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A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity

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N,N-dimethyltryptamine (DMT) is classified as a naturally occurring serotonergic hallucinogen of plant origin. It has also been found in animal tissues and regarded 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 functions. A three-step active uptake process of DMT from peripheral sources to neurons underscores a presumed physiological significance of this endogenous hallucinogen. 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 mechanisms. Suggestions are offered for future directions of indole alkaloid research in the general medical field. We provide converging evidence that while DMT is a substance which produces powerful psychedelic experiences, it is better understood not as a hallucinogenic drug of abuse, but rather an agent of significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies.
1 23
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.
References
Ahern GP (2011) 5-HT and the immune system. Curr Opin Pharmacol
11:29–33. doi:10.1016/j.coph.2011.02.004
Axelrod J (1961) Enzymatic formation of psychotomimetic metab-
olites from normally occurring compounds. Science 134:343
Aydar E, Palmer CP, Djamgoz MB (2004) Sigma receptors and
cancer: possible involvement of ion channels. Cancer Res
64:5029–5035
Barker SA, Monti JA, Christian ST (1981) N, N-dimethyltryptamine:
an endogenous hallucinogen. Int Rev Neurobiol 22:83–110
Barker SA, Beaton JM, Christian ST, Monti JA, Morris PE (1982)
Comparison of the brain levels of N, N-dimethyltryptamine and
alpha, alpha, beta, beta-tetradeutero-N, N-dimethyltryptamine
following intraperitoneal injection. The in vivo kinetic isotope
effect. Biochem Pharmacol 31:2513–2516
Barker SA, McIlhenny EH, Strassman R (2012) A critical review of
reports of endogenous psychedelic N, N-dimethyltryptamines in
humans: 1955–2010. Drug Test Anal 4:617–635. doi:10.1002/
dta.422
Beaton JM, Christian ST (1977) Stress induced changes in whole
brain indolealkylamine levels in the rat: using gas liquid
chromatography-mass spectrometry. Abstr Soc Neurosci 4:1322
Bennett JP Jr, Snyder SH (1976) Serotonin and lysergic acid
diethylamide binding in rat brain membranes: relationship to
postsynaptic serotonin receptors. Mol Pharmacol 12:373–389
Bourrie B, Bribes E, Derocq JM, Vidal H, Casellas P (2004) Sigma
receptor ligands: applications in inflammation and oncology.
Curr Opin Investig Drugs 5:1158–1163
Callaway JC (1988) A proposed mechanism for the visions of dream
sleep. Med Hypotheses 26:119–124
Caraglia M, Marra M, Tagliaferri P, Lamberts SW, Zappavigna S,
Misso G, Cavagnini F, Facchini G, Abbruzzese A, Hofland LJ,
Vitale G (2009) Emerging strategies to strengthen the anti-tumour
activity of type I interferons: overcoming survival pathways. Curr
Cancer Drug Targets 9:690–704. doi:10.2174/1568009097890
56980
Christian ST, Harrison R, Quayle E, Pagel J, Monti J (1977) The
in vitro identification of dimethyltryptamine (DMT) in mamma-
lian brain and its characterization as a possible endogenous
neuroregulatory agent. Biochem Med 18:164–183
Cloez-Tayarani I, Changeux JP (2007) Nicotine and serotonin in
immune regulation and inflammatory processes: a perspective.
J Leukoc Biol 81:599–606
Cohen I, Vogel WH (1972) Determination and physiological dispo-
sition of dimethyltryptamine and diethyltryptamine in rat brain,
liver and plasma. Biochem Pharmacol 21:1214–1216
Collina S, Gaggeri R, Marra A, Bassi A, Negrinotti S, Negri F, Rossi
D (2013) Sigma receptor modulators: a patent review. Expert
Opin Ther Pat (epub ahead of print) doi:10.1517/13543776.20
13.769522
Cozzi NV, GopalakrishnanA, Anderson LL, Feih JT, Shulgin AT, Daley
PF, Ruoho AE (2009) Dimethyltryptamine and other hallucino-
genic tryptamines exhibitsubstrate behavior at the serotonin uptake
transporter and the vesicle monoamine transporter. J Neural
Transm 116:1591–1599. doi:10.1007/s00702-009-0308-8
Cozzi NV, Mavlyutov TA, Thompson MA, Ruoho AE (2011)
Indolethylamine-N-methyltransferase expression in primate ner-
vous tissue. Abstr Soc Neurosci 37:840.19
Cuevas J, Behensky A, Deng W, Katnik C (2011a) Afobazole
modulates neuronal response to ischemia and acidosis via
activation of sigma-1 receptors. J Pharmacol Exp Ther
339:152–160. doi:10.1124/jpet.111.182774
Cuevas J, Rodriguez A, Behensky A, Katnik C (2011b) Afobazole
modulates microglial function via activation of both sigma-1 and
sigma-2 receptors. J Pharmacol Exp Ther 339:161–172. doi:
10.1124/jpet.111.182816
Daumann J, Wagner D, Heekeren K, Neukirch A, Thiel CM,Gouzoulis-
Mayfrank E (2010) Neuronal correlates of visual and auditory
alertness in the DMT and ketamine model of psychosis. J Psycho-
pharmacol 24:1515–1524. doi:10.1177/0269881109103227
Deliganis AV, Pierce PA, Peroutka SJ (1991) Differential interactions
of dimethyltryptamine (DMT) with 5-HT1A and 5-HT2 recep-
tors. Biochem Pharmacol 41:1739–1744
Derocq JM, Bourrie B, Segui M, Le Fur G, Casellas P (1995) In vivo
inhibition of endotoxin-induced pro-inflammatory cytokines
production by the sigma ligand SR-31747. J Pharmacol Exp
Ther 272:224–230
Dos Santos RG, Valle M, Bouso JC, Nomdedeu JF, Rodriguez-Espinosa
J, McIlhenny EH, Barker SA, Barbanoj MJ, Riba J (2011)
Autonomic, neuroendocrine, and immunological effects of aya-
huasca: a comparative study with d-amphetamine. J Clin Psycho-
pharmacol 31:717–726. doi:10.1097/JCP.0b013e31823607f6
Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB,
Ruoho AE (2009) The hallucinogen N, N-dimethyltryptamine
(DMT) is an endogenous sigma-1 receptor regulator. Science
323:934–937. doi:10.1126/science.1166127
Gekker G, Hu S, Sheng WS, Rock RB, Lokensgard JR, Peterson PK
(2006) Cocaine-induced HIV-1 expression in microglia involves
sigma-1 receptors and transforming growth factor-beta1. Int
Immunopharmacol 6:1029–1033
Gonzalez-Navajas JM, Lee J, David M, Raz E (2012) Immunomod-
ulatory functions of type I interferons. Nat Rev Immunol
12:125–135. doi:10.1038/nri3133
Griesmaier E, Posod A, Gross M, Neubauer V, Wegleiter K, Hermann
M, Urbanek M, Keller M, Kiechl-Kohlendorfer U (2012)
Neuroprotective effects of the sigma-1 receptor ligand PRE-
084 against excitotoxic perinatal brain injury in newborn mice.
