| Entactogen | |
|---|---|
| Drug class | |
 A selection ofMDMA pills, which are often nicknamed "Ecstasy" or "E". | |
| Class identifiers | |
| Synonyms | Entactogen; Empathogen; Connectogen[1][2][3][4] |
| Use | Recreational,spiritual,medical,microdosing |
| Mechanism of action | Serotonin–norepinephrine–dopamine releasing agent;Serotonin5-HT2 receptoragonism |
| Biological target | Serotonin transporter;Norepinephrine transporter;Dopamine transporter;Serotonin5-HT2 receptors |
| Chemical class | Amphetamines,MDxx,cathinones,benzofurans,α-alkyltryptamines,2-aminoindanes, others |
| Legal status | |
| Legal status |
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| In Wikidata | |
| Part ofa series on |
| Psychedelia |
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Entactogens, also known asempathogens orconnectogens, are a class ofpsychoactive drugs that induce the production of experiences of emotional communion, oneness, connectedness, emotional openness—that is,empathy—as particularly observed and reported for experiences withMDMA.[1][2][5][3][4] This class of drug is distinguished from the classes ofhallucinogens orpsychedelics andstimulants, although entactogens, for instance MDMA, can also have these properties.[1][4][6][7] Entactogens are used both asrecreational drugs[8] and are being investigated formedical use in the treatment ofpsychiatric disorders, for instanceMDMA-assisted therapy forpost-traumatic stress disorder (PTSD).[9][10][11]
Notable members of this class include MDMA,MDA,MDEA,MDOH,MBDB,5-APB,5-MAPB,6-APB,6-MAPB,methylone,mephedrone,αMT,αET, andMDAI, among others.[1][5] Most entactogens arephenethylamines andamphetamines, although several, such as αMT and αET, aretryptamines.[1][5] When referring to MDMA and its counterparts, the termMDxx is often used (with the exception of certain non-entactogen drugs likeMDPV).
Entactogens act asserotonin releasing agents (SRAs) as their key action.[12][13][5][14][15] However, entactogens also frequently have additional actions, such as induction ofdopamine andnorepinephrine andserotonin5-HT2 receptoragonism, which contributes to their effects as well.[12][13][5][14][15] It is thought that dopamine and norepinephrine release provide additionalstimulant,euphoriant, andcardiovascular orsympathomimetic effects, serotonin5-HT2A receptor agonism producespsychedelic effects of variable intensity, and both dopamine release and serotonin 5-HT2 receptor agonism may enhance the entactogenic effects and be critically involved in allowing for the qualitative "magic" of these drugs.[12][13][5][14][15] Entactogens that simultaneously induce serotonin and dopamine release, for instance MDMA, are known to produce long-lastingserotonergic neurotoxicity[16][17][5] with associatedcognitive andmemory deficits as well aspsychiatric changes.[18][19][20][21]
MDA and MDMA were both firstsynthesized independently in the early 1910s.[22] Thepsychoactive effects of MDA were discovered in 1930 but were not described until the 1950s, MDA and MDMA emerged asrecreational drugs in the 1960s, and the unique entactogenic effects of MDMA were first described in the 1970s.[22][23][24][25][26] Entactogens as a unique pharmacological class depending on induction of serotonin release was established in the mid-1980s and novel entactogens such as MBDB were developed at this time and after.[1][4][6]Gordon Alles discovered the psychoactive effects of MDA,[25][26]Alexander Shulgin played a key role in bringing awareness to MDMA and its unique effects,[24] andRalph Metzner[27][28][29] andDavid E. Nichols formally defined entactogens and established them as a distinct class of drugs.[1][4][6] Many entactogens likeMDMA arecontrolled substances throughout the world.[30][31]
Entactogens are used asrecreational drugs, including notably atraves.[8]
Psychiatrists began using entactogens as psychotherapy tools in the 1970s despite the lack of clinical trials.[32] In recent years, the scientific community has been revisiting the possible therapeutic uses of entactogens. Therapeutic models using MDMA have been studied because of its entactogenic properties.[33] This type of therapy would be applicable for treating a patient who was experiencing psychological trauma such as PTSD. Traumatic memories can be linked to fear in the patients which makes engaging with these memories difficult. Administration of an entactogen such as MDMA allows the patient to disconnect from the fear associated with the traumatic memories and engage in therapy.[33] MDMA acts by targeting the body's stress response in order to cause this therapeutic effect. In addition to reducing anxiety and a conditioned fear response, MDMA also reduces the avoidance of feelings.[33] Patients are then able to trust themselves and their therapist and engage with traumatic memories under the influence of MDMA.
