The plant hallucinogen N,N-dimethyltryptamine (DMT) has been used for religious and other purposes for many centuries. The psychological effects of ingested DMT are characterized as an intense dream-like state with fantastic visual imagery, altered time and space perceptions, changes in body image and sensations, and feelings ranging from euphoria to sadness to amazement. Over the past several decades, scientists have linked the psychoactive effects of DMT to various neurochemical processes including action at serotonin receptors and transporters and monoamine oxidase enzymes.
We recently identified the sigma-1 receptor as the latest molecular target for DMT. We reported that DMT binds to sigma-1 receptors at low micromolar concentrations, inhibits sigma-1 receptor-regulated sodium ion channels at higher concentrations, and induces a hypermobility response in wild-type mice that is abolished in sigma-1 receptor knockout mice (Fontanilla 2009). In a later study, we reported that DMT and other psychedelic tryptamines exhibit substrate behavior at plasma membrane and synaptic vesicle uptake transporters (Cozzi 2009). We hypothesize that these uptake processes may allow the accumulation of DMT within neurons to reach relatively high levels and, when stored in synaptic vesicles, to function as a releasable transmitter. We have now obtained direct experimental evidence in support of this hypothesis by observing that DMT can be taken up by model neuronal cells (PC12 cells) and subsequently released by these cells under conditions of controlled depolarization. The psychedelic effects of DMT and related compounds likely arise from a complex interplay among all of these enzyme, receptor, and transporter mechanisms.
