Advances and pathophysiological models of hallucinogenic drug actions in humans: A preamble to schizophrenia research

Recent research into the pharmacological mechanism of hallucinogens (LSD, psilocybin) and dissociative anesthetics (PCP, ketamine) suggest that multiple neurotransmitter systems are involved in drug-induced and possibly also in naturally occurring psychoses. Specifically, animal models suggest that a dysbalance between serotonin, glutamate, and dopamine in the limbic cortico-striato-thalamic circuitry may be critical to psychotic symptom formation. To test this hypothesis, psychometric measures and metabolic PET investigations were performed (1) with FDG to elucidate the common neuronal substrates of different hallucinogens, (2) with specific receptor ligands before and after pretreatment with specific receptor antagonists to explore the putative interactions of hallucinogens with various neurotransmitter systems. Our data demonstrate that the neuronal substrate of normal and abnormal thought and behavior is associated with a distributed neuronal network and with multiple interactive neurotransmitter systems. The data also support the view that the hallucinogen challenge paradigm constitutes a powerful tool for elucidating the pathophysiology of neuropsychiatric disorders.