Entactogen

{{Short description|Class of psychoactive drugs that produce empathic experiences}} {{Redirect|Empathogen|the album by Willow Smith|Empathogen (album){{!}}''Empathogen'' (album)}} {{Infobox drug class | Name = Entactogen | Image = File:Ecstasy monogram.jpg | ImageClass = | Alt = | Caption = A selection of MDMA pills, which are often nicknamed "Ecstasy" or "X" | Width = 200px | Pronounce = | Synonyms = Entactogen; Empathogen; Connectogen<ref name="Nichols2022" /><ref name="StockerLiechti2024" /><ref name="NicholsYensenMetzner1993">{{cite journal | vauthors = Nichols D, Yensen R, Metzner R, Shakespeare W | title = The Great Entactogen-Empathogen Debate | journal = Newsletter of the Multidisciplinary Association for Psychedelic Studies | volume = 4 | issue = 2 | date = 1993 | pages = 47–49 | url = https://maps.org/wp-content/uploads/1993/07/v4n2_47.pdf}}</ref><ref name="Nichols1986" /> <!-- Class identifiers --> | Use = Recreational, spiritual, medical, microdosing | ATC_prefix = | Mode_of_action = | Mechanism_of_action = Serotonin–norepinephrine–dopamine releasing agent; Serotonin 5-HT₂ receptor agonism | Biological_target = Serotonin transporter; Norepinephrine transporter; Dopamine transporter; Serotonin 5-HT₂ receptors | Chemical_class = Amphetamines, MDxx, cathinones, benzofurans, α-alkyltryptamines, 2-aminoindanes, others <!-- Clinical data --> | Drugs.com = <!-- {{Drugs.com|drug-class|?}} --> | Consumer_Reports = | medicinenet = | rxlist = | rxlist_name = <!-- External links --> | MeshID = <!-- Legal status --> | legal_status = Variable }} {{Psychedelic sidebar}}

'''Entactogens''', also known as '''empathogens''' or '''connectogens''', are a class of psychoactive drugs that induce experiences of emotional communion, oneness, connectedness, emotional openness—that is, empathy—as particularly observed and reported for experiences with MDMA (ecstasy).<ref name="Nichols2022" /><ref name="StockerLiechti2024" /><ref name="Oeri2021" /><ref name="NicholsYensenMetzner1993" /><ref name="Nichols1986" /> 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.<ref name="Nichols2022" /><ref name="Nichols1986" /><ref name="NicholsHoffmanOberlender1986">{{cite journal | vauthors = Nichols DE, Hoffman AJ, Oberlender RA, Jacob P, Shulgin AT | title = Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class | journal = J Med Chem | volume = 29 | issue = 10 | pages = 2009–2015 | date = October 1986 | pmid = 3761319 | doi = 10.1021/jm00160a035 | url = }}</ref><ref name="McGregorThompsonCallaghan2010">{{cite book|title=Encyclopedia of Psychopharmacology|last1=McGregor|first1=Iain S.|last2=Thompson|first2=Murray R.|last3=Callaghan|first3=Paul D.|date=2010-01-01|publisher=Springer Berlin Heidelberg|isbn=978-3-540-68698-9|editor-last=Stolerman|editor-first=Ian P.|pages=758–762|language=en|doi=10.1007/978-3-540-68706-1_154}}</ref> Entactogens are used both as recreational drugs<ref name="HillThomas2011" /> and are being investigated for medical use in the treatment of psychiatric disorders, for instance MDMA-assisted therapy for post-traumatic stress disorder (PTSD).<ref name="Baldo2024" /><ref name="Singh2025" /><ref name="WolfgangFonzoGray2025" />

Notable members of this class include the methylenedioxyphenethylamines (MDxx) MDMA, MDA, MDEA, MDOH, MBDB, and methylone, the benzofurans 5-APB, 5-MAPB, 6-APB, and 6-MAPB, the cathinone mephedrone, the 2-aminoindane MDAI, and the α-alkyltryptamine αET, among others.<ref name="Nichols2022" /><ref name="Oeri2021" /> Most entactogens are amphetamines, although some, such as αET, are tryptamines.<ref name="Nichols2022" /><ref name="Oeri2021" /> 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.<ref name="Kamilar-BrittBedi2015" /><ref name="HalberstadtNichols2020" /><ref name="Oeri2021" /><ref name="Baggott2023" /><ref name="Baggott2024" /> 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.<ref name="Kamilar-BrittBedi2015" /><ref name="HalberstadtNichols2020" /><ref name="Oeri2021" /><ref name="Baggott2023" /><ref name="Baggott2024" /> It is thought that dopamine and norepinephrine release provide additional stimulant, euphoriant, and cardiovascular or sympathomimetic effects, serotonin 5-HT_2A 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.<ref name="Kamilar-BrittBedi2015" /><ref name="HalberstadtNichols2020" /><ref name="Oeri2021" /><ref name="Baggott2023" /><ref name="Baggott2024" /> Entactogens that simultaneously induce serotonin and dopamine release, for instance MDMA, may produce serotonergic neurotoxicity<ref name="BaggottMendelson2001">{{cite book | author1-last=Baggott | author1-first=Matthew | author2-last= Mendelson | author2-first=John | chapter=Does MDMA Cause Brain Damage? | pages=110–145, 396–404 | editor1-last=Holland | editor1-first=J. | title=Ecstasy: The Complete Guide: A Comprehensive Look at the Risks and Benefits of MDMA | publisher=Inner Traditions/Bear | year=2001 | isbn=978-0-89281-857-0 | chapter-url=https://www.erowid.org/chemicals/mdma/mdma_neurotoxicity1.shtml | url=https://books.google.com/books?id=CUCcyklcO00C}}</ref><ref name="SpragueEvermanNichols1998">{{cite journal | vauthors = Sprague JE, Everman SL, Nichols DE | title = An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine | journal = Neurotoxicology | volume = 19 | issue = 3 | pages = 427–441 | date = June 1998 | pmid = 9621349 | doi = | url = https://www.researchgate.net/publication/13663847}}</ref><ref name="Oeri2021" /> with associated cognitive and memory deficits as well as psychiatric changes.<ref name="Parrott2002">{{cite journal | vauthors = Parrott AC | title = Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity | journal = Pharmacol Biochem Behav | volume = 71 | issue = 4 | pages = 837–844 | date = April 2002 | pmid = 11888574 | doi = 10.1016/s0091-3057(01)00711-0 | url = }}</ref><ref name="Parrott2013">{{cite journal | vauthors = Parrott AC | title = MDMA, serotonergic neurotoxicity, and the diverse functional deficits of recreational 'Ecstasy' users | journal = Neurosci Biobehav Rev | volume = 37 | issue = 8 | pages = 1466–1484 | date = September 2013 | pmid = 23660456 | doi = 10.1016/j.neubiorev.2013.04.016 | url = }}</ref><ref name="AguilarGarcía-PardoParrott2020">{{cite journal | vauthors = Aguilar MA, García-Pardo MP, Parrott AC | title = Of mice and men on MDMA: A translational comparison of the neuropsychobiological effects of 3,4-methylenedioxymethamphetamine ('Ecstasy') | journal = Brain Res | volume = 1727 | issue = | article-number = 146556 | date = January 2020 | pmid = 31734398 | doi = 10.1016/j.brainres.2019.146556 | url = }}</ref><ref name="MontgomeryRoberts2022">{{cite journal | vauthors = Montgomery C, Roberts CA | title = Neurological and cognitive alterations induced by MDMA in humans | journal = Exp Neurol | volume = 347 | issue = | article-number = 113888 | date = January 2022 | pmid = 34624331 | doi = 10.1016/j.expneurol.2021.113888 | url = https://researchonline.ljmu.ac.uk/id/eprint/15629/3/Montgomery_Roberts_2021%20Review.pdf}}</ref> However, these effects are tied to larger and/or more frequent doses of MDMA in humans,<ref>{{Cite journal |last=Müller |first=Felix |last2=Brändle |first2=Raphael |last3=Liechti |first3=Matthias E. |last4=Borgwardt |first4=Stefan |date=2019-01-01 |title=Neuroimaging of chronic MDMA (“ecstasy”) effects: A meta-analysis |url=https://www.sciencedirect.com/science/article/pii/S0149763418305414 |journal=Neuroscience & Biobehavioral Reviews |volume=96 |pages=10–20 |doi=10.1016/j.neubiorev.2018.11.004 |issn=0149-7634|doi-access=free }}</ref> while the doses that elicit neurotoxicity and cognitive deficits in animal models are typically larger than those used in clinical settings and by most recreational users.<ref>{{Cite journal |last=Pantoni |first=Madeline M. |last2=Anagnostaras |first2=Stephan G. |date=2019-07-01 |title=Cognitive Effects of MDMA in Laboratory Animals: A Systematic Review Focusing on Dose |url=https://pharmrev.aspetjournals.org/article/S0031-6997(24)01295-X/abstract |journal=Pharmacological Reviews |language=English |volume=71 |issue=3 |pages=413–449 |doi=10.1124/pr.118.017087 |issn=0031-6997 |pmc=6607799 |pmid=31249067}}</ref>

