N,N-Dimethyltryptamine (DMT): An Endogenous Hallucinogen - Past, Present and Future Research

REVIEW published 06 August 2018 doi 103389fnins201800536 Frontiers in Neuroscience wwwfrontiersinorg 1 August 2018 Volume 12 Article 536 Edited by Andrew Robert Gallimore Okinawa Institute of Science and Technology Japan Reviewed by Susan Powell University of California San Diego United States Tomohisa Mori Hoshi University Japan Correspondence Steven A Barker sbarke1lsuedu Specialty section This article was submitted to Neuropharmacology a section of the journal Frontiers in Neuroscience Received 09 October 2017 Accepted 17 July 2018 Published 06 August 2018 Citation Barker SA 2018 N NDimethyltryptamine DMT an Endogenous Hallucinogen Past Present and Future Research to Determine Its Role and Function Front Neurosci 12536 doi 103389fnins201800536 N NDimethyltryptamine DMT an Endogenous Hallucinogen Past Present and Future Research to Determine Its Role and Function Steven A Barker Department of Comparative Biomedical Sciences School of Veterinary Medicine Louisiana State University Baton Rouge LA United States This report provides a historical overview of research concerning the endogenous hallucinogen N Ndimethyltryptamine 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 Keywords N Ndimethyltryptamine hallucinogen psychedelic neurotransmitter brain INTRODUCTION Despite their presence in the human pharmacopeia for millennia we have yet to resolve the biochemical mechanisms by which the hallucinogens psychedelics so dramatically alter perception and consciousness It is the only class of compounds that efficiently and specifically does so For that matter we do not fully understand the biochemistry of perception itself or how we live such a vivid and complex internal life in the absence of external stimulation We do not understand the basic biochemical mechanisms of some of our most common experiences such as the many human aspects of creativity imagination or dream states This is also true for extraordinary states of consciousness such as visions or spontaneous hallucinations or phenomena such as neardeath experiences NDE And it is troubling that we have not sufficiently turned the scientific method on these latter subjects despite the profound role they have played in the evolution of our science philosophy psychology and culture The experiences derived from the administration of hallucinogens are often compared to dream states However the experience of administered hallucinogenic substances is far more intense robust and overwhelming than the subtlety of mere dreams By comparison the natural biochemical processes for our related hallucinatory experiences are obviously far more highly regulated occurring as an orchestrated and inherent function of the normal brain Nonetheless Barker DMT an Endogenous Hallucinogen it is conceivable that attaining an explanation for these related natural human phenomena may lie in resolving the biochemical mechanisms involved in the more dramatic pharmacology of hallucinogens recognizing that the complexities and intensity of the administered experience are essentially an overdose relative to corresponding natural regulatory controls Given their status as psychedelics mindmanifesting substances increased study of the hallucinogens particularly with advanced brain imaging and molecular biology approaches may provide a better understanding of the common biochemistry that creates mind Perhaps the science behind the discovery of endogenous opioids offers us a corollary We came to better understand the common human experience of pain through examining the pharmacology of administered opiates and the subsequent discovery of endogenous opioid ligands receptors and pathways that are predominantly responsible for and regulate the experience and perception of pain Such may also be the case for understanding perception and consciousness With the discovery of the endogenous hallucinogen N Ndimethyltryptamine DMT 1 Figure 1 perhaps as with the endogenous opioids we have a similar opportunity to understand perception and consciousness Recent research has stimulated a renewed interest in further study of this compound as a neuroregulatory substance and thus a potential neuropharmacological target Taking results from these and more classical studies of DMT biochemistry and pharmacology together this report examines some of the past and current data in the field and proposes several new directions and experiments to ascertain the role of endogenous DMT 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 DMTs natural occurrence in plants Goncalves de Lima 1946 DMTs 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 DMTcontaining plants as a cultural and religious ritual sacrament McKenna et al 1998 their effect on the psyche and the chemical structure of N Ndimethyltryptamine The discovery of a number of hallucinogens in the 1950s 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 psychotoxin 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 FIGURE 1 Structure of N Ndimethyltryptamine DMT 1 compounds were found the only known hallucinogens isolated were those derived from tryptophan DMT and 5methoxy 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 andor urine with a particular psychiatric diagnosis for a review see Barker et al 2012 However there has yet to be any clearcut 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 After the discovery of an indoleNmethyl 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 Nmethyltryptamine NMT 4 Figure 2 and DMT in the rat the first demonstration of DMTs formation by brain tissue in vivo Using dialyzed centrifuged wholebrain homogenate supernatant from rats and humans these same researchers determined that the rate of synthesis of DMT from TA was 350 and 450 pmolghr and 250 and 360 pmolgh using NMT as substrate in these tissues respectively In 1973 Saavedra et al characterized a nonspecific Nmethyltransferase 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 frontoparietal and temporal lobes and the cortical layers of the frontal parietal Frontiers in Neuroscience wwwfrontiersinorg 2 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen 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 Kms 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 Wyatt et al 1973ab Lin et al 1974 Narasimhachari et al 1974 Barker et al 1981 The combined data demonstrate that DMT is formed from tryptophan 2 Figure 2 a common dietary amino acid via the enzyme aromatic Lamino acid decarboxylase AADC formation of TA 3 Figure 2 and its subsequent N Ndimethylation The enzyme indolethylamineN methyltransferase INMT uses Sadenosyllmethionine as the methyl source to produce Nmethyltryptamine NMT 4 Figure 2 and then DMT 1 Figure 2 Both AADC and INMT act on other substrates as well As a historical and research note regarding DMT there was initial confusion and misidentification of the products formed when using 5methyltetrahydrofolate 5 MTHF as the methyl source in INMT studies due to formation of indoleethylamine condensation products with formaldehyde tetrahydrobetacarbolines Barchas et al 1974 Lin and Narasimhachari 1974 Rosengarten and Friedhoff 1976 Barker et al 1981 There has also been interest in the role of INMT and DMT biosynthesis in maturation and development Relatively elevated levels of INMT activity have been found in the placenta from a variety of species including humans Thompson et al 1999 INMT activity in rabbit lung was reported to be elevated in the fetus and to increase rapidly after birth peaking at 15 days of age It then declined to mature levels and remained constant through life Lin et al 1974 In this regard Beaton and Morris 1984 have examined the ontogeny of DMT biosynthesis in the brain of neonatal rats and rats of various ages Using gas chromatography mass spectrometry with isotope dilution for their analyses DMT was detected in the brain of neonatal rats from birth DMT levels remained low 14 ngg of whole brain tissue until days 12 and 17 at which time they increased significantly and then returned to the initial low levels for all subsequent ages There has yet to be any followon research as to the significance of this change in DMT concentrations during rat brain neurodevelopment or correlation with possible changes of INMT activity in other developing tissues specifically during days 12 17 Nonetheless these findings correlate well with the Lin et al 1974 data for INMT changes in rabbits and deserve further inquiry There is a significant literature concerning INMT particularly in peripheral tissues INMT and its gene have been sequenced Thompson et al 1999 commercial antibodies for its detection have been developed and commercial probes exist for monitoring its mRNA and gene