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Journal of Neural Transmission
Translational Neuroscience, Neurology
and Preclinical Neurological Studies,
Psychiatry and Preclinical Psychiatric
Studies
ISSN 0300-9564
J Neural Transm
DOI 10.1007/s00702-013-1024-y
A possibly sigma-1 receptor mediated role
of dimethyltryptamine in tissue protection,
regeneration, and immunity
Ede Frecska, Attila Szabo, Michael
J.Winkelman, Luis E.Luna & Dennis
J.McKenna
1 23
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TRANSLATIONAL NEUROSCIENCES - REVIEW ARTICLE
A possibly sigma-1 receptor mediated role of dimethyltryptamine
in tissue protection, regeneration, and immunity
Ede Frecska •Attila Szabo •Michael J. Winkelman •
Luis E. Luna •Dennis J. McKenna
Received: 27 November 2012 / Accepted: 1 April 2013
ÓSpringer-Verlag Wien 2013
Abstract N,N-dimethyltryptamine (DMT) is classified as
a naturally occurring serotonergic hallucinogen of plant
origin. It has also been found in animal tissues and regar-
ded as an endogenous trace amine transmitter. The vast
majority of research on DMT has targeted its psychotropic/
psychedelic properties with less focus on its effects beyond
the nervous system. The recent discovery that DMT is an
endogenous ligand of the sigma-1 receptor may shed light
on yet undiscovered physiological mechanisms of DMT
activity and reveal some of its putative biological func-
tions. A three-step active uptake process of DMT from
peripheral sources to neurons underscores a presumed
physiological significance of this endogenous hallucino-
gen. In this paper, we overview the literature on the effects
of sigma-1 receptor ligands on cellular bioenergetics, the
role of serotonin, and serotoninergic analogues in
immunoregulation and the data regarding gene expression
of the DMT synthesizing enzyme indolethylamine-N-
methyltransferase in carcinogenesis. We conclude that the
function of DMT may extend central nervous activity and
involve a more universal role in cellular protective mech-
anisms. Suggestions are offered for future directions of
indole alkaloid research in the general medical field. We
provide converging evidence that while DMT is a sub-
stance which produces powerful psychedelic experiences,
it is better understood not as a hallucinogenic drug of
abuse, but rather an agent of significant adaptive mecha-
nisms that can also serve as a promising tool in the
development of future medical therapies.
Keywords N,N-dimethyltryptamine Indolethylamine-
N-methyltransferase Sigma receptors Oxidative stress
Immunoregulation Carcinogenesis
Introduction
N,N-dimethyltryptamine (DMT) is a naturally occurring
methylated indolealkylamine possessing potent psychotro-
pic properties (Barker et al. 2012). This indole alkaloid is
widespread in nature and abundant in plants such as
Diplopterys cabrerana and Psychotria viridis, which are
used in preparation of sacramental psychoactive decoctions
such as yage and ayahuasca (Luna 2011). In addition to its
ubiquitous presence in the plant kingdom, DMT has also
been detected in animal tissues and is considered to act as
an endogenous trace amine (Wallach 2009). Trace amines
(such as octopamine, phenylethylamine, tyramine, trypt-
amine, and its derivatives) are generally present at low
concentrations and accumulate in high amounts only in
certain locations and under special circumstances—for
E. Frecska (&)
Department of Psychiatry, Medical and Health Science Center,
University of Debrecen, Nagyerdei krt. 98, 4012 Debrecen,
Hungary
e-mail: efrecska@hotmail.com
A. Szabo
Department of Immunology, Medical and Health Science Center,
University of Debrecen, Debrecen, Hungary
M. J. Winkelman
School of Human Evolution and Social Change, Arizona State
University, Tempe, AZ, USA
L. E. Luna
Wasiwaska Research Center for the Study of Psychointegrator
Plants, Visionary Art and Consciousness, Florianopolis, Brazil
D. J. McKenna
Center for Spirituality and Healing, Academic Health Center,
University of Minnesota, Minneapolis, MN, USA
123
J Neural Transm
DOI 10.1007/s00702-013-1024-y
Author's personal copy
example, when the catabolic mechanisms are inhibited (Su
et al. 2009), or under stressful conditions (Beaton and
Christian 1977). The significance of the extensive natural
presence of DMT and the biological role it fulfills remains
unclear.
