Pre-determined behaviorally ineffective doses of mu opioid agonists showed selective biphasic effects against DMT and LSD. Low doses antagonized the effects of both hallucinogens, whereas larger doses enhanced their effects. In contrast to the antagonistic effects of low doses of mu opioid agonists, the mu-kappa opioid antagonist (−)-naloxone enhanced the effects of DMT and LS. (−)-Naloxone enhanced the effects of DMT and LSD. Potentiation of DMT-induced behavioral disruption was attributed to a stereospecific opioid antagonist effect of (−)-naloxone in that the (+)-naloxone enantiomer failed to potentiate the effects of DMT. Further studies are indicated to determine hallucinogen-opioid interactions in various species, including man. The present findings reinforce a possible antagonist role of opioid substances in mental processes involving hallucinations.