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Barth L Wilsey,1,2 Reena Deutsch,3 Emil Samara,4 Thomas D Marcotte,3 Allan J Barnes,5 Marilyn A Huestis,5,6 Danny Le1,2 1VA Northern California Health Care System, Mather, CA, 2Department of Physical Medicine and Rehabilitation, University of California, Sacramento, CA, 3Department of Psychiatry, University of California, San Diego, La Jolla, CA, 4PharmaPolaris International, Davis, CA, 5Chemistry and Drug Metabolism, IRP, National Institute on Drug Abuse, Baltimore, MD, 6University of Maryland School of Medicine, Baltimore, MD, USA Abstract: A randomized, placebo-controlled crossover trial utilizing vaporized cannabis containing placebo and 6.7% and 2.9% delta-9-tetrahydrocannabinol (THC) was performed in 42 subjects with central neuropathic pain related to spinal cord injury and disease. Subjects received two administrations of the study medication in a 4-hour interval. Blood samples for pharmacokinetic evaluation were collected, and pain assessment tests were performed immediately after the second administration and 3 hours later. Pharmacokinetic data, although limited, were consistent with literature reports, namely dose-dependent increase in systemic exposure followed by rapid disappearance of THC. Dose-dependent improvement in pain score was evident across all pain scale elements. Using mixed model regression, an evaluation of the relationship between plasma concentrations of selected cannabinoids and percent change in items from the Neuropathic Pain Scale was conducted. Changes in the concentration of THC and its nonpsychotropic metabolite, 11-nor-9-carboxy-THC, were related to percent change from baseline of several descriptors (eg, itching, burning, and deep pain). However, given the large number of multiple comparisons, false-discovery-rate-adjusted P-values were not significant. Plans for future work are outlined to explore the relationship of plasma concentrations with the analgesic response to different cannabinoids. Such an appraisal of descriptors might contribute to the identification of distinct pathophysiologic mechanisms and, ultimately, the development of mechanism-based treatment approaches for neuropathic pain, a condition that remains difficult to treat. Keywords: cannabinoids, blood concentrations, medical marijuana, analgesia

BackgroundThe Adolescent Brain Cognitive Development ™ Study (ABCD Study®) is an open-science, multi-site, prospective, longitudinal study following over 11,800 9- and 10-year-old youth into early adulthood. The ABCD Study aims to prospectively examine the impact of substance use (SU) on neurocognitive and health outcomes. Although SU initiation typically occurs during teen years, relatively little is known about patterns of SU in children younger than 12.MethodsThis study aims to report the detailed ABCD Study® SU patterns at baseline (n = 11,875) in order to inform the greater scientific community about cohort's early SU. Along with a detailed description of SU, we ran mixed effects regression models to examine the association between early caffeine and alcohol sipping with demographic factors, externalizing symptoms and parental history of alcohol and substance use disorders (AUD/SUD).Primary resultsAt baseline, the majority of youth had used caffeine (67.6 %) and 22.5 % reported sipping alcohol (22.5 %). There was little to no reported use of other drug categories (0.2 % full alcohol drink, 0.7 % used nicotine,

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development.

AbstractSynthesis and illicit use of designer benzodiazepines are growing concerns, withthese newpsychoactive substances (NPS) posing serious health consequences and new hurdles for toxicologists. Consumption marker identification and characterization is paramount in confirming their use. The benzodiazepine core structure is a fusion of benzene and a seven-membered heterocycle with two nitrogen atoms forming the diazepine ring. Minor variations on the core structure produce different classes of benzodiazepines with marked differences in physiological effects.The present review provides a comprehensive designer benzodiazepines metabolismoverview and suggestssuitable human consumptionbiomarkers for toxicology casework. A systematic literature search of PubMed®, ScopusTM, Web of ScienceTM, and Cochranedatabaseswas conducted independently by two coauthorsadhering to PRISMA guidelines. Data from 30in vitro and in vivo models of designer benzodiazepines metabolism from January 2007 to February 2023 were included. 1,4-benzodiazepines (n = 10), 2,3-benzodiazepines (n = 1), triazolo-benzodiazepines (n = 9), and thieno-triazolo-benzodiazepines (n = 3) study design, sample pretreatment, analytical techniques and major metabolites detected in various matrices are addressed. Metabolites following hydroxylation and phase II glucuronide conjugation were the most prevalent analytes. N-Glucuronidation of parent azole-fused benzodiazepines, andnitro-reduced and N-acetylated metabolites of nitro-containing designer benzodiazepines were also common. From these data, we propose a generic metabolic pathwayfor designer benzodiazepines. The sporadic illicit market presents challenges in toxicological casework and necessitates comprehensive biomarker investigations, especially in cases with legal implications. There are fewmetabolismdata for many designer benzodiazepines, emphasizing the need for research focusing on closing these gaps. [ABSTRACT FROM AUTHOR]

Background: Maternal depression is associated with a higher incidence of behavioral problems in infants, but the effects of maternal depression as early as 1 month are not well characterized. The objective of this study is to determine the neurobehavioral effects of maternal depression on infants exposed and not exposed to methamphetamine (MA) using the NICU Network Neurobehavioral Scale (NNNS).Methods: Four hundred twelve mother-infant pairs were enrolled (MA = 204) and only biological mothers with custody of their child were included in the current analysis. At the 1-month visit (n = 126 MA-exposed; n = 193 MA-unexposed), the Beck Depression Inventory-II (BDI-II) was administered, and the NNNS was administered to the infant. Exposure was identified by self-report and/or gas chromatography/mass spectroscopy confirmation of amphetamine and metabolites in newborn meconium. Unexposed subjects were matched, denied amphetamine use, and had negative meconium screens. General Linear Models tested the effects of maternal depression and prenatal MA exposure on NNNS, with significance accepted at P < .05.Results: The MA group had an increased incidence of depression-positive diagnosis and increased depression scores on the BDI-II. After adjusting for covariates, MA exposure was associated with increased arousal and handling scores, and a decreased ability to self-regulate. Maternal depression was associated with higher autonomic stress and poorer quality of movement. No additional differences were observed in infants whose mothers were both depressed and used MA during pregnancy.Conclusions: Maternal depression is associated with neurodevelopmental patterns of increased stress and decreased quality of movement, suggesting maternal depression influences neurodevelopment in infants as young as 1 month. [ABSTRACT FROM AUTHOR]

Aims Methadone is standard pharmacotherapy for opioid-dependent pregnant women, yet the relationship between maternal methadone dose and neonatal abstinence syndrome (NAS) severity is still unclear. This research evaluated whether quantification of fetal methadone and drug exposure via meconium would reflect maternal dose and predict neonatal outcomes. Design Prospective clinical study. Setting An urban drug treatment facility treating pregnant and post-partum women and their children. Participants Forty-nine opioid-dependent pregnant women received 30DS110 mg methadone daily. Measurements Maternal methadone dose, infant birth parameters and NAS assessments were extracted from medical records. Thrice-weekly urine specimens were screened for opioids and cocaine. Newborn meconium specimens were quantified for methadone, opioid, cocaine and tobacco biomarkers. Findings Therewas no relationship between meconium methadone concentrations, presence of opioids, cocaine and/or tobacco in meconium, maternal methadone dose or NAS severity. Opioid and cocaine were also found in 36.7 and 38.8 of meconium specimens, respectively, and were associated with positive urine specimens in the third trimester. The presence of opioids other than methadone in meconium correlated with increased rates of preterm birth, longer infant hospital stays and decreased maternal time in drug treatment. Conclusions Methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentrations in meconium did not predict infant birth parameters or NAS severity. Prospective urine testing defined meconium drug detection windows for opiates and cocaine as 3months, rather than the currently accepted 6months. The presence of opioids in meconium could be used as a biomarker for infants at elevated risk in the newborn period. [ABSTRACT FROM AUTHOR]

