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The assessment of human postmortem concentrations of Δ9-THC (THC) and its metabolites, 11-nor-9-carboxy-THC (THCCOOH) and 11-hydroxy-THC (11-OH-THC), is routinely performed in forensic toxicology laboratories. However, the literature on cannabinoids postmortem redistribution (PMR) is scarce and highlights their complex postmortem changes. This study aims to investigate the postmortem behavior of THC and its metabolites in order to provide practitioners with potential indicators of PMR. To do so, antemortem and postmortem cases positive for cannabinoids were compiled in a database. Its analysis shows significantly higher THC concentrations in postmortem blood than in antemortem blood. Antemortem and postmortem blood also present significantly different profiles for their THC to THCCOOH ratios. Whereas antemortem blood generally shows THCCOOH concentrations higher or equal to THC, several postmortem cases show the opposite, with THC concentrations higher than THCCOOH. While occurrence of postmortem redistribution (PMR) is difficult to measure directly, an evaluation was performed using the central to peripheral (C/P) blood concentrations ratio as a proxy. With a C/P significantly lower than 1.0 for THC and significantly higher than 1.0 for THCCOOH, the PMR hypothesis is supported for both compounds, with redistribution towards peripheral blood for THC and towards central blood for THCCOOH. On the other hand, 11-OH-THC does not show a C/P significantly different than 1.0, suggesting the absence of PMR. Influence of body mass index, conservation state and postmortem interval on C/P was statistically analyzed and no significant impact was observed. To compare and contrast C/P observed in the database with those published in the literature, a meta-analysis was performed using a median of median (MM) model. THC PMR towards peripheral blood is supported by a global estimate of 0.81 (CI95%: 0.51 to 1.2). Redistribution towards femoral blood appears to be stronger than towards iliac blood; indeed, the median estimate of C/P decreases to 0.64 (CI95%: 0.40 to 1.1) when studies with iliac blood were removed from the meta-analysis. THCCOOH PMR towards central blood is supported by a C/P median estimate of 1.3 (CI95%: 0.97 to 1.6). THC PMR can be suspected when these indicators are observed (i) high THC blood concentration (>50 ng/mL), (ii) THC C/P lower than 1.0 (iii) blood THC/THCCOOH concentration ratios greater than 1.0 and (iv) non-detectability of THCCOOH in urine. In postmortem samples, many factors may contribute to the overestimation of THC concentration, therefore a careful interpretation is required, relying on both central and peripheral blood samples. [Display omitted] •Dataset with cannabinoids detection in 351 antemortem and 276 postmortem cases.•Difference between AM and PM cases in analyte concentrations.•Significant postmortem redistribution of THC and THCCOOH.•Meta-analysis with 6 additional references offers similar conclusions.•No correlation with BMI, body state and postmortem interval.

Introduction: Cannabinoids, primarily delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are increasingly used for medicinal purposes. Dronabinol, a THC analogue, is used for nausea, vomiting and anorexia in HIV and cancer. Medical marijuana in New York is permitted to treat neuropathy with severe nausea. Gastroparesis is a neuromuscular disorder that causes many difficult-to-treat symptoms. Neuropathy plays a large role in its pathogenesis. We showed that cannabinoids significantly improve symptoms in patients with refractory gastroparesis. Methods: The effects of cannabinoids on gastroparesis symptoms were assessed in 24 patients. All patients' symptoms were refractory to standard therapies for gastroparesis including dietary modification, medications (prokinetics, antiemetics, neuromodulators), endoscopic therapy, and some patients had gastric stimulators. Patients were prescribed either Dronabinol, medical cannabis, or both for symptom management. Patients who received both treatments were prescribed them sequentially (Dronabinol then marijuana) if Dronabinol did not adequately relieve symptoms. Medical marijuana was taken via vaporized inhalation or sublingual drops and prescribed as needed at varying THC: CBD ratios. Dosage of DronabiBenjamin nol ranged from 2- 10mg twice daily to four times daily. All patients completed a 'Gastroparesis Cardinal Symptom Index' (GCSI), a validated symptom index for gastroparesis, before and after treatment. Results: Six patients were prescribed Dronabinol, ten were prescribed marijuana and eight were prescribed Dronabinol then marijuana. Baseline patient characteristics were collected (Table 1). Paired sample T-tests were performed and statistically significant improvement in GCSI total symptom composite score was seen in patients who received either cannabinoid treatment (mean score difference of 14.097, CI 11.487-16.707; p-value < 0.001). Patients prescribed marijuana experienced statistically significant improvement in every symptom subgroup, while the Dronabinol group experienced statistically significant improvement in all symptom subgroups except 'bloating/distention' (Table 2, Figure 1). Conclusion: Our study shows that cannabinoids significantly improve symptoms of gastroparesis, which is a notoriously difficult condition to manage. Therapeutic options for gastroparesis are limited, so cannabinoids can play an important role in the treatment of the condition, especially in patients with refractory symptoms.