Exp Neurol 237:388–395. doi:10.1016/j.expneurol.2012.06.030
Guzman-Lenis MS, Navarro X, Casas C (2009) Selective sigma receptor
agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate
(PRE084)promotes neuroprotection and neurite elongation through
protein kinase C (PKC) signaling on motoneurons. Neuroscience
162:31–38. doi:10.1016/j.neuroscience.2009.03.067
Hall AA, Herrera Y, Ajmo CT Jr, Cuevas J, Pennypacker KR (2009)
Sigma receptors suppress multiple aspects of microglial activa-
tion. Glia 57:744–754. doi:10.1002/glia.20802
A possibly sigma-1 receptor mediated role of dimethyltryptamine
123
Author's personal copy
Hayashi T, Su TP (2004) Sigma-1 receptor ligands: potential in the
treatment of neuropsychiatric disorders. CNS Drugs 18:269–284
Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-
mitochondrion interface regulate Ca(2?) signaling and cell
survival. Cell 131:596–610
Hollister LE (1977) Some general thoughts about endogenous
psychotogens. In: Usdin E, Hamburg DA, Barchas JD (eds)
Neuroregulators and psychiatric disorders. Oxford University
Press, New York, pp 550–556
Jacob MS, Presti DE (2005) Endogenous psychoactive tryptamines
reconsidered: an anxiolytic role for dimethyltryptamine. Med
Hypotheses 64:930–937
Jenner P, Marsden CD, Thanki CM (1980) Behavioural changes
induced by N, N-dimethyl-tryptamine in rodents. Br J Pharmacol
69:69–80
Karkkainen J, Forsstrom T, Tornaeus J, Wahala K, Kiuru P,
Honkanen A, Stenman UH, Turpeinen U, Hesso A (2005)
Potentially hallucinogenic 5-hydroxytryptamine receptor ligands
bufotenine and dimethyltryptamine in blood and tissues. Scand J
Clin Lab Invest 65:189–199
Katnik C, Guerrero WR, Pennypacker KR, Herrera Y, Cuevas J
(2006) Sigma-1 receptor activation prevents intracellular cal-
cium dysregulation in cortical neurons during in vitro ischemia.
J Pharmacol Exp Ther 319:1355–1365
Klouz A, Said DB, Ferchichi H, Kourda N, Ouanes L, Lakhal M,
Tillement JP, Morin D (2008) Protection of cellular and
mitochondrial functions against liver ischemia by N-benzyl-N0-
(2-hydroxy-3,4-dimethoxybenzyl)-piperazine (BHDP), a sigma-
1 ligand. Eur J Pharmacol 578:292–299
Kopantzev EP, Monastyrskaya GS, Vinogradova TV, Zinovyeva MV,
Kostina MB, Filyukova OB, Tonevitsky AG, Sukhikh GT,
Sverdlov ED (2008) Differences in gene expression levels
between early and later stages of human lung development are
opposite to those between normal lung tissue and non-small lung
cell carcinoma. Lung Cancer 62:23–34
Kourrich S, Su TP, Fujimoto M, Bonci A (2012) The sigma-1
receptor: roles in neuronal plasticity and disease. Trends
Neurosci 35:762–771. doi:10.1016/j.tins.2012.09.007
Kuhn T (1970) The structure of scientific revolutions. University of
Chicago Press, Chicago
Larkin SE, Holmes S, Cree IA, Walker T, Basketter V, Bickers B,
Harris S, Garbis SD, Townsend PA, Aukim-Hastie C (2012)
Identification of markers of prostate cancer progression using
candidate gene expression. Br J Cancer 106:157–165. doi:
10.1038/bjc.2011.490
Lasfar A, Abushahba W, Balan M, Cohen-Solal KA (2011) Interferon
lambda: a new sword in cancer immunotherapy. Clin Dev
Immunol 2011:349575. doi:10.1155/2011/349575
Leon-Ponte M, Ahern GP, O’Connell PJ (2007) Serotonin provides an
accessory signal to enhance T-cell activation by signaling
through the 5-HT7 receptor. Blood 109:3139–3146
Lin RL, Sargeant S, Narasimhachari N (1974) Indolethylamine-N-
methyltransferase in developing rabbit lung. Dev Psychobiol
7:475–481
Luedtke RR, Perez E, Yang SH, Liu R, Vangveravong S, Tu Z, Mach
RH, Simpkins JW (2012) Neuroprotective effects of high affinity
sigma 1 receptor selective compounds. Brain Res 1441:17–26.
doi:10.1016/j.brainres.2011.12.047
Luna LE (2011) Indigenous and mestizo use of ayahuasca: an
overview. In: Dos Santos RG (ed) The ethnopharmacology of
ayahuasca. Transworld Research Network, Kerala, pp 1–21
Mancuso R, Oliva
´n S, Rando A, Casas C, Osta R, Navarro X (2012)
Sigma-1R agonist improves motor function and motoneuron
survival in ALS mice. Neurotherapeutics 9:814–826. doi:
10.1007/s13311-012-0140-y
Marzullo G, Rosengarten H, Friedhoff AJ (1977) A peptide-like
inhibitor of N-methyltransferase in rabbit brain. Life Sci
20:775–783
Mavlyutov TA, Epstein ML, Liu P, Verbny YI, Ziskind-Conhaim L,
Ruoho AE (2012) Development of the sigma-1 receptor in
C-terminals of motoneurons and colocalization with the N, N0-
dimethyltryptamine forming enzyme, indole-N-methyl transfer-
ase. Neuroscience 206:60–68
McEwen CM Jr, Sober AJ (1967) Rabbit serum monoamine oxidase.
