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| Routes of administration | Oral (with an MAOI), insufflated, rectal, vaporized, IM, IV |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.000.463  |
| Chemical and physical data | |
| Formula | C12H16N2 |
| Molar mass | 188.269 g/mol g·mol−1 |
| 3D model (JSmol) | |
| Density | 1.099 g/cm3 |
| Melting point | 40 °C (104 °F) |
| Boiling point | 160 °C (320 °F) @ 0.6 Torr (80 Pa) also reported as 80–135 °C (176–275 °F) @ 0.03 Torr (4.0 Pa) |
N,N-Dimethyltryptamine (DMT or N,N-DMT) is a chemical substance that occurs in many plants and animals and which is both a derivative and a structural analog of tryptamine. It can be consumed as a psychedelic drug and has historically been prepared by various cultures for ritual purposes as an entheogen. Rick Strassman labeled it "the spirit molecule". DMT is illegal in most countries.
DMT has a rapid onset, intense effects and a relatively short duration of action. For those reasons, DMT was known as the "businessman's trip" during the 1960s in the United States, as a user could access the full depth of a psychedelic experience in considerably less time than with other substances such as LSD or magic mushrooms. DMT can be inhaled, injected, vaporized or ingested, and its effects depend on the dose. When inhaled or injected, the effects last a short period of time: about 5 to 15 minutes. Effects can last 3 hours or more when orally ingested along with an MAOI, such as the ayahuasca brew of many native Amazonian tribes. DMT can produce vivid "projections" of mystical experiences involving euphoria and dynamic hallucinations of geometric forms.
DMT is a functional analog and structural analog of other psychedelic tryptamines such as O-Acetylpsilocin (4-AcO-DMT), 5-MeO-DMT, bufotenin (5-HO-DMT), psilocybin (4-PO-DMT), and psilocin (4-HO-DMT). The structure of DMT occurs within some important biomolecules like serotonin and melatonin, making them structural analogs of DMT.
Usage
DMT is produced in many species of plants often in conjunction with its close chemical relatives 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and bufotenin (5-OH-DMT). DMT-containing plants are commonly used in indigenous Amazonian shamanic practices. It is usually one of the main active constituents of the drink ayahuasca; however, ayahuasca is sometimes brewed with plants that do not produce DMT. It occurs as the primary psychoactive alkaloid in several plants including Mimosa tenuiflora, Diplopterys cabrerana, and Psychotria viridis. DMT is found as a minor alkaloid in snuff made from Virola bark resin in which 5-MeO-DMT is the main active alkaloid. DMT is also found as a minor alkaloid in bark, pods, and beans of Anadenanthera peregrina and Anadenanthera colubrina used to make Yopo and Vilca snuff, in which bufotenin is the main active alkaloid. Psilocin and its precursor psilocybin, an active chemical in many psilocybin mushrooms, are structurally similar to DMT.
The psychotropic effects of DMT were first studied scientifically by the Hungarian chemist and psychologist Stephen Szára, who performed research with volunteers in the mid-1950s. Szára, who later worked for the US National Institutes of Health, had turned his attention to DMT after his order for LSD from the Swiss company Sandoz Laboratories was rejected on the grounds that the powerful psychotropic could be dangerous in the hands of a communist country.
DMT is generally not active orally unless it is combined with a monoamine oxidase inhibitor (MAOI) such as a reversible inhibitor of monoamine oxidase A (RIMA), for example, harmaline.
Without an MAOI, the body quickly metabolizes orally administered DMT,
and it therefore has no hallucinogenic effect unless the dose exceeds
monoamine oxidase's metabolic capacity. Other means of ingestion such as
vaporizing, injecting, or insufflating
the drug can produce powerful hallucinations for a short time (usually
less than half an hour), as the DMT reaches the brain before it can be
metabolized by the body's natural monoamine oxidase. Taking a MAOI prior
to vaporizing or injecting DMT prolongs and potentiates the effects.
Effects
Subjective psychedelic experiences
Several
scientific experimental studies have tried to measure subjective
experiences of altered states of consciousness induced by drugs under
highly controlled and safe conditions.
In the 1990s, Rick Strassman and his colleagues conducted a five-year-long DMT study at the University of New Mexico.
