Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
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
References
1. A J Ferrari, D F Santomauro, A M M Herrera, J Shadid, C Ashbaugh, H E Erskine, F J Charlson, M
Naghavi, S I Hay, T Vos, and H A Whiteford. Global, regional, and national burden of 12 mental
disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of
Disease Study 2019. Lancet Psychiatry (2022); 9: 137–50.
https://doi.org/10.1016/S2215-0366(21)00395-3
2. William M Carroll. The global burden of neurological disorders. Lancet Neurology (2019) 18, 5,
418 – 419. https://doi.org/10.1016/S1474-4422(19)30029-8
3. Nguyen, L. et al. Role of sigma-1 receptors in neurodegenerative diseases. J. Pharmacol. Sci. (2015)
127, 17–29. https://doi.org/10.1016/j.jphs.2014.12.005
4. Dakic, V. et al. Short-term changes in the proteome of human cerebral organoids induced by 5-
MeO-DMT. Sci. Rep. (2017) 7, 12863. https://doi.org/10.1038/s41598-017-12779-5
5. Anna O Ermakova, Fiona Dunbar, James Rucker and Matthew W Johnson. A narrative synthesis
of research with 5-MeO-DMT. Journal of Psychopharmacology 2022, Vol. 36(3) 273–294.
https://doi.org/10.1177/02698811211050543
6. Jodi Nunnari and Anu Suomalainen. Mitochondria: In Sickness and in Health. Cell; (2012) 148 (6):
1145–1159. https://doi.org/10.1016/j.cell.2012.02.035
7. Minocherhomji, S., Tollefsbol, T. O. & Singh, K. K. Mitochondrial regulation of epigenetics and its
role in human diseases. Epigenetics (2012) 7, 326–334. https://doi.org/10.1016/j.cell.2012.02.035
8. Carlos Cardanho-Ramos and Vanessa Alexandra Morais. Mitochondrial Biogenesis in Neurons:
How and Where. Int J Mol Sci. (2021) 22 (23): 13059. https://doi.org/10.3390/ijms222313059
9. Shaw-Hwa Jou, Nan-Yin Chiu, Chin-San Liu. Mitochondrial Dysfunction and Psychiatric
Disorders. Chang Gung Med J (2009) 32, 370-9.
10. Hariharan Murali Mahadevan, Arsalan Hashemiaghdam, Ghazaleh Ashrafi and Angelika Betti
na Harbauer. Mitochondria in Neuronal Health: From Energy Metabolism to Parkinson’s Disease.
Adv. Biology (2021), 5, 2100663, 1 of 18. https://doi.org/10.1002/adbi.202100663
11. Kalainayakan, S. P., FitzGerald, K. E., Konduri, P. C., Vidal, C. & Zhang, L. Essential roles of
mitochondrial and heme function in lung cancer bioenergetics and tumorigenesis. Cell Biosci. (2018)
8, 56. https://doi.org/10.1186/s13578-018-0257-8
12. Fariss, M. W. Role of mitochondria in toxic oxidative stress. Mol. Interv. (2005) 5, 94–111.
https://doi.org/10.1124/mi.5.2.7
13. Van Houten, B., Woshner, V. & Santos, J. H. Role of mitochondrial DNA in toxic responses to
oxidative stress. DNA Repair (2006) 5, 145–152. https://doi.org/10.1016/j.dnarep.2005.03.002
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
14. Murphy, M. P. How mitochondria produce reactive oxygen species. Biochem. J. (2009) 417, 1–13.
https://doi.org/10.1042/BJ20081386
15. Hitchler, M. J. & Domann, F. E. Redox regulation of the epigenetic landscape in Cancer: A role for
metabolic reprogramming in remodeling the epigenome. Free Radic. Biol. Med. (2012) 53, 2178–2187.
https://doi.org/10.1016/j.freeradbiomed.2012.09.028
16. Wallace, D. C., Fan, W. & Procaccio, V. Mitochondrial Energetics and Therapeutics. Annu. Rev.
Pathol. Mech. Dis. (2010) 5, 297–348. https://doi.org/10.1146/annurev.pathol.4.110807.092314
17. Hanahan, D. & Weinberg, R. A. Hallmarks of Cancer: The Next Generation. Cell (2011) 144, 646–
674. https://doi.org/10.1016/j.cell.2011.02.013
18. Nakajima, E. C. & Van Houten, B. Metabolic symbiosis in cancer: Refocusing the Warburg lens.
Mol. Carcinog. (2013) 52, 329–337. https://doi.org/10.1002/mc.21863
19. Allis, C. D. & Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. (2016)
17, 487–500. https://doi.org/10.1038/nrg.2016.59
20. Hayashi, T., Rizzuto, R., Hajnoczky, G. & Su, T.-P. MAM: more than just a housekeeper. Trends
Cell Biol. (2009) 19, 81–88. https://doi.org/10.1016/j.tcb.2008.12.002
21. Rizzuto, R. & Pozzan, T. Microdomains of Intracellular Ca 2+: Molecular Determinants and
Functional Consequences. Physiol. Rev. (2006) 86, 369–408.
