Feasibility of a cannabidiol-dominant cannabis-based medicinal product for the treatment of long COVID symptoms: A single-arm open-label feasibility trial.

AIMS: To conduct a single-arm open-label feasibility trial of the safety and tolerability of a full-spectrum cannabidiol (CBD)-dominant cannabis-based medicinal product for treating the symptoms of long COVID. METHODS: The treatment phase ran for a total of 21 weeks, followed by ~3 weeks without the study drug. Participants received up to 3 mL of MediCabilis 5% CBD Oil (50 mg CBD/mL, <2 mg δ-9-tetrahydrocannabinol/mL) per day orally. Monthly patient-reported outcome measures of common symptoms and daily self-report of symptoms were collected via a smartphone app. Key measures of heart rate, activity, sleep and oxygen saturation were assessed using wearable technology. RESULTS: Twelve (1 male, 11 female) individuals diagnosed with long COVID were recruited into the trial. All participants adhered to the treatment protocol for the duration of the study and there were no serious adverse events. Response rates for the research assessments were high with over 90% completion of patient-reported outcome measures and daily self-report. CONCLUSION: The study drug was safe and well-tolerated, demonstrating feasibility of CBD-dominant cannabis-based medicinal products in individuals diagnosed with long COVID. However, there were limitations in research design related to recruitment strategy demonstrating a lack of feasibility in the approach implemented in this study. Future work with larger samples and incorporating a control group are required to test the efficacy of this treatment.

Retrospectively assessed subjective effects of initial opioid use differ between opioid misusers with opioid use disorder (OUD) and those who never progressed to OUD: Data from a pilot and a replication sample.

Attempts to identify opioid users with increased risk of escalating to opioid use disorder (OUD) have had limited success. Retrospectively assessed subjective effects of initial opioid misuse were compared in a pilot sample of opioid misusers (nonmedical use ≤60 times lifetime) who had never met criteria for OUD (N = 14) and heroin-addicted individuals in treatment for OUD (N = 15). Relative to opioid misusers without a lifetime OUD diagnosis, individuals with OUD reported greater euphoria and other positive emotions, activation, pruritus, and internalizing symptoms. Consistent with these findings, proxy Addiction Research Center Inventory (ARCI) Amphetamine Group, and Morphine Benzedrine Group scale mean item scores were significantly higher in those with OUD. Replication was attempted in opioid misusers with (N = 25) and without OUD (N = 25) who were assessed as part of an ongoing genetic study. We observed similar significant between-group differences in individual subjective effect items and ARCI scale mean item scores in the replication sample. We, thus confirm findings from prior reports that retrospectively assessed subjective responses to initial opioid exposure differ significantly between opioid users who do, and do not, progress to OUD. Our report extends these findings in comparisons limited to opioid misusers. Additional research will be necessary to examine prospectively whether the assessment of subjective effects after initial use has predictive utility in the identification of individuals more likely to progress to OUD.

Are prescription misuse and illicit drug use etiologically distinct? A genetically-informed analysis of opioids and stimulants.

BACKGROUND: Drug classes are grouped based on their chemical and pharmacological properties, but prescription and illicit drugs differ in other important ways. Potential differences in genetic and environmental influences on the (mis)use of prescription and illicit drugs that are subsumed under the same class should be examined. Opioid and stimulant classes contain prescription and illicit forms differentially associated with salient risk factors (common route of administration, legality), making them useful comparators for addressing this etiological issue. METHODS: A total of 2410 individual Australian twins [Mage = 31.77 (s.d. = 2.48); 67% women] were interviewed about prescription misuse and illicit use of opioids and stimulants. Univariate and bivariate biometric models partitioned variances and covariances into additive genetic, shared environmental, and unique environmental influences across drug types. RESULTS: Variation in the propensity to misuse prescription opioids was attributable to genes (41%) and unique environment (59%). Illicit opioid use was attributable to shared (71%) and unique (29%) environment. Prescription stimulant misuse was attributable to genes (79%) and unique environment (21%). Illicit stimulant use was attributable to genes (48%), shared environment (29%), and unique environment (23%). There was evidence for genetic influence common to both stimulant types, but limited evidence for genetic influence common to both opioid types. Bivariate correlations suggested that prescription opioid use may be more genetically similar to prescription stimulant use than to illicit opioid use. CONCLUSIONS: Prescription opioid misuse may share little genetic influence with illicit opioid use. Future research may consider avoiding unitary drug classifications, particularly when examining genetic influences.

