Monoamine neurotransmitters play a role in aggression, especially when altered by illicit substances. However, some literature suggests that not all illicit substances may lead to aggression, notably psychedelics. This narrative review investigates the associations between serotonergic psychedelics and MDMA on aggressive behaviour.

PubMed and PsycINFO were searched for original, peer-reviewed articles evaluating the effects of serotonergic psychedelics and 3,4-methyl enedioxy methamphetamine (MDMA) on violent and aggressive behaviour using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

After removing duplicates, a total of 555 articles were screened, with 16 meeting the inclusion criteria. One additional article was obtained through reference screening bringing the total to 17 articles. Of these 17 articles, 14 studies focused on MDMA and three on serotonergic psychedelics. Findings were mixed, with some results demonstrating increased aggression following psychedelics and others suggesting protective effects. Limitations in the current literature include varied definitions of psychedelics, lack of standardised objective outcome measures and failure to control for confounding.

As psychedelic research continues to expand, further assessment on the effects of serotonergic psychedelics and MDMA on aggressive behaviour is required.

Novel, evidence-based treatments are required for treatment-resistant post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine (MDMA) has beneficially augmented psychotherapy in several small clinical trials.

To review the use of MDMA-assisted psychotherapy in treatment-resistant PTSD.

Systematic searches of four databases were conducted from inception to February 2020. A meta-analysis was performed on trials which were double-blinded, randomised, and compared MDMA-assisted psychotherapy to psychotherapy and placebo. The primary outcomes were the differences in Clinician Administered PTSD Scale (CAPS-IV) score and Beck’s Depression Inventory (BDI). Secondary outcome measures included neurocognitive and physical adverse effects, at the time, and within seven days of intervention.

Four randomised controlled trials (RCTs) met inclusion criteria. When compared to active placebo, intervention groups taking 75mg (MD -46.90; 95% CI -58.78, -35.02), 125mg (MD -20.98; 95% CI -34.35, -7.61) but not 100mg (MD -12.90; 95% CI -36.09, 10.29) of MDMA with psychotherapy, had significant decreases in CAPS-IV scores, as did the inactive placebo arm (MD -33.20; 95% CI -40.53, -25.87). A significant decrease in BDI when compared to active placebo (MD -10.80; 95% CI -20.39, -1.21) was only observed at 75mg. Compared to placebo, participants reported significantly more episodes of low mood, nausea and jaw-clenching during sessions and lack of appetite after seven days.

These results demonstrate potential therapeutic benefit with minimal physical and neurocognitive risk for the use of MDMA-assisted psychotherapy in TR-PTSD, despite little effect on Beck’s Depression Inventory. Better powered RCTs are required to investigate further.

James Rucker has attended trial related meetings paid for by Compass Pathways Ltd.

Recently there has been renewal in interest of psychedelic research. Classic psychedelics such as lysergic acid diethylamide (LSD), psilocybin and mescaline act pharmacologically as agonists at the 5-HT2A receptor. The entactogens like methylenedioxymethamphetamine (MDMA), acts as a serotonin, dopamine and noradrenaline agonist. All of these drugs are potential candidates in the treatment of multiple psychiatric illnesses.

The authors intend to review the literature on the clinical application of psychedelic drugs in psychiatric disorders.

Non-systematic review of the literature.

In recent clinical trial the psychedelic is given with psychotherapeutic input. In a supportive setting, psychedelics produced immediate and significant anti-depressant and anxiolytic effects that were endured for several months. Randomized clinical trials support the efficace of psilocybin in the treatment of depression and those with anxiety and depression symptoms provoked by life-threatening cancer. There have also been studies showing efficacy in both alcohol and tobacco dependence. When administered safely LSD can reduce anxiety and have anti-addictive property. Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD. Psychedelics were well-tolerated, few adverse effects have been reported. The most common adverse effects were transient anxiety, short-lived headaches, nausea and mild increases in heart rate and blood pressure, with no persisting adverse effects. Serious adverse events, such as persistent psychosis and suicidality, have not been demonstrated.

