Exenatide Adjunct to Nicotine Patch Facilitates Smoking Cessation and May Reduce Post-Cessation Weight Gain: A Pilot Randomized Controlled Trial.

INTRODUCTION: Approved pharmacological treatments for smoking cessation are modestly effective, underscoring the need for improved pharmacotherapies. Glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the rewarding effects of nicotine in preclinical studies. We examined the efficacy of extended-release exenatide, a GLP-1R agonist, combined with nicotine replacement therapy (NRT, patch) for smoking cessation, craving, and withdrawal symptoms, with post-cessation body weight as a secondary outcome. METHODS: Eighty-four prediabetic and/or overweight smokers were randomized (1 : 1) to once-weekly placebo or exenatide, 2 mg, subcutaneously. All participants received NRT (21 mg) and brief smoking cessation counseling. Seven-day point prevalence abstinence (expired CO level ≤5 ppm), craving, withdrawal, and post-cessation body weight were assessed following 6 weeks of treatment. A Bayesian approach for analyzing generalized linear models yielded posterior probabilities (PP) to quantify the evidence favoring hypothesized effects of treatment on the study outcomes. RESULTS: Exenatide increased the risk for smoking abstinence compared to placebo (46.3% and 26.8%, respectively), (risk ratio [RR] = 1.70; 95% credible interval = [0.96, 3.27]; PP = 96.5%). Exenatide reduced end-of-treatment craving in the overall sample and withdrawal among abstainers. Post-cessation body weight was 5.6 pounds lower in the exenatide group compared to placebo (PP = 97.4%). Adverse events were reported in 9.5% and 2.3% of participants in the exenatide and placebo groups, respectively. CONCLUSIONS: Exenatide, in combination with the NRT improved smoking abstinence, reduced craving and withdrawal symptoms, and decreased weight gain among abstainers. Findings suggest that the GLP-1R agonist strategy is worthy of further research in larger, longer duration studies. IMPLICATIONS: Despite considerable progress in tobacco control, cigarette smoking remains the leading cause of preventable disease, disability, and death. In this pilot study, we showed that extended-release exenatide, a glucagon-like peptide-1 receptor agonist, added to the nicotine patch, improved abstinence and mitigated post-cessation body weight gain compared to patch alone. Further research is needed to confirm these initial positive results.

Suicidal behaviors and attention deficit hyperactivity disorder (ADHD): a cross-sectional study among Chinese medical college students.

BACKGROUNDS: Associations between attention deficit hyperactivity disorder (ADHD) subtypes and suicidal behaviors remains unclear. The current study explored the prevalence of suicidal behaviors, and its association with ADHD among Chinese medical students. METHODS: Five thousand six hundred ninety-three medical college students participated. Symptoms of suicidal behaviors, ADHD, anxiety, depression, tobacco and alcohol use were assessed using online questionnaires. RESULTS: The prevalence of lifetime suicidal ideation, suicide plans, and suicide attempts among medical college students were 27.5, 7.9 and 14.8% respectively. Participants with ADHD predominantly inattentive type (ADHD-I) had more than fivefold increased odds of suicidal behaviors, the adjusted odds ratios (ORs) of ADHD-I and ADHD combined type (ADHD-C) remained significant after controlling for confounding factors. CONCLUSIONS: ADHD is associated with high risk of suicidal behaviors. ADHD-I and ADHD-C were strongly associated with suicidal behaviors independent of comorbidities. The finding suggests the importance of addressing ADHD symptoms in suicide prevention.

The prevalence, metabolic disturbances and clinical correlates of recent suicide attempts in Chinese inpatients with major depressive disorder.

