Clicky

MDMA: An In-Depth Exploration of a Synthetic Psychoactive Drug

MDMA is the more common name for 3,4-Methylenedioxymethamphetamine. Today people mostly use this psychoactive drug, also known as ecstasy, molly, or E, recreationally to experience increased energy, altered sensations, and greater pleasure and empathy. Onset of effects from MDMA ingested by mouth start 30 to 45 minutes after consuming the drug and last 3 to 6 hours.

Originally developed by Merck in 1912 for unrelated reasons, MDMA was first used was used therapeutically in the 1970s. By the 1980s MDMA had become popular as a street drug associated with raves, dance parties, and electronic dance music (EDM). Users sometimes mix amphetamine, ephedrine, methamphetamine, and other substances to enhance the MDMA’s effects.

In 2016 about 0.3 percent of the population of the world between the ages of 15 and 64—21 million people—used ecstasy. This was lower than for opioids or cannabis but broadly similar to the percentage of people who use amphetamines or cocaine. As of 2017, around 7 percent of the United States adult and adolescent population had used MDMA at some point, with 0.9 percent using it within the past year.

MDMA has hallucinogenic and stimulant effects and belongs to the substituted amphetamine classes of drugs. It acts mainly by increasing neurotransmitter activity to enhance levels of dopamine, serotonin, and noradrenaline in regions of the brain.

Short-term negative side effects of MDMA include blurred vision, rapid heartbeat, sweating, teeth grinding, and extended use of MDMA can also lead to addiction, difficulty sleeping, difficulty with memory, and paranoia. Deaths caused by dehydration and increased body temperature have been reported due to MDMA use. Following an MDMA experience, users often feel tired and/or depressed.

Common or street names for MDMA include: Adam, Beans, Biscuit, Brownies, Clarity, Cowies, Crystal, Disco Biscuit, Dizzle, Dolphins, E, Ecstasy, Essence, Eve, Go, Hug Drug, Love Drug, Lover’s Speed, MD, Mandy, Molly, Peace, Pills, Pink Superman, Rolexs, STP, Superman, X, XTC. Street names also often reflect the imprinted logo, such as Love Doves, Mitsubishis, and others.

What is MDMA?

MDMA, more frequently called Molly or ecstasy, is the psychoactive, synthetic drug 3-4 methylenedioxymethamphetamine. Chemically similar in structure to both the hallucinogen mescaline and the stimulant methamphetamine, MDMA acts both as a psychedelic and a stimulant, producing enhanced enjoyment from tactile experiences and distortions in perception and time, as well as an energizing effect.

MDMA was first produced in 1912, and since the 1980s it has been used as a street drug. Thanks to its popularity at nightclubs, late-night EDM/dance parties called raves, and rock concerts, MDMA use increased in the 1990s among young adults and college students.

MDMA distribution and use expanded with the club and rave scene across urban and suburban regions across the US. Today, a broader group of people still use MDMA, frequently in combination with other drugs.

How Does MDMA Affect the Brain?

MDMA’s main interactions in the brain are with neurons that communicate with each other using the chemicals serotonin, norepinephrine, and dopamine. Serotonin is probably the source of sensations that MDMA is well-known for, such as elevated mood, emotional closeness with others, and empathy. These neurotransmitter systems help to regulate critical functions in the body and mind, including:

  • aggression
  • appetite
  • energy/activity and the reward system
  • heart rate, blood pressure
  • mood
  • sensitivity to pain
  • sexual activity
  • sleep

Users typically report feeling the onset of effects within 60 minutes of ingesting MDMA orally, effect within 75 to 120 minutes, and a plateau of effects that persist for approximately 3.5 hours. MDMA’s reported positive short-term psychoactive effects include:

  • altered sense of time/timewarp
  • dilated pupils
  • enhanced perception, sensation, and/or sexuality
  • improved communication
  • increased feelings of empathy or closeness with oneself and/or others and other entactogenic effects
  • euphoria
  • increased emotionality
  • increased sociability and self-confidence
  • mild hallucinations
  • reduced anxiety, relaxation
  • a sense of inner peace

Like with any psychedelic, the setting, dose, and user all greatly influence the quality of the MDMA experience. However, MDMA is somewhat different from other psychedelics in that it displays less variability in the altered state it induces in users compared to other psychedelics.

Due to its empathy-producing effects, MDMA is often described as an “empathogenic” drug. In fact, several research studies indicate that MDMA use increases empathy with others, and medium and high doses of MDMA increase arousal and hedonic continuum.

Forms of MDMA

MDMA design image

MDMA, most often called ecstasy and shortened to X, E, or XTC, is typically found in tablet form—which often includes diluents or adulterants. The phrases molly in the US and mandy in the UK generally refer to the crystalline powder form of MDMA that is ostensibly free of adulterants. MDMA can also be sold in hydrochloride salt form, either in gelcaps or as loose crystals. Standard MDMA tablets are often shaped to resemble pop culture characters, sometimes generally referred to as “fun tabs,” perhaps to keep their identity secret.

