Safety pharmacology of acute MDMA administration in healthy subjects

This analysis of data from nine double-blind, placebo-controlled studies (n=166) investigated the short-term psychological and physiological safety profile of MDMA (75-125mg) and found that effects were overall positive and risks were low, although adverse effects were more frequent in women than in men.

Abstract

“3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is being investigated in MDMA-assisted psychotherapy. The present study characterized the safety pharmacology of single-dose administrations of MDMA (75 or 125 mg) using data from nine double-blind, placebo-controlled, crossover studies performed in the same laboratory in a total of 166 healthy subjects. The duration of the subjective effects was 4.2 ± 1.3 h (range: 1.4–8.2 h). The 125 mg dose of MDMA produced greater ‘good drug effect’ ratings than 75 mg. MDMA produced moderate and transient ‘bad drug effect’ ratings, which were greater in women than in men. MDMA increased systolic blood pressure to >160 mmHg, heart rate >100 beats/min, and body temperature >38°C in 33%, 29% and 19% of the subjects, respectively. These proportions of subjects with hypertension (>160 mmHg), tachycardia, and body temperature >38°C were all significantly greater after 125 mg MDMA compared with the 75 mg dose. Acute and subacute adverse effects of MDMA as assessed by the List of Complaints were dose-dependent and more frequent in females. MDMA did not affect liver or kidney function at EOS 29 ± 22 days after use. No serious adverse events occurred. In conclusion, MDMA produced predominantly acute positive subjective drug effects. Bad subjective drug effects and other adverse effects were significantly more common in women. MDMA administration was overall safe in physically and psychiatrically healthy subjects and in a medical setting. However, the risks of MDMA are likely higher in patients with cardiovascular disease and remain to be investigated in patients with psychiatric disorders.”

Authors: Patrick Vizeli & Matthias E. Liechti

Summary

Introduction

MDMA is used recreationally and investigated clinically as a medication in MDMA-assisted psychotherapy in patients with post-traumatic stress disorder. The present study sought to provide data on the safety pharmacology of single-dose administrations of MDMA in subjects with no or minimal prior ecstasy use. The study used one or two single-dose administrations of MDMA at doses equal or similar to those used in MDMA-assisted psychotherapy. We tested the effects of MDMA on subjective effects, duration of the acute response, cardiovascular and hyperthermic effects, and acute and subacute adverse effects, as well as lasting effects on laboratory indices of liver and kidney function.

MDMA induces the release of serotonin and norepinephrine, and to a lesser extent dopamine, through interactions with the corresponding monoamine transporters, and produces unique effects on emotion processing in healthy subjects that are likely linked to its predominant effects on the 5-HT system.

MDMA produced predominantly acute positive subjective drug effects in physically and psychiatrically healthy subjects and in a medical setting, but was associated with moderate and transient ‘bad drug effect’ ratings, which were greater in women than in men. No serious adverse events occurred.

Several studies have reviewed the acute effects of MDMA in healthy volunteers, but many more have been performed since then. The present analyses used data from 166 subjects and 166 administrations of MDMA alone and 112 administrations of MDMA with another substance. The results show that MDMA produces predominantly positive mood effects, cardiostimulant and thermogenic responses, and no liver enzyme or creatinine level changes were observed.

Study design

A pooled analysis of nine Phase I double-blind, placebo-controlled, crossover studies in healthy subjects was conducted at the University Hospital Basel.

Seven studies were conducted with 112 subjects to assess the safety pharmacology of one or two single doses of MDMA in healthy subjects with no regular MDMA use and no or minimal previous use. The studies were approved by the local ethics committee and Swissmedic.

Subjects

166 healthy European/Caucasian subjects were included in the study. 30 subjects received a single 75 mg dose of MDMA, 136 subjects received a single 125 mg dose of MDMA, and 112 subjects received two single doses of 125 mg MDMA.

The detailed exclusion criteria were reported elsewhere. Fifty-nine subjects had prior drug experience, of which 34 subjects had previously used MDMA.

MDMA hydrochloride was administered orally in a single dose of 75 or 125 mg prepared as gelatin capsules. The dose per body weight was 1.7 0.4 mg/kg for men and 2.1 0.3 mg/kg for women.

Pharmacodynamic measures

Subjective effects were assessed with visual analogue scales before and 0, 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5 and 6 h after MDMA or placebo administration. The onset, offset and duration of the subjective response were determined using the VAS ‘any drug effect’-time curve.

Blood pressure, heart rate and body temperature were measured before and 0, 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5 and 6 h after MDMA or placebo administration. Tachycardia was defined as >100 beats/min and hyperthermia as >38°C and 40°C, respectively.

A list of complaints was used to assess acute and subacute adverse effects of MDMA and placebo. Bruxism was included in the list of complaints and was assessed before and 3 – 6 and 24 h after administration.

Plasma concentrations of MDMA

Blood samples were collected at various time points after administration of MDMA or placebo. The area under the concentration-time curve was calculated.

Blood sampling and EOS visit

Blood tests were performed at the screening visit and the EOS visit, which were separated by 88 – 50 days. The participants were asked to rate their subjective response to MDMA, whether the experience was positive or negative, and whether they considered taking MDMA again.

Statistical analyses

The statistical analyses were performed using Statistica 12 software (StatSoft, Tulsa, OK, USA) and repeated-measures analyses of variance (ANOVAs) with drug and dose as within-subjects factors and sex as a between-subjects factor were used to evaluate all the effects of MDMA compared with placebo.

