Psychopathological, neuroendocrine and autonomic effects of 3,4-methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy volunteers: results of an experimental double-blind placebo-controlled study

Gouzoulis-Mayfrank and colleagues situate their study within debates about how to classify the methylenedioxyamphetamines (the ‘‘ecstasy’’ family). These compounds share structural features with both stimulant amphetamines and hallucinogenic phenethylamines, and prior reports describe a mix of pleasant, empathogenic effects together with occasional anxiety, confusion and perceptual disturbances. Neuropharmacologically, MDMA-like drugs show strong serotonergic effects in addition to some noradrenergic and dopaminergic activity, leading some investigators to propose a distinct psychoactive category—entactogens—positioned between classic stimulants and hallucinogens. The authors note that experimental human data on acute effects remain limited and that comparing entactogens with prototypical hallucinogens and stimulants under blinded conditions could clarify their phenomenology and physiological signatures. This paper reports an experimental double-blind, placebo-controlled investigation that compares the acute psychological, neuroendocrine and autonomic effects of the entactogen 3,4-methylenedioxyethylamphetamine (MDE), the hallucinogen psilocybin, the stimulant d-methamphetamine and placebo in healthy volunteers. The aim was to characterise and contrast subjective experience, hormonal responses and autonomic activation across these drug classes to test whether entactogens show a distinct profile intermediate between stimulants and hallucinogens.

Design and participants: Thirty-two healthy volunteers (21 male, 11 female; mean age 34 years, range 27–47) participated. All were medically and psychiatrically screened, had no current or past significant psychiatric disorder, were medication-free and most had professional backgrounds in medicine or psychology. Subjects were randomised to one of four drug groups (MDE, psilocybin, d-methamphetamine, placebo), with n = 8 per group. Each participant underwent two identical experimental sessions with the same assigned substance separated by about 24 weeks; females were tested in the early follicular phase for the second experiment. Drugs and dosing: Study drugs were encapsulated to preserve blinding. Doses were approximately: psilocybin ~0.2 mg/kg (maximum 15 mg), MDE ~2 mg/kg (maximum 140 mg), and d-methamphetamine initially ~0.2 mg/kg then increased to ~0.4 mg/kg after an interim review (data from both dose regimens were pooled, total n = 8). Placebo capsules matched appearance. Subjects received five capsules in total with fillers as needed. Procedures and measures: Sessions began in the morning after fasting; intravenous catheters were placed for blood sampling. Cardiovascular parameters (systolic/diastolic blood pressure, heart rate) and sublingual temperature were measured frequently before and after drug administration. Blood for hormone assays and serum drug levels was collected at multiple time points up to 300 minutes post-dose. Psychological assessments included the Hallucinogen Rating Scale (HRS), the APZ questionnaire (measuring oceanic boundlessness, dread of ego dissolution, and visionary restructuralization), the State Anxiety Inventory (STAI-X1), the Vegetative Lability Scale (B-L), the Positive and Negative Symptom Scale (PANSS), and the Bech-Rafaelsen Mania and Melancholia Scales (BRMAS, BRMES). Subjects provided free written accounts and underwent neuropsychological testing and PET imaging as part of the broader project. Biochemistry and analysis: Hormones measured were serum cortisol, prolactin and growth hormone using established immunoassays; coefficients of variation are reported in the text. For hormonal responses the investigators calculated area under the curve (AUC) and maximal plasma concentration (Cmax), where AUC summarises overall exposure over time and Cmax is the peak level. Statistical analyses used non-parametric methods (Wilcoxon signed-rank tests for within-group comparisons, Kruskal-Wallis and Mann-Whitney U-tests for between-group comparisons) with Holm’s procedure to control for multiple testing. Where dose-regimen changes occurred (d-methamphetamine) data were pooled for analysis.

