Establishing an animal model of schizophrenia faces difficulties. After reviewing evidence on experimental psychopathology, particularly attention and arousal, the core feature needing modeling is some aspect of 'input dysfunction.' LSD-25 best meets this requirement because its 'model psychosis' closely parallels the natural disease, and its experimental effects in animals and humans align theoretically with schizophrenia. Work from the author's laboratory found LSD produced psychophysiological effects virtually identical to those in acute psychotic patients and normal subjects with high 'psychotic' personality traits. Rejection of LSD as a drug model was premature, especially since the preference for amphetamine has not been vindicated by its ability to mimic a central feature of psychosis or by work on dopamine as a common mediator.
LSD was once considered a potential chemical key to understanding schizophrenia but was rejected as a drug model for human psychosis, while the amphetamine model gained preference. The rejection was influenced not only by scientific factors but also by psychiatry's and society's growing disaffection with existentialist interpretations of schizophrenia, which LSD was associated with as a recreational drug. The proscription of LSD and a shift toward an organic view of schizophrenia made the simpler amphetamine (dopamine) model more acceptable. Flaws in the dopamine model and challenges from a more psychobiological approach suggest a need for a more elaborated neurochemical account, including central serotonergic influences, which could restore LSD's utility in schizophrenia research.