Clinical Chemistry 62:2
367–377 (2016)
Effect of Blood Collection Time on Measured
Δ9-Tetrahydrocannabinol Concentrations:
Implications for Driving Interpretation and Drug Policy
Rebecca L. Hartman,1 Timothy L. Brown,2 Gary Milavetz,3 Andrew Spurgin,3 David A. Gorelick,1,4
Gary R. Gaffney,5 and Marilyn A. Huestis1*
BACKGROUND: In driving-under-the-influence cases, blood
typically is collected approximately 1.5– 4 h after an in-
cident, with unknown last intake time. This complicates
blood ⌬9-tetrahydrocannabinol (THC) interpretation,
owing to rapidly decreasing concentrations immediately
after inhalation. We evaluated how decreases in blood
THC concentration before collection may affect inter-
pretation of toxicological results.
METHODS: Adult cannabis smokers (ⱖ1⫻/3 months,
ⱕ3 days/week) drank placebo or low-dose alcohol (ap-
proximately 0.065% peak breath alcohol concentration)
10 min before inhaling 500 mg placebo, 2.9%, or 6.7%
vaporized THC (within-individuals), then took simu-
lated drives 0.5–1.3 h postdose. Blood THC concentra-
tions were determined before and up to 8.3 h postdose
(limit of quantification 1 ␮g/L).
RESULTS: In 18 participants, observed Cmax (at 0.17 h)
for active (2.9 or 6.7% THC) cannabis were [median
(range)] 38.2 ␮g/L (11.4 –137) without alcohol and 47.9
␮g/L (13.0 –210) with alcohol. THC Cmax concentra-
tion decreased 73.5% (3.3%– 89.5%) without alcohol
and 75.1% (11.5%– 85.4%) with alcohol in the first
half-hour after active cannabis and 90.3% (76.1%–
100%) and 91.3% (53.8%–97.0%), respectively, by
1.4 h postdose. When residual THC (from previous self-
administration) was present, concentrations rapidly de-
creased to preinhalation baselines and fluctuated around
them. During-drive THC concentrations previously as-
sociated with impairment (ⱖ8.2 ␮g/L) decreased to me-
dian ⬍5 ␮g/L by 3.3 h postdose and ⬍2 ␮g/L by 4.8 h
postdose; only 1 participant had THC ⱖ5 ␮g/L after
3.3 h.
1
Chemistry and Drug Metabolism, Intramural Research Program, National Institute on
Drug Abuse, NIH, Baltimore, MD; 2 National Advanced Driving Simulator, University of
Iowa, Iowa City, IA; 3 College of Pharmacy, University of Iowa, Iowa City, IA; 4 Department
of Psychiatry, University of Maryland School of Medicine, Baltimore, MD; 5 Carver Col-
lege of Medicine, University of Iowa, Iowa City, IA.
* Address correspondence to this author at: Biomedical Research Center, Suite 200, Room
05A-721, 251 Bayview Blvd, Baltimore, MD 21224. Fax 443-740-2823; e-mail
mhuestis@intra.nida.nih.gov.
Drug Monitoring and Toxicology
CONCLUSIONS: Forensic blood THC concentrations may
be lower than common per se cutoffs despite greatly ex-
ceeding them while driving. Concentrations during driv-
ing cannot be back-extrapolated because of unknown
time after intake and interindividual variability in rates of
decrease.
© 2015 American Association for Clinical Chemistry
Driving under the influence of drugs is an important
public safety issue. According to the recent 2013–2014
National Roadside Survey (1 ), prevalence of weekend
nighttime drivers positive for illicit drugs in blood or oral
fluid increased to 15.1%, from 12.4% in 2007. Cannabis
is the most common illicit drug detected in drivers (1–2 ),
with driving under the influence of cannabis (DUIC)6
associated with approximately doubled crash risk (3– 4 ).
In DUIC cases, blood typically is not collected
until approximately 1.5– 4 h after the incident (5– 6 ),
with an unknown time after last drug use, complicating
interpretation. This is particularly important for ⌬9-
tetrahydrocannabinol (THC), the primary psychoactive
constituent of cannabis, because of its pharmacokinetic
profile. Blood THC concentrations peak before the end
of smoking (7 ) and decrease rapidly because of distribu-
tion into highly perfused tissues including the brain (8 ),
allowing smokers to experience effects almost immedi-
ately (9 ). By controlling inhalation techniques, people
who smoke or vaporize cannabis self-titrate individual
doses to achieve comfortable/desired subjective and car-
diovascular effects (10 ). Later, blood THC concentra-
tions decrease more slowly during distribution into adi-
pose tissue, where it accumulates with frequent cannabis
intake (8, 10 –11 ) and is slowly released back into circu-
lation and excreted. Chronic frequent smokers accrue a
Received August 27, 2015; accepted November 30, 2015.
Previously published online at DOI: 10.1373/clinchem.2015.248492
© 2015 American Association for Clinical Chemistry
6
Nonstandard abbreviations: DUIC, driving under the influence of cannabis; THC,
Δ9-tetrahydrocannabinol; BrAC, breath alcohol concentration; CUDIT, Cannabis Use Dis-
orders Identification Test; AUDIT, Alcohol Use Disorders Identification Test; LOQ, limit of
quantification.
367
high body burden of THC that is released and excreted
over days or weeks of sustained abstinence, resulting in
low residual THC concentrations (12–13 ). In occasional
smokers, blood THC is detected only for a median
(range) 4 h (1– 6) after smoking a single 54-mg THC
cigarette (11 ).
Blood THC concentration is the most reliable ob-
jective cannabis exposure measure, with psychoactive
THC concentration best reflecting potential impairing
effects. There is considerable debate over establishing per
se laws based on blood THC concentrations. Of 14 states
with currently established cannabis per se laws, 10 are