Substance use in psychiatric crisis: relationship to violence.

BACKGROUND: Substance use and psychiatric illness, particularly psychotic disorders, contribute to violence in emergency healthcare settings. However, there is limited research regarding the relationship between specific substances, psychotic symptoms and violent behaviour in such settings. We investigated the interaction between recent cannabinoid and stimulant use, and acute psychotic symptoms, in relation to violent behaviour in a British emergency healthcare setting. METHODS: We used electronic medical records from detentions of 1089 individuals under Section 136 of the UK Mental Health Act (1983 amended 2007), an emergency police power used to detain people for 24-36 h for psychiatric assessment. The relationship between recent cannabinoids and/or stimulant use, psychotic symptoms, and violent behaviour, was estimated using logistic regression. FINDINGS: There was evidence of recent alcohol or drug use in 64.5% of detentions. Violent incidents occurred in 12.6% of detentions. Psychotic symptoms increased the odds of violence by 4.0 [95% confidence intervals (CI) 2.2-7.4; p < 0.0001]. Cannabinoid use combined with psychotic symptoms increased the odds of violence further [odds ratios (OR) 7.1, 95% CI 3.7-13.6; p < 0.0001]. Recent use of cannabinoids with stimulants but without psychotic symptoms was also associated with increased odds of violence (OR 3.3, 95% CI 1.4-7.9; p < 0.0001). INTERPRETATION: In the emergency setting, patients who have recently used cannabinoids and exhibit psychotic symptoms are at higher risk of violent behaviour. Those who have used both stimulants and cannabinoids without psychotic symptoms may also be at increased risk. De-escalation protocols in emergency healthcare settings should account explicitly for substance use.

Association of extent of cannabis use and psychotic like intoxication experiences in a multi-national sample of first episode psychosis patients and controls.

BACKGROUND: First episode psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in patients and controls and whether this differs between groups. METHODS: We analysed data on patients who had ever used cannabis (n = 655) and controls who had ever used cannabis (n = 654) across 15 sites from six countries in the EU-GEI study (2010-2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use. RESULTS: Caseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences (p ⩽ 0.001). For psychotic-like experiences (PEs) there was a significant interaction for caseness × frequency of use (p < 0.001) and caseness × money spent on cannabis (p = 0.001) such that FEP patients had increased experiences at increased levels of use compared to controls. There was no significant interaction for euphoric experiences (p > 0.5). CONCLUSIONS: FEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher levels of cannabis use compared to controls. This suggests a specific psychotomimetic response in FEP patients related to heavy cannabis use. Clinicians should enquire regarding cannabis related PEs and advise that lower levels of cannabis use are associated with less frequent PEs.

Daily use of high-potency cannabis is associated with more positive symptoms in first-episode psychosis patients: the EU-GEI case-control study.

BACKGROUND: Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients. METHOD: We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses. RESULTS: In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14-0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = -0.22; 95% CI -0.37 to -0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use. CONCLUSIONS: Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.

Cannabis use in adolescence and risk of psychosis: Are there factors that moderate this relationship? A systematic review and meta-analysis.

Background: Previous research has reported increased risk for psychosis among individuals who use cannabis during adolescence. We conducted a systematic review and meta-analysis to investigate the interaction between adolescent cannabis use and other factors in moderating risk for psychosis later in life. Method: We searched four electronic databases in June 2020 for articles that assessed adolescent cannabis use, had psychosis as an outcome and analyzed for the association between adolescent cannabis use and psychosis. Analysis was done using random-effects meta-analysis and narrative synthesis. Results: A total of 63 studies were included in the narrative review and 18 studies were included in the meta-analysis. Adolescent cannabis use was found to increase risk for psychosis (RR = 1.71 (95%CI, 1.47-2.00, p < 0.00001) and predict earlier onset of psychosis. The following factors moderate the relationship between cannabis use and the risk of psychosis: age of onset of cannabis use, frequent cannabis use, exposure to childhood trauma, concurrent use of other substances and genetic factors. Conclusion: Adolescent cannabis use is associated with an increased risk for psychosis later in life. In addition, there are factors that moderate this relationship; therefore there is a need for research to assess the interaction between these factors, adolescent cannabis use and psychosis risk.

