Systematic web monitoring of drug test subversion strategies in the United States.

As negative drug tests are frequently a condition for employment, some people who use drugs will try to subvert the testing. In this study, systematic web monitoring was used to investigate how drug test subversion is discussed online. Posts pertaining to drug test subversion were obtained from public websites and the dark web (n = 634, July-December 2021). Most information from public websites came from Twitter (65%), and 94% of dark web posts were from Reddit. The posts were manually coded to extract quantitative and qualitative information about drug test subversion tactics. Most posts discussed urine drug tests (85%), followed by hair (11%) and oral fluid (2%), and the most discussed drugs were marijuana (72%) and cocaine (7.3%). Urine drug test subversion mainly pertained to specimen substitution, with synthetic urine or urine from another person. Another strategy was to mask diluted urine by ingesting creatine. Urine adulteration was rarely discussed. Hair test subversion involved harsh treatments with products such as bleach, baking soda, and/or detergent. Hair removal was also discussed. Oral fluid test subversion focused on removing drugs from the oral cavity through vigorous brushing of teeth and tongue as well as the use of mouthwash, hydrogen peroxide, gum, and commercial detox products. This study highlights subversion strategies used by donors. Although little evidence was provided as to the effectiveness of these strategies, this information may help guide future studies and development of specimen validity testing to minimize the impact of drug test subversion attempts.

Fentanyl as a marker of illicit drug use in morphine-positive urine specimens from workplace drug testing.

Total morphine is an important urinary marker of heroin use but can also be present from prescriptions or poppy seed ingestion. In specimens with morphine concentrations consistent with poppy seed ingestion (<4,000 ng/mL), 6-acetylmorphine has served as an important marker of illicit drug use. However, as illicit fentanyl has become increasingly prevalent as a contaminant in the drug supply, fentanyl might be an alternative marker of illicit opioid use instead of or in combination with 6-acetylmorphine. The aim of this study was to quantify opiates, 6-acetylmorphine, fentanyl and fentanyl analogs in 504 morphine-positive (immunoassay 2,000 ng/mL cutoff) urine specimens from workplace drug testing. Almost half (43%) of morphine-positive specimens had morphine concentrations below 4,000 ng/mL, illustrating the need for markers to differentiate illicit drug use. In these specimens, fentanyl (22% co-positivity) was more prevalent than 6-acetylmorphine (12%). Co-positivity of 6-acetylmorphine and semi-synthetic opioids increased with morphine concentration, while fentanyl prevalence did not. In 110 fentanyl-positive specimens, the median norfentanyl concentration (1,520 ng/mL) was 9.6× higher than the median fentanyl concentration (159 ng/mL), illustrating the possibility of using norfentanyl as a urinary marker of fentanyl use. The only fentanyl analog identified was para-fluorofentanyl (n = 50), with results from most specimens consistent with para-fluorofentanyl contamination in illicit fentanyl. The results confirm the use of fentanyl by employees subject to workplace drug testing and highlight the potential of fentanyl and/or norfentanyl as important markers of illicit drug use.

Pharmacokinetics and pharmacodynamics of five distinct commercially available hemp-derived topical cannabidiol products.

Products containing cannabidiol (CBD) have proliferated after the 2018 Farm Bill legalized hemp (cannabis with ≤0.3% delta-9-tetrahydrocannabinol (Δ9-THC)). CBD-containing topical products have surged in popularity, but controlled clinical studies on them are limited. This study characterized the effects of five commercially available hemp-derived high CBD/low Δ9-THC topical products. Healthy adults (N = 46) received one of six study drugs: a CBD-containing cream (N = 8), lotion (N = 8), patch (N = 7), balm (N = 8), gel (N = 6) or placebo (N = 9; matched to an active formulation). The protocol included three phases conducted over 17 days: (i) an acute drug application laboratory session, (ii) a 9-day outpatient phase with twice daily product application (visits occurred on Days 2, 3, 7 and 10) (iii) a 1-week washout phase. In each phase, whole blood, oral fluid and urine specimens were collected and analyzed via liquid chromatography with tandem mass spectrometry (LC-MS-MS) for CBD, Δ9-THC and primary metabolites of each and pharmacodynamic outcomes (subjective, cognitive/psychomotor and physiological effects) were assessed. Transdermal absorption of CBD was observed for three active products. On average, CBD/metabolite concentrations peaked after 7-10 days of product use and were highest for the lotion, which contained the most CBD and a permeation enhancer (vitamin E). Δ9-THC/metabolites were below the limit of detection in blood for all products, and no urine samples tested "positive" for cannabis using current US federal workplace drug testing criteria (immunoassay cut-off of 50 ng/mL and confirmatory LC-MS-MS cut-off of 15 ng/mL). Unexpectedly, nine participants (seven lotions, one patch and one gel) exhibited Δ9-THC oral fluid concentrations ≥2 ng/mL (current US federal workplace threshold for a "positive" test). Products did not produce discernable pharmacodynamic effects and were well-tolerated. This study provides important initial data on the acute/chronic effects of hemp-derived topical CBD products, but more research is needed given the diversity of products in this market.

