Ecstasy (3,4-methylenedioxymethamphetamine, MDMA, Molly)

"Use of hallucinogens in the past 12 months was similar for college and noncollege young adults (7.5% vs. 10.8%) in 2023. There were also no significant differences for past 12 month use of LSD (1.8% vs. 2.3%), hallucinogens other than LSD (7.4% vs. 10.4%), MDMA (ecstasy, Molly; 0.3% vs. 1.2%), and ketamine (1.8% vs. 0.9%; Table/Figure 96)."

"MDMA-assisted psychotherapy with 75 mg or 125 mg resulted in marked improvement of PTSD symptoms in veterans and first responders with chronic PTSD who had failed previous treatment. This study extends findings of significant results combining MDMA with the same manualised psychotherapy for treating crime-related PTSD,¹² and supports the durability of symptomatic improvement seen in a previous report.¹⁴"

"Findings
"Between Nov 10, 2010, and Jan 29, 2015, 26 veterans and first responders met eligibility criteria and were randomly assigned to receive 30 mg (n=7), 75 mg (n=7), or 125 mg (n=12) of MDMA plus psychotherapy. At the primary endpoint, the 75 mg and 125 mg groups had significantly greater decreases in PTSD symptom severity (mean change CAPS-IV total scores of −58·3 [SD 9·8] and −44·3 [28·7]; p=0·001) than the 30 mg group (−11·4 [12·7]). Compared with the 30 mg group, Cohen's d effect sizes were large: 2·8 (95% CI 1·19–4·39) for the 75 mg group and 1·1 (0·04–2·08) for the 125 mg group. In the open-label crossover with full-dose MDMA (100–125 mg), PTSD symptom severity significantly decreased in the group that had previously received 30 mg (p=0·01), whereas no further significant decreases were observed in the group that previously achieved a large response after 75 mg doses in the blinded segment (p=0·81). PTSD symptoms were significantly reduced at the 12-month follow-up compared with baseline after all groups had full-dose MDMA (mean CAPS-IV total score of 38·8 [SD 28·1] vs 87·1 [16·1]; p<0·0001). 85 adverse events were reported by 20 participants. Of these adverse events, four (5%) were serious: three were deemed unrelated and one possibly related to study drug treatment.

"Interpretation
"Active doses (75 mg and 125 mg) of MDMA with adjunctive psychotherapy in a controlled setting were effective and well tolerated in reducing PTSD symptoms in veterans and first responders."

"The misrepresentation of illicit drugs is a persistent problem in unregulated markets (Barratt et al., 2024, Marshman and Gibbins, 1969). Misrepresentation can take several forms, including dilution of alleged drugs with inactive fillers, adulteration with other active drugs or contaminants, and substitution with other substances. When users consume illicit drugs of unknown content, quality, and dosage, their risk of overdose and other adverse health events increases significantly (Singh et al., 2020, van Amsterdam et al., 2020). Even innocuous fillers can be harmful if administered in novel or unintended ways (Cook et al., 2021, Sehdev et al., 2022). Due to such concerns, many jurisdictions have implemented drug checking programs where users may voluntarily and anonymously submit drug samples for chemical analysis (Davis et al., 2022, Green et al., 2022, Park et al., 2023). Results about drug content, including potentially dangerous substances, are then reported back to users and the community-at-large (Barratt and Measham, 2022). Recent systematic reviews conclude that drug checking programs can effectively monitor drug trends, identify the emergence of novel and dangerous substances, and promote harm reduction and safer use practices (Giulini et al., 2023, Maghsoudi et al., 2022)."

"Most of the concern with MDMA adulteration focuses on the plethora of other substances that have been detected in the MDMA supply. This includes novel designer drugs with potentially serious health risks such as synthetic piperazine and cathinone compounds, which were detected in about 5 % of samples overall. Piperazines first appeared in 2000 but saturated the market from 2008–2013, when these compounds were detected in about one-quarter (24 %) of drug items. Cathinones first appeared in our sample in 2010 but predominated from 2012–2016, when they were detected in more than one-sixth (17 %) of samples.

