Publications by authors named "Marilyn A Huestis"

420 Publications

Influence of personality on acute smoked cannabis effects on simulated driving.

Exp Clin Psychopharmacol 2021 Jul 22. Epub 2021 Jul 22.

Department of Pharmacology and Toxicology.

A recent study of the impact of smoked cannabis on simulated driver behavior demonstrated a reduction in mean speed after smoked cannabis. Previous research identified an association between personality and individual differences and acute drug effects. The present study examined the impact of personality on the reduction in mean speed after smoking cannabis under single- and dual-task driving conditions originally reported by Brands et al. (2019). Sixty-one participants randomly assigned to the active drug condition completed a battery of self-report questionnaires measuring various personality constructs and subsequently operated a driving simulator before and 30 min after smoking a 12.5% Δ9-tetrahydrocannabinol (THC) cigarette. Linear regression modeling tested the influence of self-reported driving errors, lapses, and violations, driver vengeance, psychological distress, impulsivity, and sensation seeking on the reduction in speed after smoking cannabis. After adjusting for the influence of sex, blood THC concentration, and predrug mean speed, impulsivity was a significant predictor of change in speed under both single- (β = -.45, = -3.94, < .001) and dual- (β = -.35, = -2.74, = .008) task driving conditions after cannabis. Higher trait impulsivity was significantly associated with greater reductions in driving speed after cannabis use, which may reflect greater sensitivity to drug effects and a stronger compensatory response. Further multidisciplinary study, including neurochemical, genetic, and psychological components, would be beneficial in helping to better understand how impulsivity and other personality or individual differences may impact the effects of cannabis on driver behavior and performance. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/pha0000505DOI Listing
July 2021

Preliminary Evidence for Cannabis and Nicotine Urinary Metabolites as Predictors of Verbal Memory Performance and Learning Among Young Adults.

J Int Neuropsychol Soc 2021 07;27(6):546-558

Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, MC 0405, La Jolla, CA92093, USA.

Objective: Verbal memory deficits are linked to cannabis use. However, self-reported episodic use does not allow for assessment of variance from other factors (e.g., cannabis potency, route of consumption) that are important for assessing brain-behavior relationships. Further, co-occurring nicotine use may moderate the influence of cannabis on cognition. Here we utilized objective urinary measurements to assess the relationship between metabolites of cannabis, 11-nor-9-carboxy-∆9-tetrahydrocannabinol (THCCOOH), and nicotine (cotinine) on verbal memory in young adults.

Method: Adolescents and young adults (n = 103) aged 16-22 completed urinary drug testing and verbal memory assessment (RAVLT). Linear regressions examined the influence of THCCOOH and cotinine quantitative concentrations, and their interaction, on RAVLT scores, controlling for demographics and alcohol. Cannabis intake frequency was also investigated. Secondary analyses examined whether past month or recency of use related to performance, while controlling for THCCOOH and cotinine concentrations.

Results: THCCOOH concentration related to both poorer total learning and long delay recall. Cotinine concentration related to poorer short delay recall. Higher frequency cannabis use status was associated with poorer initial learning and poorer short delay. When comparing to self-report, THCCOOH and cotinine concentrations were negatively related to learning and memory performance, while self-report was not.

Conclusions: Results confirm the negative relationship between verbal memory and cannabis use, extending findings with objective urinary THCCOOH, and cotinine concentration measurements. No moderating relationship with nicotine was found, though cotinine concentration independently associated with negative short delay performance. Findings support the use of both urinary and self-report metrics as complementary methods in substance use research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1355617721000205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288450PMC
July 2021

Designer Benzodiazepines: A Review of Toxicology and Public Health Risks.

Pharmaceuticals (Basel) 2021 Jun 11;14(6). Epub 2021 Jun 11.

Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University of Ancona, Via Tronto 10, 60126 Ancona, Italy.

The rising use of designer benzodiazepines (DBZD) is a cat-and-mouse game between organized crime and law enforcement. Non-prohibited benzodiazepines are introduced onto the global drug market and scheduled as rapidly as possible by international authorities. In response, DBZD are continuously modified to avoid legal sanctions and drug seizures and generally to increase the abuse potential of the DBZD. This results in an unpredictable fluctuation between the appearance and disappearance of DBZD in the illicit market. Thirty-one DBZD were considered for review after consulting the international early warning database, but only 3-hydroxyphenazepam, adinazolam, clonazolam, etizolam, deschloroetizolam, diclazepam, flualprazolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam had sufficient data to contribute to this scoping review. A total of 49 reports describing 1 drug offense, 2 self-administration studies, 3 outpatient department admissions, 44 emergency department (ED) admissions, 63 driving under the influence of drugs (DUID) and 141 deaths reported between 2008 and 2021 are included in this study. Etizolam, flualprazolam flubromazolam and phenazepam were implicated in the majority of adverse-events, drug offenses and deaths. However, due to a general lack of knowledge of DBZD pharmacokinetics and toxicity, and due to a lack of validated analytical methods, total cases are much likely higher. Between 2019 and April 2020, DBZD were identified in 48% and 83% of postmortem and DUID cases reported to the UNODC, respectively, with flualprazolam, flubromazolam and etizolam as the most frequently detected substances. DBZD toxicology, public health risks and adverse events are reported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph14060560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230725PMC
June 2021

Identification and quantification of cannabinoids in postmortem fluids and tissues by liquid chromatography-tandem mass spectrometry.

J Chromatogr A 2021 Aug 15;1652:462345. Epub 2021 Jun 15.

School of Forensic Sciences, Oklahoma State University Center for Health Sciences, 1111 W. 17th St, Tulsa, OK 74107, USA; Civil Aerospace Medical Institute, Federal Aviation Administration, 6500 S MacArthur Blvd, Oklahoma City, OK 73169, USA.