https://doi.org/10.1152/physrev.00004.2005
22. Voelker, D. R. Genetic and Biochemical Analysis of Non-Vesicular Lipid Traffic. Annu. Rev. Bio
chem. (2009) 78, 827–856. https://doi.org/10.1146/annurev.biochem.78.081307.112144
23. Kelly Anne Chamberlain and Zu-Hang Sheng. Mechanisms for the maintenance and regulation
of axonal energy supply. J Neurosci Res. (2019) 97(8): 897–913. https://doi.org/10.1002/jnr.24411
24. Weng, T.-Y., Tsai, S.-Y. A. & Su, T.-P. Roles of sigma-1 receptors on mitochondrial functions rele
vant to neurodegenerative diseases. J. Biomed. Sci. (2017) 24, 74. https://doi.org/10.1186s12929-017-
0380-6
25. Mori, T., Hayashi, T., Hayashi, E. & Su, T.-P. Sigma-1 Receptor Chaperone at the ER-
Mitochondrion Interface Mediates the Mitochondrion-ER-Nucleus Signaling for Cellular Survival.
PLoS ONE (2013) 8, e76941. https://doi.org/10.1371/journal.pone.0076941
26. Rousseaux, C. G. & Greene, S. F. Sigma receptors [ σ Rs]: biology in normal and diseased states.
J. Recept. Signal Transduct. (2015) 1–62. https://doi.org/10.3109/10799893.2015.1015737
27. Hayashi, T. The Sigma-1 Receptor in Cellular Stress Signaling. Front. Neurosci. (2019) 13, 733.
https://doi.org/10.3389/fnins.2019.00733
28. Carmichael, J. et al. Bacterial and yeast chaperones reduce both aggregate formation and cell
death in mammalian cell models of Huntington’s disease. Proc. Natl. Acad. Sci. (2000) 97, 9701–
9705. https://doi.org/10.1073/pnas.170280697
29. Kabuta, T. & Wada, K. Insights into links between familial and sporadic Parkinson’s disease:
Physical relationship between UCH-L1 variants and chaperone-mediated autophagy. Autophagy
(2008) 4, 827–829. https://doi.org/10.4161/auto.6560
30. Caamaño, C. A., Morano, M. I. & Akil, H. Corticosteroid receptors: a dynamic interplay between
protein folding and homeostatic control. Possible implications in psychiatric disorders. Psychophar
macol. Bull. (2001) 35, 6–23.
31. Tsai, S.-Y., Hayashi, T., Mori, T. & Su, T.-P. Sigma-1 Receptor Chaperones and Diseases. Cent.
Nerv. Syst. Agents Med. Chem. (2009) 9, 184–189.
httpss://dx.doi.org/10.2174/1871524910909030184
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
32. Hayashi, T. The Sigma-1 Receptor in Cellular Stress Signaling. Front. Neurosci. (2019) 13, 733.
https://doi.org/10.3389/fnins.2019.00733
33. Su, T.-P., Hayashi, T., Maurice, T., Buch, S. & Ruoho, A. E. The sigma-1 receptor chaperone as an
inter-organelle signaling modulator. Trends Pharmacol. Sci. (2010) 31, 557–566.
https://doi.org/10.1016/j.tips.2010.08.007
34. Su, T.-P., Su, T.-C., Nakamura, Y. & Tsai, S.-Y. The Sigma-1 Receptor as a Pluripotent Modulator
in Living Systems. Trends Pharmacol. Sci. (2016) 37, 262–278.https://doi.org/10.1016/
j.tips.2016.01.003
35. Yano, H. et al. Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer
assays. Neuropharmacology (2018) 133, 264–275.
https://doi.org/10.1016/j.neuropharm.2018.01.042
36. Mishra, A. K. et al. The sigma-1 receptors are present in monomeric and oligomeric forms in li
ving cells in the presence and absence of ligands. Biochem. J. (2015) 466, 263–271. https://doi.org/
10.1042/BJ20141321
37. Bastianetto, S., Ramassamy, C., Poirier, J. & Quirion, R. Dehydroepiandrosterone (DHEA) protects
hippocampal cells from oxidative stress-induced damage. Mol. Brain Res. (1999) 66, 35–41.
https://doi.org/10.1016/S0169-328X(99)00002-9
38. Kaushal, N. & R. Matsumoto, R. Role of Sigma Receptors in Methamphetamine-Induced Neuro
toxicity. Curr. Neuropharmacol. (2011) 9, 54–57. https://dx.doi.org/ 10.2174/157015911795016930
39. Kaushal, N. et al. CM156, a high affinity sigma ligand, attenuates the stimulant and neurotoxic
effects of methamphetamine in mice. Neuropharmacology (2011) 61, 992–1000.
https://doi.org/10.1016/j.neuropharm.2011.06.028
40. Brammer, M. K., Gilmore, D. L. & Matsumoto, R. R. Interactions between 3,4-methylenedioxy
methamphetamine and σ1 receptors. Eur. J. Pharmacol. (2006) 553, 141–145. https://doi.org/
10.1016/j.ejphar.2006.09.038
41. Meririnne, E., Kankaanpää, A., Lillsunde, P. & Seppälä, T. The Effects of Diazepam and Zolpidem
on Cocaine- and Amphetamine-Induced Place Preference. Pharmacol. Biochem. Behav. (1999) 62,
159–164. https://doi.org/10.1016/S0091-3057(98)00139-7
42. Cormaci, G., Mori, T., Hayashi, T. & Su, T.-P. Protein Kinase A Activation Down-Regulates, Whe
reas Extracellular Signal-Regulated Kinase Activation Up-Regulates σ-1 Receptors in B-104 Cells: I
mplication for Neuroplasticity. J. Pharmacol. Exp. Ther. (2007) 320, 202–210.
