Absence of Evidence for Sustained Effects of Daily Cannabidiol Administration on Anandamide Plasma Concentration in Individuals with Cocaine Use Disorder: Exploratory Findings from a Randomized Controlled Trial.

Background: Cannabidiol (CBD) has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders, including substance use disorders. Pre-clinical evidence suggests that CBD can increase anandamide (AEA) plasma concentration, possibly mediating some of its therapeutic properties. Whether CBD exerts such an effect on AEA in individuals with cocaine use disorder (CUD) remains unknown. Aims: To explore the sustained effects of daily CBD administration on AEA plasma concentrations compared with placebo in CUD. Methods: We used data from a randomized, double-blind, placebo-controlled trial evaluating CBD's efficacy in CUD. Seventy-eight individuals were randomized to receive a daily oral dose of 800 mg CBD (n = 40) or a placebo (n = 38). Participants stayed in an inpatient detoxification setting for 10 days, after which they were followed in an outpatient setting for 12 weeks. AEA plasma concentration was measured at baseline and at 23-h post CBD ingestion on day 8 and week 4. A generalized estimating equation model was used to assess CBD's effects on AEA, and sensitivity analyses were computed using Bayesian linear regressions. Results: Sixty-four participants were included in the analysis. Similar mean AEA plasma concentrations in both treatment groups (p = 0.357) were observed. At day 8, mean AEA plasma concentrations (± standard deviation) were 0.26 (± 0.07) ng/mL in the CBD group and 0.29 (± 0.08) ng/mL in the placebo group (p = 0.832; Bayes factor [BF] = 0.190). At week 4, they were 0.27 (± 0.09) ng/mL in the CBD group and 0.30 (± 0.09) ng/mL in the placebo group (p = 0.181; BF = 0.194). Conclusion: While not excluding any potential acute and short-term effect, daily CBD administration did not exert a sustained impact on AEA plasma concentrations in individuals with CUD compared with placebo. Registration: clinicaltrials.gov (NCT02559167).

Associations of Methadone and BUP/NX Dose Titration Patterns With Retention in Treatment and Opioid Use in Individuals With Prescription-Type Opioid Use Disorder: Secondary Analysis of the OPTIMA Study.

INTRODUCTION: Methadone and buprenorphine/naloxone (BUP/NX) titration parameters (eg, range, duration, and rate) can vary during opioid use disorder (OUD) treatment. We describe methadone and BUP/NX titration patterns and their associations with treatment outcomes among individuals with a prescription-type OUD. METHODS: We used data from a 24-week open-label, multicenter randomized controlled trial, including N = 167 participants aged 18-64 years old with prescription-type OUD who received at least a first dose of treatment. Descriptive analyses of methadone and BUP/NX titration patterns were conducted, that is, range and duration from first to maximum dose, and rate (range/duration ratio). Outcomes included percentage of opioid-positive urine drug screens (UDS) and treatment retention. Adjusted linear and logistic regressions were used to study associations between titration patterns and percentage of opioid-positive UDS and treatment retention. RESULTS: Methadone doses were increased by a mean dose range of 42.4 mg over a mean duration of 42.2 days. BUP/NX doses were increased by a mean dose range of 8.4 mg over a mean duration of 28.7 days. Only methadone dose titration range (odds ratio: 1.03; 95% CI, 1.01 to 1.05) and duration (odds ratio: 1.03; 95% CI, 1.01 to 1.05) were associated with higher retention. Only methadone dose titration rate was associated with lower percentage of opioid-positive UDS at weeks 12-24 ( B : -2.77; 95% CI, -4.72 to -0.81). CONCLUSIONS: Specific parameters of methadone titration were associated with treatment outcomes and may help in personalizing treatment schedules. Sustained methadone dose titration, when indicated, may help increase retention, whereas faster dose titration for methadone may help decrease opioid use.

Prescription psychostimulants for the treatment of amphetamine-type stimulant use disorder: A systematic review and meta-analysis of randomized placebo-controlled trials.