Cannabis sativa is commonly used worldwide and is frequently detected by forensic laboratories working with biological specimens from potentially impaired drivers or pilots. To address the problem of limited published methods for cannabinoids quantification in postmortem specimens, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify Δ-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), 8β,11-dihydroxy-THC (8β-diOH-THC), 8β-hydroxy-THC (8β-OH-THC), THC-glucuronide (THC-g), THCCOOH-glucuronide (THCCOOH-g), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), Δ-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-THCV (THCVCOOH). Solid phase extraction concentrated analytes prior to analysis on a biphenyl column coupled to a mass spectrometer in electrospray positive ionization mode using multiple reaction monitoring. Linearity ranged from 0.25-50 ng/mL (THC-g), 0.5-100 ng/mL (CBN), 0.5-250 ng/mL (THC, 11-OH-THC, THCCOOH, CBD, and CBG), 1-100 ng/mL (8β-diOH-THC, THCVCOOH, 8β-OH-THC, and THCV) and 1-250 ng/mL (THCCOOH-g). Within-run imprecision was <11.2% CV, between-run imprecision <18.1% CV, and bias was less than ±15.1% of target concentration in blood for all cannabinoids at three concentrations. No carryover or interferences were observed. All cannabinoids were stable in blood at room temperature for 24 h, refrigerated (4°C) for 96 h, and following three freeze/thaw cycles. Matrix effects greater than 25% were observed for most analytes in tissues. The proof of concept for method applicability involved measurement of cannabinoids in a pilot fatally injured in an aviation crash. This new analytical method is robust and sensitive, enabling collection of additional cannabinoid postmortem distribution data to improve interpretation of postmortem cannabinoid results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chroma.2021.462345DOI Listing
August 2021

Blood and Oral Fluid Cannabinoid Profiles of Frequent and Occasional Cannabis Smokers.

J Anal Toxicol 2021 Jun 26. Epub 2021 Jun 26.

Department of Pathology, University of California, 10300 Campus Point Drive, Suite 150, San Diego, CA 92121 USA.

Increased prevalence of cannabis consumption and impaired driving are a growing public safety concern. Some states adopted per se driving laws, making it illegal to drive with more than a specified ∆9-tetrahydrocannabinol (THC) blood concentration of THC in a biological fluid (typically blood). Blood THC concentrations decrease significantly (~90%) with delays in specimen collection, suggesting use of alternative matrices, such as oral fluid (OF). We characterized 10 cannabinoids' concentrations, including THC metabolites, in blood and OF from 191 frequent and occasional users by LC-MS-MS for up to 6 h after ad libitum smoking. Subjects self-titrated when smoking placebo, 5.9 or 13.4% THC cannabis. Higher maximum blood THC concentrations (Cmax) were observed in individuals who received the 5.9% THC versus the 13.4% THC plant material. In blood, the Cmax of multiple analytes, including THC and its metabolites, were increased in frequent compared to occasional users, whereas there were no significant differences in OF Cmax. Blood THC remained detectable (≥5 ng/mL) at the final sample collection for 14% of individuals who smoked either the 5.9% or 13.4% THC cigarette, whereas 54% had detectable THC in OF when applying the same cutoff. Occasional and frequent cannabis users' profiles were compared, THC was detectable for significantly longer in blood and OF from frequent users. Detection rates between frequent and occasional users at multiple per se cutoffs showed larger differences in blood versus OF. Understanding cannabinoid profiles of frequent and occasional users and the subsequent impact on detectability with current drug per se driving limits is important to support forensic interpretations and the development of scientifically supported driving under the influence of cannabis laws.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jat/bkab078DOI Listing
June 2021

Cannabis Use and Car Crashes: A Review.

Front Psychiatry 2021 28;12:643315. Epub 2021 May 28.

Clinic and Polyclinic for Psychiatry and Psychotherapy, Clinic of the Ludwig-Maximilian-University Munich, Munich, Germany.

In this review, state-of-the-art evidence on the relationship between cannabis use, traffic crash risks, and driving safety were analyzed. Systematic reviews, meta-analyses, and other relevant papers published within the last decade were systematically searched and synthesized. Findings show that meta-analyses and culpability studies consistently indicate a slightly but significantly increased risk of crashes after acute cannabis use. These risks vary across included study type, crash severity, and method of substance application and measurement. Some studies show a significant correlation between high THC blood concentrations and car crash risk. Most studies do not support this relationship at lower THC concentrations. However, no scientifically supported clear cut-off concentration can be derived from these results. Further research is needed to determine dose-response effects on driving skills combined with measures of neuropsychological functioning related to driving skills and crash risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyt.2021.643315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195290PMC
May 2021

Recommendations for Toxicological Investigation of Drug-Impaired Driving and Motor Vehicle Fatalities-2021 Update.

J Anal Toxicol 2021 Jul;45(6):529-536

Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, 2300 Stratford Avenue, Willow Grove, PA 19090, USA.

This report describes updates to the National Safety Council's Alcohol, Drugs and Impairment Division's recommendations for drug testing in driving under the influence of drug (DUID) cases and motor vehicle fatalities. The updates are based on a survey of drug testing practices in laboratories in the USA and Canada, a comprehensive review of the prior recommendations and data and research on drugs most frequently detected in DUID cases. A consensus meeting was held with representative forensic science practitioners and the authors of this report to update recommendations. No changes were made to the Tier I scope; however, there were changes to cutoffs of some analytes for blood, urine and oral fluid. Due to increased prevalence in DUID cases, trazodone and difluoroethane were added to the Tier II scope. For clarification, Tier I cutoffs reflect free concentrations, and hydrolysis is recommended but not required. The consensus panel concluded that urine is an inferior matrix to blood and oral fluid as it may represent historical use or exposure unrelated to observed impairment; therefore, future iterations of these recommendations will not include urine as a recommended matrix. Laboratories currently testing urine should work with traffic safety partners to encourage the use of blood and oral fluid as more appropriate specimens and adjust their capabilities to provide that testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jat/bkab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272528PMC
July 2021

Sex differences in the acute pharmacological and subjective effects of smoked cannabis combined with alcohol in young adults.

Psychol Addict Behav 2021 Jun 3. Epub 2021 Jun 3.

Department of Pharmacology and Toxicology.

