Editing Entactogen (section)

==Pharmacology==
===Mechanism of action===
{{See also|Serotonin releasing agent#Effects and comparisons|MDMA#Pharmacology|Psychedelic drug#Mechanism of action}}

Entactogens like MDMA are [[serotonin releasing agent]]s and hence are indirect [[agonist]]s of [[serotonin receptor]]s.<ref name="DunlapAndrewsOlson2018">{{cite journal | vauthors = Dunlap LE, Andrews AM, Olson DE | title = Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2408–2427 | date = October 2018 | pmid = 30001118 | pmc = 6197894 | doi = 10.1021/acschemneuro.8b00155 | url = }}</ref><ref name="Martinez-PriceKrebs-ThomsonGeyer2002" /><ref name="StoveDeLetterPiette2010" /> They produce entactogenic effects in animals such as increased [[prosocial]] behavior like adjacent lying, enhanced [[empathy]]-like behavior, and [[serenic|antiaggressive]] effects.<ref name="DunlapAndrewsOlson2018" /><ref name="ReinRaymondBoustani2024" /><ref name="Kamilar-BrittBedi2015">{{cite journal | vauthors = Kamilar-Britt P, Bedi G | title = The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled studies in humans and laboratory animals | journal = Neurosci Biobehav Rev | volume = 57 | issue = | pages = 433–446 | date = October 2015 | pmid = 26408071 | pmc = 4678620 | doi = 10.1016/j.neubiorev.2015.08.016 | url = }}</ref> Likewise, MDMA increases [[sociability]], prosociality, and [[emotional empathy]] in humans.<ref name="Kamilar-BrittBedi2015" />

In animals, MDMA induced prosocial behavior and elevations in circulating [[oxytocin]] levels and these effects were abolished by pretreatment with the serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] [[receptor antagonist|antagonist]] [[WAY-100635]].<ref name="DunlapAndrewsOlson2018" /><ref name="Blanco-GandíaMateos-GarcíaGarcía-Pardo2015">{{cite journal | vauthors = Blanco-Gandía MC, Mateos-García A, García-Pardo MP, Montagud-Romero S, Rodríguez-Arias M, Miñarro J, Aguilar MA | title = Effect of drugs of abuse on social behaviour: a review of animal models | journal = Behav Pharmacol | volume = 26 | issue = 6 | pages = 541–570 | date = September 2015 | pmid = 26221831 | doi = 10.1097/FBP.0000000000000162 | url = }}</ref><ref name="ThompsonCallaghanHunt2007">{{cite journal | vauthors = Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS | title = A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine ("ecstasy") | journal = Neuroscience | volume = 146 | issue = 2 | pages = 509–514 | date = May 2007 | pmid = 17383105 | doi = 10.1016/j.neuroscience.2007.02.032 | url = }}</ref><ref name="EsakiSasakiNishitani2023">{{cite journal | vauthors = Esaki H, Sasaki Y, Nishitani N, Kamada H, Mukai S, Ohshima Y, Nakada S, Ni X, Deyama S, Kaneda K | title = Role of 5-HT1A receptors in the basolateral amygdala on 3,4-methylenedioxymethamphetamine-induced prosocial effects in mice | journal = Eur J Pharmacol | volume = 946 | issue = | pages = 175653 | date = May 2023 | pmid = 36907260 | doi = 10.1016/j.ejphar.2023.175653 | url = }}</ref><ref name="MorleyArnoldMcGregor2005">{{cite journal | vauthors = Morley KC, Arnold JC, McGregor IS | title = Serotonin (1A) receptor involvement in acute 3,4-methylenedioxymethamphetamine (MDMA) facilitation of social interaction in the rat | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 29 | issue = 5 | pages = 648–657 | date = June 2005 | pmid = 15908091 | doi = 10.1016/j.pnpbp.2005.04.009 | url = }}</ref> Conversely, the serotonin 5-HT<sub>1A</sub> receptor agonist [[8-OH-DPAT]] produced prosocial behavior and increased oxytocin levels similarly to MDMA.