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The protective effect of DMT against neurodegeneration

Profile image of Attila SzaboAttila Szabo

2025, International Review of Neurobiology - book series

https://doi.org/10.1016/BS.IRN.2025.04.010
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Abstract

This paper explores the therapeutic potential of DMT in neuroprotective strategies, particularly concerning ischemia-reperfusion injury (IRI) and neurodegenerative disorders. Besides its potent serotonin receptor actions, DMT is also an endogenous agonist of the sigma-1 receptor (Sig-1R). Sigma receptors are a unique family of proteins with high expression in the brain and spinal cord and have been involved in the etiology, symptom course and treatment of several central nervous system disorders. Our previous theoretical and experimental work strongly suggest that targeting sigma (and serotonin) receptors via DMT may be particularly useful for treatment in a number of neurological conditions like stroke, global brain ischemia, Alzheimer's disease, and amyotrophic lateral sclerosis. In this article, we briefly overview the function of Sig1-R in cellular bioenergetics with a focus on the processes International Review of Neurobiology

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The Protective Role of Dimethyltryptamine against Ischemia-Reperfusion Injury (book chapter in: Advances in Psychedelic Medicine: State-of-the-Art Therapeutic Applications; Publisher: Praeger, 2019; Editors: Michael J. Winkelman and Ben Sessa; pp. 214-231.)
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The vast majority of research on dimethyltryptamine (DMT) has targeted its psychotropic properties and serotonergic activity, with little focus on its effects beyond the nervous system and at other receptor molecules. The recent discovery that DMT is an endogenous agonist of the sigma-1 receptor (sigmaR-1) (Fontanilla et al., 2009) may shed light on yet undiscovered physiological and therapeutic mechanisms of DMT action and reveal some of its putative biological functions. Since the sigmaR-1 has an extensive role in mitigation of several forms of intracellular stress such as mitochondrion, endoplasmic reticulum, and oxidative stress, as well as protecting against apoptotic cell death and regulating immune processes, one may suppose similar effects from DMT administration. In this chapter, we present an overview of the literature on the effects of sigmaR-1 in cellular bioenergetics with a focus on the processes involved in ischemia-reperfusion injury. Ischemia-reperfusion injury is a complex phenomenon with mechanisms underlying organ transplantation, stroke, myocardial infarct, general brain hypoxia, cardiovascular surgery, neonatology, and cardiopulmonary resuscitation. We conclude that the function of DMT may extend beyond central nervous system activity and

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Impact of Two Neuronal Sigma-1 Receptor Modulators, PRE084 and DMT, on Neurogenesis and Neuroinflammation in an Aβ1-42-Injected, Wild-Type Mouse Model of AD
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International Journal of Molecular Sciences, 2022

Alzheimer’s disease (AD) is the most common form of dementia characterized by cognitive dysfunctions. Pharmacological interventions to slow the progression of AD are intensively studied. A potential direction targets neuronal sigma-1 receptors (S1Rs). S1R ligands are recognized as promising therapeutic agents that may alleviate symptom severity of AD, possibly via preventing amyloid-β-(Aβ-) induced neurotoxicity on the endoplasmic reticulum stress-associated pathways. Furthermore, S1Rs may also modulate adult neurogenesis, and the impairment of this process is reported to be associated with AD. We aimed to investigate the effects of two S1R agonists, dimethyltryptamine (DMT) and PRE084, in an Aβ-induced in vivo mouse model characterizing neurogenic and anti-neuroinflammatory symptoms of AD, and the modulatory effects of S1R agonists were analyzed by immunohistochemical methods and western blotting. DMT, binding moderately to S1R but with high affinity to 5-HT receptors, negatively i...

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Sigma-1 receptor as a potential pharmacological target for the treatment of neuropathology
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The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases
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Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases
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Frontiers in Neuroscience, 2019

Sigma-1 receptor (S1R) is a multi-functional, ligand-operated protein situated in endoplasmic reticulum (ER) membranes and changes in its function and/or expression have been associated with various neurological disorders including amyotrophic lateral sclerosis/frontotemporal dementia, Alzheimer's (AD) and Huntington's diseases (HD). S1R agonists are broadly neuroprotective and this is achieved through a diversity of S1R-mediated signaling functions that are generally pro-survival and anti-apoptotic; yet, relatively little is known regarding the exact mechanisms of receptor functioning at the molecular level. This review summarizes therapeutically relevant mechanisms by which S1R modulates neurophysiology and implements neuroprotective functions in neurodegenerative diseases. These mechanisms are diverse due to the fact that S1R can bind to and modulate a large range of client proteins, including many ion channels in both ER and plasma membranes. We summarize the effect of S1R on its interaction partners and consider some of the cell type-and disease-specific aspects of these actions. Besides direct protein interactions in the endoplasmic reticulum, S1R is likely to function at the cellular/interorganellar level by altering the activity of several plasmalemmal ion channels through control of trafficking, which may help to reduce excitotoxicity. Moreover, S1R is situated in lipid rafts where it binds cholesterol and regulates lipid and protein trafficking and calcium flux at the mitochondrial-associated membrane (MAM) domain. This may have important implications for MAM stability and function in neurodegenerative diseases as well as cellular bioenergetics. We also summarize the structural and biochemical features of S1R proposed to underlie its activity. In conclusion, S1R is incredibly versatile in its ability to foster neuronal homeostasis in the context of several neurodegenerative disorders.

