OPEN Foundation

A. Szabo

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

December 2, 2021 / DMT, Medicine, Neuroscience, Papers / Leave a Comment / By / , , , , , , , ,

Abstract

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 min 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 1 mg/kg-body weight (bw) DMT dissolved in 1 ml 7% ethanol/saline vehicle, followed by a maintenance dose of 2 mg/Kg-bw/h delivered over 24 h via osmotic minipumps. Controls (n = 10) received a vehicle bolus only. A third group (n = 10) received a Sig-1R antagonist (BD1063, 1 mg/kg-bw bolus +2 mg/kg-bw/h maintenance) in parallel with the DMT. Lesion volume was measured by MRI 24 h 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 = .0373), and better functional recovery (p = .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 ischemic brain injury following exogenous DMT administration in rats, presumably through a combined anti-apoptotic, pro-neurotrophic and anti-inflammatory treatment effect.

Nardai, S., László, M., Szabó, A., Alpár, A., Hanics, J., Zahola, P., Merkely, B., Frecska, E., & Nagy, Z. (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

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Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment

December 10, 2019 / Chemistry, DMT, Medicine, Neuroscience, Other substances, Papers, Psychopharmacology, Psychotherapy, Publications / By / , , , , ,

Abstract

Rationale

5-methoxy-N,N-dimethyltryptamine is a psychotropic substance found in various plant and animal species and is synthetically produced. 5-methoxy-N,N-dimethyltryptamine is used in naturalistic settings for spiritual exploration, recreation, or to address negative affect and mood problems. However, scientific knowledge on the effects of 5-methoxy-N,N-dimethyltryptamine in humans is scarce.

Objectives

The first objective was to assess the effects of inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine on neuroendocrine markers. The second objective was to assess effects of the substance on affect and mindfulness. In addition, we assessed whether ratings of subjective measures were associated with changes in stress biomarkers (i.e., cortisol) and immune response (i.e., IL-6, CRP, IL-1β), as well as the acute psychedelic experience.

Methods

Assessments (baseline, immediately post-session, and 7-day follow-up) were made in 11 participants. Salivary samples were collected at baseline and post-session and analyzed by high-sensitivity enzyme-linked immunosorbent assay (ELISA).

Results

5-methoxy-N,N-dimethyltryptamine significantly increased cortisol levels and decreased IL-6 concentrations in saliva immediately post-session. These changes were not correlated to ratings of mental health or the psychedelic experience. Relative to baseline, ratings of non-judgment significantly increased, and ratings of depression decreased immediately post-session and at follow-up. Ratings of anxiety and stress decreased from baseline to 7-day follow-up. Participant ratings of the psychedelic experience correlated negatively with ratings of affect and positively with ratings of non-judgment.

Conclusion

Inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine produced significant changes in inflammatory markers, improved affect, and non-judgment in volunteers. Future research should examine the effect of 5-methoxy-N,N-dimethyltryptamineamine with healthy volunteers in a controlled laboratory setting.

Uthaug, M. V., Lancelotta, R., Szabo, A., Davis, A. K., Riba, J., & Ramaekers, J. G. (2019). Prospective examination of synthetic 5-methoxy-N, N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment. Psychopharmacology, 1-13., 10.1007/s00213-019-05414-w
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Weak phantasy and visionary phantasy: the phenomenological significance of altered states of consciousness

January 3, 2017 / Other substances, Papers, Phenomenology, Philosophy, Psychology, Publications / By / , ,

Abstract

In this paper we discuss the definitional problems of altered states of consciousness and their potential relevance in phenomenological investigation. We suggest that visionary states or visionary phantasy working induced by psychedelics (VSs), as extraordinary types of altered states, are appropriate subjects for phenomenological analysis. Naturally, visionary states are not quite ordinary workings of the human mind, however certain cognitive psychological and evolutionary epistemological investigations show that they can give new insights into the nature of consciousness. Furthermore, we suggest that contemporary inquiries concerning altered states in consciousness studies give an opportunity to complete the contemporary phenomenological investigations of phantasy with the notion of visionary phantasy. Here we propose that the similarities and differences between Dieter Lohmar’s weak phantasy (which has a crucial role in empathy and typifying perception) and Benny Shanon’s concept of vision are precisely discernible, and, consequently, it may be possible that weak phantasy and visionary phantasy are situated on the two outermost poles of the colorful spectrum of phantasy activity.