<ref name="DunlapAndrewsOlson2018" /><ref name="ThompsonCallaghanHunt2007" /><ref name="TanMartinBowen2020">{{cite journal | vauthors = Tan O, Martin LJ, Bowen MT | title = Divergent pathways mediate 5-HT1A receptor agonist effects on close social interaction, grooming and aggressive behaviour in mice: Exploring the involvement of the oxytocin and vasopressin systems | journal = J Psychopharmacol | volume = 34 | issue = 7 | pages = 795–805 | date = July 2020 | pmid = 32312154 | doi = 10.1177/0269881120913150 | url = }}</ref> In addition, MDMA has been shown to activate oxytocinergic [[neuron]]s in the [[hypothalamus]] and this too is reversed by serotonin 5-HT<sub>1A</sub> receptor antagonism.<ref name="DunlapAndrewsOlson2018" /><ref name="ThompsonCallaghanHunt2007" /><ref name="HuntMcGregorCornish2011">{{cite journal | vauthors = Hunt GE, McGregor IS, Cornish JL, Callaghan PD | title = MDMA-induced c-Fos expression in oxytocin-containing neurons is blocked by pretreatment with the 5-HT-1A receptor antagonist WAY 100635 | journal = Brain Res Bull | volume = 86 | issue = 1–2 | pages = 65–73 | date = August 2011 | pmid = 21745546 | doi = 10.1016/j.brainresbull.2011.06.011 | url = }}</ref> Subsequent research found that direct injection of the serotonin 5-HT<sub>1A</sub> receptor WAY-100635 locally into the [[basolateral amygdala]] (BLA) suppressed MDMA-induced prosocial behavior and that direct injection of MDMA locally into the BLA significantly increased sociability.<ref name="HeifetsOlson2024">{{cite journal | vauthors = Heifets BD, Olson DE | title = Therapeutic mechanisms of psychedelics and entactogens | journal = Neuropsychopharmacology | volume = 49 | issue = 1 | pages = 104–118 | date = January 2024 | pmid = 37488282 | doi = 10.1038/s41386-023-01666-5 | pmc = 10700553 | url = }}</ref><ref name="EsakiSasakiNishitani2023" />

The serotonin [[5-HT2B receptor|5-HT<sub>2B</sub>]] and [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]] antagonist [[SB-206553]] has also been found to block MDMA-induced prosocial behavior, although it produced potentially [[confounding variable|confounding]] [[thigmotaxis]] (hyperactivity at periphery of testing chamber) as well.<ref name="Blanco-GandíaMateos-GarcíaGarcía-Pardo2015" /><ref name="MorleyArnoldMcGregor2005" /> Conversely, the serotonin [[5-HT1B receptor|5-HT<sub>1B</sub> receptor]] antagonist [[GR-55562]] and the serotonin [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] antagonist [[ketanserin]] were both ineffective.<ref name="Blanco-GandíaMateos-GarcíaGarcía-Pardo2015" /><ref name="EsakiSasakiNishitani2023" /><ref name="MorleyArnoldMcGregor2005" /> Likewise, another study found that [[binding selectivity|selective]] antagonists of the serotonin 5-HT<sub>1B</sub>, 5-HT<sub>2A</sub>, 5-HT<sub>2C</sub>, and [[5-HT4 receptor|5-HT<sub>4</sub> receptor]]s ([[SB-216641]]), [[volinanserin]] (MDL-100907), [[SB-242084]], and [[SB-204070]], respectively) were all ineffective in suppressing MDMA-induced prosocial activity.<ref name="HeifetsOlson2024" /><ref name="EsakiSasakiNishitani2023" /> Other research has found that serotonin 5-HT<sub>2B</sub> receptor inactivation abolishes the serotonin release induced by MDMA and attenuates many of its effects.<ref name="Martinez-PriceKrebs-ThomsonGeyer2002">{{cite journal | last1=Martinez-Price | first1=Diana | last2=Krebs-Thomson | first2=Kirsten | last3=Geyer | first3=Mark | title=Behavioral Psychopharmacology of MDMA and MDMA-Like Drugs: A Review of Human and Animal Studies | journal=Addiction Research & Theory | publisher=Informa UK Limited | volume=10 | issue=1 | date=1 January 2002 | issn=1606-6359 | doi=10.1080/16066350290001704 | pages=43–67}}</ref><ref name="StoveDeLetterPiette2010">{{cite journal | vauthors = Stove CP, De Letter EA, Piette MH, Lambert WE | title = Mice in ecstasy: advanced animal models in the study of MDMA | journal = Curr Pharm Biotechnol | volume = 11 | issue = 5 | pages = 421–433 | date = August 2010 | pmid = 20420576 | doi = 10.2174/138920110791591508 | url = }}</ref><ref name="DolyValjentSetola2008">{{cite journal | vauthors = Doly S, Valjent E, Setola V, Callebert J, Hervé D, Launay JM, Maroteaux L | title = Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro | journal = J Neurosci | volume = 28 | issue = 11 | pages = 2933–2940 | date = March 2008 | pmid = 18337424 | pmc = 6670669 | doi = 10.1523/JNEUROSCI.5723-07.2008 | url = }}</ref> In addition to the preceding findings, induction of serotonin release by MDMA in the [[nucleus accumbens]] and consequent activation of serotonin 5-HT<sub>1B</sub> receptors in this area is implicated in its enhancement of prosocial behaviors, whereas consequent activation of yet-to-be-determined serotonin receptors in this area is implicated in its enhancement of empathy-like behaviors.<ref name="Nichols2022">{{cite journal | vauthors = Nichols DE | title = Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated | journal = Front Psychiatry | volume = 13 | issue = | pages = 863088 | date = 2022 | pmid = 35401275 | pmc = 8990025 | doi = 10.3389/fpsyt.2022.863088 | doi-access = free | url = }}</ref><ref name="ReinRaymondBoustani2024">{{cite journal | vauthors = Rein B, Raymond K, Boustani C, Tuy S, Zhang J, St Laurent R, Pomrenze MB, Boroon P, Heifets B, Smith M, Malenka RC | title = MDMA enhances empathy-like behaviors in mice via 5-HT release in the nucleus accumbens | journal = Sci Adv | volume = 10 | issue = 17 | pages = eadl6554 | date = April 2024 | pmid = 38657057 | pmc = 11042730 | doi = 10.1126/sciadv.adl6554 | bibcode = 2024SciA...10L6554R | url = }}</ref><ref name="HeifetsSalgadoTaylor2019">{{cite journal | vauthors = Heifets BD, Salgado JS, Taylor MD, Hoerbelt P, Cardozo Pinto DF, Steinberg EE, Walsh JJ, Sze JY, Malenka RC | title = Distinct neural mechanisms for the prosocial and rewarding properties of MDMA | journal = Sci Transl Med | volume = 11 | issue = 522 | pages = | date = December 2019 | pmid = 31826983 | pmc = 7123941 | doi = 10.1126/scitranslmed.aaw6435 | url = }}</ref><ref name="WalshLlorachCardozoPinto2021">{{cite journal | vauthors = Walsh JJ, Llorach P, Cardozo Pinto DF, Wenderski W, Christoffel DJ, Salgado JS, Heifets BD, Crabtree GR, Malenka RC | title = Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD | journal = Neuropsychopharmacology | volume = 46 | issue = 11 | pages = 2000–2010 | date = October 2021 | pmid = 34239048 | pmc = 8429585 | doi = 10.1038/s41386-021-01091-6 | url = }}</ref> Injection of the serotonin 5-HT<sub>1B</sub> receptor antagonist [[NAS-181]] directly into the nucleus accumbens blocked the prosocial behaviors of MDMA.<ref name="HeifetsSalgadoTaylor2019" />

On the basis of the serotonin 5-HT<sub>1A</sub> receptor-mediated oxytocin release with MDMA, it has been proposed that increased oxytocinergic signaling may mediate the prosocial effects of MDMA in animals.<ref name="DunlapAndrewsOlson2018" /><ref name="ThompsonCallaghanHunt2007" /> Accordingly, [[intracerebroventricular injection]] of the [[peptide]] [[oxytocin receptor antagonist]] [[tocinoic acid]] blocked MDMA- and 8-OH-DPAT-induced prosocial effects.<ref name="DunlapAndrewsOlson2018" /><ref name="ThompsonCallaghanHunt2007" /><ref name="Wronikowska-DenysiukMrozekBudzyńska2023" /> However, in a subsequent study, [[systemic administration|systemically administered]] C25, a non-peptide oxytocin receptor antagonist, failed to affect MDMA-induced prosocial behavior, whereas the [[vasopressin]] [[V1A receptor|V<sub>1A</sub> receptor]] antagonist [[relcovaptan]] (SR-49059) was able to block MDMA-induced prosocial activity.<ref name="DunlapAndrewsOlson2018" /><ref name="Wronikowska-DenysiukMrozekBudzyńska2023" /> It might be that tocinoic acid is [[binding selectivity|non-selective]] and also blocks the vasopressin V<sub>1A</sub> receptor or that C25 is [[peripherally selective drug|peripherally selective]] and is unable to block [[oxytocin receptor]]s in the brain.