Biosynthesis and biodistribution of DMT
Structurally, DMT is related to the neurotransmitter sero-
tonin, the hormone melatonin, and other psychedelic
tryptamines such as bufotenin and psilocin. The biosyn-
thesis of DMT starts from the decarboxylation of the
essential amino acid tryptophan to tryptamine, followed by
transmethylation through the actions of the enzyme indol-
ethylamine-N-methyltransferase (INMT). Using S-adeno-
syl methionine, INMT catalyzes the addition of methyl
groups to tryptamine, a process resulting in the end product
indolealkylamine (Barker et al. 1981). The enzymatic
activity is regulated in vivo by dialyzable endogenous
inhibitors (Lin et al. 1974; Marzullo et al. 1977). INMT is
widely expressed in the body with the highest levels in the
lungs, thyroid, and adrenal gland. Intermediate levels are
found in placenta, skeletal muscle, heart, small intestine,
stomach, pancreas, and lymph nodes; it is localized densely
at the anterior horn of the spinal cord (Mavlyutov et al.
2012; Thompson et al. 1999).
Since INMT is predominantly present in peripheral tis-
sues, its main physiological function is supposedly non-
neural (Karkkainen et al. 2005). While the brain is not
known to have significant amount of INMT (with the
exception of the pineal gland [Cozzi et al. 2011]), an active
transport of DMT across the blood–brain barrier (Cohen
and Vogel 1972; Sangiah et al. 1979), nevertheless, sug-
gests that peripheral synthesis may influence central ner-
vous functions. The active uptake of DMT into the brain
makes it entirely different from most neurotransmitters,
which do not have significant blood–brain barrier perme-
ability and do not act on the central nervous system from a
distance. The same tissues that contain INMT often contain
enzymes that catabolize DMT. Only a fraction of intra-
cellularly formed DMT is released to blood, and conse-
quently is inconsistently detected either there or in the
original tissue sample (Karkkainen et al. 2005). Therefore,
a puzzling question arises: How can the peripherally syn-
thesized DMT reach the brain in a significant enough
amount to act on it?
Accumulation and storage of DMT
Based on evidence from past studies and some more recent
findings, a three-step mechanism is postulated that would
allow DMT to reach high local concentrations within
neurons. The first step entails crossing the blood–brain
barrier by an uptake across the endothelial plasma mem-
brane according to reports that described the accumulation
of DMT and other tryptamines in the brain following
peripheral administration (Barker et al. 1982; Sitaram et al.
1987; Takahashi et al. 1985; Yanai et al. 1986). The second
step involves the serotonin uptake transporter located on
the neuronal surface. This action is followed by a third one,
which is the DMT’s facilitated sequestration into synaptic
vesicles from the cytoplasm by the neuronal vesicle
monoamine transporter 2 (Cozzi et al. 2009). After its
neuronal uptake, DMT can act at intracellular modulators
of signal transduction systems (see below) or remain stored
in vesicles for up to at least 1 week and available to be
released under appropriate stimuli (Vitale et al. 2011). The
latter team has found that DMT had not only entered the
brain rapidly, but also stayed there. The injected amount
crossed the blood–brain barrier within 10 s after intrave-
nous administration and was only partially excreted in
urine. It was different in the case of tryptamine which had
also gone through a rapid brain uptake, but had been fully
excreted by 10 min after injection. In contrast, DMT per-
sisted in the brain beyond 48 h and was still detected at day
7 after injection. There were no traces of either DMT or
any other metabolite in the urine at 24 h after injection.
These authors concluded that DMT was not removed from
the brain beyond a certain point, and even after a complete
clearance from the blood, it was still present in the central
nervous system.
In essence, DMT is passing through three barriers with
the help of three different active transport mechanisms to
be compartmentalized and stored within the brain. In this
manner, high intracellular and vesicular concentrations of
DMT can be achieved within neurons. The outlined stages
of uptake reveal that considerable physiological effort is
exerted for the accumulation and storage of DMT and
suggest that it has vital importance, since only a few
compounds such as glucose and amino acids are known to
be treated with similar priority. These extensive specialized
processes would not have evolved to target a toxic com-
pound or merely because of the psychedelic effects of
DMT.
DMT as an endogenous hallucinogen
Szara (1956) reported first the psychoactive effect of DMT
in humans within research settings. Shortly thereafter,
Axelrod (1961) demonstrated the occurrence of DMT in
the rat and human brain, leading him and others (Christian
et al. 1977; Hollister 1977) to propose that DMT is an
endogenous hallucinogen. As research progressed, it was
E. Frecska et al.
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noted that DMT may fulfill the criteria for consideration as
a neurotransmitter or a neuromodulator per se (Barker et al.
