Working Memory Training for Adolescents With Cannabis Use Disorders: A Randomized Controlled Trial.

Adolescent cannabis use is associated with working memory impairment. The present randomized controlled trial assigned adolescents ages 14 to 21 enrolled in cannabis use treatment to receive either working memory training (experimental group) or a control training (control group) as an adjunctive treatment. Cognitive function, drug use, and other outcomes were assessed before and after training. We observed few differences in cognitive, functional, or self-reported drug use outcomes as a function of training group, although tetrahydrocannabinol (THC) urinalysis results favored the experimental group. These findings are similar to previous studies in substance users, which have shown limited transfer effects for working memory training.

Relapse prevention medications in community treatment for young adults with opioid addiction.

BACKGROUND: Despite the well-known effectiveness and widespread use of relapse prevention medications such as extended release naltrexone (XR-NTX) and buprenorphine for opioid addiction in adults, less is known about their use in younger populations. METHODS: This was a naturalistic study using retrospective chart review of N = 56 serial admissions into a specialty community treatment program that featured the use of relapse prevention medications for young adults (19-26 years old) with opioid use disorders. Treatment outcomes over 24 weeks included retention and weekly opioid-negative urine tests. RESULTS: Patients were of mean age 23.1, 70% male, 86% Caucasian, 82% with history of injection heroin use, and treated with either buprenorphine (77%) or XR-NTX (23%). The mean number of XR-NTX doses received was 4.1. Retention was approximately 65% at 12 weeks and 40% at 24 weeks, and rates of opioid-negative urine were 50% at 12 weeks and 39% at 24 weeks, with missing samples imputed as positive. There were no statistically significant differences in retention (t = 1.87, P = .06) or in rates of weekly opioid-negative urine tests (t = 1.96, P = .06) between medication groups, over the course of 24 weeks. The XR-NTX group had higher rates of weekly negative urine drug tests for other nonopioid substances (t = 2.83, P < .05) compared with the buprenorphine group. Males were retained in treatment longer and had higher rates of opioid-negative weeks compared with females. CONCLUSIONS: These results suggest that relapse prevention medications including both buprenorphine and XR-NTX can be effectively incorporated into standard community treatment for opioid addiction in young adults with good results. Specialty programming focused on opioid addiction in young adults may provide a promising model for further treatment development.

Flavokawains A and B from kava (Piper methysticum) activate heat shock and antioxidant responses and protect against hydrogen peroxide-induced cell death in HepG2 hepatocytes.

Context Flavokawains are secondary metabolites from the kava plant (Piper methysticum Forst. f., Piperaceae) that have anticancer properties and demonstrated oral efficacy in murine cancer models. However, flavokawains also have suspected roles in rare cases of kava-induced hepatotoxicity. Objective To compare the toxicity flavokawains A and B (FKA, FKB) and monitor the resulting transcriptional responses and cellular adaptation in the human hepatocyte cell line, HepG2. Materials and methods HepG2 were treated with 2-100 µM FKA or FKB for 24-48 h. Cellular viability was measured with calcein-AM and changes in signalling and gene expression were monitored by luciferase reporter assay, real-time PCR and Western blot of both total and nuclear protein extracts. To test for subsequent resistance to oxidative stress, cells were pretreated with 50 µM FKA, 10 µM FKB or 10 µM sulphoraphane (SFN) for 24 h, followed by 0.4-2.8 mM H2O2 for 48 h, and then viability was assessed. Results FKA (≤100 µM) was not toxic to HepG2, whereas FKB caused significant cell death (IC50=23.2 ± 0.8 µM). Both flavokawains activated Nrf2, increasing HMOX1 and GCLC expression and enhancing total glutathione levels over 2-fold (p < 0.05). FKA and FKB also activated HSF1, increasing HSPA1A and DNAJA4 expression. Also, flavokawain pretreatment mitigated cell death after a subsequent challenge with H2O2, with FKA being more effective than FKB, and similar to SFN. Conclusions Flavokawains promote an adaptive cellular response that protects hepatocytes against oxidative stress. We propose that FKA has potential as a chemopreventative or chemotherapeutic agent.

