A critical review of reports of endogenous psychedelic N, N-dimethyltryptamines in humans: 1955-2010

Barker and colleagues review the long-standing question of whether three tryptamine derivatives—N,N-dimethyltryptamine (DMT), 5-hydroxy-DMT (bufotenine, HDMT), and 5-methoxy-DMT (MDMT)—are endogenous in humans. Earlier research used a variety of analytical approaches as instrumentation evolved, and interest in these compounds has been driven both by their psychedelic properties and by recent findings that DMT interacts with molecular targets such as the sigma-1 receptor and trace amine receptors. The potential physiological or pathophysiological roles of these compounds have been discussed in relation to altered states of consciousness, psychiatric conditions (notably psychosis and schizophrenia), dreams, religious experiences and ayahuasca use, but no definitive biological role has been established. This review sets out to critically evaluate 69 published studies from 1955 to 2010 that report detection or quantitation of DMT, HDMT and MDMT in human body fluids (blood, urine and cerebrospinal fluid). The investigators examine the analytical methods and identification criteria applied across studies, summarise reported detection rates and concentration ranges, and highlight methodological strengths and weaknesses with the aim of clarifying which findings are reliable and which require further confirmation. They also outline questions for future research, including the origin, metabolism and optimal sampling strategies for these compounds.

This paper is a narrative critical review rather than a systematic review with a fully enumerated protocol. The study selection comprises 69 publications identified primarily through searches of SciFinder (Chemical Abstracts) and PubMed; the review covers reports published between 1955 and 2010. The investigators included studies that reported detection and/or quantitation of DMT, HDMT or MDMT in human biological fluids (urine, blood, cerebrospinal fluid). The authors note that additional older or obscure reports may have been inaccessible or untranslated and therefore excluded. In appraising the literature, the reviewers focused on the analytical methods used, the criteria applied for compound identification (for example Rf or retention time matching, colour reactions, detector response, mass spectral matching), and the reporting of assay performance characteristics such as limits of detection, recovery, specificity and reproducibility. The review traces methodological evolution from early paper and thin-layer chromatography with colour reagents through gas chromatography (various detectors) to modern liquid chromatography–tandem mass spectrometry (LC-MS/MS). Where numerical data were provided in the source studies, the reviewers compiled counts of individuals tested and numbers positive or negative for each analyte in each biological matrix.