Aims To quantify blood [Delta]9-tetrahydrocannabinol (THC) concentrations in chronic cannabis users over 7 days of continuous monitored abstinence. Participants Twenty-five frequent, long-term cannabis users resided on a secure clinical research unit at the US National Institute on Drug Abuse under continuous medical surveillance to prevent cannabis self-administration. Measurements Whole blood cannabinoid concentrations were determined by two-dimensional gas chromatography-mass spectrometry. Findings Nine chronic users (36%) had no measurable THC during 7 days of cannabis abstinence; 16 had at least one positive THC >=0.25 ng/ml, but not necessarily on the first day. On day 7, 6 full days after entering the unit, six participants still displayed detectable THC concentrations [mean ± standard deviation (SD), 0.3 ± 0.7 ng/ml] and all 25 had measurable carboxy-metabolite (6.2 ± 8.8 ng/ml). The highest observed THC concentrations on admission (day 1) and day 7 were 7.0 and 3.0 ng/ml, respectively. Interestingly, five participants, all female, had THC-positive whole blood specimens over all 7 days. Body mass index did not correlate with time until the last THC-positive specimen ( n = 16; r = -0.2; P = 0.445). Conclusions Substantial whole blood THC concentrations persist multiple days after drug discontinuation in heavy chronic cannabis users. It is currently unknown whether neurocognitive impairment occurs with low blood THC concentrations, and whether return to normal performance, as documented previously following extended cannabis abstinence, is accompanied by the removal of residual THC in brain. These findings also may impact on the implementation of per se limits in driving under the influence of drugs legislation. [ABSTRACT FROM AUTHOR]

Background: Generally, urinary 11-nor-9-carboxy-Delta9-tetrahydrocannabinol (THCCOOH) after alkaline hydrolysis is monitored to detect cannabis exposure, although last use may have been weeks prior in chronic cannabis users. Delta9-Tetrahydrocannabinol (THC) and 11-hydroxy-THC (11-OH-THC) concentrations in urine following Escherichia coli beta-glucuronidase hydrolysis were proposed as biomarkers of recent (within 8h) cannabis use.Objective: To test the validity of THC and 11-OH-THC in urine as indicators of recent cannabis use.Methods: Monitor urinary cannabinoid excretion in 33 chronic cannabis smokers who resided on a secure research unit under 24h continuous medical surveillance. All urine specimens were collected individually ad libidum for up to 30 days, were hydrolyzed with a tandem E. coli beta-glucuronidase/base procedure, and analyzed for THC, 11-OH-THC and THCCOOH by one- and two-dimensional-cryotrap gas chromatography mass spectrometry (2D-GCMS) with limits of quantification of 2.5 ng/mL.Results: Extended excretion of THC and 11-OH-THC in chronic cannabis users' urine was observed during monitored abstinence; 14 of 33 participants had measurable THC in specimens collected at least 24h after abstinence initiation. Seven subjects had measurable THC in urine for 3, 3, 4, 7, 7, 12, and 24 days after cannabis cessation. 11-OH-THC and THCCOOH were detectable in urine specimens from one heavy, chronic cannabis user for at least 24 days.Conclusion: For the first time, extended urinary excretion of THC and 11-OH-THC is documented for at least 24 days, negating their effectiveness as biomarkers of recent cannabis exposure, and substantiating long terminal elimination times for urinary cannabinoids following chronic cannabis smoking. [ABSTRACT FROM AUTHOR]

Background: Individuals who initiate cannabis use at an early age, when the brain is still developing, might be more vulnerable to lasting neuropsychological deficits than individuals who begin use later in life.Methods: We analyzed neuropsychological test results from 122 long-term heavy cannabis users and 87 comparison subjects with minimal cannabis exposure, all of whom had undergone a 28-day period of abstinence from cannabis, monitored by daily or every-other-day observed urine samples. We compared early-onset cannabis users with late-onset users and with controls, using linear regression controlling for age, sex, ethnicity, and attributes of family of origin.Results: The 69 early-onset users (who began smoking before age 17) differed significantly from both the 53 late-onset users (who began smoking at age 17 or later) and from the 87 controls on several measures, most notably verbal IQ (VIQ). Few differences were found between late-onset users and controls on the test battery. However, when we adjusted for VIQ, virtually all differences between early-onset users and controls on test measures ceased to be significant.Conclusions: Early-onset cannabis users exhibit poorer cognitive performance than late-onset users or control subjects, especially in VIQ, but the cause of this difference cannot be determined from our data. The difference may reflect (1). innate differences between groups in cognitive ability, antedating first cannabis use; (2). an actual neurotoxic effect of cannabis on the developing brain; or (3). poorer learning of conventional cognitive skills by young cannabis users who have eschewed academics and diverged from the mainstream culture. [ABSTRACT FROM AUTHOR]

When faced with increasing drug-related deaths and decline in practicing forensic pathologists, the need to quickly identify toxicology-related deaths is evident in order to appropriately triage cases and expedite turnaround times. Lateral flow immunoassays conducted pre-autopsy offer quick urine drug screen (UDS) results in minutes and are used to inform the need for autopsy. Over 1000 medicolegal cases were reviewed to compare UDS results to laboratory enzyme-linked immunosorbent assay (ELISA) blood results to evaluate how well autopsy UDS predicted laboratory findings. Mass spectral analysis was performed on ELISA-positive specimens and these data were used to investigate UDS false-negative (FN) results when possible. Five different UDS devices (STAT One Step Drug of Abuse dip card and cassette, Premiere Biotech multi-drug and fentanyl dip cards and ATTEST 6-acetylmorphine (6-AM) dip card) were tested encompassing 11 drug classes: 6-AM, amphetamine/methamphetamine, benzodiazepines, benzoylecgonine, fentanyl, methadone, opioids, phencyclidine, and delta-9-tetrahydrocannabinol. Sensitivity, specificity, efficiency, and positive and negative predictive values >80% indicated that UDS was useful for predicting cases involving benzoylecgonine, methadone, methamphetamine, and phencyclidine. UDS was unreliable in predicting amphetamine, benzodiazepines, fentanyl, and opiates-related cases due to a high percentage of FN (up to 11.2%, 8.0%, 12.4%, and 5.5%, respectively) when compared to ELISA blood results. For the later analytes, sensitivities were as low as 57.5%, 60.0%, 72.2%, and 66.7%, respectively. Overall results support that UDS cannot replace laboratory testing. Because UDS is subject to false-positive and FN results users must understand the limitations of using UDS for triage or decision-making purposes., (© 2024 American Academy of Forensic Sciences.)

