Safety pharmacology of acute MDMA administration in healthy subjects

Abstract

Abstract3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is being investigated in MDMAassisted psychotherapy. The present study characterized the safety pharmacology of singledose administrations of MDMA (75 or 125 mg) using data from nine double-blind, placebocontrolled, 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 the end of the study 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.

A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects

“…Doubling the LSD dose resulted in prolongation of the effect by approximately 3 h, consistent with its half-life of approximately 3 h (Dolder et al, 2017). In contrast to the pharmacokinetic–pharmacodynamic relationship of LSD (Dolder et al, 2017), other psychoactive substances, such as 3,4-methylenedioxymethamphetamine (MDMA), exhibit very marked acute pharmacological tolerance, with a rapid decline of subjective and physiological effects of MDMA within 4 h despite continuously high plasma levels and a relatively long half-life of 8 h (Hysek et al, 2010; Vizeli and Liechti, 2017). …”

Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

“…15,19,36,142 Rhabdomyolysis, cardiac arrhythmias, hyperthermia, hyponatremia, and acute renal failure are the more severe side-effects and are common causes of death following MDMA intoxication. 143,144 The more severe adverse effects of MDMA are potentially exacerbated by the intense exercise and hot environment characteristic of raves.…”

“…34,35,148,149 In addition to increasing systolic blood pressure ,19,36,92 the drug can induce cardiac arrhythmias and myocarditis. 150 Myocardial infarction can also occur following MDMA use, though this tends to happen less frequently than after cocaine or amphetamine administration.…”

“…13,14,15,16,17,18,19 These include context-dependent feelings of closeness with others, reduced social inhibition, positive mood, and increased alertness. 19,20,21,22,23,24 Regarding hallucinations, MDMA is considered to be weakly hallucinogenic. 25 Ingestion of MDMA does not cause auditory hallucinations and only 20% of recreational users have reported experiencing visual hallucinations.…”

“…28,29,30 In addition to directly binding to 5-HT2A receptors, albeit with low affinity (vide infra), MDMA can produce subjective effects by increasing the release of monoamines such as serotonin and norepinephrine. 17,31,32,33,34,35 The perceptual effects of MDMA are more intense in females than in males, 36,37 and have been shown in recent placebo-controlled studies to be clearly distinct from those produced by other psychostimulants. 38,39 …”