Intoxication due to Δ9-tetrahydrocannabinol is characterized by disrupted prefrontal cortex activity.

Neural states of impairment from intoxicating substances, including cannabis, are poorly understood. Cannabinoid 1 receptors, the main target of Δ9-tetrahydrocannabinol (THC), the primary intoxicating cannabinoid in cannabis, are densely localized within prefrontal cortex; therefore, prefrontal brain regions are key locations to examine brain changes that characterize acute intoxication. We conducted a double-blind, randomized, cross-over study in adults, aged 18-55 years, who use cannabis regularly, to determine the effects of acute intoxication on prefrontal cortex resting-state measures, assessed with portable functional near-infrared spectroscopy. Participants received oral THC (10-80 mg, individually dosed to overcome tolerance and achieve acute intoxication) and identical placebo, randomized for order; 185 adults were randomized and 128 completed both study days and had usable data. THC was associated with expected increases in subjective intoxication ratings (ES = 35.30, p < 0.001) and heart rate (ES = 11.15, p = 0.001). THC was associated with decreased correlations and anticorrelations in static resting-state functional connectivity within the prefrontal cortex relative to placebo, with weakest correlations and anticorrelations among those who reported greater severity of intoxication (RSFC between medial PFC-ventromedial PFC and DEQ scores, r = 0.32, p < 0.001; RSFC between bilateral mPFC and DEQ scores, r = -0.28, p = 0.001). Relative to placebo, THC was associated with increased variability (or reduced stability) in dynamic resting-state functional connectivity of the prefrontal cortex at p = 0.001, consistent across a range of window sizes. Finally, using frequency power spectrum analyses, we observed that relative to placebo, THC was associated with widespread reduced spectral power within the prefrontal cortex across the 0.073-0.1 Hz frequency range at p < 0.039. These neural features suggest a disruptive influence of THC on the neural dynamics of the prefrontal cortex and may underlie cognitive impairing effects of THC that are detectable with portable imaging. This study is registered in Clinicaltrials.gov (NCT03655717).

Implementation of Community Health Worker Support for Tobacco Cessation: A Mixed-Methods Study.

Objective: Adults with serious mental illness have high tobacco use disorder rates and underutilization of first-line tobacco cessation pharmacotherapy. In a randomized trial, participants offered community health worker (CHW) support and primary care provider (PCP) education had higher tobacco abstinence rates at two years, partly through increased tobacco cessation pharmacotherapy initiation. This study determined the association between participant-CHW engagement and tobacco abstinence outcomes. Methods: This was a secondary, mixed-methods analysis of 196 participants in the trial's intervention arm. Effects of CHW visit number and duration, CHW co-led smoking cessation group sessions attended, and CHW-attended PCP visit number on tobacco use disorder pharmacotherapy initiation and tobacco abstinence were modeled using logistic regression. Interviews with 12 CHWs, 16 participants, and 17 PCPs were analyzed thematically. Results: Year-two tobacco abstinence was associated with CHW visit number (OR=1.85, 95% CI=[1.29, 2.66]) and duration (OR=1.85, 95% CI=[1.33, 2.58]) and number of groups attended (OR=1.51, 95% CI=[1.00, 2.28]); effects on pharmacotherapy initiation were similar. 1-3 CHW visits per month over two years was optimal for achieving abstinence. Interviews identified engagement facilitators, including CHWs establishing trust, providing goal accountability, skills reinforcement, and assistance overcoming barriers to treatment access and adherence related to social determinants of health and illness factors. Robust training and supervision facilitated CHW effectiveness. Barriers included PCPs' and care teams' limited understanding of the CHW role. Conclusions: Feasible CHW engagement was associated with tobacco abstinence in adults with serious mental illness. CHW implementation may benefit from promoting CHW training and integration within clinical teams.

A pragmatic clinical effectiveness trial of a novel alternative to punishment for school-based substance use infractions: study protocol for the iDECIDE curriculum.

