Side-effects of mdma-assisted psychotherapy: a systematic review and meta-analysis.

Evidence suggests that MDMA-assisted psychotherapy (MDMA-AP) has therapeutic potential for treatment of psychiatric illness. We conducted the first comprehensive systematic review and meta-analysis of the side effects of MDMA-AP across indications. We also assessed the quality of side effects-reporting in published trials of MDMA-AP. PubMed, EMBASE, PsycINFO, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched. Phase 2 and 3 MDMA-AP studies were included; Phase 1 studies, which assessed MDMA without psychotherapy, were not. Quality of side effects-reporting was assessed against the CONSORT Harms 2022 guidelines. We also compared numbers of adverse events reported in publications to those recorded in ClinicalTrial.gov registers. Thirteen studies were included, with eight contributing to the meta-analysis. In Phase 2 studies, MDMA-AP was associated with increased odds of any side effect during medication sessions (OR = 1.67, 95%CI (1.12, 2.49)) and in the 7 days following (OR = 1.59, 95%CI (1.12, 2.24)) relative to control conditions. In Phase 3 studies, MDMA-AP was associated with increased odds of any adverse event during the treatment period relative to placebo-assisted psychotherapy (OR = 3.51, 95%CI (2.76, 4.46)). The majority of RCTs were rated as having high risk of bias. Certainty of the evidence was rated as very low to moderate according to the GRADE framework. No included RCT had adequate adherence to the CONSORT Harms 2022 recommendations and reporting rates were also low. Compared to placebo, MDMA-AP was associated with increased odds of side effects, which were largely transient and mild or moderate in severity. However, identified limitations in existing evidence indicate that further investigation is needed to better characterize the safety profile of MDMA-AP and guide implementation.

Underreporting of implementation strategies and barriers in physical activity interventions for young people at risk of problematic substance use: a brief report.

BACKGROUND: Several studies have assessed whether physical activity interventions can reduce substance use in young people at risk of problematic substance use. This report identifies and describes the reporting of implementation characteristics within published studies of physical activity interventions for young people at risk of problematic substance use and provides recommendations for future reporting. METHODS: Reported implementation strategies (including intervention manualization), barriers, implementation fidelity, and personnel acceptance were extracted from studies of physical activity interventions for young people aged 12-25 years at risk of problematic substance use that were included in a previous systematic review of intervention efficacy. RESULTS: Implementation strategies were reported in less than half of the included studies (42.9%), implementation barriers in only 10.7% of studies, intervention fidelity in 21.4%, and personnel acceptance in a single study (3.6%). CONCLUSIONS: Results indicate insufficient reporting of implementation strategies, barriers, fidelity, and personnel acceptance. Consideration of implementation characteristics is essential for implementing physical activity interventions in practice. Inadequate or limited reporting of these characteristics may contribute to delayed uptake and adoption of evidence-based interventions in clinical practice. Recommendations to improve the reporting of implementation information include integrating standards for reporting implementation characteristics into existing reporting guidelines, developing an international taxonomy of implementation strategies, and upskilling intervention researchers in the fundamentals of implementation science.

Laboratory method to induce state boredom increases impulsive choice in people who use cocaine and controls.

Background: Impulsive choice is associated with both cocaine use and relapse. Little is known about the influence of transient states on impulsive choice in people who use cocaine (PWUC).Objective: This study investigated the direct effects of induced boredom on impulsive choice (i.e., temporal discounting) in PWUC relative to well-matched community controls.Methods: Forty-one PWUC (≥1× cocaine use in past 3 months; 7 females) and 38 demographically matched controls (5 females) underwent two experimental conditions in counterbalanced order. Temporal discounting was assessed immediately after a standardized boredom induction task (peg-turning) and a self-selected video watched for the same duration (non-boredom). Subjective mood state and perceived task characteristics were assessed at baseline, during experimental manipulations, and after the choice task.Results: PWUC and controls were well matched on sex, age, and socioeconomic status. Groups were also similar in reported use of drugs other than cocaine, except for recent cigarette and alcohol use (PWUC > controls). As expected, peg-turning increased boredom in the sample overall, with higher boredom reported during peg-turning than the video (p < .001, η2p = .20). Participants overall exhibited greater impulsive choice after boredom than non-boredom (p = .028, η2p = .07), with no preferential effects in PWUC (p > .05, BF01 = 2.9).Conclusion: Experimentally induced boredom increased state impulsivity irrespective of cocaine use status - in PWUC and carefully matched controls - suggesting a broad link between boredom and impulsive choice. This is the first study to show that transient boredom directly increases impulsive choice. Data support a viable laboratory method to further parse the effects of boredom on impulsive choice.

