Rewarding Subjective Effects of the NMDAR Antagonist Nitrous Oxide (Laughing Gas) Are Moderated by Impulsivity and Depressive Symptoms in Healthy Volunteers.

BACKGROUND: Nitrous oxide (N2O) is an anesthetic gas with both therapeutic and abuse potential. Because N2O is an NMDA receptor (NMDAR) antagonist, its effects are expected to resemble those of the prototypical NMDAR antagonist, ketamine. In this study, we examined the subjective rewarding effects of N2O using measures previously employed in studies of ketamine. We also tested for moderation of these effects by bipolar phenotype, depressive symptoms, and impulsivity. METHODS: Healthy volunteers were randomly assigned to either 50% N2O (n = 40) or medical air (n = 40). Self-reported rewarding (liking and wanting), and alcohol-like effects were assessed pre-, peri- and post inhalation. RESULTS: Effect sizes for the various rewarding/alcohol-like effects of N2O were generally similar to those reported in studies of moderate-dose ketamine. Impulsivity moderated the subjective reinforcing (liking) effects of inhaled gas, while depressive symptoms moderated motivational (wanting [more]) effects. However, depression and impulsivity had opposite directional influences, such that higher impulsivity was associated with higher N2O liking, and higher depression, with lower N2O wanting. CONCLUSION: To the extent that static (versus longitudinal) subjective rewarding effects are a reliable indicator of future problematic drug use, our findings suggests that impulsivity and depression may predispose and protect, respectively, against N2O abuse. Future studies should examine if these moderators are relevant for other NMDAR antagonists, including ketamine, and novel ketamine-like therapeutic and recreational drugs. Similarities between moderate-dose N2O and moderate-dose ketamine in the intensity of certain subjective effects suggest that N2O may, at least to some extent, serve as substitute for ketamine as a safe and easily implemented experimental tool for probing reward-related NMDAR function and dysfunction in humans.

An assessment of rapamycin for weakening binge-eating memories via reconsolidation: a pre-registered, double-blind randomised placebo-controlled experimental study.

BACKGROUND: Maladaptive learning linking environmental food cues to high-palatability food reward plays a central role in overconsumption in obesity and binge eating disorders. The process of memory reconsolidation offers a mechanism to weaken such learning, potentially ameliorating over-eating behaviour. Here we investigated whether putatively interfering with synaptic plasticity using the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, could weaken retrieved chocolate reward memories through blockade of reconsolidation. METHODS: Seventy five healthy volunteers with a tendency to binge eat chocolate were randomised to retrieve chocolate reward memory under 10 mg rapamycin (RET + RAP, active condition), or placebo (RET + PBO), or they received 10 mg rapamycin without subsequent retrieval (NO RET + RAP). Indices of chocolate reward memory strength were assessed one week pre and post manipulation and at one month follow-up. RESULTS: Contrary to hypotheses, the RET + RAP group did not show any greater reduction than control groups on indices of motivational salience of chocolate cues, motivation to consume chocolate or liking of chocolate. Mild evidence of improvement in the RET + RAP group was found, but this was limited to reduced chocolate binge episodes and improved healthy food choices. CONCLUSIONS: We did not find convincing evidence of comprehensive naturalistic chocolate reward memory reconsolidation blockade by rapamycin. The effects on chocolate bingeing and food choices may warrant further investigation. These limited positive findings may be attributable to insufficient interference with mTOR signalling with 10 mg rapamycin, or failure to destabilise chocolate memories during retrieval.

Long-term behavioural rewriting of maladaptive drinking memories via reconsolidation-update mechanisms.

