Dimethyltryptamine: Difference between revisions

{{Short description|Chemical compound}}

| width = 200

| width2 = 170

<!--Physiological data-->| receptors = At least 13 receptors (e.g., serotonin, sigma, trace amine-associated)

<!--Clinical data-->| routes_of_administration = [[Oral administration|By mouth]] (usually with an {{Abbrlink|MAOI|monoamine oxidase inhibitor}}), [[inhalation]], [[insufflation]], [[rectal (medicine)|rectal]], [[Intramuscular injection|intramuscular]], [[intravenous injection|intravenous]]<ref name="CameronOlson2018" /><ref name="CarbonaroGatch2016" /><ref name="RodriguesAlmeidaVieira-Coelho2019" /><ref name="Brito-da-CostaDias-da-SilvaGomes2020" />

| class = [[Serotonergic psychedelic]] ([[hallucinogen]])<ref name="CameronOlson2018" /><ref name="CarbonaroGatch2016" /><ref name="Brito-da-CostaDias-da-SilvaGomes2020" />

<!--Legal status-->| legal_AU = S9

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-07-24 |title=RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |url-status=live |archive-url=https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |archive-date=2023-08-27 |access-date=2023-08-27 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-07-25}}</ref>

<!--Pharmacokinetic data-->| bioavailability = Very low and inactive (except with an {{Abbrlink|MAOI|monoamine oxidase inhibitor}})<ref name="Brito-da-CostaDias-da-SilvaGomes2020" />

| elimination_half-life = * Alone: 5–15{{nbsp}}min<ref name="CameronOlson2018" /><ref name="Brito-da-CostaDias-da-SilvaGomes2020" />

* With an {{Abbrlink|MAOI|monoamine oxidase inhibitor}}: 1–4{{nbsp}}hours<ref name="Brito-da-CostaDias-da-SilvaGomes2020" />

| duration_of_action = * [[Inhalation]]: ≤30{{nbsp}}min<ref name="CarbonaroGatch2016" /><ref name="RodriguesAlmeidaVieira-Coelho2019" />

* [[Intravenous]]: ≤30{{nbsp}}min<ref name="RodriguesAlmeidaVieira-Coelho2019" /><ref name="Barker2022">{{cite journal | vauthors = Barker SA | title = Administration of N,N-dimethyltryptamine (DMT) in psychedelic therapeutics and research and the study of endogenous DMT | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1749–1763 | date = June 2022 | pmid = 35064294 | pmc = 8782705 | doi = 10.1007/s00213-022-06065-0 | url = }}</ref>

* [[Oral administration|Oral]] with {{Abbrlink|MAOI|monoamine oxidase inhibitor}}: 4–6{{nbsp}}hours<ref name="CarbonaroGatch2016" /><ref name="RodriguesAlmeidaVieira-Coelho2019" /><ref name="Brito-da-CostaDias-da-SilvaGomes2020" />

<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}}

| synonyms = Dimethyltryptamine; DMT; ''N'',''N''-DMT

<!--Chemical data-->| IUPAC_name = 2-(1''H''-Indol-3-yl)-''N'',''N''-dimethylethanamine

<!--Physical data-->| density = 1.099

'''Dimethyltryptamine''' ('''DMT'''), also known as '''''N'',''N''-dimethyltryptamine''' ('''''N'',''N''-DMT'''), is a [[Psychedelic drug|serotonergic hallucinogen]] and [[Investigational New Drug|investigational drug]] of the [[substituted tryptamine|tryptamine]] family that [[natural product|occurs naturally]] in many plants and animals.<ref name="CameronOlson2018">{{cite journal | vauthors = Cameron LP, Olson DE | title = Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT) | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2344–2357 | date = October 2018 | pmid = 30036036 | doi = 10.1021/acschemneuro.8b00101 | url = }}</ref><ref name="CarbonaroGatch2016">{{cite journal | vauthors = Carbonaro TM, Gatch MB | title = Neuropharmacology of ''N'',''N''-dimethyltryptamine | journal = Brain Research Bulletin | volume = 126 | issue = Pt 1 | pages = 74–88 | date = September 2016 | pmid = 27126737 | pmc = 5048497 | doi = 10.1016/j.brainresbull.2016.04.016 }}</ref><ref name="RodriguesAlmeidaVieira-Coelho2019">{{cite journal | vauthors = Rodrigues AV, Almeida FJ, Vieira-Coelho MA | title = Dimethyltryptamine: Endogenous Role and Therapeutic Potential | journal = J Psychoactive Drugs | volume = 51 | issue = 4 | pages = 299–310 | date = 2019 | pmid = 31018803 | doi = 10.1080/02791072.2019.1602291 | hdl = 10216/114373 | url = | hdl-access = free }}</ref><ref>{{Cite web | work = PubChem | publisher = U.S. National Library of Medicine |title=Dimethyltryptamine |url=https://pubchem.ncbi.nlm.nih.gov/compound/Dimethyltryptamine |access-date=2025-05-22 |language=en}}</ref> DMT is used as a [[psychedelic drug]] and prepared by various cultures for [[ritual]] purposes as an [[entheogen]].<ref name="McKennaTowers1984">{{cite journal | vauthors = McKenna DJ, Towers GH, Abbott F | title = Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuasca | journal = Journal of Ethnopharmacology | volume = 10 | issue = 2 | pages = 195–223 | date = April 1984 | pmid = 6587171 | doi = 10.1016/0378-8741(84)90003-5 }}</ref>  

DMT has a rapid [[onset of action|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 [[Lysergic acid diethylamide|LSD]] or [[psilocybin mushroom]]s.<ref>{{cite journal | vauthors = Haroz R, Greenberg MI | title = Emerging drugs of abuse | journal = The Medical Clinics of North America | volume = 89 | issue = 6 | pages = 1259–1276 | date = November 2005 | pmid = 16227062 | doi = 10.1016/j.mcna.2005.06.008 | oclc = 610327022 }}</ref> DMT can be inhaled or injected and its effects depend on the dose, as well as the mode of administration. When inhaled or injected, the effects last about five to fifteen minutes. Effects can last three hours or more when orally ingested along with a [[monoamine oxidase inhibitor]] (MAOI), such as the [[Ayahuasca|ayahuasca brew]] of many native [[Amazon rainforest|Amazonian]] tribes.<ref name="Pickover 2005">{{cite book |title=Sex, Drugs, Einstein, and Elves: Sushi, Psychedelics, Parallel Universes, and the Quest for Transcendence | vauthors = Pickover C |year=2005 |publisher=Smart Publications |isbn=978-1-890572-17-4 |url=https://archive.org/details/sexdrugseinstein00clif }}</ref> DMT induces intense, often indescribable subjective experiences involving vivid visual hallucinations, altered [[Perception|sensory perception]], [[Ego death|ego dissolution]], and encounters with seemingly autonomous entities. DMT is generally considered non-addictive with low dependence and no tolerance buildup, but it may cause acute psychological distress or [[Circulatory system|cardiovascular]] effects, especially in predisposed individuals.

DMT was first synthesized in 1931. It is a [[functional analog (chemistry)|functional analog]] and [[structural analog]] of other psychedelic tryptamines such as [[O-acetylpsilocin|''O''-acetylpsilocin]] (4-AcO-DMT),<ref>{{cite journal | vauthors = Jones NT, Wagner L, Hahn MC, Scarlett CO, Wenthur CJ | title = <i>In vivo</i> validation of psilacetin as a prodrug yielding modestly lower peripheral psilocin exposure than psilocybin | language = English | journal = Frontiers in Psychiatry | volume = 14 | page = 1303365 | date = 2024-01-08 | pmid = 38264637 | doi = 10.3389/fpsyt.2023.1303365 | doi-access = free | pmc = 10804612 }}</ref> [[psilocybin]] (4-PO-DMT), [[psilocin]] (4-HO-DMT), [[NB-DMT]], [[5-MeO-DMT|''O''-methylbufotenin]] (5-MeO-DMT), and [[bufotenin]] (5-HO-DMT). Parts of the structure of DMT occur within some important biomolecules like [[serotonin]] and [[melatonin]], making them structural analogs of DMT.  

DMT exhibits broad and variable [[Ligand (biochemistry)|binding affinities]] across numerous receptors, showing its strongest interactions with serotonin receptors, especially [[5-HT2A receptor|5-HT_2A]], [[5-HT1A receptor|5-HT_1A]], and [[5-HT2C receptor|5-HT_2C]], which are believed to mediate its psychedelic effects. [[Endogeny (biology)|Endogenous]] DMT, a psychedelic compound, is naturally produced in mammals, with evidence showing its synthesis and presence in brain and body tissues, though its exact roles and origins remain debated. DMT is internationally illegal without authorization, with most countries banning its possession and trade, though some allow religious use of ayahuasca, a DMT-containing [[decoction]]. Short-acting psychedelics like DMT are considered [[scalability|scalable]] alternatives to longer-acting drugs like [[psilocybin]] for potential clinical use.<ref name="Ramaekers2025" /><ref name="RamaekersReckwegMason2025" /> DMT is currently undergoing [[clinical trial]]s for [[treatment-resistant depression]].<ref name="LucidoDunlop2025">{{cite journal | vauthors = Lucido MJ, Dunlop BW | title = Emerging Medications for Treatment-Resistant Depression: A Review with Perspective on Mechanisms and Challenges | journal = Brain Sci | volume = 15 | issue = 2 | date = February 2025 | page = 161 | pmid = 40002494 | pmc = 11853532 | doi = 10.3390/brainsci15020161 | doi-access = free | url = }}</ref>

==Use==

 

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).<ref name = "ISBN 0789026422"/> DMT-containing plants are commonly used in [[Shamanism#Amazonia|indigenous Amazonian shamanic practices]]. It is usually one of the main active constituents of the drink [[ayahuasca]];<ref name="RivierLindgren1972">{{cite journal | vauthors = Rivier L, Lindgren JE |title='Ayahuasca,' the South American hallucinogenic drink: An ethnobotanical and chemical investigation |journal=Economic Botany |volume=26 |issue=2 |year=1972 |pages=101–129 |issn=0013-0001 |doi=10.1007/BF02860772 |s2cid=34669901}}</ref><ref name="McKennaTowers1984"/> 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 [[hallucinogenic snuff]]s made from ''[[Virola]]'' bark resin in which 5-MeO-DMT is the main active alkaloid.<ref name = "ISBN 0789026422"/> DMT is also found as a minor alkaloid in bark, pods, and beans of ''[[Anadenanthera peregrina]]'' and ''[[Anadenanthera colubrina]]'' used to make [[Yopo]] and [[Anadenanthera colubrina|Vilca]] snuff, in which bufotenin is the main active alkaloid.<ref name="ISBN 0789026422">{{cite book |title=Anadenanthera: Visionary Plant Of Ancient South America |url=https://archive.org/details/anadenantheravis00torr_088 |url-access=limited | vauthors = Torres CM, Repke DB |year=2006 |publisher=Haworth Herbal |location=Binghamton, NY |isbn=978-0-7890-2642-2 |pages=[https://archive.org/details/anadenantheravis00torr_088/page/n126 107]–122}}</ref><ref name="pmid11718320">{{cite journal | vauthors = Ott J | title = Pharmañopo-psychonautics: human intranasal, sublingual, intrarectal, pulmonary and oral pharmacology of bufotenine | journal = Journal of Psychoactive Drugs | volume = 33 | issue = 3 | pages = 273–281 | year = 2001 | pmid = 11718320 | doi = 10.1080/02791072.2001.10400574 | s2cid = 5877023 | url = http://files.shroomery.org/attachments/8588382-pharmanopo_J_Ott_2001_J_Psych_Drug.pdf | access-date = 2010-11-16 | archive-date = 2011-07-26 | archive-url = https://web.archive.org/web/20110726003945/http://files.shroomery.org/attachments/8588382-pharmanopo_J_Ott_2001_J_Psych_Drug.pdf | url-status = live }}</ref> [[Psilocin]] and [[psilocybin]], the main psychoactive compounds in [[psilocybin mushroom]]s, 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 United States [[National Institutes of Health]], researched DMT after his order to acquire [[LSD]] from the Swiss company [[Sandoz Laboratories]] was rejected on the grounds that the powerful psychotropic could be dangerous in the hands of a [[Hungarian People's Republic|communist country]].<ref name="strassman">{{cite book|title=DMT: The Spirit Molecule. A Doctor's Revolutionary Research into the Biology of Near-Death and Mystical Experiences|vauthors=Strassman RJ|publisher=Park Street|year=2001|isbn=978-0-89281-927-0|location=Rochester, VT|author-link=Rick Strassman|url=https://archive.org/details/dmtspiritmolecul00rick}} ({{cite web|url=http://rickstrassman.com/index.php?option=com_content&view=article&id=61&Itemid=60|title=Chapter summaries|access-date=27 February 2012|archive-date=16 May 2016|archive-url=https://web.archive.org/web/20160516020600/https://www.rickstrassman.com/index.php?id=61&itemid=60&option=com_content&view=article|url-status=live}})</ref>

 

DMT is generally not active orally unless it is combined with a monoamine oxidase inhibitor such as a reversible inhibitor of monoamine oxidase A (RIMA), for example, [[harmaline]].<ref name="McKennaTowers1984"/> Without a MAOI, the body quickly metabolizes orally administered DMT, and it therefore has no hallucinogenic effect unless the dose exceeds the body's monoamine oxidase's metabolic capacity. Other means of consumption such as vaporizing, injecting, or [[Insufflation (medicine)|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 an MAOI prior to vaporizing or injecting DMT prolongs and enhances the effects.<ref name="DMT_Erowid">{{cite web |title=Erowid DMT (Dimethyltryptamine) Vault |url=http://www.erowid.org/chemicals/dmt/dmt.shtml |url-status=live |archive-url=https://web.archive.org/web/20220609072438/https://www.erowid.org/chemicals/dmt/dmt.shtml |archive-date=9 June 2022 |access-date=20 September 2012 |publisher=Erowid.org}}</ref>

 

 

A standard dose for vaporized DMT is 20-60&nbsp;milligrams, depending highly on the efficiency of vaporization as well as body weight and personal variation.<ref>{{cite web|url=https://erowid.org/chemicals/dmt/dmt_dose.shtml|title=DMT Dosage|website=[[Erowid]]|access-date=25 June 2018|archive-date=25 June 2018|archive-url=https://web.archive.org/web/20180625185707/https://erowid.org/chemicals/dmt/dmt_dose.shtml|url-status=live}}</ref><ref name="TiHKAL" />{{medical citation needed | date = June 2023}} 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.<ref>{{cite journal | vauthors = Haroz R, Greenberg MI | title = Emerging drugs of abuse | journal = The Medical Clinics of North America | volume = 89 | issue = 6 | pages = 1259–1276 | date = November 2005 | pmid = 16227062 | doi = 10.1016/j.mcna.2005.06.008 | quote = Use of DMT was first encountered in the United States in the 1960s, when it was known as a 'businessman's trip' because of the rapid onset of action when smoked (2 to 5 minutes) and short duration of action (20 minutes to 1 hour). | oclc = 610327022 }}</ref> 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.<ref>{{Cite web|vauthors=Power M|date=5 June 2020|title=I Sell DMT Vape Pens So People Can 'Break Through' at Their Own Speed|url=https://www.vice.com/en/article/i-sell-dmt-vape-pens-so-people-can-break-through-at-their-own-speed/|access-date=12 July 2020|website=Vice.com|language=en|archive-date=12 July 2020|archive-url=https://web.archive.org/web/20200712192852/https://www.vice.com/en_uk/article/akzgbz/i-sell-dmt-vape-pens-so-people-can-break-through-at-their-own-speed|url-status=live}}</ref> 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 (drug)|Changa]], and is typically used in pipes or other utensils meant for smoking dried plant matter.{{cn|date=June 2023}}

 

 

In 2023, a study investigated a novel method of DMT administration involving a bolus injection paired with a constant-rate infusion, with the goal of extending the DMT experience.<ref>{{cite journal | vauthors = Luan LX, Eckernäs E, Ashton M, Rosas FE, Uthaug MV, Bartha A, Jagger S, Gascon-Perai K, Gomes L, Nutt DJ, Erritzøe D, Carhart-Harris RL, Timmermann C | title = Psychological and physiological effects of extended DMT | journal = Journal of Psychopharmacology | volume = 38 | issue = 1 | pages = 56–67 | date = January 2024 | pmid = 37897244 | pmc = 10851633 | doi = 10.1177/02698811231196877 }}</ref>

The dose range of DMT via bolus intravenous injection is 4 to 30{{nbsp}}mg.<ref name="TiHKAL" /> By constant infusion, the dose is 0.6 to 1.8{{nbsp}}mg per minute.<ref name="LiechtiHolze2022">{{cite book | vauthors = Liechti ME, Holze F | title = Disruptive Psychopharmacology | chapter = Dosing Psychedelics and MDMA | series = Curr Top Behav Neurosci | volume = 56 | pages = 3–21 | date = 2022 | pmid = 34734392 | doi = 10.1007/7854_2021_270 | isbn = 978-3-031-12183-8 | chapter-url = https://www.researchgate.net/publication/355943062}}</ref><ref name="HolzeSinghLiechti2024">{{cite journal | vauthors = Holze F, Singh N, Liechti ME, D'Souza DC | title = Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile | journal = Biol Psychiatry Cogn Neurosci Neuroimaging | volume = 9 | issue = 5 | pages = 472–489 | date = May 2024 | pmid = 38301886 | doi = 10.1016/j.bpsc.2024.01.007 | url = | doi-access = free }}</ref>

