking video for use in the

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211 proposed study. Control videos (e.g., person reading a book) will serve as the neutral retrieval cue for 212 participants assigned to NR-E. The smoking and control video segments were staged and filmed by a 213 professional cinematographer with the goal of maximizing inter-video similarity on elements of lighting 214 and visual complexity. The craving and cue-reactivity potency of the smoking videos has been 215 demonstrated in smokers70. 216 Picture cues. The picture cues in the R-E training sessions will be a set of 30 smoking-related 217 images (e.g., person blowing cigarette smoke) acquired from Dr. Stephen Tiffany’s research group 218 (SUNY, University at Buffalo). These images have been used extensively by Dr. Tiffany to study 219 craving and cue-reactivity in smokers and their potency has been documented in several 220 publications37,71,72. In the proposed study, the images will be displayed on a computer monitor that is 221 located directly in front of the participant. Each image will be displayed for 8 s, with a 2-s delay between 222 images (total approximate duration will be 5 min). 223 To assess whether the effects of R-E training generalize to novel smoking stimuli, participants 224 will be administered a brief ‘novel’ smoking picture cue exposure sequence in each test session. The 225 picture sequence will occur approximately 30 min after the video cues and will consist of 12 novel 226 smoking pictures, presented for 8 s each (2-s delay between each). The pictures will be obtained from 227 stimulus sets we have used in our previous work73,74 and from the work of others75,76. 228 In vivo cues. The in vivo cues in the R-E training sessions will be based on our previous cue- 229 reactivity research with smokers77. Briefly, a pack of the participant’s preferred brand of cigarettes and 230 a lighter will be placed in a covered box. The participant will be signaled to lift the cover off the box and 231 will be instructed to look at and handle the cigarette pack and lighter for approximately 60-90 s. Then, 232 participants will be instructed to take one cigarette from the pack and hold it between their fingers as 233 they normally do while smoking (approximately 60 s). Participants will be instructed to handle the 234 cigarette and then to smell the cigarette. The participants will then be instructed to pick-up the lighter 235 and flick the lighter without actually lighting the cigarette. The duration of this experience will be 5 min. 236 237 v. Screening, Consent, Assessment and Baseline Smoking Cue-Reactivity: Generally, 238 initial contact with participants will occur via phone. A brief screening will assess participant suitability 239 via inclusion/exclusion criteria. Qualified and interested individuals will be scheduled to undergo a more 240 detailed assessment and will later complete a baseline smoking cue-reactivity assessment at the 241 Addictive Behaviors Research Laboratory (ABRL; at Medical University of South Carolina) or the 242 Clinical and Translational Research Center at MUSC. They will be informed that they will be (a) 243 required to be abstinent from alcohol and other drugs on the day of the baseline smoking cue-reactivity 244 assessment, and (b) compensated to remain abstinent from smoking starting at bedtime the night 245 before they attend their baseline assessment. Overnight smoking abstinence prior to baseline smoking 246 cue-reactivity is necessary so that baseline responses are collected under the same conditions of 247 reinforced/compensated abstinence as those that will be in force during the R-E training and initial test 248 session. We also may elect to do the consent, assessment, and baseline cue reactivity assessment all 249 in one visit in order to minimize travel burden on prospective participants. However, both the screening 250 assessment and baseline cue-reactivity assessment may be scheduled on separate days due to 251 availability. 252 Upon consent, participants will undergo a smoking abstinence assessment involving self-report 253 verification followed by breath CO assessment. Recent studies have indicated that CO cut-offs for 254 establishing 24-hr abstinence should be in the range of 3 to 8 ppm78,79. Accordingly, participants will be 255 considered overnight abstinent if their breath CO level is ≤ 10 ppm. Additionally, abstinence from 256 alcohol/other drug use will be assessed via breathalyzer and urine drug screen (UDS). A urine sample 257 will also be collected for the purpose of establishing baseline urine cotinine levels. Failure to meet 258 abstinence requirements will result in rescheduling. Next, participants will undergo a comprehensive 259 clinical assessment of nicotine dependence, general psychiatric functioning, and nicotine/other 260 substance use. It will include the following: Fagerström Test for Nicotine Dependence (FTND80), which 261 is a brief measure of nicotine dependence; Wisconsin Predicting Patients’ Relapse questionnaire 262 (WPPR81) which assesses relapse potential and may serve as covariate in the analysis of the follow-up 263 smoking outcomes data; The Mini-International Neuropsychiatric Interview or MINI82 which assesses