BACKGROUND: Alcohol use disorders can be conceptualised as a learned pattern of maladaptive alcohol-consumption behaviours. The memories encoding these behaviours centrally contribute to long-term excessive alcohol consumption and are therefore an important therapeutic target. The transient period of memory instability sparked during memory reconsolidation offers a therapeutic window to directly rewrite these memories using targeted behavioural interventions. However, clinically-relevant demonstrations of the efficacy of this approach are few. We examined key retrieval parameters for destabilising naturalistic drinking memories and the ability of subsequent counterconditioning to effect long-term reductions in drinking. METHODS: Hazardous/harmful beer-drinking volunteers (N = 120) were factorially randomised to retrieve (RET) or not retrieve (No RET) alcohol reward memories with (PE) or without (No PE) alcohol reward prediction error. All participants subsequently underwent disgust-based counterconditioning of drinking cues. Acute responses to alcohol were assessed pre- and post-manipulation and drinking levels were assessed up to 9 months. RESULTS: Greater long-term reductions in drinking were found when counterconditioning was conducted following retrieval (with and without PE), despite a lack of short-term group differences in motivational responding to acute alcohol. Large variability in acute levels of learning during counterconditioning was noted. 'Responsiveness' to counterconditioning predicted subsequent responses to acute alcohol in RET + PE only, consistent with reconsolidation-update mechanisms. CONCLUSIONS: The longevity of behavioural interventions designed to reduce problematic drinking levels may be enhanced by leveraging reconsolidation-update mechanisms to rewrite maladaptive memory. However, inter-individual variability in levels of corrective learning is likely to determine the efficacy of reconsolidation-updating interventions and should be considered when designing and assessing interventions.

Automated quantitative MRI volumetry reports support diagnostic interpretation in dementia: a multi-rater, clinical accuracy study.

OBJECTIVES: We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists' accuracy and confidence in detecting volume loss, and in differentiating Alzheimer's disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone. METHODS: Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52-81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, 'non-clinical image analysts') assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as 'normal' or 'abnormal' and if 'abnormal' as 'AD' or 'FTD'. RESULTS: The QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group's accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters' agreement (Cohen's κ) with the 'gold standard' was not significantly affected by the QReport; only the consultant group improved significantly (κs 0.41➔0.55, p = 0.04*). Cronbach's alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from 'good' to 'excellent'. CONCLUSION: Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses. KEY POINTS: • The use of quantitative report alongside routine visual MRI assessment improves sensitivity and accuracy for detecting volume loss and AD vs visual assessment alone. • Consultant neuroradiologists' assessment accuracy and agreement (kappa scores) significantly improved with the use of quantitative atrophy reports. • First multi-rater radiological clinical evaluation of visual quantitative MRI atrophy report for use as a diagnostic aid in dementia.

Clinical evaluation of automated quantitative MRI reports for assessment of hippocampal sclerosis.

OBJECTIVES: Hippocampal sclerosis (HS) is a common cause of temporal lobe epilepsy. Neuroradiological practice relies on visual assessment, but quantification of HS imaging biomarkers-hippocampal volume loss and T2 elevation-could improve detection. We tested whether quantitative measures, contextualised with normative data, improve rater accuracy and confidence. METHODS: Quantitative reports (QReports) were generated for 43 individuals with epilepsy (mean age ± SD 40.0 ± 14.8 years, 22 men; 15 histologically unilateral HS; 5 bilateral; 23 MR-negative). Normative data was generated from 111 healthy individuals (age 40.0 ± 12.8 years, 52 men). Nine raters with different experience (neuroradiologists, trainees, and image analysts) assessed subjects' imaging with and without QReports. Raters assigned imaging normal, right, left, or bilateral HS. Confidence was rated on a 5-point scale. RESULTS: Correct designation (normal/abnormal) was high and showed further trend-level improvement with QReports, from 87.5 to 92.5% (p = 0.07, effect size d = 0.69). Largest magnitude improvement (84.5 to 93.8%) was for image analysts (d = 0.87). For bilateral HS, QReports significantly improved overall accuracy, from 74.4 to 91.1% (p = 0.042, d = 0.7). Agreement with the correct diagnosis (kappa) tended to increase from 0.74 ('fair') to 0.86 ('excellent') with the report (p = 0.06, d = 0.81). Confidence increased when correctly assessing scans with the QReport (p < 0.001, η2p = 0.945). CONCLUSIONS: QReports of HS imaging biomarkers can improve rater accuracy and confidence, particularly in challenging bilateral cases. Improvements were seen across all raters, with large effect sizes, greatest for image analysts. These findings may have positive implications for clinical radiology services and justify further validation in larger groups. KEY POINTS: • Quantification of imaging biomarkers for hippocampal sclerosis-volume loss and raised T2 signal-could improve clinical radiological detection in challenging cases. • Quantitative reports for individual patients, contextualised with normative reference data, improved diagnostic accuracy and confidence in a group of nine raters, in particular for bilateral HS cases. • We present a pre-use clinical validation of an automated imaging assessment tool to assist clinical radiology reporting of hippocampal sclerosis, which improves detection accuracy.