Typically, MDMA is consumed by mouth. It is occasionally snorted.

The purity of MDMA or its derivatives vary widely, in part due to the problem of sassafras oil (of which compounds are used to synthesize MDMA). being in short supply globally. Alternative and improved modern synthesis methods have mostly solved this particular issue, but adulterants in molly remain a challenge. Some of these products contain the compounds commonly known as bath salts, such as ethylone, mephedrone, methylone, MDPV, or others in place of MDMA.

Generally speaking, due to binding and bulking agents such as lactose, ecstasy tablets (of which MDMA is among the main psychoactive agents) generally have lower purity (30-40% or less) than powdered MDMA which may be close to pure.

Though MDMA is thought to be the key psychoactive ingredient within ecstasy tablets, such tablets sometimes contain amphetamine derivatives such as 3,4-methylenedioxyethylamphetamine (MDEA) or 3,4-methylenedioxyamphetamine (MDA), opiates, caffeine, or painkillers. In fact, sometimes there is little or no MDMA in ecstasy tablets.

The proportion of ecstasy tablets seized by authorities country by country with MDMA-like impurities varies each year. However, overall, purity has increased since the 1990s, and the average content of MDMA per tablet is 70 to 120 mg.

Recreational Use of MDMA

Within rave, festival, club, and party culture, MDMA is frequently the recreational drug of choice, for several reasons. The rave setting itself provides high levels of sensory input from lighting and music that act in a synergistic way with the amphetamine and psychedelic qualities of MDMA. The compounds stimulating effects serve as party fuel, and its inhibition-reducing effects produce a welcome feeling of connection and mass communion.

Users generally partake in MDMA less often than other stimulants. They may also enjoy “candy-flipping,” using MDMA with other psychoactive drugs such as psilocybin mushrooms, LSD, and ketamine.

Other Use of MDMA

Some religious practitioners use small doses of MDMA to enhance meditation, spiritual exploration, or prayer as an entheogen. New Age believers have used MDMA to supplement their practices.

MDMA Assisted Psychotherapy and Other Therapeutic Uses of MDMA

Most clinical research on MDMA in patients has focused on treating posttraumatic stress disorder (PTSD) with MDMA-assisted psychotherapy. However, other potential therapeutic applications for MDMA therapy include MDMA-assisted psychotherapy to treat alcohol use disorder and treating anxiety associated with autism.

MDMA therapy for PTSD is in the Phase 3 stage of drug development, with researchers working to prove clinical efficacy criteria, and a target for Food and Drug Administration (FDA) licensing sometime in 2023. Accomplishment of these goals will streamline the marketing approval pathway for the clinical use of MDMA in patients with PTSD.

The Early Research on and Therapeutic Use of MDMA

Merck chemist Anton Köllisch was the first to synthesize MDMA in 1912. Merck’s contemporary interest in MDMA was in its potential to stop abnormal bleeding and compete against an existing compound, hydrastinine, which was already patented by Bayer. In Merck laboratory reports MDMA, called N-Methyl-a-Methylhomopiperonylamin and other names, was created in the synthesis of another compound, and Merck had no interest in MDMA itself, but patented the synthesis process and certain of MDMA’s chemical properties anyway.

Over the years Merck researchers worked with the compound sporadically, learning bits and pieces of information about it. Eventually, other scientists began to investigate MDMA from outside the company.

In 1953 and 1954, a study of the behavioral effects and toxicity of mescaline in animals at the University of Michigan in Ann Arbor commissioned by the United States Army injected subjects not only with mescaline, but also with analogues, including MDMA. Although these investigations were classified, they were eventually published in 1973. And before then, in 1960, a paper by Polish researchers Biniecki and Krajewski became the first published scientific paper on MDMA, describing its synthesis.

After the ban on lysergic acid diethylamide (LSD) in the late 1960’s, some therapists began exploring other psychedelics as psychotherapy enhancement tools. In 1965, while researching other compounds at Dow Chemical Company, American psychopharmacologist and psychedelic chemist Alexander Shulgin reported synthesizing MDMA. However, he did not test the compound’s psychoactivity then.

Shulgin sent instructions for MDMA synthesis around 1970 by request to the founder of a chemical company in Los Angeles, who later passed them to a Midwestern client. Not long thereafter, MDMA was seen in Chicago.

Shulgin learned of MDMA’s psychoactive effects from students around 1975 and 1976. A graduate student who had consumed 100 mg of MDMA directed him to the University of Michigan study and reported that she had positive emotional experiences on the drug. Shulgin eventually synthesized and trialled MDMA himself in September and October 1976.

That year Shulgin first presented on MDMA at a conference in Bethesda, Maryland. In 1978, Shulgin and chemist David E. Nichols published the first study on the pharmacology and effects of MDMA in humans.

