What impact could the legalisation of recreational cannabis have on the health of the UK? Lessons from the rest of the world.

Several jurisdictions across the globe have introduced legislation to legally permit the sale and consumption of recreational cannabis. This editorial considers current evidence from the rest of the world and asks how this might inform the possible consequences of 'legalisation' models in the UK.

Drug-related deaths among housed and homeless individuals in the UK and the USA: comparative retrospective cohort study.

BACKGROUND: The UK and USA currently report their highest number of drug-related deaths since records began, with higher rates among individuals experiencing homelessness. AIMS: Given that overdose prevention in homeless populations may require unique strategies, we evaluated whether substances implicated in death differed between (a) housed decedents and those experiencing homelessness and (b) between US and UK homeless populations. METHOD: We conducted an internationally comparative retrospective cohort study utilising multilevel multinomial regression modelling of coronial/medical examiner-verified drug-related deaths from 1 January 2012 to 31 December 2021. UK data were available for England, Wales and Northern Ireland; US data were collated from eight county jurisdictions. Data were available on decedent age, sex, ethnicity, housing status and substances implicated in death. RESULTS: Homeless individuals accounted for 16.3% of US decedents versus 3.4% in the UK. Opioids were implicated in 66.3 and 50.4% of all studied drug-related deaths in the UK and the USA respectively. UK homeless decedents had a significantly increased risk of having only opioids implicated in death compared with only non-opioids implicated (relative risk ratio RRR = 1.87, 95% CI 1.76-1.98, P < 0.001); conversely, US homeless decedents had a significantly decreased risk (RRR = 0.37, 95% CI 0.29-0.48, P < 0.001). Methamphetamine was implicated in two-thirds (66.7%) of deaths among US homeless decedents compared with 0.4% in the UK. CONCLUSIONS: Both the rate and type of drug-related deaths differ significantly between homeless and housed populations in the UK and USA. The two countries also differ in drugs implicated in death. Targeted programmes for country-specific implicated drug profiles appear warranted.

The clustering of physical health conditions and associations with co-occurring mental health problems and problematic alcohol use: a cross-sectional study.

BACKGROUND: There is strong evidence for the co-occurrence of mental health conditions and alcohol problems, yet physical health outcomes among this group are not well characterised. This study aimed to identify clusters of physical health conditions and their associations with mental health and problematic alcohol use in England's general population. METHODS: Cross-sectional analysis of the 2014 Adult Psychiatric Morbidity Survey (N = 7546) was conducted. The survey used standardised measures of problematic alcohol use and mental health conditions, including the Alcohol Use Disorders Identification Test (AUDIT) and the Clinical Interview Schedule-Revised. Participants self-reported any lifetime physical health conditions. Latent class analysis considered 12 common physical illnesses to identify clusters of multimorbidity. Multinomial logistic regression (adjusting for age, gender, ethnicity, education, and occupational grade) was used to explore associations between mental health, hazardous drinking (AUDIT 8 +), and co-occurring physical illnesses. RESULTS: Five clusters were identified with statistically distinct and clinically meaningful disease patterns: 'Physically Healthy' (76.62%), 'Emerging Multimorbidity' (3.12%), 'Hypertension & Arthritis' (14.28%), 'Digestive & Bowel Problems'' (3.17%), and 'Complex Multimorbidity' (2.8%). Having a mental health problem was associated with increased odds of 'Digestive & Bowel Problems' (adjusted multinomial odds ratio (AMOR) = 1.58; 95% CI [1.15-2.17]) and 'Complex Multimorbidity' (AMOR = 2.02; 95% CI [1.49-2.74]). Individuals with co-occurring mental health conditions and problematic alcohol use also had higher odds of 'Digestive & Bowel Problems' (AMOR = 2.64; 95% CI [1.68-4.15]) and 'Complex Multimorbidity' (AMOR = 2.62; 95% CI [1.61-4.23]). CONCLUSIONS: Individuals with a mental health condition concurrent with problematic alcohol use experience a greater burden of physical illnesses, highlighting the need for timely treatment which is likely to include better integration of alcohol and mental health services.

Catatonic Episodes Related to Substance Use: A Cross-Sectional Study Using Electronic Healthcare Records.

