3,4-methylenedioxy-methamphetamine (MDMA), also commonly known as Eecstasy or Molly, was first synthesised in 1912 as a research chemical although only became popular after Alexandar Shulgin ‘re-discovered’ MDMA in the mid 1970’s. The stimulant and euphoric effects of MDMA lent itself to becoming hugely popular in the late 1980s rave scene and was formally outlawed in the UK by 1977. During the 1990s, pills purportedly containing MDMA, became much less reliable, often containing a combination of other stimulants.

MDMA may best be categorized as an empathogen or entactogen, producing experiences of emotional communication and connectedness that ‘touch within’. The empathogenic and activity may be correlated with fear-inhibiting effects of MDMA, which have spurred efforts to study potential therapeutic applications, with trauma and stressor related conditions such as PTSD having accumulated the most positive data.

In non-pill or tablet form, MDMA usually appears as white/grey crystals or powder. The powder can be encapsulated or is sometimes, ingested by more crude methods, such as wrapping the powder in papers and swallowed as “bombs” or snorting it nasally.

Effects

Typical positive effects include euphoria, increased energy, increased interest in sexual activity, feelings of intimacy, sense of unity with others and the world, overall sense of well-being, feeling calm and relaxed, sense of peace and increased appreciation of music. They can also include mild hallucinations, the desire to dance, spontaneous body sensations, increased experience of time, tactile enhancement (https://pubmed.ncbi.nlm.nih.gov/16771886/)
Typical negative effects include drug mouth, increased sweating, nausea, anxiety, erectile dysfunction, tight jaw or tooth grinding, appetite suppression, and inability to fall asleep. Other negative effects can include agitation, panic, paranoia, confusion, and palpitations or pounding heart beats.
While serious adverse effects are rare, seizures, arrythmias, stroke or heart attack, liver toxicity, and death have occurred with use of MDMA.
(Psychonaut Wiki) (https://psychonautwiki.org/wiki/MDMA)

Dosage

MDMA has been safely administered in clinical studies as both a one-time administration as well as an initial dose and follow-up ‘booster’ dose equivalent to 50% of the initial dose with the booster occurring 90-150 minutes after the initial dose. For example, 100mg as an initial dose followed by 50mg about two hours later. Initial doses of 75-125mg followed by boosters of 37.5-62.5mg appear to safely produce full and characteristic effects of MDMA for the average person. Use of large initial doses >150mg, exceeding a total of 200mg per session, or using multiple boosters may increase risks of adverse effects and appear generally unnecessary for beneficial effects.

Crystal form of MDMA(4)

Initial Doses:

30mg: Threshold
40-75mg: Light
75-100mg: Common initial dose for relatively sensitive persons
100-150mg: Common initial dose for less sensitive persons
150-200mg: Common initial dose in recreational settings; larger initial doses can produce very strong effects and have not been demonstrated to be safe in clinical studies
200mg+: Heavy, likely carries unfavorable balance of benefits and risks; higher potential for toxicity associated with overdose

Booster Doses:

A booster dose can be considered after at least 90 minutes. It is likely safer to limit booster doses to ~50% of initial doses and to avoid exceeding 200mg of MDMA in total per session.

Weighing and testing doses of MDMA is strongly recommended. If weighing scales are unavailable, harm-reduction information by The Loop guides users to “crush, dab, wait.” Guidance for this method can be found here.

When in pill form, data for different pills including MDMA content can be found here. Pills can be unexpectedly strong so taking a quarter of the pill to begin with and waiting for the effects to kick-in is recommended.(Roll Safe)

Duration

Onset: 20-70 minutes however MDMA can sometimes take longer time (up to 3 hours) to have a come-up which can lead to users redosing before their first dose has taken effect. Heavy meals, concomitant use of sedatives (e.g. alcohol), or use of gastric emptying delaying medications (e.g. semaglutide) may be factors that delay onset of effects
Duration: 3-6 hours
After effects: Up to 12 hours

Dangers

Drug Interactions and what not to mix with:

Amphetamines, Cathinones, Cocaine: Use of MDMA with other strong psychostimulants can increase risks fo experiencing stimulant toxicity or serotonin toxicity. MDMA is an amphetamine itself and use in combination with other psychostimulatns can result in larger increases in body temperature, blood pressure and heart and rate, as well as increased risks of serious adverse events such as stroke, heart-attack, seizures, arrythmias, and death. Taking MDMA with amphetamines may also increase the risk of neurotoxic effects such as problems with cognition or emotional dysregulation. (6)
Caffeine: Use of large doses of caffeine (>200mg) in close proximity to ingestion of MDMA (within a few hours) may increase some of the toxic effects of MDMA.
Alcohol: MDMA is often taken in a recreational setting and combined with alcohol. Whereas alcohol is a depressant, meaning it has inhibitory effects on the nervous system, MDMA is a stimulant, meaning it has excitatory effects on the nervous system. Therefore, alcohol may limit some of the subjective effects of MDMA, which can encourage users to take more, increasing the risk of overdose, neurotoxic effects, or liver toxicity.
Lithium – Increased risks of seizures have been reported when using MDMA in combination with lithium, use in combination is contraindicated
Monoamine Oxidase Inhibitors – Increase risks of serotonin toxicity or serotonin syndrome in combination with MDMA. Several deaths and serious toxicities have occurred with the combination and is an absolute contraindication
Bupropion – Increases concentration of MDMA and prolongs duration of experience. May increase risks of seizures in combination
Strong CYP3A4 and CYP2D6 inhibitors (e.g. ritonavir/cobicistat) – Increase risks of serotonin toxicity in combination with MDMA. Fatalities reported in literature
SSRI/SNRI antidepressants – Tend to diminish effects of MDMA when in combination and for a period after antidepressants have been discontinued. Use in combination is a relative contraindication due to lowered effects of MDMA.
Serotonin blocking psychiatric medications - Agents that block or otherwise occupy 5HT2 receptors such as atypical antipsychotics, trazodone, mirtazapine, and buspirone are likely to lead to diminished effects in combinations. Use in combination is a relative contraindicated due to lower benefits of MDMA use or a contraindicated underlying condition (e.g. if taking larger doses of antipsychotics for a bipolar or psychotic condition)

What are the potential dangers?

Short-term risks

Hyperthermia: Hyperthermia is a dangerously high increase in body temperature which can lead to seizures, organ failure, and death. MDMA under usual conditions increases the core body temperature slightly, however in hot conditions (nightclubs, conditions) and with increased physical exertion (dancing for prolonged periods) can have dangerous outcomes.
Hyponatremia (drinking too much water): MDMA is an anti-diuretic meaning it makes the body retain more water than usual. As people often feel thirsty on MDMA due to increase in body temperature, they may drink excessive amounts of water. In several cases, this has led to water toxicity and death. (8)
Contaminated pills: Ecstasy may be sold in pill forms that contain very little or no MDMA. Pills may have MDMA-like chemicals added which are toxic at low doses, such as NBOMes and PMA. Ecstasy can also contain non-MDMA-like substances such as fentanyl that may increase risks of death.
Serotonin syndrome: Consuming stimulants or serotonergic acting drugs alongside MDMA increases the risk of serotonin syndrome. Read more under general psychedelic risks and harm-reduction advice.
Neurotoxic Hangovers: Use of large doses in combination with other neurotoxic agents (e.g. alcohol, methamphetamine) combined with disrupted or lack of sleep can increase risks of ‘comedowns’ or neurotoxic hangovers. This article gives some tips and advice to help avoid a comedown.
Risky behaviours and impulsive decision-making: MDMA can acutely reduce fear, anxiety, and avoidance mechanisms. This results in an emotionally expansive state in which participants are ‘more open’ than usual. Chemical and neurohormonal factors of MDMA increase the ability to ‘bond’ with or ‘feel in love’ with others. Impaired judgement and false-senses of certainty may also mean people under the influence make decisions that wouldn’t otherwise if they were sober which can lead to negative outcomes.