Shulgin was not a personal convert after his own experiences, but he felt MDMA might have therapeutic value, so he introduced therapist Leo Zeff to the compound in 1977. Zeff felt the effects of MDMA put users into a state of primordial innocence, named the drug Adam, and came out of semi-retirement to promote its therapeutic use. As MDMA was still legal, Zeff went on to safely and successfully treat many thousands of patients with the drug.

Early treating psychotherapists using MDMA, typically working in patients’ homes or their own, believed the compound increased communication and eliminated the usual fear response. Sessions minimized role of the therapist in favor of MDMA induced feelings of empathy leading the patient’s self-discovery. Anecdotally, MDMA was used to treat autism, depression, premenstrual syndrome, relationship problems, substance use disorders, and at accelerated rates.

MDMA is an entactogen rather than a classic psychedelic drug, which means it produces a more readily tolerated, gentler state compared to psychedelics such as LSD. It is also more clinically manageable in that it is shorter-acting, and because it allows users to access and process memories of emotional trauma by enhancing feelings of bonding and empathy.

In the early 1980s, psychotherapists using MDMA hoped to keep it within the research community. A mostly private network of therapeutic MDMA users consumed tens of thousands of doses in secret.

However, by the late 1970s, a small recreational market for MDMA had developed, and by the early 1980s MDMA was a regular fixture in nightclubs in urban centers.

the recreational market slowly expanded throughout the 1980s, as MDMA production was dominated by the “Boston Group,” a small cadre of manufacturers and distributors. Shortages were frequent as demand outpaced supply, and the Boston Group’s Southwest distributor, Michael Clegg, started the Texas Group. Clegg also coined the term “Ecstasy” in 1981.

As MDMA became rebranded as ecstasy, its recreational use spread—particularly on the rave scene. Recreational use also grew once some cocaine dealers experimented with MDMA and began to distribute it.

The DEA announced it would ban MDMA in 1984 in response to rising police seizures of the compound. Despite protest from the clinical MDMA research community, in May 1985 MDMA was placed in an emergency Schedule One category which later became permanent.

The scheduling of MDMA crushed most clinical research possibilities in the US. As a result, experimenters and psychotherapists formed the Multidisciplinary Association for Psychedelic Studies (MAPS), a US-based research organization which leads the world in clinical research on MDMA.

Before the ban, a series of uncontrolled case studies were conducted, and reports on them were published in the mid-1980s. These described clear therapeutic benefits to patients, both individually and in couples, from MDMA and counseling. However, until more recently, research mostly stalled.

Contemporary Clinical Research With MDMA

In 2010, scientists published the first controlled clinical study into MDMA-assisted psychotherapy. 20 study participants with treatment-resistant PTSD received either two or three sessions of MDMA in tandem with psychotherapy or a placebo with the same therapy. The results revealed that 83 percent of participants treated with MDMA no longer met the criteria for PTSD at two and 12-month follow-ups, compared to only 25 percent of patients in the placebo group. Remission was maintained for up to 6 years without any more MDMA, and there were no adverse neurocognitive effects and no serious, drug-related adverse events.

A smaller study from 2013 again, adjusted for effect size, also concluded that MDMA psychotherapy substantially improved outcomes in patients with treatment-resistant PTSD.

This prompted further teams in the USA, Canada, and Israel to begin conducting Phase 2 trials of MDMA for PTSD treatment. To date, all modern MDMA-assisted psychotherapy studies have been conducted with relatively small groups of participants. Therefore, larger trials are necessary to demonstrate the levels of safety and clinical efficacy required to license MDMA as a medicine, despite the consistently positive results from research to date. This is the phase of clinical MDMA research that is now taking place.

In August 2017, the FDA granted breakthrough therapy designation for MDMA—specifically, for MDMA-assisted psychotherapy to treat PTSD. This was in conjunction with the expansion of MAPS-sponsored MDMA therapy Phase 3 trials for PTSD, a collaborative effort between MAPS and the European Medicines Agency (EMA). American sites and locations in the EU and the UK are all working toward ultimately seeing MDMA approved for therapeutic use.

A 2021 study confirmed that MDMA-assisted therapy is highly efficacious for patients with severe PTSD compared to standard therapy with a placebo, and that treatment is well-tolerated and safe, even for those with comorbidities. The researchers found that MDMA-assisted therapy merits expedited clinical evaluation and represents a potential breakthrough treatment.

MDMA now appears to be on track for approval by 2023.

The Safety of Clinical MDMA

ecstasy tabs design

By the early to mid 2000s, a debate about the safety of MDMA was fueled by media coverage of the illicit use of the drug. However, in settings where clinical assessment of MDMA is monitored by medical professionals, patient safety is considered critical. The methods employed in such trials are demonstrative of these efforts, with results suggesting that when used for clinically-indicated purposes in monitored settings, MDMA may offer more therapeutic benefits than risks.

