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.

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REVIEW
published: 14 July 2015
doi: 10.3389/fimmu.2015.00358
Edited by:
Hans-Peter Hartung,
Heinrich-Heine University Düsseldorf,
Germany
Reviewed by:
Reinhard Hohlfeld,
Ludwig Maximilians University of
Munich, Germany
Ingo Kleiter,
Ruhr-University Bochum, Germany
*Correspondence:
Attila Szabo,
Department of Immunology,
Faculty of Medicine,
University of Debrecen,
98 Nagyerdei Boulevard,
Debrecen H-4012, Hungary
szattila@med.unideb.hu
Specialty section:
This article was submitted to Multiple
Sclerosis and Neuroimmunology,
a section of the journal
Frontiers in Immunology
Received: 30 November 2014
Paper pending published:
12 March 2015
Accepted: 30 June 2015
Published: 14 July 2015
Citation:
Szabo A (2015) Psychedelics and
immunomodulation: novel
approaches and therapeutic
opportunities.
Front. Immunol. 6:358.
doi: 10.3389/fimmu.2015.00358
Psychedelics and
immunomodulation: novel
approaches and therapeutic
opportunities
Attila Szabo*
Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Classical psychedelics are psychoactive substances, which, besides their psychophar-
macological activity, have also been shown to exert significant modulatory effects
on immune responses by altering signaling pathways involved in inflammation, cellu-
lar 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 dis-
cussed 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.
Keywords: psychedelics, inflammation, autoimmunity, cancer, 5-HTR, sigma-1 receptor, pattern-recognition
receptors
Introduction
Psychedelics are psychoactive substances that possess the ability to alter cognition and per-
ception by triggering neurotransmitter receptors in the brain. Psychedelics are members of a
wider family of psychoactive drugs known as hallucinogens, a class that also includes essentially
unrelated psychotropic substances (e.g., dissociatives, deliriants, etc.) (1). These substances affect
the mind in unique ways that result in altered states of consciousness, which are qualitatively
and phenomenologically different from the ordinary states. According to their pharmacological
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Szabo Immunoregulatory potential of psychedelics
action, psychedelics usually fall into one of the following cate-
gories: tryptamines, such as psilocin and N,N-dimethyltryptamine
(DMT); lysergamides, most importantly lysergic acid diethylamide
(LSD); phenethylamines, a large group of diverse substances
including 2,5-dimethoxy-4-iodoamphetamine (DOI), and 3,4-
methylenedioxy-methamphetamine (MDMA); cannabinoids; and
atypical psychedelics, such as salvinorin A (2,3). Tryptamines,
lysergamides, and phenethylamines are often considered as “clas-
sical psychedelics” that exert their effects via the serotonergic sys-
tem, and a growing body of evidence suggests that they may have
therapeutic effects in treating many psychiatric disorders (3,4).
Scientific investigations concerning the possible immunologi-
cal effects of psychedelics date back to the early 70s. However, the
biomedical Renaissance of psychedelic research has only begun
about a decade ago. An important antecedent was the identifica-
tion of neuro-immune communication in mammals that greatly
expanded the domain of physiological activity of psychoactive
substances. Since immune cells were found to also express many
types of neurotransmitter receptors, an entirely new aspect was
added to the biomedical paradigm. Early neuroimmunologists
considered the immune and nervous systems as separate parts,
but a crucial conceptual leap led to the emergence of the modern
approach. This new concept represents neuroimmune communi-
cation as an integrated physiological entity with the immune and
nervous systems being its two aspects (5,6).
Many of the naturally occurring psychedelics have been used
as a form of traditional medicine by indigenous people since cen-
turies or even millennia (7,8). These remedies, as inherent parts of
the shamanic practice, exert many beneficial effects on the human
body (9–11). Unfortunately, the amount of evidence-based, rig-
orous scientific data about the immunomodulatory functions of
psychedelic substances has been quite scarce to date.
In the last two decades, several neurotransmitter receptors
involved in the pharmacology of psychedelics have been identified
as also being crucial in many immunological processes pointing
out to novel therapeutic avenues (12–16). This emerging field
offers very promising treatment modalities in the therapy of
various diseases including autoimmune and chronic inflamma-
tory conditions, infections, and cancer. However, the paucity of
available review literature renders the topic unclear and obscure,
mostly posing psychedelics as illicit drugs of abuse and not as
possible and effective agents of future pharmacotherapies. In this
paper, the immunomodulatory effects of classical serotonergic
psychedelics will be discussed from a molecular immunological
and pharmacological perspective, and novel approaches will be
suggested in the treatment of various pathologies.