The results provided insight about the quality of subjective
psychedelic experiences. In this study participants received the DMT
dosage intravenously via injection and the findings suggested that
different psychedelic experiences can occur, depending on the level of
dosage. Lower doses (0.01 and 0.05 mg/kg) produced somaesthetic and
emotional responses, but not hallucinogenic experiences (e.g.,
0.05 mg/kg had mild mood elevating and calming properties).
In contrast, responses produced by higher doses (0.2 and 0.4 mg/kg)
researchers labeled as "hallucinogenic" that elicited "intensely
colored, rapidly moving display of visual images, formed, abstract or
both". Comparing to other sensory modalities the most affected was
visual domain. Participants reported visual hallucinations, less
auditory hallucinations and specific physical sensation progressing to a
sense of bodily dissociation, as well as experiences of euphoria, calm,
fear, and anxiety.
Strassman also stressed the importance of the context where the
drug has been taken. He claimed that DMT has no beneficial effects of
itself, rather the context when and where people take it plays an
important role.
It appears that DMT can produce a hallucinogenic experience. It
can induce a state or feeling to a person that he or she is able to
"communicate with other intelligent-life forms" (see "Machine Elves").
High doses of DMT produce a hallucinatory state that involves sense of
"another intelligence" that people sometimes describe as
"super-intelligent", but "emotionally detached".
In 1995 Adolf Dittrich and Daniel Lamparter did a study where
they found that DMT-induced altered state of consciousness (ASC) is
strongly influenced by habitual, rather than situative factors. In the
study researchers used three dimensions of the APZ questionnaire to
describe ASC (rating scales of ASC). First, oceanic boundlessness (OB)
refers to dissolution of ego boundaries mostly associated with positive
emotions.
Second, anxious ego-dissolution (AED) includes disorder of thoughts,
loss of autonomy and self-control and third, visionary
restructuralization (VR) that includes auditory and visual illusions,
hallucinations.
Results showed strong effects within first and third dimensions for all
conditions, especially DMT and suggested strong intrastability of
elicited reactions independently of the condition for the OB and VR
scales.
Importantly, the experiment was conducted in a safe laboratory
environment. This particular setting had a certain influence on found
results that might be very different outside the laboratory environment.
Induced DMT experiences can include profound time-dilation,
visual and auditory illusions, and other experiences that, by most
firsthand accounts, defy verbal or visual description. Some users report
intense erotic imagery and sensations and utilize the drug in a ritual
sexual context.
Reported encounters with external entities
Entities perceived during DMT inebriation have been represented in diverse forms of psychedelic art. The term machine elf was coined by ethnobotanist Terence McKenna for the entities he encountered in DMT "hyperspace", also using terms like fractal elves, or self-transforming machine elves.
McKenna first encountered the "machine elves" after smoking DMT in
Berkeley in 1965. His subsequent speculations regarding the
hyperdimensional space in which they were encountered, has inspired a
great many artists and musicians, and the meaning of DMT entities has
been a subject of considerable debate among participants in a networked
cultural underground, enthused by McKenna's effusive accounts of DMT
hyperspace. Cliff Pickover has also written about the "machine elf" experience, in the book Sex, Drugs, Einstein, & Elves, while Rick Strassman
notes many similarities between self-reports of his DMT study
participants' encounters with these "entities", and mythological
descriptions of figures such as Chayot Ha Kodesh in Ancient religions, including both angels and demons.
Strassman also argues for a similarity in his study participants'
descriptions of mechanized wheels, gears and machinery in these
encounters, with those described in visions of encounters with the Living Creatures and Ophanim of the Hebrew Bible, noting they may stem from a common neuropsychopharmacological experience.
Strassman argues that the more positive of the "external entities"
encountered in DMT experiences should be understood as analogous to
certain forms of angels:
The medieval Jewish philosophers whom I rely upon for understanding the Hebrew Bible text and its concept of prophecy portray angels as God's intermediaries. That is, they perform a certain function for God. Within the context of my DMT research, I believe that the beings that volunteers see could be conceived of as angelic - that is, previously invisible, incorporeal spiritual forces that are engarbed or enclothed in a particular form - determined by the psychological and spiritual development of the volunteers - bringing a particular message or experience to that volunteer.
However, Strassman's experimental participants also note that some
other entities can subjectively resemble creatures more like insects and
aliens.
As a result, Strassman writes these experiences among his experimental
participants "also left me feeling confused and concerned about where
the spirit molecule was leading us. It was at this point that I began to
wonder if I was getting in over my head with this research."