<ref name="DunlapAndrewsOlson2018" /><ref name="Wronikowska-DenysiukMrozekBudzyńska2023" /> More research is needed to clarify this.<ref name="Wronikowska-DenysiukMrozekBudzyńska2023" /><ref name="DunlapAndrewsOlson2018" /> In any case, in another study, the non-peptide and [[central nervous system|centrally active]] selective oxytocin receptor antagonist [[L-368899]] abolished MDMA-induced prosocial behavior.<ref name="Wronikowska-DenysiukMrozekBudzyńska2023">{{cite journal | vauthors = Wronikowska-Denysiuk O, Mrozek W, Budzyńska B | title = The Role of Oxytocin and Vasopressin in Drug-Induced Reward-Implications for Social and Non-Social Factors | journal = Biomolecules | volume = 13 | issue = 3 | date = February 2023 | page = 405 | pmid = 36979340 | pmc = 10046619 | doi = 10.3390/biom13030405 | doi-access = free | url = }}</ref><ref name="Kuteykin-TeplyakovMaldonado2014">{{cite journal | vauthors = Kuteykin-Teplyakov K, Maldonado R | title = Looking for prosocial genes: ITRAQ analysis of proteins involved in MDMA-induced sociability in mice | journal = Eur Neuropsychopharmacol | volume = 24 | issue = 11 | pages = 1773–1783 | date = November 2014 | pmid = 25241352 | doi = 10.1016/j.euroneuro.2014.08.007 | hdl = 10230/23309 | url = | hdl-access = free }}</ref> Conversely, in other studies, different oxytocin receptor antagonists were ineffective.<ref name="HeifetsSalgadoTaylor2019" />

As in animals, MDMA greatly increases circulating oxytocin levels in humans.<ref name="DunlapAndrewsOlson2018" /> [[Serotonin reuptake inhibitor]]s and [[norepinephrine reuptake inhibitor]]s reduced the subjective effects of MDMA in humans, for instance increased [[extroversion]], [[self-confidence]], [[social connectedness|closeness]], [[openness]], and [[talkative|talkativeness]].<ref name="Kamilar-BrittBedi2015" /> The 5-HT<sub>2A</sub> receptor antagonist [[ketanserin]] reduced MDMA-induced increases in friendliness.<ref name="Kamilar-BrittBedi2015" /> MDMA-induced emotional empathy was not affected by the serotonin 5-HT<sub>1A</sub> receptor antagonist [[pindolol]] or by [[intranasal]] [[oxytocin]].<ref name="KuypersdelaTorreFarre2014">{{cite journal | vauthors = Kuypers KP, de la Torre R, Farre M, Yubero-Lahoz S, Dziobek I, Van den Bos W, Ramaekers JG | title = No evidence that MDMA-induced enhancement of emotional empathy is related to peripheral oxytocin levels or 5-HT1a receptor activation | journal = PLOS ONE | volume = 9 | issue = 6 | pages = e100719 | date = 2014 | pmid = 24972084 | pmc = 4074089 | doi = 10.1371/journal.pone.0100719 | doi-access = free | bibcode = 2014PLoSO...9j0719K | url = }}</ref>  Similarly, MDMA-induced emotional empathy and prosocial behavior have not been associated with circulating oxytocin levels.<ref name="KuypersdelaTorreFarre2014" /><ref name="DunlapAndrewsOlson2018" /> As such, the role of oxytocin in the entactogenic effects of MDMA in humans is controversial.<ref name="DunlapAndrewsOlson2018" />

Other serotonin releasing agents, like [[fenfluramine]], show prosocial effects in animals similar to those of MDMA.<ref name="BeheraJogaYerram2024">{{cite journal | vauthors = Behera HK, Joga R, Yerram S, Karnati P, Mergu T, Gandhi K, M S, Nathiya D, Singh RP, Srivastava S, Kumar S | title = Exploring the regulatory framework of psychedelics in the US & Europe | journal = Asian J Psychiatr | volume = 102 | issue = | pages = 104242 | date = September 2024 | pmid = 39305768 | doi = 10.1016/j.ajp.2024.104242 | url = }}</ref><ref name="HeifetsSalgadoTaylor2019" /> Fenfluramine has likewise been reported to improve [[social deficits]] in children with [[autism]].