Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine

DMT (N,N-dimethyltryptamine) has been known chemically since 1931 and was later identified as an active ingredient in traditional Amazonian preparations such as cohoba, yopo and ayahuasca. Early reports from the 1960s and 1970s also detected DMT and related N-methylated tryptamines in human blood and urine, prompting hypotheses that endogenous DMT might contribute to psychosis and schizophrenia. Subsequent empirical work produced inconsistent results and conventional wisdom came to regard trace levels of DMT as biologically insignificant. More recently, the discovery of mammalian trace amine (TA) receptors and evidence that hallucinogenic tryptamines activate these receptors has prompted a reappraisal of the possible physiological roles of endogenous DMT. Jacob and colleagues set out to re-evaluate the biochemical and pharmacological evidence concerning endogenous DMT, with particular focus on biosynthetic enzymes (AADC and INMT), receptor targets (trace amine receptors versus serotonin receptors), and human experimental findings at low, non-hallucinogenic doses. They propose a novel hypothesis: that endogenous DMT, acting at TA receptors, may produce a calm, anxiolytic effect and therefore could suppress rather than exacerbate psychotic symptoms. The paper presents a narrative synthesis of biochemical, genetic, pharmacological and clinical observations to support this reinterpretation and to identify areas needing further empirical work.

This paper is a narrative review and theoretical synthesis rather than a report of new empirical data. The investigators collated and discussed historical biochemical assays, enzyme characterisations, in vitro receptor activity studies, animal data, and human clinical and pharmacological studies that bear on DMT biosynthesis, metabolism and receptor pharmacology. Key strands of evidence examined include: early and later measurements of DMT concentrations in human blood and urine; enzymology of DMT biosynthesis (aromatic L-amino acid decarboxylase, AADC, and indolethylamine N-methyltransferase, INMT); localisation and expression studies for INMT and TA receptor mRNA; results from controlled human DMT administration (notably Strassman et al.) covering low versus high doses; in vitro assays of TA receptor activation (cAMP production) by DMT and other psychoactive amines; and clinical/biochemical observations in schizophrenia (urinary DMT studies, AADC/MAO activity). The authors weigh methodological caveats reported in those original studies (for example, recombinant enzyme K m measurements and tissue-specific expression) when drawing their synthesis.

From the reviewed literature, several empirical observations are highlighted. DMT is widespread in nature and was reported in human blood and urine from the 1960s onward. Early quantitative reports varied: Franzen and Gross reported blood levels of about 8 × 10⁻⁹ g/mL and urine around 4 × 10⁻⁵ g/24 h, but later work found lower average concentrations (approximately 5 × 10⁻¹⁰ g/mL in blood and 4 × 10⁻⁷ g/24 h in urine). For context, the threshold subjective dose in humans is given as about 5 × 10⁻⁵ g/kg, producing peak blood concentrations of about 1 × 10⁻⁸ g/mL. Studies linking endogenous DMT to schizophrenia produced mixed findings. Some investigators reported increased urinary DMT in subsets of patients (Murray et al. reported about 1 × 10⁻⁶ g/24 h in some schizophrenic subjects), whereas other studies found no consistent differences. Biochemical observations relevant to tryptamine metabolism include reports of increased AADC activity and decreased monoamine oxidase (MAO) activity in some schizophrenic patients; smoking-induced MAO inhibition is noted as a possible modifier. On biosynthesis, the conversion pathway from tryptophan to DMT requires decarboxylation by AADC to yield tryptamine (TYP) and two successive N-methylations by INMT to produce NMT and then DMT. The authors review work showing tissue distributions of INMT: rabbit INMT transcripts were abundant in lung and present in liver and brain, whereas Thompson et al.'s cloning work reported human INMT transcripts in peripheral tissues (lung, thyroid, adrenal, heart, muscle, spinal cord) but not in brain. Recombinant human INMT exhibited higher K m values for tryptamine than older rabbit lung preparations, leading Thompson et al. to question the physiological significance of DMT biosynthesis; Jacob and colleagues urge caution in over-interpreting K m values measured from recombinant enzyme preparations. Pharmacologically, intravenous DMT administration in humans produced dose-dependent subjective and physiological effects in Strassman et al.'s double-blind, placebo-controlled experiments. High IV doses (0.2–0.4 mg/kg) induced rapid and profound hallucinatory phenomena and increases in autonomic and neuroendocrine measures; a low IV dose (0.05 mg/kg) produced a relaxed, comfortable mental state in many subjects without robust physiological changes, yet the Hallucinogen Rating Scale (HRS) detected subjective differences even at that low dose. DMT does not appear to produce tolerance in mammals, according to animal and human reports. Regarding receptor pharmacology, the trace amine (TA) receptor family is G-protein-coupled and stimulates cAMP production when activated. In vitro work at 1 μM ligand concentration showed that DMT activates the rat TA1 receptor to a degree nearly equal to the endogenous ligand tyramine, while classic serotonergic ligand 5-HT produced substantially less cAMP in the same assay. Older synaptosomal membrane studies suggested sub-nanomolar affinity of DMT and LSD for a binding site linked to cAMP production. TA1 mRNA has been detected in the human amygdala (lower copies) and stomach (higher copies), and in widespread regions in the rat brain and peripheral tissues. The genomic locus for a TA receptor maps to chromosome 6q23.2, a region that has been implicated in schizophrenia. Finally, amphetamine-class drugs (amphetamine, methamphetamine, MDMA) show efficacy at TA receptors and are noted to produce calming effects at low doses, a phenomenon the authors relate to TA receptor pharmacology.