Acute subjective effects of MDMA

The subjective response to MDMA alone was 33 min, peak effect at 1.6 h, and duration 4.2 1.3 h. There were no sex or dose differences in the duration of the subjective response to MDMA alone. MDMA significantly increased ratings of ‘any drug effect’ and ‘good drug effect’ compared with placebo, and increased ratings of ‘bad drug effect’. Women gave greater ‘bad drug effect’ ratings than men, and the difference remained significant after correction for differences in peak plasma concentrations of MDMA.

Acute effects of MDMA on vital signs

MDMA alone increased blood pressure, heart rate and body temperature. The effects peaked after 1.7 h, 2.0 h and 2.4 h, respectively. No sex differences were observed in the effects of MDMA on vital signs, but men presented greater increases in systolic blood pressure compared with women and the proportion of subjects with tachycardia was significantly greater after 125 mg MDMA administration compared with 75 mg. MDMA has no effects on vital signs when co-administered with other medications. The maximal observed body temperature value among all 278 administrations of MDMA alone or with pretreatment is 39.1°C.

Adverse effects of MDMA

MDMA increased acute and subacute adverse effects on the List of Complaints more in women than in men, and the difference remained significant after correcting for differences in the mg/kg dose of MDMA or in the plasma concentration of MDMA.

MDMA and placebo administration caused frequent and relevant complaints. Acute dry mouth, difficulty concentrating, sweating, bruxism, restless legs, dizziness and hot flushes were more frequently observed after 125 mg MDMA compared with 75 mg. Additional adverse events that were reported for the periods from 24 h until 7 – 14 days after drug administration included headache, depressed mood, common cold, diarrhoea, dizziness, gastroenteritis, emesis, toothache, jaw muscle soreness, migraine, back pain, sinusitis, abdominal pain, flu, and bronchitis. There were several adverse events that occurred only after placebo in the studies that used 125 mg MDMA. No sex differences were found in the reports of adverse events or flashbacks.

Plasma concentrations of MDMA

MDMA peak plasma concentrations were significantly higher in women after the 125 mg dose compared with the 75 mg dose, indicating nonlinear pharmacokinetics, but not in men.

Effects of MDMA on kidney and liver function and changes in blood cell counts

Plasma levels of creatinine, alanine aminotransferase and -glutamyl transpeptidase were unchanged at EOS and 30 -22 days after the last of one or two administrations of MDMA plus pretreatments. Red blood cell counts decreased.

Subjects’ interest in using MDMA again

Eighty per cent of the subjects were MDMA-naive, and the rest had very limited experience with MDMA. Ninety-five subjects reported a positive overall MDMA experience, 25 subjects reported a neutral experience, and 21 subjects reported a disappointing or bad experience.

Discussion

The present study analysed nine placebo-controlled Phase I studies on MDMA and found greater positive than negative acute subjective effects. MDMA induced a state of predominantly positive mood across different laboratories, with modest apprehension anxiety in some subjects. However, 7% of subjects reported anxiety as an acute adverse effect, which could be reduced by verbal support in all subjects, and benzodiazepines were not used.

The present study determined the exact time course of the overall subjective response to MDMA. The average onset time, peak time and effect duration were comparable to previous studies. MDMA has a short duration of action relative to its long plasma half-life, and acute pharmacological tolerance may be present. Therefore, adding more MDMA to increase the MDMA concentration in the body may not relevantly prolong the limited effect duration.

MDMA produced sympathomimetic activation and moderate hypertension and tachycardia in one-third of the participants, and transient severe hypertension was observed in 5% of the participants. No other signs or symptoms of hypertensive crises were observed in the present study.

The present study found that moderate single doses of MDMA at rest increased body temperature, but did not increase to >39.1°C, consistent with previous studies. Hyperpyrexia is a rare but important life-threatening complication of recreational MDMA use.

MDMA-induced acute and subacute adverse effects included lack of appetite, dry mouth, cold feet, sweating, restlessness and heart palpitation. Depressed mood, anxiety, difficulty concentrating, irritability and loss of appetite were also reported in some subjects.

One hundred and forty-one participants reported experiencing flashbacks after MDMA administration, but only within 8 – 50 h after drug administration.

MDMA did not influence levels of liver enzymes on average one month after administration. There was evidence of rare idiosyncratic hepatotoxicity, but this was not a consequence of MDMA use.

The 125 mg dose of MDMA produced 1.8-fold higher Cmax and AUC6 values than the 75 mg dose, indicating a nonlinear dose-exposure relationship. However, this relationship was statistically significant only in women. In the present study, women experienced greater negative subjective effects of MDMA than men, even after correcting for higher doses per body weight or higher plasma levels in women compared with men. Women may be more susceptible to the adverse effects of MDMA on the serotonin system. In a study of patients with PTSD, women had similar adverse effects scores after 75 mg MDMA administration compared with men that received 125 mg. However, women had significantly higher subjective ‘good drug effect’ ratings and comparable ‘bad drug effect’ ratings after 125 mg MDMA administration compared with 75 mg.

MDMA was used in the present study in the same way as it is used in patients, sporadically 2 – 3 times and spaced several weeks apart in addition to non-substance assisted psychotherapy. There were no serious adverse reactions reported.

We included only psychiatrically healthy subjects, and did not evaluate neurocognitive function or any other correlates of neurotoxicity or long-term problems. Additionally, laboratory markers of liver and renal function were only assessed at the end of the study and on average one month after the last MDMA administration. The sample size of the present pooled analysis was too small to exclude infrequent or rare adverse events.

Conclusion

MDMA was safe in healthy subjects and in a controlled clinical setting. It induces cardiovascular stimulation, which may be greater in men, and should be considered a significant risk for patients with cardiovascular disease.