MDA and MDMA were both first synthesized independently in the early 1910s.<ref name="Passie2023" /> 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.<ref name="Passie2023">{{cite book | last=Passie | first=Torsten | title=The History of MDMA | publisher=Oxford University Press | date=29 June 2023 | isbn=978-0-19-886736-4 | doi=10.1093/oso/9780198867364.001.0001 | url=https://books.google.com/books?id=KSvCEAAAQBAJ}}</ref><ref name="Bernschneider-ReifOxlerFreudenmann2006">{{cite journal | vauthors = Bernschneider-Reif S, Oxler F, Freudenmann RW | title = The origin of MDMA ("ecstasy")--separating the facts from the myth | journal = Pharmazie | volume = 61 | issue = 11 | pages = 966–972 | date = November 2006 | pmid = 17152992 | doi = | url = }}</ref><ref name="BenzenhöferPassie2010">{{cite journal | vauthors = Benzenhöfer U, Passie T | title = Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin | journal = Addiction | volume = 105 | issue = 8 | pages = 1355–61 | date = August 2010 | pmid = 20653618 | doi = 10.1111/j.1360-0443.2010.02948.x | url = }}</ref><ref name="Alles1959a">{{cite book | author=Gordon A. Alles | chapter = Some Relations Between Chemical Structure and Physiological Action of Mescaline and Related Compounds / Structure and Action of Phenethylamines | veditors = Abramson HA | title = Neuropharmacology: Transactions of the Fourth Conference, September 25, 26, and 27, 1957, Princeton, N. J. | location = New York | publisher = Josiah Macy Foundation | date = 1959 | pages = 181–268 | oclc = 9802642 | url = https://books.google.com/books?id=sDQLAQAAMAAJ&q=%22Some+relations+between+chemical+structure+and+physiological+action+of+mescaline+and+related+compounds%22 | chapter-url = https://bitnest.netfirms.com/external/Books/NeuropharmacologyTrans.4.181#page=5 | archive-url = https://web.archive.org/web/20250321230359/https://bitnest.netfirms.com/external/Books/NeuropharmacologyTrans.4.181#page=5 | archive-date = 21 March 2025 }}</ref><ref name="Alles1959b">{{cite book | author = Gordon A. Alles | chapter = Subjective Reactions to Phenethylamine Hallucinogens | title = A Pharmacologic Approach to the Study of the Mind | date = 1959 | publisher = CC Thomas | location = Springfield | pages = 238–250 (241–246) | isbn = 978-0-398-04254-7 | url = https://books.google.com/books?id=x45rAAAAMAAJ | chapter-url = https://archive.org/details/pharmacologicapp0000univ/page/238/mode/1up}}</ref> 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.<ref name="Nichols2022" /><ref name="Nichols1986" /><ref name="NicholsHoffmanOberlender1986" /> Gordon Alles discovered the psychoactive effects of MDA,<ref name="Alles1959a" /><ref name="Alles1959b" /> Alexander Shulgin played a key role in bringing awareness to MDMA and its unique effects,<ref name="BenzenhöferPassie2010" /> and Ralph Metzner<ref name="Eisner1989">{{cite book | last=Eisner | first=Bruce | chapter=Chapter II. What is an Empathogen? | pages=33–50 | title=Ecstasy: The MDMA Story | publisher=Ronin Pub. | location=Berkeley, California | date=1989 | isbn=978-0-914171-25-6 | ol = OL2222596M | oclc = 27935523 | url=https://books.google.com/books?id=oIM4AQAAIAAJ | archive-url=https://archive.org/details/ecstasymdmastory0000eisn_a4n2/ | archive-date=8 June 2023 | access-date=25 April 2025}}</ref><ref name="MetznerAdamson2001">{{cite book | author1-last=Metzner | author1-first=Ralph | author2-last=Adamson | author2-first=Sophia | chapter=Using MDMA in Healing, Psychotherapy, and Spiritual Practice | pages=182–207 | editor1-last=Holland | editor1-first=J. | title=Ecstasy: The Complete Guide: A Comprehensive Look at the Risks and Benefits of MDMA | publisher=Inner Traditions/Bear | year=2001 | isbn=978-0-89281-857-0 | url=https://books.google.com/books?id=CUCcyklcO00C | quote=The term "empathogenic," meaning "generating a state of empathy," was independently proposed for these substances in 1983—84 by Ralph Metzner, a psychologist and psychopharmacologist, and David Nichols, a professor of medicinal chemistry at Purdue University. Nichols subsequently rejected the term and now prefers "entactogenic," meaning "touching within," for MDMA. We continue to use the term "empathogenic."}}</ref><ref name="Metzner1983">{{cite conference | author = Ralph Metzner | title = [Lecture presented at the Psychedelics and Spirituality Conference] | conference = Psychedelics and Spirituality, University of California, Santa Barbara, May 13–14, 1983 | date = May 1983 | url = https://scholar.google.com/scholar?cluster=16938435501563008121 | quote = Another group of drugs are the phenethylamines, of which MDA [and MDMA] is an example. Instead of calling these "psychedelic drugs," I'd like to suggest the name "empathogenic." Empathogenic means "empathy generating." Everyone I've mentioned this name to thinks it is a good one. These drugs don't produce visions as LSD does. They don't produce multileveled thinking or objectivity toward your mind as LSD and the psychedelics do. They generate a profound state of empathy for self and other in the most general and profound terms. A state of empathy where the feeling is that the self, the other, and the world is basically good, is all right. This state can be referred to as the ground of being, the core of our being, a still point of our being. Then individuals using these substances in therapy can look at their own problems from the standpoint of stillness and empathy. They are able to do changework on themselves very rapidly, compared to ordinary therapy.}}</ref> and David E. Nichols formally defined entactogens and established them as a distinct class of drugs.<ref name="Nichols2022" /><ref name="Nichols1986" /><ref name="NicholsHoffmanOberlender1986" /> Many entactogens like MDMA are controlled substances throughout the world.<ref name="Shulgin1992">{{cite book | last=Shulgin | first=Alexander | title=Controlled Substances: A Chemical and Legal Guide to the Federal Drug Laws | publisher=Ronin Pub. | date=1992 | isbn=978-0-914171-50-8 | url=https://books.google.com/books?id=rO4MAAAACAAJ | access-date=25 April 2025 | page=}}</ref><ref name="ShulginManningDaley2011">{{cite book | last1=Shulgin | first1=A. | last2=Manning | first2=T. | last3=Daley | first3=P.F. | title=The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher=Transform Press | location=Berkeley | volume=1 | year=2011 | isbn=978-0-9630096-3-0 | url=https://books.google.com/books?id=68-huAAACAAJ}}</ref>