Although the therapeutic effects of entactogens may be promising, drugs such as MDMA have the potential for negative effects that are counter productive in a therapy setting. For example, MDMA may make negative cognition worse. This means that a positive experience is not a guarantee and can be contingent on aspects like the setting and the patient's expectations.[34] Additionally there is no clear model of thepsychopharmacological means for a positive or negative experience.[34] There is also a potential concern for theneurotoxic effects of MDMA on the fiber density ofserotonin neurons in theneocortex. High doses of MDMA may cause potential depletion of serotonergic axons. The same effects may not be caused by lower doses of MDMA required for treatment, however.[35]
MDMA-assisted psychotherapy (MDMA-AT) is in late-stageclinical trials to treat PTSD as of 2025.[9][10][11]
Both terms adopted and used in naming the class of therapeutic drugs forMDMA 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 classicalpsychedelic drugs such asLSD,mescaline, andpsilocybin and majorstimulants, such asmethamphetamine andamphetamine.[3] Chemically, MDMA is classified as asubstituted amphetamine (which includes stimulants like dextroamphetamine and psychedelics like2,5-dimethoxy-4-methylamphetamine), which makes MDMA asubstituted phenethylamine (which includes other stimulants likemethylphenidate and other psychedelics likemescaline) by the definition of amphetamine. While chemically related both to psychedelics and stimulants, the psychological effects experienced with MDMA were reported to provide obvious and striking aspects of personal relatedness, feelings of connectedness, communion with others, and ability to feel what others feel—in short an empathic resonance is consistently evoked.[36] While psychedelics like LSD may sometimes yield effects of empathic resonance, these effects tend to be momentary and likely passed over on the way to some other dimension or interest. In contrast, the main characteristic that distinguishes MDMA from LSD-type experiences is the consistency of the effects of emotional communion, relatedness, emotional openness—in short, empathy and sympathy.[3]
Entactogens like MDMA areserotonin releasing agents and hence are indirectagonists ofserotonin receptors.[37][38][39] They produce entactogenic effects in animals such as increasedprosocial behavior like adjacent lying, enhancedempathy-like behavior, andantiaggressive effects.[37][40][12] Likewise, MDMA increasessociability, prosociality, andemotional empathy in humans.[12]
In animals, MDMA induced prosocial behavior and elevations in circulatingoxytocin levels and these effects were abolished by pretreatment with the serotonin5-HT1A receptorantagonistWAY-100635.[37][41][42][43][44] Conversely, the serotonin 5-HT1A receptor agonist8-OH-DPAT produced prosocial behavior and increased oxytocin levels similarly to MDMA.[37][42][45] In addition, MDMA has been shown to activate oxytocinergicneurons in thehypothalamus and this too is reversed by serotonin 5-HT1A receptor antagonism.[37][42][46] Subsequent research found that direct injection of the serotonin 5-HT1A receptor WAY-100635 locally into thebasolateral amygdala (BLA) suppressed MDMA-induced prosocial behavior and that direct injection of MDMA locally into the BLA significantly increased sociability.[47][43]
The serotonin5-HT2B and5-HT2C receptor antagonistSB-206553 has also been found to block MDMA-induced prosocial behavior, although it produced potentiallyconfoundingthigmotaxis (hyperactivity at periphery of testing chamber) as well.[41][44] Conversely, the serotonin5-HT1B receptor antagonistGR-55562 and the serotonin5-HT2A receptor antagonistketanserin were both ineffective.[41][43][44] Likewise, another study found thatselective antagonists of the serotonin 5-HT1B, 5-HT2A, 5-HT2C, and5-HT4 receptors (SB-216641),volinanserin (MDL-100907),SB-242084, andSB-204070, respectively) were all ineffective in suppressing MDMA-induced prosocial activity.[47][43] Other research has found that serotonin 5-HT2B receptor inactivation abolishes the serotonin release induced by MDMA and attenuates many of its effects.[38][39][48] In addition to the preceding findings, induction of serotonin release by MDMA in thenucleus accumbens and consequent activation of serotonin 5-HT1B receptors in this area is implicated in its enhancement of prosocial behaviors, whereas consequent activation of yet-to-be-determined serotonin receptors in this area is implicated in its enhancement of empathy-like behaviors.[1][40][49][50] Injection of the serotonin 5-HT1B receptor antagonistNAS-181 directly into the nucleus accumbens blocked the prosocial behaviors of MDMA.[49]