Jacob and colleagues interpret the assembled evidence to propose that endogenous DMT may act principally via the trace amine receptor system to produce subtle anxiolytic or mood-stabilising effects at low, physiologically relevant concentrations. They argue that low-dose subjective effects observed in controlled DMT administration (mild mood elevation, relaxation) may provide a window onto the putative role of endogenous DMT, whereas high-dose hallucinogenic responses are more likely mediated via serotonergic systems (notably 5-HT2A) and reflect pharmacological, non-physiological concentrations. This DMT–TA hypothesis offers an alternate explanation for inconsistent reports of elevated urinary DMT in schizophrenia: increased DMT or tryptamine production in some patients might represent a compensatory, homeostatic response intended to calm psychotic activity rather than a causal agent of psychosis. The authors further connect several biochemical and genetic observations to this framework: reported increases in AADC activity and decreases in MAO activity in schizophrenia could raise trace amine levels; TA receptor expression in emotion-regulatory regions (amygdala) and peripheral sites (gut) is consistent with roles in mood regulation; and amphetamine-class drugs' activity at TA receptors may underlie their paradoxical calming effects at low doses. The investigators acknowledge important uncertainties and limitations. They note that recombinant enzyme K m data (used to question INMT's role in humans) should be treated cautiously because recombinant proteins are studied outside their native cellular context; absence of constitutive INMT mRNA in human brain does not preclude inducible expression under stress or peripheral production followed by blood–brain barrier crossing; and many early analytical studies of endogenous DMT used older techniques with variable results. As a result, Jacob and colleagues call for contemporary investigations using modern analytical chemistry to re-assay DMT and metabolites (for example, indoleacetic acid and dimethylkynuramine), better characterisation of INMT and AADC isoforms in vivo, and targeted studies of TA receptor function and localisation in human tissues. They position their hypothesis as a prompt for such empirical work rather than as definitive proof of an anxiolytic role for endogenous DMT.

The authors conclude that tryptamine biochemistry and the physiological roles of trace amines are more complex than previously appreciated. After reviewing evidence on INMT and AADC activity and on TA receptor pharmacology, they propose that DMT could function as a neurotransmitter within the trace amine system and that endogenous DMT or tryptamine production might act to suppress, rather than provoke, psychotic activity. Jacob and colleagues emphasise the complexity of brain chemistry and recommend further empirical characterisation before firm conclusions can be drawn.