The prevalence of co-use of alcohol and cannabis is increasing, particularly among young adults. Sex differences in the effects of alcohol alone and cannabis alone have been observed in animals and humans. However, sex differences in the acute pharmacological effects of cannabis combined with alcohol have not yet been studied. In young adults, aged 19-29 years, we aimed to examine sex differences following an intoxicating dose of alcohol (target 0.08% breath alcohol content) combined with a moderate dose of cannabis (12.5% Δ⁹-tetrahydrocannabinol; THC) using an ad libitum smoking procedure. Using a within-subjects design, 28 regular cannabis users (16 males; 12 females) received in random order: (a) placebo alcohol and placebo cannabis, (b) active alcohol and placebo cannabis, (c) placebo alcohol and active cannabis, and (d) active alcohol and active cannabis. Blood samples for THC were collected and measures of vital signs, subjective drug effects, and cognition were collected. In the alcohol-cannabis combined condition, females smoked significantly less of the cannabis cigarette compared to males ( < .001), although both sexes smoked similar amounts in the other conditions. There was minimal evidence that females and males differed in THC blood concentrations, vitals, subjective effects, or cognitive measures. In the alcohol-cannabis combined condition, females experienced the same acute pharmacological and subjective effects of alcohol and cannabis as males, after smoking less cannabis, which has potential implications for informing education and policy. Further research is warranted on sex differences in cannabis pharmacology, as well as the combined effects of alcohol and cannabis. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/adb0000749DOI Listing
June 2021

Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study.

Front Endocrinol (Lausanne) 2020 18;11:549928. Epub 2021 Feb 18.

Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States.

Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics.

Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels.

Results: PDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample.

Conclusions: Sociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2020.549928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930488PMC
May 2021

Using Population Pharmacokinetic Modeling to Estimate Exposure to Δ9-Tetrahydrocannabinol in an Observational Study of Cannabis Smokers in Colorado.

Ther Drug Monit 2021 08;43(4):536-545

Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado.

Background: Self-report questionnaires, weighing products consumed, and Δ9-tetrahydrocannabinol (THC) biomarkers are established techniques for estimating cannabis exposure. Population pharmacokinetic modeling of plasma THC and metabolite concentrations by incorporating self-reported and weighed products as covariates could improve estimates of THC exposure in regular cannabis users.

Methods: In this naturalistic study, blood samples were obtained from 36 regular smokers of cannabis for analysis of THC and its 2 metabolites at 4 time points: recruitment and during an experimental mobile laboratory assessment that included 3 time points: before, immediately after, and 1 hour after ad libitum legal market flower use. These data were analyzed using an established model of population pharmacokinetics developed from laboratory-controlled cannabis administration data. Elimination and metabolite production clearances were estimated for each subject as well as their daily THC doses and the dose consumed during the ad libitum event.

Results: A statistically significant correlation existed between the daily THC dose estimated by self-report questionnaire and population pharmacokinetic modeling (correlation coefficient = 0.79, P < 0.05) between the weighed cannabis smoked ad libitum and that estimated by population pharmacokinetic modeling (correlation coefficient = 0.71, P < 0.05).

Conclusion: Inclusion of self-reported questionnaire data of THC consumption improved pharmacokinetic model-derived estimates based on measured THC and metabolite concentrations. In addition, the pharmacokinetic-derived dose estimates for the ad libitum smoking event underestimated the THC consumption compared with the weighed amount smoked. Thus, the subjects in this study, who smoked ad libitum and used cannabis products with high concentrations of THC, were less efficient (lower bioavailability) compared with computer-paced smokers of low potency, NIDA cannabis in a laboratory setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FTD.0000000000000882DOI Listing
August 2021

Combined effect of alcohol and cannabis on simulated driving.

Psychopharmacology (Berl) 2021 Feb 5. Epub 2021 Feb 5.

Department of Pharmacology and Toxicology, University of Toronto, 27 King's College Circle, Toronto, Ontario, M5S 3H7, Canada.

Rationale: With alcohol and cannabis remaining the most commonly detected drugs in seriously and fatally injured drivers, there is a need to understand their combined effects on driving.

Objectives: The present study examined the effects of combinations of smoked cannabis (12.5% THC) and alcohol (target BrAC 0.08%) on simulated driving performance, subjective drug effects, cardiovascular measures, and self-reported perception of driving ability.

Methods: In this within-subjects, double-blind, double-dummy, placebo-controlled, randomized clinical trial, cannabis users (1-7 days/week) aged 19-29 years attended four drug administration sessions in which simulated driving, subjective effects, cardiovascular measures, and whole blood THC and metabolite concentrations were assessed following placebo alcohol and placebo cannabis (<0.1% THC), alcohol and placebo cannabis, placebo alcohol and active cannabis, and alcohol and active cannabis.

Results: Standard deviation of lateral position in the combined condition was significantly different from the placebo condition (p < 0.001). Standard deviation of lateral position was also significantly different from alcohol and cannabis alone conditions in the single task overall drive (p = 0.029 and p = 0.032, respectively), from the alcohol alone condition in the dual task overall drive (p = 0.022) and the cannabis alone condition in the dual task straightaway drive (p = 0.002). Compared to the placebo condition, the combined and alcohol conditions significantly increased reaction time. Subjective effects in the combined condition were significantly greater than with either of the drugs alone at some time points, particularly later in the session. A driving ability questionnaire showed that participants seemed unaware of their level of impairment.

Conclusion: Combinations of alcohol and cannabis increased weaving and reaction time, and tended to produce greater subjective effects compared to placebo and the single drug conditions suggesting a potential additive effect. The fact that participants were unaware of this increased effect has important implications for driving safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-021-05773-3DOI Listing
February 2021

assessment of the cytotoxic, genotoxic and oxidative stress effects of the synthetic cannabinoid JWH-018 in human SH-SY5Y neuronal cells.

Toxicol Res (Camb) 2020 Dec 4;9(6):734-740. Epub 2020 Nov 4.

Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Istanbul University, Istanbul 34126, Turkey.

