Analisis Darah Ke 2

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Drug Alcohol Depend. 2012 October 1; 125(3): 313319. doi:10.1016/j.drugalcdep.2012.03.005.
Predictive model accuracy in estimating last 9tetrahydrocannabinol (THC) intake from plasma and whole blood
cannabinoid concentrations in chronic, daily cannabis smokers
administered subchronic oral THC*
Erin L. Karschner1, David M. Schwope1, Eugene W. Schwilke1, Robert S. Goodwin1,
Deanna L. Kelly2, David A. Gorelick1, and Marilyn A. Huestis1,*
1Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug
Abuse, National Institutes of Health
2Maryland
Psychiatric Research Center, University of Maryland School of Medicine, Catonsville,
USA
Abstract
BackgroundDetermining time since last cannabis/9-tetrahydrocannabinol (THC) exposure is
important in clinical, workplace, and forensic settings. Mathematical models calculating time of
last exposure from whole blood concentrations typically employ a theoretical 0.5 whole blood-toplasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empiricallyderived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing.
MethodsTen male chronic, daily cannabis smokers received escalating around-the-clock oral
THC (40-120 mg daily) for 8 days. Cannabinoids were quantified in whole blood and plasma by
two-dimensional gas chromatography-mass spectrometry.
ResultsMaximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5 h
(4.3 days) during multiple THC dosing. Median WB/P ratios were THC 0.63 (n=196), 11hydroxy-THC 0.60 (n=189), and 11-nor-9-carboxy-THC (THCCOOH) 0.55 (n=200). Predictive
models utilizing these WB/P ratios accurately estimated last cannabis exposure in 96% and 100%
of specimens collected within 1-5 h after a single oral THC dose and throughout multiple dosing,
respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5 h after the last THC dose,
respectively.
*Supplementary material can be found by accessing the online version of this paper at http://dx.doi.org and by entering doi:...
*
Corresponding Author: Marilyn A. Huestis, Chief, Chemistry and Drug Metabolism, Intramural Research Program, NIDA, NIH,
Biomedical Research Center, 251 Bayview Blvd. Room 05A721, Baltimore, MD 21224 USA, Phone: 443-740-2524, Fax:
443-740-2823, [email protected].
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4Supplementary material can be found by accessing the online version of this paper at http://dx.doi.org and by entering doi:...
Contributors: Authors Huestis, Goodwin, Schwilke and Gorelick designed the study and wrote the protocol. Authors Huestis,
Gorelick, Goodwin, Schwilke, Karschner and Schwope managed collection of data and data management. Author Karschner
undertook the statistical analysis and wrote the first draft. All authors contributed to and have approved the final manuscript.
Author Disclosures
Conflict of Interest: None of the authors has any conflicts of interest to disclose.
Karschner et al.
Page 2
ConclusionsPredictive models estimating time since last cannabis intake from whole blood
and plasma cannabinoid concentrations were inaccurate during abstinence, but highly accurate
during active THC dosing. THC redistribution from large cannabinoid body stores and high
circulating THCCOOH concentrations create different pharmacokinetic profiles than those in less
than daily cannabis smokers that were used to derive the models. Thus, the models do not
accurately predict time of last THC intake in individuals consuming THC daily.
Keywords
9-tetrahydrocannabinol; chronic; cannabis; predictive models; cannabinoids; marijuana
1. INTRODUCTION
Knowledge of the time interval since last cannabis use is important in clinical, forensic, and
workplace contexts. If there is suspicion of driving under the influence of cannabis or
cannabis intake prior to an occupational accident, blood, plasma or serum samples are
collected to determine cannabinoid concentrations. Concentrations of 9tetrahydrocannabinol (THC) and its acid metabolite, 11-nor-9-carboxy-THC (THCCOOH),
