**4. Discussion**

The primary aim of this scoping review was to map the use of cue-reactivity paradigms in PTSD-SUD research among substance users with trauma histories and/ or PTSD. Specifically, we sought to summarize the characteristics of the samples, examine outcomes measured followed the cue-reactivity paradigm (e.g., subjective/ objective craving, negative affect), and map how such paradigms vary across the literature on several dimensions (e.g., cue type, personalization/standardization, cue presentation). Furthermore, we aimed to assess the consequences of methodological differences in cue-reactivity research. While prior literature has summarized cuereactivity methodology in substance use research [65] and one group has briefly

summarized cue-reactivity research in a comorbid PTSD-AUD population as part of a broader review of mechanisms involved in this form of comorbidity [66], we aimed to map the use of cue-reactivity paradigms in a way which could lead to further understanding of conditioned craving as a mechanism in the maintenance of comorbid PTSD-SUD. Specifically, our systematic scoping of the literature identified 28 studies that assessed craving following a cue-reactivity paradigm in a population of substance users with trauma histories and/or PTSD.

Our scoping review revealed wide variations in methodologies used to examine cue-induced craving. Specifically, characteristics of study samples, the methodological details of the cue-reactivity paradigm, and the types of outcomes assessed, all varied broadly. We have identified four themes in the studies through our scoping of the literature that may help elucidate commonalities and important distinctions across the identified studies—(1) increases in craving following trauma cue presentation; (2) the use of methodological subtypes of cue-reactivity paradigms; (3) affect as an outcome and possible mediator of craving in cue-reactivity research; and (4) the cue-reactivity paradigm as an adjunct outcome measure in intervention research.

From the above literature review, it is evident that craving has been repeatedly shown to increase following exposure to certain cues in substance users with trauma histories and/or PTSD. In particular, trauma cues tend to elicit the greatest increase from baseline in craving responses when compared to substance-related and neutral cues. This was true across studies using both personalized [43] and standardized cues [54]. However, this effect was typically magnified when a combination of traumarelated imagery and *in vivo* substances cues were paired together [45, 53]. The latter finding supports the notion that "cue chains" may be an effective means of bolstering cue-reactivity responses [67]. Indeed, while direct comparison across all studies is made difficult due to variable methodologies across studies, it appears that trauma cues, and in particular, trauma and substance cue combinations elicit strong craving responses among individuals with trauma histories who use substances. This effect was evident across different substances used by the populations of interest (e.g., alcohol, cocaine, nicotine). Several studies found that such effects were the strongest among those with higher PTSD symptom severity [45, 52] or those with the greatest cumulative trauma exposure [28]. Moreover, studies with control groups, such as healthy non-drug using controls [29] and those without trauma histories [34] were unable to find any significant change in craving with cue exposure among control groups, suggesting a lack of a conditioned cue-induced craving response among controls and specificity of these cue-reactivity effects to "experimental" groups (e.g., cocaine users with childhood trauma histories [34]). These findings are consistent with predictions that would be made on the basis of the conditioning theories presented at the outset of this chapter. Specifically, it is only those with trauma histories/PTSD who would have opportunities to learn to use substances to reduce the negative affect conditioned to trauma cues (two-factor learning theory; [10]) and to develop conditioned craving responses to trauma cues (via classical conditioning; [12]). Theoretically, such cue-induced craving effects could lead to substance seeking and consumption in response to exposure to real-world trauma reminders—both via intrusive traumatic memories and exposure to external reminders of the trauma thereby contributing to SUD development, maintenance, or exacerbation in those with trauma histories and/or PTSD.