Experts carefully screen clinical MDMA subjects, give them only pure MDMA, monitor them throughout the process, and follow up with them closely for months afterwards. In contrast, recreational users of ecstasy frequently consume other drugs and substances with ecstasy, receive adulterated or impure drugs with only a fraction of MDMA in them, and pay insufficient attention to the psychological and physiological details of their experience.

Even so, as of 2017, around 750,000 people used recreational ecstasy each weekend in the UK, yet mortality and morbidity rates remain low. At least one study reveals only three deaths annually attributable solely to MDMA after removing other drug use as a confounding factor. Other research indicates that, once confounding factors are controlled for and MDMA is used in isolation, there is no evidence of neurotoxicity or lasting neurocognitive impairment.

In fact, ecstasy—not pure MDMA, but the street version—is a popular illicit drug, second only to cannabis in terms of widespread use. This lack of data on mortality and morbidity along with the research indicate that MDMA is relatively safe.

However, MDMA use during clinical MDMA therapy can produce transient neurocognitive effects, including slow processing speeds, deficits in spatial and verbal memory, and impairments to executive functioning. Once the acute effects of MDMA wear off, these other side effects also resolve.

Researchers have administered over 1,600 doses of MDMA in clinical settings in the modern era with reports of no deaths and only one self-limiting, drug-related, serious adverse event. At least one large analysis of subjects taking MDMA in a controlled showed mostly acute, subjective, positive effects and no serious adverse events.

MDMA addiction is very rare compared to other stimulants, especially amphetamine, methamphetamine, and cocaine. Researchers have seldom observed illicit use of ecstasy following therapeutic use of the drug.

Patients that receive MDMA in a clinical setting might experience increases to their heart rate, body temperature, and blood pressure; bruxism; impaired balance; jaw tightness; poor concentration; and reduced appetite. However, more serious negative side effects have not been observed in a therapeutic setting.

Some recreational ecstasy users describe the “mid-week blues,” or feelings of fatigue, irritability, and low mood following use of the drug. Reports of these symptoms are seldom seen in clinical trials, although some low mood is seen after administration of MDMA in controlled settings in healthy subjects.

Mechanism of Action of Clinical MDMA

The effects produced by MDMA are created by multiple neurotransmitters, receptors, and intermediary processes. Principally, MDMA triggers the release of serotonin (5-HT) and this activation of the 5-HT system is responsible for the majority of the compound’s typical effects. MDMA also triggers the release of noradrenaline, and of dopamine to a lesser extent.

Activity at 5-HT1A and 5-HT1B receptors reduces the amygdala fear response, mitigates feelings of anxiety and depression, and increases self-confidence levels. Greater feelings of compassion, closeness, and empathy for others and oneself also help to create a positive mood. Meanwhile, increased levels of noradrenaline and dopamine in turn raise levels of awareness and arousal, promoting fear extinction and more generally motivating engagement in therapy.

MDMA may also help reduce the stress response in the context of social anxiety by facilitating the release of oxytocin. This hormone associated with bonding in early infancy may dampen fear-related amygdala activity and increase levels of closeness and empathy.

Therapists using MDMA with patients and healthy volunteers have observed that even the painful emotional memories that generally produce overwhelming negative effects in patients that they typically avoid thinking about can be safely recalled with this kind of assistance. This may be because MDMA creates enhanced self-compassion and empathy, increased prosocial feelings, and improved tolerance for memories that are unpleasant—all of which can help build and nurture a strong therapeutic alliance.

How Researchers and Clinicians Conduct MDMA-Assisted Psychotherapy

Much of the practice and methodology of MDMA-assisted psychotherapy was actually created in the 1950s for use with LSD. As with other psychedelics, set and setting are critical to a positive experience. “Set” refers ensuring the user takes MDMA with the right mindset, and “setting” refers to the need to create a safe, supportive environment for using the compound.

Developing ideal setting and conditions for a clinical MDMA-assisted session demands extensive preparation. The safety and security of the controlled setting is important to the clinical experience, according to 64 percent of patients in one comprehensive study.

Typically, a pair of co-therapists, male and female, deliver therapeutic sessions with MDMA. In some cases, some same sex co-therapy teams are used. The team supports the patient, encouraging them to follow the experience wherever it leads; in this sense, drug-assisted sessions are non-directive, with the notion that the patient’s innate healing ability, awaked by the medicine, will do the work. Meanwhile, the therapists communicate trust in the patient’s capabilities, create a sense of safety, and take care of basic physical needs and comfort. They also make physiological observations, taking the patient’s temperature and measuring their blood pressure.

Both non-drug therapeutic sessions and MDMA-assisted sessions make up a total course of MDMA psychotherapy, and each piece of the plan from preparation to subsequent post MDMA integration is essential to ensuring the optimal beneficial impact.

Future Directions: Broadening MDMA Beyond PTSD

Although most of the modern research into MDMA concerns PTSD, researchers are beginning to explore the potential role for MDMA therapy in the treatment of other disorders. Some degree of pre-morbid trauma, commonly emotional abuse and neglect, or sometimes secondary to physical or sexual or child abuse, is common among people with other chronic mental disorders—and this is so surprise, given that these traumas are known to be potentially damaging to human cognitive and emotional development.