Introduction: Both cannabis use and depressive symptomology increase in prevalence throughout adolescence. Concurrently, the brain is undergoing neurodevelopment in important limbic regions, such as the amygdala. Prior research indicates the amygdala may also be related to cannabis use and depressive symptoms. We aimed to investigate the effects of adolescent cannabis use on amygdala volumes as well as the interaction of cannabis use and amygdala morphometry on depressive symptoms in youth., Method: Two-hundred-twenty-four participants (ages 12-15), balanced by sex assigned at birth, were selected from a sub-sample of the Adolescent Brain Cognitive Development (ABCD) Study based on hair toxicology and self-report measures of cannabis use. Participants positive for cannabinoids in hair and/or self-reported cannabis use were demographically matched to youth with no self-reported or confirmed cannabis use. The guardians of these youth reported depression symptoms on the Child Behavioral Checklist. Linear mixed effect models were run investigating cannabis use group on amygdala volumes bilaterally, controlling for whole brain volume and random effects of scanner type. Additional analyses examined cannabis group status and bilateral amygdala volume on depression symptoms., Results: Cannabis use was not significantly associated with amygdala volume but was associated with increased depressive symptoms (p<0.01). Cannabis group interacted with amygdala volume, such that individuals with smaller volumes had increased depressive symptoms within the cannabis group (p's<0.01-0.02)., Conclusion: Aberrations in amygdala volume based on cannabis use were not found in early adolescence; however, more depressive symptoms were related to cannabis group. Youth who use cannabis and have smaller amygdala volumes were at increased risk for depressive symptomology, suggesting potential neurovulnerabilities to cannabis use., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent years, potential therapeutic applications of several different cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC), its isomer Δ8-THC and Δ9-tetrahydrocannabivarin (Δ9-THCV), have been investigated. Nevertheless, to establish dose-effect relationship and to gain knowledge of their pharmacokinetics and metabolism, sensitive and specific analytical assays are needed to measure these compounds in patients. For this reason, we developed and validated an online extraction high-performance liquid/liquid chromatography-tandem mass spectrometry (LC/LC-MS-MS) method for the simultaneous quantification of 13 cannabinoids and metabolites including the Δ8 and Δ9 isomers of THC, THCV and those of their major metabolites in human plasma. Plasma was fortified with cannabinoids at varying concentrations within the working range of the respective compound and 200 µL was extracted using a simple one-step protein precipitation procedure. The extracts were analyzed using online trapping LC/LC-atmospheric pressure chemical ionization-MS-MS running in the positive multiple reaction monitoring mode. The lower limit of quantification ranged from 0.5 to 2.5 ng/mL, and the upper limit of quantification was 400 ng/mL for all analytes. Inter-day analytical accuracy and imprecision ranged from 82.9% to 109% and 4.3% to 20.3% (coefficient of variance), respectively. Of 534 plasma samples following controlled oral administration of Δ8-THCV, 236 were positive for Δ8-THCV (median; interquartile ranges: 3.5 ng/mL; 1.8-11.9 ng/mL), 383 for the major metabolite (-)-11-nor-9-carboxy-Δ8-tetrahydrocannabivarin (Δ8-THCV-COOH) (95.4 ng/mL; 20.7-328 ng/mL), 260 for (-)-11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (Δ9-THCV-COOH) (5.8 ng/mL; 2.5-16.1 ng/mL), 157 for (-)-11-hydroxy-Δ8-tetrahydrocannabivarin (11-OH-Δ8-THCV) (1.7 ng/mL; 1.0-3.7 ng/mL), 49 for Δ8-THC-COOH (1.7 ng/mL; 1.4-2.3 ng/mL) and 42 for Δ9-THCV (1.3 ng/mL; 0.8-1.6 ng/mL). We developed and validated the first LC/LC-MS-MS assay for the specific quantification of Δ8-THC, Δ9-THC and THCV isomers and their respective metabolites in human plasma. Δ8-THCV-COOH, 11-hydroxy-Δ8-THCV and Δ9-THCV-COOH were the major Δ8-THCV metabolites in human plasma after oral administration of 98.6% pure Δ8-THCV., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Introduction: Animal studies suggest that adolescent exposure to Δ 9 -tetrahydrocannabinol (Δ 9 -THC), the intoxicating constituent of cannabis, causes lasting functional alterations in brain and other organs. Those studies often neglect the impact that age- and sex-dependent differences in the distribution and metabolism of the drug might exert on its pharmacological effects. Here, we provide a comparative analysis of Δ 9 -THC pharmacokinetics in adolescent and adult female mice, which identify significant dissimilarities in distribution and metabolism of Δ 9 -THC between females of these age groups. Materials and Methods: We administered Δ 9 -THC (5 mg/kg, intraperitoneal) to adolescent (37-day old) and young adult (70-day old) female mice and quantified Δ 9 -THC and its first-pass metabolites-11-hydroxy-Δ 9 -THC (11-OH-THC) and 11-nor-9-carboxy-Δ 9 -THC (11-COOH-THC)-in plasma and brain tissue using liquid chromatography/tandem mass spectrometry. Results: Maximal plasma concentrations of Δ 9 -THC were 8 times higher in adolescent than adult female mice. Conversely, brain concentrations and brain-to-plasma ratios were 25-50% higher in adults than adolescents. Concentrations of Δ 9 -THC metabolites were higher in plasma but lower in brain of adolescent compared to adult female mice. Conclusions: The results identify multiple age-dependent differences in the pharmacokinetic properties of Δ 9 -THC in female mice, which might influence the pharmacological response to the drug.

Objectives: Urine drug testing (UDT) is a critical tool used in medical, forensic, and occupational settings, but interpreting results can be challenging. We performed a study to assess the ability of health care professionals to interpret UDT results accurately., Methods: In total, 911 clinical and laboratory professionals in the United States and Canada responded to a survey with questions gauging expertise in UDT interpretation. Responses were analyzed to identify knowledge gaps., Results: Toxicologists and laboratory PhD scientists performed well, with means of 4.82 and 4.63 questions answered correctly (out of 6 possible), respectively. Physicians specializing in pathology, emergency medicine, primary care, and internal medicine, however, displayed concerning knowledge gaps, as did laboratorians with nondoctoral degrees. Experience and training correlated with interpretation accuracy. Identification of simulated compliance as well as understanding opioid exposure, metabolism, and immunoassay cross-reactivity were among the most clinically significant knowledge gaps. More than 30% of survey respondents indicated that they would seek UDT information from the internet or peers rather than clinical or laboratory experts., Conclusions: The study highlighted the need for targeted education and better collaboration between clinical and laboratory experts and other health care professionals to ensure that when physicians order UDT, they can accurately interpret results and reduce harm., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Although kratom use has been part of life for centuries in Southeast Asia, the availability and use of kratom in the United States (US) increased substantially since the early 2000s when there was little information on kratom pharmacology, use patterns, and effects, all critical to guiding regulation and policy. Here we provide a synthesis of research with several hundred English-language papers published in the past 5 years drawing from basic research, epidemiological and surveillance data, and recent clinical research. This review of available literature aims to provide an integrated update regarding our current understanding of kratom's benefits, risks, pharmacology, and epidemiology, which may inform United States-based kratom regulation. Recent surveillance indicates there are likely several million past-year kratom consumers, though estimates vary widely. Even without precise prevalence data, kratom use is no longer a niche, with millions of United States adults using it for myriad reasons. Despite its botanical origins in the coffee tree family and its polypharmacy, kratom is popularly characterized as an opioid with presumed opioid-system-based risks for addiction or overdose. Neuropharmacology, toxicology, and epidemiology studies show that kratom is more accurately characterized as a substance with diverse and complex pharmacology. Taken together the work reviewed here provides a foundation for future scientific studies, as well as a guide for ongoing efforts to regulate kratom. This work also informs much-needed federal oversight, including by the United States Food and Drug Administration. We conclude with recommendations for kratom regulation and research priorities needed to address current policy and knowledge gaps around this increasingly used botanical product., Competing Interests: JH and MH consult on kratom science and regulatory issues and studies paid by sponsors of potential kratom and kratom derivative-based new dietary ingredient applications and new drug applications to the United States Food and Drug Administration, and to the American Kratom Association on many of the same scientific and regulatory issues as discussed in this article through Pinney Associates. Through Pinney Associates, support of the American Kratom Association, JH has commented on kratom pharmacology, public health, and regulatory needs for state hearings and for a judicial hearing to address questions raised by the court on these same matters. MH is a paid expert witness in legal cases related to kratom. In the past year, KS has served as a paid scientific advisor to the International Plant and Herbal Alliance and to The Kratom Coalition. KS is a paid expert witness in legal cases related to kratom. OG reported representing parties in legal disputes related to kratom use resulting in impairment or death. Neither commercial nor non-profit entities had any input into the conception, content, or opinions expressed in this article, nor to its review, approval or decision to submit the manuscript for publication. The reviewer DS declared a past co-authorship with the authors JE, OG, and MA to the handling editor., (Copyright © 2024 Henningfield, Grundmann, Huestis and Smith.)

Background: Approximately 30 million people worldwide consume new psychoactive substances (NPS), creating a serious public health issue due to their toxicity and potency. Drug-induced liver injury is the leading cause of liver disease, responsible for 4% of global deaths each year., Content: A systematic literature search revealed 64 case reports, in vitro and in vivo studies on NPS hepatotoxicity. Maximum elevated concentrations of aspartate aminotransferase (136 to 15 632 U/L), alanine transaminase (121.5 to 9162 U/L), total bilirubin (0.7 to 702 mg/dL; 0.04 to 39.03 mmol/L), direct (0.2-15.1 mg/dL; 0.01-0.84 mmol/L) and indirect (5.3 mg/dL; 0.29 mmol/L) bilirubin, alkaline phosphatase (79-260 U/L), and gamma-glutamyltransferase (260 U/L) were observed as biochemical markers of liver damage, with acute and fulminant liver failure the major toxic effects described in the NPS case reports. In vitro laboratory studies and subsequent in vivo NPS exposure studies on rats and mice provide data on potential mechanisms of toxicity. Oxidative stress, plasma membrane stability, and cellular energy changes led to apoptosis and cell death. Experimental studies of human liver microsome incubation with synthetic NPS, with and without specific cytochrome P450 inhibitors, highlighted specific enzyme inhibitions and potential drug-drug interactions leading to hepatotoxicity., Summary: Mild to severe hepatotoxic effects following synthetic NPS exposure were described in case reports. In diagnosing the etiology of liver damage, synthetic NPS exposure should be considered as part of the differential diagnosis. Identification of NPS toxicity is important for educating patients on the dangers of NPS consumption and to suggest promising treatments for observed hepatotoxicity., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Δ 9 -tetrahydrocannabinol (THC), the primary intoxicating compound in cannabis, has been tested extensively in controlled administration human studies. Some studies require a high THC dose that may induce adverse events (AEs), such as those testing novel treatments for cannabinoid overdose. Although there are ethical concerns related to administering high THC doses, there is no systematic analysis on studies utilizing these doses. In this review, we examine studies that administered oral THC doses ≥30 mg ("high-dose THC"), focusing on reported tolerability, subjective effects, and pharmacokinetics (PK), with the objective to inform the design of future studies. Methods: A comprehensive PubMed search was performed to identify studies meeting pre-specified criteria. Results: Our search identified 27 publications from 17 high-dose oral THC laboratory studies, with single doses up to 90 mg and multiple doses up to 210 mg per day. The maximum plasma THC concentration (C max ) appeared to increase in a dose-proportional manner over this dose range. All high-dose THC studies enrolled participants with previous cannabis experience, although current use ranged from nonusers to regular cannabis users. High-dose THC was generally well tolerated with transient mild to moderate AE, including nausea and vomiting, anxiety, paranoia, and sedation. There were occasional participant withdrawals due to AEs, but there were no serious AE. Participants with frequent cannabis use tolerated high-dose THC best. Conclusion: Although based on limited data, THC was generally adequately tolerated with single oral doses of at least 50 mg in a controlled laboratory setting in healthy participants with past cannabis experience.

