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Journal of Analytical Toxicology, Vol. 20, October 1996

Urinary Excretion Profiles of 11-Nor-9-Carboxy-Ag- Tetrahydrocannabinol in Humans after Single Smoked Doses of Marijuana Marilyn A. Huestis 1,*, John M. Mitchell 2, and Edward J. Cone 1 I Addiction Research Center, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224 and 2Navy Drug Screening Laboratory, H2033, Naval Air Station, Jacksonville, Florida 32212

Abstract Introduction

Interpretation of marijuana-positive urine tests requires an understanding of the excretion pattern of marijuana metabolites in humans. However, limited urinary excretion data from controlled clinical studies of marijuana use are available. In this study, six subjects smoked a single marijuana cigarette (placebo, 1.75% Ag-tetrahydrocannabinol [THC], or 3.55% THC) each week while residing on the clinical ward of the Addiction Research Center. Individual urine specimens were collected for 7 days after drug administration and analyzed for 11-nor-9- carboxy-A%tetrahydrocannabinol (THCCOOH) by gas chromatography-mass spectrometry (GC-MS) with a limit of detection of 0.5 ng/mL. Substantial intersubject variability in patterns of THCCOOH excretion was noted between subjects and between doses. Mean THCCOOH concentrations in the first urine collections were 47 • 22.3 ng/mL and 75.3 • 48.9 ng/mL after the 1.75 and 3.55% THC cigarettes, respectively. Mean peak urine THCCOOH concentrations averaged 89.8 • 31.9 ng/mL and 153.4 • 49.2 ng/mL after smoking of approximately 15.8 mg and 33.8 mg THC, respectively. The mean times of peak urine concentration were 7.7 • 0.8 h after the 1.75% THC and 13.9 • 3.5 h after the 3.55% THC dose. Mean GC-MS THCCOOH detection times for the last positive urine sample after the smoking of a single 1.75 or 3.55% THC cigarette were 33.7 • 9.2 h and 88.6 • 9.5 h, respectively, when a 15-ng/mL cutoff concentration was used. An average of 93.9 • 24.5 pg THCCOOH (range, 34.6-171.6 pg) was excreted by each subject during the 7-day period after smoking of a single 1.75% THC cigarette. The average amount of THCCOOH excreted in the same time period after the high dose was 197.4 • 33.6 pg (range, 107.5-305.0 pg). This represented an average of only 0.54 • 0.14% and 0.53 • 0.09% of the original amount of THC in the low- and high-dose cigarettes, respectively. These data provide a detailed compilation of THCCOOH concentrations in urine after administration of marijuana that may aid in the interpretation of urine cannabinoid results.

*Author to whom correspondence should be addressed.

Marijuana has been self-administered for its psychoactive effects for many centuries. Currently, it is the most highly used illicit substance in the United States. Consequently, more positive urine tests for cannabinoids are obtained than for any other drug class in civilian and military workplace drug-testing programs. Drug treatment and rehabilitation clinics, forensic investigations, and emergency toxicology departments gen- erate additional positive test results. In each of these venues, an understanding of excretion of marijuana metabolites in humans is needed so that urine test results can be interpreted. Unfor- tunately, little urinary excretion data from controlled clinical studies of marijuana use are available to guide interpretation.

Detailed excretion studies of cannabinoids in urine are limited because controlled clinical studies are difficult and expensive to perform. Clinical studies must be performed in a manner that limits access to additional drugs that can con- found study results (1). Historically, this has required con- finement of subjects to restrict drug access or use of radio- labeled drug to differentiate between the administered dose and unauthorized drug use (2,3). Detailed excretion studies also re- quire the analysis of large numbers of individual urine samples. Attempts to reduce the number of required analyses include combining specimens into 12- or 24-h pools or reducing the period of collection or both (4-7). In some studies, individual measurements were made but only mean excretion data were presented (8). The advantage of measurement of drug or metabolites or both in each urine specimen and in each individual is the additional information one obtains. Presenting each subject's complete excretion profile allows one to calcu- late useful parameters, such as minimum and maximum windows of detection, peak concentration, intersubject variability, and total amount of drug excreted.

The method of measurement of urinary cannabinoids also influences analytical findings. Marijuana research performed in the 1970s and 1980s frequently used less sensitive and less specific methods of analysis. The Syva EMIT TM d.a.u. | 20-ng/mL immunoassay, which exhibited cross-reactivity to a

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wide variety of marijuana metabolites, was used in many of the studies on urinary cannabinoid excretion (8,9). Other data were collected with proprietary and commercial radioim- munoassays and enzyme immunoassays of varying sensitivities and specificities. The sensitivities and specificities of these assays have changed over time, which limits comparison of current test results with previously obtained data (10). The development of gas chromatographic-mass spectrometric (GC-MS) methods has provided the capability for sensitive and specific measurement of 11-nor-9-carboxy-Ag-tetrahydro - cannabinol (THCCOOH).

This study characterizes the urinary excretion profiles of THCCOOH in six healthy male subjects after single, short- term, smoked doses of marijuana. The subjects were restricted to a closed clinical ward and monitored throughout the study to prevent unauthorized drug use. All urine specimens were collected for 7 days after marijuana smoking and analyzed for THCCOOH by GC-MS. Individual excretion profiles and mean excretion parameters were determined.

