entactogen

Entactogens are used as recreational drugs, including notably at raves.{{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 = }}

Psychiatrists began using entactogens as psychotherapy tools in the 1970s despite the lack of clinical trials.{{Cite book|title=Encyclopedia of emotion|last1=Malamud|first1=Ozer, Yvette|last2=Yuri|first2=Ito|date=2010-01-01|publisher=Greenwood Press|isbn=9780313345746|oclc=934324453}} 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.{{Cite book|title=The therapeutic use of Ayahuasca|last1=Caiuby|first1=Labate, Beatriz|last2=Clancy|first2=Cavnar|date=2014-01-01|publisher=Springer|isbn=9783642404252|oclc=876696992}} 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. 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. 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.{{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}} Additionally there is no clear model of the psychopharmacological means for a positive or negative experience. 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.{{Cite book|title=Psychopharmacology : drugs, the brain, and behavior|last=F.|first=Quenzer, Linda|isbn=9780878935109|oclc=869923492|date = 2013-05-06|publisher=Sinauer }}

MDMA-assisted psychotherapy (MDMA-AT) is in late-stage clinical trials to treat PTSD as of 2025.{{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 }}{{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 = }}{{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 = }}

{{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. 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.{{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}} 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.

{{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. 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. Entactogens can produce long-lasting serotonergic neurotoxicity{{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}}{{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}} and associated cognitive and memory deficits as well as psychiatric changes.{{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 = }}{{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 = }}{{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 = | pages = 146556 | date = January 2020 | pmid = 31734398 | doi = 10.1016/j.brainres.2019.146556 | url = }}{{cite journal | vauthors = Montgomery C, Roberts CA | title = Neurological and cognitive alterations induced by MDMA in humans | journal = Exp Neurol | volume = 347 | issue = | pages = 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}}

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

{{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.{{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 = }}{{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 | pages = 39576 | date = 2022 | pmid = 36425231 | pmc = 9680847 | doi = 10.52965/001c.39576 | doi-broken-date = 14 May 2025 | url = }} MDMA also has the potential to interact with various other drugs.{{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 = }}{{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 = }}{{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 = }}

{{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.{{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 = }} They produce entactogenic effects in animals such as increased prosocial behavior like adjacent lying, enhanced empathy-like behavior, and antiaggressive effects.{{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 = }} Likewise, MDMA increases sociability, prosociality, and emotional empathy in humans.

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.{{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 = }}{{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 = }}{{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 }}{{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 = }} Conversely, the serotonin 5-HT_1A receptor agonist 8-OH-DPAT produced prosocial behavior and increased oxytocin levels similarly to MDMA.{{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 = }} 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.{{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 = }} 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.{{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 = }}

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. Conversely, the serotonin 5-HT_1B receptor antagonist GR-55562 and the serotonin 5-HT_2A receptor antagonist ketanserin were both ineffective. 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. Other research has found that serotonin 5-HT_2B receptor inactivation abolishes the serotonin release induced by MDMA and attenuates many of its effects.{{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}}{{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 = }}{{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 = }} 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.{{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 = }}{{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 = }}{{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 = }}{{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 = }} Injection of the serotonin 5-HT_1B receptor antagonist NAS-181 directly into the nucleus accumbens blocked the prosocial behaviors of MDMA.

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. Accordingly, intracerebroventricular injection of the peptide oxytocin receptor antagonist tocinoic acid blocked MDMA- and 8-OH-DPAT-induced prosocial effects. 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. 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. More research is needed to clarify this. In any case, in another study, the non-peptide and centrally active selective oxytocin receptor antagonist L-368899 abolished MDMA-induced prosocial behavior.{{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 = }}{{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 }} Conversely, in other studies, different oxytocin receptor antagonists were ineffective.