provide insight into the time of last THC consumption. Models for estimating time of last
cannabis/THC intake were developed in the authors laboratory based on plasma data
collected after controlled smoked cannabis administration (Huestis et al., 2005; 2006; 1992),
while accident investigations and postmortem analyses are primarily conducted on whole
blood. Thus, implementation of predictive models, and interpretation of cannabinoid
concentrations in general, requires accurate whole blood (WB) to plasma (P) ratios to enable
application of plasma-derived models to whole blood data. Previous studies of predictive
models utilized the generally accepted WB/P ratio of 0.5. We are not aware of any previous
model evaluations that employed empirically derived WB/P ratios. This may be due, in part,
to the fact that few controlled drug administration studies simultaneously analyze both
whole blood and plasma specimens.
Another limitation of existing predictive models based on plasma data, whether validated
with oral (Huestis et al., 2006) or multiple smoked cannabinoid administration (Huestis et
al., 2005), is that they were developed in less than daily cannabis smokers. Therefore, the
models application was recommended only for specimens from occasional or less than
daily cannabis smokers. This was due to limited knowledge of cannabinoid elimination in
chronic, daily cannabis smokers, and how residual THC and THCCOOH concentrations in
this population might affect predictions. We recently documented measureable THC in
whole blood (Karschner et al., 2009a) and plasma (Karschner et al., 2009b) for at least 7
days after cannabis cessation in chronic, daily smokers who consumed up to 10 joints/blunts
per day for up to 22 years.
A study of spontaneous and antagonist-elicited cannabis withdrawal in chronic, daily
cannabis smokers (Gorelick et al., 2011) provided an opportunity to characterize whole
blood THC, 11-hydroxy-THC (11-OH-THC), and THCCOOH pharmacokinetics and WB/P
cannabinoid ratios in simultaneously collected specimens. Specimens were collected for
19.5 h of abstinence from previously self-administered smoked cannabis, after a single 20mg oral THC dose, during administration of up to 120 mg oral THC per day for eight days,
and for 22.5 h after the last oral THC dose. Now, for the first time, data are available to test
the accuracy of predictive models in individuals who had a large THC body burden from
previously self-administered chronic, daily cannabis smoking, and who received subchronic
around-the-clock oral THC while abstaining from smoked cannabis. Furthermore, for the
first time predictive models utilized empirically-derived WB/P cannabinoid ratios.
Karschner et al.
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2. METHODS
2.1. Participants
Inclusion criteria for participants included ages 18-45 years, cannabis use history for 1
year, daily smoking (on average) for 3 months, and cannabinoid-positive urine specimen
within 30 days prior to enrollment. Participants with a history of clinically significant
medical or psychiatric disease, clinically significant illness within 2 weeks of study
initiation, current DSM-IV axis I disorder (other than cannabis, caffeine or nicotine
dependence, or simple phobia), current physical dependence (other than for cannabis,
nicotine or caffeine), or clinically significant adverse event associated with cannabis
intoxication or withdrawal were excluded. Additional exclusion criteria included IQ <85,
consumption of 6 alcoholic drinks/day 4 times/week, blood donation within 30 days,
sesame oil allergy, or interest in drug treatment.
Eligible participants provided written informed consent to a protocol approved by the
Institutional Review Boards of the National Institute on Drug Abuse, University of
Maryland Baltimore, and Maryland Department of Health and Mental Hygiene.
2.2. Study Design
20 mg oral synthetic THC (Marinol; Unimed Pharmaceuticals, Marietta, GA) was

