MDMA (3,4-methylenedioxy-N-methylamphetamine) is an empathogenic drug of the phenethylamine and amphetamine classes of drugs. MDMA has become widely known as “ecstasy” (shortened to “E”, “X”, or “XTC”), usually referring to its street pill form, although this term may also include the presence of possible adulterants. The term “mandy” or “molly” colloquially refers to MDMA in powder or crystalline form, usually implying a higher level of purity.MDMA can induce euphoria, a sense of intimacy with others, diminished anxiety, and mild psychedelia. Many studies, particularly in the fields of psychology and cognitive therapy, have suggested MDMA has therapeutic benefits and facilitates therapy sessions in certain individuals, a practice for which it had been formally used in the past. Clinical trials are now testing the therapeutic potential of MDMA for post-traumatic stress disorder, anxiety associated with terminal cancer and addiction.
MDMA is criminalized in most countries (though some civil society initiatives—such as the Global Commission on Drug Policy – consider educating the public about the drug more important than curtailing supply) and its possession, manufacture, or sale may result in criminal prosecution. Some limited exceptions exist for scientific and medical research. For 2008, the UN estimated between 10 and 25 million people globally used MDMA at least once in the past year. This was broadly similar to the number of cocaine, amphetamine, and opioid users, but far fewer than the global number of cannabis users. It is taken in a variety of contexts far removed from its roots in psychotherapeutic settings, and is commonly associated with dance parties (or “raves”) and electronic dance music.
Regulatory authorities in several locations around the world have approved scientific studies administering MDMA to humans to examine its therapeutic potential and its effects.
Medical Use
MDMA has been indicated as possibly useful in psychotherapy, facilitating self-examination with reduced fear. Indeed, some therapists, including Leo Zeff, Claudio Naranjo, George Greer, Joseph Downing, and Philip Wolfson, used MDMA in their practices until it was made illegal. George Greer synthesized MDMA in the lab of Alexander Shulgin and administered it to about 80 of his clients over the course of the remaining years preceding MDMA’s Schedule I placement in 1985. In a published summary of the effects, the authors reported patients felt improved in various mild psychiatric disorders and experienced other personal benefits, especially improved intimate communication with their significant others. In a subsequent publication on the treatment method, the authors reported one patient with severe pain from terminal cancer experienced lasting pain relief and improved quality of life.
Recently,[when?] two randomized, controlled trials of MDMA-assisted psychotherapy for post-traumatic stress disorder were published. Although small, these trials are consistent with earlier results. The patients treated with two or three sessions of MDMA-psychotherapy showed greater improvement than the ones treated by placebo-psychotherapy or placebo-inactive dose of MDMA. This improvement was generally maintained on a follow-up several years later.
Recreational Use
Small doses of MDMA are used as an entheogen to enhance prayer or meditation by some religious practitioners.
MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals and parties. In the rave environment, the sensorial effects from the music and setup such as lasers are often highly synergistic with the drug. The psychedelic amphetamine quality of MDMA lends it to variable reasons as to why it appeals to users in the “rave” setting. Some find ego-melting mass communion while others use it as party fuel.
MDMA is occasionally known for being taken in conjunction with psychedelic drugs, such as LSD or psilocybin mushrooms, or even common drugs such as cannabis. As this practice has become more prevalent, most of the more common combinations have been given nicknames, such as “candy flipping” for MDMA combined with LSD, “hippy flipping” for MDMA with psilocybin mushrooms, or “kitty flipping” for MDMA with ketamine. The term “flipping” may come from the subjective effects of using MDMA with a psychedelic in which the user may shift rapidly between a more lucid state and a more psychedelic state several times during the course of their experiences. Many users use mentholated products while taking MDMA for its cooling sensation while experiencing the drug’s effects. Examples include menthol cigarettes, Vicks VapoRub, NyQuil, and lozenges.
Subjective Effects
The primary effects attributable to MDMA consumption are predictable and fairly consistent among users. In general, users begin reporting subjective effects within 30–60 minutes of consumption, hitting a peak at about 75–120 minutes, reaching a plateau that lasts about 3.5 hours. This is followed by a comedown of a few hours. After the drug has run its course, many users report feeling fatigue.
The following subjective effects of MDMA were statistically significant in a placebo-controlled trial, using Altered States of Consciousness rating scale: derealization, depersonalization, altered perception of space and time, positive basic mood, mania-like experience, anxious derealization, thought disorder, fears of loss of thought or body control, visual hallucinations or pseudo-hallucinations, synesthesia, changed meaning of percepts, facilitated recollection or imagination. On an Adjective Mood rating scale, the following measurements were significantly increased: self-confidence, heightened mood, apprehension-anxiety, thoughtfulness-contemplativeness, extroversion, dazed state, sensitivity and emotional excitation.
