Learning opportunities in eclampsia care: A ten-year audit from Norway, 2013-2022.

3,4-Methylenedioxymethamphetamine (MDMA) produces strong acute emotional effects primarily via the release of serotonin, norepinephrine, and oxytocin [, ]. MDMA-assisted psychotherapy (MDMA-AT) is currently investigated as a treatment for posttraumatic stress disorder [, ], depressive disorder [], autism spectrum disorder [], and alcohol use disorder []. Clinical Phase 2 and 3 trials typically included two to three dosing sessions with MDMA administered as a split dose: an initial full dose followed by a second “booster” after 1.5–2.5 h [, , –]. An 80 mg dose followed by a 40 mg booster was administered during the first session, increasing to 120 mg plus 60 mg in all subsequent ones, making this the most widely used regimen in MDMA-AT trials. The booster dose was intended to prolong the acute subjective effects and extend the therapeutic session [, , ], but its effects have not been systematically investigated. MDMA exhibits marked acute pharmacological tolerance [], indicated by the observation that acute subjective and autonomic measures return to baseline within 3–5 h while plasma concentrations remain high beyond this time [, ]. This has been attributed to transporter-mediated presynaptic monoamine release and neurotransmitter depletion [, ]. It is unclear whether raising plasma MDMA levels with a booster dose extends its acute pharmacodynamic effects. However, this acute tolerance is not complete. Two consecutive 100 mg MDMA doses that were separated by 4 h produced two very similar effect-time profiles (the subjective effects returned to baseline before the second dose) while peak plasma concentrations doubled after the second dose []. When two 100 mg MDMA doses were separated by 24 h, comparable acute effects were also observed, whereas the second dose produced 1.3-fold higher peak plasma levels []. To directly test the effects of the split dose approach, the present study compared the effects and tolerability of a single 120 mg MDMA dose followed by either a 60 mg booster dose or placebo after 2 h, as well as placebo followed by placebo. We hypothesized that the booster would extend the duration of acute subjective effects by approximately one hour compared to MDMA followed by placebo.