"Other stimulants excluding synthetic piperazines and cathinones were found in one-quarter (25 %) of drug items overall but peaked from 2006–2009 when they were detected in the majority (52–78 %) of samples. Across all years, caffeine (18 %) and methamphetamine (9 %) were the most prevalent stimulant-class adulterants. Pseudo/ephedrine detections peaked in 2004 (17 %) but practically disappeared after 2006, when the federal ban on over-the-counter pseudoephedrine sales took effect (Rigdon, 2012). Two related designer drugs, the substituted amphetamines paramethoxyamphetamine (PMA) and paramethoxymethamphetamine (PMMA), have been singled out in the literature as particularly toxic (e.g., Refstad, 2003) but were rarely detected in our sample (n=3), the last time in 2012.

"Psychedelic and dissociative drugs showed sizable fluctuations as adulterants over time. Dextromethorphan (DXM) peaked as an adulterant in 1999 (23 %), ketamine reached maximum prevalence in 2007 (21 %), and the novel psychedelic 5-MeO-DiPT spiked in 2011 (9 %). Since 2015, neither psychedelics nor dissociatives have been detected in more than 2.5 % of samples. Notably, cannabinoids and opioids were rarely detected in alleged MDMA. Overall, just six items (0.1 %) contained cannabinoids, and opioids were detected in only 23 items (0.5 %). Very few opioid detections involved fentanyl or fentanyl analogs (n=6), all of which were reported in 2005 and 2015. Pharmaceuticals (5 %) and supplements (4 %) appeared consistently as adulterants, but their prevalence has generally declined over time. The most commonly detected pharmaceuticals were procaine (18 %), acetaminophen (16 %), lidocaine (11 %), and diphenhydramine (10 %), whereas 78 % of supplement detections involved methylsulfonylmethane (MSM), a substance often prescribed for joint health but also commonly used as an MDMA diluent. Chemical precursors and byproducts were detected in about 3 % of samples overall but reached as high as 12–13 % in certain years. The most common substances identified in this category were MDA 2-aldoxime analog (24 %), a synthesis byproduct of MDA, and dibenzylpiperazine (22 %), a synthesis byproduct of benzylpiperazine (BZP). Lastly, unidentified drugs (2 %) and samples with no active drug (3 %) recorded relatively low prevalence overall.

"Not only did patterns of adulteration vary temporally, but they also differed across representations of MDMA. In Table 3, we report the distribution of detected drugs by the type of MDMA misrepresentation. Adulterated MDMA was significantly more likely to contain other stimulants (62.3 % vs. 41.9 %, p<0.001) and supplements (13.2 % vs. 4.9 %, p<0.001). Conversely, substituted MDMA was significantly more likely to contain MDMA analogs (28.6 % vs. 23.5 %, p<0.05), piperazines (13.2 % vs. 3.1 %, p<0.001), cathinones (14.4 % vs. 2.8 %, p<0.001), psychedelics (4.3 % vs. 0.9 %, p<0.001), opioids (1.5 % vs. 0.1 %, p ≤ 0.01), and unidentified drugs (5.1 % vs. 2.4 %, p<0.05). No significant differences were observed for dissociatives, cannabinoids, pharmaceuticals, and precursors/byproducts."

"Ecstasy's effects last 3 to 6 hours. It is a mood elevator that produces feelings of empathy, openness and well-being. People who take it at all night "rave" dances say they enjoy dancing and feeling close to others. It does not produce violence or physical addiction."

According to the National Survey on Drug Use and Health, in the United States in 2023 among people aged 12 and older there were an estimated 22,276,000 lifetime users of MDMA, 2,153,000 past-year users, and 471,000 past-month users.

"The data we obtained about illicit drug use from the LTFU [Long Term Follow Up] Questionnaire supports the hypothesis that MDMA can be administered in a clinical setting with minimal risk that the subjects will subsequently seek out and self-administer 'street ecstasy,' or become dependent on the drug. This is consistent with the comments from many study subjects, who expressed the strong opinion that the therapeutic setting and close follow-up were essential elements of the treatment, and they did not think MDMA should be used without this level of clinical monitoring and therapeutic support."

