Comparison of the brain levels of N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine following intraperitoneal injection (original) (raw)
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In Vivo Long-Term Kinetics of Radiolabeled N,N-Dimethyltryptamine and Tryptamine
The Journal of Nuclear Medicine, 2011
N,N-dimethyltryptamine (DMT), a strong psychodysleptic drug, has been found in higher plants, shamanic hallucinogenic beverages, and the urine of schizophrenic patients. The aim of this work was to gain better knowledge on the relationship between this drug and hallucinogenic processes by studying DMT behavior in comparison with tryptamine. Methods: 131 I-labeled DMT and tryptamine were injected into rabbits. g-Camera and biodistribution studies were performed. Brain uptake, plasma clearance, and renal excretion were assessed for each indolealkylamine. Results: DMT and tryptamine showed different behavior when brain uptake, residence time, and excretion were compared. Labeled DMT entered the brain 10 s after injection, crossed the blood-brain barrier, and bound to receptors; then it was partially renally excreted. It was detected in urine within 24 h after injection and remained in the brain, even after urine excretion ceased; up to 0.1% of the injected dose was detected at 7 d after injection in the olfactory bulb. In contrast, tryptamine was rapidly taken up in the brain and fully excreted 10 min after injection. Conclusion: To our knowledge, this is the first demonstration that exogenous DMT remains in the brain for at least 7 d after injection. Although labeled DMT and tryptamine behave as agonists for at least 5-hydroxytryptamine 2A receptor, 5-hydroxytryptamine 2C receptor, trace amine-associated receptor, and s-1 putative receptor targets, binding to the latter can explain the different behavior of labeled DMT and tryptamine in the brain. The persistence in the brain can be further explained on the basis that DMT and other N,N-dialkyltryptamines are transporter substrates for both the plasma membrane serotonin transporter and the vesicle monoamine transporter 2. Furthermore, storage in vesicles prevents DMT degradation by monoamine oxidase. At high concentrations, DMT is taken up by the serotonin transporter and further stored in vesicles by the vesicle monoamine transporter 2, to be released under appropriate stimuli. Moreover, the 131 I-labeling proved to be a useful tool to perform long-term in vivo studies.
In Vivo Long-Term Kinetics of Radiolabeled N,N-Dimethyltryptamine and Tryptamine
Journal of Nuclear Medicine, 2011
N,N-dimethyltryptamine (DMT), a strong psychodysleptic drug, has been found in higher plants, shamanic hallucinogenic beverages, and the urine of schizophrenic patients. The aim of this work was to gain better knowledge on the relationship between this drug and hallucinogenic processes by studying DMT behavior in comparison with tryptamine. Methods: 131 I-labeled DMT and tryptamine were injected into rabbits. g-Camera and biodistribution studies were performed. Brain uptake, plasma clearance, and renal excretion were assessed for each indolealkylamine. Results: DMT and tryptamine showed different behavior when brain uptake, residence time, and excretion were compared. Labeled DMT entered the brain 10 s after injection, crossed the blood-brain barrier, and bound to receptors; then it was partially renally excreted. It was detected in urine within 24 h after injection and remained in the brain, even after urine excretion ceased; up to 0.1% of the injected dose was detected at 7 d after injection in the olfactory bulb. In contrast, tryptamine was rapidly taken up in the brain and fully excreted 10 min after injection. Conclusion: To our knowledge, this is the first demonstration that exogenous DMT remains in the brain for at least 7 d after injection. Although labeled DMT and tryptamine behave as agonists for at least 5-hydroxytryptamine 2A receptor, 5-hydroxytryptamine 2C receptor, trace amine-associated receptor, and s-1 putative receptor targets, binding to the latter can explain the different behavior of labeled DMT and tryptamine in the brain. The persistence in the brain can be further explained on the basis that DMT and other N,N-dialkyltryptamines are transporter substrates for both the plasma membrane serotonin transporter and the vesicle monoamine transporter 2. Furthermore, storage in vesicles prevents DMT degradation by monoamine oxidase. At high concentrations, DMT is taken up by the serotonin transporter and further stored in vesicles by the vesicle monoamine transporter 2, to be released under appropriate stimuli. Moreover, the 131 I-labeling proved to be a useful tool to perform long-term in vivo studies.
