Research on dimethyltryptamine (DMT) has primarily centered on its psychotropic properties and serotonergic activity, largely overlooking its potential effects beyond the nervous system and on other receptor sites. Previous findings (Fontanilla et al., 2009) have identified DMT as an endogenous agonist ligand of the sigma-1 receptor (Sig-1R), which may illuminate previously unrecognized physiological mechanisms and therapeutic potentials linked to this compound. Specifically, current authors established in vitro and in vivo that DMT interacts with Sig-1R, suggesting that its effects may extend beyond traditional serotonergic pathways and into areas of cellular protection and stress response mechanisms (Szabo & Frecska, 2016). The Sig-1R is known to play a crucial role in alleviating various forms of intracellular stress, including mitochondrial, endoplasmic reticulum (ER), and oxidative stress, while also safeguarding against apoptotic cell death and modulating immune responses (Pal et al., 2012, Weng et al., 2017). This indicates that DMT administration could similarly influence these protective pathways and can be utilized in pathological conditions apart from the field of mental and behavioral disorders.

The present chapter reviews the existing literature on Sig-1R’s role in cellular bioenergetics, particularly in the context of mitigation of cellular stress and addresses other receptor related – especially serotonin (5-hydroxytryptamine, 5-HT) mediated – mechanisms as well. For its therapeutic use we put into focus its potential effects against neurodegenerative processes and disorders with neurodegenerative-neuroinflammatory components, such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Furthermore, we also focus on potential therapeutic modalities in the prevention of ischemia-reperfusion injury (IRI) of the brain and related organs.