N,N-Dimethyltryptamine (DMT or N,N-DMT) is a psychedelic compound of the tryptamine family. Its presence is widespread throughout the plant kingdom. DMT occurs in trace amounts in mammals, including humans, where it putatively functions as a trace amineneurotransmitter/neuromodulator. It is originally derived from the essential amino acid tryptophan and ultimately produced by the enzyme INMTduring normal metabolism. The significance of its widespread natural presence remains undetermined. Structurally, DMT is analogous to theneurotransmitter serotonin (5-HT), the hormone melatonin, and other psychedelic tryptamines, such as 5-MeO-DMT, bufotenin, psilocin andpsilocybin.
When ingested, DMT acts as a psychedelic drug. Depending on the dose and method of administration, its subjective effects can range from short-lived milder psychedelic states to powerful immersive experiences; these are often described as a total loss of connection to conventional reality with the encounter of ineffable spiritual/alien realms. Indigenous Amazonian Amerindian cultures consume DMT as the primary psychoactive inayahuasca, a shamanistic brew used for divinatory and healing purposes. Pharmacologically, ayahuasca combines DMT with an MAOI, an enzyme inhibitor that allows DMT to be orally active.
History
"DMT is . . . in this flower here, in that tree over there, and in yonder animal. It is, most simply, almost everywhere you choose to look." (Shulgin A. – TIHKAL: Tryptamines I Have Known And Loved)
DMT is most abundant in plants of Latin America. There, humans have known of its amazing properties for some tens of thousands of years. However, it is only in the last 150 years that we have gained some inkling of the antiquity of DMT's relationship with our species.
Beginning in the mid-1800s, explorers of the Amazon, particularly Richard Spruce from England and Alexander von Humboldt from Germany, described the effects of exotic mind-altering snuffs and brews prepared from plants by indigenous tribes. In the twentieth century, the American botanist Richard Schultes continued this dangerous yet exciting line of fieldwork.
These early explorers heard tales of fantastic visions, "out-of-body travel," predictions of the future, location of lost objects, and contact with dead ancestors or other disembodied entities. Another plant mixture, this one consumed as a beverage, seemed to produce similar effects at a slower pace. This brew also went by severa names, including ayahuasca and yajé.
Spruce and von Humboldt brought samples of these New World psychedelic plants back home to Europe. There the plants lay undisturbed for decades, as neither the interest nor the technology existed for further analysis of their chemical makeup or effects.
While psychedelic plants languished in natural history museum archives, Canadian chemist R. Manske, in unrelated research, synthesized a new drug called N,N-dimethyltryptamine, or DMT. As he described in a 1931 scientific article, Manske had made several compounds derived by chemically modifying tryptamine.
The discovery of DMT as a natural product is generally credited to Brazialian chemist Oswaldo Gonçalves de Lima who, in 1946, isolated an alkaloid he names nigerina from the root bark of Mimosa tenuiflora.
In the early 1950s, the discoveries of LSD and serotonin rocked the staid foundations of Freudian psychiatry and laid the groundwork for the new world of neuroscience. Curiosity about psychedelic drugs was intense among the growing circle of scientists who called themselves "psychopharmacologists."
Since 1955 DMT has been found in a host of organisms: in at least 50 plant species belonging to 10 families, and in at least 4 animal species, including one gorgonian and 3 mammalian species.
In 1957, Dr. Stephen Szara discovered the psychedelic effects of DMT by injecting it into himself in his laboratory in Budapest, Hungary.
Despite Szara's and others' steady production of research papers about DMT, it remained mostly a pharmacological curiosity: intense, short-lived, and found in plants. Clearly, LSD had a leg up on DMT when it came to making a significant impression on the psychiatric research community.
This all changed, however, when researchers discovered DMT in the brains of mice and rats, and then uncovered the pathways by which these animals' bodies made this powerful psychedelic.
Did DMT exist in the human body? It seemed likely, because scientists had discovered DMT-forming enzymes in samples of human lung tissue while searching for those same enzymes in other animals.
The race was on. In 1965 two German researcher, F. Franzen and H. Gross, published a paper in the flagship British science journal Nature announcing that they had isolated DMT from human blood. In 1972 Nobel-prize winning scientist Julius Axelrod of the U.S. National Institutes of Health reported finding it in human brain tissue. Additional research showed that DMT could also be found in human urine and the cerebrospinal fluid bathing the brain.
It was not long before scientists discovered the pathways, similar to those in lower animals, by which the human body made DMT.
DMT thus became the first endogenous human psychedelic.
Now, in 2013, maybe for the lack of researches and attention dedicated to this subject, the real function of animal endogenous DMT is still unknown.
