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

This review article (2012) provides a historical perspective of the scientific study of endogenous indole alkaloids (DMT, Bufotenine, MDMT) and compares the detection and quantification methods of 69 independent studies that investigated these compounds in blood, urine, and/or cerebrospinal fluid.

Abstract

“Introduction: Three indole alkaloids that possess differing degrees of psychotropic/psychedelic activity have been reported as endogenous substances in humans; N,N‐dimethyltryptamine (DMT), 5‐hydroxy‐DMT (bufotenine, HDMT), and 5‐methoxy‐DMT (MDMT).

Review: We have undertaken a critical review of 69 published studies reporting the detection or detection and quantitation of these compounds in human body fluids. In reviewing this literature, we address the methods applied and the criteria used in the determination of the presence of DMT, MDMT, and HDMT. The review provides a historical perspective of the research conducted from 1955 to 2010, summarizing the findings for the individual compounds in blood, urine, and/or cerebrospinal fluid. A critique of the data is offered that addresses the strengths and weaknesses of the methods and approaches to date.

Discussion: The review also discusses the shortcomings of the existing data in light of more recent findings and how these may be overcome. Suggestions for the future directions of endogenous psychedelics research are offered.”

Authors: Steven A. Barker, Ethan H. McIlhennya & Rick J. Strassman

Summary

Introduction

Three indole alkaloids have been reported as endogenous substances in humans. They have been analyzed using chromatography, gas chromatography, high-performance liquid chromatography, UV detection, fluorescence detection, electrochemical detection, and liquid chromatography-tandem mass spectrometry.

There has been renewed interest in the role of DMT and trace amine receptors in humans, and their possible role in naturally occurring altered states of consciousness, such as psychosis, dreams, creativity and imagination, religious phenomena, and even near-death experiences.

Interest in DMT has increased due to the growing use of ayahuasca as a religious sacrament and the resumption of human research characterizing DMT’s psychopharmacology. This review addresses several fundamental issues regarding these three endogenous psychedelics.

Many criticisms were directed at studies that claimed to find endogenous psychedelics, including the use of non-specific chemical tests, the absence of double-blind analyses, and the failure to adequately rule out dietary or medication sources.

We have undertaken a critical review of 69 published studies that have detected DMT, MDMT, and HDMT in human body fluids. We will be addressing the following questions: are these compounds truly there, are the analytical methodologies and the identification criteria adequate, and where does the research go from here?

Historical perspective

Researchers began searching for endogenous psychedelics after discovering the psychedelic effects of mescaline and lysergic acid diethylamide (LSD) in humans. They found several indole-ethylamine psychedelics in humans and reported higher concentrations and significant differences in levels between controls and psychiatric, especially psychotic, patients.

The schizotoxin hypothesis proposed that endogenous psychedelic schizotoxins were an aberration of metabolism, but no definitive link has yet been demonstrated between these compounds and any psychiatric diagnosis.

The earliest studies on endogenous psychedelics used paper and thin-layer chromatography, and were confirmed by gas – liquid chromatography and mass spectrometry. The technologies used to detect and measure the compounds of interest evolved with the technology available at the time.

As the criteria for detecting endogenous psychedelics have become more exacting, the detection of these compounds has become less frequent and at significantly lower concentrations than originally reported.

Tables 1 – 3 contain a compilation of 69 studies on detecting and quantitating DMT, HDMT, and MDMT in human CSF, blood, and urine.

Sixty-nine studies were reviewed for this analysis. They were obtained through SciFinder and PubMed database searches.

51 studies examined urine samples for HDMT, and 7 studied HDMT after hydrolysis with HCl or enzyme treatment. The remaining 44 studies did not conduct hydrolysis or enzyme treatment. Studies of urine samples from 1912 individuals demonstrated concentrations of HDMT ranging from 1 to 62.8 mg/24 h, and from 0.48 to 218 ng/ml. The most common methods of reporting were mg/24 h and mg/g creatinine, and the analytical approaches employed were shown in Table 2.

HDMT: blood

• Of the 69 studies, 4 examined blood for the presence of HDMT. – 22 individuals were positive for HDMT and 218 were negative. – Concentrations of HDMT in blood ranged from 22 pg/ml to 40 ng/ml.

DMT: cerebrospinal fluid

Among 136 individuals, 34 were positive for DMT and 48 were negative. Thus, 56 individuals were positive for DMT and 80 were negative.

MDMT: urine

9 studies examined urine for the presence of MDMT. Two patients were positive for MDMT in urine, 92 were negative, and 2 controls were positive (10.5%).