Hallucinations of strange creatures had been reported by Szara in the Journal of Mental Science (now the British Journal of Psychiatry) (1958) "Dimethyltryptamine Experiments with Psychotics", Stephen Szara
described how one of his subjects under the influence of DMT had
experienced "strange creatures, dwarves or something" at the beginning
of a DMT trip.
Other researchers of the entities seemingly encountered by DMT
users, describe them as "entities" or "beings" in humanoid as well as
animal form, with descriptions of "little people" being common
(non-human gnomes, elves, imps, etc.). Strassman and others have speculated that this form of hallucination may be the cause of alien abduction and extraterrestrial encounter experiences, which may occur through endogenously-occurring DMT.
Likening them to descriptions of rattling and chattering auditory phenomenon described in encounters with the mythical Hayyoth in the Book of Ezekiel,
Rick Strassman notes that participants in his studies, when reporting
encounters with the alleged entities, have also described loud auditory
hallucinations, such as one subject reporting typically "the elves
laughing or talking at high volume, chattering, twittering".
Physical
According
to a dose-response study, "dimethyltryptamine does slightly elevate
blood pressure, heart rate, pupil diameter, and rectal temperature, in
addition to elevating blood concentrations of beta-endorphin, corticotropin, cortisol, and prolactin. Growth hormone blood levels rise equally in response to all doses of DMT, and melatonin levels were unaffected." Research published in Cell Reports states that DMT promotes neural plasticity in rats and flies, making neurons more likely to branch out and connect with one another.
Dependence liability
The
dependence potential of DMT and the risk of sustained psychological
disturbance are minimal when used for religious ceremonies.
DMT, like most psychedelics, is considered to be neither addictive, nor toxic.
Conjecture regarding endogenous effects
In
the 1950s, the endogenous production of psychoactive agents was
considered to be a potential explanation for the hallucinatory symptoms
of some psychiatric diseases; this is known as the transmethylation
hypothesis. Several speculative and yet untested hypotheses suggest that endogenous DMT is produced in the human brain and is involved in certain psychological and neurological states.
DMT is naturally occurring in small amounts in rat brain, human
cerebrospinal fluid, and other tissues of humans and other mammals.
A biochemical mechanism for this was proposed by the medical researcher
J. C. Callaway, who suggested in 1988 that DMT might be connected with
visual dream phenomena: brain DMT levels would be periodically elevated
to induce visual dreaming and possibly other natural states of mind. In 2011, Nicholas V. Cozzi, of the University of Wisconsin School of Medicine and Public Health, concluded that INMT,
an enzyme that may be associated with the biosynthesis of DMT and
endogenous hallucinogens, is present in the primate (rhesus macaque)
pineal gland, retinal ganglion neurons, and spinal cord.
Neurobiologist Andrew Gallimore (2013) suggested that while DMT might
not have a modern neural function, it may have been an ancestral
neuromodulator once secreted in psychedelic concentrations during REM sleep, a function now lost.
Routes of administration
Inhalation
A standard dose for vaporized DMT is 20–40 mg.
In general, this is inhaled in a few successive breaths. The effects
last for a short period of time, usually 5 to 15 minutes, dependent on
the dose. The onset after inhalation is very fast (less than 45 seconds)
and peak effects are reached within a minute. In the 1960s, DMT was
known as a "businessman's trip" in the US because of the relatively
short duration (and rapid onset) of action when inhaled. DMT can be inhaled using a bong or even an e-cigarette.
Injection
In a study conducted from 1990 through 1995, University of New Mexico psychiatrist Rick Strassman found that some volunteers injected with high doses of DMT reported experiences with perceived alien
entities. Usually, the reported entities were experienced as the
inhabitants of a perceived independent reality that the subjects
reported visiting while under the influence of DMT.
In a September 2009 interview, Strassman described the effects on
participants in the study. He stated that "subjectively, the most
interesting results were that high doses of DMT seemed to allow the
consciousness of our volunteers to enter into non-corporeal,
free-standing, independent realms of existence inhabited by beings of
light who oftentimes were expecting the volunteers, and with whom the
volunteers interacted. While 'typical' near-death and mystical states
occurred, they were relatively rare."