<ref name="HeifetsSalgadoTaylor2019" /><ref name="AmanKern1989">{{cite journal | vauthors = Aman MG, Kern RA | title = Review of fenfluramine in the treatment of the developmental disabilities | journal = J Am Acad Child Adolesc Psychiatry | volume = 28 | issue = 4 | pages = 549–565 | date = July 1989 | pmid = 2670881 | doi = 10.1097/00004583-198907000-00014 | url = }}</ref> Selective agonists of the serotonin 5-HT<sub>1A</sub> and 5-HT<sub>1B</sub> receptors and of the oxytocin receptors have been or are being investigated for the potential treatment of social deficits and [[aggression]].<ref name="deBoerKoolhaas2005">{{cite journal | vauthors = de Boer SF, Koolhaas JM | title = 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis | journal = Eur J Pharmacol | volume = 526 | issue = 1–3 | pages = 125–139 | date = December 2005 | pmid = 16310183 | doi = 10.1016/j.ejphar.2005.09.065 | url = }}</ref><ref name="Olivier2004">{{cite journal | vauthors = Olivier B | title = Serotonin and aggression | journal = Ann N Y Acad Sci | volume = 1036 | issue = 1| pages = 382–392 | date = December 2004 | pmid = 15817750 | doi = 10.1196/annals.1330.022 | bibcode = 2004NYASA1036..382O | url = }}</ref><ref name="FelthousMcCoyNassif2021">{{cite journal | vauthors = Felthous AR, McCoy B, Nassif JB, Duggirala R, Kim E, Carabellese F, Stanford MS | title = Pharmacotherapy of Primary Impulsive Aggression in Violent Criminal Offenders | journal = Front Psychol | volume = 12 | issue = | pages = 744061 | date = 2021 | pmid = 34975633 | pmc = 8716452 | doi = 10.3389/fpsyg.2021.744061 | doi-access = free | url = }}</ref><ref name="SałaciakPytka2021">{{cite journal | vauthors = Sałaciak K, Pytka K | title = Biased agonism in drug discovery: Is there a future for biased 5-HT1A receptor agonists in the treatment of neuropsychiatric diseases? | journal = Pharmacol Ther | volume = 227 | issue = | pages = 107872 | date = November 2021 | pmid = 33905796 | doi = 10.1016/j.pharmthera.2021.107872 | url = | doi-access = free }}</ref> Examples include [[batoprazine]], [[eltoprazine]] (DU-28853), [[fluprazine]] (DU-27716), [[F-15,599]] (NLX-01), [[zolmitriptan]] (ML-004), and [[LIT-001]].<ref name="FelthousMcCoyNassif2021" /><ref name="SałaciakPytka2021" /><ref name="NasharWhitfieldMikusek2022">{{cite book | vauthors = Nashar PE, Whitfield AA, Mikusek J, Reekie TA | title = Oxytocin | chapter = The Current Status of Drug Discovery for the Oxytocin Receptor | series = Methods Mol Biol | volume = 2384 | pages = 153–174 | date = 2022 | pmid = 34550574 | doi = 10.1007/978-1-0716-1759-5_10 | isbn = 978-1-0716-1758-8 | chapter-url = }}</ref> [[Serotonergic psychedelic]]s, for instance [[lysergic acid diethylamide]] (LSD) and [[psilocybin]], which act as non-selective serotonin receptor agonists including of the serotonin [[5-HT1 receptor|5-HT<sub>1</sub>]] and [[5-HT2 receptor|5-HT<sub>2</sub> receptor]]s, have shown prosocial and empathy-enhancing effects in animals and/or humans as well, both acutely and long-term.<ref name="MarkopoulosInserraDeGregorio2021">{{cite journal | vauthors = Markopoulos A, Inserra A, De Gregorio D, Gobbi G | title = Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder | journal = Front Pharmacol | volume = 12 | issue = | pages = 749068 | date = 2021 | pmid = 35177979 | pmc = 8846292 | doi = 10.3389/fphar.2021.749068 | doi-access = free | url = }}</ref><ref name="BhattWeissman2024">{{cite journal | vauthors = Bhatt KV, Weissman CR | title = The effect of psilocybin on empathy and prosocial behavior: a proposed mechanism for enduring antidepressant effects | journal = npj Ment Health Res | volume = 3 | issue = 1 | pages = 7 | date = February 2024 | pmid = 38609500 | pmc = 10955966 | doi = 10.1038/s44184-023-00053-8 | url = }}</ref><ref name="KupferbergHasler2024">{{cite journal | vauthors = Kupferberg A, Hasler G | title = From antidepressants and psychotherapy to oxytocin, vagus nerve stimulation, ketamine and psychedelics: how established and novel treatments can improve social functioning in major depression | journal = Front Psychiatry | volume = 15 | issue = | pages = 1372650 | date = 2024 | pmid = 39469469 | pmc = 11513289 | doi = 10.3389/fpsyt.2024.1372650 | doi-access = free | url = }}</ref>