Objective: Substance use has increasingly been linked to the onset of catatonic episodes; however, no large observational studies have examined this association. This study aimed to identify catatonic episodes temporally associated with acute intoxication, withdrawal or chronic substance use, investigate which substances were involved, and compare clinical characteristics of substance-related and non-substance-related catatonic episodes. Methods: This study retrospectively identified all catatonic episodes recorded in an electronic case register hosted at a large secondary mental health trust in London, UK. Episodes were categorized as substance-related if the clinical record reported either a positive urine drug screen, an ICD-10 diagnosis of a mental or behavioral disorder due to substance use, or documented substance use between two weeks prior to the catatonic episode and the date of the catatonic episode. Results: 108 of 2130 catatonic episodes (5.1%) were deemed substance-related. The number of contemporaneously reported substance-related episodes increased between 2007 and 2016 [r = 0.72, p = 0.02]. Episodes in the context of acute intoxication (n = 54) were most frequently related to cannabis (n = 31) or cocaine (n = 5) use, whilst those in the context of drug withdrawal (n = 8) were most commonly related to alcohol, opioids and benzodiazepines. There were 50 episodes of catatonia associated with chronic substance use without intoxication or withdrawal, of which the majority were related to cannabis use (n = 37). 21 episodes had overlapping intoxication, withdrawal and chronic use of different substances within an episode. Compared to catatonic episodes not related to substance use, episodes of substance-related catatonia occurred in individuals who were younger (mean age 31.3 years [SD 12.2] vs 35.7 years [SD 16.3], p = 0.01) and more likely to be men (74.0% vs 54.3%, p < 0.001). The clinical features of catatonia were similar between the two groups. Conclusions: A relatively small proportion of catatonic episodes were temporally associated with reported substance use within their electronic records. Substance-related catatonic episodes were mostly related to cannabis use, but other substances including cocaine, alcohol, opioids and benzodiazepines were sometimes implicated. This is likely an underestimate of substance-related catatonia use due to issues with documentation and appropriate investigation.

The relationship between alcohol-related hospital admission and specialist alcohol treatment provision across local authorities in England since passage of the Health and Social Care Act 2012.

To our knowledge no previous studies have been conducted at the local authority level assessing relationships between alcohol-related hospital admission, specialist alcohol treatment provision and socioeconomic deprivation since the UK government passed the Health and Social Care Act in 2012. Our results, using publicly available national data-sets, suggest that the local authority areas in England most in need of adequately funded specialist alcohol treatment, because of high prevalence of alcohol dependence and deprivation, are not receiving targeted increased funding, and that the national rise in alcohol-related hospital admissions may be fuelled by local authority funding cuts to specialist alcohol treatment.

Specialist alcohol inpatient treatment admissions and non-specialist hospital admissions for alcohol withdrawal in England: an inverse relationship.

AIMS: We assessed the relationship between specialist and non-specialist admissions for alcohol withdrawal since the introduction of the UK government Health and Social Care Act in 2012. METHODS: Using publicly available national data sets from 2009 to 2019, we compared the number of alcohol withdrawal admissions and estimated costs in specialist and non-specialist treatment settings. RESULTS: A significant negative correlation providing strong evidence of an association was observed between the fall in specialist and rise in non-specialist admissions. Significant cost reductions within specialist services were displaced to non-specialist settings. CONCLUSIONS: The shift in demand from specialist to non-specialist alcohol admissions due to policy changes in England should be reversed by specialist workforce investment to improve outcomes. In the meantime, non-specialist services and staff must be resourced and equipped to meet the complex needs of these service users.

Estimating the Prevalence of Alcohol Dependence in Europe Using Routine Hospital Discharge Data: An Ecological Study.

AIMS: This study aims to explore the feasibility of using routine hospital discharge data, at the level of countries within Europe, to estimate the general population prevalence of alcohol dependence (AD). METHODS: We utilised the European Core Health Indicators data tool to extract the annual rate of hospital discharges due to any wholly attributable alcohol condition as defined by the ICD-10. For those counties with data available, we systematically searched Medline, EMBASE, PsychINFO and Google for studies reporting an estimate of the prevalence of AD from national cross-sectional surveys. We compared these prevalence estimates with those developed from prediction models based on hospital discharge data. RESULTS: The rate of hospital discharges due to any condition from the F10 diagnostic category (mental and behavioural disorders due to alcohol) was moderately correlated with AD prevalence (r = 0.56), while the rate due to any condition from the K70 diagnostic category (alcoholic liver disease) was weakly correlated with AD prevalence (r = 0.21). Two-thirds of the estimates from cross-sectional surveys were not significantly different to those generated using the F10 discharge rate prediction model. CONCLUSIONS: Country-level AD prevalence estimates generated using annual F10 hospital discharge rates are likely to provide information of some utility, particularly when limited other sources of information are available or when examining relative trends over time or between regions. There is, however, currently insufficient evidence to make a definitive recommendation to use hospital discharge data to estimate the absolute prevalence of AD per country in Europe.

