MDMA-Induced Dissociative State not Mediated by the 5-HT2A Receptor

Classical psychedelics such as LSD, DMT and psilocybin produce prominent mind-altering and dissociative experiences; earlier work has shown that a single dose of MDMA can also acutely induce dissociative symptoms (depersonalization, derealization, amnesia) measured with scales like the Clinician-Administered Dissociative State Scale (CADSS). It is generally assumed that the characteristic subjective effects of classical psychedelics are mediated by the serotonin 2A (5-HT2A) receptor, and prior MDMA research has reported that pretreatment with the 5-HT2 antagonist ketanserin reduces some MDMA-induced perceptual and emotional changes. Biological stress markers such as heart rate and cortisol have been linked to dissociative states in some prior studies, and MDMA reliably elevates both cardiovascular measures and cortisol, so these physiological changes are candidate correlates of MDMA-induced dissociation. Kuypers and colleagues set out to test whether the 5-HT2A receptor mediates the dissociative state caused by MDMA and to examine relationships between the dissociative state and biological measures (heart rate, blood pressure, cortisol) and MDMA blood concentrations. They hypothesised that MDMA would induce a dissociative state and that ketanserin pretreatment would attenuate this effect. The study used a double-blind, placebo-controlled, within-subjects design to address these questions experimentally in healthy recreational MDMA users.

Twenty healthy recreational poly-drug users (12 males, 8 females; mean age 21.2 years, SD 2.6) who had previously used MDMA participated. Recruitment occurred via university advertisements, a website and word-of-mouth. Participants were medically screened (including ECG, blood and urine tests) and completed a training/familiarisation day. They were required to abstain from drugs for at least one week prior to testing and from caffeine and alcohol for 24 h, and women underwent pregnancy testing on test days. The design was a 2 × 2 double-blind, placebo-controlled, within-subjects study. Pre-treatment was ketanserin 40 mg (reported to block about 91% of 5-HT2 receptors) or matched placebo; treatment was MDMA 75 mg or placebo. A double-dummy procedure controlled for differences in Tmax between drugs. Each participant completed four test sessions separated by a minimum 7-day washout and was randomised to treatment sequences via a Latin Square. On test days, baseline measures were collected (questionnaires, blood samples, cardiovascular measures). Pre-treatment was administered at 9:30 AM and treatment 30 min later. Ninety minutes after treatment participants completed the CADSS (self-report items 1–19) and a second blood sample was taken; a third cardiovascular and blood sampling occurred at around 150 min after treatment (approximately 12:30 PM). Outcomes included state dissociation assessed with the CADSS (total score 0–76 and subscales depersonalization, derealization, amnesia), trait dissociation via the Dissociative Experiences Scale (DES), cardiovascular parameters (heart rate and systolic/diastolic blood pressure) and plasma cortisol. Pharmacokinetic assays measured MDMA and ketanserin concentrations using gas or liquid chromatography coupled to mass spectrometry; cortisol assays used a chemiluminescence immunoassay. Statistical analysis employed repeated-measures general linear models (GLM) with Pre-treatment (ketanserin/placebo) and Treatment (MDMA/placebo) as within-subject factors. Baseline values were tested first; where appropriate, analyses used second (pre-test) or third (post-test) measures. Paired t-tests compared drug concentrations across conditions and Pearson correlations explored relations among physiological measures, dissociation scores and MDMA concentrations. Correlations used the second measurement (coinciding with CADSS) and significance was set at p = 0.05; partial eta squared (η2) reported for effect size when relevant.

