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Cannabidiol (CBD) is a naturally occurring, non-psycho-toxic phytocannabinoid that has gained increasing attention as a popular consumer product and for its use in FDA-approved Epidiolex® (CBD oral solution) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome. CBD was previously reported to be metabolized primarily by cytochrome P450 (CYP) 2C19 and CYP3A4, with minor contributions from UDP-glucuronosyltransferases. 7-Hydroxy-CBD (7-OH-CBD) is the primary active metabolite with equipotent activity compared to CBD. Given the polymorphic nature of CYP2C19 , we hypothesized that variable CYP2C19 expression may lead to interindividual differences in CBD metabolism to 7-OH-CBD. The objectives of this study were to further characterize the roles of CYP enzymes in CBD metabolism, specifically to the active metabolite 7-OH-CBD, and to investigate the impact of CYP2C19 polymorphism on CBD metabolism in genotyped human liver microsomes. The results from reaction phenotyping experiments with recombinant CYP enzymes and CYP-selective chemical inhibitors indicated that both CYP2C19 and CYP2C9 are capable of CBD metabolism to 7-OH-CBD. CYP3A played a major role in CBD metabolic clearance via oxidation at sites other than the 7-position. In genotyped human liver microsomes, 7-OH-CBD formation was positively correlated with CYP2C19 activity but was not associated with CYP2C19 genotype. In a subset of single-donor human liver microsomes with moderate to low CYP2C19 activity, CYP2C9 inhibition significantly reduced 7-OH-CBD formation, suggesting that CYP2C9 may play a greater role in CBD 7-hydroxylation than previously thought. Collectively, these data indicate that both CYP2C19 and CYP2C9 are important contributors in CBD metabolism to the active metabolite 7-OH-CBD.
Significance Statement This study demonstrates that both CYP2C19 and CYP2C9 are involved in CBD metabolism to the active metabolite 7-OH-CBD, and CYP3A4 is a major contributor to CBD metabolism through pathways other than 7-hydroxylation. 7-OH-CBD formation was associated with human liver microsomal CYP2C19 activity, but not CYP2C19 genotype, and CYP2C9 was found to contribute significantly to 7-OH-CBD generation. These findings have implications for patients taking CBD, who may be at risk for clinically important CYP-mediated drug interactions.
Plasma concentrations ( N =1) over 24 h for THC , 11-OH-THC , and THC-COOH following administration of two doses (2.5 mg each) of synthetic THC (dronabinol) at 4.5 and 10.5 h . Reprinted and adapted with permission by Elsevier, p. 152 in [32], Fig. 2 .
Huestis and Cone conducted a controlled clinical study of the excretion profile of creatinine and cannabinoid metabolites in a group of six cannabis users, who smoked two different doses of cannabis, separated by weekly intervals [148]. As seen in Fig. 5 , normalization of urinary THC-COOH concentration to the urinary creatinine concentration produces a smoother excretion pattern and facilitates interpretation of consecutive urine drug-test results.
THC accumulation in the lung occurs because of high exposure from cannabis smoke, extensive perfusion of the lung, and high uptake of basic compounds in lung tissue. Lung tissue is readily available during postmortem analysis, and would be a good matrix for investigation of cannabis exposure.
