Use of drug purchase tasks in medications development research: orexin system regulation of cocaine and drug demand.

Commodity purchase tasks provide a useful method for evaluating behavioral economic demand in the human laboratory. Recent research has shown how responding to 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 nontreatment-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 Food and Drug Administration-approved insomnia medication suvorexant (oral; 0, 5, 10, 20 mg/day) in randomized order with experimental sessions completed after at least 3 days of maintenance on each suvorexant dose. Experimental sessions included administration of a sample dose of 0, 10 and 30 mg/70 kg intravenous cocaine. Analyses focused on purchase tasks for the blinded sample dose as well as alcohol, cigarettes and chocolate completed 15 min 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.

Differential impacts of economic and demographic variables on substance use patterns during the COVID-19 pandemic.

Background: The COVID-19 pandemic and subsequent economic crisis has provided a unique opportunity to investigate the effects of economic shifts on substance use. Existing literature on this relationship is limited and conflicting, warranting further exploration.Objective: This study aimed to identify relationships between socioeconomic status (SES), demographic variables, and substance use patterns before and after government-mandated business closures due to COVID-19.Methods: Participants were recruited based on self-reported substance use through Amazon's Mechanical Turk (MTurk). Qualifying participants (N = 315, 43% female, mean age = 35.35) reported their substance use and SES for two-week periods before and after pandemic-related business closures. Regression models analyzed relationships between substance use and study variables.Results: Regression models found that, during COVID-19 closures, greater financial strain predicted decreased benzodiazepine (ß = -1.12) and tobacco (ß = 1.59) use. Additionally, certain predictor variables (e.g., participants' age [ß = 1.22], race [ß = -4.43], psychiatric disorders including ADHD [ß = -2.73] and anxiety [ß = 1.53], and concomitant substance use [ß = 3.38]) predicted changes in substance use patterns; however, the directionality of these associations varied across substances.Conclusion: Specific substance use patterns were significantly and differentially impacted by economic strain, psychiatric diagnoses, and concomitant substance use. These results can help direct harm reduction efforts toward populations at greatest risk of harmful substance use following the pandemic.

Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine.

Opioid antagonists (eg, naltrexone) and positive modulators of γ-aminobutyric acid type A receptors (eg, alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of D-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and "positive" subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone.Eight non-treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6 to 7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected.Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like "positive" subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10-mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior.

Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9-tetrahydrocannabinol.

The aim of the present study was to examine a potential mechanism of action of gabapentin to manage cannabis-use disorders by determining the interoceptive effects of gabapentin in cannabis users discriminating [INCREMENT]-tetrahydrocannabinol ([INCREMENT]-THC) using a pharmacologically selective drug-discrimination procedure. Eight cannabis users learned to discriminate 30 mg oral [INCREMENT]-THC from placebo and then received gabapentin (600 and 1200 mg), [INCREMENT]-THC (5, 15, and 30 mg), and placebo alone and in combination. Self-report, task performance, and physiological measures were also collected. [INCREMENT]-THC served as a discriminative stimulus, produced positive subjective effects, elevated heart rate, and impaired psychomotor performance. Both doses of gabapentin substituted for the [INCREMENT]-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of [INCREMENT]-THC when administered alone. When administered concurrently, gabapentin shifted the discriminative-stimulus effects of [INCREMENT]-THC leftward/upward, and combinations of [INCREMENT]-THC and gabapentin generally produced larger effects on cannabinoid-sensitive outcomes relative to [INCREMENT]-THC alone. These results suggest that one mechanism by which gabapentin might facilitate cannabis abstinence is by producing effects that overlap with those of cannabinoids.

Relationship between intranasal cocaine self-administration and subject-rated effects: predictors of cocaine taking on progressive-ratio schedules.

OBJECTIVE: Subject-rated measures and drug self-administration represent two of the most commonly used methods of assessing abuse potential of drugs, as well as screening intervention efficacy in the human laboratory. Although the results from these methods are often consistent, dissociations between subject-rated and self-administration data have been observed. The purpose of the present retrospective analysis was to examine the relationship between subject-rated effects and intranasal cocaine self-administration to help guide future research design and intervention assessment. METHODS: Data were combined from two previous studies in which drug and an alternative reinforcer (i.e., money) were available on concurrent progressive-ratio schedules of reinforcement. Pearson correlation coefficients and regression model selection utilizing corrected Akaike information criterion were used to determine which subject-rated measures were associated with and best predicted cocaine self-administration. RESULTS: Eleven subject-rated effects were positively associated with cocaine-maintained breakpoints. A combination of three of these subject ratings (i.e., Like Drug, Performance Improved, and Rush) best predicted cocaine taking. CONCLUSIONS: The present findings suggest that, at least under certain conditions with intranasal cocaine, some, but not all, positive subject-rated effects may predict drug self-administration. These findings will be useful in guiding future examinations of putative interventions for cocaine-use disorders.

