Disposition of cannabinoids and their metabolites in serum, oral fluid, sweat patch and urine from healthy individuals treated with pharmaceutical preparations of medical cannabis.

Recently, several countries authorized the use of cannabis flowering tops (dried inflorescences) with a standardized amount of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and their acidic precursors [Δ-9-tetrahydrocannabinolic acid A (THCA-A) and cannabidiolic acid (CBDA)] to treat neurogenic pain. We studied the acute pharmacological effects and disposition of cannabinoids and their metabolites in serum, oral fluid, sweat patch and urine of 13 healthy individuals treated with medical cannabis decoction and oil. Cannabinoids and their metabolites were quantified by ultrahigh performance tandem mass spectrometry. Even if the oil contained a significantly higher amount of THC, the absorption of THC and its metabolites were similar in both herbal preparations. Conversely, whereas oil contained a significantly higher amount of CBD and a lower amount of CBDA, absorption was significantly higher after decoction intake. Only cannabinoids present in both herbal preparations (THC, CBD, THCA-A and CBDA) were found in oral fluid, due to the higher acidity compared with that of serum. THC metabolites urinary excretion was always higher after decoction administration. Decoction induced greater feeling of hunger and drowsiness than oil preparation. Pharmacokinetics of cannabinoids, their precursors and their metabolites in biological fluids of individuals treated with cannabis decoction and oil showed a high interindividual variability. The aqueous preparation was generally better absorbed than the oil, even if it contained a minor amount of THC, THCA-A and CBD.

Disposition of oral delta-9 tetrahydrocannabinol (THC) in children receiving cannabis extracts for epilepsy.

Introduction: Although over half of US states have legalized marijuana for medical indications, there is limited research in use in the pediatric population. The objective was to evaluate the disposition of oral tetrahydrocannabinol (THC) in children receiving cannabis extracts for pediatric epilepsy.Methods: Prospective, observational study, evaluating the disposition of oral THC in children receiving cannabis extracts. Subjects were less than 18 years of age, receiving oral cannabis for pediatric epilepsy. Subjects included in the study had at least 2 detectable THC and related metabolite plasma concentrations during serial blood draw over a 10-12 h study period.Results: Nine subjects with a median age of 11 years (IQR 4.75) were included in the study, with oral doses ranging from 0.02 mg/kg to 1.59 mg/kg. Peak plasma concentrations (0.8 to 3.6 ng/ml) in most patients were achieved within 2 hours, while acute phase elimination half-life ranged from 1 to 5 hours. THC-COOH and glucuronide remained elevated through the study period. There was significant variation between the dose ingested and peak concentrations (R2 = 0.05).Conclusion: In pediatric patients receiving oral THC cannabis extracts, mean time to peak plasma concentrations was 2-7 hours, while mean acute phase elimination half-life was 4.0 hours. THC-COOH and THC-COOH glucuronide metabolites persisted throughout the 10-12 hour study period. Large variation and no correlation was noted between dose of THC by weight and peak concentrations, suggesting variation of bioavailability amongst pediatric population or inaccurate reporting of THC contents.

Marijuana and alcohol use among injured drivers evaluated at level I trauma centers in Arizona, 2008-2014.

BACKGROUND: We examined marijuana and alcohol use trends among drivers aged ≥16 years evaluated at Level I trauma centers before and after Arizona legalized medical marijuana in April 2011. METHODS: We conducted interrupted time series (ITS) analysis of urine drug screens for marijuana metabolites and blood alcohol concentration (BAC) data from the 2008-2014 Arizona State Trauma Registry. RESULTS: Among 30,083 injured drivers, 14,710 had marijuana test results, and 2590 were positive for marijuana; of these, 1087 (42%) also tested positive for alcohol. Among 23,186 drivers with BAC results, 5266 exceeded the legal limit for their age. Compared with prelaw trends (models if law had not been enacted), postlaw models showed small but significant annual increases in the proportions of drivers testing positive for either substance. By the end of 2014, the proportion of drivers testing positive for marijuana was 9.6% versus a projected 5.6% if the law had not been enacted, and the proportion of drivers with illegal BACs was 15.7% versus a projected 8.2%. When ITS was restricted to only substance-tested drivers, no significant differences were detected. CONCLUSIONS: Despite the small annual postlaw increases in the proportion of marijuana-positive drivers compared with the prelaw trend, alcohol-impaired driving remains a more prevalent threat to road safety in Arizona.

Second-Hand Exposure of Staff Administering Vaporised Cannabinoid Products to Patients in a Hospital Setting.