administered as an escalating dose: twice on Day 1 (the day after admission to a closed
research unit) and every 3.5-8 h thereafter for a total of 8 days (40-120 mg/day) to
standardize THC tolerance (Supplemental Table 1 1). Dosing began at 1500 on Day 1,
17.5-21 h after admission (time 0), with the last of 37 doses administered at 0930 on day 8
(162.5 h). Dosing frequency, rather than dose amount, was increased to minimize adverse
events reported after higher single oral doses (Haney et al., 1999; Jones and Benowitz,
1976).
Whole blood (3 mL) was collected in sodium heparin at study admission, twice before and
every hour for 5 h after the first dose to evaluate single dose THC pharmacokinetics
(Supplemental Table 1 2). Daily blood collections occurred at approximately 2200 during
continuous oral THC dosing. Blood specimens also were collected before and at 2.5, 10.5,
12.5 and 22.5 h after the final oral THC dose. Whole blood for plasma (7 mL) was collected
on ice and plasma separated within 2 h. Plasma specimens were collected twice before and
every 30 min for 5 h after the first dose, at 1000, 2000, and 2200 daily during around-theclock dosing and at multiple time points up to 22.5 h following the last dose (Supplemental
Table 1 3). Specimens were stored at 4C and analyzed within 2 weeks.
2.3. Specimen Analysis