====Intramuscular or subcutaneous injection====

Threshold activity occurs at a dose of 30{{nbsp}}mg [[intramuscular injection|intramuscularly]] and full effects occur at a dose of 50 to 100{{nbsp}}mg by this route.<ref name="Shulgin1976" /><ref name="TiHKAL" /> The dose for full effects with [[subcutaneous injection]] is likewise 60 to 100{{nbsp}}mg.<ref name="Shulgin1976" />

====Oral====

{{See also|Ayahuasca|Pharmahuasca}}

[[File:Aya-preparation.jpg|thumb|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).<ref name="McKennaTowers1984"/> The traditional South American beverage [[ayahuasca]] is derived by boiling ''[[Banisteriopsis caapi]]'' with leaves of one or more plants containing DMT, such as ''[[Psychotria viridis]]'', ''[[Psychotria carthagenensis]]'', or ''[[Diplopterys cabrerana]]''.<ref name="McKennaTowers1984"/> The ''Banisteriopsis caapi'' contains [[harmala alkaloids]],<ref name="pmid9924842">{{cite journal | vauthors = Callaway JC, Grob CS | title = Ayahuasca preparations and serotonin reuptake inhibitors: a potential combination for severe adverse interactions | journal = Journal of Psychoactive Drugs | volume = 30 | issue = 4 | pages = 367–269 | year = 1998 | pmid = 9924842 | doi = 10.1080/02791072.1998.10399712 | url = http://www.mimosahostilis.com/files/Ayahuasca%20and%20SSRI%20Interactions.pdf | access-date = 10 April 2012 | archive-url = https://web.archive.org/web/20120201144245/http://www.mimosahostilis.com/files/Ayahuasca%20and%20SSRI%20Interactions.pdf | archive-date = 1 February 2012 }}</ref> a highly active reversible inhibitor of monoamine oxidase A ([[Reversible inhibitor of monoamine oxidase A|RIMA]]s),<ref name="BergströmWesterberg1997">{{cite journal | vauthors = Bergström M, Westerberg G, Långström B | title = ¹¹C-harmine as a tracer for monoamine oxidase A (MAO-A): in vitro and in vivo studies | journal = Nuclear Medicine and Biology | volume = 24 | issue = 4 | pages = 287–293 | date = May 1997 | pmid = 9257326 | doi = 10.1016/S0969-8051(97)00013-9 }}</ref> rendering the DMT orally active by protecting it from [[deamination]].<ref name="McKennaTowers1984"/> A variety of different recipes are used to make the brew depending on the purpose of the ayahuasca session,<ref name="Andritzky1989">{{cite journal | vauthors = Andritzky W | title = Sociopsychotherapeutic functions of ayahuasca healing in Amazonia | journal = Journal of Psychoactive Drugs | volume = 21 | issue = 1 | pages = 77–89 | year = 1989 | pmid = 2656954 | doi = 10.1080/02791072.1989.10472145 | url = http://www.lila.info/document_view.phtml?document_id=8 | archive-url = https://web.archive.org/web/20080226052014/http://www.lila.info/document_view.phtml?document_id=8 | archive-date = 26 February 2008 }}</ref> 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, [[Mimosa tenuiflora|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.{{citation needed|date=December 2014}}

Taken orally with an [[Reversible inhibitor of monoamine oxidase A|RIMA]], DMT produces a long-lasting (over three hours), slow, deep metaphysical experience similar to that of [[psilocybin mushrooms]], but more intense.<ref name=Peru>{{cite web |url=http://www.kirasalak.com/Peru.html |title=Hell and back |vauthors=Salak K |publisher=National Geographic Adventure |access-date=2008-10-31 |archive-date=2019-09-11 |archive-url=https://web.archive.org/web/20190911140217/http://www.kirasalak.com/Peru.html |url-status=live }}</ref>

The intensity of orally administered DMT depends on the type and dose of MAOI administered alongside it. When ingested with 120&nbsp;mg of [[harmine]] (a [[Reversible inhibition of monoamine oxidase|RIMA]] and member of the [[Harmala alkaloid|harmala alkaloids]]), 20&nbsp;mg of DMT was reported to have psychoactive effects by author and [[Ethnobotany|ethnobotanist]] [[Jonathan Ott]]. Ott reported that to produce a visionary state, the threshold oral dose was 30&nbsp;mg DMT alongside 120&nbsp;mg [[harmine]].<ref name="ott1998" /> This is not necessarily indicative of a standard dose, as dose-dependent effects may vary due to individual variations in drug metabolism.

Without an MAOI, DMT is inactive orally at doses over 1,000{{nbsp}}mg.<ref name="Shulgin1976" /><ref name="TiHKAL" />

==Effects==

{{See also|Ayahuasca#Effects}}

Subjective experiences of DMT includes profound time-dilatory, visual, auditory, tactile, and proprioceptive distortions and hallucinations, and other experiences that, by most firsthand accounts, defy verbal or visual description.<ref name="pmid8297217">{{cite journal | vauthors = Strassman RJ, Qualls CR, Uhlenhuth EH, Kellner R | title = Dose-response study of ''N'',''N''-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale | journal = Archives of General Psychiatry | url = https://jamanetwork.com/journals/jamapsychiatry/article-abstract/496497 | volume = 51 | issue = 2 | pages = 98–108 | date = February 1994 | pmid = 8297217 | doi = 10.1001/archpsyc.1994.03950020022002 | access-date = 2023-05-05 | archive-date = 2023-05-05 | archive-url = https://web.archive.org/web/20230505025912/https://jamanetwork.com/journals/jamapsychiatry/article-abstract/496497 | url-status = live | url-access = subscription }}</ref> Examples include perceiving [[hyperbolic geometry]] or seeing [[M. C. Escher|Escher]]-like [[impossible object]]s.<ref name="Hyperbolic Geometry of DMT Experiences">{{cite speech | vauthors = Gómez Emilsson A |title=The Hyperbolic Geometry of DMT Experiences |event=Harvard Science of Psychedelics Club |date=5 October 2019 |location=Harvard University, Cambridge, Massachusetts |publisher=Qualia Research Institute |url=https://www.youtube.com/watch?v=loCBvaj4eSg | archive-url=https://ghostarchive.org/varchive/youtube/20211211/loCBvaj4eSg| archive-date=2021-12-11 | url-status=live|access-date=27 April 2020 |language=en}}{{cbignore}}</ref>

[[Rick Strassman]] and his colleagues conducted a five-year-long DMT study at the [[University of New Mexico]] in the 1990s.<ref name="pmid8297216">{{cite journal | vauthors = Strassman RJ, Qualls CR | title = Dose-response study of ''N'',''N''-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects | journal = Archives of General Psychiatry | volume = 51 | issue = 2 | pages = 85–97 | date = February 1994 | pmid = 8297216 | doi = 10.1001/archpsyc.1994.03950020009001 }}</ref> The results provided insight about the quality of subjective psychedelic experiences. In this study participants received the DMT dosage via intravenous injection and the findings suggested that different psychedelic experiences can occur, depending on the level of dosage. Lower doses (0.01 and 0.05&nbsp;mg/kg) produced some aesthetic and emotional responses, but not hallucinogenic experiences (e.g., 0.05&nbsp;mg/kg had mild mood elevating and calming properties).<ref name="pmid8297216" /> In contrast, responses produced by higher doses (0.2 and 0.4&nbsp;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 the visual. Participants reported visual hallucinations, fewer auditory hallucinations and specific physical sensations progressing to a sense of bodily dissociation, as well as experiences of euphoria, calm, fear, and anxiety.<ref name="pmid8297216" /> These dose-dependent effects match well with anonymously posted "trip reports" online, where users report "breakthroughs" above certain doses.<ref>{{Cite web|title=DMT – How and Why to Get Off|url=https://users.aalto.fi/~saarit2/deoxy/gz_howy.htm|access-date=2021-03-24|website=users.aalto.fi|archive-date=2021-01-26|archive-url=https://web.archive.org/web/20210126233623/https://users.aalto.fi/%7Esaarit2/deoxy/gz_howy.htm}}</ref><ref>{{Cite journal| vauthors = St John G |date=2018|title=The Breakthrough Experience: DMT Hyperspace and its Liminal Aesthetics |journal=Anthropology of Consciousness|language=en|volume=29|issue=1|pages=57–76|doi=10.1111/anoc.12089|issn=1556-3537}}</ref><ref>{{Cite web|title=DMT – Erowid Exp – 'Break Through'|url=https://erowid.org/experiences/exp.php?ID=86700|access-date=2021-03-24|website=erowid.org|archive-date=2021-03-23|archive-url=https://web.archive.org/web/20210323022931/https://www.erowid.org/experiences/exp.php?ID=86700|url-status=live}}</ref>

Strassman also highlighted 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.<ref name="strassman" /><ref name="pmid8297216" />

It appears that DMT can induce a state or feeling wherein the person believes to "communicate with other intelligent lifeforms" (see "[[#Entity encounters|Entity encounters]]" below). High doses of DMT produce a state that involves a sense of "another intelligence" that people sometimes describe as "super-intelligent", but "emotionally detached".<ref name="pmid8297216" />

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''.<ref>{{cite book | vauthors = Strassman R |title= DMT: the Spirit Molecule: A Doctor's Revolutionary Research into the Biology of near-Death and Mystical Experiences |year=2001 |isbn=978-0-89281-927-0 |pages=[https://archive.org/details/dmtspiritmolecul00rick/page/187 187–188, also pp.173–174] |quote=I had expected to hear about some of these types of experiences once we began giving DMT. I was familiar with Terence McKenna's tales of the "self-transforming machine elves" he encountered after smoking high doses of the drug. Interviews conducted with twenty experienced DMT smokers before beginning the New Mexico research also yielded some tales of similar meetings with such entities. Since most of these people were from California, I admittedly chalked up these stories to some kind of West Coast eccentricity |url=https://archive.org/details/dmtspiritmolecul00rick/page/187 }}</ref><ref>{{cite book |title=The Invisible Landscape: Mind, Hallucinogens and the I Ching | vauthors = Oeric ON, McKenna T |year=1975 | publisher = Seabury Press | isbn = 978-0-8164-9249-7 }}</ref> 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 have 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.<ref>{{cite book | vauthors = St John G | chapter = Chapters 4, 8, and 12 |title=Mystery School in Hyperspace: A Cultural History of DMT |date=2015 |publisher= North Atlantic Books / Evolver Editions |location=Berkeley, California |isbn=978-1-58394-732-6}}</ref> [[Cliff Pickover]] has also written about the "machine elf" experience, in the book ''Sex, Drugs, Einstein, & Elves''.<ref name="Pickover 2005" /> Strassman noted similarities between self-reports of his DMT study participants' encounters with these "entities", and mythological descriptions of figures such as [[living creatures (Bible)|Ḥayyot haq-Qodesh]] in ancient religions, including both angels and demons.<ref name="Prophecy 2014">{{cite book | title = DMT and the Soul of Prophecy: A New Science of Spiritual Revelation in the Hebrew Bible | vauthors = Strassman R | publisher = Simon and Schuster | date = 2014 | isbn = 978-1-62055-168-4 }}</ref> 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 (Bible)|Living Creatures]] and [[Ophanim]] of the Hebrew Bible, noting they may stem from a common [[Neuropsychopharmacology|neuropsychopharmacological]] experience.<ref name="Prophecy 2014"/>

Strassman argues that the more positive of the "external entities" encountered in DMT experiences should be understood as analogous to certain forms of angels: {{blockquote|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.<ref>{{cite web | url = https://boingboing.net/2011/05/03/strassman.html | title = Interview: Dr. Rick Strassman | vauthors = Solomon A | date = 3 May 2011 | work = Boing Boing | access-date = 11 November 2018 | archive-date = 26 May 2024 | archive-url = https://web.archive.org/web/20240526041615/https://boingboing.net/2011/05/03/strassman.html | url-status = live }}</ref>}}

Strassman's experimental participants also note that some other entities can subjectively resemble creatures more like insects and aliens.<ref>{{cite book | vauthors = Strassman R |title=DMT: the Spirit Molecule: A Doctor's Revolutionary Research into the Biology of Near-Death and Mystical Experiences |year=2001 |isbn=978-0-89281-927-0 |pages=[https://archive.org/details/dmtspiritmolecul00rick/page/206 206–208] |url=https://archive.org/details/dmtspiritmolecul00rick/page/206 }}</ref> 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."<ref>{{cite book | vauthors = Strassman R |title=DMT: the Spirit Molecule: A Doctor's Revolutionary Research into the Biology of near-Death and Mystical Experiences |year=2001 |isbn=978-0-89281-927-0 |pages=[https://archive.org/details/dmtspiritmolecul00rick/page/202 202] |url=https://archive.org/details/dmtspiritmolecul00rick/page/202 }}</ref>

Hallucinations of strange creatures had been reported by Stephen Szara in a 1958 study in psychotic patients, in which he 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.<ref>{{cite web |url=http://www.redicecreations.com/article.php?id=12496 |title=Causal Multiplicity: The Science Behind Schizophrenia |date=10 September 2010 |vauthors=Hanks MA |access-date=18 November 2014 |archive-date=29 November 2014 |archive-url=https://web.archive.org/web/20141129020944/http://www.redicecreations.com/article.php?id=12496 |url-status=live }}</ref><ref>{{cite web|url=http://www.buildingalienworlds.com/uploads/5/7/9/9/57999785/dmt_research_1956_edge_time_arg_dpl_final.pdf |archive-url=https://web.archive.org/web/20160324035110/http://www.buildingalienworlds.com/uploads/5/7/9/9/57999785/dmt_research_1956_edge_time_arg_dpl_final.pdf |archive-date=2016-03-24 |url-status=live |title=DMT research from 1956 to the edge of time |date=15 December 2015 | vauthors = Gallimore AR, Luke DP }}</ref>

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.).<ref name="Gallimore">{{cite journal |vauthors=Gallimore, A |title=Evolutionary Implications of the Astonishing Psychoactive Effects of ''N'',''N''-Dimethyltryptamine (DMT) |journal=[[Journal of Scientific Exploration]] |volume=27 |issue=3 |pages=455–503 |date=2013 |url=https://www.researchgate.net/publication/277281153 |access-date=2016-08-15 |archive-date=2024-05-26 |archive-url=https://web.archive.org/web/20240526041619/https://www.researchgate.net/publication/277281153_ESSAY_Building_Alien_Worlds-_The_Neuropsychological_and_Evolutionary_Implications_of_the_Astonishing_Psychoactive_Effects_of_NN-Dimethyltryptamine_DMT |url-status=live }}{{unreliable source?|date=February 2020}}</ref><ref>{{Cite web |date=2022-02-21 |title=New study offers a detailed glimpse into the otherworldly encounters produced by the psychedelic drug DMT |url=https://www.psypost.org/2022/02/new-study-offers-a-detailed-glimpse-into-the-otherworldly-encounters-produced-by-the-psychedelic-drug-dmt-62617 |access-date=2022-05-25 |website=PsyPost |language=en-US }}</ref> 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 [[Endogeny (biology)|endogenously]]-occurring DMT.<ref>{{cite journal |vauthors=Luke DP |year=2011 |title=Discarnate entities and dimethyltryptamine (DMT): Psychopharmacology, phenomenology and ontology |url=https://www.scribd.com/doc/70007742/Discarnate-Entities |journal=Journal of the Society for Psychical Research |volume=75 |number=902 |pages=26–42 |access-date=2017-09-10 |archive-date=2016-04-09 |archive-url=https://web.archive.org/web/20160409215620/https://www.scribd.com/doc/70007742/Discarnate-Entities |url-status=live }}</ref><ref>{{cite journal | vauthors = Luke DP |year=2012 |title=Psychoactive substances and paranormal phenomena: A comprehensive review |journal=International Journal of Transpersonal Studies |volume=31 |pages=97–156 |doi=10.24972/ijts.2012.31.1.97 |doi-access=free }}</ref>

Likening them to descriptions of rattling and chattering auditory phenomena described in encounters with the [[Angels in Judaism#Angelic hierarchy|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".<ref name="Prophecy 2014"/>

====Near-death experience====

A 2018 study found significant relationships between a DMT experience and a [[near-death experience]] (NDE).<ref>{{cite journal | vauthors = Timmermann C, Roseman L, Williams L, Erritzoe D, Martial C, Cassol H, Laureys S, Nutt D, Carhart-Harris R | title = DMT Models the Near-Death Experience | journal = Frontiers in Psychology | volume = 9 | page = 1424 | year = 2018 | pmid = 30174629 | pmc = 6107838 | doi = 10.3389/fpsyg.2018.01424 | doi-access = free }}</ref> A 2019 large-scale study pointed that [[ketamine]], ''[[Salvia divinorum]]'', and DMT (and other classical psychedelic substances) may be linked to [[near-death experience]]s 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.<ref>{{cite journal | vauthors = Martial C, Cassol H, Charland-Verville V, Pallavicini C, Sanz C, Zamberlan F, Vivot RM, Erowid F, Erowid E, Laureys S, Greyson B, Tagliazucchi E | title = Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports | journal = Consciousness and Cognition | volume = 69 | pages = 52–69 | date = March 2019 | pmid = 30711788 | doi = 10.1016/j.concog.2019.01.011 | s2cid = 73432875 | hdl = 2268/231971 | hdl-access = free }}</ref>

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."<ref name="pmid8297216" />

