Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
1
All-natural 5-MeO-DMT sigma receptor 1 agonist and
its therapeutic impact in mental and neurodegenera-
tive diseases through mitochondrial activation
Milena Batalla, PhD
Panarum Corporation, USA; milenabatalla@panarum.com
https://orcid.org/0009-0004-7002-1701
https://doi.org/10.57098/SciRevs.Biology.2.2.1
Received May 13, 2023. Revised June 20, 2023. Accepted June 22, 2023.
Abstract: The sigma-1 receptor S1R is a chaperone that resides mainly at the mitochondrion-associated
endoplasmic reticulum ER membrane MAM, it is considered a “pluripotent modulator” in living systems, plays
a critical role in maintaining neuronal homeostasis and acts as a dynamic pluripotent modulator in living
systems. Given its specific localization at the MAM, S1R plays a major role regulating mitochondrial function,
it is a therapeutic target in mental and neurodegenerative diseases including Alzheimer’s disease, Parkinson’s
disease. N,N Dimethyl Tryptamine DMT is the S1R endogen agonists and we review the role of all-natural 5-
methoxi-N,N-dimethyltryptamine 5-MeO-DMT S1R agonist that produces high levels of ego dissolution or
oceanic boundlessness higher ratings of satisfaction with life and lower ratings of depression and stress. In vitro
the 5-Meo-DMT shows strong modulation of synaptic and cellular plasticity in neurons. 5-MeO-DMT
neuropharmacological S1R agonist is implicated in cellular bioenergetics activation, antiapoptotic and
mitochondrial regulation of epigenetic landscape in neurons. S1R has been considered as a controller of cell
survival and differentiation in neurons. The pharmacological benefits of all-natural 5-MeO-DMT are currently
under research. This review compendia results, highlighting the key molecular mechanisms of S1Rs on
mitochondrial functions and epigenetic modifications involved in the health and sickness phenotype
development, and describe the possible pharmacological use of all-natural 5-MeO-DMT to “rescue” patients
from sickness phenotype through mitochondrial activation. We focus on all-natural 5-MeO-DMT its clinical
therapeutic implications benefit long-term effects on mental health and well-being of the patient possibly
reprogramming and remodeling the epigenome, particularly in mental and neurodegenerative diseases.
Keywords: Sigma1 receptor, mitochondria, energy, dysregulation, stress, ROS, epigenetic, disease, all-natural,
5MeO-DMT, therapy.
Introduction
Hundreds of millions of people worldwide are af-
fected by the pandemic of mental
1
and neurodegen-
erative
2
diseases. Given the specific localization of
the Sig-1R at the MAM, have been very explored as
target regulations of the Sig-1R in mental and to
neurodegenerative diseases including Alzheimer’s
disease (AD), Parkinson’s disease (PD), among oth-
ers
3
. Sig-1R ligands are fundamental on mitochon-
drial dysfunction-induced neurodegeneration are
addressed. DMT is the endogen agonist of sigma
receptor and in this report, we particularly review,
the role of all-natural 5-Meo-DMT as a pharmaco-
logical agonist for the Sigma 1 receptor
4
. All-natural
5-methoxy-N,N-dimethyltryptamine, hereinafter
referred to as all-natural 5-MeO-DMT, is a entheo-
gen substance found in the secretion from the paro-
toid glands of the Bufo alvarius toad is agonist of
Sigma 1 receptor. The all-natural 5-MeO-DMT ad-
ministrated in humans in naturalistic settings as a
treatment of mental health problems and as a means
for spiritual exploration is currently researched.
Numerous patents and clinical studies that describe
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
2
the pharmacological benefits of 5-MeO-DMT are
ongoing
5
.
The mitochondria are the power station that pro-
vides the necessary energy for the processes that
sustaining life
6
. The mitochondria perform diverse
interconnected functions, producing ATP and
many biosynthetic intermediates while also contrib-
uting to cellular stress responses such as autophagy,
apoptosis and epigenetic regulation
7
. Mitochondria
form a dynamic, interconnected network that is in-
timately integrated with other cellular compart-
ments. In addition, mitochondrial functions extend
beyond the boundaries of the cellular influence and
organism's physiology by regulating communica-
tion between cells and tissues. These characteristics
define mitochondria both as fundamental compo-
nents of our cells specially in neurons
8
. Mitochon-
drial dysfunction has emerged as a key factor men-
tal
9
and neurodegenerative disorders
10
. In this re-
view we focus the regulation of cellular functions
through the mitochondrial bioenergetic, signaling,
antiapoptotic and epigenetics regulation pathways.
Hence, we provide an innovative perspective in
which we highlight the key molecular mechanisms
advances in sigma-1 receptors on mitochondrial
functions and epigenetic regulation on healthiness
and sickness, with special focus on mental and neu-
rodegenerative diseases and clinical implications of
all-natural 5-MeO-DMT S1R agonist.
Mitochondria: In Healthiness and In Sickness
Mitochondria are critical to cell and organ function;
Mitochondria play a key role in metabolic homeo-
stasis, because of their central role in energy pro-
duction, control of cytosolic Ca2+ (calcium ion) lev-
els, lipid homeostasis, steroid synthesis, generation
of Fe-S (ironsulfur) centers, heme synthesis
11
, in-
nate immune response, and metabolic cell signal-
ing
1216
. For all the above mentioned, mitochondrial
dysfunction and altered organellar regulation are
also associated with some more common diseases,
including cancers, mental, neurodegenerative dis-
eases
12,13
. Mitochondria are the main regulator of
cell survival/death as well as that for the ROS pro-
duction.