2.1.5. Transcutaneous.
In one of the latest investigations on THC distribution in tissues, the large-white-pig model was selected due to similarities with humans in drug biotransformation, including enzymes and isoenzymes of drug biotransformation, size, feeding patterns, digestive physiology, dietary habits, kidney structure and function, pulmonary vascular bed structure, coronary-artery distribution, propensity to obesity, respiratory rates, and tidal volume [75]. THC Plasma pharmacokinetics was found to be similar to those in humans. Eight pigs received 200 mg/kg intra-jugular THC injections, and two pigs were sacrificed 30 min, 2, 6, and 24 h later. At 30 min, high THC concentrations were noted in lung, kidney, liver, and heart, with comparable elimination kinetics in kidney, heart, spleen, muscle, and lung as observed in blood. The fastest THC elimination was noted in liver, where concentrations fell below measurable levels by 6 h. Mean brain concentration was approximately twice the blood concentration at 30 min, with highest levels in the cerebellum, and occipital and frontal cortex, and lowest concentrations in the medulla oblongata. THC Concentrations decreased in brain tissue slower than in blood. The slowest THC elimination was observed for fat tissue, where THC was still present at substantial concentrations 24 h later. 11-OH-THC was only found at high concentrations in the liver. The THC-COOH level was <5 ng/g in most tissues, except in bile, where it increased for 24 h following THC injection. The authors suggest that the prolonged retention of THC in brain and fat in heavy cannabis users is responsible for the prolonged detection of THC-COOH in urine and cannabis-related flashbacks. The author of this review hypothesizes that this residual THC may also contribute to cognitive deficits noted early during abstinence in chronic cannabis users.
After oral THC dosing, Nadulski et al . reported generally higher THC-COOH concentrations than those of THC almost immediately after dosing, in contrast to what is found after smoking [33]. Concentrations of 11-OH-THC also were higher than those of THC, with an extended detection window. These investigators suggest that ratios of [11-OH-THC]/[THC] >1 and >1.5 within and after 2 h after consumption, respectively, are strong indications for oral intake of THC.
Following controlled oral administration of THC in dronabinol or hemp oil, urinary cannabinoid excretion was characterized in 4,381 urine specimens [116][117]. THC Doses of 0.39−14.8 mg/d (from hemp oils or Marinol ®) were administered for 5 d. All urine voids, collected over ten weeks, were tested by immunoassay and GC/MS analysis. With the U.S. federally mandated 50 μg/l immunoassay cutoff, and during ingestion of the two low doses typical of current hemp-oil THC concentrations (<0.5 mg/d), mean detection rates were below 0.2% [116]. The two high doses (7.5 and 14.8 mg/d) produced mean detection rates of 23−46%, with intermittent positive tests up to 118 h. Maximum THC-COOH concentrations were 5.4−38.2 ng/ml for the low, and 19.0−436 μg/l for the high doses. The availability of cannabinoid-containing foodstuffs, cannabinoid-based therapeutics, and continued abuse of oral cannabis require scientific data for the accurate interpretation of cannabinoid tests. These data demonstrate that it is possible, but unlikely, for a urine specimen to test positive at the federally mandated cannabinoid cutoffs, following manufacturer's dosing recommendations for the ingestion of hemp oils of low THC concentration. Urine tests have a high likelihood of being positive following Marinol ® therapy.
Accurate prediction of the time of cannabis exposure would provide valuable information in establishing the role of cannabis as a contributing factor to events under investigation. Two mathematical models for the prediction of time of cannabis use from the analysis of a single plasma specimen for cannabinoids were developed [140]. Model I is based on THC concentrations, and model II is based on the ratio [THC-COOH]/[THC] in the plasma ( Fig. 4 ). Both models correctly predicted the times of exposure within the 95%-confidence interval for more than 90% of the specimens evaluated. Furthermore, plasma THC and THC-COOH concentrations reported in the literature, following oral and smoked cannabis exposure, in frequent and infrequent cannabis smokers, and with measurements obtained by a wide variety of methods (including radioimmunoassay and GC/MS analysis), were evaluated with these models. Plasma THC concentrations <2.0 ng/ml were excluded from use in both models, due to the possibility of residual THC concentrations in frequent smokers. Manno et al . evaluated the usefulness of these models in predicting the time of cannabis use in a controlled cannabis-smoking study [132]. The models were found to accurately predict the time of last use within the 95%-confidence intervals. Due to the limited distribution of THC and THC-COOH into red blood cells, it is important to remember, when comparing whole-blood THC and/or THC-COOH concentrations to plasma concentrations, to double the whole-blood concentration prior to comparison.
