678 M.A. Huestis
and analytical factors (e.g., assay sensitivity, specificity, accuracy). Mean detection
times in urine following smoking vary considerably between subjects, even in
controlled smoking studies where cannabis dosing is standardized and smoking is
computer-paced. During the terminal elimination phase, consecutive urine spec-
imens may fluctuate between positive and negative as THCCOOH concentrations
approach the cutoff concentration. It may be important in drug treatment settings
or in clinical trials to differentiate between new drug use and residual excretion
of previously used cannabinoids. After smoking a 1.75% THC cigarette, three of
six subjects had additional positive urine samples interspersed between negative
urine samples (Huestis et al. 1995). This had the effect of producing much longer
detection times for the last positive specimen. Using the 15 ng/ml confirmation
cutoff for THCCOOH currently used for most urine drug testing, the mean GC/MS
THCCOOH detection times for the last positive urine sample following the smok-
ing of a single 1.75% or 3.55% THC cigarette were 33.7±9.2 h (range 8–68.5) and
88.6±23.2 h (range 57–122.3), respectively.
5.2.2
Normalization of Cannabinoid Urine Concentrations
to Urine Creatinine Concentrations
Normalization of the cannabinoid drug concentration to the urine creatinine con-
centration aids in the differentiation of new vs prior cannabis use and reduces the
variability of drug measurement due to urine dilution. Due to the long half-life of
drug in the body, especially in chronic cannabis users, toxicologists and practi-
tioners are frequently asked to determine if a positive urine test represents a new
episode of drug use or represents continued excretion of residual drug. Random
urine specimens contain varying amounts of creatinine depending on the degree
of concentration of the urine. Hawks first suggested creatinine normalization of
urine test results to account for variations in urine volume in the bladder (Hawks
1983). Whereas urine volume is highly variable due to changes in liquid, salt,
and protein intake, exercise, and age, creatinine excretion is much more stable.
Manno et al. recommended that an increase of 150% in the creatinine normalized
cannabinoid concentration above the previous specimen be considered indicative
of a new episode of drug exposure (Manno et al. 1984). If the increase is greater
than or equal to the threshold selected, then new use is predicted. This approach
has received wide attention for potential use in treatment and employee assistance
programs, but there has been limited evaluation of the usefulness of this ratio
under controlled dosing conditions. Huestis et al. conducted a controlled clinical
study of the excretion profile of creatinine and cannabinoid metabolites in a group
of six cannabis users who smoked two different doses of cannabis separated by
weekly intervals (Huestis and Cone 1998b). As seen in Fig. 6, normalization of uri-
nary THCCOOH concentration to the urinary creatinine concentration produces
a smoother excretion pattern and facilitates interpretation of consecutive urine
drug test results. A relative operating characteristic (ROC) curve was constructed
from sensitivity and specificity data for 26 different cutoffs ranging from 10% to