zero-tolerance; the others have 1-, 2-, or 5-␮g/L blood
THC cutoffs, including Washington (5 ␮g/L), where
recreational cannabis is legal (14 ). Colorado’s attempt to
establish a 5 ␮g/L per se law met considerable resistance
and debate (15–16 ), ultimately resulting in a compro-
mise 5-␮g/L blood THC “permissible inference [of im-
pairment]” (not per se) law (17 ). As medical and recre-
ational cannabis legalization expand (18 ), the debate
over appropriate per se cutoffs intensifies. Since imple-
menting medical marijuana in 2000, Colorado has ob-
served increased DUIC cases (17 ). Fatal motor vehicle
crashes with cannabis-positive drivers also increased in
medical marijuana states, whereas no significant change
was observed in 34 states without medical marijuana
(19 ).
We recently evaluated effects of cannabis, with and
without low-dose alcohol, on driving performance ac-
cording to blood THC concentration (20 ). The results
documented lateral control decrements at 8.2 and 13.1
␮g/L THC, comparable to 0.05 and 0.08 g/210 L breath
alcohol concentration (BrAC) respectively, common al-
cohol per se driving limits. However, these THC concen-
trations were present while driving, 0.5–1.3 h postinha-
lation (20 ). The purpose of the present analysis was to
evaluate how drivers’ THC concentrations decreased
postinhalation before and after impaired driving, cover-
ing the typical interval between a driving incident and
blood collection in the forensic setting. These are the first
percentage THC reduction data available of which we are
aware, in a population with documented driving impair-
ment and follow-up for ⱕ8.3 h.
Methods
PARTICIPANTS
Healthy volunteers provided written informed consent
for this study that was approved by the University of Iowa
Institutional Review Board. Inclusion criteria were ages
21–55 years; self-reported cannabis consumption ⱖ1 ⫻/3
months but ⱕ3 days/week over the past 3 months [Can-
nabis Use Disorders Identification Test (CUDIT) (21 )];
self-reported light or moderate alcohol consumption ac-
cording to a quantity-frequency-variability scale (22 ), or
368 Clinical Chemistry 62:2 (2016)
if heavy consumption, a modal quantity not more than
3– 4 servings in the majority of drinking occasions; li-
censed driver for ⱖ2 years with currently valid unre-
stricted license; and self-reported driving ⱖ1300 miles in
the past year. Exclusion criteria included past or current
clinically significant medical illness; history of clinically
significant adverse event associated with cannabis/alco-
hol intoxication or motion sickness; ⱖ450 mL blood
donation in 2 weeks preceding drug administration;
pregnant/nursing; interest in drug abuse treatment
within past 60 days; current cannabis or alcohol use dis-
order by CUDIT or Alcohol Use Disorders Identifica-
tion Test (AUDIT) (CUDIT score ⬎12; AUDIT score
⬎12 for women/⬎14 for men); currently taking drugs
contraindicated with cannabis or alcohol or known to
impact driving; requirements for nonstandard driving
equipment; and prior participation in a similar driving
simulator study.
PROCEDURES
After spending a night on the clinical research unit to
preclude intoxication before dosing, participants re-
ceived placebo or low-dose alcohol (90% wt/vol grain
alcohol in fruit juice, target approximately 0.065 g/210 L
peak BrAC) over 10 min followed by vaporized placebo,
2.9%, or 6.7% THC cannabis over 10 min ad libitum as
previously described (10, 20 ). Bulk cannabis was ob-
tained through the NIDA Chemistry and Physiological
Systems Research Branch (Research Triangle Institute).
In this within-individual design, participants received all
6 alcohol/cannabis combinations in randomized order,
with sessions separated by ⱖ1 weeks. At each session,
participants drove for approximately 45 min between 0.5
and 1.3 h after start of cannabis inhalation in the Na-
tional Advanced Driving Simulator (23–24 ), located at
the University of Iowa (20 ). In this article, postdrive
refers to time after the simulated drive.
Blood was collected via indwelling peripheral ve-
nous catheter into gray-top (potassium oxalate/sodium
fluoride) Vacutainer® tubes (Becton, Dickinson and
Co.), stored on ice ⱕ2 h, and transferred to 3.6 mL
Nunc® cryotubes (Thomas Scientific) for ⫺20 °C stor-
age and analysis within 3 months (25 ). Collection times
were baseline (⫺0.8 h), immediately postdose (0.17 h),
immediately before driving (0.42 h), immediately post-
drive (1.4 h), and 2.3, 3.3, 4.8, 6.3, and 8.3 h after start
of cannabis inhalation. BrAC was measured in g/210 L
breath (equivalent to approximate blood alcohol concen-
tration in grams per deciliter) via Alco-Sensor® IV (In-
toximeters), limit of quantification (LOQ) 0.006 g/210 L.
BrAC measurement times were concurrent with blood
collection through 3.3 h, then at 4.3, 5.3, 6.3, 7.3, and
8.3 h. (Fewer blood samples were collected due to re-
quired limitation on total blood collection to ⱕ450 mL
for the entire study.)
Implications of Collection Time on Blood THC
SAMPLE AND DATA ANALYSIS
Blood THC was quantified according to a previously
published method (26 ) by protein precipitation with ice-
cold acetonitrile and solid-phase extraction followed by
LC-MS/MS analysis. The THC linear range was 1–100
␮g/L, with analytical bias and imprecision (n ⫽ 30)
ⱕ3.7% and ⱕ8.7%, respectively. For analytical pur-
poses, THC concentrations ⬍1 ␮g/L (LOQ) were con-
sidered 0 ␮g/L.