N-Ethyl-N-propyltryptamine (EPT), 4-hydroxy-N-ethyl-N-propyltryptamine (4-OH-EPT), and 5-methoxy-N-ethyl-N-propyltryptamine (5-MeO-EPT) are new psychoactive substances classified as tryptamines, sold online. Many tryptamines metabolize rapidly, and identifying the appropriate metabolites to reveal intake is essential. While the metabolism of 4-OH-EPT and 5-MeO-EPT are not previously described, EPT is known to form metabolites by indole ring hydroxylation among others. Based on general knowledge of metabolic patterns, 5-MeO-EPT is also expected to form ring hydroxylated EPT (5-OH-EPT). In the present study, the aim was to characterize the major metabolites of EPT, 4-OH-EPT, and 5-MeO-EPT, to provide markers for substance identification in forensic casework. The tryptamines were incubated with pooled human liver microsomes at 37°C for up to 4 h. The generated metabolites were separated and detected by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry analysis. The major in vitro EPT metabolites were formed by hydroxylation, N-dealkylation, and carbonylation. In comparison, 4-OH-EPT metabolism was dominated by double bond formation, N-dealkylation, hydroxylation, and carbonylation in vitro and hydroxylation or carbonylation combined with double bond loss, carbonylation, N-dealkylation, and hydroxylation in vivo. 5-MeO-EPT was metabolized by O-demethylation, hydroxylation, and N-dealkylation in vitro. The usefulness of the characterized metabolites in forensic casework was demonstrated by identification of unique metabolites for 4-OH-EPT in a human postmortem blood sample with suspected EPT or 4-OH-EPT intoxication., (© 2024 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Driving under the influence of cannabis (DUIC) is increasing worldwide, and cannabis is the most prevalent drug after alcohol in impaired driving cases, emphasizing the need for a reliable traffic enforcement strategy. ∆ 9 -tetrahydrocannabinol (THC) detection in oral fluid has great potential for identifying recent cannabis use; however, additional data are needed on the sensitivities, specificities, and efficiencies of different oral fluid devices for detecting cannabinoids at the roadside by police during routine traffic safety enforcement efforts. At the roadside, 8945 oral fluid THC screening tests were performed with four devices: AquilaScan®, Dräger DrugTest®, WipeAlyser Reader®, and Druglizer®. A total of 530 samples screened positive for THC (5.9%) and were analyzed by liquid chromatography-tandem mass spectrometry at multiple cutoff concentrations (2 ng/mL, 10 ng/mL, and manufacturers' recommended device cutoffs) to investigate device performance. Results varied substantially, with sensitivities of 0%-96.8%, specificities of 89.8%-98.5%, and efficiencies of 84.3%-97.8%. The Dräger DrugTest® outperformed the other devices with a 96.8% sensitivity, 97.1% specificity, and 97.0% efficiency at a 5-ng/mL LC-MS/MS confirmation cutoff. The WipeAlyser Reader® had good performance with a 91.4% sensitivity, 97.2% specificity, and 96.4% efficiency. AquilaScan® and Druglizer® had unacceptable performance for cannabinoid detection, highlighted by sensitivity <13%. The choice of roadside oral fluid testing device must offer good analytical performance for cannabinoids because of its high prevalence of use and impact on road safety., (© 2024 John Wiley & Sons Ltd.)

Objective: Cannabis is widely used, including in early adolescence, with prevalence rates varying by measurement method (e.g., toxicology vs. self-report). Critical neurocognitive development occurs throughout adolescence. Given conflicting prior brain-behavior results in cannabis research, improved measurement of cannabis use in younger adolescents is needed., Methods: Data from the Adolescent Brain Cognitive Development (ABCD) Study Year 4 follow-up (participant age: 13-14 years-old) included hair samples assessed by LC-MS/MS and GC-MS/MS, quantifying THCCOOH (THC metabolite), THC, and cannabidiol concentrations, and the NIH Toolbox Cognitive Battery. Youth whose hair was positive for cannabinoids or reported past-year cannabis use were included in a Cannabis Use (CU) group (n = 123) and matched with non-using Controls on sociodemographics (n = 123). Standard and nested ANCOVAs assessed group status predicting cognitive performance, controlling for family relationships. Follow-up correlations assessed cannabinoid hair concentration, self-reported cannabis use, and neurocognition., Results: CU scored lower on Picture Memory (p = .03) than Controls. Within the CU group, THCCOOH negatively correlated with Picture Vocabulary (r = -0.20, p = .03) and Flanker Inhibitory Control and Attention (r = -0.19, p = .04), and past-year cannabis use was negatively associated with List Sorting Working Memory (r = -0.33, p = .0002) and Picture Sequence Memory (r = -0.19, p = .04) performances., Conclusions: Youth who had used cannabis showed lower scores on an episodic memory task, and more cannabis use was linked to poorer performances on verbal, inhibitory, working memory, and episodic memory tasks. Combining hair toxicology with self-report revealed more brain-behavior relationships than self-report data alone. These youth will be followed to determine long-term substance use and neurocognition trajectories., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Kratom leaves, consumed by millions worldwide as tea or ground leaf powder, contain multiple alkaloids, with mitragynine being the most abundant and responsible for most effects. Mitragynine is a partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors; however, unlike morphine, it does not activate the β-arrestin-2 respiratory depression pathway. Due to few human mitragynine data, the largest randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of 500-4000 mg dried kratom leaf powder (6.65-53.2 mg mitragynine) was conducted. LC-MS/MS mitragynine and 7-hydroxymitragynine plasma concentrations were obtained after single and 15 daily doses. Mitragynine and 7-hydroxymitragynine C max increased dose proportionally, and AUC was slightly more than dose proportional. The median mitragynine T max was 1.0-1.3 h after single and 1.0-1.7 h after multiple doses; for 7-hydroxymitragynine T max , it was 1.2-1.8 h and 1.3-2.0 h. Steady-state mitragynine concentrations were reached in 8-9 days and 7-hydroxymitragynine within 7 days. The highest mean mitragynine T 1/2 was 43.4 h after one and 67.9 h after multiple doses, and, for 7-hydroxymitragynine, it was 4.7 and 24.7 h. The mean 7-hydroxy-mitragynine/mitragynine concentration ratios were 0.20-0.31 after a single dose and decreased (0.15-0.21) after multiple doses. These mitragynine and 7-hydroxymitragynine data provide guidance for future clinical kratom dosing studies and an interpretation of clinical and forensic mitragynine and 7-hydroxymitragynine concentrations.

New Psychoactive Substances (NPSs) are defined as a group of substances produced from molecular modifications of traditional drugs. These molecules represent a public health problem since information about their metabolites and toxicity is poorly understood. N-ethyl pentedrone (NEP) is an NPS that was identified in the illicit market for the first time in the mid-2010s, with four intoxication cases later described in the literature. This study aims to evaluate the metabolic stability of NEP as well as to identify its metabolites using three liver microsomes models. To investigate metabolic stability, NEP was incubated with rat (RLM), mouse (MLM) and human (HLM) liver microsomes and its concentration over time evaluated by liquid chromatography-mass spectrometry. For metabolite identification, the same procedure was employed, but the samples were analyzed by liquid chromatography-high resolution mass spectrometry. Different metabolism profiles were observed depending on the model employed and kinetic parameters were determined. The in vitro NEP elimination half-lives (t 1/2 ) were 12.1, 187 and 770 min for the rat, mouse and human models, respectively. Additionally, in vitro intrinsic clearances (Cl int, in vitro ) were 229 for rat, 14.8 for mouse, and 3.6 μL/min/mg in the human model, and in vivo intrinsic clearances (Cl int, in vivo ) 128, 58.3, and 3.7 mL/min/kg, respectively. The HLM model had the lowest rate of metabolism when compared to RLM and MLM. Also, twelve NEP metabolites were identified from all models, but at different rates of production.