Scope of the literature: Sixty-nine studies were examined. The collected reports span a range of analytical technologies and clinical populations, with many studies comparing psychiatric patients (predominantly people with schizophrenia) to control subjects. HDMT (bufotenine): Fifty-one studies assessed urine for HDMT, collectively analysing urine from 1,912 individuals (1,249 patients and 663 controls). Using studies that reported presence/absence, HDMT was detected in 71% of patients (886 of 1,249) and 55% of controls (363 of 663), yielding an overall positive rate of approximately 65%. The reviewers note that about seven studies hydrolysed conjugates and estimated roughly 50% of urinary HDMT is excreted as a glucuronide; the remaining studies measured free HDMT only. Reported urinary concentrations varied widely depending on reporting units, with ranges (in common units) from 1 to 62.8 mg/24 h and 0.48 to 218 ng/ml. Four studies examined blood for HDMT (240 individuals total: 166 patients, 74 controls); 4 patients (2.4%) and 18 controls (24%) were reported positive, a combined blood positive rate of 9% (22 positives, 218 negatives). Blood concentrations reported ranged from 22 pg/ml (HPLC-radioimmunoassay) to 40 ng/ml (direct fluorescence assay). No study in the reviewed set reported HDMT in cerebrospinal fluid (CSF). DMT: Twenty-nine studies assessed urine for DMT (861 individuals: 635 patients, 226 controls). Across these reports, 43% of patients (276 of 635) and 64% of controls (145 of 226) were reported positive; overall, 421 of 861 individuals (49%) were positive in urine. Urinary DMT concentrations reported in various units ranged from 0.02 to about 43 mg/24 h (with one mean ± SD quoted as 42.98 ± 8.6 mg/24 h) and from 0.16 to 19 ng/ml. Eleven studies examined blood (417 individuals: 300 patients, 117 controls) and reported 44 patient positives (15%) and 28 control positives (24%), for an overall blood positive rate of 17% (72 positive, 345 negative). Blood concentration ranges reported were 51 pg/ml to 55 ng/ml. Four studies assayed CSF (136 individuals: 82 patients, 54 controls); 34 patients and 22 controls were positive (41% positive overall), and reported CSF concentrations ranged from 0.12 to 100 ng/ml. MDMT (5-methoxy-DMT): Nine studies examined urine for MDMT (113 individuals: 94 patients, 19 controls) and found 2 patients positive (2%) and 2 controls positive (10.5%). Two studies analysed blood (39 individuals: 36 patients, 3 controls), reporting 20 patient positives (51%) and no positive controls; a single blood concentration of 2.0 ng/ml was cited (HPLC-radioimmunoassay). Four studies examined CSF (136 individuals: 83 patients, 53 controls); 28 patients and 12 controls were reported positive (29% overall). One study reported mean combined DMT plus MDMT concentrations in CSF of approximately 1,400 ng/ml for patients and 230 ng/ml for controls but with very large standard deviations. Analytical-method findings and trends: Early studies (1950s–early 1970s) relied heavily on paper chromatography, TLC and non-specific detection (colour reagents, UV, fluorescence) with identification based on Rf or Rt matching and colour reactions; such methods lack structural confirmation and are prone to interference. The reviewers document several methodological artefacts that could produce false positives or overestimates, including acetone forming adducts with primary amines, and reactions of extracted indoleamines with methylene chloride producing quaternary salts. From 1973 onwards the application of mass spectrometry—including isotope-dilution approaches, GC‑MS with total ion spectra, and selected ion monitoring—provided the first methodologically robust identifications of DMT and HDMT in human samples. The authors note that all studies using MS-based methods since 1973 have reported confirmation of one or more of these compounds in human body fluids. MDMT, however, lacks unequivocal MS confirmation in blood or urine; only two MS-based CSF positives were reported and both by the same group. The most recent analytical advances employ LC-MS/MS, which allow low pg/ml sensitivity and confirmation using parent ions, fragment ions and ion ratios.

Barker and colleagues conclude that DMT and HDMT are most likely endogenous in humans, reasoning that the preponderance of mass spectrometric evidence provides strong confirmation. By contrast, the evidence for endogenous MDMT is less compelling: MS-based positive reports for MDMT are limited to two CSF findings from a single group and there are no MS-confirmed detections of MDMT in blood or urine in the reviewed literature. The reviewers emphasise that many early reports probably contained misidentifications or overestimated concentrations because of nonspecific assays, lack of structural confirmation, incomplete reporting of assay performance (limits of detection, recoveries), and methodological artefacts (solvent-derived products and co-extracted compounds). They point out that peripheral concentrations of these tryptamines are often very low, their half-lives are measured in minutes, and they are excellent substrates for monoamine oxidase A (MAO-A), which rapidly degrades parent compounds to indoleacetic acids. These factors make detection in blood and urine challenging and may explain intermittent detectability in serial sampling. Studies that pre-treated subjects with MAO inhibitors generally increased detectable parent compound concentrations, but even then parent compounds remained at low levels. To improve detection and interpretation, the authors recommend future studies employ modern, fully validated mass spectrometric methods (ideally LC-MS/MS) with sensitivity at or below about 1.0 pg/ml. They further suggest assessing N-oxide metabolites—which are not substrates for MAO-A and retain the parent structure—because N-oxides may accumulate and be easier to detect; data from ayahuasca administration indicate DMT N-oxide levels can exceed parent DMT in blood and urine. Other technical recommendations include enzymatic hydrolysis to free conjugated HDMT and more frequent or prolonged sampling to address intermittent excretion. The reviewers also highlight critical gaps in knowledge about sites of synthesis: mapping of indole-N-methyltransferase (INMT) expression has suggested peripheral sites (adrenal, lung) but tissue-level confirmation and functional studies are needed, and brain INMT data remain inconclusive. Barker and colleagues advocate combining sensitive biochemical assays with molecular and cellular approaches (including tissue assays and genetic models such as an INMT knockout) to identify synthesis locations and to elucidate physiological roles. They close by calling for comprehensive studies that monitor parent compounds, N-oxides and conjugates across blood, urine, CSF and relevant tissues, ideally with MAO inhibition where appropriate, to clarify the endogenous biology of these psychedelic tryptamines.