Driving performance (SD of lateral position, lane
weave) was previously evaluated according to blood
THC concentrations during driving, modeled by indi-
vidualized fitted power curves for participants’ blood
THC concentrations during driving, from predrive (0.17
and 0.42 h) and postdrive (1.4 and 2.3 h) concentrations
(20 ). BrAC concentrations during driving were calcu-
lated by linear curves from measurements at the same
time points. Drives were subdivided into 4 segments (ur-
ban, interstate, rural, rural straightway), with approxi-
mate median postdose times 0.68, 0.87, 1.1, and 1.2 h,
respectively.
Blood THC concentration decreases between col-
lection times (and median during-drive concentration,
approximately 1 h) were quantified and evaluated for all
sessions with THC-positive blood (THC ⱖ1 ␮g/L
LOQ) during driving. Percent decreases were individu-
ally calculated within each session, and median (range)
calculated percent decreases are presented. For reference
when considering percentages, median (range) concen-
trations at starting time points also are presented in ta-
bles, since it must be considered that minor changes
would result in substantial percentages if initial concen-
trations were low (e.g., a 1-␮g/L decrease from 5 ␮g/L
would produce a 20% decrease). Sessions were catego-
rized according to whether participants received active or
placebo cannabis, and whether participants had residual
blood THC (from previous self-administration) at base-
line. Categories were not assigned by 2.9% vs 6.7% THC
administered cannabis doses, because more than half of
participants self-titrated their doses (controlling inhala-
tion to achieve desired effects) during ad libitum inhala-
tion (10 ). Blood THC percent decreases relative to pre-
vious time points were compared for differences with and
without alcohol by Wilcoxon matched-pairs tests, with
the conservative Bonferroni correction accounting for
multiple comparisons. For each nonalcohol session (n ⫽
41), median (approximately 1 h postdose) modeled
blood THC concentrations (on the basis of concentra-
tions before and after driving) were divided into quar-
tiles, each containing 10 –11 sessions. THC concentra-
tions in each quartile are provided above each graph. The
box plot for each time point before and after driving in
each quartile was calculated from the same participants’
THC concentrations. To facilitate comparison with
alcohol-positive sessions, the same concentration ranges
for each quartile were established. In addition, Supple-
mental Figs. 1 and 2, which accompany the online ver-
sion of this article at http://www.clinchem.org/content/
vol62/issue2, provide concentration–time curves on the
basis of observed THC concentrations immediately be-
fore and after the drive. Box plots at each time were
calculated in the same manner as during-driving box
plots.
Results
Nineteen healthy adults (13 men and 6 women, ages
21–37 years) completed the study. One individual was
excluded from driving performance evaluation because of
nonnormal driving behavior irrespective of dose (20 );
she also was excluded from this blood concentration anal-
ysis to ensure that reported decreases matched the driving
study population. Most participants self-reported canna-
bis intake within the prior week and alcohol intake
2–3 ⫻/week (Table 1). Despite reporting overall mean
consumption at ⱖ1 ⫻/3 months during screening (ful-
filling study inclusion criteria), participant 13 later self-
reported last intake 4 months prior (due to scheduling
delay for first dosing session).
Observed THC maximum concentration (Cmax) oc-
curred 0.17 h after start of inhalation. Median (range)
Cmax values without and with alcohol were 38.2 ␮g/L
(11.4 –137) and 47.9 ␮g/L (13.0 –210), respectively, for
active cannabis. When present (ⱖ1 ␮g/L LOQ), residual
THC concentrations ranged from 1.2 to 6.3 ␮g/L at
baseline. For placebo cannabis sessions where residual
THC was observed, 0.17 h concentrations were 3.3 ␮g/L
(1.6 – 6.0) (n ⫽ 6) and 2.4 ␮g/L (1.6 –3.7) (n ⫽ 4) with-
out and with alcohol. One placebo cannabis session (with
alcohol, participant 15) was reclassified as active cannabis
because although THC baseline was 0 ␮g/L, Cmax was
18.5 and 25.6 ␮g/L in blood and plasma, respectively.
This was likely due to his accessing active cannabis during
this session, despite being under observation throughout
his stay (10 ). A dosing error is unlikely, on the basis of
careful record review.
Blood THC concentrations and BrAC modeled
during driving adequately reflected measured concentra-
tion curves (Fig. 1). Concentrations measured after driv-
ing (1.5– 4 h postdose) in the same sessions (dotted shad-
ing) were lower than results during driving (gray
shading), except in placebo sessions with residual THC.
Percent decreases are presented in Tables 2 through 5 and
online Supplemental Tables 1–2. No significant differ-
ences with vs without alcohol were observed. In the first
0.42 h after start of active (2.9 or 6.7% THC) cannabis
inhalation, THC decreased 73.5% (3.3%– 89.5%) with-
out alcohol (Table 2) and 75.1% (11.5%– 85.4%) with
alcohol (Table 3). By 1.4 h postdose, 90.3% (76.1%–
100%) and 91.3% (53.8%–97.0%) decreases from active
Clinical Chemistry 62:2 (2016) 369
370
Table 1. Self-reported demographic characteristics and recent cannabis and alcohol consumption for 19 healthy adult occasional cannabis smokers.