Introduction: Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) are major chemical constituents of cannabis, which may interact either directly or indirectly with the endocannabinoid and endocannabinoid-like ("paracannabinoid") systems, two lipid-based signaling complexes that play important roles in physiology. Legislative changes emphasize the need to understand how THC and CBD might impact endocannabinoid and paracannabinoid signaling, and to develop analytical approaches to study such impact. In this study, we describe a sensitive and accurate method for the simultaneous quantification of THC, its main oxidative metabolites [11-hydroxy-Δ 9 -THC (11-OH-THC) and 11-nor-9-carboxy-Δ 9 -THC (11-COOH-THC)], CBD, and a representative set of endocannabinoid [anandamide and 2-arachidonoyl- sn -glycerol (2-AG)] and paracannabinoid [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] compounds. Analyte separation relies on the temperature-dependent shape selectivity properties of polymerically bonded C18 stationary phases. Materials and Methods: Analytes are extracted from tissues using acetonitrile precipitation followed by phospholipid removal. The ultrahigh-performance liquid chromatography/tandem mass spectrometry protocol utilizes a commercially available C18 polymeric-bonded phase column and a simple gradient elution system. Results: Ten-point calibration curves show excellent linearity ( R 2 >0.99) over a wide range of analyte concentrations (0.02-500 ng/mL). Lowest limits of quantification are 0.05 ng/mL for anandamide, 0.1 ng/mL for 11-OH-THC and OEA, 0.2 ng/mL for THC and CBD, 0.5 ng/mL for 11-COOH-THC, 1.0 ng/mL for 2-AG, and 2.0 ng/mL for PEA. The lowest limits of detection are 0.02 ng/mL for anandamide, 0.05 ng/mL for 11-OH-THC and OEA, 0.1 ng/mL for THC and CBD, 0.2 ng/mL for 11-COOH-THC, 0.5 ng/mL for 2-AG, and 1.0 ng/mL for PEA. Conclusions: An application of the method is presented, which showed that phytocannabinoid administration elevates endocannabinoid levels in plasma and brain of adolescent male and female mice.

Objective: Alcohol or drug impairment is a major risk factor for road traffic crashes, and studies on this issue are essential to provide evidence-based data for policymakers. In low- and middle-income countries (LMICs), such studies are often conducted in partnership with one or more organizations in high-income countries (HICs). The aim of this article is to provide recommendations for improving project planning and decision-making processes in epidemiological studies on alcohol, drug and traffic safety in LMICs involving HICs., Methods: We searched Pubmed, Google Scholar, and Google Search for articles and reports in English about lessons learned when conducting collaborative research in LMIC as well as papers presenting recommendations for effective research collaboration with partners in LMICs., Results: Based on the search results, we selected 200 papers for full text examination. Few were related to studies on the effect of alcohol or drug use on road traffic safety. However, several conclusions and recommendations from other studies were found to be relevant. We combined the findings with our own experience in a narrative review. We also present a checklist for risk and quality assessment., Conclusions: Many papers presented similar recommendations, which included the importance of addressing local needs, ensuring adequate resources, local project ownership and leadership, establishing strong partnerships among all involved stakeholders, promoting shared decision-making and planning, and implementing strategies to translate research findings into policy, practice, and publications. It is also important to avoid HIC bias, which prioritizes the interests or perspectives of HICs over those of LMICs.

ostmortem redistribution (PMR), a well-known phenomenon in forensic toxicology, can result in substantial changes in drug concentrations after death, depending on the chemical characteristics of the drug, blood collection site, storage conditions of the body and postmortem interval (PMI). Limited PMR data are available for ∆9-tetrahydrocannabinol (THC), the primary psychoactive component in Cannabis sativa. PMR was evaluated after controlled cannabis inhalation via a smoking machine and exposure chamber in New Zealand white rabbits. Necropsies were performed on five control rabbits immediately after euthanasia, whereas 27 others were stored at room temperature (21°C) or refrigerated conditions (4°C) until necropsy at 2, 6, 16, 24 or 36 h after death. THC and its Phase I and glucuronidated Phase II metabolites were quantified in blood, vitreous humor, urine, bile and tissues by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Under refrigerated temperature, heart blood THC concentrations significantly increased at PMI 2 h in rabbits, whereas peripheral blood THC concentrations showed a significant increase at PMI 16 h. Central:peripheral blood and liver:peripheral blood ratios for THC ranged from 0.13 to 4.1 and 0.28 to 8.9, respectively. Lung revealed the highest THC concentrations, while brain and liver exhibited the most stable THC concentrations over time. This report contributes much needed data to our understanding of postmortem THC behavior and can aid toxicologists in the interpretation of THC concentrations in medicolegal death investigations., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Endocannabinoids and related N-acylethanolamines (NAEs) are bioactive lipids with important physiological functions and putative roles in mental health and addictions. Although chronic cannabis use is associated with endocannabinoid system changes, the status of circulating endocannabinoids and related NAEs in people with cannabis use disorder (CUD) is uncertain., Methods: Eleven individuals with CUD and 54 healthy non-cannabis using control participants (HC) provided plasma for measurement by high-performance liquid chromatography-mass spectrometry of endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and related NAE fatty acids (N-docosahexaenoylethanolamine (DHEA) and N-oleoylethanolamine (OEA)). Participants were genotyped for the functional gene variant of FAAH (rs324420, C385A) which may affect concentrations of AEA as well as other NAEs (OEA, DHEA)., Results: In overnight abstinent CUD, AEA, OEA and DHEA concentrations were significantly higher (31-40%; p < 0.05) and concentrations of the endocannabinoid 2-AG were marginally elevated (55%, p = 0.13) relative to HC. There were no significant correlations between endocannabinoids/NAE concentrations and cannabis analytes, self-reported cannabis use frequency or withdrawal symptoms. DHEA concentration was inversely related with marijuana craving ( r = -0.86; p = 0.001). Genotype had no significant effect on plasma endocannabinoids/NAE concentrations., Conclusions: Our preliminary findings, requiring replication, might suggest that activity of the endocannabinoid system is elevated in chronic cannabis users. It is unclear whether this elevation is a compensatory response or a predating state. Studies examining endocannabinoids and NAEs during prolonged abstinence as well as the potential role of DHEA in craving are warranted.

Importance: With increasing medicinal and recreational cannabis legalization, there is a public health need for effective and unbiased evaluations for determining whether a driver is impaired due to Δ9-tetrahydrocannabinol (THC) exposure. Field sobriety tests (FSTs) are a key component of the gold standard law enforcement officer-based evaluations, yet controlled studies are inconclusive regarding their efficacy in detecting whether a person is under the influence of THC., Objective: To examine the classification accuracy of FSTs with respect to cannabis exposure and driving impairment (as determined via a driving simulation)., Design, Setting, and Participants: This double-blind, placebo-controlled parallel randomized clinical trial was conducted from February 2017 to June 2019 at the Center for Medicinal Cannabis Research, University of California, San Diego. Participants were aged 21 to 55 years and had used cannabis in the past month. Data were analyzed from August 2021 to April 2023., Intervention: Participants were randomized 1:1:1 to placebo (0.02% THC), 5.9% THC cannabis, or 13.4% THC cannabis smoked ad libitum., Main Outcome and Measures: The primary end point was law enforcement officer determination of FST impairment at 4 time points after smoking. Additional measures included officer estimation as to whether participants were in the THC or placebo group as well as driving simulator data. Officers did not observe driving performance., Results: The study included 184 participants (117 [63.6%] male; mean [SD] age, 30 [8.3] years) who had used cannabis a mean (SD) of 16.7 (9.8) days in the past 30 days; 121 received THC and 63, placebo. Officers classified 98 participants (81.0%) in the THC group and 31 (49.2%) in the placebo group as FST impaired (difference, 31.8 percentage points; 95% CI, 16.4-47.2 percentage points; P < .001) at 70 minutes after smoking. The THC group performed significantly worse than the placebo group on 8 of 27 individual FST components (29.6%) and all FST summary scores. However, the placebo group did not complete a median of 8 (IQR, 5-11) FST components as instructed. Of 128 participants classified as FST impaired, officers suspected 127 (99.2%) as having received THC. Driving simulator performance was significantly associated with results of select FSTs (eg, ≥2 clues on One Leg Stand was associated with impairment on the simulator: odds ratio, 3.09; 95% CI, 1.63-5.88; P < .001)., Conclusions and Relevance: This randomized clinical trial found that when administered by highly trained officers, FSTs differentiated between individuals receiving THC vs placebo and driving abilities were associated with results of some FSTs. However, the high rate at which the participants receiving placebo failed to adequately perform FSTs and the high frequency that poor FST performance was suspected to be due to THC-related impairment suggest that FSTs, absent other indicators, may be insufficient to denote THC-specific impairment in drivers., Trial Registration: ClinicalTrials.gov Identifier: NCT02849587.