Whole blood and plasma cannabinoids were solid phase extracted (SPE) and analyzed by
two-dimensional gas chromatography mass spectrometry (2D-GCMS) according to
previously validated procedures (Lowe et al., 2007; Schwilke et al., 2009b). Briefly, 1 mL
whole blood was mixed with 3 mL cold acetonitrile (stored at 20C) to precipitate proteins.
Samples were centrifuged, decanted into 5 mL sodium acetate buffer, mixed and added to 10
mL ZSTHC020 SPE columns (United Chemical Technologies; Bristol, PA, USA). Columns
were washed with 3 mL deionized water and 2 mL 0.1 N HCl/acetonitrile (70:30) and dried
under vacuum for 15 min. THC, 11-OH-THC and THCCOOH were eluted from SPE
columns with 5 mL hexane/ethyl acetate (80:20) and dried under nitrogen. Extracts were
derivatized with 25 L N,O-bis(trimethylsilyl)trifluoroacetamide and 1%
Karschner et al.
Page 4
trimethylchlorosilane at 70C for 30 min, injected splitless and analyzed in selected ion
monitoring mode with 2D-GCMS with cryofocusing. Split calibration curves provided
quantification through multiple orders of magnitude, THC 0.25-25, 25-100 ng/mL, 11-OHTHC 0.25-10, 10-75 ng/mL and THCCOOH 0.25-25, 25-100 ng/mL. Inter- and intra-assay
imprecision were 14.0% and analytical recovery/bias was 85.0-113%.
2.4. Statistical Analyses
Body mass index (BMI) was calculated as weight (kg)/height (m)2. Statistical analyses were
performed with SPSS, version 12.0 (SPSS, Inc., Chicago, IL). Because Shapiro-Wilk
analyses indicated non-normality, nonparametric Wilcoxon Sign Rank and chi-squared tests
were employed for statistical comparisons. Linear regression analysis was employed to
evaluate the relationship between model accuracy and increasing abstinence time. Twotailed P <0.05 was considered statistically significant. Area under the curve (AUC) from 0 to
5.0 h (AUC0-5.0 h) and from 0 to 185.0 h (AUC0-185.0 h) was determined by linear
trapezoidal non-compartmental analysis (WinNonlin; Pharsight Corp., Mountain View, CA).
Median concentration maximum (Cmax) and time to Cmax (Tmax) were assessed by
determining the Cmax and Tmax for each participant and then calculating the median Cmax
and Tmax for the group. Similarly, median peak 11-OH-THC/THC and THCCOOH/THC
ratios were calculated by determining the maximum ratio for each participant and
calculating the median of maximum ratios.
Mathematical equations for estimating time of last cannabis/THC exposure were previously
published (Supplemental Table 2 4; Huestis et al., 2005; 2006; 1992). Times of last use
estimates were calculated from THC concentrations (model I) and THCCOOH/THC ratios
(model II).
Models I and II were evaluated with empirically determined median WB/P ratio data. As
recommended previously (Huestis et al., 2005; 2006), the most accurate results are achieved
by combining 95% CI from models I and II. 95% CI for time of last use were determined for
each model and the lowest and highest CI utilized. Elapsed times after dosing were
compared to the combined CI to determine model accuracy and estimation error. Accuracy
(%) was calculated by (number of correct estimates/total number of estimates) 100. Overor underestimates were calculated by the absolute value of the mean calculated error from
the CI (actual time-calculated time). Overestimates occurred when actual times were less
than the CI lower limit and underestimates occurred when actual times were greater than the
CI upper limit.
3. RESULTS
Ten adult males last smoking cannabis within 24 h of admission completed the study (see
Table 1 for participant characteristics). Median (range) whole blood cannabinoid
concentrations on admission from previously self-administered smoked cannabis were 3.0
ng/mL (1.4-20.3), 1.7 ng/mL (0.8-7.3), and 31.0 ng/mL (12.8-86.9) for THC, 11-OH-THC,
and THCCOOH, respectively (Table 1, Figure 1). 12.5 h later, THC and 11-OH-THC
concentrations decreased to 2.3 (0.9-5.9) and 0.6 (0.5-3.5) ng/mL, respectively, while
THCCOOH concentrations were 27.2 ng/mL (11.2-89.3). 19.5 h after admission, at the time
of the first 20-mg oral THC dose, median THC, 11-OH-THC and THCCOOH whole blood
concentrations were 2.3 (1.1-6.1), 0.7 (not detected [ND]-2.4), and 16.0 (7.0-47.2) ng/mL.
11-OH-THC (P=0.008) and THCCOOH (P=0.005) concentrations significantly decreased
from admission to 19.5 h, while THC concentrations did not (P=0.051). Median percent
Karschner et al.
Page 5
decreases during this time were 20.1% for THC, 72.8% for 11-OH-THC and 47.2% for
THCCOOH. Percent decreases did not vary by self-reported cannabis smoked per day.