Public health implications of legalising the production and sale of cannabis for medicinal and recreational use.

We assess the current and describe possible future public health impacts of the legalisation of cannabis production, sale, and use in the Americas. First, we describe global patterns of cannabis use and their most probable adverse health effects. Second, we summarise evidence regarding the effectiveness of cannabinoids for medicinal use and describe approaches that have been used to regulate the use of medicinal cannabis and how these approaches might have affected medicinal and recreational use and harms (eg, road crashes). Third, we describe how jurisdictions that have legalised recreational use have regulated production and sale of cannabis. Fourth, we evaluate the effects of cannabis legalisation on cannabis use and harms and on the use of alcohol, tobacco, and other drugs. Fifth, we use alcohol and tobacco policy examples to identify possible long-term public health effects of cannabis legalisation. Finally, we outline policy approaches that could minimise harms to public health arising from the legalisation of a commercial cannabis industry.

Characterising heterogeneity in the use of different cannabis products: latent class analysis with 55 000 people who use cannabis and associations with severity of cannabis dependence.

BACKGROUND: As new cannabis products and administration methods proliferate, patterns of use are becoming increasingly heterogeneous. However, few studies have explored different profiles of cannabis use and their association with problematic use. METHODS: Latent class analysis (LCA) was used to identify subgroups of past-year cannabis users endorsing distinct patterns of use from a large international sample (n = 55 240). Past-12-months use of six different cannabis types (sinsemilla, herbal, hashish, concentrates, kief, edibles) were used as latent class indicators. Participants also reported the frequency and amount of cannabis used, whether they had ever received a mental health disorder diagnosis and their cannabis dependence severity via the Severity of Dependence Scale (SDS). RESULTS: LCA identified seven distinct classes of cannabis use, characterised by high probabilities of using: sinsemilla & herbal (30.3% of the sample); sinsemilla, herbal & hashish (20.4%); herbal (18.4%); hashish & herbal (18.8%); all types (5.7%); edibles & herbal (4.6%) and concentrates & sinsemilla (1.7%). Relative to the herbal class, classes characterised by sinsemilla and/or hashish use had increased dependence severity. By contrast, the classes characterised by concentrates use did not show strong associations with cannabis dependence but reported greater rates of ever receiving a mental health disorder diagnosis. CONCLUSIONS: The identification of these distinct classes underscores heterogeneity among cannabis use behaviours and provides novel insight into their different associations with addiction and mental health.

High-Intensity Drinking in Adult Australian Twins.

BACKGROUND: Many adult drinkers consume far beyond the binge threshold. This "high-intensity drinking" (HID), defined as 2 (HID-2) and 3 (HID-3) times the binge threshold, is of public health interest due to its role in acute alcohol-related harms. Research on HID has mostly been limited to college-aged young adults, focused on contextual factors, and neglected the potential role of genetic influences on the propensity to engage in HID. METHODS: Structured diagnostic interviews assessing past-year alcohol involvement were conducted with 3,785 individuals (1,365 men, 2,420 women; Mage  = 32, range = 21 to 46), including 3,314 twins and 471 nontwin siblings from the Australian Twin Registry. Multinomial logistic regression analyses were conducted to compare HID-2 and HID-3 to binge drinking on demographic correlates, drinking characteristics, and drinking-related consequences. Biometric modeling was conducted to estimate the role of genetic, common, and individual-specific environmental factors in HID propensity. RESULTS: Among past-year drinkers, the prevalence of HID-2 and HID-3 was both 22%, with men disproportionally represented. The frequencies of drinking, intoxication, and binge drinking significantly increased across the heavier drinking categories, which also evidenced higher average consumption quantities and higher rates of alcohol-related consequences. The propensity to engage in HID was significantly heritable (A = 37% [95% CI: 28 to 46%]), with individual-specific environmental influences accounting for the remainder of the variance. CONCLUSIONS: This study convincingly demonstrates that HID is not restricted to college-aged young adults, but also can be highly prevalent among those of working age, and that the propensity to engage in HID is partially explained by genetic influences.

A Global Meta-analysis of the Prevalence of HIV, Hepatitis C Virus, and Hepatitis B Virus Among People Who Inject Drugs-Do Gender-Based Differences Vary by Country-Level Indicators?