Background: Cannabis is increasingly used both medically and recreationally. With widespread use, there is growing concern about how to identify cannabis-impaired drivers., Methods: A placebo-controlled randomized double-blinded protocol was conducted to study the effects of cannabis on driving performance. One hundred ninety-one participants were randomized to smoke ad libitum a cannabis cigarette containing placebo or delta-9-tetrahydrocannabinol (THC) (5.9% or 13.4%). Blood, oral fluid (OF), and breath samples were collected along with longitudinal driving performance on a simulator (standard deviation of lateral position [SDLP] and car following [coherence]) over a 5-hour period. Law enforcement officers performed field sobriety tests (FSTs) to determine if participants were impaired., Results: There was no relationship between THC concentrations measured in blood, OF, or breath and SDLP or coherence at any of the timepoints studied (P > 0.05). FSTs were significant (P < 0.05) for classifying participants into the THC group vs the placebo group up to 188 minutes after smoking. Seventy-one minutes after smoking, FSTs classified 81% of the participants who received active drug as being impaired. However, 49% of participants who smoked placebo (controls) were also deemed impaired at this same timepoint. Combining a 2 ng/mL THC cutoff in OF with positive findings on FSTs reduced the number of controls classified as impaired to zero, 86 minutes after smoking the placebo., Conclusions: Requiring a positive toxicology result in addition to the FST observations substantially improved the classification accuracy regarding possible driving under the influence of THC by decreasing the percentage of controls classified as impaired., (© American Association for Clinical Chemistry 2023.)

Background: Although the association between prenatal tobacco exposure and child obesity risk is well-established, less is known about co-exposure to tobacco and cannabis., Objective: Determine the relation between prenatal substance co-exposure and obesity risk., Methods: In a diverse sample of pregnant women, we examined the association between prenatal substance exposure (tobacco-only and co-exposure) and child BMI (kg/m 2 ) trajectories from birth to mid-childhood (n = 262), overweight/obese status based on BMI percentiles from toddlerhood (24 months) to mid-childhood (9-12 years), and adiposity outcomes at mid-childhood (fat mass [kg], fat mass [%] and fat free mass [kg]; n = 128). Given that the major goal of this study was to examine the associations between prenatal substance exposure and child outcomes, we oversampled pregnant women for substance use (with tobacco as the primary focus)., Results: Multilevel models demonstrated that children in both exposure groups had a steeper increase in BMI trajectory from birth to mid-childhood and among co-exposed children, girls had a steeper increase than boys. Odds ratio of having obesity by mid-childhood was 12 times higher among those co-exposed than non-exposed. Co-exposure led to significantly greater fat mass and fat mass % compared with no exposure, but exposure to only tobacco was no different than no exposure., Conclusions: Results highlight potentiating effects of cannabis exposure in the context of maternal tobacco use in pregnancy on obesity risk and the importance of multi-method assessments of obesity., (© 2023 World Obesity Federation.)

Competing Interests: JEH, MAH and DWW provide scientific and regulatory advising on new medicines, dietary supplements, cannabinoids, and tobacco/nicotine products for FDA regulation, through PinneyAssociates, and MAH also provides forensic toxicology and related advising independently of PinneyAssociates. The following authors report no conflict declared: MCC, OG, NH, ZH, LRM, AS, DS, KES, MTS, and ZW. AGR reports serving as a paid scientific advisor to NeonMind Biosciences, InnerWell, and ETHA Natural Botanicals.

In January 2020, the World Health Organization (WHO) issued a Public Health Emergency of International Concern, declaring the COVID-19 outbreak a pandemic in March 2020. Stringent measures decreased consumption of some drugs, moving the illicit market to alternative substances, such as New Psychoactive Substances (NPS). A systematic literature search was performed, using scientific databases such as PubMed, Scopus, Web of Science and institutional and government websites, to identify reported intoxications and fatalities from NPS during the COVID-19 pandemic. The search terms were: COVID-19, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, intox*, fatal*, new psychoactive substance, novel psychoactive substance, smart drugs, new psychoactive substance, novel synthetic opioid, synthetic opioid, synthetic cathinone, bath salts, legal highs, nitazene, bath salt, legal high, synthetic cannabinoid, phenethylamine, phencyclidine, piperazine, novel benzodiazepine, benzodiazepine analogue, designer benzodiazepines, tryptamine and psychostimulant. From January 2020 to March 2022, 215 NPS exposures were reported in Europe, UK, Japan and USA. Single NPS class intoxications accounted for 25, while mixed NPS class intoxications represented only 3 cases. A total of 130 NPS single class fatalities and 56 fatalities involving mixed NPS classes were published during the pandemic. Synthetic opioids were the NPS class most abused, followed by synthetic cathinones and synthetic cannabinoids. Notably, designer benzodiazepines were frequently found in combination with fentalogues. Considering the stress to communities and healthcare systems generated by the pandemic, NPS-related information may be underestimated. However, we could not define the exact impacts of COVID-19 on processing of toxicological data, autopsy and death investigations.

Background: Accurate drug use identification through subjective self-report and toxicological biosample (hair) analysis are necessary to determine substance use sequelae in youth. Yet consistency between self-reported substance use and robust, toxicological analysis in a large sample of youth is understudied. Objectives: We aim to assess concordance between self-reported substance use and hair toxicological analysis in community-based adolescents. Methods: Hair results by LC-MS/MS and GC-MS/MS and self-reported past-year substance use from an Adolescent Brain Cognitive Development (ABCD) Study subsample ( N  = 1,390; ages 9-13; 48% female) were compared. The participants were selected for hair selection through two methods: high scores on a substance risk algorithm selected 93%; 7% were low-risk, randomly selected participants. Kappa coefficients the examined concordance between self-report and hair results. Results: 10% of youth self-reported any past-year substance use (e.g. alcohol, cannabis, nicotine, and opiates), while a mostly non-overlapping 10% had hair results indicating recent substance use (cannabis, alcohol, non-prescription amphetamines, cocaine, nicotine, opiates, and fentanyl). In randomly selected low-risk cases, 7% were confirmed positive in hair. Combining methods, 19% of the sample self-reported substance use and/or had a positive hair sample. Kappa coefficient of concordance between self-report and hair results was low (kappa = 0.07; p  = .007). Conclusions: Hair toxicology identified substance use in high-risk and low-risk ABCD cohort subsamples. Given low concordance between hair results and self-report, reliance on either method alone would incorrectly categorize 9% as non-users. Multiple methods for characterizing substance use history in youth improves accuracy. Larger representative samples are needed to assess the prevalence of substance use in youth.