On the basis of the serotonin 5-HT1A receptor-mediated oxytocin release with MDMA, it has been proposed that increased oxytocinergic signaling may mediate the prosocial effects of MDMA in animals.[37][42] Accordingly,intracerebroventricular injection of thepeptideoxytocin receptor antagonisttocinoic acid blocked MDMA- and 8-OH-DPAT-induced prosocial effects.[37][42][51] However, in a subsequent study,systemically administered C25, a non-peptide oxytocin receptor antagonist, failed to affect MDMA-induced prosocial behavior, whereas thevasopressinV1A receptor antagonistrelcovaptan (SR-49059) was able to block MDMA-induced prosocial activity.[37][51] It might be that tocinoic acid isnon-selective and also blocks the vasopressin V1A receptor or that C25 isperipherally selective and is unable to blockoxytocin receptors in the brain.[37][51] More research is needed to clarify this.[51][37] In any case, in another study, the non-peptide andcentrally active selective oxytocin receptor antagonistL-368899 abolished MDMA-induced prosocial behavior.[51][52] Conversely, in other studies, different oxytocin receptor antagonists were ineffective.[49]
As in animals, MDMA greatly increases circulating oxytocin levels in humans.[37]Serotonin reuptake inhibitors andnorepinephrine reuptake inhibitors reduced the subjective effects of MDMA in humans, for instance increasedextroversion,self-confidence,closeness,openness, andtalkativeness.[12] The 5-HT2A receptor antagonistketanserin reduced MDMA-induced increases in friendliness.[12] MDMA-induced emotional empathy was not affected by the serotonin 5-HT1A receptor antagonistpindolol or byintranasaloxytocin.[53] Similarly, MDMA-induced emotional empathy and prosocial behavior have not been associated with circulating oxytocin levels.[53][37] As such, the role of oxytocin in the entactogenic effects of MDMA in humans is controversial.[37]
Other serotonin releasing agents, likefenfluramine, show prosocial effects in animals similar to those of MDMA.[54][49] Fenfluramine has likewise been reported to improvesocial deficits in children withautism.[49][55] Selective agonists of the serotonin 5-HT1A and 5-HT1B receptors and of the oxytocin receptors have been or are being investigated for the potential treatment of social deficits andaggression.[56][57][58][59] Examples includebatoprazine,eltoprazine (DU-28853),fluprazine (DU-27716),F-15,599 (NLX-01),zolmitriptan (ML-004), andLIT-001.[58][59][60]Serotonergic psychedelics, for instancelysergic acid diethylamide (LSD) andpsilocybin, which act as non-selective serotonin receptor agonists including of the serotonin5-HT1 and5-HT2 receptors, have shown prosocial and empathy-enhancing effects in animals and/or humans as well, both acutely and long-term.[61][62][63]
The serotonin release of MDMA appears to be the key pharmacological action mediating the entactogenic, prosocial, and empathy-enhancing effects of the drug.[12][13][5] However, in addition to serotonin release, MDMA is also apotentreleasing agent ofnorepinephrine anddopamine, and hence acts as a well-balancedserotonin–norepinephrine–dopamine releasing agent.[13][5] Additionally, MDMA is a direct agonist of several serotonin receptors, including of the serotonin 5-HT2 receptors, with moderateaffinity.[13][5] These actions are thought to play an important role in the effects of MDMA, including in itspsychostimulant,euphoriant, and mildpsychedelic effects, as well as in its unique and difficult-to-replicate "magic".[13][14][5][64] It has been said byMatthew Baggott that few to no MDMAanalogues, includingMBDB,methylone,6-APDB,5-APDB,6-APB,5-APB,MDAT, andMDAI among others, reproduce the full quality and "magic" of MDMA.[14][15] Exceptions mayanecdotally include5-MAPB, particularly in specificenantiomer ratios, and theBorax combo.[14][15][65] The unique properties of MDMA are believed to be dependent on a very specific mixture and ratio of pharmacological activities, including combined serotonin, norepinephrine, and dopamine release and direct serotonin receptor agonism.[14][15]
The termempathogen, meaning "generating a state ofempathy", was independently coined byRalph Metzner in 1983 andDavid E. Nichols in 1984 as a term to denote a class of drugs that includesMDMA and other agents with similar effects.[27][28][29] Subsequently, in 1986, Nichols rejected this initial terminology and adopted, instead, the termentactogen, meaning "producing a touching within", to denote this class of drugs, asserting a concern with the potential for improper association of the termempathogen with negative connotations related to the Greek root πάθοςpáthos ("suffering; passion").[1][4][6] Additionally, Nichols wanted to avoid any association with the termpathogenesis.[66]
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.[3] Thehybrid wordentactogen is derived from the rootsen (Greek:within),tactus (Latin:touch) and-gen (Greek:produce).[4] Entactogen is not becoming dominant in usage, and, despite their difference in connotation, they are essentially interchangeable, as they refer to precisely the same chemicals.
In 2024, an additional alternative term,connectogen, was proposed and introduced by Kurt Stocker and Matthias Liechti.[2]
The chemicals below have a varying degree of entactogenic effects; some of them induce additional effects, includingserenic effects,stimulant effects,antidepressant effects,anxiolytic effects, andpsychedelic effects.[66]
{{cite book}}:ISBN / Date incompatibility (help)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."
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.
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