Background: Adolescents who use alcohol and other drugs on school campuses are at heightened risk for adverse consequences to their health and wellbeing. Schools have historically turned to punitive approaches as a first-line response to substance use. However, punishment is an ineffective deterrent for substance use and may cause harm and increase inequities. iDECIDE (Drug Education Curriculum: Intervention, Diversion, and Empowerment) was developed as a scalable and youth-centered drug education and diversion program that can be used as a skills-based alternative to punishment. We aim to evaluate the effectiveness of the iDECIDE curriculum as an alternative to punishment (ATP) for school-based substance use infractions in the context of a large pragmatic clinical effectiveness study. Methods: We will conduct a Type 1, hybrid effectiveness-implementation trial. Using a stepped wedge design with approximately 90 middle and high schools in Massachusetts, we will randomly allocate the timing of implementation of the iDECIDE curriculum compared to standard disciplinary response over approximately 36 months. We will test the overarching hypothesis that student-level outcomes (knowledge of drug effects and attitudes about substance use; frequency of substance use; school connectedness) improve over time as schools transition from a standard disciplinary response to having access to iDECIDE. The secondary aims of this trial are to (1) explore whether change in student-level outcomes vary according to baseline substance use, number of peers who use alcohol or other drugs, age, gender, and school urbanicity, and (2) determine the acceptability and feasibility of the iDECIDE curriculum through qualitative stakeholder interviews. Discussion: Substance use continues to be a major and rapidly evolving problem in schools. The importance of moving away from punishment to more restorative approaches is widely accepted; however, scalable alternatives have not yet been identified. This will be the first study to our knowledge to systematically evaluate an ATP for students who violate the school substance use policy and is well poised to have important implications for policy making.

A randomized controlled trial of varenicline and brief behavioral counseling delivered by lay counselors for adolescent vaping cessation: Study protocol.

Background: Approximately one-fifth of high-school seniors and college students currently vape nicotine. Adolescents express a desire to quit vaping, and case reports have shown promise for e-cigarette tapering with dual behavioral and pharmacologic therapies. However, there are no published clinical trials to date that test these intervention approaches for adolescent nicotine vaping cessation. In this three-arm randomized, placebo-controlled, parallel-group study, we aim to assess the efficacy of varenicline in combination with brief behavioral counseling and texting support on vaping cessation in adolescents dependent on vaped nicotine. Methods: The study will enroll 300 individuals between the ages of 16-25 with daily or near-daily nicotine vaping who reside in the Greater Boston area. Participants will be randomly assigned in a 1:1:1 ratio in blocks of six to one of the three arms: (1) a 12-week course of varenicline titrated to 1 mg bid, brief behavioral counseling delivered by a lay counselor, and an introduction to This is Quitting (TIQ) texting support created by the Truth Initiative; (2) a 12-week course of placebo, brief behavioral counseling, and TIQ; and (3) 12 weeks of enhanced usual care, consisting of advice to quit and an introduction to TIQ. The primary outcome will be biochemically verified continuous vaping abstinence at the end of the treatment (week 12). Secondary outcomes include continuous abstinence at follow-up (week 24), 7-day point prevalence abstinence at weeks 12 and 24, safety and tolerability of varenicline in an adolescent vaping population, as well as change in mood and nicotine withdrawal symptoms across the intervention period. Exploratory outcomes include change in comorbid substance use behaviors and nicotine dependence. Analysis will be intent-to-treat, with multiple imputation sensitivity analyses for participants with missing or incomplete outcome data. Discussion: This is the first study to evaluate varenicline in combination with a novel, brief, lay counselor delivered vaping cessation program for adolescents who vape nicotine. Results will inform clinicians on the effectiveness and acceptability of this promising, but not yet tested intervention.Clinical trial registration: ClinicalTrials.gov, identifier NCT05367492.

Development of cannabis use disorder in medical cannabis users: A 9-month follow-up of a randomized clinical trial testing effects of medical cannabis card ownership.

Background: Evidence for long-term effectiveness of commercial cannabis products used to treat medical symptoms is inconsistent, despite increasingly widespread use. Objective: To prospectively evaluate the effects of using cannabis on self-reported symptoms of pain, insomnia, anxiety, depression, and cannabis use disorder (CUD) after 12 months of use. Methods: This observational cohort study describes outcomes over 9 months following a 12-week randomized, waitlist-controlled trial (RCT: NCT03224468) in which adults (N = 163) who wished to use cannabis to alleviate insomnia, pain, depression, or anxiety symptoms were randomly assigned to obtain a medical marijuana card immediately (immediate card acquisition group) or to delay obtaining a card for 12 weeks delay (delayed card acquisition group). During the 9-month post-randomization period, all participants could use cannabis as they wished and choose their cannabis products, doses, and frequency of use. Insomnia, pain, depression, anxiety, and CUD symptoms were assessed over the 9-month post-randomization period. Results: After 12 months of using cannabis for medical symptoms, 11.7% of all participants (n = 19), and 17.1% of those using cannabis daily or near-daily (n = 6) developed CUD. Frequency of cannabis use was positively correlated with pain severity and number of CUD symptoms, but not significantly associated with severity of self-reported insomnia, depression, or anxiety symptoms. Depression scores improved throughout the 9 months in all participants, regardless of cannabis use frequency. Conclusions: Frequency of cannabis use was not associated with improved pain, anxiety, or depression symptoms but was associated with new-onset cannabis use disorder in a significant minority of participants. Daily or near-daily cannabis use appears to have little benefit for these symptoms after 12 months of use.