Psychedelics appear to be effective in multiple psychiatric disorders and are well-tolerated, although further evidence is required, to better see they therapeutic potential.

No significant relationships.

Post-traumatic stress disorder (PTSD) is often a chronic condition, despite the existence of evidence-based treatment options. Psychotherapy is the designated first line treatment for PTSD, although high rates of psychiatric and medical comorbidity are observed among patients who have undergone treatment. The psychoactive properties of psychedelics may be of particular interest within a substance-assisted psychotherapy approach, offering new treatment opportunities for this debilitating disorder.

Review current evidence, therapeutic context, and possible mechanisms of action of different types of psychedelics in the treatment of PTSD.

Literature review using Medline database.

3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy appears to be a potentially safe, effective, and durable treatment for individuals with treatment-refractory PTSD. Based on a small number of studies, ketamine administration appears to result in temporary symptom relief and may, in combination with psychotherapy, lead to lasting reductions in PTSD symptoms. Although these have not yet been investigated in controlled studies, it is known that psilocybin and LSD induce psychoactive effects that could as well contribute to the psychotherapeutic treatment of PTSD.

The use of psychedelic compounds within a substance-assisted psychotherapy framework offers a novel method for pharmacotherapy-psychotherapy integration, although there is still much to learn from both a clinical and neurobiological perspective. It is necessary to generate more data regarding the safety and efficacy of psychedelics, in addition to research on cost-effectiveness, its use in mental health care infrastructure and also regarding the training of specialized therapists.

Posttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Previous research has led to the designation of 3,4-methylenedioxymethamphetamine (MDMA) as a Breakthrough Therapy for treatment of post-traumatic stress disorder (PTSD) when administered as an adjunct to psychotherapy.

Here we report the findings of the first randomized, double-blind, Phase 3 trial assessing the efficacy and safety of 3 sessions with a flexible dose of MDMA or placebo administered under direct observation to participants with severe PTSD (n = 100) as an adjunct to inner-directed psychotherapy.

Change in PTSD symptoms (CAPS-5) and functional impairment (SDS) were assessed by a central, blinded Independent Rater Pool at baseline and following each treatment session. Adverse events (AEs), concomitant medications, suicidal ideation and behavior were tracked throughout the study. Vital signs were measured during experimental sessions. The primary endpoint was 18 weeks post-randomization.

Change in CAPS-5 and SDS, placebo-subtracted Cohen’s d effect size, and a responder analysis will be presented. There were three serious AEs of suicidal ideation or behavior reported. MDMA was well tolerated, with some treatment emergent AEs occurring at greater frequency for the MDMA group during and after experimental sessions.

If MDMA-assisted psychotherapy significantly attenuates PTSD symptomatology and associated functional impairment, these results will form the basis for marketing authorization applications worldwide, including among participants with dissociative subtype of PTSD, depression, history of alcohol and substance use disorders, and adverse childhood experiences.

No significant relationships.

Background – Ecstasy is a recreational drug with an anecdotal reputation for safety. However, reports of adverse effects and fatalities have increased in the medical and popular press.

Method – Literature search and review.

Results – Acute Ecstasy toxicity does not appear to be due to overdose and cannot be solely attributed to the nature of the usual ambient environment. Adverse effects include hyperthermia, seizures, cardiac arrhythmias, hepatotoxicity, hyponatraemia and many psychiatric disorders. Ecstasy causes serotonergic neurotoxicity in the brains of animals at doses close to those used by humans, but its long-term effect on the human brain is unknown.

Conclusion – Ecstasy toxicity should be considered in the differential diagnosis of a variety of medical and psychiatric conditions. Given its popularity, both the acute and the potential long-term effects are a cause for concern.

Cognitive deficits are well documented in ecstasy (3,4-methylenedioxymethamphetamine; MDMA) users, with such deficits being taken as evidence of dysregulation of the serotonin (5-hydroxytryptamine; 5-HT) system. More recently neuroimaging has been used to corroborate these deficits. The present study aimed to assess multitasking performance in ecstasy polydrug users, polydrug users and drug-naive individuals. It was predicted that ecstasy polydrug users would perform worse than non-users on the behavioural measure and this would be supported by differences in cortical blood oxygenation.

