Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities

Abstract

Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease.

Psychedelics

“…These data also demonstrate the mediation of the serotonin 5-HT 2A receptor in the immune response. Szabo (2015) recently proposed that the psychedelic tryptamines N,N-DMT and 5-MeO-DMT may have immunomodulatory effects mediated through the s-1 receptor. Pretreatment of human primary monocytederived dendritic cells with 100 mM DMT or 5-MeO-DMT was able significantly to attenuate the production of proinflammatory cytokines after treatment of the cells with bacterial lipopolysaccharide or high molecular weight polyinosinic/polycytidylic acid.…”

“…Pretreatment of human primary monocytederived dendritic cells with 100 mM DMT or 5-MeO-DMT was able significantly to attenuate the production of proinflammatory cytokines after treatment of the cells with bacterial lipopolysaccharide or high molecular weight polyinosinic/polycytidylic acid. Szabo (2015) concluded that dimethyltryptamines may serve as important regulators of both innate and adaptive immunity.…”

Trace Amines and Their Receptors

“…DMT is perhaps the most widely studied of the N-methyl derivatives due to its potent hallucinogenic properties, which likely have a polypharmacological basis (Carbonaro and Gatch, 2016). In addition to neural effects, DMT also appears to possess immunomodulatory properties (Szabo, 2015).…”

Clinical applications of hallucinogens: A review.

“…Along these lines, Szabo (2015) suggested a possible therapeutic role for psychedelics in modulating immune function and reducing inflammation, potentially through sigma-1 receptor mediated pathways. These claims are consistent with preclinical data showing administration of the 5-HT 2A R agonist (R)-2,5-dimethoxy-4-iodoamphetamine (R-DOI) greatly suppresses tumor necrosis factor alpha (TNF-α) induced inflammation in vitro (Yu et al, 2008), and in vivo (Nau et al, 2013).…”