Oral ingestion
Ayahuasca preparation
DMT is broken down by the enzyme monoamine oxidase through a process called deamination, and is quickly inactivated orally unless combined with a monoamine oxidase inhibitor (MAOI). The traditional South American beverage ayahuasca, or yage, is derived by boiling the ayahuasca vine (Banisteriopsis caapi) with leaves of one or more plants containing DMT, such as Psychotria viridis, Psychotria carthagenensis, or Diplopterys cabrerana. The Ayahuasca vine contains harmala alkaloids, highly active reversible inihibitors of monoamine oxidase A (RIMAs), rendering the DMT orally active by protecting it from deamination. A variety of different recipes are used to make the brew depending on the purpose of the ayahuasca session, or local availability of ingredients. Two common sources of DMT in the western US are reed canary grass (Phalaris arundinacea) and Harding grass (Phalaris aquatica). These invasive grasses contain low levels of DMT and other alkaloids but also contain gramine, which is toxic and difficult to separate. In addition, Jurema (Mimosa tenuiflora) shows evidence of DMT content: the pink layer in the inner rootbark of this small tree contains a high concentration of N,N-DMT.
Taken orally with an RIMA, DMT produces a long lasting (over 3 hour), slow, deep metaphysical experience similar to that of psilocybin mushrooms, but more intense. RIMAs
should be used with caution as they can have fatal interactions with
some prescription drugs such as SSRI antidepressants, and some
over-the-counter drugs known as sympathomimetics such as Ephedrine or
certain cough medicines and even some herbal remedies .
History
DMT has been used in South America since pre-Columbian times.
DMT was first synthesized in 1931 by chemist Richard Helmuth Fredrick Manske (born 1901 in Berlin, Germany – 1977). In general, its discovery as a natural product is credited to Brazilian chemist and microbiologist Oswaldo Gonçalves de Lima (1908–1989) who, in 1946, isolated an alkaloid he named nigerina (nigerine) from the root bark of jurema preta, that is, Mimosa tenuiflora. However, in a careful review of the case Jonathan Ott shows that the empirical formula
for nigerine determined by Gonçalves de Lima, which notably contains an
atom of oxygen, can match only a partial, "impure" or "contaminated"
form of DMT. It was only in 1959, when Gonçalves de Lima provided American chemists a sample of Mimosa tenuiflora roots, that DMT was unequivocally identified in this plant material. Less ambiguous is the case of isolation and formal identification of DMT in 1955 in seeds and pods of Anadenanthera peregrina by a team of American chemists led by Evan Horning (1916–1993). Since 1955, DMT has been found in a host of organisms: in at least fifty plant species belonging to ten families, and in at least four animal species, including one gorgonian and three mammalian species.
In terms of a scientific understanding, the hallucinogenic
properties of DMT were not uncovered until 1956 by Hungarian chemist and
psychiatrist Stephen Szara. In his paper published the same year titled 'Dimethyltryptamine: its metabolism in man' he references the plant Mimosa hostilis in which he injected the extract into his own muscle.
This is considered to be the converging link between the chemical
structure DMT to its cultural consumption as a psychoactive and
religious sacrament.
Another historical milestone is the discovery of DMT in plants frequently used by Amazonian natives as additive to the vine Banisteriopsis caapi to make ayahuasca
decoctions. In 1957, American chemists Francis Hochstein and Anita
Paradies identified DMT in an "aqueous extract" of leaves of a plant
they named Prestonia amazonicum (sic) and described as "commonly mixed" with B. caapi. The lack of a proper botanical identification of Prestonia amazonica in this study led American ethnobotanist Richard Evans Schultes (1915–2001) and other scientists to raise serious doubts about the claimed plant identity. The mistake likely led the writer William Burroughs to regard the DMT he experimented with in Tangier in 1961 as "Prestonia".
Better evidence was produced in 1965 by French pharmacologist Jacques
Poisson, who isolated DMT as a sole alkaloid from leaves, provided and
used by Agaruna Indians, identified as having come from the vine Diplopterys cabrerana (then known as Banisteriopsis rusbyana). Published in 1970, the first identification of DMT in the plant Psychotria viridis, another common additive of ayahuasca, was made by a team of American researchers led by pharmacologist Ara der Marderosian. Not only did they detect DMT in leaves of P. viridis obtained from Kaxinawá indigenous people, but they also were the first to identify it in a sample of an ayahuasca decoction, prepared by the same indigenous people.