BACKGROUND: Metabolic disturbances have been correlated with suicidality, but little is known about the association between suicide risk and metabolic disturbances among individuals with depression. This study was to evaluate the prevalence and clinical correlations, especially cardio-metabolic associated factors of recent suicide attempts in Chinese patients with major depressive disorder (MDD). METHODS: A total of 288 MDD inpatients were recruited. Their clinical and demographic data together with plasma glucose, lipid and thyroid function parameters were collected. Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS) and Eysenck Personality Questionnaire (EPQ) were rated for most of the patients. RESULTS: Of these MDD inpatients, 20.14% had attempted suicide during the past 1 month. Compared to those who had not attempted suicide, the suicide attempters had a significantly longer duration of illness, lower low-density lipoprotein (LDL) cholesterol, lower total cholesterol, and more psychotic symptoms. However, all these significant results did not survive after the bonferroni correction (all p > 0.05). A logistic regression analysis indicated that suicide attempts were associated with the lower total cholesterol and more psychotic symptoms. CONCLUSIONS: Our findings support the hypothesis of the association of low plasma cholesterol level and recent suicidal attempts in patients with MDD.

Use of Guanfacine for Cannabis Use Disorder and Related Symptomology.

BACKGROUND AND OBJECTIVES: No medication has Food and Drug Administration approval for cannabis use disorder (CUD), and most medication development focuses on the withdrawal syndrome. We evaluated the effects of short-term treatment using the α-2A-adrenergic receptor agonist, guanfacine, on withdrawal symptoms in volunteers with CUD and a history of early onset of cannabis use. METHODS: Non-treatment-seeking healthy volunteers (n = 7) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for CUD participated in a two-phase, within-subjects study. Volunteers received placebo or guanfacine (3 mg/day) for the first 8-day inpatient study and the alternative medication for the second 8-day inpatient study. On day 1 of both treatment periods, participants received 30 mg of synthetic Δ9 -tetrahydrocannabinol for standardization of abstinence onset. On days 2 to 7, participants received study medication. Cannabis withdrawal symptoms, sleep, craving, and physiology were assessed on all inpatient days. RESULTS: Compared with placebo, guanfacine did not show significant effects on withdrawal, craving, or sleep, although there were trends for guanfacine to increase positive mood symptoms and decrease craving-associated compulsivity. DISCUSSION AND CONCLUSIONS: Compared with former studies, we could not prove significant improvement in sleep or decrease of negative symptoms, but we found trends for increased positive mood symptoms. Our data did not show significant effects of guanfacine on withdrawal symptoms or craving. Due to early and longer cannabis use, our subjects indicate a great severity of illness increasing the likelihood of treatment resistance. SCIENTIFIC SIGNIFICANCE: On the basis of trends demonstrated here and other lines of evidence, further investigation is warranted regarding the utility of guanfacine as a potential treatment for CUD. (Am J Addict 2019;00:1-10).

Guanfacine Attenuates Adverse Effects of Dronabinol (THC) on Working Memory in Adolescent-Onset Heavy Cannabis Users: A Pilot Study.

The cannabinoid-1 receptor (CB1R) agonist Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, adversely effects working memory performance in humans. The α2A-adrenoceptor (AR) agonist guanfacine improves working memory performance in humans. The authors aimed to determine the effects of short-term (6 days) treatment with guanfacine on adverse cognitive effects produced by THC. Employing a double-blind, placebo-controlled crossover design, the cognitive, subjective, and cardiovascular effects produced by oral THC (20 mg) administration were determined twice in the same cannabis users: once after treatment with placebo and once after treatment with guanfacine (3 mg/day). Compared with performance at baseline, THC negatively affected accuracy on spatial working memory trials while participants were maintained on placebo (p=0.012) but not guanfacine (p=0.497); compared with placebo, accuracy was significantly (p=0.003, Cohen's d=-0.640) improved while individuals were treated with guanfacine. Similarly, compared with baseline, THC increased omission errors on an attentional task while participants were maintained on placebo (p=0.017) but not on guanfacine (p=0.709); compared with placebo, there were significantly (p=0.034, Cohen's d=0.838) fewer omissions while individuals were maintained on guanfacine. Although THC increased visual analog scores of subjective effects and heart rate, these increases were similar during treatment with placebo and guanfacine. THC did not significantly affect performance of a recognition memory task or blood pressure while individuals were maintained on either treatment. Although preliminary, these results suggest that guanfacine warrants further testing as a potential treatment for cannabis-induced cognitive deficits.

