Matthew B. Wall

Adolescence is a critical period of brain development during which the endocannabinoid system continues to mature. These developmental changes may contribute to age-related differences in the association between cannabis use and large-scale functional network organisation, yet this association remains incompletely characterised. We hypothesised that regular cannabis use would be associated with differential one-year changes in resting-state functional connectivity between adolescents and adults. Resting-state fMRI data at two time points, one year apart, were analysed from 66 participants (31 aged 16-17 years; 35 aged 26-29 years) including 29 with regular cannabis use and 37 age-matched cannabis-naïve controls. Seed-to-voxel analyses examined longitudinal changes in functional connectivity across age and cannabis-use groups. Year change, age × user-group interactions were identified in salience and default mode network connectivity, including divergent changes in anticorrelations with medial prefrontal, thalamic, cerebellar and juxtapositional regions. Directionality of effects differed by network and region. Additional main effects of user group were observed for executive control and associative striatal connectivity, with the cannabis-use group showing decreased positive connectivity and reduced anticorrelation, respectively. Changes in functional connectivity were developmentally dissociable and predominantly observed in regions contributing to attentional and transmodal processing. These findings suggest that cannabis may be associated with alterations in the maturational refinement of higher-order neural systems, potentially reflecting age-related differences in neurobiological sensitivity to cannabis exposure. Considering developmental stage may therefore be important for characterising cannabis-related neurobiological differences and may have implications for understanding age-dependent vulnerability to cannabis-related psychiatric outcomes.

Psychedelics have robust effects on acute brain function and long-term behavior but whether they also cause enduring functional and anatomical brain changes is largely unknown. In an exploratory, placebo-controlled, within-subjects, electroencephalography (EEG), and magnetic resonance imaging (MRI) study in 28 healthy, entirely psychedelic-naive participants, anatomical and functional brain changes are detected from one-hour to one-month after a single high-dose (25 mg) of psilocybin. Increases in cognitive flexibility, psychological insight, and well-being are seen at one-month. Diffusion tensor imaging (DTI) done before and one-month after 25 mg psilocybin reveals decreased axial diffusivity bilaterally in prefrontal-subcortical tracts that correlate with decreases in brain network modularity (fMRI) over the same month. Enduring functional brain changes are largely absent, but network modularity change (numerical decrease) negatively correlates with well-being change (significant increase), in line with previous findings in depression. Increased cortical signal entropy (EEG) at 1- and 2-hours post-dosing predicts improved psychological well-being at one-month. Next-day psychological insight mediates the entropy to well-being relationship. All effects are exclusive to 25 mg psilocybin; no effects occur with a 1 mg psilocybin placebo.

Mechanistic understanding and biomarkers of gonadotropin-releasing hormone antagonist treatment effect in paedophilic disorder are absent but may enhance outcomes and reduce sexual-offending risk. 52 help-seeking self-referred Swedish men with paedophilic disorder enrolled in a double-blinded, placebo-controlled, randomized clinical trial. Participants underwent task-based fMRI before, and two weeks after, subcutaneous injection of 120mg of degarelix or equal volume of placebo. fMRI blood-oxygen-level-dependent activation was compared between child and adult (child>adult) stimuli in task-derived regions of interest. Primary outcome was within region-of-interest child>adult activation change, whereas secondary outcomes correlated region-of-interest child>adult activation change to change in clinical measurements of risk, paedophilic interest, sexual preoccupation, hyper- and hyposexuality. 19 degarelix and 22 placebo participants had sufficient fMRI data quality. Reductions in paedophilic interest were strongly correlated with increased child>adult cerebellar (vermis) region-of-interest activation following degarelix (r=-0.740, p<0.001) but not placebo (r=0.183, p=0.41; between-group correlation coefficient z=3.347, padult region-of-interest activity. Post hoc analysis indicated that baseline autism symptoms correlated with degarelix-induced changes in paedophilic interest (r=0.717, padult cerebellar activation was associated with degarelix-induced reductions of paedophilic interest, suggesting cerebellar activity as mechanistically important to, and a prospective biomarker of, degarelix treatment effect. Additionally, autism symptoms may inform treatment prediction. Together, these findings have mechanistic and clinical implications for degarelix treatment of paedophilic disorder. EU clinical trials register identifier: 2014-000647-32 https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000647-32/SE, registered on 05/06/2014.

We investigated ketamine’s neuroplastic effects in healthy human subjects using integrated Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) measures before and 1–8 days after a single psychedelic dose of ketamine (1 mg/kg, intravenous). Eleven male participants underwent two PET/MRI scans with [ ¹¹ C]-UCBJ (synaptic density/plasticity), ¹ H-MRS (glutamate and GABA) and resting-state fMRI (intrinsic brain activity, functional connectivity), before and after ketamine. While group-level analyses showed no significant increases in PET synaptic markers, ketamine administration resulted in significantly elevated glutamate levels within the anterior cingulate cortex (ACC). Functional connectivity analyses revealed reduced coupling between the ACC and the dorsolateral prefrontal cortex (dlPFC) and increased coupling between the ACC and the amygdala in the days following ketamine administration. Our multimodal analysis revealed that participants showing an increase in [ ¹¹ C]-UCBJ volume distribution (VT), a putative index of synaptic plasticity, showed a correlated reduction in intrinsic activity within regions belonging to the default mode network (DMN). By linking molecular, cellular and network-level changes, our results point to the DMN as a central hub where ketamine may reshape brain hierarchies in the long term, providing new directions for understanding its therapeutic mechanisms and developing targeted treatments.

