- Jul 6, 2021
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MDMA (3,4-Methylenedioxy-N-methylamphetamine) (molly, mandy, emma, MD, ecstasy, E, X, XTC, rolls, beans) – is a psychoactive substance which belongs to the phenylethylamine class. The use of MDMA is associated with stimulatory effects, euphoria, contentment and so on. MDMA has a complex pharmacological profile, mainly consisting of its effects as an inhibitor of release and reuptake of monoamines and its additional effects involving limitation of the synthesis and degradation of neurotransmitters. It has a significant effect on serotonin, unlike amphetamine
Around 1975, Alexander Shulgin, also based on the West Coast, again became involved with MDMA. Shulgin met a young student who was interested in drugs, especially in “some N-methylated compounds” (as is MDMA). The student had found in self experiments that MDMA had a significant “amphetamine-like component”. In his laboratory notebook, Shulgin referred to this student a
While misselling of other drugs as MDMA pills has tailed off in recent years (although a problem that could return as 2021 data from the loop suggests), what might have been a positive development in some respects (greater certainty for consumers of the substance they are purchasing and a reduction in more risky adulterants and misselling) has been countered by the growing risks from high potency MDMA pills and powder. The EMCDDA Trendspotter notes that ‘over half (53%) of all ecstasy tablets tested in 2015 contained over 140 milligrams of MDMA, compared to just 3% in 2009. By 2018, an even greater 72% of samples contained over 150 milligrams of MDMA, with an average of 171 milligrams per pill — considerably higher than the average of 50-80 milligrams consistently seen in Europe across the 1990s and 2000s, and a steady rise from 2014. Recent years have also seen the rise of ‘superpills’- with a range of 270–340 milligrams — up to four times a normal adult dose. Rival producers, flush with low-cost raw materials, are competing with each other to market the strongest pills (even if, beyond a certain point, it is unclear whether this is something consumers actually want). The widening potential range of MDMA content in pills, combined with the emergence of super-high strength pills has been identified as a key driver in the rapid rise in MDMA-related medical emergencies and deaths since 2013. MDMA has also developed a substantial niche in online darknet markets accessed via dedicated TOR browsers and paid for using cryptocurrencies like Bitcoin. Estimates from darknet market studies in 2015 suggested that MDMA was the third most popular drug (after cannabis and pharmaceuticals) purchased on the darknet, accounting for 25% of drug sales. Of those who reported obtaining MDMA in the 2019 Global Drug Survey, 67% reported having obtained it through the darknet — higher than for any other drug. This is up from 48.7% in 2015, when the percentage was also higher than for any other drug. The EMCDDA also reported in 2019 that ‘transactions involving quantities of MDMA tablets indicative of the middle level of the market account for more than double the revenue of sales of retail-level quantities’. This is in stark contrast to other drugs sold on the darknet, like cannabis and cocaine, for which comparative sales are ‘overwhelmingly at the retail level’. User reports propose that MDMA purchased on the darknet is perceived to be better quality than supply from more conventional face-to-face dealer markets — perhaps in part because of the eBay-style user ratings system for products and vendors acting as an informal system of quality control and increased accountability of sellers. While concerns exist about the ease with which younger potential users might be able to access MDMA (and other drugs) via the darknet (the technical barriers to the market are relatively easily navigated by tech-savvy individuals), there may also be potential for reduced harm through informal quality controls and, for people without access to more established trusted sellers, reduced interaction with unknown dealers. As for MDMA legal status in Europe, depending on the country, there are differences in charges and legality of the substance. So, in the UK MDMA is classified as class A, charges for possession include the maximum of 7 years of imprisonment and/or indefinite term, lifetime for production and sale; Germany: illegal; France: illegal; Netherlands: illegal; Spain: illegal; Czech Republic: possession of 5 tablets and less is not considered a serious criminal offense. Portugal: the amount less than 1g is decriminalized. Other European countries: illegal. The USA: illegal, Schedule I class D 1995; Canada: Schedule III; Mexico: illegal; Australia: illegal; New Zealand: illegal; Singapore: illegal; Hong-Kong: illegal; Israel: illegal.
