Molecular and Medical Aspects of Psychedelics

Psychedelics, among the oldest psychoactive drugs, are gaining renewed interest for treating depression, substance use disorders, anxiety, and obsessive-compulsive disorder. This review summarizes preclinical research on the mechanisms, neurotoxicity, and behavioral effects of psychedelics, focusing on the selective 5-HT2A receptor agonists 25I- and 25B-NBOMe compared to the less selective drug psilocybin. NBOMes significantly increased glutamatergic, dopaminergic, serotonergic, and cholinergic neurotransmission in the frontal cortex, striatum, and nucleus accumbens, though not dose-dependently, likely due to 5-HT2A and subsequent 5-HT2C receptor activation.

Study at a glance

Abstract

Psychedelics belong to the oldest psychoactive drugs. They arouse recent interest due to their therapeutic applications in the treatment of major depressive disorder, substance use disorder, end-of-life anxiety,= and anxiety symptoms, and obsessive–compulsive disorder. In this review, the current state of preclinical research on the mechanism of action, neurotoxicity, and behavioral impact of psychedelics is summarized. The effect of selective 5-HT2A receptor agonists, 25I- and 25B-NBOMe, after acute and repeated administration is characterized and compared with the effects of a less selective drug, psilocybin. The data show a significant effect of NBOMes on glutamatergic, dopaminergic, serotonergic, and cholinergic neurotransmission in the frontal cortex, striatum, and nucleus accumbens. The increases in extracellular levels of neurotransmitters were not dose-dependent, which most likely resulted from the stimulation of the 5-HT2A receptor and subsequent activation of the 5-HT2C receptors. This effect was also observed in the wet dog shake test and locomotor activity. Chronic administration of NBOMes elicited rapid development of tolerance, genotoxicity, and activation of microglia. Acute treatment with psilocybin affected monoaminergic and aminoacidic neurotransmitters in the frontal cortex, nucleus accumbens, and hippocampus but not in the amygdala. Psilocybin exhibited anxiolytic properties resulting from intensification of GABAergic neurotransmission. The data indicate that NBOMes as selective 5-HT2A agonists exert a significant effect on neurotransmission and behavior of rats while also inducing oxidative DNA damage. In contrast to NBOMes, the effects induced by psilocybin suggest a broader therapeutic index of this drug.