‘Ecstasy’ as a risk factor in stroke: A laboratory investigation of 3,4-methylenedioxymethamphetamine-induced cerebrovascular dysfunction

Background and Purpose

“Ecstasy” (3,4-methylenedioxymethamphetamine; MDMA) is a popular recreational drug which is widely perceived to be “safe” by many users and some commentators. However, a growing body of clinical evidence suggests that MDMA use is a risk factor for cerebrovascular accident (CVA) in otherwise healthy young people ¹ , although the mechanism by which MDMA might effect these pathological changes remains to be fully elucidated. In order to identify the mechanism by which MDMA might induce cerebrovascular dysfunction, we have examined the cerebrovascular effects of a single acute exposure to MDMA in Dark Agouti (DA) rats.

Methods

Conscious, lightly restrained adult DA rats were injected i.p. with either 15 mg.kg⁻¹ MDMA or saline (both n=10). Local cerebral blood flow (LCBF) and glucose utilization (LCMRglu) were measured in equal numbers from each group, 25 and 15 minutes post-MDMA respectively, in 62 brain areas using [14C]- iodoantipyrine and [14C]-2-deoxyglucose quantitative autoradiography respectively. Mean arterial blood pressure (MABP) and rectal temperature were monitored throughout. Data (mean±s.e.m.) were analysed using appropriate t-tests (p<0.05).

Results

MDMA produced significant increases in rectal temperature (37.7±0.2 to 39.5±0.2oC) and MABP (142±3 to 182±4 mmHg). MDMA produced significant increases in LCMRglu in 21 brain areas, most markedly in the motor system (globus pallidus; +82%; medial striatum; +71%). Conversely no significant increases in LCBF were measured. Significant decreases in LCBF were observed in 20 brain areas, most markedly in the limbic system (anterior thalamus; −34%; dorsal subiculum; −30%). Global analysis of all 62 areas revealed a close correlation (r=0.86) between LCMRglu and LCBF with an overall ratio of 1.46 in controls. Despite the divergence of LCMRglu (increases) and LCBF (decreases) in MDMA treated groups, there was a similar close correlation (r=0.82), however the overall ratio was decreased to 1.07. In the whole brain, LCBF was coupled to metabolism in both groups, but the equations defining the best-fitting straight line for the data-points demonstrate that the gradient was decreased in the MDMA group, indicating a downward re-setting of the flow-metabolism relationship. Taking the brain areas individually the ratio of flow to metabolism was found to decrease in all but two.

Conclusions

This study indicates that acute MDMA exposure may radically alter the fundamental relationship between cerebral perfusion and metabolic demand. The local uncoupling of flow from underlying metabolism and the global re-setting of this relationship may result from the vasoconstrictor action of MDMA-induced acute 5-HT efflux, and the relative oligaemia produced might provide the mechanism for CVA in human users. Although this phenomenon may be more limited in the human brain, deficits in brain function that parallel the cognitive decline seen in multi-infarct dementia have been found in persistent MDMA users and with the scale of current ‘Ecstasy’ usage this has the potential to develop into a healthcare problem in the future.