FAAH variant Pro129Thr modulates subjective effects produced by cocaine administration.

BACKGROUND AND OBJECTIVES: The endogenous cannabinoid anandamide (AEA), an agonist at type-1 cannabinoid (CB1) receptors, is metabolized by fatty acid amide hydrolase (FAAH). The common variant rs324420 C->A within the FAAH gene on chromosome 1 codes for a missense substitution (Pro129Thr), resulting in decreased FAAH activity and increased endocannabinoid potentiation. This FAAH variant has been linked to alterations in mood and stress reactivity, as well as being independently linked to increased risk for addiction. We hypothesized that cocaine use disordered (CUD) participants with the FAAH Pro129 Thr variant would exhibit a distinct profile of cocaine-induced subjective effects in the laboratory. METHODS: A total of 70 CUD participants received intravenous doses of saline (placebo, 0 mg) and cocaine (20, 40 mg) in a lab-controlled setting and rated 10 subjective effect measures prior to and following saline and cocaine administration, using a Visual Analog Scale (VAS). RESULTS: The variant allele was associated with increased cocaine-induced subjective ratings for "Drug Effect," "High," and "Depressed." The prevalence of the variant allele A and the AA genotypes were greater in our CUD group than in the general population (A allele: 47% vs. 34%; AA genotype: 30% vs. 13%; p < .05). Finally, the reported amount and frequency of tobacco and cocaine use was higher in subjects with the AC/AA allele. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These results add to existing evidence that this variant of the FAAH genotype may be over-represented among those who have CUD, and this over-representation may result from greater subjective responses to cocaine administration. (Am J Addict 2018;27:567-573).

Subjective and Cardiovascular Effects of Intravenous Methamphetamine during Perindopril Maintenance: A Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study.

BACKGROUND: Our pilot study suggested that the angiotensin-converting enzyme inhibitor perindopril might reduce some subjective effects produced by i.v. methamphetamine. We characterized the impact of a wider range of perindopril doses on methamphetamine-induced effects in a larger group of non-treatment-seeking, methamphetamine-using volunteers. METHODS: Before treatment, participants received 30mg methamphetamine. After 5 to 7 days of perindopril treatment (0, 4, 8, or 16mg/d), participants received 15 and 30mg of methamphetamine on alternate days. Before and after treatment, participants rated subjective effects and cardiovascular measures were collected. RESULTS: Prior to treatment with perindopril, there were no significant differences between treatment groups on maximum or peak subjective ratings or on peak cardiovascular effects. Following perindopril treatment, there were significant main effects of treatment on peak subjective ratings of "anxious" and "stimulated"; compared to placebo treatment, treatment with 8mg perindopril significantly reduced peak ratings of both anxious (P=.0009) and stimulated (P=.0070). There were no significant posttreatment differences between groups on peak cardiovascular effects. CONCLUSIONS: Moderate doses of perindopril (8mg) significantly reduced peak subjective ratings of anxious and stimulated as well as attenuated many other subjective effects produced by methamphetamine, likely by inhibiting angiotensin II synthesis. Angiotensin II is known to facilitate the effects of norepinephrine, which contributes to methamphetamine's subjective effects. The lack of a classic dose-response function likely results from either nonspecific effects of perindopril or from between-group differences that were not accounted for in the current study (i.e., genetic variations and/or caffeine use). The current findings suggest that while angiotensin-converting enzyme inhibitors can reduce some effects produced by methamphetamine, more consistent treatment effects might be achieved by targeting components of the renin-angiotensin system that are downstream of angiotensin-converting enzyme.

"Just one bad high:" considering synthetic cannabinoid outcome expectancies in adolescents.

