It has recently been demonstrated that aromatic bromination at C(2) abolishes all typical psychomotor, and some key prosocial effects of the entactogen MDMA in rats. Nevertheless, the influence of ...aromatic bromination on MDMA-like effects on higher cognitive functions remains unexplored. In the present work, the effects of MDMA and its brominated analog 2Br-4,5-MDMA (1 mg/kg and 10 mg/kg i.p. each) on visuospatial learning, using a radial, octagonal Olton maze (4 × 4) which may discriminate between short-term and long-term memory, were compared with their influence on in vivo long-term potentiation (LTP) in the prefrontal cortex in rats. The results obtained indicate that MDMA diminishes both short- and long-term visuospatial memory but increases LTP. In contrast, 2Br-4,5-MDMA preserves long-term visuospatial memory and slightly accelerates the occurrence of short-term memory compared to controls, but increases LTP, like MDMA. Taken together, these data are consistent with the notion that the modulatory effects induced by the aromatic bromination of the MDMA template, which abolishes typical entactogenic-like responses, might be extended to those effects affecting higher cognitive functions, such as visuospatial learning. This effect seems not to be associated with the increase of LTP in the prefrontal cortex.
Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and D-amphetamine is a classic stimulant. All three substances are used ...recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and D-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg), and placebo in a randomized, double-blind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. LSD and MDMA increased heart rate more than D-amphetamine, and D-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and D-amphetamine. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and D-amphetamine. LSD also induced greater impairments in subjective ratings of concentration, sense of time, and speed of thinking compared with MDMA and D-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with D-amphetamine. D-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA but not LSD or D-amphetamine increased plasma concentrations of oxytocin. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and D-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.
There is mounting evidence suggesting psychedelic and entactogen medicines (namely psilocybin and 3,4-methylenedioxymethamphetamine MDMA), in conjunction with proper psychosocial support, hold the ...potential to provide safe, rapid acting, and robust clinical improvements with durable effects. In the US, both psilocybin and MDMA have been granted Breakthrough Therapy designations by the US Food and Drug Administration and may potentially receive full FDA approval with similar regulatory considerations occurring in multiple countries. At the same time, regulatory changes are poised to increase access to legal or decriminalized psychedelic use in various non-medical settings. This review provides a brief discussion on the historical use of psychedelic medicines, the status of the empirical evidence, and numerous significant policy considerations that must be thoughtfully addressed regarding standards-of-practice, consumer protection, engagement of communities, safeguarding access for all, and developing data standards, which supports the responsible, accountable, safe, and ethical uses of these medicines in clinical, faith-based, and other contexts. We provide suggestions for how public health and harm reduction can be supported through a public-private partnership that engages a community of stakeholders from various disciplines in the co-creation and dissemination of best practices and public policies.
This article is part of the Special Issue on ‘Psilocybin Research’.
•Psychedelics carry notable promise and risk when used as mental health therapies.•Public education and facilitator training are essential for risk mitigation.•Public policies must prioritize harm reduction and best practices.•Successful scaling up of psychedelic therapies requires equitable access.
BACKGROUND AND PURPOSE
3,4‐Methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) is a worldwide major drug of abuse known to elicit neurotoxic effects. The mechanisms underlying the neurotoxic effects of ...MDMA are not clear at present, but the metabolism of dopamine and 5‐HT by monoamine oxidase (MAO), as well as the hepatic biotransformation of MDMA into pro‐oxidant reactive metabolites is thought to contribute to its adverse effects.
EXPERIMENTAL APPROACH
Using mouse brain synaptosomes, we evaluated the pro‐oxidant effects of MDMA and its metabolites, α‐methyldopamine (α‐MeDA), N‐methyl‐α‐methyldopamine (N‐Me‐α‐MeDA) and 5‐(glutathion‐S‐yl)‐α‐methyldopamine 5‐(GSH)‐α‐MeDA, as well as those of 5‐HT, dopamine, l‐DOPA and 3,4‐dihydroxyphenylacetic acid (DOPAC).
