New Paradigms of Old Psychedelics in Schizophrenia

Danish Mahmood; Sattam K Alenezi; Md Jamir Anwar; Faizul Azam; Kamal A Qureshi; Mariusz Jaremko

doi:10.3390/ph15050640

New Paradigms of Old Psychedelics in Schizophrenia

Pharmaceuticals (Basel). 2022 May 23;15(5):640. doi: 10.3390/ph15050640.

Authors

Danish Mahmood¹, Sattam K Alenezi¹, Md Jamir Anwar¹, Faizul Azam², Kamal A Qureshi³, Mariusz Jaremko⁴

Affiliations

¹ Department of Pharmacology & Toxicology, Unaizah College of Pharmacy, Qassim University, Unaizah 51911, Saudi Arabia.
² Department of Pharmaceutical Chemistry & Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unaizah 51911, Saudi Arabia.
³ Department of Pharmaceutics, Unaizah College of Pharmacy, Qassim University, Unaizah 51911, Saudi Arabia.
⁴ Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia.

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.

Publication types

Review

Grants and funding

The APC was funded by King Abdullah University of Science and Technology (KAUST), Thuwal, Jeddah, Saudi Arabia.