Time stoned Time since Amount last

Cannabis on typical last cannabis consumed, Alcohol Typical
Age, BMI, intake cannabis consumed, joint or joint intake Alcohol drinks per
Participant Sex years Race/ethnicity kg/m2 frequency occasion, ha daysb equivalentc frequencyd classificatione occasiond

1 M 23.7 White 24.3 2–4 ×/month 1–2 1 1 2–3 ×/week Moderate 2–4
2 F 28.4 African American 23.8 2–4 ×/month 3–4 14 1 ≥4 ×/week Heavy 2–4
3 M 21.9 White 24.7 2–4 ×/month 1–2 6 1 2–3 ×/week Heavyf 5–6
4 M 37.8 White 26.1 2–3 ×/week 1–2 3 2.5 2–3 ×/week Moderate 2–4
5 M 26.6 White 21.6 ≤1 ×/month 1–2 11 3.5 ≤1 ×/month Light 2–4

Clinical Chemistry 62:2 (2016)

6 F 26.3 White 20.0 2–3 ×/week 3–4 1 0.25 2–3 ×/week Heavy 2–4
7 M 25.8 White 40.6 2–3 ×/week 1–2 0.3 0.5 2–4 ×/month Light 2–4
8 M 26.1 Hispanic 31.5 2–3 ×/week 1–2 3 1 2–4 ×/month Moderate 1–2
9 M 23.2 White 19.5 2–3 ×/week 3–4 2 1 2–3 ×/week Heavy 2–4
10 M 23.1 White 23.9 ≤1 ×/month 1–2 2 0.25 2–4 ×/month Light 2–4
11 M 32.3 Other, Hispanic 28.9 2–3 ×/week 1–2 4 1 2–3 ×/week Heavy 2–4
12g F 23.4 White 23.3 2–4 ×/month 3–4 4 1 2–3 ×/week Light 2–4
13 F 30.3 African American 24.1 ≤1 ×/month <1 120h 1 2–3 ×/week Heavy 2–4
14 M 24.6 White 23.3 2–4 ×/month 1–2 7 0.8 2–3 ×/week Heavy 2–4
15i M 21.8 White 32.7 2–4 ×/month 1–2 7 0.13 ≤1 ×/month Light 1–2
16 F 21.7 African American, White 23.0 2–3 ×/week 1–2 1.1 1.5 2–4 ×/month Light 1–2
17 M 28.7 White 18.3 ≤1 ×/month 3–4 45 0.5 2–3 ×/week Heavy 2–4
18 M 28.1 White 48.3 2–4 ×/month 3–4 5 1 2–4 ×/month Light 2–4
19 F 22.9 White 21.6 2–3 ×/week 3–4 1 1 2–4 ×/month Light 5–6
Median 25.8 23.9 4.0 1.0
Median excluding no. 12 25.9 24.0 3.5 1.0
a
“Hours stoned” wording originates from CUDIT, source of self-reported cannabis frequency data.
b
Self-reported at first dosing session.
c
Cannabis amount last consumed is based on empirically normalized joint consumption, to account for various administration routes and self-reported sharing between multiple individuals.
d
Metric taken from the AUDIT, to exclude drinkers with alcohol use disorder.
e
Classification according to quantity-frequency-variability (QFV) scale used for inclusion criteria during screening.
f
Participant met inclusion criteria. Modal quantity and frequency on QFV were 3– 4 and 1–2 ×/week, respectively.
g
Participant excluded for consistency with driving analyses (not included in driving evaluation because of consistently abnormal driving behavior).
h
Self-reported overall mean consumption at ≥1 ×/3 months at screening; during the study, reported last intake 4 months ago at first dose.
i
Participant’s placebo cannabis with alcohol session reclassified to active because of evidence of possible clandestine access to active cannabis before dosing.
Implications of Collection Time on Blood THC
Fig. 1. Median (interquartile range) blood THC (≥1 μg/L) (A)
and BrAC (≥0.006 g/210 L) (B) time curves.
Gray shading indicates driving time; concentrations within this
region were individually modeled. Dotted pattern represents
likely blood collection time 1.5– 4 h postdose (for drug analysis)
after traffic stop/crash.
THC Cmax were observed. Active cannabis blood THC
concentrations decreased by approximately half [44.6%
(4.1%–100%) without alcohol, 51.0% (18.6%–100%)
with alcohol] between the 1.4-h collection, which oc-
curred immediately after driving, and approximately 1 h
postdrive (2.3 h postdose).
Residual blood THC concentrations after placebo
cannabis fluctuated near the predose THC baseline
throughout 8.3 h. Concentration–time profiles and con-
centration decrease patterns were similar between active
cannabis sessions where participants had residual THC
before dosing and those without residual THC (Tables 4
and 5). However, concentrations in participants who
started with residual THC decreased to near baseline
concentrations with fluctuations around these concentra-
tions, whereas concentrations in those without residual
THC approached 0 ␮g/L, with median 100% decreases
from observed Cmax occurring 4.8 h postdose.
Quartiles were established by median during-drive
concentrations (Fig. 2) for direct comparison to driving
data; pre- and postdrive concentration quartiles (see on-
line Supplemental Figs. 1 and 2) were also evaluated be-
cause they represent actual measured THC concentra-
tions immediately before and after the drive. These
figures illustrate THC concentration decreases from spe-
cific, known ranges during or around driving, at later
time points within the same sessions. Fig. 2 presents con-
centration ranges throughout the time course based on
median during-drive concentration quartiles, to illustrate
how concentrations associated with driving effects (20 )
subsequently decreased before blood collection in foren-
sic cases. The highest quartile in Fig. 2 (with and without
alcohol) represents median during-drive THC concen-
trations (ⱖ8.2 ␮g/L) associated with lane weave similar
to 0.05 g/210 L BrAC (20 ). Concentrations decreased to
⬍5 ␮g/L by 3.3 h postdose (2 h postdrive) in all but
participant 7. By 4.8 h postdose (3.5 h postdrive), me-
dian concentrations decreased to ⬍2 ␮g/L even among
those in the ⱖ8.2 ␮g/L during-drive concentration
quartile.
Even for the highest predrive (see online Supple-
mental Fig. 1), during-drive (Fig. 2), and postdrive (see
online Supplemental Fig. 2) concentration quartiles, me-
dian blood THC concentrations did not exceed 5 ␮g/L
by 3.3 h postdose or 2 ␮g/L by 4.8 h. The only THC
concentrations ⱖ5 ␮g/L at or after 3.3 h postdose in any
dosing condition arose from participant 7, whose base-
line concentrations were 4.9 – 6.3 ␮g/L over 6 sessions
and who never had a blood THC concentration quanti-
fied ⬍3.6 ␮g/L throughout the entire study (more-
frequent smoker).
Discussion
Rapidly decreasing blood THC concentrations after in-
halation do not imply rapidly decreasing impairment.
THC effects are directly related to brain concentrations;
peak effects do not coincide with maximum blood con-
centrations (27 ). THC’s equilibration time between
blood and brain produces a delay between blood Cmax
and maximal effects (28 ). Acute psychomotor impair-
ment was documented for ⱕ6 h in recreational [mean
3.4 (SD 3.0) ⫻/month] smokers after smoking 250 and
500 ␮g/kg (approximately 17.5 and 35 mg) THC ciga-
rettes (29 ). Despite marked differences in THC’s phar-
macodynamic vs blood pharmacokinetic profiles, it is not
possible to assess brain concentrations in living drivers,
and blood remains the most representative available
sample.
We previously documented impaired driving perfor-
mance by these participants at specific blood THC con-
centrations during driving (20 ). However, concentra-
tions present after driving in the same sessions—when
Clinical Chemistry 62:2 (2016) 371
372
Table 2. Blood THC concentrations and percent blood THC decreases from specific time points in 18 participants’ THC-positive sessions (≥1 μg/L during driving) without alcohol,
arranged into categories based on active (2.9% or 6.7% THC) or placebo administered cannabis dose.a

