Pharmacodynamic and pharmacokinetic effects of the intravenously administered CB1 receptor agonist Org 28611 in healthy male volunteers.

CB1/CB2 agonists are reported to have sedative, amnestic, analgesic and anti-emetic properties, which would make them ideal drugs for outpatient treatments under conscious sedation. The main objective of this in human study was to assess the sedative properties of Org 28611, a potent water-soluble CB1 agonist. Single ascending doses were administered during a slow 25 min infusion and after a 1 min bolus administration to healthy male volunteers. In addition, the pharmacokinetics, amnestic properties, postural stability, electro-encephalography, behavioural and cardiovascular effects were studied. Midazolam 0.1 mg/kg was used as a positive control. The pharmacokinetic parameters were proportional to dose. No effects were observed after intravenous administration of doses up to Org 28611 1 microg/kg. Dose-related effects were observed at higher doses. Although subjects reported subjective sedation after administration of Org 28611 3-10 microg/kg, the observed sedation was considerably less than after midazolam. Org 28611 is, therefore, not suitable for providing sedation for outpatient surgical procedures and doses above the maximum tolerated dose of 3 microg/kg (either administered as a slow infusion or a bolus dose) can cause untoward psychotropic effects.