Entactogen: Difference between revisions

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| Caption            = A selection of [[MDMA]] pills, which are often nicknamed "Ecstasy" or "E".
| Caption            = A selection of [[MDMA]] pills, which are often nicknamed "Ecstasy" or "E"
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Although the therapeutic effects of entactogens may be promising, drugs such as MDMA have the potential for negative effects that are counter productive in a therapy setting. For example, MDMA may make negative cognition worse. This means that a positive experience is not a guarantee and can be contingent on aspects like the setting and the patient's expectations.<ref name=":2">{{Cite journal|last=Parrott|first=A. C.|date=2007-04-01|title=The psychotherapeutic potential of MDMA (3,4-methylenedioxymethamphetamine): an evidence-based review|journal=Psychopharmacology|language=en|volume=191|issue=2|pages=181–193|doi=10.1007/s00213-007-0703-5|pmid=17297639|s2cid=40322032|issn=0033-3158}}</ref> Additionally there is no clear model of the [[Psychopharmacology|psychopharmacological]] means for a positive or negative experience.<ref name=":2" />  There is also a potential concern for the [[Neurotoxicity|neurotoxic]] effects of MDMA on the fiber density of [[serotonin]] neurons in the [[neocortex]]. High doses of MDMA may cause potential depletion of serotonergic axons. The same effects may not be caused by lower doses of MDMA required for treatment, however.<ref>{{Cite book|title=Psychopharmacology : drugs, the brain, and behavior|last=F.|first=Quenzer, Linda|isbn=9780878935109|oclc=869923492|date = 2013-05-06|publisher=Sinauer }}</ref>
Although the therapeutic effects of entactogens may be promising, drugs such as MDMA have the potential for negative effects that are counter productive in a therapy setting. For example, MDMA may make negative cognition worse. This means that a positive experience is not a guarantee and can be contingent on aspects like the setting and the patient's expectations.<ref name=":2">{{Cite journal|last=Parrott|first=A. C.|date=2007-04-01|title=The psychotherapeutic potential of MDMA (3,4-methylenedioxymethamphetamine): an evidence-based review|journal=Psychopharmacology|language=en|volume=191|issue=2|pages=181–193|doi=10.1007/s00213-007-0703-5|pmid=17297639|s2cid=40322032|issn=0033-3158}}</ref> Additionally there is no clear model of the [[Psychopharmacology|psychopharmacological]] means for a positive or negative experience.<ref name=":2" />  There is also a potential concern for the [[Neurotoxicity|neurotoxic]] effects of MDMA on the fiber density of [[serotonin]] neurons in the [[neocortex]]. High doses of MDMA may cause potential depletion of serotonergic axons. The same effects may not be caused by lower doses of MDMA required for treatment, however.<ref>{{Cite book|title=Psychopharmacology : drugs, the brain, and behavior|last=F.|first=Quenzer, Linda|isbn=9780878935109|oclc=869923492|date = 2013-05-06|publisher=Sinauer }}</ref>