"Apart from warnings issued against dangerous and unexpected pills, dosage makes a difference. In terms of neurotoxicity, several scientific studies pointed out that, among other factors, the probability for possible neurotoxic damage in the serotonergic system grows with the amount of MDMA being consumed. Therefore, most pill-testing projects inform potential consumers that they should not, if at all, consume more than 1,5–1,8 mg MDMA/kg bodyweight because of possible long-term damages to an important region of the brain. These messages, that are often followed by consumers of ecstasy, are only meaningful if consumers are in a position to have their pills chemically analysed. Otherwise they are unable to follow this or similar advice."

"Hall and Henry (2006) reviewed the medical scenarios and treatment options for physicians dealing with MDMA-related medical emergencies: ‘Hyperpyrexia and multi-organ failure are now relatively well-known, other serious effects have become apparent more recently. Patients with acute MDMA toxicity may present to doctors working in Anaesthesia, Intensive Care, and Emergency Medicine. A broad knowledge of these pathologies and their treatment is necessary for those working in an acute medicine speciality’.

"Despite rapid medical intervention, some disorders are difficult to reverse and deteriorate rapidly, with occasional fatal outcomes (Schifano et al., 2003). In an early report, Henry et al. (1992) described MDMA-induced fatalities in seven young party goers, whose body temperatures at the intensive care unit ranged between 40 C and 43 C. The causes of death include various forms of organ failure. MDMA induces apoptosis, or programmed cell death, in cultured liver cells (Montiel-Duarte et al., 2002), and another form of death is from acute liver failure (Smith et al., 2005). Other fatalities result from cardiac arrest, brain seizure, ‘rhabdomyolysis’ or the destruction of skeletal muscle tissue, and ‘disseminated intravascular coagulation’ or the failure of blood clotting—which results in uncontrollable bleeding through multiple sites (Henry et al., 1992; Hall and Henry, 2006)."

"Schifano et al. (2010) analysed the government data on recreational stimulant deaths in the UK between 1997 and 2007. Over this period, there were 832 deaths related to amphetamine or methamphetamine and 605 deaths related to Ecstasy/MDMA. Many were related to multiple-drug ingestion or ‘polydrug’ use. However, in the analysis of ‘mono-intoxication’ fatalities, Schifano et al. (2010) found that deaths following Ecstasy use were significantly more represented than deaths following amphetamine/methamphetamine use (p < 0.007)."

"MDMA (3,4-methylenedioxymethamphetamine) is an amphetamine analog with stimulant and hallucinogenic effects.

"MDMA acts primarily on neurons that produce and release serotonin, but it also affects dopaminergic neurons. MDMA is usually taken as a pill; effects begin 30 to 60 minutes after ingestion and typically last 4 to 6 hours. MDMA is often used at dance clubs, concerts, and rave parties. (See also Amphetamines.)

"Symptoms and Signs of MDMA Use

"MDMA causes a state of excitement and disinhibition and accentuates physical sensation, empathy, and feelings of interpersonal closeness. Toxic effects are similar to those of the other amphetamines but are less common, perhaps because use is more likely to be intermittent. However, even with casual use, significant problems such as hyperthermia and centrally mediated hyponatremia may occur. The effects of intermittent, occasional use are uncertain. Rarely, fulminant hepatic failure occurs.

"Chronic, repeated use may cause problems similar to those of amphetamines, including dependence. Some users develop paranoid psychosis. Cognitive decline may also occur with repeated, frequent use."

"As noted previously, estimates of Ecstasy initiation in 2015 are not compared with estimates from prior years because of the addition of “Molly” as a slang term for Ecstasy in 2015. There were 839,000 past year initiates of Ecstasy aged 12 or older in 2015 (Figure 10), which averages to about 2,300 people each day who initiated Ecstasy use. In 2015, an estimated 168,000 adolescents aged 12 to 17 (Table A.8A in Appendix A), 531,000 young adults aged 18 to 25 (Table A.9A), and 141,000 adults aged 26 or older (Table A.10A) used Ecstasy for the first time in the past year. In 2015, the average age at first Ecstasy use among recent Ecstasy initiates aged 12 to 49 was 20.7 years (Figure 11)."