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.<ref name="pmid13152519">{{cite journal | vauthors = Hoffer A, Osmond H, Smythies J | title = Schizophrenia; a new approach. II. Result of a year's research | journal = The Journal of Mental Science | volume = 100 | issue = 418 | pages = 29–45 | date = January 1954 | pmid = 13152519 | doi = 10.1192/bjp.100.418.29 }}</ref> 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.<ref>{{cite web | url=https://www.sbs.com.au/news/dmt-the-psychedelic-drug-produced-in-your-brain | title=DMT: The psychedelic drug 'produced in your brain' | publisher=SBS | date=8 November 2013 | access-date=27 March 2014 | archive-date=27 September 2020 | archive-url=https://web.archive.org/web/20200927161206/https://www.sbs.com.au/news/dmt-the-psychedelic-drug-produced-in-your-brain | url-status=live }}</ref> DMT is naturally occurring in small amounts in rat brains, human cerebrospinal fluid, and other tissues of humans and other mammals.<ref name="pmid16095048" /><ref name="pmid289421" /><ref name="pmid20877" /><ref>{{cite news |url=https://www.npr.org/templates/story/story.php?storyId=104240746&sc=fb&cc=fp |title=The God Chemical: Brain Chemistry And Mysticism |newspaper=NPR.org |publisher=NPR |access-date=20 September 2012 |archive-date=8 January 2014 |archive-url=https://web.archive.org/web/20140108195911/http://www.npr.org/templates/story/story.php?storyId=104240746&sc=fb&cc=fp |url-status=live }}</ref> 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.<ref name = "Dean_2019">{{cite journal | vauthors = Dean JG, Liu T, Huff S, Sheler B, Barker SA, Strassman RJ, Wang MM, Borjigin J | title = Biosynthesis and Extracellular Concentrations of ''N'',''N''-Dimethyltryptamine (DMT) in Mammalian Brain | journal = Scientific Reports | volume = 9 | issue = 1 | page = 9333 | date = June 2019 | pmid = 31249368 | doi = 10.1038/s41598-019-45812-w | pmc = 6597727 | bibcode = 2019NatSR...9.9333D | doi-access = free }}</ref> In 2011, Nicholas Cozzi of the [[University of Wisconsin School of Medicine and Public Health]], and three other researchers, concluded that INMT, an enzyme that is associated with the biosynthesis of DMT and endogenous hallucinogens is present in the non-human primate ([[rhesus macaque]]) pineal gland, retinal ganglion neurons, and spinal cord.<ref name="Cozzi N.V., Mavlyutov T.A., Thompson M.A., Ruoho A.E. 2011 840.19" /> 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 [[Rapid eye movement sleep|REM sleep]], a function now lost.<ref name="Gallimore" />

DMT may trigger psychological reactions, known colloquially as a "[[bad trip]]", such as intense fear, paranoia, anxiety, [[panic attacks|panic-attacks]], and [[substance-induced psychosis]], particularly in predisposed individuals.<ref name="pmid29366418" /><ref name="pmid28868040">{{cite journal | title = Novel Psychoactive Substances-Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs | journal = Front Psychiatry | pmid = 28868040 | vauthors = Zurina H, Oliver B, Darshan S, Suresh N, Vicknasingam K, Erich S, Johannes K, Borid Q, and Christian M | doi = 10.3389/fpsyt.2017.00152 | date = 18 August 2017 | volume = 8 | page = 152 | pmc = 5563308 | doi-access = free }}</ref>{{better citation needed|reason=Both of these references refer to ayahuasca; it's doubtful that DMT alone (smoked or by injection) actually lasts long enough for people with normal MAO levels to cause anything but brief fear at the worst due to the suddeness of the experience. These things are also considered part of the ayahuasca experience among other side effects DMT doesn't have by some and either better references are needed or this should be removed and kept on the ayahuasca article.|date=May 2025}}

DMT, like other serotonergic psychedelics, is considered to be non-addictive with low abuse potential.<ref name="pmid8297217" /> A study examining [[substance use disorder]] for [[Diagnostic_and_Statistical_Manual_of_Mental_Disorders|DSM-IV]] reported that almost no hallucinogens produced dependence, unlike psychoactive drugs of other classes such as [[stimulants]] and [[depressant]]s.<ref name="pmid29366418">{{cite journal | journal = Current Neuropharmacology | volume = 17 | issue = 2 | pages = 1–15 | title = Ayahuasca: Psychological and Physiologic Effects, Pharmacology and Potential Uses in Addiction and Mental Illness | doi = 10.2174/1570159X16666180125095902 | issn = 1875-6190 | vauthors = Jonathan H, Jaime H, Serdar D, and Glen B | year = 2019 | url = https://www.eurekaselect.com/article/88194 | pmid = 29366418 | pmc = 6343205 | access-date = 2023-05-05 | archive-date = 2023-05-05 | archive-url = https://web.archive.org/web/20230505000155/https://www.eurekaselect.com/article/88194 | url-status = live }}</ref><ref>{{cite journal | journal = Society for the Study of Addiction | vauthors = Jon M, James L, and Erich L | date = September 1994 | title = The generalizability of the dependence syndrome across substances: an examination of some properties of the proposed DSM-IV dependence criteria | volume = 89 | issue = 9 | pages = 1105–1113 | doi = 10.1111/j.1360-0443.1994.tb02787.x | url = https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.1994.tb02787.x | pmid = 7987187 | access-date = 2023-05-05 | archive-date = 2024-05-26 | archive-url = https://web.archive.org/web/20240526041617/https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.1994.tb02787.x | url-status = live | url-access = subscription }}</ref> At present, there have been no studies that report [[Drug_withdrawal|drug withdrawal 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.<ref>{{cite journal | vauthors = Robert G | title = Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids | journal = Addiction | volume = 102 | issue = 1 | pages = 24–34 | date = January 2007 | pmid = 17207120 | doi = 10.1111/j.1360-0443.2006.01652.x | url = https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2006.01652.x | access-date = 2023-05-07 | archive-date = 2024-05-26 | archive-url = https://web.archive.org/web/20240526041617/https://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2006.01652.x | url-status = live | url-access = subscription }}</ref>

Unlike other classical psychedelics, [[drug tolerance|tolerance]] does not seem to develop to the subjective effects of DMT.<ref name="CarbonaroGatch2016" /><ref name="Halberstadt2015">{{cite journal | vauthors = Halberstadt AL | title = Recent advances in the neuropsychopharmacology of serotonergic hallucinogens | journal = Behav Brain Res | volume = 277 | issue = | pages = 99–120 | date = January 2015 | pmid = 25036425 | doi = 10.1016/j.bbr.2014.07.016 | pmc = 4642895 | url = }}</ref> Studies report that DMT did not exhibit tolerance upon repeated administration of twice a day sessions, separated by 5{{nbsp}}hours, for 5{{nbsp}}consecutive days; [[Field_research|field reports]] suggests a [[Refractory_period_(physiology)|refractory period]] of only 15 to 30{{nbsp}}minutes, while the [[Pharmacokinetics#Metrics|plasma levels]] of DMT was nearly undetectable 30{{nbsp}}minutes after [[intravenous administration]].<ref name="Halberstadt2015" /><ref name="StrassmanQuallsBerg1996">{{cite journal | vauthors = Strassman RJ, Qualls CR, Berg LM | title = Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans | journal = Biol Psychiatry | volume = 39 | issue = 9 | pages = 784–795 | date = May 1996 | pmid = 8731519 | doi = 10.1016/0006-3223(95)00200-6 | url = }}</ref> Another study of four closely spaced DMT infusion sessions with 30{{nbsp}}minute intervals also suggests no tolerance buildup to the psychological effects of the compound, while [[heart rate]] responses and [[Neuroendocrinology|neuroendocrine]] effects were diminished with repeated administration.<ref name="Halberstadt2015" /><ref name="StrassmanQuallsBerg1996" /> Similarly to DMT by itself, tolerance does not appear to develop to [[ayahuasca]].<ref name="DosSantosHallak2024">{{cite journal | vauthors = Dos Santos RG, Hallak JE | title = Ayahuasca: pharmacology, safety, and therapeutic effects | journal = CNS Spectr | volume = 30| issue = 1| pages = e2 | date = November 2024 | pmid = 39564645 | doi = 10.1017/S109285292400213X | url = | doi-access = free }}</ref><ref name="DosSantosGrasaValle2012">{{cite journal | vauthors = Dos Santos RG, Grasa E, Valle M, Ballester MR, Bouso JC, Nomdedéu JF, Homs R, Barbanoj MJ, Riba J | title = Pharmacology of ayahuasca administered in two repeated doses | journal = Psychopharmacology (Berl) | volume = 219 | issue = 4 | pages = 1039–1053 | date = February 2012 | pmid = 21842159 | doi = 10.1007/s00213-011-2434-x | url = }}</ref> A fully hallucinogenic dose of DMT did not demonstrate [[cross-tolerance]] to human subjects who are highly tolerant to [[LSD]];<ref name="RosenbergIsbellMiner1963">{{cite journal |journal=Psychopharmacologia |vauthors=Rosenberg D, Isbell H, Miner E, and Logan C |doi=10.1007/BF00413244 |date=7 August 1963 |title=The effect of N,N-dimethyltryptamine in human subjects tolerant to lysergic acid diethylamide |volume=5 |issue=3 |url=https://link.springer.com/article/10.1007/BF00413244 |pages=223–224 |pmid=14138757 |s2cid=32950588 |access-date=4 May 2023 |archive-date=4 May 2023 |archive-url=https://web.archive.org/web/20230504011825/https://link.springer.com/article/10.1007/BF00413244 |url-status=live |url-access=subscription }}</ref> hence, research suggests that DMT exhibits unique pharmacological properties compared to other classical psychedelics.<ref name="StrassmanQuallsBerg1996" />

There have been no serious adverse effects reported on long-term use of DMT, apart from acute cardiovascular events.<ref name="pmid28868040" /> Repeated and one-time administration of DMT produces marked changes in the cardiovascular system,<ref name="pmid28868040" /> with an increase in systolic and diastolic blood pressure; although the changes were not statistically significant, a robust trend towards significance{{what?|reason=So, no significance. That's like saying my bank account shows a robust trend towards having millions of dollars in it both in terms of total lack of meaning to anyone and in speculatory nature.|date=June 2025}} was observed for systolic blood pressure at high doses.<ref name="pmid11292011">{{cite journal | title = Subjective effects and tolerability of the South American psychoactive beverage Ayahuasca in healthy volunteers | journal = Psychopharmacology | pmid = 11292011 | doi = 10.1007/s002130000606 | date = February 2001 | vauthors = Jordi R, Antoni F, Gloria U, Adelaida M, Rosa A, Maria M, James C, and Mandel B | volume = 154 | issue = 1 | url = https://link.springer.com/article/10.1007/s002130000606 | pages = 85–95 | s2cid = 5556065 | access-date = 2023-05-05 | archive-date = 2023-05-05 | archive-url = https://web.archive.org/web/20230505014511/https://link.springer.com/article/10.1007/s002130000606 | url-status = live | url-access = subscription }}</ref>

==Interactions==

DMT is inactive when ingested orally due to metabolism by [[Monoamine_oxidase|MAO]], and DMT-containing drinks such as ayahuasca have been found to contain [[monoamine oxidase inhibitors|MAOI]]s, in particular, [[harmine]] and [[harmaline]].<ref name="pmid11292011" /> Life-threatening lethalities such as [[serotonin syndrome]] (SS) may occur when MAOIs are combined with certain [[Serotonin|serotonergic]] medications such as [[SSRI]] antidepressants.<ref name="pmid9924842" /><ref name="pmid29366418" /> Serotonin syndrome has also been reported with [[tricyclic antidepressant]]s, opiates, [[analgesic]], and [[antimigraine drug]]s; it is advised to exercise caution when an individual had used [[dextromethorphan]] (DXM), [[MDMA]], [[ginseng]], or ''[[Hypericum perforatum|St. John's wort]]'' recently.<ref name="pmid29366418" />

Chronic use of SSRIs, [[Tricyclic_antidepressant|TCA]]s, and MAOIs diminish subjective effects of psychedelics due to presumed SSRI-induced 5-HT_2A receptors downregulation and MAOI-induced 5-HT_2A receptor desensitization.<ref name="9780192678522-drug-interaction">{{cite book | title = Psychedelics as Psychiatric Medications | publisher = [[Oxford University Press]] | url = https://books.google.com/books?id=7lazEAAAQBAJ | date = 7 March 2023 | vauthors = David N, David C | isbn = 978-0-19-267852-2 | chapter = Drug-interaction with psychotropic drugs | access-date = 21 May 2023 | archive-date = 21 May 2023 | archive-url = https://web.archive.org/web/20230521000115/https://books.google.com/books?id=7lazEAAAQBAJ | url-status = live }}</ref>{{rp|145}} However, a clinical study of people with [[depression (mood)|depression]] found that [[selective serotonin reuptake inhibitor]]s (SSRIs) did not diminish the effects of DMT and instead resulted in greater [[mystical experience]], [[emotional breakthrough]], and [[ego dissolution]] scores with DMT than in people with depression not on [[antidepressant]]s.<ref name="JamesJoelAttwooll2024">{{cite journal | vauthors = James E, Joel Z, Attwooll V, Benway T, Good M, Tziras G, Routledge C, Macek T | title=ACNP 63rd Annual Meeting: Poster Abstracts P1-P304: P160. SPL026 (DMT Fumarate) in Combination With Selective Serotonin Reuptake Inhibitors (SSRIs) for Patients With Major Depressive Disorder | journal=Neuropsychopharmacology | volume=49 | issue=S1 | date=2024 | issn=0893-133X | pmid=39643633 | pmc=11627186 | doi=10.1038/s41386-024-02011-0 | doi-access=free | pages=65–235 (155–156) | url=https://www.nature.com/articles/s41386-024-02011-0.pdf | access-date=31 January 2025}}</ref> This was in contrast to previous research finding that SSRIs diminished the effects of serotonergic psychedelics.<ref name="HalmanKongSarris2024">{{Cite journal |vauthors=Halman A, Kong G, Sarris J, Perkins D |date=January 2024 |title=Drug-drug interactions involving classic psychedelics: A systematic review |journal=J Psychopharmacol |volume=38 |issue=1 |pages=3–18 |doi=10.1177/02698811231211219 |pmc=10851641 |pmid=37982394}}</ref> The interaction between psychedelics and [[antipsychotic]]s and [[anticonvulsant]] are not well documented, however reports reveal that co-use of psychedelics with [[mood stabilizer]]s such as [[Lithium_(medication)|lithium]] may provoke [[seizure]] and [[Dissociative_disorder|dissociative effects]] in individuals with [[bipolar disorder]].<ref>{{cite journal | journal = Drug and Alcohol Dependence | doi = 10.1016/j.drugalcdep.2022.109586 | volume = 239 | date = 1 October 2022 | vauthors = Otto S, Simon G, Richard C, Walter O, Distin L, Peter H | pmid = 35981469 | pmc = 9627432 | title = Prevalence and associations of classic psychedelic-related seizures in a population-based sample| page = 109586 }}</ref><ref name="9780192678522-drug-interaction" />{{rp|146}}

| 75->10,000 (K_i)<br />75->100,000 ({{Abbrlink|EC₅₀|Half-maximal effective concentration}})<br />68-100% ({{Abbrlink|E_max|Maximal efficacy}})

| 129->10,000

| 39-270

| 456-517

| 53-2,323 (K_i)<br />22-6,325 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />23-105% ({{Abbr|E_max|Maximal efficacy}})

| 101-184 (K_i)<br />3,400->31,600 ({{Abbr|EC₅₀|Half-maximal effective concentration}})<br />10.4% ({{Abbr|E_max|Maximal efficacy}})

| 33-424 (K_i)<br />31-114 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />85-99% ({{Abbr|E_max|Maximal efficacy}})

| 611-2,135

| 68-487

| 88-206

| 1,300-1,745

| 1,561-2,100

| [[Beta-1 adrenergic receptor|β₁]]-[[Beta-2 adrenergic receptor|β₂]]

| 271-6,000

| 3,000->10,000

| 6,300->10,000

| [[Histamine H2 receptor|H₂]]-[[Histamine H4 receptor|H₄]]

| [[Muscarinic acetylcholine M1 receptor|M₁]]-[[Muscarinic acetylcholine M5 receptor|M₅]]

| 2,200-3,300 (K_i) (rodent)<br />1,200-1,500 ({{Abbr|EC₅₀|Half-maximal effective concentration}}) (rodent)<br />>10,000 ({{Abbr|EC₅₀|Half-maximal effective concentration}}) (human)

| 3,742-6,000 (K_i)<br />2,962-3,100 ({{Abbrlink|IC₅₀|Half-maximal inhibitory concentration}})<br />81-114 ({{Abbr|EC₅₀|Half-maximal effective concentration}})

| 6,500->10,000 (K_i)<br />3,900 ({{Abbr|IC₅₀|Half-maximal inhibitory concentration}})<br />4,166 ({{Abbr|EC₅₀|Half-maximal effective concentration}})

| >10,000-22,000 (K_i)<br />52,000 ({{Abbr|IC₅₀|Half-maximal inhibitory concentration}})<br />>10,000 ({{Abbr|EC₅₀|Half-maximal effective concentration}})

