No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Gamma A, Buck A, Berthold T, Liechti ME, Vollenweider FX. 3,4-Methylenedioxymethamphetamine (MDMA) modulates cortical and limbic brain activity as measured by [H215O]-PET in healthy humans. Neuropsychopharmacology 23: 388-395
Abstract
[H(2)(15)O]-Positron Emission Tomography (PET) was used to examine regional cerebral blood flow (rCBF) after administration of a single oral dose of the serotonin realeaser and uptake inhibitor MDMA (1.7 mg/kg) or placebo to 16 MDMA-naïve subjects. Psychological changes were assessed by psychometric rating scales. MDMA produced distributed changes in regional blood flow including increases in ventromedial frontal and occipital cortex, inferior temporal lobe and cerebellum; and decreases in the motor and somatosensory cortex, temporal lobe including left amygdala, cingulate cortex, insula and thalamus. Concomitant with these changes, subjects experienced heightened mood, increased extroversion, slight derealization and mild perceptual alterations. MDMA also produced increases in blood pressure and several side effects such as jaw clenching, lack of appetite and difficulty concentrating. These results indicate that a distributed cluster of brain areas underlie the various effects of MDMA in humans.
... Pharmacological resting-state electroencephalography (EEG; Frei et al, 2001), positron emission tomography (PET; Gamma et al, 2000), and functional magnetic resonance imaging (fMRI; Carhart-Harris et al, 2015;Roseman et al, 2014) have begun to elucidate the immediate effects of MDMA on the human brain. PET imaging revealed decreased regional cerebral blood flow (rCBF) in areas including the left amygdala, dorsal anterior cingulate, posterior cingulate, medial temporal lobe (MTL), and bilateral insula (Gamma et al, 2000). ...
... Pharmacological resting-state electroencephalography (EEG; Frei et al, 2001), positron emission tomography (PET; Gamma et al, 2000), and functional magnetic resonance imaging (fMRI; Carhart-Harris et al, 2015;Roseman et al, 2014) have begun to elucidate the immediate effects of MDMA on the human brain. PET imaging revealed decreased regional cerebral blood flow (rCBF) in areas including the left amygdala, dorsal anterior cingulate, posterior cingulate, medial temporal lobe (MTL), and bilateral insula (Gamma et al, 2000). Gamma et al suggest that these results might represent dysregulation of a functional network that others have since linked to the anxiety phenome (Paulus and Stein, 2006). ...
... Of particular importance to the present study is the prior result of decreased regional brain blood flow in the insula, a region implicated in visceral and somatosensory sensation, following MDMA administration (Gamma et al, 2000). This is intriguing as MDMA is known to produce unusual bodily or 'interoceptive' effects, but the neural correlates of these phenomena are not understood. ...
Recent work with noninvasive human brain imaging has started to investigate the effects of 3, 4-methylenedioxymethamphetamine (MDMA) on large-scale patterns of brain activity. MDMA, a potent monoamine-releaser with particularly pronounced serotonin- releasing properties, has unique subjective effects that include: marked positive mood, pleasant/unusual bodily sensations and pro-social, empathic feelings. However, the neurobiological basis for these effects is not properly understood, and the present analysis sought to address this knowledge gap. To do this, we administered MDMA-HCl (100 mg p.o.) and, separately, placebo (ascorbic acid) in a randomized, double-blind, repeated-measures design with twenty-five healthy volunteers undergoing fMRI scanning. We then employed a measure of global resting-state functional brain connectivity and follow-up seed-to-voxel analysis to the fMRI data we acquired. Results revealed decreased right insula/salience network functional connectivity under MDMA. Furthermore, these decreases in right insula/salience network connectivity correlated with baseline trait anxiety and acute experiences of altered bodily sensations under MDMA. The present findings highlight insular disintegration (ie, compromised salience network membership) as a neurobiological signature of the MDMA experience, and relate this brain effect to trait anxiety and acutely altered bodily sensations-both of which are known to be associated with insular functioning.Neuropsychopharmacology accepted article preview online, 14 February 2017. doi:10.1038/npp.2017.35.
... Consistent with prosocial effects reported by recreational users, controlled laboratory administration of moderate doses of MDMA (0.5-2.0 mg/kg) relative to placebo increased selfreport ratings of a broad range of socially-relevant mood states (see Table 1). After MDMA, participants endorsed feeling 'loving' (Bedi et al., 2010;Frye et al., 2014;Kirkpatrick and de Wit, 2014;Kirkpatrick et al., 2014a;Kirkpatrick et al., 2014b;, 'talkative ' (Hysek et al., 2012a;Hysek et al., 2012c;Tancer and Johanson, 2007;Tancer and Johanson, 2003), 'extroverted' (Gamma et al., 2000;Hysek et al., 2013;Hysek et al., 2014a;Hysek et al., 2011;Hysek et al., 2012c;Liechti et al., 2000b), 'sociable' (Bedi et al., 2009;Kirkpatrick et al., 2014a;Kirkpatrick et al., 2014b;Tancer and Johanson, 2003), 'self-confident' (Gamma et al., 2000;Harris et al., 2002;Hysek et al., 2013;Kirkpatrick and de Wit, 2014;Kirkpatrick et al., 2014b), 'friendly' (Johanson et al., 2006;Kirkpatrick et al., 2014a;Kirkpatrick et al., 2014b;Kuypers et al., 2013;Kuypers et al., 2011;Tancer and Johanson, 2007;Tancer and Johanson, 2003;van Wel et al., 2012), 'playful' (Bedi et al., 2010;Kirkpatrick et al., 2014a;Kirkpatrick et al., 2014b), 'open' (Hysek et al., 2012a;Hysek et al., 2012c;Schmid et al., 2014), 'trusting' (Schmid et al., 2014), 'close to other people' (Hysek et al., 2012a;Hysek et al., 2012b;Hysek et al., 2014a;Hysek et al., 2011;Kolbrich et al., 2008;Schmid et al., 2014) and 'emotionally concerned' (Kuypers et al., 2014). ...
... Consistent with prosocial effects reported by recreational users, controlled laboratory administration of moderate doses of MDMA (0.5-2.0 mg/kg) relative to placebo increased selfreport ratings of a broad range of socially-relevant mood states (see Table 1). After MDMA, participants endorsed feeling 'loving' (Bedi et al., 2010;Frye et al., 2014;Kirkpatrick and de Wit, 2014;Kirkpatrick et al., 2014a;Kirkpatrick et al., 2014b;, 'talkative ' (Hysek et al., 2012a;Hysek et al., 2012c;Tancer and Johanson, 2007;Tancer and Johanson, 2003), 'extroverted' (Gamma et al., 2000;Hysek et al., 2013;Hysek et al., 2014a;Hysek et al., 2011;Hysek et al., 2012c;Liechti et al., 2000b), 'sociable' (Bedi et al., 2009;Kirkpatrick et al., 2014a;Kirkpatrick et al., 2014b;Tancer and Johanson, 2003), 'self-confident' (Gamma et al., 2000;Harris et al., 2002;Hysek et al., 2013;Kirkpatrick and de Wit, 2014;Kirkpatrick et al., 2014b), 'friendly' (Johanson et al., 2006;Kirkpatrick et al., 2014a;Kirkpatrick et al., 2014b;Kuypers et al., 2013;Kuypers et al., 2011;Tancer and Johanson, 2007;Tancer and Johanson, 2003;van Wel et al., 2012), 'playful' (Bedi et al., 2010;Kirkpatrick et al., 2014a;Kirkpatrick et al., 2014b), 'open' (Hysek et al., 2012a;Hysek et al., 2012c;Schmid et al., 2014), 'trusting' (Schmid et al., 2014), 'close to other people' (Hysek et al., 2012a;Hysek et al., 2012b;Hysek et al., 2014a;Hysek et al., 2011;Kolbrich et al., 2008;Schmid et al., 2014) and 'emotionally concerned' (Kuypers et al., 2014). ...
Users of ±3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') report prosocial effects such as sociability and empathy. Supporting these apparently unique social effects, data from controlled laboratory studies indicate that MDMA alters social feelings, information processing, and behavior in humans, and social behavior in rodents. Here, we review this growing body of evidence. In rodents, MDMA increases passive prosocial behavior (adjacent lying) and social reward while decreasing aggression, effects that may involve serotonin 1A receptor mediated oxytocin release interacting with vasopressin receptor 1A. In humans, MDMA increases plasma oxytocin and produces feelings of social affiliation. It decreases identification of negative facial expressions (cognitive empathy) and blunts responses to social rejection, while enhancing responses to others' positive emotions (emotional empathy) and increasing social approach. Thus, consistent with drug folklore, laboratory administration of MDMA robustly alters social processing in humans and increases social approach in humans and animals. Effects are consistent with increased sociability, with mixed evidence about enhanced empathy. These neurobiologically-complex prosocial effects likely motivate recreational ecstasy use.
... MDMA elevates levels of the neurohormone oxytocin, an effect likely mediated through direct or indirect action on 5HT1A, 5HT2A, and 5HT4 receptors (23)(24)(25), as well as elevating levels of prolactin, arginine vasopressin (AVP), adrenocorticotrophic hormone (ACTH), and cortisol (26)(27)(28)(29). MDMA possesses a unique pharmacodynamic profile in humans that includes increased emotional empathy, an increase in feelings of interpersonal closeness, greater prosocial behavior, and an increased ability to tolerate distressing memories, greater reward from pleasant memories, and less distress in response to social exclusion (30)(31)(32)(33)(34). Imaging studies found that MDMA reduced activity in brain areas associated with anxiety, including the amygdala, and increased activity in prefrontal cortex (35)(36)(37). Hypotheses for MDMA's therapeutic action include enhanced fear extinction, memory reconsolidation, enhanced therapeutic alliance, widening a window of tolerance for distressing thoughts or experiences, and re-opening or enhancing a critical period for experiencing social reward (25,38,39). It is likely through these effects that MDMA augments and enhances effectiveness of psychotherapy. ...
Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for Psychedelic Studies (MAPS) obtained Breakthrough Therapy Designation (BTD) from the FDA for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD on the basis of pooled analyses showing a large effect size for this treatment. This review covers data supporting BTD. In this treatment, MDMA is administered with psychotherapy in up to three monthly 8-h sessions. Participants are prepared for these sessions beforehand, and process material arising from the sessions in follow-up integrative psychotherapy sessions. Comparing data used for the approval of paroxetine and sertraline and pooled data from Phase 2 studies, MAPS demonstrated that MDMA-assisted psychotherapy constitutes a substantial improvement over available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-assisted psychotherapy had lower dropout rates compared to sertraline and paroxetine trials. As MDMA is only administered under direct observation during a limited number of sessions, there is little chance of diversion, accidental or intentional overdose, or withdrawal symptoms upon discontinuation. BTD status has expedited the development of MAPS phase 3 trials occurring worldwide, leading up to a planned submission seeking FDA approval in 2021. Appeared originally in Front Psychiatry 2019; 10:650.
... ( Hasler, 2022 ) Neurobiologically, this effect may arise from the fact that MDMA, LSD, and psilocybin acutely reduce the activity and responsiveness of the amygdala. ( Bedi et al., 2009 ;Gamma et al., 2000 ;Mueller et al., 2017 ;Kraehenmann et al., 2015 ) They also have strong prosocial and anxiolytic effects, which may counteract trauma-related avoidance and hyperarousal in psychotherapy sessions. ( Brewerton et al., 2021 ;Krediet et al., 2020 ;Dolder et al., 2016 ;Preller et al., 2016 ) MDMA-assisted psychotherapy has been shown to be particularly effective in the treatment of PTSD, ( JM Mitchell et al., 2021 ;Mithoefer et al., 2018 ) and though there are no controlled studies on EDs specifically, preliminary results from people with comorbid EDs show promising results. ...
