Despite many efforts to curtail drunk driving, alcohol-related traffic fatalities and injuries continue to be a major public health problem in the United States (U.S.) and most of the world. Technologies exist that prevent an automobile from starting if the driver's breath alcohol exceeds 20 milligrams per deciliter (mg/dL), but these devices are only fitted to vehicles of individuals who have been convicted of Driving Under the Influence (DUI). A new approach must be taken to reduce the incidence of drunk driving by integrating an alcohol sensor system in vehicles as part of the delivered hardware. The system must be fast, accurate, and contactless-meaning that a forced exhalation is not required to measure the concentration of alcohol on the breath. We report on a novel device, the Driver Alcohol Detection System for Safety (DADSS) Breath Alcohol Sensor System, which uses the mid-infrared region of the electromagnetic spectrum to concurrently monitor alcohol and expired carbon dioxide (CO2) to accurately quantify the breath alcohol concentration in samples that have been diluted in the atmosphere before being measured. The system was validated in a research laboratory with 70 male and female volunteers in 187 individual study days. Participants were given various doses of alcohol to consume and then breath and blood samples were collected simultaneously. Pearson correlation coefficients between the DADSS Breath Alcohol Sensor system and blood samples indicate a strong correlation between the measures, with an overall Pearson correlation of 0.8875 over an alcohol concentration range of 0-220 mg/dL. These results indicate that incorporating the DADSS system into motor vehicles has the potential to reduce the incidence of drunk driving.

INTRODUCTION:This review provides an overview of Roland R. Griffiths' history of research, and his mentoring and collaborating approach to science that contributed to his impact in behavioral and neuropsychopharmacology and psychedelic medicines development. APPROACH:The approach was to summarize studies in his major domains of research, including preclinical and clinical abuse liability assessment science, alcohol, benzodiazepines, caffeine, tobacco, and psychedelics. All the authors of this review were mentored by and collaborated with Griffiths-some over several decades-and were able to provide personal perspectives and insights into Griffiths' approach to science and scientific collaborations, including insights into how major research initiatives were conceived and evolved with personal anecdotes and quotes. OVERVIEW:Roland Griffiths is widely described as a "scientist's scientist," driven by his powerful curiosity to explore new frontiers in behavioral biology and neuropharmacology, with a passion to pursue humanity-serving science. His methodical approach to research development and then systematic extension and assessment of the generalizability of findings contributed to the evolution of thinking and scientific methods for abuse liability assessment, policy, and regulation of alcohol and other sedatives, tobacco and nicotine, caffeinated products and other stimulants, and in his last 2 decades, psychedelics. His inclusive and collegial approach to science, mentoring, and collaborating fueled his creativity and productivity and a fountain of innovation and research that will go on in perpetuity. Nowhere is this more evident than at the Johns Hopkins Center for Psychedelic and Consciousness Research established in the last few years of his life, in part because of his remarkable scientific life.

Background We previously demonstrated that standardized kudzu extract (NPI-031) reduced drinking in a four-week trial among non-treatment-seeking men diagnosed with alcohol abuse or dependence. The present study assessed the safety and efficacy of eight weeks of kudzu among treatment-seeking men and women with alcohol use disorder (AUD). Methods In this double-blind placebo-controlled study, nineteen individuals (12M, 7F; 27–65 years old) with AUD took either kudzu extract (750mg isoflavones) or matched placebo daily, combined with weekly counseling for eight weeks. Twice weekly laboratory visits monitored alcohol consumption (via daily diaries and timeline follow-back), medication adherence (via urinary riboflavin), safety (via blood chemistry), and adverse events. Results There were no significant differences in drinking at baseline, with 4.2 ± 0.7 heavy drinking days (HDDs) per week reported by the kudzu group (N=9; 5M, 4F) and 4.7 ± 0.6 in the placebo group (N=10; 7M, 3F). Medication adherence was excellent (>96%) with no adverse events or safety concerns noted. After 4 weeks of treatment, both groups decreased the number of HDDs per week by ~40%. Across the full 8-week treatment, the average reduction was 30% for kudzu extract and 44% for placebo. Conclusions In contrast to results from prior studies among non-treatment-seeking young adult men, kudzu did not perform better than placebo in reducing drinking among a treatment-seeking sample of men and women with AUD. Taken together, these data suggest that kudzu may help to reduce binge drinking but may not provide additional benefits to individuals who are enrolled in an effective AUD treatment program.