Cannabis use and sleep quality in daily life: An electronic daily diary study of adults starting cannabis for health concerns.

BACKGROUND: Real world patterns of cannabis use for health concerns are highly variable and rarely overseen by a physician. Pragmatic effectiveness studies with electronic daily diaries that capture person-specific patterns of cannabis use and health symptoms may help clarify risks and benefits. METHODS: As part of a larger, randomized trial (NCT03224468), adults (N = 181) seeking cannabis for insomnia, pain, or anxiety or depressive symptoms were randomized to obtain a medical cannabis card immediately (MCC) or a waitlist control (WLC) and completed 12-weeks of daily web-based surveys on cannabis use and sleep, pain, and depressive symptoms. RESULTS: Completion rates of daily surveys were moderate to high (median completed: 72 out of 90 days). Daily reports of cannabis use were consistent with monthly interview assessments and urinalysis. The MCC group increased cannabis use frequency in the 12 weeks following randomization, while WLC did not. Among the MCC group, self-reported sleep quality was significantly higher on cannabis use days, compared to nonuse days. The MCC group displayed long-term sleep improvements, consistent with increasing cannabis frequency. No improvements were found for pain or depressive symptoms. CONCLUSION: Cannabis use is associated with same day improvements in self-reported sleep quality, but not pain or depressive symptoms, although sleep improvements occurred in the context of increased frequency of cannabis use, raising the risk for cannabis use disorder. Daily web-based assessments of cannabis appear valid and feasible in adults seeking cannabis for health concerns, providing a flexible, complementary method for future real-world effectiveness studies with expanded and objective measures.

A Pragmatic Cluster-Randomized Trial of Provider Education and Community Health Worker Support for Tobacco Cessation.

OBJECTIVE: Individuals with serious mental illness have a high prevalence of tobacco use disorder and related early mortality but underutilize smoking cessation medication. The authors determined whether clinician-delivered education to primary care providers regarding safety, efficacy, and importance of cessation medication (provider education [PE]) alone or combined with community health worker (CHW) support would increase tobacco abstinence in this population, compared with usual care. METHODS: All adult current tobacco smokers receiving psychiatric rehabilitation for serious mental illness through two community agencies in Greater Boston were eligible, regardless of readiness to quit smoking. Primary care clinics were cluster randomized to PE or usual care, with a nested, participant-level randomization to CHW or no CHW in PE-assigned clinics. The primary outcome was blindly assessed, biochemically verified tobacco abstinence at year 2. RESULTS: Overall, 1,010 eligible participants were enrolled. PE was delivered to providers in 53 of 55 assigned clinics; 220 of 336 CHW-assigned participants consented to CHW support. Year 2 abstinence rates were significantly higher among participants assigned to PE+CHW versus usual care (12% vs. 5%; adjusted odds ratio [AOR]=2.40, 95% confidence interval [CI]=1.20-4.79) or PE alone (12% vs. 7%; AOR=1.84, 95% CI=1.04-3.24). No effect of PE alone on abstinence was detected. Compared with participants assigned to usual care, those assigned to PE+CHW had greater odds of varenicline use (OR=2.77, 95% CI=1.61-4.75), which was associated with higher year 2 abstinence (OR=1.97, 95% CI=1.16-3.33). CONCLUSIONS: Combined PE and CHW tobacco cessation support increased tobacco abstinence rates among adults with serious mental illness.

The effects of reduced nicotine content cigarettes on biomarkers of nicotine and toxicant exposure, smoking behavior and psychiatric symptoms in smokers with mood or anxiety disorders: A double-blind randomized trial.