II. Determinants of substrate specificity. J Biol Chem 242:
3068–3078
McKenna DJ, Peroutka SJ (1989) Differentiation of 5-hydroxytryp-
tamine2 receptor subtypes using 125I-R-(-)2,5-dimethoxy-4-
iodo-phenylisopropylamine and 3H-ketanserin. J Neurosci
9:3482–34890
Megalizzi V, Mathieu V, Mijatovic T, Gailly P, Debeir O, De Neve
N, Van Damme M, Bontempi G, Haibe-Kains B, Decaestecker
C, Kondo Y, Kiss R, Lefranc F (2007) 4-IBP, a sigma1 receptor
agonist, decreases the migration of human cancer cells, including
glioblastoma cells, in vitro and sensitizes them in vitro and
in vivo to cytotoxic insults of proapoptotic and proautophagic
drugs. Neoplasia 9:358–369
Mueller BH 2nd, Park Y, Daudt DR 3rd, Ma HY, Akopova I,
Stankowska DL, Clark AF, Yorio T (2013) Sigma-1 receptor
stimulation attenuates calcium influx through activated L-type
Voltage Gated Calcium Channels in purified retinal ganglion
cells. Exp Eye Res 107:21–31. doi:10.1016/j.exer.2012.11.002
Nagai F, Nonaka R, Satoh Hisashi Kamimura K (2007) The effects of
non-medically used psychoactive drugs on monoamine neuro-
transmission in rat brain. Eur J Pharmacol 559:132–137
Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181
Nuno-Ayala M, Guillen N, Arnal C, Lou-Bonafonte JM, de Martino
A, Garcia-de-Jalon JA, Gascon S, Osaba L, Osada J, Navarro
MA (2012) Cystathionine b-synthase deficiency causes infertil-
ity by impairing decidualization and gene expression networks in
uterus implantation sites. Physiol Genomics 44:702–716. doi:
10.1152/physiolgenomics.00189.2010
O’Connell PJ, Wang X, Leon-Ponte M, Griffiths C, Pingle SC, Ahern
GP (2006) A novel form of immune signaling revealed by
transmission of the inflammatory mediator serotonin between
dendritic cells and T cells. Blood 107:1010–1017
Pal A, Fontanilla D, Gopalakrishnan A, Chae YK, Markley JL, Ruoho
AE (2012) The sigma-1 receptor protects against cellular
oxidative stress and activates antioxidant response elements.
Eur J Pharmacol 682:12–20. doi:10.1016/j.ejphar.2012.01.030
Penas C, Pascual-Font A, Mancuso R, Fore
´s J, Casas C, Navarro X
(2011) Sigma receptor agonist 2-(4-morpholinethyl)1 phenylcy-
clohexanecarboxylate (Pre084) increases GDNF and BiP expres-
sion and promotes neuroprotection after root avulsion injury.
J Neurotrauma 28:831–840. doi:10.1089/neu.2010.1674
Pierce PA, Peroutka SJ (1990) Antagonist properties of d-LSD at
5-hydroxytryptamine2 receptors. Neuropsychopharmacology
3:503–508
Quirion R, Bowen WD, Itzhak Y, Junien JL, Musacchio JM, Rothman
RB, Su TP, Tam SW, Taylor DP (1992) A proposal for the
classification of sigma binding sites. Trends Pharmacol Sci
13:85–86
Reimann W, Schneider F (1993) The serotonin receptor agonist
5-methoxy-N, N-dimethyltryptamine facilitates noradrenaline
release from rat spinal cord slices and inhibits monoamine
oxidase activity. Gen Pharmacol 24:449–453
Ruscher K, Shamloo M, Rickhag M, Ladunga I, Soriano L, Gisselsson
L, Toresson H, Ruslim-Litrus L, Oksenberg D, Urfer R,
Johansson BB, Nikolich K, Wieloch T (2011) The sigma-1
receptor enhances brain plasticity and functional recovery after
E. Frecska et al.
123
Author's personal copy
experimental stroke. Brain 134:732–746. doi:10.1093/brain/
awq367
Ruscher K, Inacio AR, Valind K, Rowshan Ravan A, Kuric E,
Wieloch T (2012) Effects of the sigma-1 receptor agonist 1-(3,4-
dimethoxyphenethyl)-4-(3-phenylpropyl)-piperazine dihydro-
chloride on inflammation after stroke. PLoS One 7:e45118 doi:
10.1371/journal.pone.0045118
Sangiah S, Gomez MV, Domino EF (1979) Accumulation of N,
N-dimethyltryptamine in rat brain cortical slices. Biol Psychiatry
14:925–936
Schetz JA, Perez E, Liu R, Chen S, Lee I, Simpkins JW (2007) A
prototypical sigma-1 receptor antagonist protects against brain
ischemia. Brain Res 1181:1–9
Sitaram BR, Lockett L, Talomsin R, Blackman GL, McLeod WR
(1987) In vivo metabolism of 5-methoxy-N, N-dimethyltrypta-
mine and N, N-dimethyltryptamine in the rat. Biochem Phar-
macol 36:1509–1512
Smith RL, Canton H, Barrett RJ, Sanders-Bush E (1998) Agonist
properties of N, N-dimethyltryptamine at serotonin 5-HT2A and
5-HT2C receptors. Pharmacol Biochem Behav 61:323–330
Stahl SM (2008) The sigma enigma: can sigma receptors provide a
novel target for disorders of mood and cognition? J Clin
Psychiatry 69:1673–1674
Strassman RJ (1995) Hallucinogenic drugs in psychiatric research and
treatment. Perspectives and prospects. J Nerv Ment Dis
183:127–138
Strassman RJ (2001) DMT: the spirit molecule. A doctor’s revolu-
tionary research into the biology of near-death and mystical
experiences. Park Street Press, Rochester
Strassman RJ, Qualls CR, Berg LM (1996) Differential tolerance to
biological and subjective effects of four closely spaced doses of
N, N-dimethyltryptamine in humans. Biol Psychiatry 39:
784–795
Su TP, Hayashi T, Vaupel DB (2009) When the endogenous
hallucinogenic trace amine N,N-dimethyltryptamine meets the
sigma-1 receptor. Sci Signal 2:pe12 doi: 10.1126/scisignal.
261pe12
Su TP, Hayashi T, Maurice T, Buch S, Ruoho AE (2010) The sigma-1
receptor chaperone as an inter-organelle signaling modulator.
Trends Pharmacol Sci 31:557–566. doi:10.1016/j.tips.2010.