The subjective value of social context in people who use cannabis.

Disordered cannabis use is linked to social problems, which could be explained by a subjective devaluation of nondrug social contexts and/or an overvaluation of cannabis-paired options relative to nondrug alternatives. To examine these hypotheses, measures to assess the subjective value of social- and/or cannabis-paired contexts were collected in people who use cannabis (n = 85) and controls (n = 98) using crowdsourcing methods. Measures included a cued concurrent choice task that presented two images (cannabis, social, social cannabis, and neutral images) paired with monetary options, hypothetical purchase tasks that included access to social parties with and without a cannabis "open bar," and the Social Anhedonia Scale (SAS). Little evidence was found to suggest that the cannabis group undervalued social contexts. People who used cannabis demonstrated a preference for social- versus neutral-cued options, and no preference for cannabis- versus social cannabis-cued options on the choice task. In addition, social party demand and SAS scores did not differ between groups. In contrast, we observed evidence for an overvaluation of cannabis context in people who use cannabis, including preference for social cannabis- versus social-cued options, and more disadvantageous choices for cannabis-cued options on the choice task, as well as more intense and inelastic demand for the social cannabis party compared to the social party. These results suggest that social problems associated with cannabis use could be at least partially explained by an overvaluation of cannabis-paired options, rather than devaluation of nondrug social-paired options, in the value calculations underlying drug use decisions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A dose-ranging study of the physiological and self-reported effects of repeated, rapid infusion of remifentanil in people with opioid use disorder and physical dependence on fentanyl.

RATIONALE: Understanding mechanisms of drug use decisions will inform the development of treatments for opioid use disorder (OUD). Decision-making experiments using neurobehavioral approaches require many trials or events of interest for statistical analysis, but the pharmacokinetics of most opioids limit dosing in humans. OBJECTIVES: This experiment characterized the effects of repeated infusions of the ultra-short acting opioid remifentanil in people with OUD and physical opioid dependence. METHODS: An inpatient study using a within-subjects, single-blind, escalating, within-session, pre-post design was conducted. Seven (3 female) subjects were maintained on oral oxycodone (40-60 mg, 4x/day = 160-240 total mg/day) for seven days prior to the dose-ranging session. Subjects received infusions of three ascending remifentanil doses (0.03, 0.1, 0.3 mcg/kg/infusion in 2 subjects; 0.1, 0.3, 1.0 mcg/kg/infusion in 5 subjects) every minute for 40 min per dose, with infusions administered over 5 s to model naturalistic delivery rates. End tidal carbon dioxide, respiration rate, oxygen saturation (SpO2) and heart rate were measured continuously. Blood pressure (BP), pupil diameter and self-reported drug effects were measured every 5 min. RESULTS: Pupil diameter, SpO2 and systolic BP decreased, and ratings on prototypic subjective effects questionnaire items increased, as a function of remifentanil dose. The number of infusions held because of sedation or physiological parameters exceeding predetermined cutoffs also increased with dose. CONCLUSIONS: This experiment established doses and procedures for the safe delivery of rapid, repeated remifentanil infusions to individuals with OUD and physical fentanyl dependence, which can be applied to the mechanistic study of opioid use decisions.

The relative reinforcing strength of methamphetamine and D-amphetamine in monkeys self-administering cocaine.

Epidemiological data indicate that rates of methamphetamine misuse surpass those of D-amphetamine, but self-administration research in animals and humans has not typically demonstrated differences in their reinforcing effects. The present study used a within-session, exponentially increasing progressive-ratio schedule and extended-access conditions to assess the relative reinforcing strength of D-amphetamine and methamphetamine in rhesus monkeys (n=5) trained to self-administer cocaine. A range of doses of methamphetamine (0.003-0.1 mg/kg/injection), D-amphetamine (0.003-0.1 mg/kg/injection), and cocaine (0.003-0.3 mg/kg/injection) was tested to capture the ascending and descending limbs of the dose-effect functions. Each drug functioned as a reinforcer, but the peak number of self-administered D-amphetamine injections was significantly lower compared with methamphetamine and cocaine; the peak number of self-administered injections of cocaine and methamphetamine did not differ. Although differences in availability and other social factors likely impact relative rates of abuse, the present data suggest that the greater reinforcing strength of methamphetamine contributes to its increased use compared with D-amphetamine.