The Study of Ketamine for Youth Depression (SKY-D): study protocol for a randomised controlled trial of low-dose ketamine for young people with major depressive disorder.

BACKGROUND: Existing treatments for young people with severe depression have limited effectiveness. The aim of the Study of Ketamine for Youth Depression (SKY-D) trial is to determine whether a 4-week course of low-dose subcutaneous ketamine is an effective adjunct to treatment-as-usual in young people with major depressive disorder (MDD). METHODS: SKY-D is a double-masked, randomised controlled trial funded by the Australian Government's National Health and Medical Research Council (NHMRC). Participants aged between 16 and 25 years (inclusive) with moderate-to-severe MDD will be randomised to receive either low-dose ketamine (intervention) or midazolam (active control) via subcutaneous injection once per week for 4 weeks. The primary outcome is change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment. Further follow-up assessment will occur at 8 and 26 weeks from treatment commencement to determine whether treatment effects are sustained and to investigate safety outcomes. DISCUSSION: Results from this trial will be important in determining whether low-dose subcutaneous ketamine is an effective treatment for young people with moderate-to-severe MDD. This will be the largest randomised trial to investigate the effects of ketamine to treat depression in young people. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ID: ACTRN12619000683134. Registered on May 7, 2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377513 .

A systematic review and meta-analysis of health, functional, and cognitive outcomes in young people who use methamphetamine.

Methamphetamine use typically starts in adolescence, and early onset is associated with worse outcomes. Yet, health, functional, and cognitive outcomes associated with methamphetamine use in young people are not well understood. The aim of this study was to comprehensively assess the evidence on health, functional, and cognitive outcomes in young people (10-25 years-old) who use methamphetamine. Sixty-six studies were included. The strongest association observed was with conduct disorder, with young people who use methamphetamine some 13 times more likely to meet conduct disorder criteria than controls. They were also more likely to have justice system involvement and to perpetrate violence against others. Educational problems were consistently associated with youth methamphetamine use. The cognitive domain most reliably implicated was inhibitory control. Key limitations in the literature were identified, including heterogenous measurement of exposure and outcomes, lack of adequate controls, and limited longitudinal evidence. Outcomes identified in the present review - suggesting complex and clinically significant behavioural issues in this population - are informative for the development of future research and targeted treatments.

Behaviour change techniques in physical activity-focused interventions for young people at risk of problematic substance use: A systematic review and meta-analysis.

AIM: This systematic review investigates behaviour change techniques in interventions promoting physical activity for young people aged 12-25 years at heightened risk of problematic substance use, and the effect of these techniques on physical activity participation and substance use outcomes. METHODS: Four databases (PsycINFO, CINAHL, SPORTDiscus and Medline) were searched between November 2020 and November 2022 for randomized and non-randomized controlled studies according to inclusion criteria. Meta-analyses were calculated using weighted, standardized averages of effect sizes (Hedges' g). RESULTS: Twenty-eight studies were included, 14 studies in the meta-analysis (intervention n = 1328; control n = 845). Reported BCTs included behavioural instructions, social comparison and goal setting. There was a significant effect of behaviour change techniques on combined substance use outcomes, such as cravings and consumption, for interventions reporting multiple behaviour change techniques (g = -0.33, p < .001, 95% CI [-0.50,-0.16]) or one single behaviour change technique (g = -1.84, p < .001, 95% CI [-2.89,-0.8]). Limitations include unexplained variance and limited reporting of relevant behaviour change technique data in the included studies. CONCLUSION: The results indicate that using behaviour change techniques in interventions that promote physical activity for young people has an effect on substance use. Further research needs to be completed comparing the impact of the number and type of behaviour change technique, and improved reporting of intervention content is required.

