This review (2018) presents the historical research into DMT, focussing on its biosynthesis, metabolism, sites of action, methods of detection, and potential physiological and therapeutic roles. The author proposes several areas for further research and highlights the need to resolve the role of endogenous DMT.
Abstract
“This report provides a historical overview of research concerning the endogenous hallucinogen N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the “natural” role of an endogenous hallucinogen from the effects observed from peripheral administration are also emphasized.”
Author: Steven A. Barker
Summary
Introduction
We have yet to resolve the biochemical mechanisms by which hallucinogens (psychedelics) alter perception and consciousness, and we do not fully understand how we live such a vivid and complex internal life in the absence of external stimulation.
Hallucinogens are often compared to dream states, but the hallucinogenic experience is far more intense, robust and overwhelming than mere dreams. The biochemical mechanisms involved in hallucinogens may provide a better understanding of the “common” biochemistry that creates mind.
The discovery of endogenous opioids offers us a corollary: we can use the same method to better understand perception and consciousness through the study of endogenous hallucinogens.
A Brief History Of DMT
DMT was first synthesized by Richard Manske in 1931, but its hallucinogenic properties were not discovered until 1956, when Stephen Szara extracted DMT from the Mimosa hostilis plant and administered the extract to himself intramuscularly.
The discovery of endogenous hallucinogens in the 1950’s 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 psycho-toxin. However, there has yet to be any clear-cut correlation of the presence of DMT in peripheral body fluids with any diagnosis.
DMT Biosynthesis
In 1972, researchers discovered an indole-N-methyl transferase (INMT) in rat brain, and demonstrated that tryptamine can be converted to DMT in vivo. They determined that the rate of synthesis of DMT is 350 and 450 pmol/g/hr and 250 and 360 pmol/g/h, respectively. In 1973, Saavedra et al. reported that INMT was found in rat and human brain, and that it had a Km of 28 uM for TA as the substrate. However, INMT may exist in several isoenzyme forms between species and possibly even within the same animal.
DMT is formed from tryptophan via the enzyme aromatic L-amino acid decarboxylase (AADC) and indolethylamine-N-methyltransferase (INMT) using S-adenosyl-l-methionine as the methyl source. Both enzymes act on other substrates as well.
There has been interest in the role of INMT and DMT biosynthesis in maturation and development. In rats, DMT levels increased significantly during development from day 12 to day 17, and then returned to the initial low levels for all subsequent ages.
There is a significant literature concerning INMT, particularly in peripheral tissues. However, a study in the rabbit suggested that INMT was almost non-existent in the brain, and this data was in conflict with the many earlier studies that demonstrated INMT activity in the brain.
In 2011, Cozzi et al. examined primate nervous system tissues and found that INMT was expressed in ventral horn motoneurons, the pineal gland, and the retina. INMT was also found to be localized in postsynaptic sites of C-terminals of rat motoneurons in close proximity to sigma-1 receptors.
Future Research on the Biosynthesis of DMT
The formation of tryptamine, itself a trace biogenic amine, is essential for the formation of DMT. The colocalization of AADC and INMT in the brain may permit DMT formation locally, and mechanisms for the protection, storage, release and reuptake of DMT may exist. We should not rule out the possibility that peripheral DMT is synthesized and transported to the brain, but the immediate availability of TA for DMT biosynthesis should also be demonstrated.
Validated antibodies and probes for detection of INMT and/or its mRNA in brain and/or peripheral tissues as well as those for aromatic-L-amino acid decarboxylase (AADC) have not been previously conducted in any other study.
A thorough re-examination of possible peripheral DMT biosynthesis is needed, as INMT actually methylates other substrates, such as histamine. Without TA, the hypotheses regarding the formation of DMT in the periphery and its transport to the brain may be seen as less significant than previously thought.
In at least one study, the pineal gland has high concentrations of INMT, and another study demonstrated the presence of DMT in pineal perfusates from free-moving rats.
We will 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 create brain-specific INMT KO animals to further understand DMT biosynthesis.
