Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

Abstract

Methylenedioxymethamphetamine (MDMA) is an amphetamine analogue that preferentially stimulates the release of serotonin (5HT) and results in relatively small increases in synaptic dopamine (DA). The ratio of drug-stimulated increases in synaptic DA, relative to 5HT, predicts the abuse liability; drugs with higher DA:5HT ratios are more likely to be abused. Nonetheless, MDMA is a drug that is misused. Clinical and preclinical studies have suggested that repeated MDMA exposure produces neuroadaptive responses in both 5HT and DA neurotransmission that might explain the development and maintenance of MDMA self-administration in some laboratory animals and the development of a substance use disorder in some humans. In this paper, we describe the research that has demonstrated an inhibitory effect of 5HT on the acquisition of MDMA self-administration and the critical role of DA in the maintenance of MDMA self-administration in laboratory animals. We then describe the circuitry and 5HT receptors that are positioned to modulate DA activity and review the limited research on the effects of MDMA exposure on these receptor mechanisms.

Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD

“…MDMA induces a physiological response similar to an activated stress response, such as increased heart rate, blood pressure, oral temperature, and cortisol levels ( 40 ). MDMA and acute stress also increase levels of serotonin, dopamine, and norepinephrine ( 41 – 44 ). While the mechanisms behind acute stress induced changes in DNA methylation are not known, it is plausible that the increased monoamine and cortisol exposure induced by psychological stress may be involved in inducing a transient state of epigenetic-malleability ( 45 , 46 ).…”

Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention

“…Different classes of drugs increase dopamine via distinct molecular targets and mechanisms (see Table 3), with resultant differences in the magnitude and the speed of dopamine increase, which in turn are factors that contribute to a drug's addictive liability 36 . In this respect, the stimulant drug methamphetamine triggers the largest dopamine increases and is associated with the highest risk for developing addiction (moderate to severe SUD) among those exposed to it (50% risk within 2 years of exposure) 37 .…”

“…Different classes of drugs increase dopamine via distinct molec ular targets and mechanisms (see Table 3), with resultant differenc es in the magnitude and the speed of dopamine increase, which in turn are factors that contribute to a drug's addictive liability 36 . In this respect, the stimulant drug methamphetamine triggers the A.…”

Perioperative Considerations for Patients Exposed to Psychostimulants

“…An example of this is methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), which have differing effects on serotonin and dopamine release and will be described in detail in this article. 11 A variety of desirable psychological and physiological effects of psychostimulants promote misuse. These include heightened energy, improved focus, enhanced performance, and euphoria (Table 1).…”