BACKGROUND/OBJECTIVES: Certain medical consequences seem unique to synthetic cannabinoid (SC) and not cannabis use. We report the case of an adolescent, whose drug expectancies appear to minimize the severity of SC-related adverse events. METHODS/RESULTS: An 18-year-old male presented with altered mental status and seizure, complicated by respiratory failure. He was stabilized and on discharge, despite counseling on the harms of SC usage, the patient planned to resume use, insisting that the hospitalization was "just one bad high". DISCUSSION/CONCLUSIONS/SCIENTIFIC SIGNIFICANCE: Diminished negative expectancies related to SC use among adolescents may reflect generalizations from cannabis. Effective interventions should counter cannabis-related expectancies of minimal harm. (Am J Addict 2016;XX:1-3).

Safety and Preliminary Efficacy of the Acetylcholinesterase Inhibitor Huperzine A as a Treatment for Cocaine Use Disorder.

BACKGROUND: Cholinergic transmission is altered by drugs of abuse and contributes to psychostimulant reinforcement. In particular, acetylcholinesterase inhibitors, like huperzine A, may be effective as treatments for cocaine use disorder. METHODS: The current report describes results from a double-blind, placebo-controlled study in which participants (n=14-17/group) were randomized to huperzine A (0.4 or 0.8 mg) or placebo. Participants received randomized infusions of cocaine (0 and 40 mg, IV) on days 1 and 9. On day 10, participants received noncontingent, randomized infusions of cocaine (0 and 20mg, IV) before making 5 choices to receive additional infusions. RESULTS: Huperzine A was safe and well-tolerated and compared with placebo, treatment with huperzine A did not cause significant changes in any cocaine pharmacokinetic parameters (all P>.05). Time-course and peak effects analyses show that treatment with 0.4 mg of huperzine A significantly attenuated cocaine-induced increases of "Any Drug Effect," "High," "Stimulated," "Willing to Pay," and "Bad Effects" (all P>.05). CONCLUSIONS: The current study represents a significant contribution to the addiction field since it serves as the first published report on the safety and potential efficacy of huperzine A as a treatment for cocaine use disorder.

Safety and efficacy of varenicline to reduce positive subjective effects produced by methamphetamine in methamphetamine-dependent volunteers.

Methamphetamine use is increasing in the US. Although there are no Food and Drug Administration (FDA)-approved medications for methamphetamine dependence, preclinical and clinical studies suggest that methamphetamine users may benefit from treatments that enhance cholinergic neurotransmission. Consequently, we determined the safety and the efficacy of varenicline treatment, a partial agonist at α4ß2 and a full agonist at α7 nicotinic acetylcholine receptors, to reduce positive subjective effects produced by smoked methamphetamine. Additionally, the effects of treatment with varenicline on the cardiovascular and reinforcing effects of methamphetamine were determined. We conducted a double-blind, placebo-controlled, within-subjects trial of varenicline vs. placebo in methamphetamine-dependent volunteers who were not seeking treatment. Participants were randomly assigned to receive one dose of varenicline (0, 1, or 2 mg) po BID, titrated up to the target dose over days 1-7, during each of three separate inpatient phases. Safety measures included the frequency, duration, severity, and relatedness of adverse events reported. Positive subjective effects included 'Any drug effect', 'High', 'Good effects', 'Stimulated', and 'Drug liking', which were rated by participants before and for 1 h after smoking methamphetamine (0, 10, and 30 mg). There were no serious adverse events and no differences in adverse events reported during the three phases. Varenicline (2 mg) significantly reduced ratings of 'Any drug effect' and 'Stimulated', as well as attenuated ratings of 'High', 'Drug liking', and 'Good effects', produced by methamphetamine (30 mg). The ability of varenicline to attenuate the positive subjective effects of methamphetamine in the laboratory suggests that varenicline should continue to be explored as a treatment for methamphetamine dependence.

