Pharmacology of N,N-Dimethyltryptamine
DMT peak level concentrations (Cmax) measured in whole blood after intramuscular (IM) injection (0.7 mg/kg, n = 11) and in plasma following intravenous (IV) administration (0.4 mg/kg, n = 10) of fully psychedelic doses are in the range of ≈14 to 154 μg/L and 32 to 204 μg/L, respectively. The corresponding molar concentrations of DMT are therefore in the range of 0.074–0.818 μM in whole blood and 0.170–1.08 μM in plasma. However, several studies have described active transport and accumulation of DMT into rat and dog brain following peripheral administration.
Similar active transport, and accumulation processes likely occur in human brain and may concentrate DMT in brain by several-fold or more (relatively to blood), resulting in local concentrations in the micromolar or higher range. Such concentrations would be commensurate with serotonin brain tissue concentrations, which have been consistently determined to be in the 1.5-4 μM range.
Closely coextending with peak psychedelic effects, mean time to reach peak concentrations (Tmax) was determined to be 10–15 minutes in whole blood after IM injection, and 2 minutes in plasma after IV administration.
When taken orally mixed in an ayahuasca decoction, and in freeze-dried ayahuasca gel caps, DMT Tmax is considerably delayed: 107.59 ± 32.5 minutes, and 90–120 minutes, respectively.
The pharmacokinetics for vaporizing DMT have not been studied or reported.
Pharmacodynamics
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's high affinity for this receptor: 0.108 μM and 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, and σ1 receptors.
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) expressed in human platelets, and the rat vesicular monoamine transporter 2 (VMAT2), which was transiently expressed in fall armyworm Sf9 cells. DMT inhibited SERT-mediated serotonin uptake into platelets at an average concentration of 4.00 ± 0.70 μM and VMAT2-mediated serotonin uptake 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 functionally selective 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 the 2A receptor, 5-HT2C is also likely implicated in DMT's overall effects.
Other receptors, such as 5-HT1A σ1, may also play a role.
In 2009, it was hypothesized that DMT may be an endogenous ligand for the σ1 receptor.
The concentration of DMT needed for σ1 activation in vitro (50–100 μM) is similar to the behaviorally active concentration measured in mouse brain of approximately 106 μM.
This is minimally 4 orders of magnitude higher than the average concentrations measured in rat brain tissue or human plasma under basal conditions (see Endogenous DMT), so σ1 receptors are likely to be activated only under conditions of high local DMT concentrations.
If DMT is stored in synaptic vesicles, such concentrations might occur during vesicular release. To illustrate, while the average concentration of serotonin in brain tissue is in the 1.5–4 μM range the concentration of serotonin in synaptic vesicles was measured at 270 mM.
Following vesicular release, the resulting concentration of serotonin in the synaptic cleft, to which serotonin receptors are exposed, is estimated to be about 300 μM. Thus, while in vitro receptor binding affinities, efficacies, and average concentrations in tissue or plasma are useful, they are not likely to predict DMT concentrations in the vesicles or at synaptic or intracellular receptors. Under these conditions, notions of receptor selectivity are moot, and it seems probable that most of the receptors identified as targets for DMT (see above) participate in producing its psychedelic effects.
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