N,N-dimethyltryptamine (DMT) is classified as a naturally occurring serotonergic hallucinogen of plant origin. The vast majority of research on DMT has targeted its psychotropic 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. Since sigma-1 receptors mitigate endoplasmic reticulum stress, promote cell survival against oxidative stress, and regulate immune processes, one may attribute the same role to DMT. In the presentation, we will overview the literature on the effects of sigma-1 receptor ligands on cellular bioenergetics in focus of ischemic-hypoxic injury. Ischemia-reperfusion is a complex phenomenon with mechanisms underlying stroke, infarct, and organ transplantation. We conclude that the function of DMT may extend central nervous activity and involve a more universal role in cellular protective mechanisms.