https://doi.org/10.1124/jpet.106.108415
43. Cobos, E., Entrena, J., Nieto, F., Cendan, C. & Pozo, E. Pharmacology and Therapeutic Potential
of Sigma1 Receptor Ligands. Curr. Neuropharmacol. (2008) 6, 344–366.
https://dx.doi.org/10.2174/157015908787386113
44. Paschos, K. A., Veletza, S. & Chatzaki, E. Neuropeptide and Sigma Receptors as Novel Thera
peutic Targets for the Pharmacotherapy of Depression: CNS Drugs (2009) 23, 755–772.
https://doi.org/10.2165/11310830-000000000-00000
45. Kulkarni, S. K. & Dhir, A. σ-1 receptors in major depression and anxiety. Expert Rev. Neurother.
(2009) 9, 1021–1034. https://doi.org/10.1586/ern.09.40
46. Su, T.-P., Hayashi, T. & Vaupel, D. B. When the Endogenous Hallucinogenic Trace Amine N,N -
Dimethyltryptamine Meets the Sigma-1 Receptor. Sci. Signal. (2009) 2.
https://doi.org/10.1126/scisignal.261pe12
47. Nguyen, L., Lucke-Wold, B. P., Mookerjee, S., Kaushal, N. & Matsumoto, R. R. Sigma-1 Receptors
and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
Neurodegeneration and Neuroprotection. in Sigma Receptors: Their Role in Disease and as
Therapeutic Targets (eds. Smith, S. B. & Su, Springer International Publishing (2017) T.-P. Vol. 964
133–152. https://doi.org/10.1007/978-3-319-50174-1_10
48. Hayashi, T. & Su, T.-P. The potential role of sigma-1 receptors in lipid transport and lipid raft re
constitution in the brain: Implication for drug abuse. Life Sci. (2005) 77, 1612–1624.
https://doi.org/10.1016/j.lfs.2005.05.009
49. Gill, S. S. & Pulido, O. M. Review Article: Glutamate Receptors in Peripheral Tissues: Current
Knowledge, Future Research, and Implications for Toxicology. Toxicol. Pathol. (2001) 29, 208–223.
https://doi.org/10.1080/019262301317052486
50. Wolfe, S. A., Culp, S. G. & De Souza, E. B. σ-Receptors in Endocrine Organs: Identification, Cha
racterization, and Autoradiographic Localization in Rat Pituitary, Adrenal, Testis, and Ovary. En
docrinology (1989) 124, 1160–1172. https://doi.org/10.1210/endo-124-3-1160
51. Wolfe, S. A., Kulsakdinun, C., Battaglia, G., Jaffe, J. H. & De Souza, E. B. Initial identification and
characterization of sigma receptors on human peripheral blood leukocytes. J. Pharmacol. Exp. Ther.
(1988) 247, 1114–1119.
52. Narayanan, S., Mesangeau, C., H. Poupaert, J. & R. McCurdy, C. Sigma Receptors and Cocaine
Abuse. Curr. Top. Med. Chem. (2011) 11, 1128–1150.
https://dx.doi.org/10.2174/156802611795371323
53. Al-Saif, A., Al-Mohanna, F. & Bohlega, S. A mutation in sigma-1 receptor causes juvenile
amyotrophic lateral sclerosis. Ann. Neurol. (2011) 70, 913–919. https://doi.org/10.1002/ana.22534
54. Luty, A. A. et al. Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar
degeneration-motor neuron disease. Ann. Neurol. (2010) 68, 639–649. https://doi.org/10.1002/
ana.22274
55. Lau, A. & Tymianski, M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflüg. Arch.
- Eur. J. Physiol. (2010) 460, 525–542. https://doi.org/10.1007/s00424-010-0809-1
56. Hazell, A. Excitotoxic mechanisms in stroke: An update of concepts and treatment strategies.
Neurochem. Int. (2007) 50, 941–953. https://doi.org/10.1016/j.neuint.2007.04.026
57. Mancuso, R. et al. Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS
Mice. Neurotherapeutics (2012) 9, 814–826. https://doi.org/10.1007/s13311-012-0140-y
58. Hayashi, T. & Su, T.-P. Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regula
te Ca2+ Signaling and Cell Survival. Cell (2007) 131, 596–610.
https://doi.org/10.1016/j.cell.2007.08.036
59. Reynolds, A., Laurie, C., Lee Mosley, R. & Gendelman, H. E. Oxidative Stress and the Pathogenesis
of Neurodegenerative Disorders. in International Review of Neurobiology. Elsevier (2007) vol. 82
297–325. https://doi.org/10.1016/S0074-7742(07)82016-2
60. Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative di
seases. Nature (2006) 443, 787–795. https://doi.org/10.1038/nature05292
61. Mori, T., Hayashi, T. & Su, T.-P. Compromising σ-1 Receptors at the Endoplasmic Reticulum
Render Cytotoxicity to Physiologically Relevant Concentrations of Dopamine in a Nuclear Factor-
κB/Bcl-2-Dependent Mechanism: Potential Relevance to Parkinson’s Disease. J. Pharmacol. Exp.
