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. Author manuscript; available in PMC: 2024 Aug 1.
Published in final edited form as: Behav Pharmacol. 2023 Jun 22;34(5):275–286. doi: 10.1097/FBP.0000000000000731

Use of Drug Purchase Tasks in Medications Development Research: Orexin System Regulation of Cocaine and Drug Demand

Justin C Strickland a, Kevin W Hatton b, Lon R Hays c, Abner O Rayapati c, Joshua A Lile c,d,e, Craig R Rush c,d,e, William W Stoops c,d,e,f
PMCID: PMC10328554  NIHMSID: NIHMS1906968  PMID: 37403694

Abstract

Commodity purchase tasks provide a useful method for evaluating behavioral economic demand in the human laboratory. Recent research has shown how responding on purchase tasks for blinded drug administration can be used to study abuse liability. This analysis uses data from a human laboratory study to highlight how similar procedures may be particularly useful for understanding momentary changes in drug valuation when screening novel interventions. Eight non-treatment seeking participants with cocaine use disorder (one with partial data) were enrolled in a cross-over, double-blind, randomized inpatient study. Participants were maintained on the FDA-approved insomnia medication suvorexant (oral; 0, 5, 10, 15 mg/day) in randomized order with experimental sessions completed after at least three days of maintenance on each suvorexant dose. Experimental sessions included administration of a sample dose of 0, 10, and 30mg/70kg intravenous cocaine. Analyses focused on purchase tasks for the blinded sample dose as well as alcohol, cigarettes, and chocolate completed 15 minutes after the sample dose. As expected based on abuse liability, near-zero demand was observed for placebo with dose-related increases in cocaine demand. Suvorexant maintenance increased cocaine demand in a dose-related manner with the greatest increase observed for the 10 mg/kg cocaine dose. Increased demand under suvorexant maintenance was also observed for alcohol. No effect of cocaine administration was observed for alcohol, cigarette, or chocolate demand. These data support the validity of demand procedures for measuring blinded drug demand. Findings also parallel self-administration data from this study by showing increases in cocaine use motivation under suvorexant maintenance.

Keywords: alcohol, behavioral economics, cigarettes, cocaine, demand, orexin, suvorexant

Introduction

Behavioral economics and the concept of behavioral economic demand bridges analytic constructs and theory from microeconomics and operant behavior to understand drug consumption patterns and sensitivity to environmental manipulations (Bickel et al., 2014; Hursh, 1991; Hursh & Silberberg, 2008; MacKillop, 2016; Strickland & Lacy, 2020). Demand curves quantify the association between consumption of a good and its cost, which can be operationalized as monetary cost in humans or response cost on a programmed schedule of reinforcement across species. Analysis of demand curves effectively separates indices relating to consumption of a good at unconstrained price (sometimes referred to as “hedonic setpoint” or “demand intensity”) from those quantifying drug use motivation or changes in consumption with increases in cost. Separation of these behavioral mechanisms can help to clarify cases in which traditional measures (e.g., discrete choice procedures and progressive ratio responding) may disagree (Hursh & Silberberg, 2008; Johnson & Bickel, 2006).

The commodity purchase task procedure provides a flexible method for evaluating demand in the human laboratory and within clinical settings. Purchase tasks are a well-validated experimental procedure in which participants report hypothetical consumption of a commodity under varying conditions of constraint (e.g., increased price). These tasks also stipulate specific conditions of consumption via verbal behavior manipulations to better control the response environment (e.g., stipulating a closed economy by informing participants that this is the only location where they could buy the commodity). Meta-analyses of purchase task data support concurrent validity (Gonzalez-Roz et al., 2019; Strickland et al., 2020) and sensitivity to experimental manipulations to include pharmacological interventions (Acuff et al., 2020). Recent research has expanded the purchase task’s utility by showing how responding on the purchase task for a blinded drug administered during an experimental session can be effectively used to study abuse liability (MacKillop et al., 2019). These blinded consumption procedures can increase rigor by directly relating hypothetical consumption to a recently experienced and double-blind commodity thus isolating pharmacological effects from responding based on factors like drug expectancies. These strengths may be particularly useful for understanding momentary changes in drug valuation when screening novel medications or behavioral interventions in a treatment development pathway.

