MDMA was first synthesized in 1912 by Merck chemist Anton Köllisch.[28] It was used to enhance psychotherapy beginning in the 1970s and became popular as a street drug in the 1980s.[26][27] MDMA is commonly associated with dance parties, raves, and electronic dance music.[29] Tablets sold as ecstasy may be mixed with other substances such as ephedrine, amphetamine, and methamphetamine.[26] In 2016, about 21 million people between the ages of 15 and 64 used ecstasy (0.3% of the world population).[30] This was broadly similar to the percentage of people who use cocaine or amphetamines, but lower than for cannabis or opioids.[30] In the United States, as of 2017, about 7% of people have used MDMA at some point in their lives and 0.9% have used it in the last year.[31] The lethal risk from one dose of MDMA is estimated to be from 1 death in 20,000 instances to 1 death in 50,000 instances.[32]
MDMA has limited approved medical uses in a small number of countries,[36] but is illegal in most jurisdictions.[37] In the United States, the Food and Drug Administration (FDA) is evaluating the drug for clinical use as of 2021[update].[38] Canada has allowed limited distribution of MDMA upon application to and approval by Health Canada.[39][40] In Australia, it may be prescribed in the treatment of PTSD by specifically authorised psychiatrists.[41]
Effects
In general, MDMA users report feeling the onset of subjective effects within 30 to 60 minutes of oral consumption and reaching peak effect at 75 to 120 minutes, which then plateaus for about 3.5 hours.[42] The desired short-term psychoactive effects of MDMA have been reported to include:
The experience elicited by MDMA depends on the dose, setting, and user.[8] The variability of the induced altered state is lower compared to other psychedelics. For example, MDMA used at parties is associated with high motor activity, reduced sense of identity, and poor awareness of surroundings. Use of MDMA individually or in small groups in a quiet environment and when concentrating, is associated with increased lucidity, concentration, sensitivity to aesthetic aspects of the environment, enhanced awareness of emotions, and improved capability of communication.[15][44] In psychotherapeutic settings, MDMA effects have been characterized by infantile ideas, mood lability, and memories and moods connected with childhood experiences.[44][45]
MDMA has been described as an "empathogenic" drug because of its empathy-producing effects.[46][47] Results of several studies show the effects of increased empathy with others.[46] When testing MDMA for medium and high doses, it showed increased hedonic and arousal continuum.[48][49] The effect of MDMA increasing sociability is consistent, while its effects on empathy have been more mixed.[50]
Uses
Recreational
MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals, and house parties.[15] In the rave environment, the sensory effects of music and lighting are often highly synergistic with the drug. The psychedelic amphetamine quality of MDMA offers multiple appealing aspects to users in the rave setting. Some users enjoy the feeling of mass communion from the inhibition-reducing effects of the drug, while others use it as party fuel because of the drug's stimulatory effects.[51] MDMA is used less often than other stimulants, typically less than once per week.[52]
MDMA is sometimes taken in conjunction with other psychoactive drugs such as LSD,[53]psilocybin mushrooms, 2C-B, and ketamine. The combination with LSD is called "candy-flipping".[53] The combination with 2C-B is called "nexus flipping". For this combination, most people take the MDMA first, wait until the peak is over, and then take the 2C-B.[54]
MDMA is often co-administered with alcohol, methamphetamine, and prescription drugs such as SSRIs with which MDMA has several drug-drug interactions.[55][56][57] Three life-threatening reports of MDMA co-administration with ritonavir have been reported;[58] with ritonavir having severe and dangerous drug-drug interactions with a wide range of both psychoactive, anti-psychotic, and non-psychoactive drugs.[59]
As of 2023, MDMA therapies have only been approved for research purposes, with no widely accepted medical indications,[10][60][61] although this varies by jurisdiction. Before it was widely banned, it saw limited use in psychotherapy.[8][10][62] In 2017 the United States Food and Drug Administration (FDA) granted breakthrough therapy designation for MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD),[63][64] with some preliminary evidence that MDMA may facilitate psychotherapy efficacy for PTSD.[65][66] Pilot studies indicate that MDMA-assisted psychotherapy may be beneficial in treating social anxiety in autistic adults.[24][25] In these pilot studies, the vast majority of participants reported increased feelings of empathy that persisted after the therapy sessions.[67]
Other
Small doses of MDMA are used by some religious practitioners as an entheogen to enhance prayer or meditation.[68] MDMA has been used as an adjunct to New Age spiritual practices.[69]
Forms
MDMA has become widely known as ecstasy (shortened "E", "X", or "XTC"), usually referring to its tablet form, although this term may also include the presence of possible adulterants or diluents. The UK term "mandy" and the US term "molly" colloquially refer to MDMA in a crystalline powder form that is thought to be free of adulterants.[2][3][70] MDMA is also sold in the form of the hydrochloride salt, either as loose crystals or in gelcaps.[71][72] MDMA tablets can sometimes be found in a shaped form that may depict characters from popular culture. These are sometimes collectively referred to as "fun tablets".[73][74]
Partly due to the global supply shortage of sassafras oil—a problem largely assuaged by use of improved or alternative modern methods of synthesis—the purity of substances sold as molly have been found to vary widely. Some of these substances contain methylone, ethylone, MDPV, mephedrone, or any other of the group of compounds commonly known as bath salts, in addition to, or in place of, MDMA.[3][70][71][72] Powdered MDMA ranges from pure MDMA to crushed tablets with 30–40% purity.[10] MDMA tablets typically have low purity due to bulking agents that are added to dilute the drug and increase profits (notably lactose) and binding agents.[10] Tablets sold as ecstasy sometimes contain 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), other amphetamine derivatives, caffeine, opiates, or painkillers.[8] Some tablets contain little or no MDMA.[8][10][75] The proportion of seized ecstasy tablets with MDMA-like impurities has varied annually and by country.[10] The average content of MDMA in a preparation is 70 to 120mg with the purity having increased since the 1990s.[8]
MDMA is usually consumed by mouth. It is also sometimes snorted.[26]
Ecstasy tablets which may contain MDMA
A salt of MDMA (typically white) with impurities, resulting in a tan discoloration
Crushed MDMA (1 gram) crystals
Adverse effects
Short-term
Acute adverse effects are usually the result of high or multiple doses, although single dose toxicity can occur in susceptible individuals.[22] The most serious short-term physical health risks of MDMA are hyperthermia and dehydration.[43][76] Cases of life-threatening or fatal hyponatremia (excessively low sodium concentration in the blood) have developed in MDMA users attempting to prevent dehydration by consuming excessive amounts of water without replenishing electrolytes.[43][76][77]
The immediate adverse effects of MDMA use can include:
As of 2015[update], the long-term effects of MDMA on human brain structure and function have not been fully determined.[84] However, there is consistent evidence of structural and functional deficits in MDMA users with high lifetime exposure.[84] These structural or functional changes appear to be dose dependent and may be less prominent in MDMA users with only a moderate (typically <50 doses used and <100 tablets consumed) lifetime exposure. Nonetheless, moderate MDMA use may still be neurotoxic and what constitutes moderate use is not clearly established.[85]
Furthermore, it is not clear yet whether "typical" recreational users of MDMA (1 to 2 pills of 75 to 125mg MDMA or analogue every 1 to 4 weeks) will develop neurotoxic brain lesions.[86] Long-term exposure to MDMA in humans has been shown to produce marked neurodegeneration in striatal, hippocampal, prefrontal, and occipital serotonergic axon terminals.[84][87] Neurotoxic damage to serotonergic axon terminals has been shown to persist for more than two years.[87] Elevations in brain temperature from MDMA use are positively correlated with MDMA-induced neurotoxicity.[15][84][85] However, most studies on MDMA and serotonergic neurotoxicity in humans focus more on heavy users who consume as much as seven times or more the amount that most users report taking. The evidence for the presence of serotonergic neurotoxicity in casual users who take lower doses less frequently is not conclusive.[88]