Eating disorders are serious illnesses showing high rates of mortality and comorbidity with other mental health problems. Psychedelic-assisted therapy has recently shown potential in the treatment of several common comorbidities of eating disorders, including mood disorders, post-traumatic stress disorder, and substance use disorders. The theorized therapeutic mechanisms of psychedelic-assisted therapy suggest that it could be beneficial in the treatment of eating disorders as well. In this review, we summarize preliminary data on the efficacy of psychedelic-assisted therapy in people with anorexia nervosa, bulimia nervosa, and binge eating disorder, which include studies and case reports of psychedelic-assisted therapy with ketamine, MDMA, psilocybin, and ayahuasca. We then discuss the potential therapeutic mechanisms of psychedelic-assisted therapy in these three eating disorders, including both general therapeutic mechanisms and those which are relatively specific to eating disorders. We find preliminary evidence that psychedelic-assisted therapy may be effective in the treatment of anorexia nervosa and bulimia nervosa, with very little data available on binge eating disorder. Regarding mechanisms, psychedelic-assisted therapy may be able to improve beliefs about body image, normalize reward processing, promote cognitive flexibility, and facilitate trauma processing. Just as importantly, it appears to promote general therapeutic factors relevant to both eating disorders and many of their common comorbidities. Lastly, we discuss potential safety concerns which may be associated with these treatments and present recommendations for future research.
... Receptor functions include agonism at 5HT1A and 5HT2A receptors, and blockade of the SERT, NET, DAT and VMAT2 transporters [205,799]. Noradrenaline and cortisol may enhance arousal needed for improved fear extinction learning, while reduced amygdala activation and increased vmPFC activity may allow the difficult experiences to be navigated in a tolerable manner [822,823]. These effects also increase cognitive flexibility [811] and positive responses to emotions, and improve social interactions [824,825]. ...
This narrative state-of-the-art review paper describes the progress in the understanding and treatment of Posttraumatic Stress Disorder (PTSD). Over the last four decades, the scientific landscape has matured, with many interdisciplinary contributions to understanding its diagnosis, etiology, and epidemiology. Advances in genetics, neurobiology, stress pathophysiology, and brain imaging have made it apparent that chronic PTSD is a systemic disorder with high allostatic load. The current state of treatment yields a wide variety of pharmacological and psychotherapeutic approaches, of which many are evidence-based. However, the myriad challenges inherent in the disorder, such as individual and systemic barriers to treatment outcome, comorbidity, emotional dysregulation, suicidality, dissociation, substance use, and trauma-related guilt and shame often render treatment response suboptimal. These challenges are discussed as drivers for emerging novel treatment approaches, including early interventions in the Golden Hours, pharmacological and psychotherapeutic interventions, medication augmentation interventions, the use of psychedelics, as well as interventions targeting the brain and nervous system. All of this aims to improve symptom relief and clinical outcomes. Finally, a phase orientation to treatment is recognized as a tool to strategize treatment of the disorder, and position interventions in step with the progression of the pathophysiology. Revisions to guidelines and systems of care will be needed to incorporate innovative treatments as evidence emerges and they become mainstream. This generation is well-positioned to address the devastating and often chronic disabling impact of traumatic stress events through holistic, cutting-edge clinical efforts and interdisciplinary research.
... Single-nucleotide polymorphisms in the OXTR gene have even been detected in autistic individuals) [59][60][61], further supporting the hypothesis that ASD may be at least in part an issue of decreased empathy and increased anxiety (via oxytocin effects on the amygdala and downstream) [59][60][61]. Whilst MDMA has not been tested on autistic brains, MDMA has shown decreased amygdalar activity in healthy brains [62][63][64]. Autism is dependent on synaptic plasticity, and there is also plenty of evidence that MDMA has effects on synaptic plasticity [65][66][67]. We direct the reader to an excellent review on the molecular effects of MDMA [68], as going more into detail is beyond the scope of this RCT-focused review. ...
Background
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. Unfortunately, no gold-standard treatments exist to alleviate the core socio-behavioural impairments of ASD. Meanwhile, the prosocial empathogen/entactogen 3,4- methylene-dioxy-methamphetamine (MDMA) is known to enhance sociability and empathy in both humans and animal models of psychological disorders.
Objective
We review the evidence obtained from behavioural tests across the current literature, showing how MDMA can induce prosocial effects in animals and humans, where controlled experiments were able to be performed.
Methods
Six electronic databases were consulted. The search strategy was tailored to each database. Only Englishlanguage papers were reviewed. Behaviours not screened in this review may have affected the core ASD behaviours studied. Molecular analogues of MDMA have not been investigated.
Results
We find that the social impairments may potentially be alleviated by postnatal administration of MDMA producing prosocial behaviours in mostly the animal model.
Conclusion
MDMA and/or MDMA-like molecules appear to be an effective pharmacological treatment for the social impairments of autism, at least in animal models. Notably, clinical trials based on MDMA use are now in progress. Nevertheless, larger and more extended clinical studies are warranted to prove the assumption that MDMA and MDMA-like molecules have a role in the management of the social impairments of autism.
... MDMA also has an impact on the body via the release of cortisol, oxytocin, prolactin and vasopressin (Baumeister et al. 2014;Carhart-Harris et al. 2015;Feduccia and Mithoefer 2018). MDMA's specific release of serotonin appears to result in a bilateral reduction of the amygdala (Carhart-Harris et al. 2015;Gamma et al. 2000), a brain structure involved in the acquisition and storage of fearful memories that is also implicated in the neurocircuitry model of PTSD (Rauch et al. 1998). The reduction of activity within the amygdala coupled with increased activation of the serotonergic system has been found to alter emotional and cognitive processes by increasing cognitive flexibility (Wagner et al. 2019), diminishing responses to negative stimuli, enhancing responses to positive emotions, and positively affecting behavior and perceptions during social interactions (Bedi et al. 2009;Wardle and de Wit 2014). ...
The aim of this systematic review was to examine the efficacy of MDMA, ketamine, LSD, and psilocybin for the treatment of posttraumatic stress disorder (PTSD). A search of four databases for English language, peer-reviewed literature published from inception to 18th October 2019 yielded 2,959 records, 34 of which were screened on full-text. Observational studies and RCTs which tested the efficacy of MDMA, ketamine, LSD, or psilocybin for reducing PTSD symptoms in adults, and reported changes to PTSD diagnosis or symptomatology, were included. Nine trials (five ketamine and four MDMA) met inclusion criteria. Trials were rated on a quality and bias checklist and GRADE was used to rank the evidence. The evidence for ketamine as a stand-alone treatment for comorbid PTSD and depression was ranked "very low", and the evidence for ketamine in combination with psychotherapy as a PTSD treatment was ranked "low". The evidence for MDMA in combination with psychotherapy as a PTSD treatment was ranked "moderate".
... MDMA also leads to changes in regional blood flow including increases in the ventromedial frontal and occipital cortex, inferior temporal lobe and cerebellum as well as decreases in the motor and somatosensory cortex, temporal lobe including left amygdala, cingulate cortex, insula and thalamus (Gamma, Buck, Berthold, Hell, & Vollenweider, 2000). These are suggestive findings, since it is well known that the ventromedial prefrontal cortex and the amygdala form an emotional regulation circuit central to the maintenance and recovery of PTSD (Shin et al., 2005). ...
Anxiety-related disorders such as post-traumatic stress disorder (PTSD) rank among the most severe and disabling psychiatric diseases. While it is known that successful treatment mainly involves the revisiting as well as the restructuring of traumatic experiences, for many patients the re-experiencing of their trauma is simply intolerable. Since treatment is so painful, patients often do not respond to available interventions and become chronic sufferers for years and decades. As a consequence, novel psychotherapeutic approaches in treating anxiety-related disorders must be explored. This systematic review highlights and examines the recent research on combining the substance MDMA (3,4-Methylenedioxymethamphetamine) with non-directive psychotherapy in order to treat patients suffering from chronic post-traumatic stress disorder (PTSD). Preliminary reports and reviews have already indicated large effect sizes as well as favorable advantages over existing evidence-based interventions. A preliminary meta-analysis found that MDMA-assisted psychotherapy (MAP) has slightly larger effect sizes and considerably lower dropout rates than Prolonged Exposure (PE). Since then, new publications from recent trials have been published, so that the focus of this review is to summarize the total of five trials conducted in a randomizedcontrolled double-blind manner. Resulting conclusions from this systematic review are in line with existing findings, that MAP seems to be an effective and safe way for treating chronic and non-responding PTSD patients. This review also aims at showing patterns that emerged from the process of synthesizing the trials and finally to critically assess the results and patterns to show what they could mean for intervention science as well as psychiatry in general.
... On a neurobiological level, MDMA attenuates amygdala activity while activating the frontal cortex (Gamma et al. 2000;Carhart-Harris et al., 2015), the activity of which is often impaired in patients suffering from PTSD (see Francati et al., 2007;Dahlgren et al., 2018). MDMA also increases oxytocin levels, which is a potential contributing factor to experienced increases in interpersonal trust (Vizeli and Liechti, 2018). ...
There are few medications with demonstrated efficacy for the treatment of posttraumatic stress disorder (PTSD). Treatment guidelines have unequivocally designated psychotherapy as a first line treatment for PTSD. Yet, even after psychotherapy, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity. Meanwhile, the search for and development of drugs with new mechanisms of action has stalled. Therefore, there is an urgent need to explore not just novel compounds but novel approaches for the treatment of PTSD. A promising new approach involves the use of psychedelic drugs. Within the past few years, 2 psychedelics have received breakthrough designations for psychiatric indications from the US Food and Drug Administration, and several psychedelics are currently being investigated for the treatment of PTSD. This review discusses 4 types of compounds: 3,4-methylenedioxymethamphetamine, ketamine, classical psychedelics (e.g., psilocybin and lysergic acid diethylamide), and cannabinoids. We describe the therapeutic rationale, the setting in which they are being administered, and their current state of evidence in the treatment of PTSD. Each compound provides unique qualities for the treatment of PTSD, from their use to rapidly target symptoms to their use as adjuncts to facilitate psychotherapeutic treatments. Several questions are formulated that outline an agenda for future research.
... MDMA elevates levels of the neurohormone oxytocin, an effect likely mediated through direct or indirect action on 5HT1A, 5HT2A, and 5HT4 receptors (23)(24)(25), as well as elevating levels of prolactin, arginine vasopressin (AVP), adrenocorticotrophic hormone (ACTH), and cortisol (26)(27)(28)(29). MDMA possesses a unique pharmacodynamic profile in humans that includes increased emotional empathy, an increase in feelings of interpersonal closeness, greater prosocial behavior, and an increased ability to tolerate distressing memories, greater reward from pleasant memories, and less distress in response to social exclusion (30)(31)(32)(33)(34). Imaging studies found that MDMA reduced activity in brain areas associated with anxiety, including the amygdala, and increased activity in prefrontal cortex (35)(36)(37). Hypotheses for MDMA's therapeutic action include enhanced fear extinction, memory reconsolidation, enhanced therapeutic alliance, widening a window of tolerance for distressing thoughts or experiences, and re-opening or enhancing a critical period for experiencing social reward (25,38,39). It is likely through these effects that MDMA augments and enhances effectiveness of psychotherapy. ...
Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for Psychedelic Studies (MAPS) obtained Breakthrough Therapy Designation (BTD) from the FDA for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD on the basis of pooled analyses showing a large effect size for this treatment. This review covers data supporting BTD. In this treatment, MDMA is administered with psychotherapy in up to three monthly 8-h sessions. Participants are prepared for these sessions beforehand, and process material arising from the sessions in follow-up integrative psychotherapy sessions. Comparing data used for the approval of paroxetine and sertraline and pooled data from Phase 2 studies, MAPS demonstrated that MDMA-assisted psychotherapy constitutes a substantial improvement over available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-assisted psychotherapy had lower dropout rates compared to sertraline and paroxetine trials. As MDMA is only administered under direct observation during a limited number of sessions, there is little chance of diversion, accidental or intentional overdose, or withdrawal symptoms upon discontinuation. BTD status has expedited the development of MAPS phase 3 trials occurring worldwide, leading up to a planned submission seeking FDA approval in 2021. Clinical Trial Registration: www.ClinicalTrials.gov, identifiers NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.
... Coupled with the intentional creation of a therapeutic context, set, and setting, this neurobiological effect enables what has been theorized as an optimal zone of arousal, as well as possibly allowing for a type of fear extinction (Feduccia and Mithoefer 2018). We posit that the neurotransmitter release and changes in brain activity may also allow for flexibility in cognition, given the altered affective and sensory state, as well as increased feelings of empathy (Kuypers et al. 2014), positive or clear affect (Green et al. 2003), openness (Gamma et al. 2000), and less constrained cognitive processing (Carhart-Harris et al. 2015), which may address elements of trauma reappraisal targeted in cognitive therapies. Additionally, it is posited that the experimental expectancy effect of taking a psychedelic compound, as well as the "special" nature of the context of therapy (massed dosing, full-day sessions, significant pre-treatment discussion and consent, contact with therapists daily following MDMA sessions), may allow for optimal treatment gains. ...
Treatments for posttraumatic stress disorder (PTSD) have evolved significantly in the past 35 years. From what was historically viewed as a pervasive, intractable condition have emerged multiple evidence-based intervention options. These treatments, predominantly cognitive behavioral in orientation, provide significant symptom improvement in 50–60% of recipients. The treatment of PTSD with MDMA-assisted psychotherapy using a supportive, non-directive approach has yielded promising results. It is unknown, however, how different therapeutic modalities could impact or improve outcomes. Therefore, to capitalize on the strengths of both approaches, Cognitive Behavioral Conjoint Therapy for PTSD (CBCT) was combined with MDMA in a small pilot trial. The current article provides a case study of one couple involved in the trial, chosen to provide a demographically representative example of the study participants and a case with a severe trauma history, to offer a detailed account of the methodology and choices made to integrate CBCT and MDMA, as well as an account of their experience through the treatment and their treatment gains. This article offers a description of the combination of CBCT for PTSD and MDMA, and demonstrates that it can produce reductions in PTSD symptoms and improvements in relationship satisfaction.
... MDMA elevates levels of the neurohormone oxytocin, an effect likely mediated through direct or indirect action on 5HT1A, 5HT2A, and 5HT4 receptors (23)(24)(25), as well as elevating levels of prolactin, arginine vasopressin (AVP), adrenocorticotrophic hormone (ACTH), and cortisol (26)(27)(28)(29). MDMA possesses a unique pharmacodynamic profile in humans that includes increased emotional empathy, an increase in feelings of interpersonal closeness, greater prosocial behavior, and an increased ability to tolerate distressing memories, greater reward from pleasant memories, and less distress in response to social exclusion (30)(31)(32)(33)(34). Imaging studies found that MDMA reduced activity in brain areas associated with anxiety, including the amygdala, and increased activity in prefrontal cortex (35)(36)(37). Hypotheses for MDMA's therapeutic action include enhanced fear extinction, memory reconsolidation, enhanced therapeutic alliance, widening a window of tolerance for distressing thoughts or experiences, and re-opening or enhancing a critical period for experiencing social reward (25,38,39). It is likely through these effects that MDMA augments and enhances effectiveness of psychotherapy. ...
... MDMA has been shown to elevate 5-HT concentrations to about twofold higher degree than equivalent doses of amphetamine 53 . The dose of MDMA (1 mg/kg) in the present study is comparable with doses in previous human studies (~1.7 mg/kg oral) and is unlikely to give rise to neurotoxicity or significant adverse events [54][55][56][57] . In the present study in NHP, the decrease in [ 11 C]AZ10419369 binding was similar between 1 mg/kg of MDMA and 1 mg/kg of amphetamine. ...
The serotonin (5-HT) system plays an important role in the pathophysiology and treatment of several major psychiatric disorders. Currently, no suitable positron emission tomography (PET) imaging paradigm is available to assess 5-HT release in the living human brain. [11C]AZ10419369 binds to 5-HT1B receptors and is one of the most 5-HT-sensitive radioligands available. This study applied 5-HT concentration enhancers which can be safely studied in humans, and examined their effect on [11C]AZ10419369 binding at clinically relevant doses, including amphetamine (1 mg/kg), 3,4-methylenedioxymethamphetamine (MDMA; 1 mg/kg) or 5-hydroxy-L-tryptophan (5-HTP; 5 mg/kg). Twenty-six PET measurements (14 for amphetamine, 6 for MDMA and 6 for 5-HTP) using a bolus and constant infusion protocol were performed in four cynomolgus monkeys before or after drug administration. Binding potential (BPND) values were determined with the equilibrium method (integral interval: 63–123 min) using cerebellum as the reference region. BPND values were significantly decreased in several examined brain regions after administration of amphetamine (range: 19–31%), MDMA (16–25%) or 5-HTP (13–31%). Reductions in [11C]AZ10419369 binding were greater in striatum than cortical regions after administration of 5-HTP, while no prominent regional differences were found for amphetamine and MDMA. In conclusion, [11C]AZ10419369 binding is sensitive to changes in 5-HT concentration induced by amphetamine, MDMA or 5-HTP. The robust changes in BPND, following pretreatment drugs administered at clinically relevant doses, indicate that the applied PET imaging paradigms hold promise to be successfully used in future human studies.
... 229 Moreover, Carhart- Harris and co-workers found that while under the influence of MDMA, participants rated their best and worst memories as being significantly more positive and less negative, respectively. 230 Related to its subjective effects, MDMA increased bilateral blood flow in the ventromedial prefrontal cortex and reduced blood flow in the left amygdala 231 -two brain regions that play important roles in the processing of emotional stimuli and memories. Due to its general tendencies to reduce responses to threatening stimuli while enhancing responses to positive social cues, MDMA is being investigated for treating social anxiety in autistic adults, 232 and it has been suggested that MDMA may prove useful in other conditions with a significant social component. ...
Better known as “ecstasy”, 3,4-methylenedioxymethamphetamine (MDMA) is a small molecule that has played a prominent role in defining the ethos of today’s teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compounds like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compounds capable of reliably producing prosocial behavioral states. As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacology, metabolism, adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compound for the future of psychedelic science—having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field.
... All this in psychophysiology term, causes faster breathing, tachycardia and high blood pressure in ecstasy user [16]. Moreover, MDMA induces the release of 80% of available serotonin in synaptic cleft [17] which along with reduction in left amygdale activity [18], brings about the initiation of dopamine and NO signaling pathway take a recreational user in a euphoric condition [19]. In this condition, user feels stress free, relax, light minded and loss all judgments for risks. ...
Ecstasy is an illicit compound, use of which is very famous amongst ravers and dance clubbers. It stimulates the over-release of serotonin and other neurotransmitters which psycho-physiologically cause thermal stress, elevated breathing and heartbeat, sharpened visio-audio senses and high blood pressure. User experiences the euphoric, light-minded and optimistic feelings which are exaggerated under loud, crowded and physically wearing environment. Although these feelings are short term and after frequent consumption, wondrous, care-free sensations are superseded by depression, pessimism, sleeplessness and loss of appetite. Current review describes the molecular reasons behind the effects ecstasy poses on naïve users and highlights how addiction for this drug begins and if not controlled how it eventually brings the demise of its users.
... 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy is also associated with reduced PTSD symptom severity [75,76]. In addition to increasing activity in the vmPFC and decreasing activity of the left amygdala [77], MDMA increases levels of peripheral oxytocin, a neurohormone associated with alterations in social cognition and anxiety [78]. Given that intranasally-administered oxytocin enhances fear extinction in healthy individuals [79], reduces amygdala hyperactivity in patients with PTSD [80], and alters connectivity between the amygdala and both vmPFC and dACC [81], it may be useful for increasing top-down control over exaggerated fear responses during psychotherapy. ...
Posttraumatic stress disorder (PTSD) is associated with alterations in critical brain regions such as the amygdala, hippocampus, and prefrontal cortex. This brief review has two objectives: (1) to discuss research examining extinction and reconsolidation processes as mechanisms in PTSD psychotherapy, and (2) present possibilities for augmenting extinction and reconsolidation within treatment through alterations to therapeutic interventions and novel approaches. A key component of many effective PTSD therapies is exposure, which involves intentional confrontation and processing of the traumatic memory. Our review suggests that extinction and reconsolidation processes underlie effective exposure-based treatment, but the neurobiological mechanisms of these processes in behavioral treatments for PTSD remains unclear. We argue that enhancing extinction and/or disrupting reconsolidation of a feared memory may improve the efficacy of existing treatments (e.g., increased change for limited/non-responders, faster/greater changes for responders), which can be done through multiple channels. Potential avenues for augmentation of the processes of extinction and reconsolidation in PTSD psychotherapies are reviewed, including behavioral modifications, pharmacotherapy agents, and the use of devices during therapy. We further suggest that investigations towards understanding the extent to which extinction and reconsolidation processes are necessary in effective PTSD psychotherapy is an important future direction for enhancing clinical care among PTSD populations.
The chronic intake of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") bears a strong risk for sustained declarative memory impairments. Although such memory deficits have been repeatedly reported, their neurofunctional origin remains elusive. Therefore, we here investigate the neuronal basis of altered declarative memory in recurrent MDMA users at the level of brain connectivity. We examined a group of 44 chronic MDMA users and 41 demographically-matched controls. Declarative memory performance was assessed by the Rey Auditory Verbal Learning Test and a visual associative learning test. To uncover alterations in the whole brain connectome between groups, we employed a data-driven multi-voxel pattern analysis (MVPA) approach on participants’ resting-state functional magnetic resonance imaging data. Recent MDMA use was confirmed by hair analyses. MDMA users showed lower performance in delayed recall across tasks compared to well-matched controls with moderate-to-strong effect sizes. MVPA revealed a large cluster located in the left postcentral gyrus of global connectivity differences between groups. Post-hoc seed-based connectivity analyses with this cluster unraveled hypoconnectivity to temporal areas belonging to the auditory network and hyperconnectivity to dorsal parietal regions belonging to the dorsal attention network in MDMA users. Seed-based connectivity strength was associated with verbal memory performance in the whole sample as well as with MDMA intake patterns in the user group. Our findings suggest that functional underpinnings of MDMA-related memory impairments encompass altered patterns of multimodal sensory integration within auditory processing regions to a functional heteromodal connector hub, the left postcentral gyrus. In addition, hyperconnectivity in regions of a cognitive control network might indicate compensation for degraded sensory processing.
