The effects of N-acetyl cysteine on intrinsic functional connectivity and neural alcohol cue reactivity in treatment-seeking individuals with alcohol use disorder: a preliminary study.

N-acetyl cysteine (NAC) is a potential pharmacotherapy for alcohol use disorder (AUD), but it is not known whether it modulates neural activation to alcohol cues or intrinsic functional connectivity. We investigated whether NAC attenuates (i) alcohol cue-elicited activation, and (ii) intrinsic functional connectivity compared to placebo in patients with AUD. In this preliminary study, twenty-three individuals (7 females) with moderate-severe AUD received daily NAC (2400 mg/day, n = 9), or a placebo (n = 14) for at least 2 weeks. Participants completed a pre-treatment functional magnetic resonance imaging session (T0) and a post-treatment session (T1) comprising resting-state and visual alcohol cue reactivity task acquisitions. Activation differences between sessions, treatment, and session-by-treatment interaction were assessed. Resting-state functional connectivity examined using 377 node ROI-to-ROIs evaluated whether NAC reduced intrinsic functional connectivity after treatment. There were no differences in alcohol cue reactivity for brain activation or subjective craving between NAC and placebo during treatment or across sessions, or significant interaction. A significant treatment-by-time interaction, with reduced intrinsic connectivity was observed after treatment (T1) for NAC-treated compared to placebo-treated patients in the posterior cingulate node (9, left hemisphere) of the dorsal attentional network and connections to salience, ventral-attentional, somatosensory, and visual-peripheral networks implicated in AUD. NAC reduced intrinsic functional connectivity in patients with moderate-severe AUD after treatment compared to placebo, but did not attenuate alcohol cue-elicited activation. However, the absence of cue reactivity findings may result from low power, rather than the absence of cue reactivity findings associated with NAC. These results provide preliminary evidence that NAC treatment may modulate intrinsic functional connectivity brain activation in patients with alcohol use disorder, but replication in larger studies are required to determine the strength of this effect and any associations with clinical outcomes. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT03879759.

Oral Cannabis Extract for Secondary Prevention of Chemotherapy-Induced Nausea and Vomiting: Final Results of a Randomized, Placebo-Controlled, Phase II/III Trial.

PURPOSE: The aim of this randomized, placebo-controlled, two-stage, phase II/III trial was to determine the efficacy of an oral cannabis extract in adults with refractory nausea and/or vomiting during moderately or highly emetogenic, intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Here, we report results of the prespecified combined analysis including the initial phase II and subsequent phase III components. PATIENTS AND METHODS: Study treatment consisted of oral capsules containing either tetrahydrocannabinol 2.5 mg plus cannabidiol 2.5 mg capsules (THC:CBD) or matching placebo, taken three times a day from days -1 to 5, in addition to guideline-consistent antiemetics. The primary measure of effect was the difference in the proportions of participants with no vomiting or retching and no use of rescue medications (a complete response) during hours 0-120 after the first cycle of chemotherapy on study (cycle A). RESULTS: We recruited 147 evaluable of a planned 250 participants from 2016 to 2022. Background antiemetic prophylaxis included a corticosteroid and 5-hydroxytryptamine antagonist in 97%, a neurokinin-1 antagonist in 80%, and olanzapine in 10%. THC:CBD compared with placebo improved the complete response rate from 8% to 24% (absolute difference 16%, 95% CI, 4 to 28, P = .01), with similar effects for absence of significant nausea, use of rescue medications, daily vomits, and the nausea scale on the Functional Living Index-Emesis quality-of-life questionnaire. More frequent bothersome adverse events of special interest included sedation (18% v 7%), dizziness (10% v 0%), and transient anxiety (4% v 1%). There were no serious adverse events attributed to THC:CBD. CONCLUSION: THC:CBD is an effective adjunct for chemotherapy-induced nausea and vomiting despite standard antiemetic prophylaxis, but was associated with additional adverse events. Drug availability, cultural attitudes, legal status, and preferences may affect implementation. Future analyses will evaluate the cost-effectiveness of THC:CBD.

No improvement in AUDIT-C screening and brief intervention rates among wait-list controls following support of Aboriginal Community Controlled Health Services: evidence from a cluster randomised trial.