Molecular Basics of Serotonin and
Sigma Receptor Signaling
To understand the nature of the psychedelics-immunity cross-
talk, we need to briefly discuss the molecular biology of neuro-
transmitter receptor pathways involved in the pharmacological
actions of psychedelics. Classical psychedelics exhibit agonistic
activity mainly at the 5-hydroxytryptamine (5-HT)/serotonin
receptor 5-HT1A and 5-HT2A-C classes. These are G-protein-
coupled receptors (GPCRs) with analogous biochemical
architecture. Their intracellular domains contain sites for
phosphorylation for diverse serine–threonine kinases mediating
downstream signaling processes. The 5-HT1A subtype primarily
signals via Gαiproteins activating or inhibiting adenylyl cyclase
(AC), phospholipase C (PLC), Src kinase, mitogen-activated
protein kinases (MAPKs), and several other effector pathways
(17,18). It also induces the activity of nuclear factor-κB (NF-κB)
(19), a transcription factor that controls pro-inflammatory
cytokine and chemokine gene expression (Figure 1) (20). The
5-HT2A receptor activates PLC-βleading to the accumulation
of inositol phosphates and elevations of intracellular Ca2+in
many tissues and cell types (17,21). It also has the capability to
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.
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Szabo Immunoregulatory potential of psychedelics
increase Cyclo-oxygenase-2 (COX-2) activity and the release of
transforming growth factor beta (TGF-β) via the stimulation of
ERK MAPK activity (22,23). Furthermore, ligated 5-HT2A was
shown to interact with the Janus kinase (Jak)/signal transducers
and activators of transcription (STAT) pathway controlling a
rapid tyrosine phosphorylation of Jak2 and STAT3 that leads to
the nuclear translocation of STAT3 (24). The human 5-HT2B
receptor has 45% structural homology with the 5-HT2A and
42% homology with the 5-HT2C subtypes (25). The functional
5-HT2B protein is widely expressed not only in the brain but also
in many peripheral tissues. In early studies, it has been showed
that 5-HT2B receptors can activate the Ras and ERK1/ERK2
MAPKs involving Gαq, Gαi, and Gβγ protein activities, and
thereby modulate cellular proliferation and differentiation (26).
Similarly to 5-HT2A and 5-HT2C receptors, the 5-HT2B receptor
couples to the PLC-inositol 1,4,5-trisphosphate (IP3) system
directly controlling the release of Ca2+from intracellular stores
(Figure 1) (17). The ligation of 5-HT1and 5-HT2receptors can
directly alter cellular functions in immune cells. In an important
study, 5-HT1and 5-HT2receptor stimulation was shown to
induce intracellular Ca2+mobilization via Gαiproteins in resting,
but not lipopolysaccharide (LPS) activated DCs (27). The 5-HT2C
receptor has also been shown to modulate PLC-IP3activity
(28), and has recently been described as indispensable for the
serotonin-mediated activation of murine alveolar macrophages
(29). Interestingly, the 5-HT1and 5-HT2receptors have a high
expression profile in mammalian lymphoid tissues and involved
in many immunological processes (30–32). These include anti-
tumor and anti-viral immune responses (31,33,34), and the
neuroendocrine regulation of inflammation via serotonin as a
key factor in immune homeostasis (15,35,36).
The sigma-1 receptor (Sig-1R or sigmar-1) is a small integral
membrane protein consisting of a short N-terminus, a large C-
terminus tail, and two transmembrane domains (37,38). Sigmar-
1 localizes at the endoplasmic reticulum (ER)–mitochondrion
interface, also called mitochondria-associated ER membrane
(MAM). Previous studies have shown that sigmar-1 interacts
with numerous cellular components, such as GPCRs and ion
channels (e.g., Na+, K+, and Ca2+). Importantly, similar to 5-
HT receptors (5-HTRs), sigmar-1 can also enhance or block the
activity of Ca2+channels and thereby regulate intracellular Ca2+
levels (38–40). Recently, DMT has been identified as a natural,
endogenous ligand for sigmar-1 (41). Ligation by DMT causes the
dissociation of sigmar-1 from binding immunoglobulin protein
(BiP), allowing it to act as a molecular chaperone to IP3receptors
(42). This activation leads to enhanced Ca2+signaling and a
significant increase in the production of adenosine triphosphate
(Figure 1) (43). Although it resides primarily at the ER, sigmar-1
directly translocates from the MAM to the plasma membrane or
the subplasma membrane area following its activation by higher
concentrations of specific ligands or when the receptor is over-
expressed in cells (44–46). This may explain why the concen-
tration of DMT-modulating cellular physiology is almost 10-fold
as compared to its affinity concentration (41,42). Early stud-
ies demonstrated that sigmar-1 is expressed not only in distinct
regions of the CNS but also in immune cells (47–49). Murine stud-
ies also showed that the specific activation of sigmar-1 resulted
in immunosuppression (50), and in vivo decreased lymphocyte
activation and proliferation (51). Sigma-1 receptor ligands possess
potent immunoregulatory properties via increasing the secretion
level of anti-inflammatory IL-10 (52), and suppressing interferon
(IFN)γand GM-CSF expression (51).