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The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke
Barbro Johansson

Brain, 2011

Stroke leads to brain damage with subsequent slow and incomplete recovery of lost brain functions. Enriched housing of stroke-injured rats provides multi-modal sensorimotor stimulation, which improves recovery, although the specific mechanisms involved have not been identified. In rats housed in an enriched environment for two weeks after permanent middle cerebral artery occlusion, we found increased sigma-1 receptor expression in peri-infarct areas. Treatment of rats subjected to permanent or transient middle cerebral artery occlusion with 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride, an agonist of the sigma-1 receptor, starting two days after injury, enhanced the recovery of lost sensorimotor function without decreasing infarct size. The sigma-1 receptor was found in the galactocerebroside enriched membrane microdomains of reactive astrocytes and in neurons. Sigma-1 receptor activation increased the levels of the synaptic protein neurabin and neurexin in membrane rafts in the peri-infarct area, while sigma-1 receptor silencing prevented sigma-1 receptor-mediated neurite outgrowth in primary cortical neuronal cultures. In astrocytic cultures, oxygen and glucose deprivation induced sigma-1 receptor expression and actin dependent membrane raft formation, the latter blocked by sigma-1 receptor small interfering RNA silencing and pharmacological inhibition. We conclude that sigma-1 receptor activation stimulates recovery after stroke by enhancing cellular transport of biomolecules required for brain repair, thereby stimulating brain plasticity. Pharmacological targeting of the sigma-1 receptor provides new opportunities for stroke treatment beyond the therapeutic window of neuroprotection.

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N,N-dimethyltryptamine reduces infarct size and improves functional recovery following transient focal brain ischemia in rats
Attila Szabo

Experimental Neurology, 2020

Background and purpose: N,N-dimethyltryptamine (DMT) is an endogenous ligand of the Sigma 1 receptor (Sig-1R) with documented in vitro cytoprotective properties against hypoxia. Our aim was to demonstrate the in vivo neuroprotective effect of DMT following ischemia-reperfusion injury in the rat brain. Methods: Transient middle cerebral occlusion (MCAO) was induced for 60 minutes in male Wistar rats using the filament occlusion model under general anaesthesia. Before the removal of the filament the treatment group (n=10) received an intra-peritoneal (IP) bolus of 1mg/kg body weight (bw) DMT dissolved in 1ml 7% ethanol/saline vehicle, followed by a maintenance dose of 2mg/Kg-bw/hour delivered over 24 hours via osmotic minipumps. Controls (n=10) received a vehicle bolus only. A third group (n=10) received a Sig-1R antagonist (BD1063, 1mg/kg-bw bolus + 2mg/kg-bw/hour maintenance) in parallel with the DMT. Lesion volume was measured by MRI 24 hours following the MCAO. Shortly after imaging the animals were terminated, and the native brains and sera were removed. Four rats were perfusion fixed. Functional recovery was studied in two separate group of pre-trained animals (n=8-8) using the staircase method for 30 days. The expression levels of proteins involved in apoptosis, neuroplasticity and inflammatory regulation were assessed by real-time qPCR and ELISA. Results: DMT treated rats were characterized by lower ischemic lesion volume (p=0.0373), and better functional recovery (p= 0.0084) compared to the controls. Sig-1R was expressed both in neurons and in microglia in the peri-infarct cortex, and the DMT induced change in the lesion volume was hindered by BD1063. Lower APAF1 expression (mRNA and protein) and higher BNDF levels were documented on DTM, while decreased TNF-α, IL1-β, IL-6 and increased IL-10 expressions indicated the compound’s anti-inflammatory potential. Conclusion: Our results indicate a Sig-1R dependent reduction of the ichemic brain injury following exogenous DMT administration in rats, presumably through a combined antiapoptotic, pro-neurotrophic and anti-inflammatory treatment effect.

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Administration of a Sigma Receptor Agonist Delays MCAO-Induced Neurodegeneration and White Matter Injury
Christopher Leonardo

2010

Many pharmacological treatments for stroke have afforded protection in rodent models but failed to show efficacy in clinical trials. This discrepancy may be due to the lack of long-term functional studies. Previously, delayed administration of the sigma receptor agonist 1,3-dio-tolylguanidine (DTG) reduced infarct volume after middle cerebral artery occlusion (MCAO) in rats. The present study was conducted to determine whether the protective effects of DTG lead to improvements in behavioral functioning. Rats were subjected to MCAO and administered 7.5, 1.5, or 0.75 mg/kg DTG beginning 24 h post-surgery. Histological outcomes (96 h, 2 weeks, and 5 weeks) were compared with performance on a series of behavioral tests (2 and 4 weeks). Fluoro-Jade staining and immunohistochemistry were used to assess infarct volume and immune cell recruitment. All doses significantly reduced infarct volume and perturbation of striatal white matter tracts at 96 h. These reductions were associated with decreased numbers of CD11b-positive amoeboid microglia/ macrophages. Despite short-term efficacy, DTG failed to improve behavioral outcomes or reduce infarct volumes after 96 h. While DTG may prove beneficial as a short-term therapy, these data highlight the importance of long-term functional recovery when evaluating novel therapies to treat stroke.