BACKGROUND AND AIMS: There is currently no standard of care for pharmacological treatment of amphetamine-type stimulant (ATS) use disorder (ATSUD). This systematic review with meta-analysis (PROSPERO CRD42022354492) aimed to pool results from randomized placebo-controlled trials (RCTs) to evaluate efficacy and safety of prescription psychostimulants (PPs) for ATSUD. METHODS: Major indexing sources and trial registries were searched to include records published before 29 August 2022. Eligible studies were RCTs evaluating efficacy and safety of PPs for ATSUD. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. Risk ratio (RR) and risk difference were calculated for random-effect meta-analysis of dichotomous variables. Mean difference and standardized mean difference (SMD) were calculated for random-effect meta-analysis of continuous variables. RESULTS: Ten RCTs (n = 561 participants) were included in the meta-analysis. Trials studied methylphenidate (n = 7), with daily doses of 54-180 mg, and dextroamphetamine (n = 3), with daily doses of 60-110 mg, for 2-24 weeks. PPs significantly decreased end-point craving [SMD  -0.29; 95% confidence interval (CI) = -0.55, -0.03], while such a decrease did not reach statistical significance for ATS use, as evaluated by urine analysis (UA) (RR = 0.93; 95% CI = 0.85-1.01). No effect was observed for self-reported ATS use, retention in treatment, dropout following adverse events, early-stage craving, withdrawal and depressive symptoms. In a sensitivity analysis, treatment was associated with a significant reduction in UA positive for ATS (RR = 0.89; 95% CI = 0.79-0.99) after removing studies with a high risk of bias. In subgroup analyses, methylphenidate and high doses of PPs were negatively associated with ATS use by UA, while higher doses of PPs and treatment duration (≥ 20 weeks) were positively associated with longer retention. CONCLUSIONS: Among individuals with amphetamine-type stimulant use disorder, treatment with prescription psychostimulants may decrease ATS use and craving. While effect size is limited, it may increase with a higher dosage of medications.

Associations Between Buprenorphine\Naloxone and Methadone Treatment and non-Opioid Substance Use in Prescription-Type Opioid Use Disorder: Secondary Analyses From the OPTIMA Study: Associations entre le traitement avec la buprénorphine/naloxone et avec la méthadone et l'utilisation de substances non opioïdes dans le trouble lié à l'usage d'opioïdes de type sur ordonnance : analyses secondaires de l'étude OPTIMA.

OBJECTIVES: There is limited evidence on how opioid agonist treatment (OAT) may affect psychoactive non-opioid substance use in prescription-type opioid use disorder (POUD) and whether this effect might explain OAT outcomes. We aimed to assess the effect of methadone on non-opioid substance use compared to buprenorphine/naloxone (BUP/NX), to explore whether non-opioid substance use is associated with opioid use and retention in treatment, and to test non-opioid use as a moderator of associations between methadone with retention in OAT and opioid use compared to BUP/NX. METHODS: This is a secondary analysis of data from the OPTIMA trial, an open-label, pragmatic, parallel, two-arm, pan-Canadian, multicentre, randomized-controlled trial to compare standard methadone model of care and flexible take-home dosing BUP/NX for POUD treatment. We studied the effect of methadone and BUP/NX on non-opioid substance use evaluated by urine drug screen (UDS) and by classes of non-opioid substances (i.e., tetrahydrocannabinol [THC], benzodiazepines, stimulants) (weeks 2-24) using adjusted generalized estimation equation (GEE). We studied the association between non-opioid substance-positive UDS and opioid-positive UDS and retention in treatment, using adjusted GEE and logistic regressions. RESULTS: Overall, methadone was not associated with non-opioid substance-positive UDS compared to BUP/NX (OR: 0.78; 95%CI, 0.41 to 1.48). When non-opioid substances were studied separately, methadone was associated with lower odds of benzodiazepine-positive UDS (OR: 0.63; 95% CI: 0.40 to 0.98) and THC-positive UDS (OR: 0.47; 95% CI: 0.28 to 0.77), but not with different odds of stimulant-positive UDS (OR: 1.29; 95% CI: 0.78 to 2.16) compared to BUP/NX. Substance-positive UDS, overall and separate classes, were not associated with opioid-positive UDS or retention in treatment. CONCLUSION: Methadone did not show a significant effect on overall non-opioid substance use in POUD compared to BUP/NX treatment but was associated with lower odds of benzodiazepine and THC use in particular. Non-opioid substance use did not predict OAT outcomes. Further research is needed to ascertain whether specific patterns of polysubstance use (quantity and frequency) may affect treatment outcomes.

