Pharmacodynamics
5-MeO-DMT is a methoxylated derivative of dimethyltryptamine (DMT). While most common psychedelics are believed to primarily elicit psychological effects through agonism of serotonin 5-HT2A receptors, 5-MeO-DMT shows 1,000-fold greater affinity for the serotonin 5-HT1A receptor over the serotonin 5-HT2A receptor. In line with its affinity for serotonin 5-HT1A receptors, 5-MeO-DMT is extremely potent at suppressing the firing of dorsal raphe nucleus serotonin neurons. Further, its activity in rats was attenuated with the selective serotonin 5-HT1A receptor antagonist WAY-100635, while selective serotonin 5-HT2A receptor antagonist volinanserin failed to demonstrate any change. Additional mechanisms of action such as inhibition of monoamine reuptake may also be involved in its effects.
Similarly to other serotonergic psychedelics, 5-MeO-DMT is a non-selective serotonin receptor agonist, including of the serotonin 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors, among others. It shows pronounced biased agonism at the serotonin 5-HT2C receptor. The drug is 4- to 10-fold more potent as a hallucinogen than DMT in humans. In contrast to most serotonergic psychedelics however, it has been said that it is unclear that the hallucinogenic effects of 5-MeO-DMT are principally mediated by activation of the serotonin 5-HT2A receptor. In any case, 5-MeO-DMT does still activate the serotonin 5-HT2A receptor and does still produce psychedelic effects. It has been proposed that 5-MeO-DMT be considered an "atypical" psychedelic. This relates to the fact that 5-MeO-DMT has 100- to 1,000-fold selectivity for the serotonin 5-HT1A receptor over the serotonin 5-HT2A receptor and that the actions of 5-MeO-DMT appear to be primarily mediated by serotonin 5-HT1A receptor activation. For example, the potencies of drugs substituting for 5-MeO-DMT in drug discrimination assays is well-correlated with their serotonin 5-HT1A receptor affinities, and the discriminative stimulus effects of 5-MeO-DMT are almost completely blocked (~80%) by serotonin 5-HT1A receptor antagonists like WAY-100,635. However, there is partial generalization of 5-MeO-DMT to the selective serotonin 5-HT2 receptor agonist (–)-DOM in animals. In addition, the selective serotonin 5-HT2A receptor antagonist volinanserin subtly reduces (~20%) the 5-MeO-DMT interoceptive cue, suggesting a minor contribution of this receptor. Selective antagonists of other serotonin receptors, including the serotonin 5-HT1B, 5-HT2B, and 5-HT2C receptors, had no effect on the discriminative stimulus effects of 5-MeO-DMT. In accordance with the preceding findings, which suggest effects mediated primarily by the serotonin 5-HT1A receptor and to a lesser extent by the serotonin 5-HT2A receptor, 5-MeO-DMT is reported to produce distinct subjective effects compared to DMT and other psychedelics in humans.
Although 5-MeO-DMT shows dramatically higher affinity for the serotonin 5-HT1A receptor than for the serotonin 5-HT2A receptor, the situation appears to be very different in terms of its actual activational potencies at these receptors. Its EC50Tooltip half-maximal effective concentration values have been found to be 1.80 to 3.87nM at the serotonin 5-HT2A receptor and 3.92 to 1,060nM at the serotonin 5-HT1A receptor. For comparison, the EC50 values of DMT were found to be 38.3nM at the serotonin 5-HT2A receptor and >10,000nM at the serotonin 5-HT1A receptor in one of the same studies. Hence, 5-MeO-DMT appears to be similarly potent or as much as 200-fold more potent as an agonist of the serotonin 5-HT2A receptor than of the serotonin 5-HT1A receptor. In addition, 5-MeO-DMT is 10-fold more potent than DMT as an agonist of the serotonin 5-HT2A receptor.
Besides serotonin receptors, 5-MeO-DMT is an agonist of the melatonin MT1 and MT2 receptors. Unlike DMT, 5-MeO-DMT is not a ligand or agonist of the sigma receptors. In contrast to certain other tryptamines, 5-MeO-DMT is inactive as a monoamine releasing agent, including of serotonin, norepinephrine, and dopamine. However, it is a weak serotonin reuptake inhibitor, with an IC50Tooltip half-maximal inhibitory concentration value of 2,184nM. Conversely, it is inactive as a dopamine and norepinephrine reuptake inhibitor (IC50 = >10,000nM).
Similarly to DMT, but in contrast to most other psychedelics, like LSD and psilocybin, there appears to be very little development of tolerance with 5-MeO-DMT. In fact, there may even be sensitization to the effects of 5-MeO-DMT. The lack of tolerance development with 5-MeO-DMT may be due to biased agonism of the serotonin 5-HT2A receptor. More specifically, 5-MeO-DMT activates the Gq signaling pathway of the serotonin 5-HT2A receptor with much less potency in recruiting β-arrestin2. Activation of β-arrestin2 is linked to receptor downregulation and tachyphylaxis.
Pharmacokinetics
Absorption
5-MeO-DMT is not orally active and must be administered parenterally.
Distribution
5-MeO-DMT is lipophilic and is thought to easily cross the blood–brain barrier. Accordingly, 5-MeO-DMT readily accumulates in the brain in animals with levels higher than in blood. This is in notable contrast to bufotenin (5-HO-DMT or N,N-dimethylserotonin) and serotonin (5-HT), which are hydrophilic and have varying degrees of peripheral selectivity.
Metabolism
Bufotenin is an active metabolite of 5-MeO-DMT, formed by O-demethylation by cytochrome P450 CYP2D6. Bufotenin notably has much higher affinity for the serotonin 5-HT2A receptor than 5-MeO-DMT itself. However, bufotenin does not seem to be extensively produced from 5-MeO-DMT in the brain. In addition, peripherally formed bufotenin is less able to exert central effects due to its relative peripheral selectivity in terms of crossing into the brain. Hence, the involvement of bufotenin in the psychoactive effects of 5-MeO-DMT is uncertain.
The metabolism of 5-MeO-DMT can be dramatically reduced and its levels markedly augmented and prolonged by monoamine oxidase inhibitors (MAOIs). In addition, MAOIs allow 5-MeO-DMT to become orally active in humans. Combining 5-MeO-DMT with MAOIs has sometimes resulted in serotonin syndrome and death in humans.
Elimination
The elimination half-life of 5-MeO-DMT, administered sublingually, was found to be 28minutes.
