We generated dose-response data for the endogenous and ultra-short-acting hallucinogen, N,N-dimethyltryptamine (DMT), in a cohort of experienced hallucinogen users, measuring multiple biological and psychological outcome measures. Subjective responses were quantified with a new rating scale, the HRS, which provided better resolution of dose effects than did the biological variables. A tolerance study then was performed, in which volunteers received four closely spaced hallucinogenic doses of DMT. Subjective responses demonstrated no tolerance,while biological measures were inconsistently reduced over the course of the sessions.Thus, DMT remains unique among classic hallucinogens in its inability to induce tolerance to its psychological effects. To assess the role of the 5-HT site in mediating DMT's effects, a pindolol pre-treatment study was performed. Pindolol significantly increased psychological responses to DMT, suggesting a buffering effect of 5-HT agonism on 5-HT2-mediated psychedelic effects.These data are opposite to those described in lower animal models of hallucinogens'mechanisms of action.