However, adverse neuroplastic changes to brain microvasculature and white matter have been observed to occur in humans using low doses of MDMA.[15][84] Reduced gray matter density in certain brain structures has also been noted in human MDMA users.[15][84] Global reductions in gray matter volume, thinning of the parietal and orbitofrontal cortices, and decreased hippocampal activity have been observed in long term users.[8] The effects established so far for recreational use of ecstasy lie in the range of moderate to severe effects for serotonin transporter reduction.[89]
Impairments in multiple aspects of cognition, including attention, learning, memory, visual processing, and sleep, have been found in regular MDMA users.[8][22][90][84] The magnitude of these impairments is correlated with lifetime MDMA usage[22][90][84] and are partially reversible with abstinence.[8] Several forms of memory are impaired by chronic ecstasy use;[22][90] however, the effects for memory impairments in ecstasy users are generally small overall.[91][92] MDMA use is also associated with increased impulsivity and depression.[8]
Serotonin depletion following MDMA use can cause depression in subsequent days. In some cases, depressive symptoms persist for longer periods.[8] Some studies indicate repeated recreational use of ecstasy is associated with depression and anxiety, even after quitting the drug.[93] Depression is one of the main reasons for cessation of use.[8]
Approximately 60% of MDMA users experience withdrawal symptoms when they stop taking MDMA.[75] Some of these symptoms include fatigue, loss of appetite, depression, and trouble concentrating.[75]Tolerance to some of the desired and adverse effects of MDMA is expected to occur with consistent MDMA use.[75] A 2007 delphic analysis of a panel of experts in pharmacology, psychiatry, law, policing and others estimated MDMA to have a psychological dependence and physical dependence potential roughly three-fourths to four-fifths that of cannabis.[100]
MDMA has been shown to induce ΔFosB in the nucleus accumbens.[101] Because MDMA releases dopamine in the striatum, the mechanisms by which it induces ΔFosB in the nucleus accumbens are analogous to other dopaminergic psychostimulants.[101][102] Therefore, chronic use of MDMA at high doses can result in altered brain structure and drug addiction that occur as a consequence of ΔFosB overexpression in the nucleus accumbens.[102] MDMA is less addictive than other stimulants such as methamphetamine and cocaine.[103][104] Compared with amphetamine, MDMA and its metabolite MDA are less reinforcing.[105]
One study found approximately 15% of chronic MDMA users met the DSM-IV diagnostic criteria for substance dependence.[106] However, there is little evidence for a specific diagnosable MDMA dependence syndrome because MDMA is typically used relatively infrequently.[52]
There are currently no medications to treat MDMA addiction.[107]
During pregnancy
MDMA is a moderately teratogenic drug (i.e., it is toxic to the fetus).[108][109]In utero exposure to MDMA is associated with a neuro- and cardiotoxicity[109] and impaired motor functioning. Motor delays may be temporary during infancy or long-term. The severity of these developmental delays increases with heavier MDMA use.[90][110] MDMA has been shown to promote the survival of fetal dopaminergic neurons in culture.[111]
Overdose
MDMA overdose symptoms vary widely due to the involvement of multiple organ systems. Some of the more overt overdose symptoms are listed in the table below. The number of instances of fatal MDMA intoxication is low relative to its usage rates. In most fatalities, MDMA was not the only drug involved. Acute toxicity is mainly caused by serotonin syndrome and sympathomimetic effects.[106] Sympathomimetic side effects can be managed with carvedilol.[112][113] MDMA's toxicity in overdose may be exacerbated by caffeine, with which it is frequently cut in order to increase volume.[114] A scheme for management of acute MDMA toxicity has been published focusing on treatment of hyperthermia, hyponatraemia, serotonin syndrome, and multiple organ failure.[115]
MDMA is a racemic mixture of two enantiomers, (S)-MDMA and (R)-MDMA.[157][16] (S)-MDMA is much more potent as an SNDRA in vitro and in producing MDMA-like subjective effects in humans than (R)-MDMA.[157][153][16][186] By contrast, (R)-MDMA acts as a lower-potency serotonin–norepinephrine releasing agent (SNRA) with weak or negligible effects on dopamine.[157][153][187] Relatedly, (R)-MDMA shows weak or negligible stimulant-like and rewarding effects in animals.[157][188] Both (S)-MDMA and (R)-MDMA produce entactogen-type effects in animals and humans.[157][16] In addition, both (S)-MDMA and (R)-MDMA are weak agonists of the serotonin 5-HT2 receptors.[157][176][16][158][159] (R)-MDMA is more potent and efficacious as a serotonin 5-HT2A and 5-HT2B receptor agonist than (S)-MDMA, whereas (S)-MDMA is somewhat more potent as an agonist of the serotonin 5-HT2C receptor.[157][176][16] Despite its greater serotonin 5-HT2A receptor agonism however, (R)-MDMA did not produce more psychedelic-like effects than (S)-MDMA in humans.[162][16]
MDMA produces 3,4-methylenedioxyamphetamine (MDA) as a minor active metabolite.[116]Peak levels of MDA are about 5 to 10% of those of MDMA and total exposure to MDA is almost 10% of that of MDMA with oral MDMA administration.[116][181] As a result, MDA may contribute to some extent to the effects of MDMA.[116][160] MDA is an entactogen, stimulant, and weak psychedelic similarly to MDMA.[18] Like MDMA, it acts as a potent and well-balanced SNDRA and as a weak serotonin 5-HT2 receptor agonist.[153][158][159] However, MDA shows much more potent and efficacious serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonism than MDMA.[176][160][159][158] Accordingly, MDA produces greater psychedelic effects than MDMA in humans[18] and might particularly contribute to the mild psychedelic-like effects of MDMA.[160] On the other hand, MDA may also be importantly involved in toxicity of MDMA, such as cardiac valvulopathy.[189][181][158]
The MDMA concentration in the blood stream starts to rise after about 30 minutes,[207] and reaches its maximal concentration in the blood stream between 1.5 and 3 hours after ingestion.[208] It is then slowly metabolized and excreted, with levels of MDMA and its metabolites decreasing to half their peak concentration over the next several hours.[209] The duration of action of MDMA is about 3 to 6hours.[18] Brain serotonin levels are depleted after MDMA administration but serotonin levels typically return to normal within 24 to 48hours.[8]
MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.[211] MDMA is a chiral compound and has been almost exclusively administered as a racemate. However, the two enantiomers have been shown to exhibit different kinetics. The disposition of MDMA may also be stereoselective, with the S-enantiomer having a shorter elimination half-life and greater excretion than the R-enantiomer. Evidence suggests[212] that the area under the blood plasma concentration versus time curve (AUC) was two to four times higher for the (R)-enantiomer than the (S)-enantiomer after a 40mg oral dose in human volunteers. Likewise, the plasma half-life of (R)-MDMA was significantly longer than that of the (S)-enantiomer (5.8±2.2 hours vs 3.6±0.9 hours).[75] However, because MDMA excretion and metabolism have nonlinear kinetics,[213] the half-lives would be higher at more typical doses (100mg is sometimes considered a typical dose).[208]
There are numerous methods available to synthesize MDMA via different intermediates.[214][215][216][217] The original MDMA synthesis described in Merck's patent involves brominating safrole to 1-(3,4-methylenedioxyphenyl)-2-bromopropane and then reacting this adduct with methylamine.[218][219] Most illicit MDMA is synthesized using MDP2P (3,4-methylenedioxyphenyl-2-propanone) as a precursor. MDP2P in turn is generally synthesized from piperonal, safrole or isosafrole.[220] One method is to isomerize safrole to isosafrole in the presence of a strong base, and then oxidize isosafrole to MDP2P. Another method uses the Wacker process to oxidize safrole directly to the MDP2P intermediate with a palladium catalyst. Once the MDP2P intermediate has been prepared, a reductive amination leads to racemic MDMA (an equal parts mixture of (R)-MDMA and (S)-MDMA).[citation needed] Relatively small quantities of essential oil are required to make large amounts of MDMA. The essential oil of Ocotea cymbarum, for example, typically contains between 80 and 94% safrole. This allows 500mL of the oil to produce between 150 and 340 grams of MDMA.[221]
Synthesis of MDMA from piperonal
Synthesis of MDMA and related analogs from safrole
Detection in body fluids
MDMA and MDA may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Some drug abuse screening programs rely on hair, saliva, or sweat as specimens. Most commercial amphetamine immunoassay screening tests cross-react significantly with MDMA or its major metabolites, but chromatographic techniques can easily distinguish and separately measure each of these substances. The concentrations of MDA in the blood or urine of a person who has taken only MDMA are, in general, less than 10% those of the parent drug.[210][222][223]