==Uses== ===Recreational=== Entactogens are used as recreational drugs, including notably at raves.<ref name="HillThomas2011">{{cite journal | vauthors = Hill SL, Thomas SH | title = Clinical toxicology of newer recreational drugs | journal = Clin Toxicol (Phila) | volume = 49 | issue = 8 | pages = 705–719 | date = October 2011 | pmid = 21970769 | doi = 10.3109/15563650.2011.615318 | url = }}</ref>

===Medical=== Psychiatrists began using entactogens as psychotherapy tools in the 1970s despite the lack of clinical trials.<ref>{{Cite book|title=Encyclopedia of emotion|last1=Malamud|first1=Ozer, Yvette|last2=Yuri|first2=Ito|date=2010-01-01|publisher=Greenwood Press|isbn=978-0-313-34574-6|oclc=934324453}}</ref> 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.<ref name=":1">{{Cite book|title=The therapeutic use of Ayahuasca|last1=Caiuby|first1=Labate, Beatriz|last2=Clancy|first2=Cavnar|date=2014-01-01|publisher=Springer|isbn=978-3-642-40425-2|oclc=876696992}}</ref> 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.<ref name=":1" /> 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.<ref name=":1" /> 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.<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 psychopharmacological means for a positive or negative experience.<ref name=":2" /> 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.<ref>{{Cite book|title=Psychopharmacology: drugs, the brain, and behavior|last=F.|first=Quenzer, Linda|isbn=978-0-87893-510-9|oclc=869923492|date = 2013-05-06|publisher=Sinauer }}</ref>

MDMA-assisted psychotherapy (MDMA-AT) is in late-stage clinical trials 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 | 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>

===Doses and durations=== {{See also|Substituted methylenedioxyphenethylamine#Use and effects}}