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

Journal of Neural Transmission, 2013

N,N-dimethyltryptamine (DMT) is classified as a naturally occurring serotonergic hallucinogen of plant origin. It has also been found in animal tissues and regarded as an endogenous trace amine transmitter. The vast majority of research on DMT has targeted its psychotropic/ psychedelic properties with less focus on its effects beyond the nervous system. The recent discovery that DMT is an endogenous ligand of the sigma-1 receptor may shed light on yet undiscovered physiological mechanisms of DMT activity and reveal some of its putative biological functions. A three-step active uptake process of DMT from peripheral sources to neurons underscores a presumed physiological significance of this endogenous hallucinogen. In this paper, we overview the literature on the effects of sigma-1 receptor ligands on cellular bioenergetics, the role of serotonin, and serotoninergic analogues in immunoregulation and the data regarding gene expression of the DMT synthesizing enzyme indolethylamine-Nmethyltransferase in carcinogenesis. We conclude that the function of DMT may extend central nervous activity and involve a more universal role in cellular protective mechanisms. Suggestions are offered for future directions of indole alkaloid research in the general medical field. We provide converging evidence that while DMT is a substance which produces powerful psychedelic experiences, it is better understood not as a hallucinogenic drug of abuse, but rather an agent of significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies.

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References (98)

