The purpose of this study was to determine whether marijuana produced dose-dependent antinociception in humans and, if so, whether endogenous opiates modulate this effect. A total of five male regular marijuana users participated in three test sessions during which they smoked cigarettes containing 0% (placebo) and 3. 55% Delta(9)-tetrahydrocannabinol (Delta(9)-THC) (active). Each of four controlled smoking bouts per session, spaced at 40-min intervals, consisted of nine puffs from active and placebo cigarettes (three cigarettes, three puffs per cigarette, one puff per min). During successive bouts, participants smoked 0, 3, 6 and 9 (0, 3, 9 and 18 cumulative) puffs from active marijuana cigarettes, with the remainder of puffs from placebo cigarettes. Test sessions were identical, except for naltrexone 0, 50 or 200 mg p.o. (randomized, double-blind) administration 1 h before the first smoking bout on the different days. Before smoking, between smoking bouts and postsmoking, participants completed an assessment battery that included antinociceptive (finger withdrawal from radiant heat stimulation), biological, subjective, observer-rated signs and performance measures. Marijuana produced significant dose-dependent antinociception (increased finger withdrawal latency) and biobehavioral effects. Naltrexone did not significantly influence marijuana dose-effect curves, suggesting no role of endogenous opiates in marijuana-induced antinociception under these conditions.