Time- and temperature-dependent postmortem ∆9-tetrahydrocannabinol concentration changes in rabbits following controlled inhaled cannabis administration.

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.

Pharmacokinetic Evaluation of a Cannabidiol Supplement in Horses.

Cannabidiol (CBD) products have gained popularity among horse owners despite limited evidence regarding pharmacokinetics. The purpose of this study was to describe the pharmacokinetic profile of multiple doses of an orally administered cannabidiol product formulated specifically for horses. A randomized 2-way crossover design was used. Seven horses received 0.35 or 2.0 mg/kg CBD per os every 24 hours for 7 total doses, separated by a 2-week washout. Plasma CBD and delta-9-tetrahydrocannabinol (THC) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) daily through day 10, then on day 14 after beginning CBD administration. On the final day of CBD administration, plasma CBD and THC were quantified at multiple times. After administration of 0.35 mg/kg of CBD, the Cmax of CBD was 6.6 ± 2.1 ng/mL while Tmax was 1.8 ± 1.2 hour, whereas the Cmax for THC was 0.7 ± 0.6 ng/mL with a Tmax of 2.5 ± 1 hour. After administration of 2.0 mg/kg of CBD, the Cmax of CBD was 51 ± 14 ng/mL with a mean Tmax of 2.4 ± 1.1 hour and terminal phase half-life of 10.4 ± 6 hour, whereas the Cmax of THC was 7.5 ± 2.2 ng/mL with a Tmax of 2.9 ± 1.1 hour. Oral administration of a cannabidiol product at 0.35 mg/kg or 2.0 mg/kg once daily for 7 days was well-tolerated. Based on plasma CBD levels obtained, dose escalation trials in the horse evaluating clinical efficacy at higher mg/kg dose rates are indicated.

Cannabinoid distribution in fatally-injured pilots' postmortem fluids and tissues.

The primary psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC) impairs cognitive function and psychomotor performance, particularly for complex tasks like piloting an aircraft. The Federal Aviation Administration's (FAA) Forensic Sciences Section at the Civil Aerospace Medical Institute (Oklahoma City, OK) performs toxicological analyses on pilots fatally injured in general aviation incidents, permitting cannabinoids measurement in a broad array of postmortem biological specimens. Cannabinoid concentrations in postmortem fluids and tissues from 10 pilots involved in airplane crashes are presented. Median (range) THC blood concentration was 1.6 (1.0-13.7) ng/mL. Phase I metabolites, 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THCCOOH) and phase II glucuronide metabolite, THCCOOH-glucuronide, had median (range) blood concentrations of 1.4 (0.5-1.8), 9.9 (2.2-72.6) and 36.6 (7.1-160) ng/mL, respectively. Urine analyses revealed positive results for THCCOOH, THC-glucuronide, THCCOOH-glucuronide and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCVCOOH). THC was readily distributed to lung, brain, kidney, spleen and heart. The psychoactive metabolite, 11-OH-THC, was identified in liver and brain with median (range) concentrations 7.1 (3.5-10.5) and 2.4 (2.0-6.0) ng/g, respectively. Substantial THCCOOH and THCCOOH-glucuronide concentrations were observed in liver, lung, brain, kidney, spleen and heart. These cannabinoid concentrations from multiple types of postmortem specimens add to the limited postmortem cannabinoid research data and suggest useful biological matrices for investigating cannabinoid-related deaths.

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

Cannabis sativa is commonly used worldwide and is frequently detected by forensic laboratories working with biological specimens from potentially impaired drivers or pilots. To address the problem of limited published methods for cannabinoids quantification in postmortem specimens, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), 8ß,11-dihydroxy-THC (8ß-diOH-THC), 8ß-hydroxy-THC (8ß-OH-THC), THC-glucuronide (THC-g), THCCOOH-glucuronide (THCCOOH-g), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-THCV (THCVCOOH). Solid phase extraction concentrated analytes prior to analysis on a biphenyl column coupled to a mass spectrometer in electrospray positive ionization mode using multiple reaction monitoring. Linearity ranged from 0.25-50 ng/mL (THC-g), 0.5-100 ng/mL (CBN), 0.5-250 ng/mL (THC, 11-OH-THC, THCCOOH, CBD, and CBG), 1-100 ng/mL (8ß-diOH-THC, THCVCOOH, 8ß-OH-THC, and THCV) and 1-250 ng/mL (THCCOOH-g). Within-run imprecision was <11.2% CV, between-run imprecision <18.1% CV, and bias was less than ±15.1% of target concentration in blood for all cannabinoids at three concentrations. No carryover or interferences were observed. All cannabinoids were stable in blood at room temperature for 24 h, refrigerated (4°C) for 96 h, and following three freeze/thaw cycles. Matrix effects greater than 25% were observed for most analytes in tissues. The proof of concept for method applicability involved measurement of cannabinoids in a pilot fatally injured in an aviation crash. This new analytical method is robust and sensitive, enabling collection of additional cannabinoid postmortem distribution data to improve interpretation of postmortem cannabinoid results.

