• Source: Empathogen

Empathogens or entactogens are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, relatedness, emotional openness—that is, empathy or sympathy—as particularly observed and reported for experiences with 3,4-methylenedioxymethamphetamine (MDMA). This class of drug is distinguished from the classes of hallucinogen or psychedelic, and amphetamine or stimulants. Major members of this class include MDMA, MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, GHB, αMT, and αET, MDAI among others. Most entactogens are phenethylamines and amphetamines, although several, such as αMT and αET, are tryptamines. When referring to MDMA and its counterparts, the term MDxx is often used (with the exception of MDPV). Entactogens are sometimes incorrectly referred to as hallucinogens or stimulants, although many entactogens such as ecstasy exhibit psychedelic or stimulant properties as well.




Etymology


The term empathogen, meaning "generating a state of empathy", was coined in 1983–84 by Ralph Metzner as a term to denote a therapeutic class of drugs that includes MDMA and phenethylamine relatives. David E. Nichols in 1986 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"). Additionally, Nichols wanted to avoid any association with the term pathogenesis.
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 (Greek: within), tactus (Latin: touch) and -gen (Greek: 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.




Psychological 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. 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.




Mechanism of action


Entactogens like MDMA are serotonin releasing agents and hence are indirect agonists of serotonin receptors. They produce entactogenic effects in animals such as increased prosocial behavior like adjacent lying, enhanced empathy-like behavior, and antiaggressive effects. 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-HT1A receptor antagonist WAY-100635. Conversely, the serotonin 5-HT1A receptor agonist 8-OH-DPAT produced prosocial behavior and increased oxytocin levels similarly to MDMA. In addition, MDMA has been shown to activate oxytocinergic neurons in the hypothalamus and this too is reversed by serotonin 5-HT1A receptor antagonism. Subsequent research found that direct injection of the serotonin 5-HT1A receptor WAY-100635 locally into the basolateral amygdala (BLA) suppressed MDMA-induced prosocial behavior and that direct injection of MDMA locally into the BLA significantly increased sociability.
The serotonin 5-HT2B and 5-HT2C receptor antagonist SB-206553 has also been found to block MDMA-induced prosocial behavior, although it produced potentially confounding thigmotaxis (hyperactivity at periphery of testing chamber) as well. Conversely, the serotonin 5-HT1B receptor antagonist GR-55562 and the serotonin 5-HT2A receptor antagonist ketanserin were both ineffective. Likewise, another study found that selective antagonists of the serotonin 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4 receptors (SB-216641), volinanserin (MDL-100907), SB-242084, and SB-204070, respectively) were all ineffective in suppressing MDMA-induced prosocial activity. Other research has found that serotonin 5-HT2B receptor inactivation abolishes the serotonin release induced by MDMA and attenuates many of its effects. In addition to the preceding findings, induction of serotonin release by MDMA in the nucleus accumbens and consequent activation of serotonin 5-HT1B receptors in this area is implicated in its enhancement of prosocial behaviors, whereas consequent activation of yet-to-be-determined serotonin receptors in this area is implicated in its enhancement of empathy-like behaviors. Injection of the serotonin 5-HT1B receptor antagonist NAS-181 directly into the nucleus accumbens blocked the prosocial behaviors of MDMA.
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. 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 V1A 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 V1A 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. 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-HT2A receptor antagonist ketanserin reduced MDMA-induced increases in friendliness. MDMA-induced emotional empathy was not affected by the serotonin 5-HT1A receptor antagonist pindolol or by intranasal oxytocin. 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. Fenfluramine has likewise been reported to improve social deficits in children with autism. Selective agonists of the serotonin 5-HT1A and 5-HT1B receptors and of the oxytocin receptors have been or are being investigated for the potential treatment of social deficits and aggression. Examples include batoprazine, eltoprazine (DU-28853), fluprazine (DU-27716), F-15,599 (NLX-01), zolmitriptan (ML-004), and LIT-001. 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.
The serotonin release of MDMA appears to be the key pharmacological action mediating the entactogenic, prosocial, and empathy-enhancing effects of the drug. 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". 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. Exceptions may anecdotally include 5-MAPB, particularly in specific enantiomer ratios, and the Borax combo. 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.




Examples



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.




= Phenethylamines

=
2C-B
2C-T-2
2C-T-7
Metaescaline



Substituted amphetamines

3-Chloromethamphetamine
3-Methoxymethamphetamine
4-Fluoroamphetamine (4-FA)
5-(2-Aminopropyl)-2,3-dihydro-1H-indene (5-APDI, IAP)
6-(2-Aminopropyl)benzofuran (6-APB) (benzofury)
5-(2-aminopropyl)benzofuran (5-APB)
5-(2-methylaminopropyl)benzofuran (5-MAPB)
5-Methoxy-MDA
5-Methyl-MDA
Methylbenzodioxolylbutanamine (MBDB)
Methylenedioxyamphetamine (MDA)
Methylenedioxyethylamphetamine (MDEA)
Methylenedioxymethamphetamine (MDMA)
Methylenedioxyhydroxyamphetamine (MDOH)
Methamnetamine
Lys-MDA
Lys-MDMA
SDMA
SDA
SeDMA
ODMA
TDMA
Paramethoxyamphetamine (PMA)
Substituted aminorexes

4,4'-Dimethylaminorex (4,4'-DMAR)
Methylenedioxy-4-methylaminorex (MDMAR)
Cathinones

Mephedrone (4-MMC)
3-Methylmethcathinone (3-MMC, metaphedrone)
Methylone (βk-MDMA)
Butylone (βk-MBDB)
Flephedrone (4-FMC)
TH-PVP




= Tryptamines

=
α-Ethyltryptamine (αET)
α-Methyltryptamine (αMT)




= Aminoindanes

=
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)




Therapeutic uses


Psychiatrists began using entactogens as psychotherapy tools in the 1970s despite the lack of clinical trials. 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. 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. 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.




References






= Further reading

=
Nichols DE, Hoffman AJ, Oberlender RA, Jacob P, Shulgin AT (October 1986). "Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class". J Med Chem. 29 (10): 2009–2015. doi:10.1021/jm00160a035. PMID 3761319.
Nichols DE (1986). "Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens". J Psychoactive Drugs. 18 (4): 305–313. doi:10.1080/02791072.1986.10472362. PMID 2880944.
Nichols DE (2022). "Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated". Front Psychiatry. 13: 863088. doi:10.3389/fpsyt.2022.863088. PMC 8990025. PMID 35401275.
Stocker K, Liechti ME (August 2024). "Methylenedioxymethamphetamine is a connectogen with empathogenic, entactogenic, and still further connective properties: It is time to reconcile "the great entactogen-empathogen debate"". J Psychopharmacol. 38 (8): 685–689. doi:10.1177/02698811241265352. PMC 11311894. PMID 39068642.




External links


Media related to Entactogens at Wikimedia Commons

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