Entactogens, also known as empathogens or connectogens, are a class of

psychoactive drug A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...

s that induce the production of experiences of emotional communion, oneness, connectedness, emotional openness—that is,

empathy Empathy is generally described as the ability to take on another person's perspective, to understand, feel, and possibly share and respond to their experience. There are more (sometimes conflicting) definitions of empathy that include but are ...

—as particularly observed and reported for experiences with

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

. This class of drug is distinguished from the classes of

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

s or psychedelics and

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

s, although entactogens, for instance MDMA, can also have these properties. Entactogens are used both as

recreational drug Recreational drug use is the use of one or more psychoactive drugs to induce an altered state of consciousness, either for pleasure or for some other casual purpose or pastime. When a psychoactive drug enters the user's body, it induces an Sub ...

s and are being investigated for medical use in the treatment of

psychiatric disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

s, for instance MDMA-assisted therapy for

post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental disorder that develops from experiencing a Psychological trauma, traumatic event, such as sexual assault, domestic violence, child abuse, warfare and its associated traumas, natural disaster ...

(PTSD). Notable members of this class include MDMA, MDA,

MDEA MDEA may refer to: * Methyl diethanolamine (''N''-methyl-diethanolamine), CH3N(C2H4OH)2, a chemical used for amine gas treating, also known as gas sweetening or acid gas removal, the removal of hydrogen sulfide and carbon dioxide from gasses in the ...

, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB,

methylone Methylone, also known as 3,4-methylenedioxy-''N''-methylcathinone (MDMC), is an entactogen and stimulant drug of the amphetamine, cathinone, and benzodioxole families related to 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"). It is th ...

, mephedrone, αMT, αET, and MDAI, among others. Most entactogens are

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

s and

amphetamines Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...

, although several, such as αMT and αET, are

tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...

s. 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 agent A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter ...

s (SRAs) as their key action. However, entactogens also frequently have additional actions, such as induction of

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

and

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT₂ receptor

agonism Agonism (from Greek 'struggle') is a political and social theory that emphasizes the potentially positive aspects of certain forms of conflict. It accepts a permanent place for such conflict in the political sphere, but seeks to show how indivi ...

, which contributes to their effects as well. It is thought that dopamine and norepinephrine release provide additional

euphoriant Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...

, and

cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

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. Entactogens that simultaneously induce serotonin and dopamine release, for instance MDMA, are known to produce long-lasting serotonergic neurotoxicity with associated

cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

and memory deficits as well as psychiatric changes. MDA and MDMA were both first synthesized independently in the early 1910s. The

psychoactive A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...

effects of MDA were discovered in 1930 but were not described until the 1950s, MDA and MDMA emerged as

s in the 1960s, and the unique entactogenic effects of MDMA were first described in the 1970s. 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.

Gordon Alles Gordon A. Alles (November 26, 1901 – January 21, 1963), was an American chemist and pharmacologist who did extensive research on the isolation and properties of insulin for the treatment of diabetes, diabetics. He is also credited with discoveri ...

discovered the psychoactive effects of MDA,

Alexander Shulgin Alexander Theodore "Sasha" Shulgin (June 17, 1925 – June 2, 2014) was an American biochemist, broad researcher of synthetic psychoactive compounds, and author of works regarding these, who independently explored the organic chemistry and ph ...

played a key role in bringing awareness to MDMA and its unique effects, and

Ralph Metzner Ralph Metzner (May 18, 1936 – March 14, 2019) was a German-born American psychologist, writer and researcher, who participated in psychedelic research at Harvard University in the early 1960s with Timothy Leary and Richard Alpert (later named ...

and David E. Nichols formally defined entactogens and established them as a distinct class of drugs. Many entactogens like

are

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Sing ...

s throughout the world.

Uses

Recreational

Entactogens are used as

s, including notably at

rave A rave (from the verb: '' to rave'') is a dance party at a warehouse, club, or other public or private venue, typically featuring performances by DJs playing electronic dance music. The style is most associated with the early 1990s dance mus ...

Medical

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 Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

effects of MDMA on the fiber density of

neurons in the

neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...

. 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. MDMA-assisted psychotherapy (MDMA-AT) is in late-stage

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s to treat PTSD as of 2025.

Effects

Both terms adopted and used in naming the class of therapeutic drugs for

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 drug Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluc ...

s such as

LSD Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a semisynthetic, hallucinogenic compound derived from ergot, known for its powerful psychological effects and serotonergic activity. I ...

mescaline Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...

, and

psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...

and major

stimulants Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognitio ...

, such as

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

and

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

. Chemically, MDMA is classified as a

substituted amphetamine Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...