KEY RESULTS
5‐HT, dopamine, l‐DOPA, DOPAC and MDMA metabolites α‐MeDA, N‐Me‐α‐MeDA and 5‐(GSH)‐α‐MeDA, concentration‐ and time‐dependently increased H2O2 production, which was significantly reduced by the antioxidants N‐acetyl‐l‐cysteine (NAC), ascorbic acid and melatonin. From experiments with MAO inhibitors, it was observed that H2O2 generation induced by 5‐HT was totally dependent on MAO‐related metabolism, while for dopamine, it was a minor pathway. The MDMA metabolites, dopamine, l‐DOPA and DOPAC concentration‐dependently increased quinoproteins formation and, like 5‐HT, altered the synaptosomal glutathione status. Finally, none of the compounds modified the number of polarized mitochondria in the synaptosomal preparations, and the compounds’ pro‐oxidant effects were unaffected by prior mitochondrial depolarization, excluding a significant role for mitochondrial‐dependent mechanisms of toxicity in this experimental model.
CONCLUSIONS AND IMPLICATIONS
MDMA metabolites along with high levels of monoamine neurotransmitters can be major effectors of neurotoxicity induced by Ecstasy.
It is well established that poor inhibitory control confers both a vulnerability to, and maintenance of, addictive behaviors across the substance and behavioral spectrums. By comparison, the role of ...compulsivity in addictive behaviors has received less research focus. The neurocognitive literature to date is vast, and it is unclear whether there are any convincing lines of systematic evidence delineating whether and how aspects of impulsivity and compulsivity are shared and unique across different substance and behavioral addictive disorders. Such information has significant implications for our understanding of underlying mechanisms and clinical implications for assessing and treating neurocognitive deficits across addictions. Here, we conducted a systematic meta-review of the quantitative meta-analyses to date, specifically examining the neurocognitive functions central to impulsive-compulsive behaviors transdiagnostically across addictive behaviors. Out of 1186 empirical studies initially identified, six meta-analyses met inclusion criteria examining alcohol, cannabis, cocaine, MDMA, methamphetamine, opioid and tobacco use, as well as gambling and internet addiction. The pooled findings across the systematic meta-analyses suggest that impulsivity is a core process underpinning both substance and behavioral addictive disorders, although it is not equally implicated across all substances. Compulsivity-related neurocognition, by comparison, is important across alcohol and gambling disorders, but has yet to be examined systematically. The gestalt of findings to date suggests that both impulsivity and compulsivity are core constructs linked to addictive behaviors and may not be solely the secondary sequelae associated with the effects of prolonged substance exposure.
Introduction
Increasing evidence demonstrates 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) may be a safe and effective treatment for post-traumatic stress disorder (PTSD). ...There is growing interest in MDMA-AT to address a range of other health challenges. Chronic pain and PTSD are frequently comorbid, reciprocally interdependent conditions, though the possible role of MDMA-AT in treating chronic pain remains under-investigated. The present analysis examined the impact of manualized MDMA-AT on chronic pain severity among participants with PTSD who were enrolled in a Phase 2 clinical trial investigating MDMA-AT for PTSD (NCT03282123).
Materials and methods
Exploratory data from a subset of participants who completed chronic pain measures (
n
= 32) were drawn from a Phase 2 open-label study sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS). Multivariable analysis of variance (ANOVA) was utilized to compare pre- vs. post-treatment Chronic Pain Grade Scale (CPGS) values, adjusting for demographics (age, sex, and ethnicity). K-means clustering was then used to group the sample into three clusters to denote high (
n
= 9), medium (
n
= 11), and low (
n
= 12) baseline pain severity, and the same analysis was repeated for each cluster.
Results
Among the 32 participants included in this analysis, 59% (
n
= 19) were women, 72% (
n
= 23) were white, and median age was 38 years interquartile range (IQR) = 31–47. Overall, 84% (
n
= 27) reported having pain, and 75% (
n
= 24) reported disability associated with their pain. Significant reductions in CPGS subscales for
pain intensity
and
disability score
, and overall CPGS
severity grade
were observed among participants in the highest pain cluster (
n
= 9,
p
< 0.05), and for
pain intensity
in the medium pain cluster (
n
= 11,
p
< 0.05) post- vs. pre-treatment.
Discussion
Findings demonstrate a high prevalence of chronic pain in this sample of people with severe PTSD and that chronic pain scores among medium and high pain subgroups were significantly lower following MDMA-AT. While these data are preliminary, when considered alongside the frequency of comorbid chronic pain and PTSD and promising efficacy of MDMA-AT for treating PTSD, these findings encourage further research exploring the role of MDMA-AT for chronic pain.