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264 general psychiatric functioning and other alcohol/substance dependence (related to inclusion/exclusion 265 criteria). Other questionnaires that will be given to participants during the assessment visit include: The 266 Smoking History Form, The Delay Discounting Task Form, The Profile of Mood States Questionnaire, 267 The Quit Attempts Questionnaire, The Contemplation Ladders, The Intolerance for Smoking Abstinence 268 Questionnaire, The Nicotine Addiction Taxon Scale, and the Michigan Nicotine Reinforcement 269 Questionnaire. These forms and questionnaires are done to assess smoking habit history, frequency, 270 and urges. Quantity and frequency assessment of smoking and other substance use in the three 271 months prior to study involvement will be assessed using the Timeline Follow-Back (TLFB83 is a 272 calendar-based instrument with specific probes to obtain detailed information about substance use). 273 The TLFB data will provide pretreatment estimate of baseline smoking that may be contrasted with 274 smoking behavior over 1 month follow-up. 275 Lastly, the participants will complete baseline smoking cue-reactivity, the goal of which will be to 276 obtain pre-treatment estimates of reactivity to video cues with smoking content. Participants will be 277 seated comfortably in front of a computer monitor and have the HR and SC sensors and BP cuff affixed 278 as described above. They will remain seated comfortably for 10 min, after which 50 s of continuous HR 279 and SC data will be collected; next participants will complete the CQ, MF, and have their BP assessed. 280 Having completed the pre-cue assessments participants will remain seated for 5 min; they will then 281 view the smoking-related video described above. Continuous HR and SC will be collected during the 282 first 50 s of the video whereas the CQ, MF, and BP will be collected immediately after viewing the 283 video. Sensors will then be removed and participants will receive the scheduled compensation. 284 Participants will schedule their next visit with the study coordinator, and they will be reminded that their 285 quit attempt will begin the night before and that it will be the first of three consecutive daily visits for 286 which they will receive abstinence-based compensation (abstinence requirements same as first visit). 287 The rationale for implementing a reinforced abstinence procedure was to ensure that nicotine 288 administration/reinforcement does not interfere with the learning and memory processes that develop 289 during the R-E training sessions and that are assessed in the initial test session. 290 291 vi. Randomization: Urn randomization84 will be used to assign participants to groups R-E or 292 NR-E while balancing on two variables. Because both gender and level of nicotine dependence (FTND 293 score) are known to influence smoking cue-reactivity and/or behavior85,86, groups will be balanced on 294 both. Dependence will be balanced on FTND score ≤ 5 vs. > 6. The effects of additional factors such as 295 age and duration of smoking will be statistically controlled during the analysis (if necessary) since 296 further stratification of the randomization would yield some stratum with very small cell sizes, thereby 297 resulting in an unbalanced design. 298 299 vii. Retrieval-Extinction (R-E) Training Sessions: As already noted, the two sessions of R-E 300 training will be performed on consecutive days. Participants will arrive on the scheduled date and 301 compliance with abstinence (breath CO, UDS, and breathalyzer) will be assessed. If the participant fails 302 the abstinence assessment, they will be rescheduled; however, if the participant fails the abstinence 303 assessment on the second day, they will be dropped from the study because recycling them through 304 the protocol would result in these individuals having three sessions of R-E training (all participants will 305 be made aware of this during consent and repeatedly reminded). Pre-cue measures of craving and 306 physiological reactivity will be obtained as described above. Next, individuals in Group R-E will watch 307 the 5-min video with smoking-related content (same as seen during baseline smoking cue-reactivity 308 assessment) whereas individuals in Group NR-E will view the 5-min control video with neutral, 309 smoking-irrelevant content. The video presentation represents the putative memory retrieval feature of 310 the study and should initiate reconsolidation of memories for smoking-related learning in Group R-E but 311 not NR-E. Continuous HR and SC will be collected during the video and immediately following the video, 312 individuals will complete the CQ, MF, and BP will be obtained. Consistent with Xue et al., participants 313 will remain seated for 10 min and then the 1-hr session of extinction training will commence; this will 314 consist of four sequences of video, picture, and in vivo smoking cue exposure. Continuous HR and SC 315 will be collected during the first cue format presented in each sequence and the CQ, MF, and BP will be 316 obtained immediately following the last cue format of each sequence (i.e., during the 5-min rest period).

