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MDMA

Discriminative Stimulus Properties of MDMA: The Role of Serotonin and Dopamine

December 1, 2016 / MDMA, Neuroscience, Other subjects, Papers, Psychopharmacology, Publications / By /

Abstract

Rationale: ±3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) produces unique and complex subjective effects which distinguish it from other recreationally used drugs. An understanding of the neurochemical mechanisms that underlie these effects is important in order to assess the potential for MDMA abuse and to inform researchers exploring of the drug’s therapeutic potential. The present thesis investigated the neurochemical mechanisms underlying the subjective effects of MDMA using drug discrimination procedures in laboratory animals. Despite evidence that training dose can markedly impact the results of drug discrimination studies, the impact of training dose on the discriminative stimulus properties of MDMA has been largely overlooked. The broad aims of these experiments were 1) to test the ability of two different doses of MDMA to support drug discrimination learning, and 2) to determine the role of serotonin (5-HT) and dopamine (DA) neurotransmitter systems in producing the discriminative stimulus effects of each MDMA training dose. 

Methods: Groups of rats were trained to discriminate MDMA (1.5 or 3.0 mg/kg) from saline or to discriminate MDMA (1.5 or 3.0 mg/kg) from amphetamine (0.5 mg/kg) and saline, using two- or three-lever, food-reinforced drug discrimination procedures. The first experiments determined the impact of training dose on the acquisition of the MDMA discrimination. Reliability of the discrimination was assessed by measuring the impact of changes in acquisition criteria. Once the discrimination had been acquired, generalisation tests were carried out in two-lever experiments with the SSRIs, fluoxetine and clomipramine, the 5-HT2 agonists, mCPP and DOI, and the 5-HT1 agonists, 8-OH-DPAT and RU-24969, to investigate the role of 5-HT in the discriminative stimulus effects of 1.5 mg/kg vs 3.0 mg/kg MDMA. Next, the role of DA was investigated in further generalisation test sessions with the DA releasing stimulant, AMPH, the non-selective D1/D2 agonist, apomorphine, the D1 agonist, SKF38393, and the D2 agonist, quinpirole. Finally, experiments were carried out in which the ability of the 5-HT2A antagonist, ketanserin, the 5-HT1B/1D antagonist, GR-127935, the 5-HT1A antagonist, WAY100635, the D1 antagonist, SCH23390, and the D2 antagonist, eticlopride, to attenuate the discriminative stimulus effects of 1.5 mg/kg vs 3.0 mg/kg MDMA was assessed.

Results: A higher training dose of MDMA was associated with a more rapid acquisition of drug discrimination in both the two- and three-lever tasks, and significant differences were observed with respect to the ability of each dose of MDMA to maintain consistently accurate discrimination across both tasks. All of the serotonin agonists that were tested generalised to the discriminative stimulus effects of 1.5 mg/kg MDMA in a two-lever discrimination task. In contrast, only agonists for 5-HT1A or 5-HT2A receptors generalised to the discriminative stimulus effects of 3.0 mg/kg MDMA. Non-selective dopamine agonists generalised to the discriminative stimulus effects of 3.0 mg/kg but not 1.5 mg/kg MDMA, whereas selective D1 and D2 agonists failed to generalise to the discriminative stimulus effects of either training dose. None of the DA or 5-HT antagonists tested had a marked impact of the discrimination of 1.5 mg/kg MDMA whereas administration of a D2 antagonist produced a small but significant attenuation on the discriminative stimulus effects of 3.0 mg/kg MDMA.

Conclusions: The results of the present thesis suggest that the discriminative stimulus effects of MDMA may change both quantitatively and qualitatively as a function of dose. The subjective effects produced by lower doses appear to be mediated primarily via serotonergic mechanisms, whereas higher doses may involve the additional recruitment of dopaminergic mechanisms. These findings have implications for our understanding of MDMA in terms of the drug’s potential for dependence and abuse.

