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Ayahuasca is a natural psychoactive brew, used in traditional ceremonies in the Amazon basin. Recent research has indicated that ayahuasca is pharmacologically safe and its use may be positively associated with improvements in psychiatric symptoms. The mechanistic effects of ayahuasca are yet to be fully established. In this prospective naturalistic study, 63 self-selected participants took part in ayahuasca ceremonies at a retreat centre in the Peruvian Amazon. Participants undertook the Beck Depression Inventory (BDI-II), State-Trait Anxiety Inventory (STAI), Self-compassion Scale (SCS), Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM), as well as secondary measures, pre- and post-retreat and at 6-months. Participants also provided saliva samples for pre/post epigenetic analysis. Overall, a statistically significant decrease in BDI-II (13.9 vs. 6.1, p < 0.001), STAI (44.4 vs. 34.3 p < 0.001) scores, and CORE-OM scores were observed (37.3 vs. 22.3 p < 0.001) at post-retreat, as well as a concurrent increase in SCS (3.1 vs. 3.6, p < 0.001). Psychometric improvements were sustained, and on some measures values further decreased at 6-month follow-up, suggesting a potential for lasting therapeutic effects. Changes in memory valence were linked to the observed psychometric improvements. Epigenetic findings were equivocal, but indicated that further research in candidate genes, such as sigma non-opioid intracellular receptor 1 (SIGMAR1), is warranted. This data adds to the literature supporting ayahuasca's possible positive impact on mental health when conducted in a ceremonial context. Further investigation into clinical samples, as well as greater analyses into the mechanistic action of ayahuasca is advised., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ruffell, Netzband, Tsang, Davies, Butler, Rucker, Tófoli, Dempster, Young and Morgan.)

This review examines the role of trauma in psychiatric morbidity and analogous psychoneurobiological changes. Trauma is a necessary criterion for Post-Traumatic Stress Disorder (PTSD), however, trauma history is highly correlated with a variety of psychiatric conditions. Some evidence suggests that Major Depressive Disorder (MDD) is the most common psychiatric condition that arises following trauma. Approximately 50% of PTSD cases present with co-morbid MDD. Overlapping symptomatology and neurobiology between these conditions underlie the debate over whether these phenomena result from problematic nosology or whether comorbid MDD + PTSD is a distinct phenotype of trauma-related psychopathology. Regardless, similar treatment approaches have been employed historically, with varying success. The drug-assisted psychotherapy treatment model, which combines pharmacological and psychotherapeutic approaches, is currently being trialled as a novel treatment approach in psychiatry. Both psilocybin- and 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have received Food and Drug Administration 'breakthrough therapy' designation for the treatment of resistant MDD and PTSD, respectively. This paper reviews the therapeutic rationale of both psilocybin and MDMA for treating both trauma-related MDD and PTSD.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities., Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance., Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019., Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort., Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks., Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

The classical psychedelic drugs, including psilocybin, lysergic acid diethylamide and mescaline, were used extensively in psychiatry before they were placed in Schedule I of the UN Convention on Drugs in 1967. Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called 'psychoneurotic' disorders sometimes benefited considerably from their tendency to 'loosen' otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub-optimal, although a recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low. Since 2006, there have been several pilot trials and randomised controlled trials using psychedelics (mostly psilocybin) in various non-psychotic psychiatric disorders. These have provided encouraging results that provide initial evidence of safety and efficacy, however the regulatory and legal hurdles to licensing psychedelics as medicines are formidable. This paper summarises clinical trials using psychedelics pre and post prohibition, discusses the methodological challenges of performing good quality trials in this area and considers a strategic approach to the legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)