MDMA-assisted psychotherapy (MDMA-AT) is in late-stage [[clinical trial]]s to treat PTSD as of 2025.<ref name="Baldo2024">{{cite journal | vauthors = Baldo BA | title = The entactogen 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) as a treatment aid in psychotherapy and its safety concerns | journal = Arch Toxicol | volume = 98 | issue = 8 | pages = 2409–2427 | date = August 2024 | pmid = 38743292 | doi = 10.1007/s00204-024-03765-8 | bibcode = 2024ArTox..98.2409B | url = }}</ref><ref name="Singh2025">{{cite journal | vauthors = Singh B | title = MDMA-Assisted Therapy for Post-Traumatic Stress Disorder: Regulatory Challenges and a Path Forward | journal = CNS Drugs | volume = 39 | issue = 4 | pages = 339–343 | date = April 2025 | pmid = 39955464 | doi = 10.1007/s40263-025-01162-y | pmc = 11910333 | pmc-embargo-date = April 1, 2026 | url = }}</ref><ref name="WolfgangFonzoGray2025">{{cite journal | vauthors = Wolfgang AS, Fonzo GA, Gray JC, Krystal JH, Grzenda A, Widge AS, Kraguljac NV, McDonald WM, Rodriguez CI, Nemeroff CB | title = MDMA and MDMA-Assisted Therapy | journal = Am J Psychiatry | volume = 182 | issue = 1 | pages = 79–103 | date = January 2025 | pmid = 39741438 | doi = 10.1176/appi.ajp.20230681 | url = }}</ref>
MDMA-assisted psychotherapy (MDMA-AT) is in late-stage [[clinical trial]]s to treat PTSD as of 2025.<ref name="Baldo2024">{{cite journal | vauthors = Baldo BA | title = The entactogen 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) as a treatment aid in psychotherapy and its safety concerns | journal = Arch Toxicol | volume = 98 | issue = 8 | pages = 2409–2427 | date = August 2024 | pmid = 38743292 | doi = 10.1007/s00204-024-03765-8 | bibcode = 2024ArTox..98.2409B | url = | doi-access = free }}</ref><ref name="Singh2025">{{cite journal | vauthors = Singh B | title = MDMA-Assisted Therapy for Post-Traumatic Stress Disorder: Regulatory Challenges and a Path Forward | journal = CNS Drugs | volume = 39 | issue = 4 | pages = 339–343 | date = April 2025 | pmid = 39955464 | doi = 10.1007/s40263-025-01162-y | pmc = 11910333 | pmc-embargo-date = April 1, 2026 | url = }}</ref><ref name="WolfgangFonzoGray2025">{{cite journal | vauthors = Wolfgang AS, Fonzo GA, Gray JC, Krystal JH, Grzenda A, Widge AS, Kraguljac NV, McDonald WM, Rodriguez CI, Nemeroff CB | title = MDMA and MDMA-Assisted Therapy | journal = Am J Psychiatry | volume = 182 | issue = 1 | pages = 79–103 | date = January 2025 | pmid = 39741438 | doi = 10.1176/appi.ajp.20230681 | url = }}</ref>