Legal status
International law
DMT is classified as a Schedule I drug under the United Nations 1971 Convention on Psychotropic Substances,
meaning that international trade in DMT is supposed to be closely
monitored; use of DMT is supposed to be restricted to scientific
research and medical use. Natural materials containing DMT, including
ayahuasca, are not regulated under the 1971 Psychotropic Convention.
By country and continent
Asia
Israel – DMT is an illegal substance; production, trade and possession are prosecuted as crimes.
Europe
- France – DMT, along with most of its plant sources, is classified as a stupéfiant (narcotic).
- Germany – DMT is prohibited as a class I drug.
- Republic of Ireland – DMT is an illegal Schedule 1 drug under the Misuse of Drugs Acts. An attempt in 2014 by a member of the Santo Daime church to gain a religious exemption to import the drug failed.
- Latvia — DMT is prohibited as a Schedule I drug.
- Netherlands – The drug is banned as it is classified as a List 1 Drug per the Opium Law. Production, trade and possession of DMT are prohibited.
- Russia – Classified as a Schedule I narcotic, including its derivatives.
- Serbia – DMT, along with stereoisomers and salts is classified as List 4 (Psychotropic substances) substance according to Act on Control of Psychoactive Substances.
- United Kingdom – DMT is classified as a Class A drug.
- Belgium - DMT can't be possessed, sold, purchased or imported. Usage isn't specifically prohibited, but since usage implies possession one could be prosecuted that way.
North America
- Canada – DMT is classified as a Schedule III drug under the Controlled Drugs and Substances Act.
In 2017 the Santo Daime Church Céu do Montréal received religious exemption to use Ayahuasca as a sacrament in their rituals.
- United States – DMT is classified in the United States as a Schedule I drug under the Controlled Substances Act of 1970.
In December 2004, the Supreme Court lifted a stay, thereby allowing the Brazil-based União do Vegetal
(UDV) church to use a decoction containing DMT in their Christmas
services that year. This decoction is a tea made from boiled leaves and
vines, known as hoasca within the UDV, and ayahuasca in different cultures. In Gonzales v. O Centro Espirita Beneficente Uniao do Vegetal,
the Supreme Court heard arguments on November 1, 2005, and unanimously
ruled in February 2006 that the U.S. federal government must allow the
UDV to import and consume the tea for religious ceremonies under the
1993 Religious Freedom Restoration Act.
In September 2008, the three Santo Daime churches filed suit in federal court to gain legal status to import DMT-containing ayahuasca tea. The case, Church of the Holy Light of the Queen v. Mukasey, presided over by Judge Owen M. Panner, was ruled in favor of the Santo Daime church. As of March 21, 2009, a federal judge says members of the church in Ashland can import, distribute and brew ayahuasca. U.S. District Judge Owen Panner
issued a permanent injunction barring the government from prohibiting
or penalizing the sacramental use of "Daime tea". Panner's order said
activities of The Church of the Holy Light of the Queen are legal and
protected under freedom of religion.
His order prohibits the federal government from interfering with and
prosecuting church members who follow a list of regulations set out in
his order.
Oceania
- New Zealand – DMT is classified as a Class A drug under the Misuse of Drugs Act 1975.
Australia
- DMT is listed as a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).[82] A schedule 9 drug is outlined in the Poisons Act 1964 as "Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of the CEO."
Under the Misuse of Drugs act 1981 6.0 g of DMT is considered enough to determine a court of trial and 2.0 g is considered intent to sell and supply.
Between 2011 and 2012, the Australian Federal Government was considering changes to the Australian Criminal Code that would classify any plants containing any amount of DMT as "controlled plants".
DMT itself was already controlled under current laws. The proposed
changes included other similar blanket bans for other substances, such
as a ban on any and all plants containing Mescaline or Ephedrine. The
proposal was not pursued after political embarrassment on realisation
that this would make the official Floral Emblem of Australia, Acacia pycnantha
(Golden Wattle), illegal. The Therapeutic Goods Administration and
federal authority had considered a motion to ban the same, but this was
withdrawn in May 2012 (as DMT may still hold potential entheogenic value
to native and/or religious people).
Chemistry
DMT crystals
DMT is commonly handled and stored as a fumarate, as other DMT acid salts are extremely hygroscopic and will not readily crystallize. Its freebase
form, although less stable than DMT fumarate, is favored by
recreational users choosing to vaporize the chemical as it has a lower
boiling point.