Experimental

Subjects Six healthy male subjects with a history of marijuana use

resided on the clinical ward of the Addiction Research Center, National Institute on Drug Abuse, National Institutes of Health while participating in a protocol designed to characterize the pharmacokinetics and pharmacodynamics of short-term marijuana smoking. The protocol was approved by the Francis Scott Key Medical Center Institutional Review Board and ad- hered to federal guidelines for the conduct of research on drugs of abuse in human subjects. All subjects provided written informed consent, were under continuous medical supervi- sion, and were financially compensated for their participation. Subject characteristics and history of drug use were previously published (10). In brief, the men ranged from 28 to 36 years of age, had an average weight of 77.6 kg, and had a mean percent body fat content of 14.7%. Subjects began marijuana smoking between 13 and 16 years of age and smoked between 0.4 and 7.9 marijuana cigarettes per week (mean, 2.3 cigarettes). Subjects resided on the ward for approximately 1 week before drug administration. Studies were not initiated until a minimum of five consecutive daily negative urine test results were achieved for drugs of abuse, including cannabi- holds as measured by the Syva EMIT 100-ng/mL immunoassay, and until subjects' baseline scores on performance tests stabi- lized. Admittance to the clinical ward was restricted to prevent access to unauthorized licit or illicit drugs. In addition, frequent random urine drug tests were performed to deter additional drug exposures.

Protocol Once a week for 3 consecutive weeks, subjects smoked a

single marijuana cigarette (placebo, 1.75% A9-tetrahydrocannabinol [THC], or 3.55% THC) according to a randomized Latin square design. The low- and high-dose cigarettes contained approximately 15.8 mg and 33.8 mg THC, respectively.

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Subjects, medical staff, and investigators were blind to the order in which marijuana doses were administered. Marijuana cigarettes, assayed for THC content, were obtained from the Research Technology Branch, National Institute on Drug Abuse. Baseline measures, including urine samples, were obtained 30-60 rain before drug administration for each experimental ses- sion. Marijuana smoking was computer-paced. The number of cigarette puffs, the length of time of each inhalation, the time between puffs, and the puff hold time were controlled to reduce intersubject variability, but the depth of each inhalation was not controlled. Subjects remained within the research area for approximately 3 h after drug administration while undergoing ex- tensive monitoring. Data collection, including collection of all urine specimens, continued for 168 h.

Specimens Each individual urine specimen was collected from the six

research subjects throughout the 3-week study. Specimens (N = 957) were collected in polypropylene containers and refrigerated immediately after urination. The volume of each specimen was measured. Urine specimens were stored in 30-mL polypropylene screw-cap bottles at -30~ on the day of collection. After the 7-month protocol was complete, frozen specimens were assembled, coded, and randomized. This procedure ensured that all specimens were randomized for analysis within the large batch to eliminate any potential bias based on subject, dose, time of collection, and individual calibration. Each specimen was analyzed under blind conditions for THCCOOH by GC-MS with a one-point calibration at I5 ng/mL and a 0.5-ng/mL limit of detection according to a previously published procedure (11). A modified Jaffe method on a Hitachi 704 automated clinical analyzer (Boehringer Mannheim Corp., Indianapolis, IN) was used to obtain urine creatinine concentrations. Specimens were thawed just before analysis and subjected to a single freeze-thaw cycle. Quality control samples were included within the randomized batch and served to assure within- and between-batch reproducibility.

Results

Urine THCCOOH excretion profiles THCCOOH concentrations by GC-MS for six subjects who

smoked two doses of marijuana are shown in Table I, together with the volume of each urine collection and the creatinine concentration. Subjects produced an average of 43.7 _+ 4.6 (mean plus or minus standard error of the mean) urine specimens (range, 28-59) and 44.5 +_ 6.3 urine specimens (range, 32-69) during the 7 days after the low-dose (1.75% THC) and high-dose (3.55% THC) cigarettes, respectively. THCCOOH was still detectable (0.5-ng/mL cutoff) in all subjects' urine specimens at the end of the 7-day collection period. Substan- tial intersubject variability in the patterns of THCCOOH excretion was noted between subjects and between doses.

THCCOOH concentration in the first urine specimen Figure 1 illustrates individual THCCOOH concentrations

measured in each subject's first urine specimen (Figure 1A)


and the time of collection of first voids (Figure 1B). Except for subject B, THCCOOH concentrations were found to be dose- related; mean concentrations were 47 + 22.3 ng/mL and 75.3 • 48.9 ng/mL after the 1.75 and 3.55% THC cigarettes, respectively. The range of THCCOOH concentrations in first urine specimens was 5.5-138.4 ng/mL after the low-dose cigarette and 9.1-318 ng/mL after the high-dose cigarette. The mean time of the first urine specimen was 3.7 • 0.6 h and 3.0 • 0.5 h for the low and high doses, respectively. Times of collection ranged from 2.2 to 6.5 h after the low-close and from 1 to 4 h after the high-dose conditions. Fifty percent of the subjects' first urine specimens after the low dose and 83% of the first urine specimens after the high dose were positive by GC-MS (15-ng/mL THCCOOH cutoff concentration).

Peak urinary THCCOOH excretion Mean peak urine THCCOOH concentrations averaged 89.8 •

31.9 ng/mL and 153.4 • 49.2 ng/mL after smoking of approximately ]5.8 mg THC (1.75% THC dose) and 33.8 mg THC (3.55% THC dose), respectively (Figure 2A). Although peak concentrations appeared to be dose-related, there was a 12-fold variation between individuals. Peak concentrations ranged from 20.6 to 234.2 ng/mL after the low-dose cigarette and from 29.9 to 355.2 ng/mL after the high-dose cigarette. All subjects, except subject E, had higher peak THCCOOH concentrations after the high-dose exposure compared with the low-dose exposure. The time of peak urine THCCOOH concentration was also dose-related; the mean was 7.7 • 0.8 h after the ].75% THC dose and 13.9 • 3.5 h after the 3.55% THC dose (Figure 2B). For two individuals (subjects B and E), the peak THCCOOH concentration for the high dose occurred at an earlier time than that observed for the low dose. The times of peak excretion in the six subjects ranged from 6 to 11.3 h and from 5.6 to 28 h after the low and high doses, respectively. Sub- ject G was unusual in that his peak THCCOOH concentration of 223.2 ng/mL was collected 20.5 h after the high-dose exposure. Subject F's highest urine THCCOOH concentration was measured in a specimen collected 28 h after drug administration; however, a lower peak concentration was attained (52.5 ng/mL).