DMT Metabolism
The metabolism of DMT is thoroughly studied, and it is found that exogenously administered DMT is rapidly metabolized and cleared, with only a small fraction of IV or IM administered DMT subsequently being found in urine. DMT is not orally active, and is only active when co-administered with a MAOI.
DMT is metabolized primarily via monoamine oxidase A (MAO-A), yielding indoleacetic acid (IAA), and lesser amounts of N-methyltryptamine (NMT), which are also substrates for MAO-A. Other metabolites have also been reported, such as 6-hydroxy-DMT (6-OH-DMT) and products from a peroxidase pathway.
MAO-A is the primary enzyme in the metabolism of DMT, and this has been further confirmed by the use of MAO inhibitors and the increased half-life of D4 DMT.
Future Research on the Metabolism of DMT
A number of metabolites have been identified for DMT, but no study has ever been conducted to correlate data from body fluids with human physiological events. This is important to better understand DMT’s overall occurrence, release, clearance and relevance in the brain and periphery. DMT is produced peripherally and can be measured in tissue, blood and urine samples. However, the major MAO metabolite of DMT, IAA, is also produced in the gut. Peripheral measurements of DMT and its metabolites may not be the best way to understand the role and function of endogenous DMT, particularly in understanding DMT production in the CNS.
DMT Detection In Blood, Urine, And Cerebrospinal Fluid
Barker et al. (2012) examined 69 studies examining the relationship between DMT, HDMT and MDMT and psychiatric diagnoses. A critical review of studies found that most reported high concentrations of hallucinogens in blood and urine were most likely in error, and correlations based on these data were probably incorrect. Nevertheless, the studies showed that DMT and HDMT can be successfully measured in human body fluids.
In order to determine if a compound is endogenous, it is necessary to eliminate other possible dietary or environmental sources. However, most studies collected only a single time point or were from 24 h collections (urine), making it impossible to assess central DMT production from peripheral measurements.
Future Research Measuring DMT in the Blood, Urine, and/or Cerebrospinal Fluid
Future research should include a search for the endogenous indolealkylethylamines MDMT and HDMT in CSF. Validated methods should be applied in such analyses, and exact-mass liquid chromatography-mass spectrometry instrumentation should be the analytical method of choice.
Measurement of DMT in the Brain
Many studies have been conducted to detect and/or quantify DMT in blood and urine, but no studies have been conducted to quantify the actual levels of endogenous DMT and its metabolites in human brain.
One study examined the ontogeny of DMT in rat brain using rat pups of different ages and found that the highest levels were found at day 17 and ranged from undetected to 1, 2 or as high as 11 ng/g of brain (wet weight).
Given these facts, any speculation that DMT concentrations in brain are too low is necessarily based on speculation.
Future Research to Determine the Concentration of DMT in Brain Tissues
DMT may only be found in specific brain areas or cell types, and the concentration found in the pineal gland of an adult rat ranges between 18.9 and 10.9 ug/g (0.1 umoles/g to 0.06 mmoles/L). While converting grams to milliliters regarding tissue is by no means exact, it is clear that DMT in brain could have significant concentrations in discrete brain areas and exist in sufficient concentrations to readily affect various receptors and neuronal functions.
Receptor Binding Of DMT: 5-HT2A, TAARS, And SIGMA-1 Receptors
There is significant literature correlating the binding affinity of DMT and related hallucinogens for the 5-HT2A receptor and its subset of receptors with other hallucinogens and their subsequent behavioral effects. However, the exact mechanism of action of DMT is still not completely understood.
DMT binds to several 5-HT receptors, including 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6 and 5-HT7, and induces a head twitch response only in wild-type mice. However, the 5-HT2A antagonist pindolol potentiates the subjective effects of DMT in humans. Urban et al. (2007) found that 5-HT receptors can couple to multiple effectors, and this may explain why different serotonergic drugs modulate the serotonin system in different ways.
DMT and other hallucinogens bind to the 5-HT2A receptor, but many other compounds that lack DMT’s visual effects have a higher affinity for the 5-HT2A receptor.
