The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users.

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone.

Assessment of the physical dependence potential of difelikefalin: Randomized placebo-controlled study in patients receiving hemodialysis.

Difelikefalin is a selective kappa opioid receptor agonist approved for treating moderate-to-severe pruritus in adults undergoing hemodialysis (HD). Difelikefalin is not a controlled substance under the Controlled Substances Act. This study assessed the potential for developing physical dependence on difelikefalin in patients undergoing HD.

Evaluation of the abuse potential of difelikefalin, a selective kappa-opioid receptor agonist, in recreational polydrug users.

Difelikefalin, a selective kappa-opioid receptor agonist with limited central nervous system penetration, is being developed for the treatment of chronic pruritic conditions. This randomized, double-blind, active- and placebo-controlled, four-way crossover study was designed to evaluate the abuse potential of difelikefalin in healthy recreational polydrug users. Using a 4 × 4 Williams design, nondependent adult users of opioids and hallucinogens (N = 44) were randomized to receive single intravenous (i.

Identification of Optimal Measures of Human Abuse Potential: A Post Hoc Assessment of 19 Studies.

Background: Human abuse potential studies include multiple measures to assess the subjective effects of central nervous system-active drugs. In this retrospective analysis, measurement properties of commonly used measures were assessed, and factor analysis was conducted to identify a core battery of measures.

Methods: Measures of positive, negative and other effects, for example, bipolar "at-the-moment" Drug Liking visual analog scale (VAS), were derived for active controls and placebo from 19 studies in recreational drug users (N = 570).

Interaction of Ethanol and Oral ANS-6637, a Selective ALDH2 Inhibitor in Males: A Randomized, Double-Blind, Placebo-Controlled, Single-Ascending Dose Cohort Study.

Background: ANS-6637, an orally bioavailable selective and reversible aldehyde dehydrogenase-2 (ALDH2) inhibitor, is under development for drug and alcohol use disorders. During the elimination of alcohol, ALDH2 metabolizes acetaldehyde to acetate; inhibiting this enzyme can lead to aversive reactions due to the accumulation of acetaldehyde. Thus, understanding the safety and tolerability of ANS-6637 in combination with alcohol is essential.

Evaluation of the oral human abuse potential of Oxycodone DETERx® formulation (Xtampza® ER).

Objective: To further characterize the human abuse potential and pharmacokinetics (PK) of Oxycodone DETERx (Xtampza® ER) after intact and chewed oral administration.

Design: Randomized, double-blind, triple-dummy, active- and placebo-controlled, single-dose, six-period, crossover comparison study.

Setting: Clinical research unit.

Abuse Potential of Buprenorphine/Samidorphan Combination Compared to Buprenorphine and Placebo: A Phase 1 Randomized Controlled Trial.

Buprenorphine/samidorphan combination (BUP/SAM) is an opioid system modulator being investigated as adjunctive treatment for major depressive disorder. BUP/SAM is a fixed-dose combination of buprenorphine, a partial μ-opioid receptor agonist and κ-opioid receptor antagonist, and samidorphan, a μ-opioid receptor antagonist added to address the abuse and dependence potential of buprenorphine. In this study, we assessed the effect of samidorphan on the abuse potential of buprenorphine in the BUP/SAM combination in nondependent, recreational, adult opioid users (ClinicalTrials.

Pharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended-Release Tablets.

Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended-release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. Spearman ρ and Pearson r values were calculated for PD (maximum effect [E ] for "at the moment" Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration-time curve [AUC], maximum drug concentration [C ], time to C [T ], and abuse quotient [PK AQ; C /T ]) for all treatments.

Assessment of Pharmacokinetic and Pharmacodynamic Interactions Between Albumin-Fused Mutated Butyrylcholinesterase and Intravenously Administered Cocaine in Recreational Cocaine Users.

Unlabelled: Cocaine dependence presents a major public health issue, and to date, no pharmacotherapies are approved for its treatment. TV-1380 is a novel recombinant albumin-fused mutated butyrylcholinesterase (Albu-BChE) that has increased catalytic efficiency for cocaine compared with wild-type BChE and therefore has the potential to facilitate abstinence in cocaine-dependent subjects by decreasing exposure to cocaine and its reinforcing effects.

Methods: This randomized, double-blind, placebo-controlled, parallel-group study in nondependent cocaine users was conducted to evaluate the effect of a single intramuscular dose of Albu-BChE (50, 100, and 300 mg) on the pharmacokinetic and metabolic profile of intravenous cocaine infusions (40 mg) administered at baseline and at 24, 96, and 168 hours after Albu-BChE dosing, to assess safety of coadministering Albu-BChE and cocaine, and to explore the subjective responses to cocaine infusions after Albu-BChE dosing.

Use of Remifentanil in a Novel Clinical Paradigm to Characterize Onset and Duration of Opioid Blockade by Samidorphan, a Potent μ-Receptor Antagonist.

A novel clinical study design was used to evaluate the blockade of a selective short-acting μ-opioid agonist (remifentanil) in 24 opioid-experienced subjects. Samidorphan (3-carboxamido-4-hydroxynaltrexone) is a novel opioid modulator with μ-antagonist properties. Objective (pupil diameter) and subjective (visual analog scale) responses to repeated remifentanil and saline infusion challenges were assessed after single oral administration of placebo (day 1) and samidorphan (day 2).

Effects of stressors on the reinforcing efficacy of nicotine in adolescent and adult rats.

Rationale And Objectives: Stress increases drug intake. This depends on the stressor, drug, and aspect of drug seeking assessed. The objectives of these experiments done in adolescent and adult male rats were to (1) examine social defeat effects on acquisition of nicotine self-administration (SA) and the reinforcing efficacy of nicotine and (2) determine the effects of acute exposure to intermittent footshock (FS) or yohimbine on the reinforcing efficacy of nicotine.

Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users.

The objective of this study was to evaluate abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered, crushed reformulated OxyContin® (oxycodone HCl controlled-release) tablets (ORF), relative to crushed original OxyContin® (OC), oxycodone powder (Oxy API), and OC placebo. This randomized, double-blind, positive- and placebo-controlled crossover study enrolled healthy, adult, nonphysically dependent recreational opioid users with recent history of intranasal drug abuse (N = 27). Active treatments contained oxycodone (30 mg).

Sex differences in yohimbine-induced increases in the reinforcing efficacy of nicotine in adolescent rats.

Stress is an important factor in the initiation and maintenance of smoking in adolescents. Women are more vulnerable to the development of addiction to smoking and have more difficulty quitting than men. Women also showe enhanced responses to stress.

Differences in the in vitro and in vivo pharmacokinetic profiles of once-daily modified-release methylphenidate formulations in Canada: examination of current bioequivalence criteria.

Background: Current Canadian bioequivalence criteria rely on rate and extent of drug exposure, that is, C(max) and AUC. In the case of complex modified-release formulations, these criteria may not address pharmacokinetic differences with potential therapeutic and tolerability implications.

Objective: This study was performed to characterize in vitro dissolution and in vivo pharmacokinetic profiles of three modified-release formulations of methylphenidate (MPH) marketed in Canada, two of which meet the criteria for assuming bioequivalence as defined by Health Canada: MPH extended-release (ER-C) and osmotic controlled-release oral-delivery-system (OROS-MPH).

Evaluation of the abuse potential of extended release hydromorphone versus immediate release hydromorphone.

Immediate release (IR) hydromorphone has experienced significant misuse and abuse. An extended release (ER) hydromorphone formulation has been developed to provide sustained pain relief and may reduce the likelihood for abuse by delaying absorption. In this double-blind, placebo-controlled, randomized, 2-part crossover study, the abuse potential of single oral doses of hydromorphone ER (intact: 16-, 32-, and 64-mg; milled: 8-mg) was compared with 8-mg hydromorphone IR and placebo.

Adolescent male Wistar rats are more responsive than adult rats to the conditioned rewarding effects of intravenously administered nicotine in the place conditioning procedure.

The initiation of smoking typically begins during adolescence, suggesting that nicotine may have different motivational effects during this developmental stage compared to adulthood. Studies using the conditioned place preference (CPP) procedure have demonstrated that adolescent rats are more sensitive to the conditioned rewarding effects of subcutaneously administered nicotine compared to adult rats, whereas intravenous self-administration studies have not demonstrated consistent age differences in the reinforcing effects of nicotine. This study was designed to evaluate if intravenously administered nicotine has age-dependent conditioned rewarding effects.

Interactions between age and the aversive effects of nicotine withdrawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats.

Rationale: Adolescent onset of smoking is associated with a rapid progression to dependence. Although adolescents may exhibit a greater susceptibility to nicotine addiction, relatively little is known about the influence of the aversive effects of nicotine withdrawal in maintaining smoking behavior.

Objectives: The present study investigated age differences in the motivational effects of mecamylamine-precipitated and spontaneous nicotine withdrawal in adolescent and adult rats using the conditioned place aversion procedure (CPA).

Age differences in the spontaneous acquisition of nicotine self-administration in male Wistar and Long-Evans rats.

Rationale: Epidemiological evidence suggests that adolescents may exhibit a unique susceptibility to the motivational effects of nicotine compared to adults. In contrast to the hypothesis of an enhanced vulnerability to nicotine during adolescence, we have observed that nicotine is less reinforcing in adolescent compared to adult rats using a progressive ratio reinforcement schedule in an operant self-administration procedure, although prior operant conditioning experience may have masked differences in initial sensitivity to nicotine.

Objectives: This study examined the spontaneous acquisition of nicotine self-administration in adolescent (postnatal day (PD) 31) and adult (PD87) male Wistar and Long-Evans rats.

Nicotine self-administration, extinction responding and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence.

Initiation of smoking behavior typically occurs during adolescence and rarely occurs during adulthood. Despite this epidemiological evidence, relatively little is known about possible neurobiological differences in the response to nicotine in adolescents that might make them more vulnerable to nicotine addiction. In the current study, we assessed nicotine self-administration under fixed ratio (FR) and progressive ratio (PR) reinforcement schedules in adolescent (postnatal day (P) 33-35) and adult (P91-94) rats.

Acute nicotine enhances c-fos mRNA expression differentially in reward-related substrates of adolescent and adult rat brain.

A number of studies have demonstrated that adolescent rodents are more sensitive to the rewarding effects of nicotine compared to adults. To help determine the potential brain circuitry involved, we investigated the effect of acute nicotine administration (0.4 or 0.

Periadolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine.

Rationale: Initiation of tobacco use typically begins during adolescence, and the nature of these first experiences with nicotine may affect the probability of continued use. In rodents, a number of studies suggest that periadolescents are more responsive to the rewarding effects of nicotine compared to adults.

Objectives: This study was designed to determine if there are age differences in the rewarding and aversive effects of nicotine by using the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively.

Motor impairing effects of ethanol and diazepam in rats selectively bred for high and low ethanol consumption in a limited-access paradigm.

Background: Some clinical studies suggest that an initial low-level response in ethanol sensitivity is a good predictor of risk for developing subsequent high levels of ethanol consumption in humans; however, there are some inconsistencies in the data. In experimental research, this association between low ethanol sensitivity and high ethanol intake has not been consistently reported in studies that have used rat lines that have been genetically selected for differences in ethanol intake under continuous access conditions (e.g.