Prevalence of ∆8-tetrahydrocannabinol carboxylic acid in workplace drug testing.

∆8-Tetrahydrocannabinol (∆8-THC) recently became widely available as an alternative to cannabis. ∆8-THC is likely impairing and poses a threat to workplace and traffic safety. In the present study, the prevalence of ∆8-THC in workplace drug testing was investigated by analyzing 1,504 urine specimens with a positive immunoassay cannabinoid initial test using a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method quantifying 15 cannabinoid analytes after hydrolysis. ∆8-tetrahydrocannabinol-9-carboxylic acid (∆8-THC-COOH) was detected in 378 urine specimens (15 ng/mL cutoff), compared to 1,144 specimens containing ∆9-THC-COOH. The data could be divided into three general groups. There were 964 (76%) ∆9-THC-COOH-dominant (<10% ∆8-THC-COOH) and 139 (11%) ∆8-THC-COOH-dominant (>90% ∆8-THC-COOH) specimens, with the remaining 164 (13%) specimens showing a mixture of both analytes (>90% ∆8-THC-COOH). Similar concentrations of ∆9-THC-COOH (median 187 ng/mL) and ∆8-THC-COOH (150 ng/mL) as the dominant species support the use of similar cutoffs and decision rules for both analytes. Apart from the carboxylic acid metabolites, 11-hydroxy-∆9-tetrahydrocannabinol (11-OH-∆9-THC, n = 1,282), ∆9-tetrahydrocannabivarin-9-carboxylic acid (∆9-THCV-COOH, n = 1,058), ∆9-THC (n = 746) and 7-hydroxy-cannabidiol (7-OH-CBD, n = 506) were the most prevalent analytes. Two specimens (0.13%) contained ≥140 ng/mL ∆9-THC without ∆9-THC-COOH, which could be due to genetic variability in the drug-metabolizing enzyme CYP2C9 or an adulterant targeting ∆9-THC-COOH. The cannabinoid immunoassay was repeated, and five specimens (0.33%) generated negative initial tests despite ∆9-THC-COOH concentrations of 54-1,000 ng/mL, potentially indicative of adulteration. The use of ∆8-THC is widespread in the US population, and all forensic laboratories should consider adding ∆8-THC and/or ∆8-THC-COOH to their scope of testing. Similar urinary concentrations were observed for both analytes, indicating that the decision rules used for ∆9-THC-COOH are also appropriate for ∆8-THC-COOH.

Conversion of water-soluble CBD to ∆9-THC in synthetic gastric fluid-An unlikely cause of positive drug tests.

Cannabidiol (CBD) has been shown to convert to ∆9-tetrahydrocannabinol (∆9-THC) in acidic environments, raising a concern of conversion when exposed to gastric fluid after consumption. Using synthetic gastric fluid (SGF), it has been demonstrated that the conversion requires surfactants, such as sodium dodecyl sulfate (SDS), due to limited solubility of CBD. Recently, water-compatible nanoemulsions of CBD have been prepared as a means of fortifying beverages and water-based foods with CBD. Since these emulsions contain surfactants as part of their formulation, it is possible that these preparations might enhance the production of ∆9-THC even in the absence of added surfactants. Three THC-free CBD products, an oil, an anhydrous powder and a water-soluble formulation, were incubated for 3 h in SGF without SDS. The water-soluble CBD product produced a dispersion, while the powder and the oil did not mix with the SGF. No THC was detected with the CBD oil (<0.0006% conversion), and up to 0.063% and 0.0045% conversion to ∆9-THC was observed with the water-soluble CBD and the CBD powder, respectively. No formation of ∆8-THC was observed. In comparison, when the nano-formulated CBD was incubated in SGF with 1% SDS, 33-36% conversion to ∆9-THC was observed. Even though the rate of conversion with the water-soluble CBD was at least 100-fold higher compared to the CBD oil, it was still smaller than ∆9-THC levels reported in CBD products labeled "THC-free" or "<0.3% THC" based on the Agricultural Improvement Act of 2018 (the Farm Bill). Assuming a daily CBD dose of around 30 mg/day, it is unlikely that conversion of CBD to ∆9-THC could produce a positive urinary drug test for 11-Nor-9-carboxy-∆9-THC (15 ng/mL cut-off).

Performance of Hair Testing for Cocaine Use-Comparison of Five Laboratories Using Blind Reference Specimens.

