Image MDMA’s Effects on Serotonin, Dopamine and Norepinephrine.

MDMA increases levels of these neurotransmitters within the synapse by enhancing their release from nerve endings and/or inhibiting their reuptake.

MDMA affects the brain by increasing the activity of at least three neurotransmitters (the chemical messengers of brain cells): serotonin,89,90 dopamine, and norepinephrine.91 Like other amphetamines, MDMA enhances release of these neurotransmitters89–92 and/or blocks their reuptake,93,94 resulting in increased neurotransmitter levels within the synaptic cleft (the space between the neurons at a synapse).

MDMA causes greater release of serotonin and norepinephrine than of dopamine.91 Serotonin is a neurotransmitter that plays an important role in the regulation of mood, sleep, pain, appetite, and other behaviors. The excess release of serotonin by MDMA likely causes the mood-elevating effects people experience.

However, by releasing large amounts of serotonin, MDMA causes the brain to become significantly depleted of this important neurotransmitter, contributing to the negative psychological aftereffects that people may experience for several days after taking MDMA.95,96

Image Source: Hatzidimitriou G, et al. J Neurosci Off J Soc Neurosci. 1999 Reduced Serotonin in Cerebral Cortex Neurons Following Long-term MDMA Exposure

The left panel is brain tissue from a normal monkey. The middle and right panels illustrate the loss of serotonin-containing nerve endings following MDMA exposure.

Research in rodents and primates has shown that moderate to high doses of MDMA, given twice daily for four days, damages nerve cells that contain serotonin.10,12 MDMA-exposed primates showed reduced numbers of serotonergic neurons 7 years later, indicating that some of MDMA’s effect on the brain can be long lasting.11 MDMA has additional effects on the serotonin system. For example, 1 to 2 weeks following binge-dosing with MDMA (three or four low doses in one day), rats showed decreased expression of the serotonin transporter,13,97 a protein that allows cells to take up and recycle released serotonin. The rats also showed changes in the expression of genes that regulate tryptophan hydroxylase, an enzyme involved in serotonin synthesis.

Low serotonin is associated with poor memory and depressed mood,98 thus these findings are consistent with studies in humans that have shown that some people who use MDMA regularly experience confusion,30 depression,30,99 anxiety, paranoia,30,100 and impairment of memory83,101,102 and attention processes.79 In addition, studies have found that the extent of MDMA use in humans correlates with a decrease in serotonin metabolites and other markers of serotonin function and the degree of memory impairment.95,101 In addition, MDMA’s effects on norepinephrine contribute to the cognitive impairment,94 emotional excitation, and euphoria that accompanies MDMA use.7

Positron emission tomography (PET) brain imaging studies of people who have stopped using MDMA have shown decreases in brain activity at rest in prefrontal, parietal, and mediotemporal cortices as well as in the amygdala, cingulate, and hippocampus. These are brain regions involved in learning, memory, and emotion formation and processing.103,104 PET imaging also showed that one low dose of MDMA increased cerebral blood in the ventromedial frontal and occipital cortex and inferior temporal lobe and cerebellum. It decreased cerebral blood flow in the motor and somatosensory cortex, amygdala, cingulate cortex, insula, and thalamus. These are brain regions involved in emotion formation and processing, behavioral learning, and sensory and motor function.53 Few imaging studies have explored the effects of moderate MDMA use on the human brain, and results that do exist are inconsistent due to methodological differences across studies.105 More studies are needed to determine whether the observed changes in brain activity in people who use MDMA are caused by MDMA, other drug use, or other common risk factors that predispose people to use MDMA.

Additionally, most studies in people do not have behavioral measures from before MDMA use started, making it difficult to rule out pre-existing differences or common underlying risk factors across groups that are separate from MDMA use.83,106,107 Factors such as gender, dosage, frequency and intensity of use, age at which use began, and the use of other drugs, as well as genetic and environmental factors all may play a role in some of the cognitive deficits associated with MDMA use and should be taken into consideration when studying the effects of MDMA in humans.