08.007
Szabo A, Osman RM, Bacskai I, Kumar BV, Agod Z, Lanyi A,
Gogolak P, Rajnavolgyi E (2012) Temporally designed treat-
ment of melanoma cells by ATRA and polyI: C results in
enhanced chemokine and IFNbsecretion controlled differently
by TLR3 and MDA5. Melanoma Res 22:351–361. doi:
10.1097/CMR.0b013e328357076c
Szara S (1956) Dimethyltryptamin: its metabolism in man; the
relation to its psychotic effect to the serotonin metabolism.
Experientia 12:441–442
Szara S (1994) Are hallucinogens psychoheuristic? NIDA Res
Monogr 146:33–51
Tagashira H, Zhang C, Lu YM, Hasegawa H, Kanai H, Han F,
Fukunaga K (2013) Stimulation of r(1)-receptor restores
abnormal mitochondrial Ca(2?) mobilization and ATP produc-
tion following cardiac hypertrophy. Biochim Biophys Acta
(epub ahead of print) doi: 10.1016/j.bbagen.2012.12.029
Takahashi T, Takahashi K, Ido T, Yanai K, Iwata R, Ishiwata K,
Nozoe S (1985) 11C-labeling of indolealkylamine alkaloids and
the comparative study of their tissue distributions. Int J Appl
Radiat Isot 36:965–969
Tchedre KT, Yorio T (2008) Sigma-1 receptors protect RGC-5 cells
from apoptosis by regulating intracellular calcium, Bax levels,
and caspase-3 activation. Invest Ophthalmol Vis Sci
49:2577–2588
Thompson MA, Moon E, Kim UJ, Xu J, Siciliano MJ, Weinshilboum
RM (1999) Human indolethylamine N-methyltransferase: cDNA
cloning and expression, gene cloning, and chromosomal local-
ization. Genomics 61:285–297
Tsai SY, Hayashi T, Harvey BK, Wang Y, Wu WW, Shen RF, Zhang
Y, Becker KG, Hoffer BJ, Su TP (2009) Sigma-1 receptors
regulate hippocampal dendritic spine formation via a free
radical-sensitive mechanism involving Rac1xGTP pathway. Proc
Natl Acad Sci USA 106:22468–72243. doi:10.1073/pnas.09090
89106
Tsai SY, Rothman RK, Su TP (2012) Insights into the sigma-1
receptor chaperone’s cellular functions: a microarray report.
Synapse 66:42–51. doi:10.1002/syn.20984
Tuerxun T, Numakawa T, Adachi N, Kumamaru E, Kitazawa H,
Kudo M, Kunugi H (2010) SA4503, a sigma-1 receptor agonist,
prevents cultured cortical neurons from oxidative stress-induced
cell death via suppression of MAPK pathway activation and
glutamate receptor expression. Neurosci Lett 469:303–308. doi:
10.1016/j.neulet.2009.12.013
Vagnerova K, Hurn PD, Bhardwaj A, Kirsch JR (2006) Sigma-1
receptor agonists act as neuroprotective drugs through inhibition
of inducible nitric oxide synthase. Anesth Analg 103:430–434
Vitale AA, Pomilio AB, Can
˜ellas CO, Vitale MG, Putz EM, Ciprian-
Ollivier J (2011) In vivo long-term kinetics of radiolabeled N,
N-dimethyltryptamine and tryptamine. J Nucl Med 52:970–977.
doi:10.2967/jnumed.110.083246
Wallach JV (2009) Endogenous hallucinogens as ligands of the trace
amine receptors: a possible role in sensory perception. Med
Hypotheses 72:91–94. doi:10.1016/j.mehy.2008.07.052
Warren JM, Dham-Nayyar P, Alexander J (2012) Recreational use of
naturally occurring dimethyltryptamine—contributing to psy-
chosis? Aust N Z J Psychiatry (epub ahead of print) doi:
10.1177/0004867412462749
Watcharanurak K, Nishikawa M, Takahashi Y, Takakura Y (2012)
Controlling the kinetics of interferon transgene expression for
improved gene therapy. J Drug Target 20:764–769. doi:
10.3109/1061186X.2012.716848
Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, Kainz C,
Lahodny J, Denison U, Muller-Holzner E, Marth C (2000)
Interferon-gamma in the first-line therapy of ovarian cancer: a
randomized phase III trial. Br J Cancer 82:1138–1144
Yanai K, Ido T, Ishiwata K, Hatazawa J, Takahashi T, Iwata R,
Matsuzawa T (1986) In vivo kinetics and displacement study of
a carbon-11-labeled hallucinogen, N, N-[11C]dimethyltrypta-
mine. Eur J Nucl Med 12:141–146
Yang S, Bhardwaj A, Cheng J, Alkayed NJ, Hurn PD, Kirsch JR
(2007) Sigma receptor agonists provide neuroprotection in vitro
by preserving bcl-2. Anesth Analg 104:1179–1184
Yang ZJ, Carter EL, Torbey MT, Martin LJ, Koehler RC (2010)
Sigma receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine
modulates neuronal nitric oxide synthase/postsynaptic density-
95 coupling mechanisms and protects against neonatal ischemic
degeneration of striatal neurons. Exp Neurol 221:166–174. doi:
10.1016/j.expneurol.2009.10.019
Zhang Y, Shi Y, Qiao L, Sun Y, Ding W, Zhang H, Li N, Chen D
(2012) Sigma-1 receptor agonists provide neuroprotection
against gp120 via a change in bcl-2 expression in mouse
neuronal cultures. Brain Res 1431:13–22. doi:10.1016/j.brainres.
2011.10.053
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... The next step was to move away from the dominating psychoactive focus into the direction of somatic effects by the discovery of sigma-1 receptor (Sig-1R) binding profile of DMT and [9] with the suggestion that DMT is an endogenous agonist at this site. Our series of DMT studies got started here with a theoretical framework elaborated in the paper on "A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity" [10]. ...
... In the seminal 2013 paper [10] we went further, and concluded that the biological function of DMT may extend central nervous activity and encompass a more universal role in cellular protective mechanisms (i.e., not only neuroprotective but tissue protective in general). This theoretical work has set stage for experimental studies 3 The latter doesn't necessarily presume the former (i.e., the pharmacodynamics of an effective therapeutic agent can be unrelated to the core etiopathology of the illness). ...
... Our theoretical paper [10] was followed by two in vitro studies [22,23]. In the first study [22] we evaluated the effects of DMT, its derivative 5-MeO-DMT and the synthetic Sig-1R agonist PRE-084 on human primary monocyte-derived dendritic cells after provoking inflammation by lipopolysaccharide, polyI:C or pathogen-derived stimuli. ...
