Pharmacodynamics of DMT
DMT binds non-
selectively with
affinities < 0.6 μM to the following
serotonin receptors:
5-HT1A,
5-HT1B,
5-HT1D,
5-HT2A,
5-HT2B,
5-HT2C,
5-HT6, and
5-HT7. An
agonist action has been determined at 5-HT1A, 5-HT2A and 5-HT2C. Its
efficacies at other serotonin receptors remain to be determined. Of special interest will be the determination of its efficacy at human 5-HT2B receptor as two
in vitro assays evidenced DMT high affinity for this receptor: 0.108 μMand 0.184 μM. This may be of importance because chronic or frequent uses of serotonergic drugs showing preferential high affinity and clear agonism at 5-HT2B receptor have been causally linked to
valvular heart disease.
It has also been shown to possess affinity for the
dopamine D1,
α1-adrenergic,
α2-adrenergic,
imidazoline-1,
sigma-1 (σ1), and
trace amine-associated receptors. Agonism was demonstrated at 1 μM at the rat trace amine-associated receptor 1 (
TAAR1) and converging lines of evidence established activation of the σ1 receptor at concentrations of 50–100 μM. Its efficacies at the other receptor binding sites are unclear. It has also been shown
in vitro to be a
substrate for the cell-surface
serotonin transporter (SERT) and the intracellular
vesicular monoamine transporter 2 (VMAT2), inhibiting SERT-mediated serotonin uptake in human platelets at an average concentration of 4.00 ± 0.70 μM and VMAT2-mediated serotonin uptake in vesicles (of
army worm Sf9 cells) expressing rat VMAT-2 at an average concentration of 93 ± 6.8 μM.
As with other so-called "classical hallucinogens",a large part of DMT psychedelic effects can be attributed to a specific activation of the 5-HT2A receptor. DMT concentrations eliciting 50% of its maximal effect (half maximal effective concentration =
EC50 or Kact) at the human 5-HT2A receptor
in vitro are in the 0.118–0.983 μM range. This range of values coincides well with the range of concentrations measured in blood and plasma after administration of a fully psychedelic dose (see
Pharmacokinetics).
As DMT has been shown to have slightly better efficacy (EC50) at human serotonin 2C receptor than at 2A receptor, 5-HT2C highly likely also is implicated in DMT overall effects. Other receptors, such as 5-HT1A σ1, and TAAR1 may also play a role.
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