Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities

This review (2015) describes the immunomodulatory potential of classical serotonergic psychedelics (DMT, LSD, MDMA, etc) from a perspective of molecular immunology and pharmacology. With a particular focus on functional interaction of serotonin and sigma-1 receptors and cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signalling.

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.”

Author: Attila Szabo

Summary

Psychedelics have been shown to have significant modulatory effects on immune responses, including inflammation, cellular proliferation, and cell survival, via activating NF-B and mitogen-activated protein kinases. These effects could be used for the treatment of diseases such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease.

Introduction

Psychedelics are psychoactive substances that alter cognition and perception by triggering neurotransmitter receptors in the brain. They are often considered as “classical psychedelics” and may have therapeutic effects in treating many psychiatric disorders.

The biomedical Renaissance of psychedelic research began about a decade ago with the identification of neuro-immune communication in mammals. This discovery added an entirely new aspect to the biomedical paradigm.

Several naturally occurring psychedelics have been used as a form of traditional medicine by indigenous people since centuries or even millennia. These remedies exert many beneficial effects on the human body, but the amount of evidence-based, rigorous scientific data about the immunomodulatory functions of psychedelic substances has been scarce to date.

Molecular Basics of Serotonin and Sigma Receptor Signaling

Classical psychedelics exhibit agonistic activity at the 5-hydroxytryptamine (5-HT)/serotonin receptor 5-HT1A and 5-HT2A-C classes, which are G-protein-coupled receptors with analogous biochemical architecture. These receptors activate multiple signaling pathways, including the transcription factor nuclear factor-B (NF-B).

Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) recognize pathogenic structures and transduce signals through the NF-B/IRF pathways. 5-HTRs and sigmar-1 can use cPKC and Akt to interfere with PRR-mediated NF-B and MAPK signaling.

5-HT2A stimulates COX-2 activity and TGF- release via the ERK MAPK pathway. This leads to the nuclear translocation of STAT3. The human 5-HT2B receptor, which has 45% structural homology with the 5-HT2A and 42% homology with the 5-HT2C subtypes, is widely expressed not only in the brain but also in many peripheral tissues. It can activate the Ras and ERK1/ERK2 MAPKs and thereby modulate cellular proliferation and differentiation.

Sigma-1 receptor (Sig-1R or sigmar-1) is a small integral membrane protein that interacts with numerous cellular components, such as GPCRs and ion channels. It can also enhance or block the activity of Ca2+ channels. Recently, DMT has been identified as a natural, endogenous ligand for sigmar-1, which regulates intracellular Ca2+ signaling and adenosine triphosphate production. This may explain why the concentration of DMT-modulating cellular physiology is almost 10-fold as compared to its affinity concentration.

Innate Immune Recognition and the Biology of Inflammation and Interferon Responses

The immune system recognizes pathogen-associated molecular patterns (PAMPs) and responds by producing pattern-recognition receptors (PRRs). These PRRs also sense host-derived/”self” components that become available as a result of cellular/tissue injury. Endogenous damage-associated molecular patterns (DAMPs) are continuously growing, and two important classes of PRRs are transmembrane toll-like receptors (TLRs) and cytosolic RIG-I-like receptors (RLRs). These receptors activate the NF-B and IFN-regulatory factor 3/7 (IRF3/7) pathways, as well as MAPKs. TLR and RLR ligation results in the activation of MyD88 and MAVS, which couple to TRAF3, which in turn couples to TANK, which in turn couples to IRF3/IRF7, which in turn couples to the nucleus, inducing type I IFN genes.

Psychedelics can interfere with immune cell cytokine profiles, leading to suppression of antigen presentation, inflammatory cytokine and chemokine secretion, and inhibition of isotype switching or elevated levels of anti-inflammatory cytokines in the tissue environment.

Molecular Mechanics of Interacting PRR, Serotonin, and Sigma-1 Receptor Pathways

Many classical psychedelics have the capability to modulate both innate and adaptive immunity. They do this by inhibiting inflammatory responses and antigen presentation, and by specific, disparate regulation of certain lymphocyte subtypes.

The cross-talk between immune sensors and receptors involved in the pharmacology of psychedelics may occur at multiple levels, including the regulation of cytokines by various immune cell and tissue types, as well as the negative feedback regulation of inflammation.

Psychedelics may influence the complex cytokine-feedback regulation of immune cells through intracellular mechanisms, including the regulation of NF-B, type I IFN, and MAPK pathways.

5-HT1 and 5-HT2 receptors are potent inducers of cytokines, adhesion molecules, and growth factors, and they regulate the release of cytokines by the spatio-temporal regulation of cyokine release. Psychedelics activate NF-B and MAPK pathways via G (Gi and Gq families), and G proteins. The Gq family of subunits couples a large number of GPCRs to PLC-. PLC–IP3 axis-mediated release of Ca2+ from intracellular stores results in the activation of the second messenger conventional protein kinase C (cPKC). cPKC and NF-B signaling may be coupled through sigmar-1, and psychedelics may be useful therapeutic tools in a broad range of chronic inflammatory and autoimmune diseases.