The purpose of this study was to compare results from five commercial hair testing laboratories conducting workplace drug testing with regard to bias, precision, selectivity and decontamination efficiency. Nine blind hair specimens, including cocaine-positive drug user specimens (some contaminated with methamphetamine) and negative specimens contaminated with cocaine, were submitted in up to five replicates to five different laboratories. All laboratories correctly identified cocaine in all specimens from drug users. For an undamaged hair specimen from a cocaine user, within-laboratory Coefficients of Variation (CVs) of 5-22% (median 8%) were reported, showing that it is possible to produce a homogenous proficiency testing sample from drug user hair. Larger CVs were reported for specimens composed of blended hair (up to 29%) and curly/damaged hair (19-67%). Quantitative results appeared to be method-dependent, and the reported cocaine concentrations varied up to 5-fold between the laboratories, making interlaboratory comparisons difficult. All laboratories reported at least one positive result in specimens contaminated with cocaine powder, followed by sweat and shampoo treatments. Benzoylecgonine, norcocaine, cocaethylene and hydroxylated cocaine metabolites were all detected in cocaine powder-contaminated specimens. This indicates that current industry standards for analyzing and reporting positive cocaine results are not completely effective at identifying external contamination. Metabolite ratios between meta- or para-hydroxy-cocaine and cocaine were 6- and 10-fold lower in contaminated specimens compared to those observed in cocaine user specimens, supporting their potential use in distinguishing samples positive due to contamination and drug use.

Cannabinoid Content and Label Accuracy of Hemp-Derived Topical Products Available Online and at National Retail Stores.

Importance: Products containing cannabinoids such as cannabidiol (CBD) have proliferated since 2018, when the Agriculture Improvement Act removed hemp (ie, cannabis containing <0.3% Δ9-tetrahydrocannabinol [THC]) from the US controlled substances list. Topical cannabinoid products can be purchased nationwide at retail stores and over the internet, yet research on these products is scarce. Objective: To evaluate the cannabinoid content (ie, CBD and THC) and label accuracy of topical cannabinoid products and to quantify their therapeutic and nontherapeutic claims. Design, Setting, and Participants: Product inclusion criteria included designation as hemp products, intended for topical or transdermal application, and purported to contain cannabinoids (eg, CBD). All unique products available at each retail store were purchased. Online products were identified via Google using relevant keywords (eg, hemp or CBD topical). Various products (eg, lotions and patches) were purchased from retail stores (eg, pharmacies, grocery stores, and cosmetic or beauty stores) in Baltimore, Maryland, and online. Data analysis was performed from March to June 2022. Main Outcomes and Measures: Labeled and actual total amounts of CBD and THC, measured via gas chromatography-mass spectrometry. Therapeutic and nontherapeutic claims and references to the US Food and Drug Administration were quantified. Results: A total of 105 products were purchased, 45 from retail locations and 60 online. Of the 89 products that listed a total amount of CBD on the label, 18% (16 products) were overlabeled (ie, contained >10% less CBD than advertised), 58% (52 products) were underlabeled (ie, contained >10% more CBD than advertised), and 24% (21 products) were accurately labeled. The median (range) percentage deviation between the actual total amount of CBD and the labeled amount was 21% (-75% to 93%) for in-store products and 10% (-96% to 121%) for online products, indicating that products contained more CBD than advertised overall. THC was detected in 37 of 105 products (35%), although all contained less than 0.3% THC. Among the 37 THC-containing products, 4 (11%) were labeled as THC free, 14 (38%) indicated they contained less than 0.3% THC, and 19 (51%) did not reference THC on the label. Overall, 28% of products (29 products) made therapeutic claims, 14% (15 products) made cosmetic claims, and only 47% (49 products) noted that they were not Food and Drug Administration approved. Conclusions and Relevance: In a case series of topical cannabinoid products purchased online and at popular retail stores, products were often inaccurately labeled for CBD and many contained THC. These findings suggest that clinical studies are needed to determine whether topical cannabinoid products with THC can produce psychoactive effects or positive drug tests for cannabis.

Update on Urine Adulterants and Synthetic Urine Samples to Subvert Urine Drug Testing.

To avoid a positive urine drug test, donors might try to subvert the test, either by adulterating the specimen with a product designed to interfere with testing or by substituting the specimen for a synthetic urine. A market search conducted in December of 2020 identified 3 adulterants and 32 synthetic urines, and a selection was procured based on specific criteria. Samples prepared with the 3 adulterants and 10 synthetic urines were submitted for testing at five forensic drug testing laboratories to perform immunoassay screening, chromatographic confirmation analysis and specimen validity testing (SVT). One adulterant determined to contain iodate reduced THC-COOH concentrations by 65% and the concentrations of 6-acetylmorphine, morphine, oxycodone, oxymorphone, hydrocodone and hydromorphone by 6-27%. Another adulterant determined to contain nitrite reduced THC-COOH concentrations by 22%, while the third did not affect drug screening or confirmatory testing. Both active adulterants could be identified through positive oxidant screens as well as through signal suppression in cloned enzyme donor immunoassay (CEDIA). The synthetic urines could not be identified either through traditional SVT or by the AdultaCheck10 dipstick. The Synthetic UrineCheck dipstick produced a difference in response between the authentic urine specimen and the synthetic urine samples, but the difference was small and difficult to observe. While most synthetic urines now contain uric acid, magnesium and caffeine, the results indicated that a biomarker panel including endogenous and exogenous markers of authentic urine performed well and clearly demonstrated the absence of biomarkers in the synthetic urines. The SVT assay also offers potential targets for future screening assays.