==Effects==
==Effects==
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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" />
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" />
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 = | doi-access = free }}</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" />
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" />
Line 86: Line 86:
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" />
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>
[[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" /><ref name="Oberlender1989">{{cite web | vauthors = Oberlender RA | title = Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens | date = May 1989 | publisher = Purdue University | website = Purdue e-Pubs | url = https://bitnest.netfirms.com/external/Theses/Oberlender1989 | quote = The results of initial studies (Nichols et al., 1986) generally demonstrated the lack of LSD-Iike discriminative stimulus properties for the members of the entactogen drug class. This was confirmed and extended to other hallucinogens in tests with rats trained on entactogens. These results are summarized in Table 12. Table 12. Results of DD tests comparing entactogens and hallucinogens. [...] It seems clear that entactogen activity is distinct from that of hallucinogens. [...]}}</ref> Besides Ariadne, the [[NBOMe]] drugs such as [[25I-NBOMe]] and [[25B-NBOMe]] also partially to fully substitute for MDMA in rodents.<ref name="HerianŚwit2023">{{cite journal | vauthors = Herian M, Świt P | title = 25X-NBOMe compounds - chemistry, pharmacology and toxicology. A comprehensive review | journal = Crit Rev Toxicol | volume = 53 | issue = 1 | pages = 15–33 | date = January 2023 | pmid = 37115704 | doi = 10.1080/10408444.2023.2194907 | url = | quote = For a better understanding of the actions of different NBOMes resulting from their molecular structure and receptor binding affinity, drug discrimination studies were performed. Animals trained with 4-methyl-2,5-dimethoxyamphetamine (DOM) and 3,4-methylenedioxymethamphetamine (MDMA) were used in the drug discrimination paradigm. 25B- and 25CNBOMe completely (80%) substituted DOM, while 25INBOMe produced 74% drug-appropriate responding (Gatch et al. 2017). On the other hand, only 25B-NBOMe fully substituted for MDMA, suggesting that this compound could be used as both a hallucinogen and an entactogen.}}</ref><ref name="ZawilskaKacelaAdamowicz2020">{{cite journal | vauthors = Zawilska JB, Kacela M, Adamowicz P | title = NBOMes-Highly Potent and Toxic Alternatives of LSD | journal = Front Neurosci | volume = 14 | issue = | pages = 78 | date = 2020 | pmid = 32174803 | pmc = 7054380 | doi = 10.3389/fnins.2020.00078 | doi-access = free | url = | quote = Gatch et al. (2017) tested 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe for discriminative stimulus effects similar to a prototypical psychedelic/hallucinogen DOM and to an empathogen, 3,4-methylenedioxymethamphetamine (MDMA). In DOM-trained rats 25B-NBOMe and 25C-NBOMe, but not 25I-NBOMe, fully substituted for this drug. 25B-NBOMe also fully substituted for MDMA. In both tests, the dose-effect curves for 25B-NBOMe had an inverted U-shape. It is suggested that 25B-NBOMe and 25C-NBOMe are most likely used as recreational psychedelics, although 25B-NBOMe may also be used as an empathogenic compound (Gatch et al., 2017). However, the latter assumption should be taken with caution, as some compounds (e.g., fenfluramine) that substitute for MDMA in rats do not produce MDMA-like empathogenic effects in humans (Schechter, 1988).}}</ref><ref name="Canal2018">{{cite journal | vauthors = Canal CE | title = Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 252 | issue = | pages = 227–260 | date = 2018 | pmid = 29532180 | pmc = 6136989 | doi = 10.1007/164_2018_107 | isbn = 978-3-030-10560-0 | url = | quote = Recent studies employing drug discrimination in rats show that novel psychedelics including 25I-, 25B-, and 25C-NBOMe, and 5-MeO-DALT fully substitute for DOM; interestingly, the NBOMe drugs also substitute for MDMA, but 5-MeO-DALT does not (Gatch et al. 2017).}}</ref><ref name="GatchDolanForster2017">{{cite journal | vauthors = Gatch MB, Dolan SB, Forster MJ | title = Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents | journal = Behav Pharmacol | volume = 28 | issue = 5 | pages = 375–385 | date = August 2017 | pmid = 28537942 | pmc = 5498282 | doi = 10.1097/FBP.0000000000000309 | url = }}</ref> 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/publication/359686098| doi-access = free }}</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 book | vauthors = Baker LE | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Hallucinogens in Drug Discrimination | series = Curr Top Behav Neurosci | volume = 36 | pages = 201–219 | date = 2018 | pmid = 28484970 | doi = 10.1007/7854_2017_476 | isbn = 978-3-662-55878-2 | chapter-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>


==History==
==History==
{{See also|3,4-Methylenedioxyamphetamine#History|MDMA#History}}
{{See also|3,4-Methylenedioxyamphetamine#History|MDMA#History}}


The history of MDMA and other entactogens has been reviewed.<ref name="Passie2023" /><ref name="Bernschneider-ReifOxlerFreudenmann2006" /><ref name="Shulgin1990">{{cite book | last=Shulgin | first=Alexander T. | veditors = Peroutka SJ | title=Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA | chapter=History of MDMA | publisher=Springer US | publication-place=Boston, MA | volume=9 | date=1990 | isbn=978-1-4612-8799-5 | doi=10.1007/978-1-4613-1485-1_1 | url=http://link.springer.com/10.1007/978-1-4613-1485-1_1 | access-date=15 May 2025 | pages=1–20 }}</ref><ref name="BenzenhöferPassie2010" /><ref name="Pentney2001">{{cite journal | vauthors = Pentney AR | title = An exploration of the history and controversies surrounding MDMA and MDA | journal = J Psychoactive Drugs | volume = 33 | issue = 3 | pages = 213–221 | date = 2001 | pmid = 11718314 | doi = 10.1080/02791072.2001.10400568 | url = }}</ref><ref name="Nichols2022" />
The history of MDMA and other entactogens has been reviewed.<ref name="Passie2023" /><ref name="Bernschneider-ReifOxlerFreudenmann2006" /><ref name="Shulgin1990">{{cite book | last=Shulgin | first=Alexander T. | veditors = Peroutka SJ | title=Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA | chapter=History of MDMA | series=Topics in the Neurosciences | publisher=Springer US | publication-place=Boston, MA | volume=9 | date=1990 | isbn=978-1-4612-8799-5 | doi=10.1007/978-1-4613-1485-1_1 | chapter-url=http://link.springer.com/10.1007/978-1-4613-1485-1_1 | access-date=15 May 2025 | pages=1–20 }}</ref><ref name="BenzenhöferPassie2010" /><ref name="Pentney2001">{{cite journal | vauthors = Pentney AR | title = An exploration of the history and controversies surrounding MDMA and MDA | journal = J Psychoactive Drugs | volume = 33 | issue = 3 | pages = 213–221 | date = 2001 | pmid = 11718314 | doi = 10.1080/02791072.2001.10400568 | url = }}</ref><ref name="Nichols2022" />