History
Early research and use
German patents for MDMA synthesis and the subsequent methylhydrastinine synthesis filed by Merck on 24 December 1912 and issued in 1914
MDMA was first synthesized in 1912 by Merck chemist Anton Köllisch. At the time, Merck was interested in developing substances that stopped abnormal bleeding. Merck wanted to avoid an existing patent held by Bayer for one such compound: hydrastinine. Köllisch developed a preparation of a hydrastinine analogue, methylhydrastinine, at the request of fellow lab members, Walther Beckh and Otto Wolfes. MDMA (called methylsafrylamin, safrylmethylamin or N-Methyl-a-Methylhomopiperonylamin in Merck laboratory reports) was an intermediate compound in the synthesis of methylhydrastinine. Merck was not interested in MDMA itself at the time.[224] On 24 December 1912, Merck filed two patent applications that described the synthesis and some chemical properties of MDMA[225] and its subsequent conversion to methylhydrastinine.[226]
Merck records indicate its researchers returned to the compound sporadically. A 1920 Merck patent describes a chemical modification to MDMA.[227] In 1927, Max Oberlin studied the pharmacology of MDMA while searching for substances with effects similar to adrenaline or ephedrine, the latter being structurally similar to MDMA. Compared to ephedrine, Oberlin observed that it had similar effects on vascular smooth muscle tissue, stronger effects at the uterus, and no "local effect at the eye". MDMA was also found to have effects on blood sugar levels comparable to high doses of ephedrine. Oberlin concluded that the effects of MDMA were not limited to the sympathetic nervous system. Research was stopped "particularly due to a strong price increase of safrylmethylamine", which was still used as an intermediate in methylhydrastinine synthesis. Albert van Schoor performed simple toxicological tests with the drug in 1952, most likely while researching new stimulants or circulatory medications. After pharmacological studies, research on MDMA was not continued. In 1959, Wolfgang Fruhstorfer synthesized MDMA for pharmacological testing while researching stimulants. It is unclear if Fruhstorfer investigated the effects of MDMA in humans.[224]
Outside of Merck, other researchers began to investigate MDMA. In 1953 and 1954, the United States Army commissioned a study of toxicity and behavioral effects in animals injected with mescaline and several analogues, including MDMA. Conducted at the University of Michigan in Ann Arbor, these investigations were declassified in October 1969 and published in 1973.[228][229] A 1960 Polish paper by Biniecki and Krajewski describing the synthesis of MDMA as an intermediate was the first published scientific paper on the substance.[224][229][230]
MDMA may have been in non-medical use in the western United States in 1968.[231] An August 1970 report at a meeting of crime laboratory chemists indicates MDMA was being used recreationally in the Chicago area by 1970.[229][232] MDMA likely emerged as a substitute for its analog 3,4-methylenedioxyamphetamine (MDA),[233] a drug at the time popular among users of psychedelics[234] which was made a Schedule 1 controlled substance in the United States in 1970.[235][236]
Shulgin's research
Alexander and Ann Shulgin in December 2011
American chemist and psychopharmacologistAlexander Shulgin reported he synthesized MDMA in 1965 while researching methylenedioxy compounds at Dow Chemical Company, but did not test the psychoactivity of the compound at this time. Around 1970, Shulgin sent instructions for N-methylated MDA (MDMA) synthesis to the founder of a Los Angeles chemical company who had requested them. This individual later provided these instructions to a client in the Midwest. Shulgin may have suspected he played a role in the emergence of MDMA in Chicago.[229]
Shulgin first heard of the psychoactive effects of N-methylated MDA around 1975 from a young student who reported "amphetamine-like content".[229] Around 30 May 1976, Shulgin again heard about the effects of N-methylated MDA,[229] this time from a graduate student in a medicinal chemistry group he advised at San Francisco State University[234][237] who directed him to the University of Michigan study.[238] She and two close friends had consumed 100mg of MDMA and reported positive emotional experiences.[229] Following the self-trials of a colleague at the University of San Francisco, Shulgin synthesized MDMA and tried it himself in September and October 1976.[229][234] Shulgin first reported on MDMA in a presentation at a conference in Bethesda, Maryland in December 1976.[229] In 1978, he and David E. Nichols published a report on the drug's psychoactive effect in humans. They described MDMA as inducing "an easily controlled altered state of consciousness with emotional and sensual overtones" comparable "to marijuana, to psilocybin devoid of the hallucinatory component, or to low levels of MDA".[239]
While not finding his own experiences with MDMA particularly powerful,[238][240] Shulgin was impressed with the drug's disinhibiting effects and thought it could be useful in therapy.[240] Believing MDMA allowed users to strip away habits and perceive the world clearly, Shulgin called the drug window.[238][241] Shulgin occasionally used MDMA for relaxation, referring to it as "my low-calorie martini", and gave the drug to friends, researchers, and others who he thought could benefit from it.[238] One such person was Leo Zeff, a psychotherapist who had been known to use psychedelic substances in his practice. When he tried the drug in 1977, Zeff was impressed with the effects of MDMA and came out of his semi-retirement to promote its use in therapy. Over the following years, Zeff traveled around the United States and occasionally to Europe, eventually training an estimated four thousand psychotherapists in the therapeutic use of MDMA.[240][242] Zeff named the drug Adam, believing it put users in a state of primordial innocence.[234]
Psychotherapists who used MDMA believed the drug eliminated the typical fear response and increased communication. Sessions were usually held in the home of the patient or the therapist. The role of the therapist was minimized in favor of patient self-discovery accompanied by MDMA induced feelings of empathy. Depression, substance use disorders, relationship problems, premenstrual syndrome, and autism were among several psychiatric disorders MDMA assisted therapy was reported to treat.[236] According to psychiatrist George Greer, therapists who used MDMA in their practice were impressed by the results. Anecdotally, MDMA was said to greatly accelerate therapy.[240] According to David Nutt, MDMA was widely used in the western US in couples counseling, and was called empathy. Only later was the term ecstasy used for it, coinciding with rising opposition to its use.[243][244]
Rising recreational use
In the late 1970s and early 1980s, "Adam" spread through personal networks of psychotherapists, psychiatrists, users of psychedelics, and yuppies. Hoping MDMA could avoid criminalization like LSD and mescaline, psychotherapists and experimenters attempted to limit the spread of MDMA and information about it while conducting informal research.[236][245] Early MDMA distributors were deterred from large scale operations by the threat of possible legislation.[246] Between the 1970s and the mid-1980s, this network of MDMA users consumed an estimated 500,000 doses.[22][247]
A small recreational market for MDMA developed by the late 1970s,[248] consuming perhaps 10,000 doses in 1976.[235] By the early 1980s MDMA was being used in Boston and New York City nightclubs such as Studio 54 and Paradise Garage.[249][250] Into the early 1980s, as the recreational market slowly expanded, production of MDMA was dominated by a small group of therapeutically minded Boston chemists. Having commenced production in 1976, this "Boston Group" did not keep up with growing demand and shortages frequently occurred.[246]
Perceiving a business opportunity, Michael Clegg, the Southwest distributor for the Boston Group, started his own "Texas Group" backed financially by Texas friends.[246][251] In 1981,[246] Clegg had coined "Ecstasy" as a slang term for MDMA to increase its marketability.[241][245] Starting in 1983,[246] the Texas Group mass-produced MDMA in a Texas lab[245] or imported it from California[241] and marketed tablets using pyramid sales structures and toll-free numbers.[247] MDMA could be purchased via credit card and taxes were paid on sales.[246] Under the brand name "Sassyfras", MDMA tablets were sold in brown bottles.[245] The Texas Group advertised "Ecstasy parties" at bars and discos, describing MDMA as a "fun drug" and "good to dance to".[246] MDMA was openly distributed in Austin and Dallas–Fort Worth area bars and nightclubs, becoming popular with yuppies, college students, and gays.[233][246][247]
