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The concordance of memory impairments during intoxication and abstinence suggests a similar neuropharmacological mechanism underlying acute and chronic memory impairments. The mechanism underlying this impairment is to date not known. We hypothesized that cortisol might play an important role in this mechanism as cortisol, implicated in the regulation of memory performance, can be brought out of balance by stressors like<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In the present study, we aimed to block the<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>\u2010induced acute memory defect by giving participants a cortisol synthesis inhibitor (metyrapone) together with a single dose of<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>. Seventeen polydrug<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>users entered this placebo\u2010controlled within subject study with four treatment conditions. The treatments consisted of<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>(75\u2009mg) and metyrapone (750\u2009mg), alone and in combination, and double placebo. Pre\u2010treatment with metyrapone or<jats:styled-content style=\"fixed-case\">P<\/jats:styled-content>lacebo occurred 1\u2009h prior to<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>or<jats:styled-content style=\"fixed-case\">P<\/jats:styled-content>lacebo administration. Memory performance was tested at peak drug concentrations by means of several memory tests. Cortisol levels were determined in blood and oral fluid; this served as a control measure to see whether manipulations were effective.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Main findings indicated that whereas treatment with metyrapone blocked the expected<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>\u2010induced increase in cortisol levels in blood, it did not prevent the<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>\u2010induced memory deficit from happening.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We therefore conclude that<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>\u2010induced increments in cortisol concentrations are not related to<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>\u2010induced memory 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