Long-term risks

Addiction and Dependence: MDMA tends to carry lower risks of addiction, habituation, or dependence than other popular recreational stimulants (e.g. methamphetamine, cocaine, methylone) although has been associated with stimulant use disorders or addiction.
Neurotoxicity: Studies have implied that heavy and frequent MDMA can cause damage to serotonin neurons. Serotonin is an important chemical for the brain involved in many psychological functions, including mood and hunger. Destruction of serotonin-producing cells could therefore interfere with these functions.cognition. Damage to these neurons can result in problems with memory, learning, cognition as well as emotional dysregulation, low mood, increased anxiety, or sleep difficulties.
Valvular Heart Disease (VHD): Some reports and associated prolonged and frequent use of MDMA with VHD. Use on at least a weekly basis for several months is likely needed to increase risks of VHD with MDMA use.

How can the risks be minimised?

Fortunately, by testing the supply of MDMA for substitutes or adulterants, limiting total session doses, avoiding multiple boosters, taking weeks-months off between uses, avoiding drug or substance combinations that increase risks, and being conscientious of environmental factors, the vast majority of serious harms associated with MDMA use can be prevented.
If ingesting MDMA in nightlife environments, it is important to take regular breaks from dancing as well as go outside to cool down if the environment is hot. Avoid prolonged exposure to hot environments such as saunas or jacuzzis. Active cooling (e.g. use of ice packs on the forehead and under arm pits, cold showers, fans, A/C units) and seeking emergency support is reasonable if body temperature is >38.5C.
It is reasonable to aim to ingest typical amounts of water during an MDMA experience and to avoid both over or underhydration. Persons may mix some electrolytes such as salt into their water if they desire. Avoiding alcohol use can also limit risks of dehydration, neurotoxicity, or electrolyte imbalances.
Taking MDMA infrequently and at lower doses decreases likelihood of short and long-term risks, Use of MDMA up to 3 times with approximately a month break between uses has been studied and appears safe in clinical trials. Other sources focused on long-term use of MDMA for recreational purposes suggest use should be avoided more often than quarterly or every 3 months.

What are the potential benefits?

MDMA is most often appreciated in recreational settings for the energizing, euphoric, and pro-social effects of use. The increased feelings of empathy, closeness, and increased emotional vulnerability tend to enhance social interaction. These effects may also play a role in possible therapeutic applications of MDMA such as couples therapy.

In therapeutic settings MDMA is appreciated for its ability to lower emotional defense mechanisms, quell fear responses, expand emotional ranges, regress persons to earlier stages of neurodevelopment, and enhance memory recall of repressed memory. These effects, combined with specialized psychotherapy approaches, have been demonstrated to have significant benefit for refractory Post-Traumatic Stress Disorder (PTSD) as well as positive effects on social anxiety in autistic adults, depression and anxiety associated with life-threatening illnesses, as well as alcohol use disorders.

Weblinks

Rollsafe is an education website with lots of guidance, facts and safety information on MDMA from best supplements to take to avoid MDMA neurotoxicity, to which specific drugs to avoid in combination with MDMA: https://rollsafe.org/
Psychonaut wiki for MDMA: https://psychonautwiki.org/wiki/MDMA#Subjective_effects
A guide to taking MDMA for the first time written by author of the Global Drugs Survey: https://www.globaldrugsurvey.com/gds-2018/thinking-of-using-mdma-for-the-first-time-heres-our-checklist-to-help-you-stay-safe/
DanceSafe s a harm reduction and education website offering important safety information and testing kits that can identify if MDMA is present as well as if adulterants may be present (e.g. fentayl) https://dancesafe.org/product/mdma-testing-kit/
SpiritPharmacist is an educational and consulting website dedicated to the safe and effective use of psychedelics. It provides information on drug interactions, psychedelic pharmacology, as well as services for individuals to receive risk evaluations of existing medications or illnesses when considering psychedelics

Videos:

MDMA: Club to Clinic https://www.spiritpharmacist.com/blog/MDMAClubtoClinic
What happens to your brain on MDMA: https://www.youtube.com/watch?v=jEAr7ThsYew
Dr. Ben Sessa explaining the usefulness of MDMA in treating psychiatric disorders: https://www.youtube.com/watch?v=jEAr7ThsYew

References

Credit to Dr.’s Andrew Gibson and Ben Malcolm for contributing his medical expertise and background in harm-reduction to the process of making this content.