The Hypothesis of Subliminal Cue Reactivity in Addiction Revisited: An fMRI Study

<b><i>Introduction:</i></b> Exposure to conditioned cues is a common trigger of relapse in addiction. It has been suggested that such cues can activate motivationally relevant neurocircuitry in individuals with substance use disorders even without being consciously perceived. We aimed to see if this could be replicated in a sample with severe amphetamine use disorder and a control group of healthy subjects. <b><i>Methods:</i></b> We used fMRI to test the hypothesis that individuals with amphetamine use disorder, but not healthy controls, exhibit a specific neural reactivity to subliminally presented pictures related to amphetamine use. Twenty-four amphetamine users and 25 healthy controls were recruited and left data of sufficient quality to be included in the final analysis. All subjects were exposed to drug-related and neutral pictures of short duration (13.3 ms), followed by a backward visual mask image. The contrast of interest was drug versus neutral subliminal pictures. <b><i>Results:</i></b> There were no statistically significant differences in BOLD signal between the drug and neutral cues, neither in the limbic regions of primary interest nor in exploratory whole-brain analyses. The same results were found both in amphetamine users and controls. <b><i>Discussion/Conclusion:</i></b> We found no evidence of neural reactivity to subliminally presented drug cues in this sample of subjects with severe amphetamine dependence. These results are discussed in relation to the earlier literature, and the evidence for subliminal drug cue reactivity in substance use disorders is questioned.

Take-Home Naloxone and the Prevention of Deaths from Heroin Overdose: Pursuing Strong Science, Fuller Understanding, Greater Impact

<b><i>Background and Context:</i></b> Realization of the life-saving potential of “take-home naloxone” has been a personal journey, but it has also been a collective journey. It has been a story of individual exploration and growth, and also a story of changes at a societal level. “Take-home naloxone” has matured since its first conceptualization a quarter of a century ago. It required recognition of the enormous burden of deaths from drug overdose (particularly heroin and other opioids), and also realization of critical clusterings (such as post-release from prison). It also required realization that, since many overdose deaths are witnessed, we can potentially prevent many deaths by mobilizing drug users themselves, their families, and the wider caring community to act as intervention workforce to give life-saving interim emergency care. <b><i>Summary of Scope:</i></b> This article explores 5 areas (many illustrations UK-based where the author works): firstly, the need for strong science; secondly, our improved understanding of opioid overdose and deaths; thirdly, the search for greater impact from our policies and interventions; fourthly, developing better forms of naloxone; and fifthly, examining the challenges still to be addressed. <b><i>Key Messages:</i></b> “Take-home naloxone” is an exemplar of harm reduction with potential global impact – drug policy and practice for the public good. However, “having the potential” is not good enough – there needs to be actual implementation. This will be easier once the component parts of “take-home naloxone” are improved (better naloxone products, better training aids, revised legislation, and explicit funding support). Many improvements are already possible, but we hesitate about implementation. It is our responsibility to drive progress faster. With “take-home naloxone,” we can be proud of what we have achieved, but we must also be humble about how much more we still need to do.

Effectiveness and Safety of Low-Threshold Opioid-Agonist Treatment in Hard-To-Reach Populations with Opioid Dependence

<b><i>Objectives:</i></b> Opioid-use disorder is related to premature death worldwide. Opioid-agonist treatment (OAT) is an effective treatment for opioid dependence. OAT delivery platforms may influence treatment access and outcomes, especially for the most vulnerable groups. The aim of this study was to determine the effectiveness and safety of low-threshold OAT compared to the standard treatment. <b><i>Methods:</i></b> Patients with diagnosed opioid dependence undergoing low-threshold OAT at the Bergen delivery platform in Norway were enrolled in a cohort study in 2014–2019. A national OAT cohort was the reference group. The main outcomes were treatment retention, the use of illicit opioids, non-fatal overdose, overdose death, and all-cause mortality during the first year following treatment initiation and the full treatment period. Additionally, healthcare utilization in the periods before and during OAT was investigated. <b><i>Results:</i></b> Compared to the reference cohort, the low-threshold cohort (<i>n</i> = 128, mean age: 38 years, women: 28%) showed treatment retention rates of 95% versus 92%, illicit opioid use of 7% versus 10%, non-fatal overdose of 7% versus 6%, and death at 1.0% versus 1.3%, respectively. The incident rate ratios (IRRs) for healthcare utilization increased substantially during the OAT period compared to the period before; the IRR increased by 3.3 (95% confidence interval (CI): 2.8, 3.9) and 3.4 (95% CI: 3.1, 3.9) for all in- and outpatient healthcare, respectively. <b><i>Conclusions:</i></b> Low-threshold OAT was at least as effective and safe as the standard OAT in terms of treatment retention, the use of illicit opioids, non-fatal overdose, and death. Healthcare utilization increased during the OAT compared to the period before. Lowering the threshold for OAT entrance within proper delivery platforms should be broadly considered to reduce harm and improve healthcare access among patients with opioid dependence.