| colspan="2" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' The smaller the value, the more avidly the drug binds to the site. Proteins human unless otherwise specified. '''Refs:''' <ref name="PDSPKiDatabase">{{cite web | title=PDSP Database | website=UNC | url=https://pdspdb.unc.edu/databases/pdsp.php?testDDRadio=testDDRadio&testLigandDD=1271&kiAllRadio=all&doQuery=Submit+Query | language=zu | access-date=29 November 2024}}</ref><ref name="BindingDB">{{cite web | vauthors = Liu T | title=BindingDB BDBM50026868 2-(1H-indol-3-yl)-N,N-dimethylethanamine::2-(3-indolyl)ethyldimethylamine::3-(2-dimethylaminoethyl)indole::3-[2-(dimethylamino)ethyl]indole::CHEMBL12420::DMT::N,N-dimethyl-1H-indole-3-ethylamine::N,N-dimethyltryptamine::US20240166618, Compound DMT::WO2023019367, Compound DMT | website=BindingDB | url=https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50026868 | access-date=29 November 2024}}</ref><ref name="CameronOlson2018" /><ref name="HolzeSinghLiechti2024">{{cite journal | vauthors = Holze F, Singh N, Liechti ME, D'Souza DC | title = Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile | journal = Biol Psychiatry Cogn Neurosci Neuroimaging | volume = 9 | issue = 5 | pages = 472–489 | date = May 2024 | pmid = 38301886 | doi = 10.1016/j.bpsc.2024.01.007 | url = | doi-access = free }}</ref><ref name="RickliLuethiReinisch2015">{{cite journal | vauthors = Rickli A, Luethi D, Reinisch J, Buchy D, Hoener MC, Liechti ME | title = Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs) | journal = Neuropharmacology | volume = 99 | issue = | pages = 546–553 | date = December 2015 | pmid = 26318099 | doi = 10.1016/j.neuropharm.2015.08.034 | url = http://edoc.unibas.ch/56163/1/20170921163006_59c3cceeb8e5d.pdf}}</ref><ref name="RickliMoningHoener2016">{{cite journal | vauthors = Rickli A, Moning OD, Hoener MC, Liechti ME | title = Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens | journal = European Neuropsychopharmacology | volume = 26 | issue = 8 | pages = 1327–1337 | date = August 2016 | pmid = 27216487 | doi = 10.1016/j.euroneuro.2016.05.001 | s2cid = 6685927 | url = http://edoc.unibas.ch/53326/1/20170117174852_587e4af45b658.pdf }}</ref><ref name="Ray2010">{{cite journal | vauthors = Ray TS | title = Psychedelics and the human receptorome | journal = PLOS ONE | volume = 5 | issue = 2 | pages = e9019 | date = February 2010 | pmid = 20126400 | pmc = 2814854 | doi = 10.1371/journal.pone.0009019 | doi-access = free | bibcode = 2010PLoSO...5.9019R | url = }}</ref><ref name="BloughLandavazoDecker2014" /><br /><ref name="KozellEshlemanSwanson2023">{{cite journal | vauthors = Kozell LB, Eshleman AJ, Swanson TL, Bloom SH, Wolfrum KM, Schmachtenberg JL, Olson RJ, Janowsky A, Abbas AI | title = Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)2A Receptor (5-HT2AR), 5-HT2CR, 5-HT1AR, and Serotonin Transporter | journal = J Pharmacol Exp Ther | volume = 385 | issue = 1 | pages = 62–75 | date = April 2023 | pmid = 36669875 | pmc = 10029822 | doi = 10.1124/jpet.122.001454 | url = }}</ref><ref name="EshlemanForsterWolfrum2014">{{cite journal | vauthors = Eshleman AJ, Forster MJ, Wolfrum KM, Johnson RA, Janowsky A, Gatch MB | title = Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function | journal = Psychopharmacology (Berl) | volume = 231 | issue = 5 | pages = 875–888 | date = March 2014 | pmid = 24142203 | pmc = 3945162 | doi = 10.1007/s00213-013-3303-6 | url = https://www.researchgate.net/publication/258061356}}</ref><ref name="JanowskyEshlemanJohnson2014">{{cite journal | vauthors = Janowsky A, Eshleman AJ, Johnson RA, Wolfrum KM, Hinrichs DJ, Yang J, Zabriskie TM, Smilkstein MJ, Riscoe MK | title = Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro | journal = Psychopharmacology (Berl) | volume = 231 | issue = 14 | pages = 2771–2783 | date = July 2014 | pmid = 24488404 | pmc = 4097020 | doi = 10.1007/s00213-014-3446-0 | url = }}</ref><ref name="ChenLiYu2023a">{{cite journal | vauthors = Chen X, Li J, Yu L, Maule F, Chang L, Gallant JA, Press DJ, Raithatha SA, Hagel JM, Facchini PJ | title = A cane toad (Rhinella marina) N-methyltransferase converts primary indolethylamines to tertiary psychedelic amines | journal = J Biol Chem | volume = 299 | issue = 10 | page = 105231 | date = October 2023 | pmid = 37690691 | pmc = 10570959 | doi = 10.1016/j.jbc.2023.105231 | doi-access = free | url = }}</ref><ref name="ChenLiYu2023b">{{citation | vauthors = Chen X, Li J, Yu L, Dhananjaya D, Maule F, Cook S, Chang L, Gallant J, Press D, Bains JS, Raithatha S, Hagel J, Facchini P | title=Bioproduction platform using a novel cane toad (Rhinella marina) N-methyltransferase for psychedelic-inspired drug discovery | date=10 March 2023 | doi=10.21203/rs.3.rs-2667175/v1 | doi-access=free | url=https://www.researchsquare.com/article/rs-2667175/latest.pdf | access-date=18 March 2025 | page=}}</ref><ref name="US11440879">{{cite patent | country = US | number = 11440879 | inventor = Andrew Carry Kruegel | status = | title = Methods of treating mood disorders | pubdate = 10 February 2022 | gdate = | fdate = 25 October 2011 | pridate = 25 October 2021 | assign1 = Gilgamesh Pharmaceuticals, Inc. | url = https://patentimages.storage.googleapis.com/c9/f4/7a/7aa95d76398982/US11440879.pdf#page=45}}</ref><ref name="GainetdinovHoenerBerry2018">{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}</ref>

DMT binds non-[[binding selectivity|selectively]] with [[affinity (pharmacology)|affinities]] below 0.6&nbsp;μmol/L to the following [[serotonin receptor]]s: [[5-HT1A receptor|5-HT_1A]],<ref name="pmid19881490">{{cite journal | vauthors = Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, Jensen NH, Kuijer MB, Matos RC, Tran TB, Whaley R, Glennon RA, Hert J, Thomas KL, Edwards DD, Shoichet BK, Roth BL | title = Predicting new molecular targets for known drugs | journal = Nature | volume = 462 | issue = 7270 | pages = 175–181 | date = November 2009 | pmid = 19881490 | pmc = 2784146 | doi = 10.1038/nature08506 | bibcode = 2009Natur.462..175K }}</ref><ref name="pmid1828347">{{cite journal | vauthors = Deliganis AV, Pierce PA, Peroutka SJ | title = Differential interactions of dimethyltryptamine (DMT) with 5-HT_1A and 5-HT₂ receptors | journal = Biochemical Pharmacology | volume = 41 | issue = 11 | pages = 1739–1744 | date = June 1991 | pmid = 1828347 | doi = 10.1016/0006-2952(91)90178-8 }}</ref><ref name="pmid2540505">{{cite journal | vauthors = Pierce PA, Peroutka SJ | title = Hallucinogenic drug interactions with neurotransmitter receptor binding sites in human cortex | journal = Psychopharmacology | volume = 97 | issue = 1 | pages = 118–122 | year = 1989 | pmid = 2540505 | doi = 10.1007/BF00443425 | s2cid = 32936434 }}</ref> [[5-HT1B receptor|5-HT_1B]],<ref name="pmid19881490" /><ref name="pmid20126400">{{cite journal | vauthors = Ray TS | title = Psychedelics and the human receptorome | journal = PLOS ONE | volume = 5 | issue = 2 | pages = e9019 | date = February 2010 | pmid = 20126400 | pmc = 2814854 | doi = 10.1371/journal.pone.0009019 | bibcode = 2010PLoSO...5.9019R | doi-access = free }}</ref> [[5-HT1D receptor|5-HT_1D]],<ref name="pmid19881490" /><ref name="pmid2540505" /><ref name="pmid20126400" /> [[5-HT2A receptor|5-HT_2A]],<ref name="pmid19881490" /><ref name="pmid2540505" /><ref name="pmid20126400" /><ref name="pmid9768567">{{cite journal | vauthors = Smith RL, Canton H, Barrett RJ, Sanders-Bush E | title = Agonist properties of ''N'',''N''-dimethyltryptamine at serotonin 5-HT_2A and 5-HT_2C receptors | journal = Pharmacology, Biochemistry, and Behavior | volume = 61 | issue = 3 | pages = 323–330 | date = November 1998 | pmid = 9768567 | doi = 10.1016/S0091-3057(98)00110-5 | s2cid = 27591297 | url = http://crfdl.org:1111/xmlui/bitstream/handle/123456789/17/Agonist%20Properties%20of%20N,N-Dimethyltryptaminenext%20term%20at%20Ser.pdf }}{{Dead link|date=July 2018 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> [[5-HT2B receptor|5-HT_2B]],<ref name="pmid19881490" /><ref name="pmid20126400" /> [[5-HT2C receptor|5-HT_2C]],<ref name="pmid19881490" /><ref name="pmid20126400" /><ref name="pmid9768567" /> [[5-HT6 receptor|5-HT₆]],<ref name="pmid19881490" /><ref name="pmid20126400" /> and [[5-HT7 receptor|5-HT₇]].<ref name="pmid19881490" /><ref name="pmid20126400" /> An [[agonist]] action has been determined at 5-HT_1A,<ref name="pmid1828347" /> 5-HT_2A and 5-HT_2C.<ref name="pmid19881490" /><ref name="pmid20126400" /><ref name="pmid9768567" /> Its [[intrinsic activity|efficacies]] at other serotonin receptors remain to be determined. Of special interest will be the determination of its efficacy at human 5-HT_2B receptor as two ''in vitro'' assays evidenced DMT's high affinity for this receptor: 0.108&nbsp;μmol/L<ref name="pmid20126400" /> and 0.184&nbsp;μmol/L.<ref name="pmid19881490" /> This may be of importance because chronic or frequent uses of serotonergic drugs showing preferential high affinity and clear agonism at 5-HT_2B receptor have been causally linked to [[valvular heart disease]].<ref name="pmid19505264">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Serotonergic drugs and valvular heart disease | journal = Expert Opinion on Drug Safety | volume = 8 | issue = 3 | pages = 317–329 | date = May 2009 | pmid = 19505264 | pmc = 2695569 | doi = 10.1517/14740330902931524 }}</ref><ref name="pmid17202450">{{cite journal|author1-link=Bryan Roth | vauthors = Roth BL | title = Drugs and valvular heart disease | journal = The New England Journal of Medicine | volume = 356 | issue = 1 | pages = 6–9 | date = January 2007 | pmid = 17202450 | doi = 10.1056/NEJMp068265 }}</ref><ref>{{cite journal | vauthors = Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB | title = Functional selectivity and classical concepts of quantitative pharmacology | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 320 | issue = 1 | pages = 1–13 | date = January 2007 | pmid = 16803859 | doi = 10.1124/jpet.106.104463 | s2cid = 447937 | url = https://cdr.lib.unc.edu/concern/articles/xs55mf307 | access-date = 2019-07-12 | archive-date = 2020-04-28 | archive-url = https://web.archive.org/web/20200428163253/https://cdr.lib.unc.edu/concern/articles/xs55mf307 | url-status = live }}</ref>

It has also been shown to possess affinity for the [[dopamine]] [[D1 receptor|D₁]], [[α1-adrenergic receptor|α₁-adrenergic]], [[α2-adrenergic receptor|α₂-adrenergic]], [[Imidazoline receptor|imidazoline-1]], and [[sigma-1 receptor|σ₁]] [[receptor (biochemistry)|receptors]].<ref name="pmid2540505" /><ref name="pmid20126400" /><ref name="pmid16962229">{{cite journal | vauthors = Burchett SA, Hicks TP | title = The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain | journal = Progress in Neurobiology | volume = 79 | issue = 5–6 | pages = 223–246 | date = August 2006 | pmid = 16962229 | doi = 10.1016/j.pneurobio.2006.07.003 | s2cid = 10272684 | url = http://www.mimosahostilis.com/files/The%20mysterious%20trace%20amines%20%20protean%20neuromodulato.pdf | df = dmy-all | oclc = 231983957 | archive-date = 1 February 2012 | archive-url = https://web.archive.org/web/20120201112618/http://www.mimosahostilis.com/files/The%20mysterious%20trace%20amines%20%20protean%20neuromodulato.pdf }}</ref> Converging lines of evidence established activation of the σ₁ receptor at concentrations of 50-100&nbsp;μmol/L.<ref name="pmid19213917">{{cite journal | vauthors = Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE | title = The hallucinogen ''N'',''N''-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator | journal = Science | volume = 323 | issue = 5916 | pages = 934–937 | date = February 2009 | pmid = 19213917 | pmc = 2947205 | doi = 10.1126/science.1166127 | bibcode = 2009Sci...323..934F }}</ref> Its efficacies at the other receptor binding sites are unclear. It has also been shown ''in vitro'' to be a [[substrate (biochemistry)|substrate]] for the cell-surface [[serotonin transporter]] (SERT) expressed in human platelets, and the rat [[vesicular monoamine transporter 2]] (VMAT2), which was transiently expressed in [[fall armyworm]] Sf9 cells. DMT inhibited SERT-mediated serotonin uptake into platelets at an average concentration of 4.00 ± 0.70&nbsp;μmol/L and VMAT2-mediated serotonin uptake at an average concentration of 93 ± 6.8&nbsp;μmol/L.<ref name="pmid19756361">{{cite journal | vauthors = Cozzi NV, Gopalakrishnan A, Anderson LL, Feih JT, Shulgin AT, Daley PF, Ruoho AE | title = Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter | journal = Journal of Neural Transmission | volume = 116 | issue = 12 | pages = 1591–1599 | date = December 2009 | pmid = 19756361 | doi = 10.1007/s00702-009-0308-8 | s2cid = 15928043 | url = http://www.neurophys.wisc.edu/~cozzi/Hallucinogenic%20tryptamines%20as%20SERT%20and%20VMAT2%20substrates.%20%20Cozzi.%20%20J.%20Neural%20Transm.,%20116,%201591-1599%20(2009).pdf | access-date = 20 November 2010 | archive-url = https://web.archive.org/web/20100617172010/http://www.neurophys.wisc.edu/~cozzi/Hallucinogenic%20tryptamines%20as%20SERT%20and%20VMAT2%20substrates.%20%20Cozzi.%20%20J.%20Neural%20Transm.,%20116,%201591-1599%20(2009).pdf | archive-date = 17 June 2010 }}</ref> In addition, DMT is a potent [[serotonin releasing agent]] with an {{Abbrlink|EC₅₀|half-maximal effective concentration}} value of 81 to 114{{nbsp}}nM.<ref name="BloughLandavazoDecker2014">{{cite journal | vauthors = Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB | title = Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes | journal = Psychopharmacology (Berl) | volume = 231 | issue = 21 | pages = 4135–4144 | date = October 2014 | pmid = 24800892 | pmc = 4194234 | doi = 10.1007/s00213-014-3557-7 | url = }}</ref><ref name="US11440879" />

As with other so-called "classical hallucinogens",<ref name="nida1994">{{cite book | vauthors = Glennon RA | veditors = Lin GC, Glennon RA |title=Hallucinogens: An Update |chapter-url=http://crfdl.org:1111/xmlui/bitstream/handle/123456789/288/hallucinogens%20an%20update.pdf |archive-url=https://web.archive.org/web/20110725203539/http://crfdl.org:1111/xmlui/bitstream/handle/123456789/288/hallucinogens%20an%20update.pdf |archive-date=2011-07-25 |url-status=live |series=NIDA Research Monograph Series |volume=146 |year=1994 |publisher=U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, National Institute on Drug Abuse |location=Rockville, MD |page=4 |chapter=Classical hallucinogens: an introductory overview}}</ref> a large part of DMT psychedelic effects can be attributed to a [[functionally selective]] activation of the 5-HT_2A receptor.<ref name="pmid8297216" /><ref name="pmid19881490" /><ref name="pmid17977517">{{cite journal | vauthors = Fantegrossi WE, Murnane KS, Reissig CJ | title = The behavioral pharmacology of hallucinogens | journal = Biochemical Pharmacology | volume = 75 | issue = 1 | pages = 17–33 | date = January 2008 | pmid = 17977517 | pmc = 2247373 | doi = 10.1016/j.bcp.2007.07.018 }}</ref><ref name="pmid14761703">{{cite journal | vauthors = Nichols DE | title = Hallucinogens | journal = Pharmacology & Therapeutics | volume = 101 | issue = 2 | pages = 131–181 | date = February 2004 | pmid = 14761703 | doi = 10.1016/j.pharmthera.2003.11.002 }}</ref><ref name="pmid9875725">{{cite journal | vauthors = Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, Hell D | title = Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action | journal = NeuroReport | volume = 9 | issue = 17 | pages = 3897–3902 | date = December 1998 | pmid = 9875725 | doi = 10.1097/00001756-199812010-00024 | s2cid = 37706068 }}</ref><ref name="pmid8788488">{{cite journal | vauthors = Strassman RJ | title = Human psychopharmacology of ''N'',''N''-dimethyltryptamine | journal = Behavioural Brain Research | volume = 73 | issue = 1–2 | pages = 121–124 | year = 1996 | pmid = 8788488 | doi = 10.1016/0166-4328(96)00081-2 | s2cid = 4047951 | url = http://crfdl.org:1111/xmlui/bitstream/handle/123456789/373/Beh_Brain_Res_96.pdf }}{{Dead link|date=July 2018 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="pmid6513725">{{cite journal | vauthors = Glennon RA, Titeler M, McKenney JD | title = Evidence for 5-HT₂ involvement in the mechanism of action of hallucinogenic agents | journal = Life Sciences | volume = 35 | issue = 25 | pages = 2505–2511 | date = December 1984 | pmid = 6513725 | doi = 10.1016/0024-3205(84)90436-3 }}</ref> DMT concentrations eliciting 50% of its maximal effect (half maximal effective concentration = [[EC50|EC₅₀]]) at the human 5-HT_2A receptor ''in vitro'' are in the 0.118-0.983&nbsp;μmol/L range.<ref name="pmid19881490" /><ref name="pmid20126400" /><ref name="pmid9768567" /><ref name="pmid9023266">{{cite journal | vauthors = Roth BL, Choudhary MS, Khan N, Uluer AZ | title = High-affinity agonist binding is not sufficient for agonist efficacy at 5-hydroxytryptamine2A receptors: evidence in favor of a modified ternary complex model | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 280 | issue = 2 | pages = 576–83 | date = February 1997 | doi = 10.1016/S0022-3565(24)36476-6 | pmid = 9023266 | url = http://jpet.aspetjournals.org/content/280/2/576.full.pdf | access-date = 2010-11-29 | archive-date = 2024-05-26 | archive-url = https://web.archive.org/web/20240526042118/http://jpet.aspetjournals.org/content/280/2/576.full.pdf | url-status = live }}</ref> This range of values coincides well with the range of concentrations measured in blood and plasma after administration of a fully psychedelic dose (see [[#Pharmacokinetics|Pharmacokinetics]]).