As in animals, MDMA greatly increases circulating oxytocin levels in humans. 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. The 5-HT_2A receptor antagonist ketanserin reduced MDMA-induced increases in friendliness. MDMA-induced emotional empathy was not affected by the serotonin 5-HT_1A receptor antagonist pindolol or by intranasal oxytocin.{{cite journal | vauthors = Kuypers KP, de la Torre R, Farre M, Yubero-Lahoz S, Dziobek I, Van den Bos W, Ramaekers JG | title = No evidence that MDMA-induced enhancement of emotional empathy is related to peripheral oxytocin levels or 5-HT1a receptor activation | journal = PLOS ONE | volume = 9 | issue = 6 | pages = e100719 | date = 2014 | pmid = 24972084 | pmc = 4074089 | doi = 10.1371/journal.pone.0100719 | doi-access = free | bibcode = 2014PLoSO...9j0719K | url = }} Similarly, MDMA-induced emotional empathy and prosocial behavior have not been associated with circulating oxytocin levels. As such, the role of oxytocin in the entactogenic effects of MDMA in humans is controversial.

Other serotonin releasing agents, like fenfluramine, show prosocial effects in animals similar to those of MDMA.{{cite journal | vauthors = Behera HK, Joga R, Yerram S, Karnati P, Mergu T, Gandhi K, M S, Nathiya D, Singh RP, Srivastava S, Kumar S | title = Exploring the regulatory framework of psychedelics in the US & Europe | journal = Asian J Psychiatr | volume = 102 | issue = | pages = 104242 | date = September 2024 | pmid = 39305768 | doi = 10.1016/j.ajp.2024.104242 | url = }} Fenfluramine has likewise been reported to improve social deficits in children with autism.{{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 = }} 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.{{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 = }}{{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 = }}{{cite journal | vauthors = Felthous AR, McCoy B, Nassif JB, Duggirala R, Kim E, Carabellese F, Stanford MS | title = Pharmacotherapy of Primary Impulsive Aggression in Violent Criminal Offenders | journal = Front Psychol | volume = 12 | issue = | pages = 744061 | date = 2021 | pmid = 34975633 | pmc = 8716452 | doi = 10.3389/fpsyg.2021.744061 | doi-access = free | url = }}{{cite journal | vauthors = Sałaciak K, Pytka K | title = Biased agonism in drug discovery: Is there a future for biased 5-HT1A receptor agonists in the treatment of neuropsychiatric diseases? | journal = Pharmacol Ther | volume = 227 | issue = | pages = 107872 | date = November 2021 | pmid = 33905796 | doi = 10.1016/j.pharmthera.2021.107872 | url = | doi-access = free }} Examples include batoprazine, eltoprazine (DU-28853), fluprazine (DU-27716), F-15,599 (NLX-01), zolmitriptan (ML-004), and LIT-001.{{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 = }} 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.{{cite journal | vauthors = Markopoulos A, Inserra A, De Gregorio D, Gobbi G | title = Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder | journal = Front Pharmacol | volume = 12 | issue = | pages = 749068 | date = 2021 | pmid = 35177979 | pmc = 8846292 | doi = 10.3389/fphar.2021.749068 | doi-access = free | url = }}{{cite journal | vauthors = Bhatt KV, Weissman CR | title = The effect of psilocybin on empathy and prosocial behavior: a proposed mechanism for enduring antidepressant effects | journal = npj Ment Health Res | volume = 3 | issue = 1 | pages = 7 | date = February 2024 | pmid = 38609500 | pmc = 10955966 | doi = 10.1038/s44184-023-00053-8 | url = }}{{cite journal | vauthors = Kupferberg A, Hasler G | title = From antidepressants and psychotherapy to oxytocin, vagus nerve stimulation, ketamine and psychedelics: how established and novel treatments can improve social functioning in major depression | journal = Front Psychiatry | volume = 15 | issue = | pages = 1372650 | date = 2024 | pmid = 39469469 | pmc = 11513289 | doi = 10.3389/fpsyt.2024.1372650 | doi-access = free | url = }}

The serotonin release of MDMA appears to be the key pharmacological action mediating the entactogenic, prosocial, and empathy-enhancing effects of the drug.{{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}}{{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 = }} 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. Additionally, MDMA is a direct agonist of several serotonin receptors, including of the serotonin 5-HT₂ receptors, with moderate affinity. 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".{{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/}}{{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 }} 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.{{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}} Exceptions may anecdotally include 5-MAPB, particularly in specific enantiomer ratios, and the Borax combo.{{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}} 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.