Biosynthesis
Biosynthetic pathway for N,N-dimethyltryptamine
Dimethyltryptamine is an indole alkaloid derived from the shikimate pathway. Its biosynthesis is relatively simple and summarized in the adjacent picture. In plants, the parent amino acid L-tryptophan is produced endogenously where in animals L-tryptophan is an essential amino acid coming from diet. No matter the source of L-tryptophan, the biosynthesis begins with its decarboxylation by an aromatic amino acid decarboxylase (AADC) enzyme (step 1). The resulting decarboxylated tryptophan analog is tryptamine. Tryptamine then undergoes a transmethylation (step 2): the enzyme indolethylamine-N-methyltransferase (INMT) catalyzes the transfer of a methyl group from cofactor S-adenosyl-methionine (SAM), via nucleophilic attack, to tryptamine. This reaction transforms SAM into S-adenosylhomocysteine (SAH), and gives the intermediate product N-methyltryptamine (NMT). NMT is in turn transmethylated by the same process (step 3) to form the end product N,N-dimethyltryptamine. Tryptamine transmethylation is regulated by two products of the reaction: SAH, and DMT were shown ex vivo to be among the most potent inhibitors of rabbit INMT activity.
This transmethylation mechanism has been repeatedly and consistently proven by radiolabeling of SAM methyl group with carbon-14 (14C-CH3)SAM).
Laboratory synthesis
DMT
can be synthesized through several possible pathways from different
starting materials. The two most commonly encountered synthetic routes
are through the reaction of indole with oxalyl chloride followed by reaction with dimethylamine and reduction of the carbonyl functionalities with lithium aluminum hydride to form DMT.
The second commonly encountered route is through the n,n-dimethylation
of tryptamine using formaldehyde followed by reduction with sodium
cyanoborohydride or sodium triacetoxyborohydride. Sodium borohydride is
not used as it reduces the formaldehyde to methanol before it is able to
react with the primary amine of tryptamine.
Clandestine manufacture
DMT during various stages of purification
In a clandestine setting, DMT is not typically synthesized due to the lack of availability of the starting materials, namely tryptamine and oxalyl chloride. Instead, it is more often extracted from plant sources using a non-polar hydrocarbon solvent such as heptane, and a base such as sodium hydroxide,
due to the availability of both the plant source and chemicals. A wide
variety of plants contain DMT at sufficient levels for being viable
sources. Neither the plants nor the chemicals are controlled in most
countries.
Evidence in mammals
Published in Science in 1961, Julius Axelrod found an N-methyltransferase enzyme capable of mediating biotransformation of tryptamine into DMT in a rabbit's lung. This finding initiated a still ongoing scientific interest in endogenous DMT production in humans and other mammals.
From then on, two major complementary lines of evidence have been
investigated: localization and further characterization of the N-methyltransferase enzyme, and analytical studies looking for endogenously produced DMT in body fluids and tissues.
In 2013 researchers first reported DMT in the pineal gland microdialysate of rodents.
A study published in 2014 reported the biosynthesis of
N,N-dimethyltryptamine (DMT) in the human melanoma cell line SK-Mel-147
including details on its metabolism by peroxidases.
In a 2014 paper a group first demonstrated the immunomodulatory potential of DMT and 5-MeO-DMT through the Sigma-1 receptor
of human immune cells. This immunomodulatory activity may contribute to
significant anti-inflammatory effects and tissue regeneration.
Endogenous DMT
The first claimed detection of mammalian endogenous
DMT was published in June 1965: German researchers F. Franzen and H.
Gross report to have evidenced and quantified DMT, along with its structural analog bufotenin (5-HO-DMT), in human blood and urine.
In an article published four months later, the method used in their
study was strongly criticized, and the credibility of their results
challenged.
Few of the analytical methods used prior to 2001 to measure
levels of endogenously formed DMT had enough sensitivity and selectivity
to produce reliable results. Gas chromatography, preferably coupled to mass spectrometry (GC-MS), is considered a minimum requirement. A study published in 2005 implements the most sensitive and selective method ever used to measure endogenous DMT: liquid chromatography-tandem mass spectrometry with electrospray ionization
(LC-ESI-MS/MS) allows for reaching limits of detection (LODs) 12 to 200
fold lower than those attained by the best methods employed in the
1970s. The data summarized in the table below are from studies
conforming to the abovementioned requirements (abbreviations used: CSF =
cerebrospinal fluid; LOD = limit of detection; n = number of samples; ng/L and ng/kg = nanograms (10−9 g) per litre, and nanograms per kilogram, respectively):
A 2013 study found DMT in microdialysate obtained from a rat's pineal gland, providing evidence of endogenous DMT in the mammalian brain.