DMT is one of the only psychedelics that isn't known to produce tolerance to its hallucinogenic effects.<ref name="Halberstadt2015" /><ref name="JiménezBouso2022" /> The lack of tolerance with DMT may be related to the fact that, unlike other psychedelics such as LSD and [[DOI (drug)|DOI]], DMT does not [[receptor downregulation|desensitize]] serotonin 5-HT_2A receptors ''[[in vitro]]''.<ref name="Halberstadt2015" /><ref name="SmithCantonBarrett1998">{{cite journal | vauthors = Smith RL, Canton H, Barrett RJ, Sanders-Bush E | title = Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors | journal = Pharmacol Biochem Behav | volume = 61 | issue = 3 | pages = 323–330 | date = November 1998 | pmid = 9768567 | doi = 10.1016/s0091-3057(98)00110-5 | url = }}</ref> This may be due to the fact that DMT is a [[biased agonist]] of the serotonin 5-HT_2A receptor.<ref name="JiménezBouso2022">{{cite journal | vauthors = Jiménez JH, Bouso JC | title = Significance of mammalian N, N-dimethyltryptamine (DMT): A 60-year-old debate | journal = J Psychopharmacol | volume = 36 | issue = 8 | pages = 905–919 | date = August 2022 | pmid = 35695604 | doi = 10.1177/02698811221104054 | url = }}</ref><ref name="BloughLandavazoDecker2014" /> More specifically, DMT activates the [[Gq protein|G_q]] [[cell signaling|signaling pathway]] of the serotonin 5-HT_2A receptor without significantly recruiting [[β-arrestin2]].<ref name="JiménezBouso2022" /><ref name="BloughLandavazoDecker2014" /> Activation of β-arrestin2 is linked to [[receptor downregulation]] and [[tachyphylaxis]].<ref name="JiménezBouso2022" /><ref name="BarksdaleDossFonzo2024">{{cite journal | vauthors = Barksdale BR, Doss MK, Fonzo GA, Nemeroff CB | title = The mechanistic divide in psychedelic neuroscience: An unbridgeable gap? | journal = Neurotherapeutics | volume = 21 | issue = 2 | pages = e00322 | date = March 2024 | pmid = 38278658 | doi = 10.1016/j.neurot.2024.e00322 | pmc = 10963929 | url = }}</ref><ref name="WallachCaoCalkins2023">{{cite journal | vauthors = Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD | title = Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential | journal = Nat Commun | volume = 14 | issue = 1 | page = 8221 | date = December 2023 | pmid = 38102107 | doi = 10.1038/s41467-023-44016-1 | pmc = 10724237 | url = }}</ref> Similarly to DMT, [[5-MeO-DMT]] is a biased agonist of the serotonin 5-HT_2A receptor, with minimal β-arrestin2 recruitment, and likewise has been associated with little tolerance to its hallucinogenic effects.<ref name="ErmakovaDunbarRucker2022">{{cite journal | vauthors = Ermakova AO, Dunbar F, Rucker J, Johnson MW | title = A narrative synthesis of research with 5-MeO-DMT | journal = J Psychopharmacol | volume = 36 | issue = 3 | pages = 273–294 | date = March 2022 | pmid = 34666554 | doi = 10.1177/02698811211050543 | pmc = 8902691 | url = }}</ref><ref name="BloughLandavazoDecker2014" /> On the other hand, the lack of apparent tolerance of DMT and similar agents may simply be related to their very short [[duration of action|duration]]s.<ref name="Martin_1977">{{cite book | vauthors = Martin WR, Sloan JW | chapter = Pharmacology and Classification of LSD-like Hallucinogens | title = Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence | pages = 305–368 | date = 1977 | doi = 10.1007/978-3-642-66709-1_3 | publisher = Springer Berlin Heidelberg | publication-place = Berlin, Heidelberg | isbn = 978-3-642-66711-4 | chapter-url = https://books.google.com/books?id=gb_uCAAAQBAJ&pg=PA305 | quote = The observation that tolerance to LSD does not confer cross tolerance to several of DMT's autonomic effects suggests that these N-disubstituted compounds may differ in some respects from LSD. The duration of action of DMT is less than that of LSD. Further, we have not been able to demonstrate tachyphylaxis to the actions of tryptamine in the dog (MARTIN and EADES, 1972). Tryptamine's duration of action is less than that of DMT. It is possible that a long duration of action is a necessary attribute of LSD-like hallucinogens for them to effectively induce tolerance (see Subsect. E.III). }}</ref>

As DMT has been shown to have slightly better efficacy (EC₅₀) at human serotonin 2C receptor than at the 2A receptor,<ref name="pmid20126400" /><ref name="pmid9768567" /> 5-HT_2C is also likely implicated in DMT's overall effects.<ref name="pmid14761703" /><ref name="pmid20165943">{{cite journal | vauthors = Canal CE, Olaghere da Silva UB, Gresch PJ, Watt EE, Sanders-Bush E, Airey DC | title = The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen | journal = Psychopharmacology | volume = 209 | issue = 2 | pages = 163–174 | date = April 2010 | pmid = 20165943 | pmc = 2868321 | doi = 10.1007/s00213-010-1784-0 }}</ref> Other receptors such as 5-HT_1A<ref name="pmid2540505" /><ref name="pmid14761703" /><ref name="pmid8788488" /> and σ₁<ref name="pmid19213917" /><ref name="pmid19278957">{{cite journal | vauthors = Su TP, Hayashi T, Vaupel DB | title = When the endogenous hallucinogenic trace amine ''N'',''N''-dimethyltryptamine meets the sigma-1 receptor | journal = Science Signaling | volume = 2 | issue = 61 | pages = pe12 | date = March 2009 | pmid = 19278957 | pmc = 3155724 | doi = 10.1126/scisignal.261pe12 }}</ref> may also play a role.

In 2009, it was hypothesized that DMT may be an [[endogenous ligand]] for the σ₁ receptor.<ref name="pmid19213917" /><ref name="pmid19278957" /> The concentration of DMT needed for σ₁ activation ''in vitro'' (50-100&nbsp;μmol/L) is similar to the behaviorally active concentration measured in [[mouse brain]] of approximately 106&nbsp;μmol/L<ref name="pmid6798607">{{cite journal | vauthors = Morinan A, Collier JG | title = Effects of pargyline and SKF-525A on brain ''N'',''N''-dimethyltryptamine concentrations and hyperactivity in mice | journal = Psychopharmacology | volume = 75 | issue = 2 | pages = 179–183 | year = 1981 | pmid = 6798607 | doi = 10.1007/BF00432184 | s2cid = 43576890 }}</ref> This is minimally 4 orders of magnitude higher than the average concentrations measured in rat brain tissue or human plasma under basal conditions (see [[#Endogenous DMT|Endogenous DMT]]), so σ₁ receptors are likely to be activated only under conditions of high local DMT concentrations. If DMT is stored in synaptic vesicles,<ref name="pmid19756361" /> such concentrations might occur during vesicular release. To illustrate, while the ''average'' concentration of serotonin in brain tissue is in the 1.5-4&nbsp;μmol/L range,<ref name="pmid20723248" /><ref name="pmid16146432" /> the concentration of serotonin in synaptic vesicles was measured at 270 mM.<ref name="pmid11086995">{{cite journal | vauthors = Bruns D, Riedel D, Klingauf J, Jahn R | title = Quantal release of serotonin | journal = Neuron | volume = 28 | issue = 1 | pages = 205–220 | date = October 2000 | pmid = 11086995 | doi = 10.1016/S0896-6273(00)00097-0 | hdl-access = free | hdl = 11858/00-001M-0000-0029-D137-5 | s2cid = 6364237 }}</ref> Following vesicular release, the resulting concentration of serotonin in the synaptic cleft, to which serotonin receptors are exposed, is estimated to be about 300&nbsp;μmol/L. 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.

In September 2020, an ''[[in vitro]]'' and ''[[in vivo]]'' study found that DMT present in the ayahuasca infusion promotes [[neurogenesis]], meaning it helps with generating [[Neuron|neurons]].<ref>{{cite journal | vauthors = Morales García JA, Calleja Conde J, López Moreno JA, Alonso Gil S, Sanz San Cristobal M, Riba J, Pérez Castillo A | title = ''N'',''N''-Dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo | journal = Translational Psychiatry | volume = 10 | issue = 1 | page = 331 | date = September 2020 | pmid = 32989216 | doi = 10.1038/s41398-020-01011-0 | pmc = 7522265 }}</ref>

DMT produces the [[head-twitch response]] (HTR), a behavioral proxy of [[psychedelic drug|psychedelic]]-like effects, in rodents.<ref name="CameronOlson2018" /><ref name="CarbonaroGatch2016" /><ref name="CanalMorgan2012">{{cite journal | vauthors = Canal CE, Morgan D | title = Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model | journal = Drug Testing and Analysis | volume = 4 | issue = 7–8 | pages = 556–576 | date = July 2012 | pmid = 22517680 | pmc = 3722587 | doi = 10.1002/dta.1333 }}</ref>

<ref name="HalberstadtChathaKlein2020">{{cite journal | vauthors = Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD | title = Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species | journal = Neuropharmacology | volume = 167 | issue = | page = 107933 | date = May 2020 | pmid = 31917152 | pmc = 9191653 | doi = 10.1016/j.neuropharm.2019.107933 | url = http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Serotonergic%20Psychedelics%2020/Halberstadt%2020%20Neuropharm%20potency%20of%20hallucinogens%20%20head-twitch.pdf}}</ref> However, its effects in the HTR paradigm in mice that are highly strain-dependent, including producing an HTR comparable to other psychedelics, producing an HTR that is much weaker than that of other psychedelics, or producing no HTR at all.<ref name="CameronOlson2018" /><ref name="CarbonaroGatch2016" /><ref name="CanalMorgan2012" /> These conflicting results may be due to rapid metabolism of DMT and/or other peculiarities of DMT in different species.<ref name="CarbonaroGatch2016" /> Besides the HTR, DMT also substitutes for [[LSD]] and [[DOM (drug)|DOM]] in rodent [[drug discrimination]] tests.<ref name="HalberstadtChathaKlein2020" />

The [[cryo-EM]] [[protein–ligand complex|structure]]s of the serotonin 5-HT_2A receptor with DMT, as well as with various other psychedelics and serotonin 5-HT_2A receptor agonists, have been solved and published by [[Bryan L. Roth]] and colleagues.<ref name="GumpperJainKim2025">{{cite journal | vauthors = Gumpper RH, Jain MK, Kim K, Sun R, Sun N, Xu Z, DiBerto JF, Krumm BE, Kapolka NJ, Kaniskan HÜ, Nichols DE, Jin J, Fay JF, Roth BL | title = The structural diversity of psychedelic drug actions revealed | journal = Nature Communications | volume = 16 | issue = 1 | page = 2734 | date = March 2025 | pmid = 40108183 | doi = 10.1038/s41467-025-57956-7 | pmc = 11923220 | bibcode = 2025NatCo..16.2734G }}</ref><ref name="GumpperDiBertoJain2022">{{cite conference | vauthors = Gumpper RH, DiBerto J, Jain M, Kim K, Fay J, Roth BL | title = Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias | conference = University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center | date = September 2022 | url = https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37}}</ref>

Closely coextending with peak psychedelic effects, the mean time to reach peak concentration (''T''_max) has been determined to be 10-15 minutes in whole blood after IM injection,<ref name="pmid4607811" /> and 2 minutes in plasma after IV administration.<ref name="pmid8297216" /> The half life after IV injection is 9-12 minutes.<ref name="pharmk">{{cite journal | vauthors = Good M, Joel Z, Benway T, Routledge C, Timmermann C, Erritzoe D, Weaver R, Allen G, Hughes C, Topping H, Bowman A, James E | title = Pharmacokinetics of N,N-dimethyltryptamine in Humans | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 48 | issue = 3 | pages = 311–327 | date = May 2023 | pmid = 37086340 | doi = 10.1007/s13318-023-00822-y | pmc = 10122081 }}</ref> When taken orally mixed in an [[ayahuasca]] [[decoction]] or in [[Freeze-drying|freeze-dried]] ayahuasca [[Capsule (pharmacy)#Two-piece gel encapsulation|gel caps]], DMT ''T''_max is considerably delayed to 107.59&nbsp;±&nbsp;32.5 minutes,<ref name="pmid10404423">{{cite journal | vauthors = Callaway JC, McKenna DJ, Grob CS, Brito GS, Raymon LP, Poland RE, Andrade EN, Andrade EO, Mash DC | title = Pharmacokinetics of Hoasca alkaloids in healthy humans | journal = Journal of Ethnopharmacology | volume = 65 | issue = 3 | pages = 243–256 | date = June 1999 | pmid = 10404423 | doi = 10.1016/S0378-8741(98)00168-8 | url = http://wiki.dmt-nexus.com/w/images/2/26/Pharmacokinetics_of_hoasca_in_healthy_humans.pdf }}{{Dead link|date=July 2018 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> and 90-120 minutes,<ref name="pmid12660312">{{cite journal | vauthors = Riba J, Valle M, Urbano G, Yritia M, Morte A, Barbanoj MJ | title = Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 306 | issue = 1 | pages = 73–83 | date = July 2003 | pmid = 12660312 | doi = 10.1124/jpet.103.049882 | s2cid = 6147566 }}</ref> respectively.<ref name="McKennaTowers1984"/>

DMT peak level concentrations (''C''_max) measured in the blood after intramuscular (IM) injection (0.7&nbsp;mg/kg, ''n'' = 11)<ref name="pmid4607811">{{cite journal | vauthors = Kaplan J, Mandel LR, Stillman R, Walker RW, VandenHeuvel WJ, Gillin JC, Wyatt RJ | title = Blood and urine levels of ''N'',''N''-dimethyltryptamine following administration of psychoactive dosages to human subjects | journal = Psychopharmacologia | volume = 38 | issue = 3 | pages = 239–245 | year = 1974 | pmid = 4607811 | doi = 10.1007/BF00421376 | s2cid = 12346844 }}</ref> and in plasma following intravenous (IV) administration (0.4&nbsp;mg/kg, ''n'' = 10)<ref name="pmid8297216" /> of fully psychedelic doses are in the range of around 14 to 154&nbsp;μg/L and 32 to 204&nbsp;μg/L, respectively. The corresponding [[molar concentration]]s of DMT are therefore in the range of 0.074-0.818&nbsp;μmol/L in whole blood and 0.170-1.08&nbsp;μmol in plasma. However, several studies have described active transport and accumulation of DMT into rat and dog brains following peripheral administration.<ref name="pmid6812592">{{cite journal | vauthors = Barker SA, Beaton JM, Christian ST, Monti JA, Morris PE | title = Comparison of the brain levels of ''N'',''N''-dimethyltryptamine and ''alpha'',''alpha'',''beta'',''beta''-tetradeutero-''N'',''N''-dimethyltryptamine following intraperitoneal injection. The in vivo kinetic isotope effect | journal = Biochemical Pharmacology | volume = 31 | issue = 15 | pages = 2513–2516 | date = August 1982 | pmid = 6812592 | doi = 10.1016/0006-2952(82)90062-4 }}</ref><ref name="pmid41604">{{cite journal | vauthors = Sangiah S, Gomez MV, Domino EF | title = Accumulation of ''N'',''N''-dimethyltryptamine in rat brain cortical slices | journal = Biological Psychiatry | volume = 14 | issue = 6 | pages = 925–936 | date = December 1979 | pmid = 41604 }}</ref><ref name="pmid3472526">{{cite journal | vauthors = Sitaram BR, Lockett L, Talomsin R, Blackman GL, McLeod WR | title = In vivo metabolism of 5-methoxy-''N'',''N''-dimethyltryptamine and ''N'',''N''-dimethyltryptamine in the rat | journal = Biochemical Pharmacology | volume = 36 | issue = 9 | pages = 1509–1512 | date = May 1987 | pmid = 3472526 | doi = 10.1016/0006-2952(87)90118-3 }}</ref><ref name="pmid3866749">{{cite journal | vauthors = Takahashi T, Takahashi K, Ido T, Yanai K, Iwata R, Ishiwata K, Nozoe S | title = ¹¹C-labeling of indolealkylamine alkaloids and the comparative study of their tissue distributions | journal = The International Journal of Applied Radiation and Isotopes | volume = 36 | issue = 12 | pages = 965–969 | date = December 1985 | pmid = 3866749 | doi = 10.1016/0020-708X(85)90257-1 }}</ref><ref name="pmid3489620">{{cite journal | vauthors = Yanai K, Ido T, Ishiwata K, Hatazawa J, Takahashi T, Iwata R, Matsuzawa T | title = In vivo kinetics and displacement study of a carbon-11-labeled hallucinogen, ''N'',''N''-[¹¹C]dimethyltryptamine | journal = European Journal of Nuclear Medicine | volume = 12 | issue = 3 | pages = 141–146 | year = 1986 | pmid = 3489620 | doi = 10.1007/BF00276707 | s2cid = 20030999 }}</ref> Similar active transport and accumulation processes likely occur in human brains 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&nbsp;μmol/L range.<ref name="pmid20723248">{{cite journal | vauthors = Best J, Nijhout HF, Reed M | title = Serotonin synthesis, release and reuptake in terminals: a mathematical model | journal = Theoretical Biology & Medical Modelling | volume = 7 | issue = 1 | page = 34 | date = August 2010 | pmid = 20723248 | pmc = 2942809 | doi = 10.1186/1742-4682-7-34 | doi-access = free }}</ref><ref name="pmid16146432">{{cite journal | vauthors = Merrill MA, Clough RW, Jobe PC, Browning RA | title = Brainstem seizure severity regulates forebrain seizure expression in the audiogenic kindling model | journal = Epilepsia | volume = 46 | issue = 9 | pages = 1380–1388 | date = September 2005 | pmid = 16146432 | doi = 10.1111/j.1528-1167.2005.39404.x | s2cid = 23783863 | url = http://assets0.pubget.com/pdf/16146432.pdf | archive-url = https://web.archive.org/web/20181031214030/http://assets0.pubget.com/pdf/16146432.pdf | archive-date = 31 October 2018 }}</ref>