Bupropion for treatment of amphetamine-type stimulant use disorder: A systematic review and meta-analysis of placebo-controlled randomized clinical trials.

BACKGROUND: This meta-analysis (PROSPERO-ID: CRD42022362962), pooled effect estimates of outcomes, from placebo-controlled randomized clinical trials (RCTs) examining bupropion efficacy and safety for amphetamine-type stimulant use disorder (ATSUD) treatment. METHOD: Electronic databases were searched for records published to October 31st, 2022, including MEDLINE, CINAHL, PsycINFO, EBM Reviews, EMBASE, PubMed, Web of Science, trial registries. Inclusion criteria were RCTs comparing bupropion to placebo in ATSUD. Cochrane RoB2 tool and GRADE evidence certainty assessment were employed. Outcomes included amphetamine-type stimulant (ATS) use by urinalysis, retention in treatment, treatment adherence, ATS craving, addiction severity, depressive symptom severity, drop-out following adverse events (AEs), and serious AEs. Random-effect meta-analysis was conducted presenting standardized mean difference (SMD), risk ratio (RR), and risk difference (RD). RESULTS: Eight RCTs (total N=1239 participants) were included. Bupropion compared to placebo was associated with reduced ATS use (RR: 0.90; 95% CI: 0.84, 0.96), end-of-treatment ATS craving (SMD: -0.38; 95%CI: -0.63, -0.13), and adherence (RR: 0.91; 95%CI: 0.84, 0.99). Subgroup analysis showed greater reduction in ATS use with longer trial duration (12 weeks) (RR: 0.85; 95%CI: 0.78, 0.93) and greater reduction in end-of-treatment ATS craving in studies with mixed ATS use frequency (SMD: -0.46; 95%CI: -0.70, -0.22) and male-only samples (SMD: -1.26; 95%CI: -1.87, -0.65). CONCLUSION: Bupropion showed a significant modest reduction in ATS use and ATS craving (both rated as very low-quality evidence), larger in males (craving), and with longer treatment (ATS use). These results may inform future studies. More research is warranted on who might benefit from bupropion as ATSUD treatment.

Associations of methadone and buprenorphine-naloxone doses with unregulated opioid use, treatment retention, and adverse events in prescription-type opioid use disorders: Exploratory analyses of the OPTIMA study.

BACKGROUND AND OBJECTIVES: Buprenorphine/naloxone (BUP-NX) and methadone are used to treat opioid use disorder (OUD), yet there is insufficient evidence on the impact of doses on interventions' effectiveness and safety when treating OUD attributable to other opioids than heroin. METHODS: We explored associations between methadone and BUP-NX doses and treatment outcomes using data from OPTIMA, a 24-week, pragmatic, open-label, multicenter, pan-Canadian, randomized controlled, two-arm parallel trial with participants (N = 272) with OUD who primarily use opioids other than heroin. Participants were randomized to receive flexible take-home BUP-NX (n = 138) or standard supervised methadone treatment (n = 134). We examined associations between highest BUP-NX and methadone doses, and (1) percentage of opioid-positive urine drug screens (UDS); (2) retention in the assigned treatment; and (3) adverse events (AEs). RESULTS: The mean (SD) highest BUP-NX and methadone dose were 17.31 mg/day (8.59) and 67.70 mg/day (34.70). BUP-NX and methadone doses were not associated with opioid-positive UDS percentages or AEs. Methadone dose was associated with higher retention in treatment (odds ratio [OR]: 1.025; 95% confidence interval [CI]: 1.010; 1.041), while BUP-NX dose was not (OR: 1.055; 95% CI: 0.990; 1.124). Higher methadone doses (70-110 mg/day) offered higher odds of treatment retention. DISCUSSION AND CONCLUSION: Methadone dose was associated with higher retention, which may be related to its full µ-opioid receptor agonism. Future research should notably ascertain the effect of pace of titration on a wide range of outcomes. SCIENTIFIC SIGNIFICANCE: Our results extend previous findings of high doses of methadone increasing retention to be applied in our population using opioids other than heroin, including highly potent opioids.