Background:Ecstasy is commonly used on weekends and linked to post-use mood declines. Laboratory studies with pure MDMA rarely detect residual effects, whereas naturalistic studies more often report mood reductions. The timing and contextual drivers of these effects remain unclear. Methods:Data from seventeen participants reporting weekend ecstasy use (10 male, 7 female; 19-38 years) were drawn from a previously conducted study and analyzed for temporal mood changes not identified in the original report. Participants completed observation weeks following both ecstasy-use and nonuse weekends. Daily diaries assessed mood (0-10), other affective states, drug use, and sleep-related measures. Weekly BDI-II and BAI scores were collected. Results:A significant Weekend Ecstasy X Day interaction was present (F(3,48) = 3.41, p = 0.037), driven by lower Monday mood after ecstasy-use weekends (t(16) = 2.36, p = 0.031). This effect remained after adjusting for other drug use (β = -1.44, p = 0.018), but was attenuated when hours in bed were included (β = -0.82, p = 0.17), which independently predicted lower mood (β = -0.29, p = 0.019). Mediation analyses indicated that increased time in bed largely accounted for the Monday decrease. No differences were found for the BDI-II and BAI. Exploratory analyses showed reduced Thursday physical tension/agitation after ecstasy-use weekends (p = 0.008). Conclusions:Residual mood effects appear Monday-specific and are attenuated when inactivity is considered, suggesting recovery-related behavior-not MDMA alone-may underlie post-use mood declines. Because increased time in bed may both reflect and influence low mood, directionality cannot be determined.

Individual differences in brain intrinsic functional connectivity (FC) and reactivity to nicotine cues are linked to variability in clinical outcomes in nicotine dependence. However, the relative contributions and potential interdependencies of these brain imaging-derived phenotypes in the context of craving and nicotine dependence are unclear. Moreover, it is unknown whether these relationships differ in individuals who smoke versus vape nicotine. To investigate these questions, eighty-six individuals who use nicotine daily (n = 67 smoking, n = 19 vaping) completed either a smoking or vaping cue-reactivity task and a resting-state scan during functional magnetic resonance imaging (fMRI). Validating the efficacy of the smoking and vaping tasks, both cohorts displayed robust reactivity to nicotine versus neutral cues in the default mode network (DMN) and the anterior insula (AI), a primary node of the salience network (SN), which did not habituate over time. In the smoking and vaping groups, lower prefrontal reactivity to nicotine versus neutral cues and greater resting-state FC between nodes of the SN and DMN were associated with higher cue-induced craving. Moreover, we found that the former partially mediated the latter, suggesting a mechanism in which high resting SN-DMN connectivity increases craving susceptibility partly via a constraining effect on regulatory prefrontal reactivity to cues. These relationships were not impacted by group, suggesting that links between brain function and craving are similar regardless of smoking or vaping nicotine.