Innate Immune Recognition and the
Biology of Inflammation and
Interferon Responses
The immune system acts as an evolutionally conserved and
advanced host defense mechanism against invading pathogens.
Innate immune responses are triggered by phylogenetically con-
served microbial components that are essential for the survival
of a given type of organism. Upon pathogenic infection, these
pathogen-associated molecular patterns (PAMPs) are recognized
by specific pattern-recognition receptors (PRRs) that are germline
encoded and are usually expressed constitutively in the host (53–
55). The overall picture, however, is far more complex as success-
ful microbial moieties are also found in non-pathogenic microbes,
and thus the presence of different PAMPs per se is not sufficient to
discriminate “pathogenic” and “non-pathogenic” microbial taxa.
Furthermore, certain PRRs also sense host-derived/“self ” compo-
nents that become available as a result of cellular/tissue injury. The
list of these endogenous damage-associated molecular patterns
(DAMPs) is continuously growing but their impact on immune
homeostasis is yet to be clarified (Figures 1 and 2) (20,56). Thus
far, five classes of PRRs have been identified. Two important
classes are: (i) transmembrane toll-like receptors (TLRs), which
are integrated to cell surface or endosomal membranes of vari-
ous cell types; (ii) cytosolic RIG-I-like receptors (RLRs) (57–59).
Upon binding of their specific ligands, these PRRs activate the NF-
κB and the IFN-regulatory factor 3/7 (IRF3/7) pathways, as well
as MAPKs, such as p38, ERK1/2, and c-Jun N-terminal kinase
(JNK) (60,61). This process altogether results in the expression
of a common set of genes whose products, such as inflammatory
cytokines, chemokines, and co-stimulatory molecules, are essen-
tial for the orchestration of both innate and adaptive immunity
(Figure 1). TLR and RLR ligation results in the activation of
myeloid differentiation primary response gene 88 (MyD88) or the
TIR-domain-containing adapter-inducing IFN-β(TRIF) adapter
proteins for TLR pathways, and the mitochondrial adapter mito-
chondrial anti-viral-signaling protein (MAVS) that mediates RLR
downstream signaling (62). TRIF and MAVS then couple to the
TNF receptor-associated factor 3 (TRAF3) conveying the signal to
TANK-binding kinase 1 (TBK1) through TRAF family-member-
associated NF-κB activator (TANK) binding (63). Activated TBK1
induces the phosphorylation of IRF3/IRF7 on specific serine
residues, resulting in their homodimerization (64). These dimers
then translocate to the nucleus inducing the transcription of type
I IFN genes, a cytokine family that is highly involved in anti-viral
and anti-tumor immunity (Figure 1) (65). This pathway is impli-
cated to be connected to the NF-κB activation pathway through
the interaction of FAS-associated via death domain (FADD),
Receptor-interacting protein (RIP1) and TRAF6, which result in
the induction of pro-inflammatory cytokine genes and proteins,
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Szabo Immunoregulatory potential of psychedelics
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.
such as IL-1β, IL-6, and TNF-α(66). The activation of these
pathways are crucial in anti-pathogenic immune responses, but
are also involved in autoinflammatory and autoimmune patholo-
gies where undesirable inflammation causes chronic and severe
damage to self tissues (67).
Molecular Mechanics of Interacting PRR,
Serotonin, and Sigma-1 Receptor
Pathways
Many of the classical psychedelics have the capability to interfere
with both innate and adaptive immunity. This modulatory poten-
tial is usually manifested through the inhibition of inflammatory
responses and antigen presentation, and specific, disparate regula-
tion of the proliferation and function of certain lymphocyte sub-
types, such as cytotoxic T-lymphocytes (CTLs) or NK cells. The
receptors involved in the pharmacology of classical psychedelics
are mainly expressed by neuronal cells, and their function in
the CNS is well described. However, they are also expressed by
immune and hematopoietic cells, and the details of their mod-
ulatory potential have not been elucidated yet (68). Regrettably,
we have a very limited understanding of these neuroimmune
signaling events thus far.