Recreational use also increased after several cocaine dealers switched to distributing MDMA following experiences with the drug.[247] A California laboratory that analyzed confidentially submitted drug samples first detected MDMA in 1975. Over the following years the number of MDMA samples increased, eventually exceeding the number of MDA samples in the early 1980s.[252][253] By the mid-1980s, MDMA use had spread to colleges around the United States.[246]: 33
Media attention and scheduling
United States
27 July 1984 Federal Register notice of the proposed MDMA scheduling
In an early media report on MDMA published in 1982, a Drug Enforcement Administration (DEA) spokesman stated the agency would ban the drug if enough evidence for abuse could be found.[246] By mid-1984, MDMA use was becoming more noticed. Bill Mandel reported on "Adam" in a 10 June San Francisco Chronicle article, but misidentified the drug as methyloxymethylenedioxyamphetamine (MMDA). In the next month, the World Health Organization identified MDMA as the only substance out of twenty phenethylamines to be seized a significant number of times.[245]
After a year of planning and data collection, MDMA was proposed for scheduling by the DEA on 27 July 1984 with a request for comments and objections.[245][254] The DEA was surprised when a number of psychiatrists, psychotherapists, and researchers objected to the proposed scheduling and requested a hearing.[236] In a Newsweek article published the next year, a DEA pharmacologist stated that the agency had been unaware of its use among psychiatrists.[255] An initial hearing was held on 1 February 1985 at the DEA offices in Washington, D.C., with administrative law judge Francis L. Young presiding.[245] It was decided there to hold three more hearings that year: Los Angeles on 10 June, Kansas City, Missouri on 10–11 July, and Washington, D.C., on 8–11 October.[236][245]
Sensational media attention was given to the proposed criminalization and the reaction of MDMA proponents, effectively advertising the drug.[236] In response to the proposed scheduling, the Texas Group increased production from 1985 estimates of 30,000 tablets a month to as many as 8,000 per day, potentially making two million ecstasy tablets in the months before MDMA was made illegal.[256] By some estimates the Texas Group distributed 500,000 tablets per month in Dallas alone.[241] According to one participant in an ethnographic study, the Texas Group produced more MDMA in eighteen months than all other distribution networks combined across their entire histories.[246] By May 1985, MDMA use was widespread in California, Texas, southern Florida, and the northeastern United States.[231][257] According to the DEA there was evidence of use in twenty-eight states[258] and Canada.[231] Urged by Senator Lloyd Bentsen, the DEA announced an emergency Schedule I classification of MDMA on 31 May 1985. The agency cited increased distribution in Texas, escalating street use, and new evidence of MDA (an analog of MDMA) neurotoxicity as reasons for the emergency measure.[257][259][260] The ban took effect one month later on 1 July 1985[256] in the midst of Nancy Reagan's "Just Say No" campaign.[261][262]
As a result of several expert witnesses testifying that MDMA had an accepted medical usage, the administrative law judge presiding over the hearings recommended that MDMA be classified as a Schedule III substance. Despite this, DEA administrator John C. Lawn overruled and classified the drug as Schedule I.[236][263] Harvard psychiatrist Lester Grinspoon then sued the DEA, claiming that the DEA had ignored the medical uses of MDMA, and the federal court sided with Grinspoon, calling Lawn's argument "strained" and "unpersuasive", and vacated MDMA's Schedule I status.[264] Despite this, less than a month later Lawn reviewed the evidence and reclassified MDMA as Schedule I again, claiming that the expert testimony of several psychiatrists claiming over 200 cases where MDMA had been used in a therapeutic context with positive results could be dismissed because they were not published in medical journals.[236] In 2017, the FDA grantedbreakthrough therapy designation for its use with psychotherapy for PTSD. However, this designation has been questioned and problematized.[265]
United Nations
While engaged in scheduling debates in the United States, the DEA also pushed for international scheduling.[256] In 1985 the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the 1971 United Nations Convention on Psychotropic Substances. The committee made this recommendation on the basis of the pharmacological similarity of MDMA to previously scheduled drugs, reports of illicit trafficking in Canada, drug seizures in the United States, and lack of well-defined therapeutic use. While intrigued by reports of psychotherapeutic uses for the drug, the committee viewed the studies as lacking appropriate methodological design and encouraged further research. Committee chairman Paul Grof dissented, believing international control was not warranted at the time and a recommendation should await further therapeutic data.[266] The Commission on Narcotic Drugs added MDMA to Schedule I of the convention on 11 February 1986.[267]
Post-scheduling
A 1995 Vibe Tribe rave in Erskineville, New South Wales, Australia being broken up by police. MDMA use spread globally along with rave culture.A 2000 United States Air Force video dramatizing the dangers of MDMA misuse
The use of MDMA in Texas clubs declined rapidly after criminalization, although by 1991 the drug remained popular among young middle-class whites and in nightclubs.[246]: 46 In 1985, MDMA use became associated with acid house on the Spanish island of Ibiza.[246]: 50 [268] Thereafter in the late 1980s, the drug spread alongside rave culture to the UK and then to other European and American cities.[246]: 50 Illicit MDMA use became increasingly widespread among young adults in universities and later, in high schools. Since the mid-1990s, MDMA has become the most widely used amphetamine-type drug by college students and teenagers.[269]: 1080 MDMA became one of the four most widely used illicit drugs in the US, along with cocaine, heroin, and cannabis.[241]
According to some estimates as of 2004, only marijuana attracts more first time users in the US.[241]
"Molly", short for 'molecule', was recognized as a slang term for crystalline or powder MDMA in the 2000s.[271][272]
In 2010, the BBC reported that use of MDMA had decreased in the UK in previous years. This may be due to increased seizures during use and decreased production of the precursor chemicals used to manufacture MDMA. Unwitting substitution with other drugs, such as mephedrone and methamphetamine,[273] as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.[274]
In 2017 it was found that some pills being sold as MDMA contained pentylone, which can cause very unpleasant agitation and paranoia.[275]
According to David Nutt, when safrole was restricted by the United Nations in order to reduce the supply of MDMA, producers in China began using anethole instead, but this gives para-methoxyamphetamine (PMA, also known as "Dr Death"), which is much more toxic than MDMA and can cause overheating, muscle spasms, seizures, unconsciousness, and death. People wanting MDMA are sometimes sold PMA instead.[243]
Society and culture
Global estimates of drug users in 2016 (in millions of users)[276]
MDMA is legally controlled in most of the world under the UN Convention on Psychotropic Substances and other international agreements, although exceptions exist for research and limited medical use. In general, the unlicensed use, sale or manufacture of MDMA are all criminal offences.
Australia
In Australia, MDMA was rescheduled on 1 July 2023 as a schedule 8 substance (available on prescription) when used in the treatment of PTSD, while remaining a schedule 9 substance (prohibited) for all other uses. For the treatment of PTSD, MDMA can only be prescribed by psychiatrists with specific training and authorisation.[277]
In 1986, MDMA was declared an illegal substance because of its allegedly harmful effects and potential for misuse.[278] Any non-authorised sale, use or manufacture is strictly prohibited by law. Permits for research uses on humans must be approved by a recognized ethics committee on human research.
In Western Australia under the Misuse of Drugs Act 1981 4.0g of MDMA is the amount required determining a court of trial, 2.0g is considered a presumption with intent to sell or supply and 28.0g is considered trafficking under Australian law.[279]
The Australian Capital Territory passed legislation to decriminalise the possession of small amounts of MDMA, which took effect in October 2023.[280][281]
United Kingdom
In the United Kingdom, MDMA was made illegal in 1977 by a modification order to the existing Misuse of Drugs Act 1971. Although MDMA was not named explicitly in this legislation, the order extended the definition of Class A drugs to include various ring-substituted phenethylamines.[282][283] The drug is therefore illegal to sell, buy, or possess without a licence in the UK. Penalties include a maximum of seven years and/or unlimited fine for possession; life and/or unlimited fine for production or trafficking.