In this paper, we present the development of the Altered States Database (ASDB), an open-science project based on a systematic literature review. The ASDB contains psychometric questionnaire data on subjective experiences of altered states of consciousness (ASC) induced by pharmacological and non-pharmacological methods. The systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Scientific journal articles were identified through PubMed and Web of Science. We included studies that examined ASC using the following validated questionnaires: Altered States of Consciousness Rating Scale (APZ, 5D-ASC, 11-ASC), Phenomenology of Consciousness Inventory (PCI), Hallucinogen Rating Scale (HRS), or Mystical Experience Questionnaire (MEQ30). The systematic review resulted in the inclusion of a total of 165 journal articles, whereof questionnaire data was extracted and is now available on the Open Science Framework (OSF) website (https://osf.io/8mbru) and on the ASDB website (http://alteredstatesdb.org), where questionnaire data can be easily retrieved and visualized. This data allows the calculation of comparable psychometric values of ASC experiences and of dose-response relationships of substances inducing ASC.
BACKGROUND AND OBJECTIVE: Ketamine, a noncompetitive, high-affinity antagonist of the N-methyl-D-aspartate type glutamate receptor, has been investigated for its high efficacy and rapid antidepressant effect and, more recently, for its potential utility in post-traumatic stress disorder (PTSD). The proposal that ketamine's antidepressant and anti-suicidal mechanism may be in part due to its procognitive effect contrasts with the well-established decreased performance on spatial working memory and pattern recognition memory among long-term frequent users. We aimed to review the neurocognitive effects of subanesthetic doses of intravenous ketamine in pharmacological studies among healthy subjects and patients with PTSD or depression.
Methods:
We included studies in English, among healthy adults, or with PTSD or unipolar or bipolar depression where the primary or secondary cognitive outcomes were measured by means of validated neuropsychological test. We excluded studies that reported the use of ketamine only in combination with other drugs or psychotherapy, or studies investigating emotion-laden cognitive functions.
Results:
Ketamine administration among patients with depression and possibly with PTSD does not show significant impairment of cognitive functions in the short-term, in contrast with the immediate altered cognitive dysfunction found in healthy subjects. The potential procognitive effects of ketamine seem more pronounced in cognitive domains of executive function, which is in line with the putative molecular, cellular, and synaptic mechanisms of ketamine's therapeutic action.
Conclusions:
The potential procognitive effect of ketamine deserves further exploration. Whether ketamine has transient or sustained neurocognitive benefits beyond its antidepressant effects is unknown. Improved cognition by ketamine might be used to facilitate psychotherapy interventions for PTSD and depression.
Psychedelic science has generated hundreds of compelling published studies yet with relatively little impact on mainstream psychology. I propose that social psychologists have much to gain by incorporating psychoactive substances into their research programs. Here I use (±)-3,4-methylenedioxymethamphetamine (MDMA) as an example because of its documented ability in experiments and clinical trials to promote bonding, love, and warmth. Social connection is a fundamental human need, yet researchers still possess few tools to effectively and durably boost it. MDMA allows investigators to isolate the psychological mechanisms—as well as brain pathways—underlying felt social connection and thus reveal what should be targeted in future (nondrug) studies. Accordingly, I introduce a conceptual model that presents the proximal psychological mechanisms stimulated by MDMA (lowered fear, increased sociability, more chemistry), as well as its potential long-term impacts (improved relationships, reduced loneliness, stronger therapeutic alliances). Finally, I discuss further questions (e.g., whether using MDMA for enhancing connection can backfire) and promising research areas for building a new science of psychedelic social psychology. In sum, psychopharmacological methods can be a useful approach to illuminate commonly studied social-psychological processes, such as connectedness, prejudice, or self, as well as inform interventions to directly improve people’s lives.
Fear‐related disorders, mainly phobias and post‐traumatic stress disorder, are highly prevalent, debilitating disorders that pose a significant public health problem. They are characterized by aberrant processing of aversive experiences and dysregulated fear extinction, leading to excessive expression of fear and diminished quality of life. The gold standard for treating fear‐related disorders is extinction‐based exposure therapy (ET), shown to be ineffective for up to 35% of subjects. Moreover, ET combined with traditional pharmacological treatments for fear‐related disorders, such as selective serotonin reuptake inhibitors, offers no further advantage to patients. This prompted the search for ways to improve ET outcomes, with current research focused on pharmacological agents that can augment ET by strengthening fear extinction learning. Hallucinogenic drugs promote reprocessing of fear‐imbued memories and induce positive mood and openness, relieving anxiety and enabling the necessary emotional engagement during psychotherapeutic interventions. Mechanistically, hallucinogens induce dynamic structural and functional neuroplastic changes across the fear extinction circuitry and temper amygdala's hyperreactivity to threat‐related stimuli, effectively mitigating one of the hallmarks of fear‐related disorders. This paper provides the first comprehensive review of hallucinogens' potential to alleviate symptoms of fear‐related disorders by focusing on their effects on fear extinction and the underlying molecular mechanisms. We overview both preclinical and clinical studies and emphasize the advantages of hallucinogenic drugs over current first‐line treatments. We highlight 3,4‐methylenedioxymethamphetamine and ketamine as the most effective therapeutics for fear‐related disorders and discuss the potential molecular mechanisms responsible for their potency with implications for improving hallucinogen‐assisted psychotherapy.
MDMA's first identified potential as a therapeutic catalyst was for couple therapy. Early work in the 1970s and 1980s explored its potential amongst seasoned psychotherapists and their clients. With the completion of the first pilot trial of MDMA-assisted psychotherapy with couples for PTSD, and as the possibility of conducting MDMA-assisted psychotherapy trials expands due to new regulatory frameworks, we have an opportunity to explore and investigate how and why MDMA-assisted couples therapy works. This theoretical paper will explore the neurobiological and neurochemical effects of MDMA in a relational context, the emotional, behavioral, cognitive and somatic effects within a dyadic frame, and how empathy, communication, perception of social connection/support, non-avoidance, openness, attachment/safety, bonding/social intimacy and relationship satisfaction, are all impacted by MDMA, and can be harnessed to facilitate systems-level and interpersonal healing and growth. A model to support MDMA-assisted couple therapy is introduced, and future directions, including implications for intervention development and delivery, will be elucidated.
3,4-Methylenedioxymethamphetamine (MDMA) is a psychostimulant known for producing positive subjective effects and for enhancing social functioning and social connection in both clinical and recreational settings. Over the past two decades, scientists have begun to study the psychological effects of MDMA through rigorous placebo-controlled experimental work. However, most existing studies have small N s, and the average sizes of the reported effects are unknown, creating uncertainty about the impact of these findings. The goal of the present study was to quantify the strength of MDMA’s effects on self-reported social connection by aggregating sociability-related outcomes across multiple placebo-controlled studies. To this end, we conducted a multilevel meta-analysis based on 27 studies, 54 effect sizes, and a total of 592 participants. The results revealed a moderate-to-large effect ( d = 0.86; 95% CI [0.68, 1.04]; r = .39; 95% CI [.32, .46]) of MDMA on self-reported sociability-related outcomes (e.g., feeling loving, talkative, and friendly). Given the magnitude of its effect on felt sociability, we propose that MDMA may have powerful implications for a variety of social contexts and for clinical settings, in particular. Finally, we discuss potential mechanisms underlying the relationship between MDMA and sociability-related feelings, as well as future directions for experimental work in this area.
Résumé
On estime que le syndrome de stress post-traumatique (PTSD) reste chronique et sévère pour 25 à 50 % des patients malgré une prise en charge psychothérapeutique. La MDMA (« ecstasy ») possèderait des propriétés psychopharmacologiques qui renforcent l’alliance thérapeutique et permettent au patient de travailler sur le contenu traumatique sans être submergé par la peur et l’anxiété. Les résultats d’essais cliniques de phase II confirment que la MDMA améliore efficacement la prise en charge psychothérapeutique des patients atteints de PTSD sans effets secondaires sérieux. Des essais de phases III sont en cours. La Multidisciplinary Association for Psychedelic Studies (MAPS) a mis en ligne une proposition de méthode et forme des thérapeutes pour mener des psychothérapies assistées par la MDMA. La Food and Drug Administration (FDA) et l’European Medicines Agency (EMA) pourraient autoriser cet outil thérapeutique dans les prochaines années.
This review examines the role of trauma in psychiatric morbidity and analogous psychoneurobiological changes. Trauma is a necessary criterion for Post-Traumatic Stress Disorder (PTSD), however, trauma history is highly correlated with a variety of psychiatric conditions. Some evidence suggests that Major Depressive Disorder (MDD) is the most common psychiatric condition that arises following trauma. Approximately 50% of PTSD cases present with co-morbid MDD. Overlapping symptomatology and neurobiology between these conditions underlie the debate over whether these phenomena result from problematic nosology or whether comorbid MDD + PTSD is a distinct phenotype of trauma-related psychopathology. Regardless, similar treatment approaches have been employed historically, with varying success. The drug-assisted psychotherapy treatment model, which combines pharmacological and psychotherapeutic approaches, is currently being trialled as a novel treatment approach in psychiatry. Both psilocybin- and 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have received Food and Drug Administration ‘breakthrough therapy’ designation for the treatment of resistant MDD and PTSD, respectively. This paper reviews the therapeutic rationale of both psilocybin and MDMA for treating both trauma-related MDD and PTSD.
Background:
PTSD is a chronic condition with high rates of comorbidity, but current treatment options are limited and not always effective. One novel approach is MDMA-assisted psychotherapy for people diagnosed with treatment-resistant PTSD, where MDMA is used as a catalyst to facilitate trauma processing during psychotherapy. The aim was to review all current research into MDMA-assisted psychotherapy for PTSD.
Methods:
Articles were identified through PubMed and Science Direct for items published up to 31st March 2019 using terms "treatments for PTSD", "drug treatments for PTSD", "MDMA", "MDMA pathway", "MDMA-assisted psychotherapy" and "MDMA-assisted psychotherapy for PTSD". Articles were identified through Google Scholar and subject-specific websites. Articles and relevant references cited in those articles were reviewed.
Results:
Small-scale studies have shown reduced psychological trauma, however there has been widespread misunderstanding of the aims and implications of this work, most commonly the notion that MDMA is a 'treatment for PTSD', which to date has not been researched. This has harmful consequences, namely dangerous media reporting and impeding research progression in an already controversial field.
Conclusions:
MDMA-assisted psychotherapy may help people who have experienced psychological trauma and who have not been able to resolve their problems through existing treatments, however more research is needed. If this is to get appropriate research attention, we must report this accurately and objectively.
Background:
This study was conducted to investigate the short-term behavioral and neurophysiological effects of MDMA (3,4-methylenedioxymethamphetamine) on tinnitus perception.
Methods:
A double-blind randomized controlled cross-over design. Part 1. Behavioural measures of tinnitus following 30 mg MDMA or placebo administration (N = 5 participants) and Part 2. Behavioral measures of tinnitus and correlations between pairs of apriori regions of interest (ROI) using resting-state functional magnetic resonance imaging (rs-fMRI) before and after 70 mg of MDMA or placebo (N = 8 participants).
Results:
The results to MDMA were similar to placebo. For the 70 mg dose there was a significant reduction after 4 hours in annoyance and ignore ratings. RsMRI showed decreased connectivity compared to placebo administration between the left hippocampal, right hippocampal, left amygdala and right amygdala regions, and between the right posterior parahippocampal cortex and the left amygdala after two hours of 70 mg MDMA administration. Increased connectivity compared to placebo administration was found post MDMA between the right post-central gyrus and right posterior and superior temporal gyrus, and between the thalamus and frontoparietal network.