Percent decreaseb (from initial concentration) at subsequent postdose times (%)

Initial
postdose Session Initial blood Sessions,
time, h type THC, μg/L 0.42 h 1 hc 1.4 h 2.3 h 3.3 h 4.8 h 6.3 h 8.3 h n
0.17 Active 38.2 (11.4–137) 73.5 (3.3–89.5) 85.3 (67.5–100) 90.3 (76.1–100) 94.6 (81.6–100) 96.9 (84.2–100) 99.6 (87.2–100) 100 (84.2–100) 100 (84.9–100) 36
0.17 Placebo 3.3 (1.6–6.0) 46.6 (–0.7–62.3) 47.1 (–2.6–60.9) 51.4 (–1.8–69.5) 61.2 (–6.0–100) 87.2 (7.4–100) 59.5 (–16.9–65.0) 61.8 (–27.5–100) 83.7 (11.1–100) 6
0.42 Active 11.9 (1.6–40.8) — 44.6 (24.4–100) 64.9 (40.2–100) 80.7 (52.3–100) 88.0 (59.0–100) 98.1 (66.9–100) 100 (59.1–100) 100 (60.8–100) 36
0.42 Placebo 1.5 (1.2–6.0) — –1.9 (–8.4–3.2) 9.1 (–7.0–21.7) 17.2 (–5.3–100) 66.0 (8.0–100) 6.3 (–16.1–28.5) 23.2 (–26.6–100) 57.9 (11.6–100) 6
1c Active 6.0 (1.4–19.8) — — 31.4 (3.3–100) 61.9 (36.9–100) 76.9 (45.8–100) 90.8 (53.5–100) 100 (45.9–100) 100 (48.1–100) 35d
1c Placebo 1.5 (1.2–6.1) — — 8.3 (–1.3–25.4) 17.5 (–3.3–100) 68.6 (9.7–100) 12.3 (–13.9–29.8) 22.6 (–24.2–100) 60.1 (13.3–100) 6

Clinical Chemistry 62:2 (2016)

1.4 Active 4.1 (0–14.7) — — — 44.6 (4.1–100) 64.6 (31.4–100) 85.9 (31.8–100) 100 (31.5–100) 100 (34.4–100) 34d
1.4 Placebo 1.4 (1.0–6.1) — — — –0.6 (–17.4–100) 58.4 (9.0–100) –1.6 (–28.7–22.6) 15.1 (–25.2–100) 56.3 (–6.9–100) 6

a
Data are median (range). For space, table is truncated at decrease from 1.4 h (time point immediately after driving). See online Supplemental Table 1 for full version illustrating decreases between all time points in the time course.
b
Parameter presented is percent decrease; thus, a negative sign in this table indicates a blood THC concentration increase relative to reference time point’s concentration.
c
Median calculated concentration during driving, and median time point during driving.
d
Percent decreases from 0 μg/L blood THC were considered undefined and not included.

Table 3. Blood THC concentrations and percent blood THC decreases from specific time points in 18 participants’ THC-positive sessions (≥1 μg/L during driving) with alcohol,
arranged into categories based on active (2.9% or 6.7% THC) or placebo administered cannabis dose.a

Percent decreaseb (from initial concentration) at subsequent postdose times (%)

Initial
postdose Session Initial blood Sessions,
time, h type THC, μg/L 0.42 h 1 hc 1.4 h 2.3 h 3.3 h 4.8 h 6.3 h 8.3 h n
0.17 Active 47.9 (13.0–210) 75.1 (11.5–85.4) 87.3 (45.0–95.9) 91.3 (53.8–97.0) 95.5 (62.4–100) 97.9 (65.8–100) 100 (67.2–100) 100 (61.3–100) 100 (58.9–100) 37d
0.17 Placebo 2.4 (1.6–3.7) 23.6 (–7.3–31.7) 28.1 (–9.7–33.5) 28.9 (2.2–31.9) 38.3 (–26.9–100) 26.1 (–1.1–100) 9.0 (–14.4–39.6) –2.1 (–39.8–32.3) –13.5 (–37.5–29.9) 4
0.42 Active 11.8 (3.1–43.9) — 47.6 (21.7–72.1) 64.5 (43.5–80.1) 83.6 (57.5–100) 89.9 (61.3–100) 100 (63.0–100) 100 (56.3–100) 100 (53.6–100) 37d
0.42 Placebo 1.8 (1.1–4.0) — –1.0 (–7.3–19.0) 6.2 (–1.8–11.5) 17.4 (–18.3–100) 6.6 (–1.8–100) –3.6 (–61.9–26.5) –23.3 (–54.0–0.9) –19.1 (–94.7 to −2.6) 4
1c Active 6.2 (1.8–26.7) — — 29.3 (–4.4–51.4) 65.8 (31.6–100) 78.8 (37.8–100) 100 (40.4–100) 100 (29.7–100) 100 (25.3–100) 37d
1c Placebo 1.6 (1.1–4.1) — — 4.1 (–9.4–10.8) 14.2 (–15.7–100) 6.5 (–14.2–100) –2.6 (–51.0–9.2) –35.5 (–43.5–0.7) –31.0 (–81.5 to −2.8) 4
1.4 Active 4.4 (1.3–18.4) — — — 51.0 (18.6–100) 72.0 (26.0–100) 100 (29.1–100) 100 (16.3–100) 100 (11.1–100) 37d
1.4 Placebo 1.7 (1.1–3.6) — — — 11.7 (–29.7–100) –3.9 (–5.5–100) –7.7 (–67.9–17.0) –37.1 (–59.6–2.6) –32.4 (–102 to −0.9) 4

