The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3,4-methylenedioxymethamphetamine (Ecstasy) in healthy volunteers

3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) was already known to produce prominent mood effects but also acute cardiovascular and vegetative side-effects such as raised blood pressure, tachycardia, sweating, tremor, jaw clenching and appetite loss. Earlier animal studies had suggested that MDMA mainly releases serotonin via the serotonin uptake site, and that selective serotonin reuptake inhibitors can block this process. However, it remained unclear whether the same serotonergic mechanism explained MDMA’s physiological effects in humans, and whether other transmitters such as dopamine or norepinephrine contributed meaningfully. Liechti and colleagues set out to test whether pretreatment with the selective serotonin uptake inhibitor citalopram would reduce the cardiovascular, hyperthermic and vegetative effects of MDMA in healthy volunteers. Their hypothesis was that if these effects depended on serotonin release, citalopram would attenuate them in a double-blind placebo-controlled within-subject study.

The study was approved by the Ethics Committee of the Psychiatric University Hospital in Zurich, and the use of MDMA was authorised by the Swiss Federal Health Office. The researchers used racemic MDMA hydrochloride and citalopram hydrochloride supplied in ampoule form. MDMA was given orally at 1.5 mg/kg, with a mean dose of 100 ± 10 mg, while citalopram 40 mg was infused intravenously in 500 ml saline over 90 minutes. The dosing schedule was based on pharmacokinetic information and a pilot study. Sixteen healthy volunteers took part: 12 men and four women aged 21-39 years. They were recruited from the University Hospital and University of Zurich, were mainly university students or physicians, and were screened by medical history, examination, electrocardiography, blood tests and psychiatric interview. Exclusion criteria included a personal or family history of major psychiatric disorder in first-degree relatives, head injury, and alcohol or regular substance abuse. Six participants had minor prior recreational drug experience. The study used a double-blind placebo-controlled within-subject design with four counterbalanced conditions: placebo-placebo, citalopram-placebo, placebo-MDMA and citalopram-MDMA. Sessions were separated by 3-4 weeks. Women were tested only in the perimenstrual phase. Blood pressure, heart rate and body temperature were measured at baseline, 60 minutes and 120 minutes after drug intake. Acute and later side-effects were assessed with the 66-item List of Complaints during the session, at 24 hours, 72 hours and 2 weeks. A physician remained present throughout, and participants were monitored clinically after the acute phase. For analysis, the authors used repeated-measures ANOVA to examine drug and time effects on cardiovascular variables, with post-hoc Tukey tests where interactions were significant. To test the specific effect of citalopram on MDMA responses, they used two-way ANOVA with pretreatment and treatment factors. Side-effect scores across the four conditions were compared using one-way ANOVA, again with Tukey testing. Statistical significance was set at p < 0.05.

MDMA produced the expected subjective effects, including well-being, heightened mood, increased extroversion and moderate derealisation, beginning about 45 minutes after intake and lasting 3-5 hours. On the main physiological outcomes, MDMA significantly increased both systolic and diastolic blood pressure and raised heart rate at 60 and 120 minutes compared with baseline and placebo. The drug-by-time interaction was highly significant for blood pressure and significant for heart rate. Citalopram pretreatment reduced the MDMA-related rise in systolic blood pressure at both 60 minutes and 120 minutes, and reduced diastolic blood pressure at 120 minutes. It also reduced the heart-rate increase at 60 minutes, though not at 120 minutes. MDMA slightly increased body temperature at 60 and 120 minutes, but citalopram did not reduce this hyperthermic effect. For acute side-effects, MDMA significantly increased global complaint scores compared with placebo, and citalopram pretreatment significantly reduced these MDMA-related complaints. Common acute effects included difficulty concentrating, dizziness or vertigo, impaired balance and gait control, restlessness, restless legs, inner tension, lack of appetite, thirst and jaw clenching. During the citalopram infusion itself, tiredness, nausea without vomiting and headaches were reported. Interestingly, citalopram increased inner tension in some participants. Subacute effects were more mixed. Some acute symptoms such as reduced appetite and difficulty concentrating persisted into the next day or up to 3 days. New symptoms after MDMA included headaches, fatigue, exhaustibility, weakness and lack of energy, and signs of depressed mood such as irritability, brooding and gloomy thoughts were seen in about one-third of participants within 3 days. However, citalopram alone also produced comparable short-term adverse effects. On the day after drug intake, there was no difference in overall complaint scores among citalopram, MDMA and the combination, but all three were worse than placebo. By 3 days and 2 weeks, there were no statistical differences among the treatment conditions. In the debriefing interview, all subjects said that citalopram reduced the acute psychological and somatic effects of MDMA. Eight of 16 could not distinguish citalopram from placebo, and all but one could distinguish MDMA from placebo. Fourteen of 16 reported a mostly positive experience, two had moderate anxiety, and none said the study increased their interest in taking MDMA recreationally.

The authors interpret the study as showing that MDMA produces cardiovascular and vegetative side-effects in healthy volunteers, and that most of these are attenuated by pretreatment with citalopram. They argue that the findings support the idea that MDMA’s physiological effects are partly mediated by an action at the presynaptic serotonin uptake site and subsequent serotonin release. They also note that the main subjective effects of MDMA were not markedly uncomfortable for most participants, even though the drug clearly produced sympathomimetic symptoms such as raised blood pressure, tachycardia, palpitations, restlessness and tremor. They place their findings in the context of previous studies showing dose-dependent cardiovascular effects of MDMA and similar compounds, as well as reports in Ecstasy users of prolonged after-effects lasting 1-3 days. The authors highlight the observation that about one-third of their participants reported depressive symptoms after MDMA, which they suggest may reflect transient serotonin depletion. They caution, however, that longer-lasting psychiatric complications have been reported in vulnerable people who use Ecstasy regularly. A key point in the discussion is that citalopram did not reduce the small temperature rise caused by MDMA. The authors conclude that hyperthermia is probably not directly driven by serotonin release alone, and may involve other mechanisms, possibly including postsynaptic 5-HT2 receptors. They also state that citalopram did not fully block MDMA’s physiological effects, which could mean the dose was insufficient or that dopamine and norepinephrine also contribute. They note that this was, to their knowledge, the first controlled human study of this pharmacological interaction, and that the findings are consistent with earlier animal work and anecdotal reports from Ecstasy users. The main limitations and uncertainties they acknowledge are that the citalopram dose may have been too low to fully block MDMA effects, that the study cannot exclude roles for norepinephrine and dopamine, and that the mechanisms underlying the temperature response remain unresolved. They suggest that studies using different or higher citalopram doses, and mechanistic work on other neurotransmitter systems, would be needed to clarify these issues.