Dark loops: contagion effects, consistency and chemosocial matrices in psychedelic-assisted therapy trials.

What happens when an emerging programme of medical research overlaps with a surging social movement? In this article we draw on the anthropological term 'chemosociality' to describe forms of sociality born of shared chemical exposure. Psychedelic administration in the context of recent clinical trials appears to have been particularly chemosocial in nature. We argue that one consequence is that psychedelic-assisted therapy (PAT) clinical research trials tend to breach key assumptions underlying the logic of causal inference used to establish efficacy. We propose the concept of dark loops to describe forms of sociality variously emerging from, and impacting participant experiences in, PAT trials. These dark loops are not recorded, let alone incorporated into the causal pathways in the interpretation of psychedelic trial data to date. We end with three positions which researchers might adopt in response to these issues: chemosocial minimisation where research is designed to attenuate or eliminate the effects of dark loops in trials; chemosocial description where dark loops (and their impacts) are openly and candidly documented and chemosocial valorisation where dark loops are hypothesised to contribute to trial outcomes and actively drawn upon for positive effect. Our goal is to fold in an appreciation of how the increasingly-discussed hype surrounding psychedelic research and therapeutics continues to shape the phenomena under study in complex ways, even as trials become larger and more rigorous in their design.

Understanding the complexity, patterns, and correlates of alcohol and other substance use among young people seeking help for mental ill-health.

PURPOSE: Use of alcohol and other substances is a multifaceted issue impacting young people across multiple life domains. This paper aims to elucidate patterns of substance use and associated demographic and clinical factors among young people seeking treatment for their mental health. METHODS: Young people (12-25 years old) were recruited from five youth-specific primary mental health ("headspace") services in Australia. Self-reported substance use and harms in the past 3 months were measured using WHO-ASSIST. Network analyses were conducted to evaluate interrelationships between use and harms associated with different substances. Subgroups were then identified based on whether participants reported using high centrality substances, and associated demographic and clinical factors were assessed with multinomial logistic regression. RESULTS: 1107 youth participated. 70% reported use of at least one substance in the past 3 months, with around 30% of those reporting related health, social, legal or financial problems. Network analysis highlighted substantial interconnections between use and harm indicators for all substances, with amphetamine-type stimulants (ATS) and cannabis being high central substances. Higher levels of substance use and harms were reported in subgroups with ATS or cannabis use and different risk factors were associated with these subgroups. CONCLUSIONS: Findings highlight the importance of screening for substance use in youth primary mental healthcare settings, offering a key opportunity for early intervention. Clinicians should be aware of the inner connections of use and harms of different drugs and the role of cannabis and amphetamine use as a marker for more substance use profiles.

Smoked cannabis reduces peak cocaine plasma levels and subjective effects in a controlled drug administration study of polysubstance use in men.

BACKGROUND: Despite the high prevalence of polysubstance use, outcomes and potential risks associated with common drug combinations are not well characterized. Many individuals who use cocaine also use cannabis, yet little is known about how interactions between the two drugs might contribute to continued co-use. METHODS: The aim of this double-blind, placebo-controlled study was to determine the physiological and subjective effects of smoked cannabis with smoked cocaine, to identify variables that may contribute to the continued use of this drug combination. Healthy, non-treatment seeking volunteers who reported smoking both cocaine and cannabis (N = 9, all males) completed a 13-day inpatient protocol. On session days, cannabis [0.0 or 5.6 % tetrahydrocannabinol (THC)] was administered 28 min prior to cocaine (0, 12, or 25 mg). Dependent measures included pharmacokinetic assessment of THC and cocaine and their respective metabolites, in addition to subjective and cardiovascular effects. RESULTS: Active cannabis (5.6 % THC) increased plasma levels of THC and the metabolite 11-nor-9-carboxy-Δ9-THC (THCCOOH), as well as subjective ratings of cannabis effects and heart rate relative to inactive cannabis. Cocaine dose-dependently increased plasma cocaine and metabolites and subjective ratings of cocaine effects. Active cannabis pre-treatment decreased plasma levels of cocaine and metabolites. Furthermore, active cannabis attenuated cocaine-related reductions in 'Hunger' and 'Calm.' CONCLUSIONS: Cannabis pre-treatment altered the subjective experience of smoked cocaine and reduced peak plasma levels of cocaine. Future studies should explore additional doses of each drug and whether these changes also impact cocaine's reinforcing effects.