Technical and clinical validation of commercial automated volumetric MRI tools for dementia diagnosis-a systematic review.

Developments in neuroradiological MRI analysis offer promise in enhancing objectivity and consistency in dementia diagnosis through the use of quantitative volumetric reporting tools (QReports). Translation into clinical settings should follow a structured framework of development, including technical and clinical validation steps. However, published technical and clinical validation of the available commercial/proprietary tools is not always easy to find and pathways for successful integration into the clinical workflow are varied. The quantitative neuroradiology initiative (QNI) framework highlights six necessary steps for the development, validation and integration of quantitative tools in the clinic. In this paper, we reviewed the published evidence regarding regulatory-approved QReports for use in the memory clinic and to what extent this evidence fulfils the steps of the QNI framework. We summarize unbiased technical details of available products in order to increase the transparency of evidence and present the range of reporting tools on the market. Our intention is to assist neuroradiologists in making informed decisions regarding the adoption of these methods in the clinic. For the 17 products identified, 11 companies have published some form of technical validation on their methods, but only 4 have published clinical validation of their QReports in a dementia population. Upon systematically reviewing the published evidence for regulatory-approved QReports in dementia, we concluded that there is a significant evidence gap in the literature regarding clinical validation, workflow integration and in-use evaluation of these tools in dementia MRI diagnosis.

Reduction in the occurrence of distressing involuntary memories following propranolol or hydrocortisone in healthy women.

BACKGROUND: Pharmacological treatments targeting the neuroendocrine stress response may hold special promise in secondary prevention of posttraumatic stress disorder (PTSD). However, findings from clinical trials have been inconsistent and the efficacy of specific drugs, their temporal window of efficacy, effective doses and the characteristics of likely treatment responders remain unclear. METHOD: Using an experimental human model of distressing involuntary memory formation, we compare the effects of two drugs that have theoretical or empirical support as secondary preventive agents in PTSD. Eighty-eight healthy women (average age: 23.5 years) received oral propranolol (80 mg), hydrocortisone (30 mg), or matched placebo immediately after viewing a 'trauma film'. They then completed daily, time-stamped intrusion diaries for 1 week, at the end of which, voluntary memory was tested. RESULTS: While neither drug affected voluntary memory for the trauma narrative, propranolol treatment was associated with 42% fewer, and hydrocortisone with 55% fewer intrusions across the week, relative to placebo. Additionally, propranolol reduced general trauma-like symptoms, and post-drug cortisol levels were negatively correlated with intrusion frequency in the hydrocortisone group. CONCLUSIONS: Overall, this study shows substantial reductions in intrusive memories and preserved voluntary narrative-declarative memory following either propranolol or hydrocortisone in an experimental model of psychological trauma. As such, despite some inconsistencies in clinical trials, our findings support continued investigation of propranolol and hydrocortisone as secondary preventive agents for re-experiencing symptoms of PTSD. The findings also suggest that it is critical for future research to identify the conditions governing the preventive efficacy of these drugs in PTSD.

Which biological and self-report measures of cannabis use predict cannabis dependency and acute psychotic-like effects?

BACKGROUND: Changes in cannabis regulation globally make it increasingly important to determine what predicts an individual's risk of experiencing adverse drug effects. Relevant studies have used diverse self-report measures of cannabis use, and few include multiple biological measures. Here we aimed to determine which biological and self-report measures of cannabis use predict cannabis dependency and acute psychotic-like symptoms. METHOD: In a naturalistic study, 410 young cannabis users were assessed once when intoxicated with their own cannabis and once when drug-free in counterbalanced order. Biological measures of cannabinoids [(Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN) and their metabolites)] were derived from three samples: each participant's own cannabis (THC, CBD), a sample of their hair (THC, THC-OH, THC-COOH, CBN, CBD) and their urine (THC-COOH/creatinine). Comprehensive self-report measures were also obtained. Self-reported and clinician-rated assessments were taken for cannabis dependency [Severity of Dependence Scale (SDS), DSM-IV-TR] and acute psychotic-like symptoms [Psychotomimetic State Inventory (PSI) and Brief Psychiatric Rating Scale (BPRS)]. RESULTS: Cannabis dependency was positively associated with days per month of cannabis use on both measures, and with urinary THC-COOH/creatinine for the SDS. Acute psychotic-like symptoms were positively associated with age of first cannabis use and negatively with urinary THC-COOH/creatinine; no predictors emerged for BPRS. CONCLUSIONS: Levels of THC exposure are positively associated with both cannabis dependency and tolerance to the acute psychotic-like effects of cannabis. Combining urinary and self-report assessments (use frequency; age first used) enhances the measurement of cannabis use and its association with adverse outcomes.

