Abstract 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, p<0.001). Treatment did not significantly change child>adult region-of-interest activity. Post hoc analysis indicated that baseline autism symptoms correlated with degarelix-induced changes in paedophilic interest (r=0.717, p<0.001; between-group correlation coefficient z=2.958, p=0.003) and cerebellar activation (r=-0.581, p=0.01; between-group correlation coefficient z=-1.930, p=0.05). Increased child>adult 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.

Introduction Neural cue reactivity is increasingly being investigated as a biomarker of treatment response and relapse prediction in addiction disorders. While aberrant brain responses to salient cues (e.g., drugs) have been widely reported in addiction, it is unclear whether these brain responses persist during longer-term abstinence and how they compare between substance use disorder and obesity and relate to potential differences in eating behaviors. As part of the Gut Hormones in ADDiction (GHADD) neuroimaging study, we investigated how salient cue reactivity to drugs or food, craving and eating behaviors compare in three clinical populations where alterations have been previously observed: abstinent nicotine use disorder (NUD), alcohol use disorder (AUD), and obesity. Methods This study compared group differences in salient cue reactivity and eating behaviors among ex-smokers ( n = 25, ExS), adults with alcohol dependence but who are abstinent ( n = 26, AAD), and adults with obesity who were actively dieting ( n = 26, OB). Participants completed a high-energy food, preferred alcohol, and cigarette functional magnetic resonance imaging (fMRI) cue reactivity task, along with eating behavior questionnaires, appetite visual analogues scales, and an ad libitum test meal. Results ExS exhibited greater blood oxygen level dependent (BOLD) signal to high-energy food pictures in several reward processing regions in both whole brain and region of interest (ROI) analyses, compared with the OB and AAD groups, with no difference in their appeal rating. Compared with the OB group, ExS exhibited greater BOLD signal to cigarette pictures in the frontal gyrus, orbitofrontal cortex, frontal pole, and insula, with no difference in their appeal rating. There were no group differences in preferred alcohol cue reactivity. The AAD group rated sweet taste as more pleasant and consumed more calories from sweet dishes in the ad libitum meal than the OB and ExS groups. Conclusions The presence of heightened cue reactivity to high-energy foods in ex-smokers could contribute to post-quitting weight gain after smoking cessation. Neuroimaging findings were consistent with the persistence of some salient drug cue reactivity, despite absence of craving, after medium term abstinence in ExS, but not in AAD. This study also adds to the body of evidence supporting a sweet taste preference endophenotype predisposing individuals to AUD. These changes in eating behavior in NUD and AUD may provide targets for treatments to reduce substance misuse and facilitate abstinence.

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 [11C]-UCBJ (synaptic density/plasticity), 1H-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 [11C]-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.

Background Cannabis is one of the most widely used psychoactive substances in the world and is increasingly investigated as a treatment for neuropsychiatric conditions. Cannabis contains delta-9-tetrahydrocannabinol (THC), which is thought to underlie its main psychoactive effects, and cannabidiol (CBD), which has been proposed to modulate the effects of THC on the brain. Both have activity at CB1 receptors, whilst THC also binds to CB2 receptors. However, it is unclear how THC’s effects on brain function are related to cannabinoid receptors, or how CBD co-administration affects this. We aimed to investigate the effects of vaporised THC and the moderating effects of CBD on CB1 and CB2 receptor- enriched functional connectivity. Methods Forty-eight participants (24 adolescents and 24 adults) who used cannabis 0.5–3 days/week (mean=1.5 days/week) participated in a randomised, crossover, placebo- controlled, double-blind experiment where they inhaled vaporised cannabis containing either THC-only (8mg/75kg person), THC+CBD (8 mg THC + 24 mg CBD/75 kg person) or no psychoactive compounds (placebo). Resting-state functional MRI data were collected approximately 50 minutes post-administration. Receptor distribution maps were derived from positron emission tomography (PET) imaging for CB1 receptors and the Allen Human Brain Atlas (AHBA) for CB2 receptors. Receptor-Enriched Analysis of Connectivity by Targets (REACT) analytical methodology was used to investigate changes in functional connectivity related to specific receptor targets. Results Inhalation of both THC-only and THC+CBD cannabis induced significant decreases in CB1 and CB2 receptor-enriched functional connectivity compared to placebo. The THC+CBD condition showed more extensive reductions than THC-only cannabis for both CB1- and CB2- enriched functional connectivity, affecting regions including the dorsolateral prefrontal cortex, cingulate cortex, insula, hippocampus, amygdala, and putamen. Higher THC plasma levels were associated with greater decreases in functional connectivity in the THC+CBD condition. Exploratory analyses identified significant positive and negative relationships between subjective drug effects and receptor-enriched functional connectivity in a region- dependent manner. Conclusions Cannabis with and without CBD decreased resting-state functional connectivity in networks associated with CB1 and CB2 receptor distribution. Co-administration of CBD with THC appears to enhance these effects. The REACT analytical methodology identified changes in CB1- and CB2-enriched functional connectivity are related to THC and CBD plasma levels as well as subjective drug effects across a range of regions. ### Competing Interest Statement MBW and NE's primary employer is Perceptive LLC, a contract research organisation that performs commercial research for the pharmaceutical and biotechnology industries. OH is a part-time employee of H Lundbeck A/s. He has received investigator-initiated research funding from and/or participated in advisory/ speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/ Mylan. HVC has consulted for Janssen Research and Development. The remaining authors declare no competing interests. Medical Research Council, https://ror.org/03x94j517, MR/P012728/1

