title: Modulation of rate of onset and intensity of drug effects reduces abuse potential in healthy males.
abstract: Low, medium, and high doses of flunitrazepam were tested in three independent randomized, double-blind, balanced cross-over, placebo-controlled trials to study the influence of rate of onset of effects and dose administered on its acute effects. Three groups of 12 healthy male volunteers received six oral doses of placebo or flunitrazepam in slow and fast onset conditions as follows: six capsules of 0.16 mg (slow) and a single capsule of 0.8 mg (fast) in the low dose trial; six 0.25 mg (slow) and a single 1.25 mg (fast) capsules for medium dose; and six 0.4 mg (slow) and a single 2 mg (fast) capsule for high dose. At each dose level, slow or fast increasing flunitrazepam plasma concentrations lead to similar peak levels, but induced differential subjective and behavioral effects. In addition to objective and subjective sedation, flunitrazepam induced some pleasurable feelings, which were more intense in the fast than in the slow conditions. At the highest dose, unpleasant sedative effects surmounted positive effects, while at the lowest dose pleasurable effects were of low intensity. At the medium dose, the balance between pleasurable and unpleasant feelings resulted in euphorigenic effects, which were evident in the fast condition but were blunted in the slow condition.
authors.affiliation: Pharmacology Research Unit, Institut Municipal d'Investigació Mèdica, Carrer Doctor Aiguader 80, Universitat Autònoma de Barcelona, Universitat Pompeu Fabra, E-08003 Barcelona, Spain.
authors.forename: P N
authors.initials: PN
authors.lastname: Roset
authors.forename: M
authors.initials: M
authors.lastname: Farré
authors.forename: R
authors.initials: R
authors.lastname: de la Torre
authors.forename: M
authors.initials: M
authors.lastname: Mas
authors.forename: E
authors.initials: E
authors.lastname: Menoyo
authors.forename: C
authors.initials: C
authors.lastname: Hernández
authors.forename: J
authors.initials: J
authors.lastname: Camí
mesh_terms: D000293:Adolescent; D000328:Adult; D000339:Affect / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000097:blood; D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005445:Flunitrazepam / Q000008:administration & dosage* / Q000097:blood; D006801:Humans; D008297:Male; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D012054:Reinforcement, Psychology; D019966:Substance-Related Disorders / Q000097:blood / Q000517:prevention & control* / Q000523:psychology
chemical_list: D014151:Anti-Anxiety Agents; D005445:Flunitrazepam