BACKGROUND: The U.S. Food and Drug Administration and the government of New Zealand have proposed a reduction of the nicotine content in cigarettes to very low levels. This study examined the potential effects of this regulation in smokers with affective disorders. METHODS: In a randomized controlled parallel group trial conducted at two sites in the USA (Penn State University, Hershey, PA and Massachusetts General Hospital, Boston, MA) 188 adult smokers with a current (n = 118) or lifetime (n = 70) anxiety or unipolar mood disorder, not planning to quit in the next 6 months, were randomly assigned (1:1) to smoke either Usual Nicotine Content (UNC) (11.6 mg nicotine/cigarette) research cigarettes, or Reduced Nicotine Content (RNC) research cigarettes where the nicotine content per cigarette was progressively reduced to 0.2 mg in five steps over 18 weeks. Participants were then offered the choice to either receive assistance to quit smoking, receive free research cigarettes, or resume using their own cigarette brand during a 12-week follow-up period. Main outcomes were biomarkers of nicotine and toxicant exposure, smoking behavior and dependence and severity of psychiatric symptoms. The pre-registered primary outcome was plasma cotinine. RESULTS: A total of 143 (76.1%) randomized participants completed the randomized phase of the trial, 69 (73.4%) in the RNC group and 74 (78.8%) in the UNC group. After switching to the lowest nicotine content cigarettes, compared to smokers in the UNC group, at the last randomized visit the RNC group had significantly lower plasma cotinine (metabolite of nicotine): difference between groups, -175.7, 95% CI [-218.3, -133.1] ng/ml. Urine NNAL (metabolite of NNK, a lung carcinogen), exhaled carbon-monoxide, cigarette consumption, and cigarette dependence were also significantly lower in the RNC group than the UNC group. No between-group differences were found on a range of other biomarkers (e.g. 8-isoprostanes) or health indicators (e.g. blood pressure), or on 5 different psychiatric questionnaires, including the Kessler K6 measure of psychological distress. At the end of the subsequent 12-week treatment choice phase, those randomized to the RNC group were more likely to have quit smoking, based on initial intent-to-treat sample, n = 188 (18.1% RNC v 4.3% UNC, p = 0.004). CONCLUSION: Reducing nicotine content in cigarettes to very low levels reduces some toxicant exposures and cigarette addiction and increases smoking cessation in smokers with mood and/or anxiety disorders, without worsening mental health. TRIAL REGISTRATION: TRN: NCT01928758, registered August 21, 2013.

Effect of Medical Marijuana Card Ownership on Pain, Insomnia, and Affective Disorder Symptoms in Adults: A Randomized Clinical Trial.

Importance: Despite the legalization and widespread use of cannabis products for a variety of medical concerns in the US, there is not yet a strong clinical literature to support such use. The risks and benefits of obtaining a medical marijuana card for common clinical outcomes are largely unknown. Objective: To evaluate the effect of obtaining a medical marijuana card on target clinical and cannabis use disorder (CUD) symptoms in adults with a chief concern of chronic pain, insomnia, or anxiety or depressive symptoms. Design, Setting, and Participants: This pragmatic, single-site, single-blind randomized clinical trial was conducted in the Greater Boston area from July 1, 2017, to July 31, 2020. Participants were adults aged 18 to 65 years with a chief concern of pain, insomnia, or anxiety or depressive symptoms. Participants were randomized 2:1 to either the immediate card acquisition group (n = 105) or the delayed card acquisition group (n = 81). Randomization was stratified by chief concern, age, and sex. The statistical analysis followed an evaluable population approach. Interventions: The immediate card acquisition group was allowed to obtain a medical marijuana card immediately after randomization. The delayed card acquisition group was asked to wait 12 weeks before obtaining a medical marijuana card. All participants could choose cannabis products from a dispensary, the dose, and the frequency of use. Participants could continue their usual medical or psychiatric care. Main Outcomes and Measures: Primary outcomes were changes in CUD symptoms, anxiety and depressive symptoms, pain severity, and insomnia symptoms during the trial. A logistic regression model was used to estimate the odds ratio (OR) for CUD diagnosis, and linear models were used for continuous outcomes to estimate the mean difference (MD) in symptom scores. Results: A total of 186 participants (mean [SD] age 37.2 [14.4] years; 122 women [65.6%]) were randomized and included in the analyses. Compared with the delayed card acquisition group, the immediate card acquisition group had more CUD symptoms (MD, 0.28; 95% CI, 0.15-0.40; P < .001); fewer self-rated insomnia symptoms (MD, -2.90; 95% CI, -4.31 to -1.51; P < .001); and reported no significant changes in pain severity or anxiety or depressive symptoms. Participants in the immediate card acquisition group also had a higher incidence of CUD during the intervention (17.1% [n = 18] in the immediate card acquisition group vs 8.6% [n = 7] in the delayed card acquisition group; adjusted odds ratio, 2.88; 95% CI, 1.17-7.07; P = .02), particularly those with a chief concern of anxiety or depressive symptoms. Conclusions and Relevance: This randomized clinical trial found that immediate acquisition of a medical marijuana card led to a higher incidence and severity of CUD; resulted in no significant improvement in pain, anxiety, or depressive symptoms; and improved self-rating of insomnia symptoms. Further investigation of the benefits of medical marijuana card ownership for insomnia and the risk of CUD are needed, particularly for individuals with anxiety or depressive symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT03224468.

