N-acetylcysteine for smoking cessation among dual users of tobacco and cannabis: Protocol and rationale for a randomized controlled trial.

BACKGROUND: Tobacco and cannabis co-use is a growing public health problem. The synergistic effects of cannabis and nicotine on neurobiological systems that mediate reward and shared environmental cues reinforcing use may make tobacco smoking cessation more difficult. N-acetylcysteine (NAC), an FDA-approved medication and over-the-counter supplement, has shown promise in animal studies and randomized controlled trials (RCTs) in reducing tobacco and cannabis craving and use. NAC's potential efficacy in treating addiction may be attributable to its central nervous system effects in reducing excessive glutamatergic activity, oxidative stress, and inflammation. To date, no RCT has examined NAC for smoking cessation among dual users of tobacco and cannabis. METHOD: In a double-blind, placebo-controlled RCT, we will examine NAC for smoking cessation among dual users of tobacco and cannabis. Sixty adult cigarette-cannabis co-users are randomized to receive NAC 3600 mg per day or placebo over 8 weeks. Participants in both groups receive 8 weekly cognitive behavioral therapy sessions addressing smoking cessation and cannabis reduction. Outcomes are assessed at Weeks 0, 4, 8, and 12. Primary aims are to determine NAC's efficacy in decreasing cigarette craving, nicotine dependence, and use; and cannabis craving and use. Exploratory aims include examination of changes in neurocognition with NAC and their potential mediational effects on cigarette and cannabis use outcomes. CONCLUSION: Results will inform smoking cessation treatment among dual users of tobacco and cannabis. CLINICALTRIALS: gov Identifier: NCT04627922.

Development of a mobile mindfulness smartphone app for post-traumatic stress disorder and alcohol use problems for veterans: Beta test results and study protocol for a pilot randomized controlled trial.

BACKGROUND: Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are highly prevalent, and co-occurring among post-9/11 veterans. Mobile health (mHealth) applications, specifically those focused on mindfulness-based techniques, may be an effective avenue to intervene with veterans who cannot or will not seek care at traditional in-person settings. Thus, to address areas of improvement in mHealth for veterans, we developed Mind Guide and prepared it for testing in a pilot randomized controlled trial (RCT) with veterans. METHODS: We have completed phase 1 (treatment development) and Phase 2 (beta test) of our mobile mHealth app, Mind Guide. In this paper we describe the methods for Phase 1 as well as results for our beta test (n = 16; inclusion criteria included screen for PTSD, AUD, a post-9/11 veteran, and not currently receiving treatment) for Mind Guide as well as outline procedures for our pilot RCT of Mind Guide (Phase 3). The PTSD Checklist, self-reported alcohol use, the Perceived Stress Scale, Penn Alcohol Craving Scale, and the Emotion Regulation Questionnaire were used. RESULTS: Results of our beta test of Mind Guide show promising past 30 day effects on PTSD (d = -1.12), frequency of alcohol use (d = -0.54), and alcohol problems (d = -0.44), and related mechanisms of craving (d = -0.53), perceived stress (d = -0.88), and emotion regulation (d = -1.22). CONCLUSION: Our initial beta-test of Mind Guide shows promise for reducing PTSD and alcohol related problems among veterans. Recruitment is ongoing for our pilot RCT in which 200 veterans will be recruited and followed up for 3 months. CLINICALTRIALS: gov Identifier: NCT04769986.

Rationale and design of a multisite randomized clinical trial examining an integrated behavioral treatment for veterans with co-occurring chronic pain and opioid use disorder: The pain and opioids integrated treatment in veterans (POSITIVE) trial.

BACKGROUND: Chronic pain and opioid use disorder (OUD) individually represent a risk to health and well-being. Concerningly, there is evidence that they are frequently co-morbid. While few treatments exist that simultaneously target both conditions, preliminary work has supported the feasibility of an integrated behavioral treatment targeting pain interference and opioid misuse. This treatment combined Acceptance and Commitment Therapy (ACT) and Mindfulness-Based Relapse Prevention (ACT+MBRP). This paper describes the protocol for the adequately powered efficacy study of this integrated treatment. METHODS: A multisite randomized controlled trial will examine the efficacy of ACT+MBRP in comparison to a parallel education control condition, focusing on opioid safety and pain education. Participants include veterans (n = 160; 21-75 years old) recruited from three Veterans Administration (VA) Healthcare Systems with chronic pain who are on a stable dose of buprenorphine. Both conditions include twelve weekly 90 min group sessions delivered via telehealth. Primary outcomes include pain interference (Patient Reported Outcome Measurement Information System - Pain Interference) and hazardous opioid use (Current Opioid Misuse Measure), which will be examined at the end of the active treatment phase and through 12 months post-intervention. Secondary analyses will evaluate outcomes including pain intensity, depression, pain-related fear, and substance use, as well as treatment mechanisms. CONCLUSION: This study will determine the efficacy of an integrated behavioral treatment program for pain interference and hazardous opioid use among veterans with chronic pain and OUD who are prescribed buprenorphine, addressing a critical need for more integrated treatments for chronic pain and OUD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04648228.