Webster, J. (2016). Discriminative Stimulus Properties of MDMA: The Role of Serotonin and Dopamine. 10063/5622

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Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

December 1, 2016 / MDMA, Neuroscience, Other subjects, Other substances, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate.

Ma, K. H., Liu, T. T., Weng, S. J., Chen, C. F. F., Huang, Y. S., Chueh, S. H., … & Huang, W. S. (2016). Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT. Scientific Reports, 6. 10.1038/srep38695
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Ecstasy research: will increasing observational data aid our understanding of MDMA?

December 1, 2016 / MDMA, Neuroscience, Papers, Psychology, Psychopharmacology, Publications, Safety / By /

Abstract

Over the past three decades, millions of dollars have been spent on thousands of studies attempting to better understand the neurotoxic effects of MDMA. All of the clinical studies have recruited people who use ecstasy—a drug that does often but not always contain MDMA. Although most researchers agree that MDMA is the cause of neurocognitive deficits in ecstasy users, this consensus is based on a large body of literature with many limitations.

Amoroso, T. (2016). Ecstasy research: will increasing observational data aid our understanding of MDMA?. The Lancet Psychiatry, 3(12), 1101-1102. 10.1016/S2215-0366(16)30345-5
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Decision-making in chronic ecstasy users: a systematic review

November 15, 2016 / MDMA, Papers, Psychiatry, Psychology, Publications, Safety / By / , ,

Abstract

Different cognitive impairments have been reported as a result of long-term MDMA/ecstasy use. Increased impulsivity and altered decision-making have been shown to be associated with the development and maintenance of addictive disorders pointing towards the necessity to understand a potential impairment of decision-making due to MDMA use. Thus, assessing the long-term effects of MDMA is crucial in order to evaluate its controversially discussed therapeutic use. The aim of this systematic review is to summarize the scientific literature on potential effects of chronic MDMA use on higher order decision-making processes in humans. Therefore, a systematic search for controlled trials relevant to the topic has been performed. Only studies using specific tasks on decision-making were included that involved subjects in the drug-free interval with drug-naïve, and/or polydrug control groups. A total of twelve studies could be identified that met the inclusion criteria, all of which were cross-sectional studies. The findings on decision-making disturbances in MDMA users were heterogeneous. Seven studies reported increased risky decisions, whereas five studies did not find MDMA-specific influences on decision-making. Increased impulsivity was observed both in MDMA groups and in (poly)drug control groups in almost all studies. Thus, the current state of research does not allow for the conclusion that long-term use of MDMA affects decision-making behavior in general. More detailed specifications as well as further investigations of the relevant processes are needed. Significant tendencies towards risky decision-making among long-term MDMA use have been observed, but need to be confirmed by studies using a longitudinal design.

Betzler, F., Viohl, L., & Romanczuk‐Seiferth, N. (2016). Decision‐making in chronic ecstasy users: a systematic review. European Journal of Neuroscience. 10.1111/ejn.13480
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Cognitive and behavioural effects induced by social stress plus MDMA administration in mice

November 10, 2016 / Depression, MDMA, Papers, Psychiatry, Psychology, Publications, Safety / By / , , , ,

Abstract

Adverse life experiences such as social stress may make an individual more vulnerable to drug addiction and mental disorders associated with drug consumption. The present work aimed to evaluate the effects of stress induced by acute social defeat combined with the administration of 3,4-methylenedioxymethamphetamine (MDMA) on depression-like behaviour, memory function and motor response to drug in late adolescent male mice. Two groups of mice were exposed to social defeat (SD) during four encounters with an aggressive co-specific, which took place on alternate days. Immediately after defeat, animals were treated with saline or MDMA 10mg/kg (SD+SAL and SD+MDMA). In control groups, mice were placed in a neutral cage without an opponent (Control+SAL, Control+MDMA). Corticosterone levels and temperature were measured on the last day of this phase. During the following days, the behaviour of the animals was evaluated in the tail suspension test (an animal model of depression), memory tasks (passive avoidance and object recognition) and, after administration of 5mg/kg of MDMA, in the open-field test. Exposure of adult mice to acute social defeat plus MDMA increased immobility in the tail suspension test (depression-like behaviour), produced cognitive impairment, and reduced the motor response to MDMA. An increase in corticosterone levels and a decrease of temperature were also observed. As hypothesised, a combination of social stress and consumption of MDMA increases the risk of developing mental and cognitive disorders. Our results support the idea that stress is a common contributing factor to the high rate of comorbidity between substance abuse and mental disease.