Psilocybin is an emerging intervention for depression that may be at least as effective as selective serotonin reuptake inhibitors (SSRIs), but effects of the two treatments on the neural correlates of emotional processing have never been directly compared. The authors assessed neural responses to emotional faces using blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) in two groups with major depression. One group (N=25; 9 women and 16 men) received two dosing sessions with 25 mg psilocybin plus 6 weeks of daily inert placebo, and the second group (N=21; 6 women and 15 men) received 6 weeks of escitalopram plus two dosing sessions with a nonpsychoactive (placebo) dose of 1 mg psilocybin. Both groups had equal psychological support throughout: 3 hours of preparation, one in-person integration session following the psilocybin dosing sessions, and two further integration sessions conducted via video call or telephone. An emotional face fMRI paradigm was completed before treatment and at the 6-week posttreatment primary end point (3 weeks following psilocybin dosing sessions). Patient group (psilocybin versus escitalopram) interacted with time point (before versus after treatment) on a distributed set of cortical regions. Post hoc within-condition analyses showed that posttreatment BOLD responses to emotional faces of all types were significantly reduced in the escitalopram group, with no change or a slight increase in the psilocybin group. Analyses of amygdala responsivity showed a reduction of response to fearful faces in the escitalopram group, but lesser effects for the psilocybin group. Despite large improvements in depressive symptoms in the psilocybin group, psilocybin therapy had only a minor effect on brain responsiveness to emotional stimuli. These results are consistent with prior findings that the antidepressant action of SSRIs is often accompanied by a reduction in emotional responsiveness, but this effect may not occur in psychedelic therapy.

Introduction Lysergic acid diethylamide (LSD) and 3,4-Methylenedioxymethamphetamine (MDMA) are widely used psychoactive drugs and their potential use in psychiatric medicine is currently generating interest. The mechanism by which these drugs may assist recovery in addiction, mood disorders and post-traumatic stress disorder (PTSD) is still not well understood. Most investigations of the effects of these drugs on brain activity have focussed on cortical resting-state networks, however the striatum is a key reward and motivation hub of the brain and aberrant striatal processing may be part of the pathophysiology of these disorders. Consequently, we investigated striatal connectivity following acute MDMA and LSD administration. Method Resting-state fMRI (rs-fMRI) data were acquired, and seed-voxel functional connectivity analyses were used with the striatum subdivided into three seed regions: the associative, limbic, and sensorimotor striatum. Within-network connectivity was measured using group mean network maps and whole-brain connectivity (seed-to-voxel) was also examined. Results Neither MDMA nor LSD significantly changed within-network connectivity of any of the three striatal seed regions. However, striatal connectivity with other brain regions was significantly altered with both MDMA and LSD. Most notably, MDMA reduced connectivity between the limbic striatum and the amygdala, while LSD increased connectivity between the associative striatum and the frontal, sensorimotor, and visual cortices. Conclusion Changes in connectivity were mostly observed outside the standard striatal networks, consistent with previous findings that psychedelics reduce network modularity or between-network segregation and increase connectivity across standard networks.

Adolescence is a time of rapid neurodevelopment and the endocannabinoid system is particularly prone to change during this time. Cannabis is a commonly used drug with a particularly high prevalence of use among adolescents. The two predominant phytocannabinoids are Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which affect the endocannabinoid system. It is unknown whether this period of rapid development makes adolescents more or less vulnerable to the effects of cannabis on brain-network connectivity, and whether CBD may attenuate the effects of THC. Using fMRI, we explored the impact of vaporized cannabis (placebo, THC: 8 mg/75 kg, THC + CBD: 8 mg/75 kg THC & 24 mg/75 kg CBD) on resting-state networks in groups of semi-regular cannabis users (usage frequency between 0.5 and 3 days/week), consisting of 22 adolescents (16–17 years) and 24 young adults (26–29 years) matched for cannabis use frequency. Cannabis caused reductions in within-network connectivity in the default mode (F[2,88] = 3.97, P = 0.022, η² = 0.018), executive control (F[2,88] = 18.62, P < 0.001, η² = 0.123), salience (F[2,88] = 12.12, P < 0.001, η² = 0.076), hippocampal (F[2,88] = 14.65, P < 0.001, η² = 0.087), and limbic striatal (F[2,88] = 16.19, P < 0.001, η² = 0.102) networks compared to placebo. Whole-brain analysis showed cannabis significantly disrupted functional connectivity with cortical regions and the executive control, salience, hippocampal, and limbic striatal networks compared to placebo. CBD did not counteract THC’s effects and further reduced connectivity both within networks and the whole brain. While age-related differences were observed, there were no interactions between age group and cannabis treatment in any brain network. Overall, these results challenge the assumption that CBD can make cannabis safer, as CBD did not attenuate THC effects (and in some cases potentiated them); furthermore, they show that cannabis causes similar disruption to resting-state connectivity in the adolescent and adult brain.

Psychedelic therapies are an emerging class of treatments in psychiatry with great potential, however relatively little is known about their interactions with other commonly used psychiatric medications. As psychedelic therapies become more widespread and move closer to the clinic, they likely will need to be integrated into existing treatment models which may include one or more traditional pharmacological therapies, meaning an awareness of potential drug-drug interactions will become vital. This commentary outlines some of the issues surrounding the study of drug-drug interactions of this type, provides a summary of some of the relevant key results to date, and charts a way forward which relies crucially on multimodal neuroimaging investigations. Studies in humans which combine Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI), plus ancillary measures, are likely to provide the most comprehensive assessment of drug-drug interactions involving psychedelics and the relevant effects at multiple levels of the drug response (molecular, functional, and clinical).