High Prevalence and Early Onsets: Legal and Illegal Substance Use in an Urban Cohort of Young Adults in Switzerland

<b><i>Introduction:</i></b> Debates about the legalization of illegal substances (e.g., cannabis) continue around the globe. A key consideration in these debates is the adequate protection of young people, which could be informed by current prevalence and age-of-onset patterns. For Switzerland, such information is limited, which is particularly true for women, despite advanced political efforts to legalize cannabis. The objective of the current study was to investigate substance use prevalence rates and ages of onset in a community-representative sample of female and male young adults in Switzerland. <b><i>Methods:</i></b> Data came from the Zurich Project on the Social Development from Childhood to Adulthood (z-proso). In 2018, participants (<i>N</i> = 1,180, 50.8% females) were ∼20 years old. Lifetime and past-year use of alcohol, tobacco, cannabinoids, stimulants, hallucinogens, opioids, and benzodiazepines were assessed with an extensive substance use questionnaire. Additionally, ages of onsets of the respective substances were estimated by averaging participants’ self-reported ages of onsets from ages 13 to 20 (max. 4 assessments). <b><i>Results:</i></b> 57% of 20-year-olds had used cannabinoids, 16% stimulants, 15% opioids (mostly codeine), and 8% hallucinogens in the past year. Males had higher prevalence than females for most drugs; nevertheless, females’ prevalence rates were notably high. Legal substance use was typically initiated 1.3–2.7 years before legal selling age. Thus, almost half of the sample had consumed alcohol and tobacco by age 14. More than 40% of the total sample had smoked cannabis by age 16. Males initiated use of legal substances and cannabis earlier than females. <b><i>Discussion:</i></b> Our recent community-representative data suggested unexpectedly high levels and early onsets of substance use compared to a previous Swiss surveys and also the European average. Drug policy debates should consider urban substance use patterns when considering legalization efforts.

Interactions between Genetic, Prenatal, Cortisol, and Parenting Influences on Adolescent Substance Use and Frequency: A TRAILS Study

<b><i>Introduction:</i></b> Dynamic relations between genetic, hormone, and pre- and postnatal environments are theorized as critically important for adolescent substance use but are rarely tested in multifactorial models. This study assessed the impact of interactions of genetic risk and cortisol reactivity with prenatal and parenting influences on both any and frequency of adolescent substance use. <b><i>Methods:</i></b> Data are from the TRacking Adolescents’ Individual Lives Survey (TRAILS), a prospective longitudinal, multi-rater study of 2,230 Dutch adolescents. Genetic risk was assessed via 3 substance-specific polygenic scores. Mothers retrospectively reported prenatal risk when adolescents were 11 years old. Adolescents rated their parents’ warmth and hostility at age 11. Salivary cortisol reactivity was measured in response to a social stress task at age 16. Adolescents’ self-reported cigarette, alcohol, and cannabis use frequency at age 16. <b><i>Results:</i></b> A multivariate hurdle regression model showed that polygenic risk for smoking, alcohol, and cannabis predicted any use of each substance, respectively, but predicted more frequent use only for smoking. Blunted cortisol reactivity predicted any use and more frequent use for all 3 outcomes. There were 2 interactions: blunted cortisol reactivity exacerbated the association of polygenic risk with any smoking and the association of prenatal risk with any alcohol use. <b><i>Conclusion:</i></b> Polygenic risk seems of importance for early use but less so for frequency of use, whereas blunted cortisol reactivity was correlated with both. Blunted cortisol reactivity may also catalyze early risks for substance use, though to a limited degree. Gene-environment interactions play no role in the context of this multifactorial model.

Drug Use Changes at the Individual Level: Results from a Longitudinal, Multisite Survey in Young Europeans Frequenting the Nightlife Scene