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The vast majority of research on dimethyltryptamine (DMT) has targeted its psychotropic properties and serotonergic activity, with little focus on its effects beyond the nervous system and at other receptor sites. The recent discovery that DMT is an endogenous agonist of the sigma-1 receptor (sigmaR-1) may shed light on yet undiscovered physiological and therapeutic mechanisms of DMT action. Since the sigmaR-1 has an extensive role in mitigation of several forms of intracellular stress such as mitochondrion, endoplasmic reticulum, and oxidative stress, as well as protecting against apoptotic cell death and regulating immune processes, one may suppose similar effects from DMT administration. In this presentation, we briefly overview the function of sigmaR-1 in cellular bioenergetics with a focus on the processes involved in ischemia-reperfusion injury (IRI) and summarize the results of our in vitro and in vivo studies. IRI is a complex phenomenon with mechanisms underlying organ transplantation, stroke, myocardial infarct, general brain hypoxia, cardiovascular surgery, neonatology, and cardiopulmonary resuscitation. We conclude that the effect of DMT may extend beyond central nervous system activity and involve a universal role in cellular protective mechanisms suggesting therapeutic potentials against different types of cardiac IRI-s.
... regulação do sistema imune, de forma que esses receptores têm sido alvo de estudos recentes avaliando as potencialidades terapêuticas da sua manipulação farmacológica(Frecska et al., 2013(Frecska et al., , 2016 Cameron e Olson, 2018). Em relação às b-carbolinas, além da atividade inibitória sobre a MAO-A, diversos outros mecanismos parecem estar envolvidos em seus efeitos, com destaque para o aumento na liberação de dopamina e o bloqueio da receptação de serotonina(Hamill et al., 2019).15 ...
... Efeitos sobre a imunidade também foram reportados por participantes soropositivos, embora nesses casos seja bem mais remota a possibilidade de haver alguma influência positiva do uso da ayahuasca.Cabe, então, discutir em que medida o uso ritual da ayahuasca poderia produzir efeitos terapêuticos, a nível biológico, sobre a saúde física de pessoas acometidas por essas doenças.Em relação ao câncer, um conjunto de evidências obtidas em estudos de biologia celular sugere que os compostos contidos na ayahuasca -em especial, a DMT e a harmina -podem atuar sobre diferentes mecanismos celulares ligados ao câncer e exercer efeitos antitumorais (para revisão, verSchenberg, 2013). Além disso, estudos sobre as funções biológicas da DMT -visto que é uma substância endógena em mamíferos e outros animais -indicam que essa molécula atua em uma série de mecanismos celulares por meio da ativação de receptores sigma-1, participando inclusive de processos de regulação do sistema imune(Frecska et al., 2013). Dessa maneira, a administração de DMT exógeno, ou seja, por meio da ingestão de ayahuasca, por exemplo, pode exercer efeitos sobre o sistema imunológico. ...
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Introdução: Doenças graves levantam questões existenciais que podem ser fonte de sofrimento psicológico e prejudicar o tratamento. Estudos com substâncias psicodélicas demonstram efeitos terapêuticos para ansiedade e depressão associadas a doenças físicas graves, principalmente câncer. Evidências indicam que a ayahuasca – uma bebida psicoativa de origem indígena preparada a partir das plantas Banisteriopsis caapi e Psychotria viridis, utilizada na medicina tradicional amazônica e em contextos ritualísticos/religiosos em diversos países – pode atuar como agente terapêutico no tratamento de transtornos psiquiátricos, destacando-se a depressão e a dependência de substâncias. Estudos preliminares sugerem também que a ayahuasca pode promover efeitos terapêuticos para doenças físicas. Objetivo: O presente estudo busca explorar como o uso ritual da ayahuasca durante o tratamento de doenças físicas graves influenciou o modo como as pessoas que vivenciaram essa experiência compreendem e se relacionam com a doença, procurando identificar os processos psicológicos envolvidos nos efeitos terapêuticos relatados. Métodos: Empregaram- se métodos de pesquisa qualitativa, em abordagem retrospectiva, exploratória e descritiva. Uma amostra intencional foi construída empregando-se critérios de intensidade e heterogeneidade, sendo que o fechamento foi determinado por saturação teórica. Quatorze participantes com diagnóstico atual ou anterior de doenças físicas graves e que fizeram uso ritual da ayahuasca durante o período do tratamento médico foram incluídos, envolvendo casos de câncer, HIV+ e doenças de natureza neurológica, reumatológica, gastrointestinal ou dermatológica. Os dados foram coletados por meio de entrevistas semiestruturadas de questões abertas em profundidade e o conteúdo foi analisado por análise temática, com temas emergentes. Resultados: Os temas identificados cobrem aspectos psicológicos, físicos e espirituais. Os participantes relataram que a experiência ritual com ayahuasca promoveu um espaço de introspecção e análise de conteúdos autobiográficos, com a ocorrência de catarses emocionais e a emersão de sentimentos positivos, o que contribuiu para a redução da ansiedade e de sintomas depressivos, favorecendo o bem-estar psicoemocional. Descreve-se também que a experiência facilitou a identificação de significados sobre a origem e o propósito da doença, bem como a sua ressignificação e aceitação, com reflexos positivos sobre a relação com a doença. Reflexões existenciais amplificadas pela experiência com ayahuasca parecem ter influenciado as concepções dos participantes sobre a vida e a morte, favorecendo a diminuição do medo da morte, maior apreciação da vida, mudanças em relações interpessoais e no estilo de vida. Os participantes relataram também que a experiência com ayahuasca promoveu um fortalecimento da espiritualidade, o que teria beneficiado o tratamento médico. No âmbito da saúde física, relatou-se que os efeitos psicofisiológicos da ayahuasca poderiam ter contribuído para a boa tolerabilidade do tratamento farmacológico, a estabilidade imunológica e a redução de dores crônicas – embora não tenham sido levantadas evidências clínicas comprobatórias. Conclusão: Os resultados deste estudo sugerem que o uso ritual da ayahuasca pode atuar como facilitador no processo de aceitação da doença, por meio de efeitos psicológicos que atuam sobre os significados atribuídos à doença, à vida e à morte, podendo favorecer um relacionamento mais equilibrado com a doença.