(which includes stimulants like dextroamphetamine and psychedelics like

2,5-dimethoxy-4-methylamphetamine 2,5-Dimethoxy-4-methylamphetamine (DOM), also known as STP (standing for "Serenity, Tranquility, and Peace" and/or other phrases), is a psychedelic drug of the phenethylamine, amphetamine, and DOx families. It is generally taken orally. DOM w ...

), which makes MDMA a

substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...

(which includes other stimulants like

methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

and other psychedelics like

) 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.

Side effects

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of entactogens like MDMA include

mydriasis Mydriasis is the Pupillary dilation, dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, Physical trauma, trauma, or the use of c ...

nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) Eye movement (sensory), eye movement. People can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in visual impairment, re ...

, jaw clenching,

bruxism Bruxism is excessive teeth grinding or jaw clenching. It is an oral Parafunctional habit, parafunctional activity; i.e., it is unrelated to normal function such as eating or talking. Bruxism is a common behavior; the global prevalence of brux ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

appetite loss Anorexia is a medical term for a loss of appetite. While the term outside of the scientific literature is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while o ...

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

, and

hyperthermia Hyperthermia, also known as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme te ...

, among others. Severe

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...

s of entactogens like MDMA can include

dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...

, hyperthermia,

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

rhabdomyolysis Rhabdomyolysis (shortened as rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some o ...

disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking Microvessel, small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems ...

hyponatremia Hyponatremia or hyponatraemia is a low concentration of sodium in the Serum (blood), blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symp ...

acute renal failure Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within seven days, as shown by an increase in serum creatinine or a decrease in urine output, or both. Causes of AKI a ...

, liver injury,

serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...

, and

valvular heart disease Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). The ...

. Entactogens can produce long-lasting serotonergic neurotoxicity and associated

and memory deficits as well as psychiatric changes.

Overdose

Entactogens like MDMA show a much narrower margin of

safety Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings The word 'safety' entered the English language in the 1 ...

and greater

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

than

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

s. Whereas LSD and psilocybin have extrapolated human lethal doses relative to typical recreational doses of approximately 1,000-fold and 200-fold, respectively, a reasonable estimated fatal dose of MDMA is only about 15 or 16times a single typical recreational dose.

Interactions

Entactogens like MDMA pose high risks of severe and potentially fatal

and

hypertensive crisis Severely elevated blood pressure (equal to or greater than 180 mmHg systolic or 120 mmHg diastolic) is referred to as a hypertensive crisis (sometimes termed malignant or accelerated hypertension), due to the high risk of complications. People ...

in people on

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

s (MAOIs) due to synergistic elevations of

monoamine Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin. All monoamines are ...

s like

and

. MDMA also has the potential to interact with various other drugs.

Pharmacology

Mechanism of action

Entactogens like MDMA are

s and hence are indirect

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s of

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

s. They produce entactogenic effects in animals such as increased

prosocial Prosocial behavior is a social behavior that "benefit other people or society as a whole", "such as helping, sharing, donating, co-operating, and volunteering". The person may or may not intend to benefit others; the behavior's prosocial benefi ...

behavior like adjacent lying, enhanced

-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 Oxytocin is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. Present in animals since early stages of evolution, in humans it plays roles in behavior that include Human bonding, ...

levels and these effects were abolished by pretreatment with the serotonin 5-HT_1A receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.WAY-100635 WAY-100635 is a piperazine drug and research chemical widely used in scientific studies. It was originally believed to act as a selective 5-HT1A receptor antagonist, but subsequent research showed that it also acts as potent full agonist at the ...

. Conversely, the serotonin 5-HT_1A receptor agonist

8-OH-DPAT 8-OH-DPAT is a research chemical of the aminotetralin chemical class which was developed in the 1980s and has been widely used to study the function of the 5-HT1A receptor, 5-HT1A receptor. It was one of the first major 5-HT1A receptor full agonis ...

produced prosocial behavior and increased oxytocin levels similarly to MDMA. In addition, MDMA has been shown to activate oxytocinergic

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s in the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

and this too is reversed by serotonin 5-HT_1A receptor antagonism. Subsequent research found that direct injection of the serotonin 5-HT_1A receptor WAY-100635 locally into the

basolateral amygdala The basolateral amygdala, or basolateral complex, or basolateral nuclear complex consists of the lateral, basal and accessory-basal nuclei of the amygdala. The lateral nuclei receives the majority of sensory information, which arrives directly fr ...

(BLA) suppressed MDMA-induced prosocial behavior and that direct injection of MDMA locally into the BLA significantly increased sociability. 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 In causal inference, a confounder is a variable that influences both the dependent variable and independent variable, causing a spurious association. Confounding is a causal concept, and as such, cannot be described in terms of correlatio ...