  1. Aggarwal, S., Mannam, P., & Zhang, J. (2016). Differential regulation of autophagy and mitophagy in pulmonary diseases. American Journal of Physiology: Lung Cellular and Molecular Physiology, 311(2), L433-L452. https://doi.org/10.1152/ajplung.00128.2016.
  2. Al-Saif, A., Al-Mohanna, F., & Bohlega, S. (2011). A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Annals of Neurology, 70(6), 913-919. https://doi. org/10.1002/ana.22534.
  3. Aleksandrova, L. R., & Phillips, A. G. (2021). Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends in Pharmacological Sciences, 42(11), 929-942. https://doi.org/10.1016/j.tips.2021.08.003.
  4. Barker, S. A., McIlhenny, E. H., & Strassman, R. (2012). A critical review of reports of endogenous psychedelic N,N-dimethyltryptamines in humans: 1955-2010. Drug Testing and Analysis, 4(7-8), 617-635. https://doi.org/10.1002/dta.422.
  5. Behensky, A. A., Yasny, I. E., Shuster, A. M., Seredenin, S. B., Petrov, A. V., & Cuevas, J. (2013). Afobazole activation of sigma-1 receptors modulates neuronal responses to amyloid-beta25-35. Journal of Pharmacology and Experimental Therapeutics, 347(2), 468-477. https://doi.org/10.1124/jpet.113.208330.
  6. Bockaert, J., Claeysen, S., Becamel, C., Dumuis, A., & Marin, P. (2006). Neuronal 5-HT metabotropic receptors: Fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell and Tissue Research, 326(2), 553-572. https://doi.org/10.1007/s00441- 006-0286-1.
  7. Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., Wilcox, C. E., Barbosa, P. C., & Strassman, R. J. (2015). Psilocybin-assisted treatment for alcohol dependence: A proof- of-concept study. Journal of Psychopharmacology (Oxford, England), 29(3), 289-299. https://doi.org/10.1177/0269881114565144.
  8. Chaudhari, N., Talwar, P., Parimisetty, A., Lefebvre d'Hellencourt, C., & Ravanan, P. (2014). A molecular web: Endoplasmic reticulum stress, inflammation, and oxidative stress. Frontiers in Cellular Neuroscience, 8, 213. https://doi.org/10.3389/fncel.2014.00213.
  9. Cheng, D., Lei, Z. G., Chu, K., Lam, O. J. H., Chiang, C. Y., & Zhang, Z. J. (2024). N,N- Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer's disease by restoring neuronal sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk. Alzheimer's Research & Therapy, 16(1), 95. https://doi.org/10.1186/s13195-024-01462-3.
  10. Christian, S. T., Harrison, R., Quayle, E., Pagel, J., & Monti, J. (1977). The in vitro identification of dimethyltryptamine (DMT) in mammalian brain and its characterization as a possible endogenous neuroregulatory agent. Biochemical Medicine, 18(2), 164-183. https://doi.org/10.1016/0006-2944(77)90088-6.
  11. Crouzier, L., Denus, M., Richard, E. M., Tavernier, A., Diez, C., Cubedo, N., et al. (2021). Sigma-1 receptor Is critical for mitochondrial activity and unfolded protein response in larval zebrafish. International Journal of Molecular Sciences, 22(20), 11049. https://doi.org/10.3390/ijms222011049.
  12. Dakic, V., Minardi Nascimento, J., Costa Sartore, R., Maciel, R. M., de Araujo, D. B., Ribeiro, S., et al. (2017). Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Scientific Reports, 7(1), 12863. https://doi.org/10. 1038/s41598-017-12779-5.
  13. Dean, J. G., Liu, T., Huff, S., Sheler, B., Barker, S. A., Strassman, R. J., et al. (2019). Biosynthesis and extracellular concentrations of N,N-dimethyltryptamine (DMT) in mammalian brain. Scientific Reports, 9(1), 9333. https://doi.org/10.1038/s41598-019- 45812-w.
  14. De Gregorio, D., Popic, J., Enns, J. P., Inserra, A., Skalecka, A., Markopoulos, A., et al. (2021). Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission. Proceedings of the National Academy of Sciences, USA, 118(5), e2020705118. https://doi.org/10.1073/pnas.2020705118.
  15. Eltzschig, H. K., & Eckle, T. (2011). Ischemia and reperfusion: From mechanism to translation. Nature Medicine, 17(11), 1391-1401. https://doi.org/10.1038/nm.2507.
  16. Feher, A., Juhasz, A., Laszlo, A., Kalman, J., Jr., Pakaski, M., Kalman, J., & Janka, Z. (2012). Association between a variant of the sigma-1 receptor gene and Alzheimer's disease. Neuroscience Letters, 517(2), 136-139. https://doi.org/10.1016/j.neulet.2012.04.046.
  17. Fisher, A., Bezprozvanny, I., Wu, L., Ryskamp, D. A., Bar-Ner, N., Natan, N., et al. (2016). AF710B, a novel M1/sigma1 agonist with therapeutic efficacy in animal models of Alzheimer's disease. Neuro-degenerative Diseases, 16(1-2), 95-110. https://doi.org/10. 1159/000440864.
  18. Fontanilla, D., Johannessen, M., Hajipour, A. R., Cozzi, N. V., Jackson, M. B., & Ruoho, A. E. (2009). The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science (New York, N. Y.), 323(5916), 934-937. https://doi. org/10.1126/science.1166127.
  19. Frecska, E., Szabo, A., Winkelman, M. J., Luna, L. E., & McKenna, D. J. (2013). A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity. Journal of Neural Transmission, 120(9), 1295-1303. https://doi.org/10. 1007/s00702-013-1024-y.