The orexin system is an increasingly evaluated target for the regulation of drug use motivation and treatment development in substance use disorder. The orexin system (also known as hypocretin system) is composed of two endogenous neuropeptides, orexin-A and orexin-B, which are produced primarily by cells in the lateral hypothalamus and act on two identified g-protein coupled orexin receptors, orexin-1 and orexin-2 (Barson & Leibowitz, 2017; Boutrel et al., 2013; de Lecea et al., 1998; Sakurai et al., 1998; Wang et al., 2018). Orexin signaling modulates survival behaviors such as food intake and sleep regulation primarily within the hypothalamus while complex behaviors are further regulated through extrahypothalamic projections to regions including the locus coeruleus, limbic system, and ventral tegmental area (VTA) (Barson & Leibowitz, 2017; Boutrel et al., 2013). Efferent projections to the VTA, in particular, underlie effects on drug use motivation. VTA-based orexin administration induces burst firing and glutamate-mediated excitatory drive in dopamine neurons and also enhances stimulant-induced elevations of dopamine (Borgland et al., 2006; España et al., 2011; Korotkova et al., 2003), whereas genetic knockout or antagonism of orexin signaling reduces dopaminergic excitability and stimulant-induced nucleus accumbens dopamine uptake inhibition and release (España et al., 2010; Prince et al., 2015; Shaw et al., 2017). In light of this underlying neurobiology and promising preclinical data, orexin system antagonists have been identified among the highest priority pharmacological targets for the development of therapeutics in substance use disorder (Rasmussen et al., 2019). This target has been further supported by the recent FDA approval of several dual orexin receptor antagonists (DORAs; lemborexant, suvorexant, and daridorexant) for the treatment of insomnia – making for a class of approved compounds ready for translation to human clinical settings.

Preclinical data in rodent and non-human primate models provides in vivo evidence that antagonism of the orexin system attenuates the behavioral effects of and motivation for drugs, broadly, and stimulants, specifically. Orexin antagonism in rodent models attenuates cocaine-induced locomotor sensitization (Borgland et al., 2006; Yang et al., 2020), conditioned place preference (Gentile et al., 2018; Lu et al., 2019), and self-administration and reinstatement (Bentzley & Aston-Jones, 2015; Boutrel et al., 2005; Brodnik et al., 2015; España et al., 2010; Foltin & Evans, 2018; Hollander et al., 2012; James et al., 2011; James, Stopper, et al., 2019; Prince et al., 2015; Schmeichel et al., 2017; Smith et al., 2010) while genetic knockdown or knockout of the system comparably attenuates cocaine conditioned place preference and self-administration (Bernstein et al., 2018; Hollander et al., 2012; Pantazis et al., 2020; Schmeichel et al., 2018; Shaw et al., 2017). Several studies have demonstrated that these reductions are at least partially selective to drug self-administration with limited evidence for locomotor-impairing effects or negative effects on adaptative behaviors such as food and water consumption or sleep/wake activity (Bernstein et al., 2018; Brodnik et al., 2015; Hollander et al., 2012; Schmeichel et al., 2015).

Behavioral economic demand analyses provide some of the most compelling preclinical evidence for this regulation of drug use motivation by the orexin system. A broadly consistent finding in non-human animal models is that orexin receptor antagonism or knockdown decreases drug use motivation while leaving consumption at unconstrained price unaffected (Bentzley & Aston-Jones, 2015; España et al., 2010; Fragale et al., 2021; James, Bowrey, et al., 2019; James, Stopper, et al., 2019; Mohammadkhani et al., 2019; Mohammadkhani et al., 2020; Pantazis et al., 2020; Porter-Stransky et al., 2017). For example, research using a threshold procedure in which demand curves are generated within a single experimental session shows that pretreatment with the orexin-1 receptor selective antagonist SB-334867 renders responding maintained by cocaine more price sensitive (i.e., increases demand elasticity) (James, Bowrey, et al., 2019). Behavioral economic demand methods are easily conducted in humans, making it an ideal platform for translating preclinical findings.