BACKGROUND: While Aboriginal and Torres Strait Islander Australians are less likely to drink any alcohol than other Australians, those who drink are more likely to experience adverse alcohol-related health consequences. In a previous study, providing Aboriginal Community Controlled Health Services (ACCHSs) with training and support increased the odds of clients receiving AUDIT-C alcohol screening. A follow-up study found that these results were maintained for at least two years, but there was large variability in the effectiveness of the intervention between services. In this study, we use services that previously received support as a comparison group to test whether training and support can improve alcohol screening and brief intervention rates among wait-list control ACCHSs. METHODS: Design: Cluster randomised trial using routinely collected health data. SETTING: Australia. CASES: Twenty-two ACCHSs that see at least 1000 clients a year and use Communicare as their practice management software. Intervention and comparator: After initiating support, we compare changes in screening and brief intervention between wait-list control services and services that had previously received support. MEASUREMENT: Records of AUDIT-C screening and brief intervention activity in routinely collected data. RESULTS: During the reference period we observed 357,257 instances where one of 74,568 clients attended services at least once during a two-monthly data extraction period. Following the start of support, the odds of screening (OR = 0.94 [95% CI 0.67, 1.32], p = 0.74, [Formula: see text]≈ 0.002) and brief intervention (OR = 1.43 [95% CI 0.69, 2.95], p = 0.34, [Formula: see text]≈ 0.002) did not improve for the wait-list control group, relative to comparison services. CONCLUSIONS: We did not replicate the finding that support and training improves AUDIT-C screening rates with wait-list control data. The benefits of support are likely context dependent. Coincidental policy changes may have sensitised services to the effects of support in the earlier phase of the study. Then the COVID-19 pandemic may have made services less open to change in this latest phase. Future efforts could include practice software prompts to alcohol screening and brief intervention, which are less reliant on individual staff time or resources. TRIAL REGISTRATION: Retrospectively registered on 2018-11-21: ACTRN12618001892202.

Low Risk of Cardiac Complications During Long-Term Follow-Up of Opioid Dependence.

OBJECTIVES: To prospectively assess rates of QT prolongation, arrhythmia, syncope, and sudden cardiac death (SCD) in a cohort of people with heroin dependence. METHODS: To estimate rates of QT prolongation, arrhythmia, and syncope, a subcohort (n = 130) from the Australian Treatment Outcomes Study, a prospective longitudinal cohort study of 615 people with heroin dependence, underwent medical history, venepuncture, and ECG at the 18- to 20-year follow-up.To estimate rates of SCD, probabilistic matching for the entire cohort was undertaken with the Australian Institute of Health and Welfare National Death Index. Deaths were classified into suicide, accidental overdose, trauma, unknown, and disease, which were then further subclassified by probability of SCD. SCD rate was the number of possible or probable SCDs divided by total patient years from the cohort. RESULTS: From the subcohort, 4 participants (3%) met the criteria for QT prolongation; 3 were prescribed methadone. Seven participants (5%) reported history of arrhythmia, including 2 transferred from methadone to buprenorphine. Thirty participants (23%) reported a previous syncopal event-14 diagnosed as nonarrhythmic syncope and 13 not investigated. In the previous 12 months, 66 participants (51%) reported heroin use; 55 participants (42%) were prescribed methadone. No participant had QTc greater than 500 milliseconds.There were 3 possible SCDs, translating to an estimated SCD rate of 0.29 (CI: 0.05, 0.8) events per 1000 patient years. More cohort members died of overdose (n = 50), suicide (n = 11), and hepatitis C (n = 4). CONCLUSIONS: Low rates of QT prolongation, arrhythmia, syncope, and SCD in the cohort despite high rates of heroin use and methadone treatment.

Prevalence and factors associated with polydrug use among clients seeking treatment for alcohol misuse.

INTRODUCTION: The aim of this paper was to examine the client and psychosocial characteristics associated with polydrug use in patients with alcohol misuse as their primary drug of concern (PDC) seeking treatment from substance use treatment centres. METHODS: Self-report surveys were undertaken with clients attending 1 of 34 community-based substance use treatment centres across Australia with alcohol as their PDC. Survey items included client's socio-demographic characteristics, level of alcohol dependence, use of other drugs including tobacco, health and wellbeing factors including health-related quality of life. The factors associated with polydrug use (alcohol use concurrent with at least one other drug) were examined. RESULTS: In a sample of 1130 clients seeking treatment primarily for alcohol problems, 71% reported also using another drug. The most frequently used drug was tobacco (50%) followed by cannabis (21%) and benzodiazepines (15%). Excluding tobacco use, 35% of participants reported polydrug use. Factors associated with any polydrug use were younger age, lower education levels, lower levels of mental health related quality of life and housing risk (i.e., risk of eviction or experienced homelessness in past 4 weeks). When tobacco was excluded, factors associated with polydrug use were age, lower physical and mental health-related quality of life, and housing risk. DISCUSSION AND CONCLUSIONS: Most adults seeking treatment for alcohol misuse as their PDC reported using another drug in addition to alcohol. Treatment services should be designed accordingly to maximise the likelihood of treatment engagement and success.

