Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20

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

and neurodegen-

erative

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

. 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

. 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

the pharmacological benefits of 5-MeO-DMT are

ongoing

The mitochondria are the power station that pro-

vides the necessary energy for the processes that

sustaining life

. 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

. 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

. Mitochon-

drial dysfunction has emerged as a key factor men-

tal

and neurodegenerative disorders

. 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 (iron–sulfur) centers, heme synthesis

, in-

nate immune response, and metabolic cell signal-

ing

12–16

. 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

. 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

. 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

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

neurodegenerative diseases

. 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

. 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

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

. 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

. 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

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

, Parkinsonism

, stress

disorders

. 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

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-

. S1R bind with high affinity to several classes of

chemically unrelated ligands such as neuroster-

oids

, neuroleptics, dextrobenzomorphans [DEX]

and several psychostimulants such as cocaine

methamphetamine [METH]

37,38

methylenediox-

ymethamphetamine [MDMA]

and methacathi-

none

37,40

. Consequently, it is thought that the SR

may mediate the immunosuppressant, antipsy-

chotic

and neuroprotective effects of many drugs

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

. In fact, sev-

eral lines of research have demonstrated that S1R

play a role in the pathophysiology of neuropsychi-

atric disorders such as mood

, anxiety disorders

and schizophrenia

26,46

The acute S1R actions include the modulation of ion

channels (e.g. K+ channel), N-methyl-D-aspartate

receptors (NMDARs)

, 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

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

. 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

, 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

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

. 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

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

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

, while fragmented mi-

tochondria and elevated or modified Drp1 (i.e., in-

creased fission activity) are associated with AD, PD,

and HD

. Mitochondria-MAM dysregulation has

been proposed as the underlying cause of AD

and

may contribute to neuronal loss in other disease

contexts

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

, 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

.S1R expression may be involved in the ther-

apeutic effect of HDAC6 inhibitor on AD pathol-

ogy

. Preclinical evidences suggest that S1R ago-

nists might be useful in treating AD, no selective

S1R agonist is currently available for clinical use

specific sigma 1 receptor agonist as all-natural 5-

MeO-DMT

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

. S1R also attenuate Dopamine (DA) tox-

icity involved in the etiology of PD

. S1R agonists

were found to reduce oxidative stress via several

signaling pathways

. 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

. These data

suggest that S1Rs are one of the endogenous

Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla

substrates that counteract the dopamine cytotoxi-

city that would otherwise cause apoptosis

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

in cells periphery and central nervous

system

. DMT is Central Nervous System neuro-

transmitter involved in sensory perception

. En-

zyme indolethylamine-N-methyltransferase

(INMT), is the responsible of DMT synthesis

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

. It is densely located in the anterior horn of

the spinal cord

82–87

. Highest INMT activity has been

found within the brain in the following areas: un-

cus, medulla, amygdala, frontal cortex

, frontal-pa-

rietal and temporal lobes

87,88

, pineal gland

and pla-

centa

. DMT has been measured in several human

body fluids, including blood

, 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

Only a small fraction of endogenous DMT is re-

leased into the bloodstream

. DMT has a transport

process

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

. 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

. 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

. 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

Endogenous DMT plays a significant role in physi-

ological mechanisms via S1R-MAM-mitochondrial

pathway. S1R

agonists are neuroprotective via

several mechanisms. DMT and also 5-MeO-DMT

reduced inflammation via S1R and induced neu-

ronal plasticity

, which is a long-term regenerative

process that goes beyond neuroprotection

. DMT

and 5-MeO-DMT modulate innate and adaptive in-

flammatory responses through the S1R of human

monocyte-derived Dendritic cells

. DMT mediated

S1R activity induces neuronal plasticity changes in

newborns

. 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

, using the traditional medicine

of native peoples of South America Ayahuasca

which main component is DMT infusion

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

. 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

. 5-MeO-

DMT is a neuroregulatory substance, sigma-1 re-

ceptor

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

, cellular bioenergetics activation, antiapop-

totic

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

. 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

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

DMT has been studied the maximum concentration

(Cmax) in plasma is reached after 5–6 min following

an intraperitoneal (IP) injection, the terminal half-

life (t1/2) is 12–19 min in mice and Cmax = 5–10 min

and t1/2 = 6–16 min in rats. 5-MeO-DMT presents a

hydrophobic behavior (3.3 oil/water partition coef-

ficient) and readily crosses the blood–brain 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

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)

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

, 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-

chondria–nuclear 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

. 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

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

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

. 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

121–123

. 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 1–2% 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

5-MeO-DMT

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

. In our per-

spective is possible activation of epigenetic