Working memory impairment in cannabis- and opioid-dependent adolescents.

BACKGROUND: Cannabis and opioid use are associated with cognitive impairment, whether preexisting or substance-induced, but there have been few substance-specific assessments of cognitive functioning in adolescent substance users. Working memory impairment may be particularly important, as it has been linked to poorer performance in substance abuse treatment. METHODS: Working memory (Wechsler Intelligence Scale for Children-IV or Adult Intelligence Scale-IV) and baseline substance use were assessed in 42 youth (mean age = 17.9 years, SD = 1.3, range: 16-20; 65% Caucasian, 30% female) 1-2 weeks after admission to residential treatment with supervised abstinence, 19 for primary cannabis dependence and 23 for primary opioid dependence. RESULTS: There were substantial deficits in working memory in both groups, with significant differences (P < .001) between the opioid (M = 39.1th%ile, SD = 25.6) and cannabis (M = 16.3th%ile, SD = 13.6) groups. The primary opioid group had high rates of cannabis use, with no significant difference in past-month days of cannabis use from the primary cannabis group. The opioid group was older and had completed more years of formal education. Seventy-nine percent of the cannabis group had public health care coverage (mostly Medicaid), compared with 24% of the opioid sample. CONCLUSIONS: Working memory impairment was substantial in treatment-seeking youth with primary cannabis and opioid dependence (the latter actually having comparable rates of cannabis use), and significantly more pronounced in the primary cannabis-dependent group. Without an assessment of working memory prior to substance exposure, the differential contributions of substance-induced vs. preexisting impairment are unclear. Lower scores in the cannabis group may reflect lower socioeconomic status (SES), which is typically correlated with cognitive performance. These findings highlight underrecognized cognitive impairment in youth with SUDs, especially inner-city cannabis-dependent youth. Modification of treatments to account for cognitive capacity and/or cognitive remediation interventions may be indicated to improve treatment outcomes.

Psychometric properties of the Treatment Effectiveness Assessment in methamphetamine use disorder.

INTRODUCTION: The ability for people living with stimulant use disorder to live meaningful lives requires not only abstinence from addictive substances, but also healthy engagement with their community, lifestyle practices, and overall health. The Treatment Effectiveness Assessment (TEA) assesses components of recovery consisting of four functional domains: substance use, health, lifestyle, and community. This secondary data analysis of 403 participants with severe methamphetamine use disorder tested the reliability and validity of the TEA. METHODS: Participants were enrolled in the Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) for methamphetamine use disorder. The study used total TEA and domain scores at baseline to assess factor structure and internal consistency, as well as construct validity related to substance cravings (visual analog scale [VAS]), quality of life (quality-of-life assessment [QoL]), mental health (Patient Health Questionnaire-9 [PHQ-9], Concise Health Risk Tracking Scale Self-Report [CHRT-SR16]), and social support (CHRT-SR16). RESULTS: Individual TEA items showed moderate to large correlations with each other (r = 0.27-0.51; p < .001), and strong correlations to the total score (r = 0.69-0.78; p < .001). Internal consistency was strong (coefficient α = 0.73 [0.68-0.77]; coefficient ω = 0.73 [0.69-0.78]). Construct validity was acceptable, with the strongest correlation between the TEA Health item and the general health status item on the QoL (r = 0.53, p < .001). CONCLUSIONS: TEA has acceptable levels of reliability and validity supporting prior similar findings in a sample of participants with moderate to severe methamphetamine use disorder. Results from this study provide support for its use in assessing clinically meaningful changes beyond simply reduced substance use.

Treatment Trajectories During and After a Medication Trial for Opioid Use Disorder: Moving from Research as Usual to Treatment as Usual.

