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MDMA

Therapeutic effect of increased openness: Investigating mechanism of action in MDMA-assisted psychotherapy

June 1, 2017 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By / , , , , , ,

Abstract

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.
Wagner, M. T., Mithoefer, M. C., Mithoefer, A. T., MacAulay, R. K., Jerome, L., Yazar-Klosinski, B., & Doblin, R. (2017). Therapeutic effect of increased openness: Investigating mechanism of action in MDMA-assisted psychotherapy. Journal of Psychopharmacology, 0269881117711712.
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Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects

May 27, 2017 / MDMA, Papers, Psychology / By / , , , ,

Abstract

Rationale

3,4-Methylenedioxymethamphetamine (MDMA) is used recreationally and investigated as an adjunct to psychotherapy. Methylphenidate and modafinil are psychostimulants that are used to treat attention-deficit/hyperactivity disorder and narcolepsy, respectively, but they are also misused as cognitive enhancers. Little is known about differences in the acute effects of equally cardiostimulant doses of these stimulant-type substances compared directly within the same subjects.

Methods

We investigated the acute autonomic, subjective, endocrine, and emotional effects of single doses of MDMA (125 mg), methylphenidate (60 mg), modafinil (600 mg), and placebo in a double-blind, cross-over study in 24 healthy participants. Acute drug effects were tested using psychometric scales, the Facial Emotion Recognition Task (FERT), and the Sexual Arousal and Desire Inventory (SADI).

Results

All active drugs produced comparable hemodynamic and adverse effects. MDMA produced greater increases in pupil dilation, subjective good drug effects, drug liking, happiness, trust, well-being, and alterations in consciousness than methylphenidate or modafinil. Only MDMA reduced subjective anxiety and impaired fear recognition and led to misclassifications of emotions as happy on the FERT. On the SADI, only MDMA produced sexual arousal-like effects. Only MDMA produced marked increases in cortisol, prolactin, and oxytocin. In contrast to MDMA, methylphenidate increased subjective anxiety, and methylphenidate and modafinil increased misclassifications of emotions as angry on the FERT. Modafinil had no significant subjective drug effects but significant sympathomimetic and adverse effects.

Conclusions

MDMA induced subjective, emotional, sexual, and endocrine effects that were clearly distinct from those of methylphenidate and modafinil at the doses used.

Dolder, P. C., Müller, F., Schmid, Y., Borgwardt, S. J., & Liechti, M. E. (2017). Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects. Psychopharmacology, 1-13. 10.1007/s00213-017-4650-5
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Why Psychiatry Needs 3,4-Methylenedioxymethamphetamine: A Child Psychiatrist’s Perspective

May 5, 2017 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By /

Abstract

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.

Sessa, B. (2017). Why Psychiatry Needs 3, 4-Methylenedioxymethamphetamine: A Child Psychiatrist’s Perspective. Neurotherapeutics, 1-9. 10.1007/s13311-017-0531-1
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A Longitudinal Study of Self-Reported Psychopathology in Beginning Ecstasy and Amphetamine Users: A Third Follow-Up Evaluation

May 4, 2017 / MDMA, Papers, Psychology, Publications / By / , , , ,

Abstract

BACKGROUND: It is still unknown whether psychopathological symptoms found in ecstasy and amphetamine users were apparent before the first use or developed subsequent to its use.

OBJECTIVES: The present study presents the third follow-up evaluation of a longitudinal study to assess the nature of the relationship between ecstasy, amphetamine (AMPH) and psychopathology.

METHODS: In this sample, 69 beginning ecstasy and AMPH users were followed over a period of 4 years. To explore different psychopathological dimensions, the Symptom Checklist-90-Revised was applied. Use of ecstasy, AMPH, cannabis and was gathered by structured interviews and use of cigarettes by a questionnaire. First, linear mixed models for repeated measures (unstructured covariance matrix) on the nine primary symptoms of the SCL-90-R with a separate model for each symptom category were performed. Second, linear regression analyses with the nine primary symptom categories of the baseline assessment (T0) as predictors and with ecstasy and AMPH use as dependent variables were fitted.

RESULTS: No significant associations between ecstasy, AMPH, and psychopathology were evident. However, a significant two-way interaction between ecstasy and cigarette use at the baseline assessment, as well as a three-way interaction effect between ecstasy, cigarette use, and time on obsessive-compulsive symptoms, were found.

CONCLUSIONS: This study suggests that nicotine may moderate the effect of ecstasy on obsessive-compulsive symptoms. However, no associations between ecstasy, AMPH, and psychopathology have been found. This is one of the few studies, which highlights the role of nicotine in the study of psychopathology in beginning ecstasy and AMPH users.

