Clozapine and neutrophil response in patients of African descent: A six-month, multinational, prospective, open-label clinical trial.

INTRODUCTION: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it is markedly underutilized, particularly in the US Black population, partly because of concern over clozapine-associated low absolute neutrophil count (ANC). People of African descent have a lower normative ANC range than the White population, which is associated with a specific "ACKR1-null" ("Duffy null") CC genotype (SNP rs2814778) on the ACKR1 gene, termed benign ethnic neutropenia (BEN). The range of ANC variability and safety of clozapine have not been established in people with BEN or examined prospectively in people of African descent. METHODS: We completed a multisite, 6-month, prospective, open-label clinical trial of clozapine treatment in people of African descent with schizophrenia spectrum disorders for whom clozapine was clinically indicated, with or without the ACKR1-null genotype. We examined clozapine safety and weekly ANC during clozapine treatment and evaluated ANC variability by ACKR1-null genotype, sex, study site, and clozapine dosing using repeated measures analysis of covariance. Genotype was assayed using TaqMan® technology. RESULTS: We enrolled 274 participants, of whom 227 (82.8 %) completed 6 months of clozapine treatment. There was one case of severe neutropenia (<500 cells/mm3) (0.36 %) over 1467.6 person-months of clozapine exposure. This participant recovered without sequelae after discontinuation of clozapine. Of the 249 participants with known genotypes, 199 (79.9 %) had the ACKR1-null genotype. Neutropenia (<1500 cells/mm3) occurred significantly more often in the ACKR1-null group (33 % [65/199]) than in those with the T allele (6 % (3/50); p < 0.001). Fourteen (5 %) patients discontinued due to adverse events. Rates of infection and fever were low and sialorrhea was the commonest side effect (N = 187, 68 %). CONCLUSION: To our knowledge, this is the largest prospective clozapine trial in people of African descent. Severe neutropenia was rare, despite the high prevalence (80 %) of the ACKR1-null genotype. Our findings suggest that clozapine can be used safely in Black patients including those with BEN.

Policy Ahead of the Science: Medical Cannabis Laws Versus Scientific Evidence.

Forty-one US jurisdictions (37 states) have legalized comprehensive medical cannabis programs since 1996. The number of qualifying conditions per jurisdiction varies from 5 to 29. Five (12%) of 42 qualifying conditions have conclusive or substantial evidence of efficacy and are listed in more than half of all jurisdictions. Half (50%) of qualifying conditions have no or insufficient scientific evidence of benefit from medical cannabis; 9% of qualifying conditions have limited evidence of harm from medical cannabis. The mean number of qualifying conditions per jurisdiction and the proportion of conditions with and without evidence of benefit have not changed since 1996.

Kratom: Substance of Abuse or Therapeutic Plant?

Kratom is the common term for Mitragyna speciosa and its products. Its major active compounds are mitragynine and 7-hydroxymitragynine. An estimated 2.1 million US residents used kratom in 2020, as a "legal high" and self-medication for pain, opioid withdrawal, and other conditions. Up to 20% of US kratom users report symptoms consistent with kratom use disorder. Kratom use is associated with medical toxicity and death. Causality is difficult to prove as almost all cases involve other psychoactive substances. Daily, high-dose use may result in kratom use disorder and opioid-like withdrawal on cessation of use. These are best treated with buprenorphine.

A randomized, double-blind, placebo-controlled, pharmacogenetic study of ondansetron for treating alcohol use disorder.

BACKGROUND: In a previous study, ondansetron, a serotonin 5-HT3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European-ancestry (EA) participants with moderate-to-severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4) and 5-HT3A (HTR3A), and 5-HT3B (HTR3B) receptors. We tested whether (1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA), and (2) that reductions in DPDD are greatest among ondansetron-treated individuals with population-specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B. METHODS: In this 16-week, double-blind, placebo-controlled, parallel-group clinical trial, adults with AUD were randomized to receive low-dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" versus "nonresponsive" genotype defined using population-specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent-to-treat analysis were used to compare the treatment groups on the primary outcome-DPDD-and two secondary outcomes-heavy drinking days per week [HDD] and drinks per day [DPD] across the 16 weeks of treatment. RESULTS: Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intent-to-treat analysis, the ondansetron group averaged 0.40 more DPDD (p = 0.51), 1.35 times as many HDD (p = 0.16), and 1.06 times as many DPD (p = 0.59) as the placebo group. There were no significant interactions with genotype. There were no study-related serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems. CONCLUSIONS: We found no evidence that low-dose oral ondansetron is beneficial in the treatment of AUD, irrespective of genotype, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions.