Background: JWH-018 was the first synthetic cannabinoid introduced as a legal high and the first of the new generation of novel psychoactive substances that flooded worldwide drug markets. JWH-018 was marketed as "spice," "herbal incense," or "herbal blend," as a popular and legal (at the time) alternative to cannabis (marijuana). JWH-018 is a potent synthetic cannabinoid with considerable toxicity associated with its use. JWH-018 has qualitatively similar but quantitatively greater pharmacological effects than cannabis, leading to intoxications and even deaths. The mechanisms of action of the drug's toxicity require research, and thus, the aim of the present study was to investigate the toxicological profile of JWH-018 in human SH-SY5Y neuronal cells.

Methods: SH-SY5Y neuronal cells were exposed to increasing concentrations from 5 to 150 μM JWH-018 over 24 h. Cytotoxicity, DNA damage, the apoptotic/necrotic rate, and oxidative stress were assessed following SH-SY5Y exposure.

Results: JWH-018 did not produce a significant decrease in SH-SY5Y cell viability, did not alter apoptotic/necrotic rate, and did not cause genotoxicity in SH-SY5Y cells with 24-h exposure. Glutathione reductase and catalase activities were significantly reduced; however, there was no significant change in glutathione peroxidase activity. Also, JWH-018 treatment significantly decreased glutathione concentrations, significantly increased protein carbonylation, and significantly increased malondialdehyde (MDA) concentrations. For significance, all  < 0.05.

Discussion/conclusion: JWH-018 produced oxidative stress in SH-SY5Y cells that could be an underlying mechanism of JWH-018 neurotoxicity. Additional animal and human-based studies are needed to confirm our findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxres/tfaa078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786167PMC
December 2020

Pyrrolidinyl Synthetic Cathinones α-PHP and 4F-α-PVP Metabolite Profiling Using Human Hepatocyte Incubations.

Int J Mol Sci 2020 Dec 28;22(1). Epub 2020 Dec 28.

Chemistry & Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.

For more than ten years, new synthetic cathinones (SCs) mimicking the effects of controlled cocaine-like stimulants have flooded the illegal drug market, causing numerous intoxications and fatalities. There are often no data on the pharmacokinetics of these substances when they first emerge onto the market. However, the detection of SC metabolites is often critical in order to prove consumption in clinical and forensic settings. In this research, the metabolite profile of two pyrrolidinyl SCs, α-pyrrolidinohexaphenone (α-PHP) and 4''-fluoro-α-pyrrolidinovalerophenone (4F-α-PVP), were characterized to identify optimal intake markers. Experiments were conducted using pooled human hepatocyte incubations followed by liquid chromatography-high-resolution tandem mass spectrometry and data-mining software. We suggest α-PHP dihydroxy-pyrrolidinyl, α-PHP hexanol, α-PHP 2'-keto-pyrrolidinyl-hexanol, and α-PHP 2'-keto-pyrrolidinyl as markers of α-PHP use, and 4F-α-PVP dihydroxy-pyrrolidinyl, 4F-α-PVP hexanol, 4F-α-PVP 2'-keto-pyrrolidinyl-hexanol, and 4F-α-PVP 2'-keto-pyrrolidinyl as markers of 4F-α-PVP use. These results represent the first data available on 4F-α-PVP metabolism. The metabolic fate of α-PHP was previously studied using human liver microsomes and urine samples from α-PHP users. We identified an additional major metabolite (α-PHP dihydroxy-pyrrolidinyl) that might be crucial for documenting exposure to α-PHP. Further experiments with suitable analytical standards, which are yet to be synthesized, and authentic specimens should be conducted to confirm these results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22010230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796222PMC
December 2020

Toxicology and Analysis of Psychoactive Tryptamines.

Int J Mol Sci 2020 Dec 4;21(23). Epub 2020 Dec 4.

Institute of Emerging Health Professions, Thomas Jefferson University, 1020 Walnut St, Philadelphia, PA 19144, USA.

Our understanding of tryptamines is poor due to the lack of data globally. Tryptamines currently are not part of typical toxicology testing regimens and their contribution to drug overdoses may be underestimated. Although their prevalence was low, it is increasing. There are few published data on the many new compounds, their mechanisms of action, onset and duration of action, toxicity, signs and symptoms of intoxication and analytical methods to identify tryptamines and their metabolites. We review the published literature and worldwide databases to describe the newest tryptamines, their toxicology, chemical structures and reported overdose cases. Tryptamines are 5-HT receptor agonists that produce altered perceptions of reality. Currently, the most prevalent tryptamines are 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), 5-methoxy-N,N- diallyltryptamine (5-MeO-DALT) and dimethyltryptamine (DMT). From 2015 to 2020, 22 new analytical methods were developed to identify/quantify tryptamines and metabolites in biological samples, primarily by liquid chromatography tandem mass spectrometry. The morbidity accompanying tryptamine intake is considerable and it is critical for clinicians and laboratorians to be informed of the latest data on this public health threat.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21239279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730282PMC
December 2020

Nicotinic receptor modulation of the default mode network.

Psychopharmacology (Berl) 2021 Feb 20;238(2):589-597. Epub 2020 Nov 20.

Neuroimaging Research Branch, National Institute on Drug Abuse Intramural Research Program, 251 Bayview Blvd, Suite 200, Baltimore, MD, 21224, USA.

Rationale: Previous neuroimaging studies of cognition involving nicotinic acetylcholine receptor (nAChR) agonist administration have repeatedly found enhanced task-induced deactivation of regions of the default mode network (DMN), a group of brain systems that is more active at rest and mediates task-independent thought processes. This effect may be related to pro-cognitive nAChR agonist effects OBJECTIVES: The present study sought to test whether nAChR modulation of the DMN is bi-directional, i.e., whether a nAChR antagonist would reduce task-induced deactivation.

Methods: Eighteen healthy non-smokers underwent functional magnetic resonance imaging while performing a letter N-back task. Scans were performed after nicotine administration (7 mg/24 h, transdermally), after administration of the nAChR antagonist mecamylamine (7.5 mg, p.o.), and after double placebo, in counterbalanced sequence. Blood-oxygen-level-dependent (BOLD) signal was analyzed within ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC) regions of interest-central hubs of the DMN in which consistent nAChR agonist-induced changes had previously been identified.

