The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology

Abstract

The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.

Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential

“…Classical (serotonergic) psychedelics have undergone a resurgence of interest for their potential to produce rapid and sustained therapeutic effects 1,2 . The therapeutic properties of psychedelics are being explored both preclinically and clinically, but studies have focused on a limited number of compounds 3,4 . Psychedelics may be limited by their hallucinogenic effects, which can cause confusion and anxiety in some patients, necessitating close clinical supervision.…”

Cardiovascular safety of psychedelic medicine: current status and future directions

“…Further animal and human studies have shown that different efficacy at 5-HT2A receptors is a key pharmacological mechanism responsible for the psychedelic effects [22][23][24] and that different psychedelic substances also have affinities for other receptors: serotonergic, dopaminergic, glutamatergic, adrenergic, and histaminergic [25][26][27][28]. Psychedelic stimulation of 5-HT2A receptors disrupts the cortical rhythm and large-scale brain networks through an increase in neocortical neuron excitation and subsequent augmentation of extracellular glutamate release in the prefrontal cortex [21,29,30].…”

An Overview on the Hallucinogenic Peyote and Its Alkaloid Mescaline: The Importance of Context, Ceremony and Culture

“…Since the 1870s, the peyote cult has spread among the indigenous cultures of North America and is essential to the rituals of the Native American Church (NAC), founded in 1914 [98,99]. The plant is not conceived as a hallucinogen, but as a "teacher"; there is no distinction between medicine and religion, nor a separation between body and mind [100][101][102]. Thus, a special religious cult was created around peyote in the Native American Church (NAC) [102][103][104].…”