Pharmacokinetic Profile of ∆9-Tetrahydrocannabinol, Cannabidiol and Metabolites in Blood following Vaporization and Oral Ingestion of Cannabidiol Products.

There is limited data on the comparative pharmacokinetics of cannabidiol (CBD) across oral and vaporized formulations. This within-subject, double-blind, double-dummy, placebo-controlled laboratory study analyzed the pharmacokinetic profile of CBD, ∆9-tetrahydrocannabinol (∆9-THC) and related metabolites in blood and oral fluid (OF) after participants (n = 18) administered 100 mg of CBD in each of the following formulations: (1) oral CBD, (2) vaporized CBD and (3) vaporized CBD-dominant cannabis containing 10.5% CBD and 0.39% ∆9-THC (3.7 mg); all participants also completed a placebo condition. Oral CBD was administered in three formulations: (1) encapsulated CBD, (2) CBD suspended in pharmacy-grade syrup and (3) Epidiolex, allowing for pharmacokinetic comparisons across oral formulations (n = 6 per condition). An optional fifth experimental condition was completed for six participants in which they fasted from all food for 12 h prior to oral ingestion of 100 mg of CBD. Blood and OF samples were collected immediately before and for 57-58 h after each drug administration. Immunoassay screening and LC-MS-MS confirmatory tests were performed, the limit of quantitation was 0.5 ng/mL for ∆9-THC and 1 ng/mL for CBD. The mean Cmax and range of CBD blood concentrations for each product were as follows: vaporized CBD-dominant cannabis, 171.1 ng/mL, 40.0-665.0 ng/mL, vaporized CBD 104.6 ng/mL, 19.0-312.0 ng/mL and oral CBD, 13.7 ng/mL, 0.0-50.0 ng/mL. Of the three oral formulations, Epidiolex produced the greatest peak concentration of CBD (20.5 ng/mL, 8.0-37.0 ng/mL) relative to the capsule (17.8 ng/mL, 2.0-50.0 ng/mL) and syrup (2.8 ng/mL, 0-7.0 ng/mL). ∆9-THC was detected in the blood of 12/18 participants after vaporized CBD-dominant cannabis use, but neither ∆9-THC nor its metabolite THC-COOH were detected in the blood of any participants after vaporized or oral CBD-only administration. These data demonstrate that different oral and vaporized formulations produce substantial variability in the pharmacokinetics of CBD and that CBD alone is unlikely to convert to ∆9-THC or produce positive drug tests for ∆9-THC or its metabolite.

Prevalence of Cannabidiol, ∆9- and ∆8-Tetrahydrocannabinol and Metabolites in Workplace Drug Testing Urine Specimens.

Given the recent popularity of cannabidiol (CBD) use and the emergence of ∆8-tetrahydrocannabinol (∆8-THC), the prevalence and concentrations of these and other cannabinoids were investigated in 2,000 regulated and 4,000 non-regulated specimens from workplace drug testing. All specimens were screened using liquid chromatography coupled to mass spectrometry (LC-MS-MS) for the presence of 7-hydroxy-CBD (7-OH-CBD) and ∆9-tetrahydrocannabinol-9-carboxylic acid (∆9-THC-COOH), with a cutoff of 2 ng/mL. Specimens screening positive by LC-MS-MS were analyzed by immunoassay at 20, 50 and 100 ng/mL cutoffs and by an LC-MS-MS confirmation method for 11 cannabinoids and metabolites with a 1 ng/mL cutoff. Using a 1 ng/mL cutoff, 98 (4.9%) regulated and 331 (8.3%) non-regulated specimens were positive for ∆9-THC-COOH. Of these, 64% had concentrations below 15 ng/mL. Similarly, 59 (3.0%) regulated and 162 (4.2%) non-regulated specimens were positive for 7-OH-CBD (n = 210), CBD (n = 120) and/or 7-carboxy-cannabidiol (CBD-COOH, n = 120). The median concentrations of 7-OH-CBD, CBD and CBD-COOH in those 221 specimens were 6.3, 1.1 and 1.2 ng/mL, respectively. ∆8-Tetrahydrocannabinol-9-carboxylic acid (∆8-THC-COOH) was identified in 76 (1.3%) specimens. Parent ∆8-THC is a minor cannabinoid in marijuana, which appears to account for the typically low ∆8-THC-COOH concentrations (median 3.4 ng/mL) in most positive specimens. However, elevated concentrations suggested the use of ∆8-THC-containing products in some cases (range 1.0-415 ng/mL). Although 93% agreement was observed between confirmatory LC-MS-MS (15 ng/mL cutoff) and immunoassay (50 ng/mL cutoff), a false-negative specimen (66 ng/mL ∆9-THC-COOH) was identified.

