other classical psychedelic substances) may be linked to near-death experiences due to the semantic similarity of reports associated with the use of psychoactive compounds and nde narratives, but the study concluded that with the current data it is neither possible to corroborate nor refute the hypothesis that the release of an endogenous ketamine-like neuroprotective agent underlies nde phenomenology. physiological response according to a dose-response study in human subjects, dimethyltryptamine administered intravenously slightly elevated 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." 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. further, mrna for the enzyme necessary for the production of dmt, inmt, are expressed in the human cerebral cortex, choroid plexus, and pineal gland, suggesting an endogenous role in the human brain. in 2011, nicholas v. cozzi, of the university of wisconsin school of medicine and public health, concluded that inmt, an enzyme that is 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. adverse effects mental disorders dmt may trigger adverse psychological reactions, known colloquially as a "bad trip", such as intense fear, paranoia, anxiety, panic attacks, and substance-induced psychosis, particularly in predisposed individuals. addiction and dependence liability dmt, like other serotonergic psychedelics, is considered to be non-addictive with low abuse potential. a study examining substance use disorder for dsm-iv reported that almost no hallucinogens produced dependence, unlike psychoactive drugs of other classes such as stimulants and depressants. at present, there have been no studies that report abstinence syndrome with termination of dmt, and dependence potential of dmt and the risk of sustained psychological disturbance may be minimal when used infrequently; however, the physiological dependence potential of dmt and ayahuasca has not yet been documented convincingly. tolerance unlike other classical psychedelics, studies report that dmt did not exhibit tolerance upon repeated administration of twice a day sessions, separated by 5 hours, for 5 consecutive days; field reports suggests a refractory period of only 15 to 30 minutes, while the plasma levels of dmt was nearly undetectable 30 minutes after intravenous administration. another study of four closely spaced dmt infusion sessions with 30 minute intervals also suggests no tolerance buildup to the psychological effects of the compound, while heart rate responses and neuroendocrine effects were diminished with repeated administration. a fully hallucinogenic dose of dmt did not demonstrate cross-tolerance to human subjects who are highly tolerant to lsd; researches suggest that dmt exhibits unique pharmacological properties compared to other classical psychedelics. long-term use there have been no serious adverse effects reported on long-term use of dmt, apart from acute cardiovascular events. repeated and one-time administration of dmt produces marked changes in the cardiovascular system, with an increase in systolic and diastolic blood pressure; although the changes were not statistically significant, a robust trend towards significance was observed for systolic blood pressure at high doses. drug-interactions dmt is inactive when ingested orally due to metabolism by mao, and beta-carbolines in dmt-containing drinks such as ayahuasca have been found to contain maois, in particular, harmine and harmaline. life-threatening lethalities such as serotonin syndrome (ss) may occur when maois are combined with certain serotonergic medications such as ssri antidepressants. serotonin syndrome has also been reported with tricyclic antidepressants, opiates, analgesic, and antimigraine drugs; it is advised to exercise caution when an individual had used dextromethorphan (dxm), mdma, ginseng, or st. john’s wort recently. routes of administration inhalation a pipe designed to maximize the efficiency of vaporizing dmt a standard dose for vaporized dmt is 20–60 milligrams, depending highly on the efficiency of vaporization as well as body weight and personal variation. in general, this is inhaled in a few successive breaths, but lower doses can be used if the user can inhale it in fewer breaths (ideally one). 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, typically when sandwiched between layers of plant matter, using a specially designed pipe, or by using an e-cigarette once it has been dissolved in propylene glycol and/or vegetable glycerin. some users have also started using vaporizers meant for cannabis extracts ("wax pens") for ease of temperature control when vaporizing crystals. a dmt-infused smoking blend is called changa, and is typically used in pipes or other utensils meant for smoking dried plant matter. 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. 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 three hours), 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 such as dextromethorphan and even some herbal remedies. the intensity of orally administered dmt depends on the type and dose of maoi administered alongside it. when ingested with 120mg of harmine (a rima and member of the harmala alkaloids), 20mg of dmt was reported to have psychoactive effects by author and ethnobotanist jonathan ott. ott reported that to produce a visionary state, the threshold oral dose was 30mg dmt alongside 120mg harmine. this is not necessarily indicative of a standard dose, as dose-dependent effects may vary due to individual variations in drug metabolism. history naturally occurring substances (of both vegetable and animal origin) containing dmt have 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 (including humans). 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 “dimethyltryptamin: its metabolism in man; the relation of its psychotic effect to the serotonin metabolism”, szara employed synthetic dmt, synthesized by the method of speeter and anthony, which was then administered to 20 volunteers by intramuscular injection. urine samples were collected from these volunteers for the identification of dmt metabolites. 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 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 aguaruna 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 internationally dmt is illegal, but ayahuasca and dmt brews and preparations are lawful. dmt is controlled by the convention on psychotropic substances at the international level. the convention makes it illegal to possess, buy, purchase, sell, to retail and to dispense without a licence. by country and continent in some countries ayahuasca is a forbidden or controlled or regulated substance while in other countries it is not a controlled substance or its production, consumption, and sale, is allowed to various degrees. asia israel – dmt is an illegal substance; production, trade and possession are prosecuted as crimes. india – dmt is completely illegal to produce, transport, trade in or possess with a minimum prison or jail punishment of ten years. 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