1981). The vast majority of the initial research into the
reasons for the presence of psychoactive alkylamines in the
human body has sought their involvement in mental illness.
While DMT is no longer recognized to be a causative
(‘‘schizotoxic’’) factor of schizophrenia, it is still widely
considered to play a role in psychotic symptomatology
(Daumann et al. 2010; Warren et al. 2012). Very little is
known about the function of DMT in regulating normal
human physiological processes, and the emphasis of
research is mostly on understanding its psychedelic prop-
erties. Based on indirect evidence, DMT is supposed to be
involved in naturally occurring altered states of con-
sciousness, such as dreams, imagination, creativity, and
spiritual experiences (Callaway 1988; Strassman 2001).
DMT as a scheduled drug
The lack of solid information on its biological importance
and the overwhelming initial data on its hallucinogenic
properties resulted in an official opinion that DMT is a
neurotoxin, has no accepted medical use, and was conse-
quently classified as a Scheduled One drug by the US
Controlled Substance Act in 1970. Its psychoactive ana-
logues (such as 5-methoxy-DMT) usually fall under the
neurotoxin category in the chemical catalogs of pharma-
ceutical companies. Jacob and Presti (2005) oppose this
view: ‘‘DMT is essentially non-toxic to body organs and
does not cause physiological dependence or addictive
behaviors. Thus, its classification as a dangerous drug is
based primarily on socio-political reasons rather than
clinical-scientific evidence’’ (p. 931).
The antagonistic official stance significantly impedes
scientific research pertaining to this increasingly interesting
molecule (Strassman 1995), which is not only neuro-
chemically active but probably bioactive in the broadest
sense. The main goal of this paper is to raise attention to
other features of DMT, which go beyond its psychedelic
effects and point toward a neuroprotective role instead of
neurotoxic agency. Our proposal takes the psychoheuristic
concept (Szara 1994) of this endogenous hallucinogen to
another level.
DMT and serotonin receptors
Research has been inconclusive, thus, far on the receptors
responsible for the psychoactive properties of DMT and
other naturally occurring N-alkyltryptamines. It is generally
believed that the hallucinogenic effects of DMT are medi-
ated through serotonin receptors, particularly by the
subtypes of the 5-HT
2
receptor, which was originally iden-
tified and typically labeled using the synthetic hallucinogen
lysergic acid diethylamide (Bennett and Snyder 1976;
McKenna and Peroutka 1989). DMT has agonistic affinity at
the 5-HT
2C
receptor, but this probably plays a less significant
role—if any—in the psychedelic effect of DMT since tol-
erance develops at this site (Smith et al. 1998). On the other
hand, tolerance to the subjective effects did not occur in
clinical studies with DMT (Strassman et al. 1996). Agonist
interactions at 5-HT
1C
receptors, as opposed to 5-HT
2
receptors, have also been suggested to be a ‘‘common
mechanism of action’’ of hallucinogenic agents (Pierce and
Peroutka 1990). The 5-HT
1A
agonistic potency of DMT is
probably less relevant in this aspect since it works against
DMT’s hallucinogenic activity (Jacob and Presti 2005).
Nichols (2004) proposed that other receptor systems
have to modify or add to the serotonin response of hallu-
cinogens, since 5-HT
2A
receptor action cannot fully
account for the psychological effects of DMT. The
involvement of various other serotonergic mechanisms has
been proposed, including serotonin uptake transporters
(Nagai et al. 2007) and monoamine oxidase enzymes
(Reimann and Schneider 1993). However, certain behav-
iors (such as tremors, retropulsion, and jerking) and intra-
cellular changes (e.g., phosphatidylinositol production)
observed in rats treated with DMT do not involve the
serotonin system or other monoaminergic pathways (Del-
iganis et al. 1991; Jenner et al. 1980).