Mitochondria produce ATP via oxidative phos-
phorylation (OXPHOS). In the matrix, tricarboxylic
acid cycle (TCA) enzymes generate electron carriers
(NADH and FADH2), which donate electrons to the
IM-localized electron transport chain (ETC) and
also generate reactive oxygen species (ROS) which
can damage key components of cells, including li-
pids, nucleic acids, and proteins
15
. ROS has been
suggested to contribute to diseases associated with
mitochondrial dysfunction, including neurodegen-
eration.
Another central function of mitochondria is ROS
signaling and sensing. Mitochondria operates as re-
dox sensors that can alter energy states in response
to the chemical environment of the cell and relative
levels of endogenous metabolites such as iron (II),
succinate, and ascorbate, as well as various forms of
ROS. However, how ROS sensing is mediated by
mitochondrial function and how different ROS
sensing pathways overlap are not well understood.
Changes in redox states influence DNA methyla-
tion because the oxidation of 5-methylcytosine to 5-
hydroxymethylcytosine in CpGs can perturb recog-
nition by methyl-binding proteins and subse-
quently alter methylation patterns and epigenetic
regulation
7,15
.
Metabolic epigenetics refers to nuclear alterations of
chromatin and other factors that regulate gene ex-
pression resulting from changes in mitochondrial
energetics and metabolism. The resulting metabo-
lites, in turn, mediate gene expression changes that
control cellular processes, including energy homeo-
stasis
16
. Thus, energy status and metabolism are
able to modulate epigenetic programming via chro-
matin structural changes and dynamics, DNA
methylation, histone modifications, and non-coding
RNA expression. Epigenetic modifiers include
DNA methyltransferases, histone acetyl transfer-
ases, histone deacetylases, sirtuins (SIRTs), histone
lysine demethylases, poly(ADP-ribose) polymer-
ases, and others that work coordinately to regulate
gene expression. For instance, reprogramming of
energy metabolism has been identified as hallmark
of cancer
17
and epigenetic control
18,19
.
Mitochondrial distribution and dynamics are influ-
enced by physical interaction between the mito-
chondrial outer membrane and diverse intracellular
membranes, such as the plasma membrane, peroxi-
somes, ER, autophagosomes and lysosomes, termed
mitochondria-associated membranes (MAMs).
MAMs create unique environments or platforms for
the localization and activity of components that
function in shared inter-organellar functions, such
as Ca2+ homeostasis and lipid biosynthesis
20-22
.
MAM is critical in maintaining neuronal homeosta-
sis. Thus, given the specific localization of the S1R
at the MAM, we highlight and propose that the di-
rect or indirect regulations of the S1R on mitochon-
drial dysfunctions intervenes to mental and
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
3
neurodegenerative diseases
3
. Neurons and muscle
cells contain high levels of mitochondria due to a
high demand of energy. The Central Nervous Sys-
tem (CNS) has a high rate of metabolism because
neurons participate in facilitating the neurotrans-
mission and extending axons and dendrites to
neighboring cells for impulse transmission
23
. Neu-
rons exert plasticity, exhibiting complex morpholo-
gies, and constitutively undergo synaptic modula-
tions when stimulated. Therefore, mitochondrial
dysfunction detrimental to neurons and has been
extensively discussed in neurodegeneration
24
.
Biological and physiological function of Sigma
receptors in mitochondria
Biological and physiological function of Sigma re-
ceptors in mitochondria The S1R is a small (28 kDa),
highly conserved, chaperone that resides mainly at
the mitochondrion-associated endoplasmic reticu-
lum (ER) membrane (called the MAMs) and acts as
a dynamic pluripotent modulator in living sys-
tems
24
. Chaperones are proteins that assist the cor-
rect folding of other protein clients. The S1R is
known to play a role in regulating the Ca2+ signal-
ing between ER and mitochondria and in maintain-
ing the structural integrity of the MAM
25
. The MAM
serves as bridge between ER and mitochondria reg-
ulating multiple functions such as Ca2+ transfer,
energy exchange, lipid synthesis and transports,
and protein folding that are pivotal to cell survival
and defense. Therefore, the S1R serves as a commu-
nicator that bridges these two organelles and plays
pivotal roles in mitochondrial functions
26
.
Interestingly, the percentage of newly synthesized
proteins that are correctly folded and thus are able
to exit the ER is usually less than 10%. Because the
action of chaperones is fundamental to the cell,
chaperones are implicated in many diseases includ-
ing Huntington disease
28
, Parkinsonism
29
, stress
disorders
30
. Under pathological conditions, the S1R
is a receptor chaperone essential for the metabo-
tropic receptor signaling and for the survival
against cellular stress losing its global Ca2+ homeo-
stasis the S1R translocates and counteracts the aris-
ing apoptosis
31
.