The primary goal of this analysis was to use purchase task methods to determine the influence of dual orexin receptor antagonism on demand for cocaine. Data were collected in a double-blind randomized study evaluating whether maintenance on the dual orexin receptor antagonist suvorexant (0, 5, 10 and 20 mg/day) affected intravenous cocaine self-administration (0, 10 and 30 mg/70 kg) in human participants with cocaine use disorder (Stoops et al., 2022). We used a blinded commodity purchase task to measure responding for blinded cocaine doses under each suvorexant maintenance condition. A secondary goal was to evaluate demand for alcohol and cigarettes as well as a non-drug, hedonic alternative (i.e., chocolate) using prototypic hypothetical commodity purchase tasks. Collection of purchase tasks in each experimental session allowed us to evaluate the effect of cocaine pretreatment and the effect of suvorexant maintenance on demand for alcohol, cigarettes, and chocolate.

Methods

Participants

Participants for this secondary analysis were enrolled in a study on the influence of suvorexant on the reinforcing, subjective, and physiological effects of intravenous cocaine (see details in Stoops et al., 2022). Eight (4 women; 2 White, 5 Black, 1 Multiethnic) non-treatment seeking participants with cocaine use disorder were enrolled in that parent study. One participant provided partial data due to the COVID-19 pandemic, but was included in analyses (see analytic plan). All participants had to report recent use of smoked or intravenous cocaine, meet diagnostic criteria for cocaine use disorder according to a computerized Structured Clinical Interview for DSM-5 (SCID), and provide a benzoylecgonine positive urine sample during screening to verify current cocaine use status. Seven participants were daily cigarette smokers (mean ± SD; 10 ± 8 cigarettes/day) and four reported weekly alcohol use (21 ± 15 standard drinks/week). Three participants met criteria for alcohol use disorder, but were not physically dependent because participants with physical dependence on alcohol were excluded from participation. Additional details on screening and participant inclusion criteria are described in the primary outcomes report (Stoops et al., 2022). The Medical Institutional Review Board of the University of Kentucky approved this study.

General Experimental Procedures

This study was a cross-over, double-blind, randomized residential design in which cocaine administration experimental sessions occurred after maintenance on randomized doses of the dual orexin receptor antagonist suvorexant (or placebo). Participants were enrolled for approximately one month at a local residential research unit during participation (i.e., University of Kentucky Chandler Medical Center Inpatient Clinical Research Unit). During the residential stay, participants were maintained on 0, 5, 10 and 20 mg suvorexant/day delivered in a randomized order. Suvorexant was administered once per day orally at 2230 h consistent with clinical guidelines (i.e., approximately 30 minutes prior to bedtime). Participants completed experimental sessions after at least three days of maintenance on each target suvorexant dose and at least three days of drug washout occurred between each dose condition.

Experimental sessions began with administration of a sample dose of 0, 10, or 30 mg/70 kg of intravenous cocaine at approximately 1000 h. A battery of commodity purchase tasks (described in detail below) were collected 15 minutes after sample dose administration. A self-administration phase occurred in the afternoon in which participants completed a concurrent progressive ratio task in which they were provided 10 opportunities to choose to complete ratio requirements for either $0.50 USD or 1/10th of the dose administered during the sampling phase. Details and data for the self-administration and safety outcomes are described previously (Stoops et al., 2022). Participants completed three experimental sessions at each target suvorexant dose consisting of each of the cocaine doses administered in a randomized session order. Participants were allowed to smoke one tobacco cigarette prior to their experimental session (approximately 2 hours before the sampling dose). All demand measures reported here were collected within 2.5 hours of this last cigarette, therefore, it is not expected that tobacco withdrawal would impact study findings.