THCCOOH detection times During the terminal elimination phase, consecutive urine

specimens fluctuated between positive or negative as THCCOOH concentrations approached the cutoff concentration of the GC-MS assay (15 ng/mL). Therefore, two different windows of drug detection were determined: a detection time for consecutive positive urine specimens and a detection time for the last positive urine specimen (Figure 3). Mean THC- COOH detection times for the last consecutive positive specimen were 28.7 • 10.8 h (range, 8.0-68.5 h) and 39.0 • 13.0 h (range, 4.0-68.5 h) for the low- and high-dose conditions, respectively. After smoking the low marijuana dose, three of six subjects had additional positive urine samples interspersed between negative urine samples. This had the effect of pro- ducing much longer detection times for the last positive specimen. All six subjects had substantially longer detection times for the last positive urine specimen as compared with the last

consecutive positive specimen after the high marijuana dose. Subject F produced only a single positive urine sample at 8 h after the low dose, and although the first urine specimen was positive at 4 h after the high-dose condition, urine specimens at 5.0, 8.8, and 11.0 h were less than 15 ng/mL THCCOOH. Of the 13 urine specimens produced by subject F from 20 h through 57 h after drug administration, only one at 30 h was below the 15-ng/mL cutoff.

Mean GC-MS THCCOOH detection times for the last positive urine sample after the smoking of a single 1.75 or 3.55% THC cigarette were 33.7 • 9.2 h and 88.6 • 9.5 h, respectively, when a 15-ng/mL cutoff concentration was used. Substantial variability was noted in the range of detection time between subjects: 8-68.5 h after the low dose and 57-122.3 h after the high dose. The mean number of urine specimens containing more than 15 ng/mL THCCOOH was 6.3 • 1.7 and ranged from 1 to 11 for the six subjects after the low dose. Sub- stantially higher numbers of positive urine specimens were produced after the high dose; there were 14.7 • 1.1 positive urine specimens (range, 12-20 positive urine specimens). Three of six subjects produced negative urine specimens at the time of their first urination after the 1.75% THC cigarette, whereas only subject G's first urine specimen contained less than 15 ng/mL THCCOOH after smoking the 3.55% THC cigarette. In general, THCCOOH detection time windows by GC-MS were substantially longer after the high dose as compared with the low dose.

Percent dose and absolute amount of THCCOOH excreted An average of 93.9 • 24.5 pg THCCOOH (range, 34.6--171.6

IJg) was excreted by each subject during the 7-day period after smoking of a single 1.75% THC cigarette (Figure 4A). The average amount of THCCOOH excreted in the same time period after the high dose was 197.4 + 33.6 pg (range, 107.5-305.0 pg). This represents an average of only 0.54 • 0.14% and 0.53 + 0.09% of the original amount of THC in the low- and high-dose cigarettes, respectively (Figure 4B). Respective ranges of percent dose excreted were 0.20-0.99% (low dose) and 0.29-0.82% (high dose). When expressed as a percent of the original dose, the low- and high-dose mean values were similar. This was true for four individuals but not for the other two subjects. The extremes are exemplified by subject B, who excreted a higher percentage of THC after the low-dose cigarette (0.97% after the 1.75% THC cigarette; 0.54% after the 3.55% THC cigarette), and subject G, who excreted almost twice the percentage of THC after the high-dose cigarette (0.43% after the 1.75% THC cigarette; 0.82% after the 3.55% THC cigarette) as compared with the low-dose cigarette.

Discussion

The smoking route provides a rapid and highly efficient method of delivery of the primary psychoactive component of marijuana, THC. Because of its high lipophilicity, THC accu- mulates in fat tissue as a function of the amount and frequency of smoking and as a function of marijuana potency. Detectable levels of THC were found in fat biopsy specimens obtained

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Journal of Analyt ical Toxicology, Vol. 20, October 1996

Table I. Individual Urine Excretion Profiles

1.75% THC* 3.55% THC

Time t THCCOOH* Creatinine Volume T i m e THCCOOH Creatinine Volume (h) (ng/mL) (mg/dL) (mL) (h) {ng/mL) (m~/dL) (mL)

Subject B -3.1 0.5 165 234 -0.9 0.7 23 198 6.5 89.8 199 250 3.4 30.7 55 265

11.3 119.3 135 265 6.0 60.6 53 270 13.5 103.2 142 215 9.8 146.4 143 190 20.9 77.0 NA~ 245 11.8 73.5 74 166 24.2 27.2 71 265 20.6 139.7 210 236 29.0 33.3 121 265 23.2 86.6 133 122 33.3 24.1 100 310 30.1 66.9 146 226 35.7 23.9 85 154 34.5 45.4 105 264 44.5 29.0 164 280 36.5 28.7 95 130 47.5 16.7 100 184 40.0 60.1 193 126 53.8 15.1 127 180 45.0 27.2 78 190 57.0 12.3 112 178 51.5 24.4 86 200 59.7 12.6 114 136 55.0 24.7 111 195 62.5 10.5 103 160 58.0 23.8 83 190 66.0 7.2 102 208 69.0 18.7 131 180 69.0 11.4 150 202 71.7 25.0 156 108 75.3 7.5 143 180 78.4 28.4 224 165 79.5 7.3 125 200 82.0 5.2 43 128 83.0 12.6 182 128 87.2 3.9 43 135 87.5 7.8 131 196 92.7 1 I. I 147 125 92.7 9.7 162 194 100.0 23.3 194 230 95.0 4.9 90 175 101.5 5.4 59 152 96.5 4.9 81 170 109.5 6.7 90 110