Ther. (2012) 341, 663–671. https://doi.org/10.1124/jpet.111.190868
62. Hetz, C. & Mollereau, B. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative
diseases. Nat. Rev. Neurosci. (2014) 15, 233–249. https://doi.org/10.1038/nrn3689
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
63. Pal, A. et al. The sigma-1 receptor protects against cellular oxidative stress and activates antioxi
dant response elements. Eur. J. Pharmacol. (2012) 682, 12–20.
https://doi.org/10.1016/j.ejphar.2012.01.030
64. Halliday, M. & Mallucci, G. R. Targeting the unfolded protein response in neurodegeneration: A
new approach to therapy. Neuropharmacology (2014) 76, 169–174.
https://doi.org/10.1016/j.neuropharm.2013.08.034
65. Ishihara, N. et al. Mitochondrial fission factor Drp1 is essential for embryonic development and
synapse formation in mice. Nat. Cell Biol. (2009) 11, 958–966. https://doi.org/10.1038/ncb1907
66. Chaturvedi, R. K. & Flint Beal, M. Mitochondrial Diseases of the Brain. Free Radic. Biol. Med.
(2013) 63, 1–29. https://doi.org/10.1016/j.freeradbiomed.2013.03.018
67. Schon, E. A. & Area-Gomez, E. Mitochondria-associated ER membranes in Alzheimer disease.
Mol. Cell. Neurosci. (2013) 55, 26–36. https://doi.org/10.1016/j.mcn.2012.07.011
68. Vance, J. E. MAM (mitochondria-associated membranes) in mammalian cells: Lipids and
beyond. Biochim. Biophys. Acta BBA - Mol. Cell Biol. Lipids (2014) 1841, 595–609.
https://doi.org/0.1016/j.bbalip.2013.11.014
69. Rizzuto, R. et al. Ca2+ transfer from the ER to mitochondria: When, how and why. Biochim.
Biophys. Acta BBA - Bioenerg. (2009) 1787, 1342–1351. https://doi.org/10.1016/j.bbabio.2009.03.015
70. Tchedre, K. T. & Yorio, T. σ-1 Receptors Protect RGC-5 Cells from Apoptosis by Regulating Int
racellular Calcium, Bax Levels, and Caspase-3 Activation. Investig. Opthalmology Vis. Sci. (2008)
49, 2577. https://doi.org/10.1167/iovs.07-1101
71. Smiraglia, D., Kulawiec, M., Bistulfi, G. L., Ghoshal, S. & Singh, K. K. A novel role for mitochondria
in regulating epigenetic modifications in the nucleus. Cancer Biol. Ther. (2008) 7, 1182–1190.
https://doi.org/10.4161/cbt.7.8.6215
72. Hedskog L, Pinho CM, Filadi R, Ronnback A, Hertwig L, Wiehager B, et al. Modulation of the
endoplasmic reticulum-mitochondria interface in AD and related models. Proc Natl Acad Sci U S A.
(2013)110:7916e7921. https://doi.org/10.1073/pnas.1300677110
73. Jansen KL, Faull RL, Storey P, Leslie RA. Loss of sigma binding sites in the CA1 area of the anterior
hippocampus in AD correlates with CA1 pyramidal cell loss. Brain Res. (1993) 623: 299e302.
https://doi.org/10.1016/0006-8993(93)91441-T
74. Mishina M, Ohyama M, Ishii K, Kitamura S, Kimura Y, Oda K, et al. Low density of s1 receptors
in early AD. Ann Nucl Med. (2008); 22:151e156. https://doi.org/10.1007/s12149-007-0094-z
75. Iwamoto, M., Nakamura, Y., Takemura, M., Hisaoka-Nakashima, K. & Morioka, N. TLR4-TAK1-
p38 MAPK pathway and HDAC6 regulate the expression of sigma-1 receptors in rat primary cultured
microglia. J. Pharmacol. Sci. (2020) 144, 23–29. https://doi.org/10.1016/j.jphs.2020.06.007
76. Mishina M, Ishiwata K, Ishii K, Kitamura S, Kimura Y, Kawamura K, et al. Function of s1 recep
tors in PD. Acta Neurol Scand. (2005)112:103e107. https://doi.org/10.1111/j.1600-0404.2005.00432.x
77. Pal A, Fontanilla D, Gopalakrishnan A, Chae YK, Markley JL, Ruoho AE. The sigma-1 receptor
protects against cellular oxidative stress and activates antioxidant response elements. Eur J
Pharmacol. (2012) 682:12e20. https://doi.org/10.1016/j.ejphar.2012.01.030
78. Dominique Fontanilla et al. The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous
Sigma-1 Receptor Regulator. Science; (2009) 323 (5916): 934–937.
https://doi.org/10.1126/science.1166127
79. Carbonaro, T. M. & Gatch, M. B. Neuropharmacology of N,N-dimethyltryptamine. Brain Res.
Bull. (2016) 126, 74–88. https://doi.org/10.1016/j.brainresbull.2016.04.016
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
80. Wallach, J. V. Endogenous hallucinogens as ligands of the trace amine receptors: A possible role
in sensory perception. Med. Hypotheses (2009) 72, 91–94.
https://doi.org/10.1016/j.mehy.2008.07.052
81. Barker, S. A., Monti, J. A. & Christian, S. T. N,N-Dimethyltryptamine: An Endogenous Halluci
nogen. in International Review of Neurobiology Elsevier (1981) vol. 22 83–110.
https://doi.org/10.1016/S0074-7742(08)60291-3
82. Wyatt, R. J., Saavedra, J. M. & Axelrod, J. A Dimethyltryptamine-Forming Enzyme in Human
Blood. Am. J. Psychiatry (1973) 130, 754–760. https://doi.org/10.1176/ajp.130.7.754
83. Mandell, A. J. & Morgan, M. Indole(ethyl)amine N-Methyltransferase in Human Brain. Nature.
New Biol. (1971) 230, 85–87. https://doi.org/10.1038/newbio230085a0
84. Mavlyutov, T. A. et al. Development of the sigma-1 receptor in C-terminals of motoneurons and
colocalization with the N,N′-dimethyltryptamine forming enzyme, indole-N-methyl transferase.