... Aside from their well known interaction with the 5-HT system, most of the compounds discussed here, such as DMT, 5-MeO-DMT, DOI, ketamine, and MDMA, all bind S1R, a still-mysterious receptor whose origin remains puzzling (Fontanilla et al., 2009;Frecska et al., 2013;Szabo et al., 2014;Kourrich, 2017;Kim and Pasternak, 2018). This interaction contrasts the 5-HT 2A receptor-centric approach to psychedelic activity and suggests that the action of these compounds at S1R might be more relevant than previously thought (Brammer et al., 2006;Fontanilla et al., 2009;Ray, 2010;Nguyen et al., 2014;Szabo et al., 2014). ...
... This interaction contrasts the 5-HT 2A receptor-centric approach to psychedelic activity and suggests that the action of these compounds at S1R might be more relevant than previously thought (Brammer et al., 2006;Fontanilla et al., 2009;Ray, 2010;Nguyen et al., 2014;Szabo et al., 2014). S1R is highly expressed in limbic areas of the human brain and in several central and peripheral immunocompetent cells, such as monocyte-derived dendritic cells and microglia, which are involved in innate and adaptive immune responses (Ishikawa et al., 2007;Fujimoto et al., 2012;Frecska et al., 2013;Szabo et al., 2014. Interestingly, ibogaine is the only psychedelic to have its highest affinity at this receptor (Ray, 2010). ...
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Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin–, brain-derived neurotrophic factor–, and early growth response–related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds. Significance Statement Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.
... survival and proliferation and play a significant role in the regulation of immune processes and tumour proliferation. 29 Evidence also suggests prevention against ischaemia/reperfusion lesion in the eye and kidney cells. 30,31 DMT can be smoked (vaporized or inhaled), given intravenously (IV) or intramuscularly (IM) and ingested orally. ...
Article
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Recent years have witnessed an unprecedented increase in the search for the use of psychedelics in improving physical and mental health. Anaesthesia has evolved since very early times, born from the need to eliminate pain and reduce suffering and there are reports of the use of anaesthetics to achieve mystical states since the nineteenth century. Nowadays, the renaissance of psychedelics in anaesthesia has been inspired by their potential in the treatment of chronic pain syndromes, palliative care and in the emergency department and pre‐hospital care with the administration of psychedelics in cases of ischaemia, given their potential in neuroprotection. Although there are already some published protocols for the administration of psychedelics in patients with mental illness, little has been addressed concerning non‐mental medical applications. In this sense, in patients with multiple comorbidities, functional limitations and polymedicated, the anaesthetist may play a fundamental role, not only in clinical practice, but also in translational research. This article focuses on the description of psychedelics, with a particular focus on dimethyltryptamine (DMT) and ayahuasca pharmacology, effects, safety and toxicity. A detailed description of the role of the anaesthetist in clinical and experimental research is provided, from participant's screening to preparation and dosing session, expected adverse effects and how to manage them, based on the protocol and standard procedures of a current study with neuroimaging during the psychedelic experience. Specific considerations regarding the management of psychedelic toxicity are also provided as well as future directions for safe psychedelic use in clinical practice.
... While the acute transcendent experience occasioned by classic psychedelics may presumably induce long-term changes in health behaviour that contribute to better physical health, it is plausible that there are other key mechanisms through which classic psychedelics could influence physical health, including improvements on various indices of mental health beyond the simple absence of psychological distress (e.g. increased prosociality, trait mindfulness and purpose in life; Griffiths et al., 2018;Murphy-Beiner and Soar, 2020), many of which are well-known risk factors for physical maladies (Chaddha et al., 2016;Germann, 2020;Hernandez et al., 2018); immunomodulatory and antiinflammatory effects of relevance to physical health (Flanagan and Nichols, 2018;Frecska et al., 2013Frecska et al., , 2016Szabo, 2015Szabo, , 2019Szabo et al., 2014;Thompson and Szabo, 2020;Tourino et al., 2013;Winkelman and Sessa, 2019); and high affinity to receptor subtypes (e.g. serotonin 2A receptors) that are implicated in the pathophysiology of different physical disorders (Nichols, 2009;Thompson and Szabo, 2020). ...
Article
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Background In recent years, there has been significant research on the mental health effects of classic psychedelic use, but there is very little evidence on how classic psychedelics might influence physical health. Aims The purpose of the present study was to investigate the associations between lifetime classic psychedelic use and markers of physical health. Methods Using data from the National Survey on Drug Use and Health (2015-2018) with 171,766 (unweighted) adults aged 18 or above in the United States, the current study examined the associations between lifetime classic psychedelic use and three markers of physical health (self-reported overall health, body mass index, and heart condition and/or cancer in the past 12 months) while controlling for a range of covariates. Results Respondents who reported having tried a classic psychedelic at least once in their lifetime had significantly higher odds of greater self-reported overall health and significantly lower odds of being overweight or obese versus having a normal weight. The association between lifetime classic psychedelic use and having a heart condition and/or cancer in the past 12 months approached conventional levels of significance, with lower odds of having a heart condition and/or cancer in the past 12 months for respondents who had tried a classic psychedelic at least once. Conclusion The results of the present study suggest that classic psychedelics may be beneficial to physical health. Future research should investigate the causal effects of classic psychedelics on physical health and evaluate possible mechanisms.
... A bebida é rica em compostos bioativos e está sendo apontada em estudos sobre doenças neurológicas. Verificou-se (Frecska, Szabo, Winkelman, Luna, McKenna , 2013) que o DMT pode estar associado à proteção e regeneração de células neurais. Fisher et al. (2018) sinalizaram os alcaloides do cipó no combate a doenças degenerativas, a exemplo do Parkinson. ...
Article
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As plantas de poder são símbolos de curas e experiencias transpessoais reconhecidas como portais que ampliam a consciência. A pesquisa objetivou compreender as dimensões socioculturais de uso da bebida ayahuasca no Centro de Unificação Rosa Azul, e sua associação em atenção a saúde física e espiritual. A coleta de dados ocorreu por observação participante e aplicação de questionários e formulários. Os resultados demonstraram que os participantes portam alto nível de compreensão sobre a doutrina, as plantas, o ritual e a cura. As plantas e a bebida atuam como guias de orientação para se alcançar a evolução espiritual, além de representarem caminhos para a cura física, mental e espiritual.