DMT and the sigma-1 receptor
The latest identified target for DMT’s action is the sigma-1
receptor (Sig-1R). The sigma receptor is an endoplasmic
reticulum receptor comprising at least two subtypes: Sig-1R
and Sig-2R (Hayashi and Su 2004; Quirion et al. 1992). The
sigma site was originally thought to be an opiate receptor
subtype, but now it is recognized as a non-opioid receptor
residing specifically at the endoplasmic reticulum–mito-
chondrion interface. Sig-1Rs are intracellular modulators of
signal transduction systems which influence endoplasmic
reticulum–mitochondrial calcium transfer and regulate cel-
lular bioenergetics, particularly under stressful conditions
(Hayashi and Su 2007;Suetal.2010). DMT is considered as a
natural ligand, an endogenous agonist of the Sig-1R, and a
sigma link is implicated in its psychedelic properties (Fon-
tanilla et al. 2009). This is somewhat counterintuitive since
many drugs—including non-hallucinogens—bind promiscu-
ously to the Sig-1R with higher affinity than DMT. On the
other hand, DMT’s hallucinogenic characteristics are similar
to other classical hallucinogens acting through serotonergic
receptors and lacking Sig-1R potency. Moreover, the selec-
tive serotonin reuptake inhibitor, fluvoxamine is known to
A possibly sigma-1 receptor mediated role of dimethyltryptamine
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have Sig-1R agonistic potential higher than DMT, yet—
unexpectedly—works better in psychotic depression than
antidepressants without this property (Stahl 2008). While the
possibility that Sig-1Rs involved in hallucinations cannot be
totally excluded at present, the results of a recent surge in
sigma receptor research are pointing toward a landscape poor
in psychedelic vistas, but opening up another horizon for
DMT physiology. One can argue against the proposed func-
tional role of DMT—to be outlined below—by pointing out
that its Sig-1R-mediated effects require micromolar concen-
trations as seen in vitro (Fontanilla et al. 2009). In response, it
has to be emphasized that the three-step transporter mecha-
nism—described above—is the key process, which makes
possible the accumulation of the DMT within neurons to reach
relatively high levels for Sig-1R activation and to function as
releasable transmitter in vivo (Vitale et al. 2011).
Effects of Sig-1R modulation
Sig-1Rs are critical regulators in neuronal morphogenesis
and development via the regulation of mitochondrial
functions and oxidative stress (Pal et al. 2012; Tsai et al.
2012; Tuerxun et al. 2010). In vivo and in vitro studies
indicate that Sig-1R agonists are robustly protective in
many ischemia, organopathy, and neurotoxicity models
(Klouz et al. 2008; Mancuso et al. 2012; Penas et al. 2011;
Tagashira et al. 2013; Vagnerova et al. 2006). In experi-
mental conditions, when glutamate is used as an insult, the
role of Sig-1R activation is controversial: in organotypic
cultures of spinal cord slices, the Sig-1R agonist PRE084
defended motor neurons from glutamate excitotoxicity
(Guzman-Lenis et al. 2009), but in cytotoxic assays using a
HT-22 cell line, the Sig-1R antagonist haloperidol has
turned out to be protective (Luedtke et al. 2012). Agonists
of Sig-1R have been shown to exert neuroprotective effects
by regulating intracellular calcium levels and preventing
expression of pro-apoptotic genes in retinal ganglion cells
(Tchedre and Yorio 2008). Sig-1R agonists have also been
reported to preserve protective genes (such as Bcl-2) in a
cerebral focal ischemia model (Yang et al. 2007; Zhang
et al. 2012). Sig-1R activation has been shown to decrease
intracellular calcium overload (Mueller et al. 2013) pro-
duced by both in vitro ischemia and acidosis (Cuevas et al.
2011a; Katnik et al. 2006). Katnik et al.’s (2006) findings
indicate that tonic activation of sigma receptors or stimu-
lation of sigma receptors upon induction of ischemia
diminishes ischemia-induced elevations of intracellular
calcium. Sigma receptors suppress multiple aspects of
microglial activation and microglial deactivation attenuates
neurotoxic effects (Cuevas et al. 2011b; Hall et al. 2009).
Initial studies indicated that inhibiting Sig-1R prevents
oxidative stress-induced cell death (Schetz et al. 2007), and
subsequent investigations showed that Sig-1R stimulation
protects against ischemic lesions (Ruscher et al. 2012).
Moreover, Ruscher et al. (2011) found that Sig-1R acti-
vation induces changes in spine morphology and stimulates
neurite outgrowth in primary neural culture. They con-
cluded that Sig-1R activation induces neuronal plasticity,
which is a long-term recuperative process that goes beyond
neuroprotection. Similar neuronal plasticity changes were
described by Tsai et al. (2009) and Kourrich et al. (2012).
