Interesting stuff.

Thanks for sharing!

: ')):.

DMT metabolism
Data from clinical trials have highlighted the short-lived nature of the subjective effects
elicited by DMT, the drug’s rapid disappearance from plasma, and the low percentage of the
administered dose which can be recovered unmetabolized in urine (Kaplan et al., 1974). Also,
in vivo studies in animals have attested a very rapid clearance of DMT from various tissues
such as plasma, brain, and liver (Cohen and Vogel, 1972; Mandel et al., 1977; Sitaram et al.,
1987b), which considered together with human data is suggestive of an extensive and
efficacious metabolism. Unfortunately, as already mentioned in the pharmacokinetics section,
only one study has assessed DMT metabolism in humans. Following the i.m. administration
of DMT, Szára (1956) identified in urine IAA as the drug’s degradation product, with no
DMT being detected. This finding was in agreement with a previous study by Ersparmer
(1955), who had found this metabolite in rodent urine, and pointed at oxidative deamination, a
reaction catalyzed by MAO, as the process involved in the metabolic breakdown of DMT.
Besides monoamine oxidase-catalized oxidative deamination, in vivo and in vitro studies have
also identified N-oxidation as an important degradative pathway of DMT, and to a lesser
extent N-demethylation (Sitaram and McLeod, 1990; Sitaram et al., 1997c). Oxidative
deamination was found to be a major route in brain liver and kidney, whereas NADPHdependent
microsomal N-oxidation predominated in peripheral tissue and was a minor route
in the brain (Sitaram et al., 1997c). According to these authors, N-demethylation is a minor
degradation route for this compound in all tissues examined (Sitaram and McLeod, 1990).
Earlier in vitro studies by Fish et al. (1955b) had already identified DMT-N-oxide (DMT-NO)
and IAA as the main metabolic products of DMT. They also found NMT to be converted to
IAA, but not DMT-NO. These investigators concluded that N-oxidation was the main
metabolic route in the absence of mitochondrial MAO and that the N-oxide compound was
not an intermediate to IAA formation by MAO. In order to explore routes other than oxidative
deamination, Szára and Axelrod (1959) found that incubation of DMT in rabbit liver
microsomal fraction (in vitro experiment) pretreated with the MAO inhibitor iproniazid
yielded NMT, DMT-NO, 6-hydroxy-DMT and 6-hydroxy-DMT-NO. In the same paper, the
authors reported that the administration of DMT in vivo to rats pretreated with iproniazid
yielded NMT, tryptamine, 6-hydroxy-DMT, IAA, 6-hydroxy-IAA, but failed to detect DMTNO
and 6-hydroxy-DMT-NO, which had been found in the in vitro experiment. The presence
of hydroxylated metabolites in these experiments and the finding that 6-hydroxydiethyltryptamine
appeared to be more active than diethyltryptamine in animal studies (Szára
and Hearst, 1962) led to the speculation that some of the hydroxylated metabolites,
specifically 6-hydroxy-DMT, might be responsible for the psychedelic effects of DMT
(Szára, 1961; Szára and Hearst, 1962). Nevertheless, this was refuted in a later clinical trial in
which DMT and 6-hydroxy-DMT were administered to humans and the latter was found to be
inactive (Rosenberg et al., 1963). The relevance of hydroxylation as a metabolic pathway of
DMT has received no further attention in the most recent studies and 6-hydroxyderivatives
have not been assessed in several experiments on the in vivo and in vitro metabolism of DMT
and 5-methoxy-DMT (Sitaram and McLeod, 1990).

Besides the metabolites mentioned above, studies by Barker and coworkers (1980) have
detected cyclization derivatives of DMT. These investigators reported IAA, NMT, DMT-NO
and 2-methyl-tetrahydro-β-carboline (MTHβC) as the main DMT metabolites in rat whole
brain homogenates, together with traces of tryptamine and 1,2,3,4-tetrahydro-β-carboline. No
hydroxylated metabolites were detected and the authors justified this arguing that this reaction
takes place in peripheral tissue but not in the brain. They also reported that when DMT was
incubated in brain homogenates of rats pretreated with iproniazid, IAA formation was
reduced by 83%, but unexpectedly, NMT and DMT-NO formation were also reduced by 90%,
and no tetrahydro-β-carboline could be measured. Based on these results, the authors pointed
out that the enhancement of behavioral effects and increments in DMT half-life in tissue
observed after pretreatment with iproniazid in other studies (Kovacic and Domino, 1973, cited
in Wang Lu and Domino, 1976; Shah and Hedden, 1978; Wang Lu and Domino, 1976) might
also be due to the inhibition of N-demethylation and N-oxidation rather than to a unique and
selective inhibition of MAO. However, these results were not replicated by the group of
Sitaram, who showed iproniazid to inhibit the formation of indoleacetaldehyde and IAA from
DMT in liver homogenates (Sitaram et al., 1987c) but not the formation of DMT-NO. These
authors also found iproniazid to increase the levels of DMT in vivo in rat brain, liver, kidney
and blood and those of DMT-NO in rat liver (Sitaram et al., 1987b), and to increase rat
urinary excretion of unmetabolized DMT, DMT-NO and NMT (Sitaram et al., 1987a). These
results would indicate that after MAO inhibition, DMT metabolism is shifted to other
functioning routes. The pharmacological modulation of metabolic pathways independent of
MAO has been studied in a series of drug-interaction studies. Wang Lu et al. (1978) observed
increases in brain and liver DMT levels after pretreatment with SKF-525A, an inhibitor of the
microsomal CYP system, whereas Shah and Hedden (1978) did not. In the study by Wang Lu
et al. (1978), chronic phenobarbital administration, a drug which stimulates microsomal CYP
activity, reduced brain and liver DMT levels. Also, neuroleptics such as haloperidol and
chlorpromazine, respectively, decreased and increased, brain DMT levels. In conclusion, all
these studies point out that although oxidative deamination of the side chain by monoamine
oxidase appears to be the main metabolic pathway of DMT, the drug can also be degraded by
other routes, mainly N-oxidation, but possibly also by N-demethylation, 6-hydroxylation and
cyclization. The extent to which these pathways may be active or even predominate when the
drug is administered orally concomitantly with selective MAO inhibitors, as is the case in
ayahuasca potions, remains to be assessed.

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