100.8 3.0 97 250 116.7 15.1 241 125 104.5 5.7 110 220 122.3 16.9 224 152 106.8 3.6 89 174 126.5 6.4 133 248 110.5 6.0 155 188 129.8 7.9 152 250 116.5 6.0 160 210 141.0 5.4 142 120 121.2 3.4 85 198 143.5 1.9 27 226 124.8 3.5 136 200 150.3 6.3 157 125 131.3 6.6 177 208 154.5 2.1 45 155 134.8 6.3 159 134 158.5 6.9 185 120 140.5 5.3 ] 51 226 161.0 3.6 77 265 145.8 4.3 132 192 164.5 9.0 220 140 150.0 4.5 140 216 167.7 2.8 72 135 153.5 1.4 48 154 - 156.5 3.8 95 96 - 158.5 3.2 118 98 - 165.2 2.8 124 110 - 166.2 2.4 95 68 - 167.1 0.7 23 198 -

Subject C -3.6 0.0 167 62 -3.7 1.6 173 280 3.4 27.0 86 265 2.3 28.7 71 245 6.4 58.7 158 176 3.5 38.2 67 260

11.3 21.0 140 114 7.3 113.8 137 255 14.0 18.7 118 230 12.4 62.4 154 328 20.6 16.0 137 375 15.6 61.4 164 220 24.7 18.1 173 235 23.8 53.3 194 230 31.1 11.7 110 230 26.6 41.2 112 250

* THC = Ag-Tetrahydrocannabinol. * Elapsed time after initiation of drug administration. * THCCOOH = 11 -Nor-9-carboxy-g'~-tetrahydrocannabinol.

NA = Not available.

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Table I continued. Individual Urine Excretion Profiles

1.75% THC* 3.55% THC

Time ~ THCCOOH* Crealinine Volume T ime THCCOOH (h) (ng/mC) (mg/dC) (mL) (h) (ng/mr)

Creatinine (mg/dL)

Volume (rot)

Subject C 35.3 11.3 120 270 32.6 47.9 177 170 38.4 7.4 124 192 36.4 61.2 188 186 44.3 8.4 145 310 44.5 37.5 203 280 47.8 8.6 158 180 48.3 32.8 183 166 54.7 6.6 153 350 52.3 24.6 140 220 63.9 3.6 166 280 54,4 12.7 116 202 68.4 3.7 155 270 59.3 14,7 136 278 72.6 2.9 123 260 62.0 11.2 110 247 75.8 1.9 128 235 72.0 19.1 217 230 79.7 2,2 153 265 78.0 16.4 179 250 85.0 1.7 114 260 82.8 11.0 164 190 87.7 2.1 138 198 85.9 0,7 122 260 97.0 2,5 169 370 92.8 10.4 176 545

103.0 2.0 137 215 99.8 9.0 157 250 107.8 1.7 139 255 105.4 9.5 217 250 111.2 1.7 89 275 110.5 5.2 199 234 114.9 1.2 118 265 116.7 5.0 221 260 120.3 1.5 150 252 127.3 5.8 210 235 123,5 2.6 154 190 130.5 5.2 202 170 127.1 1,8 140 235 133.8 4.3 189 230 130.0 2.0 164 148 143.3 4.2 238 174 134.5 1.7 153 250 151.4 4.5 144 280 146.1 3.0 190 200 155.6 4.3 166 235 151.0 1.7 140 275 161.1 2.1 144 215 154.4 2.3 210 178 166.5 1.5 268 160 158.4 1.5 170 250 . . . . 164.3 1.6 170 280 - - -

Subject E -1.3 0.5 154 50 -3.3 0.0 200 260 2.2 5.5 102 363 3.4 16.5 164 218 4.4 22.9 I 17 206 5.6 29.9 105 75 8.3 39.0 153 192 7.8 17.8 58 343

11.8 9.2 110 249 8.1 6.3 20 301 15.5 12.2 114 395 11.2 23.8 93 478 20.3 8.9 94 391 15.6 15.4 103 273 22.1 10.1 78 285 18.0 26.2 150 159 23.7 15.5 87 215 20.2 16.9 98 247 26.0 3.6 34 255 22.0 11.8 64 265 27.4 6,3 65 180 24,0 21,1 104 185 30.3 11.0 142 225 27.3 19.6 114 270 34.8 9.0 115 290 28.5 7.7 51 225 36.3 5,5 100 248 30.4 11.5 81 225 44.8 5.0 119 455 31.6 12.4 97 157 47.4 8.0 169 161 33.7 5.5 37 470 48.0 4.8 134 98 35.8 11.8 121 180 50.0 6.0 158 190 37.7 11.2 104 175 52.5 5.6 157 180 39.7 16.1 127 139 54.2 4.4 179 130 45.9 17.2 173 280 56.6 4.6 220 172 48.5 16.2 182 205 58.9 4.9 159 158 50.1 10.0 118 170 60.3 2.2 76 190 51.3 8.3 107 105

* THC = Ag-TetrahydrocannabinoL t Elapsed time after initiation of drug administration. * THCCOOH = ! 1 -Nor-9-carboxy-Ag-tetrahydrocannabinol.