Introduction Medicinal cannabis is often cited as a popular alternative to common sleep aids; however, there are limited studies using complex sleep EEG methods examining its’ effects in insomnia disorder. Methods Twenty participants (16 female; mean [SD] age, 47.1 [8.7] years) with insomnia disorder (mean ISI=20.8) completed two 24-hour in-laboratory visits during which they received a single oral dose of ‘CBD/THC’ containing 200 mg cannabidiol (CBD) and 10 mg Δ9-tetrahydrocannabinol (THC) or matched placebo. Co-primary outcomes were total sleep time (TST) and wake after sleep onset (WASO). Secondary outcomes included next-day neurobehavioural function and sleep architecture metrics determined using overnight polysomnography with high-density EEG. Trial registration: ACTRN12619000714189. Results Compared to placebo, CBD/THC significantly decreased TST (-24.5 min, p=0.047) with no significant change to WASO (+10.7 min, p=0.422). CBD/THC significantly decreased time spent in REM sleep (-8.1%, p< 0.001) and increased REM sleep latency (+65.6 min, p=0.008). High-density EEG analysis revealed a significant reduction in high-frequency EEG activity overlying the posterior and frontal cortex during N2 sleep with CBD/THC treatment compared to placebo. CBD/THC treatment also reduced delta activity in the posterior region of the brain during N3 sleep and increased alpha and beta activity during REM sleep in the posterior regions of the brain relative to placebo (all p’s< 0.05). CBD/THC did not impair next-day (+12 h post-treatment) cognitive performance, alertness, or simulated driving performance (all p’s>0.05). Eighty-five mild, non-serious, adverse events were reported (55 during ETC120; most common dry mouth, drowsiness, and fatigue). Conclusion An acute dose of combined 200 mg CBD and 10 mg THC reduced TST with a clear effect of REM sleep suppression. However, no next-day residual impairment on cognitive function, alertness or simulated driving performance were observed. Further research is required to determine the impact of chronic cannabinoid dosing on REM sleep and other objective sleep outcomes in insomnia disorder. Support (if any) The study was funded by the Lambert Initiative for Cannabinoid Therapeutics, a philanthropically funded centre for cannabinoid research at the University of Sydney, Australia.

Introduction The use of cannabis as a sleep aid has increased despite inadequate evidence of its efficacy or associated risks. Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis. Acute THC administration can induce CB1R mediated reductions in total peripheral resistance resulting in dose-dependent increases in heart rate and reductions in heart rate variability (HRV) in awake subjects. However, the influence of THC on vagal-cardiac modulation during sleep is unclear. Methods 7 individuals who use cannabis (>3x/week for 3 months; CUDIT-R = 8±1) and 8 cannabis-naïve participants (combined: age range 21-32 years; 9 female) were recruited to participate in this repeated measure, single blinded, placebo-controlled study. One hour before habitual sleep, participants received either a placebo pill or 10mg of THC. Polysomnography (PSG) and ECG were recorded over these 2 nights. HRV was assessed in both time and frequency domains in 2-min epochs of stable N2, N3 and REM sleep. Repeated measures ANOVA comparisons were made for PSG and HRV variables. [(*)=p< 0.05] Results There were no significant changes in total sleep duration or sleep architecture (N2%, N3%, & REM%) between the placebo and dosing night in either group. Compared to the placebo night, both individuals who use cannabis and cannabis naïve participants exhibited significant decreases in HRV variables throughout the night when dosed with THC. R-R interval decreased by 25±10* ms [mean±SE] (2%) in the naïve group and 62±11* ms (6%) in the cannabis group. RMSSD decreased by 15±3* ms (22%) in the naïve group and 11±3* ms (23%) in the cannabis group. PNN50 decreased by 9±3* % in the naïve group and 11±3* % in the cannabis group. In naïve participants high frequency spectral power decreased by 398±76* ms^2 (32%). Conclusion Our results suggest that THC ingestion before bedtime did not systematically affect sleep depth or duration, but did significantly reduce vagal-cardiac modulation in individuals who use cannabis as well as in cannabis naïve participants. Acute reductions in parasympathetic control of the heart may indicate increased cardiovascular stress during sleep when THC is ingested. Support (if any) AASM; K01HL151745; T32HL083808; OHSU OFDIR; R35 HL155681; Oregon Institute of Occupational Health Sciences