Combining noninvasive brain stimulation with behavioral pharmacology methods to study mechanisms of substance use disorder.

Psychotropic drugs and transcranial magnetic stimulation (TMS) are effective for treating certain psychiatric conditions. Drugs and TMS have also been used as tools to explore the relationship between brain function and behavior in humans. Combining centrally acting drugs and TMS has proven useful for characterizing the neural basis of movement. This combined intervention approach also holds promise for improving our understanding of the mechanisms underlying disordered behavior associated with psychiatric conditions, including addiction, though challenges exist. For example, altered neocortical function has been implicated in substance use disorder, but the relationship between acute neuromodulation of neocortex with TMS and direct effects on addiction-related behaviors is not well established. We propose that the combination of human behavioral pharmacology methods with TMS can be leveraged to help establish these links. This perspective article describes an ongoing study that combines the administration of delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, with neuroimaging-guided TMS in individuals with problematic cannabis use. The study examines the impact of the left dorsolateral prefrontal cortex (DLPFC) stimulation on cognitive outcomes impacted by THC intoxication, including the subjective response to THC and the impairing effects of THC on behavioral performance. A framework for integrating TMS with human behavioral pharmacology methods, along with key details of the study design, are presented. We also discuss challenges, alternatives, and future directions.

Exponentiated model of drug demand is preferred over exponential models in people with daily/near daily cannabis use.

Cannabis use is a growing health concern emphasizing the need to better understand the complexities of drug choice in people with daily/near daily cannabis use. Hypothetical purchasing tasks provide a means to collect data on drug consumption behavior without requiring drug administration and have been used to isolate behavioral economic factors of choice, including facets of drug demand in substance using populations. Various models are used for analyzing hypothetical purchasing task data, but challenges exist in modeling data sets with consumption values of zero. Additionally, a single model or approach may not be best for all commodities and drug classes. This study compared two common demand models (exponential vs. exponentiated) applied to identical hypothetical purchasing task data from 21 (n = 21) individuals with daily/near daily cannabis use. The exponential model was fit using three common levels of replacement values for zero consumption (.1, .01, .001) and compared to the exponentiated model without replacement values. We found that the exponentiated model produced significantly better model fits for individual data, compared to all exponential models. Additionally, significant differences for model derived values of demand elasticity and intensity were found between the exponentiated model and different levels of the exponential model. We conclude that the exponentiated model is preferred over the exponential model for performing demand analysis on hypothetical purchasing task data from individuals with daily/near daily cannabis use. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Cocaine abstinence during the "critical period" of a contingency management trial predicts future abstinence in people with cocaine use disorder.

BACKGROUND: Contingency Management (CM) is being piloted as a treatment for stimulant use disorder in several US states, highlighting the need for treatment optimization. One important goal of optimization is decreasing drug use during the early stages of treatment, which has predicted success in other interventions. However, this "critical period" has not been reported in CM trials. The purpose of this analysis was to determine if, after accounting for baseline abstinence and incentive condition, abstinence in a CM trial for people with Cocaine Use Disorder (CUD) could be predicted by cocaine use during a first-week critical period. METHODS: Eighty-seven participants with CUD were randomized to receive contingent high or low value incentives for cocaine abstinence or were in a non-contingent control group. Generalized estimating equations (GEE) were used to analyze urine test results over 36 timepoints during the 12-week intervention. To assess for a critical period, the first three visits were included in the GEE as a covariate for remaining urine test results. RESULTS: Participants who provided more negative samples during the critical period were significantly more likely to produce a negative urine sample during the remainder of the trial, though some effects of group remained after controlling for the critical period. CONCLUSIONS: These results indicate that a critical period exists for CM trials, and it can explain a substantial amount of future performance. Early contact with an abstinence-contingent high magnitude alternative reinforcer may explain additional performance beyond the critical period, further justifying the use of high magnitude alternative reinforcers.

Cannabis Use Disorder Treatment Preferences: A Pilot Survey in Current Users of Cannabis.

