Relative abuse liability of indiplon and triazolam in humans: a comparison of psychomotor, subjective, and cognitive effects.

Indiplon [N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-alpha]pyrimidin-7-yl]phenyl]acetamide; NBI 34060] is a positive allosteric GABA(A) receptor modulator that is under development for the treatment of insomnia. This study compared the abuse potential of indiplon, a compound with preferential affinity for GABA(A) receptors containing an alpha(1) subunit, with triazolam in 21 volunteers with histories of drug abuse. Placebo, triazolam (0.25, 0.5, and 0.75 mg), and indiplon (30, 50, and 80 mg) were studied in counterbalanced order under double-blind conditions at two different residential research facilities. Both drugs impaired psychomotor and cognitive performance and produced similar dose-related increases in participant and observer ratings of drug strength. The onset of action of both drugs was rapid (30 min); however, the duration of action of indiplon (3-4 h) was shorter than that of triazolam (4-6 h). The profiles of subjective effects of triazolam and indiplon were similar; however, a maximum of 52% of participants identified indiplon as a benzodiazepine or barbiturate, compared with 81% of participants after 0.75 mg of triazolam. On participantrated subjective effects relevant to sedation, the slope of the triazolam dose-effect curve was significantly steeper than that of indiplon. Neither the largest doses of indiplon and triazolam nor the slope of the indiplon and triazolam dose-effect curves were significantly different from each other on any of the same-day or next-day measures of positive drug effects or next-day measures of reinforcing effects. Together, these data suggest that although the abuse potential of indiplon is not different from that of triazolam at these doses, psychomotor and cognitive impairment after large doses of indiplon might be less.

Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects.

CONTEXT: Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for insomnia treatment. Most approved insomnia medications have potential for abuse and cause motor and cognitive impairment. OBJECTIVE: To evaluate the potential for abuse, subjective effects, and motor and cognitive-impairing effects of ramelteon compared with triazolam, a classic benzodiazepine sedative-hypnotic drug. DESIGN: In this double-blind crossover study, each participant received oral doses of ramelteon (16, 80, or 160 mg), triazolam (0.25, 0.5, or 0.75 mg), and placebo during approximately 18 days. All participants received each treatment on different days. Most outcome measures were assessed at 0.5 hours before drug administration and repeatedly up to 24 hours after drug administration. SETTING: Residential research facility. PARTICIPANTS: Fourteen adults with histories of sedative abuse. MAIN OUTCOME MEASURES: Subject-rated measures included items relevant to potential for abuse (eg, drug liking, street value, and pharmacological classification), as well as assessments of a broad range of stimulant and sedative subjective effects. Observer-rated measures included assessments of sedation and impairment. Motor and cognitive performance measures included psychomotor and memory tasks and a standing balance task. RESULTS: Compared with placebo, ramelteon (16, 80, and 160 mg) showed no significant effect on any of the subjective effect measures, including those related to potential for abuse. In the pharmacological classification, 79% (11/14) of subjects identified the highest dose of ramelteon as placebo. Similarly, compared with placebo, ramelteon had no effect at any dose on any observer-rated or motor and cognitive performance measure. In contrast, triazolam showed dose-related effects on a wide range of subject-rated, observer-rated, and motor and cognitive performance measures, consistent with its profile as a sedative drug with abuse liability. CONCLUSION: Ramelteon demonstrated no significant effects indicative of potential for abuse or motor and cognitive impairment at up to 20 times the recommended therapeutic dose and may represent a useful alternative to existing insomnia medications.

Task-to-Task Vagal Regulation: Relations With Language and Play in 20-Month-Old Children.

In this article we report patterns of task-to-task vagal tone change across multiple language and play tasks as well as associations between these patterns of task-to-task vagal tone change and language and play performance in 20-month-old girls and boys. Although initially different in vagal tone suppression during solitary play, girls and boys exhibited similar group patterns of vagal reengagement during successive language and play tasks with their mothers and with an experimenter. In terms of individual differences, vagal suppression during solitary play and vagal reengagement during social interactive tasks predicted language and play performance. Gender differences emerged in patterns of predictive relations: Task-to-task vagal changes predicted primarily play performance in girls and language performance in boys. These findings expose the effects of social context on directional changes in task-to-task vagal tone and speak to the functional role of appropriate vagal regulation in young children's language and play performance.