The serotonin release of MDMA appears to be the key pharmacological action mediating the entactogenic, prosocial, and empathy-enhancing effects of the drug.<ref name="Kamilar-BrittBedi2015" /><ref name="HalberstadtNichols2020">{{cite book | last1=Halberstadt | first1=Adam L. | last2=Nichols | first2=David E. | title=Handbook of Behavioral Neuroscience | chapter=Serotonin and serotonin receptors in hallucinogen action | publisher=Elsevier | volume=31 | date=2020 | isbn=978-0-444-64125-0 | doi=10.1016/b978-0-444-64125-0.00043-8 | pages=843–863}}</ref><ref name="Oeri2021">{{cite journal | vauthors = Oeri HE | title = Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy | journal = J Psychopharmacol | volume = 35 | issue = 5 | pages = 512–536 | date = May 2021 | pmid = 32909493 | pmc = 8155739 | doi = 10.1177/0269881120920420 | url = }}</ref> However, in addition to serotonin release, MDMA is also a [[potency (pharmacology)|potent]] [[monoamine releasing agent|releasing agent]] of [[norepinephrine]] and [[dopamine]], and hence acts as a well-balanced [[serotonin–norepinephrine–dopamine releasing agent]].<ref name="HalberstadtNichols2020" /><ref name="Oeri2021" /> Additionally, MDMA is a direct agonist of several serotonin receptors, including of the serotonin 5-HT<sub>2</sub> receptors, with moderate [[affinity (pharmacology)|affinity]].<ref name="HalberstadtNichols2020" /><ref name="Oeri2021" /> These actions are thought to play an important role in the effects of MDMA, including in its [[psychostimulant]], [[euphoriant]], and mild [[psychedelic drug|psychedelic]] effects, as well as in its unique and difficult-to-replicate "magic".<ref name="HalberstadtNichols2020" /><ref name="Baggott2023">{{cite conference | vauthors = Baggott M | title = Beyond Ecstasy: Progress in Developing and Understanding a Novel Class of Therapeutic Medicine | conference = PS2023 [Psychedelic Science 2023, June 19-23, 2023, Denver, Colorado] | date = 23 June 2023 | publisher = [[Multidisciplinary Association for Psychedelic Studies]] | location = Denver, CO | url = https://2023.psychedelicscience.org/sessions/beyond-ecstasy-progress-in-developing-and-understanding-a-novel-class-of-therapeutic-medicine/}}</ref><ref name="Oeri2021" /><ref name="HealGosdenSmith2023">{{cite journal | vauthors = Heal DJ, Gosden J, Smith SL, Atterwill CK | title = Experimental strategies to discover and develop the next generation of psychedelics and entactogens as medicines | journal = Neuropharmacology | volume = 225 | issue = | pages = 109375 | date = March 2023 | pmid = 36529260 | doi = 10.1016/j.neuropharm.2022.109375 | url = | doi-access = free }}</ref> It has been said by [[Matthew J. Baggott|Matthew Baggott]] that few to no MDMA [[structural analog|analogue]]s, including [[MBDB]], [[methylone]], [[6-APDB]], [[5-APDB]], [[6-APB]], [[5-APB]], [[MDAT]], and [[MDAI]] among others, reproduce the full quality and "magic" of MDMA.<ref name="Baggott2023" /><ref name="Baggott2024">{{cite web | title=Better Than Ecstasy: Progress in Developing a Novel Class of Therapeutic with Matthew Baggott, PhD. | website=YouTube | date=6 March 2024 | url=https://www.youtube.com/watch?v=OnhJvKxwfZI&t=1048 | access-date=20 November 2024}}</ref> Exceptions may [[anecdotal evidence|anecdotally]] include [[5-MAPB]], particularly in specific [[enantiomer]] ratios, and the [[Borax combo]].