Identification of ∆9-tetrahydrocannabinol (THC) impairment using functional brain imaging.

The primary cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC), causes intoxication and impaired function, with implications for traffic, workplace, and other situational safety risks. There are currently no evidence-based methods to detect cannabis-impaired driving, and current field sobriety tests with gold-standard, drug recognition evaluations are resource-intensive and may be prone to bias. This study evaluated the capability of a simple, portable imaging method to accurately detect individuals with THC impairment. In this double-blind, randomized, cross-over study, 169 cannabis users, aged 18-55 years, underwent functional near-infrared spectroscopy (fNIRS) before and after receiving oral THC and placebo, at study visits one week apart. Impairment was defined by convergent classification by consensus clinical ratings and an algorithm based on post-dose tachycardia and self-rated "high." Our primary outcome, prefrontal cortex (PFC) oxygenated hemoglobin concentration (HbO), was increased after THC only in participants operationalized as impaired, independent of THC dose. ML models using fNIRS time course features and connectivity matrices identified impairment with 76.4% accuracy, 69.8% positive predictive value (PPV), and 10% false-positive rate using convergent classification as ground truth, which exceeded Drug Recognition Evaluator-conducted expanded field sobriety examination (67.8% accuracy, 35.4% PPV, and 35.4% false-positive rate). These findings demonstrate that PFC response activation patterns and connectivity produce a neural signature of impairment, and that PFC signal, measured with fNIRS, can be used as a sole input to ML models to objectively determine impairment from THC intoxication at the individual level. Future work is warranted to determine the specificity of this classifier to acute THC impairment.ClinicalTrials.gov Identifier: NCT03655717.

Integrated Smoking Cessation for Smokers With Serious Mental Illness: Protocol for a Convergent Mixed Methods Implementation Evaluation Study.

BACKGROUND: Tobacco smoking is associated with significant morbidity and premature mortality in individuals with serious mental illness. A 2-year pragmatic clinical trial (PCORI PCS-1504-30472) that enrolled 1100 individuals with serious mental illness in the greater Boston area was conducted to test 2 interventions for tobacco cessation for individuals with serious mental illness: (1) academic detailing, which delivers education to primary care providers and highlights first-line pharmacotherapy for smoking cessation, and (2) provision of community health worker support to smoker participants. Implementing and scaling this intervention in other settings will require the systematic identification of barriers and facilitators, as well as the identification of relevant subgroups, effective and unique components, and setting-specific factors. OBJECTIVE: This protocol outlines the proposed mixed methods evaluation of the pragmatic clinical trial to (1) identify barriers and facilitators to effective implementation of the interventions, (2) examine group differences among primary care physicians, and (3) identify barriers that stakeholders such as clinical, payor, and policy leaders would anticipate to impact the implementation of effective components of the intervention. METHODS: Qualitative interviews will be conducted with all study community health workers and selected smoker participants, primary care providers, and other stakeholders. Measures of performance and engagement will guide purposive sampling. The Consolidated Framework for Implementation Research will guide qualitative data collection and analysis in accordance with the following framework approach: (1) familiarization, (2) identifying a thematic framework, (3) indexing, (4) charting, and (5) mapping and interpretation. Joint display analyses will be constructed to analyze and draw conclusions across the quantitative and qualitative data. RESULTS: The 3-year cluster-randomized trial has concluded, and the analysis of primary outcomes is underway. Results from the pragmatic trial and this mixed methods implementation evaluation will be used to help disseminate, scale, and expand a systems intervention. CONCLUSIONS: The results of this mixed methods implementation evaluation will inform strategies for dissemination and solutions to potential barriers to the implementation of interventions from a smoking cessation trial for individuals with serious mental illness. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/25390.

