TRANSLATIONAL NEUROSCIENCES - REVIEW ARTICLE A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity Ede Frecska • Attila Szabo • Michael J. Winkelman • Luis E. Luna • Dennis J. McKenna Received: 27 November 2012 / Accepted: 1 April 2013 / Published online: 26 April 2013 Ó Springer-Verlag Wien 2013 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 regar- ded 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 func- tions. A three-step active uptake process of DMT from peripheral sources to neurons underscores a presumed physiological significance of this endogenous hallucino- gen. 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 mech- anisms. Suggestions are offered for future directions of indole alkaloid research in the general medical field. We provide converging evidence that while DMT is a sub- stance which produces powerful psychedelic experiences, it is better understood not as a hallucinogenic drug of abuse, but rather an agent of significant adaptive mecha- nisms that can also serve as a promising tool in the development of future medical therapies. Keywords N,N-dimethyltryptamine Á Indolethylamine- N-methyltransferase Á Sigma receptors Á Oxidative stress Á Immunoregulation Á Carcinogenesis Introduction N,N-dimethyltryptamine (DMT) is a naturally occurring methylated indolealkylamine possessing potent psychotro- pic properties (Barker et al. 2012). This indole alkaloid is widespread in nature and abundant in plants such as Diplopterys cabrerana and Psychotria viridis, which are used in preparation of sacramental psychoactive decoctions such as yage and ayahuasca (Luna 2011). In addition to its ubiquitous presence in the plant kingdom, DMT has also been detected in animal tissues and is considered to act as an endogenous trace amine (Wallach 2009). Trace amines (such as octopamine, phenylethylamine, tyramine, trypt- amine, and its derivatives) are generally present at low concentrations and accumulate in high amounts only in certain locations and under special circumstances—for E. Frecska (&) Department of Psychiatry, Medical and Health Science Center, University of Debrecen, Nagyerdei krt. 98, 4012 Debrecen, Hungary e-mail: efrecska@hotmail.com A. Szabo Department of Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary M. J. Winkelman School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, USA L. E. Luna Wasiwaska Research Center for the Study of Psychointegrator Plants, Visionary Art and Consciousness, Florianopolis, Brazil D. J. McKenna Center for Spirituality and Healing, Academic Health Center, University of Minnesota, Minneapolis, MN, USA 123 J Neural Transm (2013) 120:1295–1303 DOI 10.1007/s00702-013-1024-y