Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study

Abstract

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence.

Trial registration: Clinicaltrials.gov NCT00990067.

Conflict of interest statement

Competing Interests: One of the authors (MCH) is employed by a commercial company (Hoffmann-La Roche Ltd.). This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. CONSORT flowchart.

Figure 2. Duloxetine inhibited the psychotropic effects of MDMA.

MDMA produced stimulant-like (b–d) and “entactogenic" (e, f) effects compared with placebo (p<0.001 for all scales). Duloxetine significantly inhibited MDMA-induced elevations in all of these subjective effects (a–f) (p<0.001 for all scales). Values are expressed as mean+SEM (n  = 16).

Figure 3. Duloxetine prevented the acute emotional effects of MDMA in the Adjective Mood Rating Scale.

MDMA produced a state of well-being (a), emotional excitation (b), increased introversion at drug onset at 1.25 h (d), increased extroversion at 2 h (c), increased dreaminess (e), and decreased performance-oriented activity (f) (*p<0.05, **p<0.01, ***p<0.001, vs. placebo-placebo). Duloxetine prevented MDMA-induced elevations in well-being, emotional excitation, and extroversion (a-c) (###p<0.001, placebo-MDMA vs. duloxetine-MDMA). Values are expressed as mean+SEM (n  = 16).

Figure 4. Duloxetine prevented the acute effects of MDMA in the Altered States of Consciousness (ASC) scale.

MDMA significantly increased the ASC sum score, Oceanic Boundlessness (OB), Anxious Ego Dissolution (AED), and Visionary Restructuralization (VR) dimensions, and most of the subscales (*p#p<0.05, ##p<0.01, ###p<0.001, placebo-MDMA vs. duloxetine-MDMA). Values are expressed as mean+SEM (n  = 16).

Figure 5. Duloxetine reduced the cardiostimulant response to MDMA.

Duloxetine reduced the elevations in mean arterial blood pressure (a) and heart rate (b) in response to MDMA. Duloxetine also nonsignificantly lowered the MDMA-induced increase in body temperature (c). Values are expressed as mean+SEM of 16 subjects.

Figure 6. Duloxetine increased MDMA exposure.

Pharmacokinetics of MDMA, MDA, HMMA, and duloxetine (a–d). Duloxetine was administered 16 h and 4 h before MDMA, which was administered at the 0 h time point. Duloxetine increased the Cmax and AUC0–6 of MDMA (a), had no significant effect on MDA exposure (b), and decreased the Cmax and AUC0–6 of HMMA (c). Plasma duloxetine concentrations were similar in the duloxetine-placebo and duloxetine-MDMA groups before MDMA administration (at –4 h and 0 h). Duloxetine concentrations increased 1 h after MDMA administration in the duloxetine-MDMA vs. duloxetine-placebo group (d). Values are expressed as mean±SEM of 16 subjects. MDMA, 3,4-methylenedioxymethamphetamine; MDA, 3,4-methylenedioxyamphetamine; HMMA, 4-hydroxy-3-methoxymethamphetamine.

Figure 7. Pharmacokinetic-pharmacodynamic (PK-PD) relationship.

MDMA effects are plotted against simultaneous MDMA plasma concentrations (a, b). The time of sampling is noted next to each point in minutes or hours after MDMA administration. The clockwise hysteresis indicates acute tolerance to the effects of MDMA. Duloxetine pretreatment markedly reduced physical and subjective responses to MDMA in the hysteresis loops (a, b).

Figure 8. Duloxetine blocked MDMA- and MDA-induced 5-HT and NE efflux.

Duloxetine inhibited SERT-mediated 5-HT release by MDMA (a) and MDA (b). Duloxetine also inhibited NET-mediated NE release by MDMA (c) and MDA (d). Values are expressed as mean ± SEM (n  = 3–6) of retained radiolabeled substrate following incubation with various concentrations of MDMA and MDA.

Figure 9. Pharmacokinetic-pharmacodynamic modeling.

Duloxetine lowered Emax in the MDMA concentration-effect curve (a) with little effect on EC50, similar to the effect of MDMA on monoamine release in vitro. Diamonds and circles represent concentration-effect data pairs for ascending concentrations for placebo-MDMA and duloxetine-MDMA, respectively (a). The solid lines show the fit of a sigmoid Emax PD model to the observed PK data (a). Dashed lines indicate the 95% confidence interval (CI) of the estimation error (a). NE release predicted the observed subjective effect of MDMA in vivo (b). Predicted effects are shown as curves (mean ±95% CI) that represent the fit of the in vitro concentration-effect data to the 16 individual plasma concentration-time curves (b). Observed values are expressed as mean±SEM of 16 subjects (b). MDMA, 3,4-methylenedioxymethamphetamine; NE, norepinephrine; 5-HT, serotonin.