A phase III multisite randomised controlled trial to compare the efficacy of cannabidiol to placebo in the treatment of cannabis use disorder: the CBD-CUD study protocol.

BACKGROUND: Cannabis use disorder (CUD) is increasingly common and contributes to a range of health and social problems. Cannabidiol (CBD) is a non-intoxicating cannabinoid recognised for its anticonvulsant, anxiolytic and antipsychotic effects with no habit-forming qualities. Results from a Phase IIa randomised clinical trial suggest that treatment with CBD for four weeks reduced non-prescribed cannabis use in people with CUD. This study examines the efficacy, safety and quality of life of longer-term CBD treatment for patients with moderate-to-severe CUD. METHODS/DESIGN: A phase III multi-site, randomised, double-blinded, placebo controlled parallel design of a 12-week course of CBD to placebo, with follow-up at 24 weeks after enrolment. Two hundred and fifty adults with moderate-to-severe CUD (target 20% Aboriginal), with no significant medical, psychiatric or other substance use disorders from seven drug and alcohol clinics across NSW and VIC, Australia will be enrolled. Participants will be administered a daily dose of either 4 mL (100 mg/mL) of CBD or a placebo dispensed every 3-weeks. All participants will receive four-sessions of Cognitive Behavioural Therapy (CBT) based counselling. Primary endpoints are self-reported cannabis use days and analysis of cannabis metabolites in urine. Secondary endpoints include severity of CUD, withdrawal severity, cravings, quantity of use, motivation to stop and abstinence, medication safety, quality of life, physical/mental health, cognitive functioning, and patient treatment satisfaction. Qualitative research interviews will be conducted with Aboriginal participants to explore their perspectives on treatment. DISCUSSION: Current psychosocial and behavioural treatments for CUD indicate that over 80% of patients relapse within 1-6 months of treatment. Pharmacological treatments are highly effective with other substance use disorders but there are no approved pharmacological treatments for CUD. CBD is a promising candidate for CUD treatment due to its potential efficacy for this indication and excellent safety profile. The anxiolytic, antipsychotic and neuroprotective effects of CBD may have added benefits by reducing many of the mental health and cognitive impairments reported in people with regular cannabis use. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12623000526673 (Registered 19 May 2023).

The Long-Term Relationship Between Cannabis and Heroin Use: An 18- to 20-year Follow-Up of the Australian Treatment Outcome Study (ATOS).

OBJECTIVE: Cannabis use is common among individuals with opioid use disorder, but it remains unclear whether cannabis use is associated with an increase or a reduction in illicit opioid use. To overcome limitations identified in previous longitudinal studies with limited follow-ups, the authors examined a within-person reciprocal relationship between cannabis and heroin use at several follow-ups over 18 to 20 years. METHODS: The Australian Treatment Outcome Study (ATOS) recruited 615 people with heroin dependence in 2001 and 2002 and reinterviewed them at 3, 12, 24, and 36 months as well as 11 and 18-20 years after baseline. Heroin and cannabis use were assessed at each time point using the Opiate Treatment Index. A random-intercept cross-lagged panel model analysis was conducted to identify within-person relationships between cannabis use and heroin use at subsequent follow-ups. RESULTS: After accounting for a range of demographic variables, other substance use, and mental and physical health measures, an increase in cannabis use 24 months after baseline was significantly associated with an increase in heroin use at 36 months (estimate=0.21, SE=0.10). Additionally, an increase in heroin use at 3 months and 24 months was significantly associated with a decrease in cannabis use at 12 months (estimate=-0.27, SE=0.09) and 36 months (estimate=-0.22, SE=0.08). All other cross-lagged associations were not significant. CONCLUSIONS: Although there was some evidence of a significant relationship between cannabis and heroin use at earlier follow-ups, this was sparse and inconsistent across time points. Overall, there was insufficient evidence to suggest a unidirectional or bidirectional relationship between the use of these substances.