OBJECTIVES: Highly effective treatments for cannabis use disorder (CUD) are lacking, and patient preferences have not been considered during treatment development. We therefore conducted an exploratory crowdsourced survey of individuals reporting current cannabis use and a willingness to cut down or quit their cannabis use, to determine their interest in various treatment aspects. METHODS: Subjects (n = 63) were queried about their willingness to take medications as a function of type, route, and regimen and to participate in adherence monitoring. Subjects were also asked about their willingness to engage in behavioral/psychosocial interventions as a function of type, setting, and duration. Measures theorized to be associated with treatment preferences were also collected, including cannabis use variables, readiness to change, reduction or cessation goal, perceived cessation barriers, and medication use beliefs and behaviors. RESULTS: Survey responses indicated that efforts to develop CUD medications should focus on nonsynthetic compounds administered orally or by mouth spray no more than once per day to maximize patient acceptance. Remote adherence monitoring and one-on-one outpatient behavioral treatment approaches, especially contingency management, are also anticipated to enhance participation. Most subjects indicated a preference to reduce their cannabis use rather than quit. CONCLUSIONS: These data provide guidance for the development of CUD interventions based on the preferences of individuals interested in treatment for their cannabis use. Additional research is needed to confirm these results in a larger sample and determine if matching CUD patients with their preferred treatments improves success rates.

Naltrexone-bupropion combinations do not affect cocaine self-administration in humans.

The FDA has not yet approved a pharmacotherapy for cocaine use disorder despite nearly four decades of research. This study determined the initial efficacy, safety, and tolerability of naltrexone-bupropion combinations as a putative pharmacotherapy for cocaine use disorder. Thirty-one (31) non-treatment seeking participants with cocaine use disorder completed a mixed-design human laboratory study. Participants were randomly assigned to the naltrexone conditions (i.e., 0, 50 mg/day; between-subject factor) and maintained on escalating doses of bupropion (i.e., 0, 100, 200, 400 mg/day; within-subject factor) for at least four days prior to the conduct of experimental sessions. Cocaine self-administration (IN, 0, 40, 80 mg) was then determined using a modified progressive ratio and relapse procedure. Subjective and cardiovascular effects were also measured. Cocaine produced prototypical dose-related increases in self-administration, subjective outcomes (e.g., "Like Drug"), and cardiovascular indices (e.g., heart rate, blood pressure) during placebo maintenance. Naltrexone and bupropion alone, or in combination, did not significantly decrease self-administration on either procedure. Low doses of bupropion (i.e., 100 mg) blunted the effects of the cocaine on subjective measures of "Like Drug" and "Stimulated". No unexpected adverse effects were observed with naltrexone and bupropion, alone and combined, in conjunction with cocaine. Together, these results do not support the use of these bupropion-naltrexone combinations for the treatment of cocaine use disorder. Future research should determine if novel drug combinations may decrease cocaine self-administration.

Clinical neuropharmacology of cocaine reinforcement: A narrative review of human laboratory self-administration studies.

Cocaine use is an unrelenting public health concern. To inform intervention and prevention efforts, it is crucial to develop an understanding of the clinical neuropharmacology of the reinforcing effects of cocaine. The purpose of this review is to evaluate and synthesize human laboratory studies that assess pharmacological manipulations of cocaine self-administration. Forty-one peer-reviewed, human cocaine self-administration studies in which participants received a pretreatment drug were assessed. The pharmacological action and treatment regimen for all drugs reviewed were considered. Drugs that increase extracellular dopamine tend to have the most consistent effects on cocaine self-administration. The ability of nondopaminergic drugs to impact cocaine reinforcement might be related to their downstream effects on dopamine, though it is difficult to draw conclusions because pharmacologically selective compounds are not widely available for human testing. The ability of acute versus chronic drug treatment to differentially affect human cocaine self-administration was not determined because buprenorphine was the only pretreatment drug that was assessed under both acute and chronic dosing regimens. Future research directly comparing acute and chronic drug treatment and/or comparing drugs with different mechanisms of action, is needed to make more conclusive determinations about the clinical neuropharmacology of cocaine reinforcement.

Influence of pregabalin maintenance on cannabis effects and related behaviors in daily cannabis users.