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 Ketanserin, sold under the brand name Sufrexal, is an antihypertensive agent which is used to treat arterial hypertension and vasospasm, vasospastic disorders. It is also used in scientific research as an antiserotonergic medication, agent in th ...

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. In addition to the preceding findings, induction of serotonin release by MDMA in the

nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for ' nucleus adjacent to the septum') is a region in the basal forebrain rostral to the preoptic area of the hypo ...

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. 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 Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

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 Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...

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 receptor The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin. In humans, the oxytocin receptor is encoded by the ''OXTR'' gene which has been localized to human chromosome 3p25 ...

s 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 inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the drug action, action of the serotonin transporter (SERT). This in turn lea ...

s and

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinep ...

s reduced the subjective effects of MDMA in humans, for instance increased

extroversion Extraversion and introversion are a central trait dimension in human personality theory. The terms were introduced into psychology by Carl Jung, though both the popular understanding and current psychological usage are not the same as Jung's ...

self-confidence Confidence is the feeling of belief or trust that a person or thing is reliable. * * * Self-confidence is trust in oneself. Self-confidence involves a positive belief that one can generally accomplish what one wishes to do in the future. Sel ...

, closeness,

openness Openness is an overarching concept that is characterized by an emphasis on transparency and collaboration. That is, openness refers to "accessibility of knowledge, technology and other resources; the transparency of action; the permeability of or ...

, and talkativeness. The 5-HT_2A receptor antagonist

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 Nasal administration, popularly known as snorting, is a route of administration in which drugs are insufflation (medicine), insufflated through the nose. It can be a form of either topical administration or systemic administration, as the drugs t ...

. 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 Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treat ...

, show prosocial effects in animals similar to those of MDMA. Fenfluramine has likewise been reported to improve social deficits in children with

autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...

. 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 Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...

. Examples include batoprazine,

eltoprazine Eltoprazine (developmental code name DU-28,853) is a Serotonin, serotonergic drug of the phenylpiperazine class which is described as a serenic, or anti-aggressive agent. It acts as an agonist of the serotonin 5-HT1A, 5-HT1A and 5-HT1B, 5-HT1B r ...

(DU-28853), fluprazine (DU-27716), F-15,599 (NLX-01),

zolmitriptan Zolmitriptan, sold under the brand name Zomig among others, is a serotonergic drug, serotonergic medication which is used in the acute treatment of migraine attacks with or without aura (symptom), aura and cluster headaches. It is taken oral adm ...

(ML-004), and LIT-001.

Serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

s, for instance

lysergic acid diethylamide Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a Semisynthesis, semisynthetic, Hallucinogen, hallucinogenic compound derived from ergot, known for its powerful psychological effects and ...

(LSD) and

, 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

and

, and hence acts as a well-balanced

serotonin–norepinephrine–dopamine releasing agent A serotonin–norepinephrine–dopamine releasing agent (SNDRA), also known as a triple releasing agent (TRA), is a type of drug which induces the release of serotonin, norepinephrine/epinephrine, and dopamine in the brain and body. SNDRAs produc ...

. Additionally, MDMA is a direct agonist of several serotonin receptors, including of the serotonin 5-HT₂ receptors, with moderate

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

. These actions are thought to play an important role in the effects of MDMA, including in its

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

, 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,

, 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 In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

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.

Ariadne In Greek mythology, Ariadne (; ; ) was a Cretan princess, the daughter of King Minos of Crete. There are variations of Ariadne's myth, but she is known for helping Theseus escape from the Minotaur and being abandoned by him on the island of N ...

, 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. This property is unusual among psychedelics, and is in notable contrast to DOM, which at best partially substitutes for MDMA. Besides Ariadne, the

NBOMe The 25-NB (25''x''-NB''x'') series, or NBOMe series, also known as the ''N''-benzylphenethylamines, is a family of serotonergic psychedelics. They are substituted phenethylamines and were derived from the 2C (psychedelics), 2C family. The most c ...

drugs such as

25I-NBOMe 25I-NBOMe, also known as 2C-I-NBOMe, Cimbi-5, and shortened to "25I", is a psychedelic drug of the phenethylamine, 2C, and NBOMe (25-NB) families. Since 2010, it has circulated in the recreational drug scene, often misrepresented as LSD. It is ...

and 25B-NBOMe also partially to fully substitute for MDMA in rodents. 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. MDMA itself is notable in being a lower-efficacy partial agonist of the serotonin 5-HT_2A receptor as well. 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. Similarly, the psychoactive effects of MDMA are partially blocked by the relatively selective serotonin 5-HT_2A receptor antagonist ketanserin in humans.