Some researchers such as David Nutt have criticized the scheduling of MDMA, which he determined to be a relatively harmless drug.[284][285] An editorial he wrote in the Journal of Psychopharmacology, where he compared the risk of harm for horse riding (1 adverse event in 350) to that of ecstasy (1 in 10,000) resulted in his dismissal as well as the resignation of his colleagues from the ACMD.[286]
United States
In the United States, MDMA is listed in Schedule I of the Controlled Substances Act.[287] In a 2011 federal court hearing, the American Civil Liberties Union successfully argued that the sentencing guideline for MDMA/ecstasy is based on outdated science, leading to excessive prison sentences.[288] Other courts have upheld the sentencing guidelines. The United States District Court for the Eastern District of Tennessee explained its ruling by noting that "an individual federal district court judge simply cannot marshal resources akin to those available to the Commission for tackling the manifold issues involved with determining a proper drug equivalency."[289]
Netherlands
In the Netherlands, the Expert Committee on the List (Expertcommissie Lijstensystematiek Opiumwet) issued a report in June 2011 which discussed the evidence for harm and the legal status of MDMA, arguing in favor of maintaining it on List I.[289][290][291]
UNODC map showing the use of ecstasy by country in 2014 for the global population aged 15–64
In 2014, 3.5% of 18 to 25 year-olds had used MDMA in the United States.[8] In the European Union as of 2018, 4.1% of adults (15–64 years old) have used MDMA at least once in their life, and 0.8% had used it in the last year.[296] Among young adults, 1.8% had used MDMA in the last year.[296]
In Europe, an estimated 37% of regular club-goers aged 14 to 35 used MDMA in the past year according to the 2015 European Drug report.[8] The highest one-year prevalence of MDMA use in Germany in 2012 was 1.7% among people aged 25 to 29 compared with a population average of 0.4%.[8] Among adolescent users in the United States between 1999 and 2008, girls were more likely to use MDMA than boys.[297]
Economics
Europe
In 2008 the European Monitoring Centre for Drugs and Drug Addiction noted that although there were some reports of tablets being sold for as little as €1, most countries in Europe then reported typical retail prices in the range of €3 to €9 per tablet, typically containing 25–65mg of MDMA.[298] By 2014 the EMCDDA reported that the range was more usually between €5 and €10 per tablet, typically containing 57–102mg of MDMA, although MDMA in powder form was becoming more common.[299]
North America
The United Nations Office on Drugs and Crime stated in its 2014 World Drug Report that US ecstasy retail prices range from US$1 to $70 per pill, or from $15,000 to $32,000 per kilogram.[300] A new research area named Drug Intelligence aims to automatically monitor distribution networks based on image processing and machine learning techniques, in which an Ecstasy pill picture is analyzed to detect correlations among different production batches.[301] These novel techniques allow police scientists to facilitate the monitoring of illicit distribution networks.
As of October 2015[update], most of the MDMA in the United States is produced in British Columbia, Canada and imported by Canada-based Asian transnational criminal organizations.[70] The market for MDMA in the United States is relatively small compared to methamphetamine, cocaine, and heroin.[70] In the United States, about 0.9 million people used ecstasy in 2010.[26]
Australia
MDMA is particularly expensive in Australia, costing A$15–A$30 per tablet. In terms of purity data for Australian MDMA, the average is around 34%, ranging from less than 1% to about 85%. The majority of tablets contain 70–85mg of MDMA. Most MDMA enters Australia from the Netherlands, the UK, Asia, and the US.[302]
A 2014 review of the safety and efficacy of MDMA as a treatment for various disorders, particularly post-traumatic stress disorder (PTSD), indicated that MDMA has therapeutic efficacy in some patients.[90] Four clinical trials provide moderate evidence in support of this treatment.[305] Some authors have concluded that because of MDMA's potential to cause lasting harm in humans (e.g., serotonergic neurotoxicity and persistent memory impairment), "considerably more research must be performed" on its efficacy in PTSD treatment to determine if the potential treatment benefits outweigh its potential to harm a patient.[22][90] Other authors have argued that the neurotoxic effects of MDMA are dose-dependent,[306] with lower doses exhibiting lower neurotoxicity or even neuroprotection,[307] and that MDMA assisted psychotherapy is considerably safer than current treatments.[308]
Animal models suggest that postnatal exposure may ameliorate social impairments in autism.[309]
Recent evidence suggests the safe and potentially effective use of MDMA to treat the negative symptoms of schizophrenia.[310] Unlike other treatments for mental illness, MDMA would be intended to be used infrequently and alongside psychotherapy in treatment.
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^ abHysek CM, Simmler LD, Nicola VG, Vischer N, Donzelli M, Krähenbühl S, et al. (4 May 2012). Laks J (ed.). "Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study". PLOS ONE. 7 (5): e36476. Bibcode:2012PLoSO...736476H. doi:10.1371/journal.pone.0036476. PMC3344887. PMID22574166. Fig. 7 shows the mean PD effects of MDMA plotted against simultaneous plasma concentrations at the different time points (hysteresis loops). The increases in "any drug effect" (Fig. 7a) and MAP (Fig. 7b) returned to baseline within 6 h when MDMA concentrations were still high. This clockwise hysteresis indicates that a smaller MDMA effect was seen at a given plasma concentration later in time, indicating rapid acute pharmacodynamic tolerance, which was similarly described for cocaine [33]. [...] Figure 7. Pharmacokinetic-pharmacodynamic (PK-PD) relationship. MDMA effects are plotted against simultaneous MDMA plasma concentrations (a, b). The time of sampling is noted next to each point in minutes or hours after MDMA administration. The clockwise hysteresis indicates acute tolerance to the effects of MDMA.
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^ abcdefghGarg A, Kapoor S, Goel M, Chopra S, Chopra M, Kapoor A, et al. (2015). "Functional Magnetic Resonance Imaging in Abstinent MDMA Users: A Review". Current Drug Abuse Reviews. 8 (1): 15–25. doi:10.2174/1874473708666150303115833. PMID25731754.
^ abHalpin LE, Collins SA, Yamamoto BK (February 2014). "Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine". Life Sciences. 97 (1): 37–44. doi:10.1016/j.lfs.2013.07.014. PMC3870191. PMID23892199. In contrast, MDMA produces damage to serotonergic, but not dopaminergic axon terminals in the striatum, hippocampus, and prefrontal cortex (Battaglia et al., 1987, O'Hearn et al., 1988). The damage associated with Meth and MDMA has been shown to persist for at least 2 years in rodents, non-human primates and humans (Seiden et al., 1988, Woolverton et al., 1989, McCann et al., 1998, Volkow et al., 2001a, McCann et al., 2005)
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^Mack AH, Brady KT, Miller SI, Frances RJ (12 May 2016). Clinical Textbook of Addictive Disorders. Guilford Publications. p. 171. ISBN978-1-4625-2169-2. Archived from the original on 19 January 2023. Retrieved 13 October 2020. There are no known pharmacological treatments for MDMA addiction.
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^ abMeamar R, Karamali F, Sadeghi HM, Etebari M, Nasr-Esfahani MH, Baharvand H (June 2010). "Toxicity of ecstasy (MDMA) towards embryonic stem cell-derived cardiac and neural cells". Toxicology in Vitro. 24 (4): 1133–8. Bibcode:2010ToxVi..24.1133M. doi:10.1016/j.tiv.2010.03.005. PMID20230888. In summary, MDMA is a moderate teratogen that could influence cardiac and neuronal differentiation in the ESC model and these results are in concordance with previous in vivo and in vitro models.
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^Silins E, Copeland J, Dillon P (August 2007). "Qualitative review of serotonin syndrome, ecstasy (MDMA) and the use of other serotonergic substances: hierarchy of risk". The Australian and New Zealand Journal of Psychiatry. 41 (8): 649–55. doi:10.1080/00048670701449237. PMID17620161. S2CID25832516.
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^ abcdefghijklmFonseca DA, Ribeiro DM, Tapadas M, Cotrim MD (July 2021). "Ecstasy (3,4-methylenedioxymethamphetamine): Cardiovascular effects and mechanisms". Eur J Pharmacol. 903: 174156. doi:10.1016/j.ejphar.2021.174156. PMID33971177.
^ abSchmid Y, Rickli A, Schaffner A, Duthaler U, Grouzmann E, Hysek CM, et al. (April 2015). "Interactions between bupropion and 3,4-methylenedioxymethamphetamine in healthy subjects". J Pharmacol Exp Ther. 353 (1): 102–111. doi:10.1124/jpet.114.222356. PMID25655950.
