Isradipine enhancement of virtual reality cue exposure for smoking cessation: Rationale and study protocol for a double-blind randomized controlled trial

Abstract

Cigarette smoking remains a leading cause of preventable death in the United States, contributing to over 480,000 deaths each year. Although significant strides have been made in the development of effective smoking cessation treatments, most established interventions are associated with high relapse rates. One avenue for increasing the effectiveness of smoking cessation interventions is to design focused, efficient, and rigorous experiments testing engagement of well-defined mechanistic targets. Toward this aim, the current protocol will apply a pharmacologic augmentation strategy informed by basic research in animal models of addiction. Our goal is to evaluate the enhancing effect of isradipine, an FDA-approved calcium channel blocker, on the extinction of craving—a key mechanism of drug relapse after periods of abstinence. To activate craving robustly in human participants, we will use multimodal smoking cues including novel 360° video environments developed for this project and delivered through consumer virtual reality headsets. Adult smokers will take either isradipine or placebo and complete the cue exposure protocol in a double-blind randomized control trial. In order to test the hypothesis that isradipine will enhance retention of craving extinction, participants will repeat cue exposure 24 h later without the administration of isradipine or placebo. The study will be implemented in a primary care setting where adult smokers receive healthcare, and smoking behavior will be tracked throughout the trial with ecological momentary assessment.

1. Introduction

Cigarette smoking contributes to over 480,000 deaths each year in the United States, or about 1 of every 5 deaths [1]. Moreover, an estimated 8.6 million individuals live with chronic diseases caused by tobacco use including lung cancer, heart disease, and COPD [2,3]. Consequently, at least 6–9% of total US personal health expenditures, or approximately $170 billion in direct medical costs, as well as $156 billion in lost productivity, can be attributed to smoking-related conditions [4,5]. Significant strides have been made in the development of effective smoking cessation treatments, yet most established interventions are associated with relatively low long-term abstinence rates (15–35%) [6]. A promising avenue for increasing the effectiveness of existing smoking-cessation interventions is to target phase-specific challenges, such as preventing relapse after a successful period of abstinence. Toward this aim, the current protocol is designed to test an intervention targeting self-reported craving, which plays a key role in relapse [7].

Pavlovian learning mechanisms play a key role in craving and provide a systematic framework for testing the efficacy of interventions targeting craving. Addictive drugs have profound effects on reward learning in the brain, where overstimulation of dopaminergic neurons engages mechanisms of synaptic plasticity that establish functional connections between cues that are proximal to drug use and the satisfaction of craving [8]. Even in the absence of the addictive drug, exposure to cues is sufficient to trigger dopamine release, which plays a role in motivation, thus promoting drug-seeking behavior [9]. These mechanisms are highly conserved across species and play a central role in cigarette addiction where strong associations are formed between smoking and a variety of sensory cues, including proximal (e.g., cigarettes, lighters, ashtrays), contextual (e.g., social and physical environments in which smoking commonly occurs), or interoceptive (e.g., negative mood state) [10–12]. Among smokers who quit, strong cravings can be triggered by drug-associated cues even after periods of abstinence and beyond the withdrawal phase [13–17]. Thus, targeting these associations is key to the long-term impact on craving-induced relapse.

The current research protocol builds upon recent work that tested pharmacologic augmentative strategies in rats using conditioned place preference (CPP), a Pavlovian learning model of cue-induced drug relapse. Synaptic plasticity underlies learning and memory, and is regulated by L-type Ca2+ channels (LTCC) that can be targeted by antagonists to reduce glutamatergic transmission in the ventral tegmental area, a key region in the processing of drug-associated cues that can trigger relapse [11]. In a series of experiments, LTCC blockage with isradipine enhanced and prolonged extinction of drug-associated CPP [11]. Although several preclinical studies with human subjects have examined off-label use of isradipine to target a variety of effects associated with acute and chronic stimulant use, none have administered isradipine in combination with a cue exposure protocol [18–23]. As an extension of CPP findings in animals, we will test whether isradipine, an FDA-approved calcium-channel blocker used to treat hypertension, can facilitate the effects of cue exposure on craving in cigarette smokers.