After a single 20-mg oral THC dose (Figure 1), median Cmax occurred at 3 h and were 6.4,
3.4, and 36.6 ng/mL for THC, 11-OH-THC, and THCCOOH, respectively (Table 2). THC
(P=0.007), 11-OH-THC (P=0.009), and THCCOOH (P=0.007) concentrations significantly
increased between 1 and 2 h following the first oral THC dose. THC (P=0.005) and 11-OHTHC (P=0.022) concentrations significantly decreased between 3 and 5 h, while THCCOOH
concentrations did not (P=0.059).
During multiple THC dosing up to 120 mg/day, median whole blood Cmax were 16.3 ng/mL
at 103.5 h (day 5), 9.8 ng/mL at 103.5 h (day 5), and 120.7 ng/mL at 163.8 h (day 8) after
the first dose for THC, 11-OH-THC (Figure 1c), and THCCOOH (Figure 1d), respectively
(Table 2). THC concentrations significantly increased between days 2 and 3 (P=0.047),
when THC dose increased from 80 to 100 mg/day. THCCOOH concentrations also
significantly increased when dose escalated from 80 (day 2) to 100 mg/day (day 3)
(P=0.037).
After the final THC dose, peak whole blood concentrations occurred 2.5 h post-dose for all
analytes and then generally decreased until discharge. Whole blood (plasma) maximum
THC concentrations were 11.5 (17.8), 6.5 (9.1), 7.2 (7.6), and 5.2 (5.2) at 2.5, 10.5, 12.5,
and 22.5 h after the last oral THC dose, respectively. Median concentrations at 22.5 h after
the last oral THC dose were 2.5 (1.5-5.2), 1.2 (0.6-4.4), and 85.1 (17.1-191.5) ng/mL for
THC, 11-OH-THC and THCCOOH, respectively. Median percent decreases from the final
dose (162.5 h) to the last specimen at 185 h were 54.7% for THC, 76.1% for 11-OH-THC
and 22.7% for THCCOOH.
3.1. Whole blood metabolite/parent ratios
Whole blood 11-OH-THC/THC ratios significantly decreased (P=0.017) between admission
and time of first THC dose (Figure 2). After the initial 20-mg dose, 11-OH-THC/THC ratios
significantly increased at 2 h (P=0.028) and continued to rise until the final oral THC dose at
162.5 h. 11-OH-THC/THC ratios declined following the last oral THC dose. Median peak
11-OH-THC/THC ratios were 1.4 (0.7-1.9) at 162.5 h (Day 8) after the first THC dose.
THCCOOH/THC ratios were highly variable during the pre-dose period, gradually increased
during repeated dosing, and peaked at the last time point (185 h). Median peak THCCOOH/
THC ratios were 36.3 (10.7-119.7) at 173.0 h (Day 8).
3.2.Whole blood/plasma ratios
Median whole blood/plasma (WB/P) ratios on admission (n = 10) were 0.61 (0.56-0.74)
THC, 0.63 (0.52-0.76) 11-OH-THC, and 0.59 (0.47-0.84) THCCOOH. Inter-individual
ratios showed a 30.6% coefficient of variation (CV) for THC, 26.6% for 11-OH-THC, and
24.2% for THCCOOH across all individuals and time points. There were significant
differences among participants WB/P ratios for all analytes (P<0.001). Intra-individual ratio
CVs ranged from 6.4-59.1, 4.7-56.5, and 4.4-39.3% for THC, 11-OH-THC, and
THCCOOH, respectively. Intra-subject paired comparisons revealed THC WB/P ratios were
significantly greater than 11-OH-THC (P<0.001) and THCCOOH ratios (P<0.001), and 11OH-THC WB/P ratios were significantly higher than THCCOOH ratios (P<0.001). Analyte
WB/P ratios did not significantly differ (P>0.05) during the initial smoked cannabis
abstinence, 1-5 h post first oral THC dose, during multiple THC dosing, and after the last
THC dose. When combined across all participants and time points, median WB/P ratios
were 0.63 (0.3-1.7) THC (n=196), 0.60 (0.1-1.3) 11-OH-THC (n=189), and 0.55 (0.2-1.5)
THCCOOH (n=200).
Karschner et al.
Page 6
3.3.Predictive models of last THC exposure
Predictive accuracy (Figure 3) based on plasma concentrations was only 10.0% 0.5 h after
the first THC dose, with overestimations from 0.1-0.6 h (Figure 4); whole blood was not
collected at this time. Over-(Figure 4c) and underestimates (Figure 4a-c) outside 95% CI are
displayed in Figure 4. Models were 98.8% accurate 1-5 h after a single THC dose utilizing
plasma concentrations, 90.0% with an assumed WB/P ratio of 0.5 (Huestis et al., 2005;
2006), and 96.0% with the empirically-derived median WB/P ratios determined in the
present study (0.63 and 0.55 for THC and THCCOOH, respectively). During 37 multiple
THC doses, the estimated time of last intake was within the 95% CI 96.6% of the time with
plasma concentrations and 100% with both WB/P ratios. Model accuracy significantly
decreased (P=0.018; R2= 0.965) with increasing abstinence time. Accuracy was 100% for
plasma and both WB/P ratios 2.5 h after the last dose (Figure 3), decreasing to 20%
(underestimates 1.2-14.9 h) for plasma and 12.5% (underestimates 2.2-17.9 h) for both WB/
P ratios 22.5 h after the final dose.
4. DISCUSSION