Results: Nicotine enhanced hit rate in both the 0-back and 2-back condition, while mecamylamine slowed reaction time in the 2-back condition. Mecamylamine reduced task-induced deactivation of vmPFC and PCC. Nicotine had no significant effects on the BOLD signal.

Conclusions: The finding that nAChR tone reduction by mecamylamine weakened task-induced DMN deactivation indicates that a constant tone of nAChR activation helps regulate DMN activity in healthy individuals. This suggests that low nAChR tone may play a causal role in DMN dysregulation seen in conditions such as mild cognitive impairment or Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-020-05711-9DOI Listing
February 2021

Behavior Problems During Early Childhood in Children With Prenatal Methamphetamine Exposure.

Pediatrics 2020 12 10;146(6). Epub 2020 Nov 10.

Brown Center for the Study of Children at Risk, Warren Alpert Medical School, Brown University and Women and Infants Hospital of Rhode Island, Providence, Rhode Island.

Background And Objectives: The effects of in utero methamphetamine exposure on behavioral problems in school-aged children are unclear. Our objective for this study was to evaluate behavior problems in children at aged 3, 5, and 7.5 years who were prenatally exposed to methamphetamine.

Methods: Subjects were enrolled in the Infant Development, Environment, and Lifestyle study, a longitudinal prospective study of prenatal methamphetamine exposure and child outcomes. Exposed and comparison groups were matched on birth weight, race, education, and health insurance.  At ages 3, 5, and 7.5 years, 339 children (171 exposed) were assessed for behavior problems by using the Child Behavior Checklist. Generalized estimating equations were used to determine the effects of prenatal methamphetamine exposure, age, and the interaction of exposure and age on behavior problems. Caregiver psychological symptoms were assessed by using the Brief Symptom Inventory.

Results: Analyses adjusted for covariates revealed that relative to age 3, children at 5 years had less externalizing and aggressive behavior and more internalizing behavior, somatic complaints, and withdrawn behavior.  By age 7.5, aggressive behavior continued to decrease, attention problems increased and withdrawn behavior decreased. There were no main effects for methamphetamine exposure and no interactions of exposure and age.  Caregiver psychological symptoms predicted all behavior problems and the quality of the home predicted externalizing problems and externalizing syndrome scores.

Conclusions: Behavioral effects longitudinally from ages 3 to 7.5 years were not associated with prenatal methamphetamine exposure, whereas caregiver psychological symptoms and the quality of the home were predictors of behavior problems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2019-0270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706113PMC
December 2020

Preliminary data on the potential for unintentional antidoping rule violations by permitted cannabidiol (CBD) use.

Drug Test Anal 2021 Mar 14;13(3):539-549. Epub 2020 Dec 14.

Institute of Biochemistry, German Sport University Cologne, Cologne, Germany.

According to the World Anti-Doping Agency (WADA) regulations, cannabinoids use is prohibited in competition except for cannabidiol (CBD) use. For an adverse analytical finding (AAF) in doping control, cannabinoid misuse is based on identification of the pharmacologically inactive metabolite 11-nor-delta-9-carboxy-tetrahydrocannabinol-9-carboxylic acid (carboxy-THC) in urine at a concentration greater than 180 ng/ml. All other (minor) cannabinoids are reported as AAF when identified, except for CBD that has been explicitly excluded from the class of cannabinoids on WADA's Prohibited List since 2018. However, due to the fact that CBD isolated from cannabis plants may contain additional minor cannabinoids, the permissible use of CBD can lead to unintentional violations of antidoping regulations. An assay for the detection of 16 cannabinoids in human urine was established. The sample preparation consisted of enzymatic hydrolysis of glucuronide conjugates, liquid-liquid extraction, trimethylsilylation, and analysis by gas chromatography/tandem mass spectrometry (GC-MS/MS). Spot urine samples from CBD users, as well as specimens obtained from CBD administration studies conducted with 15 commercially available CBD products, were analyzed, and assay characteristics such as selectivity, reproducibility of detection at the minimum required performance level, limit of detection, and limit of identification were determined. An ethical committee approved controlled single dose commercially available CBD products administration study was conducted to identify 16 cannabinoids in urine samples collected after ingestion or application of the CBD products as well as their presence in spot urine samples of habitual CBD users. Variable patterns of cannabinoids or their metabolites were observed in the urine samples, especially when full spectrum CBD products were consumed. The presence of minor cannabinoids or their metabolites in an athlete's in-competition urine sample represents a substantial risk of an antidoping rule violation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dta.2959DOI Listing
March 2021

Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids.

Pharmacol Biochem Behav 2020 12 18;199:173059. Epub 2020 Oct 18.

UCLA Cannabis Research Initiative, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.

The phytocannabinoid Δ-tetrahydrocannabinol (THC) was isolated and synthesized in the 1960s. Since then, two synthetic cannabinoids (SCBs) targeting the cannabinoid 1 (CB1R) and 2 (CB2R) receptors were approved for medical use based on clinical safety and efficacy data: dronabinol (synthetic THC) and nabilone (synthetic THC analog). To probe the function of the endocannabinoid system further, hundreds of investigational compounds were developed; in particular, agonists with (1) greater CB1/2R affinity relative to THC and (2) full CB1/2R agonist activity. This pharmacological profile may pose greater risks for misuse and adverse effects relative to THC, and these SCBs proliferated in retail markets as legal alternatives to cannabis (e.g., novel psychoactive substances [NPS], "Spice," "K2"). These SCBs were largely outlawed in the U.S., but blanket policies that placed all SCB chemicals into restrictive control categories impeded research progress into novel mechanisms for SCB therapeutic development. There is a concerted effort to develop new, therapeutically useful SCBs that target novel pharmacological mechanisms. This review highlights the potential therapeutic efficacy and safety considerations for unique SCBs, including CB1R partial and full agonists, peripherally-restricted CB1R agonists, selective CB2R agonists, selective CB1R antagonists/inverse agonists, CB1R allosteric modulators, endocannabinoid-degrading enzyme inhibitors, and cannabidiol. We propose promising directions for SCB research that may optimize therapeutic efficacy and diminish potential for adverse events, for example, peripherally-restricted CB1R antagonists/inverse agonists and biased CB1/2R agonists. Together, these strategies could lead to the discovery of new, therapeutically useful SCBs with reduced negative public health impact.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pbb.2020.173059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725960PMC
December 2020

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

Traffic Inj Prev 2020 10 9;21(sup1):S123-S129. Epub 2020 Oct 9.

iChemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, Maryland (currently at Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, Pennsylvania).