Conclusions:
Following 70 mg of MDMA two tinnitus rating scales significantly improved. There was, however, a placebo effect. Compared to placebo the rsMRI following the MDMA showed reductions in connectivity between the amygdala, hippocampus and parahippocampal gyrus. There is sufficient proof of concept to support future investigation of MDMA as a treatment for tinnitus.
Background
Recognition of emotions in facial expressions (REFE) is a key aspect of social cognition. Anxiety and mood disorders are associated with deficits in REFE, and anxiolytics and antidepressants reverse these deficits. Recent studies have shown that serotonergic hallucinogens (i.e. ayahuasca, dimethyltryptamine, psilocybin, lysergic acid diethylamide [LSD], and mescaline) have anxiolytic and antidepressant properties, but their effects on REFE are not well understood. The purpose of the study was to conduct a systematic review analyzing the effects of serotonergic hallucinogens on REFE in humans.
Methods
Studies published in the PubMed, PsycINFO, and Web of Science databases until 19 October 2018 which analyzed the effects of serotonergic hallucinogens on REFE in humans were included.
Results
Of the 62 studies identified, 8 studies were included. Included studies involved the administration of a single or a few doses of LSD or psilocybin, and most trials were randomized and controlled with placebo. LSD and psilocybin reduced the recognition of negative emotions in most studies and modulated amygdala activity to these stimuli, which was correlated with antidepressive effects in patients. Both drugs were well tolerated.
Conclusions
Serotonergic hallucinogens reduced the recognition of negative emotions by modulating amygdala activity. Despite the small sample sizes, results suggest that serotonergic hallucinogens show promising beneficial effects on deficits in REFE.
Since the early 1990s, hallucinogenic drugs, such as psilocybin, have been increasingly used to investigate the neuronal basis of altered states of consciousness and psychosis. Furthermore, renewed interest has emerged in using these drugs as an adjunct to psychotherapy. Nevertheless, the therapeutic and experimental use of these substances is still controversial due to fears of potential harm. Although the experience of many in- vestigators suggests that potential risks are minimal when these drugs are administered in a carefully monitored clinical or research environment, the subjective tolerability of these drugs under these conditions has not yet been evaluated in large samples. The revival of hallucinogen research during the past 20 years has also greatly increased the need for well-validated instruments assessing the the acute subjective effects of these drugs. Although Adolf Dittrich’s questionnaires for the assessment of altered states of consciousness (ASCs) were frequently used for this purpose, especially in Europe, the factorial structure of these questionnaires is not clearly established because previ- ous psychometric investigations have serious methodological limitations. Finally, the effects of hallucinogens are believed to be critically dependent on non-pharmacological variables (e.g., the user’s personality, current mood state and environment), but few empirical studies have investigated several of these predictor variables at a time. Thus, little is known about the order of importance of these variables. To solve these problems, three empirical studies were conducted, all of which were based on pooled data from Prof. Vollenweider’s research group at the University Hospital of Psychiatry in Zurich. Vollenweider’s group was one on the first to restart human hallucinogen research in the early 1990s and since then has collected an amount of data that is unrivaled in the world. In the first study, acute, subacute, and long-term subjective effects of psilocybin were investigated by analyzing the pooled data of eight double-blind placebo-controlled experimental studies. The sample included 110 healthy subjects who had received 1-4 oral doses of psilocybin in a dose range of 45-315 μg/kg body weight. It was found that the effects of psilocybin were generally well tolerated. Most subjects described the experience as pleasurable, enriching, and non-threatening. Strong anxiety and/or dysphoria occurred only in the two highest dose conditions in a relatively small proportion of subjects and in all cases resolved by providing emotional support and without pharmacological intervention. Complaints 24 h after drug intake were mild and mostly included headache and fatigue. Furthermore, follow-up interviews conducted 8-16 months after the psilocybin sessions indicated that all of the subjects were healthy and that none of them had experienced any of the most feared negative consequences of hallucinogen exposure, that is, flashbacks, prolonged psychosis, or subsequent drug abuse.
Background::
Posttraumatic stress disorder often does not resolve after conventional psychotherapies or pharmacotherapies. Pilot studies have reported that 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy reduces posttraumatic stress disorder symptoms.
Aims::
This pilot dose response trial assessed efficacy and safety of MDMA-assisted psychotherapy across multiple therapy teams.
Methods::
Twenty-eight people with chronic posttraumatic stress disorder were randomized in a double-blind dose response comparison of two active doses (100 and 125 mg) with a low dose (40 mg) of MDMA administered during eight-hour psychotherapy sessions. Change in the Clinician-Administered PTSD Scale total scores one month after two sessions of MDMA served as the primary outcome. Active dose groups had one additional open-label session; the low dose group crossed over for three open-label active dose sessions. A 12-month follow-up assessment occurred after the final MDMA session.
Results::
In the intent-to-treat set, the active groups had the largest reduction in Clinician-Administered PTSD Scale total scores at the primary endpoint, with mean (standard deviation) changes of -26.3 (29.5) for 125 mg, -24.4 (24.2) for 100 mg, and -11.5 (21.2) for 40 mg, though statistical significance was reached only in the per protocol set ( p=0.03). Posttraumatic stress disorder symptoms remained lower than baseline at 12-month follow-up ( p<0.001) with 76% ( n=25) not meeting posttraumatic stress disorder criteria. There were no drug-related serious adverse events, and the treatment was well-tolerated.
Conclusions::
Our findings support previous investigations of MDMA-assisted psychotherapy as an innovative, efficacious treatment for posttraumatic stress disorder.
The chapter focuses on the mechanisms through which the serotoninergic system can induce hallucinations, altering sensory perceptive functions. The hallucinogenic activity of the serotoninergic receptors has been noticed since perceptual alterations induced by the consumption of some recreational drugs, such as LSD and ecstasy, were observed. Hallucinogenic effects and specific molecular mechanisms of action are discussed in this chapter. Hallucinogens and entactogens can both produce hallucinations through an increase of the serotoninergic pathway activity, which is thought to be one of the pathophysiological processes underlying positive symptoms. LSD and MDMA seem to act with a different molecular mechanism. The main molecular effect of classical hallucinogens consists of increasing 5-HT brain levels, since they act as 5-HT receptor agonists. 5-HT2A receptors, mainly localized in medial prefrontal cortex, thalamic reticular nucleus, locus coeruleus and raphe nucleus, seem to be the most important hallucinogenic target, even if it has been demonstrated that 5-HT2C receptors could also be required. Hallucinogens therefore alter ascending sensory information processed through the thalamus. This could be mediated through alterations in different systems leading to a sensorial information overload. Classical hallucinogens should be considered as potent modulators of cortex network activity through the augmented 5-HT2A agonist activity in the medial prefrontal cortex, the reduced inhibitory activity by thalamic reticular nucleus, the altered firing of raphe nucleus, and the increased activity in the locus coeruleus. Entactogens seem to act increasing intracellular and extracellular 5-HT levels by inhibiting the SERT activity, reversing its action through TAAR1 agonism, inhibiting VMAT2, and inhibiting the MAO enzymes. Entactogens also act on NET, and to a lesser extent on DAT. The hallucinogenic effect of entactogens is probably also due to a partial agonist activity on 5-HT2A activity.
Rationale
Standard therapeutic approaches to reduce social anxiety in autistic adults have limited effectiveness. Since 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy shows promise as a treatment for other anxiety disorders, a blinded, placebo-controlled pilot study was conducted.
Objectives
To explore feasibility and safety of MDMA-assisted psychotherapy for reduction of social fear and avoidance that are common in the autistic population.
Methods
Autistic adults with marked to very severe social anxiety were randomized to receive MDMA (75 to 125 mg, n = 8) or inactive placebo (0 mg, n = 4) during two 8-h psychotherapy sessions (experimental sessions) in a controlled clinical setting. Double-blinded experimental sessions were spaced approximately 1 month apart with 3 non-drug psychotherapy sessions following each. The primary outcome was change in Leibowitz Social Anxiety Scale (LSAS) Total scores from Baseline to one month after the second experimental session. Outcomes were measured again six months after the last experimental session.
Results
Improvement in LSAS scores from baseline to the primary endpoint was significantly greater for MDMA group compared to the placebo group (P = 0.037), and placebo-subtracted Cohen’s d effect size was very large (d = 1.4, CI − 0.074, 2.874). Change in LSAS scores from baseline to 6-month follow-up showed similar positive results (P = 0.036), with a Cohen’s d effect size of 1.1 (CI − 0.307, 2.527). Social anxiety remained the same or continued to improve slightly for most participants in the MDMA group after completing the active treatment phase.
Conclusions
This pilot trial demonstrated rapid and durable improvement in social anxiety symptoms in autistic adults following MDMA-assisted psychotherapy. Initial safety and efficacy outcomes support expansion of research into larger samples to further investigate this novel treatment for social anxiety.
Trial registration
clinicaltrials.gov identifier, NCT00302744
The pervasive impact of trauma across populations and stages of life has made it imperative that the field of social work remain at the forefront of trauma-informed theory, research, and practice. The limited, adjunctive use of 3,4-methylenedioxymethamphetamine (MDMA) in the psychotherapeutic treatment of posttraumatic stress disorder (PTSD) is a promising new treatment model that has shown impressive efficacy in phase I and II clinical trials. Preliminary meta-analysis suggests that MDMA-assisted psychotherapy (MDMA-PT) may be superior to prolonged exposure, a first-line treatment for PTSD, and the U.S. Food and Drug Administration (FDA) has granted the treatment “breakthrough therapy” designation, a process of expedited review which signals that a treatment may demonstrate substantial improvement over existing therapies. Though these results are encouraging, much remains unknown and it is essential that the field of social work become informed and engaged in this new body of research. This paper will review the existing literature on MDMA-PT for PTSD, examine ethical and safety concerns, present a preliminary conceptualization of MDMA-PT’s impact on the therapeutic process, and discuss implications for future social work research and practice. This paper finds that the current literature suggests that MDMA-PT is a safe and efficacious treatment that has the potential to revolutionize the treatment of trauma. At the same time, issues of safety, cost, and accessibility should be examined in depth to ensure that this treatment—if approved by the FDA—is accessible to racially and economically marginalized clients.
3,4-Methylenedioxymethamphetamine (MDMA), also known as ecstasy, was first synthesized in 1912 but first reached widespread popularity as a legal alternative after the much sought-after recreational drug 3,4-methylenedioxy-amphetamine (MDA) was made illegal in 1970. Because of its benign, feeling-enhancing, and nonhallucinatory properties, MDMA was used by a few dozen psychotherapists in the United States between 1977 and 1985, when it was still legal. This article looks into the contexts and practices of its psychotherapeutic use during these years. Some of the guidelines, recommendations, and precautions developed then are similar to those that apply to psychedelic drugs, but others are specific for MDMA. It is evident from this review that the therapists pioneering the use of MDMA were able to develop techniques (and indications/counterindications) for individual and group therapy that laid the groundwork for the use of MDMA in later scientific studies. In retrospect, it appears that the perceived beneficial effects of MDMA supported a revival of psycholytic/psychedelic therapy on an international scale.
Rationale:
Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial "psychedelic effect," which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy.
Objective:
Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories.
Results:
We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition.
Conclusions:
Metaplasticity may be the process in common between cannabinoids and ketamine/ketamine-like substance effects on the mediation and potential manipulation of maladaptive memories.