"In the context of new synthetic drugs there are some well-established approaches to reduce harm such as handing out condoms for free or giving out drinking water to reduce or stabilise body temperature and to avoid heatstroke. In addition, there are possible harms in the party scene that can be countered by pill-testing projects only. All pill-testing projects inform consumers about very dangerous and unexpected pills on site, through magazines and posters or through the Internet."

"MDMA is not a new drug. It was first synthesized by the German pharmaceutical firm Merck in 1912. Human experimentation, however, has been traced back to the early 1970s (Eisner, 1989; Shulgin, 1990)."

"Nutt et al. (2007) attempted to compare the relative dangers of the main types of psychosocial drug, using a series of subjective rating scales. Heroin and cocaine were graded as the two most harmful drugs, whereas Ecstasy/MDMA emerged as one of the least harmful (18th out of 20). Unfortunately, it was unclear how this low harm rating score for Ecstasy/MDMA was given, as they cited no empirical research studies or reviews. Instead, Nutt et al. (2007) suggested that: ‘for drugs which have only recently become popular e.g. Ecstasy or MDMA, the longer term health and social consequences can only be estimated from animal toxicology at present’. Nutt et al. (2007) noted that the most pleasurable drugs tended to be the most problematic, and on the ‘intensity of pleasure’ scale, heroin and cocaine were given maximum scores of 3.0. In contrast, Ecstasy/MDMA was given an ‘intensity of pleasure’ score of 1.5, which was lower than cigarette smoking at 2.2. It is unclear why Ecstasy was rated as less pleasurable than smoking a cigarette, although the low pleasure score contributed to its low harm score.

"Another question concerned drug injections, with Nutt et al. (2007) noting that ‘The potential for intravenous use is taken into account in the Misuse of Drugs classification and was treated as a separate parameter in our exercise’. Cocaine and heroin were given maximum scores of 3.0, whereas Ecstasy/MDMA was given a score of 0. Again, this did not accord with the empirical literature. In their survey of 329 recreational Ecstasy/MDMA users, Topp et al. (1999) reported that 54 (16%) had injected Ecstasy. MDMA injecting may be atypical and only occurs amongst the more experienced Ecstasy users, although this pattern would also describe cocaine. Most cocaine users never inject, and it is only found with experienced users. Hence, the injection score for MDMA should be similar to that for cocaine. Many of the other Ecstasy harm values in Nutt et al. (2007) were surprisingly low. With revised values based on the empirical literature, MDMA rises to the fifth most harmful drug (Parrott, 2009b)."

The Drug Abuse Warning Network estimates that ecstasy was involved in -- though not necessarily the cause of -- nine deaths in 1998. According to DAWN's 2002 mortality report: "The DAWN metropolitan area profiles include information on 'club drugs' as a group, combining all mentions of methylenedioxymethamphetamine (MDMA or Ecstasy), Ketamine, gamma hydroxy butyrate (GHB) and its precursor gamma butyrolactone (GBL), and flunitrazepam (Rohypnol). As in prior years, these substances accounted for very few deaths in any of the DAWN metropolitan areas. Seven metropolitan areas reported no deaths involving these drugs, and only 7 metropolitan areas reported more than 5 mentions of club drugs. The areas with the highest numbers in 2002 were New York (19 mentions), Miami (9), Chicago (7), New Orleans (7), Philadelphia (9), Boston (6), and San Diego (6). Club drugs were rarely reported alone."

"Deaths associated with club drugs other than methamphetamine are quite rare in DAWN data.
"• Cumulatively, 2,601 deaths associated with methamphetamine abuse, 46 deaths associated with Ketamine, and 27 with MDMA were reported by participating medical examiners over the 5-year period from 1994 to 1998.
"• There were no notable increases in deaths involving club drugs from 1994 to 1998."

Deaths from adulterated drugs are another consequence of a zero tolerance approach. The drug should be tested for purity to minimize the risk from adulterated drugs by those who consume it.

