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The Center for Disease Control and Prevention estimates that 75% of reported cases of traumatic brain injury (TBI) are mild, where chronic pain and depression are 2 of the most common symptoms. In this study, we used a murine model of repeated mild TBI to characterize the associated pain hypersensitivity and affective-like behavior and to what extent microglial reactivity contributes to these behavioral phenotypes. Male and female C57BL/6J mice underwent sham or repeated mild traumatic brain injury (rmTBI) and were tested for up to 9 weeks postinjury, where an anti-inflammatory/neuroprotective drug (minocycline) was introduced at 5 weeks postinjury in the drinking water. Repeated mild traumatic brain injury mice developed cold nociceptive hypersensitivity and negative affective states, as well as increased locomotor activity and risk-taking behavior. Minocycline reversed negative affect and pain hypersensitivities in male but not female mice. Repeated mild traumatic brain injury also produced an increase in microglial and brain-derived neurotropic factor mRNA transcripts in limbic structures known to be involved in nociception and affect, but many of these changes were sex dependent. Finally, we show that the antiepileptic drug, gabapentin, produced negative reinforcement in male rmTBI mice that was prevented by minocycline treatment, whereas rmTBI female mice showed a place aversion to gabapentin. Collectively, pain hypersensitivity, increased tonic-aversive pain components, and negative affective states were evident in both male and female rmTBI mice, but suppression of microglial reactivity was only sufficient to reverse behavioral changes in male mice. Neuroinflammation in limbic structures seems to be a contributing factor in behavioral changes resulting from rmTBI.

IntroductionCo-use of tobacco and marijuana is common, and research suggests that marijuana use may be a barrier to smoking cessation. Research to date has not evaluated how marijuana use affects e-cigarette switching behaviors and related outcomes in a harm reduction trial.Aims and methodsThis secondary analysis includes African American (48%) and Latinx (52%) adult smokers randomized to the e-cigarette group (N = 114) of a harm reduction clinical trial from 2018 to 2019. Participants were provided JUUL e-cigarettes and encouraged to make an exclusive switch for 6 weeks. Our primary outcome was cigarettes smoked per week. Secondary health outcomes were e-cigarette substitution (calculated by measuring e-cigarette pod use), expired carbon monoxide (CO), and respiratory symptoms. Marijuana products were recorded at three timepoints and coded for combustion.ResultsMarijuana use during the study (n = 52, 46%) was not associated with week 6 cigarettes smoked or e-cigarette substitution, and combustible marijuana use was not associated with week 6 respiratory symptoms (ps > .05). After controlling for cigarettes smoked at week 6, combustible marijuana use was significantly associated with a 4.4 ppm increase in CO compared with no use of marijuana (p = .001).ConclusionsMarijuana use was not a barrier to switching to e-cigarettes in this 6-week trial. Marijuana use contributed to elevated CO, reflecting greater exposure to toxic combustion products, beyond the effects of cigarette smoking. Marijuana co-use may increase risk of adverse health outcomes and may be a confounding factor when using CO as an endpoint to bioverify exclusive e-cigarette use.ImplicationsThis is the first known study to examine the effects of marijuana use on smokers switching to e-cigarettes. Marijuana use was not a barrier to cigarette reduction in a 6-week randomized clinical trial. Marijuana use uniquely contributed to higher carbon monoxide among cigarette smokers, indicating greater exposure to toxic combustion products, which could increase risk of adverse health outcomes. Furthermore, combustible marijuana use may be a confounding factor when CO is used as an endpoint to bioverify exclusive e-cigarette use.