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Journal of Analytical Toxicology, Vo[. 20, October 1996

Table I cont inued. Indiv idual Ur ine Excretion Profiles

1.75% THC* 3.55% THC

Time * THCCOOH* Creatinine Volume Time THCCOOH (h) (ng/mL) (mg/dL) (mL) (h) (ng/mL)

Creatinine (mg/dL)

Volume (mt)

Subject E 61.6 3.3 109 126 55.1 10.8 116 165 63.5 2.2 95 204 58.5 9.2 137 260 68.7 3.7 157 276 60.4 7.1 143 155 71.8 2.6 102 250 62.2 10.7 205 145 74.3 3.5 169 168 68.2 6.4 172 365 75.9 2.6 116 154 71.6 6.0 175 205 78.5 0.0 160 170 74.0 6.0 136 155 82.3 3.4 159 270 75.4 3.4 84 190 84.6 2.2 I50 I85 77.2 3,8 132 160 86.2 1.8 I35 130 79.2 4.4 103 232 92,8 1.7 157 325 81.4 6.8 120 220 95.8 4.2 126 230 83.6 5.3 138 196 98.0 2.9 198 110 86.6 3.6 113 212

101.7 1.4 95 265 87.8 2.5 94 120 102.3 2.0 115 210 92.8 3.9 159 275 105.0 0.8 57 265 98.0 2.9 99 507 107.5 1.9 179 140 101.0 4.0 141 240 110.8 1.7 162 220 102.1 2.1 92 142 116.8 1.3 168 240 105.0 3.2 116 250 122.3 1.8 224 265 106.4 2.0 78 176 125.0 1.3 172 115 108.0 1.9 180 240 127.2 1.2 156 170 110.0 2.4 103 196 129.9 1.6 231 174 111.7 2.0 77 222 132.5 0.8 177 250 116.7 1.5 78 526 134.3 0.8 119 210 121.8 1.2 67 500 138.0 0.0 147 213 126.4 2.9 229 210 140.0 1.1 115 193 128.2 2.2 170 116 142.3 1.3 124 173 129.8 2.1 143 142 143.7 1.0 118 130 132.5 3.1 23~ 182 146.2 0.7 182 175 134.8 1.4 106 112 147.7 0.6 83 188 136.3 1.6 94 166 149.7 0.0 81 260 138.0 1.7 115 134 152.8 1.1 137 204 140.5 1.1 65 355 155.5 1.1 224 155 143.5 2.2 152 192 159.0 1.1 150 245 145.8 1,9 136 192 164.8 1.3 165 340 147.2 1.1 80 180

- - - 148,4 0.0 60 174 - - 148.8 0.0 23 214 - - 149.7 0,0 30 260 - - 151.2 0.0 75 214 - - 152.5 0,8 96 137 - - 155.5 1.7 133 270 - - - 159.2 1.2 156 134 - - 161.0 1.2 126 149 - - 164.6 1.7 204 177 - - - 165.9 0.6 ] 10 82

Subject F -1.5 0.0 47 77 -3.0 0.0 165 105

3.5 11.3 150 265 4.0 49.0 340 134 8,0 20.6 ~ 96 194 5,0 0,0 47 34

11.5 10.7 110 429 8,8 6.6 26 222

' THC = A'~-Tetrahydrocannabinol. '~ Elapsed time after initiation of drug administration.

THCCOOH = l l-Nor-9-carboxy-A'J-tetrahyclrocannabinol.

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1.75% THC* 3.55% THC

Time ~ THCCOOH* Creatinine Volume Time THCCOOH (h) (ng/mL) (mg/clL) (mL) (h) (ng/mL)

Creatinine (mg/dL)

Volume (mL)

Subject F 20.5 8.0 85 384 11.0 13.7 63 210 24.0 8.7 123 240 20.0 47.6 208 198 28.5 12.2 143 220 23.5 16.8 73 310 30.5 3.4 57 205 28.0 52.5 209 159 34.5 6.7 133 225 30.0 12.1 56 280 36.5 2.4 56 275 34.5 36.1 170 158 41.0 5.5 176 130 36.5 26.5 158 125 43,5 1.1 13 270 38.8 19.3 131 275 44.5 1.0 33 275 44.5 23.3 160 190 48.5 3.8 i 41 790 48.0 16.5 126 160 53.5 3.5 129 270 50.5 16.5 69 110 56.5 3.5 119 185 51.5 28.8 176 50 58.5 3.7 143 155 54.0 19.9 95 150 65.0 2.2 63 235 57.0 20.1 147 158 71.5 2.5 121 210 59.5 10.3 54 250 75.5 1.7 58 235 61.5 2.7 17 212 77.5 1,3 34 265 63.5 7.2 64 195 82.0 2.6 138 265 65.0 7.3 49 225 84.0 1.8 107 160 67.0 6.3 39 265 85.0 1.0 52 205 71.5 11.4 96 235 86.5 1.1 26 250 74.5 6.2 64 155 89.5 2.3 86 255 78.0 3.1 46 235 92.5 0.0 28 555 78.5 3.4 63 245 97.5 1.4 119 265 83.5 6.0 70 240

102.0 2.6 219 171 84.0 3.4 38 180 105.5 2.2 ] 21 162 84.5 3.0 40 155 106.5 0.0 29 455 87.2 7.7 120 175 110.5 2.1 182 165 91.5 8.7 80 205 112.5 0.9 59 240 92.0 4.7 70 170 121.0 1.1 149 270 92.5 3.8 30 245 125.0 1.9 246 185 98.5 2.4 50 245 129.0 1.1 146 258 99.0 6.0 70 205 131.5 05 82 265 100.0 10.4 130 110 134.0 1.4 144 135 105.0 6.5 ] 30 285 ] 36.0 0.0 40 225 107.5 6.5 110 195 142.5 1.0 123 150 110.5 4.7 1 O0 265 145.0 0.0 47 260 120.0 6.1 140 270 146.0 0.7 69 225 123.0 3.1 80 270 152.5 1.2 287 120 127.0 2.4 60 255 155.5 0.6 65 415 128.0 1.9 50 240 160.0 1.3 178 180 131.5 4.8 160 215 165.0 1.1 177 225 134.0 2.2 70 260