Prevalence and Correlates of Tobacco Use in Young People Presenting to Australian Primary Mental Health Services.

INTRODUCTION: In Australian youth primary mental health settings it is unclear as to the rates and correlates of tobacco use at service entry. AIMS AND METHODS: We aimed to delineate the prevalence and correlates of recent tobacco use (eg, cigarettes, chewing tobacco, cigars, etc) in the past 3 months in young people at their first presentation to primary mental health services as a function of age. Cross-sectional self-report measures were collected using a tablet device from young people presenting to one of five Australian primary mental health (headspace) services. Logistic regression assessed correlates of past 3-month tobacco use in adolescents (12-17 years) and young adults (18-25 years). RESULTS: Regular (at least monthly) tobacco use in the past 3 months was found in 23.4% (n = 247, N = 1055) of the sample. Increasing age (odds ratio [OR] =1.47 per year; 95% confidence interval [CI]: 1.15 to 1.89), male sex (OR = 1.98; 95% CI: 1.02 to 3.83), being in a relationship (OR = 1.96; 95% CI: 1.01 to 3.82), and poorer functioning (OR = 0.95 per unit Social and Occupational Functioning Assessment Scale increase; 95% CI: 0.91 to 0.99) predicted regular tobacco use in adolescents, but not in young adults. Living in a regional location (OR = 2.10; 95% CI: 1.40 to 3.13) and not studying (OR = 0.47; 95% CI: 0.31 to 0.73) predicted tobacco use in young adults. Having a diagnosed mental illness other than depression and/or anxiety predicted tobacco use in both groups (adolescents OR = 2.49; 95% CI: 1.26 to 4.94; young adults OR = 1.80; 95% CI: 1.13 to 2.89). CONCLUSIONS: Nearly a quarter of young people with mental illness are using tobacco, supporting the need for early intervention approaches. Adapting treatment targets by age could improve the impact of interventions in adolescents versus young adults. Poor functioning and lack of engagement in education were associated with tobacco use in both age groups, respectively; however, more research is needed to determine the direction of these relationships. IMPLICATIONS: Young people with mental illness have a high prevalence of recent tobacco use and this is evident when they first present to youth primary mental health services. Youth-oriented mental health settings may provide a unique window for tobacco use prevention and early intervention to reduce smoking in people with mental illness, a priority population. Age-specific targeted approaches might be needed in adolescents and young adults.

MDMA-assisted psychotherapy for post-traumatic stress disorder: The devil is in the detail.

Recent years have seen escalating media, public and scientific interest in psychedelic medicine. Australia and New Zealand have been late to this research; however, in the past 2 years, rapid developments suggest that this is changing. Here, we argue for the need to critically review existing evidence in this field to guide future directions. We focus on (±)3,4-methylenedioxymethamphetamine-assisted psychotherapy for post-traumatic stress disorder, currently the most advanced area of clinical psychedelic research. Food and Drug Administration approval of this approach is likely in 2023, based on a series of promising findings. We provide a detailed overview of Phase 2 and 3 studies published to date. We identify several concerns related to this body of evidence, including methodological/design limitations and broader factors - such as robust involvement of advocacy groups in research and reliance on non-government financing leading to simplistic public messaging - that compound the methodological issues identified. We propose steps for future improvement, including the need for large, high-quality, independent efficacy trials with design enhancements, effectiveness trials and for researchers to consider their own engagement with media and public messaging around these modalities. We argue that, notwithstanding promising findings to date, rigorous and dispassionate science is needed to move the field forward and safeguard the welfare of participants.

Impact of cyclooxygenase-2 inhibition on cannabis withdrawal and circulating endocannabinoids in daily cannabis smokers.

