(''R'')-3,4-Methylenedioxy-''N''-methylamphetamine ((''R'')-MDMA), also known as (''R'')-midomafetamine or as ''levo''-MDMA, is the (''R'')- or

levorotatory Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circul ...

(''l''-)

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 ...

of 3,4-methylenedioxy-''N''-methylamphetamine (MDMA; midomafetamine; "ecstasy"), a

racemic mixture In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

of (''R'')-MDMA and (''S'')-MDMA. Like MDMA, (''R'')-MDMA is an

entactogen Entactogens, also known as empathogens or connectogens, are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, connectedness, emotional openness—that is, empathy—as particularly observe ...

empathogen Entactogens, also known as empathogens or connectogens, are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, connectedness, emotional openness—that is, empathy—as particularly observe ...

. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. The drug is a

serotonin–norepinephrine releasing agent A serotonin–norepinephrine releasing agent (SNRA) is a type of drug which induces the release of serotonin and norepinephrine (and epinephrine) in the body and/or brain. Only a few SNRAs are known, examples of which include norfenfluramine ...

(SNRA) and weak

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-HT_2A receptor

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 ...

. It has substantially less or no significant dopamine-releasing activity compared to MDMA and (''S'')-MDMA. In preclinial studies, (''R'')-MDMA shows equivalent therapeutic-like effects to MDMA, 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, but shows reduced

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 ...

-like effects, addictive potential, and serotonergic neurotoxicity. In

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

, (''R'')-MDMA produces similar effects to MDMA and (''S'')-MDMA, but is less potent and has a longer duration. (''R'')-MDMA was first described in

enantiopure In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities which are mirror images of each other and non-superpos ...

form by 1978. Under the developmental code names EMP-01, developed by atai Life Sciences, and MM-402, developed by

MindMed Mind Medicine (MindMed) Inc., doing business as MindMed, is a New York-based biotechnology company that is currently developing clinical and therapeutic applications for psychedelic and, more broadly, psychoplastogenic drugs. History MindMed ...

, it is under development for the treatment of

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),

social phobia Social anxiety disorder (SAD), also known as social phobia, is an anxiety disorder characterized by sentiments of fear and anxiety in social situations, causing considerable distress and impairing ability to function in at least some as ...

, and pervasive development disorders (PDDs) such as

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 ...

. It is thought that (''R'')-MDMA might have a better

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 ...

profile than MDMA itself whilst retaining its therapeutic benefits.

Pharmacology

Pharmacodynamics

Preclinical studies

MDMA is 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 ...

(SNDRA). (''R'')-MDMA and (''S'')-MDMA are both SNDRAs similarly. However, (''R'')-MDMA is several-fold less potent than (''S'')-MDMA ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' and is also less potent than (''S'')-MDMA ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' in non-human primates. In addition, whereas MDMA and (''S'')-MDMA are well-balanced SNDRAs, (''R'')-MDMA is comparatively much less potent as a

dopamine releasing agent A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the Body (biology), body and/or brain. No binding selectivity, selective DRAs are currently known. However, non-selective DRAs, including norepinephrin ...

(~11-fold less potent in releasing dopamine than serotonin), and could be thought of instead more as a

(SNRA) than as an SNDRA. In non-human primates, (''S'')-MDMA demonstrated significant

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(DAT) occupancy, whereas DAT occupancy with (''R'')-MDMA was undetectable. Similarly, MDMA and (''S'')-MDMA were found to increase

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 ...

levels in the

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

in rodents and non-human primates, whereas (''R'')-MDMA did not increase striatal dopamine levels. As such, (''R'')-MDMA may be less

-like than MDMA or (''S'')-MDMA. In addition to its actions as an SNDRA, MDMA has weak

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 ...

for the

5-HT_2A, 5-HT_2B, and 5-HT_2C receptors, where it acts as an

. (''R'')-MDMA shows higher affinity for the serotonin 5-HT_2A receptor than (''S'')-MDMA or MDMA. In addition, (''R'')-MDMA is more potent as an

of the serotonin 5-HT_2A receptor, acting as a weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of this receptor, whereas (''S'')-MDMA shows very little effect. Conversely however, (''S'')-MDMA is more potent as an agonist of the serotonin 5-HT_2C receptor. Based on these findings, it has been hypothesized that (''R'')-MDMA may be more

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 ...

-like than (''S'')-MDMA. However, although (''R'')-MDMA partially substitutes for

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) in animal

drug discrimination Drug discrimination (DD) is a technique in behavioral neuroscience used to evaluate the discriminative stimulus properties or interoceptive cues of psychoactive drugs. In drug discrimination, a subject is trained on a training drug, and then i ...

tests, it did not produce the

head-twitch response The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats in association with serotonin 5-HT2A receptor activation. Serotonergic psychedelics like lys ...

, a behavioral proxy of psychedelic effects, at any tested dose. In any case, findings in this area are conflicting. (''R'')-MDMA is inactive as an agonist of the human

TAAR1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is p ...

, whereas (''S'')-MDMA shows very weak potency as an agonist of the receptor ( = 74,000nM). MDMA is a well-known

serotonergic neurotoxin A monoamine neurotoxin, or monoaminergic neurotoxin, is a drug that selectively damages or destroys monoaminergic neurons. Monoaminergic neurons are neurons that signal via stimulation by monoamine neurotransmitters including serotonin, dopamine ...

and this has been demonstrated both in animals and in humans. There is evidence that the serotonergic neurotoxicity of MDMA may be driven primarily by (''S'')-MDMA rather than (''R'')-MDMA. (''R'')-MDMA shows substantially lower or potentially no neurotoxicity compared to (''S'')-MDMA in

animal studies Animal studies is a recently recognised field in which animals are studied in a variety of cross-disciplinary ways. Scholars who engage in animal studies may be formally trained in a number of diverse fields, including art history, anthropology ...