. . . . 138.0 1.8 80 280

. . . . 140.0 1.1 30 255

. . . . 144.5 2.3 70 255

. . . . 145.3 3.4 130 162

. . . . 146.5 1.9 140 181

. . . . 149.5 4.3 140 248

. . . . 153.5 4.2 140 170

. . . . 156.0 3.5 40 162

. . . . 158.0 3.7 90 1~8

. . . . 160.3 3.7 150 95

. . . . 163.0 1.9 50 285

. . . . 166.8 4.5 180 62

* THC = Ag-Tetrahydrocannabinol. ~" Elapsed time after initiation of drug administration.

THCCOOH = 1 t-Nor-9-carboxy-Ag-tetrahydrocannabinol.

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1.75% THC* 3.55% THC

Time t THCCOOH* Creatinine Volume T i m e THCCOOH (h) (n&/mL) (mg/dL) (mt) (h) (ng/mL)

Creatinine (m~/dL)

Volume (mL)

Subject G -3.3 0.0 45 245 -3.5 1.2 142 175

3.3 10.0 29 515 1.0 9.1 30 525

3.8 24.6 76 40 3.5 123.8 84 200 6.4 66.9 149 130 8.5 178.5 95 200 8,6 42,2 96 150 10.5 118.4 62 230

9.3 11.4 28 190 20.5 223.2 184 320 11.0 11.2 29 196 23.0 27.1 39 195 12.4 8.0 23 367 24.0 13.7 23 260 14.8 29.7 87 200 30.5 79.5 115 240 20.4 15.8 76 265 35.7 81.2 152 245 23.3 18.7 98 194 44.0 47.8 140 365 25.3 13.2 89 190 46.5 31.3 96 200 26.2 5.7 31 210 48.3 7.3 32 265 29.0 7.1 45 192 52.0 27.0 98 255 32.0 6.5 51 210 54.0 20.3 77 195 33.5 4.2 43 280 58.0 20.3 91 280 35.0 2.4 24 285 60.0 4.0 19 260

42.7 7.6 131 280 69.5 18.1 153 95 50.2 7.9 151 232 74.0 5.0 47 248 52.0 2.6 48 260 78.3 9.2 99 270 54.3 2.5 58 226 84.7 15.9 217 240 56.3 2.8 66 142 92.5 3.8 57 285 57.0 1.5 27 200 96.0 10.5 133 160 60.4 0.0 12 466 99.5 7.2 103 260 68.7 2.9 113 270 101.0 3.3 34 255 73.5 5.0 154 218 103.0 1.5 24 290 76.0 1.8 52 258 106.0 5.3 78 24-5 79.3 1.8 85 273 1I 6.5 4.6 134 280

83.5 1.7 68 215 118.0 0.0 12 325 86.0 1.7 46 261 121.5 1.7 35 390 92.3 1.7 63 525 126.5 5.3 89 120 94.0 0.8 28 260 130.0 0.8 14 255 94.8 0.0 13 280 133.0 0.9 17 260 96.5 0.0 15 292 136.3 1.3 25 300

102.5 1.2 54 308 139.0 1.2 36 290 105.5 1.0 68 320 143.5 1.2 20 385 t09.0 2.0 120 248 145.0 1.4 46 280 116.3 5.9 98 459 156.8 5.9 258 190 118,3 0.8 54 223 159,3 3.0 t 61 190 119.0 0.5 14 300 160.5 0.0 10 275 121.0 0.0 25 283 163.0 1.2 30 330 124.0 1.4 73 267 - - - 126.3 0,9 59 245 - - - 129.1 1.2 39 294 - - - 131.8 0.9 72 275 - - -

134.1 0.7 55 275 - - - 140.5 1.1 119 310 - - - 144.8 1.6 147 170 . . . .

150.0 1.4 146 290 . . . . 153.3 1.6 116 195 - - -

158.5 0.9 95 455 - - - 164.5 1.2 142 175 - - -

"THC = Ag-Tetrahydrocannabinol. ~" Elapsed time after initiation of drug administration. * THCCOOH = 11 -Nor-9-carboxy-Ag-tetrahydracannabinol.

448


more than 4 weeks after marijuana smoking (12). The redis- tribution of THC from tissue to blood was demonstrated to be the rate-limiting step in its metabolism (13). THC is rapidly metabolized to the inactive metabolite, THCCOOH, and to numerous other cannabinoids, primarily by cytochrome P450 enzymes in the liver and other tissues (14). Most of the THC- COOH is conjugated and excreted as the water-soluble glu- curonic acid. Wall et al. (15) were the first to demonstrate that THCCOOH was the primary cannabinoid metabolite excreted in the urine; 15-20% ofa THC dose was eliminated as acidic urinary metabolites, whereas approximately 65% was excreted in the feces as 11-hydroxy-A9-THC and THCCOOH (13). Of the 15-20% of the dose eliminated as acidic urinary metabolites, it was estimated that 27% was conjugated and unconjugated THCCOOH (16).