Neurocognitive Correlates of Cerebellar Volumetric Alterations in Youth with Pediatric Bipolar Spectrum Disorders and Bipolar Offspring.

BACKGROUND: Emerging evidence points towards the involvement of the cerebellum in the processing of emotions and pathophysiology of mood disorders. However, cerebellar and related cognitive alterations in youth with pediatric bipolar disorder (PBD) and those at high risk to develop the disorder, such as bipolar offspring (BD-OFF) are not clearly defined. OBJECTIVE: To investigate cerebellar gray and white matter volumes, cognition, and their relationship in youth with PBD and BD-OFF. METHODS: Thirty youth (7 to 17 years, inclusive) with PBD, 30 BD-OFF and 40 healthy controls (HC) were recruited. Study participants underwent a computer-based cognitive battery assessing affective processing, executive function, attention, psychomotor speed, and learning. Three-tesla MRI scan was performed to assess cerebellar white and gray matter volumes. Cerebellar segmentation was performed with FreeSurfer. Statistical analyses include between-group differences in cognitive domains, cerebellar gray, and white matter volumes. Relationships between cerebellar volumes and cognitive domains were examined. RESULTS: Youth with PBD showed greater cerebellar gray matter volumes than both BD-OFF and HC, whereas no differences were present between BD-OFF and HC. Both youth with PBD and BD-OFF showed altered processing of negative emotions and a bias towards positive emotions. In youth with PBD and BD-OFF, greater impairment in the processing of emotions correlated with greater cerebellar gray matter volumes. CONCLUSION: The present findings corroborate hypotheses on cerebellar involvement in the processing of emotions and the pathophysiology of PBD. The presence of cerebellar dysfunction in BD-OFF is unclear.

Exenatide as an adjunct to nicotine patch for smoking cessation and prevention of postcessation weight gain among treatment-seeking smokers with pre-diabetes and/or overweight: study protocol for a randomised, placebo-controlled clinical trial.

INTRODUCTION: Obesity and smoking are the two leading causes of preventable death in the USA. Unfortunately, most smokers gain weight after quitting. Postcessation weight gain (PCWG) is frequently cited as one of the primary barriers to a quit attempt and a common cause of relapse. Further, excessive PCWG may contribute to the onset or progression of metabolic conditions, such as hyperglycaemia and obesity. The efficacy of the current treatments for smoking cessation is modest, and these treatments have no clinically meaningful impact on mitigating PCWG. Here, we outline a novel approach using glucagon-like peptide 1 receptor agonists (GLP-1RA), which have demonstrated efficacy in reducing both food and nicotine intake. This report describes the design of a double-blind, placebo-controlled, randomised clinical trial that evaluates the effects of the GLP-1RA exenatide as an adjunct to nicotine patches on smoking abstinence and PCWG. METHODS AND ANALYSIS: The study will be conducted at two university-affiliated research sites in Houston, Texas, the UTHealth Center for Neurobehavioral Research on Addiction and Baylor College of Medicine Michael E. DeBakey VA Medical Centre. The sample will consist of 216 treatment-seeking smokers with pre-diabetes (haemoglobin A1c of 5.7%-6.4%) and/or overweight (body mass index of 25 kg/m2 or above). Participants will be randomised (1:1) to receive subcutaneous injections of placebo or 2 mg exenatide, once weekly for 14 weeks. All participants will receive transdermal nicotine replacement therapy and brief smoking cessation counselling for 14 weeks. The primary outcomes are 4-week continuous abstinence and changes in body weight at the end of treatment. The secondary outcomes are (1) abstinence and changes in body weight at 12 weeks post end of treatment and (2) changes in neuroaffective responses to cigarette-related and food-related cues as measured by electroencephalogram. ETHICS AND DISSEMINATION: The study has been approved by the UTHealth Committee for the Protection of Human Subjects (HSC-MS-21-0639) and Baylor College of Medicine Institutional Review Board (H-50543). All participants will sign informed consent. The study results will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT05610800.