Some assertions about the negative health affects of MDMA use are exaggerated, and researchers have been forced to retract their more extreme claims. Dr. George Ricuarte wrote the journal Science on Sept. 12, 2003:
"We write to retract our report 'Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA ('ecstasy')' (1), following our recent discovery that the drug used to treat all but one animal in that report came from a bottle that contained methamphetamine instead of the intended drug, MDMA. Notably, methamphetamine would be expected to produce the same pattern of combined dopaminergic/serotonergic neurotoxicity (2) as that seen in the animals reported in our paper (1)."

"The number of 'ecstasy' laboratories seized worldwide declined from 52 in 2009 to 44 laboratories in 2010. Countries reporting 'ecstasy' manufacture in 2010 (by number of laboratories seized) were Australia (17), Canada (13), Indonesia (12), Malaysia (1) and Argentina (1). Despite a decline in reported 'ecstasy' manufacture, it is worth noting that some countries, such as Australia and Indonesia, reported an increase in the manufacturing capability or size of laboratories. Also of note is the fact that some countries, such as Canada, New Zealand and Turkey, reported incidences of possible polydrug manufacture, in which 'ecstasy' was also being manufactured in illicit methamphetamine laboratories. In Europe, despite increased seizures of the drug, no 'ecstasy' laboratories were reported to UNODC as having been seized in 2010 (see figure 46). However, several 'ecstasy' laboratories were discovered in 2011."

"Pill testing interventions are important measures to enter into contact with hard-to-reach populations and to raise their interest in preventive and harm reduction messages."

"• Despite the lack of empirical data - for health systems in general and information and prevention projects in particular - it is crucial to know about new substances and consumption trends, otherwise there is a high risk of loosing credibility with well-informed users of psychoactive substances. Pill-testing projects can be an important source of information on new substances and consumption trends as they are in closest possible contact with the relevant scenes, more so than other organisations within the prevention system. They have, furthermore, an insight into most substances that are actually being consumed, and know who and where, in which manner, and why these substances are being consumed.
"• Pill-testing interventions have to be part of a global strategy for prevention and harm reduction in recreational settings.
"• By using the information from on-site pill-testing interventions, a national warning system could deepen its data pool in terms of social contexts: who are the people consuming these substances, how, where and why are they consuming these substances in this and that particular way and which information can be passed on to potential consumers in a meaningful and successful manner?
"• Due to the lack and difficulties of evaluation, on one hand there is still no strict scientific proof for the protective impact of on-site pill testing interventions, but on the other hand there is also no scientific evidence to conclude that such interventions would rather promote drug use or might be used by dealers for marketing purposes. Bringing together pieces of evidence is however often a first step for deciding on new intervention models."

"The results of the present study have implications for understanding the abuse of hallucinogens. Although psilocybin is regulated by the federal government under the most restrictive category (Schedule I) of the Controlled Substances Act, the National Institute on Drug Abuse (2001, 2005) does not consider psilocybin and the other classical hallucinogens to be drugs of 'addiction' because they do not produce compulsive drug-seeking behavior as do classic addicting drugs such as cocaine, amphetamine, heroin, and alcohol. This conclusion is consistent with observations that psilocybin and other classic hallucinogens do not maintain reliable drug self-administration in animal laboratory models of drug abuse (Griffiths et al. 1980; Fantegrossi et al. 2004) and that most recreational users of classical hallucinogens decrease or stop their use over time (National Institute on Drug Abuse 2001). In the present study, psilocybin did not produce a classic euphorigenic profile of effects: measures of anxiety and dysphoria (monitor ratings of anxiety: AIA scale on the APZ Questionnaire, LSD scale on the ARCI) were significantly greater after psilocybin than after methylphenidate"

"In summary, our data suggest that ecstasy use over a period of months or a few years may cause long term impairment of cognitive performance even when ecstasy is taken in typical recreational and not necessarily very high doses."

"We found that MDMA (1.5 mg/kg only) altered a behavioral indicator of social cognition. Specifically, it robustly reduced recognition of fearful faces, without changing recognition of other emotions from facial or vocal cues. Although previous studies have confirmed that the drug induces subjective feelings related to sociability and empathy, this is the first published demonstration of an overt behavioral effect of MDMA in humans."