  20. Fukunaga, K. (2014). Orphan receptor and chaperon functions of sigma-1 receptor. Folia pharmacologica Japonica, 143(5), 263-264. https://doi.org/10.1254/fpj.143.263.
  21. Fukunaga, K., Shinoda, Y., & Tagashira, H. (2015). The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis. Journal of Pharmacological Sciences, 127(1), 36-41. https://doi.org/10.1016/j.jphs.2014.12.012.
  22. Gable, R. S. (2007). Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids. Addiction (Abingdon, England), 102(1), 24-34. https://doi.org/10. 1111/j.1360-0443.2006.01652.x.
  23. Hayashi, T. (2019). The sigma-1 receptor in cellular stress signaling. Frontiers in Neuroscience, 13, 733. https://doi.org/10.3389/fnins.2019.00733.
  24. Hayashi, T., & Su, T. P. (2004). Sigma-1 receptor ligands: Potential in the treatment of neuropsychiatric disorders. CNS Drugs, 18(5), 269-284. https://doi.org/10.2165/ 00023210-200418050-00001.
  25. Hayashi, T., & Su, T. P. (2007). Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell, 131(3), 596-610. https://doi. org/10.1016/j.cell.2007.08.036.
  26. Hetz, C., & Mollereau, B. (2014). Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nature Reviews. Neuroscience, 15(4), 233-249. https://doi. org/10.1038/nrn3689.
  27. Hiramatsu, N., Chiang, W. C., Kurt, T. D., Sigurdson, C. J., & Lin, J. H. (2015). Multiple mechanisms of unfolded protein response-induced cell death. American Journal of Pathology, 185(7), 1800-1808. https://doi.org/10.1016/j.ajpath.2015.03.009.
  28. Hollister, L. E. (1977). Some general thoughts about endogenous psychotogens. In In. E. Usdin, D. A. Hamburg, & J. D. Barchas (Eds.). Neuroregulators and psychiatric disorders (pp. 550-556). Oxford University Press.
  29. Hosszu, A., Antal, Z., Lenart, L., Hodrea, J., Koszegi, S., Balogh, D. B., et al. (2017). Sigma1- receptor agonism protects against renal ischemia-reperfusion injury. Journal of the American Society of Nephrology, 28(1), 152-165. https://doi.org/10.1681/ASN.2015070772.
  30. Inserra, A., De Gregorio, D., & Gobbi, G. (2021). Psychedelics in psychiatry: Neuroplastic, immunomodulatory, and neurotransmitter mechanisms. Pharmacological Reviews, 73(1), 202-277. https://doi.org/10.1124/pharmrev.120.000056.
  31. Jarrott, B., & Williams, S. J. (2016). Chronic brain inflammation: The neurochemical basis for drugs to reduce inflammation. Neurochemical Research, 41(3), 523-533. https://doi. org/10.1007/s11064-015-1661-7.
  32. Jin, M., Liu, X., & Klionsky, D. J. (2013). SnapShot: selective autophagy. Cell, 152(1-2), 368.e2. https://doi.org/10.1016/j.cell.2013.01.004.
  33. Kalogeris, T., Baines, C. P., Krenz, M., & Korthuis, R. J. (2012). Cell biology of ischemia- reperfusion injury. International Review of Cell and Molecular Biology, 298, 229-317. https://doi.org/10.1016/B978-0-12-394309-5.00006-7.
  34. Lahmy, V., Long, R., Morin, D., Villard, V., & Maurice, T. (2015). Mitochondrial pro- tection by the mixed muscarinic/sigma1 ligand ANAVEX2-73, a tetrahydrofuran deri- vative, in Abeta25-35 peptide-injected mice, a nontransgenic Alzheimer's disease model. Frontiers in Cellular Neuroscience, 8, 463. https://doi.org/10.3389/fncel.2014.00463.
  35. Lahmy, V., Meunier, J., Malmstrom, S., Naert, G., Givalois, L., Kim, S. H., et al. (2013). Blockade of Tau hyperphosphorylation and Abeta(1)(-)(4)(2) generation by the amino- tetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and sigma-1 receptor agonist, in a nontransgenic mouse model of Alzheimer's disease. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 38(9), 1706-1723. https://doi.org/10.1038/npp.2013.70.
  36. Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., et al. (2018). Psychedelics promote structural and functional neural plasticity. Cell Reports, 23(11), 3170-3182. https://doi.org/10.1016/j.celrep.2018.05.022.
  37. Mancuso, R., Olivan, S., Rando, A., Casas, C., Osta, R., & Navarro, X. (2012). Sigma-1R agonist improves motor function and motoneuron survival in ALS mice. Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics, 9(4), 814-826. https://doi.org/10.1007/s13311-012-0140-y.
  38. Marrazzo, A., Caraci, F., Salinaro, E. T., Su, T. S., Copani, A., & Ronsisvalle, G. (2005). Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity. Neuroreport, 16(11), 1223-1226. https://doi.org/10.1097/00001756-200508010-00018.
  39. Maurice, T. (2016). Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments. Behavioural Brain Research, 296, 270-278. https://doi.org/10.1016/j.bbr.2015.09.020.
  40. Maurice, T., & Goguadze, N. (2017). Sigma-1 receptor in memory and neurodegenerative diseases. Handbook of Experimental Pharmacology, 244, 81-108. https://doi.org/10.1007/ 164_2017_15.
  41. Maurice, T., Su, T. P., & Privat, A. (1998). Sigma-1 receptor agonists and neurosteroids attenuate B25-35-amyloid peptide-induced amnesia in mice through a common mechanism. Neuroscience, 83(2), 413-428. https://doi.org/10.1016/s0306-4522(97)00405-3.
