Opioid-hallucinogen interactions

Abstract

Before the advent of neuroleptics, opioids such as morphine were used occasionally in the treatment of schizophrenia and other mental disorders. Recent interest in the possible therapeutic role of endogenous opioid peptides in various mental states has prompted a new look at the opioids. The present paper summarizes the research to date in the author's laboratory on opioid-hallucinogen interactions. A model behavioral state was induced in rats with N,N-dimethyltryptamine (DMT) or lysergic acid diethylamide-25 (LSD). Several mu opioid agonists, antagonists, and synthetic enkephalin analogs interacted with DMT and LSD. Adult male Holtzman rats trained on a positive reinforcement fixed ratio four (FR4) behavioral schedule (i.e., a reward of 0.01 ml sugar-sweetened milk was earned on every fourth bar press) were used in these studies. DMT (3.2 and 10.0 mg/kg) given with a 0.9% NaCl pretreatment IP, disrupted established food rewarded FR4 bar pressing behavior in a dose related fashion. 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.(ABSTRACT TRUNCATED AT 250 WORDS)