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15389588.2020.1814956DOI Listing
October 2020

Development and Validation of a Method for Quantification of 28 Psychotropic Drugs in Postmortem Blood Samples by Modified Micro-QuEChERS and LC-MS-MS.

J Anal Toxicol 2020 Sep 30. Epub 2020 Sep 30.

Campinas Poison Control Center, University of Campinas, Campinas, São Paulo 13083‑859, Brazil.

The development of new sample preparation alternatives in analytical toxicology leading to quick, effective, automated and environmentally friendly procedures is growing in importance. One of these alternatives is the QuEChERS, originally developed for the analysis of pesticide residues, producing cleaner extracts than liquid-liquid extraction, and easier separation of aqueous and organic phases. However, there are few published studies on the miniaturization of this technique for forensic toxicology, especially in postmortem analysis. We developed and validated a modified micro-QuEChERS and LC-MS-MS assay to quantify 16 antidepressants, seven antipsychotics and three metabolites, and semi-quantify norfluoxetine and norsertraline in postmortem blood. The calibration curve was linear from 1-500 ng/mL, achieved a r>0.99, with all standards quantifying within ±15% of target except ±20% at the limit of quantification (LOQ) of 1 ng/mL for 26 substances. The F test was applied to evaluate if the variance between replicates remained constant for all calibrators. Six weighting factors were analyzed (1/x, 1/x2, 1/x0,5, 1/y, 1/y2, 1/y0,5), with the weighting factor with the lowest sum of residual regression errors (1/x2) selected. No endogenous or exogenous interferences were observed. Method imprecision and bias were less than 19.0% and 19.7%, respectively. Advantages of this method include a low sample volume of 100 µL, simple but effective sample preparation and a rapid 8.5 min run time. The validated analytical method was successfully applied to the analysis of 100 authentic postmortem samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jat/bkaa138DOI Listing
September 2020

Pharmacokinetic, behavioral, and brain activity effects of Δ-tetrahydrocannabinol in adolescent male and female rats.

Neuropsychopharmacology 2021 04 14;46(5):959-969. Epub 2020 Sep 14.

Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA.

Δ-tetrahydrocannabinol (THC) is the intoxicating constituent of cannabis and is responsible for the drug's reinforcing effects. Retrospective human studies suggest that cannabis use during adolescence is linked to long-term negative psychological outcomes, but in such studies it is difficult to distinguish the effects of THC from those of coexisting factors. Therefore, translationally relevant animal models are required to properly investigate THC effects in adolescents. However, though the relevance of these studies depends upon human-relevant dosing, surprisingly little is known about THC pharmacology and its effects on behavior and brain activity in adolescent rodents-especially in females. Here, we conducted a systematic investigation of THC pharmacokinetics, metabolism and distribution in blood and brain, and of THC effects upon behavior and neural activity in adolescent Long Evans rats of both sexes. We administered THC during an early-middle adolescent window (postnatal days 27-45) in which the brain may be particularly sensitive to developmental perturbation by THC. We determined the pharmacokinetic profile of THC and its main first-pass metabolites (11-hydroxy-THC and 11-nor-9-carboxy-THC) in blood and brain following acute injection (0.5 or 5 mg/kg, intraperitoneal). We also evaluated THC effects on behavioral assays of anxiety, locomotion, and place conditioning, as well as c-Fos expression in 14 brain regions. Confirming previous work, we find marked sex differences in THC metabolism, including a female-specific elevation in the bioactive metabolite 11-hydroxy-THC. Furthermore, we find dose-dependent and sex-dependent effects on behavior, neural activity, and functional connectivity across multiple nodes of brain stress and reward networks. Our findings are relevant for interpreting results of rat adolescent THC exposure studies, and may lend new insights into how THC impacts the brain in a sex-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-020-00839-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115040PMC
April 2021

Urinary Acrylonitrile Metabolite Concentrations Before and after Smoked, Vaporized, and Oral Cannabis in Frequent and Occasional Cannabis Users.

Int J Environ Res Public Health 2020 09 4;17(18). Epub 2020 Sep 4.

Tobacco and Volatiles Branch, Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA.

Cannabis use through smoking, vaping, or ingestion is increasing, but only limited studies have investigated the resulting exposure to harmful chemicals. N-acetyl-S-(2-cyanoethyl)-L-cysteine (2CYEMA), a urinary metabolite of acrylonitrile, a possible carcinogen, is elevated in the urine of past-30-day cannabis users compared to non-cannabis users. Five frequent and five occasional cannabis users smoked and vaped cannabis on separate days; one also consumed cannabis orally. Urine samples were collected before and up to 72 h post dose and urinary 2CYEMA was quantified. We compared 2CYEMA pre-exposure levels, maximum concentration, time at maximum concentration for occasional versus frequent users following different exposure routes, and measured half-life of elimination. Smoking cannabis joints rapidly (within 10 min) increased 2CYEMA in the urine of occasional cannabis users, but not in frequent users. Urine 2CYEMA did not consistently increase following vaping or ingestion in either study group. Cigarette smokers had high pre-exposure concentrations of 2CYEMA. Following cannabis smoking, the half-lives of 2CYEMA ranged from 2.5 to 9.0 h. 2CYEMA is an effective biomarker of cannabis smoke exposure, including smoke from a single cannabis joint, however, not from vaping or when consumed orally. When using 2CYEMA to evaluate exposure in cannabis users, investigators should collect the details about tobacco smoking, route of consumption, and time since last use as possible covariates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph17186438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558117PMC
September 2020

A Review of Synthetic Cathinone-Related Fatalities From 2017 to 2020.