Attenuating enzymatic degradation of endocannabinoids (eCBs) by fatty acid amide hydrolase (FAAH) reduces cannabis withdrawal symptoms in preclinical and clinical studies. In mice, blocking cyclooxygenase-2 (COX-2) activity increases central eCB levels by inhibiting fatty acid degradation. This placebo-controlled study examined the effects of the FDA-approved COX-2 selective inhibitor, celecoxib, on cannabis withdrawal, 'relapse', and circulating eCBs in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (12M, 3F) completed a crossover study comprising two 11-day study phases (separated by >14 days for medication clearance). In each phase, the effects of daily BID placebo (0 mg) or celecoxib (200 mg) on cannabis (5.3% THC) intoxication, withdrawal symptoms (4 days of inactive cannabis self-administration) and 'relapse' (3 days of active cannabis self-administration following abstinence) were assessed. Outcome measures included mood, cannabis self-administration, sleep, food intake, cognitive performance, tobacco cigarette use and circulating eCBs and related lipids. Under placebo maintenance, cannabis abstinence produced characteristic withdrawal symptoms (negative mood, anorexia and dreaming) relative to cannabis administration and was associated with increased OEA (a substrate of FAAH) and oleic acid (metabolite of OEA), with no change in eCB levels. Compared to placebo, celecoxib improved subjective (but not objective) measures of sleep and did not affect mood or plasma levels of eCBs or associated lipids and increased cannabis craving. The overall absence of effects on cannabis withdrawal symptoms, self-administration or circulating eCBs relative to placebo, combined with an increase in cannabis craving, suggests celecoxib does not show promise as a potential pharmacotherapy for CUD.

A placebo-controlled investigation of the analgesic effects, abuse liability, safety and tolerability of a range of oral cannabidiol doses in healthy humans.

AIMS: Preclinical studies demonstrate that cannabidiol (CBD) elicits an antinociceptive response in animal models of neuropathic pain; in humans, limited data are available to support such analgesic effects. Few studies have examined CBD's analgesic effects when administered without other compounds, and little is known regarding dose-dependent effects in noncannabis users. METHODS: This double-blind, placebo-controlled, within-subject outpatient clinical laboratory study sought to determine the analgesic effects, abuse liability, safety and tolerability of acute CBD (0, 200, 400 and 800 mg orally) in healthy noncannabis-using volunteers (n = 17; 8 men, 9 women). Outcomes included experimental pain threshold and pain tolerance using the cold pressor test (CPT), subjective ratings of CPT painfulness and bothersomeness, subjective ratings of abuse liability and mood, and cardiovascular measures, which were assessed at baseline and several time points after drug administration. Data analyses included repeated measures analysis of variance (ANOVA) with planned comparisons. RESULTS: CBD failed to consistently affect pain threshold and tolerance in the CPT relative to placebo. All doses of CBD increased ratings of painfulness compared to placebo (P < .01). Further, CBD had dose-dependent, modest effects on mood and subjective drug effects associated with abuse liability. Oral CBD was safe and well tolerated, producing small decreases in blood pressure (P < .01). CONCLUSION: CBD did not elicit consistent dose-dependent analgesia and in fact increased pain on some measures. Future studies exploring CBD-induced pain relief should consider using a more extensive pain assessment paradigm in different participant populations.

Responses to social evaluative stress in regular cannabis smokers.

BACKGROUND: Aspects of the canonical stress response differ in stimulant, opioid, and alcohol users relative to controls, and dysregulated responses to stress may contribute to continued use of these drugs. Little prior research has focused on stress responses in regular cannabis smokers. We assessed responses to a standardized laboratory social stress assay (the Trier Social Stress Task; TSST) in regular cannabis smokers (CANs) compared with controls (CONs). METHODS: Healthy, non-treatment-seeking adult CANs (⩾4×/week; smoking cannabis as usual) and demographically matched CONs completed the TSST. Outcome measures were subjective mood, heart rate, and salivary cortisol. RESULTS: Nineteen CANs (1 female) and 20 CONs (2 female) participated; groups were matched on trauma exposure, sex, race, and age. CANs smoked cannabis 6.4 ± 1.1 days/week. Eight CANs and one CON smoked tobacco cigarettes daily. Overall, the TSST produced expected increases in anxiety, negative mood states, cortisol, and heart rate. CANs had blunted subjective response to stress relative to CONs, but they did not differ in physiological (cortisol and cardiovascular) stress responding. CONCLUSION: These results indicate that CANs have blunted mood responses to social stress, but normative physiological stress responding. Observed differences could be due to residual effects of cannabis, reluctance to endorse negative mood states, or to issues related to identifying (i.e., emotional identification) or feeling (i.e., interoception) stress-related affective states. Further research is warranted to characterize the mechanisms of these differences and assess implications for daily functioning and treatment outcomes.