BACKGROUND: Women-specific factors exist that increases vulnerability to drug-related harms from injection drug use, including blood-borne viruses (BBVs), but gender-based differences in BBV prevalence have not been systematically examined. METHODS: We conducted meta-analyses to estimate country, regional, and global prevalence of serologically confirmed human immunodeficiency virus (HIV), hepatitis C virus (HCV; based on detection of anti-HCV antibody), and hepatitis B virus (HBV; based on detection of HBV surface antigen) in people who inject drugs (PWID), by gender. Gender-based differences in the BBV prevalence (calculated as the risk among women relative to the risk among men) were regressed on country-level prevalence and inequality measures (Gender inequality index, Human development index, Gini coefficient, and high, low or middle income of the country). RESULTS: Gender-based differences varied by countries and regions. HIV prevalence was higher among women than men in sub-Saharan Africa (relative risk [RR], 2.8; 95% confidence interval [CI], 1.8-4.4) and South Asia (RR, 1.7; 95% CI, 1.1-2.7); anti-HCV was lower among women in the Middle East and North Africa (RR, 0.6; 95% CI, .5-.7) and East and Southeast Asia (RR, 0.8; 95% CI, .7-.9). Gender-based differences varied with country-levels of the BBV prevalence in the general population, human development, and income distribution. CONCLUSION: HIV was more prevalent in women who inject drugs as compared to their male counterparts in some countries, but there is variation between and within regions. In countries where women are at higher risks, there is a need to develop gender-sensitive harm-reduction services for the particularly marginalized population of women who inject drugs.

Psychotic-like experiences with cannabis use predict cannabis cessation and desire to quit: a cannabis discontinuation hypothesis.

BACKGROUND: Evidence suggests that cannabis-induced psychotic-like experiences may be a marker of psychosis proneness. The effect of such experiences on cannabis use has not systematically been examined. METHODS: We undertook a mixed-methods online survey of 1231 cannabis users (including 926 continued users) using the Cannabis Experiences Questionnaire. We examined the effect of psychotic-like and pleasurable experiences on cessation of cannabis and intention to quit. Socio-demographic variables, cannabis use parameters and substance misuse history were included as covariates. Free-text data explored subjective reasons for changes in use. RESULTS: Cessation of cannabis use was associated with greater psychotic-like experiences [p < 0.001, Exp(B) 1.262, 95% confidence interval (CI) 1.179-1.351], whilst continued cannabis users were more likely to report pleasurable experiences [p < 0.001, Exp(B) 0.717, 95% CI 0.662-0.776]. Intention to quit cannabis in continued users was associated with greater psychotic-like experiences [p < 0.003, Exp(B) 1.131, 95% CI 1.044-1.225], whilst intention to not quit was significantly associated with increased pleasurable experiences [p < 0.015, Exp(B) 0.892, 95% CI 0.814-0.978]. Whereas former users clearly ascribed cessation to negative experiences, continued users who expressed intention to quit less readily ascribed the intention to negative experiences. CONCLUSIONS: Elucidation of psychotic-like experiences may form the basis of a therapeutic intervention for those who wish to quit. Cessation in those with cannabis-induced psychotomimetic experiences may offset the risk for the development of a psychotic disorder, in this higher risk group.

Genetic and environmental influences on gambling disorder liability: a replication and combined analysis of two twin studies.

BACKGROUND: Gambling disorder (GD), recognized in Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM-5) as a behavioral addiction, is associated with a range of adverse outcomes. However, there has been little research on the genetic and environmental influences on the development of this disorder. This study reports results from the largest twin study of GD conducted to date. METHODS: Replication and combined analyses were based on samples of 3292 (mean age 31.8, born 1972-79) and 4764 (mean age 37.7, born 1964-71) male, female, and unlike-sex twin pairs from the Australian Twin Registry. Univariate biometric twin models estimated the proportion of variation in the latent GD liability that could be attributed to genetic, shared environmental, and unique environmental factors, and whether these differed quantitatively or qualitatively for men and women. RESULTS: In the replication study, when using a lower GD threshold, there was evidence for significant genetic (60%; 95% confidence interval (CI) 45-76%) and unique environmental (40%; 95% CI 24-56%), but not shared environmental contributions (0%; 95% CI 0-0%) to GD liability; this did not significantly differ from the original study. In the combined analysis, higher GD thresholds (such as one consistent with DSM-5 GD) and a multiple threshold definitions of GD yielded similar results. There was no evidence for quantitative or qualitative sex differences in the liability for GD. CONCLUSIONS: Twin studies of GD are few in number but they tell a remarkably similar story: substantial genetic and unique environmental influences, with no evidence for shared environmental contributions or sex differences in GD liability.