Urinary Pharmacokinetic Profile of Cannabidiol (CBD), Δ9-Tetrahydrocannabinol (THC) and Their Metabolites following Oral and Vaporized CBD and Vaporized CBD-Dominant Cannabis Administration.

The market for products containing cannabidiol (CBD) is booming globally. However, the pharmacokinetics of CBD in different oral formulations and the impact of CBD use on urine drug testing outcomes for cannabis (e.g., 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (Δ9-THCCOOH)) are understudied. This study characterized the urinary pharmacokinetics of CBD (100 mg) following vaporization or oral administration (including three formulations: gelcap, pharmacy-grade syrup and or Epidiolex) as well as vaporized CBD-dominant cannabis (containing 100 mg CBD and 3.7 mg Δ9-THC) in healthy adults (n = 18). A subset of participants (n = 6) orally administered CBD syrup following overnight fasting (versus low-fat breakfast). Urine specimens were collected before and for 58 h after dosing on a residential research unit. Immunoassay (IA) screening (cutoffs: 20, 50 and 100 ng/mL) for Δ9-THCCOOH was performed, and quantitation of cannabinoids was completed via LC-MS-MS. Urinary CBD concentrations (ng/mL) were higher after oral (mean Cmax: 734; mean Tmax: 4.7 h, n = 18) versus vaporized CBD (mean Cmax: 240; mean Tmax: 1.3 h, n = 18), and oral dose formulation significantly impacted mean Cmax (Epidiolex = 1,274 ng/mL, capsule = 776 ng/mL, syrup = 151 ng/mL, n = 6/group) with little difference in Tmax. Overnight fasting had limited impact on CBD excretion in urine, and there was no evidence of CBD conversion to Δ8- or Δ9-THC in any route or formulation in which pure CBD was administered. Following acute administration of vaporized CBD-dominant cannabis, 3 of 18 participants provided a total of six urine samples in which Δ9-THCCOOH concentrations ≥15 ng/mL. All six specimens screened positive at a 20 ng/mL IA cutoff, and two of six screened positive at a 50 ng/mL cutoff. These data show that absorption/elimination of CBD is impacted by drug formulation, route of administration and gastric contents. Although pure CBD is unlikely to impact drug testing, it is possible that hemp products containing low amounts of Δ9-THC may produce a cannabis-positive urine drug test.

Conversion of 7-Carboxy-Cannabidiol (7-COOH-CBD) to 11-Nor-9-Carboxy-Tetrahydrocannabinol (THC-COOH) during Sample Preparation for GC-MS Analysis.

The growing use of cannabidiol (CBD) products by the general public is expected to result in an increase in the prevalence of CBD and the CBD metabolites in drug testing laboratories. CBD converts into tetrahydrocannabinol (THC) under acid conditions which could produce false-positive results, but little is known about how the presence of the urinary metabolite of CBD, 7-carboxy-cannabidiol (7-COOH-CBD), would affect urine drug testing for 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH). As the operators of the National Laboratory Certification Program (NLCP), we prepared a set of performance testing samples containing 7-COOH-CBD for cannabinoid testing at the laboratories accredited by the NLCP to investigate if 7-COOH-CBD can produce false-positive results for THC-COOH during immunological screening analysis and if 7-COOH-CBD can be converted to THC-COOH. At concentrations up to 2,500 ng/mL, 7-COOH-CBD was not reactive by immunoassay in any of the four different immunoassay kits used. Additionally, we did not observe any significant conversion of 7-COOH-CBD to THC-COOH in assays used by NLCP-certified laboratories. However, we did see conversion when we requested that selected laboratories retest their samples using derivatization with perfluorinated anhydrides in combination with perfluorinated alcohols or when samples containing 7-COOH-CBD were exposed to acid for an extended time.

Pharmacokinetics of Cannabis Brownies: A Controlled Examination of Δ9-Tetrahydrocannabinol and Metabolites in Blood and Oral Fluid of Healthy Adult Males and Females.