Individual differences in distress, impulsivity, and coping motives for use as predictors of problematic ecstasy use.

BACKGROUND: Ecstasy users who report problematic use of ecstasy experience adverse social, psychological, and health-related consequences not reported by non-problem users. Relatively little is known about the risk factors for the development of problematic ecstasy use. Such information would be valuable for targeted intervention, prevention, and education AIMS: The current study aimed to fill this gap by investigating several hypothesised risk factors for problematic use and the relationships between them. METHODS: Self-reported impulsivity, psychological distress, sex, and coping motives for ecstasy use were investigated as predictors of problematic ecstasy use in a cross-sectional online survey. RESULTS: The sample consisted of 483 individuals (60.5% male, 38.3% female, 1.2% other) aged 18-62 years, reporting ecstasy use on an average of 59.7 occasions (SD = 167.8). Both higher self-reported impulsivity and psychological distress predicted problem ecstasy use, and both these relationships were partially mediated by coping motives. When these variables were examined in a combined mediation model accounting for their covariance, psychological distress still predicted problematic use partially via an effect on coping motives, while impulsivity showed only a direct effect on problem use. No sex differences in problem ecstasy use were observed. CONCLUSIONS: Increased trait impulsivity and psychological distress appear to confer greater risk of problematic ecstasy use. Targeting these factors, as well as coping motives for ecstasy use, may be useful in efforts to prevent and reduce problematic ecstasy use among those who use the drug.

Detection of acute 3,4-methylenedioxymethamphetamine (MDMA) effects across protocols using automated natural language processing.

The detection of changes in mental states such as those caused by psychoactive drugs relies on clinical assessments that are inherently subjective. Automated speech analysis may represent a novel method to detect objective markers, which could help improve the characterization of these mental states. In this study, we employed computer-extracted speech features from multiple domains (acoustic, semantic, and psycholinguistic) to assess mental states after controlled administration of 3,4-methylenedioxymethamphetamine (MDMA) and intranasal oxytocin. The training/validation set comprised within-participants data from 31 healthy adults who, over four sessions, were administered MDMA (0.75, 1.5 mg/kg), oxytocin (20 IU), and placebo in randomized, double-blind fashion. Participants completed two 5-min speech tasks during peak drug effects. Analyses included group-level comparisons of drug conditions and estimation of classification at the individual level within this dataset and on two independent datasets. Promising classification results were obtained to detect drug conditions, achieving cross-validated accuracies of up to 87% in training/validation and 92% in the independent datasets, suggesting that the detected patterns of speech variability are associated with drug consumption. Specifically, we found that oxytocin seems to be mostly driven by changes in emotion and prosody, which are mainly captured by acoustic features. In contrast, mental states driven by MDMA consumption appear to manifest in multiple domains of speech. Furthermore, we find that the experimental task has an effect on the speech response within these mental states, which can be attributed to presence or absence of an interaction with another individual. These results represent a proof-of-concept application of the potential of speech to provide an objective measurement of mental states elicited during intoxication.

Cognitive function in aging cocaine smokers.