<b><i>Background:</i></b> Monitoring emerging trends in the increasingly dynamic European drug market is vital; however, information on change at the individual level is scarce. In the current study, we investigated changes in drug use over 12 months in European nightlife attendees. <b><i>Method:</i></b> In this longitudinal online survey, changes in substances used, use frequency in continued users, and relative initiation of use at follow-up were assessed for 20 different substances. To take part, participants had to be aged 18–34 years; be from Belgium, Italy, the Netherlands, Sweden, or the UK; and have attended at least 6 electronic music events in the past 12 months at baseline. Of 8,045 volunteers at baseline, 2,897 completed the survey at both time points (36% follow-up rate), in 2017 and 2018. <b><i>Results:</i></b> The number of people using ketamine increased by 21% (<i>p</i> &#x3c; 0.001), and logarithmized frequency of use in those continuing use increased by 15% (<i>p</i> &#x3c; 0.001; 95% CI: 0.07–0.23). 4-Fluoroamphetamine use decreased by 27% (<i>p</i> &#x3c; 0.001), and logarithmized frequency of use in continuing users decreased by 15% (<i>p</i> &#x3c; 0.001, 95% CI: −0.48 to −0.23). The drugs with the greatest proportion of relative initiation at follow-up were synthetic cannabinoids (73%, <i>N</i> = 30), mephedrone (44%, <i>N</i> = 18), alkyl nitrites (42%, <i>N</i> = 147), synthetic dissociatives (41%, <i>N</i> = 15), and prescription opioids (40%, <i>N</i> = 48). <b><i>Conclusions:</i></b> In this European nightlife sample, ketamine was found to have the biggest increase in the past 12 months, which occurred alongside an increase in frequency of use in continuing users. The patterns of uptake and discontinuation of alkyl nitrates, novel psychoactive substances, and prescription opioids provide new information that has not been captured by existing cross-sectional surveys. These findings demonstrate the importance of longitudinal assessments of drug use and highlight the dynamic nature of the European drug landscape.

A 6-Month Randomized Trial of a Smartphone Application, UControlDrink, in Aiding Recovery in Alcohol Use Disorder

<b><i>Background and Aims:</i></b> Alcohol use disorder (AUD) is a substantial problem, causing early death and great economic burden. Research has highlighted the potential positive impact of technological interventions, such as smartphone applications (app) in treatment of AUD. The aim of this study was to explore the effectiveness of a smartphone app, incorporating computerized cognitive behavioural therapy and text messaging support, on alcohol outcomes over 6 months in a post-rehabilitation setting. <b><i>Methods:</i></b> A total of 111 participants with AUD were recruited into this randomized controlled trial, following completion of a 30-day rehabilitation programme. The intervention group (<i>n</i> = 54) used the smartphone app “UControlDrink” (UCD) over 6 months with treatment as usual (TAU), and the control group (<i>n</i> = 57) received TAU. All subjects suffered from AUD as the primary disorder, with other major psychiatric disorders excluded. All intervention subjects used the UCD smartphone app in the treatment trial, and all subjects underwent TAU consisting of outpatient weekly support groups. Drinking history in the previous 90 days was measured at baseline and at 3- and 6-month follow-ups. Additional measurements were made to assess mood, anxiety, craving, and motivation. Results were analysed using intention-to-treat analyses. <b><i>Results:</i></b> Retention in the study was 72% at 3 months and 52% at 6 months. There was a significant reduction in heavy drinking days in the intervention group relative to TAU over the 6 months, <i>p</i> &#x3c; 0.02. <b><i>Conclusions:</i></b> The UCD smartphone app demonstrates a significant benefit to reducing heavy drinking days over a 6-month post-rehabilitation period in AUD.

Indicators of Drug-Related Community Impacts of Open Drug Scenes: A Scoping Review

<b><i>Introduction:</i></b> Places where people deal and/or use drugs publicly are known as open drug scenes (ODSs). Drug-related community impacts (DRCIs) refer to drug-related issues that negatively influence public and individual health, communities, businesses, and recreational and public space enjoyment. There are no well-established criteria for identification of DRCIs. We therefore performed a scoping review of literature to determine DRCIs indicators associated with ODSs. <b><i>Methods:</i></b> The review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for scoping reviews (PRISMA-ScP). We searched English articles in PubMed, Scopus, Web of Science, and EMBASE databases from 1990 to 2021. The keywords were drug-related crime, drug-related offense, misconduct, social marginalization, homeless drug users, open drug scene, drug-related street disorder, public nuisance, and community impact. <b><i>Results:</i></b> Sixty-four studies were identified. Twenty-five studies were included. Two studies (8%) were about drug-related public nuisance, 1 (4%) considered drug-related social problems, 2 (8%) focused on drug-related social disorder, and 18 studies (72%) discussed indicators of community impacts such as crime, drug-related litter, safety, noise, and drug use in public. Two studies (8%) included the frequency of drug use in ODSs. <b><i>Discussion:</i></b> DRCI indicators are heterogenic, and various factors affect the indicators. The factors include social mores, political discourse, and historical approaches to dealing with and using drugs. Some societies do not tolerate the existence of ODSs. In contrast, many countries have adopted harm reduction programs to manage DRCIs. Identified DRCI indicators were drug using and dealing in public, drug-related litter, crime, drug-related loitering, street-based income generation activities, noise, and unsafety feelings in inhabitants. To solve the problems associated with DRCIs and to make a major change in ODSs, it is necessary to pay attention to the improvement of the economic conditions (e.g., employment opportunities), amendment (e.g., determine the limits of criminalization in drug use), and adoption of social policies (e.g., providing low-threshold and supportive services for homeless drug users).