Common genetic contributions to high-risk trauma exposure and self-injurious thoughts and behaviors.

BACKGROUND: Prior research has documented shared heritable contributions to non-suicidal self-injury (NSSI) and suicidal ideation (SI) as well as NSSI and suicide attempt (SA). In addition, trauma exposure has been implicated in risk for NSSI and suicide. Genetically informative studies are needed to determine common sources of liability to all three self-injurious thoughts and behaviors, and to clarify the nature of their associations with traumatic experiences. METHODS: Multivariate biometric modeling was conducted using data from 9526 twins [59% female, mean age = 31.7 years (range 24-42)] from two cohorts of the Australian Twin Registry, some of whom also participated in the Childhood Trauma Study and the Nicotine Addiction Genetics Project. RESULTS: The prevalences of high-risk trauma exposure (HRT), NSSI, SI, and SA were 24.4, 5.6, 27.1, and 4.6%, respectively. All phenotypes were moderately to highly correlated. Genetic influences on self-injurious thoughts and behaviors and HRT were significant and highly correlated among men [rG = 0.59, 95% confidence interval (CI) (0.37-0.81)] and women [rG = 0.56 (0.49-0.63)]. Unique environmental influences were modestly correlated in women [rE = 0.23 (0.01-0.45)], suggesting that high-risk trauma may confer some direct risk for self-injurious thoughts and behaviors among females. CONCLUSIONS: Individuals engaging in NSSI are at increased risk for suicide, and common heritable factors contribute to these associations. Preventing trauma exposure may help to mitigate risk for self-harm and suicide, either directly or indirectly via reductions in liability to psychopathology more broadly. In addition, targeting pre-existing vulnerability factors could significantly reduce risk for life-threatening behaviors among those who have experienced trauma.

Genetic Epidemiology of Liability for Alcohol-Induced Blacking and Passing Out.

BACKGROUND: Individuals differ in their sensitivity to alcohol's physiological effects, including blacking and passing out. Blackouts are periods of impaired memory formation when an individual engages in activities they later cannot recall, while passing out results in loss of consciousness. METHODS: The sample consisted of 3,292 adult twins from the Australian Twin Registry. Univariate twin analyses were conducted to examine the contributions of genetic and environmental influences to blacking and passing out occurrence and susceptibility (accounting for frequency of intoxication). Evidence for shared etiology of susceptibility to blacking and passing out was examined using bivariate twin analyses. RESULTS: Although blacking and passing out were strongly associated (odds ratio (OR) = 4.45, 95% confidence interval (CI): [3.85, 5.14]), the genetic epidemiology was quite different. Genetic (43%) and nonshared environmental (57%) influences contributed to liability for blackout occurrence. For passing out occurrence, there was evidence of sex differences. Among men, genetic (32%) and nonshared environmental (68%) influences contributed, whereas among women, there were shared (29%) and nonshared environmental (72%) influences. After accounting for frequency of intoxication, genetic influences on blackout susceptibility remained significant; in contrast, only nonshared environmental influences were significant for passing out susceptibility. There was evidence for overlapping genetic and nonshared environmental factors influencing susceptibility to blacking and passing out among men; among women, there were overlapping nonshared environmental influences. CONCLUSIONS: Blacking and passing out are 2 common sedative-like effects of heavy drinking, and people differ considerably in their susceptibility to these effects. This study suggests that differences in blackout susceptibility can be explained by genetic factors in both men and women, while differences in susceptibility to pass out after consuming alcohol may be attributable to environmental influences, particularly among women. These environmental factors may include changing social and cultural norms about alcohol use, drinking context, and the type(s) of alcohol consumed.

Overlap of heritable influences between cannabis use disorder, frequency of use and opportunity to use cannabis: trivariate twin modelling and implications for genetic design.