Wagner, D., Sauder, T., Koester, P., Gouzoulis-Mayfrank, E., & Daumann, J. (2017). A Longitudinal Study of Self-Reported Psychopathology in Beginning Ecstasy and Amphetamine Users: A Third Follow-Up Evaluation. Substance Use & Misuse, 1-8. 10.1080/10826084.2017.1290113
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MDMA does not alter responses to the Trier Social Stress Test in humans

April 21, 2017 / MDMA, Papers, Philosophy & Religious Studies / By / , ,

Abstract

Rationale

±3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a stimulant-psychedelic drug with unique social effects. It may dampen reactivity to negative social stimuli such as social threat and rejection. Perhaps because of these effects, MDMA has shown promise as a treatment for post-traumatic stress disorder (PTSD). However, the effect of single doses of MDMA on responses to an acute psychosocial stressor has not been tested.

Objectives

In this study, we sought to test the effects of MDMA on responses to stress in healthy adults using a public speaking task. We hypothesized that the drug would reduce responses to the stressful task.

Methods

Volunteers (N = 39) were randomly assigned to receive placebo (N = 13), 0.5 mg/kg MDMA (N = 13), or 1.0 mg/kg MDMA (N = 13) during a stress and a no-stress session. Dependent measures included subjective reports of drug effects and emotional responses to the task, as well as salivary cortisol, heart rate, and blood pressure.

Results

The stress task produced its expected increase in physiological responses (cortisol, heart rate) and subjective ratings of stress in all three groups, and MDMA produced its expected subjective and physiological effects. MDMA alone increased ratings of subjective stress, heart rate, and saliva cortisol concentrations, but contrary to our hypothesis, it did not moderate responses to the Trier Social Stress Test.

Conclusions

Despite its efficacy in PTSD and anxiety, MDMA did not reduce either the subjective or objective responses to stress in this controlled study. The conditions under which MDMA relieves responses to negative events or memories remain to be determined.

Bershad, A. K., Miller, M. A., & de Wit, H. (2017). MDMA does not alter responses to the Trier Social Stress Test in humans. Psychopharmacology, 1-8. 10.1007/s00213-017-4621-x
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Multifaceted empathy of healthy volunteers after single doses of MDMA: A pooled sample of placebo-controlled studies

April 3, 2017 / MDMA, Papers, Psychology, Publications / By / , , ,

Abstract

Previous placebo-controlled experimental studies have shown that a single dose of MDMA can increase emotional empathy in the multifaceted empathy test (MET) without affecting cognitive empathy. Although sufficiently powered to detect main effects of MDMA, these studies were generally underpowered to also validly assess contributions of additional parameters, such as sex, drug use history, trait empathy and MDMA or oxytocin plasma concentrations. The present study examined the robustness of the MDMA effect on empathy and investigated the moderating role of these additional parameters. Participants ( n = 118) from six placebo-controlled within-subject studies and two laboratories were included in the present pooled analysis. Empathy (MET), MDMA and oxytocin plasma concentrations were assessed after oral administration of MDMA (single dose, 75 or 125 mg). Trait empathy was assessed using the interpersonal reactivity index. We confirmed that MDMA increased emotional empathy at both doses without affecting cognitive empathy. This MDMA-related increase in empathy was most pronounced during presentation of positive emotions as compared with negative emotions. MDMA-induced empathy enhancement was positively related to MDMA blood concentrations measured before the test, but independent of sex, drug use history and trait empathy. Oxytocin concentrations increased after MDMA administration but were not associated with behavioral effects. The MDMA effects on emotional empathy were stable across laboratories and doses. Sex did not play a moderating role in this effect, and oxytocin levels, trait empathy and drug use history were also unrelated. Acute drug exposure was of significant relevance in the MDMA-induced emotional empathy elevation.
Kuypers, K. P., Dolder, P. C., Ramaekers, J. G., & Liechti, M. E. (2017). Multifaceted empathy of healthy volunteers after single doses of MDMA: A pooled sample of placebo-controlled studies. Journal of Psychopharmacology, 31(5), 589-598. 10.1177/0269881117699617
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Safety pharmacology of acute MDMA administration in healthy subjects