... N,N-dimethyltryptamine (DMT) is a natural compound found in numerous plant species and botanical preparations, such as the hallucinogenic infusion known as ayahuasca 1 classified as a hallucinogenic compound that induces intense modifications in perception, emotion, and cognition in humans [2][3][4] . DMT is present in several animal tissues, such as the lung 5 and brain 6 , being considered as an endogenous trace neurotransmitter with different physiological roles, including neural signaling and brain/peripheral immunological actions [7][8][9][10] . DMT is also present in human blood, urine, and cerebrospinal fluid [11][12][13] . ...
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N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.
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Objective: Reports have indicated possible uses of ayahuasca for the treatment of conditions including depression, addictions, post-traumatic stress disorder, anxiety and specific psychoneuroendocrine immune system pathologies. The article assesses potential ayahuasca and N,N-dimethyltryptamine (DMT) integration with contemporary healthcare. The review also seeks to provide a summary of selected literature regarding the mechanisms of action of DMT and ayahuasca; and assess to what extent the state of research can explain reports of unusual phenomenology. Design: A narrative review. Results: Compounds in ayahuasca have been found to bind to serotonergic receptors , glutaminergic receptors, sigma-1 receptors, trace amine-associated receptors , and modulate BDNF expression and the dopaminergic system. Subjective effects are associated with increased delta and theta oscillations in amygdala and hippocampal regions, decreased alpha wave activity in the default mode network, and stimulations of vision-related brain regions particularly in the visual association cortex. Both biological processes and field of consciousness models have been proposed to explain subjective effects of DMT and ayahuasca, however, the evidence supporting the proposed models is not sufficient to make confident conclusions. Ayahuasca plant medicine and DMT represent potentially novel treatment modalities. Conclusions: Further research is required to clarify the mechanisms of action and develop treatments which can be made available to the general public. Integration between healthcare research institutions and reputable practitioners in the Amazon is recommended.
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Fear‐related disorders, mainly phobias and post‐traumatic stress disorder, are highly prevalent, debilitating disorders that pose a significant public health problem. They are characterized by aberrant processing of aversive experiences and dysregulated fear extinction, leading to excessive expression of fear and diminished quality of life. The gold standard for treating fear‐related disorders is extinction‐based exposure therapy (ET), shown to be ineffective for up to 35% of subjects. Moreover, ET combined with traditional pharmacological treatments for fear‐related disorders, such as selective serotonin reuptake inhibitors, offers no further advantage to patients. This prompted the search for ways to improve ET outcomes, with current research focused on pharmacological agents that can augment ET by strengthening fear extinction learning. Hallucinogenic drugs promote reprocessing of fear‐imbued memories and induce positive mood and openness, relieving anxiety and enabling the necessary emotional engagement during psychotherapeutic interventions. Mechanistically, hallucinogens induce dynamic structural and functional neuroplastic changes across the fear extinction circuitry and temper amygdala's hyperreactivity to threat‐related stimuli, effectively mitigating one of the hallmarks of fear‐related disorders. This paper provides the first comprehensive review of hallucinogens' potential to alleviate symptoms of fear‐related disorders by focusing on their effects on fear extinction and the underlying molecular mechanisms. We overview both preclinical and clinical studies and emphasize the advantages of hallucinogenic drugs over current first‐line treatments. We highlight 3,4‐methylenedioxymethamphetamine and ketamine as the most effective therapeutics for fear‐related disorders and discuss the potential molecular mechanisms responsible for their potency with implications for improving hallucinogen‐assisted psychotherapy.
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Prized medicinal spice true nutmeg is obtained from Myristica fragrans Houtt. Rest species of the family Myristicaceae are known as wild nutmegs. Nutmegs and wild nutmegs are a rich reservoir of bioactive molecules and used in traditional medicines of Europe, Asia, Africa, America against madness, convulsion, cancer, skin infection, malaria, diarrhea, rheumatism, asthma, cough, cold, as stimulant, tonics, and psychotomimetic agents. Nutmegs are cultivated around the tropics for high‐value commercial spice, used in global cuisine. A thorough literature survey of peer‐reviewed publications, scientific online databases, authentic webpages, and regulatory guidelines found major phytochemicals namely, terpenes, fatty acids, phenylpropanoids, alkanes, lignans, flavonoids, coumarins, and indole alkaloids. Scientific names, synonyms were verified with www.theplantlist.org. Pharmacological evaluation of extracts and isolated biomarkers showed cholinesterase inhibitory, anxiolytic, neuroprotective, anti‐inflammatory, immunomodulatory, antinociceptive, anticancer, antimicrobial, antiprotozoal, antidiabetic, antidiarrhoeal activities, and toxicity through in‐vitro, in‐vivo studies. Human clinical trials were very few. Most of the pharmacological studies were not conducted as per current guidelines of natural products to ensure repeatability, safety, and translational use in human therapeutics. Rigorous pharmacological evaluation and randomized double‐blind clinical trials are recommended to analyze the efficacy and therapeutic potential of nutmeg and wild nutmegs in anxiety, Alzheimer's disease, autism, schizophrenia, stroke, cancer, and others.
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Sigma-1 receptors (σ-1rs) exert neuroprotective effects on retinal ganglion cells (RGCs) both in vivo and in vitro. This receptor has unique properties through its actions on several voltage-gated and ligand-gated channels. The purpose of this study was to investigate the role that σ-1rs play in regulating cell calcium dynamics through activated L-type Voltage Gated Calcium Channels (L-type VGCCs) in purified RGCs. RGCs were isolated from P3-P7 Sprague-Dawley rats and purified by sequential immunopanning using a Thy 1.1 antibody. Calcium imaging was used to measure changes in intracellular calcium after depolarizing the cells with potassium chloride (KCl) in the presence or absence of two σ-1r agonists [(+)-SKF10047 and (+)-Pentazocine)], one σ-1r antagonist (BD1047), and one L-type VGCC antagonist (Verapamil). Finally, co-localization studies were completed to assess the proximity of σ-1r with L-type VGCCs in purified RGCs. VGCCs were activated using KCl (20mM). Pre-treatment with a known L-type VGCC blocker demonstrated a 57% decrease of calcium ion influx through activated VGCCs. Calcium imaging results also demonstrated that σ-1r agonists, (+)-N-allylnormetazocine hydrochloride [(+)-SKF10047] and (+)-Pentazocine, inhibited calcium ion influx through activated VGCCs. Antagonist treatment using BD1047 demonstrated a potentiation of calcium ion influx through activated VGCCs and abolished all inhibitory effects of the σ-1r agonists on VGCCs, implying that these ligands were acting through the σ-1r. An L-type VGCC blocker (Verapamil) also inhibited KCl activated VGCCs and when combined with the σ-1r agonists there was not a further decline in calcium entry suggesting similar mechanisms. Lastly, co-localization studies demonstrated that σ-1rs and L-type VGCCs are co-localized in purified RGCs. Taken together, these results indicated that σ-1r agonists can inhibit KCl induced calcium ion influx through activated L-type VGCCs in purified RGCs. This is the first report of attenuation of L-type VGCC signaling through the activation of σ-1rs in purified RGCs. The ability of σ-1rs to co-localize with L-type VGCCs in purified RGCs implied that these two proteins are in close proximity to each other and that such interactions regulate L-type VGCCs.