Evaluating preferences for online psychological interventions to decrease cannabis use in young adults with psychosis: An observational study.

Innovative technology-based solutions have the potential to improve access to clinically proven interventions for cannabis use disorder (CUD) in individuals with first episode psychosis (FEP). High patient engagement with app-based interventions is critical for achieving optimal outcomes. 104 individuals 18 to 35 years old with FEP and CUD from three Canadian provinces completed an electronic survey to evaluate preferences for online psychological intervention intensity, participation autonomy, feedback related to cannabis use, and technology platforms and app functionalities. The development of the questionnaire was informed by a qualitative study that included patients and clinicians. We used Best-Worst Scaling (BWS) and item ranking methodologies to measure preferences. Conditional logistic regression models for BWS data revealed high preferences for moderate intervention intensity (e.g., modules with a length of 15 min) and treatment autonomy that included preferences for using technology-based interventions and receiving feedback related to cannabis use once a week. Luce regression models for rank items revealed high preferences for smartphone-based apps, video intervention components, and having access to synchronous communications with clinicians and gamification elements. Results informed the development of iCanChange (iCC), a smartphone-based intervention for the treatment of CUD in individuals with FEP that is undergoing clinical testing.

Differential effect of cannabis use on opioid agonist treatment outcomes: Exploratory analyses from the OPTIMA study.

INTRODUCTION: Conflictual evidence exists regarding the effects of cannabis use on the outcomes of opioid agonist therapy (OAT). In this exploratory analysis, we examined the effect of recent cannabis use on opioid use, craving, and withdrawal symptoms, in individuals participating in a trial comparing flexible buprenorphine/naloxone (BUP/NX) take-home dosing model to witnessed ingestion of methadone. METHODS: We analyzed data from a multi-centric, pragmatic, 24-week, open label, randomized controlled trial in individuals with prescription-type opioid use disorder (n = 272), randomly assigned to BUP/NX (n = 138) or methadone (n = 134). The study measured last week cannabis and opioid use via timeline-follow back, recorded at baseline and every two weeks during the study. Craving symptoms were measured using the Brief Substance Craving Scale at baseline, and weeks 2, 6, 10, 14, 18 and 22. The study measured opioid withdrawal symptoms via Clinical Opiate Withdrawal Scale at treatment initiation and weeks 2, 4, and 6. RESULTS: The mean maximum dose taken during the study was 17.3 mg/day (range = 0.5-32 mg/day) for BUP/NX group and 67.7 mg/day (range = 10-170 mg/day) in the methadone group. Repeated measures generalized linear mixed models demonstrated that cannabis use in the last week (mean of 2.3 days) was not significantly associated with last week opioid use (aß ± standard error (SE) = -0.06 ± 0.04; p = 0.15), craving (aß ± SE = -0.05 ± 0.08, p = 0.49), or withdrawal symptoms (aß ± SE = 0.09 ± 0.1, p = 0.36). Bayes factor (BF) for each of the tested models supported the null hypothesis (BF < 0.3). CONCLUSIONS: The current study did not demonstrate a statistically significant effect of cannabis use on outcomes of interest in the context of a pragmatic randomized-controlled trial. These findings replicated previous results reporting no effect of cannabis use on opioid-related outcomes.

Childhood abuse/neglect and temporal patterns in late-life anxiety.

OBJECTIVES: Anxiety has been associated with childhood abuse/neglect, but this relationship and its mechanisms are poorly documented in older adults. This study examined the association between childhood abuse/neglect and late-life anxiety temporal patterns (i.e. absence, remission, incidence, persistence), testing for mediators. METHODS: Data were derived for 724 French-speaking community-living older adults participating in the Étude sur la santé des ainés - Services study with available information at baseline and 4-year follow-up. Past-month anxiety was based on a cutoff score ≥5 on a French translation of the 7-item Generalized Anxiety Disorder at interviews. Questions on childhood abuse/neglect (e.g. psycho-emotional, physical, sexual) were administered. Adjusted multinomial regression analyses and mediation bootstrapping models were used. Tested mediators included traumatic events (excluding childhood abuse/neglect), daily hassles, psychological resilience, and cortisol activity. RESULTS: The absence, remission, incidence and persistence of anxiety was found in 45.3%, 25.3%, 8.7% and 20.7% of the sample, respectively. Participants with incident and persistent late-life anxiety experienced more childhood abuse/neglect. Participants with persistent anxiety also reported lower psychological resilience. The association between childhood abuse/neglect with anxiety incidence was mediated by daily hassles, while its association with anxiety persistence was mediated by daily hassles and psychological resilience. CONCLUSION: Past childhood abuse/neglect was associated with late-life anxiety incidence and persistence, with psychological resilience and daily hassles potentially explaining this relationship. Further research should focus on ascertaining the clinical applications of psychosocial and biological profiles in informing the prevention and personalized treatment of anxiety in older adults.