DMT easily crosses the [[blood–brain barrier|blood-brain barrier]].<ref name="Brito-da-CostaDias-da-SilvaGomes2020" /> Studies on the llipophilicity of DMT have been contradictory -- most studies find DMT to be either lipophilic or slightly lipophilic, but a 2023 study found it to be lipophobic.<ref name="pharmk2">{{cite journal | vauthors = van der Heijden KV, Otto ME, Schoones JW, van Esdonk MJ, Borghans LG, van Hasselt JG, van Gerven JM, Jacobs G | title = Clinical Pharmacokinetics of N,N-Dimethyltryptamine (DMT): A Systematic Review and Post-hoc Analysis | journal = Clinical Pharmacokinetics | volume = 64 | issue = 2 | pages = 215–227 | date = February 2025 | pmid = 39838235 | doi = 10.1007/s40262-024-01450-8 | pmc = 11782443 }}</ref>

DMT is primarily metabolized by [[monoamine oxidase A]] (MAO-A) into [[indole-3-acetic acid]] and to a much lesser extent in the liver by [[CYP2D6]] and [[CYP2C19]].<ref name="pharmk2"/><ref name="CYOP">{{cite journal | vauthors = Eckernäs E, Macan-Schönleben A, Andresen-Bergström M, Birgersson S, Hoffmann KJ, Ashton M | title = <i>N, N</i>-dimethyltryptamine forms oxygenated metabolites via CYP2D6 - an <i>in vitro</i> investigation | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 53 | issue = 8–9 | pages = 515–522 | date = December 2023 | pmid = 37916667 | doi = 10.1080/00498254.2023.2278488 | hdl = 10067/2011610151162165141 | hdl-access = free }}</ref> When taken orally it is metabolized by MAO-A in the liver and gut, and is thus not orally bioavailable unless a monoamine oxidase inhibitor is taken (as is naturally found in the ayahuasca brew).<ref name="McKennaTowers1984"/> When taken intravenously, DMT is primarily metabolized MAO-A in the circulatory system and brain.<ref name="pharmk" /> When smoked, a more substantial fraction (possibly as high as 10-20%) is metabolized in the liver by [[CYP2D6]] and [[CYP2C19]].<ref>{{cite journal | vauthors = Riba J, McIlhenny EH, Bouso JC, Barker SA | title = Metabolism and urinary disposition of N,N-dimethyltryptamine after oral and smoked administration: a comparative study | journal = Drug Testing and Analysis | volume = 7 | issue = 5 | pages = 401–406 | date = May 2015 | pmid = 25069786 | doi = 10.1002/dta.1685 }}</ref>  

Detailed pharmacokinetic analyses for inhaling or vaporizing DMT appear to be lacking.{{Citation needed|date=April 2025}}

DMT is commonly handled and stored as a [[hemifumarate]],<ref name="TiHKAL">{{cite web|url=https://www.erowid.org/library/books_online/tihkal/tihkal06.shtml|title=Erowid Online Books: "TIHKAL" – #6 DMT|website=Erowid.org|access-date=2015-09-10|archive-date=2015-09-16|archive-url=https://web.archive.org/web/20150916005755/https://www.erowid.org/library/books_online/tihkal/tihkal06.shtml|url-status=live}}</ref><ref name="pmid32608093">{{cite journal | vauthors = Cozzi NV, Daley PF | title = Synthesis and characterization of high-purity ''N'',''N''-dimethyltryptamine hemifumarate for human clinical trials | journal = Drug Testing and Analysis | volume = 12 | issue = 10 | pages = 1483–1493 | date = October 2020 | doi = 10.1002/dta.2889| pmid = 32608093 | s2cid = 220290037 }}</ref> as other DMT acid salts are extremely [[Hygroscopy|hygroscopic]] and will not readily crystallize. Its [[Freebase (chemistry)|freebase]] form, although less stable than DMT hemifumarate, is favored by recreational users choosing to vaporize the chemical as it has a lower boiling point.<ref name="TiHKAL" />

DMT is a [[lipophilic]] [[chemical compound|compound]], with an experimental [[log P]] of 2.57.<ref name="Brito-da-CostaDias-da-SilvaGomes2020">{{cite journal | vauthors = Brito-da-Costa AM, Dias-da-Silva D, Gomes NG, Dinis-Oliveira RJ, Madureira-Carvalho Á | title = Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact | journal = Pharmaceuticals (Basel) | volume = 13 | issue = 11 | date = October 2020 | page = 334 | pmid = 33114119 | pmc = 7690791 | doi = 10.3390/ph13110334 | doi-access = free | url = }}</ref>

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 aluminium hydride]] to form DMT.<ref name="TiHKAL" /> 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]] can be used but requires a larger excess of reagents and lower temperatures due to it having a higher selectivity for carbonyl groups as opposed to [[imines]].<ref>{{cite journal | vauthors = Bosch J, Roca T, Armengol M, Fernández-Forner D |title=Synthesis of 5-(sulfamoylmethyl)indoles |journal=Tetrahedron |date=4 February 2001 |volume=57 |issue=6 |pages=1041–1048 |doi=10.1016/S0040-4020(00)01091-7 }}</ref> Procedures using sodium cyanoborohydride and sodium triacetoxyborohydride (presumably created ''in situ'' from cyanoborohydride though this may not be the case due to the presence of water or [[methanol]]) also result in the creation of cyanated tryptamine and [[Beta-carboline|''beta''-carboline]] byproducts of unknown toxicity while using sodium borohydride in absence of acid does not.<ref>{{cite journal | vauthors = Brandt SD, Moore SA, Freeman S, Kanu AB | title = Characterization of the synthesis of ''N'',''N''-dimethyltryptamine by reductive amination using gas chromatography ion trap mass spectrometry | journal = Drug Testing and Analysis | volume = 2 | issue = 7 | pages = 330–338 | date = July 2010 | pmid = 20648523 | doi = 10.1002/dta.142 }}</ref> Bufotenine, a plant extract, can also be synthesized into DMT.<ref>{{cite journal | vauthors = Moreira LA, Murta MM, Gatto CC, Fagg CW, dos Santos ML | title = Concise synthesis of ''N'',''N''-dimethyltryptamine and 5-methoxy-''N'',''N''-dimethyltryptamine starting with bufotenine from Brazilian Anadenanthera ssp | journal = Natural Product Communications | volume = 10 | issue = 4 | pages = 581–584 | date = April 2015 | pmid = 25973481 | doi = 10.1177/1934578X1501000411 | s2cid = 34076965 | doi-access = free }}</ref>  

Alternatively, an excess of [[methyl iodide]] or [[Methyl p-toluenesulfonate|methyl ''p''-toluenesulfonate]] and [[sodium carbonate]] can be used to over-methylate tryptamine, resulting in the creation of a [[quaternary ammonium salt]], which is then dequaternized (demethylated) in [[ethanolamine]] to yield DMT. The same two-step procedure is used to synthesize other ''N'',''N''-dimethylated compounds, such as 5-MeO-DMT.<ref>{{cite web | url=https://hyperlab.info/inv/index.php?lang=en&act=ST&f=17&t=913&st=120 | title=Hyperlab.info -> Мелатонин и 5-MeO-DMT | access-date=2023-09-27 | archive-date=2023-09-27 | archive-url=https://web.archive.org/web/20230927010145/https://hyperlab.info/inv/index.php?lang=en&act=ST&f=17&t=913&st=120 | url-status=live }}</ref>

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 nonpolar hydrocarbon solvent such as [[naphtha]] or [[heptane]], and a [[Base (chemistry)|base]] such as [[sodium hydroxide]].{{cn | date = June 2023}}

A variety of plants contain DMT at sufficient levels for being viable sources,<ref name="CarbonaroGatch2016" /> but specific plants such as ''[[Mimosa tenuiflora]], [[Acacia acuminata]],'' and ''[[Acacia confusa]]'' are most often used.

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.{{Citation needed|reason=Such precise values range needs one or more reliable sources|date=January 2012}} Less than 0.1% of an oral dose is eliminated unchanged in the 24-hour urine of humans.<ref>{{cite journal | vauthors = Callaway JC, Raymon LP, Hearn WL, McKenna DJ, Grob CS, Brito GS, Mash DC | title = Quantitation of ''N'',''N''-dimethyltryptamine and harmala alkaloids in human plasma after oral dosing with ayahuasca | journal = Journal of Analytical Toxicology | volume = 20 | issue = 6 | pages = 492–497 | date = October 1996 | pmid = 8889686 | doi = 10.1093/jat/20.6.492 | doi-access = free }}</ref><ref>{{cite book | vauthors = Baselt R | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 9th | publisher = Biomedical Publications | location = Seal Beach, CA | date = 2011 | pages = 525–526 | isbn = 978-0-9626523-8-7 }}</ref>{{Clarify|date=March 2014|reason=unclear language, eliminated unchanged?}}

Before techniques of [[molecular biology]] were used to localize [[indolethylamine N-methyltransferase|indolethylamine ''N''-methyltransferase]] (INMT),<ref name="pmid9852119" /><ref name="pmid10552930" /> 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<ref name="pmid779022" /> or with addition of a radiolabeled substrate like (¹⁴C)NMT to demonstrate [[in vivo]] formation.<ref name="pmid6792104" /><ref name="pmid14361" /> 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. The essentially qualitative method [[thin layer chromatography]] (TLC) was thus used in a vast majority of studies.<ref name="pmid779022" /> Also, robust evidence that INMT can catalyze transmethylation of tryptamine into NMT and DMT could be provided with [[Isotopic dilution|reverse isotope dilution analysis]] coupled to [[mass spectrometry]] for rabbit<ref name="pmid5150167">{{cite journal | vauthors = Mandel LR, Rosenzweig S, Kuehl FA | title = Purification and substrate specificity of indoleamine-''N''-methyl transferase | journal = Biochemical Pharmacology | volume = 20 | issue = 3 | pages = 712–716 | date = March 1971 | pmid = 5150167 | doi = 10.1016/0006-2952(71)90158-4 }}</ref><ref name="pmid1056183">{{cite journal | vauthors = Lin R, Narasimhachari N | title = ''N''-Methylation of 1-methyltryptamines by indolethylamine ''N''-methyltransferase | journal = Biochemical Pharmacology | volume = 24 | issue = 11–12 | pages = 1239–1240 | date = June 1975 | pmid = 1056183 | doi = 10.1016/0006-2952(75)90071-4 }}</ref> and human<ref name="pmid5034200">{{cite journal | vauthors = Mandel LR, Ahn HS, VandenHeuvel WJ | title = Indoleamine-''N''-methyl transferase in human lung | journal = Biochemical Pharmacology | volume = 21 | issue = 8 | pages = 1197–1200 | date = April 1972 | pmid = 5034200 | doi = 10.1016/0006-2952(72)90113-X }}</ref> lung during the early 1970s.

Selectivity rather than sensitivity proved to be a challenge 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,<ref name="pmid779022" /><ref name="pmid6792104" /><ref name="pmid1067427">{{cite journal | vauthors = Rosengarten H, Meller E, Freidhoff AJ | title = Possible source of error in studies of enzymatic formation of dimethyltryptamine | journal = Journal of Psychiatric Research | volume = 13 | issue = 1 | pages = 23–30 | year = 1976 | pmid = 1067427 | doi = 10.1016/0022-3956(76)90006-6 }}</ref> and negligible amounts of DMT in brain tissue.<ref name="pmid779022" /> 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.<ref name="pmid779022" /> These findings are a blow for all previous claims of evidence of INMT activity and DMT biosynthesis in avian<ref name="pmid5793241">{{cite journal | vauthors = Morgan M, Mandell AJ | title = Indole(ethyl)amine ''N''-methyltransferase in the brain | journal = Science | volume = 165 | issue = 3892 | pages = 492–493 | date = August 1969 | pmid = 5793241 | doi = 10.1126/science.165.3892.492 | bibcode = 1969Sci...165..492M | s2cid = 43317224 }}</ref> and mammalian brain,<ref name="pmid5279043">{{cite journal | vauthors = Mandell AJ, Morgan M | title = Indole(ethyl)amine ''N''-methyltransferase in human brain | journal = Nature | volume = 230 | issue = 11 | pages = 85–87 | date = March 1971 | pmid = 5279043 | doi = 10.1038/newbio230085a0 }}</ref><ref name="pmid4703789">{{cite journal | vauthors = Saavedra JM, Coyle JT, Axelrod J | title = The distribution and properties of the nonspecific ''N''-methyltransferase in brain | journal = Journal of Neurochemistry | volume = 20 | issue = 3 | pages = 743–752 | date = March 1973 | pmid = 4703789 | doi = 10.1111/j.1471-4159.1973.tb00035.x | s2cid = 42038762 }}</ref> including [[in vivo]],<ref name="pmid5059565">{{cite journal | vauthors = Saavedra JM, Axelrod J | title = Psychotomimetic ''N''-methylated tryptamines: formation in brain in vivo and in vitro | journal = Science | volume = 175 | issue = 4028 | pages = 1365–1366 | date = March 1972 | pmid = 5059565 | doi = 10.1126/science.175.4028.1365 | url = http://crfdl.org:1111/xmlui/bitstream/handle/123456789/392/1733285.pdf?sequence=1 | format = PDF | bibcode = 1972Sci...175.1365S | s2cid = 30864349 }}{{Dead link|date=July 2018 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="pmid4725358">{{cite journal | vauthors = Wu PH, Boulton AA | title = Distribution and metabolism of tryptamine in rat brain | journal = Canadian Journal of Biochemistry | volume = 51 | issue = 7 | pages = 1104–1112 | date = July 1973 | pmid = 4725358 | doi = 10.1139/o73-144 }}</ref> as they all relied upon use of the problematic TLC methods:<ref name="pmid779022" /> 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.<ref name="pmid963555">{{cite journal | vauthors = Boarder MR, Rodnight R | title = Tryptamine-''N''-methyltransferase activity in brain tissue: a re-examination | journal = Brain Research | volume = 114 | issue = 2 | pages = 359–364 | date = September 1976 | pmid = 963555 | doi = 10.1016/0006-8993(76)90680-6 | s2cid = 36334101 }}</ref><ref name="pmid823298">{{cite journal | vauthors = Gomes UR, Neethling AC, Shanley BC | title = Enzymatic N-methylation of indoleamines by mammalian brain: fact or artefact? | journal = Journal of Neurochemistry | volume = 27 | issue = 3 | pages = 701–705 | date = September 1976 | pmid = 823298 | doi = 10.1111/j.1471-4159.1976.tb10397.x | s2cid = 6043841 }}</ref> 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".<ref name="pmid279646">{{cite journal | vauthors = Stramentinoli G, Baldessarini RJ | title = Lack of enhancement of dimethyltryptamine formation in rat brain and rabbit lung in vivo by methionine or ''S''-adenosylmethionine | journal = Journal of Neurochemistry | volume = 31 | issue = 4 | pages = 1015–1020 | date = October 1978 | pmid = 279646 | doi = 10.1111/j.1471-4159.1978.tb00141.x | s2cid = 26099031 }}</ref> Capability of the method used in this latter study to resolve DMT from tetrahydro-β-carbolines is questioned later.<ref name="pmid6792104"/>

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 (human)|chromosome 7]].<ref name="pmid10552930" /> [[Northern blot|Northern blot analyses]] reveal INMT [[messenger RNA]] (mRNA) to be highly expressed in rabbit lung,<ref name="pmid9852119" /> and in human [[thyroid]], [[adrenal gland]], and lung.<ref name="pmid10552930" /><ref name="UniProtO95050">{{cite web|url=https://www.uniprot.org/uniprot/O95050|title=INMT – Indolethylamine ''N''-methyltransferase – ''Homo sapiens'' (Human) – INMT gene & protein|website=Uniprot.org|access-date=2018-03-24|archive-date=2018-09-20|archive-url=https://web.archive.org/web/20180920111803/https://www.uniprot.org/uniprot/O95050|url-status=live}}</ref> Intermediate levels of expression are found in human heart, skeletal muscle, trachea, stomach, small intestine, pancreas, testis, prostate, placenta, [[lymph node]], and spinal cord.<ref name="pmid10552930" /><ref name="UniProtO95050" /> Low to very low levels of expression are noted in rabbit brain,<ref name="pmid10552930" /> and human [[thymus]], liver, [[spleen]], kidney, colon, ovary, and [[bone marrow]].<ref name="pmid10552930" /><ref name="UniProtO95050" /> INMT mRNA expression is absent in human peripheral blood [[White blood cell|leukocytes]], whole brain, and in tissue from seven specific brain regions (thalamus, subthalamic nucleus, caudate nucleus, hippocampus, amygdala, substantia nigra, and corpus callosum).<ref name="pmid10552930" /><ref name="UniProtO95050" /> [[Immunohistochemistry]] showed INMT to be present in large amounts in [[Goblet cell|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.<ref name="Cozzi N.V., Mavlyutov T.A., Thompson M.A., Ruoho A.E. 2011 840.19">{{cite journal | vauthors = Cozzi NV, Mavlyutov TA, Thompson MA, Ruoho AE | title = Indolethylamine N-methyltransferase expression in primate nervous tissue. | journal = Society for Neuroscience Abstracts | date = 2011 | volume = 37 | pages = 840.19 |url=http://www.neurophys.wisc.edu/~cozzi/Indolethylamine%20N-methyltransferase%20expression%20in%20primate%20nervous%20tissue.pdf |access-date=20 September 2012|archive-url=https://web.archive.org/web/20120913184820/http://www.neurophys.wisc.edu/~cozzi/Indolethylamine%20N-methyltransferase%20expression%20in%20primate%20nervous%20tissue.pdf|archive-date=13 September 2012}}</ref> A 2020 study using [[in-situ hybridization]], a far more accurate tool than the northern blot analysis, found mRNA coding for INMT expressed in the human cerebral cortex, choroid plexus, and pineal gland.<ref name = "Dean_2019" />

