5-Methoxy-N,N-dimethyltryptamine (acronymized as 5-MeO-DMT) is arguably the most powerful and psychologically profound compound among the various naturally-occurring psychoactive indolealkylamine substances and its phenomenology is incommensurable to its structural analogs. Research indicates that 5-MeO-DMT may be endogenously synthesized in human pineal and retina. Moreover, it has been detected in blood, urine, and cerebrospinal fluid (Shen, Jiang, Winter, & Yu, 2010). Anthropological evidence suggests that various cultures utilised 5-MeO-DMT containing plants in ritualistic (spiritual) contexts because of their phytochemical properties (Furst, 1972). The molecule acts as a nonselective partial agonist at the 5-HT1A/2A receptor subtypes (associated with emotions, cognition, and memory, inter alia). Phenomenologically, 5-MeO-DMT can occasion “nondual experiences” (cf. Josipovic, 2014) analogous to those described in several ancient Asian knowledge traditions (e.g., Advaita Vedānta (Silberstein, 2017)) and it has been characterised as a prototypical entheogen (Metzner, 2015; Ruck, Bigwood, Staples, Ott, & Wasson, 1979). Accumulating evidence indicates that it is a ligand of the Trace amine-associated receptors (TAARs), a class of G protein-coupled receptors that were discovered in 2001. TAARs have been associated with pathological neuroadaptations caused by prolonged exposure to addictive drugs (e.g., alcohol, heroin, cocaine, etc.). Ergo, this molecular target might partially explain 5-MeO-DMTs promising neurorestorative and neuroprotective effects in addiction treatment. Furthermore, a recent cutting-edge neuroscientific in vivo and in silico study using human cerebral organoids found that 5-MeO-DMT matches the σ1 receptor which regulates cytoskeletal dendritic spine morphology and neurite outgrowth (Dakic et al., 2017). Therefore, σ1R agonism may mediate neuroplastic processes which accompany positive cognitive/behavioural changes. In addition, 5-MeO-DMT has been shown to downregulate the metabotropic glutamate receptor 5 (mGluR5) which is involved in the hedonic rewarding effects of addictive drugs (Knapp & Kornetsky, 2009). The effects of the extraordinary tryptamine on the dopaminergic system (e.g., nucleus accumbens, ventral tegmental area) are currently not well defined and more research is evidently needed to elucidate its exact neuropsychopharmacological mechanisms of action and potential associated epigenetic effects.
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