{{Sticky}} {| class="wikitable sortable sticky-header" style="font-size: 98%;" |+ {{Nowrap|Oral doses and durations of entactogens^a}} |- ! Compound !! Class !! Dose !! Duration |- | MDA (Sally, Sassafras) || Amphetamine || 80–160 mg (20–200 mg+) || 4–8 hours |- | {{Nbsp}}{{Nbsp}}(''S'')-MDA || Amphetamine || 160–225 mg || 3 hours |- | {{Nbsp}}{{Nbsp}}(''R'')-MDA || Amphetamine || 70–200 mg || 4–8 hours |- | MDMA (Ecstasy; Molly; Adam) || Amphetamine || 80–150 mg (25–200 mg+) || 3–6 hours |- | {{Nbsp}}{{Nbsp}}(''S'')-MDMA || Amphetamine || 60–125 mg || 5 hours |- | {{Nbsp}}{{Nbsp}}(''R'')-MDMA || Amphetamine || 250–300 mg || 4–5 hours |- | MDEA (MDE; Eve) || Amphetamine || 100–200 mg (30–225 mg+) || 3–5 hours |- | MDOH (MDHA) || Amphetamine || 100–160 mg || 3–6 hours |- | FLEA (MDMOH, MDHMA) || Amphetamine || 100–160 mg || 4–8 hours |- | Lys-MDA || Amphetamine || ~164 mg || ~6 hours |- | MMDA (5-methoxy-MDA) || Amphetamine || 100–250 mg || "Moderate" |- | BDB (J) || Phenylisobutylamine || 150–230 mg || 4–8 hours |- | MBDB (methyl-J; Eden) || Phenylisobutylamine || 180–210 mg (150–250 mg+) || 4–6 hours |- | Methylone (βk-MDMA) || Cathinone || 100–250 mg (60–325 mg+) || 2–5 hours |- | Ethylone (βk-MDEA) || Cathinone || 150–250 mg (80–400 mg) || 2–6 hours |- | Butylone (βk-MBDB) || Cathinone || 100–250 mg (20–250 mg) || 2–5 hours |- | Mephedrone (4-MMC) || Cathinone || 100–200 mg (15–300 mg+) || 2–5 hours |- | 5-APB || Benzofuran || 60–80 mg (20–100 mg+) || 3–8 hours |- | 5-MAPB || Benzofuran || 30–70 mg || 5–6 hours |- | 6-APB || Benzofuran || 80–100 mg (15–125 mg+) || 6–9 hours |- | 6-MAPB || Benzofuran || 50–100 mg || 6–8 hours |- | 5-APDB || Dihydrobenzofuran || 50–200 mg+ || Unknown |- | 5-MAPDB || Dihydrobenzofuran || 50–150 mg+ || Unknown |- | 6-APDB || Dihydrobenzofuran || 20–130 mg+ || Unknown |- | MDAI || 2-Aminoindane || 100–200 mg (20–300 mg+) || 2–5 hours |- | MMAI || 2-Aminoindane || Unknown || Unknown |- | MEAI (5-MeO-AI) || 2-Aminoindane || 100–250 mg || Unknown |- | 5-IAI || 2-Aminoindane || 100–200 mg || 2–4 hours |- | AMT || Tryptamine || 15–30 mg || 12–16 hours |- | AET || Tryptamine || 100–150 mg || 6–8 hours |- | BK-NM-AMT (βk-NM-AMT) || Tryptamine || Unknown || Unknown |- | Borax combo^b || Multiple^b || Variable || Variable |- |- class="sortbottom" | colspan="5" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Footnotes:''' ^a = Some of these drugs also act as robust psychedelics and/or stimulants. Examples of psychedelics include MDA, MMDA, and AMT, while examples of stimulants include mephedrone. ^b = The Borax combo is a combination of 5-MAPB or MDAI, 2-FMA, and 5-MeO-MiPT or 4-HO-MET and is said to closely mimic the effects and unique "magic" of MDMA. '''Refs:''' <ref name="PiHKAL">{{CitePiHKAL}}</ref><ref name="TrachselLehmannEnzensperger2013">{{cite book | vauthors = Trachsel D, Lehmann D, Enzensperger C | title = Phenethylamine: von der Struktur zur Funktion | location = Solothurn | year = 2013 | trans-title = Phenethylamines: From Structure to Function | edition = 1 | publisher = Nachtschatten-Verlag | series = Nachtschatten-Science | isbn = 978-3-03788-700-4 | oclc = 858805226 | url = https://books.google.com/books?id=-Us1kgEACAAJ | language = de | archive-url = https://web.archive.org/web/20251020222809/https://books.google.com/books?id=-Us1kgEACAAJ | archive-date = 20 October 2025 | pages = 465–468, 555–557, 578–630, 659–660, 721, 745–746, 828–831, 905–906 | access-date = 30 October 2025 | url-status = bot: unknown }}</ref><ref name="Oeri2021" /><ref name="ShulginManningDaley2011" /><ref name="JacobShulgin1994">{{cite book | vauthors = Jacob P, Shulgin AT | chapter = Structure-Activity Relationships of the Classic Hallucinogens and Their Analogs | pages = 74–91 | veditors = Lin GC, Glennon RA | title = Hallucinogens: An Update | series = National Institute on Drug Abuse Research Monograph Series | volume = 146 | date = 1994 | publisher = National Institute on Drug Abuse | pmid = 8742795 | url = https://archives.nida.nih.gov/sites/default/files/monograph146.pdf | chapter-url = https://bibliography.maps.org/resources/download/11534 | archive-url = https://web.archive.org/web/20250713011914/https://bibliography.maps.org/resources/download/11534 | archive-date = 13 July 2025 }}</ref><ref name="Shulgin2003">{{cite book | vauthors = Shulgin AT | veditors = Laing RR | chapter = Basic Pharmacology and Effects | title = Hallucinogens: A Forensic Drug Handbook | pages = 67–137 | year = 2003 | publisher = Elsevier Science | series = Forensic Drug Handbook Series | isbn = 978-0-12-433951-4 | url = https://books.google.com/books?id=l1DrqgobbcwC | chapter-url = https://bibliography.maps.org/resources/download/12634 | archive-url = https://web.archive.org/web/20250713013624/https://bibliography.maps.org/resources/download/12634 | archive-date = 13 July 2025 }}</ref><ref name="Shulgin1976">{{cite book | veditors=Gordon M | title=Psychopharmacological Agents: Use, Misuse and Abuse | series=Medicinal Chemistry: A Series of Monographs | volume=4 | vauthors = Shulgin AT | chapter=Psychotomimetic Agents | date=1976 | isbn=978-0-12-290559-9 | doi=10.1016/b978-0-12-290559-9.50011-9 | pages=59–146 | publisher=Academic Press | chapter-url=https://bitnest.netfirms.com/external/10.1016/B978-0-12-290559-9.50011-9}}</ref><ref name="Shulgin1978">{{cite book | veditors = Iversen LL, Iversen SD, Snyder SH | last=Shulgin | first=Alexander T. | title=Stimulants | chapter=Psychotomimetic Drugs: Structure-Activity Relationships | publisher=Springer US | publication-place=Boston, MA | date=1978 | isbn=978-1-4757-0512-6 | doi=10.1007/978-1-4757-0510-2_6 | pages=243–333 | chapter-url=https://bitnest.netfirms.com/external/10.1007/978-1-4757-0510-2_6 | url=https://books.google.com/books?id=h0_uBwAAQBAJ&pg=PA261}}</ref><ref name="LuethiLiechti2018">{{cite journal | vauthors = Luethi D, Liechti ME | title = Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics | journal = Int J Neuropsychopharmacol | volume = 21 | issue = 10 | pages = 926–931 | date = October 2018 | pmid = 29850881 | pmc = 6165951 | doi = 10.1093/ijnp/pyy047 }}</ref><ref name="BallentineFriedmanBzdok2022">{{cite journal |last1=Ballentine |first1=Galen |last2=Friedman |first2=Samuel Freesun |last3=Bzdok |first3=Danilo |date=March 2022 |title=Trips and neurotransmitters: Discovering principled patterns across 6850 hallucinogenic experiences |journal=Sci Adv |volume=8 |issue=11 |bibcode=2022SciA....8L6989B |doi=10.1126/sciadv.abl6989 |pmc=8926331 |pmid=35294242 |article-number=eabl6989}}</ref><ref name="LuethiLiechti2020" /> ''Individual:'' <ref name="LiechtiHolze2022">{{cite book | vauthors = Liechti ME, Holze F | title = Disruptive Psychopharmacology | chapter = Dosing Psychedelics and MDMA | series = Curr Top Behav Neurosci | volume = 56 | pages = 3–21 | date = 2022 | pmid = 34734392 | doi = 10.1007/7854_2021_270 | isbn = 978-3-031-12183-8 | chapter-url = }}</ref><ref name="AndersonBraunBraun1978">{{cite book | vauthors = Anderson GM, Braun G, Braun U, Nichols DE, Shulgin AT | chapter = Absolute Configuration and Psychotomimetic Activity | pages = 8–15 | veditors = Barnett G, Trsic M, Willette RE | title = QuaSAR: Quantitative Structure Activity Relationships Of Analgesics, Narcotic Antagonists, And Hallucinogens | series = National Institute on Drug Abuse Research Monograph Series | volume = 22 | date = 1978 | publisher = National Institute on Drug Abuse | pmid = 101890 | url = https://archives.nida.nih.gov/sites/default/files/monograph22.pdf | chapter-url = https://archives.nida.nih.gov/sites/default/files/monograph22.pdf#page=19}}</ref><ref name="StraumannAvedisianKlaiber2024">{{cite journal | vauthors = Straumann I, Avedisian I, Klaiber A, Varghese N, Eckert A, Rudin D, Luethi D, Liechti ME | display-authors = 6 | title = Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants | journal = Neuropsychopharmacology | volume = 50| issue = 2| date = August 2024 | pages = 362–371 | pmid = 39179638 | doi = 10.1038/s41386-024-01972-6 | doi-access = free | pmc = 11631982 }}</ref><ref name="BaggottGarrisonCoyle2019">{{cite journal | vauthors = Baggott MJ, Garrison KJ, Coyle JR, Galloway GP, Barnes AJ, Huestis MA, Mendelson JE | title = Effects of the Psychedelic Amphetamine MDA (3,4-Methylenedioxyamphetamine) in Healthy Volunteers | journal = Journal of Psychoactive Drugs | volume = 51 | issue = 2 | pages = 108–117 | date = 2019-03-15 | pmid = 30967099 | doi = 10.1080/02791072.2019.1593560 | s2cid = 106410946 }}</ref><ref name="StraumannVizeliAvedisian2025">{{cite journal | vauthors = Straumann I, Vizeli P, Avedisian I, Erne L, Noorshams D, Vukalovic I, Eckert A, Luethi D, Rudin D, Liechti ME | title = Acute effects of MDMA, MDA, lysine-MDMA, and lysine-MDA in a randomized, double-blind, placebo-controlled, crossover trial in healthy participants | journal = Neuropsychopharmacology | volume = 51| issue = 2| pages = 476–485| date = September 2025 | pmid = 40999236 | doi = 10.1038/s41386-025-02248-3 | url = | doi-access = free }}</ref><ref name="GreenKingShortall2014">{{cite journal | vauthors = Green AR, King MV, Shortall SE, Fone KC | title = The preclinical pharmacology of mephedrone; not just MDMA by another name | journal = Br J Pharmacol | volume = 171 | issue = 9 | pages = 2251–2268 | date = May 2014 | pmid = 24654568 | pmc = 3997268 | doi = 10.1111/bph.12628 | url = | quote = The normal routes of mephedrone administration in recreational users are reported to be oral and insufflation. Extrapolation from dosing to plasma levels is difficult as there are no detailed dose–concentration curves available and pharmacokinetic studies on the drug in humans have yet to be performed. However, it is suggested that a ‘normal’ recreational oral dose is 100–200 mg, while somewhat lower doses are used when the drug is insufflated (EROWID, 2013). This oral dose is similar to the usual oral MDMA dose typically resulting from ingestion of two tablets (140–180 mg), but an important difference with mephedrone is that the reported short duration of the psychoactive response often leads to rapid repeat dosing (Schifano et al., 2012).}}</ref><ref name="PapaseitMoltóMuga2017">{{cite book | vauthors = Papaseit E, Moltó J, Muga R, Torrens M, de la Torre R, Farré M | title = Neuropharmacology of New Psychoactive Substances (NPS) | chapter = Clinical Pharmacology of the Synthetic Cathinone Mephedrone | series = Curr Top Behav Neurosci | volume = 32 | pages = 313–331 | date = 2017 | pmid = 28012094 | doi = 10.1007/7854_2016_61 | chapter-url = | quote = Mephedrone oral dosage ranges from 15 to 300 mg, whereas nasal insufflation dosage is somewhat lower and ranges from 5 to 200 mg. Intravenous/intramuscular injection has been reported at approximately half or one-third of oral dosage, whilst 100 mg is described as a usual rectal dose [26, 38]. The initial impact is felt by recreational users approximately 30 min after oral ingestion, with effects lasting for 2–5 h [39]; in contrast, intravenous and rectal administration produce earlier onset of action and shorter duration [40].| doi-access = free | isbn = 978-3-319-52442-9 }}</ref><ref name="AngererSchmidFranz2024">{{cite journal | vauthors = Angerer V, Schmid Y, Franz F, Gnann H, Speer JM, Gnann A, Helmecke S, Buchwald A, Brandt SD, Passie T, Liechti ME, Auwärter V | title = Acute psychotropic, autonomic, and endocrine effects of 5,6-methylenedioxy-2-aminoindane (MDAI) compared with 3,4-methylenedioxymethamphetamine (MDMA) in human volunteers: A self-administration study | journal = Drug Test Anal | volume = 16 | issue = 9 | pages = 1002–1011 | date = September 2024 | pmid = 38056906 | doi = 10.1002/dta.3622 | url = | doi-access = free }}</ref><ref name="CorkeryElliottSchifano2013">{{cite journal | vauthors = Corkery JM, Elliott S, Schifano F, Corazza O, Ghodse AH | title = MDAI (5,6-methylenedioxy-2-aminoindane; 6,7-dihydro-5H-cyclopenta[f][1,3]benzodioxol-6-amine; 'sparkle'; 'mindy') toxicity: a brief overview and update | journal = Hum Psychopharmacol | volume = 28 | issue = 4 | pages = 345–355 | date = July 2013 | pmid = 23881883 | doi = 10.1002/hup.2298 | url = | quote = Doses range from 70–300 mg; typical doses appear to be 150–200 mg of active ingredient (equivalent to half of a 300 mg capsule or a whole 200 mg capsule). A ‘low’ dose of 70–80 mg produces subtle but noticeable effects; a strong dose is considered to be 250–300 mg. Redosing often occurs; typically a ‘booster’ of 100–150 mg is administered after the initial positive effects have worn off (Drugs-Forum, 2009a; Bluelight, 2010a; Herbalhighs, 2012a; Partyvibe, 2012).}}</ref><ref name="TiHKAL">{{CiteTiHKAL}}</ref><ref name="GlennonDukat2023">{{cite journal | vauthors = Glennon RA, Dukat MG | title = α-Ethyltryptamine: A Ratiocinatory Review of a Forgotten Antidepressant | journal = ACS Pharmacol Transl Sci | volume = 6 | issue = 12 | pages = 1780–1789 | date = December 2023 | pmid = 38093842 | pmc = 10714429 | doi = 10.1021/acsptsci.3c00139 | url = }}</ref><ref name="Aipsin-MEAI">{{cite web | title=5-MeO-AI | website=АИПСИН | url=https://aipsin.com/newsubstance/472/ | language=ru | access-date=1 January 2026}}</ref><ref name="Busby2025">{{cite web | last=Busby | first=Mattha | title=Pillheads, Rejoice: There's a New, Improved Ecstasy | website=VICE | date=18 August 2025 | url=https://www.vice.com/en/article/new-improved-ecstasy-blue-bliss/ | access-date=8 May 2026}}</ref> |}