a
Data are median (range). For space, table is truncated at decrease from 1.4 h (time point immediately after driving). See online Supplemental Table 1 for full version illustrating decreases between all time points in the time course.
b
Parameter presented is percent decrease; thus, a negative sign in this table indicates a blood THC concentration increase relative to reference time point’s concentration.
c
Median calculated concentration during driving, and median time point during driving.
d
Participant 15’s placebo with alcohol session was reclassified to active cannabis due to a pharmacokinetic profile inconsistent with placebo dose.
 Table 4. Blood THC concentrations and percent blood THC decreases from specific time points in 18 participants’ active cannabis sessions without alcohol, arranged into categories
based on presence or absence of residual THC before dosing.a

Percent decreaseb (from initial concentration) at subsequent postdose times (%)

Initial Residual THC
postdose presence/ Initial blood Sessions,
time, h absence THC, μg/L 0.42 h 1 hc 1.4 h 2.3 h 3.3 h 4.8 h 6.3 h 8.3 h n
0.17 Residual THC 37.8 (11.4–137) 74.9 (3.3–89.5) 86.2 (67.5–100) 90.6 (76.1–100) 94.8 (82.8–100) 97.1 (90.9–100) 100 (94.1–100) 100 (94.6–100) 100 (95.0–100) 31
0.17 No residual THC 46.5 (24.3–105) 63.6 (59.1–75.9) 76.6 (70.9–85.1) 83.0 (77.0–89.1) 88.6 (81.6–93.9) 90.4 (84.2–96.9) 92.9 (87.2–97.2) 92.3 (84.2–97.7) 92.7 (84.9–97.5) 5
0.42 Residual THC 10.5 (1.6–40.8) — 48.5 (34.3–100) 66.1 (51.6–100) 81.9 (62.3–100) 88.9 (75.5–100) 100 (82.8–100) 100 (84.2–100) 100 (85.4–100) 31
0.42 No residual THC 17.9 (10.0–30.8) — 35.6 (24.4–44.1) 52.9 (40.2–68.2) 68.7 (52.3–76.1) 73.5 (59.0–87.0) 80.5 (66.9–88.2) 78.7 (59.1–90.3) 79.8 (60.8–89.7) 5
1c Residual THC 5.8 (1.4–16.7) — — 32.3 (3.3–100) 63.8 (42.1–100) 78.9 (62.4–100) 100 (73.5–100) 100 (70.8–100) 100 (75.1–100) 30d
1c No residual THC 13.5 (5.6–19.8) — — 27.0 (21.0–43.2) 51.5 (36.9–59.3) 58.8 (45.8–78.9) 69.7 (53.5–80.9) 69.2 (45.9–84.3) 70.7 (48.1–83.4) 5
1.4 Residual THC 4.0 (0–10.9) — — — 45.3 (4.1–100) 65.9 (31.9–100) 100 (56.1–100) 100 (58.1–100) 100 (51.6–100) 29d
1.4 No residual THC 10.7 (3.2–14.7) — — — 24.7 (20.2–44.2) 40.2 (31.4–71.1) 52.8 (31.8–73.8) 47.5 (31.5–78.5) 55.7 (34.4–77.2) 5

a
Data are median (range). For space, table is truncated at decrease from 1.4 h (time point immediately after driving). See online Supplemental Table 2 for full version illustrating decreases between all time points in the time course.
b
Parameter presented is percent decrease; thus, a negative sign in this table indicates a blood THC concentration increase relative to reference time point’s concentration.
Implications of Collection Time on Blood THC

c
Median calculated concentration during driving, and median time point during driving.
d
Percent decreases from 0 μg/L blood THC were considered undefined and not included.

Table 5. Percent blood THC decreases from specific time points in 18 participants’ active cannabis sessions with alcohol, arranged into categories based on presence or absence of
residual THC before dosing.a

Percent decreaseb (from initial concentration) at subsequent postdose times (%)