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317 At the completion of extinction training, participants will be asked to sit comfortably for 5 min while the 318 study coordinator removes the HR/SC sensors and the BP cuff. Participants will be reminded that they 319 are being compensated (escalating schedule of compensation) to remain abstinent from smoking and 320 other substance use during these three laboratory sessions (two R-E sessions and the first test 321 session). 322 323 viii. Test Sessions: Participants will complete three test sessions: 24 hr, 2 weeks, and 1 month 324 after the second R-E training session (monetary compensation will be employed to minimize test 325 session “no-shows” or attrition). Consistent with Xue et al. 2012, each of the test sessions will involve a 326 cue-reactivity assessment identical to the baseline cue-reactivity assessment described above except 327 that a brief novel smoking picture cue sequence will be presented. Importantly, there are some 328 procedural elements that are not present in all test sessions. First, only the test session performed 24 329 hr after the second R-E training session will be performed under conditions of reinforced abstinence 330 (see participant compensation; however, participants will undergo breath CO/alcohol assessment and 331 UDS at all laboratory sessions). The goal will be to assess the acute effects of R-E training under the 332 same conditions of abstinence (i.e., in the absence of potential interference from nicotine reinforced 333 learning via smoking) that occurred during the R-E training. Participants will be encouraged to maintain 334 their smoking abstinence at the conclusion of this session but will not be compensated for it 335 (participants will be given a referral to the SC state Quitline, a free, anonymous service that supports 336 abstinence). Second, at the end of the first (24-hr) and second (2-week) test session, participants will 337 receive a smoking diary in which to record the occurrence of daily smoking behavior over the ensuing 338 2-week follow-up period. These diaries will be collected at 2nd and 3rd test sessions, respectively, and 339 extracted data will permit the assessment of the effects of the R-E training on smoking behavior during 340 follow-up (research staff will perform a TLFB assessment of smoking behavior if participants do not 341 present with their smoking dairy). Third, a urine sample will be collected at the 2-week and 1-month test 342 sessions in order to biochemically corroborate via cotinine levels, self-report smoking/abstinence. 343 Finally, at the completion of the 3rd/final test session debriefing will occur and will involve the research 344 coordinator (a) addressing any questions that a participant may have, and (b) providing 345 recommendations for additional cessation treatment. 346 347 ix. Participant Compensation: Participants will be compensated as follows: Screening, 348 assessment = $30.00; baseline cue-reactivity = $30.00; R-E training sessions 1 & 2 = $75.00 & 100.00, 349 respectively; Test session 1 = $125.00; Test sessions 2 & 3 = $100.00. Maximum compensation for 350 participation is $560.00. 351 352 x. Data Analysis Plan: Baseline demographic and clinical measures will be compared across 353 treatment groups using standard statistical methods (i.e., categorical variables compared using 354 Pearson chi square test of independence; continuous variables compared using t-tests). Characteristics 355 that display imbalance at the baseline measure, association with the dependent variable, or are known 356 to be predictive of craving or cue-reactivity will be assessed for final model inclusion. Primary 357 hypotheses 1 & 2 (Group R-E will evidence lower craving and cue-reactivity to test cues and novel 358 picture cues) will be assessed using a generalized linear mixed effects model. Overall statistical 359 significance for the effects of treatment group, time, and their interaction will be assessed using a 360 likelihood ratio test that compares the final model to a model consisting of an intercept term alone. The 361 pre-specified hypothesis will be tested using model-based estimates to construct group level 362 comparisons at the planned time points. Secondary hypothesis 3 involves testing the effect of R-E vs. 363 NR-E on several measures of smoking behavior over the 1-month follow-up. Group differences in the 364 mean number of cigarettes smoked during each follow-up week will be analyzed using a general linear 365 model similar to that specified for hypotheses 1 & 2; days to the first cigarette smoked after study 366 treatment (i.e., after first test session) will be assessed using a Cox Proportional Hazards model; and 367 the percent of days smoke-free during 1-month follow-up will be assessed using a 1-way ANOVA 368 model. Abstinence outcomes will be measured as 7-day point prevalence abstinence at the 2- and 4- 369 week visits (cotinine corroborated) as well as continuous abstinence over the duration of the study