  42. Mavlyutov, T. A., Epstein, M. L., Liu, P., Verbny, Y. I., Ziskind-Conhaim, L., & Ruoho, A. E. (2012). 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, 206, 60-68. https://doi.org/10.1016/j.neuroscience.2011.12.040.
  43. Mavlyutov, T. A., Guo, L. W., Epstein, M. L., & Ruoho, A. E. (2015). Role of the sigma-1 receptor in amyotrophic lateral sclerosis (ALS). Journal of Pharmacological Sciences, 127(1), 10-16. https://doi.org/10.1016/j.jphs.2014.12.013.
  44. Meunier, J., Ieni, J., & Maurice, T. (2006). The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor. British Journal of Pharmacology, 149(8), 998-1012. https://doi.org/10.1038/sj.bjp.0706927.
  45. Mishina, M., Ohyama, M., Ishii, K., Kitamura, S., Kimura, Y., Oda, K., et al. (2008). Low density of sigma-1 receptors in early Alzheimer's disease. Annals of Nuclear Medicine, 22(3), 151-156. https://doi.org/10.1007/s12149-007-0094-z.
  46. Mizuma, A., & Yenari, M. A. (2017). Anti-inflammatory targets for the treatment of reperfusion injury in stroke. Frontiers in Neurology, 8, 467. https://doi.org/10.3389/ fneur.2017.00467.
  47. Moebius, F. F., Reiter, R. J., Hanner, M., & Glossmann, H. (1997). High affinity of sigma1-binding sites for sterol isomerization inhibitors: Evidence for a pharmacological relationship with the yeast sterol C8 ± C7 isomerase. British Journal of Pharmacology, 121(1), 1-6. https://doi.org/10.1038/sj.bjp.0701079.
  48. Nardai, S., Laszlo, M., Szabo, A., Alpar, A., Hanics, J., Zahola, P., et al. (2020). N,N- dimethyltryptamine reduces infarct size and improves functional recovery following transient focal brain ischemia in rats. Experimental Neurology, 327, 113245. https://doi. org/10.1016/j.expneurol.2020.113245.
  49. Nguyen, L., Lucke-Wold, B. P., Mookerjee, S. A., Cavendish, J. Z., Robson, M. J., Scandinaro, A. L., & Matsumoto, R. R. (2015). Role of sigma-1 receptors in neuro- degenerative diseases. Journal of Pharmacological Sciences, 127(1), 17-29. https://doi.org/ 10.1016/j.jphs.2014.12.005.
  50. Nichols, D. E. (2016). Psychedelics. Pharmacological Reviews, 68(2), 264-355. https://doi. org/10.1124/pr.115.011478.
  51. Omi, T., Tanimukai, H., Kanayama, D., Sakagami, Y., Tagami, S., Okochi, M., et al. (2014). Fluvoxamine alleviates ER stress via induction of sigma-1 receptor. Cell Death & Disease, 5(7), e1332. https://doi.org/10.1038/cddis.2014.301.
  52. Ono, Y., Tanaka, H., Takata, M., Nagahara, Y., Noda, Y., Tsuruma, K., et al. (2014). SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in vitro and in vivo amyotrophic lateral sclerosis models. Neuroscience Letters, 559, 174-178. https://doi. org/10.1016/j.neulet.2013.12.005.
  53. Pabba, M. (2013). The essential roles of protein-protein interaction in sigma-1 receptor func- tions. Frontiers in Cellular Neuroscience, 7, 50. https://doi.org/10.3389/fncel.2013.00050.
  54. Pal, A., Fontanilla, D., Gopalakrishnan, A., Chae, Y. K., Markley, J. L., & Ruoho, A. E. (2012). The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements. European Journal of Pharmacology, 682(1-3), 12-20. https://doi.org/10.1016/j.ejphar.2012.01.030.
  55. Penke, B., Fulop, L., Szucs, M., & Frecska, E. (2018). The role of sigma-1 receptor, an intracellular chaperone in neurodegenerative diseases. Current Neuropharmacology, 16(1), 97-116. https://doi.org/10.2174/1570159X15666170529104323.
  56. Peviani, M., Salvaneschi, E., Bontempi, L., Petese, A., Manzo, A., Rossi, D., et al. (2014). Neuroprotective effects of the sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation. Neurobiology of Disease, 62, 218-232. https://doi.org/10.1016/j.nbd.2013.10.010.
  57. Prause, J., Goswami, A., Katona, I., Roos, A., Schnizler, M., Bushuven, E., et al. (2013). Altered localization, abnormal modification and loss of function of sigma receptor-1 in amyotrophic lateral sclerosis. Human Molecular Genetics, 22(8), 1581-1600. https://doi. org/10.1093/hmg/ddt008.
  58. Ramakrishnan, N. K., Visser, A. K., Rybczynska, A. A., Nyakas, C. J., Luiten, P. G., Kwizera, C., et al. (2016). Sigma-1 agonist binding in the aging rat brain: A microPET study with [(11)C]SA4503. Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging, 18(4), 588-597. https://doi.org/10.1007/s11307-015-0917-6.
  59. Ray, T. S. (2010). Psychedelics and the human receptorome. PLoS ONE, 5(2), e9019. https://doi.org/10.1371/journal.pone.0009019.
  60. Remondelli, P., & Renna, M. (2017). The endoplasmic reticulum unfolded protein response in neurodegenerative disorders and its potential therapeutic significance. Frontiers in Molecular Neuroscience, 10, 187. https://doi.org/10.3389/fnmol.2017.00187.
  61. Ruoho, A. E., Chu, U. B., Ramachandran, S., Fontanilla, D., Mavlyutov, T., & Hajipour, A. R. (2012). The ligand binding region of the sigma-1 receptor: Studies utilizing photoaffinity probes, sphingosine and N-alkylamines. Current Pharmaceutical Design, 18(7), 920-929. https://doi.org/10.2174/138161212799436584.