Oral cannabis products (a.k.a. "edibles") have increased in popularity in recent years. Most prior controlled pharmacokinetic evaluations of cannabis have focused on smoked cannabis and included males who were frequent cannabis users. In this study, 17 healthy adults (8 females), with no cannabis use in at least the past 2 months, completed 4 double-blind outpatient sessions where they consumed cannabis brownies containing Δ9-tetrahydrocannabinol (THC) doses of 0, 10, 25 or 50 mg. Whole blood and oral fluid specimens were collected at baseline and for 8 h post-brownie ingestion. Enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) were used to measure THC and relevant metabolites. In whole blood, concentrations of THC and 11-hydroxy-THC (11-OH-THC) peaked 1.5-2 h after brownie consumption, decreased steadily thereafter, and typically returned to baseline within 8 h. Blood concentrations for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) and THCCOOH-glucuronide were higher than THC and 11-OH-THC and these metabolites were often still detected 8 h post-brownie consumption. Women displayed higher peak concentrations for THC and all metabolites in whole blood compared to men, at least partially owing to their lower body weight/body mass index. Detection of THC in oral fluid was immediate and appeared to reflect the degree of cannabis deposition in the oral cavity, not levels of THC circulating in the blood. THC concentrations were substantially higher in oral fluid than in blood; the opposite trend was observed for THCCOOH. Agreement between ELISA and LC-MS-MS results was high (i.e., over 90%) for blood THCCOOH and oral fluid THC but comparatively low for oral fluid THCCOOH (i.e., 67%). Following oral consumption of cannabis, THC was detected in blood much later, and at far lower peak concentrations, compared to what has been observed with inhaled cannabis. These results are important given the widespread use of toxicological testing to detect recent use of cannabis and/or to identify cannabis intoxication.

Pharmacodynamic dose effects of oral cannabis ingestion in healthy adults who infrequently use cannabis.

BACKGROUND: Prior controlled cannabis research has mostly focused on smoked cannabis and predominantly included frequent cannabis users. Oral cannabis products ("edibles") make up a large and growing segment of the retail cannabis market. This study sought to characterize the pharmacodynamic effects of oral cannabis among infrequent cannabis users. METHODS: Seventeen healthy adults who had not used cannabis for at least 60 days completed four experimental sessions in which they consumed a cannabis-infused brownie that contained 0, 10, 25, or 50 mg THC. Subjective effects, vital signs, cognitive/psychomotor performance, and blood THC concentrations were assessed before and for 8 h after dosing. RESULTS: Relative to placebo, the 10 mg THC dose produced discriminable subjective drug effects and elevated heart rate but did not alter cognitive/psychomotor performance. The 25 and 50 mg THC doses elicited pronounced subjective effects and markedly impaired cognitive and psychomotor functioning compared with placebo. For all active doses, pharmacodynamic effects did not manifest until 30-60 min after ingestion, and peak effects occurred 1.5-3 h post-administration. Blood THC levels were significantly correlated with some pharmacodynamic drug effects, but were substantially lower than what is typically observed after cannabis inhalation. CONCLUSION: Ingestion of oral cannabis dose-dependently altered subjective drug effects and impaired cognitive performance. Unlike inhaled forms of cannabis for which acute effects occur almost immediately, effects of oral cannabis were considerably delayed. In an era of legalization, education about the time course of drug effects for cannabis edibles is needed to facilitate dose titration and reduce acute overdose incidents.

Pharmacodynamic effects of vaporized and oral cannabidiol (CBD) and vaporized CBD-dominant cannabis in infrequent cannabis users.

INTRODUCTION: The use and availability of oral and inhalable products containing cannabidiol (CBD) as the principal constituent has increased with expanded cannabis/hemp legalization. However, few controlled clinical laboratory studies have evaluated the pharmacodynamic effects of oral or vaporized CBD or CBD-dominant cannabis. METHODS: Eighteen healthy adults (9 men; 9 women) completed four, double-blind, double-dummy, drug administration sessions. Sessions were separated by ≥1 week and included self-administration of 100 mg oral CBD, 100 mg vaporized CBD, vaporized CBD-dominant cannabis (100 mg CBD; 3.7 mg THC), and placebo. Study outcomes included: subjective drug effects, vital signs, cognitive/psychomotor performance, and whole blood THC and CBD concentrations. RESULTS: Vaporized CBD and CBD-dominant cannabis increased ratings on several subjective items (e.g., Like Drug Effect) relative to placebo. Subjective effects did not differ between oral CBD and placebo and were generally higher for CBD-dominant cannabis compared to vaporized CBD. CBD did not increase ratings for several items typically associated with acute cannabis/THC exposure (e.g., Paranoid). Women reported qualitatively higher ratings for Pleasant Drug Effect than men after vaporized CBD and CBD-dominant cannabis use. CBD-dominant cannabis increased heart rate compared to placebo. Cognitive/psychomotor impairment was not observed in any drug condition. CONCLUSIONS: Vaporized CBD and CBD-dominant cannabis produced discriminable subjective drug effects, which were sometimes stronger in women, but did not produce cognitive/psychomotor impairment. Subjective effects of oral CBD did not differ from placebo. Future research should further elucidate the subjective effects of various types of CBD products (e.g., inhaled, oral, topical), which appear to be distinct from THC-dominant products.