School absenteeism as a risk factor for self-harm and suicidal ideation in children and adolescents: a systematic review and meta-analysis.

Self-harm and suicidal ideation in children and adolescents are common and are risk factors for completed suicide. Social exclusion, which can take many forms, increases the risk of self-harm and suicidal ideation. One important marker of social exclusion in young people is school absenteeism. Whether school absenteeism is associated with these adverse outcomes, and if so to what extent, remains unclear. To determine the association between school absenteeism and both self-harm (including completed suicide) and suicidal ideation in children and adolescents, we conducted a systematic review of observational studies. We conducted meta-analysis and report a narrative synthesis where this was not possible. Meta-analysis of cross-sectional studies showed that school absenteeism was associated with an increased risk of self-harm [pooled adjusted odds ratio (aOR) 1.37, 95% confidence interval 1.20-1.57, P = 0.01] and of suicidal ideation (pooled aOR 1.20, 95% CI 1.02-1.42, P = 0.03). A small number of studies showed that school absenteeism had a longitudinal association with both adverse outcomes. Heterogeneity in the exposure and outcome variables, study design and reporting was prominent and limited the extent to which it was appropriate to pool results. School absenteeism was associated with both self-harm and suicidal ideation in young people, but this evidence was derived from a small number of cross-sectional studies. Further research into the mechanisms of this association could help to inform self-harm and suicide prevention strategies at clinical, school and population levels.

Memantine for dementia.

