Neuroimaging in human MDMA (Ecstasy) users

Abstract

MDMA (3,4 methylenedioxymethamphetamine) has been used by millions of people worldwide as a recreational drug. The terms "MDMA" and "Ecstasy" are often used synonymously, but it is important to note that the purity of Ecstasy sold as MDMA is not certain. MDMA use is of public health concern, not so much because MDMA produces a common or severe dependence syndrome, but rather because rodent and nonhuman primate studies have indicated that MDMA (when administered at certain dosages and intervals) can cause long-lasting reductions in markers of brain serotonin (5-HT) that appear specific to fine-diameter axons arising largely from the dorsal raphe nucleus (DR). Given the popularity of MDMA, the potential for the drug to produce long-lasting or permanent 5-HT axon damage or loss, and the widespread role of 5-HT function in the brain, there is a great need for a better understanding of brain function in human users of this drug. To this end, neuropsychological, neuroendocrine, and neuroimaging studies have all suggested that human MDMA users may have long-lasting changes in brain function consistent with 5-HT toxicity. Data from animal models leads to testable hypotheses regarding MDMA's effects on the human brain. Because neuropsychological and neuroimaging findings have focused on the neocortex, a cortical model is developed to provide a context for designing and interpreting neuroimaging studies in MDMA users. Aspects of the model are supported by the available neuroimaging data, but there are controversial findings in some areas and most findings have not been replicated across different laboratories and using different modalities. This paper reviews existing findings in the context of a cortical model and suggests directions for future research.

Figure 1

Figure one depicts a cortical model for designing and interpreting neuroimaging studies in MDMA users. Upper left panel indicates idealized cortical anatomy in Pre-MDMA condition. Serotonergic dorsal raphe (DR) and median raphe (MR) nuclei of the brainstem are depicted in brown. MR axons are larger to reflect wider diameter. Blood vessel is shown in red, pyramidal cell neuron in green, glial cell in magenta, inhibitory interneuron in blue. Red circle indicates region of enlargement (lower left and lower right). In Post-MDMA condition (upper right), DR axons are shown as dashed lines to represent either actual axotomy or functional loss of signaling and serotonin (5-HT) release. Lower panel (left) depicts normal anatomy, and right depicts Post-MDMA model. Blood vessel is included in the enlargement because monoamines innervate brain arterioles that contribute to the fMRI response. Pyramidal cell (green) is shown with 5-HT2A receptors (R) on the surface. Pyramidal cell is shown smaller in Post-MDMA setting due to putative loss of neurotrophic factor coupling. N-acetylaspartate (NAA) is a neuronal marker found in pyramidal (and other) neurons. NAA levels would be predicted to decrease if pyramidal neurons shrink in the Post-MDMA condition. 5-HT2A receptors are shown as increasing in the Post-MDMA condition due to potential loss of agonist signaling from 5-HT axotomy or functional loss. MI (magenta) is depicted as contained in glial cells which may hypertrophy in the Post-MDMA condition (but, see text). Gray Matter includes elements assayed by structural neuroimaging studies as gray matter and includes blood vessel, neuronal, and glial elements. Gray Matter is depicted as reduced in Post-MDMA condition due to potential loss of neurotrophic factors or other conditions.