Prefrontal and striatal glutamate plays an important role in modulating striatal dopamine levels and an imbal-ance in regional glutamate has been identified in several psychiatric conditions. We hypothesized that this imbalance also exists in cannabis use disorder (CUD). We recently quantified the difference in glutamate of dorsal anterior cingulate (dACC) and striatum regions in the frontostriatal pathway using proton MRS at baseline and on verified abstinent days 7 and 21 in chronic users of cannabis (n = 20) in comparison with age-and sex-matched non-using controls (n = 10). In addition, the Barratt Impulsiveness Scale-11 (BIS) was collected as a measure of inhibitory impulse control of the participants. We found that the difference in glutamate concentrations between the dACC and striatum (Delta dACC-strGlu) of the controls was significantly higher than that of cannabis users across the study timeline (F(1,28) = 18.32, p < 0.0005). The group difference was not affected by age, sex, or alcohol/ cigarette consumption. On abstinent day 7, Delta dACC-strGlu was significantly correlated with the corresponding Delta dACC-strGABA among the users (r = 0.837, p < 0.00001). On day 21, Delta dACC-strGlu was negatively associated with monthly cannabis use days (Spearman's rho =-0.444, p = 0.05). Self-reported BIS and its subscales were significantly altered among the users compared to the controls across the study timeline (total F(1,28) = 7.0, p = 0.013; non-planning F(1,28) = 16.1, p < 0.0005; motor F(1,28) = 5.9, p = 0.022; cognitive F(1,28) = 6.1, p = 0.019). These data provide preliminary evidence that chronic cannabis use may lead to a dACC-striatal glutamate imbalance in conjunction with poor impulse control.

Cues associated with smoking can induce relapse, which is likely driven by cue-induced neurobiological and physiological mechanisms. For instance, greater relapse vulnerability is associated with increases in cue-induced insula activation and heightened cortisol concentrations. Determining if there is a link between such cue-induced responses is critical given the need for biomarkers that can be easily measured in clinical settings and used to drive targeted treatment. Further, comprehensively characterising biological reactions to cues promises to aid in the development of therapies that address this specific relapse risk factor. To determine whether brain and cortisol responses to smoking cues are linked, this study recruited 27 nicotine-dependent tobacco-smoking individuals and acquired whole-brain functional activation during a cue reactivity task; salivary cortisol was measured before and after scanning. The results showed that increases in blood-oxygen-level-dependent activation in the right anterior insula and right dorsolateral prefrontal cortex (DLPFC) when viewing smoking versus neutral cues were positively correlated with a post-scan rise in salivary cortisol concentrations. These brain regions have been previously implicated in substance use disorders for their role in salience, interoception and executive processes. These findings show that those who have a rise in cortisol following smoking cue exposure also have a related rise in cue-induced brain reactivity, in brain regions previously linked with heightened relapse vulnerability. This is clinically relevant as measuring cue-induced cortisol responses is a more accessible proxy for assessing the engagement of cue-induced neurobiological processes associated with the maintenance of nicotine dependence.

Glutamate plays an important role in continued use of and relapse to abused substances. However, its involvement in cannabis withdrawal is still unclear. We hypothesize that regional glutamate is associated with the cannabis withdrawal syndrome and recently examined possible association of glutamate with cannabis withdrawal, using magnetic resonance spectroscopy (MRS), in non-treatment-seeking cannabis users. We recruited 26 frequent cannabis users and 11 age-matched non-using controls. Of the 37, 20 users (8f/12m) and 10 controls (5f/5m) completed a verified 21-day abstinence protocol. Dorsal anterior cingulate cortex (dACC) glutamate and γ-amino butyric acid (GABA) were measured with proton MRS at baseline and on abstinent days 7 and 21 in conjunction with measures of cannabis withdrawal and craving (MCQ), sleep difficulties (PSQI) and mood state. We used ANOVA to examine group differences in glutamate and GABA from baseline through day 21 and used linear regression to evaluate correlations between intra-individual glutamate and withdrawal symptoms. We found that self-reported anxiety severity (HAMA) was correlated with urinary THC/Cr ratios at baseline (r = 0.768, p = 0.000076) and abstinent day 7 (r = 0.5636, p = 0.0097), dACC glutamate was significantly lower in the users compared with the controls from baseline through day 21 (F = 5.90, p = 0.022), changes in glutamate between baseline and abstinent day 21 had a significantly negative correlation with corresponding changes in craving (r = −0.72, p = 0.005) after adjusting for age, consumption of alcohol/cigarettes, sleep difficulties, and urinary THC levels. These findings provide preliminary evidence that dACC glutamate is associated with the cannabis withdrawal syndrome.

