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.

Randomised controlled trials (RCTs) of psilocybin have reported large antidepressant effects in adults with major depressive disorder and treatment-resistant depression (TRD). Given psilocybin's psychedelic effects, all published studies have included psychological support. These effects depend on serotonin 2A (5-HT2A) receptor activation, which can be blocked by 5-HT2A receptor antagonists like ketanserin or risperidone. In an animal model of depression, ketanserin followed by psilocybin had similar symptomatic effects as psilocybin alone.

To conduct a proof-of-concept RCT to (a) establish feasibility and tolerability of combining psilocybin and risperidone in adults with TRD, (b) show that this combination blocks the psychedelic effects of psilocybin and (c) provide pilot data on the antidepressant effect of this combination (compared with psilocybin alone).

In a 4-week, three-arm, ‘double dummy’ trial, 60 adults with TRD will be randomised to psilocybin 25 mg plus risperidone 1 mg, psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 12 h of manualised psychotherapy. Measures of feasibility will include recruitment and retention rates; tolerability and safety will be assessed by rates of drop-out attributed to adverse events and rates of serious adverse events. The 5-Dimensional Altered States of Consciousness Rating Scale will be a secondary outcome measure.

This trial will advance the understanding of psilocybin's mechanism of antidepressant action.

This line of research could increase acceptability and access to psilocybin as a novel treatment for TRD without the need for a psychedelic experience and continuous monitoring.