Neuroscience (2012) 206, 60–68. https://doi.org/10.1016/j.neuroscience.2011.12.040
85. Thompson, M. A. & Weinshilboum, R. M. Rabbit Lung Indolethylamine N-Methyltransferase. J.
Biol. Chem. (1998) 273, 34502–34510. https://doi.org/10.1074/jbc.273.51.34502
86. Morgan, M. & Mandell, A. J. Indole(ethyl)amine N -Methyltransferase in the Brain. Science
(1969) 165, 492–493. https://doi.org/10.1126/science.165.3892.492
87. Nichols, D. E. N,N -dimethyltryptamine and the pineal gland: Separating fact from myth. J.
Psychopharmacol. (Oxf.) (2018) 32, 30–36. https://doi.org/10.1177/0269881117736919
88. Jiménez, J. H. & Bouso, J. C. Significance of mammalian N, N-dimethyltryptamine (DMT): A 60-
year-old debate. J. Psychopharmacol. (Oxf.) (2022) 36, 905–919.
https://doi.org/10.1177/02698811221104054
89. Mavlyutov, T. A. et al. Development of the sigma-1 receptor in C-terminals of motoneurons and
colocalization with the N,N′-dimethyltryptamine forming enzyme, indole-N-methyl transferase.
Neuroscience (2012) 206, 60–68. https://doi.org/10.1016/j.neuroscience.2011.12.040
90. Vitale, A. A. et al. In Vivo Long-Term Kinetics of Radiolabeled N , N -Dimethyltryptamine and
Tryptamine. J. Nucl. Med. (2011) 52, 970–977. https://doi.org/10.2967/jnumed.110.083246
91. Frecska, E., Szabo, A., Winkelman, M. J., Luna, L. E. & McKenna, D. J. A possibly sigma-1 recep
tor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity. J. Neural
Transm. (2013) 120, 1295–1303. https://doi.org/10.1007/s00702-013-1024-y
92. Cozzi, N. V. et al. Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate
behavior at the serotonin uptake transporter and the vesicle monoamine transporter. J. Neural
Transm. (2009) 116, 1591–1599. https://doi.org/10.1007/s00702-009-0308-8
93. B R Sitaram, L Lockett, R Talomsin, G L Blackman, W R McLeod. In vivo metabolism of 5-me
thoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine in the rat. Biochem Pharmacol; (1987)
36 (9):1509-12. https://doi.org/10.1016/0006-2952(87)90118-3
94. Ryskamp, D. A., Korban, S., Zhemkov, V., Kraskovskaya, N. & Bezprozvanny, I. Neuronal Sigma-
1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases. Front.
Neurosci. (2019) 13, 862. https://doi.org/10.3389/fnins.2019.00862
95. Kourrich, S., Su, T.-P., Fujimoto, M. & Bonci, A. The sigma-1 receptor: roles in neuronal plasticty
and disease. Trends Neurosci. (2012) 35, 762–771. https://doi.org/10.1016/j.tins.2012.09.007
96. Ruscher, K. et al. The sigma-1 receptor enhances brain plasticity and functional recovery after
experimental stroke. Brain (2011) 134, 732–746. https://doi.org/10.1093/brain/awq367
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
97. Szabo, A., Kovacs, A., Frecska, E. & Rajnavolgyi, E. Psychedelic N,N-Dimethyltryptamine and 5-
Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through
the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells. PLoS ONE (2014) 9, e106533.
https://doi.org/10.1371/journal.pone.0106533
98. Osório, F. de L. et al. Antidepressant effects of a single dose of ayahuasca in patients with recur
rent depression: a preliminary report. Rev. Bras. Psiquiatr. (2015) 37, 13–20.
https://doi.org/10.1590/1516-4446-2014-1496
99. Uthaug, M. V. et al. A placebo-controlled study of the effects of ayahuasca, set and setting on
mental health of participants in ayahuasca group retreats. Psychopharmacology (Berl.) (2021) 238,
1899–1910. https://doi.org/10.1007/s00213-021-05817-8
100. Morales-Garcia, J. A. et al. N,N-dimethyltryptamine compound found in the hallucinogenic tea
ayahuasca, regulates adult neurogenesis in vitro and in vivo. Transl. Psychiatry (2020) 10, 331.
https://doi.org/10.1038/s41398-020-01011-0
101. Weil AT, Davis W. Bufo alvarius: a potent hallucinogen of animal origin. J Ethnopharmacol
(1994) 41:1–8. https://doi.org/10.1016/0378-8741(94)90051-5
102. Fiona G. Sleight, Steven Jay Lynn, Richard E. Mattson, Charlie W. McDonald. A novel ego
dissolution scale: A construct validation study. Consciousness and Cognition (2023) 109, 103474.
