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.

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.

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.

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.

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.

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.

Influence of n-acetylcysteine maintenance on the pharmacodynamic effects of oral ethanol.

Rationale: Glutamate systems play an important role in the abuse related effects of alcohol. n-Acetylcysteine, a drug that promotes glutamate homeostasis, attenuates a range of alcohol effects in preclinical models.

Objectives: This human laboratory study determined the influence of n-acetylcysteine maintenance on alcohol self-administration using a model predictive of treatment effectiveness, along with the subjective, performance and physiological effects of alcohol.

Pharmacological validation of a translational model of cocaine use disorder: Effects of d-amphetamine maintenance on choice between intravenous cocaine and a nondrug alternative in humans and rhesus monkeys.

Drug self-administration procedures are the gold standard for laboratory research to study mechanisms of drug use disorders and evaluate candidate medications. However, preclinical-to-clinical translation has been hampered by a lack of coordination. To address this limitation, we previously developed homologous intravenous (IV) cocaine choice self-administration procedures in rhesus monkeys and humans, and then demonstrated their functional equivalence.

Influence of phendimetrazine maintenance on the reinforcing, subjective, performance, and physiological effects of intranasal cocaine.

Rationale: No pharmacotherapies are approved for cocaine use disorder. Phendimetrazine, a prodrug of the monoamine-releaser phenmetrazine, attenuates the reinforcing effects of cocaine in preclinical models, has minimal abuse potential, and is safe when combined with cocaine.

Objectives: This study determined the influence of phendimetrazine maintenance on the reinforcing effects of cocaine (i.

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

No medications are approved for cannabis use disorder (CUD). Gamma-aminobutyric acid (GABA) reuptake is modulated by cannabinoid (CB) receptor agonists, and there are shared effects between CB agonists and the GABA reuptake inhibitor tiagabine. This overlapping neuropharmacology suggested that tiagabine might be useful for CUD.

N-Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order.

Background: Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans.

Development of a translational model to screen medications for cocaine use disorder II: Choice between intravenous cocaine and money in humans.

Background: A medication for treating cocaine use disorder has yet to be approved. Laboratory-based evaluation of candidate medications in animals and humans is a valuable means to demonstrate safety, tolerability and initial efficacy of potential medications. However, animal-to-human translation has been hampered by a lack of coordination.

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.

Safety and tolerability of intranasal cocaine during phendimetrazine maintenance.

Rationale: Phendimetrazine appears to have limited abuse potential and reduces cocaine self-administration in preclinical studies. No human studies have evaluated the safety and tolerability of cocaine in combination with phendimetrazine, which is a necessary next step in evaluating the efficacy of phendimetrazine for treating cocaine use disorder.

Objectives: This study determined the safety and tolerability of acute cocaine doses during chronic phendimetrazine treatment.

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.

Naltrexone and bupropion, alone or combined, do not alter the reinforcing effects of intranasal methamphetamine.

Naltrexone and bupropion, when administered alone in clinical trials, modestly reduce amphetamine use. Whether combining these drugs would result in greater reductions in methamphetamine taking relative to either drug alone is undetermined. This study examined the influence of naltrexone, bupropion and a naltrexone-bupropion combination on methamphetamine self-administration in humans.

Methamphetamine self-administration in humans during D-amphetamine maintenance.

Agonist replacement may be a viable treatment approach for managing stimulant use disorders. This study sought to determine the effects of D-amphetamine maintenance on methamphetamine self-administration in stimulant using human participants. We predicted that D-amphetamine maintenance would reduce methamphetamine self-administration.

Separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ⁹-THC in humans discriminating Δ⁹-THC.

Background: Our previous research suggested the involvement of γ-aminobutyric acid (GABA), in particular the GABAB receptor subtype, in the interoceptive effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC). The aim of the present study was to determine the potential involvement of the GABAA receptor subtype by assessing the separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ(9)-THC using pharmacologically selective drug-discrimination procedures.

Methods: Ten cannabis users learned to discriminate 30 mg oral Δ(9)-THC from placebo and then received diazepam (5 and 10mg), Δ(9)-THC (5, 15 and 30 mg) and placebo, alone and in combination.

Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of Δ(9) -THC in cannabis users.

Oral Δ(9) -tetrahydrocannabinol (Δ(9) -THC) has been evaluated as a medication for cannabis dependence, but repeated administration of acute oral doses up to 40 mg has not been effective at reducing drug-taking behavior. Larger doses might be necessary to affect cannabis use. The purpose of the present study was therefore to determine the physiological and behavioural effects of oral Δ(9) -THC at acute doses higher than those tested previously.

Lack of tolerance to the disinhibiting effects of alcohol in heavy drinkers.

Rationale: Alcohol tolerance is observed as a diminished response to a given dose as a function of repeated administrations of the drug. Research has consistently shown that heavier drinkers display reduced reactions to alcohol (i.e.

Separate and combined effects of the GABA(B) agonist baclofen and Δ9-THC in humans discriminating Δ9-THC.

Background: Our previous research with the GABA reuptake inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ9-THC. The aim of the present study was to determine the potential involvement of the GABA(B) receptor subtype by assessing the separate and combined effects of the GABA(B)-selective agonist baclofen and Δ9-THC using pharmacologically specific drug-discrimination procedures.

Methods: Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received baclofen (25 and 50mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination.

Influence of acute bupropion pre-treatment on the effects of intranasal cocaine.

Aims: The aim of this experiment was to determine the influence of acute bupropion pre-treatment on subject-rated effects and choice of intranasal cocaine versus money.

Design: A randomized, within-subject, placebo-controlled, double-blind experiment.

Setting: An out-patient research unit.

Alternative reinforcer response cost impacts cocaine choice in humans.

Cocaine use disorders are an unrelenting public health concern. Behavioral treatments reduce cocaine use by providing non-drug alternative reinforcers. The purpose of this human laboratory experiment was to determine how response cost for non-drug alternative reinforcers influenced cocaine choice.

Separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ9-THC in humans discriminating Δ9-THC.

Background: The involvement of non-cannabinoid neurotransmitter systems in the abuse-related behavioral effects of cannabis has not been well characterized in humans. GABAergic drugs have overlapping effects with cannabis and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) on certain behavioral measures, but those measures lack the specificity to draw conclusions regarding the involvement of GABA in cannabinoid effects. The aim of this study was to assess the separate and combined effects of the GABA reuptake inhibitor tiagabine and Δ(9)-THC using more pharmacologically specific drug-discrimination procedures.