expression A study using Northern blot detection of the INMT mRNA conducted by Thompson et al 1999 in the rabbit suggested that INMT was present in significant quantities in the periphery and particularly the lung but that it was almost nonexistent low to absent in the brain These data became the foundation for several hypotheses that any neuropharmacological effects of endogenous DMT must lie in its formation in the periphery and its subsequent transport into the brain This idea was strengthened by the fact that DMT has been shown to be readily and perhaps actively transported into the brain Cozzi et al 2009 However the data concerning the apparent absence of INMT in brain would appear to be in conflict with the many earlier studies that demonstrated both in vivo and in vitro biosynthesis of DMT in the brain Indeed several studies had identified INMT activity or the enzyme itself in the central nervous system CNS including the medulla the amygdala uncus and frontal cortex Morgan and Mandell 1969 the frontoparietal and temporal lobes Saavedra et al 1973 and more recently the anterior horn of the spinal cord as well as the pineal gland Cozzi et al 2011 Thus in 2011 Cozzi et al sought to determine why earlier studies Thompson et al 1999 had not detected significant INMT in brain using Northern blots despite several reports that brain tissue had been shown to synthesize DMT from TA One possibility was that INMT was expressed in nervous tissue but that in some situations INMT mRNA is not detectable by Northern analysis eg the INMT gene is inducible INMT expression is limited to specific brain nuclei or INMT mRNA in brain is shortlived Examining primate nervous system tissues Rhesus macaque spinal cord pineal gland and retina probed with rabbit polyclonal antibodies to human INMT all three tissues tested positive INMT immunoreactivity in spinal cord was found to be localized in ventral horn motoneurons The study also showed that INMT response was robust and punctuate in the pineal gland Further intense INMT immunoreactivity was detected in retinal ganglion neurons and at synapses in the inner and outer plexiform layers Cozzi et al 2011 In 2012 Mavlyutov et al reported that INMT is also localized in postsynaptic sites of Cterminals of rat motoneurons in close proximity to sigma1 receptors which have been linked to control of the activities of ion channels and Gproteincoupled receptors It was proposed that the close association of INMT and sigma1 receptors suggests that DMT is synthesized locally to effectively activate sigma1 in motoneurons It has been further proposed that DMT is an endogenous sigma1 receptor regulator Fontanilla et al 2009 Su et al 2009 Taking these newer data together with historical in vitro and in vivo results regarding INMT enzyme activity in the brain and CNS it is now clear that the work of Thompson and Weinshilboum 1998 is not the final word on DMT biosynthesis in the brain Future Research on the Biosynthesis of DMT Considering that tryptamine formation itself a trace biogenic amine is essential for the formation of DMT and given its own rapid metabolism by monoamine oxidase MAO as well demonstrating its availability for the biosynthesis of DMT is also relevant to a complete elucidation of the overall pathway Indeed Frontiers in Neuroscience wwwfrontiersinorg 3 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen FIGURE 2 Pathways for the biosynthesis and metabolism of DMT 1 Biosynthesis Tryptophan 2 is converted to tryptamine TA 3 by aromatic amino acid decarboxylase AADC TA is dimethylated to first yield Nmethyltryptamine NMT 4 and then DMT 1 by indoleNmethyltransferase INMT using Sadenosylmethionine SAM as the methyl source Metabolism TA NMT and DMT are all substrates for monoamine oxidase yielding indole3acetic acid 5 IAA as both a common precursor metabolite and the most abundant metabolite of DMT itself DMT is also converted to DMTNoxide 6 as the secondmost abundant metabolite Two 1234tetrahydrobetacarbolines THBCs have also been identified as metabolites 2methylTHBC 7 MTHBC and THBC 8 demonstrating the colocalization of AADC and INMT should be a necessary endeavor in any future research regarding DMT biosynthesis in both the brain and periphery The colocalization of AADC in discreet brain cells and areas with INMT permits TA and subsequently DMT formation locally With demonstration of colocalization of the necessary biosynthetic machinery in the brain both AADC and INMT mechanisms for a rapid biochemical response to signaling and DMT formation may be shown to exist Furthermore the demonstration of mechanisms for the protection storage release and reuptake of DMT would demonstrate that higher concentrations of DMT could be reached in the synaptic cleft and at neuronal receptors than would have to occur from based on previous thought formation and transport from the periphery Pursuit of research of these mechanisms as well as detailed mapping of INMTAADC in the brain is needed We should not rule out the possibility that the biosynthesis and transport of DMT can and does occur from the periphery however Peripheral DMT especially if synthesized in tissues that bypass liver metabolism on first pass may also serve as a signaling compound from the periphery to the brain Such signaling may occur in maintaining homeostasis or in response to extreme changes in physiology However the immediate availability of TA for the biosynthesis of DMT in the periphery should also be demonstrated and studies examining the co localization of AADC and INMT in the periphery should also be performed This will require using highly sensitive and well Frontiers in Neuroscience wwwfrontiersinorg 4 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen validated antibodies and probes for detection of INMT andor its mRNA in brain andor peripheral tissues as well as those for aromaticLamino acid decarboxylase AADC Demonstration of colocalization with AADC has not been previously conducted in any other study seeking to identify INMTs presence or to demonstrate INMT activity Such a determination may prove fruitful since a preliminary examination for the possible colocalization of INMT and AADC in the brain is supported by the data provided in the Allen Brain Atlas mapping INMT and AADC gene expression brainmaporg A thorough reexamination of possible peripheral DMT biosynthesis is needed Indeed INMT actually methylates other substrates such as histamine Herman et al 1985 Thus much of the INMT in the periphery may be involved to a greater degree with methylation of other substances than TA alone In this regard in vitro studies of INMT as it relates to DMT biosynthesis necessarily added TA to their incubations making TA artificially available in regions where natural levels may be absent or at significantly lower levels Without a source for TA the hypotheses regarding the formation of DMT in the periphery and its transport to the brain as a mechanism of actionfunction of endogenous DMT may be seen to be based on a less significant pathway than previously thought Failure to demonstrate colocalization of INMT and AADC in the periphery would alter to some degree the focus of studies of peripheral synthesis and detection for understanding the role of endogenous DMT At least one study has now shown that the pineal gland has high concentrations of INMT Cozzi et al 2011 These data are underscored by the findings of Barker et al 2013 demonstrating the presence of DMT in pineal perfusates from freemoving rats Clearly further research into the biosynthesis and role of DMT in the pineal is needed as is a further assessment of our current knowledge of pineal function We will also need to examine protein and gene arrays to determine the factors that assist or work in concert with the up and down regulation of the INMT system in brain and how it responds to selected physiological changes Such analyses will be essential in examining the possible role of DMT biosynthesis in changing biochemical and physiological events We will also need to create brainspecific INMT KO animals to further understand DMT biosynthesis and the normal role of DMT in vivo It would also be of interest to better understand the possible role of DMT in neurodevelopment as suggested by the work of Beaton and Morris 1984 and Lin et al 1974 in rats and rabbits respectively While DMT appears to clearly be biosynthesized in the pineal mechanisms for its biosynthesis and release may exist in other brain areas as well and research into these other possibilities will also need to proceed DMT METABOLISM 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 016 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 1015 min and was below the limits of detection within 1 h It was estimated that only 18 