The cross-talk between immune sensors and receptors involved
in the pharmacology of psychedelics may occur at multiple lev-
els. Two possible ways of this communication will be proposed.
First, an inter-cellular interaction may be established by means of
cytokine regulation among various immune cell and tissue types.
The classical psychedelics discussed in this paper are acting at
either one or all of the 5-HT1A, 5-HT2A, 5-HT2B , and 5-HT2C
serotonin receptor subtypes. The activation of these 5-HTR sub-
types displays an unique effect on the production of cytokines,
which has similar immunological functions, such as IL-1βand
TNFα(69). 5-HT receptor activation results in a decrease of
TNFα, but an increase in IL-1βsecretion in human peripheral
blood mononuclear cells (PBMCs) (70), DCs (27), and mono-
cytes stimulated with PRR ligands (71). Furthermore, serotonin
was shown to facilitate the production of the pro-inflammatory
IL-16 and IFNγby activated CTLs and NK cells (72). Thus
5-HT receptor agonism appears to control the inflammatory
response by regulating different patterns of cytokine secretion
(69). Additionally, another key factor here is the negative feedback
regulation of inflammation via the induction of the release of anti-
inflammatory IL-10 and TGFβoccurring subsequent of 5-HT1
and 5-HT2receptor activation (Figure 2) (73–75).
Second, 5-HTR activation, besides its influence on the com-
plex cytokine-feedback regulation, may also interfere with the
chemokine, inflammatory cytokine, and/or type I IFN receptor
signaling of immune cells through intracellular mechanisms. Most
of the receptors that are involved in psychedelic effects belong to
the GPCR family or interact with GPCRs (e.g., sigmar-1) (68).
The role of 5-HTR/GPCR-coupled signals in the intracellular
regulation and orchestration of NF-κB, type I IFN, and MAPK
pathways may be of particular importance regarding the com-
plex immunological effects of psychedelics. GPCR agonists have
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Szabo Immunoregulatory potential of psychedelics
already been described as potent inducers of cytokines, adhesion
molecules, and growth factors [reviewed in Ref. (76)]. Specific
stimulation of the 5-HT1and 5-HT2receptor subtypes leads to the
activation of NF-κB and several MAPKs in many cell types includ-
ing immune cells (77–81). This 5-HTR-mediated, coordinated
cross-talk between MAPKs (including p38, MEKK1, ERK, and
PI3K/Akt) and NF-κB leads to an intricate fine-tuning of inflam-
matory responses by the spatio-temporal regulation of cyokine
release. The inhibitory or stimulatory effect of GPCR activation
on NF-κB and MAPK pathway kinetics is largely depending on
the G-proteins that are involved. Psychedelics, acting through
mainly 5-HT1and 5-HT2receptors subtypes, regulate NF-κB and
MAPKs via Gα(Giand Gqfamilies), and Gβγ proteins (17–19,26).
The Gqfamily of αsubunits couples a large number of GPCRs to
PLC-β, and many of these have been shown to activate NF-κB.
This mechanism is based on the activity of IκBαand the IκB
kinases (IKKs), IKKαand IKKβ, as well as the phosphatidyli-
nositol 3-kinase (PI3K) pathway involving the serine/threonine
protein kinase Akt (82). The PLC-β-IP3 axis-mediated release of
Ca2+from intracellular stores results in the activation of the sec-
ond messenger conventional protein kinase C (cPKC) (Figure 1).
As mentioned above, this calcium signal can also be attenuated by
the activation of sigmar-1 (42,43), and it is tempting to speculate
that sigmar-1 may couple to MAPK and NF-κB signaling and
regulate inflammation through this mechanism as well. Several
PKC isoforms are known to activate NF-κB, consequently, the Gq-
mediated activation of NF-κB is the result of PLC-β-controlled
convergence of IKK and cPKC signaling (76). The Giproteins do
not activate PLC-β, but use the Gβγ class to signal through MAPKs
and induce NF-κB phosphorylation and nuclear translocation
(83,84). Following GPCR activation, Gβγ dissociates from Gαand
can per se stimulate both PLC-βand PI3K. This allows a direct
control of NF-κB transcriptional regulation of chemokines, pro-
inflammatory, and anti-inflammatory cytokines, and thus render-
ing psychedelics as potentially useful therapeutic tools in a broad
range of chronic inflammatory and autoimmune diseases (85).