No medications are approved for cannabis use disorder (CUD), though a small clinical trial demonstrated that the voltage-dependent calcium channel (VDCC) ligand gabapentin reduced cannabis use in treatment seekers. VDCCs are modulated by cannabinoid (CB) ligands, and there are shared effects between CB agonists and VDCC ligands. This overlapping neuropharmacology and the initial clinical results supported the evaluation of pregabalin, a "next-generation" VDCC ligand, as a CUD medication. Two separate placebo-controlled, double-blind, counterbalanced, within-subjects human laboratory studies tested placebo and 300 (N = 2 females, 11 males; Experiment [EXP] 1) or 450 (N = 3 females, 11 males; EXP 2) mg/day pregabalin in cannabis users who were not seeking treatment or trying to reduce/quit their cannabis use. The protocol consisted of two outpatient maintenance phases (11 days in EXP 1 and 15 days in EXP 2) that concluded with four experimental sessions within each phase. During experimental sessions, maintenance continued, and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% delta9-tetrahydrocannabinol [THC]), as well as subjective, attentional bias, performance, and physiological responses. In addition, naturalistic cannabis use, side effects, sleep quality, craving, and other self-reported substance use were measured during pregabalin maintenance. Cannabis was self-administered and produced prototypical effects, but pregabalin generally did not impact the effects of cannabis or alter naturalistic use. These human laboratory results in cannabis users not trying to reduce/quit their use do not support the efficacy of pregabalin as a stand-alone pharmacotherapy for CUD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Exploratory examination of the effects of d-amphetamine on active-state functional connectivity: Influence of impulsivity and sensation-seeking status.

Recent advances in diagnostic research identified that individuals with higher impulsivity and sensation-seeking scores tend to report more positive subjective responses to stimulant drugs such as amphetamine. The current exploratory study hypothesized that differences in underlying mesocorticolimbic circuitry may mediate the relationship between personality and responses to stimulants due to its previously established implication in reward processes as well as the overlap between its dopaminergic projections and the pharmacodynamics of many stimulants. Forty participants (20 female) were recruited with relatively high- and low-impulsivity and sensation-seeking scores as defined by the Zuckerman-Kuhlman Personality Questionnaire (Form IIIR; Zuckerman, Kuhlman, Joireman, Teta, & Kraft, 1993) for a double-blind, placebo-controlled, intranasal amphetamine administration study conducted within an MRI scanner. Active state seed-to-voxel connectivity analyses assessed the effects of amphetamine, personality, subjective responses to amphetamine, and their interactions with mesocorticolimbic seeds on data collected during monetary incentive delay and go/no-go task performance. Results indicated that amphetamine administration largely disrupted brain activity as evidenced by connectivity values shifting toward no correlation among brain stem, striatal, and frontal cortex regions. Additionally, associations of impulsivity and connectivity between ventral tegmental and medial orbitofrontal as well as lateral orbitofrontal and putamen regions were inverted from negative to positive during the placebo and amphetamine conditions, respectively. Personality was unrelated to subjective responses to amphetamine. Results are interpreted as providing evidence of underlying differences in mesocorticolimbic circuitry being a potential target for requisite diagnostic and treatment strategies implicated with stimulant use disorders, but further research is needed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Suvorexant maintenance enhances the reinforcing but not subjective and physiological effects of intravenous cocaine in humans.

Preclinical research has sought to understand the role of the orexin system in cocaine addiction given the connection between orexin producing cells in the lateral hypothalamus and brain limbic areas. Exogenous administration of orexin peptides increased cocaine self-administration whereas selective orexin-1 receptor antagonists reduced cocaine self-administration in non-human animals. The first clinically available orexin antagonist, suvorexant (a dual orexin-1 and orexin-2 receptor antagonist), attenuated motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding, in rodents. This study aimed to translate those preclinical findings and determine whether suvorexant maintenance altered the pharmacodynamic effects of cocaine in humans. Seven non-treatment seeking subjects with cocaine use disorder completed this within-subject human laboratory study, and a partial data set was obtained from one additional subject. Subjects were maintained for at least three days on 0, 5, 10 and 20 mg oral suvorexant administered at 2230 h daily in random order. Subjects completed experimental sessions in which cocaine self-administration of 0, 10 and 30 mg/70 kg of intravenous cocaine was evaluated on a concurrent progressive ratio drug versus money choice task. Subjective and physiological effects of cocaine were also determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g., increased ratings of "Stimulated" and heart rate). Suvorexant (10, 20 mg) increased self-administration of 10 mg/70 kg cocaine and decreased oral temperature but did not significantly alter any other effects of cocaine. Future research may seek to evaluate the effects of orexin-1 selective antagonists in combination with cocaine.

Progesterone effects on the discriminative stimulus, subjective and performance effects of triazolam in healthy, premenopausal women.