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370 (cotinine corroborated). The treatment effect of R-E on abstinence outcomes versus NR-E will be 371 assessed using logistic regressions models; the resulting estimates will primarily be used to inform the 372 power and necessary sample size for a larger efficacy study. 373 374 xi. Timeline: Since we have an experienced research coordinator ready to assume study- 375 related duties, an active recruitment network and extensive experience conducting smoking cue- 376 reactivity protocols, we anticipate start-up to occur in approximately 2 months. During this period, the 377 study coordinator will receive any necessary training, the protocol will be IRB-approved at MUSC, and 378 laboratory procedures and database(s) will be established. We will actively recruit participants for 20 379 months and plan to allow two months for final data cleaning/reduction, analysis and manuscript 380 preparation (albeit manuscript preparation will begin sooner). Submission of a proposal for a more 381 extensive controlled trial if the results are promising will occur as soon as possible. At a modest 382 recruitment rate of approximately 3 participants per month, we should have no difficulty completing the 383 study in the two-yr timeframe. With regard to recruitment milestones, we anticipate being able to recruit 384 approximately 36 nicotine dependent smokers in each year of the grant period. 385 386 D. Protection of Human Subjects 387 388 1. Risks to Human Participants 389 390 1.1 Human Participants Involvement and Characteristics 391 Admission into the study is open to men and women, ages 18 to 65, and to all racial and ethnic groups. 392 Based on our previous work with nicotine dependent smokers, we anticipate we will screen (by 393 telephone or in person) about 120-180 potential participants. A total of 88 male and female participants 394 with smoking-related nicotine dependence who are interested in making a cessation attempt 395 (treatment-seeking) will be enrolled. We will recruit participants from multiple sources, primarily through 396 advertising in local media via television, newspaper, flyers, Internet, and by word of mouth among 397 participants. 398 399 Inclusion Criteria 400 a) Participants must be able to provide informed consent and function at an intellectual level sufficient 401 to allow accurate completion of all assessment instruments. 402 b) Participants must meet DSM-IV criteria for current nicotine dependence and be a daily cigarette 403 smoker of 10+ cigarettes/day for a minimum duration of three years. 404 c) Participants must live within a 50-mile radius of the research facility and have reliable 405 transportation. 406 d) Participants must be treatment-seeking and be willing to make a quit attempt beginning the night 407 before the three consecutive daily laboratory sessions (i.e., two R-E training sessions and the test 408 session performed 24 hr after the second R-E training session). 409 e) Participants must be willing to (a) be overnight smoking abstinent (CO verified) prior to the baseline 410 smoking cue-reactivity assessment, and (b) make a cessation attempt and be smoking abstinent 411 (CO verified) over the three-day period that corresponds to the two R-E training sessions and the 412 test session performed 24 hr after the second R-E training session. 413 f) Participants must be willing to submit to a breathalyzer (alcohol) assessment and urine drug 414 screen (for benzodiazepines, methamphetamine, cocaine, marijuana, and opiates) and produce a 415 negative test result on (a) the day of the baseline smoking cue-reactivity assessment, and (b) each 416 of the three consecutive days that correspond to the two R-E training sessions and the test session 417 performed 24 hr after the second R-E training session. 418 g) Participants must be willing to submit a urine sample for the purposes of determining cotinine 419 levels (as a means of biochemically verifying self-report abstinence and changes in smoking 420 behavior). 421 h) Participants must consent to random assignment to the R-E vs. NR-E conditions/groups. 422 i) Participants must not use smokeless tobacco.

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423 j) Participants must be willing to forego any other medication or behavioral treatment for smoking 424 cessation during their enrollment in this study (with the exception of a referral, upon request, to the 425 SC Quitline). Additional treatment referrals will be provided at the end of the study. 426 427 Exclusion Criteria 428 a) Participants with current/active (untreated) psychotic disorder, current major depressive disorder 429 (severe), bipolar affective disorder, or a severe anxiety disorder as these conditions would likely 430 interfere with their ability to fulfill the requirements for successful participation (e.g., provide 431 accurate interview data, complete study assessments, attend scheduled laboratory visits, etc.). 432 b) Participants meeting DSM-IV criteria for substance dependence (other than nicotine) within the 433 past 60 days. 434 c) Participants who are unwilling or unable to maintain abstinence from alcohol and other drugs of 435 abuse (benzodiazepines, methamphetamine, cocaine, marijuana, and opiates) in order to comply 436 with Inclusion Criterion f above. 437 d) Participants currently taking ß-blockers, anti-arrhythmic agents, psychostimulants, or any other 438 agents known to interfere with heart rate, skin conductance, or blood pressure responses. 439 e) Current use of any pharmacotherapy or psychotherapy for smoking cessation. 440 f) Pregnant women (because pregnancy can influence responding during study procedures). 441 g) COPD complicated by severe cough as coughing will interfere with heart rate and skin 442 conductance. 443 h) Participants who currently use any form of smokeless tobacco or e-cigarettes. 444 445 1.2 Sources of Materials 446 a) Research material obtained from individual participants includes questionnaires and interviews 447 with study personnel as well as blood and urine samples and data obtained at the laboratory- 448 based sessions. To ensure confidentiality, all participant data will be number coded, and only the 449 investigators will have access to the master lists of codes. 