Editing Dimethyltryptamine (section)

===Pharmacodynamics===
{| class="wikitable floatright" style="font-size:small;"
|+ {{Nowrap|Activities of DMT}}
|-
! [[Biological target|Target]] !! [[Affinity (pharmacology)|Affinity]] (K<sub>i</sub>, nM)
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]]
| 75–>10,000 (K<sub>i</sub>)<br />75–>100,000 ({{Abbrlink|EC<sub>50</sub>|Half-maximal effective concentration}})<br />68–100% ({{Abbrlink|E<sub>max</sub>|Maximal efficacy}})
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]]
| 129–>10,000
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]]
| 39–270
|-
| [[5-HT1E receptor|5-HT<sub>1E</sub>]]
| 456–517
|-
| [[5-HT1F receptor|5-HT<sub>1F</sub>]]
| {{Abbr|ND|No data}}
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]]
| 53–2,323 (K<sub>i</sub>)<br />22–6,325 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />23–105% ({{Abbr|E<sub>max</sub>|Maximal efficacy}})
|-
| [[5-HT2B receptor|5-HT<sub>2B</sub>]]
| 101–184 (K<sub>i</sub>)<br />3,400–>31,600 ({{Abbr|EC<sub>50</sub>|Half-maximal effective concentration}})<br />10.4% ({{Abbr|E<sub>max</sub>|Maximal efficacy}})
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]]
| 33–424 (K<sub>i</sub>)<br />31–114 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />85–99% ({{Abbr|E<sub>max</sub>|Maximal efficacy}})
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]]
| >10,000
|-
| [[5-HT4 receptor|5-HT<sub>4</sub>]]
| {{Abbr|ND|No data}}
|-
| [[5-HT5A receptor|5-HT<sub>5A</sub>]]
| 611–2,135
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]]
| 68–487
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]]
| 88–206
|-
| [[Alpha-1A adrenergic receptor|α<sub>1A</sub>]]
| 1,300–1,745
|-
| [[Alpha-1B adrenergic receptor|α<sub>1B</sub>]]
| 974
|-
| [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]]
| 1,561–2,100
|-
| [[Alpha-2B adrenergic receptor|α<sub>2B</sub>]]
| 258
|-
| [[Alpha-2C adrenergic receptor|α<sub>2C</sub>]]
| 259
|-
| [[Beta-1 adrenergic receptor|β<sub>1</sub>]]–[[Beta-2 adrenergic receptor|β<sub>2</sub>]]
| >10,000
|-
| [[Dopamine receptor D1|D<sub>1</sub>]]
| 271–6,000
|-
| [[Dopamine receptor D2|D<sub>2</sub>]]
| 3,000–>10,000
|-
| [[Dopamine receptor D3|D<sub>3</sub>]]
| 6,300–>10,000
|-
| [[Dopamine receptor D4|D<sub>4</sub>]]
| >10,000
|-
| [[Dopamine receptor D5|D<sub>5</sub>]]
| >10,000
|-
| [[Histamine H1 receptor|H<sub>1</sub>]]
| 220
|-
| [[Histamine H2 receptor|H<sub>2</sub>]]–[[Histamine H4 receptor|H<sub>4</sub>]]
| >10,000
|-
| [[Muscarinic acetylcholine M1 receptor|M<sub>1</sub>]]–[[Muscarinic acetylcholine M5 receptor|M<sub>5</sub>]]
| >10,000
|-
| [[TAAR1|TAAR<sub>1</sub>]]
| 2,200–3,300 (K<sub>i</sub>) (rodent)<br />1,200–1,500 ({{Abbr|EC<sub>50</sub>|Half-maximal effective concentration}}) (rodent)<br />>10,000 ({{Abbr|EC<sub>50</sub>|Half-maximal effective concentration}}) (human)
|-
| [[Sigma-1 receptor|σ<sub>1</sub>]]
| 5,209
|-
| [[Sigma-2 receptor|σ<sub>2</sub>]]
| >10,000
|-
| [[Imidazoline I1 receptor|I<sub>1</sub>]]
| 650
|-
| {{Abbrlink|SERT|Serotonin transporter}}
| 3,742–6,000 (K<sub>i</sub>)<br />2,962–3,100 ({{Abbrlink|IC<sub>50</sub>|Half-maximal inhibitory concentration}})<br />81–114 ({{Abbr|EC<sub>50</sub>|Half-maximal effective concentration}})
|-
| {{Abbrlink|NET|Norepinephrine transporter}}
| 6,500–>10,000 (K<sub>i</sub>)<br />3,900 ({{Abbr|IC<sub>50</sub>|Half-maximal inhibitory concentration}})<br />4,166 ({{Abbr|EC<sub>50</sub>|Half-maximal effective concentration}})
|-
| {{Abbrlink|DAT|Dopamine transporter}}
| >10,000–22,000 (K<sub>i</sub>)<br />52,000 ({{Abbr|IC<sub>50</sub>|Half-maximal inhibitory concentration}})<br />>10,000 ({{Abbr|EC<sub>50</sub>|Half-maximal effective concentration}})
|- class="sortbottom"
| 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<sub>1A</sub>]],<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<sub>1A</sub> and 5-HT<sub>2</sub> 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<sub>1B</sub>]],<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<sub>1D</sub>]],<ref name="pmid19881490" /><ref name="pmid2540505" /><ref name="pmid20126400" /> [[5-HT2A receptor|5-HT<sub>2A</sub>]],<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<sub>2A</sub> and 5-HT<sub>2C</sub> 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<sub>2B</sub>]],<ref name="pmid19881490" /><ref name="pmid20126400" /> [[5-HT2C receptor|5-HT<sub>2C</sub>]],<ref name="pmid19881490" /><ref name="pmid20126400" /><ref name="pmid9768567" /> [[5-HT6 receptor|5-HT<sub>6</sub>]],<ref name="pmid19881490" /><ref name="pmid20126400" /> and [[5-HT7 receptor|5-HT<sub>7</sub>]].<ref name="pmid19881490" /><ref name="pmid20126400" /> An [[agonist]] action has been determined at 5-HT<sub>1A</sub>,<ref name="pmid1828347" /> 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub>.<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<sub>2B</sub> 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<sub>2B</sub> 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|D<sub>1</sub>]], [[α1-adrenergic receptor|α<sub>1</sub>-adrenergic]], [[α2-adrenergic receptor|α<sub>2</sub>-adrenergic]], [[Imidazoline receptor|imidazoline-1]], and [[sigma-1 receptor|σ<sub>1</sub>]] [[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 σ<sub>1</sub> 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|EC<sub>50</sub>|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<sub>2A</sub> 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-HT<sub>2</sub> 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|EC<sub>50</sub>]]) at the human 5-HT<sub>2A</sub> 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<sub>2A</sub> 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<sub>2A</sub> 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<sub>q</sub>]] [[cell signaling|signaling pathway]] of the serotonin 5-HT<sub>2A</sub> 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<sub>2A</sub> 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" />