https://doi.org/10.1016/j.concog.2023.103474
103. S. F. Cooke and T. V. P. Bliss. Plasticity in the human central nervous system. Brain, (2006) 129,
1659–1673. https://doi.org/10.1093/brain/awl082
104. Ruscher, K. et al. The sigma-1 receptor enhances brain plasticity and functional recovery after
experimental stroke. Brain (2011) 134, 732–746. https://doi.org/10.1093/brain/awq367
105. Tsai, S.-Y. et al. Sigma-1 receptors regulate hippocampal dendritic spine formation via a free ra
dical-sensitive mechanism involving Rac1·GTP pathway. Proc. Natl. Acad. Sci. (2009) 106, 22468–
22473. https://doi.org/10.1073/pnas.0909089106
106. Endris, V. et al. The novel Rho-GTPase activating gene MEGAP / srGAP3 has a putative role in
severe mental retardation. Proc. Natl. Acad. Sci. (2002) 99, 11754–11759.
https://doi.org/10.1073/pnas.162241099
107. Mueller, B. H. et al. Sigma-1 receptor stimulation attenuates calcium influx through activated L-
type Voltage Gated Calcium Channels in purified retinal ganglion cells. Exp. Eye Res. (2013) 107, 21–
31. https://doi.org/10.1016/j.exer.2012.11.002
108. Tchedre, K. T. & Yorio, T. σ-1 Receptors Protect RGC-5 Cells from Apoptosis by Regulating
Intracellular Calcium, Bax Levels, and Caspase-3 Activation. Investig. Opthalmology Vis. Sci. (2008)
49, 2577. https://doi.org/10.1167/iovs.07-1101
109. Griffiths, R. R., Richards, W. A., McCann, U. & Jesse, R. Psilocybin can occasion mystical-type
experiences having substantial and sustained personal meaning and spiritual significance. Psycho
pharmacology (Berl.) (2006) 187, 268–83 discussion 284–92. https://doi.org/10.1007/s00213-006-
0457-5
110. Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, Van Houten B,
Mostoslavsky R, Bultman SJ, Baccarelli AA, Begley TJ, Sobol RW, Hirschey MD, Ideker T, Santos JH,
Copeland WC, Tice RR, Balshaw DM, Tyson FL. Mitochondria, energetics, epigenetics, and cellular
responses to stress. Environ Health Perspect (2014) 122:1271–1278.
https://doi.org/10.1289/ehp.1408418
111. Kourrich, S., Su, T.-P., Fujimoto, M. & Bonci, A. The sigma-1 receptor: roles in neuronal plastici
ty and disease. Trends Neurosci. (2012) 35, 762–771. https://doi.org/10.1016/j.tins.2012.09.007
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
112. Thomas Misgeld and Thomas L. Schwarz. Mitostasis in neurons: Maintaining mitochondria in
an extended cellular architecture. Neuron. (2017) 96(3): 651–666.
https://doi.org/10.1016/j.neuron.2017.09.055
113. Teresa E. Daniels, Elizabeth M. Olsen and Audrey R. Tyrka. Stress and Psychiatric Disorders:
The Role of mitochondria. The Annual Review of Clinical Psychology (2020) 16:165–86.
https://doi.org/10.1146/annurev-clinpsy-082719-104030
114. Bertogliat, M. J., Morris-Blanco, K. C. & Vemuganti, R. Epigenetic mechanisms of
neurodegenerative diseases and acute brain injury. Neurochem. Int. (2020) 133, 104642.
https://doi.org/10.1016/j.neuint.2019.104642
115. Feinberg, A. P. Epigenetics at the Epicenter of Modern Medicine. JAMA (2008) 299, 1345.
https://doi.org/10.1001/jama.299.11.1345
116. Chandra, D. & Singh, K. K. Genetic insights into OXPHOS defect and its role in cancer. Biochim.
Biophys. Acta BBA - Bioenerg. (2011) 1807, 620–625. https://doi.org/10.1016/j.bbabio.2010.10.023
117. Szulwach, K. E. & Jin, P. Integrating DNA methylation dynamics into a framework for under
standing epigenetic codes: Prospects & Overviews. BioEssays (2014) 36, 107–117.
https://doi.org/10.1002/bies.201300090
118. Kriaucionis, S. & Heintz, N. The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in
Purkinje Neurons and the Brain. Science (2009) 324, 929–930.
https://doi.org/10.1126/science.1169786
119. Tahiliani, M. et al. Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian
DNA by MLL Partner TET1. Science (2009) 324, 930–935. https://doi.org/10.1126/science.1170116
120. Shock, L. S., Thakkar, P. V., Peterson, E. J., Moran, R. G. & Taylor, S. M. DNA methyltransferase
1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc. Natl.
Acad. Sci. (2011) 108, 3630–3635. https://doi.org/10.1073/pnas.1012311108
121. Barile, M., Brizio, C., Valenti, D., De Virgilio, C. & Passarella, S. The riboflavin/FAD cycle in rat
liver mitochondria: Riboflavin/FAD cycle in RLM. Eur. J. Biochem. (2000) 267, 4888–4900.
https://doi.org/10.1046/j.1432-1327.2000.01552.x
122. Berkich, D. A., Xu, Y., LaNoue, K. F., Gruetter, R. & Hutson, S. M. Evaluation of brain
mitochondrial glutamate and alpha-ketoglutarate transport under physiologic conditions. J.