Urinary Excretion Profile of 11-Nor-9-Carboxy-Δ9-Tetrahydrocannabinol (THCCOOH) Following Smoked and Vaporized Cannabis Administration in Infrequent Cannabis Users.

As cannabis has become more accessible, use of alternative methods for cannabis administration such as vaporizers has become more prevalent. Most prior controlled pharmacokinetic evaluations have examined smoked cannabis in frequent (often daily) cannabis users. This study characterized the urinary excretion profile of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH), the primary analytical outcome for detection of cannabis use, among infrequent cannabis users following controlled administration of both smoked and vaporized cannabis. Healthy adults (N = 17), with a mean of 398 (range 30-1,825) days since last cannabis use, smoked and vaporized cannabis containing 0, 10, and 25 mg of Δ9-tetrahydrocannabinol (THC) across six outpatient sessions. Urinary concentrations of THCCOOH were measured at baseline and for 8 h after cannabis administration. Sensitivity, specificity, and agreement between three immunoassays (IA) for THCCOOH (with cutoffs of 20, 50, and 100 ng/mL) and gas chromatography-mass spectrometry (GC/MS) results (confirmatory concentration of 15 ng/mL) were assessed. THCCOOH concentrations peaked 4-6 h after cannabis administration. Median maximum concentrations (Cmax) for THCCOOH were qualitatively higher after administration of vaporized cannabis compared to equal doses of smoked cannabis. Urine THCCOOH concentrations were substantially lower in this study relative to prior examinations of experienced cannabis users. The highest agreement between IA and GC/MS was observed at the 50 ng/mL IA cutoff while sensitivity and specificity were highest at the 20 and 100 ng/mL IA cutoffs, respectively. Using federal workplace drug-testing criteria (IA cutoff of 50 ng/mL and GC/MS concentration ≥15 ng/mL) urine specimens tested positive in 47% of vaporized sessions and 21% of smoked sessions with active THC doses (N = 68). Urinary concentrations of THCCOOH are dissimilar after administration of smoked and vaporized cannabis, with qualitatively higher concentrations observed after vaporization. Infrequent users of cannabis may excrete relatively low concentrations of THCCOOH following acute inhalation of smoked or vaporized cannabis.

Urinary Pharmacokinetic Profile of Cannabinoids Following Administration of Vaporized and Oral Cannabidiol and Vaporized CBD-Dominant Cannabis.

Cannabis products in which cannabidiol (CBD) is the primary chemical constituent (CBD-dominant) are increasingly popular and widely available. The impact of CBD exposure on urine drug testing has not been well studied. This study characterized the urinary pharmacokinetic profile of 100-mg oral and vaporized CBD, vaporized CBD-dominant cannabis (100-mg CBD; 3.7-mg ∆9-THC) and placebo in healthy adults (n = 6) using a within-subjects crossover design. Urine specimens were collected before and for 5 days after drug administration. Immunoassay (IA) screening (cutoffs of 20, 50 and 100 ng/mL) and LC-MS-MS confirmatory tests (cutoff of 15 ng/mL) for 11-nor-9-carboxy-∆9-tetrahydrocannabinol (∆9-THCCOOH) were performed; urine was also analyzed for CBD and other cannabinoids. Urinary concentrations of CBD were higher after oral (mean Cmax: 776 ng/mL) versus vaporized CBD (mean Cmax: 261 ng/mL). CBD concentrations peaked 5 h after oral CBD ingestion and within 1 h after inhalation of vaporized CBD. After pure CBD administration, only 1 out of 218 urine specimens screened positive for ∆9-THCCOOH (20-ng/mL IA cutoff) and no specimens exceeded the 15-ng/mL confirmatory cutoff. After inhalation of CBD-dominant cannabis vapor, nine samples screened positive at the 20-ng/mL IA cutoff, and two of those samples screened positive at the 50-ng/mL IA cutoff. Four samples that screened positive (two at 20 ng/mL and two at 50 ng/mL) confirmed positive with concentrations of ∆9-THCCOOH exceeding 15 ng/mL. These data indicate that acute dosing of pure CBD will not result in a positive urine drug test using current federal workplace drug testing guidelines (50-ng/mL IA cutoff with 15-ng/mL confirmatory cutoff). However, CBD products that also contain ∆9-THC may produce positive urine results for ∆9-THCCOOH. Accurate labeling and regulation of ∆9-THC content in CBD/hemp products are needed to prevent unexpected positive drug tests and unintended drug effects.

Acute Pharmacokinetic Profile of Smoked and Vaporized Cannabis in Human Blood and Oral Fluid.