Horváth, L., Szummer, C., & Szabo, A. (2017). Weak phantasy and visionary phantasy: the phenomenological significance of altered states of consciousness. Phenomenology and the Cognitive Sciences, 1-13. 10.1007/s11097-016-9497-4

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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

September 14, 2016 / DMT, Neuroscience, Other subjects, Papers, Psychopharmacology, Publications / By / , , , , ,

Abstract

N,N-dimethyltryptamine (DMT) is a potent endogenous hallucinogen present in the brain of humans and other mammals. Despite extensive research, its physiological role remains largely unknown. Recently, DMT has been found to activate the sigma-1 receptor (Sig-1R), an intracellular chaperone fulfilling an interface role between the endoplasmic reticulum (ER) and mitochondria. It ensures the correct transmission of ER stress into the nucleus resulting in the enhanced production of antistress and antioxidant proteins. Due to this function, the activation of Sig-1R can mitigate the outcome of hypoxia or oxidative stress. In this paper, we aimed to test the hypothesis that DMT plays a neuroprotective role in the brain by activating the Sig-1R. We tested whether DMT can mitigate hypoxic stress in in vitro cultured human cortical neurons (derived from induced pluripotent stem cells, iPSCs), monocyte-derived macrophages (moMACs), and dendritic cells (moDCs). Results showed that DMT robustly increases the survival of these cell types in severe hypoxia (0.5% O2) through the Sig-1R. Furthermore, this phenomenon is associated with the decreased expression and function of the alpha subunit of the hypoxia-inducible factor 1 (HIF-1) suggesting that DMT-mediated Sig-1R activation may alleviate hypoxia-induced cellular stress and increase survival in a HIF-1-independent manner. Our results reveal a novel and important role of DMT in human cellular physiology. We postulate that this compound may be endogenously generated in situations of stress, ameliorating the adverse effects of hypoxic/ischemic insult to the brain.

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. http://dx.doi.org/10.3389/fnins.2016.00423
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[Psychedelics and quasi-psychedelics in the light of contemporary research: medical cannabis, MDMA, salvinorin A, ibogaine and ayahuasca]

September 17, 2015 / Ayahuasca, Iboga / Ibogaine, MDMA, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Salvia / Salvinorin A / By / , , ,

Abstract

In lack of professional research and appropriate concepts our scientific knowledge of psychedelic agents is limited. According to the long-held official view these drugs are entirely harmful and have no medical use. However, a recent surge of clinical and pharmacological studies in the field indicates that many psychedelic-like agents have therapeutic potentials under proper circumstances. In this paper, from a biomedical and psychological perspective, we provide a brief review of the general effects and promising treatment uses of medical cannabis, 3,4-methylenedioxy-methamphetamine (MDMA), salvinorin A, ibogaine and the dimethyltryptamine-(DMT)-containing ayahuasca. In Hungary – similarly to many other countries – these compounds are classified as “narcotic drugs” and their research is difficult due to strict regulations.

Szabo, A., Kazai, A., Frecska, E., & Brys, Z. (2015). [Psychedelics and quasi-psychedelics in the light of contemporary research: medical cannabis, MDMA, salvinorin A, ibogaine and ayahuasca]. Neuropsychopharmacologia Hungarica: a Magyar Pszichofarmakologiai Egyesulet lapja= official journal of the Hungarian Association of Psychopharmacology, 17(3), 120-128.
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Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities

July 14, 2015 / DMT, LSD, MDMA, Medicine, Neuroscience, Other substances, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Abstract

Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease.

Szabo, A. Psychedelics and immunomodulation: Novel approaches and therapeutic opportunities. Frontiers in Immunology, 0. https://dx.doi.org/10.3389/fimmu.2015.00358
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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

August 29, 2014 / Ayahuasca, DMT, Medicine, Other subjects, Other substances, Papers, Publications / By / , , ,

Abstract

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

Szabo, A., Kovacs, A., Frecska, E., & Rajnavolgyi, E. (2014). 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, 9(8). https://dx.doi.org/10.1371/journal.pone.0106533
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A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity

April 26, 2013 / DMT, Medicine, Other subjects, Papers, Publications / By / , , , ,

Abstract

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

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. http://dx.doi.org/10.1007/s00702-013-1024-y
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30 April - Q&A with Rick Strassman

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