Mechanisms of Action
MDMA is a triple monoamine reuptake inhibitor which effectively means that it prevents the reuptake of the three monoamine neurotransmitters which are serotonin, norepinephrine, and dopamine.
Other medicines which fall in the triple monoamine reuptake inhibitor category have been shown to have strong antidepressant activity and favourable safety profiles in existing clinical research (Marks et al., 2008; Millan, 2009).
While most of MDMA’s effects are connected to its reuptake inhibition of norepinephrine, dopamine, and especially serotonin, it also plays an unknown role in relation to acetylcholine and histamine receptors (Bonkale & Austin, 2008; Fitzgerald & Reid, 1990; Hysek et al., 2014; Kalant, 2001; Kankaanpää et al., 1998; Rudnick & Wall, 1992; Schenk et al., 2013; Verrico et al., 2007; Vollenweider et al., 2002).
Additionally, MDMA is known to reversibly inhibit a synaptic process that prevents the production and release of additional serotonin (Adori et al., 2011; Bonkale & Austin, 2008; Hysek et al., 2014; Schenk et al., 2013). These effects on serotonin are what differentiate it from amphetamine and methamphetamine, which primarily act on dopamine and norepinephrine (Han & Gu, 2006; Rudnick & Wall, 1992).
Brain Activity
The majority of the effects caused by MDMA can be attributed to the inhibition of serotonin reuptake. Dopamine and norepinephrine raise levels of arousal, awareness, and openness and reduce levels of fear (Sessa et al., 2019). Furthermore, some of MDMA’s effects may be linked to MDMA's capacity to reduce amygdala activity, as amygdala stimulation in animal models has previously been shown to be associated with states of conditioned fear which resemble PTSD in humans. Reducing activation of the amygdala may also serve to enhance interaction with the health professionals during MDMA-assisted therapy because it triggers the release of oxytocin which is associated with dampening of the amygdala stress response and an increase in empathy and closeness (Sessa et al., 2019; Davis & Shi, 1999; Rasmusson & Charney, 1997). MDMA also increases blood flow to the prefrontal cortex as well as increases blood levels of arginine vasopressin (Bedi et al., 2009; Carhart-Harris et al., 2015; Dumont et al., 2009; Fallon et al., 2002; Gamma et al., 2000; Hysek et al., 2012; Hysek et al., 2014; Kirkpatrick, Francis, et al., 2014; Wolff et al., 2006).
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