2. Materials and method

2.1. Clinical trial funding and registration

The study is funded by the National Institute on Drug Abuse (NIDA; 1R21DA049539–01) and is registered on clinicaltrials.gov (NCT03083353). Prior to acquisition of grant funding, an earlier version of the protocol was initiated under this trial registration but paused due to low recruitment (N = 7). The key changes to the protocol since funding acquisition are: an increase in participant compensation designed to increase recruitment, the addition of scenes to the virtual reality cue exposure protocol, and the addition of EMA data collection. The registration has been updated to reflect the procedures described below, which have been approved by the Institutional Review Board of the University of Texas at Austin. A Data Safety and Monitoring Board will oversee the study throughout the recruitment phase.

2.2. Overview of design

The current research protocol is designed to test the hypothesis that isradipine (ISR), compared to placebo (PBO), administered in conjunction with cue exposure will enhance long-term extinction of selfreported craving to smoking cues, assessed in a subsequent medicationfree cue exposure session. Fig. 1 illustrates participant study flow. Participants will be prescreened by internet and phone for basic inclusion and exclusion criteria prior to a final in-person medical evaluation. Eligible participants will initiate an abstinence challenge 24 h prior to the first cue exposure (verified by expired carbon monoxide levels ≤4 ppm). Isradipine (ISR) or placebo (PBO) will be administered in a double-blind randomization, and cue exposure session 1 will begin 90 m after administration when isradipine peaks in the brain [24]. Participants will return 24 h later to repeat the procedure without the administration of isradipine or placebo. Isradipine follows biphasic elimination with an early half-life of 1.5–2 h and terminal half-life of 8 h, therefore, any traces at 24 h post-administration are not expected to have acute effects on the second cue exposure session [24]. This second cue exposure session will be used to test whether the isradipine group exhibits enhanced long-term extinction. During the period between the initiation of the abstinence challenge and completion of the study, ecological momentary assessment (EMA) of self-reported craving, exposure to smoking cues, and smoking behavior will be collected via smartphone application.

Fig. 1.

Participant study flow.

2.3. Participant recruitment and compensation

Individuals interested in participating in the study will be directed via various recruitment strategies to an internet prescreen. Recruitment sources include: 1) posting newspaper and Craigslist advertisements; 2) utilizing fliers in community-based organizations, bulletin boards, stores, and handing them out at events and various other sites; 3) utilizing social media sites (e.g., Facebook, Twitter, LinkedIn) to post status updates with links to our online prescreen; 4) utilizing ResearchMatch; and 5) seeking organizations (e.g. Live Tobacco Free Austin).

Individuals that meet the following criteria will have the option to enroll in the study: Inclusion Criteria: (1) 18–65 years old; (2) Willing and able to provide informed consent, attend all study visits, and comply with the protocol; (3) Daily smoker for at least one year; and (4) Currently smoke an average of at least 5 cigarettes per day. Inclusion criteria (3) and (4) are designed to enhance the ecological validity of our intervention by testing it on regular, daily smokers. Exclusion Criteria: (1) Current diagnosis of a psychotic, eating, developmental or bipolar disorder, or significant suicide risk; (2) Current treatment for smoking cessation or use of other nicotine products, including e-cigarettes; (3) Exclusion criteria related to isradipine administration: (a) known allergy or sensitivity to isradipine, (b) hypertension, (c) congestive heart failure, (d) any type of liver disease, (e) current pregnancy, (f) women of childbearing potential who are not using medically accepted forms of contraception, (g) current use of Rifampin, which decreases the availability of calcium channel blockers, or of Tagamet, which can increase hypotensive effects and inhibit hepatic metabolism of isradipine, (h) any other significant medical condition that increases risk, as determined by the study physician; (4) Significant vision problems that would prevent engagement with the 360° video environment; and (5) Past six month substance use disorders, other than nicotine use disorder, will be ruled out to limit potential drug interactions with isradipine. The phase and method of assessment of these criteria are described in the next section (2.4. Screening procedures and measures).

Participants will receive up to $150 in compensation. Payment will be made as follows: $10 for completing the medical screen, up to $60 for ecological momentary assessment (up to $30 each for Day 1 and Day 2 at $2 per response, 15 times per day), $30 for completing the first cue exposure session, and $50 for completing the second cue exposure session. This payment is not contingent upon smoking status at the time of the final visit. Compensation is based on the time commitment required for each component of the study.