Another possible mechanism has been raised by recent meta-
analyses showing that serotonin signaling could prevent the type
I IFN-mediated depressive behavior of HCV patients (86,87).
The signaling behind this phenomenon has not been uncovered
yet; however, it is possible that chronic 5-HTR stimulation may
block either the PRR-IRF3/7 or type I IFN receptor pathways.
Since both NF-κB and type I IFN signaling contribute to the
transcriptional regulation of genes that are involved in cellular
proliferation and survival, and many psychedelics exhibit in vitro
anti-cancer potential through 5-HTRs, these compounds could be
promising candidates in novel therapies of cancer (88–90).
Tryptamines: Endogenous Regulators of
Inflammation and Tumor Immunity?
Tryptamines are members of a large family of monoamine alka-
loids that are widespread in nature and abundant in all the three
Kingdoms of life (plants, fungi, and animals). Their main feature
is a common indole ring, a backbone that is structurally related
to the amino acid tryptophan. This tryptamine backbone desig-
nates many biologically active compounds, such as psychedelics
and neurotransmitters (91). To date, our knowledge about the
immunomodulatory capacity of tryptamines is quite scarce. DMT
is the only member of the family that has been investigated so far.
N,N-dimethyltryptamine is related to the neurotransmit-
ter serotonin, the hormone melatonin, and other psychedelic
tryptamines, such as bufotenin and psilocin. It is a naturally
occurring indole alkaloid that is ubiquitous in plants, such as
Diplopterys cabrerana and Psychotria viridis, which are used for
the preparation of sacramental psychoactive brews including yage
and ayahuasca (92). In addition to its ubiquitous presence in plant
species, DMT has also been detected in animal tissues and is
considered to be an endogenous trace amine (93). The milestones
of DMT research were laid down by Szara (94) and Axelrod (95)
who reported first the psychoactive effects and occurrence of this
compound in the human brain. This led to the hypothesis that
DMT is an endogenous hallucinogen (96,97), and later it was
proposed to be a neurotransmitter or neuromodulator (98). DMT
was shown to act as an agonist at several serotonin receptors
including 5-HT1A, 5-HT2A, and 5-HT2C (99–102) as well as at
sigmar-1 (41).
The vast majority of the initial research into the reasons for
the presence of psychoactive tryptamines in the human body has
sought their involvement in mental illness. Until now, very little
has been known about the function of DMT in cellular and gen-
eral physiological processes, and the emphasis of research mostly
aimed the understanding of its psychedelic properties (103).
Recently, we and others demonstrated that DMT has the capability
to modulate immune responses in in vitro human primary cell
cultures (88,104). In these studies, DMT was shown to act as a
non-competitive inhibitor of indoleamine 2,3-dioxygenase (IDO)
and as a strong inducer of anti-tumor cytotoxic activity in the
co-cultures of human PBMCs and a glioma cell line (88). Further-
more, DMT and its analog 5-methoxy-N,N-dimethyltryptamine
(5-MeO-DMT) were found to exert potent anti-inflammatory
activity through the sigmar-1 in human monocyte-derived den-
dritic cell (moDC) cultures. MoDCs are key cell types of the mam-
malian immune system connecting and orchestrating innate and
adaptive immune responses as professional antigen-presenting
cells (APCs) (20). DMT or 5-MeO-DMT treatment of LPS, polyI:C
or pathogen-activated human primary moDCs resulted in a sig-
nificant inhibition of the secretion of the inflammatory cytokines,
IL-1β, IL-6, TNFα, and the chemokine CXCL8/IL-8. In contrast,
secreted levels of the anti-inflammatory IL-10 increased markedly
following in vitro DMT/5-MeO-DMT administration. DMT and
5-MeO-DMT exhibited the effective inhibitory potential at the
level of adaptive immune responses (T helper cell 1 and 17 prim-
ing by moDCs), as well (104). These are in line with previous
findings showing the immunomodulatory potential of ayahuasca
in humans mostly affecting the number and ratio of lymphocyte
subpopulations. Notably, the number of circulating NK cells, a
cell type involved in anti-viral and anti-cancer immune responses,
increased significantly (105,106). The anti-cancer activity of
ayahuasca has already been reviewed in a paper by Schenberg
(89). However, it is important to keep in mind that ayahuasca is
a complex decoction that, besides DMT, contains several other
components according to the admixture plants used in the making
process. Furthermore, ayahuasca can be administered in various
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Szabo Immunoregulatory potential of psychedelics
ways (single-time, long-term, etc.), thus one should be particularly
careful with the study design and interpretation of the data. Nev-
ertheless, ayahuasca consumption in a highly controlled clinical
setting emerges as a very promising model for investigating the
possible immunomodulatory effects of DMT in humans (107).