BACKGROUND: Memantine is a moderate affinity uncompetitive antagonist of glutamate NMDA receptors. It is licensed for use in moderate and severe Alzheimer's disease (AD); in the USA, it is also widely used off-label for mild AD. OBJECTIVES: To determine efficacy and safety of memantine for people with dementia. To assess whether memantine adds benefit for people already taking cholinesterase inhibitors (ChEIs). SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register of trials (http://www.medicine.ox.ac.uk/alois/) up to 25 March 2018. We examined clinical trials registries, press releases and posters of memantine manufacturers; and the web sites of the FDA, EMEA and NICE. We contacted authors and companies for missing information. SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomised trials of memantine in people with dementia. DATA COLLECTION AND ANALYSIS: We pooled and analysed data from four clinical domains across different aetiologies and severities of dementia and for AD with agitation. We assessed the impact of study duration, severity and concomitant use of ChEIs. Consequently, we restricted analyses to the licensed dose (20 mg/day or 28 mg extended release) and data at six to seven months duration of follow-up, and analysed separately results for mild and moderate-to-severe AD.We transformed results for efficacy outcomes into the difference in points on particular outcome scales. MAIN RESULTS: Across all types of dementia, data were available from almost 10,000 participants in 44 included trials, most of which were at low or unclear risk of bias. For nearly half the studies, relevant data were obtained from unpublished sources. The majority of trials (29 in 7885 participants) were conducted in people with AD.1. Moderate-to-severe AD (with or without concomitant ChEIs). High-certainty evidence from up to 14 studies in around 3700 participants consistently shows a small clinical benefit for memantine versus placebo: clinical global rating (CGR): 0.21 CIBIC+ points (95% confidence interval (CI) 0.14 to 0.30); cognitive function (CF): 3.11 Severe Impairment Battery (SIB) points (95% CI 2.42 to 3.92); performance on activities of daily living (ADL): 1.09 ADL19 points (95% CI 0.62 to 1.64); and behaviour and mood (BM): 1.84 Neuropsychiatric Inventory (NPI) points (95% CI 1.05 to 2.76). There may be no difference in the number of people discontinuing memantine compared to placebo: risk ratio (RR) 0.93 (95% CI 0.83 to 1.04) corresponding to 13 fewer people per 1000 (95% CI 31 fewer to 7 more). Although there is moderate-certainty evidence that fewer people taking memantine experience agitation as an adverse event: RR 0.81 (95% CI 0.66 to 0.99) (25 fewer people per 1000, 95% CI 1 to 44 fewer), there is also moderate-certainty evidence, from three additional studies, suggesting that memantine is not beneficial as a treatment for agitation (e.g. Cohen Mansfield Agitation Inventory: clinical benefit of 0.50 CMAI points, 95% CI -3.71 to 4.71) .The presence of concomitant ChEI does not impact on the difference between memantine and placebo, with the possible exceptions of the BM outcome (larger effect in people taking ChEIs) and the CF outcome (smaller effect).2. Mild AD (Mini Mental State Examination (MMSE) 20 to 23): mainly moderate-certainty evidence based on post-hoc subgroups from up to four studies in around 600 participants suggests there is probably no difference between memantine and placebo for CF: 0.21 ADAS-Cog points (95% CI -0.95 to 1.38); performance on ADL: -0.07 ADL 23 points (95% CI -1.80 to 1.66); and BM: -0.29 NPI points (95% CI -2.16 to 1.58). There is less certainty in the CGR evidence, which also suggests there may be no difference: 0.09 CIBIC+ points (95% CI -0.12 to 0.30). Memantine (compared with placebo) may increase the numbers of people discontinuing treatment because of adverse events (RR 2.12, 95% CI 1.03 to 4.39).3. Mild-to-moderate vascular dementia. Moderate- and low-certainty evidence from two studies in around 750 participants indicates there is probably a small clinical benefit for CF: 2.15 ADAS-Cog points (95% CI 1.05 to 3.25); there may be a small clinical benefit for BM: 0.47 NOSGER disturbing behaviour points (95% CI 0.07 to 0.87); there is probably no difference in CGR: 0.03 CIBIC+ points (95% CI -0.28 to 0.34); and there may be no difference in ADL: 0.11 NOSGER II self-care subscale points (95% CI -0.35 to 0.54) or in the numbers of people discontinuing treatment: RR 1.05 (95% CI 0.83 to 1.34).There is limited, mainly low- or very low-certainty efficacy evidence for other types of dementia (Parkinson's disease and dementia Lewy bodies (for which CGR may show a small clinical benefit; four studies in 319 people); frontotemporal dementia (two studies in 133 people); and AIDS-related Dementia Complex (one study in 140 people)).There is high-certainty evidence showing no difference between memantine and placebo in the proportion experiencing at least one adverse event: RR 1.03 (95% CI 1.00 to 1.06); the RR does not differ between aetiologies or severities of dementia. Combining available data from all trials, there is moderate-certainty evidence that memantine is 1.6 times more likely than placebo to result in dizziness (6.1% versus 3.9%), low-certainty evidence of a 1.3-fold increased risk of headache (5.5% versus 4.3%), but high-certainty evidence of no difference in falls. AUTHORS' CONCLUSIONS: We found important differences in the efficacy of memantine in mild AD compared to that in moderate-to-severe AD. There is a small clinical benefit of memantine in people with moderate-to-severe AD, which occurs irrespective of whether they are also taking a ChEI, but no benefit in people with mild AD.Clinical heterogeneity in AD makes it unlikely that any single drug will have a large effect size, and means that the optimal drug treatment may involve multiple drugs, each having an effect size that may be less than the minimum clinically important difference.A definitive long-duration trial in mild AD is needed to establish whether starting memantine earlier would be beneficial over the long term and safe: at present the evidence is against this, despite it being common practice. A long-duration trial in moderate-to-severe AD is needed to establish whether the benefit persists beyond six months.

Systematic review of fit note use for workers in the UK.