OBJECTIVE: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. METHODS: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). RESULTS: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. CONCLUSIONS: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.

Abstract Major Depressive Disorder (MDD) is a highly prevalent mental health condition characterized by symptoms including anhedonia, which is defined as diminished pleasure, and impulsivity, which has been linked to increased substance abuse, self-harm and suicidal tendencies. Both anhedonia and impulsivity have been contributed to alterations in reward system function, with the striatum being a central hub involved in processing and regulating reward-related information. Selective serotonin reuptake inhibitors are currently the first-line treatment for patients with MDD. In recent years, there has been growing interest in the potential therapeutic benefits of psilocybin for the treatment of depression and there is mounting evidence suggesting that psychedelics may modulate the reward system.Here, we aim to employ seed-voxel analysis on resting-state functional magnetic resonance imaging (fMRI) data to investigate the effects of escitalopram and psychedelic therapy on the reward pathways within the associative, limbic and sensorimotor striatal subdivisions as well as the amygdala and hippocampus in patients with MDD. In this secondary analysis of a trial, 45 MDD patients were randomly assigned to either psilocybin therapy (n=24) or escitalopram (n=21) treatment groups. Participants underwent a 10 min long resting- state functional magnetic resonance imaging scan both before and after a 6-week intervention. Analyses examined the connectivity of three striatal networks and the amygdala and hippocampus using seed- based analysis methods. Changes in between-network connectivity, within-network connectivity and intra-striatal connectivity were examined. Changes in anhedonia and impulsivity from pre- to post- treatment were assessed. Both Escitalopram and psilocybin therapy groups demonstrated reductions in impulsivity and anhedonia scores. Significant interaction effects were found with the amygdala network, where there was a significant psilocybin >escitalopram change in connectivity with a region in the left anterior insula extending into the left putamen. There was a significant escitalopram >psilocybin change in connectivity with a region in the right cerebellum around Crus I extending up to the occipital cortex. There was a significant psilocybin >escitalopram change in connectivity in the limbic striatal network with the bilateral insula, the paracingulate and the temporoparietal junction. Post-hoc analysis revealed this interaction effect was driven by a reduction in connectivity in with the insula in the escitalopram group. A significant correlation was found between the escitalopram induced reduction in connectivity with the insula and the limbic striatum and a reduction in anhedonia. Reduced connectivity between the limbic striatal network and insula correlated with reductions in anhedonia in the escitalopram group. The insula is an area linked to salience and attentional control, which may reveal the reduction in influence of emotional processing from the limbic regions on the bottom-up detection of salient events. In psilocybin, an increase in connectivity between the amygdala and temporoparietal regions was observed, which may indicate enhanced sensory integration and with reward processing. These results show varying treatment effects on striatal connectivity and the implicit difference in treatment effect on underlying neural circuitry.

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 various disorders such as addiction and post-traumatic stress disorder (PTSD) is still not well understood. Most investigations of the effects of these drugs on brain activity have focused 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. Resting-state fMRI (rs-fMRI) data were acquired from two separate previous studies, 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. 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. 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.