Changes in cannabis potency and first-time admissions to drug treatment: a 16-year study in the Netherlands.

BACKGROUND: The number of people entering specialist drug treatment for cannabis problems has increased considerably in recent years. The reasons for this are unclear, but rising cannabis potency could be a contributing factor. METHODS: Cannabis potency data were obtained from an ongoing monitoring programme in the Netherlands. We analysed concentrations of δ-9-tetrahydrocannabinol (THC) from the most popular variety of domestic herbal cannabis sold in each retail outlet (2000-2015). Mixed effects linear regression models examined time-dependent associations between THC and first-time cannabis admissions to specialist drug treatment. Candidate time lags were 0-10 years, based on normative European drug treatment data. RESULTS: THC increased from a mean (95% CI) of 8.62 (7.97-9.27) to 20.38 (19.09-21.67) from 2000 to 2004 and then decreased to 15.31 (14.24-16.38) in 2015. First-time cannabis admissions (per 100 000 inhabitants) rose from 7.08 to 26.36 from 2000 to 2010, and then decreased to 19.82 in 2015. THC was positively associated with treatment entry at lags of 0-9 years, with the strongest association at 5 years, b = 0.370 (0.317-0.424), p < 0.0001. After adjusting for age, sex and non-cannabis drug treatment admissions, these positive associations were attenuated but remained statistically significant at lags of 5-7 years and were again strongest at 5 years, b = 0.082 (0.052-0.111), p < 0.0001. CONCLUSIONS: In this 16-year observational study, we found positive time-dependent associations between changes in cannabis potency and first-time cannabis admissions to drug treatment. These associations are biologically plausible, but their strength after adjustment suggests that other factors are also important.

The Acute Effects of a Dopamine D3 Receptor Preferring Agonist on Motivation for Cigarettes in Dependent and Occasional Cigarette Smokers.

Background: Dopaminergic functioning is thought to play critical roles in both motivation and addiction. There is preliminary evidence that dopamine agonists reduce the motivation for cigarettes in smokers. However, the effects of pramipexole, a dopamine D3 receptor preferring agonist, have not been investigated. The aim of this study was to examine the effects of an acute dose of pramipexole on the motivation to earn cigarettes and nondrug rewards. Methods: Twenty dependent and 20 occasional smokers received 0.5 mg pramipexole using a double-blind, placebo-controlled crossover design. Motivation for cigarettes and consummatory nondrug rewards was measured using the DReaM-Choice task, in which participants earned, and later "consumed," cigarettes, music, and chocolate. Demand for cigarettes was measured using the Cigarette Purchase Task (CPT). Self-reported craving, withdrawal, and drug effects were also recorded. Results: Dependent smokers chose (p < .001) and button-pressed for (p < .001) cigarettes more, and chose chocolate less (p < .001), than occasional smokers. Pramipexole did not affect the number of choices for or amount of button-pressing for any reward including cigarettes, which was supported by a Bayesian analysis. The dependent smokers had greater demand for cigarettes than occasional smokers across all CPT outcomes (ps < .021), apart from elasticity. Pramipexole did not affect demand for cigarettes, and this was supported by Bayesian analyses. Pramipexole produced greater subjective "feel drug" and "dislike drug" effects than placebo. Conclusions: Dependent and occasional cigarette smokers differed in their motivation for cigarettes but not for the nondrug rewards. Pramipexole did not acutely alter motivation for cigarettes. These findings question the role of dopamine D3 receptors in cigarette-seeking behavior in dependent and occasional smokers. Implications: This study adds to the growing literature about cigarette versus nondrug reward processing in nicotine dependence and the role of dopamine in cigarette-seeking behavior. Our results suggest nicotine dependence is associated with a hypersensitivity to cigarette rewards but not a hyposensitivity to nondrug rewards. Furthermore, our results question the importance of dopamine D3 receptors in motivational processing of cigarettes in occasional and dependent smokers.