BACKGROUND: In many health settings, administration of medicinal cannabis poses significant implementation barriers including drug storage and safety for administering staff and surrounding patients. Different modes of administration also provide different yet potentially significant issues. One route that has become of clinical interest owing to the rapid onset of action and patient control of the inhaled amount (via breath timing and depth) is that of vaporisation of cannabinoid products. Although requiring a registered therapeutic device for administration, this is a relatively safe method of intrapulmonary administration that may be particularly useful for patients with difficulty swallowing, and for those in whom higher concentrations of cannabinoids are needed quickly. A particular concern expressed to researchers undertaking clinical trials in the hospital is that other patients, nurses, and clinical or research staff may be exposed to second-hand vapours in the course of administering vaporised products to patients. OBJECTIVE: The objective of this study was to take samples from two research staff involved in administering vaporised Δ9-tetrahydrocannabinol to participants in a clinical trial, to examine and quantitate cannabinoid presence. METHODS: Blood samples from two research staff were taken during the exposure period for three participants (cannabis users) over the course of approximately 2.5 h and analysed using tandem mass spectrometry. RESULTS: Blood samples taken over a vaporised period revealed exposure below the limit of detection for Δ9-tetrahydrocannabinol and two metabolites, using tandem mass spectrometry analytical methods. CONCLUSIONS: These results are reassuring for hospital and clinical trial practices with staff administering vaporised cannabinoid products, and helpful to ethics committees wishing to quantify risk.

Simple and Fast Gas-chromatography Mass Spectrometry Assay to Assess Delta 9-Tetrahydrocannabinol and Cannabidiol in Dogs Treated with Medical Cannabis for Canine Epilepsy.

BACKGROUND: To date, an increasing number of pet owners, especially in the USA, are using cannabis-derived products containing generally delta 9-tetrahydrocannabinol (THC) and cannabidiol (CBD) to help their animals' health. Unfortunately, studies on the clinical use of cannabinoids in veterinary medicine are still limited, and the application of analytical methodologies for the determination of cannabinoids in animal (especially dog) biological matrices such as plasma, is still missing. METHODS: A reliable, fast, accurate, simple gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the quantification of THC and CBD in plasma samples of eight dogs under therapeutic treatment for epilepsy and receiving oral administration of medical cannabis (Bediol). RESULTS: The method was linear for both the analytes under investigation with coefficients of determination (r2) of at least 0.99. Absolute analytical recovery (mean ± SD) ranged from 80.6 ± 6.2% for THC and 81.7 ± 4.3% for CBD. The matrix effect showed less than 10% analytical suppression due to endogenous substances for both the analytes. The intra-assay and inter-assay precision values ranged from 4.9% to 12.7%, and from 5.2% to 8.7% respectively. The intra-assay and inter-assay accuracy values ranged from 2.3% to 9.6% and from 3.4% to 13.0%, respectively. CONCLUSION: The validated method was successfully applied to real samples; moreover, to assess the potential of the method applicability and robustness in future veterinary clinical studies on cannabinoids therapy, we attempted to follow the kinetic of THC and CBD in the plasma of two dogs under therapy at different times after Bediol administration.

Controlled Cannabis Vaporizer Administration: Blood and Plasma Cannabinoids with and without Alcohol.

BACKGROUND: Increased medical and legal cannabis intake is accompanied by greater use of cannabis vaporization and more cases of driving under the influence of cannabis. Although simultaneous Δ(9)-tetrahydrocannabinol (THC) and alcohol use is frequent, potential pharmacokinetic interactions are poorly understood. Here we studied blood and plasma vaporized cannabinoid disposition, with and without simultaneous oral low-dose alcohol. METHODS: Thirty-two adult cannabis smokers (≥1 time/3 months, ≤3 days/week) drank placebo or low-dose alcohol (target approximately 0.065% peak breath-alcohol concentration) 10 min before inhaling 500 mg placebo, low-dose (2.9%) THC, or high-dose (6.7%) THC vaporized cannabis (6 within-individual alcohol-cannabis combinations). Blood and plasma were obtained before and up to 8.3 h after ingestion. RESULTS: Nineteen participants completed all sessions. Median (range) maximum blood concentrations (Cmax) for low and high THC doses (no alcohol) were 32.7 (11.4-66.2) and 42.2 (15.2-137) µg/L THC, respectively, and 2.8 (0-9.1) and 5.0 (0-14.2) µg/L 11-OH-THC. With alcohol, low and high dose Cmax values were 35.3 (13.0-71.4) and 67.5 (18.1-210) µg/L THC and 3.7 (1.4-6.0) and 6.0 (0-23.3) µg/L 11-OH-THC, significantly higher than without alcohol. With a THC detection cutoff of ≥1 µg/L, ≥16.7% of participants remained positive 8.3 h postdose, whereas ≤21.1% were positive by 2.3 h with a cutoff of ≥5 µg/L. CONCLUSIONS: Vaporization is an effective THC delivery route. The significantly higher blood THC and 11-OH-THC Cmax values with alcohol possibly explain increased performance impairment observed from cannabis-alcohol combinations. Chosen driving-related THC cutoffs should be considered carefully to best reflect performance impairment windows. Our results will help facilitate forensic interpretation and inform the debate on drugged driving legislation.