The S1R receptor has a unique and versatile phar-
macological profile
4,32
and its endogenous agonist is
Dimethyl tryptamine (DMT). S1R ligands have
therapeutic usages in regulating the stability of IP3
receptors as well as the associated interorganelle
Ca2+ signaling from the ER to mitochondrion un-
der normal or otherwise pathological conditions
33-
36
. S1R bind with high affinity to several classes of
chemically unrelated ligands such as neuroster-
oids
37
, neuroleptics, dextrobenzomorphans [DEX]
and several psychostimulants such as cocaine
37
,
methamphetamine [METH]
37,38
methylenediox-
ymethamphetamine [MDMA]
39
and methacathi-
none
37,40
. Consequently, it is thought that the SR
may mediate the immunosuppressant, antipsy-
chotic
41
and neuroprotective effects of many drugs
42
S1Rs regulate a number of neurotransmitter sys-
tems, including the glutamatergic [Glu], dopamin-
ergic [DA], serotonergic [5HT], noradrenergic [NE]
and cholinergic [Ch] systems. As these transmitters,
which interact with the S1Rs, are involved in many
neuropsychiatric disorders their role has been eval-
uated in a number of these disorders
43
. In fact, sev-
eral lines of research have demonstrated that S1R
play a role in the pathophysiology of neuropsychi-
atric disorders such as mood
44
, anxiety disorders
45
and schizophrenia
26,46
.
The acute S1R actions include the modulation of ion
channels (e.g. K+ channel), N-methyl-D-aspartate
receptors (NMDARs)
47
, IP3R and s1R translocation.
Chronic actions of S1Rs are considered to be the re-
sult of an up- or down regulation of the S1R itself.
Recent in vitro and in vivo studies strongly point
that S1Rs participate in membrane remodeling and
cellular differentiation in the nervous system recon-
stitution in the brain implicated on drug abuse
48
.
Metabolic studies support the view that S1R have
functional significance in brain glucose metabolism
as glucose utilization is affected by ligands in areas
of brain that show high densities of sRs
48
. S1R might
possess a constitutive biological activity, and that
S1R ligands might merely work as modulators of
the innate activity of this protein. The lack of post-
natal development of receptors in the CNS, and the
fact that S1R sites are much denser in peripheral or-
gans, such as the liver
49
, immune and endocrine tis-
sues
50,51
, suggest a universal role for sRs in cellular
function. Because of their widespread modulatory
role, S1R ligands have been proposed to be useful
in several therapeutic fields such as amnesic and
cognitive deficits, depression and anxiety, schizo-
phrenia, analgesia and against some effects of drugs
of abuse such as cocaine and METH and neuro-
degenerative diseases
40,52
.
The mitochondrial role of the sigma1 receptor
in neurodegenerative diseases
Given the specific localization of the S1R at the
MAM, we highlight and propose that the direct or
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
4
indirect regulations of the S1R on mitochondrial
functions intervenes to neurodegenerative diseases.
These receptors represent compelling putative tar-
gets for pharmacologically treating neurodegenera-
tive disorders. Neurodegenerative diseases with
distinct genetic etiologies and pathological pheno-
types appear to share common mechanisms of neu-
ronal cellular dysfunction, including excitotoxicity,
calcium dysregulation, oxidative damage, ER stress
and mitochondrial dysfunction
53,54
.
Sustained release of glutamate causes persistent ac-
tivation of NMDARs leading to neuronal excitotox-
icity, increasing intracellular calcium levels, fol-
lowed by stochastic failure of calcium homeostasis
and necrotic cell death
52
. This toxicity results from
activation of the mitochondrial permeability transi-
tion pore opening triggered by membrane poten-
tial-dependent uptake of calcium into the mito-
chondrial matrix
53,54
, contributing to neurodegener-
ation in acute and chronic CNS diseases, including
ALS, AD, and PD disease
55-57
. Hence, one major
mechanism by which S1R ligands may confer neu-
roprotection is through the regulation of intracellu-
lar calcium homeostasis
58
.
The best evidence that ROS may be an underlying
cause of neurodegeneration is the strong associa-
tion between the detection of increased ROS pro-
duction and the increased oxidative damage ob-
served in CNS disorders such as PD, AD and
ALS
59,60
. Activation of Sig-1Rs may also mitigate
ROS accumulation, possibly through modulation of
ROS-neutralizing proteins. Furthermore, Sig-1R
knockout or knockdown can increase oxidative
damage
61
.
Protein aggregation occurs under calcium dysregu-
lation, oxidative stress or aging, altering ER func-
tion and leading to the accumulation of unfolded or
misfolded proteins within the ER lumen. This trig-
gers a stress response by the ER known as the un-
folded protein response (UPR) to restore protein
folding homeostasis. The failure of protein homeo-
stasis is a common mechanism for many neuro-
degenerative diseases AD, PD, and HD
62,63,64
.
Mitochondrial fission and fusion are part of normal
organellar maintenance, and are particularly signif-
icant in axons, in which mitochondria may have to
travel long distances. Recent work has identified
that the dynamin-related protein 1 (Drp1) is re-
cruited to ER-mitochondria contact sites and medi-
ates fission and it’s been shown that homozygous
knockout of Drp1 is lethal
65
, while fragmented mi-
tochondria and elevated or modified Drp1 (i.e., in-
creased fission activity) are associated with AD, PD,
and HD
66
. Mitochondria-MAM dysregulation has
been proposed as the underlying cause of AD
67
and
may contribute to neuronal loss in other disease
contexts
68
.
S1Rs may also influence the expression of anti- and
pro-apoptotic signals that target the mitochondria.
Sig-1R activity positively regulates Bcl-2 expres-
sion, possibly through nuclear factor kappa B (NF-
kB) and/or extracellular signal-regulated kinase
(ERK) pathways
68,69
. Since Bcl-2 has also been
shown to interact with IP3Rs and enhance their ac-
tivity
69
, this positive regulation of Bcl-2 level may be
another mechanism by which sigma 1 activity in-
creases IP3R-mediated mitochondrial calcium up-
take and ATP production, in addition to the S1R-
IP3R interaction described above. Activation of
S1Rs may also decrease expression of Bax and apop-
tosis associated caspases, further promoting cell
survival
3,70,71
.