==Society and culture==
==Society and culture==

Latest revision as of 20:17, 18 June 2025

Template:Short description

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Entactogens, also known as empathogens or connectogens, are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, connectedness, emotional openness—that is, empathy—as particularly observed and reported for experiences with MDMA.[1][2][3][4][5] This class of drug is distinguished from the classes of hallucinogens or psychedelics and stimulants, although entactogens, for instance MDMA, can also have these properties.[1][5][6][7] Entactogens are used both as recreational drugs[8] and are being investigated for medical use in the treatment of psychiatric disorders, for instance MDMA-assisted therapy for post-traumatic stress disorder (PTSD).[9][10][11]

Notable members of this class include MDMA, MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, αMT, αET, and MDAI, among others.[1][3] Most entactogens are phenethylamines and amphetamines, although several, such as αMT and αET, are tryptamines.[1][3] When referring to MDMA and its counterparts, the term MDxx is often used (with the exception of certain non-entactogen drugs like MDPV).

Entactogens act as serotonin releasing agents (SRAs) as their key action.[12][13][3][14][15] However, entactogens also frequently have additional actions, such as induction of dopamine and norepinephrine and serotonin 5-HT2 receptor agonism, which contributes to their effects as well.[12][13][3][14][15] It is thought that dopamine and norepinephrine release provide additional stimulant, euphoriant, and cardiovascular or sympathomimetic effects, serotonin 5-HT2A receptor agonism produces psychedelic effects of variable intensity, and both dopamine release and serotonin 5-HT2 receptor agonism may enhance the entactogenic effects and be critically involved in allowing for the qualitative "magic" of these drugs.[12][13][3][14][15] Entactogens that simultaneously induce serotonin and dopamine release, for instance MDMA, are known to produce long-lasting serotonergic neurotoxicity[16][17][3] with associated cognitive and memory deficits as well as psychiatric changes.[18][19][20][21]

MDA and MDMA were both first synthesized independently in the early 1910s.[22] The psychoactive effects of MDA were discovered in 1930 but were not described until the 1950s, MDA and MDMA emerged as recreational drugs in the 1960s, and the unique entactogenic effects of MDMA were first described in the 1970s.[22][23][24][25][26] Entactogens as a unique pharmacological class depending on induction of serotonin release was established in the mid-1980s and novel entactogens such as MBDB were developed at this time and after.[1][5][6] Gordon Alles discovered the psychoactive effects of MDA,[25][26] Alexander Shulgin played a key role in bringing awareness to MDMA and its unique effects,[24] and Ralph Metzner[27][28][29] and David E. Nichols formally defined entactogens and established them as a distinct class of drugs.[1][5][6] Many entactogens like MDMA are controlled substances throughout the world.[30][31]

Uses

Recreational

Entactogens are used as recreational drugs, including notably at raves.[8]

Medical

Psychiatrists began using entactogens as psychotherapy tools in the 1970s despite the lack of clinical trials.[32] In recent years, the scientific community has been revisiting the possible therapeutic uses of entactogens. Therapeutic models using MDMA have been studied because of its entactogenic properties.[33] This type of therapy would be applicable for treating a patient who was experiencing psychological trauma such as PTSD. Traumatic memories can be linked to fear in the patients which makes engaging with these memories difficult. Administration of an entactogen such as MDMA allows the patient to disconnect from the fear associated with the traumatic memories and engage in therapy.[33] MDMA acts by targeting the body's stress response in order to cause this therapeutic effect. In addition to reducing anxiety and a conditioned fear response, MDMA also reduces the avoidance of feelings.[33] Patients are then able to trust themselves and their therapist and engage with traumatic memories under the influence of MDMA.