Initial Residual THC
postdose presence/ Initial blood Sessions,
time, h absence THC, μg/L 0.42 h 1 hc 1.4 h 2.3 h 3.3 h 4.8 h 6.3 h 8.3 h n
0.17 Residual THC 49.8 (13.4–145) 74.8 (36.9–85.4) 88.2 (75.2–95.9) 92.0 (78.0–97.0) 96.1 (89.0–100) 98.1 (90.9–100) 100 (91.6–100) 100 (91.6–100) 100 (91.0–100) 30d
0.17 No residual THC 37.0 (13.0–210) 75.1 (11.5–79.1) 85.7 (45.0–87.3) 90.1 (53.8–91.2) 94.0 (62.4–95.5) 95.3 (65.8–96.7) 97.0 (67.2–100) 96.2 (61.3–97.3) 96.5 (58.9–100) 7
0.42 Residual THC 12.0 (3.1–40.9) — 49.9 (27.1–72.1) 65.1 (43.5–80.1) 83.8 (73.0–100) 90.6 (77.6–100) 100 (79.4–100) 100 (79.3–100) 100 (78.0–100) 30d
0.42 No residual THC 11.5 (7.7–43.9) — 39.1 (21.7–51.9) 58.1 (46.5–64.0) 73.9 (57.5–83.6) 81.1 (61.3–88.2) 86.7 (63.0–100) 84.1 (56.3–88.8) 83.3 (53.6–100) 7
1c Residual THC 5.9 (1.8–22.7) — — 28.9 (–4.4–51.4) 67.9 (50.5–100) 83.1 (59.7–100) 100 (63.0–100) 100 (62.7–100) 100 (60.3–100) 30d
1c No residual THC 7.2 (4.2–26.7) — — 31.1 (16.0–34.9) 60.3 (31.6–65.8) 67.1 (37.8–75.4) 77.4 (40.4–100) 73.2 (29.7–81.5) 72.5 (25.3–100) 7
1.4 Residual THC 4.1 (1.3–16.8) — — — 53.4 (20.1–100) 74.6 (33.7–100) 100 (39.1–100) 100 (38.6–100) 100 (34.8–100) 30d
1.4 No residual THC 6.0 (3.2–18.4) — — — 41.8 (18.6–54.4) 54.4 (26.0–67.2) 69.0 (29.1–100) 61.6 (16.3–71.6) 60.1 (11.1–100) 7

a
Data are median (range). For space, table is truncated at decrease from 1.4 h (time point immediately after driving). See online Supplemental Table 2 for full version illustrating decreases between all time points in the time course.
b
Parameter presented is percent decrease; thus, a negative sign in this table indicates a blood THC concentration increase relative to reference time point’s concentration.
c
Median calculated concentration during driving, and median time point during driving.
d
Participant 15’s placebo with alcohol session was reclassified to active cannabis due to a pharmacokinetic profile inconsistent with placebo dose.

Clinical Chemistry 62:2 (2016) 373

 Fig. 2. Median (range) positive blood THC concentrations over time (18 participants; after 0.5 g placebo, 2.9%, and 6.7% THC
vaporized bulk cannabis with and without concurrent alcohol).
Left, Nonalcohol sessions quartiles by median modeled during-drive (⬃1 h postinhalation) THC concentrations irrespective of participant or
dose. Right, Same concentration ranges (matched bins) for alcohol-positive sessions. n, sessions/bin; dotted lines, 2 and 5 μg/L THC.