CONTEXT:Kisspeptin is a critical endogenous activator of the reproductive system, with escalating clinical interest as a novel therapeutic for common reproductive and psychosexual disorders. However, conflicting animal data suggest that kisspeptin can have anxiolytic, neutral, or anxiogenic effects. OBJECTIVE:Given the rapid development of kisspeptin-based therapeutics, it is important to comprehensively investigate the effects of kisspeptin administration on behavioral, biochemical, and physiological measures of anxiety in humans. METHODS:Ninety-five participants (N = 63 male, N = 32 female) completed a double-blind, randomized, placebo-controlled, crossover protocol (mean age ± SEM 30.9 ± 0.9 y, body mass index 24.0 ± 0.4), attending both for a 75-minute intravenous kisspeptin-54 infusion (1 nmol/kg/h) and rate-matched placebo (in random order). Behavioral, biochemical, and physiological measures of anxiety were compared between kisspeptin and placebo visits, using a state-anxiety psychometric questionnaire before and at the end of the infusions, and blood sampling (for reproductive hormones and cortisol) and heart rate measurements at 15-minute intervals. Blood pressure assessment took place before and at the end of the infusions. RESULTS:Kisspeptin administration robustly increased serum luteinizing hormone to similar levels previously described using this administration protocol, confirming that the dose was biologically active (P < .001). State anxiety was not significantly altered by kisspeptin, compared to placebo (P = .13). Moreover, kisspeptin had no significant effects on circulating cortisol (P = .73), systolic (P = .74) or diastolic blood pressure (P = .90), or heart rate (P = .52). CONCLUSION:This is the first study demonstrating that a biologically active dose of kisspeptin to men and women does not affect behavioral, biochemical, or physiological measures of anxiety. Given that animal studies have yielded contradictory results, this provides key clinical data and reassurance that kisspeptin does not induce anxiety in humans and so informs the current development of kisspeptin-based therapeutics for common reproductive and psychosexual disorders.

Abstract Disclosure: J. Tsoutsouki: None. N. Ertl: None. E.G. Mills: None. M.B. Wall: None. L. Thurston: None. L. Yang: None. S. Suladze: None. T. Hunjan: None. M. Phylactou: None. B. Patel: None. J. Howard: None. A. Abbara: None. D. Golmeier: None. A.N. Comninos: None. W.S. Dhillo: None. Background: Distressing low sexual desire, termed Hypoactive Sexual Desire Disorder (HSDD), affects 10% of women and 8% of men. The established ‘top-down’ neurofunctional model of HSDD in women suggests that in response to erotic cues, excessive activation of higher-level cognitive brain regions (involved in introspection/self-monitoring) suppresses lower-level sexual brain centres, thereby impeding normal sexual function. By contrast, the neurodysfunction in men with HSDD remains to be fully characterised and crucially unlike in women, there are currently no licensed therapies. Herein, we report the first direct comparison of the neural bases of HSDD in women and men. Methods: 32 premenopausal women with HSDD [mean age±SD (y) 29.2±6.7] and 32 men with HSDD [age 37.9±8.6] underwent a task-based functional MRI (fMRI) measuring sexual brain activity during erotic versus control (exercise) videos. Participants completed psychometric questionnaires before and after the fMRI scan, providing functional relevance for the brain activity changes. Results: Women displayed significantly greater activation in higher-level cortical regions (e.g. inferior frontal gyrus, superior frontal gyrus) and lower-level limbic brain regions (e.g. amygdala, striatum, thalamus) in response to erotic videos, compared to the men. Lower activation in lower-limbic sexual regions in women correlated with more severe HSDD, which along with a hyperactivation in the inferior-frontal gyrus relative to the men, supports the ‘top-down’ mechanism underlying HSDD in women. By contrast, men exhibited lower activation in both higher-cortical and lower-limbic regions, but greater activation than the women in the visual cortex in response to erotic videos. Hence, a heightened sensitivity to visual erotic cues in men might not be effectively relayed to the limbic system. In women only, hypothalamic hyperactivation in response to erotic videos correlated with ‘increased heartbeat’ (r=0.5, P=0.001), and ‘tingling all over’ (r=0.6, P<0.001), while higher striatal activation correlated with feeling more ‘stimulated’ (r=0.4, P=0.001) and ‘genital tingling’ (r=0.6, P<0.001) on the psychometric questionnaires. Crucially, these findings were specific to erotic stimuli as no differences were identified in the control comparison (exercise>baseline contrast). Discussion: This is the first study to directly compare the neural bases of distressing low sexual desire in women and men. While supporting the ‘top-down’ mechanism of HSDD in women, it suggests a different neurodysfunctional process in men with HSDD, highlighting a potential functional disconnection between sensory/attention and sexual centres. Our findings have key clinical implications as they identify a sexual dimorphism in the neural bases of low sexual desire relevant to the escalating development of therapeutics for patients with HSDD. Presentation: 6/3/2024