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 itsstructural analog bufotenin (5-OH-DMT), in human blood and urine.
In 2001, surveys, made in research articles, point that few of the analytical methods previously used 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 to reach limits of detection (LODs) 12 to 200 fold lower (that is, better) 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):
DMT biosynthesis is relatively simple and summarized in the picture below. 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.
Metabolism
Tryptamine were found to be metabolized by a solubilized and partially purified monoamine oxidase (MAO) preparation. MAO is the only enzyme which catalyzes the deamination of tryptamine.
MAOs belong to the protein family of flavin-containing amine oxidoreductases and in humans there are two types of MAO: MAO-A and MAO-B .
Both are found in neurons and astroglia, while outside the central nervous system: MAO-A is also found in the liver, gastrointestinal tract, and placenta;
MAO-B is mostly found in blood platelets.
The oxidation of tryptamine by the two forms of monoamine oxidase in human tissues
Tryptamine was found to be a substrate for both forms of the enzyme (MAO-A and MAO-B) in human liver, kidney cortex and medulla and in seven different brain regions. The Km (concentration of substrate that leads to half-maximal velocity of enzymes) values of the two forms towards this substrate were similar in all the human tissues examined but the maximum velocities differed. Thus the A-form would contribute approximately 50% of the total monoamine oxidase activity towards this substrate in human cerebral cortex, whereas it would contribute about 60% in kidney cortex and medulla and 75% in liver. These results suggest that both forms of monoamine oxidase would contribute to the metabolism of tryptamine in human tissues.
Pharmacodynamics
DMT binds non-selectively 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.
It has also been shown to possess affinity for the dopamine D1, a1-adrenergic, a2-adrenergic, imidazoline-1, sigma-1 (s1), and trace amine-associated receptors (TAAR).
As with other so-called "classical hallucinogens", a large part of DMT psychedelic effects can be attributed to a specific activation of the 5-HT2A receptor.
As DMT has been shown to have slightly better efficacy (EC50) at human serotonin 2C receptor than at 2A receptor, 5-HT2C highly likely also is implicated in DMT's overall effects. Other receptors, such as 5-HT1A s1, and TAAR1 may also play a role.
Psychotria viridis and Ayahuasca (oral ingestion)
DMT is produced naturally in many species of plants often in conjunction with its close chemical relatives 5-MeO-DMT and bufotenin (5-OH-DMT).
DMT-containing plants are commonly used in South American shamanic practices. It is one of the main active constituents of the drink ayahuasca.
It occurs as the primary psychoactive alkaloid in several plants including Mimosa tenuiflora, Diplopterys cabrerana, and Psychotria viridis.
Dried Psychotria vidris contains about 0.10–0.66% alkaloids. Approximately 99% of that is DMT. Other alkaloids such as beta-carbolines (harmala alkaloids) and N-methyltryptamine (NMT) have been found.
The concentrations of alkaloids in the ayahuasca beverages are, not surprisingly, several times greater than in the source plants from which they are prepared. Based on a quantitative analysis of the major alkaloids in several samples of ayahuasca collected it's been calculated that a 200 ml dose of ayahuasca contained an average of 30 mg of harmine (reversible MAOI beta-carbolines), 10 mg tetrahydroharmine, and 25 mg DMT.
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, harmala alkaloids. Without a MAOI, the body quickly metabolizes orally administered DMT, and it therefore has no psychedelic effect unless the dose exceeds MAOs' metabolic capacity.
Inhalation
A standard dose for vaporized DMT is between 15–60 mg. This is generally 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 lunch" in the US because of the relatively short duration (and rapid onset) of action when smoked.The most common way to administer DMT among people who use it is to vaporize it. The inhalation of DMT is most effectively achieved by vaporizing it through the use of a glass pipe. Combining DMT with plant matter or depositing it upon a substrate of ash also facilitates use of an ordinary smoking pipe or a vaporizer. The vapor is sometimes described as harsh, and some users even compare its flavor and aroma to that of burning plastic or mothballs.
Insufflation
Insufflating DMT (commonly as a freebase or fumarate) requires a higher dose than inhalation. The duration is markedly increased, and some users report diminished euphoria but an intensified otherworldly experience. A dose of approximately 70 to 120 mg of insufflated DMT will induce medium to strong effects. If successful in containing this pain inducing insufflation, the trip should last anywhere from 20 to 50 minutes, with undefinable peak(s).
Injection
Injected DMT produces an experience that is similar to inhalation in duration, intensity, and characteristics.
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 had experiences with perceived alien entities. Usually, the reported entities were experienced as the inhabitants of a perceived independent reality the subjects reported visiting while under the influence of DMT. In a September 2009 interview with Examiner.com, Strassman described the effects on participants in the study: "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."