Alzheimer Disease (AD) is a complex, multifactorial
disease characterized by severe cognitive impair-
ment and memory loss. Decreased S1R protein lev-
els were observed in the human living
and cortical
postmortem brain tissue
72,73
and similar results
were found in PET scan studies, in which Sig-1R ex-
pressions were lower in the brain of early AD pa-
tients
74
.S1R expression may be involved in the ther-
apeutic effect of HDAC6 inhibitor on AD pathol-
ogy
75
. Preclinical evidences suggest that S1R ago-
nists might be useful in treating AD, no selective
S1R agonist is currently available for clinical use
3
,
specific sigma 1 receptor agonist as all-natural 5-
MeO-DMT
4
has advantages to be consider in clini-
cal use.
Parkinson’s disease (PD) is a slowly progressing
disorder, causing impaired motor functions such as
bradykinesia or tremor, and other non-motor com-
plications. The pathological characteristic of PD is a
massive death of dopaminergic neurons in substan-
tia nigra pars compacta (SNpc) and the deposit of
Lewy bodies composed of α-synuclein, ubiquitin
and neurofilaments. S1R expressions were lower in
putamen of PD patients as demonstrated by PET
studies
76
. S1R also attenuate Dopamine (DA) tox-
icity involved in the etiology of PD
61
. S1R agonists
were found to reduce oxidative stress via several
signaling pathways
77
. Endogenous S1Rs could toni-
cally inhibit DA-induced NF-κB activation, which
protects cell from death. Thus, S1R ligands may rep-
resent new therapeutic targets for PD
3
. These data
suggest that S1Rs are one of the endogenous
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
5
substrates that counteract the dopamine cytotoxi-
city that would otherwise cause apoptosis
61
.
Endogenous DMT and all-natural 5-MeO-DMT are
sigma 1 receptor agonists - Mode of action
Endogenous DMT is Sigma 1 receptor agonist a
molecule synthesized, stored, and released it is ag-
onist of S1R
78
in cells periphery and central nervous
system
79
. DMT is Central Nervous System neuro-
transmitter involved in sensory perception
80
. En-
zyme indolethylamine-N-methyltransferase
(INMT), is the responsible of DMT synthesis
81
.
INMT is widely expressed in the body, primarily in
peripheral tissue such as the lungs, thyroid and ad-
renal gland, skeletal muscle, heart, small intestine,
stomach, retina, pancreas, lymph nodes and
blood
82
. It is densely located in the anterior horn of
the spinal cord
8287
. Highest INMT activity has been
found within the brain in the following areas: un-
cus, medulla, amygdala, frontal cortex
83
, frontal-pa-
rietal and temporal lobes
87,88
, pineal gland
87
and pla-
centa
88
. DMT has been measured in several human
body fluids, including blood
82
, urine and cerebral
spinal fluid. Endogenous DMT binds to sigma-1 re-
ceptors as an agonist at half maximal effective con-
centration EC50 = 14 μM. INMT co-localizes with
sigma 1 receptor in C-terminals of motor neurons
89
.
Only a small fraction of endogenous DMT is re-
leased into the bloodstream
90
. DMT has a transport
process
91
accomplished via ATP-dependent uptake
similar to the biological priority of glucose and
amino acids, showing the universal role DMT in bi-
ological processes. The three-step process by which
DMT is accumulated and stored in neurons are de-
scribed
92
. Once uptake and storage of DMT has
been completed, it has remained stored in vesicles
for at least 1 week and to be released under appro-
priate stimuli
93
. Through these three steps, periph-
eral synthesis of DMT, consumption of DMT con-
taining plant matter, or systemic administration of
DMT can influence central nervous system func-
tions
91
. In cardiovascular system the effect of DMT
was determined, by administration of DMT to hu-
man volunteers, a progressive decrease in heart rate
was observed over the four doses, but not in blood
pressure
79
.
Endogenous DMT plays a significant role in physi-
ological mechanisms via S1R-MAM-mitochondrial
pathway. S1R
94
agonists are neuroprotective via
several mechanisms. DMT and also 5-MeO-DMT
reduced inflammation via S1R and induced neu-
ronal plasticity
95
, which is a long-term regenerative
process that goes beyond neuroprotection
96
. DMT
and 5-MeO-DMT modulate innate and adaptive in-
flammatory responses through the S1R of human
monocyte-derived Dendritic cells
97
. DMT mediated
S1R activity induces neuronal plasticity changes in
newborns
96
. Exogeneous DMT stimulates the in
vitro differentiation of neural progenitors toward a
neuronal phenotype through S1R. DMT in vivo ac-
tion mediated by S1R improved performance in
learning tasks that has been linked to hippocampal
neurogenesis. Moreover, previous studies per-
formed in humans
98
, using the traditional medicine
of native peoples of South America Ayahuasca
which main component is DMT infusion
99
has anti-
depressant activity, a therapeutic effect usually
linked to hippocampal neurogenesis
100
.