Consumption of hemp products is continuously growing, with an expanding scope of applications. Suppliers operate through different distribution channels, but the Internet is a major retail platform. Hemp products are prepared from cannabis plants and, therefore, might contain a variety of different natural cannabinoids. According to the regulations of the World Anti-Doping Agency, all natural and synthetic cannabinoids are prohibited in-competition, with the explicit exemption of cannabidiol. Therefore, an investigation of 23 hemp products for the presence of cannabinoids was performed to determine the likelihood of unintentional violations of anti-doping regulations. An assay for the detection of 16 cannabinoids in nutritional supplements was developed and validated. The sample preparation consisted of QuEChERS extraction, trimethylsilylation, and analysis by gas chromatography/tandem mass spectrometry. All 23 commercially available hemp products were analyzed, and assay characteristics such as selectivity, limit of detection, limit of identification, limit of quantification, linearity, imprecision, recovery, and accuracy were determined. Twenty of 23 hemp products included a variety of cannabinoids at, occasionally, substantial concentrations, with four products covering the entire spectrum of tested cannabinoids. An ethics committee-approved single-dose administration study was conducted with the commercially available hemp products, investigating the presence of 16 cannabinoids in urine collected pre- and post-consumption. Variable patterns of cannabinoids or their metabolites in urine were observed. In 30% of the urine samples collected 8 h after ingestion, the presence of a prohibited cannabinoid would have resulted in an unintentional violation of anti-doping regulations., (© 2022 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Background: Exposure to tobacco and cannabis during developmental periods of enhanced vulnerability (e.g., in utero and early childhood) may have long-lasting effects on child health. One potential mechanism underlying these associations is the alteration of inflammatory pathways. Using data from a longitudinal study of mother/child dyads, we examined the adjusted and combined associations of prenatal and postnatal tobacco and cannabis exposure with inflammation in early childhood. Furthermore, we explored the relations between different measures of exposure, partly reflecting differences in timing, dose, and level of fetal exposure (e.g., self-report vs. biomarker), and inflammation. Finally, we explored child sex as a moderator of prenatal and postnatal tobacco and cannabis exposure and inflammation., Method: Women were recruited from a local hospital during their first prenatal appointment. Repeated assessments were conducted at each trimester, at birth, and when children were 2, 9, 16, 24, 36, and 60 months old (N = 215; 112 female children). To evaluate associations with different measurement approaches, prenatal tobacco and cannabis exposure were assessed using: 1) continuous dose-response variables of maternal self-reported tobacco and cannabis use during each trimester to assess associations with timing and severity of exposure, 2) categorization of children into exposure groups based on drugs and metabolites present in infant meconium reflecting later pregnancy fetal exposure, and 3) categorization into exposure groups using a combination of maternal self-report data and biomarker data derived from maternal saliva samples and infant meconium taking advantage of multiple methods of assessment to examine group differences. Postnatal exposure to tobacco (assessed using child salivary cotinine) and cannabis (assessed using maternal self-reported average joints smoked per day) was measured at each infancy/early childhood assessment. Adjusted pre- and postnatal exposure associations with child inflammation were assessed by including both measures as predictor variables in linear regression models predicting child salivary C-reactive protein (CRP) concentrations at 60 months. Interactions between pre- and postnatal exposure variables were then modeled to investigate the combined relations between pre- and postnatal substance exposure with child salivary CRP concentrations at 60 months., Results: Adjusting for postnatal exposure variables, there was a significant interaction between the average daily cigarettes and the average daily cannabis joints smoked during the third trimester predicting salivary CRP concentrations in early childhood. At high tobacco exposure, the effect of cannabis on CRP concentrations was negligible, whereas at low tobacco exposure, the effect of cannabis exposure on CRP concentrations was positive. Adjusting for postnatal tobacco and cannabis exposure, children for whom meconium data indicated co-exposure to tobacco and cannabis showed approximately 43% lower CRP concentrations at age 60 months compared to children with no exposure. However, when mother/child dyads were categorized based on a combination of maternal self-report data and biomarker data from saliva samples and infant meconium, there were no differences in salivary CRP concentrations at age 60 months across the three groups (no prenatal exposure, prenatal tobacco exposure only, prenatal co-exposure to tobacco and cannabis), controlling for postnatal associations. Regardless of the measurement method used to assess prenatal exposures in adjusted analyses, prenatal tobacco exposure alone did not predict CRP concentrations in early childhood, nor did postnatal tobacco exposure. Among boys, postnatal cannabis exposure was associated with higher concentrations of CRP at age 60 months, controlling for prenatal exposure relations. There were no significant combined associations of pre- and postnatal exposure with CRP concentrations., Conclusion: This study expands upon known relations between prenatal and postnatal substance exposure and immunological outcomes in early childhood, underscoring the importance of assessing cannabis exposure during gestation and early life in combination with tobacco exposure., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2022. Published by Elsevier Inc.)

Passive aerosol exposure to Δ 9 -tetrahydrocannabinol (THC) in laboratory animals results in faster onset of action and less extensive liver metabolism compared to most other administration routes and might thus provide an ecologically relevant model of human cannabis inhalation. Previous studies have, however, overlooked the possibility that rodents, as obligate nose breathers, may accumulate aerosolized THC in the nasal cavity, from where the drug might directly diffuse to the brain. To test this, we administered THC (ten 5-s puffs of 100 mg/mL of THC) to adolescent (31-day-old) Sprague-Dawley rats of both sexes. We used liquid chromatography/tandem mass spectrometry to quantify the drug and its first-pass metabolites - 11-hydroxy-Δ 9 -THC (11-OH-THC) and 11-nor-9-carboxy-Δ 9 -THC (11-COOH-THC) - in nasal mucosa, lungs, plasma, and brain (olfactory bulb and cerebellum) at various time points after exposure. Apparent maximal THC concentration and area under the curve were ∼5 times higher in nasal mucosa than in lungs and 50-80 times higher than in plasma. Concentrations of 11-OH-THC were also greater in nasal mucosa and lungs than other tissues, whereas 11-COOH-THC was consistently undetectable. Experiments with microsomal preparations confirmed local metabolism of THC into 11-OH-THC (not 11-COOH-THC) in nasal mucosa and lungs. Finally, whole-body exposure to THC deposited substantial amounts of THC (∼150 mg/g) on fur but suppressed post-exposure grooming in rats of both sexes. The results indicate that THC absorption and metabolism in nasal mucosa and lungs, but probably not gastrointestinal tract, contribute to the pharmacological effects of aerosolized THC in male and female rats., Competing Interests: Declaration of Competing Interest No competing interests exist., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like decoctions, and commercial extracts are taken orally, primarily for health and well-being by millions of people globally. Others take kratom to eliminate opioid use for analgesia and manage opioid withdrawal and use disorder. There is debate over the possible respiratory depressant overdose risk of the primary active alkaloid, mitragynine, a partial μ-opioid receptor agonist, that does not signal through ß-arrestin, the primary opioid respiratory depressant pathway., Objectives: Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188-197, 2020)., Methods: Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride., Findings: Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related., Conclusions: Consistent with mitragynine's pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating β-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans., (© 2022. The Author(s).)

Background: 4-Hydroxy- N,N -methylpropyltryptamine (4-OH-MPT) is a psychedelic tryptamine whose use is regulated in several countries. Due to unspecific effects, consumption can be ascertained only through toxicological analyses. However, the trace amounts of tryptamines are usually challenging to detect in biological samples. 4-OH-MPT metabolism was characterized to identify optimal metabolite markers of intake in clinical/forensic toxicology., Research Design and Methods: 4-OH-MPT was incubated with 10-donor-pooled human hepatocytes to simulate in vivo conditions; samples were analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS), and data were processed with Compound Discoverer from Thermo Scientific. LC-HRMS/MS and data mining were supported by in silico metabolite predictions (GLORYx)., Results: Three phase I and four phase II metabolites were identified, including N -oxidation and N -demethylation at the alkylamine chain, and O -glucuronidation and sulfation at the hydroxylindole core., Conclusions: 4-OH-MPT metabolic fate was consistent with the human metabolism of tryptamine analogues: we suggest 4-OH-MPT- N -oxide and 4-hydroxy- N,N -propyltryptamine (4-OH-PT) as metabolite biomarkers of 4-OH-MPT consumption after glucuronide/sulfate hydrolysis in biological samples to improve detection of 4-OH-MPT and phase I metabolites; 4-OH-MPT-glucuronide is suggested as an additional biomarker when hydrolysis is not performed. Further research on the metabolism of structural analogues is necessary to evaluate the specificity of 4-OH-MPT metabolite biomarkers.