Cases of adult alcohol use disorder are a new focus area for MDMA research, because child maltreatment is frequently prevalent in cases of addiction in adults. Although MDMA-assisted psychotherapy is not yet proven treatment for substance use disorders, it may be a tool for overcoming a history of childhood trauma safely, leading to better results. MDMA might also increase feelings of compassion and empathy, causing improved self-awareness and insight into the destructive actions that alcoholism can cause, reducing denial.

Other contemporary areas of research with MDMA therapy include study of MDMA therapy as treatment for autism, specifically the social anxiety associated with it, and the potential for MDMA-assisted psychotherapy as an alternative to electro-convulsive therapy and in treating mood disorders more generally.

Like any medication or therapeutic intervention, MDMA is beneficial, but not 100 percent safe. However, it is critical to judge MDMA-assisted psychotherapy not solely on its association with recreational ecstasy, but but based on evidence and the guidelines of clinical governance. Comparing recreational ecstasy and clinical MDMA is like comparing apples and oranges due to differences in administration, drug purity, and the monitoring and screening patients.

Adverse Effects of MDMA

Like any medication or psychoactive substance, MDMA has possible adverse side effects, both short-term and long-term.

Short-term effects

Most immediate negative side effects result from multiple or high doses, although some individuals might be susceptible to single dose toxicity. The short-term physical health risks that can arise from MDMA which most dangerous are dehydration and hyperthermia. MDMA users have developed cases of life-threatening hyponatremia or even fatal events after experiencing dehydration and consuming excessive amounts of water. This causes the blood to have excessively low sodium concentrations if the user does not replenish their electrolytes.

Other acute adverse side effects of MDMA use may include:

  • bruxism (grinding, jaw clenching, clenching of the teeth)
  • dehydration
  • diarrhea
  • erectile dysfunction
  • hyperthermia
  • increased blood pressure and heart rate
  • increased psychomotor activity
  • increased sweating, perspiration
  • insomnia, increased wakefulness
  • loss of appetite
  • nausea and vomiting
  • auditory and visual hallucinations (rare)

Moderate MDMA use over time may produce other adverse effects. These may occur or remain for up to one week after stopping MDMA:

Physiological health effects:

  • insomnia
  • lethargy, fatigue, tiredness
  • loss of appetite
  • trismus (lockjaw)

Psychological health effects:

  • anhedonia (loss of pleasure)
  • anxiety or paranoia
  • depression
  • impulsiveness
  • irritability
  • memory impairment
  • restlessness

Long-term effects

Among MDMA users with high lifetime exposure, consistent evidence of functional and structural deficits exists. However, in MDMA users with only a moderate lifetime exposure (between 50 and 100 doses or tablets used), there is no evidence of such changes in the brain.

Even so, even moderate use of MDMA could be neurotoxic. Furthermore, it remains unclear whether typical MDMA users could develop neurotoxic brain lesions—typical use being 1 to 2 75 to 125 mg doses of MDMA or an analogue every 1 to 4 weeks.

Long-term MDMA exposure in humans produces marked neurodegeneration in the serotonergic axon terminals of the hippocampal, occipital, prefrontal, and striatal regions of the brain—neurotoxic damage that has been shown to persist for over two years. MDMA-induced neurotoxicity and MDMA-induced elevations in brain temperature also are positively correlated.

That said, most research on serotonergic neurotoxicity and MDMA in humans focuses on those who consume over seven times as much MDMA as the average—the heaviest users. It is therefore possible that in most casual users no serotonergic neurotoxicity is present.

Depletion of serotonin following use of MDMA can cause depression even after the drug has long cleared the user’s system. Depressive symptoms may persist for extended periods in some cases. In fact, depression is one of the principal motivating factors behind cessation of use.

At high doses, MDMA increases the blood-brain barrier’s permeability by inducing a neuroimmune response. This renders the brain more susceptible to pathogens and toxins in the environment. MDMA also has pro-inflammatory effects in the central nervous system and immunosuppressive effects in the peripheral nervous system.

Finally, due to activation of serotonin 5-HT2B receptors, in long-term or heavy users MDMA may increase the risk of cardiac valvulopathy.

MDMA Use During Pregnancy

MDMA is moderately teratogenic, meaning that in utero exposure is somewhat toxic to the fetus. In utero MDMA exposure is associated with impaired motor functioning and a neuro- and cardiotoxicity. Motor and other developmental delays may be limited to infancy or persist over the long-term. Heavier MDMA use increases the severity of such delays.

Reinforcement Disorders and MDMA: Withdrawal and Dependence

Some MDMA users experience withdrawal symptoms when they stop using the substance. Symptoms can include depression, fatigue, loss of appetite, and trouble concentrating. Consistent MDMA use can create tolerance to some of its effects, both desired and adverse.