All-natural 5-MeO-DMT is found as a natural ex-
tract from the secretions of the Sonoran Desert Bufo
alvarius toad gland and is considered an Amerin-
dian medicine Seris, an aboriginal group from the
state of Sonora, in Mexico
5
. Some reports suggest
that the secretion of the Bufo alvarius toad have been
used historically by native peoples in the south-
western territory of the USA and northern Mex-
ico
101
. This entheogenic sigma 1 receptor agonist
has recently been associated with cognitive gains,
antidepressant effects and changes in brain areas re-
lated to attention and neural regeneration
4
. 5-MeO-
DMT is a neuroregulatory substance, sigma-1 re-
ceptor
4
is its neuropharmacological target. 5-MeO-
DMT is the most potent entheogen with strong dis-
solution of the ego, a conscious state marked by a
loss or diminution of one’s sense of self and a lack
of first-person experience
102
, influence on percep-
tion
5
, cellular bioenergetics activation, antiapop-
totic
4
and mitochondrial regulation of epigenetics.
5-MeO-DMT mechanism of action is mediated S1R
signaling pathway a “pluripotent modulator” in
living systems, as a controller of cell survival and
differentiation
25,58
. The S1R is the primary pharma-
cological molecular targets for 5-MeO-DMT and its
mitochondrial activation play roles dissolving
symptoms of some psychiatric and neurodegenera-
tive disorders by the epigenetic regulate
91
. Possibly,
5-MeO-DMT shed light into the therapy on recov-
ery patients health from mental diseases and neuro-
degenerative diseases.
In vivo pharmacology studies of 5-MeO-DMT
93
have
been conducted in mice, rats, gerbils, hamsters,
guinea pigs, rabbits, goldfish, cats, dogs, sheep, pigs
and primates. The pharmacokinetics of 5-MeO-
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
6
DMT has been studied the maximum concentration
(Cmax) in plasma is reached after 56 min following
an intraperitoneal (IP) injection, the terminal half-
life (t1/2) is 1219 min in mice and Cmax = 510 min
and t1/2 = 616 min in rats. 5-MeO-DMT presents a
hydrophobic behavior (3.3 oil/water partition coef-
ficient) and readily crosses the bloodbrain barrier
(BBB). 5-MeO-DMT is distributed to the liver, kid-
neys and brain. Brain concentrations of 5-MeO-
DMT in the rat were 1.7-fold higher compared to
plasma after IP injection, with highest concentra-
tions in the cortex, thalamus, hippocampus, basal
ganglia, medulla, pons and cerebellum. In the
mouse brain, 5-MeO-DMT distributes to the cortex,
hippocampus, hypothalamus and striatum after IP
administration
4,92
. It has been demonstrated that
the pharmacokinetics of 5-MeO-DMT follows a
non-linear pattern for both IP and intravenous (IV)
administration of high doses in mice. This non-line-
arity is also reflected in corresponding increases in
brain concentration of 5-MeO-DMT. This enzyme
mediates the production of the psychoactive metab-
olite bufotenine from 5-MeO-DMT
5
.
Long-term potentiation (LTP) is a persistent
strengthening of synapsis based on recent patterns
of activity. These are patterns of synaptic activity
that produce a long-lasting increase in signal trans-
mission between two neurons
103
. The opposite of
LTP is long-term depression, which produces a
long-lasting decrease in synaptic strength. Specifi-
cally, 5-MeO-DMT modulates proteins associated
with long-term potentiation. Proteins found upreg-
ulated by 5-Meo-DMT are NMDAR, CaMK2
(Ca2+/calmodulin-dependent protein kinase), and
CREB (cyclic AMP-responsive element-binding
protein)
20
.
5-MeO-DMT is a weak 5-HT reuptake inhibitor but
has no appreciable effects on monoamine release
nor on noradrenaline or dopamine. S1R contributes
to the brain plasticity effects of 5-MeO-DMT. S1R is
an endogenous regulator of dendritic spine mor-
phology and neurite outgrowth
104,105
. 5-MeO-DMT
is a direct molecular mediator of plasticity, which
has effects on cell surface and extracellular proteins
involved in regulating synaptic architecture. An up-
regulation of integrins
98
, netrins, plexins, and sem-
aphorins were observed in 5-MeO-DMT-treated or-
ganoids, was also found in major depressive disor-
der patients who responded well to antidepres-
sants, suggesting the importance of this class of pro-
teins in brain plasticity. srGAP, an intracellular
signaling molecule with a role in processes under-
lying synaptic plasticity, higher cognitive function,
learning, and memory is significantly downregu-
lated
106
. S1R agonists exert neuroprotective effects
by regulating intracellular calcium levels
107
, pre-
venting expression of pro-apoptotic genes
108
, and
protecting mRNA against anti-apoptotic genes such
as Bcl-23. Psychological effects such as changes in
perception and thought, renewed sensation of nov-
elty, ineffability, and awe
109
possible is derive di-
rectly from the strong modulation of synaptic and
cellular plasticity promoted by 5-MeO-DMT.
Mitochondria-directed epigenetic changes and
role of 5-MeO-DMT
Cells respond to environmental stressors through
several key pathways, including
response to ROS, nutrient and ATP sensing, DNA
damage response, and epigenetic alterations. Mito-
chondria play a central role in these pathways
through energetics, ATP production, metabolites
generated in TCA cycle, also through and mito-
chondrianuclear signaling related to mitochondria
morphology, biogenesis, fission/fusion, mitoph-
agy, apoptosis, and epigenetic regulation
110
.