In summary, accumulating evidences suggest that sigma
receptors regulate cell survival and proliferation (Collina
et al. 2013). DMT signaling through Sig-1Rs may shed
light on its physiological relevance. Once inside a neu-
ron—with the help of the three-step uptake mechanism
discussed above—cytoplasmic DMT can interact with
intracellular Sig-1Rs located in the mitochondrion-associ-
ated endoplasmic reticulum membrane (Hayashi and Su
2007). From vesicular storage, it can be released into the
synapse in micromolar concentrations to stimulate cell-
surface Sig-1Rs or to act on the intracellular Sig-1R of
neighboring cells. The data presented suggest that DMT
may regulate intracellular calcium overload and pro-
apoptotic gene expression via activation of Sig-1R recep-
tors. This mechanism can result in a DMT-mediated neu-
roprotection during and after ischemia and acidosis. The
pathological consequences of hypoxic–anoxic damages can
be further mitigated by DMT-facilitated Sig-1R dependent
plasticity changes (Kourrich et al. 2012; Ruscher et al.
2011; Tsai et al. 2009).
One peculiarity of the indolethylamine-sigma link is the
co-localization of INMT with Sig-1R at the C terminal of
‘‘C boutons’’ in motor neurons of the spinal cord. C ter-
minals were found to modulate the excitability of anterior
horn neurons, particularly under stressful conditions
(Mavlyutov et al. 2012). Agonist activation of the Sig-1R
at C terminals reduces motor neuron excitability and firing
frequency. Motor circuits in the anterior horn of the spinal
cord are the final neural arbiters of movement. The force
and duration of muscle contraction is determined by motor
neuron firing, which can be decreased by DMT action. One
may hypothesize that by decreasing the energy consump-
tion of skeletal muscles such an effect may be part of an
adaptive process in hypoxic stress.
DMT in clinical death
The neuroprotective function of DMT can become very
important after cardiac arrest when the main goal of physio-
logical adaptation is to extend the survival of the brain. Based
on the available evidence, we speculate that DMT functions
in the following manner. In response to a life threatening
situation or the physical signals of agony, the lungs can
E. Frecska et al.
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synthesize large amount of DMT (by quick removal of the
endogenous dialyzable INMT inhibitors without the need of
new enzyme synthesis) and release it into the arterial blood
within seconds. Once DMT enters blood circulation, it is
relatively safe from degradation since extracellular, circu-
lating monoamine oxidase enzymes deaminate only primary
amines (McEwen and Sober 1967). Therefore, the tertiary
DMT is not a substrate for the plasma monoamine oxidase
and can reach the brain with minimal degradation.
As the heart has its last systolic contractions, the brain
does not have too much time: It must use the multiple active
transport mechanisms for taking DMT up from the blood,
passing it through the neural membranes, and concentrating
it in synaptic vesicles. A fast and even distribution is nec-
essary, which can hardly be accomplished if the brain would
be the source of DMT. The lung is a good candidate to fulfill
this physiological role. As a part of a desperate recuperative
process, the DMT uptake mechanism has the potential to
keep the brain alive longer. Evidence for this role of DMT is
found in the psychedelic feature of subjective reports pro-
vided after clinical death and near death experiences, which
are phenomenologically similar to those of DMT. These
observations suggest that DMT is very probably involved in
the dying process (Strassman 2001).
Perinatal INMT activity
A similar protective mechanism might come useful in the
perinatal period, especially during delivery. However, the
lungs do not have a central position in fetal circulation, rather
the placenta does. Perhaps, placental sources or a higher-
than-adult INMT activity in the fetal lung compensate for the
difference. Indeed, the activity of INMT in the rabbit lung is
relatively high in the fetus, increases rapidly after birth, and
peaks at 15 days of age. The activity declines to the mature
level and remains constant thereafter (Lin et al. 1974). If it
parallels with increased DMT synthesis, then Sig-1R medi-
ated neuronal plasticity changes can be expected in the
newborn. Systemic treatment with a highly selective Sig-1R
agonist was protective against excitotoxic perinatal brain
injury (Griesmaier et al. 2012) and ischemic neurodegener-
ation in neonatal striatum (Yang et al. 2010). In prenatal life,
the expression of INMT in a gene network seems to be
important for pregnancy success (Nuno-Ayala et al. 2012).
While direct data is lacking in support of this hypothesis,
each step is easily testable.