Second, the cue-reactivity methodologies used in the studies identified through our scoping review tended to vary widely. While the majority of studies utilized imagery-based audio cues to elicit cue-reactivity craving responses, some used

combinations of imagery-based trauma and substance-related *in vivo* cues to understand how to cue combinations may further bolster craving responses [39, 40]. These combined cues serve as an in-lab analog of real-world exposure to a trauma reminder simultaneous with exposure to substance-related cues, such as when an individual with PTSD experiences an intrusive memory about their trauma within proximity of substance-related cues like a bottle of alcohol. Less commonly, standardized cues (e.g., standardized trauma-related videos) were used to elicit cue reactivity craving responses [54]. While such standardized cues often did elicit an increase in craving responses relative to the pre-exposure baseline, there were typically caveats to such effects which may indicate a less robust elicitation of craving given the use of nonpersonalized cues. For example, one study [54] found an increase in craving following a standardized trauma film only in females, which could perhaps be attributed to the fact that the film subject was also female. Generally, a more consistent craving response was found in studies that utilized personalized cues. Additionally, several studies used cue-reactivity paradigms involving tasks that were being used for other purposes (e.g., Stroop color-naming task [31] to assess attentional bias) but that contained relevant trauma or substance cues, allowing for a secondary test of cueinduced craving [28–30]. Indeed, combining a craving assessment with a cognitive task containing relevant cue exposures may be useful in simultaneously assessing outcomes directly related to the cognitive task and assessing cue-induced craving. For example, this was accomplished by Garland and colleagues [28] who aimed to assess participants' ability to regulate emotions related to trauma-related images on their emotional regulation task which simultaneously served as a cue reactivity craving assessment.

Third, while we did not systematically aim to include effect as an outcome in the present scoping review, we decided to cover this outcome as many of the studies included in the review (50%) did include a measure of effect as an additional outcome alongside craving. Our findings elucidated the importance of effect in helping explain the relationship between trauma cue-reactivity and craving. To elaborate, negative affect has quite consistently been shown to increase following trauma cue exposure [44, 59]. This is consistent with suggestions that conditioned *relief* craving may be an important motivator of continued substance use in those with trauma histories who use substances. Relief craving involves the urge to use substances to reduce negative affective states—the very mood states that are triggered when those with trauma histories are faced with trauma reminders. This is consistent with Stasiewicz and Maisto's application of the two-factor avoidance theory to substance use [10]. They suggested that trauma reminders can be classically conditioned to elicit fear themselves, which motivates avoidance responses such as substance abuse to escape the aversive emotional state. Through this two-factor learning process, an individual may become motivated to reduce the negative affect triggered through trauma cue exposure and to crave the relief that can be achieved through substance use. This theory is partially supported by the results of the present scoping review. Specifically, one study [61] found trauma cue-induced craving decreased following prolonged exposure treatment, and this decrease was associated with a concurrent decrease in negative emotional responses to trauma stimuli. While causality cannot be determined from these data, perhaps a decrease in trauma cue-induced negative affective responses may be responsible for the decreases in trauma cue-induced substance cravings following prolonged exposure treatment. The present scoping review found no studies which tested the links of cue-induced craving with cue-induced emotional responses; further, only one study [28] alluded to the distinction between reward and

relief craving. We suggest that the roles of both cue-induced negative and positive affect in eliciting reward and relief craving should be explored further in future research.

Finally, it is important to note that seven studies utilized cue-reactivity paradigms as an additional outcome in trauma and/or substance-related therapeutic interventions. Notably, neither of the two pharmacological studies found an effect of the respective medications (oxytocin and neurokinin-1 receptor antagonist aprepitant) relative to placebo as a means of reducing either PTSD symptoms or stress cue- or substance cue-induced craving (see [32, 35]). Conversely, all studies examining the efficacy of PE therapy for PTSD or PTSD-SUD found that trauma cue-induced craving, as well as other forms of cue-reactivity (e.g., salivation, distress), decreased over time in those who received PE when compared to patients who received a control intervention [36, 37, 39, 53, 61]. Indeed, behavioral interventions seem to be more efficacious than pharmacological interventions in reducing reactivity to both trauma and substance-related cues among trauma-exposed substance users, at least for the few pharmacotherapies that have been investigated with this paradigm thus far, and at least in comparison to PE therapy. Furthermore, the use of cue-reactivity paradigms as a secondary outcome in randomized controlled trials of therapeutic interventions speaks to the multifaceted functionality of the cue-reactivity paradigm in the PTSD/trauma-exposed population, offering a mechanism-based outcome that informs beyond the decrease of symptoms.