Brain derived neurotrophic factor (BDNF) promotes the growth, differentiation, maintenance and survival of neurons. These attributes make BDNF a potentially powerful therapeutic agent. However, its charge, instability in blood, and poor blood brain barrier (BBB) penetrability have impeded its development. Here, we show that engineered clathrin triskelia (CT) conjugated to BDNF (BDNF-CT) and delivered intranasally increased hippocampal BDNF concentrations 400-fold above that achieved previously with intranasal BDNF alone. We also show that BDNF-CT targeted Tropomyosin receptor kinase B (TrkB) and increased TrkB expression and downstream signaling in iTat mouse brains. Mice were induced to conditionally express neurotoxic HIV Transactivator-of-Transcription (Tat) protein that decreases BDNF. Down-regulation of BDNF is correlated with increased severity of HIV/neuroAIDS. BDNF-CT enhanced neurorestorative effects in the hippocampus including newborn cell proliferation and survival, granule cell neurogenesis, synaptogenesis and increased dendritic integrity. BDNF-CT exerted cognitive-enhancing effects by reducing Tat-induced learning and memory deficits. These results show that CT bionanoparticles efficiently deliver BDNF to the brain, making them potentially powerful tools in regenerative medicine.

BACKGROUND:Anhedonia is a core symptom of depression that predicts worse treatment outcomes. Dysfunction in neural reward circuits is thought to contribute to anhedonia. However, whether laboratory-based assessments of anhedonia and reward-related neural function translate to adolescents' subjective affective experiences in real-world contexts remains unclear. METHODS:We recruited a sample of adolescents (n = 82; ages 12-18; mean = 15.83) who varied in anhedonia and measured the relationships among clinician-rated and self-reported anhedonia, behaviorally assessed reward learning ability, neural response to monetary reward and loss (as assessed with functional magnetic resonance imaging), and repeated ecological momentary assessment (EMA) of positive affect (PA) and negative affect (NA) in daily life. RESULTS:Anhedonia was associated with lower mean PA and higher mean NA across the 5-day EMA period. Anhedonia was not related to impaired behavioral reward learning, but low PA was associated with reduced nucleus accumbens response during reward anticipation and reduced medial prefrontal cortex (mPFC) response during reward outcome. Greater mean NA was associated with increased mPFC response to loss outcome. CONCLUSIONS:Traditional laboratory-based measures of anhedonia were associated with lower subjective PA and higher subjective NA in youths' daily lives. Lower subjective PA and higher subjective NA were associated with decreased reward-related striatal functioning. Higher NA was also related to increased mPFC activity to loss. Collectively, these findings demonstrate that laboratory-based measures of anhedonia translate to real-world contexts and that subjective ratings of PA and NA may be associated with neural response to reward and loss.

BackgroundDespite evidence that standard substance use disorder (SUD) treatment may be less effective in people with intellectual disability (ID), there is an absence of appropriate clinical tools with which to support them.ObjectivesThis study examined the clinical utility of an alcohol and other drug refusal skills intervention designed to be cognitively accessible to adults with IDMethodsThirty individuals at high risk for or in recovery from a SUD in developmental disability services (DDS) community residential and day habilitation settings participated in the two-week refusal skills group. Measures included pretest versus posttest improvement in refusal skill competency and baseline performance on a standardized verbal learning test.ResultsThere was a strong effect for refusal skill acquisition (p < .001); and the magnitude of skill acquisition was predicted by group attendance (p < .001) and not by individual differences in verbal learning ability (p = .074) or efficiency (p = .35).ConclusionsThe Refusal Skills Group is developmentally appropriate for people with mild ID in that: (1) they can learn and demonstrate refusal skills and (2) their skill acquisition is predicted more strongly by exposure to the intervention than by individual differences in learning characteristics. Delivering refusal skills in DDS settings familiar to clients increased their access to services and minimized disruption to their usual routines and schedules.