  62. Ruscher, K., & Wieloch, T. (2015). The involvement of the sigma-1 receptor in neuro- degeneration and neurorestoration. Journal of Pharmacological Sciences, 127(1), 30-35. https://doi.org/10.1016/j.jphs.2014.11.011.
  63. Sabino, V., Cottone, P., Zhao, Y., Iyer, M. R., Steardo, L., Jr., Steardo, L., et al. (2009). The sigma-receptor antagonist BD-1063 decreases ethanol intake and reinforcement in animal models of excessive drinking. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 34(6), 1482-1493. https://doi.org/10.1038/ npp.2008.192.
  64. Safra, M., Ben-Hamo, S., Kenyon, C., & Henis-Korenblit, S. (2013). The ire-1 ER stress- response pathway is required for normal secretory-protein metabolism in C. elegans. Journal of Cell Science, 126(Pt 18), 4136-4146. https://doi.org/10.1242/jcs.123000.
  65. Salvan, P., Fonseca, M., Winkler, A. M., Beauchamp, A., Lerch, J. P., & Johansen-Berg, H. (2023). Serotonin regulation of behavior via large-scale neuromodulation of serotonin receptor networks. Nature Neuroscience, 26(1), 53-63. https://doi.org/10.1038/s41593- 022-01213-3.
  66. Sies, H., Berndt, C., & Jones, D. P. (2017). Oxidative stress. Annual Review of Biochemistry, 86, 715-748. https://doi.org/10.1146/annurev-biochem-061516-045037.
  67. Sinha, J. K., Trisal, A., Ghosh, S., Gupta, S., Singh, K. K., Han, S. S., et al. (2024). Psychedelics for Alzheimer's disease-related dementia: Unveiling therapeutic possibilities and pathways. Ageing Research Reviews, 96, 102211. https://doi.org/10.1016/j.arr.2024.102211.
  68. Sovolyova, N., Healy, S., Samali, A., & Logue, S. E. (2014). Stressed to death: Mechanisms of ER stress-induced cell death. Biological Chemistry, 395(1), 1-13. https://doi.org/10. 1515/hsz-2013-0174.
  69. Strassman, R. J., & Qualls, C. R. (1994a). Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects. Archives of General Psychiatry, 51(2), 85-97. https://doi.org/10.1001/archpsyc.1994.03950020009001.
  70. Strassman, R. J., & Qualls, C. R. (1994b). Dose-response study of N,N-dimethyl- tryptamine in humans. II. Subjective effects and preliminary results of a new rating scale. Archives of General Psychiatry, 51(2), 98-108. https://doi.org/10.1001/archpsyc.1994. 03950020022002.
  71. Su, T. P., Hayashi, T., Maurice, T., Buch, S., & Ruoho, A. E. (2010). The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends in Pharmacological Sciences, 31(12), 557-566. https://doi.org/10.1016/j.tips.2010.08.007.
  72. Su, T. P., Hayashi, T., & Vaupel, D. B. (2009). When the endogenous hallucinogenic trace amine N,N-dimethyltryptamine meets the sigma-1 receptor. Science Signaling, 2(61), pe12. https://doi.org/10.1126/scisignal.261pe12.
  73. Su, T. P., London, E. D., & Jaffe, J. H. (1988). Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science (New York, N. Y.), 240(4849), 219-221. https://doi.org/10.1126/science.2832949.
  74. Su, T. P., Su, T. C., Nakamura, Y., & Tsai, S. Y. (2016). The sigma-1 receptor as a pluripotent modulator in living systems. Trends in Pharmacological Sciences, 37(4), 262-278. https://doi.org/10.1016/j.tips.2016.01.003.
  75. Svob Strac, D., Pivac, N., & Muck-Seler, D. (2016). The serotonergic system and cognitive function. Translational Neuroscience, 7(1), 35-49. https://doi.org/10.1515/tnsci-2016-0007.
  76. Szabo, A., & Frecska, E. (2016). Dimethyltryptamine (DMT): A biochemical Swiss Army knife in neuroinflammation and neuroprotection? Neural regeneration research, 11(3), 396-397. https://doi.org/10.4103/1673-5374.179041.
  77. Szabo, A., Kovacs, A., Frecska, E., & Rajnavolgyi, E. (2014). Psychedelic N,N-dime- thyltryptamine 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, 9(8), e106533. https://doi.org/10.1371/journal.pone. 0106533. Szabo, A., Kovacs, A., Riba, J., Djurovic, S., Rajnavolgyi, E., & Frecska, E. (2016). The endogenous hallucinogen and trace amine N,N-dimethyltryptamine (DMT) displays potent protective effects against hypoxia via sigma-1 receptor activation in human primary iPSC-derived cortical neurons and microglia-like immune cells. Frontiers in Neuroscience, 10, 423. https://doi.org/10.3389/fnins.2016.00423.
  78. Szabo, I., Varga, V. E., Dvoracsko, S., Farkas, A. E., Kormoczi, T., Berkecz, R., et al. (2021). N,N-Dimethyltryptamine attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain. Neuropharmacology, 192, 108612. https://doi.org/10.1016/j.neuropharm.2021.108612.
  79. Tagashira, H., Zhang, C., Lu, Y. M., Hasegawa, H., Kanai, H., Han, F., & Fukunaga, K. (2013). Stimulationof sigma1-receptor restores abnormal mitochondrial Ca(2)(+) mobilization and ATP production following cardiac hypertrophy. Biochimica et Biophysica Acta, 1830(4), 3082-3094. https://doi.org/10.1016/j.bbagen.2012.12.029.
  80. Teter, B., & Ashford, J. W. (2002). Neuroplasticity in Alzheimer's disease. Journal of Neuroscience Research, 70(3), 402-437. https://doi.org/10.1002/jnr.10441.