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.{{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]}}{{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 = }} This property is unusual among psychedelics, and is in notable contrast to DOM, which at best partially substitutes for MDMA.{{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. [...]}} 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. 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.{{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).}}{{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.}}{{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 }} MDMA itself is notable in being a lower-efficacy partial agonist of the serotonin 5-HT_2A receptor as well.{{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 = }}{{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}} 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.{{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 = }} Similarly, the psychoactive effects of MDMA are partially blocked by the relatively selective serotonin 5-HT_2A receptor antagonist ketanserin in humans.{{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 = }}{{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 = }}{{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 = }}

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

The history of MDMA and other entactogens has been reviewed.{{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 }}{{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 = }}

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. 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").{{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}} Additionally, Nichols wanted to avoid any association with the term pathogenesis.{{Cite book|title=Dictionary of Psychology - Oxford Reference|language=en|doi=10.1093/acref/9780199657681.001.0001|year=2015|isbn=9780199657681|last1=Colman|first1=Andrew M.}}

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. The hybrid word entactogen is derived from the roots en ({{langx|el|within}}), tactus ({{langx|la|touch}}) and -gen ({{langx|el|produce}}). 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.{{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 = }}

{{See also|Substituted methylenedioxyphenethylamine}}

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.

• 2C-B
• 2C-T-2{{Citation needed|date=April 2025}}
• 2C-T-7{{Citation needed|date=April 2025}}
• Metaescaline{{Citation needed|date=April 2025}}

• 3-Chloromethamphetamine{{Citation needed|date=April 2025}}
• 3-Methoxymethamphetamine{{Citation needed|date=April 2025}}
• 4-Fluoroamphetamine (4-FA){{Citation needed|date=April 2025}}
• para-Methoxyamphetamine (PMA)
• 4-Methylthioamphetamine (4-MTA)

• MMDA (5-methoxy-MDA)
• 5-Methyl-MDA
• Methylbenzodioxolylbutanamine (MBDB)
• Methylenedioxyamphetamine (MDA)
• Methylenedioxyethylamphetamine (MDEA)
• Methylenedioxymethamphetamine (MDMA)
• Methylenedioxyhydroxyamphetamine (MDOH)
• Lys-MDA
• Lys-MDMA

• 6-(2-Aminopropyl)benzofuran (6-APB) (benzofury)
• 5-(2-Aminopropyl)benzofuran (5-APB)
• 5-(2-Methylaminopropyl)benzofuran (5-MAPB)

• 5-APDI (indanylaminopropane; IAP)
• Methamnetamine (PAL-1046)
• SeDMA
• ODMA
• TDMA

• Mephedrone (4-MMC)
• 3-Methylmethcathinone (3-MMC, metaphedrone)
• Methylone (MDMC; βk-MDMA)
• Butylone (βk-MBDB)
• Flephedrone (4-FMC){{Citation needed|date=April 2025}}
• TH-PVP{{Citation needed|date=April 2025}}

• 4,4'-Dimethylaminorex (4,4'-DMAR){{Citation needed|date=April 2025}}
• Methylenedioxy-4-methylaminorex (MDMAR){{Citation needed|date=April 2025}}

• α-Ethyltryptamine (αET)
• α-Methyltryptamine (αMT)
• BK-NM-AMT
• BK-5F-NM-AMT

• 5-Iodo-2-aminoindane (5-IAI)
• 5,6-Methylenedioxy-2-aminoindane (MDAI)
• 5,6-Methylenedioxy-N-methyl-2-aminoindane (MDMAI)
• 5-Methoxy-6-methyl-2-aminoindane (MMAI)
• 5-Methoxy-2-aminoindane (MEAI, 5-MeO-AI)

• 1Z2MAP1O

{{Reflist}}

• {{Commonscat-inline|Entactogens}}
• [https://pageviews.wmcloud.org/massviews/?platform=all-access&agent=user&source=category&range=last-year&subjectpage=0&subcategories=1&sort=views&direction=1&view=list&target=https://en.wikipedia.org/wiki/Category:Entactogens Entactogens - Massviews Analysis - Wikipedia]

{{Entactogens}}

{{Monoamine releasing agents}}

{{Major Drug Groups}}

{{Chemical classes of psychoactive drugs}}

{{DEFAULTSORT:Empathogen-Entactogen}}

Category:Serotonin releasing agents