The Subjective Response to Nitrous Oxide is a Potential Pharmaco-Endophenotype for Alcohol Use Disorder: A Preliminary Study with Heavy Drinkers.

Background: Healthy people with a family history of alcohol problems show a pattern of subjective responses to alcohol that resemble those of affected probands. Studies on ketamine suggest that up-regulation of N-methyl-D-aspartate receptors (NMDARs) underlies these effects, and point to a pharmacologically-responsive endophenotype reflecting enhanced risk for alcohol-use disorders. Methods: Subjective stimulant and sedative effects were assessed before and during nitrous oxide (N2O; 50%) inhalation in heavy drinkers who were otherwise healthy. Results: Participants with an ostensible family history of alcohol-use disorders (n = 23) were distinguishable from those without such familial risk (n = 37) by an enhanced stimulation-to-sedation ratio during N2O inhalation. Conclusion: The pattern of subjective effects of N2O according to familial risk is remarkably similar to that previously seen with ketamine, supporting the idea of a common, NMDAR-mediated mechanism of action. N2O may prove to be a safe and accessible alternative to ketamine for probing heritable NMDAR dysregulation in neuropsychiatric disorders.

Ultra-Brief Mindfulness Training Reduces Alcohol Consumption in At-Risk Drinkers: A Randomized Double-Blind Active-Controlled Experiment.

Background: Like other complex psychosocial interventions, mindfulness-based treatments comprise various modality-specific components as well as nonspecific therapeutic ingredients that collectively contribute to efficacy. Consequently, the isolated effects of mindfulness strategies per se remain unclear. Methods: Using a randomized double-blind design, we compared the isolated effects of 11-minutes of "supervised" mindfulness instruction against a closely matched active control (relaxation) on subjective, physiological, and behavioral indices of maladaptive alcohol responding in drinkers at risk of harm from alcohol use (n = 68). Simple follow-up instructions on strategy use were provided, but practice was unsupervised and not formally monitored. Results: Both groups showed acute reductions in craving after training, although a trend group x time interaction (P = .056) suggested that this reduction was greater in the relaxation group (d = 0.722 P < .001) compared with the mindfulness group (d = 0.317, P = .004). Furthermore, upregulation of parasympathetic activity was found after relaxation (d = 0.562; P < .001) but not mindfulness instructions (d = 0.08; P > .1; group x time interaction: P = .009). By contrast, only the mindfulness group showed a reduction in past-week alcohol consumption at 7-day follow-up (-9.31 units, d = 0.593, P < .001), whereas no significant reduction was seen in the relaxation group (-3.00 units, d = 0.268, P > .1; group x time interaction: P = .026). Conclusion: Very brief mindfulness practice can significantly reduce alcohol consumption among at-risk drinkers, even with minimal encouragement to use this strategy outside of the experimental context. The effects on consumption may therefore represent a lower bound of efficacy of "ultra-brief" mindfulness instructions in hazardous drinkers, at least at short follow-up intervals.

The challenge of memory destabilisation: From prediction error to prior expectations and biomarkers.

The re-ignition of memory reconsolidation research sparked by Karim Nader in the early 2000s led to great excitement that 'reconsolidation-based' interventions might be developed for mental health disorders such as post-traumatic stress disorder and substance use disorder. Two decades on, it is clear that reconsolidation-based interventions have been more challenging to translate to the clinic than initially thought. We argue that this challenge could be addressed with a better understanding of how prior expectations interact with information presented in a putative memory reactivation / cue reminder session, and through the identification of non-invasive biomarkers for memory destabilisation that would allow reminder sessions to be 'tuned' to enhance memory lability in an ad hoc manner.

A systematic review of the pharmacological modulation of autobiographical memory specificity.