Neurocircuitry basis of the opioid use disorder-post-traumatic stress disorder comorbid state: conceptual analyses using a dimensional framework.

Understanding the interface between opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) is challenging. By use of a dimensional framework, such as research domain criteria, convergent and targetable neurobiological processes in OUD-PTSD comorbidity can be identified. We hypothesise that, in OUD-PTSD, circuitry that is implicated in two research domain criteria systems (ie, negative valence and cognitive control) underpins dysregulation of incentive salience, negative emotionality, and executive function. We also propose that the OUD-PTSD state might be systematically investigated with approaches outlined within a neuroclinical assessment framework for addictions and PTSD. Our dimensional analysis of the OUD-PTSD state shows how first-line therapeutic approaches (ie, partial µ-type opioid receptor [MOR1] agonism) modulate overlapping neurobiological and clinical features and also provides mechanistic rationale for evaluating polytherapeutic strategies (ie, partial MOR1 agonism, κ-type opioid receptor [KOR1] antagonism, and α-2A adrenergic receptor [ADRA2A] agonism). A combination of these therapeutic mechanisms is projected to facilitate recovery in patients with OUD-PTSD by mitigating negative valence states and enhancing executive control.

Comorbid alcohol use and post-traumatic stress disorders: Pharmacotherapy with aldehyde dehydrogenase 2 inhibitors versus current agents.

The increased risk of alcohol use disorder (AUD) in individuals with post-traumatic stress disorder (PTSD) is well-documented. Compared to individuals with PTSD or AUD alone, those with co-existing PTSD and AUD exhibit greater symptom severity, poorer quality of life, and poorer treatment outcomes. Although the treatment of comorbid AUD is vital for the effective management of PTSD, there is a lack of evidence on how to best treat comorbid PTSD and AUD, and currently, there are no FDA-approved treatments for the PTSD-AUD comorbidity. The objective of this manuscript is to review the evidence of a promising target for treating the AUD-PTSD comorbidity. First, we summarize the epidemiological evidence and review the completed clinical studies that have tested pharmacotherapeutic approaches for co-existing AUD and PTSD. Next, we summarize the shared pathological factors between AUD and PTSD. We conclude by providing a rationale for selectively inhibiting aldehyde dehydrogenase-2 as a potential target to treat comorbid AUD in persons with PTSD.

Cognitive correlates of impulsive aggression in youth with pediatric bipolar disorder and bipolar offspring.

BACKGROUND: Youth with bipolar disorder (BD) and offspring of individuals with BD (BD-OFF) are characterized by higher levels of impulsive and overt aggression. The cognitive basis underlying these aggressive behaviors are not clarified in this population. The aim of this study was to investigate the relationship between cognitive alterations and aggressive behavior in youth with BD and BD-OFF. METHODS: Forty-two youth with BD, 17 BD-OFF and 57 healthy controls (HCs) were administered the Modified Overt Aggression Scale (MOAS), the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Young Mania Rating Scale (YMRS) and the Children's Depression Rating Scale (CDRS). Multiple linear regression analyses were performed in the three groups separately. In each group, tests scores from the CANTAB were predictors. MOAS subscale scores and MOAS total scores were dependent variables. Results are corrected for age, IQ and mood state. RESULTS: Both youth with BD and BD-OFF showed positive correlations between impairment in executive functions and levels of verbal aggression. In youth with BD, altered processing of either positive and negative stimuli positively correlated with MOAS total scores, whereas in BD-OFF, such relationship was negative. CONCLUSIONS: Impulsive aggressive behaviors in youth with BD arise from a combination of altered affective processing and executive dysfunction. The negative relationship between affective processing and aggression in BD-OFF suggested the presence of possible mechanisms of resilience in this population.

Cortical Correlates of Impulsive Aggressive Behavior in Pediatric Bipolar Disorder.