Importantly, it is possible that the observed anti-inflammatory
and immunosuppressive effects may counteract with the anti-
cancer activity, therefore further investigations are needed to elu-
cidate the complex in vivo consequences of DMT administration.
The mentioned studies demonstrate and propose new biologi-
cal roles for DMT, which may act as a systemic endogenous regula-
tor of inflammation and immune homeostasis. According to these
new results, DMT and 5-MeO-DMT possess the capability to
inhibit the polarization of human moDC-primed CD4+T helper
cells toward the inflammatory Th1 and Th17 effector subtypes in
inflammatory settings. This is of particular importance, since Th1
and Th17 cells and the cytokines they secrete are key players in
the etiology and symptomatology of many chronic inflammatory
and autoimmune diseases of the CNS and other tissues (108,109).
Moreover, the mobilization of innate immune mechanisms is also
well established in many psychiatric and neurological disorders
(6). Thus, as a target for future pharmacological investigations,
DMT emerges as a potent and promising candidate in novel
therapies of peripheral and CNS autoimmune diseases (such as
multiple sclerosis or amyotrophic lateral sclerosis) and cancer.
Lysergamides: Modulating
Lymphocyte Functions
Lysergic acid diethylamide (also know as LSD-25 or lysergide) is a
psychedelic substance of the ergoline family. Its pharmacological
effects are very complex as it affects several serotonin, as well as all
dopamine and adrenoreceptor subtypes. Since most serotonergic
psychedelics do not exhibit dopaminergic activity, LSD is quite
unique in this regard (110). In humans, LSD mostly affects the 5-
HT1A, 5-HT2A , 5-HT2B, and 5-HT2C serotonin receptor subtypes
(111). Furthermore, LSD has a functional selectivity at the 5-
HT2A and 5-HT2C receptors by specifically activating PLA2 but
not PLC (112).
An early study demonstrated that LSD was able to interfere
with antibody production in rabbit (113). In this report, LSD
was shown to skew the antibody profile of activated B cells to
produce low molecular weight proteins by influencing the process
of translation. Excess tryptophan abrogated the effect of LSD on
protein synthesis suggesting that the phenomenon may occur at
the point of tryptophan insertion during translation. However,
the data provided did not adequately support a peptide termi-
nation mechanism rather reflected an amino acid analog effect
being simulated by LSD (113). These results were in line with
the findings of another group showing that in vitro exposure to
high LSD concentration (100µM) could significantly inhibit the
proliferation and IL-2, IL-4, and IL-6 secretion of B cells, as well
as blocked CD8+CTL activation (90). Hundred micromoles of
LSD also suppressed NK cell responses in vitro; however, inversely,
lower concentrations of LSD (0.0001 and 0.1 µM) augmented
NK cell functions (90). This latter, low concentration can easily
be achieved by recreational doses of LSD in humans (111), and
therefore may have a significant impact on in vivo anti-tumor
and anti-viral immune responses. Human lymphocytes express
the 5-HT1A, 5-HT2A , 5-HT2B, and 5-HT2C subtypes suggesting
that LSD may directly modulate cellular functions through these
receptors (114,115). The results obtained so far suggest that LSD
may interfere with the elements of the immune system by alter-
ing mainly the activity of lymphocytes in mammals. High doses
of this substance may alleviate or inhibit adaptive autoimmune
responses, while lower doses may positively influence the anti-
viral or anti-cancer immunity through the modulation of NK cell
activation. However, detailed analyses on the complex in vivo
effects of LSD on immune functions are yet to be performed.
Phenethylamines: Regulating
Inflammation and Cytotoxicity
Phenethylamines (or substituted phenethylamines) are members
of a large and diverse group of organic compounds, which
derive from phenethylamine itself. Some of them are neuro-
transmitters, such as dopamine and epinephrine, other members
of the family are psychoactive substances (e.g., entactogens or
psychedelics), which directly modulate the monoamine neuro-
transmitter systems, such as the substituted amphetamines, the
substituted methylenedioxyphenethylamines, and several other
naturally occurring alkaloids (116,117). This large family also
includes a variety of drug classes, such as dopamine agents
(e.g., bupropion), serotonin agents (e.g., the psychedelic 2,5-
dimethoxy-4-bromoamphetamine), adrenergic agents (e.g., the
adrenergic uptake inhibitor methamphetamine), and monoamine
oxidase inhibitors (MAOIs) (118).