Ther Drug Monit 2021 02;43(1):52-68

Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, Pennsylvania.

Background: Synthetic cathinones (SCs) are designer analogs of the natural active principle of khat. Since their appearance on the black market in 2003, their popularity has increased annually, and they have become the most seized class of new psychoactive substances reported to the UNODC Early Warning Advisory system. The constant introduction of newly synthesized molecules makes this issue difficult to monitor. The authors reviewed the most recent SC-related fatalities worldwide to highlight new trends of consumption, reporting acute pharmacological and toxicological symptoms, scene investigations, analytical methods, and reported SC concentrations in diverse biological matrices.

Methods: A literature search was performed using scientific databases such as PubMed, Scopus, Science Direct, Web of Science, and Research Gate to identify relevant scientific publications from 2017 to 2020. In addition, a search was conducted through the EU EWS.

Results: From 2017 to 2020, 31 different SCs were identified in 75 reported fatal intoxications in the literature, alone or in combination with other substances. The most abused SCs were N-ethylpentylone, N-ethylhexedrone, and 4-chloromethcathinone. The EU EWS included less detail on 72 additional SC-related fatalities from 2017 to 2020.

Conclusions: New SCs continuously replace older natural and synthetic stimulant drugs, making determining the cause of death difficult. Analytical methods and high-performance mass spectrometry instruments are essential to detect the low concentrations of these potent new SCs. Little data are available on the pharmacology of these new drugs; the evaluation of toxicological antemortem and postmortem findings provides critical data on the drug's pharmacology and toxicology and for the interpretation of new SC cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FTD.0000000000000808DOI Listing
February 2021

Development and Validation of an LC-MS-MS Method for the Detection of 40 Benzodiazepines and Three Z-Drugs in Blood and Urine by Solid-Phase Extraction.

J Anal Toxicol 2020 Oct;44(7):708-717

Toxicology Department, Cuyahoga County Medical Examiner's Office (CCMEO), 11001 Cedar Avenue, Cleveland, OH 44106, USA.

An analytical method for the detection of 40 benzodiazepines, (±)-zopiclone, zaleplon and zolpidem in blood and urine by solid-phase extraction liquid chromatography-tandem mass spectrometry was developed and validated. Twenty-nine of 43 analytes were quantified in 0.5 mL whole blood for investigating postmortem, drug-facilitated sexual assault (DFSA) and driving under the influence of drugs cases (DUID). The four different dynamic ranges of the seven-point, linear, 1/x weighted calibration curves with lower limits of quantification of 2, 5, 10 and 20 μg/L across the analytes encompassed the majority of our casework encountered in postmortem, DFSA and DUID samples. Reference materials were available for all analytes except α-hydroxyflualprazolam, a hydroxylated metabolite of flualprazolam. The fragmentation of α-hydroxyflualprazolam was predicted from the fragmentation pattern of α-hydroxyalprazolam, and the appropriate transitions were added to the method to enable monitoring for this analyte. Urine samples were hydrolyzed at 55°C for 30 min with a genetically modified β-glucuronidase enzyme, which resulted in >95% efficiency measured by oxazepam glucuronide. Extensive sample preparation included combining osmotic lysing and protein precipitation with methanol/acetonitrile mixture followed by freezing and centrifugation resulted in exceptionally high signal-to-noise ratios. Bias and between-and within-day imprecision for quality controls (QCs) were all within ±15%, except for clonazolam and etizolam that were within ±20%. All 29 of the 43 analytes tested for QC performance met quantitative reporting criteria within the dynamic ranges of the calibration curves, and 14 analytes, present only in the calibrator solution, were qualitatively reported. Twenty-five analytes met all quantitative reporting criteria including dilution integrity. The ability to analyze quantitative blood and qualitative urine samples in the same batch is one of the most useful elements of this procedure. This sensitive, specific and robust analytical method was routinely employed in the analysis of >300 samples in our laboratory over the last 6 months.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jat/bkaa072DOI Listing
October 2020

Erratum to "Miniaturized extraction method for analysis of synthetic opioids in urine by microextraction with packed sorbent and liquid chromatography-tandem mass spectrometry" [J. Chromatogr. A 1624 (2020) 461241].

J Chromatogr A 2020 08 10;1625:461321. Epub 2020 Jun 10.

Campinas Poison Control Center, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo 13083-859, Brazil; Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, São Paulo 13083-859, Brazil. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chroma.2020.461321DOI Listing
August 2020

Screening of 104 New Psychoactive Substances (NPS) and Other Drugs of Abuse in Oral Fluid by LC-MS-MS.

J Anal Toxicol 2020 Oct;44(7):697-707

Campinas Poison Control Center, University of Campinas (UNICAMP), Campinas, SP 13083-859, Brazil.

New psychoactive substances (NPS) are a major public health problem, primarily due to the increased number of acute poisoning cases. Detection of these substances is a challenge. The aim of this research was to develop and validate a sensitive screening method for 104 drugs of abuse, including synthetic cannabinoids, synthetic cathinones, fentanyl analogues, phenethylamines and other abused psychoactive compounds (i.e., THC, MDMA, LSD and their metabolites) in oral fluid by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The Quantisal™ oral fluid device was used to collect oral fluid samples. The oral fluid-elution buffer mixture (500-μL sample) was extracted with t-butyl methyl ether, and chromatographic separation was performed on a Raptor™ biphenyl column (100 × 2.1 mm ID, 2.7 μm), with a total run time of 13.5 min. Limits of detection were established at three concentrations (0.05, 0.1 or 1 ng/mL) for most analytes, except for acetyl norfentanyl and mescaline (5 ng/mL). Matrix effects were generally <20% and overall extraction recoveries >60%. The highest matrix effect was observed within the synthetic cannabinoid group (PB22, -55.5%). Lower recoveries were observed for 2C-T (47.2%) and JWH-175 (58.7%). Recoveries from the Quantisal™ device were also evaluated for all analytes (56.7-127%), with lower recoveries noted for 25I-NBOMe, valerylfentanyl and mCPP (56.7, 63.0 and 69.9%, respectively). Drug stability in oral fluid was evaluated at 15, 60 and 90 days and at 25, 4 and -20°C. As expected, greater stability was observed when samples were stored at -20°C, but even when frozen, some NPS (e.g., synthetic cannabinoids) showed more than 20% degradation. The method was successfully applied to the analysis of seven authentic oral fluid samples positive for 17 different analytes. The method achieved good sensitivity and simultaneous detection of a wide range of NPS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jat/bkaa089DOI Listing
October 2020