OBJECTIVES: The effectiveness of treatment incorporating relapse prevention medications for opioid use disorder (OUD) is typically examined in research using rigidly predefined endpoints of success versus failure, usually over a single episode of care. But this perspective may not adequately portray the nonlinear trajectories typical of real-world treatment courses in this chronic, remitting, and relapsing disorder. METHODS: This descriptive study examined 12-month treatment trajectories of n = 60 patients enrolled at a single site of a larger multisite randomized controlled trial examining the comparative effectiveness of buprenorphine versus extended-release naltrexone. While the parent study provided medication treatment through the research protocol for 6 months, this study documents treatment up to 12 months, including medications, provided through standard community resources (treatment as usual) outside of the protocol. RESULTS: Some patients continued medications past the end of the study intervention, whereas others did not. Some patients initiated medications other than the one assigned by the study. Some patients switched from 1 medication to the other. Many patients returned to treatment after 1 or more periods of dropout and/or relapse. Patients utilized multiple episodes of bed-based care, including short-term acute residential and long-term residential treatment, and also recovery housing supports. Described trajectories are also depicted graphically. At 12 months, while rates of continuous treatment retention were low (8%), rates of cross-sectional treatment engagement including return to treatment after drop out were higher (35%). CONCLUSIONS: This description of nonlinear treatment trajectories highlights the potential benefits of flexibility and optimism in the promotion of re-engagement, despite interim outcomes that might traditionally be considered "failure" endpoints.

Working memory training and high magnitude incentives for youth cannabis use: A SMART pilot trial.

The purpose of this sequential multiple-assignment randomization treatment pilot study was to examine if (a) adding working memory training to contingency management (CM) for youth with cannabis use disorder (CUD) and (b) switching nonresponding youth to higher magnitude CM incentives boosts outcomes. In Phase 1, youth with CUD (n = 59, M age = 16, male = 71%) attending an intensive outpatient program were randomly assigned to 14 weeks of CM only or CM plus working memory training (WMT). In Week 4, a Phase 2 treatment was assigned. Those with negative urine drug tests (responders) continued in their Phase 1 treatment. Those who were drug positive (nonresponders) were randomly assigned to remain in their Phase 1 treatment or to higher magnitude CM. Zero-inflated negative binomial models comparing those assigned to CM versus CM + WMT indicated no differences in the likelihood of having ≥ 1 week of continuous abstinence or longer abstinence duration. Those assigned to WMT showed greater but nonsignificant improvements in working memory (n = 35; ß = .69, p = .06). Working memory improvements were associated with achieving any abstinence (odds ratio = 3.50, 95% CI [1.01, 12.10], p = .05). Phase 2 randomization to higher magnitude CM did not boost outcomes. Overall results suggest that WMT appears promising, but the sample size was small, attrition was high, and replication is important. Alternative strategies should continue to be explored to improve outcomes for adolescent substance use disorders, such as different approaches for nonresponders, tailoring to other baseline or response characteristics, or more robust first-line interventions. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Home-based delivery of XR-NTX in youth with opioid addiction.

Early experience with relapse prevention medications in the treatment of opioid addiction in youth has been positive, but barriers to effectiveness and broader adoption have included problems with adherence and retention, and lack of evidence or consensus about implementation. In particular there is relatively little known about either the effectiveness of extended release naltrexone (XR-NTX) in youth, or optimal models of care for its delivery. The purpose of this study is to report on a pilot initiative to improve the effectiveness of XR-NTX by delivering doses at home with assertive outreach to patients enrolled in a community treatment outpatient program. This is a naturalistic case series based on retrospective chart abstractions of 14 young adults (mean age=20.5), who enrolled in the pilot program, and in particular, the 9 who received home-based doses of XR-NTX. They are compared to a historical group of patients (n=21) prior to the pilot, who were referred to receive standard clinic-based doses of XR-NTX. Home-based administration was viewed favorably by patients and families. Although the small sample size is not amenable to statistical analysis, patients in the home based group, compared to the historical clinic-based group, received a greater number of doses overall and over 16 weeks of treatment, had longer retention, and attended similar numbers of clinic-based counseling sessions. These preliminary findings suggest that home-based delivery of XR-NTX and assertive outreach are feasible and promising in this critical target population, may compare favorably to clinic-based treatment as usual, and should be explored further in more rigorous evaluations.