Currently no MDMA addiction medications exist.

Harm assessment

A 2007 study from the UK ranked 20 recreational drugs in terms of harmfulness; it ranked MDMA 18th of the 20. Rankings were based on propensity for psychological and physical dependency, risk of acute physical harm, and negative societal and familial impacts—but not negative impact on cognitive health.

MDMA Overdose

The symptoms of MDMA overdose vary widely because such an overdose typically involves multiple organ systems.

Minor or moderate MDMA overdose affects the central nervous system, potentially causing:

  • agitation
  • confusion
  • hyperreflexia
  • paranoia
  • stimulant psychosis

However, severe MDMA overdose involves most of the body, including the cardiovascular, respiratory, musculoskeletal, urinary, central nervous systems. Symptoms may include:

  • acute kidney injury
  • acute respiratory distress syndrome
  • cerebral edema
  • cognitive and memory impairment up to anterograde or retrograde amnesia
  • coma
  • convulsions
  • disseminated intravascular coagulation
  • hallucinations
  • hepatitis
  • hyperpyrexia (a extremely elevated body temperature that is life-threatening, greater than or equal to 104.0 or 106.7 °F (40.0 or 41.5 °C)
  • hyponatremia
  • hypotensive bleeding
  • intracranial hemorrhage
  • loss of consciousness
  • muscle rigidity
  • rhabdomyolysis (rapid muscle breakdown)
  • serotonin syndrome
  • severe hypertension or hypotension

It is important to remember that cases of fatal MDMA overdoses are low compared to rates of use. In most of these cases, MDMA was not the only substance used.

Acute MDMA toxicity is caused by primarily by serotonin syndrome and its sympathomimetic effects. Carvedilol can be used to manage those side effects.

To increase volume MDMA is frequently cut with caffeine, which can exacerbate its overdose toxicity. Users should avoid caffeine and report caffeine use to medical personnel.

A professor of emergency medicine published a plan for clinical management of acute MDMA toxicity for healthcare professionals. This plan focuses on treating serotonin syndrome, hyponatraemia, hyperthermia, and multiple organ failure.

Is MDMA Popular?

MDMA use is much lower than use of other substances such as alcohol or cannabis. Considered an illicit drug by the National Institute on Drug Abuse (NIDA), MDMA is one of the substances that NIDA tracks as it monitors illegal drug use trends in American adolescents and adults. Here are a few MDMA use statistics from NIDA and other agencies and organizations:

In 2019, 2.2 of every 100 12th graders reported using MDMA during the past year, with 1.7 of every 100 10th graders and 1.1 of every 100 8th graders responding in kind (2019 Monitoring the Future report)

In 2018, 3.1 percent of people age 18 to 25 years had used MDMA, making this the highest use group, down from 3.5 percent in 2017; 0.9 percent of respondents 12 years or older reported past-year MDMA use (from the 2018 National Survey on Drug Use and Health)

In 2018, 4.1 percent of adults 15 to 64 years old in the European Union had used MDMA at least once ever, with 0.8 percent using it in the past year. Pst year use of MDMA was highest among young adults, at 1.8 percent.

In 2015, an estimated 37 percent of Europeans ages 14 to 35 who regularly went to clubs had used MDMA in the past year. (2015 European Drug Report)

In 2014, 3.5 percent of Americans 18 to 25 years old had used MDMA.

From 1999 to 2008, adolescent girls were more likely to use MDMA than adolescent boys in the US.

Business of MDMA

According to the 2014 World Drug Report from the United Nations Office on Drugs and Crime, retail  per pill prices for ecstasy in the US range from US$1 to $70. This amounts to $15,000 to $32,000 per kilogram.

Most of the MDMA used in the US is produced in British Columbia, Canada which is why the border between Western Canada and the US is most frequently where illegal MDMA and ecstasy are seized by authorities. Compared to cocaine, methamphetamine, and heroin, the market for MDMA in the United States is relatively small.

Some ecstasy manufacturers brand their products, and many ecstasy tablets feature logos. Some logos belong to unrelated businesses products or popular shows or movies.

Is MDMA Addictive?

Research on whether MDMA is addictive is inconclusive, but some users do experience symptoms of addiction. Almost 60 percent of ecstasy users report some withdrawal symptoms, including depressed feelings, fatigue, appetite loss, and trouble concentrating.

After one week of moderate use of MDMA, physical and psychological withdrawal effects may include:

  • aggression
  • anxiety
  • decreased appetite
  • depression
  • impulsiveness
  • irritability
  • loss of attention
  • loss of interest in sex
  • memory deficits
  • muscle cramps
  • nausea
  • sleep disturbance

Interactions With MDMA

Drugs that are chemically similar to MDMA or ecstasy are sometimes sold as ecstasy. For example, the parent drug of MDMA, MDA (methylenedioxyamphetamine,) and the occasionally fatal PMA (paramethoxyamphetamine) can pose the user additional health risks and be toxic to the brain.