Although the therapeutic effects of entactogens may be promising, drugs such as MDMA have the potential for negative effects that are counter productive in a therapy setting. For example, MDMA may make negative cognition worse. This means that a positive experience is not a guarantee and can be contingent on aspects like the setting and the patient's expectations.[34] Additionally there is no clear model of the psychopharmacological means for a positive or negative experience.[34] There is also a potential concern for the neurotoxic effects of MDMA on the fiber density of serotonin neurons in the neocortex. High doses of MDMA may cause potential depletion of serotonergic axons. The same effects may not be caused by lower doses of MDMA required for treatment, however.[35]

MDMA-assisted psychotherapy (MDMA-AT) is in late-stage clinical trials to treat PTSD as of 2025.[9][10][11]

Effects

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Both terms adopted and used in naming the class of therapeutic drugs for MDMA and related compounds were chosen with the intention of providing some reflection of the reported psychological effects associated with drugs in the classification and distinguishing these compounds from classical psychedelic drugs such as LSD, mescaline, and psilocybin and major stimulants, such as methamphetamine and amphetamine.[4] Chemically, MDMA is classified as a substituted amphetamine (which includes stimulants like dextroamphetamine and psychedelics like 2,5-dimethoxy-4-methylamphetamine), which makes MDMA a substituted phenethylamine (which includes other stimulants like methylphenidate and other psychedelics like mescaline) by the definition of amphetamine. While chemically related both to psychedelics and stimulants, the psychological effects experienced with MDMA were reported to provide obvious and striking aspects of personal relatedness, feelings of connectedness, communion with others, and ability to feel what others feel—in short an empathic resonance is consistently evoked.[36] While psychedelics like LSD may sometimes yield effects of empathic resonance, these effects tend to be momentary and likely passed over on the way to some other dimension or interest. In contrast, the main characteristic that distinguishes MDMA from LSD-type experiences is the consistency of the effects of emotional communion, relatedness, emotional openness—in short, empathy and sympathy.[4]

Side effects

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Side effects of entactogens like MDMA include mydriasis, nystagmus, jaw clenching, bruxism, insomnia, appetite loss, tachycardia, hypertension, and hyperthermia, among others.[3][9] Severe adverse effects of entactogens like MDMA can include dehydration, hyperthermia, seizures, rhabdomyolysis, disseminated intravascular coagulation, hyponatremia, acute renal failure, liver injury, serotonin syndrome, and valvular heart disease.[9][37] Entactogens can produce long-lasting serotonergic neurotoxicity[16][17][3] and associated cognitive and memory deficits as well as psychiatric changes.[18][19][20][21]

Overdose

Entactogens like MDMA show a much narrower margin of safety and greater toxicity in overdose than serotonergic psychedelics.[38] Whereas LSD and psilocybin have extrapolated human lethal doses relative to typical recreational doses of approximately 1,000-fold and 200-fold, respectively,[39] a reasonable estimated fatal dose of MDMA is only about 15 or 16Template:Nbsptimes a single typical recreational dose.[38]

Interactions

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Entactogens like MDMA pose high risks of severe and potentially fatal serotonin syndrome and hypertensive crisis in people on monoamine oxidase inhibitors (MAOIs) due to synergistic elevations of monoamines like serotonin and norepinephrine.[40][41] MDMA also has the potential to interact with various other drugs.[42][43][44]

Pharmacology

Mechanism of action

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Entactogens like MDMA are serotonin releasing agents and hence are indirect agonists of serotonin receptors.[45][46][47] They produce entactogenic effects in animals such as increased prosocial behavior like adjacent lying, enhanced empathy-like behavior, and antiaggressive effects.[45][48][12] Likewise, MDMA increases sociability, prosociality, and emotional empathy in humans.[12]