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 coadministered 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 1560 min depending on dose and route The primary route of metabolism for DMT 1 Figure 2 is via monoamine oxidase A MAOA yielding indoleacetic acid IAA auxin 5 Figure 2 The other metabolites formed include DMTNoxide DMTNO 6 Figure 2 the second most abundant metabolite and lesser amounts of Nmethyltryptamine NMT 4 Figure 2 which along with TA is also a substrate for MAOA 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 6hydroxyDMT 6OHDMT Szára 1961 as well as products from a peroxidase pathway reported to yield N NdimethylNformylkynuramine and N Ndimethylkynuramine 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 2methyl 1234 tetrahydrobetacarboline MTHBC 7 Figure 2 and THBC 8 Figure 2 Barker et al 1980 1981 The primary role of MAOA 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 halflife and extended effects of an α α β βtetradeuteroDMT D4DMT 9 Figure 3 which is less susceptible to MAOA metabolism due to the kinetic isotope effect Barker et al 1982 1984 Beaton et al 1982 Future Research on the Metabolism of DMT While the metabolism of DMT has been thoroughly studied and a number of metabolites both major and minor have been identified Figure 2 one of the complications in understanding Frontiers in Neuroscience wwwfrontiersinorg 5 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen FIGURE 3 Structure of α α β βteradeuteroDMT 9 D deuterium the role and function of endogenous DMT has been the fact that to date no study examining body fluids blood urine saliva has ever been conducted to correlate such data with human physiological events such as circadian changes sex differences etc Sitaram and McLeod 1990 Barker et al 2012 Of greater impact is the fact that despite DMTs rapid metabolism and multiple metabolites no study has fully assessed all of these compounds simultaneously to better understand DMTs overall occurrence or rate of endogenous synthesis release clearance andor the overall assessment of the relevance of endogenous levels in the brain or periphery All of these factors need to be examined Given that peripherally administered DMT at what must be considered as much higher doses than would be expected to occur naturally in the entire organism is rapidly metabolized and cleared measuring endogenous DMT alone in an attempt to assess its role and function is probably doomed to failure This is particularly true if endogenous DMT is mainly produced stored and metabolized in discreet brain areas and that DMT and its metabolites so produced never attain measurable levels in peripheral fluids To the degree that DMT is produced peripherally measurement of IAA DMTNO Nmethyltryptamine and the precursor for the synthesis of both DMT and NMT tryptamine would be advantageous These compounds have been variously reported in tissue blood and urine samples However this approach is complicated by the fact that the major MAO metabolite of all three of these latter compounds IAA Figure 2 is also derived from dietary sources and is produced from the action of bacteria in the gut It is not unreasonable to question whether measurement of DMT and its metabolites and thus the role and function of endogenous DMT can be understood by simply trying to measure these compounds in the periphery This is particularly true in understanding DMT production in the CNS Peripheral measurements may not be the way to determine the central role of DMT and DMT produced in the brain may never be available for measurement in the periphery Nonetheless additional studies should determine if there is validity in such measurements and examine possible circadian ultradian or diurnal variations in DMT synthesis as well as the changes that may occur due to alterations in other physiological parameters DMT DETECTION IN BLOOD URINE AND CEREBROSPINAL FLUID Barker et al 2012 have published a thorough overview of the 69 published studies examining blood urine and cerebrospinal fluid detection of endogenous N Ndimethylated tryptamines N Ndimethyltryptamine DMT 5hydroxyDMT bufotenine HDMT and 5methoxyDMT MDMT Nearly all of the studies were directed at establishing a relationship between the presence andor level of these compounds and a psychiatric diagnosis In total the 69 studies examined DMT in thousands of subjects A critical review of these data determined however that most early studies reporting rather high concentrations of these compounds in blood andor urine were most likely in error and any correlations based on these data were likewise probably incorrect The reasons for this conclusion were 1 Based on current analytical requirements for unequivocal structure identification it is highly probable that many of these studies misidentified the target analyte 2 If properly identified the studies showed that a psychiatric diagnosis was not a necessary or sufficient criterion for finding one or more of these hallucinogens in various body fluids normal controls were also positive and sometimes higher for these compounds Nevertheless it was also concluded that particularly where mass spectral evidence was provided DMT and HDMT are endogenous and can often be successfully measured in human body fluids The evidence was less compelling for MDMT where the only two MSbased positive studiesin CSFwere performed by the same research group There was no mass spectral data demonstrating detection of MDMT in blood or urine There was also no study that attempted a determination of HDMT in CSF In conducting studies to determine the natural occurrence of a compound as being endogenous it is also necessary to eliminate other possible dietary or environmental sources Of the 69 studies reviewed many addressed the possible source of DMT as being from diet or gut bacteria Barker et al 2012 by using special diets Of those conducted it was determined that neither was a source but additional research in this area using more modern technology and a more standard diet across studies is a necessity There have also been only a few efforts to examine the many variables that may influence the levels of these compounds such as circadian or diurnal variations sleep stages and genderage related differences Indeed most of the studies collected only a single time point or were from 24 h collections urine Such infrequent sampling makes it impossible to assess central DMT production from peripheral measurements and suggests perhaps incorrectly that DMT only appears intermittently or not at all In trying to compare the results interpretations and correlation of the data were hampered by variability in sampling methods amount of sample assayed type of sample plasma serum andor whole blood divergent techniques and analytical methodology that also had highly variable or unspecified limits of detection Frontiers in Neuroscience wwwfrontiersinorg 6 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen Future Research Measuring DMT in the Blood Urine andor Cerebrospinal Fluid In terms of pursuing future research on the presence of the endogenous indolealkylethylamines further studies are necessary to determine whether MDMT actually exists in humans Similarly there are no data on the possible presence of HDMT in CSF although it has been routinely identified in urine Barker et al 2012 Future analyses to determine endogenous N N dimethylindolethylamines should also include a search for their major metabolites The methodology applied in such analyses must include rigorous validated protocols for sample collection storage extraction and analyte stability and appropriate criteria for unequivocal detection and confirmation of the analytes using validated methods Modern exactmass liquid chromatography mass spectrometry instrumentation should be the analytical method of choice Such capabilities may then be applied to address the many variables that may influence the ability to measure DMT andor its precursors and metabolites Figure 2 in the periphery Measurement of DMT in the Brain Many studies have been conducted to detect andor quantitate DMT in blood and urine and only a few in the CSF of humans Barker et al 2012 However the CSF studies made no effort to quantitate the DMT detected Christian et al 1975 Corbett et al 1978 Smythies et al 1979 In fact there have been no efforts to quantify the actual levels of endogenous DMT and its metabolites in human brain and only a few have attempted to address the issue in rats Barker et al 2013 described the presence of DMT in pineal gland perfusates from freemoving rats but no quantitation was conducted since the perfusates were essentially dilutions of the surrounding tissue effluent and were collected at a single pointintime As noted no circadian studies of DMT production or release from the pineal