Neurosci. Res. (2005) 79, 106–113. https://doi.org/10.1002/jnr.20325
123. Gibson, G. E., Starkov, A., Blass, J. P., Ratan, R. R. & Beal, M. F. Cause and consequence: Mito
chondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavio
ral abnormalities in age-associated neurodegenerative diseases. Biochim. Biophys. Acta BBA - Mol.
Basis Dis. (2010) 1802, 122–134. https://doi.org/10.1016/j.bbadis.2009.08.010
124. Singh, K. Mitochondria damage checkpoint in apoptosis and genome stability. FEMS Yeast Res.
(2004) 5, 127–132. https://doi.org/10.1016/j.femsyr.2004.04.008
125. Balinang, J. The Regulation of Mitochondrial DNMT1 During Oxidative Stress.
Theses/Dissertations (2012). https://doi.org/10.25772/4ZS0-8P80
126. Dostal, V. & Churchill, M. E. A. Cytosine methylation of mitochondrial DNA at CpG sequences
impacts transcription factor A DNA binding and transcription. Biochim. Biophys. Acta BBA - Gene
Regul. Mech. (2019) 1862, 598–607. https://doi.org/10.1016/j.bbagrm.2019.01.006
127. Van der Wijst, M. G. P. & Rots, M. G. Mitochondrial epigenetics: an overlooked layer of
regulation? Trends Genet. (2015) 31, 353–356. https://doi.org/10.1016/j.tig.2015.03.009
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
128. Michela Fagiolini, Catherine L Jensen and Frances A Champagne. Epigenetic influences on
brain development and plasticity. Current Opinion in Neurobiology (2009), 19:207–212.
https://doi.org/10.1016/j.conb.2009.05.009
129. Ali Jawaid, Martin Roszkowski, Isabelle M. Mansuy. Transgenerational Epigenetics of Traumatic
Stress. Progress in Molecular Biology and Translational Science (2018) 1-20.
https://doi.org/10.1016/bs.pmbts.2018.03.003
130. Dora L. Costaa, Noelle Yetterb, and Heather DeSomerb. Intergenerational transmission of
paternal trauma among US Civil War ex-POWs. PNAS (2018) 115, 44, 11215–11220.
https://doi.org/10.1073/pnas.1803630115
131. Natan P.F. Kellermann. Epigenetic Transmission of Holocaust Trauma: Can Nightmares Be
Inherited? Isr J Psychiatry Relat Sci (2013) 50, 1.
132. Yehuda, R. & Bierer, L. M. The relevance of epigenetics to PTSD: Implications for the DSM-V:
Epigenetics and PTSD: Implications for the DSM-V. J. Trauma. Stress (2009) 22, 427–434.
https://doi.org/10.1002/jts.20448
133. Pérez-Mediavilla, A. & Zamarbide, M. Maternal imprinting, mitochondrial DNA, nuclear DNA
and Alzheimer’s disease. Explor. Neuroprotective Ther. (2021) 1, 121–126.
https://doi.org/10.37349/ent.2021.00010
134. Bai, Q. & Burton, E. A. Zebrafish models of Tauopathy. Biochim. Biophys. Acta BBA - Mol. Ba
sis Dis. (2011) 1812, 353–363. https://doi.org/10.1016/j.bbadis.2010.09.004
135. Das, S. & Rajanikant, G. K. Huntington disease: Can a zebrafish trail leave more than a ripple?
Neurosci. Biobehav. Rev. (2014) 45, 258–261. https://doi.org/10.1016/j.neubiorev.2014.06.013
136. Laird, A. S., Mackovski, N., Rinkwitz, S., Becker, T. S. & Giacomotto, J. Tissue-specific models of
spinal muscular atrophy confirm a critical role of SMN in motor neurons from embryonic to adult
stages. Hum. Mol. Genet. (2016) 25, 1728–1738. https://doi.org/10.1093/hmg/ddw044
137. Crouzier, L. et al. Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein
Response in Larval Zebrafish. Int. J. Mol. Sci. (2021) 22, 11049.
https://doi.org/10.3390/ijms222011049
138. Goguadze, N., Zhuravliova, E., Morin, D., Mikeladze, D. & Maurice, T. Sigma-1 Receptor Ago
nists Induce Oxidative Stress in Mitochondria and Enhance Complex I Activity in Physiological
Condition but Protect Against Pathological Oxidative Stress. Neurotox. Res. (2019) 35, 1–18.
https://doi.org/10.1007/s12640-017-9838-2
139. Batalla, M. Therapeutic uses of all-natural 5-meo-dmt enrichment from glandular secretion of
Bufo alvarius toad from the Sonoran Desert. Patent application number (2022) US63/415407.
140. Yaden, Andrew B. Newberg. The Varieties of Spiritual Experience: 21st Century Research and
Perspectives. Chapter 12, Mystical Experiences: Unity and Ego-Dissolution. (2022) Pages 224–
C12.P140. https://doi.org/10.1093/oso/9780190665678.001.0001
141. Reckweg, J. T. et al. The clinical pharmacology and potential therapeutic applications of 5‐
methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT). J. Neurochem. (2022) 162, 128–146.
https://doi.org/10.1111/jnc.15587
142. Use of Benefit Enhancement Strategies among 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-
DMT) Users: Associations with Mystical, Challenging, and Enduring Effects.
https://doi.org/10.1080/02791072.2020.1737763
143. Reckweg, J. et al. A Phase 1, Dose-Ranging Study to Assess Safety and Psychoactive Effects of a
Vaporized 5-Methoxy-N, N-Dimethyltryptamine Formulation (GH001) in Healthy Volunteers. Front.