Intranasal naloxone and related strategies for opioid overdose intervention by nonmedical personnel: a review.

Deaths due to prescription and illicit opioid overdose have been rising at an alarming rate, particularly in the USA. Although naloxone injection is a safe and effective treatment for opioid overdose, it is frequently unavailable in a timely manner due to legal and practical restrictions on its use by laypeople. As a result, an effort spanning decades has resulted in the development of strategies to make naloxone available for layperson or "take-home" use. This has included the development of naloxone formulations that are easier to administer for nonmedical users, such as intranasal and autoinjector intramuscular delivery systems, efforts to distribute naloxone to potentially high-impact categories of nonmedical users, as well as efforts to reduce regulatory barriers to more widespread distribution and use. Here we review the historical and current literature on the efficacy and safety of naloxone for use by nonmedical persons, provide an evidence-based discussion of the controversies regarding the safety and efficacy of different formulations of take-home naloxone, and assess the status of current efforts to increase its public distribution. Take-home naloxone is safe and effective for the treatment of opioid overdose when administered by laypeople in a community setting, shortening the time to reversal of opioid toxicity and reducing opioid-related deaths. Complementary strategies have together shown promise for increased dissemination of take-home naloxone, including 1) provision of education and training; 2) distribution to critical populations such as persons with opioid addiction, family members, and first responders; 3) reduction of prescribing barriers to access; and 4) reduction of legal recrimination fears as barriers to use. Although there has been considerable progress in decreasing the regulatory and legal barriers to effective implementation of community naloxone programs, significant barriers still exist, and much work remains to be done to integrate these programs into efforts to provide effective treatment of opioid use disorders.

Genetic Screen in Drosophila Larvae Links ird1 Function to Toll Signaling in the Fat Body and Hemocyte Motility.

To understand how Toll signaling controls the activation of a cellular immune response in Drosophila blood cells (hemocytes), we carried out a genetic modifier screen, looking for deletions that suppress or enhance the mobilization of sessile hemocytes by the gain-of-function mutation Toll10b (Tl10b). Here we describe the results from chromosome arm 3R, where five regions strongly suppressed this phenotype. We identified the specific genes immune response deficient 1 (ird1), headcase (hdc) and possibly Rab23 as suppressors, and we studied the role of ird1 in more detail. An ird1 null mutant and a mutant that truncates the N-terminal kinase domain of the encoded Ird1 protein affected the Tl10b phenotype, unlike mutations that affect the C-terminal part of the protein. The ird1 null mutant suppressed mobilization of sessile hemocytes, but enhanced other Tl10b hemocyte phenotypes, like the formation of melanotic nodules and the increased number of circulating hemocytes. ird1 mutants also had blood cell phenotypes on their own. They lacked crystal cells and showed aberrant formation of lamellocytes. ird1 mutant plasmatocytes had a reduced ability to spread on an artificial substrate by forming protrusions, which may explain why they did not go into circulation in response to Toll signaling. The effect of the ird1 mutation depended mainly on ird1 expression in hemocytes, but ird1-dependent effects in other tissues may contribute. Specifically, the Toll receptor was translocated from the cell membrane to intracellular vesicles in the fat body of the ird1 mutant, and Toll signaling was activated in that tissue, partially explaining the Tl10b-like phenotype. As ird1 is otherwise known to control vesicular transport, we conclude that the vesicular transport system may be of particular importance during an immune response.

Initial feasibility and validity of a prospective memory training program in a substance use treatment population.