To the best of our knowledge, this is the first study to evaluate the accuracy of estimation
models for time since last THC intake utilizing empirically derived (rather than theoretical)
WB/P ratios in individuals administered subchronic oral THC. In addition, this is the first
study to evaluate the time course of cannabinoid disposition in whole blood and plasma
during around-the-clock oral THC dosing and initiation of abstinence in such a population.
The models overestimated time of last exposure at the first time point (0.5 h) after a single
oral THC dose by as much as 0.6 h (Figure 4a). Although this represents a clear
overestimation error in the predictive model, the absolute error may not be as critical for
interpreting results in a criminal or occupational case. Residual THCCOOH concentrations
from previously smoked cannabis were 4.2 to 13.8-fold higher than residual THC
concentrations at this time. We hypothesize that residual THC and THCCOOH
concentrations following chronic cannabis smoking combined with THC just beginning to
be absorbed from the first administered oral dose resulted in overestimations of time of last
use. This differs from the case with cannabis smoking, where cannabinoid absorption after
smoking is much more rapid than after oral administration, resulting in immediate
concentration increases to much higher Cmax. One to 5 h after the first oral THC dose,
residual THC was a minor contributor to total THC, yielding high accuracy for predictive
models with plasma concentrations (98.8%). For predictive models with blood
concentrations, utilizing the empirically derived WB/P ratios (0.63/0.55) improved accuracy
compared to the previously suggested theoretical ratio (0.5/0.5): 96.0% vs. 90.0%,
respectively. Additionally, model accuracy was high during 37 multiple THC doses using
plasma (96.6%) and whole blood concentrations with both WB/P ratios (100%).
The models underestimated time of last THC intake in 80% of cases 22.5 h after the last
oral THC dose, based on plasma or whole blood concentrations and both WB/P ratios. At
this time, there was little cannabinoid contribution from the final THC dose; rather, the
primary contributor to total THC was suspected to be residual drug from the body burden of
previously self-administered smoked cannabis prior to study entry and the previous 37
controlled oral THC administrations. Evaluating the models with theoretical cannabinoid
concentrations revealed that plasma THC concentrations must be 0.35 ng/mL (model I:
95% CI 22.5 h) or plasma THCCOOH/THC concentrations 83.6 (model II: 95% CI 22.5
h) for models to accurately estimate time of last THC dose. Both are highly unlikely within
24 h of abstinence initiation in this cohort due to THC accumulation in the tissues. As
recently reported, we observed cannabinoid release into blood for many days after last use in
chronic, daily cannabis smokers (Karschner et al., 2009a; 2009b). Therefore, as previously
recommended (Huestis et al., 1992), these predictive models are not appropriate for
Karschner et al.
Page 7
predicting last cannabis intake in chronic, daily cannabis smokers, as others also suggested
(Skopp and Potsch, 2008; Toennes et al., 2008). Although we do not recommend the use of
predictive models in this population, this study demonstrates that the models had a high
degree of predictive accuracy during subchronic oral THC dosing in recently abstinent
chronic, daily cannabis smokers, and may be appropriate for individuals prescribed oral
THC for medical reasons.
Maximum cannabinoid concentrations for all analytes after multiple THC doses were almost
three-fold higher than following a single 20-mg oral THC dose. When daily THC doses
increased from 100 to 120 mg/day on day 5, THC and 11-OH-THC concentrations
decreased. As proposed by Schwilke et al. (2009c), repeated oral THC dosing in daily
cannabis smokers may induce gastrointestinal THC metabolism, resulting in lower
concentrations later in the dosing regimen. Although these individuals were chronic, daily
cannabis smokers at the time of study initiation and hepatic metabolism was expected to be
at steady state, oral ingestion was uncommon, suggesting that gastrointestinal metabolism
might be inducible with chronic oral THC exposure.

