New Paradigms of Old Psychedelics in Schizophrenia

Psychedelics like LSD, psilocybin, and mescaline produce intense effects on the brain and behavior and have recently shown efficacy in treating conditions such as anxiety, depression, mood disorders, obsessive-compulsive disorders, suicidal ideation, posttraumatic stress disorder, and substance use disorders when administered in low, medically supervised doses. Their primary mode of action involves activating serotonin 5-HT2A receptors, which modulates cognition and brain connectivity through downstream signaling pathways. Atypical antipsychotic drugs also target these receptors, and both psychedelics and some antipsychotics may act via a common serotonin–glutamate receptor interaction in cortical pyramidal neurons. Emerging hypotheses propose that psychedelics work through brain resetting mechanisms, highlighting the need for deeper research into their neurobiology to benefit psychiatric disorders including schizophrenia.

Study at a glance

Abstract

Psychedelics such as lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), and mescaline exhibit intense effects on the human brain and behaviour. In recent years, there has been a surge in studies investigating these drugs because clinical studies have shown that these once banned drugs are well tolerated and efficacious in medically supervised low doses called microdosing. Psychedelics have demonstrated efficacy in treating neuropsychiatric maladies such as difficult to treat anxiety, depression, mood disorders, obsessive compulsive disorders, suicidal ideation, posttraumatic stress disorder, and also in treating substance use disorders. The primary mode of action of psychedelics is activation of serotonin 5-HT2A receptors affecting cognition and brain connectivity through the modulation of several downstream signalling pathways via complex molecular mechanisms. Some atypical antipsychotic drugs (APDs) primarily exhibit pharmacological actions through 5-HT2A receptors, which are also the target of psychedelic drugs. Psychedelic drugs including the newer second generation along with the glutamatergic APDs are thought to mediate pharmacological actions through a common pathway, i.e., a complex serotonin–glutamate receptor interaction in cortical neurons of pyramidal origin. Furthermore, psychedelic drugs have been reported to act via a complex interplay between 5HT2A, mGlu2/3, and NMDA receptors to mediate neurobehavioral and pharmacological actions. Findings from recent studies have suggested that serotoninergic and glutamatergic neurotransmissions are very closely connected in producing pharmacological responses to psychedelics and antipsychotic medication. Emerging hypotheses suggest that psychedelics work through brain resetting mechanisms. Hence, there is a need to dig deeply into psychedelic neurobiology to uncover how psychedelics could best be used as scientific tools to benefit psychiatric disorders including schizophrenia.