Background: Over-general autobiographical memory (AM) retrieval is proposed to have a causal role in the maintenance of psychological disorders like depression and PTSD. As such, the identification of drugs that modulate AM specificity may open up new avenues of research on pharmacological modeling and treatment of psychological disorders. Aim: The current review summarizes randomized, placebo-controlled studies of acute pharmacological modulation of AM specificity. Method: A systematic search was conducted of studies that examined the acute effects of pharmacological interventions on AM specificity in human volunteers (healthy and clinical participants) measured using the Autobiographical Memory Test. Results: Seventeen studies were identified (986 total participants), of which 16 were judged to have low risk of bias. The presence and direction of effects varied across drugs and diagnostic status of participants (clinical vs. healthy volunteers). The most commonly studied drug-hydrocortisone-produced an overall impairment in AM specificity in healthy volunteers [g = -0.28, CI (-0.53, -0.03), p = 0.03], although improvements were reported in two studies of clinical participants. In general, studies of monoamine modulators reported no effect on specificity. Conclusion: Pharmacological enhancement of AM specificity is inconsistent, although monaminergic modulators show little promise in this regard. Drugs that reduce AM specificity in healthy volunteers may be useful experimental-pharmacological tools that mimic an important transdiagnostic impairment in psychological disorders. Systematic review registration: PROSPERO, identifier CRD42020199076, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020199076.

Accelerated forgetting of a trauma-like event in healthy men and women after a single dose of hydrocortisone.

Posttraumatic stress disorder (PTSD) is characterised by dysregulated hypothalamic-pituitary-adrenal axis activity and altered glucocorticoid receptor sensitivity. Early treatment with glucocorticoids may reduce PTSD risk, although the effect of such treatment on the aetiologically critical step of traumatic-memory-formation remains unclear. Here we examine the effects of exogenous cortisol (hydrocortisone) in a preclinical model of PTSD, using a factorial (Drug × Sex), randomised-controlled, double-blind design. Healthy men and women (n = 120) were randomised to receive 30 mg oral hydrocortisone or matched placebo immediately after watching a stressful film. Effects on film-related intrusions were assessed acutely in the lab, and ecologically using daily memory diaries for one week. We found that participants receiving hydrocortisone showed a faster reduction in daily intrusion frequency. Voluntary memory was assessed once, at the end of the week, but was unaffected by hydrocortisone. Exploratory analyses indicated sex-dependent associations between intrusions and baseline estradiol and progesterone levels. In men receiving hydrocortisone, higher baseline estradiol levels were associated with fewer intrusions, whereas women exhibited the opposite pattern. By contrast, progesterone levels were positively associated with intrusions only in men treated with hydrocortisone. The findings suggest that hydrocortisone promotes an accelerated degradation of sensory-perceptual representations underlying traumatic intrusive memories. In addition, while sex alone was not an important moderator, the combination of sex and sex-hormone levels (especially estradiol) influenced hydrocortisone's effects on involuntary aversive memories. Future well-powered experimental studies may provide a basis for a precision-psychiatry approach to optimising early post-traumatic glucocorticoid treatments that target intrusive memories, based on individual endocrinological profiles.

Pharmacological modelling of dissociation and psychosis: an evaluation of the Clinician Administered Dissociative States Scale and Psychotomimetic States Inventory during nitrous oxide ('laughing gas')-induced anomalous states.

RATIONALE: A significant obstacle to an improved understanding of pathological dissociative and psychosis-like states is the lack of readily implemented pharmacological models of these experiences. Ketamine has dissociative and psychotomimetic effects but can be difficult to use outside of medical and clinical-research facilities. Alternatively, nitrous oxide (N2O) - like ketamine, a dissociative anaesthetic and NMDAR antagonist - has numerous properties that make it an attractive alternative for modelling dissociation and psychosis. However, development and testing of such pharmacological models relies on well-characterized measurement instruments. OBJECTIVES: To examine the factor structures of the Clinician Administered Dissociative States Scale (CADSS) and Psychotomimetic States Inventory (PSI) administered during N2O inhalation in healthy volunteers. METHODS: Secondary analyses of data pooled from three previous N2O studies with healthy volunteers. RESULTS: Effect sizes for N2O-induced dissociation and psychotomimesis were comparable to effects reported in experimental studies with sub-anaesthetic ketamine in healthy volunteers. Although, like ketamine, a three-factor representation of N2O-induced dissociation was confirmed, and a more parsimonious two-factor model might be more appropriate. Bayesian exploratory factor analysis suggested that N2O-induced psychosis-like symptoms were adequately represented by two negative and two positive symptom factors. Hierarchical cluster analysis indicated minimal item overlap between the CADSS and PSI. CONCLUSION: N2O and ketamine produce psychometrically similar dissociative states, although parallels in their psychosis-like effects remain to be determined. The CADSS and PSI tap largely non-overlapping experiences under N2O and we propose the use of both measures (or similar instruments) to comprehensively assess anomalous subjective states produced by dissociative NMDAR antagonists.