Variations of cannabis-related adverse mental health and addiction outcomes across adolescence and adulthood: A scoping review.

Introduction: Evidence supporting associations between cannabis use and many health outcomes is growing, however it remains unclear how such associations vary across the lifespan. We therefore aim to answer the following questions: (1) Are the risks of cannabis's adverse effects on mental health and addiction-related outcomes different in adolescents than in adults? (2) What are the relationships between these cannabis's adverse effects and (a) an individual's age at first cannabis use, (b) age at assessment, and (c) duration of cannabis use? Methods: We searched Medline, Embase, CINAHL, and PsychINFO from inception to 18 October 2021. Two reviewers independently screened studies and descriptively synthesized results. Results: We included 140 studies. Cannabis effects on mental health and addiction-related outcomes were worse in adolescents, early cannabis initiators and cannabis users who consumed for longest periods. Evidence of worse long-term adverse effects in adolescents was substantial for psychosis, cannabis, and nicotine use disorders; mixed for depression, suicidality, other substance use and disorders; and limited for anxiety. Additionally, acute cannabis exposure had the opposite trend with adults more often reporting adverse effects than adolescents. Conclusion: The available evidence suggests that cannabis use should be delayed as late as possible in adulthood and shortened in duration across the lifespan to decrease the risk of negative outcomes, while emphasizing the need for adapted harm reduction approaches. This scoping review provides evidence on the role of age and duration of exposure as determinants of cannabis-related adverse effects, which may inform prevention and harm reduction strategies. Systematic review registration: https://doi.org/10.17605/OSF.IO/BYG72.

Temporal patterns of anxiety disorders and cortisol activity in older adults.

INTRODUCTION: Studies focusing on anxiety temporal patterns and cortisol activity in older adults are scarce. The objectives of this study were to examine in older adults the relationship between anxiety temporal patterns and cortisol activity and ascertain the presence of sex differences. METHODS: Data were retrieved from the Étude sur la santé des ainés - Services study in Quebec and included N = 762 community living adults aged ≥ 65 years having participated in interviews at baseline (T1) and at 4 years follow-up (T2). A standardized questionnaire, based on DSM-5 criteria, was used to ascertain in the past 6 months the presence of anxiety (absence, remission, incidence, persistence). Cortisol activity during the interview and cortisol concentration on a regular day (at T2) were the dependent variables. Adjusted multivariable linear regression models, stratified by sex, were used. RESULTS: Results showed higher cortisol activity during the interview in participants with anxiety in remission (Beta: 2.59; 95% CI: 0.62 , 4.57), specifically in males, and lower activity in participants with persistent anxiety (Beta: -3.97; 95% CI: -7.05, -0.88). Cortisol concentration on a regular day was higher in males reporting incident anxiety (Beta: 8.07; 95% CI: 2.39 , 13.76). LIMITATIONS: The convenience sample with losses to follow-up may have led to a potential selection bias. CONCLUSION: Anxiety temporal patterns were associated with cortisol activity profiles in older adults with sex being a significant moderator. Future studies are recommended to ascertain the longitudinal changes in cortisol activity and anxiety temporal patterns, which may further inform personalized treatment of anxiety.

Cognition and drug adherence to oral hypoglycemic and antihypertensive agents in older adults.

