ALH and HVC (Grant number: L-023032) is registered at ClinicalTrials.gov (ID: NCT02649231).We would furthermore like to thank Dr. Evgeny Krupitsky for his pioneering research into ketamine as a treatment and his input into the design of the study. This paper is dedicated to the memory of our colleague Dr. David Gilhooly.

Chronic use of drugs may alter the brain’s reward system, though the extant literature concerning long-term cannabis use and neural correlates of reward processing has shown mixed results. Adolescents may be more vulnerable to the adverse effects of cannabis than adults; however, this has not been investigated for reward processing. As part of the ‘CannTeen’ study, in the largest functional magnetic resonance imaging study of reward processing and cannabis use to date, we investigated reward anticipation and feedback in 125 adult (26–29 years) and adolescent (16–17 years) cannabis users (1–7 days/week cannabis use) and gender- and age-matched controls, using the Monetary Incentive Delay task. Blood-oxygen-level-dependent responses were examined using region of interest (ROI) analyses in the bilateral ventral striatum for reward anticipation and right ventral striatum and left ventromedial prefrontal cortex for feedback, and exploratory whole-brain analyses. Results showed no User-Group or User-Group × Age-Group effects during reward anticipation or feedback in pre-defined ROIs. These null findings were supported by post hoc Bayesian analyses. However, in the whole-brain analysis, cannabis users had greater feedback activity in the prefrontal and inferior parietal cortex compared to controls. In conclusion, cannabis users and controls had similar neural responses during reward anticipation and in hypothesised reward-related regions during reward feedback. The whole-brain analysis revealed tentative evidence of greater fronto-parietal activity in cannabis users during feedback. Adolescents showed no increased vulnerability compared with adults. Overall, reward anticipation and feedback processing appear spared in adolescent and adult cannabis users, but future longitudinal studies are needed to corroborate this.

Background: 3,4-Methylenedioxymethamphetamine (MDMA) is being actively researched as an adjunct to psychotherapy. It may be beneficial to trust, empathy and cooperative behaviour due to its acute prosocial effects. Aim: To test (a) the acute effects of MDMA on measures of empathy, trust and cooperative behaviour, and (b) subacute changes in mood three days after MDMA administration. Methods: Twenty-five participants ( n=7 female), participated in this double-blind, repeated-measures, placebo-controlled experiment. Participants attended two acute sessions, one week apart. Each acute session was followed by a subacute session three days later. Participants received placebo (100 mg ascorbic acid) during one acute session, and MDMA (100 mg MDMA-HCl) at the other, with order counterbalanced. Participants completed the following tasks assessing prosocial behaviour: a trust investment task, a trustworthy face rating task, an empathic stories task, a public project game, a dictator game and an ultimatum game. Participants reported subjective effects. Blood was taken pre-drug, 2 and 4 hours post-drug, and tested for plasma MDMA levels. Results: MDMA acutely increased self-reported ‘closeness to others’ and ‘euphoria’ and increased plasma concentrations of MDMA. MDMA did not significantly change task-based empathy, trust or cooperative behaviour. Using Bayesian analyses, we found evidence that MDMA and placebo did not differ in their effects on empathy and cooperative behaviour. MDMA did not significantly change subacute mood and this was supported by our Bayesian analyses. Conclusion: Despite augmentation in plasma MDMA levels and subjective drug effects, we found no increase in prosocial behaviour in a laboratory setting.

Esketamine was recently licensed by the US Food and Drug Administration (FDA) and European Drug Agency (EDA) for use in treatment resistant depression (TRD), and promising research indicates ketamine as a possible treatment in other mental health conditions. While the underlying mechanisms remain unclear, it has been hypothesized that acute psychoactive effects during ketamine administration may be associated with psychiatric treatment efficacy. We systematically reviewed the evidence for this association. The databases Medline, Embase and PsychInfo were searched up to June 2019. Studies were included if they enrolled adults with a psychiatric diagnosis, assessed acute psychoactive effects using a quantitative measure, and reported on the relationship between acute effects and treatment outcome. We included 21 studies, involving 891 patients. Seventeen studies assessed patients with depression (TRD [k=14]), three assessed substance use disorders, and one assessed social anxiety disorder. Overall, 41 associations were assessed, of which 26% were significant. The studies reviewed displayed great variability in terms of methodology and quality of reporting. The most commonly assessed effect was dissociation, measured by the CADSS. Our results suggest that the CADSS total is not consistently associated with antidepressant outcomes. Apart from this, the current literature is too limited to draw definite conclusions on the presence of an association between acute psychoactive effects and mental health outcomes. The field would benefit from consistently employing a priori hypotheses, more transparent reporting and sufficiently powered statistical analyses. Furthermore, the use of a broader range of assessments tools of acute psychoactive effects during ketamine administration would be beneficial.