Detection in body fluids
DMT
may be measured in blood, plasma or urine using chromatographic
techniques as a diagnostic tool in clinical poisoning situations or to
aid in the medicolegal investigation of suspicious deaths. In general,
blood or plasma DMT levels in recreational users of the drug are in the
10–30 μg/L range during the first several hours post-ingestion. Less than 0.1% of an oral dose is eliminated unchanged in the 24-hour urine of humans.
INMT
Before techniques of molecular biology were used to localize indolethylamine N-methyltransferase (INMT),
characterization and localization went on a par: samples of the
biological material where INMT is hypothesized to be active are subject
to enzyme assay. Those enzyme assays are performed either with a radiolabeled methyl donor like (14C-CH3)SAM to which known amounts of unlabeled substrates like tryptamine are added or with addition of a radiolabeled substrate like (14C)NMT to demonstrate in vivo formation.
As qualitative determination of the radioactively tagged product of the
enzymatic reaction is sufficient to characterize INMT existence and
activity (or lack of), analytical methods used in INMT assays are not
required to be as sensitive as those needed to directly detect and
quantify the minute amounts of endogenously formed DMT (see DMT
subsection below). The essentially qualitative method thin layer chromatography (TLC) was thus used in a vast majority of studies. Also, robust evidence that INMT can catalyze transmethylation of tryptamine into NMT and DMT could be provided with reverse isotope dilution analysis coupled to mass spectrometry for rabbit and human lung during the early 1970s.
Selectivity rather than sensitivity proved to be an Achilles'
heel for some TLC methods with the discovery in 1974–1975 that
incubating rat blood cells or brain tissue with (14C-CH3)SAM and NMT as substrate mostly yields tetrahydro-β-carboline derivatives, and negligible amounts of DMT in brain tissue.
It is indeed simultaneously realized that the TLC methods used thus far
in almost all published studies on INMT and DMT biosynthesis are
incapable to resolve DMT from those tetrahydro-β-carbolines. These findings are a blow for all previous claims of evidence of INMT activity and DMT biosynthesis in avian and mammalian brain, including in vivo, as they all relied upon use of the problematic TLC methods:
their validity is doubted in replication studies that make use of
improved TLC methods, and fail to evidence DMT-producing INMT activity
in rat and human brain tissues. Published in 1978, the last study attempting to evidence in vivo
INMT activity and DMT production in brain (rat) with TLC methods finds
biotransformation of radiolabeled tryptamine into DMT to be real but
"insignificant". Capability of the method used in this latter study to resolve DMT from tetrahydro-β-carbolines is questioned later.
To localize INMT, a qualitative leap is accomplished with use of modern techniques of molecular biology, and of immunohistochemistry. In humans, a gene encoding INMT is determined to be located on chromosome 7. Northern blot analyses reveal INMT messenger RNA (mRNA) to be highly expressed in rabbit lung, and in human thyroid, adrenal gland, and lung. Intermediate levels of expression are found in human heart, skeletal muscle, trachea, stomach, small intestine, pancreas, testis, prostate, placenta, lymph node, and spinal cord. Low to very low levels of expression are noted in rabbit brain, and human thymus, liver, spleen, kidney, colon, ovary, and bone marrow. INMT mRNA expression is absent in human peripheral blood leukocytes, whole brain, and in tissue from 7 specific brain regions (thalamus, subthalamic nucleus, caudate nucleus, hippocampus, amygdala, substantia nigra, and corpus callosum). Immunohistochemistry showed INMT to be present in large amounts in glandular epithelial cells of small and large intestines. In 2011, immunohistochemistry revealed the presence of INMT in primate nervous tissue including retina, spinal cord motor neurons, and pineal gland.
Pharmacology
Pharmacokinetics
DMT peak level concentrations (Cmax) measured in whole blood after intramuscular (IM) injection (0.7 mg/kg, n = 11) and in plasma following intravenous (IV) administration (0.4 mg/kg, n = 10) of fully psychedelic doses are in the range of ≈14 to 154 μg/L and 32 to 204 μg/L, respectively.