as a function of time have ever been conducted In Kärkkäinen et al 2005 using multiple extraction and cleanup steps and an LCMS method for analysis reported the level of DMT in whole rat brain n 2 taken from animals pretreated with a MAOI as being 10 and 15 ngkg This studys information is unfortunately quite limited in terms of sample number and did not address extraction recoveries method validation or brain distribution of DMT As noted earlier one study using rat pups of different ages 140 days after birth and conducted using a validated extractiongas chromatographicmass spectrometric analysis of wholebrain extracts Beaton and Morris 1984 examined the ontogeny of DMT in rat brain and found significant changes in the concentrations of DMT as a function of age The highest levels were 175 418 ngg of brain wet weight at day 17 Values for other days ranged from undetected limit of detection of 10 ngg to 1 2 or as high as 11 ngg A n 6 and a total of 46 brains were pooled for each daypostbirth analysis Since pooled whole brain 20 g total weight was used for the analysis it is still not known how the DMT was distributed in the brain or if the DMT observed actually arose from a discrete brain area or areas alone The data necessarily expressed the DMT concentration as if it was homogeneously distributed Rats were also sacrificed at constant times during the study and no accounting was made for possible circadian or ultradian variations Given these facts any speculation that attempts to dismiss the relevance of DMT in vivo because the concentrations in brain are too low Nichols 2017 necessarily ignores the fact that data concerning the actual levels of DMT in brain particularly humans and levels that may be observed in different brain areas simply does not exist Future Research to Determine the Concentration of DMT in Brain Tissues While more research into the brain concentrations and distribution of DMT is obviously warranted it is possible as with many other substances that it may only be found in specific brain areas or cell types For example the pineal gland of an adult rat weighs between 09 and 156 mg and the total brain weight is approximately 20 g If all of the DMT found on average at day 17 175 ngg in the Beaton and Morris 1984 study were to be located solely in the pineal the tissue concentration would range between 189 and 109 ugg or converting ug to moles and gram to liter the concentrations would be about 01 umolesg or 01 mmolesL to 006 umolesg or 006 mmolesL While converting g to ml regarding tissue is by no means exact the point to be made is that DMT in brain could have significant concentrations in discrete brain areas and exist in sufficient concentrations in such areas to readily affect various receptors and neuronal functions Lower concentrations could occur in other brain areas as well with their concentrations being enhanced by mechanisms for DMT uptake and vesicular storage What is obvious from these speculative calculations is the fact that more research into DMT brain distribution and concentrations is needed recognizing its rapid metabolism and possible sequestration It is quite clear that we have no good estimates at present concerning brainneuronal distribution or concentration of endogenous DMT particularly in humans that will permit informed decisions or conclusions to be drawn regarding its function or the relevance of in vitro binding studies and relative Kms Nichols 2017 to endogenous levels As with measurements in other matrices well validated and sensitive methods for such quantitative analyses will be required RECEPTOR BINDING OF DMT 5HT2A TAARS AND SIGMA1 RECEPTORS There is a significant literature correlating the binding affinity of DMT and related hallucinogens for the 5HT2A receptor and its subset of receptors with other hallucinogens and their subsequent behavioral effects Glennon et al 1978 Nichols 2004 2016 Blough et al 2014 Carbonaro and Gatch 2016 However DMT has been shown to interact with a variety of ionotropic and metabotropic receptors While the subjective behavioral effects of exogenously administered DMT appear to be primarily acting via 5HT2A receptors the interaction of other receptors such as other serotonergic and glutaminergic receptors may also play a synergistic and confounding role Indeed the activation Frontiers in Neuroscience wwwfrontiersinorg 7 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen of frontocortical glutamate receptors secondary to serotonin 5HT2A receptormediated glutamate release appears to be a controlling mechanism of serotonergic hallucinogens dos Santos et al 2016ab However although this type of receptor research is quite mature these findings have yet to define and accurately correlate what makes a compound hallucinogenic vs compounds that have similar binding characteristics that are not hallucinogenic Clearly we are missing some pieces to the hallucinogen receptormodeofaction puzzle For example Keiser et al 2009 have shown that DMT binds to a variety of 5HT receptors and that such binding does have physiological relevance In their study the role of 5 HT2A agonism in DMTinduced cellular and behavioral effects was examined in both cellbased and 5HT2A knockout mouse models It was reported that DMT binds to 5HT1A 5HT1B 5HT1D 5HT2A 5HT2B 5HT2C 5HT5A 5HT6 and 5 HT7 receptors with affinities from 39 nM to 21 µM Keiser et al 2009 Nonetheless it was observed that DMT was not only a potent partial agonist at 5HT2A but also that the DMTinduced head twitch response a common measure of hallucinogenic activity occurred only in wildtype mice but not in 5HT2A knockout mice However it has been shown Strassman 1996 that the mixed 5HT1A1B antagonist pindolol markedly potentiates the subjective effects of DMT in humans Furthermore DMTenhanced inositol trisphosphate production has been shown to persist even in the presence of the 5HT2A antagonist ketanserin Deliganis et al 1991 suggesting other receptor sites for DMTs effects Of interest is the finding of Urban et al 2007 that receptors such as the 5HT family can couple to multiple effectors which allows receptor agonists to produce different pharmacological endpoints Thus certain compounds may selectively activate a specific subset of effectors producing a functional selectivity that complicates the interpretation of observed psychopharmacological or biochemical effects In this regard CarhartHarris and Nutt 2017 have recently offered a novel bipartite model of serotonin neurotransmission involving comodulation of the 5HT1A and 5HT2A receptors This bipartite model purports to explain how different serotonergic drugs including psychedelics modulate the serotonergic system in different ways to achieve their observed pharmacology Clearly the 5HT2A receptor is involved in the mode of action of DMT and other hallucinogens but is it also clear that this is not the sole receptor on which we should rely for an overall explanation Ray 2010 Halberstadt and Geyer 2011 Nichols 2012 2016 Despite the failure of serotonin receptor binding theory to completely explain hallucinogenic activity these observations support the 5HT2A receptor as being a possible primary target for DMTs hallucinogenic effects Keiser et al 2009 While DMT has been shown to bind to the 5HT2A receptor with relative high affinity IC50 75 1 nM McKenna et al 1990 many other compounds that lack DMTs visual effects have a higher affinity for the 5HT2A receptor McKenna et al 1990 In examining the possible complex interaction of multiple systems that may be necessary to explain the effects of compounds such as DMT attention has also turned toward additional possible binding sites Another set of functionally relevant binding sites for DMT is the family of trace amine associated receptors TAARs Burchett and Hicks 2006 Wallach 2009 DMT has been shown to be an agonist in binding to TAAR1 with high affinity causing activation of adenylyl cyclase and cAMP accumulation in TAAR1 transfected HEK293 cells However as is the case with the 5HT2A receptor other psychedelics and nonpsychedelics also stimulate cAMP production following binding at TAAR1 There has yet to be sufficient research of TAAR to determine what role if any this class of receptors plays in the pharmacology or endogenous function of DMT Thus the research to date regarding the role of TAAR receptors suffers from the same lack of explanation for the mode of action of the hallucinogens as the 5HT2A but may comprise a piece of what is obviously a complex set of interactions Another receptor family has also been implicated the sigma 1 receptor One of the possible roles of the sigma1 receptor appears to be to act as an intracellular chaperone between the endoplasmic reticulum ER and mitochondria In this role it is involved in the transmission of