The above table does not include atypical agents with some reported entactogen-like effects, such as the phenethylamine serotonergic psychedelic 2C-B<ref name="LuethiLiechti2020" /><ref name="WillsErickson2012" /><ref name="GonzálezTorrensFarré2015" /><ref name="Oeri2021" /> and the atypical tryptamine serotonergic psychedelics 5-MeO-DiPT<ref name="TiHKAL" /><ref name="ShulginCarter1980">{{cite journal | vauthors = Shulgin AT, Carter MF | title = N, N-Diisopropyltryptamine (DIPT) and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT). Two orally active tryptamine analogs with CNS activity | journal = Commun Psychopharmacol | volume = 4 | issue = 5 | pages = 363–369 | date = 1980 | pmid = 6949674 | doi = | url = https://bitnest.netfirms.com/external/Commun.Psychopharmacol/4.5.363}}</ref><ref name="PalamarAcosta2020">{{cite journal | vauthors = Palamar JJ, Acosta P | title = A qualitative descriptive analysis of effects of psychedelic phenethylamines and tryptamines | journal = Hum Psychopharmacol | volume = 35 | issue = 1 | article-number = e2719 | date = January 2020 | pmid = 31909513 | pmc = 6995261 | doi = 10.1002/hup.2719 | url = | quote = [...] These increased sensations of touch [with 5-methoxytryptamines like 5-MeO-DiPT and 5-MeO-MiPT] are likely why some users compared the “body high” with the high associated with MDMA use. [...] I would actually say that it is closer to MDMA in its effects. The whole series of 5-MeO and 4-MeO … they're both very closely related in their effects so it tends to be a body high kind of thing. At higher doses it can get more psychedelic, but it's not that psychedelic. [...]}}</ref><ref name="Oeri2021" /> and 5-MeO-MiPT.<ref name="TiHKAL" /><ref name="Carpenter2022">{{Cite web | vauthors = Carpenter DE | title = DEA Proposes Adding Five Psychedelic Compounds to Schedule 1 | date = 2022-01-25 | url = https://www.lucid.news/dea-proposes-five-psychedelic-compounds-schedule-1/ | access-date = 2022-01-26 | website = Lucid News | language = en-US | quote = Baggott says his team regularly uses one of the compounds on the list in his lab. “When my team synthesizes and characterizes a new compound, we need to compare it to compounds with known effects. We use 5-MeO-MiPT as one of these known comparison compounds,” he says. “It is scientifically interesting to my team because, although it has classical psychedelic effects at higher doses, it has some MDMA-like effects at low doses.”}}</ref><ref name="PalamarAcosta2020" />