Sigma and serotonin receptors in immunoregulation
As an endogenous ligand of Sig-1R and serotonin recep-
tors, DMT may also play a significant role in the regulation
of immune processes and tumor proliferation. Sigma
receptors exist not only in the peripheral and central ner-
vous system, but are also expressed by many cells of the
immune system (Gekker et al. 2006) suggesting their
involvement in immune functions. In addition, Sig-Rs have
been shown to be expressed in many cancer tissues from
both neural and non-neural origins (Aydar et al. 2004;
Megalizzi et al. 2007). Sig-1R agonists have the ability to
reduce pro-inflammatory cytokines and enhance the pro-
duction of the anti-inflammatory cytokine IL-10 (Derocq
et al. 1995). In pathological conditions where a cytokine
imbalance is present, similar effects were suggested as
being useful (Bourrie et al. 2004).
Through effects at the 5-HT
2A
receptor, DMT can exert
a strong impact on the effector functions of immunity.
There is a vast literature about the immunological influence
of serotonin (Ahern 2011; Cloez-Tayarani and Changeux
2007). It is well-known that serotonin has multiple effects
on cellular immune functions that are critical in the elim-
ination of pathogens or cancer cells, such as antigen pre-
sentation and T cell polarization (Leon-Ponte et al. 2007;
O’Connell et al. 2006). An in vivo study by Dos Santos
et al. (2011) found that the DMT-containing ayahuasca
increased the level of blood-circulating NK cells in humans
with concentrations as low as 1.0 mg DMT/kg body
weight. Furthermore, in a pilot study, we observed a sig-
nificant increase in the levels of secreted interferon-gamma
and interferon-beta in cultures of human NK cells and
dendritic cells after DMT administration in vitro. This
increase was consistent with our further findings showing
an increase in type I and type II interferon gene expressions
in these cells, but interestingly was not associated with
alterations in the mRNA and protein levels of inflammatory
cytokines (Szabo et al. unpublished results). Since inter-
ferons are not only antiviral agents, but also considered as
potent anticancer factors (Caraglia et al. 2009; Gonzalez-
Navajas et al. 2012; Szabo et al. 2012; Windbichler et al.
2000), here, we hypothesize that DMT-modulation of the
immune response may be beneficial in contributing to or
resulting in a much better elimination of infected or
malignantly altered self cells. Indeed, modern pharmaco-
logical strategies target the modulation of interferon
response to enhance the effectiveness of cancer therapy
(Caraglia et al. 2009; Lasfar et al. 2011; Watcharanurak
et al. 2012).
INMT expression in cancer
The association of the down-regulation of INMT gene (Inmt)
expression with cancer was reported by several groups (Ko-
pantzev et al. 2008; Larkin et al. 2012). According to these
results, Inmt was identified as a candidate gene in prevention
A possibly sigma-1 receptor mediated role of dimethyltryptamine
123
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of cancer progression. Its expression showed a dramatic
decrease in the recurrenceof malignant prostate (Larkinet al.
2012) and lung cancers (Kopantzev et al. 2008). One of the
possible regulating roles of INMT (via its product DMT) in
carcinogenesis could be a direct tumor suppressor effect.
However, this is unlikely since it has no known impact on the
tissue dynamics of differentiating embryonic or proliferative
adult tissues per se (Nuno-Ayala et al. 2012). On the other
hand, DMT synthesized locally by INMT may represent a
significant stimulus for tissue resident immune cells in the
tumor environment. It can also act as a non-dispensable
defensive factor in the protection of higher vertebrate tissues
by controlling the cytokine response of local immune cells.
As mentioned above, DMT can increase the level of circu-
lating NK cells (a natural source of interferon-gamma) in vivo
and also initiate the production of type I and type II inter-
ferons by human dendritic cells. Thus, it is tempting to
speculate that INMT has an important function by generating
DMT to regulate, support, or complement the local immune
responses, thereby preventing malignant processes.
INMT, via the control of DMT synthesis, may play role
in the immune regulation of carcinogenesis. DMT—its
biochemical product—can act as a non-selective agonist on
serotonin receptors altering the effector functions and
cytokine profile of immune cells leading to a tolerogenic,
non-inflammatory state. On the other hand, serotonin
receptor activation also plays a pivotal role in the immu-
nological synapse between T cells and antigen presenting
dendritic cells (Ahern 2011; O’Connell et al. 2006). We
suggest that this very effect can stand in the background of
the increased sensitivity to different cancerous transfor-
mations described by others (Kopantzev et al. 2008; Larkin
et al. 2012), where the decrease in or lack of INMT activity
might be consequently associated with a disrupted immune
surveillance. Further studies are needed to clarify the exact
role of INMT/DMT in this process. Since the down-regu-
lation of Inmt expression may provide a massive survival
benefit for cancer cells, it would be also important to
examine the expression of Inmt in malignantly differenti-
ated human tissues.