Possibly the neuroprotective, neuroregeneration,
anti-apoptosis and neuroplasticity
111
effects from 5-
MeO-DMT agonist S1R is mediated through mito-
chondrial epigenetic regulation pathway. Each neu-
ron contains up to 2 million mitochondria
112
. The
energy-hungry brain is especially vulnerable to
power station problems during mitochondrial dam-
age
113
. Mitochondrial regulation of epigenetic land-
scape alterations are reversible, epigenetic pro-
cesses early in life might play a role in defining in-
ter-individual trajectories of human behavior and
epigenetic mechanisms contribute to later-onset
neurological dysfunction and disease
19
. Some epi-
genetics diseases targets with significant neuronal
death and neurological dysfunction include Alz-
heimer’s Disease (AD), Parkinson’s Disease (PD),
Huntington’s Disease (HD), epilepsy, stroke and
traumatic brain injury (TBI)
114
. Alterations of the
S1R gene have been associated with severe neuro-
degenerative disorders
24
.
mtDNA damage or mitochondrial damage has been
associated with a mitochondrial damage check-
point “mitocheckpoint”
115
. OXPHOS defect is
checkpoint mechanism induced due to instability of
the nuclear genome
116
. The mitocheckpoint coordi-
nates and maintains the proper balance between
apoptotic and anti-apoptotic signals. Upon damage
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
7
to mitochondria, mitocheckpoint is activated to
help repair damage to mitochondria, restore normal
mitochondrial function, avoid induction of mito-
chondria-defective cells and induce changes to the
nuclear epigenome
117
. Cross talk between the nu-
cleus and mitochondria of individual cells may lead
to a mitochondrial damage response as a result of
incurred damage. If mitochondria are severely
damaged, such an event will trigger apoptosis. If
damage to mitochondria is persistent and defective
mitochondria accumulate in the cell, it would lead
to instability of the nuclear genome
114
.
DNA methylation is a major epigenetic modifica-
tion of DNA gene expression possible mitochondria
regulated
71
. Epigenetic modifications within the
mammalian nuclear genome include DNA methyl-
ation (5-mC) or hydroxymethylation (5-hmC)
118,120
.
Mammalian mitochondria have recently been iden-
tified to have mitochondrial DNA methyltransfer-
ase 1 (mtDNMT1) activity, 5-mC and 5-hmC. Shock
et al. identified translocation of nuclear DNMT1 to
the mitochondrial matrix is regulated by expression
of a conserved mitochondria targeting sequence,
upstream of the gene’s transcription start site
within the nuclear encoded gene
120
. Alterations in
mtDNMT1 directly affected transcription from the
light and heavy strands of mtDNA suggesting a cor-
relation between 5-hmC and 5-mC mediated tran-
scriptional regulation of mtDNA by a nuclear en-
coded gene. These findings provide new evidence
implicating epigenetic regulation of the mitochon-
drial genome by nuclear encoded translocated
mtDNMT1 relative to mitochondrial dysfunc-
tion
121123
. Reduced levels of co-factors due to mito-
chondrial impairment/ dysfunction could have sig-
nificant effects on regulation of the nuclear genome.
Mitochondrial dysfunctions invoke mitochondria-
to-nucleus retrograde responses in human cells
124
.
Mitochondrially targeted DNMT1 transcript vari-
ant (mtDNMT1) comprises about 12% of total
DNMT1 transcripts and is upregulated by the hy-
poxia-responsive transcription factors peroxisome
proliferator-activated receptor gamma coactivator 1
alpha (PGC1a) and nuclear respiratory factor 1
(NRF1) and via the release of p53 from the DNMT1
promoter
125
. This finding suggests that mtDNMT1
plays a regulatory role during oxidative stress, con-
firming the link between oxidative stress and mito-
chondrial function. Similar capacities for
mtDNMT1 and its nuclear counterpart were indi-
cated by the finding that mtDNMT1 shows clear
CpG-dependent mtDNA interactions proportional
to the amount of CpGs in the target amplicons
126
.
The reduced mtDNA methylation is the result or a
consequence of this mitochondrial dysfunction.
mtDNA methylation activation would be involved
in mitochondrial biogenesis (LSP, HSP1) and
maintenance of the electron transport chain
(HSP2)
127
.
Maternal mitochondrial imprinting and chromo-
somes imprinting from parents’ patterns, would
represent a biological memory of what the parents
experienced
128
. Transmission caused by environ-
mental factors, such as the parents’ childrearing be-
havior
129
. That these transgenerational effects have
been also epigenetically transmitted to their chil-
dren. Integrating both hereditary and environmen-
tal factors through the lifetime, epigenetics adds a
new and more comprehensive transgenerational
transmission of trauma
130
, nightmares
131
, posttrau-
matic stress disorder PTSD
132
, symptoms in mental
diseases and the neurodegeneration. Moreover, the
transmission may continue beyond the second gen-
eration and also include the grandchildren, great
grandchildren and perhaps others as well. This pro-
cess of transgenerational transmission of trauma
(TTT) has been repeatedly described in the aca-
demic literature for more than half a century
131
. The
epigenetic marks affect gene expression patterns in
the nervous system and mitochondrial dysfunction
and epigenetic imbalance show to influence the pro-
gression of many mental and neurological disor-
ders
128
. S1R agonist
4
5-MeO-DMT
5
are possible
through epigenetic regulation by activation mito-
chondrial pathway reversible promote restoring to
healthy cellular functions by restoring the epige-
netic landscape.
Familial early-onset Alzheimer’s disease (AD) is
more probable in individuals coming from mothers
diagnosed with AD than from fathers diagnosed
with AD. Studies in animal models have shown ma-
ternal imprinting in the ovum lead to alterations ge-
netic and/or epigenetic in the nuclear and/or the
mitochondrial DNA. These modifications that are
transmitted to the new living beings affect more mi-
tochondrial proteins and, therefore, the mitochon-
drial function may be affected in adulthood by
trends present in the ovum
133
.