History

The history of MDMA and other entactogens has been reviewed.

Society and culture

Etymology

The term ''empathogen'', meaning "generating a state of

", was independently coined by

in 1983 and David E. Nichols in 1984 as a term to denote a class of drugs that includes

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"). Additionally, Nichols wanted to avoid any association with the term

pathogenesis In pathology, pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes . Descript ...

. 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 A hybrid word or hybridism is a word that etymologically derives from at least two languages. Such words are a type of macaronic language. Common hybrids The most common form of hybrid word in English combines Latin and Greek parts. Since m ...

''entactogen'' is derived from the roots ''en'' (), ''tactus'' () and ''-gen'' (). 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.

List of entactogens

The chemicals below have a varying degree of entactogenic effects; some of them induce additional effects, including

serenic A serenic, or anti-aggressive drug, is a type of drug which reduces the capacity for aggression. Examples Serotonergic agents The recreational drug MDMA ("ecstasy") and a variety of related drugs have been described as '' empathogen-entactogens ...

effects,

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

effects,

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

effects, and psychedelic effects.

Phenethylamines

* 2C-B * 2C-T-2 * 2C-T-7 * Metaescaline

Amphetamines

* 3-Chloromethamphetamine * 3-Methoxymethamphetamine *

4-Fluoroamphetamine 4-Fluoroamphetamine (4-FA; 4-FMP; PAL-303; "Flux"), also known as ''para''-fluoroamphetamine (PFA) is a psychoactive drug, psychoactive research chemical of the phenethylamine and substituted amphetamine chemical classes. It produces stimulant a ...

(4-FA) * ''para''-Methoxyamphetamine (PMA) * 4-Methylthioamphetamine (4-MTA)

=Methylenedioxyamphetamines (benzodioxoles)

= * MMDA (5-methoxy-MDA) * 5-Methyl-MDA *

Methylbenzodioxolylbutanamine MBDB, also known as ''N''-methyl-1,3-benzodioxolylbutanamine or as 3,4-methylenedioxy-''N''-methyl-α-ethylphenylethylamine, is an entactogen of the phenethylamine, amphetamine, and phenylisobutylamine families related to MDMA. It is known by th ...

(MBDB) * Methylenedioxyamphetamine (MDA) *

Methylenedioxyethylamphetamine 3,4-Methylenedioxy-''N''-ethylamphetamine (MDEA; also called MDE and colloquially, Eve) is an empathogenic psychoactive drug. MDEA is a substituted amphetamine and a substituted methylenedioxyphenethylamine. MDEA acts as a serotonin, norepineph ...

(MDEA) *

Methylenedioxymethamphetamine 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor psychedelic properties. In studies, it has been used alongside psych ...

(MDMA) *

Methylenedioxyhydroxyamphetamine 3,4-Methylenedioxy-''N''-hydroxyamphetamine (MDOH, MDH, N-hydroxytenamphetamine) is an entactogen, psychedelic, and stimulant of the phenethylamine and amphetamine chemical classes. It is the ''N''- hydroxy homologue of MDA, and the ''N''- de ...

(MDOH) * Lys-MDA * Lys-MDMA

=Benzofurans

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

=Others

= * 5-APDI (indanylaminopropane; IAP) * Methamnetamine (PAL-1046) * SeDMA *

ODMA The Open Document Management API is an API that simplifies the communication of desktop applications with document management systems (DMS). ODMA standardizes the access to the DMS, which makes getting to these files as easy as if the files wer ...

* TDMA

=Cathinones

= * Mephedrone (4-MMC) * 3-Methylmethcathinone (3-MMC, metaphedrone) *

Methylone Methylone, also known as 3,4-methylenedioxy-''N''-methylcathinone (MDMC), is an entactogen and stimulant drug of the amphetamine, cathinone, and benzodioxole families related to 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"). It is th ...

(MDMC; βk-MDMA) *

Butylone Butylone, also known as β-keto-''N''-methylbenzodioxolylbutanamine (βk-MBDB), is a psychoactive drug of the substituted phenethylamine, phenethylamine, substituted amphetamine, amphetamine, phenylisobutylamine, and substituted cathinone, cathin ...

(βk-MBDB) * Flephedrone (4-FMC) * TH-PVP

=Aminorexes

= * 4,4'-Dimethylaminorex (4,4'-DMAR) * Methylenedioxy-4-methylaminorex (MDMAR)

Tryptamines

α-Alkyltryptamines

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

2-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)

Indolizines

* 1Z2MAP1O

References

External links

*
Entactogens - Massviews Analysis - Wikipedia
{{DEFAULTSORT:Empathogen-Entactogen Serotonin releasing agents