Trends in Mortality From Novel Psychoactive Substances as "Legal Highs": Gender Differences in Manner of Death and Implications for Risk Differences for Women.

Introduction: This study aimed to examine drug-related deaths in the UK in which novel psychoactive substances (NPS) are an implicated substance, and to focus on female deaths in comparison with male deaths. While male overdoses dominate epidemiological statistics, there is an increase in female drug-related deaths and a narrowing of the gap between gender mortality rates which is to date unexplained. Method: This study analyzed data from the National Programme for Substance Abuse Deaths (NPSAD) database that records drug-related deaths in the UK from coronial records. A dataset was constructed using parameters to capture all drug-related cases during the period 2007-2017 when NPS were legal and highly available in the UK, in order to capture deaths recorded among both regular and occasional drug users, and to include all cases recorded during that period regardless of NPS status in order to make comparisons. The final dataset comprised 10,159 cases, with 456 NPS-related deaths. Data for NPS and non-NPS were compared, and comparisons were made between cohorts by gender. The dataset also includes coronial narrative notes which allowed a qualitative analysis of NPS female deaths to add contextual explanation. Results: The proportion of male NPS deaths is significantly higher than that for female NPS deaths but does not reflect the generalized difference between male and female drug-related mortality of this period studied. Demographic and outcome data by gender difference were significant for all drug-related deaths, but not for NPS-only deaths, indicating a greater homogeneity among NPS deaths by gender. Older women using NPS were more likely to have methadone or diazepam as another drug implicated and have established histories of drug misuse. Conclusion: Where NPS have been used, differences in drug death profiles are less likely to be accounted for by gender than other demographic or behavioral differences more typically found in opiate deaths. The social and health problems of older women may be key characteristics that differentiate female deaths from male deaths. These findings also support evidence of increasing uptake of NPS among older established drug users that adds further risk to polydrug use.

Seeing sadness: Comorbid effects of loneliness and depression on emotional face processing.

BACKGROUND/OBJECTIVE: Loneliness and depression are highly comorbid, and both are associated with social processing deficits. However, there is a paucity of research aimed at differentiating emotional face-processing deficits that are comorbid to loneliness and depression versus those attributable to loneliness or depression only. METHODS: 502 participants were recruited and screened for loneliness (UCLA Loneliness Scale) and depression (Beck Depression Inventory). Of those, seventy-seven took part in a fully crossed 2 (loneliness; low/high) * 2 (depression; low/high) factorial between-subjects design study to assess individual and comorbid effects of loneliness and depression on a computerized morphed facial emotion processing task. RESULTS: Comorbidity was confirmed by a significant positive correlation between loneliness and depression. On the emotion processing task, loneliness was associated with an increased accuracy for sad faces and decreased accuracy for fearful faces and depression with decreased accuracy in identifying happy faces. Comorbid loneliness and depression resulted in an increased misattribution of neutral faces as sad, an effect that was also seen in those who were either only lonely or only depressed. CONCLUSION: This if the first study to tease out comorbid versus independent effects of loneliness and depression on social information processing. To the extent that emotional biases may act as risk factors for detrimental outcomes, our findings highlight the importance of treating both loneliness and depression.

Neuroticism related differences in working memory tasks.

Two influential theories relating to personality traits, i.e. arousal-based theory (ABT) and attentional control theory (ACT), made predictions on how neuroticism may affect task performance. ABT suggested that high neurotics perform worse than low neurotics in all difficult tasks, whereas they perform similar in easy tasks. On the other hand, ACT suggested that high neurotics perform worse than low neurotics only if the task relies on central executive functions of working memory (WM), such as switching or inhibition. However, currently it is still unclear whether neuroticism affects all difficult tasks, as proposed by ABT, or whether it is specific to certain tasks, as proposed by ACT. To test this, we used the Cambridge Neuropsychological Tasks Automated Battery (CANTAB) as our test tool and we selected three working memory tasks which tested the effect of neuroticism on both the central executive system (CES) and the WM storage system (i.e. visuospatial sketchpad) in 21 low and 24 high neurotics. Results showed that high neurotics, as compared to low neurotics, exhibited lower performance only when the working memory task is specifically associated with switching and/or inhibition, but not in a task which is associated with the visuospatial sketchpad. We conclude that the results support the ACT rather than the ABT, because high levels of neuroticism impaired behavioural performance specifically in demanding tasks associated with switching and inhibition, but not in tasks associated with the visuospatial sketchpad.

Does perception of drug-related harm change with age? A cross-sectional online survey of young and older people.