Most THC plasma data have been collected following acute exposure; less is known of plasma THC concentrations in frequent users. Peat reported THC, 11-OH-THC, and THC-COOH plasma concentrations in frequent cannabis users of 0.86±0.22, 0.46±0.17, and 45.8±13.1 ng/ml, respectively, a minimum of 12 h after the last smoked dose [136]. No difference in terminal half-life in frequent or infrequent users was observed. Johansson et al . administered radiolabeled THC to frequent cannabis users, and found a terminal elimination half-life of 4.1 d for THC in plasma, due to extensive storage and release from body fat [109].
Phase-II metabolism of THC-COOH involves addition of glucuronic acid, and, less commonly, of sulfate, glutathione, amino acids, and fatty acids via the 11-COOH group. The phenolic OH group may be a target as well. It is also possible to have two glucuronic acid moieties attached to THC-COOH, although steric hindrance at the phenolic OH group could be a factor. Addition of the glucuronide group improves water solubility, facilitating excretion, but renal clearance of these polar metabolites is low due to extensive protein binding [72]. No significant differences in metabolism between men and women have been reported [27].
3.1.5. Prediction Models for Estimation of Cannabis Exposure.
After oral and sublingual administration of THC, THC-containing food products, or cannabis-based extracts, the concentrations of THC and 11-OH-THC are much lower than those found upon smoked administration. Plasma concentrations of THC in patients receiving 10−15 mg of Marinol ® as an anti-emetic were low or even non-measurable in 57 patients [134]. After daily administration of 10−15 mg of Marinol ®, Brenneisen et al . found peak plasma concentrations of THC and THC-COOH of 2.1−16.9 ng/ml within 1−8 h, and of 74.5−244 ng/ml within 2−8 h, respectively [42]. In our oral, controlled THC-administration studies, peak plasma THC, 11-OH-THC, and THC-COOH concentrations were less than 6.5, 5.6, and 24.4 ng/ml, respectively, following up to 14.8 mg/d of THC in the form of THC-containing food products or Marinol ® [135]. Peak concentrations and time-to-peak concentrations varied sometimes considerably between subjects. Plasma THC and 11-OH-THC were negative for all participants and for all doses by 16 h after administration of the last THC dose. Plasma THC-COOH persisted for a longer period of time, following the two highest doses of 7.5 mg/d of dronabinol, and 14.8 mg/d of THC in hemp oil. Ohlsson et al . reported that orally administered THC (20 mg) in a cookie yielded low and irregular plasma concentrations, compared to intravenous and inhaled THC [5].
Manno et al . recommended that an increase of 150% in the creatinine-normalized cannabinoid concentration above the previous specimen can be considered indicative of a new episode of drug exposure [147]. If the increase is greater than or equal to the threshold selected, then new use is predicted. This approach has received wide attention for potential use in treatment and employee-assistance programs, but there was limited evaluation of the usefulness of this ratio under controlled dosing conditions.
Currently, synthetic THC ( Marinol ®) is approved in the U.S.A. for reduction of nausea and vomiting in cancer chemotherapy, and to increase appetite in HIV-wasting disease. Potential new indications include the reduction of spasticity, analgesia, and as an agonist-replacement pharmacotherapy for cannabis dependence. Thus, the pharmacokinetics of oral THC is of great importance to the successful application of new therapeutic approaches. In a study of the plasma concentrations of THC, 11-OH-THC, and THC-COOH in 17 volunteers upon intake of a single Marinol ® capsule (10 mg of THC), mean peak concentrations of 3.8 ng/ml of THC (range 1.1−12.7 ng/ml), 3.4 ng/ml of 11-OH-THC (range 1.2−5.6 ng/ml), and 26 ng/ml of THC-COOH (range 14−46 ng/ml) were found 1−2 h after ingestion [28]. Similar THC and 11-OH-THC concentrations were observed with consistently higher THC-COOH concentrations. Interestingly, two THC peaks frequently were observed due to enterohepatic circulation. Onset is delayed, peak concentrations are lower, and duration of pharmacodynamic effects generally are extended with a delayed return to baseline, when THC is administered by the oral as compared to the smoked route [29][30].