Blinded Commodity Purchase Task

A blinded commodity purchase task was used to evaluate hypothetical demand for the sampling dose administered in each session. The instructions were based on vignettes used for other commodity purchase tasks (e.g., alcohol or cigarette purchase tasks) and modified to reflect the blinded drug administration consistent with prior studies on blinded drug demand (MacKillop et al., 2019). Participants read a vignette detailing that they were to indicate the number of doses of the drug they had received that morning that they would purchase at a series of prices per dose. Instructions stipulated that responding should occur in a closed economy (i.e., “assume this is the only opportunity to buy this drug”), that the dose could not be stockpiled (i.e., “you would not be able to take any leftover drugs away with you”), and that the drugs could be taken in any way (any frequency or quantity) over a 12-hour period. The price sequence included Free consumption and 15 ascending prices ($0.01, $0.05, $0.13, $0.25, $0.50, $1, $2, $3, $4, $5, $6, $11, $35, $70, $140/dose) intended to capture variations in responding and suppressed consumption at the higher price range. Participants were instructed that all responding was hypothetical and would not result in drug delivery. The blinded commodity purchase task was completed approximately 15 minutes after sample drug dose administration.

Alcohol, Cigarette, and Chocolate Purchase Tasks

Participants also completed standardized alcohol, cigarette, and chocolate purchase tasks (Jacobs & Bickel, 1999; MacKillop et al., 2008; Murphy & MacKillop, 2006; Strickland & Stoops, 2017). These tasks were included to evaluate other proposed targets for orexin system regulation of health behavior (i.e., alcohol and cigarette use) as well as a non-drug, hedonic alternative (i.e., chocolate). Commodity units in each task were standardized and identical across sessions (alcohol = 1 standard drink; cigarette = 1 own brand cigarette; chocolate = 1 Hershey Kiss size chocolate candy). All participants completed the three tasks. One participant did not report tobacco cigarette use with no consumption on the cigarette purchase ask at all timepoints and price points and was not included in analysis of those data. All participants reported consumption at least one price for alcohol and chocolate purchase tasks. The price range used in the blinded commodity purchase task was also used in these tasks. Task instructions were also modified from standard vignettes to indicate that consumption would occur over a 12-hour period for consistency with the blinded commodity purchase task in order to simplify completion. Tasks were completed following the blinded commodity purchase task (i.e., approximately 15 minutes after sample dose administration). Measurement at this timepoint allowed for evaluation of the acute effects of cocaine, as well as the effects of suvorexant maintenance, on drug demand.

Data Analysis

Curves were first examined for systematicity according to standard three-point criteria (Stein et al., 2015) with the exception that all zero consumption was considered systematic in order to detect suppressed consumption in medication conditions. All curves were considered systematic according to these criteria and used in the analyses. Demand analyses were conducted on curve observed values given the occurrence of zero consumption curves in the blinded drug administration. Curve-observed demand indices were then computed including Intensity (consumption at Free price), Pmax (price at maximum expenditure), Omax (maximum expenditure), and Breakpoint (price of last non-zero consumption) (Kaplan et al., 2018). If no consumption was observed at any price these values were set to zero. Linear mixed-effect models evaluated demand indices for each commodity task with Suvorexant Dose (0, 5, 10 and 20 mg/day) and Cocaine Dose (0, 10 and 30 mg/70 kg) as within-subject factors. For the blinded commodity task, the effect of Cocaine Dose reflected changes in demand for the blinded drug by dose. For the alcohol, cigarette, and chocolate tasks, the effect of Cocaine Dose reflected dose-related effects of cocaine pretreatment on other commodity demand. Post-hoc comparisons relative to placebo were conducted following significant omnibus effects. Supplemental analyses of the association between alcohol and cigarette use collected at baseline and alcohol and cigarette demand during placebo sessions are included in the Supplemental Materials. Analyses were conducted in Prism Version 9.2.0.

Results

Blinded Drug (Cocaine) Demand

Figure 1 shows demand for the blinded drug (i.e., cocaine or placebo) administered in the experimental session. There was a main effect of cocaine dose for all demand measures (p values < .001 for all measures). This main effect reflected a dose-related increase in demand with increases in cocaine dose. In all cases, demand for blinded placebo was lower than both active doses and was near zero. Breakpoint and Pmax were significantly higher for 30 mg compared to 10 mg cocaine, whereas no significant differences were observed between active cocaine doses for Omax or Intensity.