Abstract Disclosure: E.G. Mills: None. L. Thurston: None. L. Yang: None. S. Suladze: None. T. Hunjan: None. M. Phylactou: None. B. Patel: None. S.A. Clarke: None. A.J. Shah: None. C. Izzi-Engbeaya: None. J. Tsoutsouki: None. P. Bech: None. N. Ertl: None. L. Demetriou: None. M.B. Wall: None. D. Goldmeier: None. A. Abbara: None. A.N. Comninos: None. W.S. Dhillo: None. Background: The neuropeptide kisspeptin is a critical endogenous activator of the reproductive system. Due to its key role in regulating reproductive and behavioural processes, there has been escalating interest in targeting kisspeptin-pathways to treat reproductive and psychosexual disorders. However, conflicting evidence from pre-clinical animal models proposes that kisspeptin can have an anxiolytic, anxiogenic or have no effects on anxiety. Given the rapid development of kisspeptin-based therapeutics, it is important to clarify kisspeptin’s effects on anxiety in humans. Herein, we report the largest study examining the effects of kisspeptin on psychometric measures of anxiety and circulating cortisol levels in humans. Methods: Ninety-three eugonadal participants (n=29 healthy men, n=32 men with low sexual desire, n=32 women with low sexual desire) completed a double-blind, randomised, placebo-controlled, crossover study. Participants attended twice: once for intravenous infusion of kisspeptin-54 (1nmol/kg/h) over 75mins and for a rate-matched placebo. Blood sampling took place at 15-minute intervals from -30 to 75mins to measure circulating kisspeptin, LH, testosterone and cortisol [in men] and oestradiol [in women]. The validated ‘State-Trait Anxiety Inventory (STAI) Y2-Trait’ was completed prior to the infusions to exclude abnormal anxiety traits, with all scores within normal limits. Participants also completed the ‘STAI Y1-State’ before and prior to the end of the infusions to assess for any dynamic effects of the infusions on anxiety. Results: Ninety-three participants (mean age ±SD 30.9±8.7yrs, BMI 24.0±3.7kg/m2) completed the study. Intravenous kisspeptin significantly increased serum LH to similar levels previously described using this administration protocol, confirming that the dose was biologically active (P<0.001). Importantly, state anxiety was unaltered by kisspeptin, compared to placebo (mean difference in ‘STAI Y1-State’ scores during the infusions: kisspeptin -0.03±8.11, placebo 0.77±8.08, P=0.43). Moreover, kisspeptin had no effect on circulating cortisol compared to placebo during the 75minute study period (P=0.92). As expected, kisspeptin had no significant effects on downstream sex-steroid levels during the 75minute study period, thereby excluding these as confounders. Discussion: This is the largest study demonstrating that a biologically active dose of kisspeptin to healthy volunteers and patients with psychosexual disorders does not affect psychometric measures of anxiety and associated circulating cortisol levels. Given that animal studies have yielded conflicting results, this provides important clinical data and reassurance that kisspeptin administration in humans does not induce anxiety and so informs the rapid development of kisspeptin-based therapeutics for reproductive and psychosexual disorders. Presentation: 6/3/2024

Distressing low sexual desire, termed Hypoactive Sexual Desire Disorder (HSDD), affects approximately 10% of women and 8% of men. In women, the ‘top-down’ theory of HSDD describes hyperactivity in higher-level cognitive brain regions, suppressing lower-level emotional/sexual brain areas. However, it is unknown how this neurofunctional disturbance compares to HSDD in men. To investigate this, we employed task-based functional MRI in 32 women and 32 men with HSDD to measure sexual-brain processing during sexual versus non-sexual videos, as well as psychometric questionnaires to assess sexual desire/arousal. We demonstrate that women had greater activation in higher-level and lower-level brain regions, compared to men. Indeed, women who had greater hypothalamic activation in response to sexual videos, reported higher psychometric scores in the evaluative (r = 0.55, P = 0.001), motivational (r = 0.56, P = 0.003), and physiological (r = 0.57, P = 0.0006) domains of sexual desire and arousal after watching the sexual videos in the scanner. By contrast, no similar correlations were observed in men. Taken together, this is the first direct comparison of the neural correlates of distressing low sexual desire between women and men. The data supports the ‘top-down’ theory of HSDD in women, whereas in men HSDD appears to be associated with different neurofunctional processes.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

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).