==Effects== {{See also|MDMA#Effects}}

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.<ref name="NicholsYensenMetzner1993" /> 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.<ref>{{cite journal|last1=Metzner|first1=Ralph|title=Letter from Ralph Metzner|journal=Newsletter of the Multidisciplinary Association for Psychedelic Studies MAPS|date=1993|volume=4|issue=1|url=http://www.maps.org/news-letters/v04n1/04143met.html|access-date=8 January 2015}}</ref> 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.<ref name="NicholsYensenMetzner1993" />

==Side effects== {{See also|MDMA#Side effects}}

Side effects of entactogens like MDMA include mydriasis, nystagmus, jaw clenching, bruxism, insomnia, appetite loss, tachycardia, hypertension, and hyperthermia, among others.<ref name="Oeri2021" /><ref name="Baldo2024" /> 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.<ref name="Baldo2024" /><ref name="LuethiLiechti2020" /> Entactogens can produce long-lasting serotonergic neurotoxicity<ref name="BaggottMendelson2001"/><ref name="SpragueEvermanNichols1998"/><ref name="Oeri2021" /> and associated cognitive and memory deficits as well as psychiatric changes.<ref name="Parrott2002"/><ref name="Parrott2013"/><ref name="AguilarGarcía-PardoParrott2020"/><ref name="MontgomeryRoberts2022"/>