Figure 1. Blinded Drug Demand (Cocaine and Placebo).

Figure 1.

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Presented are demand curves (left panels) and demand indices from the blinded drug purchase task. Data are presented for responding under different suvorexant conditions. Datapoints are mean +/− SEM.

A significant main effect of suvorexant was also observed for Pmax (p = .035). An omnibus test revealed that responding for the blinded drug was higher under 10 mg suvorexant (p = .008) and 20 mg suvorexant (p = .03) conditions. Planned post-hoc comparisons indicated that for the 10 mg cocaine dose, Pmax was higher during maintenance on 10 mg suvorexant (p = .009) and 20 mg suvorexant (p = .039) relative to placebo maintenance. Similarly, for the 30 mg cocaine dose, Pmax was higher during maintenance on 10 mg suvorexant (p = .028).

Alcohol Demand

Figure 2 shows demand curves and demand indices for responding on the alcohol purchase task following blinded drug challenge and under varied suvorexant maintenance doses. A significant main effect of suvorexant was observed for Pmax (p = .021) and Omax (p = .022). Post-hoc comparisons indicated that this effect reflected higher alcohol Pmax (p = .014) and Omax (p = .011) under the 10 mg suvorexant maintenance condition relative to placebo suvorexant.

Figure 2. Alcohol Demand.

Figure 2.

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Presented are demand curves (left panels) and demand indices from the alcohol purchase task. Data are presented for responding under different suvorexant conditions. Datapoints are mean +/− SEM.

Cigarette Demand

Figure 3 shows demand curves and demand indices for responding on the cigarette purchase task following blinded drug challenge and under varied suvorexant maintenance doses. No significant effects of cocaine or suvorexant were observed.

Figure 3. Cigarette Demand.

Figure 3.

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Presented are demand curves (left panels) and demand indices from the cigarette purchase task. Data are presented for responding under different suvorexant conditions. Datapoints are mean +/− SEM.

Chocolate Demand

Figure 4 shows demand curves and demand indices for responding on the chocolate purchase task following blinded drug challenge and under varied suvorexant maintenance doses. No significant effects of cocaine or suvorexant were observed.

Figure 4. Chocolate Demand.

Figure 4.

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Presented are demand curves (left panels) and demand indices from the chocolate purchase task. Data are presented for responding under different suvorexant conditions. Datapoints are mean +/− SEM.

Discussion

This study provides an analysis of demand data collected in a recently completed randomized, placebo-controlled human laboratory study of suvorexant in cocaine use disorder. Responding on a blinded commodity purchase task for experimentally administered intravenous placebo and cocaine mirrored abuse liability (Fischman & Schuster, 1982; Walsh et al., 2010) with near-zero demand for placebo and dose-related increases in demand for cocaine. No effects of cocaine administration were observed for alcohol, cigarettes, or chocolate demand. Suvorexant maintenance increased demand for the blinded cocaine in a dose-related manner with the greatest increase observed for the low-dose of cocaine (10 mg/kg). Increased demand was also observed for alcohol on a traditional alcohol purchase task procedure. These findings contribute to advances in the understanding of orexin system regulation of drug use motivation as well as methodological approaches to understanding drug demand in the human laboratory.

These data support the validity of demand procedures for measuring blinded drug demand by showing an expected dose-related increase in demand for the blinded doses of cocaine and low responding for placebo alongside high rates of systematic data. This finding provides a conceptual replication of a recent study evaluating demand for blinded d-amphetamine (20 mg oral) versus placebo in stimulant-naïve participants (MacKillop et al., 2019). That study found that responses on the drug purchase task showed clear differentiation from placebo and related to traditional measures of abuse liability supporting concurrent validity. Here we show that these measures can be effectively used to also understand how a potential pharmacotherapy might impact drug intake wherein responding can be directly connected to experienced drug sampling. This approach stands to benefit medications development because of the rapid nature of data collection and effective isolation of behavioral mechanisms underlying drug reinforcement without requiring extensive or repeated experimental sessions (c.f., operant procedures involving lever pulls or other operant responses to evaluate effort). These procedures also may avoid artificial ceiling effects present in human drug administration studies due to ethical or practical concerns with high levels of drug exposure and can be directly translated to ambulatory clinical settings.