OBJECTIVES: The fit note, introduced in England, Wales and Scotland in 2010, was designed to change radically the sickness certification process from advising individuals on their inability to work to advising them on what they could do if work could be adapted. Our review aimed to evaluate the following: (1) Is the 'maybe fit' for work option being selected for patients? (2) Are work solutions being recommended? (3) Has the fit note increased return to work? (4) Has the fit note reduced the length of sickness absence? We considered the way in which outcomes vary according to patient demographics including type of health problem. METHODS: Studies were identified by a systematic search. We included all studies of any design conducted in the UK with working age adults, aged 16 or over, from 1 April 2010 to 1 Nov 2017. Risk of bias was assessed using a modified Newcastle-Ottawa Scale. RESULTS: Thirteen papers representing seven studies met inclusion criteria. In the largest study, 'maybe fit' for work was recommended in 6.5% of fit notes delivered by general practitioners (GP; n=361 801) between April 2016 and March 2017. 'Maybe fit' recommendations were made in 8.5%-10% of fit notes received by primary care patients in employment, and in 10%-32% of patients seen by GPs trained in the Diploma in Occupational Medicine. 'Maybe fit' was recommended more for women, those with higher socioeconomic status, and for physical, as opposed to psychiatric disorders. The majority of fit notes with the 'maybe fit' option selected included work solutions. There was inconclusive evidence to suggest that the introduction of the fit note has reduced sickness absence among patients in employment. CONCLUSIONS: Fit notes represent a major shift in public policy. Our review suggests that they have been incompletely researched and not implemented as intended.

Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register.

BACKGROUND: Mortality associated with chronic fatigue syndrome is uncertain. We investigated mortality in individuals diagnosed with chronic fatigue syndrome in secondary and tertiary care using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) register. METHODS: We calculated standardised mortality ratios (SMRs) for all-cause, suicide-specific, and cancer-specific mortality for a 7-year observation period using the number of deaths observed in SLaM records compared with age-specific and sex-specific mortality statistics for England and Wales. Study participants were included if they had had contact with the chronic fatigue service (referral, discharge, or case note entry) and received a diagnosis of chronic fatigue syndrome. FINDINGS: We identified 2147 cases of chronic fatigue syndrome from CRIS and 17 deaths from Jan 1, 2007, to Dec 31, 2013. 1533 patients were women of whom 11 died, and 614 were men of whom six died. There was no significant difference in age-standardised and sex-standardised mortality ratios (SMRs) for all-cause mortality (SMR 1·14, 95% CI 0·65-1·85; p=0·67) or cancer-specific mortality (1·39, 0·60-2·73; p=0·45) in patients with chronic fatigue syndrome when compared with the general population in England and Wales. This remained the case when deaths from suicide were removed from the analysis. There was a significant increase in suicide-specific mortality (SMR 6·85, 95% CI 2·22-15·98; p=0·002). INTERPRETATION: We did not note increased all-cause mortality in people with chronic fatigue syndrome, but our findings show a substantial increase in mortality from suicide. This highlights the need for clinicians to be aware of the increased risk of completed suicide and to assess suicidality adequately in patients with chronic fatigue syndrome. FUNDING: National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London.

Paracetamol: not as safe as we thought? A systematic literature review of observational studies.

OBJECTIVES: We conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol. METHODS: We searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome. RESULTS: Of 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose-response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose-response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose-response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose-response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43). DISCUSSION: Given the observational nature of the data, channelling bias may have had an important impact. However, the dose-response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.

Does the advent of depot therapy represent a step change in our understanding of opioid use disorder and its treatment?

After years of minimal innovation in pharmacotherapeutics, impressive outcomes in the treatment of opioid use disorder are being obtained from a new way of delivering an old medication; long-acting injectable formulations of buprenorphine appear to produce compelling reductions in relapse to illicit opioid use not only during use but also following depot discontinuation. This commentary discusses potential mechanisms behind this observation, asks if the removal of the need for daily oral opioid agonist dosing furthers our understanding of addiction treatment and whether we should therefore consider expanding access to depot formulations.

The Pharmacological Management of Ketamine Use Disorder: A Systematic Review.

OBJECTIVES: There has been limited evidence synthesis examining treatment of ketamine use disorder. We aimed to conduct a systematic review to assess the efficacy and tolerability of pharmacological interventions in the management of ketamine use disorder. METHODS: We searched MEDLINE, EMBASE, PsychINFO, and CENTRAL (Cochrane Central Register of Controlled Trials) from database inception to November 14, 2023, for studies of any design that reported on any pharmacological intervention in the management of ketamine use disorder. We extracted any reported measure of efficacy or tolerability and assessed outcome quality using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. We planned to combine outcomes using random-effects meta-analysis, where this was not possible results were reported narratively. RESULTS: Twelve studies met the inclusion criteria reporting on 368 participants. These comprised 1 controlled trial, 2 retrospective case series, and 9 case reports. Two studies reported on ketamine intoxication, 6 on withdrawal, and 4 on craving/relapse prevention. All studies reported only descriptive outcomes, and all evidence was of very low quality. Benzodiazepine regimens and haloperidol were reported to have potential utility in intoxication and withdrawal, whereas naltrexone, lamotrigine, and a combination of paliperidone palmitate and bupropion were reported to have potential utility in craving/relapse prevention. CONCLUSIONS: There is a paucity of research into pharmacological management of ketamine use disorder. The limited very low-quality evidence suggests benzodiazepine regimens may be most salient for future exploration in management of ketamine intoxication and withdrawal, whereas case reports suggest naltrexone, lamotrigine, and paliperidone palmitate plus bupropion may potentially merit further investigation with regard to craving/relapse prevention.