Pharmacotherapy is often used to target symptoms of posttraumatic stress disorder (PTSD), but does not provide definitive treatment, and side effects of daily medication are often problematic. Trauma-focused psychotherapies are more likely than drug treatment to achieve PTSD remission, but have high dropout rates and ineffective for a large percentage of patients. Therefore, research into drugs that might increase the effectiveness of psychotherapy is a logical avenue of investigation. The most promising drug studied as a catalyst to psychotherapy for PTSD thus far is 3,4-methylenedioxymethamphetamine (MDMA), commonly known as the recreational drug “Ecstasy.” MDMA stimulates the release of hormones and neurochemicals that affect key brain areas for emotion and memory processing. A series of recently completed phase 2 clinical trials of MDMA-assisted psychotherapy for treatment of PTSD show favorable safety outcomes and large effect sizes that warrant expansion into multi-site phase 3 trials, set to commence in 2018. The nonprofit sponsor of the MDMA drug development program, the Multidisciplinary Association for Psychedelic Studies (MAPS), is supporting these trials to explore whether MDMA, administered on only a few occasions, can increase the effectiveness of psychotherapy. Brain imaging techniques and animal models of fear extinction are elucidating neural mechanisms underlying the robust effects of MDMA on psychological processing; however, much remains to be learned about the complexities of MDMA effects as well as the complexities of PTSD itself.
Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.
Given the plethora of new studies and published papers in the scientific press and the increasingly emerging presence of articles about positive psychedelic experiences appearing in the popular media, there is little doubt that we are in the midst of a Psychedelic Renaissance. The classical psychedelic drugs LSD and psilocybin and the entactogen MDMA are showing promise as tools to assist psychotherapy for a wide range of mental disorders, with multiple pilot studies demonstrating their safety and efficacy. In this article, the author describes how MDMA in particular has inherent characteristics that make it well suited for assisting trauma-focused psychotherapy in a population of patients who have experienced child abuse. But despite these advances, there remain many obstacles ahead of the widespread mainstream acceptance of psychedelic medicines. The author argues that the Misuse of Drugs Act 1971 is one such obstacle. Other impediments include a prevailing attitude of pseudoscience and rigidity from within the non-scientific psychedelic community itself. Resolution of these conflicts must be sought if medicine and society are to see psychedelics gaining a place in mainstream culture and science.
Background:
MDMA has been shown to induce feelings of sociability, a positive emotional bias and enhanced empathy. While previous research has used only visual emotional stimuli, communication entails more than that single dimension and it is known that auditory information is also crucial in this process. In addition, it is, however, unclear what the neurobiological mechanism underlying these MDMA effects on social behaviour is. Previously, studies have shown that MDMA-induced emotional excitability and positive mood are linked to the action on the serotonin (5-HT) 2A receptor.
Aim:
The present study aimed at investigating the effect of MDMA on processing of sounds (Processing of Affective Sounds Task (PAST)) and cognitive biases (Approach-Avoidance Task (AAT)) towards emotional and social stimuli and the role of 5-HT2A receptor in these effects.
Methods:
Twenty healthy recreational users entered a 2 × 2, placebo-controlled, within-subject study with ketanserin (40 mg) as pre-treatment and MDMA (75 mg) as treatment. Behavioural (PAST, AAT) measures were conducted 90 min after treatment with MDMA, respectively, 120 min after ketanserin. Self-report mood measures and oxytocin concentrations were taken at baseline and before and after behavioural tests.
Results:
Findings showed that MDMA reduced arousal elicited by negative sounds. This effect was counteracted by ketanserin pre-treatment, indicating involvement of the 5-HT2 receptor in this process. MDMA did not seem to induce a bias towards emotional and social stimuli. It increased positive and negative mood ratings and elevated oxytocin plasma concentrations. The reduction in arousal levels when listening to negative sounds was not related to the elevated subjective arousal.
Conclusion:
It is suggested that this decrease in arousal to negative stimuli reflects potentially a lowering of defences, a process that might play a role in the therapeutic process.
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 within-subject 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 minutes 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.
A growing body of research suggests that traumatic events lead to persisting personality change characterized by increased neuroticism. Relevantly, enduring improvements in Post-Traumatic Stress Disorder (PTSD) symptoms have been found in response to 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. There is evidence that lasting changes in the personality feature of “openness” occur in response to hallucinogens, and that this may potentially act as a therapeutic mechanism of change. The present study investigated whether heightened Openness and decreased Neuroticism served as a mechanism of change within a randomized trial of MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD. The Clinician-Administered PTSD Scale (CAPS) Global Scores and NEO PI-R Personality Inventory (NEO) Openness and Neuroticism Scales served as outcome measures. Results indicated that changes in Openness but not Neuroticism played a moderating role in the relationship between reduced PTSD symptoms and MDMA treatment. Following MDMA-assisted psychotherapy, increased Openness and decreased Neuroticism when comparing baseline personality traits with long-term follow-up traits also were found. These preliminary findings suggest that the effect of MDMA-assisted psychotherapy extends beyond specific PTSD symptomatology and fundamentally alters personality structure, resulting in long-term persisting personality change. Results are discussed in terms of possible mechanisms of psychotherapeutic change.
Since the late 1980s the psychoactive drug 3,4-methylenedioxymethamphetamine (MDMA) has had a well-known history as the recreationally used drug ecstasy. What is less well known by the public is that MDMA started its life as a therapeutic agent and that in recent years an increasing amount of clinical research has been undertaken to revisit the drug’s medical potential. MDMA has unique pharmacological properties that translate well to its proposed agent to assist trauma-focused psychotherapy. Psychological trauma—especially that which arises early in life from child abuse—underpins many chronic adult mental disorders, including addictions. Several studies of recent years have investigated the potential role of MDMA-assisted psychotherapy as a treatment for post-traumatic stress disorder, with ongoing plans to see MDMA therapy licensed and approved within the next 5 years. Issues of safety and controversy frequently surround this research, owing to MDMA’s often negative media-driven bias. However, accurate examination of the relative risks and benefits of clinical MDMA—in contrast to the recreational use of ecstasy—must be considered when assessing its potential benefits and the merits of future research. In this review, the author describes these potential benefits and explores the relatives risks of MDMA-assisted psychotherapy in the context of his experience as a child and adolescent psychiatrist, having seen the relative limitations of current pharmacotherapies and psychotherapies for treating complex post-traumatic stress disorder arising from child abuse.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-017-0531-1) contains supplementary material, which is available to authorized users.
The brain’s serotonergic system plays a crucial role in the processing of emotional stimuli, and several studies have shown that a reduced serotonergic neurotransmission is associated with an increase in amygdala activity during emotional face processing. Prolonged recreational use of ecstasy (3,4-methylene-dioxymethamphetamine [MDMA]) induces alterations in serotonergic neurotransmission that are comparable to those observed in a depleted state. In this functional magnetic resonance imaging (fMRI) study, we investigated the responsiveness of the amygdala to emotional face stimuli in recreational ecstasy users as a model of long-term serotonin depletion. Fourteen ecstasy users and 12 non-using controls underwent fMRI to measure the regional neural activity elicited in the amygdala by male or female faces expressing anger, disgust, fear, sadness, or no emotion. During fMRI, participants made a sex judgement on each face stimulus. Positron emission tomography with ¹¹C-DASB was additionally performed to assess serotonin transporter (SERT) binding in the brain. In the ecstasy users, SERT binding correlated negatively with amygdala activity, and accumulated lifetime intake of ecstasy tablets was associated with an increase in amygdala activity during angry face processing. Conversely, time since the last ecstasy intake was associated with a trend toward a decrease in amygdala activity during angry and sad face processing. These results indicate that the effects of long-term serotonin depletion resulting from ecstasy use are dose-dependent, affecting the functional neural basis of emotional face processing.
There is a range of therapies to treat Post Traumatic Stress Disorder (PTSD) but treatment resistance remains high, with many sufferers experiencing the chronic condition. Engagement in trauma-focused psychotherapy is difficult for some patients with PTSD, especially those with extreme affect dysregulation associated with recall of traumatic memories. In recent years there have been a number of neuroscientific and clinical studies examining the potential role for adjunctive drug-assisted psychotherapy using 3,4,-methylenedioxmethamphetamine (MDMA) as a treatment for PTSD. re-visiting of a novel approach to trauma-focused psychotherapy with Used just two or three times, under careful medical supervision and specialised psychotherapy support MDMA appears to facilitate the recall of traumatic memories without the user feeling overwhelmed by the negative affect that usually accompanies such memories. This therapeutic approach began in the 1980s and was subsequently shelved in the midst of public health concerns surrounding the recreational use of the drug ecstasy. When pharmaceutical grade MDMA is used in a clinical setting it does not share the same risk profiles as ecstasy. Recent phase one neurophysiological studies and phase two clinical studies are showing promise as a potential new approach to managing treatment-resistant PTSD.
Hallucinogenic substances extend back into pre-history as religious sacraments, as shamanic medicines, and as part of some tribal rituals, but the reader is likely most familiar with their recreational, illicit use. Since the most potent hallucinogen, lysergic acid diethylamide, “escaped” the research laboratory and fueled, starting in the 1960s, a popular movement of awareness about the potentials for hallucinogen intoxication, “modern” societies have resisted their acceptance. Despite prohibition, some 35 million Americans are estimated to have tried a hallucinogen at least once in their lifetime and approximately 4 million are active users (at least one use in a year); yet less than 17,000 emergency room visits per year are associated with hallucinogen use. This chapter reviews basic pharmacology, including psychological and physiological effects, and then presents the most common hallucinogen use disorders (with assessment, differential diagnosis, and treatment options) that are likely to be encountered by medical and allied health care providers. The chapter concludes with a brief update on research suggesting that hallucinogens may assist in recovery from other substance abuse and dependence, and a caution for current research to avoid the methodological flaws and excesses that took place some 40–50 years ago.
4-phosphorloxy-N,N-dimethyltryptamine (psilocybin) and methylenedioxymethamfetamine (MDMA), best known for their illegal use as psychedelic drugs, are showing promise as therapeutics in a resurgence of clinical research during the past 10 years. Psilocybin is being tested for alcoholism, smoking cessation, and in patients with advanced cancer with anxiety. MDMA is showing encouraging results as a treatment for refractory post-traumatic stress disorder, social anxiety in autistic adults, and anxiety associated with a life-threatening illness. Both drugs are studied as adjuncts or catalysts to psychotherapy, rather than as stand-alone drug treatments. This model of drug-assisted psychotherapy is a possible alternative to existing pharmacological and psychological treatments in psychiatry. Further research is needed to fully assess the potential of these compounds in the management of these common disorders that are difficult to treat with existing methods.
Like mescaline, the primary psychoactive ingredient in peyote, MDMA belongs to a group of ring-substituted amphetamine congeners, commonly called “methoxylated amphetamines” (Fig. 6). The drug MDMA is a potent indirect monoaminergic agonist, which is thought to act by both increasing the release and inhibiting the reuptake of serotonin and, to a lesser extent, dopamine [14]. Serotonin is involved in the regulation of a variety of behavioral functions, including mood, anxiety, aggression, appetite, and sleep. Dopamine is the primary neuro-transmitter of the “reward pathway” and is involved in motivational processes such as reward and reinforcement. Norepinephrine has important roles in the process of attention and arousal. In vitro studies have shown, that MDMA causes release of serotonin, dopamine, and norepinephrine from synaptosomes [15, 16] and from rat brain slices [14]. In freely moving rats, MDMA increases both serotonin and dopamine release in the caudate [14]. In a similar study, MDMA increased dopamine release in awake rats, resulting in region-, time-, and dose-dependent behavior [17]. In rat brain synaptosomes, MDMA inhibited the uptake of serotonin and norepinephrine and, to a lesser extent, dopamine. The local administration of MDMA to the rat nucleus accumbens resulted in increases in the extracellular levels of both serotonin and dopamine in this region, which is part of the reward pathway activated by other abused substances such as amphetamine and cocaine. These actions in the nucleus accumbens may account for the euphoric effects produced by MDMA.