García-Pardo, M. P., Roger-Sánchez, C., Rodríguez-Arias, M., Miñarro, J., & Aguilar, M. A. (2017). Cognitive and behavioural effects induced by social stress plus MDMA administration in mice. Behavioural Brain Research, 319, 63-72. 10.1016/j.bbr.2016.11.012
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Potential Psychiatric Uses for MDMA

November 9, 2016 / Anxiety disorders / PTSD, Depression, MDMA, Papers, Psychiatry, Psychology, Psychotherapy, Publications / By / ,

Abstract

Phase 2 trials of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have demonstrated initial safety and efficacy for treatment of PTSD, with potential for expansion to depression and anxiety disorders. In these trials, single doses of MDMA are administered in a model of medication-assisted psychotherapy, differing from trials involving daily drug administration without psychotherapy. This model presents an opportunity to utilize accelerated regulatory pathways, such as FDA Breakthrough Therapy Designation, to most effectively and expeditiously test such novel approaches.

Klosinski, B. B., & Mithoefer, M. C. (2016). Potential Psychiatric Uses for MDMA. Clinical Pharmacology & Therapeutics. 10.1002/cpt.565
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Psychological effects of MDMA

October 4, 2016 / MDMA, Papers, Personal development, Personality, Psychology, Publications / By /

Abstract

Zinberg’s Interaction Model implies that the content of a drug-induced experience is a function of the pharmacological properties of the drug, the set (the user’s characteristics e.g. motivation and personality), and the setting (the physical and social context). The current research investigated the function of the set and setting and their role in shaping the psychological effects of 3,4-methylenedioxmethamphetamine (MDMA), as well as their role in reducing the risk of drug abuse.
An online survey was distributed among adult MDMA polydrug users (n = 158) and MDMA-naïve controls (alcohol, nicotine and cannabis users, n = 138). Participants answered questions regarding their pattern of drug use, their motivation for MDMA use and the setting (e.g. clubbing, home with friends), as well as the subjective effects of MDMA. Participants also completed a range of self-report measures of self-reflection and insight, emotional intelligence, and personality, as well as a drug dependency measure.
MDMA users displayed higher levels of self-reflection and insight, openness to new experience and lower levels of neuroticism and conscientiousness, in comparison to the control group. The significant predictors of self-reflection and insight were openness, emotional intelligence, MDMA use, extraversion and neuroticism. When the analysis was rerun only for the MDMA group, the significant predictors of self-reflection and insight were openness, emotional intelligence and self-insight effects of MDMA. High levels of self-reported negative effects of MDMA were predictors of a problematic drug use.
These findings suggest that there might be a relationship between MDMA use and higher levels of self-reflection and insight; however, longitudinal studies are required to further investigate the causality of this relationship. The results add to existing evidence that MDMA has potential for altering emotional experiences. Further research utilising a prospective design is warranted.

Wieliczko, M. J. (2016). Psychological effects of MDMA (Doctoral dissertation, Canterbury Christ Church University).

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The Relationship between depression and use of ecstasy among adolescents in Taiwan

October 1, 2016 / Depression, MDMA, Papers, Psychology, Publications / By / , , ,

Abstract

Introduction: The aim of this cross-sectional study was to examine the relationship between depression and ecstasy use among adolescents in Taiwan by controlling for the effects of demographic characteristics and cannabis use.