Drug Use Reported by U.S. Pilots, 2009-2014.

INTRODUCTION: There is a growing trend in the use of drugs, which could increase the likelihood of an aircraft accident. Evidence exists that pilots do not report all medications to the Federal Aviation Administration (FAA). The purpose of this study was to compare medications discovered by postaccident toxicology testing to those reported to the FAA to determine the veracity of pilot reported medications.METHODS: Medications reported on applications for U.S. medical certificates were compared to those discovered during postaccident toxicology testing. Logistic regressions were performed using Age, Gender, Type of Flight Operation, Medical Class Issued, and whether a Special Issuance (SI) medical certificate was issued as independent covariates. Truth in Reporting a medication was the outcome variable.RESULTS: Age and an SI medical certificate were good predictors of the likelihood of truthfully reporting medications. For each year of age the probability of a subject drug record being truthfully reported increased by 5%, while a pilot with an SI was 3.12 times more likely to be truthful than a pilot without an SI. When reported medications were limited to cardiovascular drugs, Age was the only good predictor of truthful reporting and, for every additional year of age, the probability of a subject drug record being truthfully reported increased by 3%.CONCLUSIONS: This study showed that the probability of a pilot truthfully reporting medication use increases with Age and an SI medical certificate. When reported medications were limited to cardiovascular drugs, Age was the only good predictor of truthful reporting.DeJohn CA, Greenhaw R, Lewis R, Cliburn K. Drug use reported by U.S. pilots, 2009-2014. Aerosp Med Hum Perform. 2020; 91(7):586-591.

Pilots using selective serotonin reuptake inhibitors compared to other fatally injured pilots.

Selective Serotonin Reuptake Inhibitors (SSRI) were a disqualifying medication for U.S. civil pilots before April 5, 2010. After this date, a Federal Aviation Administration policy was created that allowed airmen, on select SSRIs, a pathway to hold a valid medical certificate. The purpose of this study was to provide a detailed look at SSRIs in the U.S. pilot population since the inception of this new policy. We examined the toxicology results from fatally injured airmen in addition to outcomes concerning pilots who are participating in the program. This study examined data from the Civil Aerospace Medical Institute's Bioaeronautical Sciences Research Laboratory in conjunction with the Medical Analysis Tracking Registry and the Document Imaging and Workflow System. A count-based regression model quantified the relationships between positive SSRI findings with additional factors of interest. These factors included pilot rating, ethanol, and first generation antihistamines. There were 1484 fatally injured airmen over the six year study period, of which 44-tested positive for an SSRI. First-generation antihistamines were statistically associated with positive findings of SSRIs.

Tricyclic Antidepressants Found in Pilots Fatally Injured in Civil Aviation Accidents.

Prevalence of tricyclic antidepressants (TCAs) has not been explored in pilots. The National Transportation Safety Board (NTSB) aviation accident and the Federal Aviation Administration's Civil Aerospace Medical Institute (CAMI) toxicology and medical certification databases were searched for pilots fatally injured in aviation accidents. During 1990-2012, CAMI received bio-samples of pilots from 7037 aviation accidents. Of these, 2644 cases were positive for drugs. TCAs were present in 31. TCA blood concentrations ranged from therapeutic to toxic levels. The NTSB determined that the use of drugs and ethanol as the probable cause or contributing factor in 35% (11 of 31) of the accidents. None of the 31 pilots reported the use of TCAs during their aviation medical examination. The prevalence of TCAs in aviators was less than 0.5% (31 of 7037 cases). There is a need for aviators to fully disclose the use of medications at the time of their medical examination.