Identifying and Quantifying Cannabinoids in Biological Matrices in the Medical and Legal Cannabis Era.

Clin Chem 2020 07;66(7):888-914

Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, PA.

Background: Cannabinoid analyses generally included, until recently, the primary psychoactive cannabis compound, Δ9-tetrahydrocannabinol (THC), and/or its inactive metabolite, 11-nor-9-carboxy-THC, in blood, plasma, and urine. Technological advances revolutionized the analyses of major and minor phytocannabinoids in diverse biological fluids and tissues. An extensive literature search was conducted in PubMed for articles on cannabinoid analyses from 2000 through 2019. References in acquired manuscripts were also searched for additional articles.

Content: This article summarizes analytical methodologies for identification and quantification of multiple phytocannabinoids (including THC, cannabidiol, cannabigerol, and cannabichromene) and their precursors and/or metabolites in blood, plasma, serum, urine, oral fluid, hair, breath, sweat, dried blood spots, postmortem matrices, breast milk, meconium, and umbilical cord since the year 2000. Tables of nearly 200 studies outline parameters including analytes, specimen volume, instrumentation, and limits of quantification. Important diagnostic and interpretative challenges of cannabinoid analyses are also described. Medicalization and legalization of cannabis and the 2018 Agricultural Improvement Act increased demand for cannabinoid analyses for therapeutic drug monitoring, emergency toxicology, workplace and pain-management drug testing programs, and clinical and forensic toxicology applications. This demand is expected to intensify in the near future, with advances in instrumentation performance, increasing LC-MS/MS availability in clinical and forensic toxicology laboratories, and the ever-expanding knowledge of the potential therapeutic use and toxicity of phytocannabinoids.

Summary: Cannabinoid analyses and data interpretation are complex; however, major and minor phytocannabinoid detection windows and expected concentration ranges in diverse biological matrices improve the interpretation of cannabinoid test results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/clinchem/hvaa113DOI Listing
July 2020

The effect of prenatal adversity on externalizing behaviors at 24 months of age in a high-risk sample: Maternal sensitivity as a moderator.

Infant Ment Health J 2020 07 28;41(4):530-542. Epub 2020 Jun 28.

School of Medicine, University of Maryland, College Park, Maryland, USA.

The purpose of this study was to examine the moderating role of maternal sensitivity on the association between prenatal adversity and externalizing behaviors at 24 months of age in a diverse, high-risk sample. We hypothesized that among children with higher prenatal adversity, high maternal sensitivity would serve as a protective factor. Participants were 247 primarily low-income, diverse dyads. Results indicated a significant interaction effect of maternal sensitivity and prenatal adversity on externalizing problems. The association between prenatal adversity and externalizing behaviors was significant only among children who experienced low prenatal adversity, with higher maternal sensitivity associated with lower externalizing behaviors. These findings indicate that, in the absence of high prenatal risk, responsive and sensitive parenting can buffer children in an otherwise high-risk sample from the development of externalizing behaviors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/imhj.21863DOI Listing
July 2020

Miniaturized extraction method for analysis of synthetic opioids in urine by microextraction with packed sorbent and liquid chromatography-tandem mass spectrometry.

J Chromatogr A 2020 Aug 24;1624:461241. Epub 2020 May 24.

Campinas Poison Control Center, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, 13083-859, Brazil; Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, São Paulo, 13083-859, Brazil. Electronic address:

Synthetic opioids are responsible for numerous overdoses and fatalities worldwide. Currently, fentanyl and its analogs are also mixed with heroin, cocaine and methamphetamine, or sold as oxycodone, hydrocodone and alprazolam in counterfeit medications. Microextraction techniques became more frequent in analytical toxicology over the last decade. A method to simultaneously quantify nine synthetic opioids, fentanyl, sufentanil, alfentanil, acrylfentanyl, thiofentanyl, valerylfentanyl, furanylfentanyl, acetyl fentanyl and carfentanil, and two metabolites, norfentanyl and acetyl norfentanyl, in urine samples by microextraction with packed sorbent (MEPS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated. A multivariate optimization was performed to establish the number and speed (stroke) of draw-eject sample cycles and the extraction solvent. The best extraction condition was eight draw-eject sample cycles, with a velocity of 3.6 µL/sec and acetonitrile as elution solvent. Linearity was achieved between 1 to 100 ng/mL, with a limit of detection (LOD) of 0.1 ng/mL and limit of quantification (LOQ) of 1 ng/mL. Imprecision (% relative standard deviation) and bias (%) were less than 12.8% and 5.7%, respectively. The method had good specificity and selectivity when challenged with 10 different matrix sources and 36 pharmaceuticals and drugs of abuse at concentrations of 100 or 500 ng/mL. The method was successfully applied to authentic urine samples. MEPS was an efficient semi-automatic extraction technique, requiring small volumes of organic solvents (640 µL) and sample (200 µL). The cartridges can be cleaned and reused (average of 150 sample extractions/barrel inside and needle).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chroma.2020.461241DOI Listing
August 2020

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

Clin Pharmacol Ther 2020 12 11;108(6):1203-1212. Epub 2020 Jul 11.

Department of Psychiatry, Baylor College of Medicine, Houston, Texas, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.1929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669583PMC
December 2020
-->