The use of psychoactive substances for ritual, spiritual and medicinal purposes stretches back into prehistory and has been a common feature of many diverse cultures and societies globally. Psychedelics, with their unique ability to amplify feelings of connectedness and openness, may have also served as tools for promoting tribal cohesion and trust in ancient cultures. Psychedelic is a broad term derived from the Greek words ‘psyche’, meaning soul or mind, and ‘deloun’, which means to manifest. Classic psychedelics, such as psilocybin (the active ingredient in magic mushrooms), act directly on the serotonin 5-HT2A receptor, while atypical psychedelics, such as MDMA and ketamine, have different pharmacological modes of action and tend to have less of a hallucinogenic effect. They all produce (as the origin of their name suggests) a profound shift in consciousness, generally positive emotional states and feelings of connectedness and openness. Lysergic acid diethylamide (LSD) is in many ways the prototypical psychedelic and began the first wave of psychedelic research in western medicine after it was first synthesized in the early 1940s. By the 1960s, thousands of patients had received LSD therapy in the USA, the UK, Czech Republic and elsewhere for depression, anxiety, addiction and a number of other disorders. This period concurrently saw the development of other key psychiatric drugs such as monoamine oxidase inhibitors as antidepressants and dopamine antagonist drugs as antipsychotics. This revolution in psychiatric treatment ushered in a wave of research and entirely new perspectives on the biological mechanisms underpinning psychiatric disorders.

Psychedelic-assisted psychotherapy with psilocybin is an emerging therapy with great promise for depression, and modern psychedelic therapy (PT) methods incorporate music as a key element. Music is an effective emotional/hedonic stimulus that could also be useful in assessing changes in emotional responsiveness following psychedelic therapy. Brain responses to music were assessed before and after PT using functional Magnetic Resonance Imaging (fMRI) and ALFF (Amplitude of Low Frequency Fluctuations) analysis methods. Nineteen patients with treatment-resistant depression underwent two treatment sessions involving administration of psilocybin, with MRI data acquired one week prior and the day after completion of the second of two psilocybin dosing sessions. Comparison of music-listening and resting-state scans revealed significantly greater ALFF in bilateral superior temporal cortex for the post-treatment music scan, and in the right ventral occipital lobe for the post-treatment resting-state scan. ROI analyses of these clusters revealed a significant effect of treatment in the superior temporal lobe for the music scan only. Somewhat consistently, voxelwise comparison of treatment effects showed relative increases for the music scan in the bilateral superior temporal lobes and supramarginal gyrus, and relative decreases in the medial frontal lobes for the resting-state scan. ALFF in these music-related clusters was significantly correlated with intensity of subjective effects felt during the dosing sessions. These data suggest a specific effect of PT on the brain’s response to a hedonic stimulus (music), implying an elevated responsiveness to music after psilocybin therapy that was related to subjective drug effects felt during dosing.

Background/aim: Cannabis use is highly prevalent in adolescents; however, little is known about its effects on adolescent brain function. Method: Resting-state functional magnetic resonance imaging was used in matched groups of regular cannabis users (N = 70, 35 adolescents: 16–17 years old, 35 adults: 26–29 years old) and non-regular-using controls (N = 70, 35 adolescents/35 adults). Pre-registered analyses examined the connectivity of seven major cortical and sub-cortical brain networks (default mode network, executive control network (ECN), salience network, hippocampal network and three striatal networks) using seed-based analysis methods with cross-sectional comparisons between user groups and age groups. Results: The regular cannabis use group (across both age groups), relative to controls, showed localised increases in connectivity only in the ECN analysis. All networks showed localised connectivity differences based on age group, with the adolescents generally showing weaker connectivity than adults, consistent with the developmental effects. Mean connectivity across entire network regions of interest (ROIs) was also significantly decreased in the ECN in adolescents. However, there were no significant interactions found between age group and user group in any of the seed-based or ROI analyses. There were also no associations found between cannabis use frequency and any of the derived connectivity measures. Conclusion: Regular cannabis use is associated with changes in connectivity of the ECN, which may reflect allostatic or compensatory changes in response to regular cannabis intoxication. However, these associations were not significantly different in adolescents compared to adults.