IntroductionDenial, or lack of awareness of problems related to substance misuse, is a common feature of drug use disorders and can affect engagement in treatment and recovery. This study tested for association of denial with severity of symptoms used in the diagnosis of Methamphetamine Dependence.MethodsThis secondary analysis used data from 69 participants (52.2% male) who met criteria for the diagnosis of Methamphetamine Dependence on the Structured Clinical Interview for DSM-IV (SCID). The association between diagnostic severity, determined from a SCID summary score (8 items), and denial, measured by the University of Rhode Island Change Assessment Scale (URICA) Precontemplation score, was tested by Pearson correlation. In post hoc t-tests, participants who differed on individual SCID items were compared on the Precontemplation score. The additional URICA subscales (Contemplation, Maintenance, Action) were also tested on a secondary basis.ResultsSCID summary scores were negatively correlated with URICA Precontemplation scores (P = .003). Post-hoc tests revealed that participants who denied continued methamphetamine use despite persistent or recurrent problems (SCID item 6) had significantly higher Precontemplation scores than those who endorsed these problems (t = 3.066, P = .003). In contrast, positive correlations were observed between diagnostic severity and greater openness/willingness to change on the URICA (eg, Maintenance, r = .26; P = .01).ConclusionsThe findings highlight the importance of a patient's insight regarding their addiction in clinical diagnosis. Because minimizing the impact of methamphetamine use may preclude or delay treatment, it is advised that self-report be supplemented to improve accuracy of diagnosis.

ImportanceFourth-generation nicotine salt pod system (NSPS) electronic cigarettes (e-cigarettes) are the leading class of e-cigarettes. They contain high nicotine concentrations, which may facilitate switching among smokers, but could also lead to increased exposure to nicotine and biomarkers of potential harm. African American and Latinx smokers experience significant tobacco-related health disparities. The potential of NSPS e-cigarettes to reduce smoking-related harm among these groups is unknown.ObjectiveTo compare the harm reduction potential of NSPS e-cigarette vs combustible cigarettes.Design, setting, and participantsThis unblinded randomized clinical trial compared 6 weeks of e-cigarette use vs cigarettes as usual from to 2018 to 2019 among smokers in the San Diego, California, and Kansas City, Missouri, areas. Participants included African American and Latinx adult combustible cigarette smokers who smoked at least 5 cigarettes/d on at least 25 of the past 30 days for at least 6 months and were interested in switching to e-cigarettes. Data were analyzed from September 18, 2019, to September 4, 2020.Interventions6 weeks of e-cigarette use in a choice of pod flavors (5% nicotine) along with brief education, training, and action planning to completely switch to e-cigarettes from combustible cigarettes. The control group smoked combustible cigarettes as usual.Main outcomes and measuresThe primary outcome was reduction in urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentration at week 6. Secondary outcomes were change in urinary cotinine, expired carbon monoxide (CO), respiratory symptoms, lung function, blood pressure, past 7-day consumption of combustible cigarettes, and switching rates (e-cigarette group only) at weeks 2 and 6.ResultsThis study included 186 participants, including 92 African American participants and 94 Latinx participants. The mean (SD) age was 43.3 (12.5) years, and 75 (40.3%) were women. Participants smoked a mean (SD) of 12.1 (7.2) cigarettes/d on 6.8 (0.6) d/wk at baseline. A total of 125 participants were randomized to the e-cigarette group and 61 were randomized to the control group. At baseline, median (interquartile range) NNAL was 124 (45-197) pg/mL in the e-cigarette group and 88 (58-197) pg/mL in the control group. At week 6, the e-cigarette group had significantly greater reductions in NNAL (relative risk [RR], 0.36 [95% CI, 0.23-0.54]; P