Post-traumatic stress disorder (PTSD) is a serious psychiatric consequence of trauma that occurs in a proportion of individuals exposed to life-threatening events. Trauma-focused psychotherapy is often recommended as first choice for those who do not recover spontaneously. But many individuals require medications. In the US, only paroxetine (PRX) and sertraline (SRT) are FDA approved for PTSD. But response and remission rates with these medications are low, so numerous other pharmacologic interventions have been tried. To date, there has not been a systematic review of the data on what are the best next-step pharmacologic strategies for individuals who fail standard treatments. To that end, we review 167 published trials of medications other than PRX or SRT and provide a detailed analysis of the 88/167 studies that describe alternative pharmacologic interventions in patients refractory to other treatment. We also review clinical factors relevant to treatment-refractory PTSD; the neurobiology of extinction, as well as evidence-based psychotherapy and neuromodulation strategies for this condition.
MDMA ("ecstasy") has been widely reported as a drug of abuse and as a neurotoxin. This report describes the mechanism of MDMA action at serotonin transporters from plasma membranes and secretory vesicles. MDMA stimulates serotonin efflux from both types of membrane vesicle. In plasma membrane vesicles isolated from human platelets, MDMA inhibits serotonin transport and [3H]imipramine binding by direct interaction with the Na(+)-dependent serotonin transporter. MDMA stimulates radiolabel efflux from plasma membrane vesicles preloaded with [3H]serotonin in a stereo-specific, Na(+)-dependent, and imipramine-sensitive manner characteristic of transporter-mediated exchange. In membrane vesicles isolated from bovine adrenal chromaffin granules, which contain the vesicular biogenic amine transporter, MDMA inhibits ATP-dependent [3H]serotonin accumulation and stimulates efflux of previously accumulated [3H]serotonin. Stimulation of vesicular [3H]serotonin efflux is due to dissipation of the transmembrane pH difference generated by ATP hydrolysis and to direct interaction with the vesicular amine transporter.
This study was undertaken to identify brain structures associated with emotion in normal elderly subjects.
Eight normal subjects aged 55-78 years were shown film clips intended to provoke the emotions of happiness, fear, or disgust as well as a neutral state. During emotional activation, regional cerebral blood flow was measured with the use of [15O]H2O positron emission tomography imaging, and subjective emotional responses were recorded. Data were analyzed by subtracting the values during the neutral condition from the values in the various emotional activations.
The stimuli produced a general activation in visual pathways that included the primary and secondary visual cortex, involving regions associated with object and spatial recognition. In addition, the specific emotions produced different regional limbic activations, which suggests that different pathways may be used for different types of emotional stimuli.
Emotional activation in normal elderly subjects was associated with increases in blood flow in limbic and paralimbic brain structures. Brain activation may be specific to the emotion being elicited but probably involves complex sensory, association, and memory circuitry. Further studies are needed to identify activations that are specific for emotion.
3, 4-methylenedioxymethamphetamine (MDMA, "Ecstasy") is a recreational drug reported to produce a different psychological profile than that of classic hallucinogens and stimulants. It has, therefore, been tentatively classified into a novel pharmacological class termed entactogens. This double-blind placebo-controlled study examined the effects of a typical recreational dose of MDMA (1.7 mg/kg) in 13 MDMA-naïve healthy volunteers. MDMA produced an effective state of enhanced mood, well-being, and increased emotional sensitiveness, little anxiety, but no hallucinations or panic reactions. Mild depersonalization and derealization phenomena occurred together with moderate thought disorder, first signs of loss of body control, and alterations in the meaning of percepts. Subjects also displayed changes in the sense of space and time, heightened sensory awareness, and increased psychomotor drive. MDMA did not impair selective attention as measured by the Stroop test. MDMA increased blood pressure moderately, with the exception of one subject who showed a transient hypertensive reaction. This severe increase in blood pressure indicates that the hypertensive effects of MDMA, even at recreational doses, should not be underestimated, particularly in subjects with latent cardiovascular problems. Most frequent acute somatic complaints during the MDMA challenge were jaw clenching, lack of appetite, impaired gait, and restless legs. Adverse sequelae during the following 24 hours included lack of energy and appetite, feelings of restlessness, insomnia, jaw clenching, occasional difficulty concentrating, and brooding. The present findings are consistent with the hypothesis that MDMA produces a different psychological profile than classic hallucinogens or psychostimulants.
This paper concerns the spatial and intensity transformations that map one image onto another. We present a general technique that facilitates nonlinear spatial (stereotactic) normalization and image realignment. This technique minimizes the sum of squares between two images following nonlinear spatial deformations and transformations of the voxel (intensity) values. The spatial and intensity transformations are obtained simultaneously, and explicitly, using a least squares solution and a series of linearising devices. The approach is completely noninteractive (automatic), nonlinear, and noniterative. It can be applied in any number of dimensions.
Various applications are considered, including the realignment of functional magnetic resonance imaging (MRI) time-series, the linear (affine) and nonlinear spatial normalization of positron emission tomography (PET) and structural MRI images, the coregistration of PET to structural MRI, and, implicitly, the conjoining of PET and MRI to obtain high resolution functional images.
This study assessed the modulatory effect of a serotonergic agonist, d-fenfluramine, on localized neuronal firing as indexed by changes in regional cerebral blood flow (rCBF). Previously, we reported the effect of oral d,l-fenfluramine on neuronal activity as measured by change in [18F]fluorodeoxyglucose uptake. Improvements in the current study include: a more specific serotonin agonist, d-fenfluramine; a more reliable administration route, intravenous; and a one session paradigm made possible with the radiotracer [15O]H2O. Changes in relative rCBF (P < 0.001) were observed: increases within the frontal cortex bilaterally and decreases within the temporal cortex bilaterally, and left thalamus. Other significant findings were elevated cortisol and growth hormone; increased euphoria and panic symptoms and decreased tiredness. These results support further investigation with intravenous d-fenfluramine to study the net functional effects of serotonergic stimulation in health and illness.
We investigated the effects of acute i.v. administration of 2 mg of delta 9-tetrahydrocannabinol (THC) on regional brain glucose metabolism using 18F-2-fluoro-2-deoxyglucose and positron emission tomography (PET) in eight normal subjects. Subjects were tested twice: during baseline conditions and 30-40 min after THC administration. Changes in global cerebral glucose metabolism in response to THC were variable: three subjects showed an increase, three showed a decrease, and two showed no change. In contrast, all subjects showed an increase in normalized metabolism in the cerebellum following THC administration. Cerebellar changes were the only significant regional metabolic changes due to THC administration. The increase in metabolic activity in the cerebellum was correlated with the subjective sense of THC intoxication and with plasma THC concentration. Cerebellar localization of metabolic effects due to THC administration corresponds well with the high density of cannabinoid receptors known to be in this area.
The neurochemical effects of the unique psychedelic agent, methylenedioxymethamphetamine (MDMA), indicate it may be a serotonergic neurotoxin related to agents such as p-chloroamphetamine. MDMA had a biphasic effect on cortical serotonin concentrations beginning with an acute depletion of the transmitter which reached a maximum between 3 and 6 hr after drug administration. This early phase of depletion was reversible because cortical serotonin concentrations had recovered to control levels by 24 hr. However, transmitter concentrations were reduced significantly 1 week later, indicating a second phase of depletion. The latter phase of depletion was associated with a decrease in synaptosomal [3H]serotonin uptake due to a loss in the number of uptake sites with no change in the affinity of the carrier for serotonin. This neurotoxic effect of MDMA was found to be a property of the (+)-stereoisomer of the drug as only this enantiomer produced the depletion of cortical serotonin and the decrease in synaptosomal serotonin uptake at 1 week. In contrast to this, both stereoisomers of the drug could produce the acute depletion of cortical serotonin measured 3 hr after drug administration. Coadministration of the selective serotonin uptake inhibitor, fluoxetine, completely blocked the reduction in cortical serotonin concentrations 1 week after MDMA. Administration of fluoxetine at various times after MDMA revealed that the long-term effects of the drug developed independently of the acute depletion of serotonin and could be partially blocked by the uptake inhibitor as long as 6 hr after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of the recently classified Schedule I amphetamine analog, 3,4-methylenedioxymethamphetamine [+/-)-MDMA) on caudate and nucleus accumbens dopamine release and metabolism were studied by in vivo voltammetry and HPLC with electrochemical detection. Monitored over a 3 h period, the magnitude of increase in dopamine release and the onset of effect were dose-dependent and similar for both brain areas following the 2.5 and 5 mg/kg dose of the drug. However, responses were different for these brain regions using 10 mg/kg of MDMA; the magnitude of increase was greater and the onset of effect more immediate in caudate. Analysis of dopamine and DOPAC tissue content in both caudate and nucleus accumbens verified the voltammetry results. This study provides the first evidence that MDMA induces dopamine release in vivo and that this effect is region, time- and dose-dependent.
The specific brain regions involved in the normal emotional states of transient sadness or happiness are poorly understood. The authors therefore sought to determine if H2(15)O positron emission tomography (PET) might demonstrate changes in regional cerebral blood flow (rCBF) associated with transient sadness or happiness in healthy adult women.
Eleven healthy and never mentally ill adult women were scanned, by using PET and H2(15)O, during happy, sad, and neutral states induced by recalling affect-appropriate life events and looking at happy, sad, or neutral human faces.
Compared to the neutral condition, transient sadness significantly activated bilateral limbic and paralimbic structures (cingulate, medial prefrontal, and mesial temporal cortex), as well as brainstem, thalamus, and caudate/putamen. In contrast, transient happiness had no areas of significantly increased activity but was associated with significant and widespread reductions in cortical rCBF, especially in the right prefrontal and bilateral temporal-parietal regions.
Transient sadness and happiness in healthy volunteer women are accompanied by significant changes in regional brain activity in the limbic system, as well as other brain regions. Transient sadness and happiness affect different brain regions in divergent directions and are not merely opposite activity in identical brain regions. These findings have implications for understanding the neural substrates of both normal and pathological emotion.
Cerebral blood flow and glucose utilization were measured in rat neocortex, hippocampus and striatum following methylenedioxymethamphetamine injection (5 mg/kg, i.v.), using the tracers [14C]iodoantipyrine and [14C]2-deoxyglucose, respectively. In control rats, blood flow was coupled to glucose metabolism, but in methylenedioxymethamphetamine-treated rats, marked hyperperfusion was measured in frontal and parietal cortex with no change in glucose use. This suggests that methylenedioxymethamphetamine has the potential to disrupt cerebrovascular control.
Procaine activates limbic structures in animals. In humans, acute intravenous administration of procaine yields emotional and psychosensory experiences and temporal lobe fast activity. We studied procaine's acute effects on cerebral blood flow (CBF) in relationship to clinical responses.
Cerebral blood flow was assessed by positron emission tomography with oxygen-15-labeled water in 32 healthy volunteers. Data were analyzed with statistical parametric mapping and magnetic resonance imaging-directed regions of interest.