OBJECTIVES: To investigate how young and older people perceive the harms associated with legal and illegal drugs. DESIGN: Cross-sectional study: adults aged 18-24 years versus 45+ completed an online survey ranking the perceived harms associated with 11 drugs on 16 drug-related harm criteria. SETTING: Online survey. PARTICIPANTS: 184 participants aged 18-24 years (113 female: mean age 21: SD 1.3) and 91 participants aged 45+ (51 female: mean age 60: SD 8.5). MAIN OUTCOME MEASURES: 'Perception of drug-related harms': This was measured using a rating scale ranging from 1 (no risk of harm) to 4 (high risk of harm). Participants were also asked about sources which informed their perception on drug-related harms as well as their own personal self-reported drug experiences. RESULTS: Of the illegal drugs, heroin, methamphetamine and cocaine were rated as the most harmful and cannabis was rated as the least harmful. Alcohol and tobacco were also rated as less harmful. The results showed that perceptions of drug-related harms were inconsistent with current knowledge from research on drugs. Furthermore, perceptions on drug harms were more conservative in the 45+ group for a number of illegal drugs and tobacco. However, the 45+ age group did not perceive alcohol as any more harmful than the younger group. CONCLUSIONS: This survey demonstrates that the greatest misperception was in relation to alcohol-related harms which did not change with age. In order to minimise harms, this misperception needs to be addressed through education and policies that legislate drug use.

Low identification of alcohol use disorders in general practice in England.

AIMS: The prevalence of alcohol use disorders (AUDs) in the United Kingdom is estimated at 25%, and primary care has been identified as the first line of treatment for this population. However, there is a paucity of evidence regarding the current rates of identification of AUDs in primary care. The aim of the present study was to compare the observed rates of AUDs in general practice with expected rates, which are based on general population prevalence rates of AUDs. DESIGN, PARTICIPANTS AND MEASUREMENTS: Epidemiological data on individuals aged 16-64 years with an AUD was obtained from the General Practice Research Database. General population prevalence rates of AUDs were obtained from the Psychiatric Morbidity Survey. Chi(2) tests and identification ratios were used to analyse the data. RESULTS: There was a significant relationship between type of AUD and identification (chi(2)=1466.89, P<0.001), and general practitioners were poorer at identifying harmful/hazardous drinkers when compared with dependent drinkers. No gender differences in the identification of hazardous/harmful drinking were found, but female dependent drinkers were significantly more likely to be identified than males (identification ratio 0.07; 95% confidence interval 0.06-0.07). The identification of AUDs was significantly lower for the 16-24-year age group compared with all other age groups. CONCLUSION: Despite attempts at targeting hazardous/harmful drinkers for brief interventions in primary care, the present findings suggest that this group are still under-identified. Furthermore, this under-identification is even more apparent in men and in young people who have high general population prevalence rates for AUDs. In conclusion, increasing identification rates could be incorporated into brief intervention strategies in primary care.

Antidepressant-related deaths and antidepressant prescriptions in England and Wales, 1998-2000.

BACKGROUND: Deaths from antidepressants continue to account for a substantial proportion of drug-related deaths. AIMS: To investigate the relative toxicity of the major classes of antidepressant drugs, with the specific objective of assessing this in relation to the cause of death; and to analyse the deaths where there were multiple mentions of antidepressant drugs or other psychoactive drugs with antidepressants. METHOD: Mortality data were collected from the National Programme of Substance Abuse Deaths, and antidepressant prescription data were collected. RESULTS: Most deaths from antidepressant drugs were suicides (80%). Tricyclic antidepressants (TCAs) accounted for more drug mentions than did other antidepressant drugs (12 per million prescriptions). Selective serotonin reuptake inhibitors (SSRIs) were associated with a significantly lower risk of toxicity, but 93% of deaths from SSRIs occurred in combination with other drugs, especially TCAs (24.5%). In 'combination' deaths patients were significantly more likely to have had a history of drug misuse. CONCLUSIONS: The efficacy and safety of augmentation therapy with TCAs in SSRI-resistant patients should be monitored carefully, and patients prescribed antidepressants should be screened for drug use/misuse.

Cause and manner of death in drug-related fatality: an analysis of drug-related deaths recorded by coroners in England and Wales in 2000.

This study investigated causes and manner of drug-related fatalities recorded in 2000 in the United Kingdom, measuring the 'masked' manner of death in cases typically recorded as overdose. A retrospective cohort study was used of 1037 cases of accidental drug-related fatalities reported by coroners in England and Wales to the National Programme of Substance Abuse Deaths. Whilst 802 cases were identified as direct acute overdose, representing 77% of the total accidental deaths, 23% of 'overdose' fatalities were caused by asphyxiation (7%), drug-related medical conditions (7%), non-drug-related conditions (4%), traumatic accidents (3%) and infections (2%). Younger people show higher risk of overdose and asphyxiation; older people show higher risk from pre-existing medical conditions. This study not only confirmed the high risk of overdose associated with heroin and polydrug use, but it also identified other high fatality risk factors for heroin/morphine users such as contracting an acute infection leading to septicaemia or endocarditis, or contracting a chronic infection such as HIV, HBV or HCV. In contrast, stimulants particularly featured in traumatic accidents, with amphetamine use most associated with cardio-vascular fatality. These findings highlight the 'masked' manner of death in cases commonly recorded as overdose and demonstrate the need for a more-detailed and systematic method of recording drug-related deaths in order to inform drug education and harm reduction strategies.

Corticotropin releasing factor antagonist, alpha-helical CRF(9-41), reverses nicotine-induced conditioned, but not unconditioned, anxiety.