Tobacco treatment incorporating contingency management, nicotine replacement therapy, and behavioral counseling for pregnant women who use substances: a feasibility trial.

Introduction: Most pregnant women with substance use problems smoke, and few will quit during their pregnancy. Tobacco treatment is often overlooked, with the focus usually placed on other substance use. Additionally, few targeted effective treatments for this group exist. To address this, the feasibility of an intensive tobacco treatment incorporating contingency management (CM) that featured non-face-to-face delivery was examined. Methods: A single-arm pre-post design feasibility trial was conducted in three antenatal services that support women who use substances in metropolitan Australia. Participants were over the age of 15, had <33-week gestation, and smoked tobacco daily. They received financial incentives for daily carbon monoxide-verified smoking abstinence or reduction through an internet-based CM programme, nicotine replacement therapy (NRT) posted to women and partners or household members who smoked and telephone-delivered behavioral counseling from study enrolment to birth. Results: Of the 101 referrals, 46 women (46%) consented. The mean (SD) age was 31(±6) years, and the gestation period was 22(±6) weeks. Nineteen (41%) of those enrolled were retained for 12-week postpartum. Of 46 women, 32 (70%) utilized CM; 32 (70%) used NRT for ≥2 weeks; 23 (50%) attended ≥1 counseling session; and 15 (22%) received NRT for partners/household members. Fifteen (33%) were verified abstinent from tobacco at delivery after a median (IQR) period of abstinence of 65(36-128) days. All non-smokers at birth utilized NRT and financial incentives, and 9/15 (60%) utilized counseling. Four (9%) were abstinent at 12-week postpartum. Median cigarettes smoked/day reduced from baseline to delivery (10(6-20) to 1(0-6) p =< 0.001). Women who quit smoking had more education (72% vs. 33% p =< 0.02), completed more CO samples (median (IQR) 101(59-157) vs. 2(0-20) p =< 0.001), and received more incentives (median (IQR) $909($225-$1980) vs. $34($3-$64) p =< 0.001). Intervention acceptability was rated favorably by participants (9 items rated 0-10 with scores >5 considered favorable). Discussion: This study demonstrated the feasibility and acceptability of a consumer-informed, non-face-to-face intensive tobacco treatment, highlighting the potential of remotely delivered technology-based CM to reduce the health impact of tobacco smoking in high-priority populations. The intervention demonstrates scale-up potential. Future studies should extend treatment into the postpartum period, utilizing new technologies to enhance CM delivery and improve counseling provision and partner support. Clinical trial registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374196, ACTRN1261800056224.

N acetylcysteine in the treatment of alcohol use disorder: a randomized, double-blind, placebo-controlled trial.

N-acetyl cysteine (NAC) is a potent antioxidant that modulates glutamatergic signalling which is thought to play a role in alcohol use disorder (AUD). There have been no clinical trials investigating NAC for AUD. We aimed to conduct a 28 day double-blind, placebo-controlled (PL) randomized trial of NAC in the treatment of AUD (NCT03879759). A total of 42 participants with AUD (56% alcohol-related liver disease) were randomized to receive placebo or NAC 2400 mg/day. Feasibility outcomes included treatment retention and adverse events. Primary clinical outcomes included alcohol consumption (heavy drinking days, standard drinks per drinking day). Secondary clinical outcome measures included craving, liver tests, and psychological outcomes. There were no significant differences in overall retention between treatment groups (χ2(1) = 0.14, P = 0.71: 86% vs 76% for placebo and NAC, respectively). The most commonly reported adverse event in NAC-treated individuals included headache (14%). For standard drinks per drinking day, there was a significant overall effect of time (F = 9.18, P < 0.001), no significant effect of treatment (F = 0.75, P = 0.79), and a significant time x treatment (NAC vs PL) effect (F = 2.73, P < 0.05). For number of heavy drinks per day, there was a significant overall effect of time (F = 3.16, P < 0.05) but no significant effect of treatment or time x treatment (P = 0.17). There were no significant NAC vs PL effects on secondary clinical outcome measures. In the first trial of NAC for the management of AUD, NAC appears to be feasible and safe. Although there was a significant effect of NAC vs placebo on some alcohol measures such as drinks per drinking day, there does appear to be a variable pattern of effect across time suggesting that a larger trial incorporating a longer treatment duration is now required to determine efficacy.