^Vuori E, Henry JA, Ojanperä I, Nieminen R, Savolainen T, Wahlsten P, et al. (March 2003). "Death following ingestion of MDMA (ecstasy) and moclobemide". Addiction. 98 (3): 365–8. doi:10.1046/j.1360-0443.2003.00292.x. PMID12603236.
^ abMendelson J, Baggott MJ, Li L, Coyle J, Galloway GP (2012). "Poster Session II (PII 1-111): PII-41. MDMA-Induced Increases in Blood Pressure Are Not Mediated by α-Adrenergic Mechanisms and Are Not Due To Elevated Peripheral Vascular Resistance". Clinical Pharmacology & Therapeutics. 91 (S1 [American Society for Clinical Pharmacology and Therapeutics Abstract of papers, 2012 Annual Meeting Gaylord National Hotel and Convention Center National Harbor, Maryland March 14–17, 2012]): S51–S93 (S66–S66). doi:10.1038/clpt.2011.361. ISSN0009-9236. MDMA increased heart rate (HR) by 25 bpm (p<.001), [cardiac output (CO)] by 1.75 L/min (p<0.01) but did not alter [stroke volume (SV)] or [systemic vascular resistance (SVR)]. Compared to MDMA alone the combination of MDMA + prazosin further increased HR by 24 bpm (p<0.001) and CO by 3.3L/min (p<0.02). MDMA increased systolic and diastolic blood pressure (SBP, DBP) by 26 mmHg (p<0.001 each); prazosin attenuated MDMA effects on DBP by 9.3 mmHg (p<001) but did not alter SBP. [...] MDMA increases HR, producing elevations in CO. The hypertensive effects of MDMA are not due to elevated peripheral vascular resistance and the blood pressure effects of MDMA are not attenuated by α-adrenergic blockade, suggesting that MDMA may produce CV effects through non-α-adrenergic mechanisms.
^Liechti ME, Saur MR, Gamma A, Hell D, Vollenweider FX (October 2000). "Psychological and physiological effects of MDMA ("Ecstasy") after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans". Neuropsychopharmacology. 23 (4): 396–404. doi:10.1016/S0893-133X(00)00126-3. PMID10989266.
^Hart XM, Spangemacher M, Defert J, Uchida H, Gründer G (April 2024). "Update Lessons from PET Imaging Part II: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antidepressants". Ther Drug Monit. 46 (2): 155–169. doi:10.1097/FTD.0000000000001142. PMID38287888.
^Hysek CM, Brugger R, Simmler LD, Bruggisser M, Donzelli M, Grouzmann E, et al. (February 2012). "Effects of the α₂-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers". J Pharmacol Exp Ther. 340 (2): 286–294. doi:10.1124/jpet.111.188425. PMID22034656.
^Hysek CM, Fink AE, Simmler LD, Donzelli M, Grouzmann E, Liechti ME (October 2013). "α₁-Adrenergic receptors contribute to the acute effects of 3,4-methylenedioxymethamphetamine in humans". J Clin Psychopharmacol. 33 (5): 658–666. doi:10.1097/JCP.0b013e3182979d32. PMID23857311.
^Liechti ME, Vollenweider FX (July 2000). "Acute psychological and physiological effects of MDMA ("Ecstasy") after haloperidol pretreatment in healthy humans". Eur Neuropsychopharmacol. 10 (4): 289–295. doi:10.1016/s0924-977x(00)00086-9. PMID10871712.
^Richards JR, Hollander JE, Ramoska EA, Fareed FN, Sand IC, Izquierdo Gómez MM, et al. (May 2017). "β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon". J Cardiovasc Pharmacol Ther. 22 (3): 239–249. doi:10.1177/1074248416681644. PMID28399647.
^ abSimmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, et al. (January 2013). "Pharmacological characterization of designer cathinones in vitro". Br J Pharmacol. 168 (2): 458–470. doi:10.1111/j.1476-5381.2012.02145.x. PMC3572571. PMID22897747. β-Keto-analogue cathinones also exhibited approximately 10-fold lower affinity for the TA1 receptor compared with their respective non-β-keto amphetamines. [...] Activation of TA1 receptors negatively modulates dopaminergic neurotransmission. Importantly, methamphetamine decreased DAT surface expression via a TA1 receptor-mediated mechanism and thereby reduced the presence of its own pharmacological target (Xie and Miller, 2009). MDMA and amphetamine have been shown to produce enhanced DA and 5-HT release and locomotor activity in TA1 receptor knockout mice compared with wild-type mice (Lindemann et al., 2008; Di Cara et al., 2011). Because methamphetamine and MDMA auto-inhibit their neurochemical and functional effects via TA1 receptors, low affinity for these receptors may result in stronger effects on monoamine systems by cathinones compared with the classic amphetamines.
^Simmler LD, Rickli A, Hoener MC, Liechti ME (April 2014). "Monoamine transporter and receptor interaction profiles of a new series of designer cathinones". Neuropharmacology. 79: 152–160. doi:10.1016/j.neuropharm.2013.11.008. PMID24275046.
^ abcdefghDocherty JR, Alsufyani HA (August 2021). "Pharmacology of Drugs Used as Stimulants". J Clin Pharmacol. 61 (Suppl 2): S53 –S69. doi:10.1002/jcph.1918. PMID34396557. Receptor-mediated actions of amphetamine and other amphetamine derivatives [...] may involve trace amine-associated receptors (TAARs) at which amphetamine and MDMA also have significant potency.85–87 Many stimulants have potency at the rat TAAR1 in the micromolar range but tend to be about 5 to 10 times less potent at the human TAAR1, [...] Activation of the TAAR1 receptor causes inhibition of dopaminergic transmission in the mesocorticolimbic system, and TAAR1 agonists attenuated psychostimulant abuse-related behaviors.89 It is likely that TAARs contribute to the actions of specific stimulants to modulate dopaminergic, serotonergic, and glutamate signaling,90 and drugs acting on the TAAR1 may have therapeutic potential.91 In the periphery, stimulants such as MDMA and cathinone produce vasoconstriction, part of which may involve TAARs, although only relatively high concentrations produced vascular contractions resistant to a cocktail of monoamine antagonist drugs.86
^ abcRothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID14612135.
^ abcdefRothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID17017961.
^ abSulzer D, Sonders MS, Poulsen NW, Galli A (April 2005). "Mechanisms of neurotransmitter release by amphetamines: a review". Prog Neurobiol. 75 (6): 406–433. doi:10.1016/j.pneurobio.2005.04.003. PMID15955613.
^ abcdefghiPitts EG, Curry DW, Hampshire KN, Young MB, Howell LL (February 2018). "(±)-MDMA and its enantiomers: potential therapeutic advantages of R(-)-MDMA". Psychopharmacology. 235 (2): 377–392. doi:10.1007/s00213-017-4812-5. PMID29248945.
^ abcdefSetola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, et al. (June 2003). "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology. 63 (6): 1223–1229. doi:10.1124/mol.63.6.1223. PMID12761331. S2CID839426.
^ abcdNash JF, Roth BL, Brodkin JD, Nichols DE, Gudelsky GA (August 1994). "Effect of the R(-) and S(+) isomers of MDA and MDMA on phosphatidyl inositol turnover in cultured cells expressing 5-HT2A or 5-HT2C receptors". Neurosci Lett. 177 (1–2): 111–115. doi:10.1016/0304-3940(94)90057-4. PMID7824160.
^ abcdSimmler LD, Liechti ME (2018). "Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 252: 143–164. doi:10.1007/164_2018_113. ISBN978-3-030-10560-0. PMID29633178. MDMA is also a low-potency partial agonist of the 5-HT2A receptor. Although not frequent, mild hallucinogen-like effects of MDMA have been reported, which may be attributable to 5-HT2A agonism (Nichols 2004; Liechti et al. 2000). MDA, the active metabolite of MDMA (Hysek et al. 2011), shows a tenfold higher potency for 5-HT2A agonism than MDMA (Rickli et al. 2015c). MDA likely contributes to the mode of action of MDMA and might contribute to the mild hallucinogenic effects of MDMA.
^Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 36: 159–199. doi:10.1007/7854_2016_466. ISBN978-3-662-55878-2. PMC5787039. PMID28224459. [MDxx] have been assessed in head twitch studies. Racemic [MDA] and S-(+)-MDA reportedly induce WDS in monkeys and rats, respectively (Schlemmer and Davis 1986; Hiramatsu et al. 1989). Although [MDMA] does not induce the HTR in mice, both of the stereoisomers of MDMA have been shown to elicit the response (Fantegrossi et al. 2004, 2005b). 5-HT depletion inhibits the response to S-(+)-MDMA but does not alter the response to R-(−)-MDMA, suggesting the isomers act through different mechanisms (Fantegrossi et al. 2005b). This suggestion is consistent with the fact that S-(+)- and R-(−)-MDMA exhibit qualitatively distinct pharmacological profiles, with the S-(+)isomer working primarily as a monoamine releaser (Johnson et al. 1986; Baumann et al. 2008; Murnane et al. 2010) and the R-(−)-enantiomer acting directly through 5-HT2A receptors (Lyon et al. 1986; Nash et al. 1994). In contrast to their effects in mice, Hiramatsu reported that S-(+)- and R-(−)-MDMA fail to produce WDS in rats (Hiramatsu et al. 1989). The discrepant findings with MDMA in mice and rats may reflect species differences in sensitivity to the HTR (see below for further discussion).
^Dunlap LE (2022). Development of Non-Hallucinogenic Psychoplastogens (Thesis). University of California, Davis. Retrieved 18 November 2024. Finally, since R-MDMA is known to partially substitute for LSD in animal models we decided to test both compounds in the head twitch response assay (HTR) (FIG 3.3C).3 The HTR is a well-validated mouse model for predicting the hallucinogenic potential of test drugs. Serotonergic psychedelics will cause a rapid back and forth head movement in mice. The potency measured in the HTR assay has been shown to correlate very well with the human potencies of psychedelics.18 Neither R-MDMA or LED produced any head twitches at all doses tested, suggesting that neither has high hallucinogenic potential.
^Espinoza S, Gainetdinov RR (2014). "Neuronal Functions and Emerging Pharmacology of TAAR1". Taste and Smell. Topics in Medicinal Chemistry. Vol. 23. Cham: Springer International Publishing. pp. 175–194. doi:10.1007/7355_2014_78. ISBN978-3-319-48925-4. Interestingly, the concentrations of amphetamine found to be necessary to activate TAAR1 are in line with what was found in drug abusers [3, 51, 52]. Thus, it is likely that some of the effects produced by amphetamines could be mediated by TAAR1. Indeed, in a study in mice, MDMA effects were found to be mediated in part by TAAR1, in a sense that MDMA auto-inhibits its neurochemical and functional actions [46]. Based on this and other studies (see other section), it has been suggested that TAAR1 could play a role in reward mechanisms and that amphetamine activity on TAAR1 counteracts their known behavioral and neurochemical effects mediated via dopamine neurotransmission.
^Kuropka P, Zawadzki M, Szpot P (May 2023). "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse". Hum Psychopharmacol. 38 (3): e2866. doi:10.1002/hup.2866. PMID36866677. Another feature that distinguishes [synthetic cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] It is worth noting, however, that for TAAR1 there is considerable species variability in its interaction with ligands, and it is possible that the in vitro activity of [rodent TAAR1 agonists] may not translate into activity in the human body (Simmler et al., 2016). The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013).
^Esaki H, Sasaki Y, Nishitani N, Kamada H, Mukai S, Ohshima Y, et al. (May 2023). "Role of 5-HT1A receptors in the basolateral amygdala on 3,4-methylenedioxymethamphetamine-induced prosocial effects in mice". Eur J Pharmacol. 946: 175653. doi:10.1016/j.ejphar.2023.175653. PMID36907260.
^Blanco-Gandía MC, Mateos-García A, García-Pardo MP, Montagud-Romero S, Rodríguez-Arias M, Miñarro J, et al. (September 2015). "Effect of drugs of abuse on social behaviour: a review of animal models". Behav Pharmacol. 26 (6): 541–570. doi:10.1097/FBP.0000000000000162. PMID26221831.
^ abcdKaur H, Karabulut S, Gauld JW, Fagot SA, Holloway KN, Shaw HE, et al. (2023). "Balancing Therapeutic Efficacy and Safety of MDMA and Novel MDXX Analogues as Novel Treatments for Autism Spectrum Disorder". Psychedelic Medicine. 1 (3): 166–185. doi:10.1089/psymed.2023.0023. It is postulated that MDMA-induced neuronal apoptosis arises from directly stimulating the 5HT2A receptor. However, it is unclear whether MDMA binds here directly or whether one of its active metabolites (for example, MDA exhibits a 5-HT2A affinity almost 10-fold better than MDMA) is responsible.70,80,81 In addition, R-MDMA more potently activates 5-HT2A second messenger signaling, with S-MDMA having a minimal effect and racemic MDMA acting as a weak partial agonist.
^McIntyre RS (2023). "Serotonin 5-HT2B receptor agonism and valvular heart disease: implications for the development of psilocybin and related agents". Expert Opin Drug Saf. 22 (10): 881–883. doi:10.1080/14740338.2023.2248883. PMID37581427.
^ abcTagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R (September 2023). "The risk of chronic psychedelic and MDMA microdosing for valvular heart disease"(PDF). J Psychopharmacol. 37 (9): 876–890. doi:10.1177/02698811231190865. PMID37572027. [...] Both [MDMA and MDA] bind to the human 5-HT2B receptor, although with a 5-fold lower Ki value for MDA compared to MDMA (Ray, 2010; Setola et al., 2003). Both compounds were agonists in an assay of PI hydrolysis, with MDA (EC50=190nM) 10-fold more potent than MDMA (EC50=2000 nM) in addition to greater intrinsic efficacy (90% vs 32%) (Setola et al., 2003). [...] A 50mg dose of MDMA resulted in a mean plasma Cmax 266nM for MDMA and 28.5nM for MDA (de la Torre et al., 2000).
^Acquas E, Pisanu A, Spiga S, Plumitallo A, Zernig G, Di Chiara G (July 2007). "Differential effects of intravenous R,S-(+/-)-3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)- and R(-)-enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core". Journal of Neurochemistry. 102 (1): 121–132. doi:10.1111/j.1471-4159.2007.04451.x. PMID17564678.
^Luethi D, Liechti ME (2021). "Drugs of Abuse Affecting 5-HT2B Receptors". 5-HT2B Receptors. The Receptors. Vol. 35. Cham: Springer International Publishing. pp. 277–289. doi:10.1007/978-3-030-55920-5_16. ISBN978-3-030-55919-9. Notably, in a study by Rickli and colleagues, MDMA did not activate the 5-HT2B receptor in the functional assay at investigated concentrations (EC50 > 20 μM); however, [MDA], the main psychoactive N-demethylated phase I metabolite of MDMA, potently activated the receptor at submicromolar concentrations [14]. This suggests that the metabolite MDA rather than MDMA itself may lead to valvulopathy and that there could be a signifcant metabolic contribution to MDMA-induced effects and adverse effect.
^Mead J, Parrott A (May 2020). "Mephedrone and MDMA: A comparative review". Brain Res. 1735: 146740. doi:10.1016/j.brainres.2020.146740. PMID32087112. A controlled study on eight experienced MDMA users reported that 1.5 mg/kg (comparable to what was deemed a typical dosage amount) consumed orally resulted in the subjective effects peaking within 2 h of ingestion (Harris et al., 2002). Other research indicates effects to emerge between 20 and 60 min, with them peaking between 60 and 90 min and lasting up to 5 h (Green et al., 2003). A dose of 100 mg has a half-life of 8–9h(De la Torre et al., 2004), although as mentioned above, users are unaware of the dose they ingest.