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The radioligand binding characteristics of 125I-R-(-)4-iodo-2,5-dimethoxyphenylisopropylamine (125I-R-(-)DOI) and 3H-ketanserin were compared in rat and bovine cortical membranes. In rat cortex, 125I-R-(-)DOI labels a relatively low density of binding sites (Bmax = 2.5 +/- 0.2 pmol/gm tissue) with high affinity (KD = 0.63 +/- 0.09 nM). In bovine cortex, specific binding of 125I-R-(-)DOI represents less than 20% of total binding at radioligand concentrations above 0.6 nM, and, therefore, the data cannot be analyzed adequately by Scatchard transformation. By contrast, 3H-ketanserin displays saturable, specific high-affinity binding in both rat cortex (KD = 1.0 +/- 0.1 nM; Bmax = 11 +/- 0.4 pmol/gm tissue) and bovine cortex (KD = 1.2 +/- 0.2 nM; Bmax = 5.3 +/- 0.4 pmol/gm tissue). Ki values for 30 drugs were determined for 125I-R-(-)DOI-labeled sites in rat cortex and 3H-ketanserin-labeled sites in bovine cortex. 5-Hydroxytryptamine (5-HT) displays 250-fold higher selectivity for the 125I-R-(-)DOI-labeled sites (Ki = 3.0 +/- 0.7 nM) than for the 3H-ketanserin-labeled sites (Ki = 750 +/- 50 nM). Structural congeners of R-(-)DOI display 80- to 160-fold higher affinity for the 125I-R-(-)DOI binding site than for the 3H-ketanserin-labeled binding site. d-LSD and putative 5-HT2 antagonists are approximately equipotent at both sites. Significant correlations were found between drug affinities for 125I-R-(-)DOI-labeled sites in rat cortex and putative 5-HT2A sites labeled previously by 77Br-R-(-)DOB (r = 0.93, p less than 0.01), putative 5-HT2B sites labeled by 3H-ketanserin in bovine cortex (r = 0.63, p less than 0.01), and 5-HT1C binding sites that have been characterized by other investigators (r = 0.78, p less than 0.01). No significant correlations were found between drug affinities for 125I-R-(-)DOI-labeled sites in rat cortex and 5-HT1A, 5-HT1B, 5-HT1D, or 5-HT3 sites, as determined by previous investigators.
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Introduction: Sigma receptors are involved in several central nervous system (CNS) disorders, including mood disorders (depression and anxiety), psychosis, schizophrenia, movement disorders (i.e., Parkinson's disease) and memory deficits (i.e., Alzheimer's disease). Recently, the involvement of sigma receptors in neuropathic pain and cancer has also been observed. Areas covered: This review aims at highlighting the research advancements published in the patent literature between 1986 and 2012, dividing patents according to both their time frame and applicants. The review especially focuses on the development of sigma receptor modulators and their application over the years with respect to CNS diseases, neuropathic pain and neurodegenerative pathologies. The literature was sought through Espacenet, Orbit, ISI Web and PubMed databases. Expert opinion: In recent years, considerable progress in the knowledge of the biology and pharmacology of sigma receptors has encouraged research on the potential benefits of sigma modulators in a wide range of pathologies. So far, only few potent agonists and antagonists of sigma receptors are in clinical trial for acute and chronic neurodegenerative diseases (SA4503 and ANAVEX 2-73) or neuropathic pain (E-52862).
Article
Background: We previously reported that the σ1-receptor (σ1R) is down-regulated following cardiac hypertrophy and dysfunction in transverse aortic constriction (TAC) mice. Here we address how σ1R stimulation with the selective σ1R agonist SA4503 restores hypertrophy-induced cardiac dysfunction through σ1R localized in the sarcoplasmic reticulum (SR). Methods: We first confirmed anti-hypertrophic effects of SA4503 (0.1-1μM) in cultured cardiomyocytes exposed to angiotensin II (Ang II). Then, to confirm the ameliorative effects of σ1R stimulation in vivo, we administered SA4503 (1.0mg/kg) and the σ1R antagonist NE-100 (1.0mg/kg) orally to TAC mice for 4weeks (once daily). Results: σ1R stimulation with SA4503 significantly inhibited Ang II-induced cardiomyocyte hypertrophy. Ang II exposure for 72h impaired phenylephrine (PE)-induced Ca(2+) mobilization from the SR into both the cytosol and mitochondria. Treatment of cardiomyocytes with SA4503 largely restored PE-induced Ca(2+) mobilization into mitochondria. Exposure of cardiomyocytes to Ang II for 72h decreased basal ATP content and PE-induced ATP production concomitant with reduced mitochondrial size, while SA4503 treatment completely restored ATP production and mitochondrial size. Pretreatment with NE-100 or siRNA abolished these effects. Chronic SA4503 administration also significantly attenuated myocardial hypertrophy and restored ATP production in TAC mice. SA4503 administration also decreased hypertrophy-induced impairments in LV contractile function. Conclusions: σ1R stimulation with the specific agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca(2+) mobilization and ATP production via σ1R stimulation. General significance: Our observations suggest that σ1R stimulation represents a new therapeutic strategy to rescue the heart from hypertrophic dysfunction.
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Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. Sig-1Rs are intracellular chaperones that reside specifically at the endoplasmic reticulum (ER)-mitochondrion interface, referred to as the mitochondrion-associated ER membrane (MAM). Here, Sig-1Rs regulate ER-mitochondrion Ca(2+) signaling. In this review, we discuss the current understanding of Sig-1R functions. Based on this, we suggest that the key cellular mechanisms linking Sig-1Rs to neurological disorders involve the translocation of Sig-1Rs from the MAM to other parts of the cell, whereby Sig-1Rs bind and modulate the activities of various ion channels, receptors, or kinases. Thus, Sig-1Rs and their associated ligands may represent new avenues for treating aspects of neurological and psychiatric diseases.