Fusion pores with low conductance are cation selective.

Many neurotransmitters are organic ions that carry a net charge, and their release from secretory vesicles is therefore an electrodiffusion process. The selectivity of early exocytotic fusion pores is investigated by combining electrodiffusion theory, measurements of amperometric foot signals from chromaffin cells with anion substitution, and molecular dynamics simulation. The results reveal that very narrow fusion pores are cation selective, but more dilated fusion pores become anion permeable. The transition occurs around a fusion pore conductance of ∼300 pS. The cation selectivity of a narrow fusion pore accelerates the release of positively charged transmitters such as dopamine, noradrenaline, adrenaline, serotonin, and acetylcholine, while glutamate release may require a more dilated fusion pore.

A Bidirectional-Current CMOS Potentiostat for Fast-Scan Cyclic Voltammetry Detector Arrays.

A potentiostat circuit for the application of bipolar electrode voltages and detection of bidirectional currents using a microelectrode array is presented. The potentiostat operates as a regulated-cascode amplifier for positive input currents, and as an active-input regulated-cascode mirror for negative input currents. This topology enables constant-potential amperometry and fast-scan cyclic voltammetry (FSCV) at microelectrode arrays for parallel recording of quantal release events, electrode impedance characterization, and high-throughput drug screening. A 64-channel FSCV detector array, fabricated in a 0.5-$\mu$m, 5-V CMOS process, is also demonstrated. Each detector occupies an area of 45  $\mu$m $\times$ 30 $\mu$m and consists of only 14 transistors and a 50-fF integrating capacitor. The system was validated using prerecorded input stimuli from actual FSCV measurements at a carbon-fiber microelectrode.

Surface-modified CMOS IC electrochemical sensor array targeting single chromaffin cells for highly parallel amperometry measurements.

Amperometry is a powerful method to record quantal release events from chromaffin cells and is widely used to assess how specific drugs modify quantal size, kinetics of release, and early fusion pore properties. Surface-modified CMOS-based electrochemical sensor arrays allow simultaneous recordings from multiple cells. A reliable, low-cost technique is presented here for efficient targeting of single cells specifically to the electrode sites. An SU-8 microwell structure is patterned on the chip surface to provide insulation for the circuitry as well as cell trapping at the electrode sites. A shifted electrode design is also incorporated to increase the flexibility of the dimension and shape of the microwells. The sensitivity of the electrodes is validated by a dopamine injection experiment. Microwells with dimensions slightly larger than the cells to be trapped ensure excellent single-cell targeting efficiency, increasing the reliability and efficiency for on-chip single-cell amperometry measurements. The surface-modified device was validated with parallel recordings of live chromaffin cells trapped in the microwells. Rapid amperometric spikes with no diffusional broadening were observed, indicating that the trapped and recorded cells were in very close contact with the electrodes. The live cell recording confirms in a single experiment that spike parameters vary significantly from cell to cell but the large number of cells recorded simultaneously provides the statistical significance.

Detecting extracellular carbonic anhydrase activity using membrane inlet mass spectrometry.

Current research into the function of carbonic anhydrases (CAs) in cell physiology emphasizes the role of membrane-bound CAs such as CA IX, which has been identified in malignant tumors and is associated with extracellular acidification as a response to hypoxia. Here we present a mass spectrometric method to determine the extent to which total CA activity is due to extracellular CA in whole cell preparations. The method is based on the biphasic rate of depletion of (18)O from CO(2) measured by membrane inlet mass spectrometry. The slopes of the biphasic depletion are a sensitive measure of the presence of CA inside and outside of the cells. This property is demonstrated here using suspensions of human red cells in which external CA was added to the suspending solution. It is also applied to breast and prostate cancer cells, both of which express exofacial CA IX. Inhibition of external CA is achieved by the use of a membrane impermeant inhibitor that was synthesized for this purpose, p-aminomethylbenzenesulfonamide attached to a polyethylene glycol polymer.