<ref name="Baggott2023" /><ref name="Baggott2024" /><ref name="US11767305B2">{{cite web | title=Advantageous benzofuran compositions for mental disorders or enhancement | website=Google Patents | date=8 December 2022 | url=https://patents.google.com/patent/US11767305B2/ | access-date=21 November 2024}}</ref> The unique properties of MDMA are believed to be dependent on a very specific mixture and ratio of pharmacological activities, including combined serotonin, norepinephrine, and dopamine release and direct serotonin receptor agonism.<ref name="Baggott2023" /><ref name="Baggott2024" />

[[Ariadne (drug)|Ariadne]], the α-[[ethyl group|ethyl]] [[structural analog|analogue]] of the serotonergic psychedelic [[DOM (drug)|DOM]], fully substitutes for MDMA in rodent [[drug discrimination]] tests, suggesting that it may have entactogen-like effects.<ref name="CunninghamBockSerrano2023">{{cite journal | vauthors = Cunningham MJ, Bock HA, Serrano IC, Bechand B, Vidyadhara DJ, Bonniwell EM, Lankri D, Duggan P, Nazarova AL, Cao AB, Calkins MM, Khirsariya P, Hwu C, Katritch V, Chandra SS, McCorvy JD, Sames D | title = Pharmacological Mechanism of the Non-hallucinogenic 5-HT<sub>2A</sub> Agonist Ariadne and Analogs | journal = ACS Chemical Neuroscience | volume = 14 | issue = 1 | pages = 119–135 | date = January 2023 | pmid = 36521179 | pmc = 10147382 | doi = 10.1021/acschemneuro.2c00597 | quote = In rat drug discrimination assays, Ariadne substituted responding in LSD trained animals in one study, in another showed full substitution for MDMA stimulus.14,15 [...] 15). Glennon RA MDMA-like Stimulus Effects of α-Ethyltryptamine and the α-Ethyl Homolog of Dom. Pharmacology Biochemistry and Behavior 1993, 46 (2), 459–462. [PubMed: 7903460]}}</ref><ref name="Glennon1993">{{cite journal | vauthors = Glennon RA | title = MDMA-like stimulus effects of alpha-ethyltryptamine and the alpha-ethyl homolog of DOM | journal = Pharmacol Biochem Behav | volume = 46 | issue = 2 | pages = 459–462 | date = October 1993 | pmid = 7903460 | doi = 10.1016/0091-3057(93)90379-8 | url = }}</ref> This property is unusual among psychedelics, and is in notable contrast to DOM, which at best partially substitutes for MDMA.<ref name="Glennon1993" /> Unlike conventional entactogens, Ariadne shows no activity at the monoamine transporters, and instead acts as a selective serotonin 5-HT<sub>2</sub> receptor partial agonist, including as a lower-efficacy agonist of the serotonin 5-HT<sub>2A</sub> receptor.<ref name="CunninghamBockSerrano2023" /> Certain other psychedelics and related compounds, like low doses of [[2C-B]], are also selective serotonin 5-HT<sub>2</sub> receptor partial agonists that have likewise been implicated as having entactogenic effects.<ref name="LuethiLiechti2020">{{cite journal | vauthors = Luethi D, Liechti ME | title = Designer drugs: mechanism of action and adverse effects | journal = Arch Toxicol | volume = 94 | issue = 4 | pages = 1085–1133 | date = April 2020 | pmid = 32249347 | pmc = 7225206 | doi = 10.1007/s00204-020-02693-7 | bibcode = 2020ArTox..94.1085L | quote = In one of the few clinical studies of a designer drug, 4-bromo-2,5-dimethoxyphenylethylamine (2C-B) was shown to induce euphoria, well-being, and changes in perception, and to have mild stimulant properties (Gonzalez et al. 2015). 2C-B may thus be classified as a psychedelic with entactogenic properties, an effect profile that is similar to various other phenethylamine psychedelics (Shulgin and Shulgin 1995).