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A Brief History of DMT
In terms of Western culture, DMT was first synthesized by a Canadian chemist, Richard Manske, in 1931 (Manske, 1931) but was, at the time, not assessed for human pharmacological effects. In 1946 the microbiologist Oswaldo Gonçalves de Lima discovered DMT’s natural occurrence in plants (Goncalves de Lima, 1946). DMT’s hallucinogenic properties were not discovered until 1956 when Stephen Szara, a pioneering Hungarian chemist and psychiatrist, extracted DMT from the Mimosa hostilis plant and administered the extract to himself intramuscularly (Szára, 1956). This sequence of events formed the link between modern science and the historical use of many DMT-containing plants as a cultural and religious ritual sacrament (McKenna et al., 1998), their effect on the psyche and the chemical structure of N, N-dimethyltryptamine.buy dmt drug online
The discovery of a number of hallucinogens in the 1950’s and observations of their effects on perception, affect and behavior prompted hypotheses that the syndrome known as schizophrenia might be caused by an error in metabolism that produced such hallucinogens in the human brain, forming a schizo- or psycho-toxin (Osmond and Smythies, 1952). The presence of endogenous hallucinogenic compounds, related mainly to those resembling dopamine (mescaline) or serotonin (DMT), were subsequently sought. Although several interesting new compounds were found, the only known hallucinogens isolated were those derived from tryptophan (DMT, and 5-methoxy-DMT). Data were subsequently developed illustrating pathways for their endogenous synthesis in mammalian species, including humans. Over 60 studies were eventually undertaken in an attempt to correlate the presence or concentration of these compounds in blood and/or urine with a particular psychiatric diagnosis (for a review see Barker et al., 2012). However, there has yet to be any clear-cut or repeatable correlation of the presence or level of DMT in peripheral body fluids with any psychiatric diagnosis. Nonetheless, the discovery of endogenous hallucinogens and the possibilities rendered in various hypotheses surrounding their role and function in mental illness, normal and “extraordinary” brain function spurred further research into the mechanisms for their biosynthesis, metabolism and mode of action as well as for their known and profound effects on consciousness (Mishor et al., 2011; Araújo et al., 2015).
DMT Biosynthesis,buy dmt drug online
After the discovery of an indole-N-methyl transferase (INMT; Axelrod, 1961) in rat brain, researchers were soon examining whether the conversion of tryptophan (2, Figure 2) to tryptamine (TA; 3, Figure 2) could be converted to DMT in the brain and other tissues from several mammalian species. Numerous studies subsequently demonstrated the biosynthesis of DMT in mammalian tissue preparations in vitro and in vivo (Saavedra and Axelrod, 1972; Saavedra et al., 1973). In 1972, Juan Saavedra and Julius Axelrod reported that intracisternally administered TA was converted to N-methyltryptamine (NMT; 4, Figure 2) and DMT in the rat, the first demonstration of DMT’s formation by brain tissue in vivo. Using dialyzed, centrifuged whole-brain homogenate supernatant from rats and humans, these same researchers determined that the rate of synthesis of DMT from TA was 350 and 450 pmol/g/hr and 250 and 360 pmol/g/h, using NMT as substrate, in these tissues, respectively. In 1973, Saavedra et al. characterized a nonspecific N-methyltransferase in rat and human brain, reporting a Km for the enzyme of 28 uM for TA as the substrate in rat brain. The highest enzyme activity in human brain was found in the subcortical layers of the fronto-parietal and temporal lobes and the cortical layers of the frontal parietal lobe. However, an INMT found in rabbit lung was shown to have a much higher Km (270 uM, Thompson and Weinshilboum, 1998; 340 uM, Raisanen and Karkkainen, 1978) than the brain enzyme in rats. This suggested that INMT may exist in several isoenzyme forms between species and possibly even within the same animal, each having different Km’s and substrate affinities. INMT activity has subsequently been described in a variety of tissues and species. There have also been several reports of an endogenous inhibitor of INMT in vivo that may help regulate its activity and, thus, DMT biosynthesis
The metabolism of DMT has been thoroughly studied, with a great deal of newer data being provided from studies of ayahuasca administration (McIlhenny et al., 2012; Riba et al., 2012). All of the in vivo metabolism studies have shown that exogenously administered (IV, IM, smoking, etc.) DMT is rapidly metabolized and cleared, with only a small fraction of IV or IM administered DMT subsequently being found in urine. For example, 0.16% of an intramuscular dose of DMT was recovered as the parent compound following a 24 h urine collection (Kaplan et al., 1974). DMT administered in this manner reached a peak concentration in blood within 10–15 min and was below the limits of detection within 1 h. It was estimated that only 1.8% of an injected dose was present in blood at any one time. Due to rapid metabolism in the periphery, DMT is not orally active, being converted to inactive metabolites before sufficient penetration to the brain can occur (low bioavailability). DMT is only orally active if co-administered with a monoamine oxidase inhibitor (MAOI). DMT is pharmacologically active following administration by injection (intravenous or intramuscular routes) or smoking (vaporization and inhalation), pathways which can avoid first-pass metabolism by the liver to some degree (Riba et al., 2015). The time to onset of effects is rapid (seconds to minutes) by these routes and short lived (15–60 min depending on dose and route).buy dmt drug online
The primary route of metabolism for DMT (1, Figure 2) is via monoamine oxidase A (MAO-A), yielding indoleacetic acid (IAA; auxin; 5, Figure 2). The other metabolites formed include DMT-N-oxide (DMT-NO; 6, Figure 2), the second most abundant metabolite, and lesser amounts of N-methyltryptamine (NMT; 4, Figure 2), which, along with TA, is also a substrate for MAO-A (Fish et al., 1955; Szara and Axelrod, 1959; Barker et al., 1980, 1981; Figure 2), with both yielding IAA. Inhibition of MAO leads to a shift in favor of the amounts of DMT-NO and NMT formed (Riba et al., 2003). Other metabolites have been reported, such as 6-hydroxy-DMT (6-OH-DMT), (Szára, 1961) as well as products from a peroxidase pathway, reported to yield N, N-dimethyl-N-formyl-kynuramine, and N, N-dimethyl-kynuramine (Tourino et al., 2013; Gomes et al., 2014). However, these latter metabolites have yet to be identified in vivo. Metabolites also result from the cyclization of an intermediate iminium ion that forms during demethylation of DMT, yielding 2-methyl- 1,2,3,4- tetrahydro-beta-carboline (MTHBC; 7, Figure 2) and THBC (8, Figure 2; Barker et al., 1980, 1981).
The primary role of MAO-A in the metabolism of DMT has been further confirmed by pretreatment of experimental subjects with the MAO inhibitor (MAOI) iproniazid as well as other MAOIs (Lu and Domino, 1974; Moore et al., 1975; Shah and Hedden, 1978; Barker et al., 1980, 1981), the ability of the MAO-inhibiting harmala alkaloids of ayahuasca to make DMT orally active (McKenna, 2004) and the increased half-life and extended effects of an α, α, β, β-tetradeutero-DMT (D4DMT; 9, Figure 3), which is less susceptible to MAO-A metabolism due to the kinetic isotope effect