Currently, an unprecedented number of individuals can legally access cannabis. Vaporization is increasingly popular as a method to self-administer cannabis, partly due to perception of reduced harm compared with smoking. Few controlled laboratory studies of cannabis have used vaporization as a delivery method or evaluated the acute effects of cannabis among infrequent cannabis users. This study compared the concentrations of cannabinoids in whole blood and oral fluid after administration of smoked and vaporized cannabis in healthy adults who were infrequent users of cannabis. Seventeen healthy adults, with no past-month cannabis use, self-administered smoked or vaporized cannabis containing Δ9-tetrahydrocannabinol (THC) doses of 0, 10 and 25 mg in six double-blind outpatient sessions. Whole blood and oral fluid specimens were obtained at baseline and for 8 h after cannabis administration. Cannabinoid concentrations were assessed with enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) methods. Sensitivity, specificity and agreement between ELISA and LC-MS-MS results were assessed. Subjective, cognitive performance and cardiovascular effects were assessed. The highest concentrations of cannabinoids in both whole blood and oral fluid were typically observed at the first time point (+10 min) after drug administration. In blood, THC, 11-OH-THC, THCCOOH and THCCOOH-glucuronide concentrations were dose-dependent for both methods of administration, but higher following vaporization compared with smoking. THC was detected longer in oral fluid compared to blood and THCCOOH detection in oral fluid was rare and highly erratic. For whole blood, greater detection sensitivity for ELISA testing was observed in vaporized conditions. Conversely, for oral fluid, greater sensitivity was observed in smoked sessions. Blood and/or oral fluid cannabinoid concentrations were weakly to moderately correlated with pharmacodynamic outcomes. Cannabis pharmacokinetics vary by method of inhalation and biological matrix being tested. Vaporization appears to be a more efficient method of delivery compared with smoking.

Development of a Quantitative LC-MS-MS Assay for Codeine, Morphine, 6-Acetylmorphine, Hydrocodone, Hydromorphone, Oxycodone and Oxymorphone in Neat Oral Fluid.

Recent advances in analytical capabilities allowing for the identification and quantification of drugs and metabolites in small volumes at low concentrations have made oral fluid a viable matrix for drug testing. Oral fluid is an attractive matrix option due to its relative ease of collection, reduced privacy concerns for observed collections and difficulty to adulterate. The work presented here details the development and validation of a liquid chromatography tandem mass spectrometry (LC-MS-MS) method for the quantification of codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone and oxymorphone in neat oral fluid. The calibration range is 0.4-150 ng/mL for 6-acetylmorphine and 1.5-350 ng/mL for all other analytes. Within-run and between-run precision were <5% for all analytes except for hydrocodone, which had 6.2 %CV between runs. Matrix effects, while evident, could be controlled using matrix-matched controls and calibrators with deuterated internal standards. The assay was developed in accordance with the proposed mandatory guidelines for opioid confirmation in federally regulated workplace drug testing. The use of neat oral fluid, as opposed to a collection device, enables collection of a single sample that can be split into separate specimens.

Pharmacokinetic Characterization of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol in Urine Following Acute Oral Cannabis Ingestion in Healthy Adults.

Understanding the urine excretion profile for Δ9-tetrahydrocannabinol (THC) metabolites is important for accurate detection and interpretation of toxicological testing for cannabis use. Prior literature has primarily evaluated the urinary pharmacokinetics of the non-psychoactive THC metabolite 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) following smoked cannabis administration. The present study examined the urine THCCOOH excretion profile following oral cannabis administration in 18 healthy adults. Following ingestion of a cannabis-containing brownie with 10, 25 or 50 mg of THC (N = 6 per dose), urine specimens were collected on a closed residential research unit for 6 days, followed by three outpatient visits on Days 7-9. Average maximum concentrations (Cmax) of THCCOOH were 107, 335 and 713 ng/mL, and average times to maximum concentration (Tmax) were 8, 6 and 9 h for the 10, 25 and 50 mg THC doses, respectively. Detection windows to first positive and last positive varied as a function of dose; higher doses had shorter time to first positive and longer time to last positive. Considerable inter-subject variability was observed on study outcomes. Gas chromatography/mass spectrometry (GC/MS; 15 ng/mL cutoff) was used as the criterion to assess sensitivity, specificity and agreement for THCCOOH qualitative immunoassay tests using 20, 50 and 100 ng/mL cutoffs. The 50 ng/mL cutoff displayed good sensitivity (92.5%), specificity (92.4%) and overall agreement (92.4%), whereas the 20 ng/mL cutoff demonstrated poor specificity (58.4%), and the 100 ng/mL cutoff exhibited reduced sensitivity (70.9%). Ingestion of cannabis brownies containing the 10 and 25 mg THC doses yielded THCCOOH concentrations that differed in magnitude and time course from those previously reported for the smoked route of administration of comparable doses.