Suvorexant failed to reduce demand and instead resulted in increased demand in both a cocaine dose-related and suvorexant dose-related manner. These findings contrast with preclinical studies reviewed in the Introduction showing reductions in cocaine demand metrics underlying use motivation (e.g., Pmax, breakpoint) following pretreatment with orexin system antagonists. However, these findings are consistent with drug self-administration data from the parent study which showed that suvorexant maintenance at 10 and 20 mg increased self-administration of the same low-dose of cocaine (10 mg/kg intravenous) using a concurrent drug versus money choice procedure (Stoops et al., 2022). The lack of correspondence with preclinical findings could be explained by experimental features including the method of drug administration, timing of drug administration, and/or selectivity of the orexin receptor antagonist studied. Specifically, preclinical studies evaluating effects of orexin system antagonism on cocaine demand have exclusively focused on dosing immediately prior to experimental sessions, under acute conditions, and with orexin-1 receptor selective antagonists, often delivered via VTA-specific injections (Bentzley & Aston-Jones, 2015; España et al., 2010; James, Bowrey, et al., 2019; James, Stopper, et al., 2019; Pantazis et al., 2022). Prior research has documented similar examples in which the acute versus chronic effects of potential pharmacotherapies diverge (e.g., acute versus chronic effects of d-amphetamine in cocaine self-administration) (Czoty et al., 2011; Negus & Mello, 2003; Thomsen et al., 2013).

We also observed increases in alcohol demand during active suvorexant maintenance that mirrored those for cocaine using a traditional alcohol purchase task approach. No preclinical studies have used behavioral economic demand procedures to evaluate alcohol demand, however, reductions in alcohol use motivation have been observed with orexin receptor antagonism (e.g., Jupp et al., 2011; Lawrence et al., 2006; Shoblock et al., 2011). Similar differences in experimental procedures (e.g., time of dosing and acute versus chronic effects) may have contributed to the failure to observe decreases in alcohol use motivation here. In contrast, we did not observe changes in cigarette or chocolate demand. Visual inspection of cigarette demand (Figure 3) suggests a possible signal for increases in demand under suvorexant maintenance, but also significant variability in responding. Replication of these alcohol and cigarette findings in clinical populations for which these are the primary drug used is needed.

This apparent increase in cocaine and alcohol use motivation following suvorexant maintenance is relevant in the context of potential abuse liability of DORAs. Several human abuse potential studies have demonstrated modest abuse potential for DORAs among people with recreational sedative use (e.g., Landry et al., 2022; Schoedel et al., 2016; Ufer et al., 2022), which resulted in DORAs placement in Schedule IV. It is possible that the enhanced demand for cocaine and alcohol observed here is partly related to potential additive effects stemming from suvorexant’s abuse liability. However, a recent study evaluating the effect of suvorexant maintenance among people with opioid use disorder during a buprenorphine taper failed to demonstrate abuse potential on subjective measures of High or Liking (Huhn et al., 2022). Important to note is that this latter study also used a clinically relevant dosing design (i.e., nightly dosing) consistent with that used here. These findings collectively suggest a need for more comprehensive analyses of DORA abuse potential in varied populations should their therapeutic potential be further investigated.

