MDMA-Induced Dissociative State not Mediated by the 5-HT2A Receptor, Drew J. Puxty et al., 2017

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

Drew J. Puxty, Johannes G. Ramaekers, Rafael de la Torre, Magí Farré, Neus Pizarro, Mitona Pujadas and Kim P. C. Kuypers

Frontiers in Pharmacology, 2017, Volume 8, Article 455

Doi : 10.3389/fphar.2017.00455


Previous research has shown that a single dose of MDMA induce a dissociative state, by elevating feelings of depersonalization and derealization. Typically, it is assumed that action on the 5-HT2A receptor is the mechanism underlying these psychedelic experiences. In addition, other studies have shown associations between dissociative states and biological parameters (heart rate, cortisol), which are elevated by MDMA. In order to investigate the role of the 5-HT2 receptor in the MDMA-induced dissociative state and the association with biological parameters, a placebo-controlled withinsubject
study was conducted including a single oral dose of MDMA (75 mg), combined with placebo or a single oral dose of the 5-HT2 receptor blocker ketanserin (40 mg). Twenty healthy recreational MDMA users filled out a dissociative states scale (CADSS) 90 min after treatments, which was preceded and followed by assessment of a number of biological parameters (cortisol levels, heart rate, MDMA blood concentrations). Findings showed that MDMA induced a dissociative state but this effect was not
counteracted by pre-treatment with ketanserin. Heart rate was the only biological parameter that correlated with the MDMA-induced dissociative state, but an absence of correlation between these measures when participants were pretreated with ketanserin suggests an absence of directional effects of heart rate on dissociative state. It is suggested that the 5-HT2 receptor does not mediate the dissociative effects caused by a single dose of MDMA. Further research is needed to determine the exact neurobiology underlying this effect and whether these effects contribute to the therapeutic potential
of MDMA.

Keywords : MDMA, dissociative state, cortisol, heart rate, 5-HT2 receptor, MDMA concentration,
depersonalization, derealization



Classical psychedelics like lysergic acid diethylamide (LSD), N,N-Dimethyltryptamine (DMT) and
psilocybin are known for their mind-altering and dissociative states, as well as the spiritual or
mystical-like experience often reported by users (Goodman, 2002; Trichter et al., 2009; Griffiths
et al., 2011). These dissociative experiences, characterized by a disruption of cognitive and motor
processes, can be viewed as a continuum ranging from excessive daydreaming and memory problems to more severe forms of depersonalization or derealization disorders (Association, 2013). Previously, it has
been shown that a single dose of MDMA can also acutely induce a dissociative state, as measured with the Altered States of Consciousness Scale and the Clinician-Administered Dissociative State Scale (CADSS) (Vollenweider et al., 1998; van Heugten-Van der Kloet et al., 2015). It was found to exceed the non-psychotic state of schizophrenic patients, yet to be milder than the dissociative state induced by a typical psychedelic (psilocybin) or a dissociative (ketamine), and to be experienced as non-problematic by the psychedelic user (Vollenweider et al., 1998; Jansen, 2000; van Heugten-Van der Kloet et al., 2015). This effect has been shown to be dose-dependent, i.e., whereas low doses of MDMA (25–50 mg) did not induce a dissociative state, a higher dose (100 mg) did, 90 min after administration (van Heugten-Van der Kloet et al., 2015).

It is generally assumed that the hallucinogenic actions of classical psychedelics arise from their action on the serotonin 2A (5-HT2A) receptor (Glennon et al., 1984; Vollenweider and Kometer, 2010). Likewise, studies have demonstrated that 5-HT2A receptors mediate MDMA-induced alterations in mood and perception (Liechti et al., 2000; van Wel et al., 2012). Specifically, pre-treatment with the 5-HT2 antagonist ketanserin selectively reduced MDMA-induced perceptual changes, emotional excitation, and alterations in positive affect (Liechti et al., 2000, 2001; Liechti and Vollenweider, 2001; van Wel et al., 2012). Based on this it was hypothesized that the 5-HT2 receptor could play a role in the MDMA-induced dissociative symptoms.

In addition, studies have demonstrated relationships between specific biological parameters like cortisol levels and heart rate, and state and/or trait dissociation in healthy and patient populations (Giesbrecht et al., 2007; Simeon et al., 2007). Previous studies have for example suggested a blunting of the
autonomic responses, i.e., heart rate, skin conductance, and (nor)epinephrine levels, to stressful traumatic stimuli in acute dissociative states (Griffin et al., 1997; Delahanty et al., 2003). One study even showed an inverse relationship between cortisol stress reactivity and dissociation in dissociative disorder patients and post-traumatic stress disorder patients (Simeon et al., 2007). In healthy participants the cortisol response to a psychological stressor was shown to correlate positively with trait dissociation as measured with the depersonalization-derealization subscale of the Dissociative Experiences Scale (DES). Participants with the highest scores on dissociation also had the largest cortisol response to a stressor (Giesbrecht et al., 2007). In all these studies the stressor was psychological by nature, i.e., real-life
events or stimuli, or laboratory procedures, causing the exposed person to experience psychological stress. It is also known that psychedelics, dissociatives, and MDMA produce a robust acute increase the body’s stress system, e.g., causing an elevation in cortisol levels and in cardiovascular parameters, making those substances to be categorized as ‘biological’ stressors (White and Ryan, 1996; Harris et al., 2002; Hasler et al., 2004; Parrott, 2009; Kuypers et al., 2013; van Heugten-Van der Kloet et al.,
2015). Given this information, it would be relevant to study the association between these biological correlates of stress and MDMA-induced dissociation. In addition, since previous studies have shown MDMA concentrations in blood to correlate positively with the MDMA-induced changes in behavioral
measures (e.g., emotional empathy and prospective memory) (Ramaekers et al., 2009; Kuypers et al., 2017), it would be relevant to explore the relation between MDMA concentrations and the dissociative state.

In order to study the effects of the 5-HT2 receptor in the MDMA-induced dissociative state, and the relationship to cortisol levels, heart rate, and MDMA concentrations, a placebocontrolled experimental study was set up including pretreatment with ketanserin, a 5-HT2A blocker, and treatment with a single dose of MDMA (75 mg). It was hypothesized that MDMA would induce a dissociative state and that ketanserin would counteract this MDMA effect.