450 b) The research material will be obtained specifically for research purposes. Written research 451 material obtained will be stored in a locked file cabinet in a research office that will be locked 452 when not in use. 453 454 1.3 Potential Risks 455 Questionnaires and interviews are all non-invasive and, as such, involve minimal physical risk to the 456 participants. Potential risks incurred by participants include: 457 a) Loss of confidentiality: There is a risk of loss of confidentiality regarding the information obtained 458 during study participation. 459 b) Craving induction via cue-reactivity/exposure: There is risk of increased craving for cigarettes or 460 distress as a result of the cue-reactivity procedures. 461 c) Adverse events unrelated to study participation may occur during the course of study 462 participation. 463 There are no alternative methods of obtaining this information. 464 465 2. Adequacy of Protection Against Risks 466 467 2.1 Recruitment and Informed Consent 468 Participants will be recruited primarily through the use of advertisements (newspaper, radio, and 469 television, Internet, flyers). Medical records will NOT be reviewed to identify potential study participants. 470 The study PI, co-investigators, or other research team members will obtain informed consent. The 471 informed consent form will include a detailed description of the study procedures, along with statements 472 regarding participants’ rights to withdraw from the procedure at any time without consequences. The 473 informed consent form will be explained to participants in easy-to-understand language, and 474 participants will be instructed to read the form carefully prior to signing it. Consent will be documented

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475 by the signature of the participant on the informed consent agreement, accompanied by the signature 476 of the individual obtaining the consent. 477 478 2.2 Protection Against Risk 479 Drs. Saladin and/or Carpenter will monitor all study participants for general psychological well- 480 being/stability. The instrumentation to be used for physiological recordings meets all safety standards 481 for non-invasive recordings, and participants will be located out of reach of any AC-powered devices in 482 the laboratory. All laboratory sessions will be conducted under the supervision of experienced 483 personnel. If crisis intervention is necessary, senior staff (Saladin/Carpenter) will be available to 484 evaluate the subject and provide an intervention or referral. All participants will be fully informed that 485 they may withdraw from the experiment at any time without penalty. 486 487 To ensure confidentiality, participant data will be number coded, and only the investigators will have 488 access to the master list of codes and participant names. All participant records will be kept in a locked 489 file cabinet in an office that will be locked at times when not in use. All research staff undergo rigorous 490 training on the ethical treatment of human subjects in research and receive continuous feedback about 491 the need to maintain confidentiality. 492 493 3. Potential Benefits of the Proposed Research to the Participants and Others 494 Benefits of study participation include detailed assessment of smoking and other substance use, 495 potential reductions in craving to smoke and other reactions to smoking cues, reductions in smoking, 496 abstinence from smoking, and referral for additional treatment outside the context of study participation. 497 Also, regular contact with and monitoring by research staff may serve to motivate participants in future 498 attempts to abstain from cigarette use. Overall, given the potential benefits, it would appear that 499 exposure to the risks associated with study participation are well-justified. The risk/benefit ratio appears 500 to favor the study participant. 501 502 4. Importance of the Knowledge to be Gained 503 This study may yield important information that can expand knowledge about the learning and memory 504 processes that subserve cigarette-related nicotine addiction and may improve treatment for future 505 patients with nicotine dependence. If this exploratory treatment is found to have appreciable efficacy, it 506 could be easily modified for administration to individuals with addictions to other substances. 507 508 5. Data and Safety Monitoring Plan 509 Adverse Event Monitoring 510 Adverse events will be monitored throughout the study and all events will be followed to resolution or 511 stabilization. All serious adverse events will be collected and reported immediately to the IRB and the 512 federal funding agency. A serious adverse event is one that meets any of the following criteria: 513 1. Fatal or life threatening 514 2. Requires or prolongs inpatient hospitalization 515 3. Results in persistent or significant disability/incapacity 516 4. Congenital anomaly 517 5. Important medical event that may jeopardize the patient or require intervention to prevent a 518 serious outcome 519 6. Cancer 520 7. Overdose 521 8. Results in the development of drug dependency or abuse. 522 523 Data and Safety Monitoring Board 524 A Data and Safety Monitoring Board (DSMB) will be created to ensure the safety of participants and the 525 validity and integrity of data collected during the tenure of the project. The board will consist of Robert 526 Malcolm, M.D., Aimee McRae-Clark, Pharm.D., and Sudie Back, Ph.D. This multidisciplinary group has 527 extensive experience with management and monitoring of clinical research involving cue-

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