BACKGROUND: Little is known about the functional status of older drug users, who may pose challenges to public health systems in coming years. Here, we assessed cognitive function in aging cocaine smokers compared to demographically matched controls. METHODS: A total of 22 non-treatment-seeking aging (50-60 years old) cocaine smokers (⩾twice/week; ⩾15 years of weekly use) and 19 controls completed a comprehensive cognitive battery. Controls with cannabis, tobacco, and alcohol use were included to better match the cocaine users. All cocaine users, and current cannabis- or alcohol-using controls, completed testing after 4 drug-free inpatient days to better control for acute and residual drug effects. RESULTS: Cocaine users (52.9 ± 2.5 years old, four female; cocaine use 3.9 ± 1.4 days/week) and controls (52.7 ± 2.6 years old, four female) were well matched demographically, but cocaine users reported a more extensive substance use profile. Cocaine users showed marginally worse verbal learning than controls, recalling on average one word fewer across immediate and delayed word recall trials. Their performance was intact relative to controls across all other measures of cognitive function. Bayesian analysis indicated the absence of group differences was not due to power limitations. CONCLUSION: These data suggest that aging, long-term cocaine users have similar cognitive functioning to appropriately matched controls when tested under drug-free conditions, with only marginal decreases in verbal learning. Findings, although reassuring with regard to broad cognitive capacities in aging cocaine smokers, suggest that future investigations of cognitive function in aging drug users are warranted.

Guanfacine decreases symptoms of cannabis withdrawal in daily cannabis smokers.

The α2a-adrenergic agonist, lofexidine, reduced cannabis withdrawal-related sleep disruption in the laboratory, but side effects (e.g. fatigue, hypotension) limit its utility as a treatment for cannabis use disorder. This study tested the potential efficacy and tolerability of a daily bedtime administration of the FDA-approved α2a-adrenergic agonist, guanfacine, in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (13M, 2F) completed a within-subject study comprising two 9-day inpatient study phases. Each phase tested the effects of daily placebo or immediate-release guanfacine (2 mg) on cannabis intoxication (5.6 percent THC; 2 days), withdrawal (4 days of abstinence) and subsequent 'relapse' (3 days of cannabis self-administration). Ratings of mood, sleep, cardiovascular effects, food intake, psychomotor performance and cannabis self-administration were assessed. An outpatient phase preceded each inpatient phase for medication clearance or dose induction. Under placebo medication conditions, cannabis abstinence produced significant withdrawal, including irritability, sleep disruption and anorexia. Guanfacine reduced ratings of irritability and improved objective measures of sleep during cannabis withdrawal relative to placebo but did not reduce cannabis self-administration. Guanfacine was well tolerated with little evidence of fatigue and only small decreases in blood pressure: no dose was held due to hypotension. Thus, a single daily administration of guanfacine at bedtime improved sleep and mood during cannabis withdrawal relative to placebo. This positive signal supports further studies varying the guanfacine dose, formulation or frequency of administration, or combining it with other medications to increase the likelihood of having an impact on cannabis use.

Social motivational processing and interpersonal function in aging cocaine smokers.

Illicit drug use among aging cohorts is increasing, yet little is known about functional impairments in older drug users. Given the importance of social integration for aging and documented social decrements in cocaine users, we examined social function and its neurocognitive substrates in aging cocaine users relative to carefully matched non-cocaine users. Regular (≥twice/week), long-term (≥15 years) cocaine smokers 50-60 years old (COCs; n = 22; four women) and controls (CTRLs; n = 19; four women) underwent standardized probes of social reward and threat processing during functional magnetic resonance imaging and a behavioral facial affect recognition task. Self-report and peer-report of daily interpersonal function were also collected. COCs, and CTRLs reporting current marijuana or alcohol use, were tested after four drug-free inpatient days. COCs had pronounced problems in daily social function relative to CTRLs indicated by both their own and their peers' reports. Compared with CTRLs, COCs had stronger amygdala responses to social threat versus control stimuli, with no other differences in social processing or cognition. Aging cocaine users appear to have marked, generalized difficulties in 'real-world' interpersonal function but largely intact social processing on laboratory-based measures when compared with appropriately matched controls and tested under well-controlled conditions. Daily social difficulties may be related to transient factors such as acute/residual drug effects or cocaine-related changes in health behaviors (e.g. disrupted sleep and poor diet). These data suggest that interpersonal function may be a valid intervention target for aging cocaine users and warrants further study in older drug users.