ER stress to the nucleus Carbonaro and Gatch 2016 This process would be expected to result in the enhanced production of antistress and antioxidant proteins with the activation of sigma1 mitigating the possible damage done by hypoxia or oxidative stress Szabo et al 2014 2016 Szabo and Frecska 2016 Using in vitro cultured human cortical neurons derived from induced pluripotent stem cells monocytederived macrophages and dendritic cells Szabo et al 2014 have shown that DMT greatly increases the survival of these cell types in severe hypoxia 05 O2 apparently via its interaction with sigma1 receptors A decreased expression and function of the alpha subunit of the hypoxiainducible factor HIF1 was also observed suggesting that DMTmediated sigma1 activation may alleviate hypoxiainduced cellular stress and increase survival via decreased expression and function of the stress factor HIF1α in severe hypoxia Such a mechanism has relevance to stroke myocardial infarct or similar arterial occlusive disorders cardiac arrest and perinatal asphyxia all conditions associated with hypoxic consequences Carbonaro and Gatch 2016 Szabo et al 2016 and Szabo and Frecska 2016 have speculated that DMT may also contribute to neuroregenerative and neurorestorative processes by modulating the survival of microglialike cells These sigma1 associated effects may also be related to findings that DMT affects the rate of genetic transcription associated with synaptic plasticity ODonovan et al 1999 GonzálezMaeso et al 2007 increased expression of brain derived neurotrophic factor BDNF expression associated with synaptic plasticity ODonovan et al 1999 cognitive processes such as memory and attention DeSteno and Schmauss 2008 and modulation of efficacy and plasticity of synapses Soulé et al 2006 The sigma1 receptor has been implicated in several neurobiological disorders and conditions and is found widely distributed though out the body including in the CNS However both hallucinogens and nonhallucinogens bind to sigma1 receptors again complicating an attribution to this receptor as the primary site of DMTs action Further DMT binds to Frontiers in Neuroscience wwwfrontiersinorg 8 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen sigma1 receptors at what should be considered as a high concentration EC50 14 µM vs about 75 nM for 5HT2A but does nonetheless have agonist activity INMT has been shown to be colocalized with sigma1 receptors in Cterminals of motor neurons Mavlyutov et al 2012 and such intracellular synthesis would allow for DMT accumulation and storage producing the necessary µM concentrations for its action It is also important to consider that the role of endogenous DMT is not necessarily to produce the same effects as observed from exogenous administration and such a normal role may be one of its biological assets It has also been observed that sigma1 receptor agonists are potentially neuroprotective Frecska et al 2013 DMT has been shown to reduce neuronal inflammation via the sigma 1 receptor Szabo et al 2014 and can also induce neuronal plasticity a longterm recuperative process that goes beyond neuroprotection Tsai et al 2009 Ruscher et al 2011 Kourrich et al 2012 Sigma1 receptors can also influence cell survival and proliferation Collina et al 2013 and Frecska et al 2013 have suggested that DMT is protective during cardiac arrest and perinatal development With respect to the ontogeny of DMT Lin et al 1974 and Beaton and Morris 1984 have examined changes in INMT activity and DMT biosynthesis respectively with age in the rat Taken together changes in INMT levels consequently yielded increased DMT synthesis It is possible that DMTmediated sigma1 receptor activity is also increased during this period to induce neuronal changes in newborns Several selective sigma1 receptor agonists have been shown to be protective against excitotoxic perinatal brain injury Griesmaier et al 2012 and ischemic neurodegeneration in neonatal striatum Yang et al 2010 In addition it has been suggested that adequate expression of placental INMT may be necessary for pregnancy success NunoAyala et al 2012 Future DMT Receptor Binding Studies Studies examining nonserotonergic receptors for DMT such as TAAR and sigma1 have begun to bear useful and insightful evidence for the possible normal roles of endogenous DMT and should be extended and expanded Molecular biological studies of DMTs effects on these receptors and DMTs effects on their up ordown regulation will also prove informative Mapping of these receptors in brain tissues with a determination of the nature and degree of colocalization of DMTs enzymes for synthesis in mind will also add impetus to the growing recognition of DMTs possible normal functions in brain This understanding may also lead to new therapeutic applications for regulating and altering endogenous DMT levels and function providing new avenues for understanding hallucinogen pharmacology and their possible therapeutic use The data suggest that the 5HT2A receptor is only part of the story The data further suggest there may well remain a hallucinogen receptor or receptor complex that has yet to be discovered A more integrative mechanism to explain hallucinogenic activity as suggested by Urban et al 2007 Ray 2010 Halberstadt and Geyer 2011 and Carhart Harris and Nutt 2017 is also intriguing and requires further inquiry Perhaps the true hallucinogen receptor has already been discovered and is simply mislabeled as being one of the many 5HT receptors Perhaps it is their interaction with many receptors and their complex functional connectivity that produces the observed effects Ray 2010 Halberstadt and Geyer 2011 Indeed the data suggest that DMT is both endogenous and possesses the properties of a neurotransmitter see below Studies have clearly shown that it binds with respectable affinity to the 5HT2A receptor as well as other members of the serotonin family of receptors and elicits biochemical and physiological activity that can be correlated to some degree with such binding These data support the idea that it is therefore an endogenous ligand for such receptors and intrinsically involved in serotonergic function This being the case there is already a significant body of work regarding DMTs binding and effects especially relative to effects on serotonin acting as a serotonergic modulator Additional work in this area while acknowledging DMT as an endogenous ligand will prove essential It is also unlikely that DMT acts alone in exerting it effects Changes in relevant metabolomic and array profiles following DMT administration will further add to our understanding of its endogenous role ADMINISTRATION OF DMT Szára 1956 1961 originally reported that the effects of a medium dose 07 mgkg of DMT given intramuscularly were similar to those of mescaline and LSD including visual illusions and hallucinations distortion of body image speech disturbances mood changes and euphoria or anxiety dependent on set and setting Several other studies have replicated these findings using either IV or IM administrations Turner and Merlis 1959 Rosenberg et al 1964 Gillin et al 1976 Strassman et al 1994ab Intramuscular effects of DMT at a reported dose of 021 mgkg Szára 2007 generally had a rapid onset 25 min and lasted 3060 min The IM effects are usually less intense than intravenous or inhalationofvapor routes of administration The subjective effects of DMT from ayahuasca administration 06085 mgkg DMT Riba et al 2003 usually appear within 60 min peak at 90 min and can last for approximately 4 h Cakic et al 2010 The prolongation of effect is attributed to the MAOI effects of the constituent harmala alkaloids Riba et al 2015 have also reported the effects of oral and vaporized DMT alone As expected oral ingestion of pure DMT produced no psychotropic effects Vaporized DMT was found to be quite psychoactive This study also showed that smoked DMT caused a shift from the MAOdependent route to the less active CYPdependent route for DMT metabolism Commonly used doses for vaporized or inhaled freebase DMT are 4050 mg although a dose may be as much as 100 mg Shulgin and Shulgin 1997 The onset of vaporized DMT is rapid similar to that of iv administration but lasts less than 30 min It is of interest to note that intranasal free base DMT is inactive 007028 mgkg Turner and Merlis 1959 as is DMT administered rectally De Smet 1983 Frontiers in Neuroscience wwwfrontiersinorg 9 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen There is also additional significant literature concerning the administration of DMT via consumption of ayahuasca While of great scientific interest this subject is not reviewed here This is mainly due to the complexity of composition of ayahuasca especially the presence of significant MAOI effects Strassman