DMT has been shown to bind to the family of trace amine-associated receptors (TAARs) with high affinity, causing activation of adenylyl cyclase and cAMP accumulation in TAAR1 transfected HEK293 cells. However, there has yet to be sufficient research of TAARs to determine what role they play.
DMT increases the survival of human cortical neurons, monocyte-derived macrophages, and dendritic cells in severe hypoxia (0.5% O2), apparently via its interaction with sigma-1 receptors. This may have relevance to stroke, myocardial infarction, cardiac arrest, and perinatal asphyxia, all conditions associated with hypoxic consequences.
Sigma-1 may affect the rate of genetic transcription associated with synaptic plasticity, increase expression of brain-derived neurotrophic factor, and modulate cognitive processes such as memory and attention.
The sigma-1 receptor is found widely distributed though out the body, including in the CNS. DMT binds to sigma-1 receptors at a high concentration, but does nonetheless have agonist activity, suggesting that INMT may be involved in DMT’s action.
Sigma-1 receptor agonists are potentially neuroprotective, and DMT can induce neuronal plasticity, a long-term recuperative process that goes beyond neuroprotection. In addition, DMT is protective during cardiac arrest and perinatal development, and adequate expression of placental INMT may be necessary for pregnancy success.
Future DMT Receptor Binding Studies
Studies on non-serotonergic receptors for DMT are beginning to bear useful and insightful evidence for the possible “normal” roles of endogenous DMT. Mapping of these receptors in brain tissues will also prove informative, and may lead to new therapeutic applications for regulating and altering endogenous DMT levels and function.
Studies have shown that DMT binds to the 5-HT2A receptor and other members of the serotonin family of receptors and elicits biochemical and physiological activity that can be correlated, to some degree, with such binding. This suggests that DMT is an endogenous ligand for these receptors.
Administration Of DMT
Szára reported that intramuscular administration of DMT produces similar effects to those of mescaline and LSD, including visual illusions and hallucinations, distortion of body image, speech disturbances, mood changes and euphoria or anxiety.
The effects of DMT from ayahuasca administration usually appear within 60 min, peak at 90 min and can last for approximately 4 h. Vaporized DMT is more potent than oral DMT and shifts the metabolism of DMT from the MAO-dependent route to the CYP-dependent route.
Strassman et al. (1994a,b) administered intravenously administered DMT fumarate to 11 experienced hallucinogen users and found that the lowest dose that produced statistically significant effects relative to placebo and that was also hallucinogenic was 0.2 mg/kg.
Exogenously administered DMT may exert a more complex pharmacology than that observed from its natural role as an endogenous substance, but this may also be true of any physiological change that produced a “normal” elevation in endogenous DMT, such as a response to stress or hypoxia.
Future DMT Administration Studies
DMT administration studies will need to be renewed to assess the many prospects raised by recent and current research. A target-controlled continuous, low-dose, IV infusion could be conducted to better discern the physiology and pharmacology of DMT.
DMT users have consistently reported a complete replacement of normal subjective experience with a novel ‘alternative universe,’ often densely populated with strange objects and other highly complex visual content, including what appears to be sentient ‘beings’.
DMT administration by the IV route will require determination of an effective continuous dose, and a threshold above which further higher dose administrations may be examined.
Analogs of DMT that are structurally altered may inhibit the ability of the molecule to be metabolized by MAO-A, but may have other untoward effects.
D4 DMT produced a greater disruption of behavior, a longer duration of action and a shorter time to onset than non-deuterated DMT at equivalent doses. This potentiation was apparently due to the kinetic isotope effect. Similar data have recently been presented for tetra deutero-5-MeO-DMT, and the authors reached a similar conclusion: deuterated tryptamines may be useful in behavioral and pharmacological studies to mimic the effects of tryptamine/MAOI combinations, but without the MAOI.
Gallimore and Strassman (2016) propose to use a continuous infusion of DMT to treat severe brain injury and trauma, as well as conditions resulting from a hypoxic insult.
Imaging Research
There have been several studies reporting neuroimaging data from volunteers consuming ayahuasca, but minimal neuroimaging data for the administration of DMT alone. The effects of hallucinogens include activation of the frontolateral/frontomedial cortex, medial temporal lobe, and occipital cortex, and inhibition of the default mode network.