"The main finding of the current longitudinal study is that continued use of MDMA is associated with different aspects of memory decline. For example, the ability to recall a short passage of prose being read aloud immediately and after a delay was found to decline significantly. This decline suggests impairment in retrospective memory, given that performance on the three RBMT prospective tests—1) remembering to ask the experimenter to telephone for a taxi; 2) remembering to deliver a message; and 3) remembering to ask for the return of a personal belonging—did not decline with continued MDMA use. Moreover, no changes in test scores were observed in terms of orientation for time and place and knowing the date.
"This investigation also indicates that vocabulary and the ability to recall first and second names may be adversely affected by the frequency of MDMA use, and that the ability to immediately recall a route may be related to the duration of MDMA use."

"Using this rigorous approach, we found few consistent differences between ecstasy users and non-users on wide-ranging measures of verbal and visuospatial memory, verbal fluency, attention, processing speed, manipulative dexterity and executive cortical functions. Ecstasy users exhibited lower vocabulary scores than non-users, but this finding probably indicates differences in pre-morbid ability rather than neurotoxicity of ecstasy, as vocabulary is generally preserved even after neurological insults [26,45,46]. Indeed, assuming that these differences in pre-morbid verbal ability are valid, the absence of significant differences on most other tests, including tests of verbal memory, becomes even more striking. Although we found a few other significant differences between the overall groups of users and non-users, these differences proved to be concentrated primarily in moderate users, rather than heavy users—suggesting that they were unlikely due to neurotoxicity of ecstasy. More likely, such differences represent chance associations—a phenomenon to be fully expected, given that we performed multiple comparisons without formal statistical correction."

In 2004, the Drug Enforcement Administration gave permission for the first US trial of MDMA for use in treating trauma:
"Capping a 17-year effort by a small but committed group of activists, the federal Drug Enforcement Administration has agreed to let a South Carolina physician treat 12 trauma victims with the illegal street drug ecstasy in what will be the first U.S.-approved study of the recreational drug's therapeutic potential.
"The DEA's move marks a historic turn for a drug that has long been both venerated and vilified."

"This pilot study demonstrates that MDMA-assisted psychotherapy with close follow-up monitoring and support can be used with acceptable and short-lived side effects in a carefully screened group of subjects with chronic, treatment-resistant PTSD. In this group, MDMA-assisted psychotherapy compared with the same psychotherapy with inactive placebo produced clinically and statistically significant improvements in PTSD symptoms as measured by standard symptom scales. This difference was immediate and was maintained throughout the time period. There were no drug-related serious adverse events and no evidence of impaired cognitive function as measured by neuropsychological testing."

"Favorable reports about cognitive function, memory, and concentration on the LTFU Questionnaire were consistent with findings from formal measures of cognitive function that were taken before and after psychotherapy with MDMA versus placebo, in the original study. Though reports from actual testing are more reliable than reports of perceived cognitive function, this long-term self-reported evidence is still important, because of the controversy surrounding theories that there are potential risks of neurocognitive decline resulting from MDMA administration, as has been suggested by animal studies and some retrospective studies in recreational drug users (Thomasius et al., 2006; Kalechstein et al., 2007; Laws and Kokkalis, 2007; Zakzanis et al., 2007; De Sola Llopis et al., 2008; Jager et al., 2008; Schilt et al., 2008; Brown et al., 2010; Kish et al., 2010; Verbaten, 2010) and one prospective study (Schilt et al., 2007)."

"It is notable that no subjects reported any harm from study participation and all of them reported some degree of benefit. Consistent with the investigators‘ clinical observations in the original study, the responses we obtained on the questionnaire indicated that participants often experienced benefits beyond decreased PTSD symptoms. This is not a radical idea; many forms of psychotherapy produce benefits in terms of psychological growth and development that are not limited to improvements in a specific disorder that may have been the original target of therapy (Tedeschi and Calhoun, 2006; Zoellner and Maercker, 2006). Such benefits may prove to be a particularly prominent and valuable feature of MDMA-assisted psychotherapy. Some of the areas of benefit that were endorsed on the LTFU [Long Term Follow Up] Questionnaire, such as an increased self-awareness, improved relationships, an enhanced spiritual life, and more involvement in the community or world, represent effects that are not fully measured by the PTSD symptom scales."