Acute psychological and physiological effects of MDMA (“Ecstasy”) after haloperidol pretreatment in healthy humans
Introduction
MDMA (3,4-methylenedioxymethamphetamine, “Ecstasy”) is an amphetamine derivative that produces feelings of well-being, euphoria, increased extroversion, moderate derealisation and slight perceptual changes as well as a moderate activation of psychomotor drive (Liester et al., 1992, Vollenweider et al., 1998a). The physiological responses to acute MDMA administration include elevated blood pressure, increased heart rate, and other side effects such as palpitations, sweating, jaw clenching, anorexia and insomnia (Grob, 1998, Vollenweider et al., 1998a, Mas et al., 1999). Preclinical studies suggest that these psycho-physiological effects of MDMA are due to release of serotonin and dopamine. MDMA increases serotonin release via interaction with the presynaptic serotonin transporter (Hekmatpanah and Peroutka, 1990, Gu and Azmitia, 1993, Rudnick and Wall, 1992, Geyer, 1994). We have recently shown that pretreatment with the selective serotonin reuptake inhibitor citalopram significantly reduced most of the psychological and physiological effects of MDMA, indicating that this mechanism is also relevant in humans (Liechti et al., 2000, Liechti and Vollenweider, 2000). In animals, MDMA has also been shown to increase striatal dopamine (DA) levels (Schmidt et al., 1987, Yamamoto and Spanos, 1988). This increase is probably due to both a direct interaction of MDMA with the DA-carrier (Schmidt et al., 1987, Nash and Brodkin, 1991, Koch and Galloway, 1997) and an amplification of DA release through activation of postsynaptic 5-HT2 receptors by MDMA-induced serotonin 5-hydroxytryptamine, 5-HT release (Nash, 1990, Schmidt et al., 1994, Yamamoto et al., 1995, Gudelsky and Nash, 1996, Koch and Galloway, 1997). Dopamine has been implicated in the mediation of euphoria induced by classical stimulants such as d-amphetamine and cocaine (Lieberman et al., 1990, Laruelle et al., 1995, Volkow et al., 1997, Schlaepfer et al., 1997). Thus, increased dopaminergic activity may also contribute to MDMA-induced euphoria. The role of dopamine in mediating responses to MDMA in humans has not yet been studied. Therefore, the present study examined the effect of the dopamine D2 antagonist haloperidol (1.4 mg i.v.) on psychological and physiological responses to MDMA (1.5 mg/kg p.o.) in healthy human volunteers. We hypothesised that haloperidol would attenuate some of the stimulant-like effects of MDMA.
Section snippets
Experimental procedures
The study was approved by the Ethics Committee of the University Hospital of Psychiatry, Zurich, and was conducted in accordance with the Declaration of Helsinki. The use of MDMA was authorised by the Swiss Federal Health Office, Department of Pharmacology and Narcotics, Berne.
Psychological effects
MDMA (1.5 mg/kg) predominately produced an affective state of well-being associated with increased extroversion and sociability. MDMA also induced moderate depersonalisation and derealisation, an altered perception of time, slight changes in sensory perception and moderate psychomotor activation. Subjective effects began about 60 min after drug intake and lasted for 3.5 to 4 h.
OAV-ASC rating
Fig. 1 shows scores of the Altered State of Consciousness scale (OAV-ASC). MDMA significantly increased the three
Discussion
The main finding of the present study is that haloperidol pretreatment changed the pattern of subjective MDMA effects from a pleasurable state of well-being and euphoria to a more dysphoric state with slightly increased anxiety, while having no effect on the cardiovascular response to MDMA.
We are not aware of any previous description of the pharmacodynamic interaction of MDMA with haloperidol or any mechanistic investigation into the role of dopamine in mediating MDMA effects in humans.
Acknowledgements
This study was supported by the Heffter Research Institute, Santa Fe, NM, USA. The authors especially thank Alex Gamma for critical comments on the manuscript.
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