PD, AD
133
, HD and other neurodegenerative dis-
eases
123
and forms of acute brain injury
24
. In our per-
spective is possible activation of epigenetic
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
8
mechanism
7
through S1-R and mitochondrial func-
tion in mental and neurodegenerative diseases,
whose restore by 5-MeO-DMT agonist promote ac-
tivation mitochondrial pathways, mitochondria bi-
oenergetics function
134137
, mitochondrial oxidative
respiration
138
and mitochondrial epigenetic regula-
tion, restored mtDNMT nuclear activity, increasing
levels mitochondrial FAD and α-KG co-factors who
have significant effects on regulation of the nuclear
genome. 5-MeO-DMT modulates proteins involved
in long-term potentiation (LTP), in addition to mor-
phogenesis and maturation of dendritic spines,
while inhibiting neurodegeneration and apoptosis.
5-MeO-DMT activate score for dendritic spine and
cellular protrusion formation, microtubule and cy-
toskeletal organization. Biological functions such as
neurodegeneration, apoptosis, and neuron lesion
are inhibited by 5-MeO-DMT
4
through S1R-mito-
chondria pathway.
Figure 1: 5-MeO-DMT Sigma 1 receptor agonist nuclear epigenetic regulation/chromatin modification through mito-
chondriavia sirtuins (e.g., SIRT1 and SIRT6), HDACs, and HATs, which require acetyl CoA from the TCA cycle; nu-
trient sensing through the NAD+/NADH and ATP/AMP sensing; catalysis of H3K4me2 and H3K27me3, demethyla-
tion mediated by LSD1 and the JMJD protein family, catalyzed using mitochondria synthesized co-factors FAD and α-
ketoglutarate. DNA repair and redox signaling pathways. Dialog mitochondria and nucleus: mtDNMTs are associated
with healthy mitochondria. The reduced mtDNA methylation is the result of mitochondrial dysfunction. mtDNMT1
from nucleus are translocated in mitochondrial dysfunction.
Clinical implications of the therapeutic use of
all-natural 5-MeO-DMT
All-natural 5-MeO-DMT
139
is high potency, ultra-
rapid onset, and short duration of entheogen ef-
fects, primarily is sigma 1 receptor agonist. Native
peoples of North, Central, South America, included
Amazon region America possibly used the ancestral
medicine in millenary sacred ritualist healing and
consciousness evolution purposes according their
cosmovision. All-natural 5-MeO-DMT produces
profound altered state of consciousness and ego
dissolution, including mystical experiences as inner
experiences involving an intensely felt fading of the
sense of self and/or feelings of increased connect-
edness, up to and including the sense of complete
unity
163
. These kinds of feelings go well beyond our
normal day to day sense of self-awareness. In ordi-
nary consciousness, there is generally the impres-
sion that there is a me on the one hand and then, on
the other hand, everything else. Under some cir-
cumstances, however, this sense of self ––during
such moments, one’s sense of self can fade into the
background and become a part of, rather than apart
Metabolites for
epigenetic regulation
• NAD+
• ATP
• SAM
α-Ketoglutarate
• Acetyl CoA
5-MeO-DMT
Sigma 1 Receptor
ER
FAD FADH2
O2 H2O2
α–KG
Fe
LSD1
JMJD
DNMTs
REDOX signaling
Nutrient
sensing
Target
Genes
Target
Genes
DNA repair
Apoptosis
Cell cycle
arrest
NAD+
NADH
H2O2
SOD
O2
O2
ADP+ Pi
ATP
Epigenetic
regulation
ATP/AMP
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
9
from, everything else
140
, with beneficial long-term
effects on mental health and well-being of the pa-
tient
139
.
Naturalistic use of toad secretion containing 5-
MeO-DMT was reported that the intensity of the ex-
perience is associated with improvements in
measures of satisfaction with life and reduction of
psychological distress in participants without an
underlying mental health condition
141
. Effects fol-
lowing natural 5-MeO-DMT administration are al-
teration in auditory and time perception, emotional
states amplifications, and strong ego dissolution
short-lasting, and reliably induces a “peak” mysti-
cal spiritual experience
141
, state consider to be a core
predictor of the efficacy of entheogen all-natural 5-
MeO-DMT
139
. 5-MeO-DMT cause rapid and sus-
tained reductions in symptoms of depression, anxi-
ety, and stress. 5-MeO-DMT also stimulates neuro-
endocrine function and immunoregulation
93
.
Formulations of interest are smoked, vaped, IM, in-
tranasal, intravenous for high bioavailability of 5-
MeO-DMT because they avoid first-pass metabo-
lism. Smoked and vaporized administration pro-
vides fast onset of subjective experiences with high
intensity and short duration. At present, biophar-
maceutical companies with an interest in synthetic
5-MeO-DMT are exploring and developing vapor-
ized, intranasal, IM, and intravenous formulations
for delivering 5-MeO-DMT
141,142
. In a dose-ranging
Phase I clinical trial to assess safety and psychoac-
tive effects of 5-MeO-DMT, demonstrated the safety
of vaporized dosing up to 18 mg for administration
via inhalation. Importantly, the rapid onset and
short duration of the 5-MeO-DMT experience ren-
der it more suitable for individual dose-finding
strategies compared with longer-acting psychedel-
ics
143
.