Background and objectives: Chronic disorders such as diabetes mellitus type II and hypertension have been associated with cognitive decline in older adults. It is unclear whether adherence to antihypertensive and oral hypoglycemic agents impact cognitive health. The objectives are to study the association between adherence to antihypertensive and oral hypoglycemic agents and cognitive status in community-living older adults. Methods: We used data from a large representative sample of older adults (N=2,286) covered under a public drug insurance plan in Quebec and participating in Quebec's health survey on older adults (ESA-study) with a Mini-Mental State Examination (MMSE) score ≥22 at baseline (T1) and examined one year later (T2). Participants with hypertension and diabetes mellitus type II were identified according to criteria used in the Canadian Chronic Disease Surveillance System. Antihypertensive and oral hypoglycemic prescriptions delivered were ascertained via Quebec's pharmaceutical database (RAMQ). Medication adherence was calculated using the medication possession ratio as a continuous variable in the year prior to and following baseline interview. Multivariate linear regressions were used to study the percentage change in MMSE scores between interviews (T1,T2) as a function of adherence to antihypertensive and oral hypoglycemic agents (before and after T1) controlling for potential confounders. Results: In participants with diabetes mellitus type II only, adherence to oral hypoglycemics was not associated with a change in MMSE scores. In participants with hypertension only, the change in MMSE scores was associated with adherence to antihypertensives (ß 1.23; 95%CI: 0.29-2.17). In participants with comorbid hypertension and diabetes mellitus type II, the change in MMSE scores was associated with adherence to both antihypertensive and oral hypoglycemic agents (ß 0.75; 95%CI: 0.01-1.48). Conclusions: Adherence to oral hypoglycemic agents and antihypertensive agents among older adults with hypertension and comorbid diabetes mellitus type II can have a preserving effect on cognitive health in older adults. Further research on the long-term impact on cognition is recommended.

Off-label use of antipsychotics and associated factors in community living older adults.

BACKGROUND: Given the common off-label use of antipsychotics (AP), we aimed to assess the factors associated with this use in community living older adults. METHODS: The study sample consisted of a large representative sample of older adults (n = 4108), covered under a public drug insurance plan in Canada. Off-label use of antipsychotics was defined by the absence of an approved indication for this use, according to Health Canada's drug product database. Multinomial logistic regression was used to assess the factors associated with off-label use. RESULTS: The prevalence of antipsychotics use was 2.5%, of which 78% was off-label. Compared to non-use, off-label antipsychotics use was negatively associated with advanced age (≥75 vs. 65-74 years old) (OR: 0.46; 95%CI: 0.27-0.78); and positively associated with higher education level (OR: 2.68; 95% CI: 1.64-4.40), higher number of outpatient visits (≥6) (OR: 2.39; 95%CI: 1.34-4.25), antidepressant or benzodiazepine use (OR: 5.81; 95%CI: 3.31-10.21), and the presence of an organic brain syndrome & Alzheimer's (OR: 5.73; 95%CI: 1.74-18.89). Compared to labeled use, off-label use was less likely in those with major depression (OR: 0.02; 95%CI: <0.01-0.11) and with insomnia (OR: 0.13; 95%CI: 0.02-0.91). CONCLUSIONS: The majority of antipsychotics prescribed to community living older adults were off-label. This off-label use was more likely in complex clinical cases with multiple outpatient visits and other psychotropic drugs use. Further research should focus on the long-term effects associated with off-label use of antipsychotics.

One-year prospective study on the presence of chronic diseases and subsequent cognitive decline in older adults.

Background: The literature is inconsistent regarding the effect of the presence of chronic physical and mental diseases on cognitive decline in older adults. The objectives of this study were to explore the effect of chronic diseases on subsequent cognitive decline assessed via the Mini Mental State Examination (MMSE) in community living older adults. Methods: We used data from individuals (n = 2010) participating in the ESA (Étude sur la Santé des Aînés) study. Cognitive status was measured with the MMSE at baseline and after 1 year. Chronic diseases were identified via administrative databases in accordance with International Classification of Diseases 9/10. Multivariate linear regression was used to assess the change in MMSE as a function of chronic physical and mental disorders, while adjusting for socio-demographic and clinical factors. Results: Significant decreases in MMSE scores were found in patients who had a stroke (ß value: -2.83) or diabetes (ß value: -1.06) and in older adults aged older than 75 years (ß value: -0.91). Conclusions: When adjusting for other chronic diseases, stroke, diabetes and advanced age were associated with subsequent cognitive decline in older adults during a one-year follow-up. Longer follow-up is recommended to assess long-term effect.