Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration.

BACKGROUND: Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. METHODS: Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 µg/L. RESULTS: Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (C(max)) and areas under the curve from 0-10.5 h postdose (AUC(0→10.5)) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in C(max), time to maximum concentration or in the AUC(0→10.5) between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. CONCLUSION: These data suggest that CBD modulation of THC's effects is not due to a pharmacokinetic interaction at these therapeutic doses.

Urinary excretion of ecgonine and five other cocaine metabolites following controlled oral, intravenous, intranasal, and smoked administration of cocaine.

Urinary excretion of ecgonine (EC) was compared to that of cocaine, benzoylecgonine, ecgonine methyl ester and minor metabolites, meta-hydroxybenzoylecgonine, para-hydroxybenzoylecgonine, and norbenzoylecgonine, following controlled administration of oral, intravenous, intranasal, and smoked cocaine. Urine EC concentrations peaked later than all other analytes and had longer detection times than the other minor metabolites. With a 50 ng/mL cutoff concentration and following low doses of 10 to 45 mg cocaine by multiple routes, detection times extended up to 98 h. Maximum concentrations (Cmax) were 6-14 mole % of those for benzoylecgonine, Cmax increased with dose, time to maximum concentration (Tmax) was independent of dose, and route of administration did not have a significant impact on Cmax or Tmax for metabolites. EC is an analyte to consider for identifying cocaine use due to its stability in urine and long detection times.

Implications of plasma Delta9-tetrahydrocannabinol, 11-hydroxy-THC, and 11-nor-9-carboxy-THC concentrations in chronic cannabis smokers.

Delta(9)-Tetrahydrocannabinol (THC) is commonly found in toxicological specimens from driving under the influence and accident investigations. Plasma cannabinoid concentrations were determined in 18 long-term heavy cannabis smokers residing on an in-patient research unit for seven days of monitored abstinence. THC, 11-hydroxy-THC, and 11-nor-9-carboxy-THC (THCCOOH) were quantified by two-dimensional gas chromatography-mass spectrometry with cryofocusing. THC concentrations were > 1 ng/mL in nine (50.0%) participants (1.2-5.5 ng/mL) on abstinence day 7. THCCOOH was detected (2.8-45.6 ng/mL) in all participants on study day 7. THC and THCCOOH median percent concentration decreases (n = 18) were 39.5% and 72.9% from day 1 to 7, respectively. Most (88.9%) of the participants had at least one specimen with increased THC compared to the previous day. Cannabis use duration and plasma THCCOOH concentrations were positively correlated on days 1-3 (R = 0.584-0.610; p = 0.007-0.011). There were no significant correlations between THC concentrations > 0.25 ng/mL and body mass index on days 1-7 (R = -0.234-0.092; p = 0.350-0.766). Measurable THC concentrations after seven days of abstinence indicate a potential mechanism for residual neurocognitive impairment observed in chronic cannabis users. THC's presence in plasma for seven days of abstinence suggests its detection may not indicate recent use in daily cannabis users.

Do Delta9-tetrahydrocannabinol concentrations indicate recent use in chronic cannabis users?

AIMS: To quantify blood Delta(9)-tetrahydrocannabinol (THC) concentrations in chronic cannabis users over 7 days of continuous monitored abstinence. PARTICIPANTS: Twenty-five frequent, long-term cannabis users resided on a secure clinical research unit at the US National Institute on Drug Abuse under continuous medical surveillance to prevent cannabis self-administration. MEASUREMENTS: Whole blood cannabinoid concentrations were determined by two-dimensional gas chromatography-mass spectrometry. FINDINGS: Nine chronic users (36%) had no measurable THC during 7 days of cannabis abstinence; 16 had at least one positive THC > or =0.25 ng/ml, but not necessarily on the first day. On day 7, 6 full days after entering the unit, six participants still displayed detectable THC concentrations [mean +/- standard deviation (SD), 0.3 +/- 0.7 ng/ml] and all 25 had measurable carboxy-metabolite (6.2 +/- 8.8 ng/ml). The highest observed THC concentrations on admission (day 1) and day 7 were 7.0 and 3.0 ng/ml, respectively. Interestingly, five participants, all female, had THC-positive whole blood specimens over all 7 days. Body mass index did not correlate with time until the last THC-positive specimen (n = 16; r = -0.2; P = 0.445). CONCLUSIONS: Substantial whole blood THC concentrations persist multiple days after drug discontinuation in heavy chronic cannabis users. It is currently unknown whether neurocognitive impairment occurs with low blood THC concentrations, and whether return to normal performance, as documented previously following extended cannabis abstinence, is accompanied by the removal of residual THC in brain. These findings also may impact on the implementation of per se limits in driving under the influence of drugs legislation.