2.4. Screening procedures and measures

An overview of assessments through the course of the study is provided in Table 1 below, followed by a procedural description of each study phase.

Table 1.

Assessment schedule.

Measure	Internet Prescreen	Phone Screen	Medical Visit	24 h EMA	1st Cue Exposure	24 h EMA	2nd Cue Exposure
Fagerstrom Test for Nicotine Dependence	×
Medical, psychiatric, & substance criteria	×	×
Demographics	×				×
Smoking history	×	×			×
Columbia Suicide Severity Rating Scale		×
Smoking Cue Appeal Survey					×		×
Medical evaluation			×
Carbon monoxide			×		×		×
Alcohol breathalyzer			×		×		×
Vital signs			×		×		×
Craving, smoking cues & cigarette use				×		×
Craving ratings to in-lab smoking cues					×		×
Minnesota Withdrawal Scale					×		×

Note. EMA=Ecological Momentary Assessment.

Individuals interested in participating in the study will be directed via various recruitment strategies to an internet prescreen using REDCap, an online data collection platform that meets HIPAA compliance standards. The first page of the prescreen survey will include the informed consent document (ICD) for the prescreen survey. Participants who consent to the prescreen will complete the following measures:

Demographics

Participants will provide their age, sex assigned at birth, and (if they are eligible) name and contact information.

Medical and psychiatric status

Participants will answer questions addressing current diagnosis of a psychotic, eating, developmental or bipolar disorder, as an initial assessment of psychiatric exclusion criteria, and medical status questions assessing basic exclusion criteria associated with isradipine administration.

Fagerström Test for Nicotine Dependence (FTND) [25]

The FTND is a 6-item scale designed to assess severity of nicotine dependence.

Smoking history

Inclusion/exclusion criteria related with smoking behavior will be assessed by participant report of smoking frequency and quantity, and use of other nicotine or smoking cessation products.

Participants who pass the initial internet prescreen will be called for a phone screen. Ineligible participants will be provided with a list of referrals for affordable smoking cessation counselling services in the area.

Participants who pass the internet prescreen will be contacted by a research assistant for a scripted phone screen. Responses for the phone screen are stored in REDCap. The phone screen will assess the following:

Mini International Neuropsychiatric Interview (MINI) [26]

Substance use disorders will be ruled out with the MINI 7.0.2, a short structured clinical interview that assesses DSM-5 criteria [27]. In addition to shorter administration time, the MINI demonstrates good psychometric properties with respect to validity and reliability for substance use disorders [26,28]. The MINI will be administered by trained research personnel with a B.S. or B.A. in psychology and will be supervised by the PIs.

Medical and psychiatric history

Current medication use, recent hospitalizations, and history of high or low blood pressure will be collected to assess basic exclusion criteria related to isradipine administration, and vision problems will be assessed for exclusion criteria related to virtual reality (VR).

Columbia Suicide Severity Rating Scale (CSSR) [29]

Suicidality exclusion criteria will be assessed with the CSSRS, a structured questionnaire used for suicide assessment in clinical practice. For individuals with current suicidal ideation, the research staff member will follow a separate Suicide Ideation Protocol to contact a senior lab member, such as the Principal Investigator, to speak with the individual. All individuals endorsing suicidal ideation will be informed of the National Suicide Prevention Lifeline and instructed to call 911 or go to the nearest ER if they feel that their life is in danger.

Individuals who pass the phone screen and are willing to adhere to the 48 h smoking abstinence will be scheduled for an in-person medical screening. Referrals will be provided to individuals who are not interested in participating or ineligible.

Medical screening will be conducted or supervised by the study physician. Participants will review the informed consent document before the appointment. Upon arrival, a study coordinator will be available to answer questions the participant may have about the study. The following medical criteria must be met: vital signs within normal limits (i.e., temperature < 100.4, blood pressure > 90/60 and < 140/90, pulse rate > 60 and < 100, respiratory rate < 20), no significant cardiovascular or respiratory problems, no history or current diagnosis of diabetes, cancer, autoimmune disorder, cirrhosis or any liver disease, hepatitis, COPD, asthma, GERD, hypertension, hyperlipidemia, and (female only) the participant is not pregnant, not breastfeeding and, if recently or currently sexually active, is on contraception.