Introduction∆-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid and structural isomer of ∆-9 THC that is technically legal under United States Federal law. Commercial ∆-8-THC products being sold are currently unregulated. This study aims to (1) describe the advertising and labeling of Δ-8 THC retail products; (2) compare the advertised amount of Δ-8 THC for each product to that found during independent laboratory analysis; and (3) evaluate the presence and amount of other cannabinoids in those products.MethodsTwenty ∆-8 THC products were purchased from retail stores in Pittsburgh, PA, USA. Samples were analyzed to determine cannabinoid content using a validated UPLC-MS/MS method. Descriptive statistics were calculated for all variables. Spearman’s rank order correlation was calculated for the labeled ∆-8 THC content compared to ∆-8 THC content found on our analysis. Differences in continuous variables were compared using ANOVA, Wilcoxon Rank Sum, or Kruskal–Wallis tests.Results∆-8 THC was detected in 95% (N=19) of the sample products. A weakly positive correlation (Spearman’s rho =0.40) was found between the advertised ∆-8 THC content and our analysis results. Factors associated with decreased difference in these variables included (1) solid matrix (chocolate, gummies) and (2) absence of a “lab-tested” label. Δ-9 THC was found in 35% (N=7) of the products, and CBD was found in one.ConclusionA majority of the products analyzed contained ∆-8 THC in amounts that could cause intoxication. The range of ∆-8 THC content on independent analysis was wide and weakly correlated to the advertised content. ∆-8 THC, ∆-9 THC, and CBD were the only cannabinoids detected.

A simple and sensitive analytical method was developed for qualitative and quantitative analysis of Δ9-tetrahydrocannabinol (Δ9-THC) and its metabolite 11-nor-Δ9-tetrahydrocannabinol-carboxylic acid (Δ9-THC-COOH) in human postmortem blood using gas chromatography/mass spectrometry (GC-MS) in selected ion monitoring (SIM) mode. The method involved a liquid-liquid extraction in two steps, one for Δ9-THC and a second one for Δ9-THC-COOH. The first extract was analyzed using Δ9-THC-D3 as internal standard. The second extract was derivatized and analyzed using Δ9-THC-COOH-D3 as internal standard. The method was shown to be very simple, rapid, and sensitive. The method was validated for the two compounds, including linearity (range 0.05–1.5 µg/mL for Δ9-THC and 0.08–1.5 µg/mL for Δ9-THC-COOH), and the main precision parameters. It was linear for both analytes, with quadratic regression of calibration curves always higher than 0.99. The coefficients of variation were less than 15%. Extraction recoveries were superior to 80% for both compounds. The developed method was used to analyze 41 real plasma samples obtained from the Forensic Toxicology Service of the Institute of Forensic Sciences of Santiago de Compostela (Spain) from cases in which the use of cannabis was involved, demonstrating the usefulness of the proposed method.