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 antagonist WAY-100635.[45][49][50][51][52] Conversely, the serotonin 5-HT1A receptor agonist 8-OH-DPAT produced prosocial behavior and increased oxytocin levels similarly to MDMA.[45][50][53] In addition, MDMA has been shown to activate oxytocinergic neurons in the hypothalamus and this too is reversed by serotonin 5-HT1A receptor antagonism.[45][50][54] Subsequent research found that direct injection of the serotonin 5-HT1A 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.[55][51]

The serotonin 5-HT2B and 5-HT2C receptor antagonist SB-206553 has also been found to block MDMA-induced prosocial behavior, although it produced potentially confounding thigmotaxis (hyperactivity at periphery of testing chamber) as well.[49][52] Conversely, the serotonin 5-HT1B receptor antagonist GR-55562 and the serotonin 5-HT2A receptor antagonist ketanserin were both ineffective.[49][51][52] Likewise, another study found that selective antagonists of the serotonin 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4 receptors (SB-216641), volinanserin (MDL-100907), SB-242084, and SB-204070, respectively) were all ineffective in suppressing MDMA-induced prosocial activity.[55][51] Other research has found that serotonin 5-HT2B receptor inactivation abolishes the serotonin release induced by MDMA and attenuates many of its effects.[46][47][56] In addition to the preceding findings, induction of serotonin release by MDMA in the nucleus accumbens and consequent activation of serotonin 5-HT1B 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.[1][48][57][58] Injection of the serotonin 5-HT1B receptor antagonist NAS-181 directly into the nucleus accumbens blocked the prosocial behaviors of MDMA.[57]

On the basis of the serotonin 5-HT1A receptor-mediated oxytocin release with MDMA, it has been proposed that increased oxytocinergic signaling may mediate the prosocial effects of MDMA in animals.[45][50] Accordingly, intracerebroventricular injection of the peptide oxytocin receptor antagonist tocinoic acid blocked MDMA- and 8-OH-DPAT-induced prosocial effects.[45][50][59] However, in a subsequent study, systemically administered C25, a non-peptide oxytocin receptor antagonist, failed to affect MDMA-induced prosocial behavior, whereas the vasopressin V1A receptor antagonist relcovaptan (SR-49059) was able to block MDMA-induced prosocial activity.[45][59] It might be that tocinoic acid is non-selective and also blocks the vasopressin V1A receptor or that C25 is peripherally selective and is unable to block oxytocin receptors in the brain.[45][59] More research is needed to clarify this.[59][45] In any case, in another study, the non-peptide and centrally active selective oxytocin receptor antagonist L-368899 abolished MDMA-induced prosocial behavior.[59][60] Conversely, in other studies, different oxytocin receptor antagonists were ineffective.[57]

As in animals, MDMA greatly increases circulating oxytocin levels in humans.[45] Serotonin reuptake inhibitors and norepinephrine reuptake inhibitors reduced the subjective effects of MDMA in humans, for instance increased extroversion, self-confidence, closeness, openness, and talkativeness.[12] The 5-HT2A receptor antagonist ketanserin reduced MDMA-induced increases in friendliness.[12] MDMA-induced emotional empathy was not affected by the serotonin 5-HT1A receptor antagonist pindolol or by intranasal oxytocin.[61] Similarly, MDMA-induced emotional empathy and prosocial behavior have not been associated with circulating oxytocin levels.[61][45] As such, the role of oxytocin in the entactogenic effects of MDMA in humans is controversial.[45]

Other serotonin releasing agents, like fenfluramine, show prosocial effects in animals similar to those of MDMA.[62][57] Fenfluramine has likewise been reported to improve social deficits in children with autism.[57][63] Selective agonists of the serotonin 5-HT1A and 5-HT1B receptors and of the oxytocin receptors have been or are being investigated for the potential treatment of social deficits and aggression.[64][65][66][67] Examples include batoprazine, eltoprazine (DU-28853), fluprazine (DU-27716), F-15,599 (NLX-01), zolmitriptan (ML-004), and LIT-001.[66][67][68] Serotonergic psychedelics, for instance lysergic acid diethylamide (LSD) and psilocybin, which act as non-selective serotonin receptor agonists including of the serotonin 5-HT1 and 5-HT2 receptors, have shown prosocial and empathy-enhancing effects in animals and/or humans as well, both acutely and long-term.[69][70][71]