2.5. Abstinence challenge

Participants will be required to abstain from smoking beginning 24 h prior to the first cue exposure session. Our group has applied this challenge in past studies in order to increase ecological validity of early stage trials, which are designed to inform relapse prevention strategies that would be employed after successful smoking cessation [30]. After completion of the first cue exposure session, participants will be asked to remain abstinent for the 24 h prior to the second cue exposure session. However, participants who fail to remain abstinent between the first and second cue exposure session, as measured by EMA responses, self-report in-session, or carbon monoxide levels exceeding the ≤4 ppm cutoff, will not be excluded from the study so that all data of randomized participants can be collected and reported.

2.6. Intervention procedures and measures

2.6.1. Randomization and pill administration

Eligible participants will return to the clinic for the first cue exposure session. Isradipine (ISR) or placebo (PBO) will be administered in a double-blind randomization stratified by sex and baseline craving rating collected prior to the administration of the study pill. Stratification by sex is based on findings that men and women differ in their sensitivity to smoking cues [31] and their response to smoking cessation [32–34]. Stratification by baseline craving rating is to ensure that treatment effects are not due to differing baseline craving levels between groups before the study pill is administered. For the purposes of stratification, four levels of baseline craving will be coded on the 0–100 scale: 0–25, 26–50, 51–75, and 76–100. The randomization list was computer generated using R 3.6.1 [35] using the package blockrand [36] with a 1:1 treatment to control allocation stratified by sex (male or female) and the baseline craving (four levels described above) using a block size of four. The randomization list will be uploaded to REDCap prior to enrollment, after which point the list is inaccessible by research staff, and randomization will proceed by the stratified sampling functionality using the variables stored in REDCap for each participant as they are enrolled. Both participants and study personnel will be blind to study conditions, and study medication will be stored in a bottle labeled either “A” or “B” by the pharmacy (MedSavers, Austin, TX) in order to blind the medication administration. If deemed medically necessary or to meet reporting requirements, only the MPIs (Young and Smits) will be able to break the blind by contacting the pharmacy. Prior to randomization the following data will be collected:

Abstinence verification

Abstinence status will be verified by a Vitalograph Breathco Carbon Monoxide monitor (≤4 ppm) [37]. Participants that do not meet this criterion at the first cue exposure session will not be randomized but will be allowed to reschedule once. Participants who fail this criterion a second time at the first cue exposure session will not be randomized to the study.

Vital signs

Temperature (Temp), pulse (P), and blood pressure (BP) will be obtained. Vital signs outside normal limits will be handled thusly, (a) BP < 90/60 or > 140/90, BP will be reassessed in 5 min. If BP is still outside limits participants will reschedule their research session for 1-week. If upon return BP is < 90/60 or > 140/90 participants will be excluded from the study; (b) P < 60 or > 100, recheck in 5 min. If P is still outside limits, the participant will reschedule their research session for 1-week. If upon return P is < 60 or > 100, the participant will be excluded from the study; (c) Temp > 100.4, participants will reschedule their research session for 1-week. If upon return Temp is > 100.4 participants will be excluded from the study.

Alcohol screening

Participants will be asked to breathe into an AlcoBreath tube in order to assess for the presence of alcohol. Although there are no absolute contraindications to co-administration of isradipine with alcohol, both substances are metabolized through the liver. Participants are advised to refrain from alcohol for at least 24 h prior to administration of isradipine and 24 h after administration of isradipine.

Baseline Craving

Baseline craving will be assessed with a Likert scale. There are no inclusion/exclusion criteria related to baseline craving; however, randomization will be stratified by sex and the baseline craving collected prior to the administration of study pill.

Minnesota Withdrawal Scale [38]

Withdrawal severity will be assessed with the Minnesota Withdrawal Scale, a reliable and sensitive 10-item scale that also assesses changes in craving. This will also be collected during the second cue exposure session. Although the 24 h abstinence challenge is predicted to induce withdrawal symptoms, there are no inclusion/exclusion criteria related to withdrawal, nor do we hypothesize that isradipine will have a direct impact on withdrawal symptoms. Group characteristics on this scale will be reported to characterize the sample during the intervention phase.