Published in ''[[Science (journal)|Science]]'' in 1961, [[Julius Axelrod]] found an ''N''-[[methyltransferase]] enzyme capable of mediating biotransformation of tryptamine into DMT in a rabbit's lung.<ref name="pmid13685339" /> This finding initiated a still ongoing scientific interest in endogenous DMT production in humans and other mammals.<ref name="pmid779022" /><ref name="pmid16095048">{{cite journal | vauthors = Kärkkäinen J, Forsström T, Tornaeus J, Wähälä K, Kiuru P, Honkanen A, Stenman UH, Turpeinen U, Hesso A | title = Potentially hallucinogenic 5-hydroxytryptamine receptor ligands bufotenine and dimethyltryptamine in blood and tissues | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 65 | issue = 3 | pages = 189–199 | date = April 2005 | pmid = 16095048 | doi = 10.1080/00365510510013604 | s2cid = 20005294 }}</ref> From then on, two major complementary lines of evidence have been investigated: Localization and further characterization of the ''N''-methyltransferase enzyme, and [[Analytical chemistry|analytical studies]] looking for endogenously-produced DMT in body fluids and tissues.<ref name="pmid779022" />

It is assumed that more than half of the amount of DMT produced by the acidophilic cells of the pineal gland is secreted before and during death,{{Citation needed|date=July 2021}} the amount being 2.5-3.4&nbsp;mg/kg. However, this claim by Strassman has been criticized by David Nichols who notes that DMT does not appear to be produced in any meaningful amount by the pineal gland. Removal or calcification of the pineal gland does not induce any of the symptoms caused by removal of DMT. The symptoms presented are consistent solely with reduction in melatonin, which is the pineal gland's known function. Nichols instead suggests that [[dynorphin]] and other [[endorphins]] are responsible for the reported euphoria experienced by patients during a [[near-death experience]].<ref name= "pmid29095071">{{cite journal | vauthors = Nichols, DE | title = ''N'',''N''-Dimethyltryptamine and the pineal gland: Separating fact from myth | journal = Journal of Psychopharmacology | volume = 32 | issue = 1 | pages = 30–36 | date = Nov 2017 |pmid =29095071 |doi = 10.1177/0269881117736919 | doi-access = free }}</ref>

In 2014, researchers demonstrated the [[Immunomodulation|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.<ref name="pmid25171370">{{cite journal | vauthors = Szabo A, Kovacs A, Frecska E, Rajnavolgyi E | title = Psychedelic ''N'',''N''-dimethyltryptamine and 5-methoxy-''N'',''N''-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells | journal = PLOS ONE | volume = 9 | issue = 8 | pages = e106533 | date = 29 August 2014 | pmid = 25171370 | pmc = 4149582 | doi = 10.1371/journal.pone.0106533 | bibcode = 2014PLoSO...9j6533S | doi-access = free }}</ref>

''N'',''N''-Dimethyltryptamine (DMT), a psychedelic compound identified endogenously in mammals, is biosynthesized by aromatic {{sc|L}}-amino acid decarboxylase (AADC) and indolethylamine-''N''-methyltransferase (INMT). Studies have investigated brain expression of INMT transcript in rats and humans, coexpression of INMT and AADC mRNA in rat brain and periphery, and brain concentrations of DMT in rats. INMT transcripts were identified in the cerebral cortex, pineal gland, and choroid plexus of both rats and humans via ''in situ'' hybridization. Notably, INMT mRNA was colocalized with AADC transcript in rat brain tissues, in contrast to rat peripheral tissues where there existed little overlapping expression of INMT with AADC transcripts. Additionally, extracellular concentrations of DMT in the cerebral cortex of normal behaving rats, with or without the pineal gland, were similar to those of canonical monoamine neurotransmitters including serotonin. A significant increase of DMT levels in the rat visual cortex was observed following induction of experimental cardiac arrest, a finding independent of an intact pineal gland. These results show for the first time that the rat brain is capable of synthesizing and releasing DMT at concentrations comparable to known monoamine neurotransmitters and raise the possibility that this phenomenon may occur similarly in human brains.<ref>{{cite journal | vauthors = Dean JG, Liu T, Huff S, Sheler B, Barker SA, Strassman RJ, Wang MM, Borjigin J | title = Biosynthesis and Extracellular Concentrations of ''N'',''N''-dimethyltryptamine (DMT) in Mammalian Brain | journal = Scientific Reports | volume = 9 | issue = 1 | page = 9333 | date = June 2019 | pmid = 31249368 | pmc = 6597727 | doi = 10.1038/s41598-019-45812-w | bibcode = 2019NatSR...9.9333D }}</ref>

! style="background:azure; vertical-align:middle; text-align:center; width:30px;" | Species

! style="background:azure; vertical-align:middle; text-align:center; width:60px;" | Sample

! style="background:azure; vertical-align:middle; text-align:center; width:400px;" | Results

! rowspan="8" style="background:oldLace; vertical-align:top; text-align:center; width:30px;" | Human

| style="vertical-align:middle; background:oldLace; width:60px;" | [[Blood serum]]

| style="vertical-align:middle; background:oldLace; width:400px;" | < LOD (''n'' = 66)<ref name="pmid16095048" />

| style="vertical-align:middle; background:oldLace; width:60px;" | [[Blood plasma]]

| style="vertical-align:middle; background:oldLace; width:400px;" | < LOD (''n'' = 71)<ref name="pmid16095048" /> &nbsp;♦&nbsp; < LOD (''n'' = 38); 1,000 & 10,600ng/L (''n'' = 2)<ref name="pmid4517484">{{cite journal | vauthors = Wyatt RJ, Mandel LR, Ahn HS, Walker RW, Vanden Heuvel WJ | title = Gas chromatographic-mass spectrometric isotope dilution determination of ''N'',''N''-dimethyltryptamine concentrations in normals and psychiatric patients | journal = Psychopharmacologia | volume = 31 | issue = 3 | pages = 265–270 | date = July 1973 | pmid = 4517484 | doi = 10.1007/BF00422516 | s2cid = 42469897 }}</ref>

| style="vertical-align:middle; background:oldLace; width:60px;" | Whole blood

| style="vertical-align:middle; background:oldLace; width:400px;" | < LOD (''n'' = 20); 50-790ng/L (''n'' = 20)<ref name="pmid803203">{{cite journal | vauthors = Angrist B, Gershon S, Sathananthan G, Walker RW, López-Ramos B, Mandel LR, Vandenheuvel WJ | title = Dimethyltryptamine levels in blood of schizophrenic patients and control subjects | journal = Psychopharmacology | volume = 47 | issue = 1 | pages = 29–32 | date = May 1976 | pmid = 803203 | doi = 10.1007/BF00428697 | s2cid = 5850801 }}</ref>

| style="vertical-align:middle; background:oldLace; width:60px;" | Urine

| style="vertical-align:middle; background:oldLace; width:400px;" | < 100ng/L (''n'' = 9)<ref name="pmid16095048" /> &nbsp;♦&nbsp; < LOD (''n'' = 60); 160-540ng/L (''n'' = 5)<ref name="pmid11763413" /> &nbsp;♦&nbsp; Detected in ''n'' = 10 by GC-MS<ref name="pmid271509">{{cite journal | vauthors = Oon MC, Rodnight R | title = A gas chromatographic procedure for determining N, N-dimethyltryptamine and N-monomethyltryptamine in urine using a nitrogen detector | journal = Biochemical Medicine | volume = 18 | issue = 3 | pages = 410–419 | date = December 1977 | pmid = 271509 | doi = 10.1016/0006-2944(77)90077-1 }}</ref>

|- style="vertical-align:middle; background:oldLace;"

| style="width:400px;" | < 50ng/kg (n&nbsp;= 12); 130ng/kg (''n'' = 1)<ref name="pmid16095048" />

|- style="vertical-align:middle; background:oldLace;"

| style="width:400px;" | 15ng/kg (''n'' = 1)<ref name="pmid16095048" />

|- style="vertical-align:middle; background:oldLace;"

| style="width:400px;" | 14ng/kg (''n'' = 1)<ref name="pmid16095048" />

| style="vertical-align:middle; background:oldLace; width:60px;" | [[Lumbar puncture|Lumbar]] CSF

| style="vertical-align:middle; background:oldLace; width:400px;" | 100,370ng/L (''n'' = 1); 2,330-7,210ng/L (''n'' = 3); 350 & 850ng/L (''n'' = 2)<ref name="pmid289421">{{cite journal | vauthors = Smythies JR, Morin RD, Brown GB | title = Identification of dimethyltryptamine and O-methylbufotenin in human cerebrospinal fluid by combined gas chromatography/mass spectrometry | journal = Biological Psychiatry | volume = 14 | issue = 3 | pages = 549–556 | date = June 1979 | pmid = 289421 }}</ref>

! rowspan="4" style="background:#dcdcdc; vertical-align:top; text-align:center; width:30px;" | Rat

| style="vertical-align:middle; background:#dcdcdc; width:60px;" | Kidney

| style="vertical-align:middle; background:#dcdcdc; width:400px;" | 12 &amp; 16ng/kg (''n'' = 2)<ref name="pmid16095048" />

|- style="vertical-align:middle; background:#dcdcdc;"

| style="width:400px;" | 22 & 12ng/kg (''n'' = 2)<ref name="pmid16095048" />

|- style="vertical-align:middle; background:#dcdcdc;"

| style="width:400px;" | 6 & 10ng/kg (''n'' = 2)<ref name="pmid16095048" />

| style="vertical-align:middle; background:#dcdcdc; width:60px;" | Brain

| style="vertical-align:middle; background:#dcdcdc; width:400px;" | 10 &amp; 15ng/kg (''n'' = 2)<ref name="pmid16095048" /> &nbsp;♦ &nbsp;Measured in [[Synaptic vesicle|synaptic vesicular]] [[Fractionation|fraction]]<ref name="pmid20877">{{cite journal | vauthors = Christian ST, Harrison R, Quayle E, Pagel J, Monti J | title = The in vitro identification of dimethyltryptamine (DMT) in mammalian brain and its characterization as a possible endogenous neuroregulatory agent | journal = Biochemical Medicine | volume = 18 | issue = 2 | pages = 164–183 | date = October 1977 | pmid = 20877 | doi = 10.1016/0006-2944(77)90088-6 }}</ref>

! style="vertical-align:middle; background:honeyDew; width:30px;" | Rabbit

| style="vertical-align:middle; background:honeyDew; width:60px;" | Liver

| style="vertical-align:middle; background:honeyDew; width:400px;" | < 10ng/kg (''n'' = 1)<ref name="pmid16095048" />

A 2013 study found DMT in [[Microdialysis|microdialysate]] obtained from a rat's pineal gland, providing evidence of endogenous DMT in the mammalian brain.<ref name="pmid23881860" /> In 2019 experiments showed that the rat brain is capable of synthesizing and releasing DMT. These results raise the possibility that this phenomenon may occur similarly in human brains.<ref name = "Dean_2019" />

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|{{sc|L}}-tryptophan]] is produced endogenously where in animals {{sc|L}}-tryptophan is an [[essential amino acid]] coming from diet. No matter the source of {{sc|L}}-tryptophan, the biosynthesis begins with its [[decarboxylation]] by an [[aromatic amino acid decarboxylase]] (AADC) [[enzyme]] (step 1). The resulting decarboxylated tryptophan [[Analog (chemistry)|analog]] is [[tryptamine]]. Tryptamine then undergoes a [[transmethylation]] (step 2): the enzyme [[tryptamine-N-methyltransferase|indolethylamine-''N''-methyltransferase]] (INMT) [[Catalysis|catalyzes]] the transfer of a [[methyl group]] from [[Cofactor (biochemistry)|cofactor]] [[S-adenosyl-methionine|''S''-adenosylmethionine]] (SAM), via [[nucleophilic]] attack, to tryptamine. This reaction transforms SAM into [[S-adenosylhomocysteine|''S''-adenosylhomocysteine]] (SAH), and gives the intermediate product [[N-methyltryptamine|''N''-methyltryptamine]] (NMT).<ref name="pmid13685339">{{cite journal | vauthors = Axelrod J | title = Enzymatic formation of psychotomimetic metabolites from normally occurring compounds | journal = Science | volume = 134 | issue = 3475 | page = 343 | date = August 1961 | pmid = 13685339 | doi = 10.1126/science.134.3475.343 | bibcode = 1961Sci...134..343A | s2cid = 39122485 }}</ref><ref name="pmid779022">{{cite journal | vauthors = Rosengarten H, Friedhoff AJ | title = A review of recent studies of the biosynthesis and excretion of hallucinogens formed by methylation of neurotransmitters or related substances | journal = Schizophrenia Bulletin | volume = 2 | issue = 1 | pages = 90–105 | year = 1976 | pmid = 779022 | doi = 10.1093/schbul/2.1.90 | doi-access = free }}</ref> 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,<ref name="pmid6792104">{{Cite book | vauthors = Barker SA, Monti JA, Christian ST |title=International Review of Neurobiology Volume 22 |chapter=N,N-Dimethyltryptamine: An Endogenous Hallucinogen |volume=22 |pages=83–110 |year=1981 |pmid=6792104 |doi=10.1016/S0074-7742(08)60291-3 |isbn=978-0-12-366822-6}}</ref><ref name="pmid4756800">{{cite journal | vauthors = Lin RL, Narasimhachari N, Himwich HE | title = Inhibition of indolethylamine-''N''-methyltransferase by ''S''-adenosylhomocysteine | journal = Biochemical and Biophysical Research Communications | volume = 54 | issue = 2 | pages = 751–759 | date = September 1973 | pmid = 4756800 | doi = 10.1016/0006-291X(73)91487-3 | bibcode = 1973BBRC...54..751L }}</ref><ref name="pmid9852119">{{cite journal | vauthors = Thompson MA, Weinshilboum RM | title = Rabbit lung indolethylamine ''N''-methyltransferase. cDNA and gene cloning and characterization | journal = The Journal of Biological Chemistry | volume = 273 | issue = 51 | pages = 34502–34510 | date = December 1998 | pmid = 9852119 | doi = 10.1074/jbc.273.51.34502 | doi-access = free }}</ref> and DMT<ref name="pmid6792104" /><ref name="pmid9852119" /> were shown ''ex vivo'' to be among the most potent inhibitors of rabbit INMT activity.