Oral fluid also is a suitable specimen for monitoring cannabinoid exposure, and is being evaluated for driving under the influence of drugs, drug treatment, workplace drug testing, and for clinical trials [154-159]. Adequate sensitivity is best achieved with an assay directed toward detection of THC, rather than of 11-OH-THC or THC-COOH. The oral mucosa is exposed to high concentrations of THC during smoking, and serves as the source of THC found in oral fluid. Only minor amounts of drug and metabolites diffuse from the plasma into oral fluid [146]. Following intravenous administration of radiolabeled THC, no radioactivity could be demonstrated in oral fluid [160]. No measurable 11-OH-THC or THC-COOH were found by GC/MS (detection limit 0.5 ng/ml) in oral fluid for 7 d, following cannabis smoking [161], or in oral fluid from 22 subjects positive for THC-COOH in the urine [162]. Oral fluid collected with the Salivette collection device was positive for THC in 14 of these 22 participants. Although no 11-OH-THC or THC-COOH was identified by GC/MS, CBN and CBD were found in addition to THC. Several hours after smoking, the oral mucosa serves as a depot for release of THC into the oral fluid. In addition, as detection limits continue to decrease with the development of new analytical instrumentation, it may be possible to measure low concentrations of THC-COOH in oral fluid.
2.3.2. Extrahepatic Metabolism.
1 Unless noted otherwise, THC always refers to the Δ 9 -variant.
Cannabis is one of the oldest and most commonly abused drugs in the world, and its use is associated with pathological and behavioral toxicity. Thus, it is important to understand cannabinoid pharmacokinetics and the disposition of cannabinoids into biological fluids and tissues. Understanding the pharmacokinetics of a drug is essential to understanding the onset, magnitude, and duration of its pharmacodynamic effects, maximizing therapeutic and minimizing negative side effects.
Distribution of THC into peripheral organs and the brain was found to be similar in THC-tolerant vs . non-tolerant dogs [71]. In addition, these investigators found that tolerance to the behavioral effects of THC in pigeons was not due to decreased uptake of cannabinoids into the brain. Tolerance also was evaluated in humans. Hunt and Jones found that tolerance in humans developed during oral administration of 30 mg of THC every 4 h, for 10−12 d [72]. Few pharmacokinetic changes were noted during chronic administration, although average total metabolic clearance and initial apparent volume of distribution increased from 605 to 977 ml/min, and from 2.6 to 6.4 l/kg, respectively. Pharmacokinetic changes after chronic oral THC administration could not account for observed behavioral and physiologic tolerance, suggesting rather that tolerance was due to pharmacodynamic adaptation.
Within 5 d, a total of 80−90% of THC is excreted, mostly as hydroxylated and carboxylated metabolites [21][95]. More than 65% is excreted in the feces, ca . 20% being eliminated in the urine [27]. Numerous acidic metabolites are found in the urine, many of which are conjugated with glucuronic acid to increase their water solubility. The primary urinary metabolite is the acid-linked THC-COOH glucuronide conjugate [108], while 11-OH-THC predominates in the feces [21]. The concentration of free THC-COOH, and the cross-reactivity of glucuronide-bound THC-COOH enable cannabinoid immunoassays to be performed directly on non-hydrolyzed urine, but confirmation and quantification of THC-COOH is usually performed after alkaline hydrolysis or β -glucuronidase hydrolysis to free THC-COOH for measurement by GC/MS. It was initially thought that little or no THC and 11-OH-THC were excreted in the urine.
Cannabidiol (CBD) is a natural, non-psychoactive [49][50] constituent of Cannabis sativa , but possesses pharmacological activity, which is explored for therapeutic applications. CBD has been reported to be neuroprotective [51], analgesic [37][38][52], sedating [37][38][53][54], anti-emetic [54], anti-spasmodic [55], and anti-inflammatory [56]. In addition, it has been reported that CBD blocks anxiety produced by THC [57], and may be useful in the treatment of autoimmune diseases [53]. CBD also has been reported to decrease some of the side effects of THC [36]. These potential therapeutic applications alone warrant investigation of CBD pharmacokinetics. Further, the controversy over whether CBD alters the pharmacokinetics of THC in a clinically significant manner needs to be resolved [58][59].
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