Additionally, because the sale of MDMA is illegal, it is prone to being “cut” with other substances—many of which are also illicit, toxic, or potentially even deadly. Some other substances alongside MDMA that are often found in street ecstasy include:

  • bath salts (synthetic cathinones)
  • caffeine
  • cocaine
  • dextromethorphan (a cough suppressant bought over the counter that has effects similar to PCP at high doses)
  • ephedrine (a stimulant)
  • ketamine (a veterinary anesthetic that also has effects similar to PCP)
  • methamphetamine

MDMA combined with one or more of these drugs has the potential to be inherently dangerous. This risk is compounded by voluntary multidrug combinations tried by users, who frequently mix MDMA with alcohol, cannabis, or opioids, opening the door to further risk of overdose.

However, even some prescription drugs have the potential to interact badly with MDMA, particularly serotonergic drugs. Combination of high doses of MDMA and other serotonergic drugs can cause serotonin syndrome, a life-threatening condition.

MDMA also interacts dangerously with drugs that inhibit CYP450 enzymes, particularly CYP2D6 inhibitors. An example is ritonavir (Norvir), which can together with MDMA cause life-threatening reactions and death.

MDMA in combination with certain monoamine oxidase inhibitors, such as moclobemide (Aurorix, Manerix), tranylcypromine (Parnate), or phenelzine (Nardil), can cause severe overdose or death.

Certain drugs inhibit the effects of MDMA. Serotonin reuptake inhibitors (SSRIs) block most of MDMA’s subjective effects; such SSRIs include duloxetine (Cymbalta), citalopram (Celexa), paroxetine (Paxil), and fluoxetine (Prozac). Norepinephrine reuptake inhibitors don’t appear to influence the mood-elevating effects of MDMA, but they do reduce feelings of stimulation and emotional excitation.

Psychopharmacology of MDMA

MDMA has both psychedelic and stimulant properties. Standard phenethylamines which lack ring substitution typically behave as stimulants, but molecules such as MDMA exhibit ring substitution which modifies their pharmacological properties.

As a result, ingesting MDMA causes increased sensory awareness, euphoria, and mild central stimulation. MDMA’s lower homologue, methylenedioxyamphetamine (MDA), is more hallucinogenic, with MDMA producing more entactogenic and empathogenic socializing effects.

After ingesting MDMA, users excrete most of the dose unchanged in their urine. The major metabolites of MDMA are O-demethylated compounds and 3,4-methylenedioxyamphetamine (MDA). Maximum plasma concentration of around 0.13 mg/L is reached with a dose of 75 mg within two hours. The half-life of the plasma is 6 to 7 hours.

MDMA causes neurotoxicity in animals as evidenced by a persistent reduction in serotonin levels in the brain and anatomical changes to axon structure. Although some cognitive impairment is associated with MDMA use, the significance of this research to human users remains unclear.

Monoamine transporters

MDMA increases serotonin levels in humans in the synaptic clefts of serotonergic neurons. It achieves this by inhibiting neurons from taking up serotonin and releasing the serotonin directly from the neurons. MDMA causes intoxication because as the released serotonin binds to various serotonin receptors, they are activated to excess.

Receptor binding

MDMA binds to the following receptors in humans as an agonist:

  • 5-HT1A-, 5-HT2A-, 5-HT2B- ja 5-HT2C-serotonin receptors
  • D1- ja D2-dopamine receptors
  • α1-, α2A-, β-adrenergic receptors
  • H1-histamine receptor
  • M1- ja M2-muscarinic receptors
  • TA1-receptor (TAAR1)

Pharmacokinetics of MDMA

About 30 minutes after ingestion, the MDMA concentration in the blood stream starts to rise, reaching its peak blood stream concentration in 1.5 to 3 hours. Over the next several hours, levels of MDMA and its metabolites decrease to half their peak concentration as the drug is slowly metabolized and excreted. MDMA’s duration of action is typically four to six hours. After that interval, the brain’s levels of serotonin are depleted, but they then return to normal within 48 hours.

Metabolites of MDMA include:

  • 3,4-methylenedioxyamphetamine (MDA)
  • 4-hydroxy-3-methoxyamphetamine (HMA)
  • 4-hydroxy-3-methoxymethamphetamine (HMMA)
  • 3,4-methylenedioxyphenylacetone (MDP2P)
  • 3,4-dihydroxyamphetamine (DHA) (also called alpha-methyldopamine (α-Me-DA))
  • 3,4-Methylenedioxy-N-hydroxyamphetamine (MDOH)

How these metabolites contribute to MDMA’s toxic and psychoactive effects are under research. The liver metabolizes about 80 percent of MDMA, with the remaining 20 percent is excreted in the urine unchanged.

Chemistry of MDMA

MDMA is in the substituted amphetamine and substituted methylenedioxyphenethylamine chemical classes. MDMA is a free base, a colorless oil that is insoluble in water. However, pure MDMA hydrochloride, the most common salt of MDMA, is a white or off-white crystal or powder that is water-soluble.