In the study, 20 ecstasy-polydrug users, 17 polydrug users and 19 drug-naive individuals took part. On day 1, drug use history was taken and questionnaire measures were completed. On day 2, participants completed a 20-min multitasking stressor while brain blood oxygenation was measured using functional near infrared spectroscopy (fNIRS).

There were no significant differences between the three groups on the subscales of the multitasking stressor. In addition, there were no significant differences on self-report measures of perceived workload (NASA Task Load Index). In terms of mood, ecstasy users were significantly less calm and less relaxed compared with drug-naive controls. There were also significant differences at three voxels on the fNIRS, indicating decreased blood oxygenation in ecstasy users compared with drug-naive controls at voxel 2 (left dorsolateral prefrontal cortex), voxel 14 and voxel 16 (right dorsolateral prefrontal cortex), and compared with polydrug controls at V14.

The results of the present study provide support for changes in brain activation during performance of demanding tasks in ecstasy polydrug users, which could be related to cerebral vasoconstriction.

The use of dantrolene in the treatment of hyperpyrexia related to MDMA (3,4-methylenedioxymethamphetamine) is controversial, with little data available to guide clinical decision-making. Although the treatment is recommended by several poison control centres, published data are primarily in the form of case reports and animal and in vitro experiments. We conducted a systematic review to investigate the published evidence regarding the safety and benefits of dantrolene for MDMA-related hyperpyrexia in humans.

A systematic search of Embase and MEDLINE was conducted from the earliest possible date to November 2008.

All human trials and case reports of MDMA-related hyperpyrexia were considered.

Data were abstracted systematically and characteristics including use of dantrolene, adverse reactions attributed to dantrolene, peak temperature, complications from MDMA-related hyperpyrexia and survival were recorded.

Our search yielded 668 articles of which 53, reporting 71 cases of MDMA-induced hyperpyrexia, met our inclusion criteria. No clinical trials, randomized controlled trials, observational studies or meta-analyses were identified. Dantrolene was used in 26 cases. Patient characteristics were similar in the dantrolene and no dantrolene groups. The proportion of survivors was higher in the dantrolene group (21/26) than in the no dantrolene group (25/45). This difference was especially pronounced in those with extreme (≥ 42°C) and severe (≥ 40°C) fever, with a survival rate of 8 of 13 and 10 of 10, respectively, in the dantrolene group compared with 0 of 4 and 15 of 27 in the no dantrolene group. There were no reports of adverse events attributable to dantrolene with the exception of a possible association with an episode of transient hypoglycemia.

Our systematic review suggests that dantrolene is safe for patients with MDMA-related hyperpyrexia. Dantrolene may also be associated with improved survival and reduced complications, especially in patients with extreme (≥ 42°C) or severe (≥ 40°C) hyperpyrexia, although this conclusion must be interpreted with caution given the risk of reporting or publication bias.

A large number of studies, reviews and meta-analyses have reported cognitive deficits in ecstasy users. However most ecstasy users are polydrug users, and therefore it cannot be excluded that these deficits are (partly) the result of drugs other than ecstasy. The current study, part of the Netherlands XTC Toxicity (NeXT) study, investigates the specific sustained effects of ecstasy relative to amphetamine, cocaine and cannabis on the brain using neuropsychological examination.

A stratified sample of 67 subjects with such a variation in type and amount of drug use was included that correlations between the consumption of the various drugs were relatively low allowing stepwise linear multiple regression analyses to differentiate between the effects of ecstasy and those of other substances. Subjects were assessed with neuropsychological tests measuring attention, working memory, verbal and visuospatial memory, and visuospatial ability.

Ecstasy use [mean 327 (s.d.=364) tablets in lifetime] had a specific significant dose-related negative effect on verbal delayed recall after adjusting for the use of other drugs.

These findings strongly suggest a specific sustained negative effect of ecstasy use on verbal memory. The clinical relevance is not immediately clear, because test performance generally remained within the normal range. However the magnitude of the effect is substantial (d>0.5) and long-term consequences cannot be excluded.