Future Imaging Research
Recent imaging data suggest that hallucinogens create a brain-image patterning that resembles dream states, and that endogenous DMT may be the signaling molecule responsible for the up-and-down regulation of specific brain areas that occurs during different dream states.
DMT As A Neurotransmitter, Neurohormone, Or Neuroregulatory Substance
DMT was first shown to be a naturally occurring transmitter in 1976, when Christian et al. demonstrated that it was present in human CSF and isolated synaptic vesicles from rat brain tissue. Additional criteria have been added over the years, such as demonstration of electrophysiological activity.
A high-affinity binding site for DMT was found on purified rat synaptosomal membranes, and DMT led to the production of cAMP in rat brainstem slices and rat cerebrum in vivo. Unfortunately, no additional research on these findings has been reported.
DMT has been shown to be taken up into neuronal cells via serotonin uptake transporters on neuronal plasma membrane and sequestered into synaptic vesicles by the neuronal vesicle monoamine transporter 2. It has also been shown to release 5-HT via SERT with an EC50 in the low nM range.
DMT is concentrated into vesicles and released at the synaptic cleft, where it may elicit its known pharmacological actions as well as other effects. It may also be inducible in response to specific physiological effects.
Future Studies Characterizing DMT as a Neurotransmitter
The effects of administered psychedelics must be recognized as acting via existing, naturally occurring, neuropharmacological pathways and mechanisms. If endogenous DMT is a neurotransmitter, neurohormone and/or neuroregulatory substance, then we should consider all of the more well understood properties of agonists and antagonists acting on such a system.
DMT may be involved in schizophrenia, autism, perceptual anomalies, creativity, imagination and dream states, as well as in visions, NDEs and extraordinary states of consciousness occurring without exogenous administration of a hallucinogenic substance.
DMT is synthesized, stored, and released in the brain, and its uptake, metabolism, and removal have all been established. It is following the same path to recognition as other neurotransmitters.
DMT As A Therapeutic
There has been renewed interest in using hallucinogenic drugs as therapeutics in clinical research to address depression, obsessive-compulsive disorder, the psychological impacts of terminal illness, prisoner recidivism, and substance abuse disorders.
Ayahuasca, a DMT-containing “remedy”, has been shown to produce measurable changes in the brain itself, as well as improved ratings of hopelessness and depressive symptoms in long-term users. However, it is impossible to say whether DMT itself or the elevation of other brain neurotransmitters in combination is responsible for the perceived positive clinical effects.
While other classic hallucinogens are beginning to show promise in the treatment of addictions, post-traumatic stress, and other mental disorders, there is yet to be generated conclusive evidence regarding the efficacy of DMT in any of them.
DMT may be involved in significant adaptive mechanisms, but more research is needed to determine its role in normal or disease states.
Future Study of DMT as a Therapeutic
At present, there is not enough evidence to support the use of DMT as a therapeutic, particularly via administration. Research should pursue whether or not D4 DMT is orally active, which would enhance opportunities to examine its potential as a therapeutic.
DMT may be a neurotransmitter and may be responsible for modulation of serotonergic or other neurotransmitter systems. This may explain the mechanism of action of certain serotonergic drugs.
Conclusions
DMT has been characterized as a neurotransmitter for 41 years, and its hallucinogenic properties have been 86 years in the making.
Observations of hallucinogenic phenomena 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, and NDEs.
Recent research has shown that DMT is present in and released from the pineal gland of live, freely-moving rodents, and that it may have a role as a neuroprotectant and/or neuroregenerative agent.
Research on DMT’s natural role and function is needed, as well as new methods for peripheral and central detection, and data from administration, imaging and therapeutic trial studies. However, regulatory blockades to hallucinogen research must be removed in order to advance.
It is evident that we have ignored the field of hallucinogen research, and that the newest technologies can be used to acquire new knowledge and ask new questions about DMT and other psychedelics.
Study details
Compounds studied
DMT