There is accumulating evidence that sex plays a critical role in drug abuse. Female sex hormones have been shown to affect central nervous system function and modulate the effects of drugs of abuse. For example, γ-aminobutyric acid type A (GABA(A)) receptor function is positively modulated by progesterone metabolites. There is evidence from preclinical in-vitro and in-vivo studies as well as some clinical research suggesting that progesterone and its metabolites may enhance the behavioral effects of benzodiazepines, which also serve as positive modulators of GABA(A) receptors. The purpose of this experiment was to determine the independent and combined discriminative stimulus, subjective and psychomotor effects of progesterone and triazolam in healthy adult premenopausal women. Oral micronized progesterone (100 mg), triazolam (0.06, 0.12 and 0.25 mg/70 kg) and placebo were administered to healthy, premenopausal women (n=9) under conditions of low circulating sex hormones. Triazolam alone functioned as a discriminative stimulus and produced prototypical sedative-like effects (e.g., performance impairment, enhanced reports of sedative effects). Progesterone alone produced sedative-like effects on several subjective and performance measures, and the dose combination effects of progesterone and triazolam on several subjective measures of drug effect were similar to the summation of the two drug effects in isolation. Progesterone did not substitute for or modify the discriminative stimulus effects of triazolam. These results suggest that the parent hormone, progesterone, and triazolam have discordant neuropharmacological mechanisms of action. Additional research is necessary to determine the degree to which neurosteroids influence sex differences in benzodiazepine use and abuse.

Sexually dimorphic neuroimmune response to chronic opioid treatment and withdrawal.

Opioid use disorder is a leading cause of morbidity and mortality in the United States. Increasing pre-clinical and clinical evidence demonstrates sex differences in opioid use and dependence. However, the underlying molecular mechanisms contributing to these effects, including neuroinflammation, are still obscure. Therefore, in this study, we investigated the effect of oxycodone exposure and withdrawal on sex- and region-specific neuroimmune response. Real-time PCR and multiplex cytokine array analysis demonstrated elevated neuroinflammation with increased pro-inflammatory cytokine levels, and aberrant oligodendroglial response in reward neurocircuitry, following withdrawal from chronic oxycodone treatment. Chronic oxycodone and withdrawal treated male mice had lower mRNA expression of TMEM119 along with elevated protein levels of pro-inflammatory cytokines/chemokines and growth factors (IL-1ß, IL-2, IL-7, IL-9, IL-12, IL-15, IL17, M-CSF, VEGF) in the prefrontal cortex (PFC) as compared to their female counterparts. In contrast, reduced levels of pro-inflammatory cytokines/chemokines (IL-1ß, IL-6, IL-9, IL-12, CCL11) was observed in the nucleus accumbens (NAc) of oxycodone and withdrawal-treated males as compared to female mice. No treatment specific effects were observed on the mRNA expression of putative microglial activation markers (Iba1, CD68), but an overall sex specific decrease in the mRNA expression of Iba1 and CD68 was found in the PFC and NAc of male mice as compared to females. Moreover, a sex and region-specific increase in the mRNA levels of oligodendrocyte lineage markers (NG2, Sox10) was also observed in oxycodone and withdrawal treated animals. These findings may open a new avenue for the development of sex-specific precision therapeutics for opioid dependence by targeting region-specific neuroimmune signaling.

Topiramate-phentermine combinations reduce cocaine self-administration in humans.

RATIONALE: Cocaine use disorder is an unrelenting public health concern. Despite nearly four decades of research, an FDA approved medication is not yet available. OBJECTIVES: The objective of this human laboratory study was to demonstrate the initial efficacy, safety and tolerability of topiramate-phentermine combinations for cocaine use disorder. METHODS: Thirty-one (31) participants with cocaine use disorder completed this mixed-model inpatient laboratory study. Participants were maintained on topiramate (0 [N = 11], 50 [N = 9] or 100 [N = 11] mg/day). Each topiramate group was concurrently maintained on phentermine (0, 15, 30 mg). Drug self-administration, subjective responses and cardiovascular effects following acute doses of intranasal cocaine (0, 40, 80 mg) were determined during separate experimental sessions after at least seven (7) days of maintenance on each condition. RESULTS: The three groups of participants were well matched demographically and generally did not differ significantly in their responses to a range of doses of intranasal cocaine (0, 10, 20, 40, 80 mg) during a medical safety session. Maintenance on topiramate and phentermine alone significantly decreased cocaine self-administration although these effects were modest in magnitude. Combining topiramate and phentermine robustly decreased cocaine self-administration. Topiramate and phentermine were well tolerated alone and combined, as well as in conjunction with cocaine. CONCLUSIONS: The results of the present study support advancing topiramate-phentermine combinations as a putative pharmacotherapeutic for cocaine use disorder.