Free and Glucuronide Whole Blood Cannabinoids' Pharmacokinetics after Controlled Smoked, Vaporized, and Oral Cannabis Administration in Frequent and Occasional Cannabis Users: Identification of Recent Cannabis Intake

Abstract

BACKGROUND There is increasing interest in markers of recent cannabis use because following frequent cannabis intake, Δ9-tetrahydrocannabinol (THC) may be detected in blood for up to 30 days. The minor cannabinoids cannabidiol, cannabinol (CBN), and THC-glucuronide were previously detected for ≤2.1 h in frequent and occasional smokers' blood after cannabis smoking. Cannabigerol (CBG), Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-THCV might also be recent use markers, but their blood pharmacokinetics have not been investigated. Additionally, while smoking is the most common administration route, vaporization and edibles are frequently used. METHODS We characterized blood pharmacokinetics of THC, its phase I and phase II glucuronide metabolites, and minor cannabinoids in occasional and frequent cannabis smokers for 54 (occasional) and 72 (frequent) hours after controlled smoked, vaporized, and oral cannabis administration. RESULTS Few differences were observed between smoked and vaporized blood cannabinoid pharmacokinetics, while significantly greater 11-nor-9-carboxy-THC (THCCOOH) and THCCOOH-glucuronide concentrations occurred following oral cannabis. CBG and CBN were frequently identified after inhalation routes with short detection windows, but not detected following oral dosing. Implementation of a combined THC ≥5 μg/L plus THCCOOH/11-hydroxy-THC ratio <20 cutoff produced detection windows <8 h after all routes for frequent smokers; no occasional smoker was positive 1.5 h or 12 h following inhaled or oral cannabis, respectively. CONCLUSIONS Vaporization and smoking provide comparable cannabinoid delivery. CBG and CBN are recent-use cannabis markers after cannabis inhalation, but their absence does not exclude recent use. Multiple, complimentary criteria should be implemented in conjunction with impairment observations to improve interpretation of cannabinoid tests. Clinicaltrials.gov Identifier: NCT02177513

Population pharmacokinetic modeling of plasma Δ9‐tetrahydrocannabinol and an active and inactive metabolite following controlled smoked cannabis administration

“…In contrast to similar clearance estimates between this study and that of Heuberger et al ., our estimate of V SS (sum of V1, V2 and V3) was 3401 L and was considerably larger than their estimate of 236 L. Using the THC typical value parameters in Table , the estimated terminal phase half‐life for THC is calculated to be approximately 3.5 days, indicating its distribution to deep, presumably lipid tissues. Despite the reliance of only a few data points near the low limit of quantification near the terminal slope (Figure ), this estimate is consistent with the persistence of THC and observed similar half‐lives after cessation of chronic cannabis use …”

“…Despite the reliance of only a few data points near the low limit of quantification near the terminal slope (Figure 4), this estimate is consistent with the persistence of THC and observed similar half-lives after cessation of chronic cannabis use. 12,16,22 From the perspective of plasma sampling we estimated that 74% of inhaled THC is metabolized to 11-OH-THC. This percentage should be viewed as the minimum amount of THC converted first to 11-OH-THC as models of hepatic metabolism estimated from plasma samples model only the 11-OH-THC that circulated in the blood before returning to the liver for subsequent metabolism to THCCOOH or other products.…”

“…body sway, feeling high). 11 Because THC is often not present in measurable concentrations in blood after only a few hours since last use 5 and because its metabolites, which have longer half-lives, are measureable, [5][6][7]12 it is desirable to extend the pharmacokinetic model of THC to include its metabolites. Also, the first metabolite, 11-hydroxy-THC, is equipotent to THC and should be included in any analysis.…”

Correlation of creatinine‐ and specific gravity‐normalized free and glucuronidated urine cannabinoid concentrations following smoked, vaporized, and oral cannabis in frequent and occasional cannabis users

“…The study design was within‐subject, randomized, double‐blind, double‐dummy, and placebo‐controlled, with each participant receiving the active drug by all three routes of administration and placebo oral and inhaled doses within four sessions as previously described . In each session, participants ingested a brownie (Duncan Hines ® Double Fudge brownie mix) and either smoked a cigarette or inhaled from a vaporizer (210°C, Volcano Medic, Storz & Bickel).…”

“…Newmeyer et al conducted a placebo‐controlled, within‐subject, randomized study of eight chronic frequent and eight occasional cannabis users following administration of a single 50.6 mg THC dose by oral, smoked, and vaporized routes . This published study examined blood concentrations and reported free and glucuronide cannabinoid concentrations as well as pharmacokinetic parameters.…”