Considering the vast number and diversity of substituted
phenethylamines, a comprehensive review about the complex
immunological effects of these compounds would exceed the lim-
its of this paper. Therefore, this section focuses on two phenethy-
lamines, DOI and MDMA, which have already been described as
potential immunomodulators in higher vertebrate species. These
psychedelics have several similarities in their pharmacological
action as both of them exhibit a certain degree of agonistic activity
at serotonin receptors. DOI acts as a 5-HT2A, 5-HT2B , 5-HT2C,
and mGlu2 receptor agoinst (119,120), while MDMA is primarily
a presynaptic releasing agent of serotonin, norepinephrine, and
dopamine, but also a weak-to-medium agonist at 5-HT1and
5-HT2receptor subtypes (121–123).
Dimethoxy-4-iodoamphetamine was originally designed and
used as a radioligand for the mapping of 5-HT2receptors (124,
125). As a 5-HT2A agonist, DOI was reported to block IL-1β
and TNFαrelease by human PBMCs (70) as well as to inhibit
LPS or TNFα-stimulated inducible nitric oxide synthase (iNOS)
activity in C6 glioma cells (126,127). In a landmark paper, the
Nichols lab described DOI as an extremely potent inhibitor of
TNFα-induced inflammation in rat’s primary aortic smooth mus-
cle cell cultures (128). In this report, DOI was shown to inhibit
the constitutively high protein-level expression of intracellular
adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1
(VCAM-1), the inflammatory cytokine IL-6, and the activity
Frontiers in Immunology | www.frontiersin.org July 2015 | Volume 6 | Article 3586

Szabo Immunoregulatory potential of psychedelics
of NOS, as well as NF-κB signaling. DOI exhibited a fast and
effective blocking capacity on the expression and function of
TNFα-mediated pro-inflammatory markers within a few hours
post-administration suggesting that DOI could be used not only
to prevent inflammation but also to treat already ongoing inflam-
matory tissue damage, such as in allergic asthma (128,129).
The most researched phenethylamine, MDMA, has also been
described as an anti-inflammatory and immunosuppressive agent.
Early studies reported that MDMA could increase the activity of
mouse NK and T helper cells in in vitro cultures at low concen-
trations (0.0001–1.0 µM). The TNFαproduction of macrophages
and the induction of CTLs were suppressed upon MDMA admin-
istration (130). Acute administration of MDMA led to significant
immunosuppression by directly decreasing lymphocyte prolifer-
ation and blocking the mitogen or LPS-induced cytokine (IL-
1βand TNFα) production of T cells in in vivo animal models
(131–133). Later, IL-10 was shown to be the critical mediator in
these immunosuppressive effects on IL-12 and IFNγproduction
in mice (134). MDMA has also been demonstrated to inter-
fere with isotype switching blocking the conversion of IgM to
IgG2a (135), as well as decreasing the expression of MHC-II
and the co-stimulatory molecules, CD40, CD80, ICAM-1 sup-
pressing the T cell-priming capacity of professional APCs (134).
Furthermore, several groups reported that MDMA negatively
affected in vivo immune responses to various pathogens in ani-
mal models (132,136–140). In agreement with these findings,
both acute and chronic MDMA administrations were demon-
strated to cause immunosuppression in humans characterized
by a significant decrease in T lymphocyte and parallel increase
in NK cell functions. Long-term use of MDMA, however, was
associated with a decrease in the total number of circulating
lymphocyte populations. These alterations also involved a sig-
nificant decrease in the plasma level of IL-2 and increase of
TGF-βin human volunteers (141–144). These results suggest
that acute administration of MDMA favors anti-inflammatory
immune responses and has a tendency to polarize adaptive immu-
nity toward antibody production. Simultaneously, the activity of
NK cells is increased pointing to a complex effect on immune
homeostasis. This may reflect to an anti-inflammatory potential of
MDMA without significantly decreasing the effectiveness of anti-
viral or anti-tumor immunity; however, further in vivo studies are
needed to unravel the details of this complex immunomodulatory
action.