Introduction: University community members are critical to the success of their smoke and tobacco free (STF) policies. The present study evaluates changes in social enforcement-related attitudes and behaviors following introduction of a new online Tobacco Tracker tool in two university settings.Methods: Campus wide surveys were administered to current students, faculty, and staff at two California public universities with 100% STF policies before (November 2018; N = 5078) and after (December 2019-January 2020; N = 4853) introduction of Tobacco Tracker in February 2019. Prospective surveillance reports over 12 months from Tobacco Tracker, a GIS tool for the campus community to report tobacco use and related litter that displays crowdsourced maps of hotspots, were analyzed. Outcomes included awareness and self-reported use of a tobacco reporting tool, readiness for policy social enforcement, an Intellectual Social Affective (ISA) Engagement scale, and environmental surveillance reports from Tobacco Tracker.Results: In campus surveys, awareness of a tobacco reporting tool doubled (8.0%-16.9%, p < .0001), use of an online reporting tool tripled (1.1%-3.2%, p < .0001), and readiness to enforce the policy increased (p = .0008). ISA engagement did not change (p = .72). In Tobacco Tracker campus reports (N = 1163), active tobacco use was reported more frequently than tobacco-related litter.Conclusions: Tobacco Tracker is a promising tool for college communities to support STF policy. Introduction of Tobacco Tracker was associated with an increase in campus awareness and utilization of a reporting tool, readiness to enforce policy, and campus tobacco surveillance. Future research should determine how Tobacco Tracker may improve policy compliance.Implications: Tobacco Tracker is a promising tool for college communities to support smoke and tobacco free (STF) policy through active surveillance of smoking, vaping, and related litter on campus. Introduction of Tobacco Tracker was associated with changes in social enforcement-related attitudes and behaviors critical to realizing the preventive potential of STF policies. A crowdsourcing-based tool for monitoring tobacco use on college campuses can address a major barrier to social enforcement: discomfort confronting tobacco users. Further, it provides an alternative to punitive enforcement approaches and promises a sustainable solution to an infrastructure issue faced by many universities lacking resources to collect data on campus tobacco use and related litter. [ABSTRACT FROM AUTHOR]

Background and Aims: For electronic cigarettes (e‐cigarettes) to be a viable substitute for combustible cigarettes, it is likely that they must be rewarding enough for regular use, indicated by factors such as craving and dependence, important aspects of reinforcement. This study aimed to understand short‐term changes in measures of nicotine dependence between groups differing by use trajectory in a switching trial, and within group changes of these measures. Design Secondary data analysis of one arm of an e‐cigarette randomized clinical trial. Setting: San Diego, California and Kansas City, Missouri, United States. Participants: 114 African American (n = 60) and Latinx (n = 54) smokers (58.8% male) attempting to switch to nicotine salt pod system (NSPS) e‐cigarettes in a 6‐week trial. Measurements At week 6, participants were classified by use trajectory: exclusive smokers (n = 16), exclusive e‐cigarette (n = 32), or dual users (n = 66). E‐cigarette, cigarette, and total nicotine dependence (cigarette + e‐cigarette), use patterns, cigarette craving and nicotine withdrawal, and cotinine were assessed at baseline and week 6 using standard measures. Findings In between group comparisons, exclusive e‐cigarette and dual users showed greater reductions in cigarette dependence (e‐cigarette: −32.38, 95% CI = −37.7,−27.1; dual: −18.48, 95% CI = −22.2,−14.7), withdrawal (e‐cigarette: −6.25, 95% CI = −8.52,−3.98; dual: −3.18, 95% CI = −5.02,−1.34), craving (e‐cigarette: −11.44, 95% CI = −14.2,8.7; dual: −9.59, 95% CI = −11.6,−7.59), and cigarettes per day (CPD; e‐cigarette: −11.19, 95% CI = −13.1,−9.27; dual: −9.39, 95% CI = −11.3, −7.52) compared with exclusive smokers. In within group analyses, e‐cigarette and dual users showed reductions in craving and withdrawal from baseline to week 6. Exclusive e‐cigarette and dual users, maintained cotinine levels (all Ps > 0.05) and showed reductions in CPD and cigarette dependence (all Ps < 0.01). Findings were inconclusive regarding changes in total nicotine dependence from baseline to week 6 among exclusive e‐cigarette users (P = 0.123). Dual users showed increased total nicotine dependence (P < 0.001) and smokers showed decreased total dependence (P = 0.004). Conclusions: Smokers who switch to nicotine salt pod system e‐cigarettes maintain their nicotine levels and transfer their dependence, suggesting that nicotine salt pod system e‐cigarettes have a similar reinforcement potential to cigarettes and facilitate switching. [ABSTRACT FROM AUTHOR]