The development and internal validation of a multivariable model predicting 6-month mortality for people with opioid use disorder presenting to community drug services in England: a protocol.

BACKGROUND: People with opioid use disorder have substantially higher standardised mortality rates compared to the general population; however, lack of clear individual prognostic information presents challenges to prioritise or target interventions within drug treatment services. Previous prognostic models have been developed to estimate the risk of developing opioid use disorder and opioid-related overdose in people routinely prescribed opioids but, to our knowledge, none have been developed to estimate mortality risk in people accessing drug services with opioid use disorder. Initial presentation to drug services is a pragmatic time to evaluate mortality risk given the contemporaneous routine collection of prognostic indicators and as a decision point for appropriate service prioritisation and targeted intervention delivery. This study aims to develop and internally validate a model to estimate 6-month mortality risk for people with opioid use disorder from prognostic indicators recorded at initial assessment in drug services in England. METHODS: An English national dataset containing records from individuals presenting to drug services between 1 April 2013 and 1 April 2023 (n > 800,000) (the National Drug Treatment Monitoring System (NDTMS)) linked to their lifetime hospitalisation and death records (Hospital Episode Statistics-Office of National Statistics (HES-ONS)). Twelve candidate prognostic indicator variables were identified based on literature review of demographic and clinical features associated with increased mortality for people in treatment for opioid use disorder. Variables will be extracted at initial presentation to drug services with mortality measured at 6 months. Two multivariable Cox regression models will be developed one for 6-month all-cause mortality and one for 6-month drug-related mortality using backward elimination with a fractional polynomial approach for continuous variables. Internal validation will be undertaken using bootstrapping methods. Discrimination of both models will be reported using Harrel's c and d-statistics. Calibration curves and slopes will be presented comparing expected and observed event rates. DISCUSSION: The models developed and internally validated in this study aim to improve clinical assessment of mortality risk for people with opioid use disorder presenting to drug services in England. External validation in different populations will be required to develop the model into a tool to assist future clinical decision-making.

"Safe Supply" Initiatives: Are They a Recipe for Harm Through Reduced Health Care Input and Supply-Induced Toxicity and Overdose?

Within the addiction field, some advocates support a suite of de-regulatory policies that aim to reduce harm by providing people who use drugs with a "safe supply" of pharmaceutical-grade medications. Such initiatives have commenced without the evidence standards normally used to label medication provision as "safe." This perspective suggests that continued debate and research in this area acknowledge the potential toxicity of any provided safe supply medications and highlights that these initiatives could result in an unhelpful reduction in interactions between people who use drugs and health care professionals.

Pattern and prevalence of vaping nicotine and non-nicotine drugs in the United Kingdom: a cross-sectional study.

OBJECTIVES: Electronic vaping devices are being used to consume nicotine and non-nicotine psychoactive drugs. We aimed to determine the pattern and prevalence of using vaping devices for nicotine and/or non-nicotine drug administration in the United Kingdom and how these differ by drug type and individual sociodemographic characteristics. We explored reasons for vaping onset and continuation. DESIGN: An online cross-sectional survey PARTICIPANTS: A convenience sample of adults (aged ≥18 years) in the UK. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was prevalence of current use (within the last 30 days) of a vaping device to administer either nicotine or 18 types of non-nicotine drugs. We additionally evaluated reasons for onset and continuation of vaping. Sociodemographic characteristics were compared between the UK general population using census data and those vaping non-nicotine drugs. RESULTS: We recruited 4027 participants of whom 1637 (40.7%) had ever used an electronic vaping device; 1495 (37.1%) had ever vaped nicotine and 593 (14.7%) had ever vaped a non-nicotine drug. Overall, 574 (14.3%) currently vaped nicotine and 74 (1.8%) currently vaped a non-nicotine drug. The most common currently vaped non-nicotine drug was cannabis (n=58, 1.4%). For nicotine, people's modal reasons to start and continue vaping was to quit smoking tobacco. For almost all other drugs, people's modal reason to start vaping was curiosity and to continue was enjoyment. Compared with the general population, the population who had ever vaped a non-nicotine drug were significantly younger, had more disabilities and fewer identified as white, female, heterosexual or religious. CONCLUSIONS: A non-trivial number of people report current use and ever use of an electronic vaping device for non-nicotine drug administration. As vaping technology advances and drug consumption changes, understanding patterns of use and associated behaviours are likely to be increasingly important to both users and healthcare professionals.