Metabolism of the hallucinogen N,N-dimethyltryptamine in rat brain homogenates
Biochemical Pharmacology, 1980
The metabolism of the hallucinogen N,N-dimethyltryptamine (DMT) in whole rat brain homogenate is reported. Studies were conducted using tritiated DMT and DMT-N-oxide (DMT-NO), and metabolites were identified and quantified using thin-layer chromatography and liquid scintillation counting techniques. Metabolite confirmation was obtained by incubation of cu,a$$-tetradeutero-DMT (DDMT) with whole brain homogenate followed by combined gas chromatographiclmass spectrometric analyses. The metabolites of DMT were identified as indoleacetic acid (IAA), DMT-NO, N-methyltryptamine (NMT), 2-methyl-1,2,3,4-tetrahydro-P-carboline (2-MTHBC), tryptamine (TA) and 1,2,3,4tetrahydro-p-carboline (THBC). DMT-NO was metabolized to give DMT, NMT, IAA and 2-MTHBC. Formation of these metabolites from DMT-NO was stimulated by anaerobic incubation. Mechanisms for the formation of @-carbolines from DMT and DMT-NO are discussed. The effects of the monamine oxidase inhibitor iproniazid phosphate on DMT metabolism were also studied. Iproniazid inhibited the formation of IAA from DMT by 83 per cent. However, the formation of NMT and DMT-NO was inhibited by 90 per cent under these conditions. Thus, the reported extension of half-life and potentiation of DMT behavioral effects by iproniazid may be due to inhibition of NMT and DMT-NO formation rather than inhibition of monoamine oxidase. A cyclic pathway for the synthesis and metabolism of DMT in brain tissue is proposed.
Frontiers in Neuroscience, 2018
This report provides a historical overview of research concerning the endogenous hallucinogen N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the "natural" role of an endogenous hallucinogen from the effects observed from peripheral administration are also emphasized.
Biosynthesis and extracellular Concentrations of N,N- dimethyltryptamine (DMt) in Mammalian Brain
N,N-dimethyltryptamine (DMT), a psychedelic compound identified endogenously in mammals, is biosynthesized by aromatic-L-amino acid decarboxylase (AADC) and indolethylamine-N-methyltransferase (INMt). Whether DMt is biosynthesized in the mammalian brain is unknown. We investigated brain expression of INMt transcript in rats and humans, co-expression of INMt and AADC mRNA in rat brain and periphery, and brain concentrations of DMt in rats. INMt transcripts were identified in the cerebral cortex, pineal gland, and choroid plexus of both rats and humans via in situ hybridization. Notably, INMt mRNA was colocalized with AADC transcript in rat brain tissues, in contrast to rat peripheral tissues where there existed little overlapping expression of INMt with AADC transcripts. Additionally, extracellular concentrations of DMt in the cerebral cortex of normal behaving rats, with or without the pineal gland, were similar to those of canonical monoamine neurotransmitters including serotonin. A significant increase of DMT levels in the rat visual cortex was observed following induction of experimental cardiac arrest, a finding independent of an intact pineal gland. These results show for the first time that the rat brain is capable of synthesizing and releasing DMT at concentrations comparable to known monoamine neurotransmitters and raise the possibility that this phenomenon may occur similarly in human brains. N,N-dimethyltryptamine (DMT) belongs to a class of serotonergic psychedelics that includes lysergic acid dieth-ylamide (LSD) and psilocybin 1. DMT, like all serotonergic psychedelics, reliably elicits a wide spectrum of subjective effects on brain functions including perception, affect, and cognition 2. These compounds share structural and functional similarities with serotonin (5-hydroxytryptamine, 5-HT), and interact with 5-HT and other receptors to produce their effects 3-5. Unlike other psychedelics, however, DMT is endogenously produced in animals 6-8 , including humans 9-11. In addition to the subjective psychedelic effects exogenous administration of DMT has on conscious experience, it has other well-documented anti-hypoxic 12 , antidepressant 13 , and plasticity-promoting actions 14. Taking these facts together, a further understanding of why DMT is present in mammals is of interest. Biosynthesis of DMT from tryptamine requires double methylation reactions catalyzed