The present study aimed at investigating the effect of MDMA on measures of empathy and social interaction, and the roles of oxytocin and the 5-HT1A receptor in these effects. The design was ...placebo-controlled within-subject with 4 treatment conditions: MDMA (75 mg), with or without pindolol (20 mg), oxytocin nasal spray (40 IU+16 IU) or placebo. Participants were 20 healthy poly-drug MDMA users, aged between 18-26 years. Cognitive and emotional empathy were assessed by means of the Reading the Mind in the Eyes Test and the Multifaceted Empathy Test. Social interaction, defined as trust and reciprocity, was assessed by means of a Trust Game and a Social Ball Tossing Game. Results showed that MDMA selectively affected emotional empathy and left cognitive empathy, trust and reciprocity unaffected. When combined with pindolol, these effects remained unchanged. Oxytocin did not affect measures of empathy and social interaction. Changes in emotional empathy were not related to oxytocin plasma levels. It was concluded that MDMA (75 mg) selectively enhances emotional empathy in humans. While the underlying neurobiological mechanism is still unknown, it is suggested that peripheral oxytocin does not seem to be the main actor in this; potential candidates are the serotonin 2A and the vasopressin 1A receptors. Trial registration: MDMA & PSB NTR 2636.
•The acute mood effects are broadly similar, although with some differences in strength and duration.•Both drugs can cause acute abreactions, rare/occasional deaths and neuropsychobiological ...problems.•Acute tolerance occurs with MDMA but is not apparent with mephedrone.•The regular use of MDMA can cause neurotoxic damage, whereas the evidence for mephedrone is inconclusive.•In overall terms, mephedrone appears somewhat safer and less damaging than MDMA based on the current research.
Mephedrone and MDMA are both constituents of party drugs, with mephedrone being relatively new compared to MDMA. This review compares current knowledge regarding the patterns of usage and neuropsychobiological effects of both mephedrone and MDMA. Both drugs share common psychoactive effects, the duration of which is significantly shorter with mephedrone use, attributing towards a pattern of binge use among users. Both drugs have also been associated with adverse health, psychiatric, and neurocognitive problems. Whilst there is extensive research into the psychobiological problems induced by MDMA, the evidence for mephedrone is comparatively limited. The adverse effect profile of mephedrone appears to be less severe than that of MDMA. Users often believe it to be safer, although both drugs have been associated with overdoses. The neurotoxic potential of mephedrone appears to be low, whereas MDMA can cause long-term damage to the serotonergic system, although this needs further investigation. The abuse liability of mephedrone is significantly greater than that of MDMA, raising concerns regarding the impact of lifetime usage on users. Given that mephedrone is relatively new, the effects of long-term exposure are yet to be documented. Future research focused on lifetime users may highlight more severe neuropsychobiological effects from the drug.
The use of recreational drugs like ephedrine, norephedrine, 3,4-methylenedioxymethamphetamine (MDMA), and mescaline can lead to intoxication and, at worst, to death. One reason for a fatal course of ...intoxication with these drugs might lie in cardiac arrhythmias. To the best of our knowledge, their inotropic effects have not yet been studied in isolated human cardiac preparations. Therefore, we measured inotropic effects of the hallucinogenic drugs ephedrine, norephedrine, mescaline, and MDMA in isolated mouse left atrial (mLA) and right atrial (mRA) preparations as well as in human right atrial (hRA) preparations obtained during cardiac surgery. Under these experimental conditions, ephedrine, norephedrine, and MDMA increased force of contraction (mLA, hRA) and beating rate (mRA) in a time- and concentration-dependent way, starting at 1–3 µM but these drugs were less effective than isoprenaline. Mescaline alone or in the presence of phosphodiesterase inhibitors did not increase force in mLA or hRA. The positive inotropic effects of ephedrine, norephedrine, or MDMA were accompanied by increases in the rate of tension and relaxation and by shortening of time of relaxation and, moreover, by an augmented phosphorylation state of the inhibitory subunit of troponin in hRA. All effects were greatly attenuated by cocaine (10 µM) or propranolol (10 µM) treatment. In summary, the hallucinogenic drugs ephedrine, norephedrine, and MDMA, but not mescaline, increased force of contraction and increased protein phosphorylation presumably, in part, by a release of noradrenaline in isolated human atrial preparations and thus can be regarded as indirect sympathomimetic drugs in the human atrium.
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