Cocaine and metabolites urinary excretion after controlled smoked administration.

Understanding cocaine and metabolites urinary excretion following smoking is important for interpretation of urine test results in judicial, workplace and treatment settings. In National Institute on Drug Abuse approved studies on a secure research unit, six subjects smoked placebo, 10, 20, and 40 mg cocaine with a precise dose delivery device and six different subjects smoked 42 mg cocaine in a glass pipe. Urine specimens (n = 700) were collected for up to seven days and analyzed for cocaine (COC), benzoylecgonine (BE), ecgonine methylester (EME), m-hydroxybenzoylecgonine (mOHBE), p-hydroxybenzoylecgonine (pOHBE), norbenzoylecgonine (NBE), and ecgonine (EC) by gas chromatography-mass spectrometry. Results (mean +/- SE) for the 40-mg precise delivery doses are as follows: (Table can not be represented) Mean C(max) for all analytes linearly increased with increasing dose. T(max) was not dose-dependent. All metabolites were detected in some subjects within 2 h. EC concentrations were significantly higher after smoked cocaine in a precise delivery coil compared to a glass "crack" pipe.

Intra- and interindividual variations in urinary concentrations of endogenous gamma-hydroxybutyrate.

This study was designed to determine the urinary concentrations of endogenous GHB over a one-week period, the variations that occur within those concentrations, and whether those variations are affected by normalization to urinary creatinine. Its purpose was to ascertain whether endogenous concentrations fluctuate to such an extent that they may be misinterpreted as due to GHB ingestion. Every urine void produced by eight GHB-free subjects (five males and three females) over a one-week period was individually collected and analyzed for the presence of endogenous GHB and creatinine. The results of the non-normalized and normalized concentrations were statistically analyzed. Non-normalized GHB concentrations ranged from 0.00 to 6.63 microg/mL over seven days. The coefficients of variation (CV) for the individual non-normalized data were 44.0% to 77.7%. When the data were normalized to creatinine, the concentrations ranged from 0.00 to 6.79 microg/mg. The CVs for the creatinine-normalized results were between 29.7% and 76.8%. Analysis of the differences in CVs by the paired t-test (alpha = 0.05) found these improvements to be statistically insignificant. Such normalization allows for correction of urinary dilution or concentration by the kidneys which may affect endogenous GHB concentrations. The data also suggest significant (p < 0.001) differences in median endogenous urinary concentrations of GHB between males and females using the Mann-Whitney test. Because of the small number of subjects in this study, further investigations are required to substantiate this observation. Some of the subjects in this study demonstrated a strong tendency to produce higher or lower GHB concentrations at consistent periods during the day. This was most evident when looking at the creatinine-normalized concentrations. The results of our study indicate that there are significant intra- and interindividual variations in the urinary concentrations of endogenous GHB. Furthermore, there are also wide variations between individuals in the total daily amount of GHB excreted in the urine. Nonetheless, no specimen's GHB concentration approached 10 microg/mL (non-normalized) or 10 microg/mg (normalized). This study of the variability in endogenous urinary GHB excretion supports the recommendation of 10 microg/mL as an appropriate cutoff to identify exogenous GHB exposure in the absence of rare genetic deficiencies such as GHB aciduria. Patients with such a deficiency should be readily identifiable through prominent symptoms, repeated urinalysis, or genetic testing.