The corresponding molar concentrations
of DMT are therefore in the range of 0.074–0.818 µM in whole blood and
0.170–1.08 µM in plasma. However, several studies have described active
transport and accumulation of DMT into rat and dog brain following
peripheral administration.
Similar active transport, and accumulation processes likely occur in
human brain and may concentrate DMT in brain by several-fold or more
(relatively to blood), resulting in local concentrations in the
micromolar or higher range. Such concentrations would be commensurate
with serotonin brain tissue concentrations, which have been consistently
determined to be in the 1.5-4 μM range.
Closely coextending with peak psychedelic effects, mean time to reach peak concentrations (Tmax) was determined to be 10–15 minutes in whole blood after IM injection, and 2 minutes in plasma after IV administration. When taken orally mixed in an ayahuasca decoction, and in freeze-dried ayahuasca gel caps, DMT Tmax is considerably delayed: 107.59 ± 32.5 minutes, and 90–120 minutes, respectively.
The pharmacokinetics for vaporizing DMT have not been studied or reported.
Pharmacodynamics
DMT binds non-selectively with affinities < 0.6 μM to the following serotonin receptors: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7. An agonist action has been determined at 5-HT1A, 5-HT2A and 5-HT2C. Its efficacies
at other serotonin receptors remain to be determined. Of special
interest will be the determination of its efficacy at human 5-HT2B receptor as two in vitro assays evidenced DMT's high affinity for this receptor: 0.108 μM and 0.184 μM.
This may be of importance because chronic or frequent uses of
serotonergic drugs showing preferential high affinity and clear agonism
at 5-HT2B receptor have been causally linked to valvular heart disease.
It has also been shown to possess affinity for the dopamine D1, α1-adrenergic, α2-adrenergic, imidazoline-1, and σ1 receptors. Converging lines of evidence established activation of the σ1 receptor at concentrations of 50–100 μM. Its efficacies at the other receptor binding sites are unclear. It has also been shown in vitro to be a substrate for the cell-surface serotonin transporter (SERT) and the intracellular vesicular monoamine transporter 2
(VMAT2), inhibiting SERT-mediated serotonin uptake in human platelets
at an average concentration of 4.00 ± 0.70 μM and VMAT2-mediated
serotonin uptake in vesicles (of army worm Sf9 cells) expressing rat VMAT2 at an average concentration of 93 ± 6.8 μM.
As with other so-called "classical hallucinogens", a large part of DMT psychedelic effects can be attributed to a functionally selective activation of the 5-HT2A receptor. DMT concentrations eliciting 50% of its maximal effect (half maximal effective concentration = EC50 or Kact) at the human 5-HT2A receptor in vitro are in the 0.118–0.983 μM range.
This range of values coincides well with the range of concentrations
measured in blood and plasma after administration of a fully psychedelic
dose.
As DMT has been shown to have slightly better efficacy (EC50) at human serotonin 2C receptor than at the 2A receptor, 5-HT2C is also likely implicated in DMT's overall effects. Other receptors, such as 5-HT1A σ1, may also play a role.
In 2009, it was hypothesized that DMT may be an endogenous ligand for the σ1 receptor. The concentration of DMT needed for σ1 activation in vitro (50–100 μM) is similar to the behaviorally active concentration measured in mouse brain of approximately 106 μM
This is minimally 4 orders of magnitude higher than the average
concentrations measured in rat brain tissue or human plasma under basal
conditions, so σ1
receptors are likely to be activated only under conditions of high
local DMT concentrations. If DMT is stored in synaptic vesicles, such concentrations might occur during vesicular release. To illustrate, while the average concentration of serotonin in brain tissue is in the 1.5-4 μM range, the concentration of serotonin in synaptic vesicles was measured at 270 mM.
Following vesicular release, the resulting concentration of serotonin
in the synaptic cleft, to which serotonin receptors are exposed, is
estimated to be about 300 μM. Thus, while in vitro receptor
binding affinities, efficacies, and average concentrations in tissue or
plasma are useful, they are not likely to predict DMT concentrations in
the vesicles or at synaptic or intracellular receptors. Under these
conditions, notions of receptor selectivity are moot, and it seems
probable that most of the receptors identified as targets for DMT (see
above) participate in producing its psychedelic effects.