Patient Experience and Predictors of Improvement in a Group Behavioral and Educational Intervention for Individuals With Diabetes and Serious Mental Illness: Mixed Methods Case Study.

BACKGROUND: In a previous study, participation in a 16-week reverse integrated care and group behavioral and educational intervention for individuals with diabetes and serious mental illness was associated with improved glycemic control (hemoglobin A1c) and BMI. To inform future implementation efforts, more information about the effective components of the intervention is needed. OBJECTIVE: The goal of this study is to identify the aspects of the intervention participants reported to be helpful and to evaluate the predictors of outcomes. METHODS: This study involved qualitative evaluation and post hoc quantitative analysis of a previous intervention. Qualitative data were collected using semistructured interviews with 69% (24/35) of the individuals who attended 1 or more group sessions and 35% (9/26) of the individuals who consented but attended no sessions. Quantitative mixed effects modeling was performed to test whether improved diabetes knowledge, diet, and exercise or higher group attendance predicted improved hemoglobin A1c and BMI. These interview and modeling outcomes were combined using a mixed methods case study framework and integrated thematically. RESULTS: In qualitative interviews, participants identified the application of health-related knowledge gained to real-world situations, accountability for goals, positive reinforcement and group support, and increased confidence in prioritizing health goals as factors contributing to the success of the behavioral intervention. Improved knowledge of diabetes was associated with reduced BMI (ß=-1.27, SD 0.40; P=.003). No quantitative variables examined were significantly associated with improved hemoglobin A1c levels. CONCLUSIONS: In this mixed methods analysis of predictors of success in a behavioral diabetes management program, group participants highlighted the value of positive reinforcement and group support, accountability for goals set, and real-world application of health-related knowledge gained. Improved diabetes knowledge was associated with weight loss.

Alcohol substitution during one month of cannabis abstinence among non-treatment seeking youth.

OBJECTIVE: Cannabis and alcohol use are correlated behaviors among youth. It is not known whether discontinuation of cannabis use is associated with changes in alcohol use. This study assessed alcohol use in youth before, during, and after 4 weeks of paid cannabis abstinence. METHODS: Healthy, non-treatment seeking, cannabis users (n = 160), aged 14-25 years, 84% of whom used alcohol in the last month, were enrolled for a 4-week study with a 2-4 week follow-up. Participants were randomly assigned to 4 weeks of either biochemically-verified cannabis abstinence achieved through a contingency management framework (CB-Abst) or monitoring with no abstinence requirement (CB-Mon). Participants were assessed at baseline and approximately 4, 6, 10, 17, 24, and 31 days after enrollment. A follow-up visit with no cannabis abstinence requirement for CB-Abst was conducted after 2-4 weeks. RESULTS: Sixty percent of individuals assigned to the CB-Abst condition increased in frequency and quantity of alcohol consumption during the 4-week period of incentivized cannabis abstinence. As a whole, CB-Abst increased by a mean of 0.6 drinking days and 0.2 drinks per day in the initial week of abstinence (p's < 0.006). There was no evidence for further increases in drinking frequency or quantity during the 30-day abstinence period (p's > 0.53). There was no change in drinking frequency or quantity during the 4-week monitoring or follow-up periods among CB-Mon. CONCLUSIONS: On average, 4 weeks of incentivized (i.e., paid) cannabis abstinence among non-treatment seeking youth was associated with increased frequency and amount of alcohol use in week 1 that was sustained over 4 weeks and resolved with resumption of cannabis use. However, there was notable variability in individual-level response, with 60% increasing in alcohol use and 23% actually decreasing in alcohol use during cannabis abstinence. Findings suggest that increased alcohol use during cannabis abstinence among youth merits further study to determine whether this behavior occurs among treatment seeking youth and its clinical significance.

Delta-9-tetrahydrocannabinol intoxication is associated with increased prefrontal activation as assessed with functional near-infrared spectroscopy: A report of a potential biomarker of intoxication.