We did not observe changes in alcohol, cigarette, or chocolate demand as a function of cocaine pretreatment. Surprisingly few experimental studies have evaluated the impact of cocaine challenge on subsequent cigarette or alcohol self-administration in humans despite the clinical relevance of these forms of polysubstance use. One placebo-controlled study found that acute intranasal cocaine administration increased the total number of cigarettes smoked and latency to first cigarette during a 3-hour monitored cigarette smoking period (Roll et al., 1997). In contrast, another found that repeated intravenous cocaine self-administration in a residential unit failed to alter smoking patterns (Radzius et al., 1997). This latter finding is consistent with the results here insofar as cigarette purchase task responses occurred in the context of repeated cocaine administration on the residential unit over the 30 day period. We are not aware of any human laboratory study that has evaluated acute pretreatment with cocaine on alcohol self-administration. However, preclinical studies have shown mixed effects with cocaine administration increasing (e.g., Cepko et al., 2014; Hauser et al., 2014; Knackstedt et al., 2006), decreasing (e.g., Hammad et al., 2017; Uemura et al., 1998), or having no effect (Cailhol & Mormède, 2000) on alcohol intake in rodents potentially depending on varying factors like dose, rodent strain/species, and route/schedule of administration. These findings suggest that the acute pharmacological effects of cocaine on alcohol use are likely nuanced and require further research. Studies using the purchase task procedure are well positioned to address these gaps given its flexibility for use across varied clinical contexts.

The current analysis is primarily limited by the small sample size and focus on hypothetical responding in the purchase task procedure. Regarding sample size, the small size is partly a practical limitation of shutdowns related to the COVID-19 pandemic. Offsetting this limitation is the clear dose-related increases in demand observed as well as the systematic changes in demand as a function suvorexant maintenance. Participants also did not sample other commodities (alcohol, cigarettes, and chocolate) prior to completion of the purchase task procedures so responding was completely hypothetical for these commodities. This concern is partly lessened by the supplemental analyses (Supplemental Materials) showing expected positive associations between baseline alcohol and cigarette use and alcohol and cigarette demand, respectively. The hypothetical nature of responding is a broader limitation of the purchase task procedure, but is offset by prior studies demonstrating that correspondence between hypothetical and incentivized responding (Amlung et al., 2012; Amlung & MacKillop, 2015; Wilson et al., 2016). Hypothetical responding allows for remote task delivery and use among treatment-seeking populations or people with medical contraindications – groups of people for whom interventions development efforts would ideally generalize, but that are often not represented in initial preclinical-to-human translation. The hypothetical nature of responding is also balanced by the comparisons to self-administration data from the parent study showing similar dose-related effects of cocaine and a similar dose-related effect of suvorexant for increasing cocaine versus money choice.

This study demonstrates the flexibility of the purchase task procedure for evaluating behavioral economic demand in medications development settings. Here, we provide an example of the use of these procedures in the context of a study on orexin system regulation of cocaine (and other drug) use motivation. A principle empirical finding was that the dual orexin receptor antagonist suvorexant failed to reduce demand for cocaine or alcohol and instead resulted in increased demand in a suvorexant dose-related manner. Notably, the increased demand for cocaine during active suvorexant maintenance aligned with the cocaine self-administration results from the parent trial. Clinically, these findings somewhat reduce enthusiasm for the clinical use of DORAs like suvorexant to the treatment of cocaine use disorder (or alcohol intake in individuals with cocaine use disorder) at least with respect to direct effects on drug use motivation. It is nonetheless possible that clinical utility may still be achieved for other therapeutic indications including the already approved indication of sleep promotion. For example, a recent randomized, double-blind study found that suvorexant improved sleep quality, decreased opioid withdrawal, and reduced opioid craving relative to placebo among patients with opioid use disorder ongoing a buprenorphine taper (Huhn et al., 2022). These data suggest the possibility of therapeutic benefit that may depend on the population and indication studied. Ultimately, future research is needed to test more selective orexin antagonists in combination with cocaine and other substances on diverse clinical endpoints to determine dual versus single orexin receptor targeting effects in varied clinical populations.

Supplementary Material

Supplemental Digital Content

Source of Funding:

The authors gratefully acknowledge research support from the National Institute on Drug Abuse (R01DA048617) and from the National Center for Advancing Translational Sciences (UL1TR001998) of the National Institutes of Health.

Footnotes

Conflicts of Interest: None

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