==Overdose== Entactogens like MDMA show a much narrower margin of safety and greater toxicity in overdose than serotonergic psychedelics.<ref name="Henríquez-HernándezRojas-HernándezQuintana-Hernández2023">{{cite journal | vauthors = Henríquez-Hernández LA, Rojas-Hernández J, Quintana-Hernández DJ, Borkel LF | title = Hofmann vs. Paracelsus: Do Psychedelics Defy the Basics of Toxicology?-A Systematic Review of the Main Ergolamines, Simple Tryptamines, and Phenylethylamines | journal = Toxics | volume = 11 | issue = 2 | date = February 2023 | page = 148 | pmid = 36851023 | pmc = 9963058 | doi = 10.3390/toxics11020148 | doi-access = free | bibcode = 2023Toxic..11..148H | url = }}</ref> Whereas LSD and psilocybin have extrapolated human lethal doses relative to typical recreational doses of approximately 1,000-fold and 200-fold, respectively,<ref name="Thomas2024">{{cite book | last=Thomas | first=Kelan | title=Toxicology and Pharmacological Interactions of Classic Psychedelics | series=Current Topics in Behavioral Neurosciences | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | date=2024 | doi=10.1007/7854_2024_508 | url=https://link.springer.com/10.1007/7854_2024_508 | access-date=14 May 2025 | page=| pmid=39042251 }}</ref> a reasonable estimated fatal dose of MDMA is only about 15 or 16{{nbsp}}times a single typical recreational dose.<ref name="Henríquez-HernándezRojas-HernándezQuintana-Hernández2023" />

==Interactions== {{See also|MDMA#Interactions|Trip killer#Antidotes of other hallucinogens|MDMA/citalopram}}

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.<ref name="MalcolmThomas2022">{{cite journal | vauthors = Malcolm B, Thomas K | title = Serotonin toxicity of serotonergic psychedelics | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1881–1891 | date = June 2022 | pmid = 34251464 | doi = 10.1007/s00213-021-05876-x | url = }}</ref><ref name="EdinoffSwinfordOdisho2022">{{cite journal | vauthors = Edinoff AN, Swinford CR, Odisho AS, Burroughs CR, Stark CW, Raslan WA, Cornett EM, Kaye AM, Kaye AD | title = Clinically Relevant Drug Interactions with Monoamine Oxidase Inhibitors | journal = Health Psychol Res | volume = 10 | issue = 4 | article-number = 39576 | date = 2022 | pmid = 36425231 | pmc = 9680847 | doi = 10.52965/001c.39576 | doi-broken-date = 2 April 2026 | url = }}</ref> MDMA also has the potential to interact with various other drugs.<ref name="PapaseitPérez-MañáTorrens2020">{{cite journal | vauthors = Papaseit E, Pérez-Mañá C, Torrens M, Farré A, Poyatos L, Hladun O, Sanvisens A, Muga R, Farré M | title = MDMA interactions with pharmaceuticals and drugs of abuse | journal = Expert Opin Drug Metab Toxicol | volume = 16 | issue = 5 | pages = 357–369 | date = May 2020 | pmid = 32228243 | doi = 10.1080/17425255.2020.1749262 | url = }}</ref><ref name="SarparastThomasMalcolm2022">{{cite journal | vauthors = Sarparast A, Thomas K, Malcolm B, Stauffer CS | title = Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1945–1976 | date = June 2022 | pmid = 35253070 | pmc = 9177763 | doi = 10.1007/s00213-022-06083-y | url = }}</ref><ref name="MohamedBenHamidaCassel2011">{{cite journal | vauthors = Mohamed WM, Ben Hamida S, Cassel JC, de Vasconcelos AP, Jones BC | title = MDMA: interactions with other psychoactive drugs | journal = Pharmacol Biochem Behav | volume = 99 | issue = 4 | pages = 759–774 | date = October 2011 | pmid = 21756931 | doi = 10.1016/j.pbb.2011.06.032 | url = }}</ref>

==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 agents and hence are indirect agonists of serotonin receptors.<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 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-HT_1A receptor 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 = | article-number = 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_1A 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 neurons in the hypothalamus and this too is reversed by serotonin 5-HT_1A 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_1A 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-HT_2B and 5-HT_2C 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.<ref name="Blanco-GandíaMateos-GarcíaGarcía-Pardo2015" /><ref name="MorleyArnoldMcGregor2005" /> Conversely, the serotonin 5-HT_1B receptor antagonist GR-55562 and the serotonin 5-HT_2A receptor antagonist ketanserin were both ineffective.<ref name="Blanco-GandíaMateos-GarcíaGarcía-Pardo2015" /><ref name="EsakiSasakiNishitani2023" /><ref name="MorleyArnoldMcGregor2005" /> Likewise, another study found that selective antagonists of the serotonin 5-HT_1B, 5-HT_2A, 5-HT_2C, and 5-HT₄ receptors (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_2B 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 = | hdl = 1854/LU-1035632 | hdl-access = free }}</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_1B 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 = | article-number = 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 | article-number = 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 | date = December 2019 | article-number = eaaw6435 | 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_1B 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_1A 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, systemically administered C25, a non-peptide oxytocin receptor antagonist, failed to affect MDMA-induced prosocial behavior, whereas the vasopressin V_1A 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 non-selective and also blocks the vasopressin V_1A receptor or that C25 is peripherally selective and is unable to block oxytocin receptors 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 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 inhibitors and norepinephrine reuptake inhibitors reduced the subjective effects of MDMA in humans, for instance increased extroversion, self-confidence, closeness, openness, and talkativeness.<ref name="Kamilar-BrittBedi2015" /> The 5-HT_2A 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_1A 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 |author5-link=Isabel Dziobek | 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 | article-number = 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 = | article-number = 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_1A and 5-HT_1B 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 = | article-number = 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 = | article-number = 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 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.<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 = | article-number = 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 | article-number = 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 = | article-number = 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 = | quote = While an argument can be made that compounds like 4-bromo-2,5-dimethoxyphenethylamine (2CB) or N,N-diisopropyl-5-methoxytryptamine (5-MeO-DiPT) are also entactogenic, and they have been described as such in the past (González et al., 2015; Palamar and Acosta, 2020; Schifano et al., 2019), they were also excluded due to their high affinity as agonists at post-synaptic 5-HT2 and 5-HT1A receptors (Fantegrossi et al., 2006; Nugteren-van Lonkhuyzen et al., 2015; Taylor et al., 1986; Villalobos et al., 2004), which would indicate that their effects also include a marked psychedelic component.}}</ref> 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.<ref name="HalberstadtNichols2020" /><ref name="Oeri2021" /> Additionally, MDMA is a direct agonist of several serotonin receptors, including of the serotonin 5-HT₂ receptors, with moderate 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 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 = | article-number = 109375 | date = March 2023 | pmid = 36529260 | doi = 10.1016/j.neuropharm.2022.109375 | url = | doi-access = free }}</ref> 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.<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 anecdotally include 5-MAPB, particularly in specific enantiomer ratios, and the Borax combo.<ref name="Busby2025" /><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" />