Discussion
The classical psychedelics discussed in this paper have been shown
to exert strong anti-cancer and anti-inflammatory effects through
the modulation of innate and adaptive immune processes. The
molecular biological background of these effects has not been
investigated so far. Two models are proposed here to cover the
possible biochemical dynamics of these interactions.
On the one hand, (i) regulation may occur through the
alteration of the cytokine-pattern of activated cells. The anti-
inflammatory cytokines, IL-10 and TGFβ, and pro-inflammatory
cytokines, TNFαand IFNγ, seem to be key players in this reg-
ulation (Figure 2) (73–75). On the other hand, (ii) a complex
intracellular cross-talk of PRRs, serotonin, and sigma-1 recep-
tors might 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-κB,
common components of signaling pathways highly involved in
cellular proliferation, survival, and inflammation (Figure 1). Fur-
thermore, interacting PRR and 5-HTR/sigmar-1 pathways may
compete for common elements of downstream signaling (e.g.,
kinases, adaptor proteins), a phenomenon that can also lead to a
significant inhibition of one of the interacting partners. A sim-
ilar mechanism may lead to the preference of a given pathway
through kinase or receptor–adaptor bias (145). An interesting
contemporary approach to the topic has been carried out by
using systems biology, bioinformatics, and biophysics, as tools
of better understanding. This approach emphasizes that instead
of single cell analyses, one should move toward a more holistic
understanding of signaling systems. The meta-network of bio-
logical entities is considered to possess both microscopic and
macroscopic dynamics as observed in physical sciences. The ori-
gin of averaging effects from stochastic responses of a single cell
when collected to form a population should also be taken into
account (146,147). It is very likely that the emergence of an
average cell deterministic response (e.g., following a PRR and/or
5-HTR stimulus) from single cell stochastic responses comple-
ments each other (20,148,149). Consequently, the stochastic
fluctuations in the inflammatory response of a single immune
cell or a single signaling pathway are necessary to induce prob-
abilistic differentiation from identical cells or interacting path-
ways of the same receptor family. This might allow multicellular
organisms or complex, interacting signaling networks to switch
cell fates or states to yield diversity, fine-tuning, and reach the
proper response that cannot be achieved by a purely deterministic
system. Recent studies of multi-component, non-linear model-
ing of different TLR pathways verified the success of this idea
by identifying cross-talk mechanisms between the MyD88- and
TRIF-dependent pathways and led to the concept of signaling
flux redistribution (SFR) (149,150). This proposal is based on
the law of conservation where the removal of MyD88 leads
to increased activation of the entire alternative TRIF-pathway.
Thus, total signaling flux information from a receptor through
final downstream gene activation in the network is conserved.
The group experimentally validated the SFR theory by using
MyD88−/−and TRAF6−/−KO mice and their data generated
interesting interpretations (150), which may open up new aspects
toward the deeper understanding of cellular signaling processes
(20). An important limitation of this double-model hypothe-
sis is that available experimental data supporting the proposed
interactions is mostly scarce. Thus, further studies are needed to
confirm its relevance in future immunopharmacotherapies, espe-
cially as far as translational aspects and human clinical trials are
concerned.
While PRRs were shown to be crucial for innate and adap-
tive host defense, their inappropriate activation has been associ-
ated with autoimmunity and inflammatory diseases. Psychedelics,
by modulating the activity of 5-HT1, 5-HT2, and sigmar-1
receptors, are potent anti-inflammatory agents (70,104,128,130–
134). A more complete appreciation of the PRR-5-HTR/sigmar-1
Frontiers in Immunology | www.frontiersin.org July 2015 | Volume 6 | Article 3587

Szabo Immunoregulatory potential of psychedelics
cross-talk and their complex signaling processes would provide
important insights into new therapeutic modalities that can either
enhance immune responses or inhibit functions to diminish the
deleterious effects of uncontrolled inflammation. Thus, these
compounds emerge as very promising candidates in many dis-
eases with chronic inflammatory etiology and pathology, such
as atherosclerosis, psoriasis, rheumatoid arthritis, systemic lupus
erythematosus, type I diabetes, multiple sclerosis, schizophrenia,
depression, and Alzheimer’s disease.
Acknowledgments
I am thankful to Eva Rajnavolgyi, Ede Frecska, and Luis Eduardo
Luna for their helpful feedback and comments on the manuscript.
I am also very grateful to the Reviewers for their appropriate
and constructive suggestions. This research was supported by
the European Union and the State of Hungary, co-financed by
the European Social Fund in the framework of TÁMOP 4.2.4.
A/2-11-1-2012-0001 “National Excellence Program.”
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