February 21, 2017 / MDMA, Papers, Psychology, Publications / By / ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is being investigated in MDMA-assisted psychotherapy. The present study characterized the safety pharmacology of single-dose administrations of MDMA (75 or 125 mg) using data from nine double-blind, placebo-controlled, crossover studies performed in the same laboratory in a total of 166 healthy subjects. The duration of the subjective effects was 4.2 ± 1.3 h (range: 1.4–8.2 h). The 125 mg dose of MDMA produced greater ‘good drug effect’ ratings than 75 mg. MDMA produced moderate and transient ‘bad drug effect’ ratings, which were greater in women than in men. MDMA increased systolic blood pressure to >160 mmHg, heart rate >100 beats/min, and body temperature >38°C in 33%, 29% and 19% of the subjects, respectively. These proportions of subjects with hypertension (>160 mmHg), tachycardia, and body temperature >38°C were all significantly greater after 125 mg MDMA compared with the 75 mg dose. Acute and subacute adverse effects of MDMA as assessed by the List of Complaints were dose-dependent and more frequent in females. MDMA did not affect liver or kidney function at EOS 29 ± 22 days after use. No serious adverse events occurred. In conclusion, MDMA produced predominantly acute positive subjective drug effects. Bad subjective drug effects and other adverse effects were significantly more common in women. MDMA administration was overall safe in physically and psychiatrically healthy subjects and in a medical setting. However, the risks of MDMA are likely higher in patients with cardiovascular disease and remain to be investigated in patients with psychiatric disorders.

Vizeli, P., & Liechti, M. E. (2017). Safety pharmacology of acute MDMA administration in healthy subjects. Journal of Psychopharmacology, 0269881117691569. 10.1177/0269881117691569
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Altered Insula Connectivity Under MDMA

February 14, 2017 / MDMA, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

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.

Walpola, I. C., Nest, T., Roseman, L., Erritzoe, D., Feilding, A., Nutt, D. J., & Carhart-Harris, R. L. (2017). Altered Insula Connectivity Under MDMA. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. 10.1038/npp.2017.35
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Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects

January 20, 2017 / MDMA, Papers, Publications / By / , , , ,

Abstract

In vitro studies showed that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) to 3,4-methylenedioxyamphetamine (MDA). However, the role of genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 in the metabolism of MDMA in humans is unknown. The effects of genetic variants in these CYP enzymes on the pharmacokinetics and pharmacodynamics of MDMA were characterized in 139 healthy subjects (69 male, 70 female) in a pooled analysis of eight double-blind, placebo-controlled studies. MDMA-MDA conversion was positively associated with genotypes known to convey higher CYP2C19 or CYP2B6 activities. Additionally, CYP2C19 poor metabolizers showed greater cardiovascular responses to MDMA compared with other CYP2C19 genotypes. Furthermore, the maximum concentration of MDA was higher in tobacco smokers that harbored the inducible CYP1A2 rs762551 A/A genotype compared with the non-inducible C-allele carriers. The findings indicate that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of MDMA to MDA in humans. Additionally, genetic polymorphisms in CYP2C19 may moderate the cardiovascular toxicity of MDMA.

Vizeli, P., Schmid, Y., Prestin, K., zu Schwabedissen, H. E. M., & Liechti, M. E. (2017). Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects. European Neuropsychopharmacology, 27(3), 232-238. 10.1016/j.euroneuro.2017.01.008
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Hyperthermia Severely Affects the Vascular Effects of MDMA and Metabolites in the Human Internal Mammary Artery In Vitro

January 13, 2017 / MDMA, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a recreational drug used worldwide for its distinctive psychotropic effects. Although important cardiovascular effects, such as increased blood pressure and heart rate, have also been described, the vascular effects of MDMA and metabolites and their correlation with hyperthermia (major side effect of MDMA) are not yet fully understood and have not been previously reported. This study aimed at evaluating the effects of MDMA and its main catechol metabolites, alpha-methyldopamine (α-MeDA), N-methyl-alpha-methyldopamine (N-Me-α-MeDA), 5-(glutathion-S-yl)-alpha-methyldopamine [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][5-(GSH)-α-MeDA] and 5-(glutathion-S-yl)-N-methyl-alpha-methyldopamine [5-(GSH)-N-Me-α-MeDA], on the 5-HT-dependent vasoactivity in normothermia (37 °C) and hyperthermia (40 °C) of the human internal mammary artery (IMA) in vitro. The results showed the ability of MDMA, α-MeDA and N-Me-α-MeDA to exert vasoconstriction of the IMA which was considerably higher in hyperthermic conditions (about fourfold for MDMA and α-MeDA and twofold for N-Me-α-MeDA). The results also showed that all the compounds may influence the 5-HT-mediated concentration-dependent response of IMA, as MDMA, α-MeDA and N-Me-α-MeDA behaved as partial agonists and 5-(GSH)-α-MeDA and 5-(GSH)-N-Me-α-MeDA as antagonists. In conclusion, MDMA abuse may imply a higher cardiovascular risk associated both to MDMA and its metabolites that might be relevant in patients with underlying cardiovascular diseases, particularly in hyperthermia.

Fonseca, D. A., Guerra, A. F., Carvalho, F., Fernandes, E., Ferreira, L. M., Branco, P. S., … & Cotrim, M. D. (2017). Hyperthermia Severely Affects the Vascular Effects of MDMA and Metabolites in the Human Internal Mammary Artery In Vitro. Cardiovascular Toxicology, 1-12. 10.1007/s12012-017-9398-y
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