Psychotomimetic effects of PCP, LSD, and Ecstasy: pharmacological models of schizophrenia?

Phencyclidine (PCP), ketamine, LSD, and MDMA have been called psychotomimetics for their ability to induce psychotic symptoms such as hallucinations, delusions, and thought disorder without delirium. PCP clearly can cause lasting psychotic disorder beyond acute intoxication, but LSD and MDMA lack clear evidence of inducing psychotic disorder or schizophrenia in people without preexisting vulnerability. PCP and ketamine act as noncompetitive antagonists of the NMDA glutamate receptor, while LSD is a serotonin 5HT2A receptor agonist and MDMA an indirect serotonin agonist. Animal models using PCP show construct validity for schizophrenia, and ketamine serves as a safe human model, though more translational research is needed.

Study at a glance

Abstract

Facts box Phencyclidine (PCP), ketamine, D-lysergic acid diethylamide (LSD) and 3, 4-methylenedioxy-methamphetamine (MDMA) have been variously referred to as schizophrenomimetics, psychotogens, or psychotomimetics. There have been many reports that these drugs can induce psychotic symptoms (hallucinations, delusions, formal thought disorder, or catatonia-like abnormalities) in the absence of delirium. here is abundant evidence that PCP induces psychotic disorder beyond the acute symptoms of intoxication. There is no clear evidence that either LSD or MDMA induces psychotic disorder, let alone schizophrenia, in individuals who did not have vulnerability to schizophrenia premorbidly. PCP and ketamine are noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) glutamatergic receptor that bind at the intrachannel site of the receptor to prevent calcium ion flux into the cell. LSD is a serotonin-like hallucinogenic indoleamine that acts as an agonist at the serotonin-subtype-2A (5HT2A) receptor, and MDMA is an indirect serotonin agonist. Rodent and primate models induced by PCP and analogues have been presented as models of human schizophrenia, with construct validity, showing homologous behavior, cognitive deficits, alterations in regional brain activation, and underlying neuronal dysfunction, to PCP-induced psychotomimetic effects in healthy volunteers and patients with schizophrenia. Ketamine is considered to be a safe and valid model of PCP psychosis and applicable to preclinical human studies. More translational science is needed to relate animal findings to humans and vice versa. In this chapter, the potential role of glutamatergic and serotonergic neurotransmitter systems in the pathophysiology of schizophrenia is examined from the perspective of the psychotomimetic effects of i) phencyclidine (PCP) and ketamine, noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) glutamatergic receptor that bind at the intrachannel site of the receptor to prevent calciumion flux into the cell; ii) D-lysergic acid diethylamide (LSD), a serotonin-like hallucinogenic indoleamine that acts as an agonist at the serotonin-subtype-2A (5HT2A) receptor; and iii) 3, 4-methylenedioxy-methamphetamine (MDMA), an indirect serotonin agonist.