BACKGROUND: The genetic component of Cannabis Use Disorder may overlap with influences acting more generally on early stages of cannabis use. This paper aims to determine the extent to which genetic influences on the development of cannabis abuse/dependence are correlated with those acting on the opportunity to use cannabis and frequency of use. METHODS: A cross-sectional study of 3303 Australian twins, measuring age of onset of cannabis use opportunity, lifetime frequency of cannabis use, and lifetime DSM-IV cannabis abuse/dependence. A trivariate Cholesky decomposition estimated additive genetic (A), shared environment (C) and unique environment (E) contributions to the opportunity to use cannabis, the frequency of cannabis use, cannabis abuse/dependence, and the extent of overlap between genetic and environmental factors associated with each phenotype. RESULTS: Variance components estimates were A = 0.64 [95% confidence interval (CI) 0.58-0.70] and E = 0.36 (95% CI 0.29-0.42) for age of opportunity to use cannabis, A = 0.74 (95% CI 0.66-0.80) and E = 0.26 (95% CI 0.20-0.34) for cannabis use frequency, and A = 0.78 (95% CI 0.65-0.88) and E = 0.22 (95% CI 0.12-0.35) for cannabis abuse/dependence. Opportunity shares 45% of genetic influences with the frequency of use, and only 17% of additive genetic influences are unique to abuse/dependence from those acting on opportunity and frequency. CONCLUSIONS: There are significant genetic contributions to lifetime cannabis abuse/dependence, but a large proportion of this overlaps with influences acting on opportunity and frequency of use. Individuals without drug use opportunity are uninformative, and studies of drug use disorders must incorporate individual exposure to accurately identify aetiology.

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.

From alcohol initiation to tolerance to problems: Discordant twin modeling of a developmental process.

The current study examined a stage-based alcohol use trajectory model to test for potential causal effects of earlier drinking milestones on later drinking milestones in a combined sample of two cohorts of Australian monozygotic and same-sex dizygotic twins (N = 7,398, age M = 30.46, SD = 2.61, 61% male, 56% monozygotic twins). Ages of drinking, drunkenness, regular drinking, tolerance, first nontolerance alcohol use disorder symptom, and alcohol use disorder symptom onsets were assessed retrospectively. Ages of milestone attainment (i.e., age-of-onset) and time between milestones (i.e., time-to-event) were examined via frailty models within a multilevel discordant twin design. For age-of-onset models, earlier ages of onset of antecedent drinking milestones increased hazards for earlier ages of onset for more proximal subsequent drinking milestones. For the time-to-event models, however, earlier ages of onset for the "starting" milestone decreased risk for a shorter time period between the starting and the "ending" milestone. Earlier age of onset of intermediate milestones between starting and ending drinking milestones had the opposite effect, increasing risk for a shorter time period between the starting and ending milestones. These results are consistent with a causal effect of an earlier age of drinking milestone onset on temporally proximal subsequent drinking milestones.

Neuroticism and the Overlap Between Autistic and ADHD Traits: Findings From a Population Sample of Young Adult Australian Twins.

Neuroticism, a 'Big Five' personality trait, has been associated with sub-clinical traits of both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The objective of the current study was to examine whether causal overlap between ASD and ADHD traits can be accounted for by genetic and environmental risk factors that are shared with neuroticism. We performed twin-based structural equation modeling using self-report data from 12 items of the Neo Five-Factor Inventory Neuroticism domain, 11 Social Responsiveness Scale items, and 12 Adult ADHD Self-Report Scale items obtained from 3,170 young adult Australian individual twins (1,081 complete pairs). Univariate analysis for neuroticism, ASD, and ADHD traits suggested that the most parsimonious models were those with additive genetic and unique environmental components, without sex limitation effects. Heritability of neuroticism, ASD, and ADHD traits, as measured by these methods, was moderate (between 40% and 45% for each respective trait). In a trivariate model, we observed moderate phenotypic (between 0.45 and 0.62), genetic (between 0.56 and 0.71), and unique environmental correlations (between 0.37and 0.55) among neuroticism, ASD, and ADHD traits, with the highest value for the shared genetic influence between neuroticism and self-reported ASD traits (r g = 0.71). Together, our results suggest that in young adults, genetic, and unique environmental risk factors indexed by neuroticism overlap with those that are shared by ASD and ADHD.