Some entactogens, such as the benzofurans 5-MAPB, 6-MAPB, BK-5-MAPB, and BK-6-MAPB, have unexpectedly been found to be potent serotonin 5-HT_1B receptor agonists.<ref name="US20230150963" /> In addition to serotonin release and other actions, this property may be involved in their entactogenic effects.<ref name="US20230150963">{{cite patent | country = US | number = 20230150963 | inventor = Matthew Baggott | status = | title = Advantageous benzofuran compositions for mental disorders or enhancement | pubdate = 2023 May 18 | gdate = | fdate = 2022 December 8 | pridate = 2022 December 8 | assign1 = Tactogen | url = https://patents.google.com/patent/US20230150963A1/en}}</ref> Conversely, MDMA is much less potent as an agonist of the serotonin 5-HT_1B receptor.<ref name="US20230150963" />

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.<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_2A 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 = | page = 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-HT₂ receptor partial agonist, including as a lower-efficacy agonist of the serotonin 5-HT_2A receptor.<ref name="CunninghamBockSerrano2023" /> 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.<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 | article-number = 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_2A 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><ref name="Oeri2021" /> The stimulus effects of MDMA in the drug discrimination paradigm are partially blocked by the selective serotonin 5-HT_2A 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_2A 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 | article-number = e40187 | date = 2012 | pmid = 22808116 | pmc = 3393729 | doi = 10.1371/journal.pone.0040187 | doi-access = free | bibcode = 2012PLoSO...740187V | url = }}</ref>

==Chemistry== Entactogens belong to a few chemical families, including phenethylamines or amphetamines, cyclized phenethylamines, and tryptamines. Phenethylamine entactogens can be divided into methylenedioxyphenethylamines (MDxx) like MDA and MDMA, benzofurans like 5-APB and 6-APB, and dihydrobenzofurans like 5-APDB and 6-APDB. They can also be further divided into additional subgroups such as cathinones like methylone BK-5-MAPB and phenylisobutylamines like MBDB. Cyclized phenethylamine entactogens include 2-aminoindanes like MDAI and 2-aminotetralins like MDAT. Tryptamine entactogens are α-alkyltryptamines and include α-methyltryptamine (AMT) and α-ethyltryptamine (AET) as well as β-keto-α-alkyltryptamines like BK-NM-AMT. Other possible structural families also exist, such as benzothiophenes and other bioisosteres like ODMA, TDMA, and SeDMA.

{{Hidden | header = Chemical structures of entactogens of different structural families | content = {{Gallery | height = 110 | width = 180 | File:MDA structure.svg | class1=skin-invert-image | MDA (MDxx) | File:MDMA.png | class2=skin-invert-image | MDMA (MDxx) | File:5-APB chemical structure.svg | class3=skin-invert-image | 5-APB (benzofuran) | File:6APB.svg | class4=skin-invert-image | 6-APB (benzofuran) | File:3-desoxy-MDA.svg | class5=skin-invert-image | 5-APDB (dihydrobenzofuran) | File:4-desoxy-MDA.svg | class6=skin-invert-image | 6-APDB (dihydrobenzofuran) | File:Methylone structure.svg | class7=skin-invert-image | Methylone (cathinone) | File:MBDB structure.svg | class8=skin-invert-image | MBDB (phenylisobutylamine) | File:MDAI structure.svg | class9=skin-invert-image | MDAI (2-aminoindane) | File:MDAT structure.svg | class10=skin-invert-image | MDAT (2-aminotetralin) | File:AET.svg | class11=skin-invert-image | α-Ethyltryptamine (tryptamine) | File:Β-Keto-N-methyl-αMT.svg | class12=skin-invert-image | BK-NM-AMT (β-keto-tryptamine) }} }}

==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 | 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== ===Etymology=== The term ''empathogen'', meaning "generating a state of empathy", was coined by Ralph Metzner in 1983 as a term to denote a class of drugs that includes MDMA and other agents with similar effects.<ref name="Eisner1989" /><ref name="MetznerAdamson2001" /><ref name="Metzner1983" /> Subsequently, in 1986, Nichols introduced 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").<ref name="Nichols2022" /><ref name="Nichols1986">{{cite journal|last1=Nichols|first1=D.|title=Differences Between the Mechanism of Action of MDMA, MBDB, and the Classic Hallucinogens. Identification of a New Therapeutic Class: Entactogens|journal=Journal of Psychoactive Drugs|date=1986|volume=18|issue=4|pages=305–13|doi=10.1080/02791072.1986.10472362|pmid=2880944}}</ref><ref name="NicholsHoffmanOberlender1986" /> Additionally, Nichols wanted to avoid any association with the term pathogenesis.<ref name="Colman2015">{{Cite book|title=Dictionary of Psychology - Oxford Reference|language=en|doi=10.1093/acref/9780199657681.001.0001|year=2015|isbn=978-0-19-965768-1|last1=Colman|first1=Andrew M.}}</ref>

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.<ref name="NicholsYensenMetzner1993" /> The hybrid word ''entactogen'' is derived from the roots ''en'' ({{langx|el|within}}), ''tactus'' ({{langx|la|touch}}) and ''-gen'' ({{langx|el|produce}}).<ref name="Nichols1986" /> 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.<ref name="StockerLiechti2024">{{cite journal | vauthors = Stocker K, Liechti ME | title = Methylenedioxymethamphetamine is a connectogen with empathogenic, entactogenic, and still further connective properties: It is time to reconcile "the great entactogen-empathogen debate" | journal = J Psychopharmacol | volume = 38 | issue = 8 | pages = 685–689 | date = August 2024 | pmid = 39068642 | pmc = 11311894 | doi = 10.1177/02698811241265352 | url = }}</ref>

==See also== * List of entactogens * List of investigational hallucinogens and entactogens * Serenic (antiaggressive drug)

==References== {{Reflist}}

==External links== * {{Commonscat-inline|Entactogens}} * [https://pageviews.wmcloud.org/massviews/?platform=all-access&agent=user&source=category&range=latest-365&subjectpage=0&subcategories=1&sort=views&direction=1&view=list&target=https://en.wikipedia.org/wiki/Category:Entactogens Entactogens - Wikipedia Massviews Analysis (Wikipedia Page Views of Individual Entactogens)]

{{Entactogens}} {{Monoamine releasing agents}} {{Major Drug Groups}} {{Chemical classes of psychoactive drugs}}

{{DEFAULTSORT:Empathogen-Entactogen}}

Category:Alexander Shulgin Category:David E. Nichols Category:Entactogens Category:Serotonin releasing agents