374 Clinical Chemistry 62:2 (2016)

Implications of Collection Time on Blood THC
blood would be collected after the incident—were con-
siderably lower. Unlike alcohol, which displays compar-
atively slow and consistent zero-order elimination kinet-
ics (30 ) and can be assessed in real time by breath-testing
instruments (31 ), blood THC concentrations decrease
rapidly after inhalation, with measured concentrations in
delayed collections not reflecting concentrations present
during driving. This is a crucial consideration in drugged
driving interpretation and policy development because,
in most cases, blood THC concentrations are substan-
tially lower than those present at the time of the incident.
Substantial inter- and intraindividual variability in can-
nabis intake, metabolism, and cannabis use history and
lack of zero-order pharmacokinetics preclude back-
extrapolation used with alcohol concentrations (30 ). For
example, we found overlapping THC concentration
ranges later in the time course between quartiles of par-
ticipants who had nonoverlapping concentration ranges
earlier after smoking. Without reliable information
about time of last intake, cannabis history, administra-
tion route, and individual metabolism, it is impossible to
determine precisely how much or how rapidly concentra-
tions decreased before collection.
We detected SD of lateral position impairment
comparable to 0.05 and 0.08 g/210 L BrAC at 8.2 and
13.1 ␮g/L during-drive blood THC, respectively (20 ),
but during-drive concentrations associated with driving
performance results already represented 45%–100% de-
creases from maximum observed concentrations after ac-
tive cannabis doses. If participants’ blood collection did
not occur until 1.4 – 4.8 h postdose, median THC con-
centration decreases would exceed 90% relative to Cmax.
Additionally, in most forensic cases, time since last intake
relative to crash or traffic stop is unknown, and the 1.5– 4
h collection delay (5– 6 ) is measured from the time the
incident occurred (rather than last intake). For this rea-
son, we evaluated percent decreases from concentrations
at other time points as well as 0.17 h (immediately post-
dose) concentrations. If time postinhalation were known,
concentration decreases would be most comparable to
percent decreases from 0.17 h; otherwise, concentration
decrease percentages might more closely resemble those
presented for subsequent time points.
Prior frequent cannabis intake history produces the
additional complication of residual THC, as we demon-
strated. Because subsets of participants with and without
residual THC for different sessions were not completely
matched, differences in THC concentration decreases
with vs without residual THC could not be directly com-
pared. In forensic cases, it is not possible to know whether
there was residual THC or not before acute self-
administration; baseline concentrations are a crucial con-
sideration in chronic frequent smokers. The use of more
conservative decrease estimates (Tables 4 and 5) deter-
mined from the sessions with residual THC would afford
suspects the benefit of the doubt. Concentrations re-
turned to individual baselines within approximately 4.8 –
6.3 h. Residual blood THC concentrations’ fluctuation
in this study’s participants after placebo cannabis was
consistent with gradual extended THC release after
chronic frequent smoking (11–13 ). Because of the large
THC body burden, residual THC may be detected in
chronic frequent smokers’ blood up to a month after start
of sustained abstinence (LOQ 0.25 ␮g/L) (13 ), raising
concerns about the impact of per se on individuals not
acutely intoxicated. Karschner et al. (12 ) reported blood
THC concentrations ⱖ1 ␮g/L after a day’s abstinence in
4 of 25 chronic frequent smokers, with 1 individual’s
blood THC as high as 7.0 ␮g/L on day 1 and fluctuating
between 2.2 and 3.7 ␮g/L over the following 6 days’
sustained abstinence. In another study, 1 frequent
smoker had blood THC ⱖ5 ␮g/L reported as long as
129 h postsmoking (32 ). Although evidence suggests
partial tolerance to some acute cannabis psychomotor
impairment effects with chronic frequent intake, not all
effects show tolerance (33–34 ).
THC blood concentration decreases and related is-
sues complicate debates over appropriate per se cutoffs
for DUIC (14 ). Many jurisdictions adopted zero-
tolerance laws to counteract blood THC pharmacokinet-
ics’ challenges, but increasing medical and recreational
cannabis legalization intensifies the debate over zero-
tolerance and per se laws for frequent smokers. In our
study, blood THC concentrations were ⬍1 ␮g/L by
4.8 h (1.4 h to ⬎8.3 h) postdose, ⬍2 ␮g/L by 3.3 h
(0.42 h to ⬎8.3 h) postdose, and ⬍5 ␮g/L by 1.4 h
(0.42 h to ⬎8.3 h) postdose (10 ). In cannabis-only fatal
crash cases, blood THC detected at any concentration in
drivers was significantly associated with 2.7⫻ greater cul-
pability odds, which increased to 6.6⫻ for cases with
blood THC ⱖ5 ␮g/L (35 ). Serum THC concentrations
previously showed poor correlation with magnitude of
neurocognitive performance impairment; however, 2–5
␮g/L serum THC was associated with significantly
greater proportions of “impairment” than “no impair-
ment” observations in a critical tracking task (36 ). Sig-
nificantly greater impairment proportions in critical
tracking, stop reaction time, and Tower of London (cog-
nitive performance) tasks were observed with 5–10 ␮g/L
serum THC. After evaluating epidemiological and exper-
imental evidence, an international group of experts (37 )
suggested appropriate serum per se limits in the 7–10
␮g/L range. Blood/plasma THC ratios vary, but medians
are approximately 0.7 (10 –11, 38 ); thus, these serum
concentration ranges were comparable to common blood
per se thresholds. In our data, participants with driving
blood THC concentrations associated with impaired lat-
eral control (ⱖ8.2 ␮g/L) (20 ) had median concentra-
tions of 2–5 ␮g/L 3.3 h postdose (2 h postdrive); but
median concentrations did not exceed 5 ␮g/L after the
Clinical Chemistry 62:2 (2016) 375
2.3 h postdose collection (without alcohol) or the 1.4 h
postdose collection (with alcohol). Thus, for these par-
ticipants’ driving, applying 5 or 2 ␮g/L per se limits
would identify most impaired drivers only if blood were
collected in the first approximately 2–3 h postdose (ap-
proximately 1–2 h after simulated drive ended).
Apart from more stringent per se laws, other possible
strategies to combat blood THC decreases in DUIC in-
clude implementation of alternative matrices testing.
Dried blood spots or breath collection represent promis-
ing alternatives, due to noninvasiveness and roadside col-
lections; however, cannabinoid concentrations are low in
these matrices, and much additional research is required
before either is feasible. Breath detection windows are
currently limited to approximately 2 h postsmoking
(39 ), whereas impairing effects may extend beyond this
period. Oral fluid is a promising noninvasive matrix,
with roadside screening applicability and detection win-
dows comparable to acute impairment windows if recent
use markers are included (40 ).
Conclusion
In DUIC, it is crucial to consider sample collection time
relative to when the incident occurred. Blood THC con-
centrations measured in forensic cases may be lower than
common per se cutoffs despite greatly exceeding them
during driving. Although the interval between traffic stop
and blood collection—and THC concentration at the
time of collection—are known, the time of cannabis in-
take in relation to driving is unknown. There also is in-
dividual variability around the THC concentration dur-
ing driving, and the rate of decrease varies on the basis of
an individual’s intake frequency, metabolism, and elim-
ination rate. In our data, THC concentration ranges
hours after driving were similar across multiple quartiles
despite there being no overlap in THC concentrations
across quartiles during driving. These data provide THC
concentration decreases over time for documenting de-
creases with delayed blood collection. Improvement in
interpretation of blood THC concentrations requires
blood collection as soon as possible after the incident or
traffic stop due to rapid concentration decreases over
time. Blood should be collected at the start of any impair-
ment evaluation or collected roadside by trained police
officers.
As legalized medical and recreational cannabis access
expand, residual THC and potential partial tolerance
with chronic frequent intake will be relevant to more
individuals, further complicating per se debates. An al-
ternative is requiring documentation of impairment, or a
combination of statues that includes penalties on the ba-
sis of per se or impairment. Decisions regarding DUIC
legislation are driven by objective scientific data and so-
cietal priorities. Legislative policy is established by soci-
eties’ balance of individual rights vs public safety, a bal-
ance that varies over time.
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 require-
ments: (a) significant contributions to the conception and design, acquisi-
tion of data, or analysis and interpretation of data; (b) drafting or revising
the article for intellectual content; and (c) final approval of the published
article.
Authors’ Disclosures or Potential Conflicts of Interest: Upon man-
uscript submission, all authors completed the author disclosure form. Dis-
closures and/or potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: The Intramural Research Program, National Insti-
tute on Drug Abuse, NIH, and the US Office of National Drug Con-
trol Policy. T.L. Brown, National Institute on Drug Abuse, National
Highway Traffic Safety Administration.
Expert Testimony: None declared.
Patents: None declared.
Other Remuneration: T.L. Brown, International Association of
Chiefs of Police; A.L. Spurgin, International Association of Chiefs of
Police.
Role of Sponsor: The funding organizations played a direct role in the
design of study.
Acknowledgments: We thank University of Iowa Clinical Research
Unit and National Advanced Driving Simulator staff (especially Cheryl
Roe, Jennifer Henderson, Rose Schmitt, Kayla Smith); Dr. Russell
Pierce (VariableSolutions); and Drs. Dereece Smither and Richard
Compton, National Highway Traffic Safety Administration.

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