The primary psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), binds to cannabinoid receptors (CB1) present in high concentrations in the prefrontal cortex (PFC). It is unknown whether the PFC hemodynamic response changes with THC intoxication. We conducted the first double-blind, placebo-controlled, cross-over study of the effect of THC intoxication on functional near infrared spectroscopy (fNIRS) measures of PFC activation. Fifty-four adult, regular (at least weekly) cannabis users received a single oral dose of synthetic THC (dronabinol; 5-50 mg, dose individually tailored to produce intoxication) and identical placebo on two visits at least one week apart. fNIRS recordings were obtained during a working memory task (N-Back) at three timepoints: before THC/placebo, at 100 min (when peak effects were expected), and at 200 min after THC/placebo administration. Functional data were collected using a continuous-wave NIRS device, with 8 sources and 7 detectors arrayed over the forehead, resulting in 20 channels covering PFC regions. Participants also completed frequent heart rate measures and subjective ratings of intoxication. Approximately half of participants reported significant intoxication. Intoxication ratings were not correlated with dose of THC. Increases in heart rate significantly correlated with intoxication ratings after THC dosing. Results indicated that 100 min after THC administration, oxygenated hemoglobin (HbO) response significantly increased from pre-dose HbO levels throughout the PFC in participants who reported significant intoxication. Changes in HbO response significantly correlated with self-reported intoxication at 100 min after THC administration. Among those who reported intoxication, HbO response decreased at 200 min after THC, when intoxication had largely resolved, compared to the peak THC time point. This study demonstrates that THC intoxication causes increased PFC activity, and fNIRS of the PFC can measure this effect. Increased neural activation in PFC represents a potential biomarker for cannabis intoxication.

A placebo-controlled randomized trial of D-cycloserine augmentation of cue exposure therapy for smoking cessation.

Recent studies underscore the importance of studying d-cycloserine (DCS) augmentation under conditions of adequate cue exposure treatment (CET) and protection from reconditioning experiences. In this randomized trial, we evaluated the efficacy of DCS for augmenting CET for smoking cessation under these conditions. Sixty-two smokers attained at least 18 hours abstinence following 4 weeks of smoking cessation treatment and were randomly assigned to receive a single dose of DCS (n=30) or placebo (n=32) prior to each of two sessions of CET. Mechanistic outcomes were self-reported cravings and physiologic reactivity to smoking cues. The primary clinical outcome was 6-week, biochemically-verified, continuous tobacco abstinence. DCS, relative to placebo, augmentation of CET resulted in lower self-reported craving to smoking pictorial and in vivo cues (d = 0.8 to 1.21) in a relevant subsample of participants who were reactive to cues and free from smoking-related reconditioning experiences. Select craving outcomes were correlated with smoking abstinence, and DCS augmentation was associated with a trend toward a higher continuous abstinence rate (33% vs. 13% for placebo augmentation). DCS augmentation of CET can significantly reduce cue-induced craving, supporting the therapeutic potential of DCS augmentation when applied under appropriate conditions for adequate extinction learning.

Phase IIb Trial of an α7 Nicotinic Receptor Partial Agonist With and Without Nicotine Patch for Withdrawal-Associated Cognitive Deficits and Tobacco Abstinence.

PURPOSE/BACKGROUND: The objective of this study was to determine whether a novel α7 nicotinic acetylcholine receptor partial agonist improves cognition during nicotine withdrawal and improves abstinence rates. To do so, the effect of the α7 nicotinic acetylcholine receptor partial agonist, encenicline, on cognition and abstinence was evaluated when given as monotherapy and when combined with transdermal nicotine patch (nicotine replacement therapy [NRT]). METHODS: Adult daily smokers, n = 160, who were motivated to quit smoking completed cognitive testing at satiated baseline and after overnight abstinence and then were randomized to receive a 12-week trial of encenicline 1 mg twice daily or identical placebo the day of the overnight abstinent cognitive testing. In the first 6 weeks of the 12-week encenicline administration, participants were also randomized to 6 weeks of NRT patch or placebo patch. Primary outcomes were cognition during abstinence and 7-day point-prevalence abstinence at week 12. RESULTS: No beneficial effects of encenicline were observed on cognition or abstinence when compared with placebo or when combined with NRT compared with placebo capsule + NRT. Of the 4 conditions, abstinence rates were lowest among those assigned to encenicline alone. CONCLUSIONS: Beneficial effects of NRT were observed on cognitive and abstinence outcomes when combined with encenicline compared with encenicline plus placebo patch. Addition of NRT to encenicline improved odds of abstinence approximately 3-fold compared with encenicline plus placebo patch. We conclude that encenicline, 1 mg/d, did not improve abstinence-associated cognitive impairment or abstinence rates as monotherapy or adjunctive therapy to NRT patch.