Participants who meet the abstinence and medical criteria above will be randomized to receive isradipine (ISR) or placebo (PBO). Study capsules will be prepared containing: (a) 15 mg immediate release isradipine or (b) pill placebo consisting of Avicel microcrystalline cellulose powder (non-digestible pass-through). Isradipine and placebo capsules will be identical in appearance to maintain the double-blind. The dosage of 15 mg is based on prior human addiction studies with isradipine [18–23]. Individual doses will be dispensed to participants by blinded personnel 75 m prior to the first cue exposure session and patients will be asked to remain in the clinic until session time.

Once participants have taken the study pill and entered the waiting period, several measures will be collected to further describe the randomized sample:

Demographic Questionnaire

Participants will provide their selfidentified gender, race, ethnicity, and educational level.

Smoking History Questionnaire (SHQ)

Smoking history and pattern will be assessed with the SHQ, a 30-item measure that includes smoking rate, age of onset of initiation, and years of being a regular smoker [39]

Smoking Cue Appeal Survey (SCAS) [40]

The SCAS measures cue appeal to sensory smoking cues, and has demonstrated associations to smoking status and craving. This will also be collected during the second cue exposure session.

2.6.2. Cue exposure protocol and rationale

The current protocol incorporates multimodal drug cues, including the innovative use of 360° video environments (Fig. 2A & B) to deliver immersive and realistic proximal, contextual, and complex cues through affordable and disseminable consumer VR headsets [38]. To our knowledge, our study is the first to apply 360° video environments for cue exposure, which were produced in house using the Samsung Gear 360 camera (Model #: SM-C200, $159.00), which films 360° Ultra High Definition video to create immersive VR from real environments and people (as opposed to computer-generated environments). Participants with corrective lenses (i.e., glasses) are able to easily and comfortably wear VR headsets, and the craving scale (Fig. 2C) will be displayed in the VR environment so that participants do not have to remove the headset during the cue exposure session.

Fig. 2.

Sample scenes depicting smoking cues (A & B) and self-reported craving scale (C).

We examined pilot data to assess the feasibility of our novel cue exposure method and make adjustments where necessary. Prior to grant funding, data were collected for 7 participants completing an earlier version of the two-day cue exposure protocol, including study pill administration. In preparation for the current study, we conducted two additional pilots with 13 additional participants who completed a single cue exposure session after 24 h abstinence challenge without study pill administration. We evaluated and modified our cue exposure protocol based on data from these pilot studies. Specifically, in the first pilot participants alternated between VR and handling cigarette packs, in the second pilot participants maintained the VR headset on for all 10 trials and concurrently handled cigarette packs, and in the third pilot participants could alternate between several scenes while handling cigarette packs. Fig. 3 shows peak craving data from our pilot phases, during which our 360° environments were tested.

Fig. 3.

Mean craving ratings ±1 SE from the pilot phase. In Pilot 1 (N = 7) participants first watched a 3 m scene displayed through a Galaxy 8 phone (Model #: SM-G950W, $606.25) +Samsung Gear VR Headset (Model #: SMR324, $102.57) and then handled a pack of their preferred brand of cigarettes for 1 m. In Pilot 2 (N =8) participants handled cigarettes while viewing 10 trials of the same scene delivered through the Oculus Go VR headset (Model #: MH-A32, $199.00). In Pilot 3 (N = 5), several scenes were used, which resulted in weaker extinction of craving.

Results from Pilot 1 suggested that the incorporation of VR with traditional approaches (e.g., handling cigarette packs) was tolerable and effective in activating robust cravings. Additionally, there were no reports of side effects on the day of study pill administration, and day two data (examined without knowledge of group assignment) showed a wide range of craving activation (M = 47.17, SD = 34.49, range: 17–100, N = 6) on the first trial of the second cue exposure session. In Pilot 2 we sought to simplify the procedure by conducting the entire exposure session with the VR headset on. Results from Pilot 2 suggested that participants were able to wear the headset continuously while handling the cigarette pack without reporting dizziness or discomfort, and that the simplified procedure activated robust cravings. In Pilot 3 we sought to evaluate the differential impact of scenes on participants. Results from Pilot 3 suggested that craving may be more consistently activated across participants when they select a scene that is closest to their craving-eliciting environments, but that alternating between scenes within participants resulted in poorer extinction of craving.