Synthesis of MDMA

Four basic precursors can be used to synthesize MDMA and related drugs: piperonal, isosafrole, 3,4-methylenedioxyphenyl-2-propanone (PMK), and safrole—all listed in Table I of the United Nations 1988 Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. Safrole is the principal starting material because one can synthesize the other three from it.

In the original 1914 Merck MDMA patent, safrole and hydrobromic acid reacted to form bromosafrole, and via methylamine converted to MDMA. Various illicit MDMA operations start with PMK as the precursor and use the aluminium foil method or other reductive aminations or the Leuckart route to produce racemic MDMA.

Detection of MDMA in body fluids

It is possible to quantitate MDMA and MDA in plasma, blood, or urine to confirm a diagnosis of poisoning, monitor for use, conduct a forensic investigation, or investigate a sudden death. Most commercial immunoassay screening tests for amphetamines significantly cross-react with MDMA or its major metabolites, but each of these substances can easily be distinguished and measured separately using chromatographic techniques.

Legality of MDMA

United States

MDMA first received official notice from the Drug Enforcement Administration (DEA) in 1982 when a spokesman stated the agency would ban the substance should they gather sufficient evidence for abuse. In 1984, a San Francisco Chronicle article reported on “Adam,” but misidentified it as methyloxymethylenedioxyamphetamine (MMDA). Also that year, the World Health Organization (WHO) identified MDMA as the single example among twenty phenethylamines which was seized a notable number of times.

The DEA proposed scheduling MDMA after a year of data collection in 1984 with a request for comments and objections. To the surprise of the DEA, a large number of psychotherapists, psychiatrists, and researchers requested a hearing as they objected to the proposed scheduling.

In a 1985 Newsweek article, a DEA pharmacologist admitted that previous to that time, the agency had been unaware that MDMA was used clinically among psychiatrists. Four hearings were held in 1985, and both the proposed criminalization and the pushback from proponents of MDMA were sensationalized.

This had the effect, ironically, of publicizing recreational MDMA. In the months before MDMA was made illegal, the Texas Group increased production of ecstasy tablets from 30,000 a month up to 8,000 daily. 500,000 Texas Group tablets were distributed monthly in Dallas alone. In fact, in an eighteen month span, the Texas Group outproduced all other distribution networks in the drug’s history.

Unsurprisingly, MDMA use was widespread in Texas, California, Florida, New York, and twenty-eight states in the northeastern US and Canada by May 1985. The DEA announced an emergency Schedule I classification of MDMA that month, citing escalating street use, increased distribution in Texas, and new evidence of MDA neurotoxicity to support the emergency measure.

Because various expert witnesses testified that there was an accepted medical usage for MDMA, the presiding administrative law judge recommended that MDMA be classified as a Schedule III substance. However, this judgment was overruled by DEA administrator John C. Lawn and MDMA was classified as Schedule I.

In 2017 the FDA granted breakthrough therapy designation for its use with psychotherapy for PTSD. Since that time, research has progressed steadily, and today we see the beginning of the end of Schedule I for MDMA.

International

The DEA also pushed for international scheduling during the domestic scheduling debates in the US. In 1985 the Expert Committee on Drug Dependence of the WHO recommended Schedule I placement for MDMA vis-a-vis the 1971 United Nations Convention on Psychotropic Substances. The recommendation was based on reports of illicit trafficking in Canada, a lack of a well-defined therapeutic use, MDMA’s pharmacological similarity to previously scheduled drugs, and drug seizures in the United States.

The committee was interested in reports of MDMA’s psychotherapeutic uses, but felt the existing research lacked appropriate methodological design. As a result, MDMA was added to Schedule I of the convention by the Commission on Narcotic Drugs on 11 February 1986.

For most people and places in the world, MDMA is legally controlled under various international agreements including the UN Convention on Psychotropic Substances, although there are exceptions for limited medical use and research. The unlicensed sale, use, or manufacture of MDMA remain criminal offenses in most cases.

Final Thoughts on MDMA

As promising results suggesting the applicability of MDMA for PTSD treatment accrue in conjunction with the changing legal tide, the current research climate is primed for continued exploration of MDMA’s therapeutic utility. As barriers of stigma fall to reveal previously neglected avenues of treatment on equal footing for scientific evaluation and assessment, a rippling of efforts may extend to the clinical evaluation of other psychedelics that could possibly be of merit to treating a gamut of psychological afflictions and medical conditions.

Author

  • Ed Markey

    Ed Markey is a former special education teacher turned psychedelics enthusiast. His goal is to help shine a light on the emerging potential of psychedelics to help improve people's lives--focusing especially on writing in-depth pieces, research based, to help educate those interested in how psilocybin, MDMA, ketamine, and more can potentially help improve mental health (when taken in conjunction with medical supervision, in states where it is legal to do so).