The effects of response inhibition training following binge memory retrieval in young adults binge eaters: a randomised-controlled experimental study.

Binge eating is increasingly prevalent among adolescents and young adults and can have a lasting harmful impact on mental and physical health. Mechanistic insights suggest that aberrant reward-learning and biased cognitive processing may be involved in the aetiology of binge eating. We therefore investigated whether recently developed approaches to catalyse brief interventions by putatively updating maladaptive memory could also boost the effects of cognitive bias modification training on binge eating behaviour. A non-treatment-seeking sample of 90 binge eating young adults were evenly randomised to undergo either selective food response inhibition training, or sham training following binge memory reactivation. A third group received training without binge memory reactivation. Laboratory measures of reactivity and biased responses to food cues were assessed pre-post intervention and bingeing behaviour and disordered eating assessed up to 9 months post-intervention. The protocol was pre-registered at https://osf.io/82c4r/ . We found limited evidence of premorbid biased processing in lab-assessed measures of cognitive biases to self-selected images of typical binge foods. Accordingly, there was little evidence of CBM reducing these biases and this was not boosted by prior 'reactivation' of binge food reward memories. No group differences were observed on long-term bingeing behaviour, caloric consumption or disordered eating symptomatology. These findings align with recent studies showing limited impact of selective inhibition training on binge eating and do not permit conclusions regarding the utility of retrieval-dependent memory 'update' mechanisms as a treatment catalyst for response inhibition training.

The CannTeen Study: Cannabis use disorder, depression, anxiety, and psychotic-like symptoms in adolescent and adult cannabis users and age-matched controls.

BACKGROUND: Adolescence is characterised by psychological and neural development. Cannabis harms may be accentuated during adolescence. We hypothesised that adolescents would be more vulnerable to the associations between cannabis use and mental health and addiction problems than adults. METHOD: As part of the 'CannTeen' study, we conducted a cross-sectional analysis. There were 274 participants: split into groups of adolescent users (n = 76; 16-17 years old) and controls (n = 63), and adult users (n = 71; 26-29 years old) and controls (n = 64). Among users, cannabis use frequency ranged from 1 to 7 days/week, while controls had 0-10 lifetime exposures to cannabis. Adolescent and adult cannabis users were matched on cannabis use frequency (mean=4 days/week). We measured Diagnostic and Statistical Manual (DSM-5) Cannabis Use Disorder (CUD), Beck Depression Inventory, Beck Anxiety Inventory and Psychotomimetic States Inventory-adapted. RESULTS: After adjustment for covariates, adolescent users were more likely to have severe CUD than adult users (odd ratio = 3.474, 95% confidence interval (CI) = 1.501-8.036). Users reported greater psychotic-like symptoms than controls (b = 6.004, 95% CI = 1.211-10.796) and adolescents reported greater psychotic-like symptoms than adults (b = 5.509, 95% CI = 1.070-9.947). User-group was not associated with depression or anxiety. No significant interactions between age-group and user-group were identified. Exploratory analyses suggested that cannabis users with severe CUD had greater depression and anxiety levels than cannabis users without severe CUD. CONCLUSION: Adolescent cannabis users are more likely than adult cannabis users to have severe CUD. Adolescent cannabis users have greater psychotic-like symptoms than adult cannabis users and adolescent controls, through an additive effect. There was no evidence of an amplified vulnerability to cannabis-related increases in subclinical depression, anxiety or psychotic-like symptoms in adolescence. However, poorer mental health was associated with the presence of severe CUD.