This study has several limitations. Cannabis is typically used by the smoked route both
recreationally and medically, but oral cannabis and THC are prescribed medically around
the world (Gorter RW, 2005; Hagenbach et al., 2006; Lynch et al., 2006; Smith, 2010) and
also sometimes taken recreationally (Andr C, 2006; Chaudry HR, 1991). Aside from
decreased bioavailability, delayed peak cannabinoid concentrations, and greater 11-OHTHC concentrations via the oral route, both oral and smoked THC routes of administration
have comparable pharmacokinetic parameters after a few hours. Thus, our findings, derived
from subchronic oral THC administration, would be generally applicable to smoked
cannabis. A second limitation was the small sample size, which limits statistical power. A
third limitation was the presence of residual cannabinoid concentrations (whole blood THC
at admission 1.4 ng/mL) from prior self-administered smoked cannabis before the first oral
THC dose, which obscured the accuracy of the predictive models at the earliest (0.5 h) time
point. However, this was unavoidable, given that chronic, daily cannabis smokers were
needed to achieve the scientific objectives of the primary study, viz., to evaluate antagonistelicited and spontaneous cannabis withdrawal (Gorelick et al., 2011). However, this is also
an advantage, as this design provided the first opportunity to test the accuracy of the
predictive models after subchronic oral THC dosing in recently abstinent chronic, daily
cannabis smokers. A further advantage was specimen analysis within 2 weeks of collection
following storage at 4C, rather than after extended frozen storage. Schwilke et al. (2009a)
examined cannabinoid stability in fortified whole blood specimens and found that
cannabinoids were stable at 4C for two weeks in fortified specimens, but decreased >20%
when stored at 20C for the same period.
5. Conclusions
An accurate predictive model to determine the time of last exposure to cannabis or THC is
important in clinical, workplace, and forensic contexts, although the degree of accuracy
needed may vary with the context. For example, in a drug abuse treatment setting, a positive
test may trigger significant consequences, regardless of the time of last exposure, whereas
accuracy to within minutes may be important in the context of an accident or crime. These
data reaffirm our recent research (Karschner et al., 2009a; 2009b) documenting that low
concentrations of THC in whole blood and plasma do not necessarily indicate recent THC
exposure. Although plasma and whole blood concentrations and WB/P data predicted time
of last THC exposure with acceptable accuracy after single and during multiple oral THC
doses, the models were inaccurate during extended abstinence due to residual THC and
THCCOOH concentrations. These data document under controlled conditions that predictive
Karschner et al.
Page 8
models for the estimation of time of last THC exposure are not applicable to individuals
consuming oral THC on a daily basis.
Supplementary Material
References
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
The authors would like to acknowledge the clinical staffs of the National Institute on Drug Abuse Intramural
Research Program, including Kathie Demuth, David Darwin, Janeen Nichels, and John Etter; the Maryland
Psychiatric Research Center; and the Johns Hopkins Behavioral Pharmacology Research Unit, and Tsadik
Abraham, Ross Lowe, and Allan Barnes for technical assistance.
Role of Funding Sources: Funding for this study was provided by the Intramural Research Program, NIH,
National Institute on Drug Abuse; NIDA Residential Research Support Services Contract
HHSN271200599091CADB (D. Kelly, PI) to the Maryland Psychiatric Research Center (MPRC); and a
Cooperative Research and Development Agreement between Sanofi-aventis and the National Institutes of Health.
NIDA and MPRC had no further role in the study design; in the collection, analysis, and interpretation of data; in
the writing of the report; or in the decision to submit the paper for publication. Sanofi-aventis contributed to study
design and data management, but played no further role in the collection, analysis, and interpretation of data, in the
writing of the report; or in the decision to submit the paper for publication.
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Karschner et al.
Page 10