Validation of serotonin transporter mRNA as a quantitative biomarker of heavy drinking and its comparison to ethyl glucuronide/ethyl sulfate: A randomized, double-blind, crossover trial.

BACKGROUND: The serotonin transporter (SERT) mRNA was previously reported to be a quantitative and pathophysiology-based biomarker of heavy drinking in 5HTTLPR:LL genotype-carriers treated with ondansetron. Here, we validated the potential use of SERT mRNA for quantitative prediction of recent alcohol consumption (in the absence of treatment) and compared it with the known biomarkers ethyl glucuronide (EtG) and ethyl sulfate (EtS). METHODS: Binge drinking men and women of European ancestry aged 21 to 65 years were enrolled in a 12-day, in-patient, randomized, double-blind, crossover study, where they were administered three beverage doses (placebo, 0.5 g/kg [0.4 g/kg] ethanol, and 1 g/kg [0.9 g/kg] ethanol for men [women]) individually in three 4-day periods (experiments), separated by minimum 7-day washout period. Diet, sleep, and physical activity were controlled throughout the inpatient experiments. Twenty-nine participants were randomized to receive beverage doses counterbalancing the sequence of treatment and gender within subgroups stratified by SERT genotypes 5HTTLPR:LL+rs25531:AA (LA LA ) versus 5HTTLPR:LS/SS. Peripheral venous blood was collected daily for (1) quantification of SERT mRNA (the primary outcome measure) using qRT-PCR and (2) plasma EtG and EtS levels using tandem mass-spectrometry. RESULTS: The association between administered beverage dose and SERT mRNA from completers of at least one 4-day experiment (N = 18) assessed by a linear mixed model was not statistically significant. Significant positive associations were found with beverage dose and plasma EtG, EtS and EtG/EtS ratio (ß = 5.8, SE = 1.2, p < 0.0001; ß = 1.3, SE = 0.6, p = 0.023; and ß = 3.0, SE = 0.7, p < 0.0001, respectively; the C-statistics for discriminating outcomes were 0.97, 0.8, and 0.92, respectively). Additionally, we observed a sequence effect with a greater placebo effect on SERT mRNA when it was administered during the first experiment (p = 0.0009), but not on EtG/EtS measures. CONCLUSION: The findings do not validate the use of SERT as a biomarker of heavy drinking. Larger and more innovative studies addressing the effects of placebo, race, gender, and response to treatment with serotonergic agents are needed to fully assess the utility of SERT as a biomarker of heavy and binge drinking.

20-year mortality after discharge in a cohort of 1,099 former trauma inpatients with and without substance use disorders.

INTRODUCTION: Psychoactive substance use disorders (SUDs) are common in trauma patients and substance use has become a leading cause of death in the United States. The purpose of this study is to examine the impact of a lifetime SUD and SUD characteristics (substance used, current SUD versus in remission from dependence, etc.) on the long-term survival of trauma patients. METHODS: Cohort study of consecutive adult trauma inpatients who were discharged alive from a level-one trauma center (1994-1996). The presence of lifetime SUD was determined at the time of admission by the Structured Clinical Interview for the Diagnostic and Statistical Manual III-R. Mortality follow-up through the end of 2017 was obtained by linking patients to a national database of death certificates. Cox proportional hazards analysis was used to determine the association of lifetime SUD and death after adjusting for age and tobacco use. RESULTS: 1,220 patients were approached, 1,118 consented to participate, and 1,099 had personal identifiers for matching. 789 (71.8%) of subjects were men, 596 (54.2%) had lifetime SUDs, and 325 (29.6%) died. Injury was the most common cause of death (24.6%, 80/325), with poisonings (40.0%, 32/80) being the most common injury-related cause of death. Compared to those without a lifetime SUD, lifetime SUD was associated with increased all-cause mortality (adjusted hazard ratio [HRadj]=1.83; 95% CI, 1.4 to 2.4), injury death (HRadj=2.47; 95% CI: 1.4 to 4.2), and fatal opioid overdose (HRadj=12.96; 95% CI, 1.7 to 100.4)(p ≤ 0.01 for all HRadj). CONCLUSIONS: The presence of a lifetime SUD was associated with early death, particularly from reinjury, in trauma patients. It is important to address a patient's SUD during admission to decrease their chances of dying after discharge, especially due to injury-related causes.