Amphetamine-Type Stimulant Dependence and Association with Concurrent Use of Cocaine, Alcohol, and Cannabis: A Cross-Sectional Study

<b><i>Introduction:</i></b> Amphetamine-type stimulants (ATSs) are the second most commonly used class of illegal substances in Europe. Although concurrent substance use has been subject to research, little is known about associations between concurrent use of cocaine, alcohol, or cannabis and ATS dependence. We expect that the concurrent use of any of the substance, especially cannabis and cocaine, is associated with ATS dependence. <b><i>Methods:</i></b> Cross-sectional data were gathered within the European ATTUNE study in 2018/2019. Participants (<i>N</i> = 721) were asked about their consumption patterns and social, psychological, and economic situation. Multivariate logistic regressions were carried out for associations between ATS dependence and use combinations of frequent cocaine, alcohol, or cannabis, with the reference group of no frequent concurrent use (model 1). Model 2 calculated associations for ATS dependence with lifetime methamphetamine use for respective use combinations. <b><i>Results:</i></b> The study population was on average 28.9 years old (SD = 7.7), with the majority being male (63.5%). In model 1, the adjusted odds ratio (aOR) for frequent alcohol use was 0.70 (confidence interval [CI] 0.41–1.20). Similar results were shown for model 2 (aOR 0.82, CI 0.42–1.62). Frequent cannabis use significantly reduced the chance for ATS dependence by 50% in adjusted model 1 (aOR 0.50, CI 0.28–0.89) and by 62% in model 2 (aOR 0.38, CI 0.18–0.82). For frequent cocaine use, models 1 and 2 report an aOR at 1.37 (CI 0.58–3.25) and 2.39 (CI 0.77–7.43), although not statistically significant. Frequent users of all 3 substances had a significant 3-fold chance for ATS dependence (model 1: aOR 2.98, CI 1.16–7.63; model 2: aOR 2.95, CI 1.02–8.58). <b><i>Discussion:</i></b> Against initial hypotheses, frequent concurrent use of alcohol or cannabis generally decreased chances for ATS dependence. An explanation could be the study population, which consists of many irregular users of ATS, who mainly consume alcohol or cannabis. Cocaine generally increased chances, although results were not significant. The frequent use of all 3 substances together with ATS in the last year was significantly associated with dependence, thus reporting important information for treatment services. Further research is needed for disentangling causal relationships underlying these associations and for pinpointing consequences for relapse prevention and retention success.

Perception of a New Prolonged-Release Buprenorphine Formulation in Patients with Opioid Use Disorder: The PREDEPO Study

<b><i>Aim:</i></b> The aim of the study was to assess the acceptance of patients with opioid use disorder (OUD) to switching their opioid dependence treatment (ODT) for a prolonged-release buprenorphine (PRB) injection according to their prior ODT (buprenorphine/naloxone [B/N] or methadone). <b><i>Methods:</i></b> This was an observational, retrospective/cross-sectional, multicentre study of adult patients diagnosed with OUD on ODT. Data collected from diaries were analysed to know their interest and opinion on PRB. Questions with fixed response options were included, and several Likert scales were used. <b><i>Results:</i></b> A total of 98 patients were enrolled (B/N: 50.0%, methadone: 50.0%). The mean age was 46.9 ± 8.43 years and 79.6% were males. PRB was similarly perceived by both groups in most variables analysed, receiving a mean score of 7.2/10 (B/N: 7.4, methadone: 7.0; <i>p</i> = 0.520), and approximately 65% of patients said they were willing to switch to PRB (B/N: 63.3%, methadone: 65.3%; <i>p</i> = 0.833). Of these, a higher percentage in the B/N group considered that switching would be easy/very easy (B/N: 90.3%, methadone: 46.9%; <i>p</i> &#x3c; 0.001) and that they would start PRB when available (B/N: 64.5%, methadone: 34.3%; <i>p</i> = 0.005). More than 90% would prefer the monthly injection (B/N: 93.6%, methadone: 100%; <i>p</i> = 0.514). One-third of patients in both groups were unsure/would not switch their ODT to PRB (B/N: 36.7%, methadone: 34.7%; <i>p</i> = 0.833). The main reason was administration by injection. <b><i>Conclusion:</i></b> Two-thirds of patients would switch their treatment for PRB, and most patients on B/N considered that switching would be easy. PRB could be a suitable alternative for OUD management.