et al 1994ab have reported doseresponse data for intravenously administered DMT fumarates neuroendocrine cardiovascular autonomic and subjective effects in a group of experienced hallucinogen users DMT was administered at doses of 005 01 02 and 04 mgkg to 11 experienced hallucinogen users The results of these studies showed peak DMT blood levels and subjective effects were attained within 2 min after drug administration and were negligible at 30 min DMT was also shown to dosedependently elevate blood pressure heart rate pupil diameter and rectal temperature in addition to elevating blood concentrations of βendorphin corticotropin and cortisol Prolactin and growth hormone levels rose equally at all doses of DMT Levels of melatonin were unaffected The lowest dose that produced statistically significant effects relative to placebo and that was also hallucinogenic was 02 mgkg Strassman 1991 1996 The effects observed and the biochemical and physiological parameters measured in these studies add needed insight into the role and function of endogenous DMT However we must distinguish the effects of exogenously administered DMT from that which may be observed from its natural role as an endogenous substance Exogenous administration of a bolus of DMT represents an overdose of a naturally occurring compound that may when administered in this manner exert a more complex pharmacology However this could also be true of any physiological change that produced a normal elevation in endogenous DMT such as a response to stress or hypoxia but with the entire process still remaining under a greater degree of biochemical control and response and the elevation possibly occurring in only certain brain areas or systems For exogenously administered DMT we know plasma concentrations between 12 and 90 ngml Callaway et al 1999 Yritia et al 2002 Riba et al 2003 must be attained in order to produce hallucinogenic effects The concentrations actually attained in whole brain or in specific areas required to produce hallucinogenic effects from such administrations are unknown Future DMT Administration Studies While these overdoses have given us valuable data regarding DMTs pharmacology and hints as to DMTs normal role and function it will be necessary to lower the doses and expose the brain only to more natural levels or ranges to more fully ascertain why DMT is in the brain and what it is doing there Part of that research will require the renewal of drug administration studies to assess the many prospects that have been raised by recent and current research Gallimore and Strassman 2016 have offered an interesting proposal regarding the future conduct of DMT administration research a targetcontrolled continuous lowdose IV infusion This approach would be conducted to better discern the physiology and pharmacology of DMT and to produce a prolonged and immersive psychedelic state The short duration of DMTs effects prevents the use of single dose administration as the research model for such studies Target controlled continuous IV infusion is a technology developed to maintain a stable brain concentration of anesthetic drugs during surgery The rationale for this approach and the conduct of such research lies in the fact that DMT users have consistently reported the complete replacement of normal subjective experience with a novel alternate universe often densely populated with a variety of strange objects and other highly complex visual content including what appears to be sentient beings A further stated purpose of this approach and one that would be quite informative is to allow greater functional neuroimaging of the DMT experience with subjects remaining under the influence of DMT for the extended periods necessary to collect the best data The administration of DMT by the IV route will require determination of an effective continuous dose such that the desired level of experience is both attained and maintained The lower the dose necessary the less likely volunteers will be to experience some of DMTs other peripheral and central sideeffects and will establish a threshold above which further higher dose administrations may be examined Concomitant administration of a MAOI would assist in attaining this goal but has the drawback of affecting levels of many other amine neurotransmitters as well complicating the effects and subsequent data interpretation However one alternative method of administration may be to use analogs of DMT that are structurally altered as so to inhibit the ability of the molecule to be metabolized by MAOA such as an alpha methyl or 2N Ndimethylpropyl sidechain structure However such molecules may not bind in the same manner as DMT itself and may have other untoward effects Another alternative that may assist in the ability to use lower doses and to prolong the effect of the DMT administered however may be the use of a deuterated analog In 1982 Beaton et al reported on the behavioral effects of DMT and ααββtetradeuteroDMT 9 Figure 3 D4DMT administered interperitoneally to rats at a dose level of 25 and 50 mgkg The D4DMT was observed to produce at equivalent doses to DMT itself a significantly greater disruption of behavior a longer duration of action and a shorter time to onset than non deuterated DMT This potentiation was apparently due to the kinetic isotope effect which in theory makes it harder for the MAO enzyme to extract a deuterium vs a hydrogen from the alpha position Figure 3 thus inhibiting degradation by MAO In a companion study Barker et al 1982 also showed that at the same dose D4DMT attained a significantly higher brain concentration than DMT itself and that the elevation in brain level lasted for a longer period of time Similar data have recently been presented for a tetra deutero5MeODMT Halberstadt et al 2012 and the authors reached a similar conclusion these results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacological studies to mimic the effects of tryptamineMAOI combinations but without the MAOI While the synthesis of deuterated analogs may be more expensive initially newer methods for such synthesis Brandt et al 2008 may overcome these concerns Furthermore the pharmacological properties of D4DMT may render it orally Frontiers in Neuroscience wwwfrontiersinorg 10 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen active Such a possibility has yet to be explored It is also possible that oral administration and kinetic isotope effect inhibition of metabolism may prolong the effects of a deuterated analog sufficiently to also be of use in imaging studies It would be of interest to determine if the proposal of Gallimore and Strassman 2016 using a continuous infusion of DMT would also be of use in in an animal model for the treatment of severe brain injury and trauma or in conditions resulting from a hypoxic insult such as arterial occlusive disorders cardiac arrest and perinatal asphyxia promoting the possible neuroprotective and neuroregenerative effects of DMT that have been recently described Such studies will also allow validation or refutation of the recent data in this area IMAGING RESEARCH While there have been several studies reporting neuroimaging data from volunteers consuming ayahuasca Bouso et al 2015 dos Santos et al 2016ab there is minimal neuroimaging data for the administration of DMT alone Daumann et al 2008 2010 Using functional magnetic resonance imagining fMRI techniques administration of DMT caused a decreased blood oxygenation leveldependent response during performance of an alertness task particularly in the extrastriate regions during visual alerting and in temporal regions during auditory alerting Daumann et al 2010 It was concluded that the effects for the visual modality were more pronounced Imaging data for other hallucinogens such as psilocybin and LSD have been generated dos Santos et al 2016b dos Santos et al 2016b have concluded that the acute effects of hallucinogen administration as interpreted from imaging studies included excitation of frontolateralfrontomedial cortex medial temporal lobe and occipital cortex and inhibition of the default mode network For longterm use the administration of hallucinogens was associated with thinning of the posterior cingulate cortex thickening of the anterior cingulate cortex and decreased neocortical 5HT2A receptor binding It was also suggested that hallucinogens increase introspection and a positive mood by modulating brain activity in the frontotemporoparieto occipital cortex dos Santos et al 2016b Future Imaging Research The data to be derived in such imaging studies are highly dependent on the instrumentation and methods used and the interpretation of the data can often be somewhat subjective However any such data may provide the necessary roadmaps to understand brain