Acute psychological effects: Both psilocybin and MDE produced significant increases from baseline on most total and subscale psychometric scores (except STAI-X1 state anxiety), whereas the methamphetamine group showed significant increases only on the HRS intensity and affect subscales and trend-level increases on some measures. Placebo produced a decrease in state anxiety. Across groups, mean scores were generally highest for psilocybin, followed by MDE, with methamphetamine and placebo showing substantially lower scores. Psilocybin exceeded placebo on nearly all psychometric instruments; MDE exceeded placebo on most instruments except the HRS volition subscale and STAI-X1. Methamphetamine differed from placebo only on the PANSS positive symptom scale, driven mainly by the agitation item. Direct comparisons showed that psilocybin produced significantly greater perceptual alterations and more frequent anxious, ‘‘bad-trip’’ experiences than MDE: psilocybin scored higher than MDE on the HRS perception subscale, the APZ AIA subscale (dread of ego dissolution), the APZ total score, the PANSS general psychopathology scale and the BRMES melancholia scale. MDE tended to score slightly higher than psilocybin on affective/energising measures (HRS affect, BRMAS mania) but these differences were not significant. Delayed psychological effects were limited: psilocybin produced a significant temporary increase in vegetative lability at 24 h and trend increases in some negative-symptom/melancholia scores at 24 h, whereas MDE showed no significant changes at 24 h or 7 days; methamphetamine showed a decrease in vegetative lability at 7 days and placebo reductions in state anxiety at 24 h. Subjective and observational accounts: Psilocybin produced complex, variable perceptual alterations (visual, auditory, tactile), somatic sensations and occasional hallucinations; insight was mostly preserved, though four cases had transient paranoid or anxious episodes manageable by verbal reassurance. Cognitive and affective responses varied widely. MDE effects were more homogeneous: subjects reported pleasant emotional states (relaxation, happiness, increased closeness and empathy), preserved ego-control and insight, increased energy and talkativeness in most cases, and subtler perceptual changes than with psilocybin. Methamphetamine produced relatively subtle activation in most participants, with one individual at the higher dose showing pronounced alterations. Neuroendocrine and autonomic results: MDE elicited the most robust endocrine responses: both AUC and Cmax for serum cortisol and prolactin were significantly higher after MDE than in the other groups (MDE versus placebo P < 0.01 for cortisol AUC/Cmax; other pairwise comparisons P < 0.05). Psilocybin and d-methamphetamine did not produce statistically significant hormone changes compared to placebo, though time-course plots suggested small tendencies consistent with expected pharmacology. Autonomic effects were strongest with MDE, which produced systolic blood pressure increases of about 30–40 mmHg, heart rate rises of about 40–45 beats/min, trend increases in diastolic pressure and a moderate body temperature increase (~0.6°C). Psilocybin produced weaker but significant increases in systolic blood pressure and temperature; methamphetamine produced moderate but significant elevations in systolic and diastolic blood pressure. Notably, participants under MDE often reported feeling relaxed and were relatively unconcerned about somatic arousal—an apparent psycho-vegetative uncoupling observed by the investigators.

Gouzoulis-Mayfrank and colleagues interpret their findings as supporting the view that entactogens like MDE occupy an intermediate position between stimulants and hallucinogens. Psilocybin produced pronounced perceptual, affective and cognitive disruptions that in some respects resembled both positive and negative symptoms of psychosis, while methamphetamine mainly produced mild activation and increased vigilance. MDE combined subjective emotional openness, empathy and pleasant mood with measurable stimulant-like autonomic activation and strong serotonergic endocrine effects. The investigators link the robust cortisol and prolactin responses after MDE to its serotonergic pharmacology; they argue the cortisol rise is unlikely to reflect stress—because psilocybin produced more distressing subjective effects yet did not raise cortisol comparably—but rather a potent acute enhancement of serotonergic transmission. The prolactin response further distinguishes MDE from dopaminergically mediated stimulant effects, since increased prolactin is not expected after typical amphetamine stimulation. The paper highlights a clinically relevant dissociation: despite marked autonomic arousal (tachycardia, hypertension, raised temperature), subjects under MDE often reported relaxation and low concern about somatic signs, a ‘‘psycho-vegetative uncoupling’’ that the authors suggest could contribute to risks at recreational events. The authors acknowledge two principal limitations: drugs were administered as single, non-maximal doses chosen to allow experimental participation, so higher doses might produce quantitatively or qualitatively different effects; and the methamphetamine condition produced only subtle effects in this sample, with a mid-study dose increase and apparent interindividual insensitivity, limiting interpretation of stimulant comparisons. They note that these practical constraints—restricted dosing and limited pre-testing—are common in controlled human research with regulated substances. Overall, the study team concludes that moderate doses of representative stimulant, hallucinogen and entactogen compounds elicited distinguishable psychological and physiological profiles, and that their data support the entactogen concept as a distinct psychoactive class with mixed serotonergic and sympathomimetic features.