Based on these pilot studies, the current research protocol will implement the following cue exposure procedure: (1) Participants will receive visual and written descriptions of the three available scenes and instructed to select the scene that is most likely to activate strong cravings, or urges to smoke. The scene that is selected will be used throughout the entire procedure in order to avoid the poor extinction observed in Pilot 3, which allowed participants to change scenes between trials; (2) Participants will be instructed to handle the pack throughout the exposure in a way that is most likely to activate strong cravings or urges to smoke. Prior to initializing the VR, participants will practice handling the cigarette pack for 1 m and; (3) Participants will put on the VR headset and begin the cue exposure session.

2.7. Assessment of primary outcome

Self-reported craving will be collected after each cue exposure trial (10 per session). Participants will be asked to state the highest level of craving experienced using a Likert scale (range: 0–100) displayed in the VR environment. We selected a 0–100 range because previous research targeting cue reactivity hypothesized that a 10-point scale may lack the sensitivity to detect small but meaningful differences [42]. Participants will be oriented to the craving anchors, which are also put in terms of “urges” in order to reduce ambiguity [43], and will also be reminded that they can select any number in the 0–100 range. After the first trial, participants will identify the moment in the scene when their craving was the highest. For subsequent trials, participants will be reminded to focus (as opposed to avoid) the most activating part of the scene and report their craving.

From the 24 h prior to the first cue exposure session to the end of the study, participants will complete EMA of craving, exposure to smoking cues, and cigarette use once per hour up to 15 times per day within a time window chosen by the participant on a smartphone application we developed for this project using the HIPAA-compliant Qualtrics platform (Fig. 4). The EMA serves as a reminder of the abstinence challenge and will be reported to provide a description of participant smoking behavior across the study phase.

Fig. 4.

Craving application for ecological momentary assessment.

In the 24 h period after the first cue exposure phase, during which participants who fail to remain abstinent will not be excluded from participating in the second cue exposure session. However, given the potential impact of relapse on the primary outcome of this study (e.g., individuals who resume smoking are likely to report lower craving during the second cue exposure session), these data will be examined to ensure proper interpretation of primary outcome results (see 3. Data analysis and power).

3. Data analysis and power

The effects of Group (ISR vs. PBO), Trial (1−10), and Group × Trial on self-reported craving during the second cue exposure session will be examined in a mixed model with random subject effects to account for the within-subject correlation between trials. To avoid applying potentially invalid assumptions about the shape of craving curves on session 2, we will fit several models to the complete dataset prior to breaking the blind (e.g., linear, quadratic, exponential, non-parametric, etc.). Once the best fitting model is selected, the effect of isradipine on craving will be tested by the Group × Trial interaction or main effect of Group (depending on the model selected). Significant effects of isradipine that demonstrate either a lower initial craving or faster rate of extinction on the second cue exposure session will be interpreted as evidence of target engagement and provide the evidence necessary to guide next-stage research.

The analytic plan for the primary outcome depends on several assumptions that will be checked prior to breaking the blind using dummy coded group labels (e.g., A vs. B). Although isradipine administration has demonstrated acute effects on cocaine-seeking behavior in rats after prolonged abstinence [44], an acute effect was not observed in the extinction of conditioned place preference in rats [11]. Given our experiment is modeled after the latter preclinical research, we are not predicting an acute effect of isradipine on session 1 craving. To check this assumption, the same analytical strategy described for session 2 will be applied to session 1. If these analyses indicate that groups significantly differ in the level of craving activation or craving extinction, then the analytic plan for the primary outcome will be adjusted to account for this unanticipated difference. Additionally, we will examine cigarette use in the 24 h between session 1 and 2, and adjust the analytic strategy to account for group differences in abstinence, which may impact craving levels and the interpretation of primary outcome results.

Recruitment target has been set at N = 102 (51 per group). Fig. 5 illustrates results from power simulations conducted in the open source R statistical software [35,45] using the simr package [41]. These simulations assumed linear mixed models would best fit the data, and applied intercept, slope, random intercept effects, and residual variance estimates from the second pilot study, which followed a procedure that most closely matched the final protocol. Across the three simulations, which capture different ways in which long-term extinction can be enhanced, the power to detect a medium effect was > 90% for our target sample size, and remained > 85% for group sample sizes above 40. Therefore, our target sample size assures that even with a 20% dropout rate our study has at least 85% power to detect medium effect sizes. Although stratification by sex and initial cravings was not incorporated to the power simulations, the inclusion of these stratifying covariates in the protocol is designed to increase power. Full code for the power simulations, including all outputs and package versions is available in the Open Science Foundation (OSF) site for this project (DOI 10.17605/OSF.IO/PK9YF).