distribution of administered and endogenous DMT and the activationdeactivation profiles created naturally or artificially in various states of consciousness Indeed recent imaging data CarhartHarris et al 2012 2016 Tagliazucchi et al 2014 and pharmacological studies of 5HT2A receptor activation Kraehenmann 2017 Kraehenmann et al 2017 suggest that hallucinogens create a brainimage patterning that resembles dream states Such studies of DMT have yet to be reported and should be undertaken The involvement of DMT in various dream states has been hypothesized Callaway 1988 One possible mechanism is the possibility that endogenous DMT is the signaling molecule responsible for the upanddown regulation of specific brain areas that occurs during different dream states Understanding the DMT related functional connectivity or connectome either from administration andor from endogenous production stimulation will expand our research frontiers in this field Administration studies such as proposed by Gallimore and Strassman 2016 could provide imaging data that will permit interpretation of the neural pathways relevant to DMTs effects particularly in eliciting hallucinations but also as part of its normal function DMT AS A NEUROTRANSMITTER NEUROHORMONE OR NEUROREGULATORY SUBSTANCE In 1976 Christian et al published the accumulated evidence that DMT was a naturally occurring transmitter in mammalian brain having met the criteria for such a designation at the time 1 the synthetic enzymes and substrates are present in the CNS for the production of DMT 2 a binding site is present to react with the compound and 3 the compound is found in human CSF and isolated synaptic vesicles from rat brain tissue Christian et al 1976 Additional criteria have been added over the years such as demonstration of electrophysiological activity Indeed DMT had also been shown to change the transepithelial and intracellular potentials of the blowfly salivary gland and to increase the production of cyclic AMP Berridge 1972 Berridge and Prince 1974 early on Another added criterion is that a pathway for DMTs metabolism and removal must be demonstrated Pathways of DMT metabolism in the brain are well understood Barker et al 1980 and newer data offers other mechanisms such as uptake into synaptic vesicles and neurons for controlling its synaptic levels Cozzi et al 2009 Blough et al 2014 Like any neurotransmitter uptake and storage can allow a reservoir of DMT to remain stored in vesicles ready for release and provide a mechanism for protecting and concentrating the compound Frecska et al 2013 Christian et al 1977 subsequently described a specific high affinity Kd 30 nM binding site for DMT on purified rat synaptosomal membranes that was also sensitive to LSD but not to serotonin DMT was also shown to lead to the production of cAMP in synaptosomal membrane preparations as well as in rat brainstem slices and rat cerebrum in vivo Christian et al 1977 Unfortunately no additional research on these findings has been reported Other studies have also demonstrated that administered DMT becomes localized in the synaptosomal fraction of rat brain following administration and is detected in the vesicular fraction of such preparations Barker et al 1984 Further the Mg2 and ATP dependent uptake of DMT Corbett et al 1975 into rat brain vesicles has also been demonstrated as has apparent high and low affinity uptake sites for active transport of DMT in rat brain cortical slices The supporting data for DMT as a neurotransmitter have continued to accumulate DMT has also been shown to be taken up into neuronal cells via serotonin uptake transporters SERT on neuronal plasma membrane Berge et al 1983 Whipple et al Frontiers in Neuroscience wwwfrontiersinorg 11 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen 1983 Nagai et al 2007 Cozzi et al 2009 and Cozzi et al 2009 have shown sequestration of DMT into synaptic vesicles from the cytoplasm by the neuronal vesicle monoamine transporter 2 VMAT2 Blough et al 2014 have also shown that DMT releases 5HT via SERT with an EC50 in the low nM range This indicates that DMT is a substrate for the SERT transporter and provides a further mechanism for the neuronal accumulation of DMT Newer data concerning INMT in specific brain areas Cozzi et al 2011 and its presence in perfusates of the pineal gland of living rats Barker et al 2013 add additional evidence for DMTs potential role as a neurotransmitter At a minimum the anatomy pharmacology and physiology of DMT have been sufficiently characterized and demonstrated to afford DMT the classification as a putative neurotransmitter The concentration of DMT into vesicles and its release at the synaptic cleft would permit elevated concentrations of DMT perhaps sufficient to elicit its known pharmacological actions as well as other effects It would also be protected from MAO degradation Peripheral production of DMT would not be required It may also be the case that brain DMT biosynthesis is inducible in response to specific physiological effects causing an increase in concentration in specific cell types and areas This being the case the idea that a pharmacologically relevant blood level of DMT must be attained before such effects are observed Nichols 2017 from endogenous production of DMT would not be relevant Future Studies Characterizing DMT as a Neurotransmitter Setting aside speculation in favor of what has been scientifically proven the effects of administered psychedelics must be recognized as acting via existing naturally occurring neuropharmacological pathways and mechanisms Perhaps we should first consider research into the possible role of endogenous DMT in explaining the elusive mode of action of the varied class of compounds possessing hallucinogenic properties There is no doubt that DMT acts on the serotonergic system as well as other known neurotransmitter systems Nonetheless if DMT is a neurotransmitter neurohormone andor neuroregulatory substance then we should consider all of the more well understood properties of agonists and antagonists acting on such a system While many hallucinogens have been shown to act on many different neurotransmitters and receptors we may now add the need to examine their effects on the synthesis binding release reuptake storage degradation etc of an endogenous hallucinogen DMT This is especially true in relation to serotonin regulation As with our more recent understanding of the mode of action of opiates finding new endogenous ligands and receptors can actually lead to a more complete understanding of the effect of what often appear to be divergent substances Hypothetically the mode of action of hallucinogens may be via their effects on an endogenous hallucinogen neuronal system Barker et al 1981 Establishing DMT as a neurotransmitter makes such research not only somewhat obvious and relevant but necessary If such a system is found to be responsible for these phenomena it may lead to more discoveries explaining other normal or pathological conditions such as for example delirium certain symptoms of psychoses spontaneous hallucinations and sleep disorders autism and other perceptual anomalies Perhaps it may yet be shown to be involved in schizophrenia just not necessarily by previously expressed mechanisms Certainly it could give us insight into the proposals of its involvement in our more human attributes of creativity imagination and dream states Callaway 1988 and of our less common experiences of visions NDEs and extraordinary states of consciousness occurring without exogenous administration of a hallucinogenic substance Thus we need to better understand the molecular biology physiology and anatomy surrounding endogenous DMT and its potential regulatory role Taken together the evidence for DMT as a neurotransmitter is compelling Recent research and more classical data have established that it is synthesized stored and released in the brain and mechanisms for its uptake metabolism and removal have all been established While more work remains to establish DMT as a neurotransmitter such as more electrophysiological and iontophoretic data it appears to be following the same path to recognition as other neurotransmitters have followed before final acceptance Carlsson 2001 DMT AS A THERAPEUTIC There has been a renewed interest in using hallucinogenic drugs as therapeutics in clinical research to address depression Berman et al 2000 Aan het Rot et al 2010 Buchborn et al 2014 obsessivecompulsive disorder Moreno and Delgado 1997 the psychological impacts of terminal illness Grof et al 1973 Grob et al 2011 prisoner recidivism Hendricks et al 2014 and substance abuse disorders including alcohol Bogenschutz et al 2015 and tobacco Mangini 1998 Krebs and Johansen 2012 Most of these studies have examined the