The present study details excretion of THCCOOH in urine during a period of 7 days in six healthy male subjects who

smoked 1.75% THC (low dose) and 3.55% THC (high dose) cigarettes. A total of 957 urine specimens were analyzed for THCCOOH by GC-MS. The concentration of THCCOOH in the first specimen after smoking marijuana was evaluated to determine how rapidly the metabolite appeared in urine; however, this study was not specifically designed to address this concern. Subjects were encouraged to delay urination for the initial 3 h after smoking because of intensive monitoring of pharmacodynamic parameters during this time period. Con- sequently, the first specimens may have been more concen- trated than would be expected because of the imposed delay in urination. No other information was found in the literature on THCCOOH concentrations of first urine specimens analyzed by GC-MS. The THCCOOH concentration in first urine specimens increased with the THC dose, except for subject B. The time that elapsed before subject B produced his first urine specimen was substantially different for the low (6.5 h) and


1.75% THC* 3.55% THC

Time t THCCOOH* Creatinine Volume T i m e THCCOOH Creatinine Volume (h) (ng/mL) (mg/d/) (mL) (h) (ng/mL) (mg/dL) (mE)

Subject H -3.2 5.2 212 254 -3.2 5.6 190 180

3.2 138.4 221 224 4.0 318.0 297 185 6.0 234.2 174 116 10.0 256.6 168 209 9.5 59.6 45 390 12.0 355.2 291 91

20.0 65.3 128 275 15.3 246.4 259 110 24.0 37.7 127 135 20.8 155.0 206 185 27.5 42.7 124 225 22.8 96.6 221 90 30.0 22.1 77 255 27.0 73.6 165 169 36.3 3.1 144 215 36.2 72.6 215 230 45.0 48,2 224 265 44.8 68.7 238 155 48.5 25.2 176 205 48.0 42.8 273 100 57.8 31.4 233 170 51.5 24.0 215 200 68.5 21.1 234 225 57.0 27,6 207 230 72.3 9.6 190 115 60.0 30.5 309 116 76.0 7.0 227 220 68.5 21.0 326 234 80.0 11.6 184 210 75,8 9.6 147 151 82.5 9.0 173 150 78,2 9.4 249 205 92.8 8.3 186 365 81.5 17.5 300 165

101.4 7.5 158 190 92,8 12.3 190 258 106.6 4.3 134 240 100.0 13.1 219 205 116.5 6.8 144 265 102.8 9.8 269 140 122.0 7.7 224 252 106.8 11.2 228 135 127.2 8.3 185 185 116.8 11.2 185 160 140.5 4.6 109 425 124.0 12.0 270 124 149.8 3.1 74 255 126.5 10.4 260 184 151.1 2.6 56 265 131.0 8.5 191 166 154.0 8.1 161 185 134.0 7,9 175 180 164.8 5.6 190 180 140.5 10.7 192 250

. . . . 147.0 7.3 186 238

. . . . 149.8 8.0 179 176

. . . . 164,0 7.9 222 250

. . . . 168.0 7.8 252 94

9 * THC = A -Tetrahydrocannabinol. Elapsed time after initiation of drug administration. THCCOOH = 11 -Nor-9-carboxy-A~-tetrahydrocannabinol.

449

high (3.4 h) doses and may account for this apparent discrep- ancy. The THCCOOH concentration in the first urine specimen appeared to be dependent on the relative potency of the marijuana cigarette, the elapsed time after drug administration, smoking efficiency, and individual differences in drug metabolism and excretion.

Mean peak urine THCCOOH concentrations (89.8 and 153.4 ng/mL) were consistent with the finding of a mean of 71 ng/mL 7 h after the smoking of one 2.8% THC cigarette (17). Kelly and Jones (6) reported a mean peak THCCOOH concentration of 55.5 ng/mL in the first daily 24-h urine collection after intravenous administration of 5 mg THC. Kemp et al. (7) reported a mean peak THCCOOH concentration of approximately 180 ng/mL at 6 h after one 3.58% THC cigarette was smoked. McBurney et al. (5) monitored urine THCCOOH concentrations for 22 h after approximately 10.5 mg THC was smoked and reported a mean peak THCCOOH concentration of approximately 30 ng/mL by GC-MS.

Drug detection time, or the time after drug administration that an individual tests positive, is an important factor in the interpretation of urine drug-testing results. Detection time is dependent on pharmacological factors (e.g., drug dose, route of administration, and rates of metabolism and excretion) and


analytical factors (e.g., assay sensitivity, specificity, and accu- racy). In the present study, the 15-ng/mL GC-MS cutoff for THCCOOH was chosen for evaluation because of its required use in Department of Health and Human Services and Depart- ment of Transportation-regulated laboratories and in military drug-testing facilities. Mean detection times of smoked marijuana varied considerably between subjects despite attempts to standardize marijuana dosing with a computer-paced smoking protocol. Mean THCCOOH detection times of 33.7 and 88.6 h after the low and high doses, respectively, were in agreement with other reports of mean detection times of up to 3 days in infrequent and up to 4 days in frequent drug users after injec- tion of a 5-rag intravenous THC dose (6). GC-MS detection times were shorter than those obtained with less specific immunoassays. Law et al. (4) measured cannabinoid metabolites in 24-h urine pools by radioimmunoassay for 12 days after oral administration of 20 mg THC. Individual case studies from drug-treatment programs report fluctuating positive and negative test results for consecutively collected urine specimens late in the excretion timeline; most results were generated with a 20-ng/mL immunoassay (8,18,19). In the present study, GC-MS detection times for the last positive urine specimen were found to be moderately increased after the low dose and

A Mean -

H

L~ u~

4.~7.0 75.3

,:..'-~::'.] 138.4

10.0 G- 9.1

11.3 F- BIB 49.0

5 1.5 ~ 27.0

c - �9 28.7

B- ~ 89.8

i i i

0 100 200 THCCOOH (ng/mL)

318.0

i

300 400

B Mean -

H-

G-

F- @)

u) E -

C-

B I o

[]

4.0

~ 3.3

~ 3 . 4 3.4

~/.:-:'-':':'.:.y'.7.:.7,%':.@::.7.s 6.5 3.4

i i i

2 4 6 Time (h)

1.75% THC �9 3.55% THC

Figure 1. (A) Concentration of 11-nor-9-carboxy-Ag-tetrahydrocannabinol (THCCOOH) in the first urine specimen collected after smoking a single 1.75 or 3.55% Ag-tetrahydrocannabinol (THC) cigarette for six male subjects. (B) The time after marijuana smoking that the first urine specimen was collected.