. This has been the case even when doses of (''R'')-MDMA were increased to account for its lower potency than (''S'')-MDMA. However, more research is needed to confirm this in other species, such as non-human primates. In contrast to (''S'')-MDMA, (''R'')-MDMA does not produce

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 ...

in rodents, and this may be involved in its reduced risk of neurotoxicity, as hyperthermia augments and is essential for the serotonergic neurotoxicity of MDMA. The reduced potency of (''R'')-MDMA as a dopamine releasing agent may also be involved in its reduced neurotoxic potential, as dopamine release is likewise essential for the neurotoxicity of MDMA. The hyperthermia of MDMA may in fact be mediated by dopamine release. As (''R'')-MDMA is less neurotoxic than (''S'')-MDMA and MDMA or even non-neurotoxic, it may allow for greater clinical viability and prolonged regimens of drug-assisted psychotherapy. (''R'')-MDMA and (''S'')-MDMA have shown equivalent effects in terms of inducing

behavior in monkeys. However, (''S'')-MDMA shows higher potency, whereas (''R'')-MDMA shows greater maximal effects. Conversely, (''S'')-MDMA does not increase prosocial behavior in mice, whereas both MDMA and (''R'')-MDMA do so. MDMA and (''S'')-MDMA increase locomotor activity, a measure of psychostimulant-like effect, in rodents, whereas (''R'')-MDMA does not do so. (''R'')-MDMA likewise showed fewer reinforcing effects than (''S'')-MDMA in non-human primates. These findings further add to (''R'')-MDMA showing reduced psychostimulant-like and addictive effects compared to MDMA and (''S'')-MDMA.

Clinical studies

The first modern clinical study of the comparative effects of MDMA, (''R'')-MDMA, and (''S'')-MDMA was published in August 2024. It compared 125mg MDMA, 125mg (''S'')-MDMA, 125 and 250mg (''R'')-MDMA, and

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

. (''R'')-MDMA increased any drug effect, good drug effect, drug liking, stimulation, drug high, alteration of vision, and alteration of sense of time ratings similarly to MDMA and (''S'')-MDMA. However, (''S'')-MDMA 125mg was more potent in increasing subjective effects, including stimulation, drug high, happy, and open, among others, than (''R'')-MDMA 125 or 250mg or MDMA 125mg. Ratings of bad drug effect and fear were minimal with MDMA, (''R'')-MDMA, and (''S'')-MDMA. In contrast to expectations, (''R'')-MDMA did not produce more psychedelic-like effects than (''S'')-MDMA. Besides subjective effects, (''R'')-MDMA increased

heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

, and

body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...

similarly to MDMA and (''S'')-MDMA, though it was less potent in producing these effects. Body temperature was notably increased to the same extent with (''R'')-MDMA 250mg as with MDMA 125mg and (''S'')-MDMA 125mg. The differences in effects between (''R'')-MDMA and (''S'')-MDMA may reflect the higher potency of (''S'')-MDMA rather than actual qualitative differences between the effects of (''S'')-MDMA and (''R'')-MDMA. It was estimated that equivalent effects would be expected with (''S'')-MDMA 100mg, MDMA 125mg, and (''R'')-MDMA 300mg. The findings of the study were overall regarded as not supporting the hypothesis that (''R'')-MDMA would produce equivalent therapeutic effects as (''S'')-MDMA or MDMA whilst reducing safety concerns. However, more clinical studies were called for to assess the revised estimated equivalent doses of MDMA, (''R'')-MDMA, and (''S'')-MDMA.

Pharmacokinetics

The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of (''S'')-MDMA is 4.1hours, whereas the half-life of (''R'')-MDMA is 12 to 14hours. In the case of racemic MDMA administration, the half-life of (''S'')-MDMA is 5.1hours and the half-life of (''R'')-MDMA is 11hours. (''R'')-MDMA shows

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

inhibition Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransm ...

and lower levels of the

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

4-hydroxy-3-methoxymethamphetamine 4-Hydroxy-3-methoxymethamphetamine (HMMA) is an active metabolite of 3,4-methylenedioxymethamphetamine (MDMA). It is a slightly more potent stimulant than MDMA in rodents. The drug is substantially less potent than MDMA as a monoamine releasi ...

(HMMA) than (''S'')-MDMA.

History

(''R'')-MDMA was first described in the

scientific literature Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...

form by 1978. It was described in a paper authored by

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 ...

David E. Nichols David Earl Nichols (born December 23, 1944, Covington, Kentucky) is an American pharmacologist and medicinal chemist. Previously the Robert C. and Charlotte P. Anderson Distinguished Chair in Pharmacology at Purdue University, Nichols has worke ...

, and other colleagues.

Clinical development

(''R'')-MDMA is under development separately by Empath Biosciences (EmpathBio) and MindMed. It is being developed by Empath Biosciences for the treatment of PTSD and social phobia and it is being developed by MindMed for the treatment of PDDs or autism. As of 2024, the drug is in phase 1

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 for both PTSD, social phobia, and PDDs/autism.

References

{{DEFAULTSORT:MDMA, (R)- 5-HT2A agonists Enantiopure drugs Entactogens Entheogens Experimental entactogens Experimental hallucinogens Experimental psychiatric drugs Methamphetamines Methylenedioxyphenethylamines Psychedelic phenethylamines Serotonin-norepinephrine releasing agents Serotonin receptor agonists VMAT inhibitors