by indolethylamine-N-methyltransferase (INMT) 15,16. INMT mRNA was identified at high levels in peripheral tissues in rabbits 17 and in humans 18. However, this peripheral INMT also methylates other ligands such as hista-mine 17,19. In the brain, INMT mRNA was found at very low levels in rabbits 17 and was undetectable in humans 18. No study to date has yet identified INMT in the cerebral cortex in any species. In addition to INMT, production of DMT requires aromatic-L-amino acid decarboxylase (AADC), which removes the carboxyl group from dietary tryptophan to form tryptamine, the essential DMT precursor that can be rapidly metabolized by monoamine oxidase 20. While high levels of INMT mRNA expression in the periphery 17,18 have been assumed to indicate the
Pharmacokinetics of N,N-dimethyltryptamine in Humans
European Journal of Drug Metabolism and Pharmacokinetics, 2023
Background and Objective N,N-dimethyltryptamine (DMT) is a psychedelic compound under development for the treatment of major depressive disorder (MDD). This study evaluated the preclinical and clinical pharmacokinetics and metabolism of DMT in healthy subjects. Methods The physiochemical properties of DMT were determined using a series of in vitro experiments and its metabolic profile was assessed using monoamine oxidase (MAO) and cytochrome P450 (CYP) inhibitors in hepatocyte and mitochondrial fractions. Clinical pharmacokinetics results are from the phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial (NCT04673383). Healthy adults received single escalating doses of DMT fumarate (SPL026) via a two-phase intravenous (IV) infusion. Dosing regimens were calculated based on pharmacokinetic modelling and predictions with progression to each subsequent dose level contingent upon safety and tolerability. Results In vitro clearance of DMT was reduced through the inhibition of MAO-A, CYP2D6 and to a lesser extent CYP2C19. Determination of lipophilicity and plasma protein binding was low, indicating that a high proportion of DMT is available for distribution and metabolism, consistent with the very rapid clinical pharmacokinetics. Twenty-four healthy subjects received escalating doses of DMT administered as a 10-min infusion over the dose range of 9-21.5 mg (DMT freebase). DMT was rapidly cleared for all doses: mean elimination half-life was 9-12 min. All doses were safe and well tolerated and there was no relationship between peak DMT plasma concentrations and body mass index (BMI) or weight. Conclusion This is the first study to determine, in detail, the full pharmacokinetics profile of DMT following a slow IV infusion in humans, confirming rapid attainment of peak plasma concentrations followed by rapid clearance. These findings provide evidence which supports the development of novel DMT infusion regimens for the treatment of MDD. Clinical Trial Registration Registered on ClinicalTrials.gov (NCT04673383).
Biochemical Medicine, 1977
Materials d-[3H]Lysergic acid diethylamide was obtained from the New England Nuclear Corporation (17.1 Ci/mmole) and from Amersham/Searle (2 1 .O Ci/mmole). Tritiated cyclic AMP (27.5 Ci/mmole) was also obtained from the latter company. Toluene was obtained from the J. T. Baker Chemical Company and from Burdick and Jackson Laboratories. Methylene chloride was also obtained from Burdick and Jackson. Triton X-100, 2,5-diphenyloxazole (PPO), 1,4-bis[2-(4-methyl-5phenyloxazolyl)]benzene (dimethyl POPOP), tryptamine hydrochloride, serotonin binoxylate (5HT), sucrose, adenosine 5'-triphosphate (ATP), theophylline, ethyleneglycol-bis(B-aminoethylether)-N,N-tetracetic acid (EGTA), and dopamine hydrochloride were obtained from the Sigma Chemical Company. Pargyline was obtained from Abbott Laboratories and Ficoll was obtained from Pharmacia Fine Chemical Incorporated. Cellulose acetate filters (0.45 pm pore size) with a diameter of 25 mm were obtained from the Nucleopore Corporation. Cyclic AMP specific binding protein was obtained from Calbiochem. Dimenthyltryptamine, 0-methylbufotenine and d-LSD were obtained from the National Institute of Mental Health. Heptafluorobutyryl imidazole was obtained from Pierce Chemical Company and the pure heptafluorobutyryl derivatives of dimethyltrypatmine and tryptamine were prepared by us as previously described (6). All other reagents and materials were of the highest available purity.
