Effects of the α₂-Adrenergic Agonist Clonidine on the Pharmacodynamics and Pharmacokinetics of 3,4-Methylenedioxymethamphetamine in Healthy Volunteers

Abstract

The mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) involves the carrier-mediated and potentially vesicular release of monoamines. We assessed the effects of the sympatholytic ␣ 2 -adrenergic receptor agonist clonidine (150 g p.o.), which inhibits the neuronal vesicular release of norepinephrine, on the cardiovascular and psychotropic response to MDMA (125 mg p.o.) in 16 healthy subjects. The study used a randomized, double-blind, placebo-controlled crossover design with four experimental sessions. The administration of clonidine 1 h before MDMA reduced the MDMA-induced increases in plasma norepinephrine concentrations and blood pressure but only to the extent that clonidine lowered norepinephrine levels and blood pressure compared with placebo. Thus, no interaction was found between the cardiovascular effects of the two drugs. Clonidine did not affect the psychotropic effects or pharmacokinetics of MDMA. The lack of an interaction of the effects of clonidine and MDMA indicates that vesicular release of norepinephrine, which is inhibited by clonidine, does not critically contribute to the effects of MDMA in humans. Although clonidine may be used in the treatment of stimulant-induced hypertensive reactions, the present findings do not support a role for ␣ 2 -adrenergic receptor agonists in the prevention of psychostimulant dependence.

MDMA enhances “mind reading” of positive emotions and impairs “mind reading” of negative emotions

“…This was a prospectively designed pooled analysis of three double-blind, placebo-controlled, randomized, within-subjects studies (Hysek et al 2011(Hysek et al , 2012Simmler et al 2011a, b). The pre-specified primary endpoint of the pooled analysis was to demonstrate an effect of MDMA on RMET performance compared with placebo in 48 subjects.…”

“…VAS scores were assessed before and 0, 0.33, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, and 6 h after drug administration. The study included additional pharmacodynamic and pharmacokinetic outcomes as reported elsewhere (Hysek et al 2011(Hysek et al , 2012Simmler et al 2011a, b). All outcome measures were assessed identically and at the same time points following MDMA or placebo administration across all three studies.…”

“…The dual serotonin and norepinephrine transporter inhibitor duloxetine was used to block the MDMA-induced release of both serotonin and norepinephrine (Simmler et al 2011a). Clonidine was used to block any MDMA-induced transporter-independent vesicular release of norepinephrine (Hysek et al 2012).…”

Interactions between Bupropion and 3,4-Methylenedioxymethamphetamine in Healthy Subjects

“…The inclusion criterion was 18-45 years of age. Subjects with a personal or first-degree-relative history of psychiatric disorders or chronic or acute physical illness were excluded as previously described (Hysek et al, 2012a). Additional exclusion criteria were tobacco smoking (.10 cigarettes/day) and a lifetime history of using illicit drugs more than five times, with the exception of past cannabis use.…”

“…Blood samples for the determination of MDMA, MDA, HMMA, bupropion, hydroxybupropion, and hydrobupropion were collected 2 hours before and 0, 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 hours after MDMA or placebo administration. Plasma MDMA, MDA, and HMMA concentrations were determined using high-performance liquid chromatography-tandem mass spectrometry as described previously (Hysek et al, 2012a(Hysek et al, , 2013. Bupropion, hydroxybupropion, and hydrobupropion were included into the analytical method, and slight modifications were made.…”