Cannabis withdrawal symptoms contribute to relapse, but the underlying mechanism remains unclear. We hypothesize that cannabis withdrawal may be associated with a reset of regional gamma-amino butyric acid (GABA) and glutamate concentrations secondary to changes in the endocannabinoid system during abstinence and conducted a study on this issue. We used magnetic resonance spectroscopy (MRS) to detect the associated changes of these neurochemicals in twenty-six frequent, recreational cannabis users and eleven age-matched non-using controls. Twenty users (8F/12M) and ten control (5F/5M) participants completed a verified 21-day abstinence period. Striatal GABA and glutamine concentrations were measured at baseline and on abstinence days 7 and 21 in conjunction with measures of cannabis withdrawal symptoms and mood state. Cannabis users reported increased self-reported ratings of cannabis-withdrawal-symptoms on abstinence day 7 relative to controls. Striatal glutamate + glutamine (Glx) group concentrations were elevated in cannabis users at baseline and abstinence days 7 and 21 (F = 7.16, p = 0.012), and changes in GABA concentration and withdrawal symptoms between baseline and abstinence day 7 were positively correlated (r = 0.550, p = 0.010). In addition, baseline striatal GABA concentrations were negatively correlated with withdrawal symptoms on abstinence day 7 (r = -0.680, p = 0.003). Our data demonstrate that striatal Glx was elevated in cannabis users and baseline striatal GABA correlated with withdrawal during the abstinence. In addition, striatal GABA may temporally correlate with selfreported withdrawal symptoms during the initial days of abrupt cannabis abstinence. These findings provide preliminary evidence that striatal GABA and Glx are associated with the severity of cannabis withdrawal.

Introduction: Orthodontic tooth movement is reliant on the process of bone remodeling, and a variety of medications impact the ability of teeth to move through bone. Marijuana is the most widely used recreational drug in the world, and early studies suggest the drug impacts bone remodeling as tetrahydrocannabinol binds to cannabinoid receptors which play a role in bone homeostasis. This study aimed to assess the impact of dronabinol on alveolar bone remodeling in rats with otherwise healthy tissue when subjected to orthodontic forces. Methods: Thirty male Sprague Dawley rats were equally allocated into 2 groups. Orthodontic appliances were placed in all animals, which consisted of a nickel-titanium coil ligated from the maxillary first molar to the central incisor. The appliance was activated to deliver a force to move teeth together. Over 21 days, daily injections of either dronabinol or the control (solvent) were given to the rats. Cephalometric analysis, histology, and bone remodeling profiles of both groups were analyzed and compared. Results: Teeth moved in both the dronabinol and control groups (P <0.05). Tooth movement in the control group followed the typical process of orthodontic tooth movement: periodontal width narrowing and bone resorption on the compression side of the tooth, with an overall decrease in the height of the alveolar bone. In contrast, the dronabinol group showed an abnormal response to tooth movement: no bone resorption on the compression side of the tooth, increased bone formation on the tension side, and the maintenance of the height of the alveolar crest. In the dronabinol group, there were also significantly more osteoclasts and osteoblasts in the alveolar bone than in the control group. Conclusions: These results demonstrate that dronabinol attenuates orthodontic tooth movement by decreasing bone resorption, which could have implications for other bone-related recovery processes.

Pooling magnetic resonance imaging (MRI) data across research studies, or utilizing shared data from imaging repositories, presents exceptional opportunities to advance and enhance reproducibility of neuroscience research. However, scanner confounds hinder pooling data collected on different scanners or across software and hardware upgrades on the same scanner, even when all acquisition protocols are harmonized. These confounds reduce power and can lead to spurious findings. Unfortunately, methods to address this problem are scant. In this study, we propose a novel denoising approach that implements a data-driven linked independent component analysis (LICA) to identify scanner-related effects for removal from multimodal MRI to denoise scanner effects. We utilized multi-study data to test our proposed method that were collected on a single 3T scanner, pre- and post-software and major hardware upgrades and using different acquisition parameters. Our proposed denoising method shows a greater reduction of scanner-related variance compared with standard GLM confound regression or ICA-based single-modality denoising. Although we did not test it here, for combining data across different scanners, LICA should prove even better at identifying scanner effects as between-scanner variability is generally much larger than within-scanner variability. Our method has great promise for denoising scanner effects in multi-study and in large-scale multi-site studies that may be confounded by scanner differences.