Tolerance of the behavioral effects of the short-acting, endogenous hallucinogen, N,N-dimethyltryptamine (DMT) is seen inconsistently in animals, and has not been produced in humans. The nature and time course of responses to repetitive, closely spaced administrations of an hallucinogenic dose of DMT were characterized. Thirteen experienced hallucinogen users received intravenous 0.3 mg/kg DMT fumarate, or saline placebo, four times, at 30 min intervals, on 2 separate days, in a randomized, double-blind, design. Tolerance to "psychedelic" subjective effects did not occur according to either clinical interview or Hallucinogen Rating Scale scores. Adrenocorticotropic hormone (ACTH), prolactin, cortisol, and heart rate responses decreased with repeated DMT administration, although blood pressure did not. These data demonstrate the unique properties of DMT relative to other hallucinogens and underscore the differential regulation of the multiple processes mediating the effects of DMT.