Impact of cannabis and low alcohol concentration on divided attention tasks during driving.

OBJECTIVE: To assess divided-attention performance when driving under the influence of cannabis with and without alcohol. Three divided-attention tasks were performed following administration of placebo, cannabis, and/or alcohol. METHODS: Healthy adult cannabis users participated in 6 sessions, receiving combinations of cannabis (placebo/low-THC/high-THC) and alcohol (placebo/active) in randomized order, separated by washout periods of ≥1 week. At 0.5 hours post-dosing, participants performed simulator drives in the University of Iowa National Advanced Driving Simulator (NADS-1), a full vehicle cab simulator with a 360° horizontal field of view and motion base that provides realistic feedback. Drives contained repeated instances of three tasks: a side-mirror task (reaction to a triangle appearing in the side-mirrors), an artist-search task (select a specified artist from a navigable menu on the vehicle's console), and a message-reading task (read aloud a message displayed on the console). Blood THC and breath alcohol concentration (BrAC) were interpolated using individual power curves from samples collected approximately 0.17, 0.42, 1.4, and 2.3 hours post-dose. Driving measures during tasks were compared to equal-duration control periods occurring just prior to the task. Performance shifts, task completion, and lane departures were modeled relative to blood THC and BrAC using mixed-effects regression models. RESULTS: Each 1 µg/L increase in blood THC concentration predicted increased odds of failing to complete the artist-search task (OR: 1.05, 95% CI: 1.01-1.11, p = 0.046), increased odds of selecting at least one incorrect response (OR: 1.05, 95% CI: 1.00-1.09, p = 0.041), declines in speed during the side-mirror task (0.005 m/s, 95% CI: 0.001-0.009, p = 0.023), and longer lane departure durations during the artist-search task (0.74% of task-period, 95% CI: 0.12-1.36 p = 0.020). BrAC (approximately 0.05%) was not associated with task performance, though each 0.01 g/210 L increase predicted longer departure durations during the side-mirror task (1.41% of task-period, 95% CI: 0.08-2.76, p = 0.040) and increased standard deviation of lane position in the message-reading task (0.61 cm, 95% CI: 0.14-1.08, p = 0.011). CONCLUSIONS: With increasing medical and legal cannabis use, understanding the impact of acute cannabis use on driving performance, including divided-attention, is essential. These data indicate that impaired divided-attention performance is a safety concern.

Decreased Cannabinoid CB1 Receptors in Male Tobacco Smokers Examined With Positron Emission Tomography.

BACKGROUND: Previous studies showed reduction of brain cannabinoid CB1 receptors in adults with cannabis and alcohol use disorders. Preclinical data suggest that these receptors also contribute to nicotine reward and dependence. Tobacco smoking may confound clinical studies of psychiatric disorders because many patients with such disorders smoke tobacco. Whether human subjects who smoke tobacco but are otherwise healthy have altered CB1 receptor binding in brain is unknown. METHODS: We measured CB1 receptors in brains of 18 healthy men who smoke tobacco (frequent chronic cigarette smokers), and 28 healthy men who do not smoke tobacco, using positron emission tomography and [18F]FMPEP-d2, a radioligand for CB1 receptors. We collected arterial blood samples during scanning to calculate the distribution volume (VT), which is nearly proportional to CB1 receptor density. Repeated-measures analysis of variance compared VT between groups in various brain regions. RESULTS: Brain CB1 receptor VT was about 20% lower in subjects who smoke tobacco than in subjects who do not. Decreased VT was found in all brain regions, but reduction did not correlate with years of smoking, number of cigarettes smoked per day, or measures of nicotine dependence. CONCLUSIONS: Tobacco-smoking healthy men have a widespread reduction of CB1 receptor density in brain. Reduction of CB1 receptors appears to be a common feature of substance use disorders. Future clinical studies on the CB1 receptor should control for tobacco smoking.

Test characteristics of a drug CAGE questionnaire for the detection of non-alcohol substance use disorders in trauma inpatients.