Adverse Effects
In January 2001, an overview of the subjective side effects of MDMA based on clinical research conducted over several years involving 74 healthy volunteers. The researchers found a number of common side effects, and many of the effects seemed to occur in different amounts based on the sex of the user. The top side effects reported were difficulty concentrating, jaw clenching, grinding of the teeth during sleep, lack of appetite, and dry mouth/thirst (all occurring in more than 50% of the 74 volunteers). They also measured some of the test subjects for blood pressure, heart rate, and body temperature against a placebo control, but no statistically significant changes were seen.
A 2008 study found a slight but significant correlation of cognitive deficiency in MDMA users, but admitted these data may be confounded by other illicit drug use. The significant finding of the article was the serotonergic neurotoxicity in stacked doses and a lasting decrease in serotonin reuptake (SERT) binding. In rats, high doses and in high temperatures, serotonergic neurotoxicity is limited and dopaminergic neurotoxicity occurs. However, rats may not be a generalizable model for human neurotoxicity studies.
A 2010 study found changes in EEG measured brain activity believed to confirm neurotoxicity to serotonergic neurotransomission systems, and noted that the recorded brain activity data were “in line with the observation of attentional and memory impairments in Ecstasy users with moderate to high misuse”.
However, a 2011 study found no signs of cognitive impairment due to MDMA use, and it did not decrease mental ability. The report also raised concerns that previous methods used to conduct that research on the drug had been flawed, and the experiments overstated the cognitive differences between users and nonusers.
Aftereffects
Effects reported by some users once the acute effects of MDMA have worn off include:
- Psychological
- Anxiety and paranoia
- Depression
- Irritability
- Fatigue
- Impaired attention, focus, and concentration, as well as drive and motivation (due to depleted serotonin levels)
- Residual feelings of empathy, emotional sensitivity, and a sense of closeness to others (afterglow)
- Physiological
- Dizziness, lightheadedness, or vertigo
- Loss of appetite
- Gastrointestinal disturbances, such as diarrhea or constipation
- Insomnia
- Aches and pains, usually from excessive physical activity (e.g., dancing)
- Exhaustion
- Jaw soreness, from bruxism
A slang term given to the depressive period following MDMA consumption is Tuesday Blues (or “Suicide Tuesday”), referring to the low mood that can be experienced midweek by depleted serotonin levels following MDMA use on the previous Friday or Saturday when raves or dance concerts were frequently scheduled. Some users reported consuming 5-HTP, L-tryptophan and vitamins the day after use can reduce the depressive effect by replenishing serotonin levels (magnesium supplements are also used prior to or during use, in an attempt to prevent jaw/muscle clenching).
Overdose
Upon overdose, the potentially serious serotonin syndrome, stimulant psychosis, and/or hypertensive crisis, among other dangerous adverse reactions, may come to prominence, the symptoms of which can include:
- Psychological
- Disorientation and/or confusion
- Agitation, restlessness and paranoia
- Hallucinations and/or delusions
- Thought disorder or disorganized thinking
- Cognitive and memory impairment potentially to the point of retrograde or anterograde amnesia
- Physiological
- Muscle rigidity
- Convulsions
- Hyperreflexia or overresponsive or overreactive reflexes
- Hyperactivity
- Hypertension or hypotension
- Tachycardia
- Tachypnoea or rapid breathing and/or dyspnea or shortness of breath
- Palpitations
- Angina pectoris or severe chest pain, as well as pulmonary hypertension (PH)
- Vasculitis or destruction of blood vessels
- Cardiotoxicity or damage to the heart
- Cardiac dysfunction, arrest, myocardial infarction, and/or heart failure
- Hemorrhage and/or stroke
- Severe hyperthermia, potentially resulting in organ failure
- Loss of consciousness
- Renal failure
- Coma or death
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Chronic Use
Some studies indicate repeated recreational users of MDMA have increased rates of depression and anxiety, even after quitting the drug. Other meta analyses have reported possibility of impairment of executive functioning. Despite these findings, many factors, including total lifetime MDMA consumption, the duration of abstinence between uses, dosage, the environment of use, multiple drug use/abuse, quality of mental health, various lifestyle choices, and predispositions to develop clinical depression and other disorders, have made the results of many studies difficult to verify. A study that attempted to eliminate these confounding factors found few differences in the cognitive functioning of MDMA-using ravers versus non-MDMA-using ravers, “In a study designed to minimize limitations found in many prior investigations, we failed to demonstrate marked residual cognitive effects in ecstasy users. This finding contrasts with many previous findings-including our own-and emphasizes the need for continued caution in interpreting field studies of cognitive function in illicit ecstasy users.” MDMA use has been occasionally associated with liver damage, excessive wear of teeth, and (very rarely) hallucinogen persisting perception disorder.