  81. Tsai, S. Y., Chuang, J. Y., Tsai, M. S., Wang, X. F., Xi, Z. X., Hung, J. J., et al. (2015). Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope. Proceedings of the National Academy of Sciences, USA, 112(47), E6562-E6570. https://doi.org/10.1073/pnas.1518894112.
  82. Tsai, S. Y., Pokrass, M. J., Klauer, N. R., De Credico, N. E., & Su, T. P. (2014). Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders. Expert Opinion on Therapeutic Targets, 18(12), 1461-1476. https://doi.org/10.1517/14728222.2014.972939.
  83. Vaidya, V. A., Marek, G. J., Aghajanian, G. K., & Duman, R. S. (1997). 5-HT2A receptor- mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. Journal of Neuroscience, 17(8), 2785-2795. https://doi.org/10.1523/ jneurosci.17-08-02785.1997.
  84. Vann Jones, S. A., & O'Kelly, A. (2020). Psychedelics as a treatment for Alzheimer's disease dementia. Frontiers in Synaptic Neuroscience, 12, 34. https://doi.org/10.3389/ fnsyn.2020.00034.
  85. Villard, V., Espallergues, J., Keller, E., Alkam, T., Nitta, A., Yamada, K., et al. (2009). Antiamnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1- 41 against amyloid beta(25-35)-induced toxicity in mice. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 34(6), 1552-1566. https://doi. org/10.1038/npp.2008.212.
  86. Volgyi, K., Juhász, G., Kovacs, Z., & Penke, B. (2015). Dysfunction of endoplasmic reticulum (ER) and mitochondria (MT) in Alzheimer's disease: The role of the ER-MT cross-talk. Current Alzheimer Research, 12(7), 655-672. https://doi.org/10.2174/ 1567205012666150710095035.
  87. Wang, J., Shanmugam, A., Markand, S., Zorrilla, E., Ganapathy, V., & Smith, S. B. (2015). Sigma-1 receptor regulates the oxidative stress response in primary retinal Muller glial cells via NRF2 signaling and system xc(-), the Na(+)-independent glutamate-cystine exchanger. Free Radical Biology & Medicine, 86, 25-36. https://doi.org/10.1016/j. freeradbiomed.2015.04.009.
  88. Wang, P., He, Y., Li, D., Han, R., Liu, G., Kong, D., & Hao, J. (2016). Class I PI3K inhibitor ZSTK474 mediates a shift in microglial/macrophage phenotype and inhibits inflammatory response in mice with cerebral ischemia/reperfusion injury. Journal of Neuroinflammation, 13(1), 192. https://doi.org/10.1186/s12974-016-0660-1.
  89. Watanabe, S., Ilieva, H., Tamada, H., Nomura, H., Komine, O., Endo, F., et al. (2016). Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1-and SOD1-linked ALS. EMBO Molecular Medicine, 8(12), 1421-1437. https://doi.org/10.15252/emmm.201606403.
  90. Weng, T. Y., Tsai, S. A., & Su, T. P. (2017). Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases. Journal of Biomedical Science, 24(1), 74. https://doi.org/10.1186/s12929-017-0380-6.
  91. Winkelman, M. J., Szabo, A., & Frecska, E. (2023). The potential of psychedelics for the treatment of Alzheimer's disease and related dementias. European Neuropsychopharmacology, 76, 3-16. https://doi.org/10.1016/j.euroneuro.2023.07.003.
  92. Winstock, A. R., Kaar, S., & Borschmann, R. (2014). Dimethyltryptamine (DMT): Prevalence, user characteristics and abuse liability in a large global sample. Journal of Psychopharmacology (Oxford, England), 28(1), 49-54. https://doi.org/10.1177/0269881113513852.
  93. Yabuki, Y., Shinoda, Y., Izumi, H., Ikuno, T., Shioda, N., & Fukunaga, K. (2015). Dehydroepiandrosterone administration improves memory deficits following transient brain ischemia through sigma-1 receptor stimulation. Brain Research, 1622, 102-113. https://doi.org/10.1016/j.brainres.2015.05.006.
  94. Zhang, G., & Stackman, R. W., Jr. (2015). The role of serotonin 5-HT2A receptors in memory and cognition. Frontiers in Pharmacology, 6, 225. https://doi.org/10.3389/fphar. 2015.00225.
  95. Zhang, M., Liu, Q., Meng, H., Duan, H., Liu, X., Wu, J., et al. (2024). Ischemia-reper- fusion injury: Molecular mechanisms and therapeutic targets. Signal Transduction and Targeted Therapy, 9(1), 12. https://doi.org/10.1038/s41392-023-01688-x.
  96. Zhao, Q., Yu, S., Ling, Y., Hao, S., & Liu, J. (2021). The protective effects of dexme- detomidine against hypoxia/reoxygenation-induced inflammatory injury and perme- ability in brain endothelial cells mediated by sigma-1 receptor. ACS Chemical Neuroscience, 12(11), 1940-1947. https://doi.org/10.1021/acschemneuro.1c00032.
  97. Zhao, X., Zhu, L., Liu, D., Chi, T., Ji, X., Liu, P., et al. (2019). Sigma-1 receptor protects against endoplasmic reticulum stress-mediated apoptosis in mice with cerebral ischemia/ reperfusion injury. Apoptosis: an International Journal on Programmed Cell Death, 24(1-2), 157-167. https://doi.org/10.1007/s10495-018-1495-2.
  98. Zimmerman, B. J., & Granger, D. N. (1994). Mechanisms of reperfusion injury. American Journal of the Medical Sciences, 307(4), 284-292. https://doi.org/10.1097/00000441- 199404000-00009.

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