}}</ref><ref name="WillsErickson2012">{{cite book | vauthors = Wills B, Erickson T | chapter = Psychoactive Phenethylamine, Piperazine, and Pyrrolidinophenone Derivatives | editor-last=Barceloux | editor-first=Donald G. | title=Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants | publisher=Wiley | date=9 March 2012 | isbn=978-0-471-72760-6 | doi=10.1002/9781118105955.ch10 | pages=156–192 | quote=DOSE EFFECT: Anecdotal data suggests that recreational doses of 2C-B range from 4—30 mg with lower doses (4—10 mg) producing entactogenic effects, whereas high doses (10— 20 mg) cause psychedelic and sympathomimetic effects.}}</ref><ref name="GonzálezTorrensFarré2015">{{cite journal | vauthors = González D, Torrens M, Farré M | title = Acute Effects of the Novel Psychoactive Drug 2C-B on Emotions | journal = BioMed Research International | volume = 2015 | pages = 643878 | date = 2015-10-12 | pmid = 26543863 | doi = 10.1155/2015/643878 | pmc = 4620274 | doi-access = free }}</ref> MDMA itself is notable in being a lower-efficacy partial agonist of the serotonin 5-HT<sub>2A</sub> receptor as well.<ref name="PittsCurryHampshire2018">{{cite journal | vauthors = Pitts EG, Curry DW, Hampshire KN, Young MB, Howell LL | title = (±)-MDMA and its enantiomers: potential therapeutic advantages of R(-)-MDMA | journal = Psychopharmacology (Berl) | volume = 235 | issue = 2 | pages = 377–392 | date = February 2018 | pmid = 29248945 | doi = 10.1007/s00213-017-4812-5 | url = }}</ref><ref name="KolaczynskaDucretTrachsel2022">{{cite journal | vauthors = Kolaczynska KE, Ducret P, Trachsel D, Hoener MC, Liechti ME, Luethi D | title = Pharmacological characterization of 3,4-methylenedioxyamphetamine (MDA) analogs and two amphetamine-based compounds: N,α-DEPEA and DPIA | journal = Eur Neuropsychopharmacol | volume = 59 | issue = | pages = 9–22 | date = June 2022 | pmid = 35378384 | doi = 10.1016/j.euroneuro.2022.03.006 | url = https://www.researchgate.net/profile/Dino-Luethi/publication/359686098_Pharmacological_characterization_of_34-methylenedioxyamphetamine_MDA_analogs_and_two_amphetamine-based_compounds_Na-DEPEA_and_DPIA/links/626181468cb84a40ac7f0d9a/Pharmacological-characterization-of-3-4-methylenedioxyamphetamine-MDA-analogs-and-two-amphetamine-based-compounds-N-a-DEPEA-and-DPIA.pdf}}</ref> The stimulus effects of MDMA in the [[drug discrimination]] paradigm are partially blocked by the selective serotonin 5-HT<sub>2A</sub> receptor antagonist volinanserin in rodents.<ref name="Baker2018">{{cite journal | vauthors = Baker LE | title = Hallucinogens in Drug Discrimination | journal = Curr Top Behav Neurosci | volume = 36 | issue = | pages = 201–219 | date = 2018 | pmid = 28484970 | doi = 10.1007/7854_2017_476 | url = }}</ref> Similarly, the psychoactive effects of MDMA are partially blocked by the relatively selective serotonin 5-HT<sub>2A</sub> receptor antagonist ketanserin in humans.<ref name="HalberstadtNichols2020" /><ref name="LiechtiSaurGamma2000">{{cite journal | vauthors = Liechti ME, Saur MR, Gamma A, Hell D, Vollenweider FX | title = Psychological and physiological effects of MDMA ("Ecstasy") after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans | journal = Neuropsychopharmacology | volume = 23 | issue = 4 | pages = 396–404 | date = October 2000 | pmid = 10989266 | doi = 10.1016/S0893-133X(00)00126-3 | url = }}</ref><ref name="LiechtiVollenweider2001">{{cite journal | vauthors = Liechti ME, Vollenweider FX | title = Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies | journal = Hum Psychopharmacol | volume = 16 | issue = 8 | pages = 589–598 | date = December 2001 | pmid = 12404538 | doi = 10.1002/hup.348 | url = }}</ref><ref name="vanWelKuypersTheunissen2012">{{cite journal | vauthors = van Wel JH, Kuypers KP, Theunissen EL, Bosker WM, Bakker K, Ramaekers JG | title = Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors | journal = PLOS ONE | volume = 7 | issue = 7 | pages = e40187 | date = 2012 | pmid = 22808116 | pmc = 3393729 | doi = 10.1371/journal.pone.0040187 | doi-access = free | bibcode = 2012PLoSO...740187V | url = }}</ref>