Conclusions
Explanations of the role of DMT in humans and nature
remain elusive. Indeed, there is no comprehensive theory
of DMT, a particular perplexing situation given the ubiq-
uity of DMT across the plant and animal kingdoms (Barker
et al. 2012). To place this situation in the context of sci-
entific theories (e.g., Kuhn 1970), we may state that there is
no existing scientific paradigm explaining the significance
of DMT. While the dominant construal of DMT is that it
belongs to hallucinogens, there is no explanation as to why
humans (as well as other animals) have evolved an
endogenous compound to produce hallucinations, espe-
cially since there are no reasons to expect such false per-
ceptions of reality to be adaptive.
Our efforts, here, are not to be construed as a general
theory or model of the role of DMT as a hallucinogen, but
rather to present some examples of the potential role of
DMT in adaptive biological processes. The outlined indi-
rect—though converging—evidence and speculative cases
of DMT function can orient research toward new directions
and may offer components for a general framework
regarding some of the fundamental roles of DMT in cel-
lular adaptation. Instead of supporting a pathological
model, these exemplars suggest a significant physiological
function of DMT and provide a conceptual framework that
is an alternative to the reigning ‘‘hallucinogen paradigm.’’
The literature reviewed suggests that the traditional con-
ceptualization of DMT as primarily a hallucinogenic or
psychedelic compound is too biased and narrow in advo-
cating a pathological role in humans and other species.
Our main conclusion is that DMT is not only neuro-
chemically active, but also bioactive in general. Its sigma
receptor actions are not so revealing for its psychedelic
effects, but rather point to a universal regulatory role in
oxidative stress-induced changes at the endoplasmic retic-
ulum–mitochondria interface. This hypothesized physio-
logical function provides adaptations in cases of general
hypoxia (e.g., cardiac arrest or postnatal asphyxia) and in
local anoxia (e.g., myocardial infarct or stroke). Moreover,
DMT can positively influence immunoregulation and delay
tumor recurrence. In essence, DMT probably is a natural
participant of a biological recuperative-defense mecha-
nism, and the medical ramifications of this possibility are
vast. Obviously, supportive experimental data are neces-
sary for advancing the outlined concepts.
Ingestion of exogenous DMT in combination with a
reversible monoamine oxidase inhibitor—such as in the
formula of ayahuasca preparation—can result in blood
levels up to 1.0 mg/ml or more (Dos Santos et al. 2011).
With the help of the detailed DMT transport mechanisms,
this blood level can lead to local concentrations sufficient
for Sig-1R (and serotonin receptor) mediated therapeutic
effects. The assumed role of DMT in cell protection,
regeneration, and immunity helps understanding why
ayahuasca has been used traditionally in healing ceremo-
nials among the indigenous and mestizo cultures of the
Amazon Basin (Luna 2011). DMT or—more practically—
some of its analogues may turn out to be useful in emer-
gency medicine (cardiac arrest), cardiopulmonary resusci-
tation, intensive care (myocardial infarct), neurology
(stroke), neonatal care (treatment of newborns with poor
Apgar score), cardiac surgery, anesthesiology (protection
against transient hypoxia), oncology, and hospice care.
E. Frecska et al.
123
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These very bold recommendations are based on indirect
evidence, and experimental verification is needed before any
further consideration. Nevertheless, the evidence reviewed
here indicates that there is already a substantial base of sci-
entific findings providing support for a paradigm which
construes DMT as an adaptive mechanism. We hopefully
have presented in this paper convincing evidence that DMT
is not best understood as a psychedelic drug, but rather a
substance with adaptive features which provide a promising
tool for the advancement of general medical practice.
Acknowledgments The authors acknowledge the assistance of
Eszter Acs in the preparation of the manuscript.
Conflict of interest No financial support was necessary for the
preparation of this paper. All authors contributed in a significant way
to the manuscript and all authors have read and approved the final
manuscript. The authors declare that they have no conflicts of interest
in the research.
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