Short Term Health Concerns
Short-term physical health risks of MDMA consumption include hyperthermia, and hyponatremia. Continuous activity without sufficient rest or rehydration may cause body temperature to rise to dangerous levels, and loss of fluid via excessive perspiration puts the body at further risk as the stimulatory and euphoric qualities of the drug may render the user oblivious to their energy expenditure for quite some time. Diuretics such as alcohol may exacerbate these risks further.
Long Term Effects on Serotonin and Dopamine
MDMA causes a reduction in the concentration of serotonin transporters in the brain. The rate at which the brain recovers from serotonergic changes is unclear. One study demonstrated lasting serotonergic changes in some animals exposed to MDMA. Other studies have suggested that the brain may recover from serotonergic damage.
Some studies show MDMA may be neurotoxic in humans. Other studies, however, suggest that any potential brain damage may be at least partially reversible following prolonged abstinence from MDMA. Depression and deficits in memory have been shown to occur more frequently in long-term MDMA users. However, some recent studies have suggested MDMA use may not be associated with chronic depression.
One study on MDMA toxicity, by George A. Ricaurte of Johns Hopkins School of Medicine, which claimed a single recreational dose of MDMA could cause Parkinson’s disease in later life due to severe dopaminergic stress, was actually retracted by Ricaurte himself after he discovered his lab had administered not MDMA but methamphetamine, which is known to cause dopaminergic changes similar to the serotonergic changes caused by MDMA. Ricaurte blamed this mistake on a labeling error by the chemical supply company that sold the material to his lab, but the supply company responded there was no evidence of a labeling error on their end. Most studies have found the levels of the dopamine transporter (or other markers of dopamine function) in MDMA users deserve further study or are normal.
Several studies have indicated a possible mechanism for neurotoxicity of a metabolite of MDMA, through the reaction of alpha-methyldopamine, a principal metabolite, and glutathione, the major antioxidant in the human body. One possible product of this reaction, 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine, has been demonstrated to produce the same toxic effects observed in MDMA, while MDMA, and alpha-methyldopamine themselves have been shown to be non-neurotoxic. It is, however, impossible to avoid the metabolism of MDMA in the body, and the production of this toxic metabolite. Some studies have demonstrated possible ways to minimize the production of this particular metabolite, though evidence at this point is sparse at best.
Purity and Dosage of “Ecstasy”
Another concern associated with MDMA use is toxicity from chemicals other than MDMA in ecstasy tablets. Due to its near-universal illegality, the purity of a substance sold as ecstasy is unknown to the typical user. The MDMA content of tablets varies widely between regions and different brands of pills and fluctuates somewhat each year. Pills may contain other active substances meant to stimulate in a way similar to MDMA, such as amphetamine, mephedrone, methamphetamine, ephedrine, caffeine, all of which may be comparatively cheap to produce and can help to boost overall profits. In some cases, tablets sold as ecstasy do not even contain any MDMA. Instead they may contain an assortment of undesirable drugs and substances, such as paracetamol, ibuprofen, talcum powder, etc.
A number of deaths have been attributed to para-methoxyamphetamine (PMA), a hallucinogenic amphetamine, being sold as ecstasy. PMA is unique in its ability to quickly elevate body temperature and heart rate at relatively low doses, especially in comparison to MDMA. Hence, users believing they are consuming two 120-mg pills of MDMA could actually be consuming a dose of PMA that is potentially lethal, depending on the purity of the pill. Not only does PMA cause the release of serotonin, but it also acts as a monoamine oxidase inhibitor. When combined with an MDMA or an MDMA-like substance, serotonin syndrome can result. Combining MAO inhibitors with certain legal prescription and over-the-counter medications can also lead to (potentially fatal) serotonin syndrome.
Drug Interactions
A number of reported potentially dangerous possible interactions occur between MDMA and other drugs, including serotonergic drugs. Several cases have been reported of death in individuals who ingested MDMA while taking ritonavir (Norvir), which inhibits multiple CYP450 enzymes. Toxicity or death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors, such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix). Conversely, MAOB inhibitors such as selegiline (Deprenyl; Eldepryl, Zelapar, Emsam) do not seem to carry these risks when taken at selective doses, and have been used to completely block neurotoxicity in rats.