^Cruickshank CC, Dyer KR (July 2009). "A review of the clinical pharmacology of methamphetamine". Addiction. 104 (7): 1085–1099. doi:10.1111/j.1360-0443.2009.02564.x. PMID19426289. Metabolism does not appear to be altered by chronic exposure, thus dose escalation appears to arise from pharmacodynamic rather than pharmacokinetic tolerance [24]. [...] The terminal plasma half-life of methamphetamine of approximately 10 hours is similar across administration routes, but with substantial inter-individual variability. Acute effects persist for up to 8 hours following a single moderate dose of 30 mg [30]. [...] peak plasma methamphetamine concentration occurs after 4 hours [35]. Nevertheless, peak cardiovascular and subjective effects occur rapidly (within 5–15 minutes). The dissociation between peak plasma concentration and clinical effects indicates acute tolerance, which may reflect rapid molecular processes such as redistribution of vesicular monoamines and internalization of monoamine receptors and transporters [6,36]. Acute subjective effects diminish over 4 hours, while cardiovascular effects tend to remain elevated. This is important, as the marked acute tachyphylaxis to subjective effects may drive repeated use within intervals of 4 hours, while cardiovascular risks may increase [11,35].
^Abbas K, Barnhardt EW, Nash PL, Streng M, Coury DL (April 2024). "A review of amphetamine extended release once-daily options for the management of attention-deficit hyperactivity disorder". Expert Review of Neurotherapeutics. 24 (4): 421–432. doi:10.1080/14737175.2024.2321921. PMID38391788. For several decades, clinical benefits of amphetamines have been limited by the pharmacologic half-life of around 4 hours. Although higher doses can produce higher maximum concentrations, they do not affect the half-life of the dose. Therefore, to achieve longer durations of effect, stimulants had to be dosed at least twice daily. Further, these immediate-release doses were found to have their greatest effect shortly after administration, with a rapid decline in effect after reaching peak blood concentrations. The clinical correlation of this was found in comparing math problems attempted and solved between a mixed amphetamine salts preparation (MAS) 10 mg once at 8 am vs 8 am followed by 12 pm [14]. The study also demonstrated the phenomenon of acute tolerance, where even if blood concentrations were maintained over the course of the day, clinical efficacy in the form of math problems attempted and solved would diminish over the course of the day. These findings eventually led to the development of a once daily preparation (MAS XR) [15], which is a composition of 50% immediate-release beads and 50% delayed release beads intended to mimic this twice-daily dosing with only a single administration.
^van Gaalen MM, Schlumbohm C, Folgering JH, Adhikari S, Bhattacharya C, Steinbach D, et al. (April 2019). "Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine". The Journal of Pharmacology and Experimental Therapeutics. 369 (1): 107–120. doi:10.1124/jpet.118.254508. PMID30733244. Acute tolerance has been demonstrated for methamphetamine in rats (Segal and Kuczenski, 2006), and for D-amphetamine in rats (Lewander, 1971), [non-human primates (NHPs)] (Jedema et al., 2014) and humans (Angrist et al., 1987; Brauer et al., 1996; Dolder et al., 2017). In vivo measurement of dopamine by microdialysis was used in rats and NHPs to evaluate these time-dependent effects. In humans, various subjective measures of mood related to the drug's euphoric effects were observed to decline more rapidly than plasma concentrations following D-amphetamine oral doses ranging from 20 to 40 mg (Angrist et al., 1987; Brauer et al., 1996; Dolder et al., 2017). Whereas peak plasma concentrations and subjective effects occurred between 2 and 4 hours following administration, drug effect measures had largely returned to baseline values by 8 hours despite continued exposure to the drug (mean half-life = 8 hours following a 40 mg dose (Dolder et al., 2017)).
^Bisagno V, Cadet JL (2021). "Methamphetamine and MDMA Neurotoxicity: Biochemical and Molecular Mechanisms". Handbook of Neurotoxicity. Cham: Springer International Publishing. p. 1–24. doi:10.1007/978-3-030-71519-9_80-1. ISBN978-3-030-71519-9. Injections of large doses of MDMA cause massive release of 5-HT from presynaptic vesicles, followed by a rapid decrease in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels and decreased TPH activity (Górska et al., 2018; Lyles & Cadet, 2003). There do not appear to be losses of 5-HT uptake sites at early time points after MDMA administration (Lyles & Cadet, 2003). [...] MDMA also perturbs the function of SERT (Green et al., 2003), a marker of the integrity of serotonin neurons (Blakely et al., 1994). By virtue of its moderating synaptic 5-HT levels, SERT is crucial for the process of 5-HT neurotransmission (Green et al., 2003). MDMA downregulates SERT function without altering SERT mRNA or protein expression, and this rapid downregulation is sustained for at least 90 min and is dose-dependent (Kivell et al., 2010).
^Kivell B, Day D, Bosch P, Schenk S, Miller J (June 2010). "MDMA causes a redistribution of serotonin transporter from the cell surface to the intracellular compartment by a mechanism independent of phospho-p38-mitogen activated protein kinase activation". Neuroscience. 168 (1): 82–95. doi:10.1016/j.neuroscience.2010.03.018. PMID20298763.
^Kittler K, Lau T, Schloss P (March 2010). "Antagonists and substrates differentially regulate serotonin transporter cell surface expression in serotonergic neurons". Eur J Pharmacol. 629 (1–3): 63–67. doi:10.1016/j.ejphar.2009.12.010. PMID20006597. Our results show that exposure to the SSRIs citalopram, fluoxetine, sertraline and paroxetine all induced SERT internalization, but with different efficacies. The substrates 5-HT and MDMA also induced SERT internalization, while cocaine elevated SERT cell surface expression.
^Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID11071707. S2CID15573624.
^Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology. 559 (2–3): 132–137. doi:10.1016/j.ejphar.2006.11.075. PMID17223101.
^Mas M, Farré M, de la Torre R, Roset PN, Ortuño J, Segura J, et al. (July 1999). "Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans". The Journal of Pharmacology and Experimental Therapeutics. 290 (1): 136–45. doi:10.1016/S0022-3565(24)34877-3. PMID10381769.
^Shima N, Kamata H, Katagi M, Tsuchihashi H, Sakuma T, Nemoto N (September 2007). "Direct determination of glucuronide and sulfate of 4-hydroxy-3-methoxymethamphetamine, the main metabolite of MDMA, in human urine". Journal of Chromatography B. 857 (1): 123–9. doi:10.1016/j.jchromb.2007.07.003. PMID17643356.
^Mueller M, Peters FT, Maurer HH, McCann UD, Ricaurte GA (October 2008). "Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its major metabolites in squirrel monkeys at plasma concentrations of MDMA that develop after typical psychoactive doses". The Journal of Pharmacology and Experimental Therapeutics. 327 (1): 38–44. doi:10.1124/jpet.108.141366. PMID18591215. S2CID38043715.
^Milhazes N, Martins P, Uriarte E, Garrido J, Calheiros R, Marques MP, et al. (July 2007). "Electrochemical and spectroscopic characterisation of amphetamine-like drugs: application to the screening of 3,4-methylenedioxymethamphetamine (MDMA) and its synthetic precursors". Analytica Chimica Acta. 596 (2): 231–41. Bibcode:2007AcAC..596..231M. doi:10.1016/j.aca.2007.06.027. hdl:10316/45124. PMID17631101.
^Baxter EW, Reitz AB (April 2004). "Reductive aminations of carbonyl compounds with borohydride and borane reducing agents". Organic Reactions. 59. Hoboken, New Jersey, United States: 59. doi:10.1002/0471264180.or059.01. ISBN0471264180.
^Gimeno P, Besacier F, Bottex M, Dujourdy L, Chaudron-Thozet H (December 2005). "A study of impurities in intermediates and 3,4-methylenedioxymethamphetamine (MDMA) samples produced via reductive amination routes". Forensic Science International. 155 (2–3): 141–57. doi:10.1016/j.forsciint.2004.11.013. PMID16226151.
^Palhol F, Boyer S, Naulet N, Chabrillat M (September 2002). "Impurity profiling of seized MDMA tablets by capillary gas chromatography". Analytical and Bioanalytical Chemistry. 374 (2): 274–81. doi:10.1007/s00216-002-1477-6. PMID12324849. S2CID42666306.
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^Baselt RC (2011). Disposition of toxic drugs and chemicals in man (9th ed.). Seal Beach, Ca.: Biomedical Publications. pp. 1078–1080. ISBN978-0-9626523-8-7.
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Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as the List of trace amines, TAAR, and TAAR1 pages. See also:Receptor/signaling modulators
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