Clinical implication of the all-natural 5-MeO-DMT
receptor sigma agonist and its role on mitochon-
drial activation it is possible applicated to the ther-
apy of serious psychiatric disordersSchizophre-
nia (SCZ), major depressive disorder (MDD), and
borderline personality disorder (BPD) diseases with
a different range of debilitating symptoms and
prognosis, and show similar alterations in energy
metabolism processes
144
. Proteomic data show that
SCZ and BPD share 32 altered proteins, mostly re-
lated to mitochondrial electron transport, response
to ROS and glycolysis. They share some pathophys-
iological traits and data analysis revealed seven
proteins altered both in BPD and MDD, while five
of those are different subunits of the NADH dehy-
drogenase complex in the electron transport
chain
144
. This is consistent with previous reports of
impaired functioning of OXPHOS complexes in
MDD
144,145
and decreased nuclear expression of
genes coding for mitochondrial respiratory mecha-
nisms in BPD
146
both of which lead to reduced mi-
tochondrial energy production. major depression
has been described as the initial symptom of mito-
chondrial disease in a large sample size of adult pa-
tients
147
. Mitochondrial function and energy metab-
olism were shown to play an important role in reg-
ulating social behaviors
148
. Limited energy produc-
tion impairs adaptive neuronal capacity and con-
tribute to the development of psychopathologies
such as SCZ, BPD, and MDD under stressful stimu-
lus
149
.
All-natural 5-MeO-DMT patented composition
comprise its possible use in the therapy to mental
and neurodegenerative diseases
139
. One of the most
important benefit uses of all-natural 5-MeO-DMT
reported are the patient’s recovery from addiction
prompted by cocaine
5
. S1R mediated cocaine has
dose-dependent interaction between histone
deacetylase (HDAC)1, HDAC3 and HDAC3 and to
therefore affect chromatin compaction and gene ex-
pression
149
. All-natural 5-MeO-DMT via S1R activa-
tion trigger patients’ recovery from symptom with
persistent improvements in life satisfaction and
psychopathological symptoms
139,141,150,151,152
. A sin-
gle dose, 24-hour-treatment with 5-MeO-DMT,
showed major downregulation of mGluR5 after
treatment with 5-MeO-DMT. mGluR5 has a role in
the rewarding effects for several drugs of abuse. It
was shown that mice lacking the mGluR5 gene do
not self-administer cocaine and show no cocaine-in-
duced hyperactivity
153
. They also have attenuated
somatic signs of nicotine withdrawal, and reduced
ethanol consumption behavior
154
, suggesting
mGluR5 is involved in addiction
4,155
.
All-natural 5-MeO-DMT-mediated S1R is involved
in the reported retrieval and healing of traumatic
memories
139,156
: Epigenetic modifications, such as
DNA methylation, occur in response to environ-
mental influences to alter the functional expression
of genes in an enduring and potentially, intergener-
ationally transmissible manner. As such, they may
explain interindividual variation, as well as the
long-lasting effects of trauma exposure”
132
. The
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
10
reconsolidation and fear extinction of traumatic
memories require the involvement of epigenetic
mechanisms. Several countries where 5-MeO-DMT
is unregulated offer retreats and treatment pro-
grams
157
. A survey of 51 US Special Operations
Forces Veterans from one such retreat, with com-
bined 5-MeO-DMT and ibogaine treatments, indi-
cated the experience was therapeutic for their trau-
matic experiences, suicidal ideation, depression and
anxiety
155,157
In a survey of 20 individuals from the
same retreat center, 75% reported a ‘complete mys-
tical experience’, as measured by MEQ-30
155,158
.
Notable features of natural 5-MeO-DMT are the re-
ported high rates of the ego-dissolution and mysti-
cal experiences, with long-term positive therapeutic
outcomes is calling for consistent pharmacognosy
and clinical exploration
158
. Some of the benefits re-
lated to 5-MeO-DMT mediated by S1R and mito-
chondrial function to mitigate symptoms of some
psychiatric and neurodegenerative disorders symp-
toms are linked possibly to these extensive epige-
netic modifications produced by 5-MeO-DMT-S1R-
mitochondrial epigenetic pathway. For this reason,
all-natural 5-MeO-DMT S1R ligand is of great inter-
est as possible therapeutic agent against CNS disor-
ders
24,148
.
Conclusion
Mental
159
and neurodegenerative
160
diseases are the
possible epigenetics regulation complex products
from under environmental or epigenetically inher-
itance stress manifested and controlled by S1R-
MAM-mitochondrial dysfunction with large degree
of variation depending on the neurons tissue af-
fected. Endogenous and exogenous DMTs are
sigma 1 receptor agonist and regulate adult neuro-
genesis in vitro and in vivo with mental health ben-
efits and antidepressant
effects in patients
98,99,100
. We
have reviewed comprehensively a possible strong-
est neurobiological reprogrammed with the novel
pharmacological sigma 1 receptor agonist the all-
natural 5-MeO-DMT
139
ancestral healing via Sig-1R-
MAM-mitochondrial activation. S1R is an ER resi-
dent chaperone that is highly enriched at the MAMs
that controls mitochondria Ca2+ flux, bioenergetic,
oxidative and stress responses and mitochondrial
epigenetic regulation. Pharmacological S1R agonist
5-MeO-DMT therapeutic implications in mental
and neurodegenerative diseases such as Alzheimer,
Parkinson will drive the most important resources
for expansion of all-natural 5-MeO-DMT successful
legal therapy.
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The study did not involve humans or animals.
Conflict of Interest statement
The author is inventor on patent application describing therapeutic uses of all-natural 5-MeO-DMT.