Trait dissociation (DES) scores had a sample mean DES total of 13.8 (SE 2.8), consistent with healthy populations. DES subscale means were reported but trait dissociation did not correlate consistently with state dissociation (CADSS); correlations between DES-T or DES-Total and CADSS-Total ranged between -0.15 and 0.34 across conditions. Primary CADSS outcomes: GLM analyses showed a main effect of Treatment (MDMA) on the three CADSS subscales (Depersonalization, Derealization, Amnesia) (F1,19 = 11.62, p = 0.003; η2 = 0.38), indicating that MDMA increased dissociative ratings relative to placebo. There was a main effect of Scale (F2,38 = 10.02, p < 0.001; η2 = 0.34) with derealization ratings higher than depersonalization and amnesia, and a Treatment × Scale interaction (F2,38 = 10.97, p < 0.001; η2 = 0.37) showing MDMA's effect was most pronounced on derealization. Crucially, there was no Pre-treatment (ketanserin) × Treatment interaction: ketanserin pretreatment did not significantly alter MDMA-induced increases in CADSS scores. Baseline CADSS ratings did not differ between conditions. Cardiovascular and cortisol results: Baseline cardiovascular measures did not differ between conditions (mean systolic BP 123.4 ± 1.8 mmHg, diastolic 71.6 ± 1.4 mmHg, HR 74.3 ± 1.5 bpm). At the pre-test (second) measurement MDMA elevated systolic BP by 12.5 mmHg, diastolic BP by 6.2 mmHg and HR by 10.4 bpm versus placebo. At the post-test (third) measurement MDMA effects remained (systolic +10.9 mmHg, diastolic +8.2 mmHg, HR +13.2 bpm). Pre-treatment with ketanserin had reducing effects on BP and HR (systolic -7.8 mmHg, diastolic -6.1 mmHg, HR -3.4 bpm) and there was a Pre-treatment × Treatment interaction on heart rate: ketanserin partially attenuated the MDMA-induced heart rate increase (heart rate in the combined condition remained above placebo but lower than MDMA alone). Cortisol concentrations showed no baseline differences. MDMA increased cortisol at 90 min (F1,10 = 9.70, p = 0.01; η2 = 0.49) and 150 min (F1,11 = 65.67, p < 0.001; η2 = 0.86) after administration, with levels roughly 1.6 times higher after MDMA than placebo. Pretreatment effects were seen at later time points: ketanserin reduced cortisol and there was a Pre-treatment × Treatment interaction at 150 min and 180 min after pretreatment, such that combining ketanserin with MDMA produced cortisol concentrations 1.9 times lower than MDMA alone, though still about 1.4 times above placebo. Pharmacokinetics: Paired t-tests indicated MDMA plasma concentrations did not differ significantly between MDMA-alone and combined ketanserin+MDMA conditions (90 min and 150 min post-dose reported). Ketanserin concentrations likewise did not differ when administered alone versus combined with MDMA. Correlational findings: Heart rate and cortisol correlated significantly only in the MDMA-alone condition at 90 min (r = 0.69, p = 0.005). Heart rate correlated with CADSS derealization (r = 0.62, p = 0.004), amnesia (r = 0.52, p = 0.02) and CADSS total (r = 0.60, p = 0.001) in the MDMA condition; these correlations were not present in other conditions. Cortisol correlated with the CADSS amnesia subscale only in the ketanserin-only (r = 0.68, p = 0.001) and placebo (r = 0.49, p = 0.04) conditions. MDMA blood concentrations correlated with CADSS total only in the combined ketanserin+MDMA condition (r = 0.47, p = 0.05). Overall, the main pattern was that MDMA induced dissociative symptoms and physiological activation, ketanserin attenuated physiological but not subjective dissociative effects, and heart rate showed the strongest positive association with dissociation but only when MDMA was given without ketanserin.

Kuypers and colleagues interpret their findings as evidence that the MDMA-induced dissociative state observed 90 min after administration is not mediated by the 5-HT2A receptor, because pretreatment with ketanserin (40 mg) did not reduce increases in CADSS depersonalization, derealization or amnesia scores. The dissociative effects were most pronounced for derealization, and the finding that ketanserin attenuated MDMA's effects on cardiovascular parameters and cortisol at later time points while leaving subjective dissociation unchanged supports a dissociation between physiological and subjective effects: physiological responses appear at least partly 5-HT2A-dependent, whereas the dissociative experience is not. The authors note limitations and caveats. Dissociative symptoms were measured once at 90 min after treatment; because ketanserin altered physiological measures at later time points (around 150–180 min post-dose), the absence of an effect on subjective measures might reflect timing rather than absence of 5-HT2A involvement. The sample size limited the ability to preselect or stratify high and low cortisol responders, which could clarify relationships between stress reactivity and dissociation. Dose considerations are also discussed: higher doses of ketanserin might yet block dissociative effects, so dose–response blockade studies are warranted. The authors also acknowledge that correlations between heart rate and dissociation in the MDMA-only condition do not establish causality, and the lack of correlation in the ketanserin+MDMA condition suggests heart rate per se is not the mechanistic driver of dissociation. For future research the investigators recommend human experimental studies combining MDMA with measures of brain glutamate (for example 1H-MRS) to test whether glutamatergic mechanisms underlie MDMA-induced dissociation, and dose–response blockade studies with different ketanserin doses and multiple CADSS assessments over time. They also suggest studying preselected high/low cortisol responders and exploring whether MDMA-induced dissociation relates to psychophysiological states (for example reduced emotionality, altered pain sensitivity or attentional changes) that might be therapeutically relevant. In terms of clinical context, the authors note that MDMA's effects on prefrontal and amygdala activity reported elsewhere—together with derealization and mood effects—could plausibly facilitate processing of traumatic memories, but further mechanistic work is required to substantiate therapeutic implications.

The study concludes that the 5-HT2A receptor does not appear to mediate the acute dissociative state induced by a single 75 mg dose of MDMA, as ketanserin pretreatment did not reduce MDMA-induced increases in depersonalization, derealization or amnesia. Heart rate correlated positively with the dissociative state when MDMA was given alone, but this association does not demonstrate a causal role for heart rate. Further research is needed to identify the neurobiological mechanisms underlying MDMA-induced dissociation and to determine whether these subjective effects contribute to MDMA's putative therapeutic actions.