Journal of Pharmaceutical and Biomedical Analysis, 2020
The orthogonal heart-cutting liquid chromatography (LC) modes coupled to high-resolution tandem mass spectrometry (HRMS/MS) provide a number of possibilities to enhance selectivity and sensitivity for the determination of targeted compounds in complex biological matricies. Here we report the development of a new fast 2D-LC-(HRMS/MS) method and its successful application for quantitative determination of the level of plasma and brain N,N-dimethyltriptamine (DMT) using ␣-methyltryptamine (AMT) as internal standard in an experimental model of cerebral ischemia/reperfusion using DMT administration. The 2D-LC separation was carried out by a combination of hydrophilic interaction liquid chromatography (HILIC) in the first dimension followed by second-dimensional reversed-phase (RP) chromatography within a total run time of 10 min. The enrichment of HILIC effluent of interest containing DMT was performed using a C18 trapping column. During method development several parameters of sample preparation procedures, chromatographic separation and mass spectrometric detection were optimised to achieve high DMT recovery (plasma: 90 %, brain: 88 %) and sensitivity (plasma: 0.108 ng/mL of LOD, brain: 0.212 ng/g of LOD) applying targeted analytical method with strict LC and HRMSMS confirmatory criteria. Concerning rat plasma sample, the concentration of DMT before hypoxia (49.3-114.3 ng/mL plasma) was generally higher than that after hypoxia (10.6-96.1 ng/mL plasma). After treatment, the concentration of DMT in brain was elevated up to the range of 2-6.1 ng/g. Overall, our analytical approach is suitable to detect and confirm the presence of DMT administered to experimental animals with therapeutic purpose in a reliable manner.
Pharmaceuticals, 2023
Aboriginals of Latin America have used DMT (N,N-dimethyltryptamine) in ritualistic ceremonies for centuries. Nevertheless, there are limited data on web users’ interest concerning DMT. We aim to review the literature and explore the spatial–temporal mapping of online search behavior concerning DMT, 5-MeO-DMT, and the Colorado River toad via Google Trends over the past 10 years (2012–2022) while using 5 search terms: “N,N-dimethyltryptamine”, “5-methoxy-N,N-dimethyltryptamine”, “5-MeO-DMT”, “Colorado River toad”, and “Sonoran Desert toad”. Literature analysis conveyed novel information concerning DMT’s past shamanic and present-day illicit uses, showcased experimental trials on DMT uses for neurotic disorders, and highlighted potential uses in modern medicine. DMT’s geographic mapping signals originated mainly from Eastern Europe, the Middle East, and Far East Asia. In contrast, 5-MeO-DMT signals prevailed in Western Europe, Indo-China, and Australasia. Signals concerning the toad originated from the Americas, Australia, India, the Philippines, and Europe. Web users searched the most for “N,N-dimethyltryptamine” and “5-MeO-DMT”. Three terms exhibited significant upgoing linear temporal trends: “5-MeO-DMT” (β = 0.37, p < 0.001), “Sonoran Desert toad” (β = 0.23, p < 0.001), and “Colorado River toad” (β = 0.17, p < 0.001). The literature and Infoedemiology data provided crucial information concerning DMT’s legal status, risks and benefits, and potential for abuse. Nonetheless, we opine that in the upcoming decades, physicians might use DMT to manage neurotic disorders pending a change in its legal status.