(−)-Δ-9-tetrahydrocannabinol ((−)-Δ-9-THC) is the main psychoactive constituent in cannabis. During phase I metabolism, it is metabolized to (−)-11-hydroxy-Δ-9-tetrahydrocannabinol ((−)-11-OH-Δ-9-THC), which is psychoactive, and to (−)-11-nor-9-carboxy-Δ-9-tetrahydrocannabinol ((−)-Δ-9-THC-COOH), which is psychoinactive. It is glucuronidated during phase II metabolism. The biotransformation of (−)-Δ-9-tetrahydrocannabinol-glucuronide ((−)-Δ-9-THC-Glc) and (−)-11-nor-9-carboxy-Δ-9-tetrahydrocannabinol-glucuronide ((−)-Δ-9-THC-COOH-Glc) is well understood, which is mainly due to the availability of commercial reference standards. Since such a standardized reference is not yet available for (−)-11-hydroxy-Δ-9-tetrahydrocannabinol-glucuronide ((−)-11-OH-Δ-9-THC-Glc), its biotransformation is harder to study and the nature of the glucuronide bonding—alcoholic and/or phenolic—remains unclear. Consequently, the aim of this study was to investigate the biotransformation of (−)-11-OH-Δ-9-THC-Glc in vitro as well as in vivo and to identify the glucuronide by chemically synthesis of a reference standard. For in vitro analysis, pooled human S9 liver fraction was incubated with (−)-Δ-9-THC. Resulting metabolites were detected by high-performance liquid chromatography system coupled to a high-resolution mass spectrometer (HPLC-HRMS) with heated electrospray ionization (HESI) in positive and negative full scan mode. Five different chromatographic peaks of OH-Δ-9-THC-Glc have been detected in HESI positive and negative mode, respectively. The experiment set up according to Wen et al. indicates the two main metabolites being an alcoholic and a phenolic glucuronide metabolite. In vivo analysis of urine (n = 10) and serum (n = 10) samples from cannabis users confirmed these two main metabolites. Thus, OH-Δ-9-THC is glucuronidated at either the phenolic or the alcoholic hydroxy group. A double glucuronidation was not observed. The alcoholic (−)-11-OH-Δ-9-THC-Glc was successfully chemically synthesized and identified the main alcoholic glucuronide in vitro and in vivo. (−)-11-OH-Δ-9-THC-Glc is the first reference standard for direct identification and quantification. This enables future research to answer the question whether phenolic or alcoholic glucuronidation forms the predominant way of metabolism.

Abstract Background Cannabis use can induce acute and long-lasting psychosis and cognitive dysfunction. Some evidence suggests that the acute behavioral and neurocognitive effects of the main active ingredient in cannabis, (−)-trans-Δ9-tetrahydrocannabinol (∆9-THC), might be modulated by previous cannabis exposure. However, this has not been investigated either using a control group of non-users, or following abstinence in modest cannabis users, who represent the majority of recreational users. Methods Twenty-four healthy men participated in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject, ∆9-THC challenge study. Results Compared to non-users (N=12; <5 lifetime cannabis joints smoked), abstinent modest cannabis users (N=12; 24.5 ± 9 lifetime cannabis joints smoked) showed worse performance and stronger right hemispheric activation during cognitive processing, independent of the acute challenge (all P≤0.047). Acute ∆9-THC administration produced transient anxiety and psychotomimetic symptoms (all P≤0.02), the latter being greater in non-users compared to users (P=0.040). Non-users under placebo (control group) activated specific brain areas to perform the tasks, while deactivating others. An opposite pattern was found under acute (∆9-THC challenge in non-users) as well as residual (cannabis users under placebo) effect of ∆9-THC. Under ∆9-THC, cannabis users showed brain activity patterns intermediate between those in non-users under placebo (control group), and non-users under ∆9-THC (acute effect) and cannabis users under placebo (residual effect). In non-users, the more severe the ∆9-THC-induced psychotomimetic symptoms and cognitive impairments, the more pronounced was the neurophysiological alteration (all P≤0.036). Discussion Previous modest cannabis use blunts the acute behavioral and neurophysiological effects of ∆9-THC, which are more marked in people who have never used cannabis.

Prolonged cannabis users show a lower prevalence of obesity and associated comorbidities. In rodent models, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) from the plant Cannabis sativa L. have shown anti-obesity properties, suggesting a link between the endocannabinoid system (ECS) and obesity. However, the oral administration route has rarely been studied in this context. The aim of this study was to investigate the effect of prolonged oral administration of pure THC and CBD on obesity-related parameters and peripheral endocannabinoids. C57BL/6 male mice were fed with either a high-fat or standard diet and then received oral treatment in ramping doses, namely 10 mg/kg of THC or CBD for 5 weeks followed by 30 mg/kg for an additional 5 weeks. Mice treated with THC had attenuated weight gain and improved glucose tolerance, followed by improvement in steatosis markers and decreased hypertrophic cells in adipose epididymal tissue. Mice treated with CBD had improved glucose tolerance and increased markers of lipid metabolism in adipose and liver tissues, but in contrast to THC, CBD had no effect on weight gain and steatosis markers. CBD exclusively decreased the level of the endocannabinoid 2-arachidonoylglycerol in the liver. These data suggest that the prolonged oral consumption of THC, but not of CBD, ameliorates diet-induced obesity and metabolic parameters, possibly through a mechanism of adipose tissue adaptation.