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Cited by 150Psychedelics and Drug StudiesTryptophan and brain disordersPharmacological Receptor Mechanisms and Effects

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Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities

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Szabo, Attila·2015·Frontiers in Immunology
DOI 10.3389/fimmu.2015.00358PMC PMC4500993
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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.

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Figure 1 Cross-talk of PRR, 5-HTR, and sigmar-1 pathways. Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) are expressed on the cell surface, localized on intracellular membranes or in the cytoplasm, respectively. These PRRs recognize various sets of pathogenic structures and transduce signals through the NF-κB/IRF pathways. The interaction of a specific PAMP/DAMP with TLRs/RLRs results in downstream signaling through the MyD88/TRIF (TLRs) or MAVS (RLRs) adaptor proteins. This receptor–adaptor interaction leads to the activation of TBK1, MAP-kinase kinases (MKKs), or IKKs via TRAF3 or TRAF6, and leads to the subsequent phosphorylation of IRF3/IRF7, MAPKs-AP-1, or NF-κB, respectively. These transcription factors then translocate to the nucleus regulating the transcription of type I IFN, chemokine, and inflammatory cytokine genes, such as IFNβ, IL-8, IL-1β, IL-6, and TNFα. Classical psychedelics can trigger 5-HT1A, 5-HT2A-C, and/or sigma-1 receptor (Sigmar-1) signaling and thereby control intracellular Ca2+ levels through IP3. 5-HTRs and sigmar-1 can use cPKC and Akt to interfere with PRR-mediated NF-κB and MAPK signaling. Thus, NF-κB and MAPK have a cardinal role in both the collaboration and essential signaling processes of PRRs, 5-HTRs, and sigmar-1.
Figure 1 Cross-talk of PRR, 5-HTR, and sigmar-1 pathways. Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) are expressed on the cell surface, localized on intracellular membranes or in the cytoplasm, respectively. These PRRs recognize various sets of pathogenic structures and transduce signals through the NF-κB/IRF pathways. The interaction of a specific PAMP/DAMP with TLRs/RLRs results in downstream signaling through the MyD88/TRIF (TLRs) or MAVS (RLRs) adaptor proteins. This receptor–adaptor interaction leads to the activation of TBK1, MAP-kinase kinases (MKKs), or IKKs via TRAF3 or TRAF6, and leads to the subsequent phosphorylation of IRF3/IRF7, MAPKs-AP-1, or NF-κB, respectively. These transcription factors then translocate to the nucleus regulating the transcription of type I IFN, chemokine, and inflammatory cytokine genes, such as IFNβ, IL-8, IL-1β, IL-6, and TNFα. Classical psychedelics can trigger 5-HT1A, 5-HT2A-C, and/or sigma-1 receptor (Sigmar-1) signaling and thereby control intracellular Ca2+ levels through IP3. 5-HTRs and sigmar-1 can use cPKC and Akt to interfere with PRR-mediated NF-κB and MAPK signaling. Thus, NF-κB and MAPK have a cardinal role in both the collaboration and essential signaling processes of PRRs, 5-HTRs, and sigmar-1.CC BY · PubMed Central
Figure 2 Pharmacological modulation of APC and lymphocyte cytokine signaling by psychedelics. Psychedelics can significantly interfere with immune cell cytokine profiles. This may lead to suppression of antigen presentation and inflammatory cytokine and chemokine secretion, as well as inhibition of isotype switching or elevated levels of anti-inflammatory cytokines in the tissue environment. Arrows represent activation or migration of cells, or secretion of cytokines. T-arrows mean inhibition. Abbreviations: Mo, monocyte; DC, dendritic cell; MΦ, macrophage; colored halos around cells represent activation/cytokine secretion.
Figure 2 Pharmacological modulation of APC and lymphocyte cytokine signaling by psychedelics. Psychedelics can significantly interfere with immune cell cytokine profiles. This may lead to suppression of antigen presentation and inflammatory cytokine and chemokine secretion, as well as inhibition of isotype switching or elevated levels of anti-inflammatory cytokines in the tissue environment. Arrows represent activation or migration of cells, or secretion of cytokines. T-arrows mean inhibition. Abbreviations: Mo, monocyte; DC, dendritic cell; MΦ, macrophage; colored halos around cells represent activation/cytokine secretion.CC BY · PubMed Central

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  1. [97]Holister L Some general thoughts about endogenous psychotogens. In: Usdin E Hamburg DA Barchas JD, editors. Neuroregulators and Psychiatric Disorders. New York, NY: Oxford University Press (1977). p. 550– 6.

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Metadata

Authors
Szabo, A.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2015-07-14
Volume
6
Pages
358-358
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2015.00358
PMC
PMC4500993
OpenAlex
W1522923028
Cited by
150
References
154
Citations by year
2026: 13 · 2025: 16 · 2024: 16 · 2023: 35 · 2022: 17 · 2021: 17 · 2020: 7 · 2019: 6 · 2018: 8 · 2017: 3 · 2016: 11
FWCI
1.06
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
  • University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, cc-by)
Funders
  • European Commission (-2012-0001, A/2-11-1-2012-0001, TÁMOP‐4.2.4.A/2‐11/1‐2012‐0001, 4.2.4.A/2-11-1-2012-0001)
  • European Social Fund (A/2–11/1-2012-0001, TÁMOP 4.2.4, -2012-0001)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
Keywords
psychedelics, immunomodulation, serotonergic psychedelics, serotonin receptors, sigma-1 receptor, N,N-dimethyltryptamine, 5-MeO-DMT, LSD, MDMA, NF-κB signaling, MAPK signaling, pattern recognition receptors, Toll-like receptors, RIG-I-like receptors, autoimmune disease, chronic inflammation, atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, Alzheimer's disease, cancer immunotherapy

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