Assessment of human abuse potential of dasotraline compared to methylphenidate and placebo in recreational stimulant users.

AIMS: The aim of this study was to evaluate the abuse potential of dasotraline, a novel dopamine and norepinephrine reuptake inhibitor with slow absorption (tmax, 10-12h) and elimination (t1/2=47-77 h) that is in development for the treatment of attention deficit hyperactivity disorder (ADHD). METHODS: Recreational stimulant users (N=48) who had specific experience with cocaine, and who were able to distinguish methylphenidate (60 mg) versus placebo in a qualification session, were randomized, in a 6-period, double-blind, crossover design, to receive single doses of dasotraline 8 mg, 16 mg, and 36 mg, methylphenidate (MPH) 40 mg and 80 mg, and placebo. The primary endpoint was the Drug Liking Visual Analog Scale (VAS) score at the time of peak effect (Emax). RESULTS: There were no significant differences between the 3 doses of dasotraline and placebo on the drug liking VAS at Emax, and on most secondary endpoints. Both doses of MPH had significantly higher VAS-drug liking scores at Emax relative to both placebo (P<0.001 for all comparisons) and dasotraline 8 mg (P<0.001), 16 mg (P<0.001) and 36 mg (P<0.01). The increase in heart rate for MPH and dasotraline 36 mg showed a time-course that closely matched subject-rated measures such as Any Effects VAS. CONCLUSIONS: In this study, dasotraline was found to have low potential for abuse, which may be, in part, related to its established pharmacokinetics (PK) profile, which is characterized by slow absorption and gradual elimination.

Update on tamper-resistant drug formulations.

An expert panel convened in 2005 by the College on Problems of Drug Dependence (CPDD) to consider strategies to reduce the risk of prescription medication abuse concluded that drug formulation plays a significant role in determining risk of abuse. Efforts on the part of the pharmaceutical industry to develop drugs that deter abuse have focused primarily on opioid formulations resistant to common forms of tampering, most notably crushing or dissolving the tablet to accelerate release. Several opioid formulations developed to be tamper resistant have been approved, but the US Food and Drug Administration has not approved explicit label claims of abuse deterrence and has stated that any such claim will require substantial postmarketing data. Drug development efforts in this area raise questions about the relative impact of abuse-deterrent formulations, not only on individuals who might abuse a medication, but also on patients who are compliant with therapy. This review discusses progress since the 2005 CPDD meeting with an emphasis on opioids. Articles cited in the review were identified via a PubMed search covering the period between January 1, 2000, and October 5, 2011. Scientific work presented by the authors and their colleagues at meetings held through May 2012 also was included. Published literature suggests that development of abuse-deterrent products will require broad public health support and continued encouragement from regulatory authorities so that such products will become the expected standard of care for certain drug classes.

Evaluation of the abuse potential of lorcaserin, a serotonin 2C (5-HT2C) receptor agonist, in recreational polydrug users.

Lorcaserin is a selective and potent serotonin 2C receptor subtype (5-HT(2C)) agonist under development for the treatment of obesity. This study assessed the drug's abuse potential on the basis of its pharmacological profile. For this purpose, a double-blind, double-dummy, placebo-controlled, randomized seven-way crossover study with single oral doses of lorcaserin (20, 40, and 60 mg), zolpidem (15 and 30 mg), ketamine (100 mg), and placebo was conducted in recreational polydrug users (N = 35). Subjective and objective measures were assessed up to 24 h after the dose. We found that zolpidem and ketamine had significantly higher peak scores relative to placebo on the primary measures as well as on most of the secondary measures. The subjective effects of a 20-mg dose of lorcaserin were similar to those of placebo, whereas supratherapeutic doses of lorcaserin were associated with significant levels of dislike by users as compared with placebo, zolpidem, and ketamine. Perceptual effects were minimal after administration of lorcaserin and significantly lower than after administration of either ketamine or zolpidem. The findings suggest that, at supratherapeutic doses, lorcaserin is associated with distinct, primarily negative, subjective effects and has low abuse potential.

Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users.

Tesofensine is a (triple) reuptake inhibitor of noradrenaline, dopamine, and serotonin that is in development for the treatment of obesity. The abuse potential of triple reuptake inhibitors is not yet known, and so this study was undertaken to evaluate the potential abuse-related effects of tesofensine in humans. It was designed as a single-dose, randomized, double-blind, crossover study involving tesofensine vs. placebo, D-amphetamine (positive control for dopaminergic/stimulant effects), bupropion, and atomoxetine (negative/unscheduled controls) in recreational stimulant users (N = 52). Subjective and objective measures were assessed for 48 h after drug administration. The study results show that the effects of D-amphetamine were significantly greater than those of placebo on all primary and secondary subjective measures. The effects of tesofensine were not significantly different from those of placebo and were lower than those of D-amphetamine 30 mg on all primary and most secondary measures. The effects of tesofensine were either lower than or not different from those of bupropion or atomoxetine. These results demonstrate that the abuse potential for tesofensine is no greater than that of bupropion or atomoxetine, and tesofensine is therefore unlikely to be recreationally abused.

Assessing abuse liability during drug development: changing standards and expectations.

As public health concerns have changed, regulatory expectations for assessing abuse liability of new central nervous system (CNS) drugs have increased. All CNS-active drugs with any properties indicating stimulant, depressant, hallucinogenic, or mood-elevating effects will require an evaluation of abuse liability. Abuse liability assessment involves the collection, analysis, and interpretation of data on chemistry and tampering, animal behavioral pharmacology, clinical trial adverse events (AEs), diversion and overdose, and potentially reinforcing (subjective) effects in recreational drug users.

Induction of CYP2B1/2 and nicotine metabolism by ethanol in rat liver but not rat brain.

A higher proportion of alcoholics than non-alcoholics smoke (>80 vs 30%). In animals, chronic administration of alcohol induces tolerance to some effects of nicotine. To investigate if chronic ethanol (EtOH) induces alterations in CYP2B1/2 and nicotine C-oxidation activity, male rats (N = 4-6/group) were treated once daily with saline or EtOH (0.3, 1.0, and 3.0 g/kg, p.o./by gavage) for 7 days. A quantitative immunoblotting assay was developed to detect CYP2B1/2 in the brain, where constitutive expression is low, and in the liver. Using this method, it was determined that EtOH did not alter CYP2B1/2 protein expression significantly in six brain regions (olfactory bulbs, olfactory tubercles, frontal cortex, hippocampus, cerebellum, and brainstem). However, a dose-dependent induction of CYP2B1/2 protein expression was detected in the liver. Significant induction of 2-, 3-, and 2.7-fold were observed for the 0.3, 1.0, and 3.0 g/kg doses, respectively. Increases were also observed in CYP2B1 mRNA, which was induced by 14, 38, and 43% at the same doses. Liver microsomal nicotine C-oxidation also was increased (1.3 to 4.5-fold). CYP2B selective inactivators demonstrated that approximately 70% of nicotine C-oxidation was mediated by CYP2B1/2 in both EtOH-induced and uninduced hepatic microsomes. In summary, chronic, behaviorally relevant doses of EtOH induce CYP2B1/2 protein, mRNA, and nicotine C-oxidation activity in rat liver but not in rat brain, and these increases could contribute to cross-tolerance and co-abuse of ethanol and nicotine.