Figure 1.
Median (n=10) whole blood 9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OHTHC), and 11-nor-9-carboxy-THC (THCCOOH) concentrations.

Karschner et al.
Page 11
Figure 2.
Median (n=10) 11-hydroxy-9-tetrahydrocannabinol (11-OH-THC) to THC ratios and 11nor-9-carboxy-THC (THCCOOH) to THC ratios in whole blood after multiple 20-mg oral
THC doses across 8 days.

Karschner et al.
Page 12

Figure 3.
Predictive model accuracy (%) in estimating last THC exposure in 10 male recently
abstinent chronic, daily cannabis smokers administered subchronic oral THCa.

Karschner et al.
Page 13

Figure 4.
Predictions outside of 95% CI (in hours) utilizing plasma cannabinoid concentrations or

whole blood to plasma (WB/P) ratios from 10 male recently abstinent chronic, daily
cannabis smokers administered subchronic oral THC*. Left y-axis corresponds to filled
circles () and the right y-axis corresponds to open circles ().


4.5
AA
AA
25
27
25
22
23.9
24
Mean
SD
Median
AA
Body mass index
26.9
29.7
30.5
28.7
30.6
22.9
6.7
24
Cannabis smoking
frequency (joints/
day)
4.4
7.5
10
10
15
12
Lifetime cannabis
use (y)
NA, not available due to analytical error
13.5
1.8
13.6
12
12
11
14
17
13
14
13
14
16
Age of first cannabis

use (y)
T, tobacco; A, alcohol; Amp, amphetamines; O, opiates; Coc, cocaine; B, benzodiazepines; H, hallucinogens
A, African American; W, White
26
Multiple
21
21.1
23.7
AA
23
AA
18
25.1
29.8
17.8
AA
AA
BMI
32
AA
(kg/m2)
26
20
Age (y)
Participant
a
Race
T, A
T, A, O, Amp
T, A, Coc
T, A
T, A, Coc, B, H
T, A
T, A, O
T, A, Amp
T, A
T, A
Other drug use (in prior

c
year)
3.0
5.6
5.0
2.2
7.1
2.4
3.0
1.4
3.7
3.0
3.0
20.3
4.3
THC
1.7
2.1
2.2
1.2
3.5
NA
1.8
0.8
1.7
0.9
1.0
7.3
2.0
11-OH-THC
31.0
21.5
36.5
28.9
57.0
31.9
35.2
17.6
30.0
24.9
12.8
86.9
39.9
THCCOOH
At admission (ng/mL)
Demographic and self-reported substance use characteristics for 10 adult male chronic daily cannabis smokers at time of study screening
Table 1
Karschner et al.
Page 14

3.1 1.0
147 61.1
THCCOOH Tmax
THCCOOH AUC
134
3.0
36.6
10.0
3.0
3.4
74.1 - 261
2.0 - 5.0
19.7 - 68.7
6.4 - 20.2
2.0 - 5.0
1.8 - 7.8
13.2 - 35.4
2.0 - 4.0
4.1 - 17.5
Range
15,985 6701
144.0 40.3
142.2 63.5
1077 503
106 21.2
11.0 5.4
1780.7 957.6
101 26.6
22.4 16.1
Mean SD
14,220
163.8
120.7
1040
104
9.8
1430
104
16.3
Median
8,107 - 25,256
79.0 - 185
60.2 - 253.0
438 - 2094
79.0 - 152
3.9 - 20.9
698 - 3317
55.0 - 152
7.5 - 51.9
Range
Multiple 20-mg THC doses
Participants were chronic, daily cannabis smokers with the last smoked dose within 24 h of the first 20 mg oral THC dose.
11.9 5.6
38.4 15.9
THCCOOH Cmax
2.8 0.9
11-OH-THC Tmax
11-OH-THC AUC
4.0 2.1
11-OH-THC Cmax
24.8
3.0
3.0 0.9
24.4 7.2
THC Tmax, h
6.4
Median
8.7 4.8
THC AUC, h ng/L
THC Cmax, ng/mL
Mean SD
Single 20-mg THC dose
adult, males after a single oral 20-mg THC dose and 37 multiple 20-mg oral THC doses up to 120 mg/day.
Whole blood pharmacokinetics for 9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) in 10
Table 2
Karschner et al.
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Psychiatric Research Center, University of Maryland School of Medicine, Catonsville,

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20 mg oral synthetic THC (Marinol; Unimed Pharmaceuticals, Marietta, GA) was

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2.3. Specimen Analysis

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3.3.Predictive models of last THC exposure

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Refer to Web version on PubMed Central for supplementary material.

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Predictions outside of 95% CI (in hours) utilizing plasma cannabinoid concentrations or

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Body mass index

NA, not available due to analytical error

Age of first cannabis

T, tobacco; A, alcohol; Amp, amphetamines; O, opiates; Coc, cocaine; B, benzodiazepines; H, hallucinogens

A, African American; W, White

Other drug use (in prior

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Multiple 20-mg THC doses

THC AUC, h ng/L

THC Cmax, ng/mL

Single 20-mg THC dose

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