Abstract
d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles’ reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD’s mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT2A receptor as a partial agonist and 5-HT1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D2, Trace Amine Associate receptor 1 (TAAR1) and 5-HT2A. More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD’s effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR1 receptors.
Highlights
IntroductionLysergic Acid Diethylamide (LSD) has potent psychotropic effects, described as inducing “mystical experiences” [3]; alterations of the state of consciousness, euphoria, enhanced capacity for introspection, altered psychological functioning, a sense of unity, transcendence of time and space, and positive mood; feelings of joy, blessedness and peace; a sense of sacredness; and a positive attitude towards others and the self [2,4,5,6]
Lysergic Acid Diethylamide (LSD) (3–100 nM) excites GABAergic interneurons in the layer III of rat pyriform cortex; the effect is blocked by the 5-HT2A antagonist MDL 100 907 [112]; 5HT2 antagonist LY 53857 reverts the inhibitory effect of systemic administration of LSD (5–10 μg/kg) on the spontaneous activity of Locus Coeruleus (LC) neurons in rats [110]
There is a paucity of recent human studies and clinical reports concerning LSD-induced psychotic effects, preclinical and clinical studies suggest that LSD-induced psychosis may represent a valid model of psychosis that may allow researchers to investigate the pathogenesis of psychosis and the effectiveness of novel antipsychotic drugs that act through synergistic effects on the serotonergic and dopaminergic systems
Summary
LSD has potent psychotropic effects, described as inducing “mystical experiences” [3]; alterations of the state of consciousness, euphoria, enhanced capacity for introspection, altered psychological functioning, a sense of unity, transcendence of time and space, and positive mood; feelings of joy, blessedness and peace; a sense of sacredness; and a positive attitude towards others and the self [2,4,5,6] It stimulates the sympathetic system, causing hyperthermia, sweating, palpitation, the elevation of blood pressure, convulsions, an increase in muscle tension, tremors, and muscular incoordination [7,8,9]. One of the main effect of LSD is the mystical experience and the “transcendence of time and space”, meaning that the subject feels himself to be beyond past, present, and future, and beyond ordinary three-dimensional space; the subject feels himself to exist in a realm of eternity or infinity [10]
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