DMT derived from [[plant]]-based sources has been used as an [[entheogen]] in [[South America]] for thousands of years.<ref name="MillerAlbarracin-JordanMoore2019">{{cite journal | vauthors = Miller MJ, Albarracin-Jordan J, Moore C, Capriles JM | title = Chemical evidence for the use of multiple psychotropic plants in a 1,000-year-old ritual bundle from South America | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 23 | pages = 11207–11212 | date = June 2019 | pmid = 31061128 | pmc = 6561276 | doi = 10.1073/pnas.1902174116 | bibcode = 2019PNAS..11611207M | doi-access = free }}</ref><ref name="Anwar2019">{{Cite web|url=https://news.berkeley.edu/2019/05/06/ayahuasca-sacred-bundle/|title=Ayahuasca fixings found in 1,000-year-old Andean sacred bundle|vauthors=Anwar Y|date=6 May 2019|website=Berkeley News|language=en-US|access-date=21 May 2019|archive-date=12 May 2019|archive-url=https://web.archive.org/web/20190512172214/https://news.berkeley.edu/2019/05/06/ayahuasca-sacred-bundle/|url-status=live}}</ref>

DMT was first synthesized in 1931 by Canadian chemist Richard Helmuth Fredrick Manske.<ref name="Shulgin1976">{{cite journal | vauthors = Shulgin AT | title=Profiles of Psychedelic Drugs: DMT & TMA-2 | journal=Journal of Psychedelic Drugs | volume=8 | issue=2 | date=1976 | issn=0022-393X | doi=10.1080/02791072.1976.10471846 | pages=167–169 | url=https://www.tandfonline.com/doi/full/10.1080/02791072.1976.10471846 | access-date=8 April 2025| url-access=subscription }}</ref><ref name="Manske R.H.F. 1931 592–600">{{cite journal|year=1931|title=A synthesis of the methyltryptamines and some derivatives|url=http://rparticle.web-p.cisti.nrc.ca/rparticle/AbstractTemplateServlet?calyLang=eng&journal=cjr&volume=5&year=&issue=5&msno=cjr31-097|journal=Canadian Journal of Research|volume=5|issue=5|pages=592–600|doi=10.1139/cjr31-097| vauthors = Manske RH |bibcode=1931CJRes...5..592M|url-access=subscription}}{{Dead link|date=July 2018 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="bdmxab">{{cite journal|date=November 1977|title=DMT: the fifteen minute trip|url=http://jeremybigwood.net/JBsPUBS/DMT/|journal=Head|volume=2|issue=4|pages=56–61| vauthors = Bigwood J, Ott J |access-date=28 November 2010|archive-url=https://web.archive.org/web/20060127003553/http://jeremybigwood.net/JBsPUBS/DMT/|archive-date=27 January 2006}}</ref> In general, its discovery as a natural product is credited to Brazilian chemist and [[microbiologist]] Oswaldo Gonçalves de Lima, who isolated an alkaloid he named ''nigerina'' (nigerine) from the root bark of ''[[Mimosa tenuiflora]]'' in 1946.<ref name="bdmxab" /><ref name="strassman" /><ref name="ott1996">{{cite book |title=Pharmacotheon: Entheogenic Drugs, Their Plant Sources and History | vauthors = Ott J |author-link=Jonathan Ott |edition=2nd, densified |year=1996 |publisher=Natural Products |location=Kennewick, WA |isbn=978-0-9614234-9-0}}</ref> 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.<ref name="ott1998">{{cite book |vauthors=Ott J |author-link1=Jonathan Ott |veditors=Müller-Ebeling C |title=Special: Psychoactivity |series=Yearbook for Ethnomedicine and the Study of Consciousness |volume=6/7 (1997/1998) |year=1998 |publisher=VWB |location=Berlin |isbn=978-3-86135-033-0 |chapter=Pharmahuasca, anahuasca and vinho da jurema: human pharmacology of oral DMT plus harmine |chapter-url=https://www.erowid.org/references/texts/show/7105docid6446 |access-date=2010-11-29 |archive-date=2018-10-31 |archive-url=https://web.archive.org/web/20181031212537/https://www.erowid.org/references/texts/show/7105docid6446 |url-status=live }}</ref> 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.<ref name="ott1998" /><ref>{{cite journal| vauthors = Pachter IJ, Zacharias DE, Ribeiro O |title=Indole alkaloids of ''Acer saccharinum'' (the silver maple), ''Dictyoloma incanescens'', ''Piptadenia colubrina'', and ''Mimosa hostilis'' |journal=Journal of Organic Chemistry |date=September 1959 |volume=24 |issue=9 |pages=1285–1287 |doi=10.1021/jo01091a032}}</ref> 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).<ref name="ott1998" /><ref>{{cite journal | vauthors = Fish MS, Johnson NM, Horning EC |date=November 1955 |title=Piptadenia alkaloids. Indole bases of ''P. peregrina'' (L.) Benth. and related species |journal=Journal of the American Chemical Society |volume=72 |issue=22 |pages=5892–5895 |doi=10.1021/ja01627a034|bibcode=1955JAChS..77.5892F }}</ref> Since 1955, DMT has been [[#Endogenous DMT|found in a number of organisms]]: in at least fifty plant species belonging to ten [[Family (biology)|families]],<ref name="ott1994">{{cite book|title=Ayahuasca Analogues: Pangæan Entheogens| vauthors = Ott J |publisher=Natural Products|year=1994|isbn=978-0-9614234-5-2|edition=1st|location=[[Kennewick, WA]], USA|pages=81–83|oclc=32895480|author-link=Jonathan Ott}}</ref> and in at least four animal species, including one [[gorgonian]]<ref name="ReferenceA">{{cite journal|year=1978|title=Chemistry of Mediterranean gorgonians: simple indole derivatives from ''Paramuricea chamaeleon''|journal=Comparative Biochemistry and Physiology C|volume=61|issue=2|pages=361–362|doi=10.1016/0306-4492(78)90070-9| vauthors = Cimino G, De Stefano S }}</ref> and three mammalian species (including humans).{{citation needed|date=October 2022}}

In terms of a scientific understanding, the [[hallucinogen]]ic effects of DMT were not uncovered until 1956 by Hungarian chemist and psychiatrist [[Stephen Szára|Stephen Szara]].<ref name="Shulgin1976" /><ref name="Szara1956" /> 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.<ref name="Szara1956">{{cite journal | vauthors = Szara S | title = Dimethyltryptamin: its metabolism in man; the relation to its psychotic effect to the serotonin metabolism | journal = Experientia | volume = 12 | issue = 11 | pages = 441–442 | date = November 1956 | pmid = 13384414 | doi = 10.1007/bf02157378 | s2cid = 7775625 }}</ref> This is considered to be the converging link between the chemical structure DMT to its cultural consumption as a psychoactive and religious sacrament.<ref name="McKennaCallawayGrob1998">{{cite journal | vauthors = McKenna DJ, Callaway JC, Grob CS | year = 1998 | title = The scientific investigation of Ayahuasca: a review of past and current research | journal = The Heffter Review of Psychedelic Research | volume = 1 | issue = 65–77| pages = 195–223 }}</ref>

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''.<ref>{{cite journal | vauthors = Hochstein FA, Paradies AM |year=1957 |title=Alkaloids of ''Banisteria caapi'' and ''Prestonia amazonicum'' |journal=Journal of the American Chemical Society |volume=79 |issue=21 |pages=5735–5736 |doi=10.1021/ja01578a041 |bibcode=1957JAChS..79.5735H }}</ref> The lack of a proper botanical identification of ''[[Prestonia amazonica]]'' in this study led American [[ethnobotany|ethnobotanist]] [[Richard Evans Schultes]] (1915-2001) and other scientists to raise serious doubts about the claimed plant identity.<ref>{{cite journal |vauthors=Schultes RE, Raffauf RF |year=1960 |title=''Prestonia'': An Amazon narcotic or not? |journal=Botanical Museum Leaflets, Harvard University |volume=19 |issue=5 |pages=109–122 |doi=10.5962/p.168526 |s2cid=91123988 |issn=0006-8098 |url=https://www.biodiversitylibrary.org/item/31906#page/126/mode/1up |doi-access=free |access-date=2018-01-14 |archive-date=2018-08-10 |archive-url=https://web.archive.org/web/20180810224847/https://www.biodiversitylibrary.org/item/31906#page/126/mode/1up |url-status=live }}</ref><ref name="pmid14337385">{{cite journal | vauthors = Poisson J | title = Note on "Natem", A Toxic Peruvian Beverage, and ITS Alkaloids | language = fr | journal = Annales Pharmaceutiques Françaises | volume = 23 | pages = 241–244 | date = April 1965 | pmid = 14337385 | trans-title = Note on "Natem", a toxic Peruvian beverage, and its alkaloids }}</ref> The mistake likely led the writer [[William S. Burroughs|William Burroughs]] to regard the DMT he experimented with in Tangier in 1961 as "Prestonia".<ref>{{Cite book|title=Mystery School in Hyperspace: A Cultural History of DMT| vauthors = St John G |publisher=North Atlantic Books / Evolver|year=2015|isbn=978-1-58394-732-6|location=Berkeley, CA.|page=29}}</ref> 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 people|Aguaruna]] Indians, identified as having come from the vine ''[[Diplopterys cabrerana]]'' (then known as ''Banisteriopsis rusbyana'').<ref name="pmid14337385" /> Published in 1970, the first identification of DMT in the plant ''[[Psychotria viridis]]'',<ref name="ott1996" /> another common additive of ayahuasca, was made by a team of American researchers led by pharmacologist Ara der Marderosian.<ref>{{cite journal | vauthors = Der Marderosian AH, Kensinger KM, Chao JM, Goldstein FJ |year=1970 |title=The use and hallucinatory principles of a psychoactive beverage of the Cashinahua tribe (Amazon basin) |journal=Drug Dependence |volume=5 |pages=7–14 |issn=0070-7368 |oclc=1566975}}</ref> 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.<ref name="ott1996" />

Internationally DMT is illegal to possess without authorisation, exemption or license, 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.

* [[India]] - DMT is illegal to produce, transport, trade in, or possess with a minimum prison or jail punishment of ten years.<ref>{{Cite web |title=THE GOD DRUG- DMT |url=https://www.mangaloretoday.com/opinion/THE-GOD-DRUG-DMT.html |url-status=live |archive-url=https://web.archive.org/web/20200921184859/http://www.mangaloretoday.com/opinion/THE-GOD-DRUG-DMT.html |archive-date=21 September 2020 |access-date=10 August 2020 |website=Mangaloretoday.com}}</ref>

* [[Belgium]] - DMT cannot be possessed, sold, purchased or imported. Usage is not specifically prohibited, but since usage implies possession one could be prosecuted that way.<ref>{{Cite web |title=Wetgeving rond LSD en tripmiddelen |url=https://www.druglijn.be/drugs-abc/lsd-en-tripmiddelen/wetgeving |url-status=live |archive-url=https://web.archive.org/web/20190420154514/https://www.druglijn.be/drugs-abc/lsd-en-tripmiddelen/wetgeving |archive-date=2019-04-20 |access-date=2019-04-20 |website=Druglijn.be}}</ref>

=====North-America=====

* [[United States]] - DMT is classified in the United States as a [[List of Schedule I drugs (US)|Schedule I]] drug under the [[Controlled Substances Act|Controlled Substances Act of 1970]].

* [[Australia]] - DMT is listed as a Schedule 9 prohibited substance in [[Australia]] under the [[Standard for the Uniform Scheduling of Medicines and Poisons|Poisons Standard]] (October 2015).<ref name="Poisons Standard">{{cite web |date=30 September 2015 |title=Poisons Standard October 2015 |url=https://www.comlaw.gov.au/Details/F2015L01534 |url-status=live |archive-url=https://web.archive.org/web/20160119074606/https://www.comlaw.gov.au/Details/F2015L01534/ |archive-date=2016-01-19 |access-date=2016-01-06 |work=comlaw.gov.au}}</ref> 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".<ref>{{cite web |date=1964 |title=Poisons Act |url=http://www.slp.wa.gov.au/pco/prod/FileStore.nsf/Documents/MRDocument:26063P/$FILE/Poisons%20Act%201964%20-%20%5B09-f0-04%5D.pdf?OpenElement |archive-url=https://web.archive.org/web/20151222191725/http://www.slp.wa.gov.au/pco/prod/FileStore.nsf/Documents/MRDocument%3A26063P/%24FILE/Poisons%20Act%201964%20-%20%5B09-f0-04%5D.pdf?OpenElement |archive-date=22 December 2015 |work=slp.wa.gov.au}}</ref> Between 2011 and 2012, the [[Australian federal government]] was considering changes to the [[Criminal law of Australia|Australian Criminal Code]] that would classify any plants containing any amount of DMT as "controlled plants".<ref>{{cite web |date=24 June 2010 |title=Consultation on implementation of model drug schedules for Commonwealth serious drug offenses |url=http://www.ag.gov.au/www/agd/agd.nsf/Page/Consultationsreformsandreviews_ConsultationonimplementationofmodeldrugschedulesforCommonwealthseriousdrugoffences |archive-url=https://web.archive.org/web/20111107074102/http://www.ag.gov.au/www/agd/agd.nsf/Page/Consultationsreformsandreviews_ConsultationonimplementationofmodeldrugschedulesforCommonwealthseriousdrugoffences |archive-date=7 November 2011 |publisher=[[Attorney-General's Department (Australia)|Australian Government, Attorney-General's Department]]}}</ref> 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 [[List of Australian floral emblems|Floral Emblem of Australia]], [[Acacia pycnantha]] (Golden Wattle), illegal.{{citation needed|date=January 2021}} 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).<ref>{{cite journal |date=August 2012 |title=AUSSIE DMT BAN |url=http://connection.ebscohost.com/c/articles/79564875/aussie-dmt-ban |journal=American Herb Association Quarterly Newsletter |volume=27 |issue=3 |page=14 |archive-url=https://web.archive.org/web/20141216060822/http://connection.ebscohost.com/c/articles/79564875/aussie-dmt-ban |archive-date=16 December 2014}}</ref> Under the [[Misuse of Drugs Act 1981]] 6.0g (3/16oz) of DMT is considered enough to determine a court of trial and 2.0g (1/16oz) is considered intent to sell and supply.<ref>{{cite web |title=Misuse of Drugs Act 1981 (2015) |url=http://www.slp.wa.gov.au/pco/prod/FileStore.nsf/Documents/MRDocument:28280P/$FILE/Misuse%20Of%20Drugs%20Act%201981%20-%20%5B06-e0-00%5D.pdf?OpenElement |archive-url=https://web.archive.org/web/20151222180141/http://www.slp.wa.gov.au/pco/prod/FileStore.nsf/Documents/MRDocument%3A28280P/%24FILE/Misuse%20Of%20Drugs%20Act%201981%20-%20%5B06-e0-00%5D.pdf?OpenElement |archive-date=22 December 2015 |work=slp.wa.gov.au}}</ref>

 

Short-acting psychedelics like DMT and 5-MeO-DMT show rapid and sustained antidepressant effects in treatment-resistant depression, potentially offering a more scalable alternative to psilocybin, though larger controlled trials are needed to confirm efficacy.<ref name="Ramaekers2025">{{cite journal |vauthors=Ramaekers JG |date=May 2025 |title=Less is more? Antidepressant effects of short-acting psychedelics |journal=Neuropsychopharmacology |volume=50 |issue=6 |pages=875–876 |doi=10.1038/s41386-025-02103-5 |pmc=12032289 |pmid=40258989 |pmc-embargo-date=May 1, 2026}}</ref><ref name="RamaekersReckwegMason2025">{{cite journal |vauthors=Ramaekers JG, Reckweg JT, Mason NL |date=January 2025 |title=Benefits and Challenges of Ultra-Fast, Short-Acting Psychedelics in the Treatment of Depression |url=https://cris.maastrichtuniversity.nl/en/publications/fb3d3cba-472c-42bf-b665-bf9607461199 |journal=The American Journal of Psychiatry |volume=182 |issue=1 |pages=33–46 |doi=10.1176/appi.ajp.20230890 |pmid=39741439}}</ref>

A recent Phase 1/2 clinical trial evaluated the safety, tolerability, pharmacokinetics, and antidepressant effects of SPL026, an intravenous formulation of DMT [[Fumaric acid|fumarate]], in both healthy volunteers and patients with moderate-to-severe major depressive disorder, using randomized, placebo-controlled and open-label dosing protocols.<ref>{{ClinicalTrialsGov|NCT04673383|A Double-blind, Randomised, Placebo-controlled Study of Intravenous Doses of SPL026 (DMT Fumarate), a Serotonergic Psychedelic, in Healthy Subjects (Part A) and Patients With Major Depressive Disorder (Part B) }}</ref> It found that inhaled 5-MeO-DMT (GH001) was well tolerated and produced rapid antidepressant effects in treatment-resistant depression, with individualized dosing showing the highest remission rates.<ref>{{cite journal | vauthors = James E, Erritzoe D, Benway T, Joel Z, Timmermann C, Good M, Agnorelli C, Weiss BM, Barba T, Campbell G, Baker Jones M, Hughes C, Topping H, Boyce M, Routledge C | title = Safety, tolerability, pharmacodynamic and wellbeing effects of SPL026 (dimethyltryptamine fumarate) in healthy participants: a randomized, placebo-controlled phase 1 trial | journal = Frontiers in Psychiatry | volume = 14 | pages = 1305796 | date = 2023 | pmid = 38274414 | pmc = 10810248 | doi = 10.3389/fpsyt.2023.1305796 | doi-access = free }}</ref>

In a phase 2a open-label trial, inhaled DMT produced rapid, well-tolerated, and sustained antidepressant effects in patients with treatment-resistant depression, showing high response and remission rates within 7 days and lasting up to 3 months.<ref name="Falchi-CarvalhoPalhano-FontesWießner2025">{{cite journal | vauthors = Falchi-Carvalho M, Barros H, Bolcont R, Laborde S, Wießner I, ((Ruschi B Silva S)), Montanini D, Barbosa DC, Teixeira E, Florence-Vilela R, Almeida R, de Macedo RK, Arichelle F, Pantrigo ÉJ, Costa-Macedo JV, Arcoverde E, Galvão-Coelho N, Araujo DB, Palhano-Fontes F | title = Rapid and sustained antidepressant effects of vaporized N,N-dimethyltryptamine: a phase 2a clinical trial in treatment-resistant depression | journal = Neuropsychopharmacology | volume = 50 | issue = 6 | pages = 895–903 | date = May 2025 | pmid = 40258990 | doi = 10.1038/s41386-025-02091-6 | pmc = 12032144 | pmc-embargo-date = May 1, 2026 }}</ref>

A single-day, open-label trial found that vaporized DMT produced rapid and sustained antidepressant effects in treatment-resistant depression, with up to 50% of participants maintaining remission one month post-dose.<ref name="Falchi-CarvalhoBarrosBolcont2025">{{cite journal | vauthors = Falchi-Carvalho M, Barros H, Bolcont R, Laborde S, Wießner I, ((Ruschi B. Silva S)), Montanini D, Barbosa DC, Teixeira E, Florence-Vilela R, Almeida R | title = The Antidepressant Effects of Vaporized <i>N</i>,<i>N</i>-Dimethyltryptamine: An Open-Label Pilot Trial in Treatment-Resistant Depression | journal = Psychedelic Medicine | volume = 3 | issue = 1 | pages = 48–52 | date = March 2025 | pmid = 40337754 | pmc = 12054606 | doi = 10.1089/psymed.2024.0002 | pmc-embargo-date = February 27, 2026 }}</ref>

DMT exists naturally in humans and other animals; it may play significant roles in mammalian physiology-potentially as a [[neurotransmitter]], [[hormone]], and [[immunomodulator]]-despite longstanding skepticism based on outdated or flawed evidence.<ref name="JiménezBouso2022" />

==See also==

* [[List of entheogens]]

 

==References==

==External links==