RATIONALE: Unconditioned anxiogenic effects of nicotine have been observed in the social interaction (SI) test 5 min after injection of a low dose and both 5 min and 30 min after injection of a high dose. Conditioned anxiety has also been observed 24 h after testing in the SI with a high dose of nicotine. OBJECTIVES: In order to determine whether these three anxiogenic effects shared a common mechanism, we investigated the role of corticotropin releasing factor (CRF). We therefore examined whether the CRF antagonist alpha-helical CRF(9-41) could block these three anxiogenic effects of nicotine. METHODS: To test the unconditioned anxiogenic effects, pairs of male rats were tested in SI 5 min after s.c. vehicle or nicotine (0.1 mg/kg) or 30 min after s.c. vehicle or nicotine (0.45 mg/kg), and 30 min after i.c.v. artificial cerebrospinal fluid (aCSF) or alpha-helical CRF(9-41). To test conditioned anxiety, rats were exposed to the SI test on day 1, 5 min after vehicle or nicotine (0.1 mg/kg). On day 2, they were re-tested in SI 30 min after i.c.v. aCSF or alpha-helical CRF(9-41) (5 microg). RESULTS: alpha-Helical CRF(9-41) did not block the unconditioned anxiogenic effect of either dose of nicotine. Nicotine (0.1 mg/kg, 5 min) elicited a conditioned anxiogenic response that was significantly reversed by alpha-helical CRF(9-41). The CRF antagonist alone had no effect. CONCLUSIONS: CRF is an important mediator of the conditioned anxiety to nicotine, but may not play a role in mediating the acute anxiogenic effects.

Conditioned anxiety to nicotine.

RATIONALE: Despite its reinforcing properties nicotine has also been reported to produce anxiety in humans and anxiogenic effects in animal tests of anxiety. OBJECTIVE: The aims of this study were three-fold: (a) to investigate whether anxiety can be conditioned to cues associated with an acute anxiogenic dose of nicotine, (b) to investigate whether the conditioned anxiety is specific to a particular test of anxiety, and (c) to investigate whether nicotine pre-exposure influences the development of a conditioned anxiogenic effect. METHODS: An anxiogenic dose of nicotine was administered to rats either before or after experience with the social interaction (SI) test. The retention of a conditioned anxiogenic response was examined when the rats were re-tested undrugged in the SI test 24 h later. To test whether conditioned anxiety was test specific, rats that had been tested in the elevated plus-maze with an anxiogenic dose of nicotine were retested undrugged in the SI test 24 h later, and vice versa. We then examined the effects of 4 days or 4 weeks pre-exposure to nicotine on the development of a conditioned anxiogenic response in the SI test. RESULTS: Rats injected with nicotine (0.45 mg/kg s.c.) 5 min before the social interaction test spent significantly less time in SI, indicating an unconditioned anxiogenic effect than did vehicle-injected controls or rats injected with nicotine after the test. After 24 h when all groups were tested undrugged only those previously tested in SI after nicotine injection showed a significant conditioned anxiogenic effect. This conditioned anxiety was test specific. Rats injected with nicotine before the SI test did not show an anxiogenic response when tested 24 h later undrugged in the plus-maze, and vice versa. Furthermore, although 4 days exposure to nicotine (0.45 mg/kg s.c.) did not prevent the development of a conditioned anxiogenic response, 4 weeks self-administration of nicotine (total dose, 0.45 mg/kg i.v) in an operant chamber did not affect the acute anxiogenic response to nicotine in the SI test, but it did prevent the development of conditioned anxiety. CONCLUSIONS: The present findings suggest that anxiety can be conditioned following exposure to an anxiogenic dose of nicotine, and that this anxiety is specific to the contextual cues associated with the SI test.

Nicotinic--serotonergic interactions in brain and behaviour.

This review focuses on nicotinic--serotonergic interactions in the central nervous system (CNS). Nicotine increases 5-hydroxytryptamine (5-HT) release in the cortex, striatum, hippocampus, dorsal raphé nucleus (DRN), hypothalamus, and spinal cord. As yet, there is little firm evidence for nicotinic receptors on serotonergic terminals and thus nicotine's effects on 5-HT may not necessarily be directly mediated, but there is strong evidence that the 5-HT tone plays a permissive role in nicotine's effects. The effects in the cortex, hippocampus, and DRN involve stimulation of 5-HT(1A) receptors, and in the striatum, 5-HT(3) receptors. The 5-HT(1A) receptors in the DRN play a role in mediating the anxiolytic effects of nicotine and the 5-HT(1A) receptors in the dorsal hippocampus and lateral septum mediate its anxiogenic effects. The increased startle and anxiety during nicotine withdrawal is mediated by 5-HT(1A) and 5-HT(3) receptors. The locomotor stimulant effect of acute nicotine is mediated by 5-HT(1A) receptors and 5-HT(2) receptors may play a role in the expression of a sensitised response after chronic nicotine treatment. Unfortunately, the role of 5-HT(1A) receptors in mediating nicotine seeking has not yet been investigated and would seem an important area for future research. There is also evidence for nicotinic--serotonergic interactions in the acquisition of the water maze, passive avoidance, and impulsivity in the five-choice serial reaction task.