As DMT has been shown to have slightly better efficacy (EC<sub>50</sub>) at human serotonin 2C receptor than at the 2A receptor,<ref name="pmid20126400" /><ref name="pmid9768567" /> 5-HT<sub>2C</sub> 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<sub>1A</sub><ref name="pmid2540505" /><ref name="pmid14761703" /><ref name="pmid8788488" /> and σ<sub>1</sub><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 σ<sub>1</sub> receptor.<ref name="pmid19213917" /><ref name="pmid19278957" /> The concentration of DMT needed for σ<sub>1</sub> 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 σ<sub>1</sub> 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" />

DMT has been found to be a [[psychoplastogen]], a compound capable of promoting rapid and sustained [[neuroplasticity]] that may have wide-ranging therapeutic benefit.<ref>{{cite journal | vauthors = Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, Burbach KF, Soltanzadeh Zarandi S, Sood A, Paddy MR, Duim WC, Dennis MY, McAllister AK, Ori-McKenney KM, Gray JA, Olson DE | title = Psychedelics Promote Structural and Functional Neural Plasticity | journal = Cell Reports | volume = 23 | issue = 11 | pages = 3170–3182 | date = June 2018 | pmid = 29898390 | pmc = 6082376 | doi = 10.1016/j.celrep.2018.05.022 }}</ref>

The [[cryo-EM]] [[protein–ligand complex|structure]]s of the serotonin 5-HT<sub>2A</sub> receptor with DMT, as well as with various other psychedelics and serotonin 5-HT<sub>2A</sub> 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>