The signaling behind the phenomenon of chronic 5-HTR stimulation preventing type I IFN-mediated depressive behavior in HCV patients has not been uncovered yet, but it may block either the PRR-IRF3/7 or type I IFN receptor pathways.

Tryptamines: Endogenous Regulators of Inflammation and Tumor Immunity?

Tryptamines are a large family of monoamine alkaloids that are widespread in nature and abundant in all three Kingdoms of life. DMT is the only member of the family that has been investigated so far.

DMT is a naturally occurring indole alkaloid that has been detected in animal tissues and is considered to be an endogenous trace amine. It has been shown to act as an agonist at several serotonin receptors as well as at sigmar-1.

The vast majority of research into the reasons for the presence of psychoactive tryptamines in the human body has focused on mental illness. DMT has been shown to inhibit inflammatory cytokines, increase anti-inflammatory IL-10, and induce anti-tumor cytotoxic activity in human primary cell cultures. DMT also increases the number of circulating NK cells, which are important in anti-viral and anti-cancer immune responses. Ayahuasca is a complex decoction that contains several other components according to the admixture plants used in the making process. It is possible that the observed anti-inflammatory and immunosuppressive effects may counteract with the anti-cancer activity.

DMT, a natural compound, may act as a systemic endogenous regulator of inflammation and immune homeostasis, and may be a promising target in future therapies of peripheral and CNS autoimmune diseases and cancer.

Lysergamides: Modulating Lymphocyte Functions

Lysergic acid diethylamide (LSD) is a psychedelic substance that affects several serotonin, dopamine and adrenoreceptor subtypes. It has a functional selectivity at the 5-HT2A and 5-HT2C receptors by specifically activating PLA2 but not PLC.

LSD was shown to skew antibody production by activated B cells by influencing the process of translation. Excess tryptophan abrogated the effect of LSD on protein synthesis. LSD inhibits the proliferation of B cells, inhibits the secretion of IL-2, IL-4, and IL-6, and blocks CD8+ CTL activation. However, lower doses of LSD augment NK cell functions, and may have a significant impact on in vivo anti-tumor and anti-viral immune responses.

Phenethylamines: Regulating Inflammation and Cytotoxicity

Phenethylamines are a large and diverse group of organic compounds, which derive from phenethylamine itself. They include neurotransmitters, psychoactive substances, and adrenergic uptake inhibitors.

This section focuses on two phenethylamines, DOI and MDMA, which have already been described as potential immunomodulators in higher vertebrate species. They both exhibit a certain degree of agonistic activity at serotonin receptors.

Dimethoxy-4-iodoamphetamine (DOI) is a 5-HT2A agonist that inhibits IL-1 and TNF release as well as iNOS activity in C6 glioma cells and NF-B signaling. It may be used to prevent inflammation and treat already ongoing inflammatory tissue damage, such as in allergic asthma.

MDMA has been described as an anti-inflammatory and immunosuppressive agent, and has been shown to decrease lymphocyte proliferation, block the production of IL-1 and TNF, and decrease the expression of MHC-II and the co-stimulatory molecules, CD40, CD80, ICAM-1, suppressing the T cell-priming capacity of professional APCs. Acute administration of MDMA favors anti-inflammatory immune responses and increases the activity of NK cells, suggesting a complex effect on immune homeostasis.

Discussion

The classical psychedelics discussed in this paper exert strong anti-cancer and anti-inflammatory effects through the modulation of innate and adaptive immune processes. Two models are proposed here to cover the possible biochemical dynamics of these interactions.

Intracellular cross-talk between PRRs, serotonin, and sigma-1 receptors may be involved in the immunomodulatory process. This may happen via the 5-HTR/sigmar-1-mediated modulation of intracellular Ca2+ levels and the activity of MAPKs and NF-B. Systems biology, bioinformatics, and biophysics have been used to study signaling systems. The meta-network of biological entities possesses both microscopic and macroscopic dynamics as observed in physical sciences, and the emergence of an average cell deterministic response from single cell stochastic responses complements each other. Recent studies have verified the success of the double-model hypothesis by identifying cross-talk mechanisms between the MyD88- and TRIF-dependent pathways. This leads to the concept of signaling flux redistribution (SFR), which may open new aspects toward the deeper understanding of cellular signaling processes.

PRRs are crucial for innate and adaptive host defense, but their inappropriate activation has been associated with autoimmunity and inflammatory diseases. Psychedelics can modulate PRRs and inhibit sigmar-1 to diminish the deleterious effects of uncontrolled inflammation.

Acknowledgments

I am grateful to the Reviewers for their appropriate and constructive suggestions, and to Eva Rajnavolgyi, Ede Frecska, and Luis Eduardo Luna for their helpful feedback and comments on the manuscript.

Copyright 2015 Szabo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).