Individuals with substance use disorders have shown deficits in the ability to implement future intentions, called prospective memory. Deficits in prospective memory and working memory, a critical underlying component of prospective memory, likely contribute to substance use treatment failures. Thus, improvement of prospective memory and working memory in substance use patients is an innovative target for intervention. We sought to develop a feasible and valid prospective memory training program that incorporates working memory training and may serve as a useful adjunct to substance use disorder treatment. We administered a single session of the novel prospective memory and working memory training program to participants (n = 22; 13 men, 9 women) enrolled in outpatient substance use disorder treatment and correlated performance to existing measures of prospective memory and working memory. Generally accurate prospective memory performance in a single session suggests feasibility in a substance use treatment population. However, training difficulty should be increased to avoid ceiling effects across repeated sessions. Consistent with existing literature, we observed superior performance on event-based relative to time-based prospective memory tasks. Performance on the prospective memory and working memory training components correlated with validated assessments of prospective memory and working memory, respectively. Correlations between novel memory training program performance and established measures suggest that our training engages appropriate cognitive processes. Further, differential event- and time-based prospective memory task performance suggests internal validity of our training. These data support the development of this intervention as an adjunctive therapy for substance use disorders. (PsycINFO Database Record

Biomarkers of basic activities of daily living in Alzheimer's disease.

Functional impairment is common in Alzheimer's disease (AD) and related to increased caregiver burden and institutionalization. There is a dearth of research investigating the relationship between specific biomarkers and basic activities of daily living (BADLs) such as toileting, feeding, dressing, grooming, bathing, and ambulating. The present study examined the relationship between serum based biomarkers and specific ADLs in a sample of AD patients. Data were collected from 196 participants enrolled in the Texas Alzheimer's Research and Care Consortium Project and diagnosed with AD. BADLs were measured using the Lawton-Brody Physical Self-Maintenance Scale. A panel of 22 biomarkers previously found to be related to AD pathology was used for the analysis. Stepwise regression modeling was used to assess the link between the biomarkers and BADLs. Results were also examined by gender. Nine of the 22 biomarkers were significantly related to BADLs. When stratified by gender, the biomarkers accounted for 32% of the variance in the males and 27% in females. The pattern of significant biomarkers differed by gender with IL 7 and Tenascin C significantly related to BADLs for females and IL 15 significantly related to BADLs for males. The results of this study indicated that a small number of serum based biomarkers are related to BADLs, and these biomarkers differed by gender.

Performance on a measure of category fluency in cognitively impaired elderly.

Measures of verbal fluency are widely used in the assessment of cognitive functioning of the elderly. However, limited research has evaluated patterns (across specific timed intervals) of performance on tasks of language fluency in different forms of dementia. The current study investigated semantic fluency in 488 elderly individuals (249 with Alzheimer's dementia, 97 Vascular dementia, 97 Mild Cognitive Impairment and 45 cognitively intact) across 15-second intervals in an animal naming task using retrospective chart review. Normal controls produced significantly more exemplars and AD patients produced fewer animal names than the other groups. After the first 15- second time interval, the demented groups produced significantly fewer exemplars than the non-demented. At the end of 30 seconds it was possible to differentiate normal aging from MCI who no longer differed from the VaD group. Overall, it appears that the greatest and most clinically meaningful differences between the diagnostic groups were detected in the first three 15-second intervals. The present findings support the use of time intervals and total scores on tasks of verbal fluency in clinical settings and for research purposes.

The Link between Cognitive Measures and ADLs and IADL Functioning in Mild Alzheimer's: What Has Gender Got to Do with It?

Objectives. To investigate the link between neurocognitive measures and various aspects of daily living (ADL and IADL) in women and men with mild Alzheimer's disease (AD). Methods. Participants were 202 AD patients (91 male, 111 female) with CDR global scores of ≤1. ADLs and IADLs ratings were obtained from caregivers. Cognitive domains were assessed with neuropsychological testing. Results. Memory and executive functioning were related to IADL scores. Executive functioning was linked to total ADL. Comparisons stratified on gender found attention predicted total ADL score in both men and women. Attention predicted bathing and eating ability in women only. Language predicted IADL functions in men (food preparation) and women (driving). Conclusions. Associations between ADLs/IADLs and memory, learning, executive functioning, and language suggest that even in patients with mild AD, basic ADLs require complex cognitive processes. Gender differences in the domains of learning and memory area were found.