MDMT: blood

Among 39 individuals, 20 were positive for MDMT and 16 were negative. One study reported a single estimate of 2.0 ng/ml.

MDMT: cerebrospinal fluid

Of 69 studies, 4 examined CSF for MDMT. Of the 136 individuals assayed, 40 were positive for MDMT, 96 were negative, and the mean concentrations were 1400 ng/ml for patients and 230 ng/ml for controls.

The above does not address the analytical methods’ sensitivity and specificity, and assumes that all data as collected and reported are accurate. However, it is almost certainly not the case, as almost every study used paper or TLC for detection, quantitation, and confirmation of one or more of these compounds.

In many studies, large volumes of urine were extracted and concentrated, resulting in a final extract less than optimal for such analysis.

The earliest studies used a combination of methods to extract urine, but none reported analyte recoveries. The most recent studies have all employed ion exchange solid-phase extraction for the isolation of the target compounds from urine.

Misidentifications of compounds may have occurred due to methodological complications, subjective interpretation of results, or co-injection of extracted indole-ethylamines in GC analyses using the solvent methylene chloride.

Early studies used packed column technology, which had low resolving power and was often a composite of several compounds. Capillary chromatography has consistently demonstrated that these results are incorrect.

Investigators added GC with ECD or NP detectors to increase sensitivity and specificity, but did not generate structural data. Others used ultraviolet spectrometry and/or spectrofluorometry, but did not provide data regarding structural identity.

Consistent findings in previous research suggest that sensitivity was also an issue. Data concerning extraction efficiency and recovery, limits of detection, specificity, reproducibility, storage stability, and other variables are lacking in earlier studies.

In 1973, the first applications of mass spectrometry to the detection and quantitation of putative endogenous psychedelics in man occurred. Narasimhachari and Himwich used GC-MS with single ion monitoring (m/z 58) to detect DMT from urine extracts, and demonstrated its identity with authentic DMT. DMT, NMT, and HDMT were detected in human blood and urine using SIM. MDMT has yet to be unequivocally detected by any MS-based method.

Continual improvement in MS technologies has greatly enhanced detection, sensitivity, and specificity of analytic studies searching for these compounds. Most studies using MS methodology since 1973 have confirmed the presence of one or more of these compounds in human body fluids.

Discussion and conclusions

The preponderance of the mass spectral evidence proves that DMT and HDMT are indeed endogenous and can be measured in human body fluids. There is less compelling evidence for MDMT, and further studies are necessary to determine whether MDMT exists in humans.

Many early studies attempted to determine if diet or gut bacteria were responsible for positive results. However, more recent studies suggest that cells of the intestinal epithelium or the kidney may be responsible.

Studies of DMT and HDMT in humans have been negative, but one longitudinal study and one assessing diurnal rhythms of DMT in human urine suggest that measurable concentrations occur only intermittently.

Indole-N-methyltransferase (INMT) is an enzyme responsible for the synthesis of psychedelic compounds in humans, and it has been reported to occur in adrenal and lung. However, recent studies have shown that INMT may also be present in spinal cord, brain, retina, and pineal.

In humans, only a small percentage of exogenously administered psychedelics are excreted in urine as the parent compound. This is because these substances are excellent substrates for MAO-A, which converts them into indoleacetic acids, which are indistinguishable from the acids resulting from other better-known sources, such as tryptamine and serotonin.

In MAO-inhibited rats, metabolism of psychoactive tryptamines is shifted away from MAO-A and indoleacetic acid formation to the N-oxidase and the respective N-oxides. Monitoring the N-oxide metabolites rather than the parent compounds alone may provide a substantial advantage in detecting and quantitating the endogenous psychedelic compounds.

Several studies suggested that the corresponding NMT was detected, but this data must now also be questioned. MAO inhibition in humans may enhance detection and quantification of endogenous psychedelics, especially if the N-oxide metabolites are monitored.

Monitoring these compounds in biological samples such as CSF, blood and/or urine is the most accessible way to begin to determine their possible role in human psychophysiology.

This review has illustrated the convincing evidence that DMT and HDMT are endogenous in humans, but MDMT has not been reported in human blood or urine. Future studies should monitor all three compounds and their N-oxides using superior, fully validated mass spectrometric methodology.

Future research should improve the sensitivity of the assays to 1.0 pg/ml or less, and collection times should be longer.

The search for endogenous psychedelic tryptamines should turn towards other human tissues than blood, urine and CSF, and should also include cell and molecular biology approaches. An INMT knockout mouse could greatly assist in understanding the role of this enzyme and, by inference, the endogenous psychedelics.