use of LSD psilocybin or ayahuasca instead of DMT alone In the history of use of DMTcontaining remedies ayahuasca has perhaps the longest record Dos Santos et al 2011 Alonso et al 2015 PicTaylor et al 2015 Longterm use of ayahuasca has been shown to produce measurable changes in the brain itself such as differences in midline brain structures as determined from MRI studies dos Santos et al 2016ab While such effects may not appear to be of therapeutic value long term ayahuasca users 10 years have shown reduced ratings of hopelessness Santos et al 2007 Longterm ayahuasca use has also produced marked improvement in depressive symptoms with no concomitant mania or hypomania for up to 21 days after a single dose Osório et al 2015 These data suggest evidence for a potential antidepressant effect for DMT However ayahuasca is a complex mixture containing MAOIs harmala alkaloids which as a class of drugs have also been used alone to treat depression Thus it is impossible to say from such studies that DMT itself or the elevation of other brain neurotransmitters in combination is responsible for the perceived positive clinical effects or even if the hallucinations produced by DMT consumed under these conditions are themselves somehow cathartic Frontiers in Neuroscience wwwfrontiersinorg 12 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen While other classic hallucinogens LSD psilocybin etc are beginning to show promise in the treatment of addictions drugs alcohol etc as well as posttraumatic stress PTSD and other mental disorders Bogenschutz and Pommy 2012 there has yet to be generated conclusive evidence regarding the efficacy of DMT in any of them DMT has been shown to exert antianxietyantipsychotic properties at the trace amino acid receptor TAAR and others have suggested that the possible positive symptoms observed in schizophrenia may be mediated by the effects of endogenous DMT Cakic et al 2010 Grammenos and Barker 2015 These findings do not necessarily support the conclusion that DMT is useful for treatment of anxiety or mental illness however The possible use of DMT as an adjunct to psychiatric therapy has been proposed by numerous investigators a proposal that contravenes the tenets of the transmethylation hypothesis Frecska et al 2013 have suggested that DMT may be involved in significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies and there have been proposals that DMT might be useful to treat substance abuse inflammation or even cancer However at this point the necessary data to support such proposals have not been presented and it would be premature to propose that DMT will become commonly used for clinical purposes If it is a neurotransmitter then understanding its role and function in normal or disease states could provide pharmacological targets to alter these functions however Future Study of DMT as a Therapeutic At present the data arguing for the use of DMT as a therapeutic particularly via administration is thin The claimed therapeutic effects for DMT in combination with harmala MAOIs as in ayahuasca or pharmahuasca Ott 1999 is of interest but presents a complex data set that prevents an understanding of the contribution of each component To further study DMT without the effects of an MAOI research should pursue whether or not D4DMT is orally active as previously noted which would enhance the opportunities to examine its potential as a therapeutic The use of hallucinogens in psychotherapy is gaining renewed interest and certainly DMT should be among the drugs in the psychiatric pharmacopeia Any proposal to pursue this avenue will require more than the current combined body of scientific evidence Both Federal and State laws will have to change in order to make the manufacture and use of such compounds easier and to make conducting the necessary research feasible However if DMT is a neurotransmitter and is responsible for modulation of serotonergic or other neurotransmitter systems it may well be that many existing pharmaceuticals already exert their pharmacology via DMTrelatedeffect mechanisms This may be the case for the other hallucinogens as noted but may also be true for part of the mode of action of certain serotonergic drugs such as antidepressants Further characterization of DMT cellular distribution receptors and general biochemistry may lead to new targets for more effective pharmaceutical substances and interventions CONCLUSIONS It has been 86 years since DMTs first synthesis by Manske and 61 years since Szara discovered its hallucinogenic properties It has been 41 years since Christian et al characterized DMT as a neurotransmitter Further research has better defined the latters characteristics such that a compelling case can be made at a minimum to consider DMT as a putative neurotransmitter Over time the observations of the hallucinogenic phenomena experienced following the administration of DMT have led to speculation that endogenous DMT is possibly involved in psychosis normal attributes and experiences such as creativity imagination and dream states maintenance of waking reality altered states of consciousness including religious andor spiritual phenomena and NDEs Even more far reaching and other worldly hypotheses have also been offered suggesting that DMT as well as other hallucinogens may provide actual proof of andor philosophical insights into many of our unanswered questions regarding extraordinary states of consciousness Regardless of the level and cause of such speculation and hypotheses it is only scientific research that can inform or refute such thinking There is no doubt that hallucinogen research has been a forbidden fruit long ripening on the tree of knowledge Recent research has demonstrated that DMT is present in and is released from the pineal gland of live freelymoving rodents Although older data suggested that DMT might not be synthesized to any great extent in brain studies have now shown that the necessary enzymatic components for the biosynthesis of DMT are present in discreet brain cell types and areas as well as other tissues not previously examined New receptors for DMT have been identified and a potential role for DMT as a neuroprotectant andor neuroregenerative agent has been suggested Hallucinogens have been shown to produce brain patterning resembling dream states apparently mediated through 5HT2A receptor activation DMTs effect in this regard has yet to be examined but raises speculation as to one of the possible roles of endogenous DMT As discussed and delineated above more research is needed on DMTs natural role and function and interaction with other neurotransmitter systems This will require the recommended future research into DMT biosynthesis metabolism and binding new methods for peripheral and central detection and data from administration imaging and therapeutic trial studies The data derived from the areas of research addressed above will no doubt suggest several possible new avenues for additional future research on DMT In order to advance however regulatory blockades to hallucinogen research must be removed Progress in hallucinogen research in these areas has been slowed due to overregulation For at least the last 50 years research on DMT and other hallucinogens has been impeded in the United States by passage of the Congressional Amendment of 1965 and the Controlled Substances Act of Frontiers in Neuroscience wwwfrontiersinorg 13 August 2018 Volume 12 Article 536 Barker DMT an Endogenous Hallucinogen 1970 by the United States Congress that classified DMT and other major hallucinogens as ScheduleI substances Given the endogenous nature of DMT it deserves a special status for future research It is evident that we have too long ignored the field of hallucinogen research in all of its potential aspects This is especially true if continuing research demonstrates a clear role for one of its more prominent members DMT as an endogenous regulator of brain function It is my opinion that these and many other possible approaches and hypotheses regarding DMT and other psychedelics are research endeavors that have great potential and are worthy of attention and support Turning the newest technologies to this work in genetics analytical chemistry molecular biology imaging and others we will no doubt acquire both new knowledge and ask new questions If the politics of any one nation forbid it perhaps others will take up the challenge to further the knowledge of our own potential and the further development and understanding of what we prize as our most unique human characteristic the untapped possibilities of the mind AUTHOR CONTRIBUTIONS The work presented is the sole effort of SB who agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or 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