The serotonin release of MDMA appears to be the key pharmacological action mediating the entactogenic, prosocial, and empathy-enhancing effects of the drug.[12][13][3] However, in addition to serotonin release, MDMA is also a potent releasing agent of norepinephrine and dopamine, and hence acts as a well-balanced serotonin–norepinephrine–dopamine releasing agent.[13][3] Additionally, MDMA is a direct agonist of several serotonin receptors, including of the serotonin 5-HT2 receptors, with moderate affinity.[13][3] These actions are thought to play an important role in the effects of MDMA, including in its psychostimulant, euphoriant, and mild psychedelic effects, as well as in its unique and difficult-to-replicate "magic".[13][14][3][72] It has been said by Matthew Baggott that few to no MDMA analogues, including MBDB, methylone, 6-APDB, 5-APDB, 6-APB, 5-APB, MDAT, and MDAI among others, reproduce the full quality and "magic" of MDMA.[14][15] Exceptions may anecdotally include 5-MAPB, particularly in specific enantiomer ratios, and the Borax combo.[14][15][73] 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.[14][15]

Ariadne, the α-ethyl analogue of the serotonergic psychedelic DOM, fully substitutes for MDMA in rodent drug discrimination tests, suggesting that it may have entactogen-like effects.[74][75] This property is unusual among psychedelics, and is in notable contrast to DOM, which at best partially substitutes for MDMA.[75][76] Besides Ariadne, the NBOMe drugs such as 25I-NBOMe and 25B-NBOMe also partially to fully substitute for MDMA in rodents.[77][78][79][80] Unlike conventional entactogens, Ariadne shows no activity at the monoamine transporters, and instead acts as a selective serotonin 5-HT2 receptor partial agonist, including as a lower-efficacy agonist of the serotonin 5-HT2A receptor.[74] Certain other psychedelics and related compounds, like low doses of 2C-B, are also selective serotonin 5-HT2 receptor partial agonists that have likewise been implicated as having entactogenic effects.[37][81][82] MDMA itself is notable in being a lower-efficacy partial agonist of the serotonin 5-HT2A receptor as well.[83][84] The stimulus effects of MDMA in the drug discrimination paradigm are partially blocked by the selective serotonin 5-HT2A receptor antagonist volinanserin in rodents.[85] Similarly, the psychoactive effects of MDMA are partially blocked by the relatively selective serotonin 5-HT2A receptor antagonist ketanserin in humans.[13][86][87][88]

History

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The history of MDMA and other entactogens has been reviewed.[22][23][89][24][90][1]

Society and culture

Etymology

The term empathogen, meaning "generating a state of empathy", was independently coined by Ralph Metzner in 1983 and David E. Nichols in 1984 as a term to denote a class of drugs that includes MDMA and other agents with similar effects.[27][28][29] Subsequently, in 1986, Nichols rejected this initial terminology and adopted, instead, the term entactogen, meaning "producing a touching within", to denote this class of drugs, asserting a concern with the potential for improper association of the term empathogen with negative connotations related to the Greek root πάθος páthos ("suffering; passion").[1][5][6] Additionally, Nichols wanted to avoid any association with the term pathogenesis.[91]

Nichols also thought the original term was limiting, and did not cover other therapeutic uses for the drugs that go beyond instilling feelings of empathy.[4] The hybrid word entactogen is derived from the roots en (Template:Langx), tactus (Template:Langx) and -gen (Template:Langx).[5] Entactogen is not becoming dominant in usage, and, despite their difference in connotation, they are essentially interchangeable, as they refer to precisely the same chemicals.

In 2024, an additional alternative term, connectogen, was proposed and introduced by Kurt Stocker and Matthias Liechti.[2]

List of entactogens

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The chemicals below have a varying degree of entactogenic effects; some of them induce additional effects, including serenic effects, stimulant effects, antidepressant effects, anxiolytic effects, and psychedelic effects.[91]

Phenethylamines

Amphetamines

Methylenedioxyamphetamines (benzodioxoles)
Benzofurans
Others
Cathinones
Aminorexes

Tryptamines

α-Alkyltryptamines

2-Aminoindanes

Indolizines

References

Template:Reflist

External links

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