Prescription opioid abuse is a global crisis. New treatment strategies for pain and opioid use disorders are urgently required. We evaluated the effects of R -VK4-40, a highly selective dopamine (DA) D 3 receptor (D 3 R) antagonist, on the rewarding and analgesic effects of oxycodone, the most commonly abused prescription opioid, in rats and mice. Systemic administration of R -VK4-40 dose-dependently inhibited oxycodone self-administration and shifted oxycodone dose-response curves downward in rats. Pretreatment with R -VK4-40 also dose-dependently lowered break-points for oxycodone under a progressive-ratio schedule. To determine whether a DA-dependent mechanism underlies the impact of D 3 antagonism in reducing opioid reward, we used optogenetic approaches to examine intracranial self-stimulation (ICSS) maintained by optical activation of ventral tegmental area (VTA) DA neurons in DAT-Cre mice. Photoactivation of VTA DA in non-drug treated mice produced robust ICSS behavior. Lower doses of oxycodone enhanced, while higher doses inhibited, optical ICSS. Pretreatment with R -VK4-40 blocked oxycodone-enhanced brain-stimulation reward. By itself, R -VK4-40 produced a modest dose-dependent reduction in optical ICSS. Pretreatment with R -VK4-40 did not compromise the antinociceptive effects of oxycodone in rats, and R -VK4-40 alone produced mild antinociceptive effects without altering open-field locomotion or rotarod locomotor performance. Together, these findings suggest R -VK4-40 may permit a lower dose of prescription opioids for pain management, potentially mitigating tolerance and dependence, while diminishing reward potency. Hence, development of R -VK4-40 as a therapy for the treatment of opioid use disorders and/or pain is currently underway. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'. • R -VK4-40 is a novel, highly selective D 3 R antagonist. • R -VK4-40 inhibits oxycodone self-administration under FR and PR reinforcement schedules. • R -VK4-40 attenuates oxycodone-enhanced optogenetic brain-stimulation reward. • R -VK4-40 enhances the analgesic effects of oxycodone. [ABSTRACT FROM AUTHOR]

Introduction: Denial, or lack of awareness of problems related to substance misuse, is a common feature of drug use disorders and can affect engagement in treatment and recovery. This study tested for association of denial with severity of symptoms used in the diagnosis of Methamphetamine Dependence., Methods: This secondary analysis used data from 69 participants (52.2% male) who met criteria for the diagnosis of Methamphetamine Dependence on the Structured Clinical Interview for DSM-IV (SCID). The association between diagnostic severity, determined from a SCID summary score (8 items), and denial, measured by the University of Rhode Island Change Assessment Scale (URICA) Precontemplation score, was tested by Pearson correlation. In post hoc t -tests, participants who differed on individual SCID items were compared on the Precontemplation score. The additional URICA subscales (Contemplation, Maintenance, Action) were also tested on a secondary basis., Results: SCID summary scores were negatively correlated with URICA Precontemplation scores ( P  = .003). Post-hoc tests revealed that participants who denied continued methamphetamine use despite persistent or recurrent problems (SCID item 6) had significantly higher Precontemplation scores than those who endorsed these problems ( t  = 3.066, P  = .003). In contrast, positive correlations were observed between diagnostic severity and greater openness/willingness to change on the URICA (eg, Maintenance, r  = .26; P  = .01)., Conclusions: The findings highlight the importance of a patient's insight regarding their addiction in clinical diagnosis. Because minimizing the impact of methamphetamine use may preclude or delay treatment, it is advised that self-report be supplemented to improve accuracy of diagnosis., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)