Procaine increased global CBF and, to a greater extent, anterior paralimbic CBF. Subjects with intense procaine-induced fear compared with those with euphoria had greater increases in left amygdalar CBF. Absolute and normalized left amygdalar CBF changes tended to correlate positively with fear and negatively with euphoria intensity. Procaine-induced visual hallucinations appeared associated with greater global and occipital CBF increases. Absolute occipital CBF increases appeared to correlate positively with visual hallucination intensity.
Procaine increased anterior paralimbic CBF, and different clinical responses appeared to be associated with different patterns of CBF changes.
Positron emission tomography was used to study the effects of experimentally controlled mood states on cerebral blood flow (CBF), measured with the quantitative equilibrium infusion method and 15O-labeled water. Twenty-seven brain regions in each hemisphere were assessed in 16 normal subjects. CBF and heart rate were measured during happy and sad mood induction, and during two nonemotional control conditions: sex differentiation and resting baseline. Valence-specific effects of mood on CBF were obtained for subcortical, but not for frontal-temporal or control regions. CBF increased in left amygdala and decreased in right amygdala during sad mood relative to the averaged control conditions. These changes correlated with shifts toward negative affect. Correlations were opposite for subcortical (negative affect associated with lower left hemispheric CBF) compared with frontal-temporal cortical regions. Results support limbic involvement in regulating emotional states and suggest some reciprocity between subcortical and frontal-temporal regulation of emotional experience.
Happiness, sadness, and disgust are three emotions that differ in their valence (positive or negative) and associated action tendencies (approach or withdrawal). This study was designed to investigate the neuroanatomical correlates of these discrete emotions.
Twelve healthy female subjects were studied. Positron emission tomography and [15O]H2O were used to measure regional brain activity. There were 12 conditions per subject: happiness, sadness, and disgust and three control conditions, each induced by film and recall. Emotion and control tasks were alternated throughout. Condition order was pseudo-randomized and counterbalanced across subjects. Analyses focused on brain activity patterns for each emotion when combining film and recall data.
Happiness, sadness, and disgust were each associated with increases in activity in the thalamus and medial prefrontal cortex (Brodmann's area 9). These three emotions were also associated with activation of anterior and posterior temporal structures, primarily when induced by film. Recalled sadness was associated with increased activation in the anterior insula. Happiness was distinguished from sadness by greater activity in the vicinity of ventral mesial frontal cortex.
While this study should be considered preliminary, it identifies regions of the brain that participate in happiness, sadness, and disgust, regions that distinguish between positive and negative emotions, and regions that depend on both the elicitor and valence of emotion or their interaction.
Functional magnetic resonance imaging (fMRI) techniques were used to identify the neural circuitry underlying emotional processing in control and depressed subjects. Depressed subjects were studied before and after treatment with venlafaxine. This new technique provides a method to noninvasively image regional brain function with unprecedented spatial and temporal resolution.
Echo-planar imaging was used to acquire whole brain images while subjects viewed positively and negatively valenced visual stimuli. Two control subjects and two depressed subjects who met DSM-IV criteria for major depression were scanned at baseline and 2 weeks later. Depressed subjects were treated with venlafaxine after the baseline scan.
Preliminary results from this ongoing study revealed three interesting trends in the data. Both depressed patients demonstrated considerable symptomatic improvement at the time of the second scan. Across control and depressed subjects, the negative compared with the positive pictures elicited greater global activation. In both groups, activation induced by the negative pictures decreased from the baseline scan to the 2-week scan. This decrease in activation was also present in the control subjects when they were exposed to the positive pictures. In contrast, when the depressed subjects were presented with the positive pictures they showed no activation at baseline, whereas after 2 weeks of treatment an area of activation emerged in right secondary visual cortex.
While preliminary, these results demonstrate the power of using fMRI to study emotional processes in normal and depressed subjects and to examine mechanisms of action of antidepressant drugs.
A total of 11 children with attention deficit disorder (ADD) and nine control children performed a continuous performance test (CPT) of the A-X type with concurrent neuroelectric brain mapping to assess preparatory processing, purportedly mediated by the frontal lobes. This cued CPT task proved to be a highly specific task. The groups could be clearly differentiated both at the behavioral and electrophysiological level. ADD children detected fewer signals and made more false alarms. There were no major group differences in topographical distribution of the event-related potential microstates, but ADD children displayed reduced global field power (GFP) in an early CNV/P3 microstate to cues. This indicated that impaired orienting to cues, rather than impaired executive target processing, determines the initial processing stages in ADD. In comparison with data from the same task run in Utrecht, the same orienting deficit in clinically diagnosed ADHD children was demonstrated. Low resolution electromagnetic tomography (LORETA) estimated posterior sources underlying these orienting processes and the orienting deficit. This argued against frontal lobe involvement at this stage and suggested involvement of a posterior attention system.
The APZ questionnaire was developed in order to explore hypotheses on ASCs. First -- in a series of 11 experiments using different induction methods on N = 393 healthy subjects -- the hypothesis was tested that ASCs have major dimensions in common irrespective of the mode of their induction. In the International Study on Altered States of Consciousness (ISASC) the external validity of the experimental results was assessed. The ISASC was carried out on a total of N = 1133 subjects in six countries. The main results of the experimental studies were corroborated in the field studies. The results can be summarized as follows: the common denominator of ASCs is described by three oblique dimensions, designated as "Oceanic Boundlessness (OSE)", "Dread of Ego Dissolution (AIA)" and "Visionary Restructuralization (VUS)". The reliability and validity of the scales are satisfactory. Tested versions of the APZ scales are available in English (UK, USA), German, Italian and Portuguese. Psychometrically as yet untested versions exist in Dutch, Finnish, French, Greek, Spanish and Russian. The APZ questionnaire has become the international standard for the assessment of ASCs, thus helping to integrate research. A psychometrically improved version exists in German (OAV questionnaire). The BETA questionnaire, which measures the dimensions "Vigilance Reduction (VIR)" and "Auditive Alteration (AVE)" is also available in German. These dimensions are most likely etiology-dependent.
The neurometabolic effects of the hallucinogen psilocybin (PSI; 0.2 mg/kg), the entactogen 3,4-methylenedioxyethylamphetamine (MDE; 2 mg/kg) and the stimulant d-methamphetamine (METH; 0.2-0.4 mg/kg) and the drugs' interactions with a prefrontal activation task were investigated in a double-blind, placebo-controlled human [F-18]fluorodeoxyglucoseFDG-positron emission tomographicPET study (each group: n = 8). Subjects underwent two scans (control: word repetition; activation word association) within 2-4 weeks. Psilocybin increased rMRGlu in distinct right hemispheric frontotemporal cortical regions, particularly in the anterior cingulate and decreased rMRGlu in the thalamus. Both MDE and METH induced cortical hypometabolism and cerebellar hypermetabolism. In the MDE group, cortical hypometabolism was more pronounced in frontal regions, with the exception of the right anterior cingulate, which tended to be hyperactive. Cognitive activation-related increases in left frontocortical regions were attenuated under all three psychoactive substances, but less so under MDE. Taking into account performance data and subjective reports on task difficulty, these effects may result from different mechanisms across the three groups. Our PSI data are in line with studies on acute schizophrenic patients suggesting frontal overactivity at rest, but diminished capacity to activate prefrontal regions upon cognitive demand. The MDE data support the hypothesis that entactogens constitute a distinct psychoactive substance class, which takes an intermediate position between stimulants and hallucinogens.
Drs. Gijsman, Verkes, van Gerven, and Cohen are of the opinion that the risk of long-term MDMA-produced serotonin reductions makes MDMA too dangerous to administer to humans, even when using a single moderate dose in research contexts.
These are strange and exciting times for researchers who work in the field of psychiatry. Technological advances and the ascendance of the new field of neuroscience, combined with our country's economic prosperity and consequent increases in the National Institutes of Health budget allocations, have created the potential for a virtual Golden Age of Biomedical Research. At the same time, psychiatric researchers are besieged by accusations from lay advocates and their organizations as well as inquiries by government agencies, including the Office of Protection from Research Risks (OPRR) and the National Bioethics Advisory Commission (NBAC) (1998). Among the most controversial issues have been studies employing high-risk designs, such as in pharmacologic challenge studies. Despite the fact that provocative testing is commonly used in medicine for both clinical and research purposes, this research design has evoked strong criticism particularly when used in psychiatric research.
3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a recreational drug that has been shown to release serotonin (5-HT) and dopamine (DA) in animals. The effect of MDMA on 5-HT release can be blocked by 5-HT uptake inhibitors such as citalopram, suggesting that MDMA interacts with the 5-HT uptake site. It is unknown whether this mechanism is also responsible for the psychological effects of MDMA in humans. We investigated the effect of citalopram pretreatment (40 mg iv) on the psychological effects of MDMA (1.5 mg/kg po) in a double-blind placebo-controlled psychometric study in 16 healthy human volunteers. MDMA produced an emotional state with heightened mood, increased self-confidence and extroversion, moderate derealization, and an intensification of sensory perception. Most of these effects were markedly reduced by citalopram. This finding suggests that the psychological effects of MDMA are mediated via action at the 5-HT uptake site to increase 5-HT release through the carrier, as expected from animal studies.
from 2 h before up to drug administration)
- A Gamma
A. Gamma et al. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 4 from 2 h before up to drug administration), 0–75 min
Die Eigenschaftswörterliste (EWL-K) -Ein Verfahren zur Erfassung der Befindlichkeit
- W Janke
- G Debus
Janke W, Debus G (1978): Die Eigenschaftswörterliste
(EWL-K) -Ein Verfahren zur Erfassung der Befindlichkeit. Göttingen, Hogrefe
Konstruktion des Fragebogens OAV zur quantitativen Erfassung aussergewöhnlicher Bewusstseinszustände
- I Bodmer
Bodmer I (1989): Konstruktion des Fragebogens OAV zur
quantitativen Erfassung aussergewöhnlicher Bewusstseinszustände. Zurich, Psychologisches Institut der
Universität Zürich
Regional cerebral blood flow changes during anticipatory anxiety
- Wc Drevets
- To Videen
- Az Snyder
- Ak Macleod
- Me Raichle
Drevets WC, Videen TO, Snyder AZ, MacLeod AK, Raichle
ME (1994): Regional cerebral blood flow changes during
anticipatory anxiety. Soc Neurosci Abstra 20:368
- W C Drevets
- T O Videen
- A Z Snyder
- A K Macleod
- M E Raichle
Drevets WC, Videen TO, Snyder AZ, MacLeod AK, Raichle
ME (1994): Regional cerebral blood flow changes during
anticipatory anxiety. Soc Neurosci Abstra 20:368
Acute psychological effects of 3,4-methylenedioxymethamphetamine (MDMA
- M E Liechti
- C Baumann
- A Gamma
- F X Vollenweider
Liechti ME, Baumann C, Gamma A, Vollenweider FX (1999):
Acute psychological effects of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") are attenuated
by the serotonin uptake inhibitor citalopram. Neuropsychopharmacology 22(5):513-521
Serotonin transporters are targets for MDMAinduced serotonin release
- G Rudnick
- S C Wall
Rudnick G, Wall SC (1992): The molecular mechanism
of "ecstasy" [3,4-methylenedioxymethamphetamine
(MDMA)]: Serotonin transporters are targets for MDMAinduced serotonin release. Proc Natl Acad Sci 89:1817-1821