MDMA. Methylenedioxymethamphetamine (also known as ecstasy, E, XTC, emma, molly, mandy, and MDMA) is a classical entactogen substance of the amphetamine class. It is considered to be the prototypical entactogen, a diverse group of substances that includes MDA, methylone, mephedrone, and 6-APB. It primarily acts by increasing the activity of the neurotransmitters serotonin, dopamine, and norepinephrine in the brain.
MDMA was first developed in 1912 by the pharmaceutical company Merck. However, there is no evidence of human use prior to the 1970s, when it became known in underground psychotherapy circles in the United States. In the early 1980s, MDMA spread into nightlife and rave culture, eventually leading to its federal prohibition in 1985. By 2014, MDMA was estimated to be one of the most popular recreational drugs in the world, alongside cocaine and cannabis.Recreational use is popularly associated with dance parties, electronic dance music, and the club and rave scene. Researchers are currently investigating whether MDMA may assist in treatment-resistant post-traumatic stress disorder (PTSD), social anxiety in autistic adults, and anxiety in those with life-threatening illness.
Subjective effects include stimulation, anxiety suppression, disinhibition, enhanced empathy and sociability, relaxation, and euphoria. MDMA is classified as an entactogen due to how it facilitates feelings of closeness with one’s self and others. Tolerance to MDMA builds unusually quickly and many users report that it dramatically loses its effectiveness if used on a frequent basis. It is commonly recommended to wait one to three months between each use to give the brain adequate time to restore serotonin levels and avoid toxicity. Additionally, using excessively high doses and multiple redosing is highly discouraged as these are thought to significantly increase toxicity.
Acute adverse effects of MDMA are usually the result of high or multiple doses, although single dose toxicity can occur in susceptible individuals. The most serious short-term physical health risks of MDMA are overheating and dehydration, which has resulted in deaths. MDMA has also been shown to be neurotoxic at high doses; however, it is unclear how much this risk applies to typical recreational usage. It has moderate to high abuse potential and can produce psychological dependence in some users. As a result, it is highly advised to use harm reduction practices if using this substance.
MDMA, or 3,4-methylenedioxy-N-methylamphetamine, is a synthetic molecule of the substituted amphetamine class. Molecules of the amphetamine class all contain a phenethylamine core comprised of a phenyl ring bound to an amino (NH2) group through an ethyl chain, with an additional methyl substitution at Rα. In addition to this, MDMA contains a methyl substitution on RN, a feature it shares with methamphetamine. Critically, the MDMA molecule also contains substitutions at R3 and R4 of the phenyl ring with oxygen groups — these oxygen groups are incorporated into a methylenedioxy ring through a methylene bridge. MDMA shares this methylenedioxy ring with other entactogens and stimulants like MDA, MDEA and MDAI.
MDMA inhibits both vesicular monoamine transporters (VMATs), the second of which (VMAT2) is highly expressed within monoamine neurons vesicular membranes. Once inside a monoamine neuron, acts as a VMAT2 inhibitor and a TAAR1 agonist. The inhibition of VMAT2 by results in increased concentrations of the aforementioned monoamine neurotransmitters in the cytosol of the neuron. Activation of TAAR1 by MDMA triggers protein kinase signaling events which then phosphorylates the associated monoamine transporters of the neuron.
Subsequently, these phosphorylated monoamine transporters either reverse transport direction – i.e. move neurotransmitters from inside the cell to the synaptic cleft – or withdraw into the neuron, respectively producing the inflow of neurotransmitters and noncompetitive reuptake inhibition at the neuronal membrane transporters. has ten times more affinity for uptake at serotonin transporters compared to dopamine and norepinephrine transporters and consequently has mainly serotonergic effects.
also has weak agonist activity at postsynaptic serotonin receptors 5-HT1 and 5-HT2 receptors, and its more efficacious metabolite MDA likely augments this action. Cortisol, prolactin, and oxytocin quantities in serum are increased
Additionally, is a ligand at both sigma receptor subtypes, though its efficacies at these receptors and the role that they play have yet to be elucidated.