Background: Impulsive aggression represents a frequent characteristic of pediatric bipolar disorder (PBD). Cortical alterations associated with impulsive aggression and its multiple facets have not been investigated yet in youth with bipolar disorder. Aim: To investigate the relationship between cortical thickness and facets of impulsive aggression in youth with PBD. Materials and Methods: Twenty-three youth with PBD and 23 healthy controls (HC) were administered the aggression questionnaire (AQ) and underwent 3T magnetic resonance imaging scan. Cortical thickness was assessed with FreeSurfer. Canonical correlation analyses were used to investigate the relationship between AQ total and subscale scores and cortical thickness in youth with PBD. Results: Youth with PBD had increased scores in the subscales of AQ-anger and AQ-hostility and cortical thinning in in areas belonging to the affective network (AN), frontoparietal network (FPN) and cingulo-opercular network (CON), i.e., right rostral anterior cingulate, right caudal anterior cingulate, right lateral orbitofrontal, right medial orbitofrontal, left and right inferior parietal, left posterior cingulate, left and right supramarginal left lingual cortices. Greater thickness in these networks positively correlated with the AQ-hostility subscale and negatively correlated with AQ-anger subscale. Conclusions: The opposite patterns observed between areas belonging to AN, FPN, CON, and the two facets of IA, namely anger and hostility, corroborate clinical findings supporting the different nature of these two constructs.

A randomized trial of safety and pharmacodynamic interactions between a selective glucocorticoid receptor antagonist, PT150, and ethanol in healthy volunteers.

PT150, a novel competitive glucocorticoid receptor (GR) antagonist, has proven safe in animal models, healthy volunteers, and people with depression. Our study is the first to investigate PT150's safety with alcohol use. The primary objective of this study was to evaluate pharmacodynamic interactions between ethanol and PT150 in healthy subjects. This single-site, Phase I pilot trial consisted of community-recruited, healthy, alcohol-experienced participants aged 21-64 years. Of 32 participants screened, 11 were enrolled and randomized, one of which withdrew before intervention. PT150 (900 mg/day) was administered orally to all participants for five days. All participants received two beverage challenges on Day 1 (before PT150 administration) and Day 5 (after PT150 administration). On challenge days, they received both alcohol (16% ethanol) and placebo (1% ethanol) beverages in random order. Primary outcomes included breath alcohol level, blood pressure, heart rate, adverse events, and electrocardiogram changes. There were no statistically significant differences in vital signs or estimated blood alcohol concentrations between PT150 non-exposed and exposed groups during the ethanol challenge. There were no clinically significant abnormal electrocardiograms or serious adverse events. These data show that administration of PT150 with concurrent alcohol use is safe and well-tolerated. This study supports a future pharmacokinetic interaction study between PT150 and alcohol.Trial Registration ClinicalTrials.gov Identifier: NCT03548714.

Recovery from impaired working memory performance during chronic Δ-9-tetrahydrocannabinol administration to adolescent rhesus monkeys.

BACKGROUND: The relationship between adolescent cannabis use and susceptibility to persistent cognitive impairments is poorly understood. AIMS: We examined the effects of repeated exposure to Δ-9-tetrahydrocannabinol (THC) on reinforcement-related learning and performance of spatial working memory (WM) tasks of varying difficulty in adolescent monkeys. METHODS: Seven pairs of male adolescent rhesus monkeys, matched for baseline cognitive performance, received vehicle or THC intravenously 5 days/week for 12 months. Performance on 4-item spatial WM trials was assessed throughout the 12-month study period. At the 6-month time point, more difficult novel and distractor 8-item spatial WM trials were added. Residual effects on performance were determined 23 or 71 h after THC or vehicle administration throughout the study. RESULTS/OUTCOMES: Relative to vehicle-exposed animals, repeated THC exposure was initially associated with significantly slower improvement in performance accuracy on 4-item spatial WM trials; however, this performance difference gradually diminished such that by month 12, accuracy did not significantly differ between vehicle and THC groups. Similarly, for the novel and distractor 8-item trials introduced at month 6, performance accuracy improved more slowly in the THC than in the vehicle group, despite comparable performance between groups on the 4-item task during this same period. CONCLUSIONS/INTERPRETATION: These findings suggest that compared to vehicle exposure, THC exposure during adolescence impairs the reinforcement-related learning process required for improved performance on spatial WM tasks, but this impairment might be overcome with continued training, even in the face of ongoing THC exposure.