BACKGROUND: Non-alcohol substance use disorders (drug use disorders [DUDs]) are common in trauma patients. OBJECTIVE: To determine the test characteristics of a 4-item drug CAGE questionnaire to detect DUDs in a cohort of adult trauma inpatients. METHODS: Observational cross-sectional cohort of 1,115 adult patients admitted directly to a level-one trauma center between September, 1994 and November, 1996. All participants underwent both a 4-item drug CAGE questionnaire and the substance use disorder section of a structured psychiatric diagnostic clinical interview (SCID) (DSM-IIIR criteria), administered by staff unaware of their clinical status. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV), positive (LR+) and negative likelihood ratios (LR-), and the area under the receiver operating curve (AUC) were calculated for each individual question and the overall questionnaire, using SCID-generated DUD diagnoses as the standard. Performance characteristics of the screen were also compared across selected sociodemographic, injury mechanism, and diagnostic sub-groups. RESULTS: Subjects with DUDs were common (n = 349, 31.3%), including cannabis (n = 203, 18.2%), cocaine (n = 199, 17.8%), and opioids (n = 156, 14.0%). The screen performed well overall (AUC = 0.90, 95% CI: 0.88-0.91) and across subgroups based on age, sex, race, marriage status, income, education, employment status, mechanism of injury, and current/past DUD status (AUCs 0.75-1.00). Answering any one question in the affirmative had a sensitivity = 83.4% (95% CI: 79.1-87.1), specificity = 92.3% (95% CI: 90.2-94.1), PPV = 83.1%, LR+ = 10.8. CONCLUSIONS: The 4-item drug CAGE and its individual questions had good-to-excellent ability to detect DUDs in this adult trauma inpatient population, suggesting its usefulness as a screening tool.

Cannabis Withdrawal in Adults With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Cannabis withdrawal has not been studied in adults with attention-deficit/hyperactivity disorder (ADHD) who have high rates of cannabis use. We aimed to describe cannabis withdrawal, motivations to quit, and strategies to quit cannabis use in cannabis-dependent adults with ADHD. METHODS: Twenty-three adults with ADHD enrolled in a controlled clinical trial of pharmacotherapy (atomoxetine) for cannabis dependence (DSM-IV criteria) completed the Marijuana Quit Questionnaire (MJQQ) to provide information on their "most serious" quit attempt made without formal treatment. The study was conducted between November 2005 and June 2008. RESULTS: Participants were predominantly male (82.6%, n = 19), with a mean (SD) age of 27.4 (8.5) years (range, 18-53) at the start of their index quit attempt. The most common motive for quitting cannabis was "to save money" (87%, n = 20); the most common strategy to maintain abstinence was "stopped associating with people who smoke marijuana" (43%, n = 10). Almost all (96%, n = 22) subjects reported ≥ 1 cannabis withdrawal symptom; 7 (30%) met DSM-5 diagnostic criteria for cannabis withdrawal syndrome. CONCLUSIONS: Participants with comorbid ADHD and cannabis dependence reported withdrawal symptoms similar to other samples of non-treatment-seeking cannabis-dependent adults with no psychiatric comorbidity. These findings suggest that ADHD does not influence cannabis withdrawal in the way that it does tobacco (nicotine) withdrawal. TRIAL REGISTRATION: Data used in this secondary analysis came from ClinicalTrials.gov identifier: NCT00360269.

Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses.

BACKGROUND: Food intake and use of drugs of abuse like cocaine share common central and peripheral physiological pathways. Appetitive hormones play a major role in regulating food intake; however, little is known about the effects of acute cocaine administration on the blood concentrations of these hormones in cocaine users. METHODS: We evaluated serum concentrations of six appetitive hormones: ghrelin (total and acyl-ghrelin), amylin, glucagon-like peptide-1 (GLP-1), insulin, leptin and peptide YY (PYY), as well as acute cardiorespiratory and subjective responses of 8 experienced cocaine users who received 25mg intravenous (IV) cocaine. RESULTS: Serum concentrations of GLP-1 (p=0.014) and PYY (p=0.036) were significantly decreased one hour following IV cocaine administration; there was a trend towards a decrease for insulin (p=0.055) and amylin (p=0.063) concentrations, while no significant IV cocaine effect was observed for ghrelin (total or acyl-ghrelin) or leptin concentrations (p's≫>0.5). We also observed associations between hormone concentrations acutely affected by IV cocaine (GLP-1, PYY, insulin, amylin) and some cocaine-related cardiorespiratory and subjective responses (e.g., increased heart and respiratory rates; feeling high and anxious). DISCUSSION: These findings show a significant effect of acute IV cocaine administration on some appetitive hormones and suggest potential associations between these hormones and cocaine-related cardiorespiratory and subjective responses. Additional research is needed to further investigate the potential mechanisms underlining these associations.