Fig. 5.

Potential long-term extinction effects of isradipine on the second cue exposure session. Model 1 simulated a main effect of isradipine (A), model 2 simulated an interaction effect with group difference on the early trials (B), and model 3 simulated an interaction effect with group difference at the latter trials (C). Power simulations for the respective models showed >90% power to detect medium sized effects with the target sample size (50 per group).

4. Discussion

4.1. Significance

Cigarette tobacco use is a leading cause of death that constitutes a major public health problem with significant personal and societal costs. Clinical trials that apply cue exposure for smoking relapse prevention have yielded inconsistent findings, suggesting a need for improved procedures [46,47]. The current research protocol applies the experimental therapeutics approach to measure target engagement in a pharmacologic augmentation strategy informed by basic research in animal models of addiction. Our protocol also seeks to address the limitations posed by cue exposure protocol that limit extinction training to select substance-use cues (e.g., the sight and smell of cigarettes), which do not capture the variety of environmental and social cues that form part of a smoker’s rich conditioning history [47–49]. The increased availability of VR technology helps address this limitation by providing an immersive and standardized context that can be systematically applied to activate and extinguish cigarette cravings [50]. The use of VR is supported by recent reviews and meta-analysis of computer-generated smoking environments which found robust craving effects in cue-reactivity research [50–52]. However, there are several limitations of traditional, computer-generated VR environments, including the time and technical expertise required to produce them, and the video game quality of the graphics, which have not yet achieved an optimal level of realism. Recent advances in consumer-level 360° video cameras have made it possible to film high-definition scenes that can be delivered through VR headsets. The cue exposure protocol developed for this trial incorporates multimodal drug cues, including the innovative use 360° video environments to deliver immersive and realistic proximal, contextual, and complex cues through affordable and disseminable consumer VR headsets. To our knowledge, our study will be the first to apply 360° video environments, which are produced inhouse and are often rated as more realistic than computer-generated environments.

4.2. Design limitations

A key limitation of our primary outcome measure of self-reported craving is that it is not a direct measure of isradipine’s action on the brain, which could be assessed through the use of functional magnetic resonance imaging (fMRI). However, we selected self-reported craving as our primary outcome for several reasons. Whereas a variety of indirect measures of craving have been proposed for humans, including behavioral indicators (e.g., rate and latency of consumption, inter-puffinterval), psychophysiological measures (e.g., startle eye-blink, skin conductance response, and heart rate) and cognitive measures (e.g., attentional and cognitive biases to drug cues), the advantages of these measures over self-report for clinical applications remains unclear [53]. Meta-analysis of cue reactivity research shows robust increases in selfreported craving compared to physiological indices, including heart rate, skin conductance, and skin temperature [14]. Although fMRI is a powerful tool for understanding the neural mechanisms of human addiction [9,54,55], it remains cost prohibitive as a routine clinical assessment tool. Importantly, treatment research employing prospective analyses [16] and ecological momentary assessment [56] have demonstrated that self-reported craving post-cessation and through the abstinence phase is a robust predictor of relapse, indicating the value of a simple and direct measure of craving as a potential mechanistic target.

There are multiple methods for conducting cue exposure therapy, including guided imagery approaches that may offer a more personalized experience for activating craving. Our aim was to strike a balance between standardization and personalization by creating several scenes that participants can choose from based on what they expect to activate the strongest cravings. This level of standardization allows our protocol to achieve its primary aim of examining the enhancing effects of isradipine, without the additional clinical burden of conducting guided imagery exposures, which may increase variability in the results and reduce power to detect the effect of isradipine.

4.3. Conclusion

The proposed study will evaluate the enhancing effect of isradipine, an FDA-approved calcium channel blocker, on the extinction of craving—a pathophysiologically relevant mechanism of drug relapse after periods of abstinence. Findings will be used to guide next-stage research designed to target key clinical outcomes including smoking cessation and prolonged abstinence.