Neuromodulatory mechanisms of N,N-dimethyltryptamine

DMT is a naturally occurring psychedelic with potent subjective effects and preliminary evidence for antidepressive, anxiolytic, and antiaddictive properties. Its effects arise from neuromodulation of glutamatergic, monoaminergic, and cholinergic systems, causing acute shifts in brain networks including visual, auditive, and default-mode networks. Top-down cognitive processing becomes restricted while bottom-up processing is enhanced. DMT also induces neuroplasticity via sigma 1 receptor, BDNF, TrkB, and 5-HT2A, which may underlie therapeutic benefits. This review updates the neuromodulatory mechanisms of DMT, covering molecular targets, changes in cortical function and structure, neuroplasticity, and therapeutic relevance and risks.

Study at a glance

Abstract

N,N-dimethyltryptamine (DMT) is the simplest psychedelic tryptamine and is produced naturally by many plant and animal species, including humans. While classical psychedelics, such as lysergic acid diethylamide, or psilocybin, are gaining interest because of their therapeutic potential, DMT has yet to be fully investigated. However, preliminary clinical evidence suggests that DMT and/or ayahuasca, a DMT-containing psychoactive beverage, both possess antidepressive, anxiolytic, and antiaddictive properties. In addition, the subjective effects of DMT are particularly potent. Both subjective and therapeutic cues can be largely explained via the neuromodulatory properties of DMT. In addition, DMT interacts with several neurochemical systems, including the glutamatergic, monoaminergic, and cholinergic systems. Consequently, large-scale brain dynamics can suffer acute and dramatic shifts in several networks, including visual and auditive networks, and the default-mode network. More broadly, top-down cognitive processes (predictive and contextual processing) can become restricted while bottom-up and stimuli-related processing is enhanced. Furthermore, the acute effects of DMT can crystallize to some extent by virtue of its plastogenic effects which are mediated by sigma 1 receptor, brain-derived neurotrophic factor, tropomyosin receptor kinase B, and serotonin receptor 2A. DMT-induced plasticity has been related mental well-being and therapeutic benefits. Here, I provide an updated review of the neuromodulatory effects of DMT and the mechanisms that underlie these effects. I consider the molecular targets that influence neurochemical systems, changes in large-scale cortical function and structure, and DMT-dependent neuroplasticity. Finally, I highlight the therapeutic relevance and/or risks associated with the neuromodulatory mechanisms of DMT.