New Paradigms of Old Psychedelics in Schizophrenia

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-HT_2A 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-HT_2A 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 5HT_2A, 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.

Keywords: LSD-like drugs; glutamate; mGl2/3 receptors; psychedelics; schizophrenia; serotonin.

Figure 1

Neurobiological mechanisms of action of psychedelic drugs beside 5HT_2A agonism. Psychedelic drugs mediate increase expression of gene relating to synaptic plasticity in the brain initiating downstream neuronal signaling leading to the activation of neurones showing high expression of 5-HT_2A receptors in the brain regions such as claustrum and frontal cortex, and which underlie changes in the cortical network and entropic brain activity using psychedelics. The changes in brain activity may lead to the subjective psychedelic experience such as mystic feeling, perceptual changes, increase positive mood and therapeutic efficacy in depression, psychosis, etc. Arc: activity-regulated cytoskeleton-associated protein; Egr1 and Egr2: early growth response protein 1 and 2; cFos: a marker of neuronal activation [56].

Figure 2

(a): The diagrammatic elucidation of the neuronal circuits mediating the responses of psychoactive chemicals and APDs. 5-HT_2A–mGlu2 receptor complexes expressed by cortical pyramidal neurons are believed to be the site of action for both psychoactive 5-HT_2A receptor agonists and mGlu2 receptor antagonists, in addition to antipsychotic 5-HT2A receptor antagonists and mGlu2 receptor agonists [51]. (b): The diagrammatic elucidation of the neuronal circuits mediating the responses of psychoactive chemicals and APDs. PCP-like psychoactive drugs activate subcortical NMDA receptors to mediate the release of serotonin and glutamate in the cortex, which is believed to affect the signalling activities of cortical 5-HT_2A–mGlu2 receptor complexes [51].