Anterior insula activation during inhibition to smoking cues is associated with ability to maintain tobacco abstinence.

Relapse to smoking after initial abstinence is a major clinical challenge with significant public health consequences. At the brain and behavioral level, those who relapse to tobacco smoking have both greater cue-reactivity and lower inhibitory control than those who remain abstinent. Little is known about neural activation during inhibitory control tasks in the presence of drug-related cues. In the current study, tobacco smokers (SMK; n = 22) and non-smoking controls (CON; n = 19) completed a Go/NoGo task involving smoking cues during a functional magnetic resonance imaging (fMRI) scan. Following the scan session, smokers were required to quit smoking, and maintenance of abstinence was evaluated as part of a 12-week smoking cessation trial. We evaluated pre-cessation brain activity during NoGo trials in smokers who were versus were not able to quit smoking. We then compared fMRI and inhibitory control measures between smokers and non-smokers. We did not find differences between SMK and CON in performance or activation to smoking or neutral cues. However, compared to SMK who relapsed, SMK who attained biochemically-validated abstinence at the end of the smoking cessation trial had greater neural activation in the anterior insula during NoGo trials specifically with smoking-related cues. Results indicate that within SMK, decreased inhibitory control activation during direct exposure to drug-related stimuli may be a marker of difficulty quitting and relapse vulnerability.

Using Functional Near-Infrared Spectroscopy to Measure Effects of Delta 9-Tetrahydrocannabinol on Prefrontal Activity and Working Memory in Cannabis Users.

Intoxication from cannabis impairs cognitive performance, in part due to the effects of Δ9-tetrahydrocannabinol (THC, the primary psychoactive compound in cannabis) on prefrontal cortex (PFC) function. However, a relationship between impairment in cognitive functioning with THC administration and THC-induced change in hemodynamic response has not been demonstrated. We explored the feasibility of using functional near-infrared spectroscopy (fNIRS) to examine the functional changes of the human PFC associated with cannabis intoxication and cognitive impairment. Eighteen adult regular cannabis users (final sample, n = 13) performed a working memory task (n-back) during fNIRS recordings, before and after receiving a single dose of oral synthetic THC (dronabinol; 20-50 mg). Functional data were collected using a continuous-wave NIRS device, in which 8 Sources and 7 detectors were placed on the forehead, resulting in 20 channels covering PFC regions. Physiological changes and subjective intoxication measures were collected. We found a significant increase in the oxygenated hemoglobin (HbO) concentration after THC administration in several channels on the PFC during both the high working memory load (2-back) and the low working memory load (0-back) condition. The increased HbO response was accompanied by a trend toward an increased number of omission errors after THC administration. The current study suggests that cannabis intoxication is associated with increases in hemodynamic blood flow to the PFC, and that this increase can be detected with fNIRS.

Achieving Smoking Cessation in Individuals with Schizophrenia: Special Considerations.

Premature mortality due to cardiovascular disease in those with schizophrenia is the largest lifespan disparity in the US and is growing; adults in the US with schizophrenia die, on average, 28 years earlier than those in the general population. The rate of smoking prevalence among individuals with schizophrenia is estimated to be from 64 to 79%. Smokers with schizophrenia have historically been excluded from most large nicotine-dependence treatment studies. However, converging evidence indicates that a majority of smokers with schizophrenia want to quit smoking, and that available pharmacotherapeutic smoking cessation aids are well tolerated by this population of smokers and are effective when combined with behavioral treatment. The aim of this review is to present updated evidence for safety and efficacy of smoking cessation interventions for those with schizophrenia spectrum illness. We also highlight implications of the very low abstinence rates for smokers with schizophrenia who receive placebo plus behavioral treatment in randomized trials, and review treatment approaches to address the high rate of rapid relapse observed upon pharmacologic treatment discontinuation in this population. Recommendations for monitoring for treatment-emergent nicotine withdrawal symptoms, side effects, and effects of cessation on antipsychotic medication are also provided. Smokers with schizophrenia spectrum disorders should be encouraged to quit smoking and should receive varenicline, bupropion with or without nicotine replacement therapy (NRT), or NRT, all in combination with behavioral treatment for at least 12 weeks. Maintenance pharmacotherapy may reduce relapse and improve sustained abstinence rates. Controlled trials in smokers with schizophrenia consistently show no greater rate of neuropsychiatric adverse events with pharmacotherapeutic cessation aids than with placebo.