Subtherapeutic Acetazolamide Doses as a Noninvasive Method for Assessing Medication Adherence.

Adherence monitoring is a vital component of clinical efficacy trials, as the regularity of medication consumption affects both efficacy and adverse effect profiles. Pill-counts do not confirm consumption, and invasive plasma assessments can only assist post hoc assessments. We previously reported on the pharmacokinetics of a potential adherence marker to noninvasively monitor dosage consumption during a trial without breaking a blind. We reported that consumption cessation of subtherapeutic 15 mg acetazolamide (ACZ) doses showed a predictable urinary excretion decay that was quantifiable for an extended period. The current study describes the clinical implementation of 15 mg ACZ doses as an adherence marker excipient in distinct cohorts taking ACZ for different "adherence" durations. We confirm that ACZ output did not change (accumulate) during 18-20 days of adherence, and developed and assessed urinary cutoffs as nonadherence indicators. We demonstrate that whereas an absolute concentration cutoff (989 ng/mL) lacked sensitivity, a creatinine normalized equivalent (1,376 ng/mg ACZ) was highly accurate at detecting nonadherence. We also demonstrate that during nonadherent phases of three trials, creatinine-normalized urinary ACZ elimination was reproducible within and across trials with low variability. Excretion was first order, with a decay half-life averaging ~ 2.0 days. Further, excretion remained quantifiable for 14 days, providing a long period during which the date of last consumption might be determined. We conclude that inclusion of 15 mg ACZ as a dosage form adherence marker excipient, provides a reliable and sensitive mechanism to confirm medication consumption and detect nonadherence during clinical efficacy trials.

An Evaluation of Yoga and Meditation to Improve Attention, Hyperactivity, and Stress in High-School Students.

Objective: Problems with attention and stress are common in children and predict academic difficulties and other behavioral and emotional problems. Mind-body interventions such as yoga and meditation improve attention and reduce stress. In this study, we examined the impact of Hatha yoga on attention and stress in ninth graders. Design: A total of 174 ninth graders from a Texas high school were enrolled in the study. Teachers assigned students to a yoga group (YG) or control group (CG) based on their class schedule. The YG participated in 25-min Hatha yoga classes twice weekly over 12 weeks (n = 123). The CG included 51 students. Student self-reports on measures of inattention and hyperactivity (the strengths and weaknesses of ADHD [attention-deficit/hyperactivity disorder] symptoms and normal behavior rating scale for ADHD) and stress (perceived stress scale) were obtained at baseline and at 12 weeks. Results: There were no significant differences in baseline levels of inattention (p = 0.86), hyperactivity (p = 0.25), and perceived stress (p = 0.28) between the YG and CG. Regarding inattention scores, there was a significant interaction of group and time (b = -1.09, standard error [SE] = 0.30, p < 0.001). Pairwise t-tests showed a significant reduction in inattention for the YG (d = 0.27) but a significant increase in inattention for the CG. Regarding hyperactivity, there was no significant interaction of group and time (b = -0.43, SE = 0.26, p = 0.1). Pairwise t-tests demonstrated a significant reduction in hyperactivity for the YG (d = 0.22), but not the CG. The interaction of group and time was not significant in predicting the slope of change in perceived distress (b = -0.93, SE = 1.19, p = 0.43). Pairwise t-tests did not show a significant reduction in perceived distress for either group. Conclusion: These findings suggest that Hatha yoga may improve attention and hyperactivity in high school students.