Pharmacol. (2021) 12, 760671. https://doi.org/10.3389/fphar.2021.760671
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
144. Moylan, S., Maes, M., Wray, N. R. & Berk, M. The neuroprogressive nature of major depressive
disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol. Psychia
try (2013) 18, 595–606. https://doi.org/10.1038/mp.2012.33
145. Konradi, C. et al. Molecular Evidence for Mitochondrial Dysfunction in Bipolar Disorder. Arch.
Gen. Psychiatry (2004) 61, 300. https://doi.org/10.1001/archpsyc.61.3.300
146. Fattal, O., Link, J., Quinn, K., Cohen, B. H. & Franco, K. Psychiatric Comorbidity in 36 Adults
with Mitochondrial Cytopathies. CNS Spectr. (2007) 12, 429–438.
https://doi.org/10.1017/S1092852900015303
147. Hollis, F. et al. Mitochondrial function in the brain links anxiety with social subordination. Proc.
Natl. Acad. Sci. (2015) 112, 15486–15491. https://doi.org/10.1073/pnas.1512653112
148. Zuccoli, G. S., Saia-Cereda, V. M., Nascimento, J. M. & Martins-de-Souza, D. The Energy
Metabolism Dysfunction in Psychiatric Disorders Postmortem Brains: Focus on Proteomic Evidence.
Front. Neurosci. (2017) 11, 493. https://doi.org/10.3389/fnins.2017.00493
149. Tsai, S.-Y. A. et al. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by
recruiting chromatin-remodeling factors at the nuclear envelope. Proc. Natl. Acad. Sci. (2015) 112.
https://doi.org/10.1073/pnas.1518894112
150. Sha, S. et al. Sigma-1 Receptor Knockout Impairs Neurogenesis in Dentate Gyrus of Adult
Hippocampus Via Down-Regulation of NMDA Receptors. CNS Neurosci. Ther. (2013) 19, 705–713.
https://doi.org/10.1111/cns.12129
151. Uthaug, M. V. et al. A single inhalation of vapor from dried toad secretion containing 5-me
thoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhan
cement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopatholo
gical symptoms. Psychopharmacology (Berl.) (2019) 236, 2653–2666.
https://doi.org/10.1007/s00213-019-05236-w
152. Davis, A. K., Barsuglia, J. P., Lancelotta, R., Grant, R. M. & Renn, E. The epidemiology of 5-
methoxy- N, N -dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use,
subjective effects, and reasons for consumption. J. Psychopharmacol. (Oxf.) (2018) 32, 779–792.
https://doi.org/10.1177/0269881118769063
153. Chiamulera, C. et al. Reinforcing and locomotor stimulant effects of cocaine are absent in
mGluR5 null mutant mice. Nat. Neurosci. (2001) 4, 873–874.
https://doi.org/10.1177/0269881118769063
154. Bird, M. K., Kirchhoff, J., Djouma, E. & Lawrence, A. J. Metabotropic glutamate 5 receptors
regulate sensitivity to ethanol in mice. Int. J. Neuropsychopharmacol. (2008) 11.
https://doi.org/10.1017/S1461145708008572
155. Barsuglia, J. P. et al. A case report SPECT study and theoretical rationale for the sequential
administration of ibogaine and 5-MeO-DMT in the treatment of alcohol use disorder. in Progress in
Brain Research (2018) vol. 242, 121–158. https://doi.org/10.1016/bs.pbr.2018.08.002
156. Inserra, A. Hypothesis: The Psychedelic Ayahuasca Heals Traumatic Memories via a Sigma 1
Receptor-Mediated Epigenetic-Mnemonic Process. Front. Pharmacol. (2018) 9, 330.
https://doi.org/10.3389/fphar.2018.00330
157. Davis, A. K., Averill, L. A., Sepeda, N. D., Barsuglia, J. P. & Amoroso, T. Psychedelic Treatment
for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces
Veterans. Chronic Stress (2020) 4, 247054702093956. https://doi.org/10.1177/2470547020939564
158. Kourrich, S., Su, T.-P., Fujimoto, M. & Bonci, A. The sigma-1 receptor: roles in neuronal plasticity
and disease. Trends Neurosci. (2012) 35, 762–771. https://doi.org/10.1016/j.tins.2012.09.007
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
159. Ben-Shachar, D. & Karry, R. Neuroanatomical Pattern of Mitochondrial Complex I Pathology
Varies between Schizophrenia, Bipolar Disorder and Major Depression. PLoS ONE (2008) 3, e3676.
https://doi.org/10.1371/journal.pone.0003676
160. Tsai, S.-Y. A., Pokrass, M. J., Klauer, N. R., De Credico, N. E. & Su, T.-P. Sigma-1 receptor
chaperones in neurodegenerative and psychiatric disorders. Expert Opin. Ther. Targets (2014) 1–16.
https://doi.org/10.1517/14728222.2014.972939