Introduction: Studies in rodent models have shown that adolescent exposure to Δ 9 -THC, the psychotropic constituent of cannabis, produces long-lasting alterations in brain function and behavior. However, our understanding of how age and sex might influence the distribution and metabolism of THC in laboratory rodents is still incomplete. In the present report, we provide a comparative analysis of the pharmacokinetic (PK) properties of THC in adolescent and adult rats of both sexes, and outline several dissimilarities across these groups. Materials and Methods: A single (acute) or 2-week daily (subchronic) administration of THC (0.5 or 5 mg/kg, acute; 5 mg/kg, subchronic; intraperitoneal) was given to adolescent (33-day-old, acute; 30-44-day-old, subchronic) and young adult (70-day-old, acute only) male and female rats. THC and its first-pass metabolites-11-hydroxy-Δ 9 -THC (11-OH-THC) and 11-nor-9-carboxy-Δ 9 -THC (11-COOH-THC)-were quantified in plasma and brain tissue using a selective isotope-dilution liquid chromatography/tandem mass spectrometry assay. Changes in body temperature were measured using abdominally implanted microchips. Biotransformation of THC to its metabolites using freshly prepared liver microsomes was assessed. Results: At the acute 5 mg/kg dose, maximal plasma concentrations of THC were twice as high in adult than in adolescent rats. Conversely, in adults, brain concentrations and brain-to-plasma ratios for THC were substantially lower (25-50%) than those measured in adolescents. Similarly, plasma and brain concentrations of THC metabolites were higher in adolescent male rats compared with adult males. Interestingly, plasma and brain concentrations of the psychoactive THC metabolite 11-OH-THC were twofold to sevenfold higher in female animals of both ages compared with males. Moreover, liver microsomes from adolescent males and adolescent and adult females converted THC to 11-OH-THC twice as fast as adult male microsomes. A dose-dependent hypothermic response to THC was observed in females with 0.5 and 5 mg/kg THC, whereas only the highest dose elicited a response in males. Finally, subchronic administration of THC during adolescence did not significantly affect the drug's PK profile. Conclusions: The results reveal the existence of multiple age and sex differences in the distribution and metabolism of THC in rats, which might influence the pharmacological response to the drug.

The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50-200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in plasma. The study was a randomized, cross-over, double-blinded and placebo-controlled study, with a total of 468 plasma samples collected. First, 10 µL of MDMA-d 5 , MDA-d 5 and methylone-d 3 internal standards were added to 100 µL of plasma. Two mL of chloroform and ethyl acetate 9:1 ( v / v ) were then added, mixed well and centrifuged. The supernatant was fortified with 0.1 mL acidified methanol and evaporated under nitrogen. Samples were reconstituted with a mobile phase and injected into the LC-MS/MS instrument. The method was fully validated according to OSAC guidelines (USA). Methylone plasma concentrations increased in a dose-proportional manner, as demonstrated by the increasing maximum concentration (Cmax) and area under the curve of concentrations (AUC). Methylone Cmax values were reported as 153, 304, 355 and 604 ng/mL, AUC0-24 values were reported as 1042.8, 2441.2, 3524.4 and 5067.9 h·ng/mL and T 1/2 values as 5.8, 6.4, 6.9 and 6.4 h following the 50, 100, 150 and 200 mg doses, respectively. Methylone exhibited rapid kinetics with a Tmax of 1.5 h for the 50 mg dose and 2 h approximately after all the other doses. HMMC exhibited faster kinetics compared to methylone, with a Cmax value that was 10-14-fold lower and an AUC0-24 value that was 21-29-fold lower. Methylone pharmacokinetics was linear across 50-200 mg oral doses in humans, unlike the previously described non-linear oral MDMA pharmacokinetics. An LC-MS/MS method for the quantification of methylone, MDMA and their metabolites in human plasma was achieved. Methylone exhibited linear pharmacokinetics in humans with oral doses of 50-200 mg.

Adulteration is a well-known practice of drug manufacturers at different stages of drug production. The intentional addition of active ingredients to adulterate the primary drug may enhance or mask pharmacological effects or may produce more potent drugs to increase the number of available doses and the dealer's profit. Adulterants found in different drugs change over time in response to different factors. A systematic literature search in PubMed and Scopus databases and official international organizations' websites according to PRISMA guidelines was performed. A total of 724 studies were initially screened, with 145 articles from PubMed and 462 from Scopus excluded according to the criteria described in the Method Section. The remaining 117 records were further assessed for eligibility to exclude articles without sufficient data. Finally, 79 studies were classified as "non-biological" ( n = 35) or "biological" ( n = 35 case reports; n = 9 case series) according to the samples investigated. Although the seized samples analyses revealed the presence of well-established adulterants such as levamisole for cocaine or paracetamol/acetaminophen for heroin, the reported data disclosed new adulteration practices, such as the use of NPS as cutting agents for classic drugs of abuse and other NPS. For example, heroin adulterated with synthetic cannabinoids or cocaine adulterated with fentanyl/fentalogues raised particular concern. Notably, adulterants play a role in some adverse effects commonly associated with the primary drug, such as levamisole-adulterated cocaine that may induce vasculitis via an autoimmune process. It is essential to constantly monitor adulterants due to their changing availability that may threaten drug consumers' health.

Δ9-tetrahydrocannabinol (Δ9-THC) isomers, especially Δ8-tetrahydrocannabinol (Δ8-THC), are increasing in foods, beverages, and e-cigarettes liquids. A major factor is passage of the Agriculture Improvement Act (AIA) that removed hemp containing less than 0.3 % Δ9-THC from the definition of "marijuana" or cannabis. CBD-rich hemp flooded the market resulting in excess product that could be subjected to CBD cyclization to produce Δ8-THC. This process utilizes strong acid and yields toxic byproducts that frequently are not removed prior to sale and are currently inadequately studied. Pharmacological activity is qualitatively similar for Δ8-THC and Δ9-THC, but most preclinical studies in mice, rats, and monkeys documented greater ∆9-THC potency. Both isomers caused graded dose-response effects on euphoria, blurred vision, mental confusion and lethargy, although Δ8-THC was at least 25 % less potent. The most common analytical methodologies providing baseline resolution of ∆8-THC and ∆9-THC in non-biological matrices are liquid-chromatography coupled to diode-array detection (LC-DAD or LC-PDA), while liquid chromatography coupled to mass spectrometry is preferred for biological matrices. Other available analytical methods are gas-chromatography-mass spectrometry (GC-MS) and quantitative nuclear magnetic resonance (QNMR). Current knowledge on the pharmacology of ∆8-THC and other ∆9-THC isomers are reviewed to raise awareness of the activity of these isomers in cannabis products, as well as analytical methods to discriminate ∆9-THC qualitatively, and quantitatively and ∆8-THC in biological and non-biological matrices., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cannabidiol (CBD) exhibits anti-inflammatory, anxiolytic, antiseizure, and neuroprotective proprieties without addictive or psychotropic side effects, as opposed to Δ 9 -tetrahydrocannabinol (THC). While recreational cannabis contains higher THC and lower CBD concentrations, medical cannabis contains THC and CBD in different ratios, along with minor phytocannabinoids, terpenes, flavonoids and other chemicals. A volumetric absorptive microsampling (VAMS) method combined with ultra-high-performance liquid chromatography coupled with mass spectrometry in tandem for quantification of CBD, THC and their respective metabolites: cannabidiol-7-oic acid (7-COOH-CBD); 7-hydroxy-cannabidiol (7-OH-CBD); 6-alpha-hydroxy-cannabidiol (6-α-OH-CBD); and 6-beta-hydroxycannabidiol (6-β-OH-CBD); 11- Hydroxy-Δ 9 -tetrahydrocannabinol (11-OH-THC) and 11-Nor-9-carboxy-Δ 9 -tetrahydrocannabinol (THCCOOH). After overnight enzymatic glucuronide hydrolysis at 37°C, samples underwent acidic along with basic liquid-liquid extraction with hexane: ethyl acetate (9:1, v/v). Chromatographic separation was carried out on a C18 column, with the mass spectrometer operated in multiple reaction monitoring mode and negative electrospray ionization. Seven patients with intractable epilepsy were dosed with various CBD-containing formulations and blood collected just before their daily morning administration. The method was validated following international guidelines in toxicology. Linear ranges were (ng/ml) 0.5-25 THC, 11-OH-THC, THCCOOH, 6-α-OH-CBD and 6-β-OH-CBD; 10-500 CBD and 7-OH-CBD; and 20-5000 7-COOH-CBD. 7-COOH-CBD was present in the highest concentrations, followed by 7-OH-CBD and CBD. This analytical method is useful for investigating CBD, THC and their major metabolites in epilepsy patients treated with CBD preparations employing a minimally invasive microsampling technique requiring only 30 µL blood., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pigliasco, Malaca, Lo Faro, Tini, Cangemi, Cafaro, Barco, Riva, Pisati, Amadori, Striano, Tagliabracci, Huestis and Busardò.)