Methods: A total of 10,262 adolescents aged 12-18 years completed research questionnaires that assessed their severity of depression, status of ecstasy use, and history of cannabis use. The participants were grouped into non-users, ex-users, and current users. Severity of depression among these three adolescent groups was compared using analysis of covariance (ANCOVA), considering the history of cannabis use and demographic characteristics as covariates.
Results: After controlling for history of cannabis use and age, the study found that current ecstasy users experienced more severe depressive symptoms than ex-users and non-users. The difference between ex-users and non-users was not significant.
Conclusion: This study found that current ecstasy users had more severe depressive symptoms than non-users and ex-users. Psychological health professionals must monitor depressive symptoms among adolescent ecstasy users and provide emotional regulation strategies and psychological intervention for those with significant depression.
Lee, K. H., Su, C. H., Hsiao, R. C., Yen, C. N., & Yen, C. F. (2016). The Relationship between depression and use of ecstasy among adolescents in Taiwan. Neuropsychiatry (London), 6(4), 124-127. 10.4172/Neuropsychiatry.1000130
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Psychedelic Psychotherapy Insights From 25 Years of Research

September 29, 2016 / DMT, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy, Publications / By /

Abstract

Presented at a conference titled “Psychedelic Science 2013,” highlighting the resumption of investigations with psychedelic substances (i.e., psilocybin, DMT, LSD, MDMA, etc.) in the United States and Europe after a dormant period of more than two decades, the author presents insights and perspectives gleaned from his 25 years of clinical research experience. After acknowledging the vastness and potential significance of this research frontier, the article focuses on the “cartography of inner space”; the unique therapeutic potential of transcendental states of consciousness; the entelechy of the interpersonally grounded psyche; the importance of integration in drug-free therapy sessions; the roles of expectation, religious education and faith; the role of music; and future research directions.

Richards, W. A. (2016). Psychedelic Psychotherapy Insights From 25 Years of Research. Journal of Humanistic Psychology, 0022167816670996. 10.1177/0022167816670996
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A Case of 3,4-Dimethoxyamphetamine (3,4-DMA) and 3,4 Methylendioxymethamphetamine (MDMA) Toxicity with Possible Metabolic Interaction

September 16, 2016 / MDMA, Medicine, Papers, Psychopharmacology, Publications, Safety, Toxicology / By / , , ,

Abstract

BACKGROUND: We present a case of “ecstasy” ingestion revealing 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-dimethoxyamphetamine (3,4-DMA) and absence of cytochrome P450 (CYP)-2D6 MDMA metabolites.

CASE REPORT: A 19-year-old presented following a seizure. Initial vital signs were normal. Laboratories were normal with the exception of sodium 127 mEq/L and urine drugs of abuse screen positive for amphetamines. Twelve hours later, serum sodium was 114 mEq/L and a second seizure occurred. After receiving hypertonic saline (3%), the patient had improvement in mental status and admitted to taking “ecstasy” at a rave prior to her initial presentation. Liquid chromatography-time-of-flight mass spectrometry (LC-TOF/MS) of serum and urine revealed MDMA, 3,4-DMA, and the CYP-2B6 MDMA metabolites 3,4-methylendioxyamphetamine (MDA) and 4-hydroxy-3-methoxyamphetamine (HMA). The CYP2D6 metabolites of MDMA, 3,4-dihydromethamphetamine (HHMA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), were detected at very low levels.

CONCLUSION: This case highlights the polypharmacy which may exist among users of psychoactive illicit substances and demonstrates that concurrent use of MDMA and 3,4-DMA may predispose patients to severe toxicity. Toxicologists and other healthcare providers should be aware of this potential toxicity.

Darracq, M. A., Thornton, S. L., Minns, A. B., & Gerona, R. R. (2016). A Case of 3, 4-Dimethoxyamphetamine (3, 4-DMA) and 3, 4 Methylendioxymethamphetamine (MDMA) Toxicity with Possible Metabolic Interaction. Journal of Psychoactive Drugs, 1-4. 10.1080/02791072.2016.1225324
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