According to US Government DEA reports: in 2015, many drugs that were sold as MDMA/molly turned out to be synthetic cathinones, such as methylone or ethylone, as a replacement for the advertised drug. New Jersey: In 2014, reporting indicated that much of the MDMA being trafficked in New Jersey was actually methylone. True MDMA was too expensive to make a profit, so methylone was substituted. New York: In 2014, laboratory analyzis showed most of the purported pure MDMA/“molly” contained cathinones such as methylone. 87% of “Molly” analyzed by the DEA between 2009 and 2013 contained 0% MDMA, instead mostly containing “bath salts” like methylone. In West Florida, 0% of analyzed “Molly” contained any MDMA, also instead mostly containing “bath salts.” “Laboratory analyses on drug seizures by DEA in New York and submitted as Molly between 2011 and 2012 revealed the exhibits were actually a variety of controlled and noncontrolled substances, such as 3,4-methylenedioxymethcathinone (methylone), 4-methyl-n-ethylcathinone (4-MEC), 3,4-methylene-dioxymethamphetamine (MDA), and 3,4-methylene-dioxyprovalerone (MDPV) but not MDMA”. As of 2017, Ecstasy pills in the US have been relatively pure, with most Ecstasy pills sold in the US now containing primarily MDMA. Some pills, particularly in Europe are dangerous as they contain real MDMA, but at too high/unsafe dosages.
Pharmacokinetics and pharmacodynamics.
The primary routes for metabolism of MDMA are N-demethylation and loss of the methylene bridge connecting the catechol, both of which are mediated by various cytochrome P450s. The common metabolites of MDMA include MDA, 3,4-dihydroxymethamphetamine, 3,4-dihydroxyamphetamine, 4-hydroxy-3-methoxy-methamphetamine, and 4-hydroxy-3-methoxy-amphetamine. The
Pharmacodynamic characteristics of MDMA involve release, inhibition of reuptake of serotonin, norepinephrine and dopamine in the synaptic cleft. Generally, MDMA belongs to a unique class of psychoactive substances named entactogens, which are considered to cause changes in mood and social interactions with a sense of intimacy. Firstly, the substance binds to and inhibits SERT,
Dumont and co-workers were the first to demonstrate in a controlled laboratory setting that MDMA increases oxytocin levels. They also found that increases in blood oxytocin levels were correlated with the subjective prosocial feelings induced by MDMA more so than blood levels of the drug itself. While numerous other studies have replicated the finding that MDMA elevates oxytocin levels,
A lot of data obtained as a result of using human monoamine transporters expressed in cells, shows higher affinity of MDMA to NET, than to serotonin or dopamine transporter. MDMA induces more detectable release of serotonin comparing to, for instance, norepinephrine. This fact indicates the importance of both systems, regardless of the degree of affinity for certain receptors. Since NET has higher affinity to dopamine than DAT, it is predominantly expressed in the brain areas, where NET concentration is higher, for example, in frontal cortex. The relative affinities of MDMA for various monoamine reuptake transporters, and the affinity of the respective transporters for each neurotransmitter, can thus influence the selectivity of signaling pathways MDMA activates in a region-specific manner depending on transporter density and availability. Some of MDMA effects (e.g. the level of anxiety or mood) correlate to dopamine release, since there is evidence consisting of studies, which involved pretreatment with dopamine receptors antagonist. Surprisingly, methylphenidate doesn't enhance or reduce MDMA effects, when used together with the latter. Disrupted calcium homeostasis and depletion of cAMP in neurons occurring after use of MDMA, allows assuming that its metabolites affect mitochondrial dynamics. So, impaired mitochondrial events regulation in neurons of hippocampus (which express Mfn2, Mfn2 R94Q) indicates an impairment in their "transfer" and an increase in fragmentation. Thus, this information gives an idea about the main aspects of negative neurotoxic effect of this substance. When performing a PET against the background of MDMA use, there is a decrease in the activity of the left amygdala and an increase in the activity of the frontal part; regional cerebral blood flow (rCBF) increase in the ventromedial prefrontal and cerebellar regions, and a decrease in this indicator in the left amygdala. An activity decrease in the amygdala may indicate a decrease in responding potential threats. Also, during functional MRI, a weakening of activity in the left anterior temporal region is detected, which may increase the probability of “negative” or “undesirable” memories during ecstasy use. According to the studies on MDMA effects on immune system, there is a decrease in CD4 cells, a decrease in the CD4/CD8 ratio, inhibition of lymphocyte proliferation in response to mitogen and an increase in the number of NK cells. The effects level over time, but within 24 hours it remains. Also, ecstasy reduces the production of pro-inflammatory cytokines, including IL-6, IL-1, TNF и INF, and increases the production of anti-inflammatory cytokines, including IL-10 and TGF-ß. Generally, MDMA reduces the concentration of Th1 cytokines and increases the concentration of Th-2 cytokines. Based on the study findings, MDMA causes an obvious increase in body temperature with a certain influence of ambient temperature.
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