OPEN Foundation

E. Frecska

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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The hyperassociative mind: The psychedelic experience and Merleau-Ponty’s “wild being”

July 20, 2017 / Cacti / Mescaline, Papers, Phenomenology, Philosophy / By / , , , ,

Abstract

Purpose

In contemporary phenomenology, Dieter Lohmar has suggested that the new task of phenomenological research is to analyze the “alternative representational systems” of fantasy. In line with this program, we propose that psychedelic experience could also be suitable subject to this project subsumed under the wider category of fantasy activity. The aim of this paper is to show that psychedelic experiences offer a favorable situation to study the imagination.

Method

The paper applies the conceptual framework of the late Merleau-Ponty, developed in The Visible and the Invisible, using his mescaline analyses which have been elaborated in The Phenomenology of Perception.

Results

We demonstrate that psychedelic visions and emotional states can be discussed within the Merleau-Pontian framework of “wild world.” From the viewpoint of phenomenology, we suggest that psychedelic visions represent an ongoing sense-making and Gestalt-formation process in which the role of the elaborative activity of the subject is crucial. These – often unsettling – visions show the basic volatility and ambiguity of perception and fantasy, which also sheds light to the hidden schemes of perception, thinking, and emotion of normal consciousness.

Conclusions

Freud claimed that dreams are “the royal road” to the unconscious. In an analogous manner, while dreams were the primary psychoscope to the unconscious of psychoanalysis, in contemporary phenomenology psychedelic experiences may show a possible way to an another kind of unconscious, the phenomenological unconscious. This unconscious comprises the hidden schemes and basic affective emotional attitudes of the knowing subject.

Szummer, C., Horváth, L., SzabÓ, A., Frecska, E., & OrzÓi, K. (2017). The hyperassociative mind: The psychedelic experience and Merleau-Ponty’s “wild being”. Journal of Psychedelic Studies, (0), 1-10. 10.1556/2054.01.2017.006
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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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The potential use of ayahuasca in psychiatry

June 1, 2016 / Ayahuasca, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Safety / By / , , ,

Abstract

Ayahuasca is a decoctum made of admixture plants containing dimethyltryptamine and harmine. For millennia it has been used as a central element of spiritual, religious, initiation, and other – foremost healing – rituals, originally by the indigenous groups of the Amazon basin and later by the mestizo populations of the region. During the last two decades the brew has raised increased scientific and lay interest about its healing potentials within the framework of Western therapeutic settings. The typical ayahuasca effects consist of strong somatic reactions, vivid visions, relived personal memories, cathartic emotions, and insightful, introspective experiences when the emerging mental contents take different context and get deeper perspectives. The ayahuasca-experience can be exhausting necessitating the presence of an experienced leader for helping participants to pass difficult phases and for maximizing therapeutic benefits. No health damaging adverse effect has been confirmed thus far as result of its well-structured, institutionalized use. The scientific investigation of ayahuasca is hindered by legal issues, methodical problems, and sociocultural preconceptions. The present review outlines the therapeutic potentials of ayahuasca use in psychiatry with its psychobiological and spiritual background.

Frecska, E., Bokor, P., Andrassy, G., & Kovacs, A. (2016). The potential use of ayahuasca in psychiatry. Neuropsychopharmacologia Hungarica: a Magyar Pszichofarmakologiai Egyesulet lapja= official journal of the Hungarian Association of Psychopharmacology, 18(2), 79.
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The therapeutic potentials of ayahuasca: possible effects against various diseases of civilization

February 8, 2016 / Addiction, Ayahuasca, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications / By / , ,

Abstract

Ayahuasca is an Amazonian psychoactive brew of two main components. Its active agents are β-carboline and tryptamine derivatives. As a sacrament, ayahuasca is still a central element of many healing ceremonies in the Amazon Basin and its ritual consumption has become common among the mestizo populations of South America. Ayahuasca use amongst the indigenous people of the Amazon is a form of traditional medicine and cultural psychiatry. During the last two decades, the substance has become increasingly known among both scientists and laymen, and currently its use is spreading all over in the Western world. In the present paper we describe the chief characteristics of ayahuasca, discuss important questions raised about its use, and provide an overview of the scientific research supporting its potential therapeutic benefits. A growing number of studies indicate that the psychotherapeutic potential of ayahuasca is based mostly on the strong serotonergic effects, whereas the sigma-1 receptor agonist effect of its active ingredient dimethyltryptamine raises the possibility that the ethnomedical observations on the diversity of treated conditions can be scientifically verified. Moreover, in the right therapeutic or ritual setting with proper preparation and mindset of the user, followed by subsequent integration of the experience, ayahuasca has proven effective in the treatment of substance dependence. This article has two important take-home messages: 1) the therapeutic effects of ayahuasca are best understood from a bio-psycho-socio-spiritual model, and 2) on the biological level ayahuasca may act against chronic low grade inflammation and oxidative stress via the sigma-1 receptor which can explain its widespread therapeutic indications.

Frecska, E., Bokor, P., & Winkelman, M. (2016). The therapeutic potentials of ayahuasca: possible effects against various diseases of civilization. Frontiers in Pharmacology, 7, 35. http://dx.doi.org/10.3389/fphar.2016.00035
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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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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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