The efficacy and tolerability of pharmacologically active interventions for alcohol-induced hangover symptomatology: a systematic review of the evidence from randomised placebo-controlled trials.

AIMS: To compare quantitatively the efficacy and tolerability of pharmacologically active interventions in the treatment and prevention of alcohol-induced hangover. METHODS: Systematic review of placebo-controlled randomised trials in healthy adults that evaluated any pharmacologically active intervention in the treatment or prevention of hangover. We searched Medline, Embase, PsycINFO and CENTRAL from database inception until 1 August 2021. The primary efficacy outcome was any continuous measure of overall hangover symptoms and the primary tolerability outcome the number of people dropping out because of adverse events (AEs). Quality was assessed using the Grading of Recommendations Assessment Development and Evaluation (GRADE) framework. RESULTS: A total of 21 studies were included reporting on 386 participants. No two studies reported on the same intervention; as such, meta-analysis could not be undertaken. Methodological concerns and imprecision resulted in all studied efficacy outcomes being rated as very low quality. When compared with placebo, individual studies reported a statistically significant reduction in the mean percentage overall hangover symptom score for clove extract (42.5% vs 19.0%, P < 0.001), tolfenamic acid (84.0% vs 50.0%, P < 0.001), pyritinol (34.1% vs 16.2%, P < 0.01), Hovenia dulcis fruit extract (P = 0.029), L-cysteine (P = 0.043), red ginseng (21.1% vs 14.0%, P < 0.05) and Korean pear juice (41.5% vs 33.3%, P < 0.05). All studied tolerability outcomes were of low or very low quality with no studies reporting any drop-outs because of AEs. CONCLUSIONS: Only very low quality evidence of efficacy is available to recommend any pharmacologically active intervention for the treatment or prevention of alcohol-induced hangover. Of the limited interventions studied, all had favourable tolerability profiles and very low quality evidence suggests clove extract, tolfenamic acid and pyritinol may most warrant further study.

The effectiveness and tolerability of anti-seizure medication in alcohol withdrawal syndrome: a systematic review, meta-analysis and GRADE of the evidence.

BACKGROUND AND AIMS: Anti-seizure medications (ASMs) have been used historically as treatment options in alcohol withdrawal syndrome (AWS). In the past 10 years, there have been no large-scale meta-analyses comparing ASMs with placebo or the current AWS treatment standard, benzodiazepines. We aimed to evaluate the efficacy and tolerability of ASMs in AWS. METHODS: Systematic review and meta-analysis of randomised controlled trials (RCTs) via searching Medline, Embase and PsychINFO from database inception to March 2020 involving adults age >18 years with AWS. We included 24 RCTs reporting on a total of 2223 participants. Efficacy outcomes included the number of participants experiencing AWS related seizures or delirium, Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) score reduction and rescue medication requirements. Tolerability outcomes included adverse event rate and dropout because of adverse events, alongside severe and life-threatening adverse event rates. Quality was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: There was no evidence of significant improvements in any efficacy outcomes when comparing ASMs with placebo or benzodiazepines. When compared with benzodiazepines, ASMs demonstrated significantly increased odds of requiring rescue medications (OR = 3.50, 95% CI = 1.32, 9.28; P = 0.012). When comparing ASMs with placebo, there were significantly more dropouts because of adverse events (OR = 1.86, 95% CI = 1.05, 3.28; P = 0.034). Most results were of very low quality with the majority of included studies conducted before 2000. CONCLUSIONS: This systematic review and meta-analysis found no evidence to support general first line clinical use of anti-seizure medications in alcohol withdrawal syndrome treatment.