A Mean -

H

C , 9

9.8 153.4

:-~..-~.:I::'.~Z.:":I:Z.'Z:~'.?.::':",!:k'.':'~Z::d 234.2

G - ~ 223.2

F %5 E - ~ 39.0

29.9

C - ~ 113.0 B ~ 1 9 . 3

146.4

0 100

355.2

i i i i

200 300 400

THCCOOH (ng/mL)

B Mean -

H-

G

c9 C-

~ - - ~ 13.9

12.0

~ 6.4

~ 8.0

0

20.5

i i i

10 20 30

Time (h)

[ ] 1.75%THC �9 3.55%THC

28.0

Figure 2. (A) Peak urine concentrations of 11-nor-9-carboxy-A9-tetrahydrocannabinol (THCCOOH) excreted after smoking a single 1.75 or 3.55% Ag-tetrahydrocannabinol (THC) cigarette for six subjects. (B) The time after marijuana smoking that peak urine THCCOOH concentrations were observed.

450


substantially increased after the high dose when compared with detection times for the last consecutive positive specimen.

The percentage of THC excreted by subjects during the 7-day monitoring period was less than 1% of the THC initially present in the marijuana cigarettes. These percentages represent only a small fraction (0.20-0.99%) of the available dose, that is, 15.8 and 33.8 mg for the 1.75 and 3.55% THC cigarettes, respectively. The small percentage of the total dose found in the urine as THCCOOH is not surprising considering the many factors that influence THCCOOH excretion after marijuana smoking. Before harvesting, cannabis plant material contains little active THC (20). When marijuana is smoked, THC carboxylic acids spontaneously decarboxylate to produce THC, and there is nearly complete conversion on heating. Pyrolysis of THC during smoking destroys approximately 31% of the drug (21). Drug availability is further reduced by loss of drug in sidestream smoke. Agurell et al. (16) estimated that the sys- temic availability of smoked THC is approximately 18% and has a range of 10-14% for light users and 23-27% for heavy marijuana users. In the present study, use of the paced smoking

protocol did not permit consumption of the entire marijuana cigarette. The major route of excretion of THC and metabolites is in the feces (65%) rather than in the urine (20%) (14). In addition, numerous cannabinoid metabolites are known to be produced through human metabolism of THC. THC bioavail- ability is reduced because of the combined effect of these factors; the actual available dose is much lower than the amount of THC and THC precursor present in the marijuana cigarette.

In summary, urinary excretion of the primary marijuana metabolite, THCCOOH, was documented in six male subjects for 7 days after smoking of a single 1.75 or 3.55% THC marijuana cigarette using a sensitive GC-MS method. Wide intersubject variability was noted in the THCCOOH concentrations in the first and peak urine specimens, in the detection times of the last consecutive positive specimen and the last positive specimen, and in the amount of THCCOOH and percentage of THC dose excreted during 7 days. These data provide a detailed compilation of THCCOOH concentrations in urine after administration of marijuana that should aid in the interpretation of urine cannabinoid results.

A Mean H

G

F

E- -~ C-

1.75% THC

B -

0 20

68

23

24 2s 25

l

i

40 60 80

THCCOOH (ng/mL)

B Mean

H-

G-

~ F. e,, = E

C.

B

0

3.55% THC

~ . ~ 1 3 9 I - ~ m

~ 8 5

57 ~ 8

79

50

108

122 ! i

100 150 ~me (h)

[ ] Consecutive Positives �9 Last Positive

Figure 3. Detection times of 11-nor-9-carboxy-Ag-tetrahydrocannabinol (THCCOOH) in urine using gas chromatography-mass spectrometry with a 15-ng/mL cutoff for six male subjects. Detection times are shown for the last consecutive positive urine specimen (consecutive positives) or the last positive urine specimen (last positive) after the smoking of a single (A) 1.75% A%tetrahydrocannabinol (THC) or (B) 3.55% THC cigarette.

A Mean -

H

G

~ F -

o 9 E - ~ ~

C-

B - ~ 6 8 i i i

0 11111 200

~ ~ 197.4 171.6

305.0

~ 5 5 . 7 278.1

107.5

~ 8 110.5

183.3

i i

3OO 4OO THCCOOH (pg)

B Mean

H

G

F- (1)

f f l

~ ~ ' : - : ? ; : : ' : ~ ? ; " ? - ' i ~ " i - , " ; | 0.99

0.4o 0.75

v , , ~ , , J

C - ~ 0.55

B-

0.00 0.25 0.50 0.75 % THC Dose

0.97

1

1.00

i~J 1.75% THC �9 3.55% THC

Figure 4. (A) The total amount of 11-nor-9-carboxy-Ag-tetrahydro - cannabinol (THCCOOH) excreted in urine during a 7-day period after the smoking of a single 1.75 or 3.55% Ag-tetrahydrocannabinol (THC) cigarette. (B) The percent THC excreted in the urine during a 7-day period after the smoking of a low-dose marijuana cigarette (15.8 mg THC) or a high-dose (33.8 mg THC) marijuana cigarette.

451


Acknowledgments

We gratefully acknowledge the technical support and dedi- cation of Ms. Rosalind Jones.

References

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Manuscript received April 2, 1996; revision received May 13, 1996.

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