MARIHUANA AND DRIVING: WHAT IS THE SIGNIFICANCE OF CANNABINOID CONCENTRATIONS? * * A. McBay, M.D. ; and A. P. Mason SYNOPSIS

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1 MARIHUANA AND DRIVING: WHAT IS THE SIGNIFICANCE OF CANNABINOID CONCENTRATIONS? * * A. McBay, M.D. ; and A. P. Mason SYNOPSIS It has been inferred that significant driving impairment can result from marihuana use. If this is true and if there is a significant number of drivers impaired, it will be necessary to establish that the impairment is due to marihuana by some testing method. Can cannabinoid concentrations be related to impairment? Cannabinoid metabolites appear in urine in about 2 hours after ingestion, and they are detectable for weeks. Cannabinoids are detectable in saliva. It is doubtful that concentrations in saliva or urine could be correlated with performance. Plasma appears to be the only specimen which might be suitable. It appears that tetrahydrocannabinol concentrations alone will not be relatable to impairment but together with the concentrations of the carboxy acid metabolite there might be a relationship. At the present, there is insufficient evidence to prove that marihuana use is a factor in a significant number of motor vehicle crashes. INTRODUCTION Anything that affects the safe operation of a motor vehicle is very important. Most drugs have the potential to have some effect on drivers, particularly those drugs that affect the central nervous system. Large overdoses of drugs that excessively depress or stimulate central nervous system mediated functions would be expected to alter driving behavior. In order to establish that an operator operator who has taken a drug is hazardous, it is necessary to establish the following: 1) That the drug has an adverse effect on driving or skills associated with driving; 2) That the magnitude of this effect can be measured; 3) That the behavioral changes can be correlated with impaired driving; * Office of the Chief Medical Examiner and the University of North Carolina, Chapel Hill, North Carolina 27514, U.S.A. 949

2 4) That the amount of drug causing such changes can be measured; 5) That controlled driving studies be reported along with drug concentrations; 6) That there are a significant number of impaired drivers with certain concentrations of drugs; 7) That the number of drivers in the impaired group who have the drug in that concentration is greater that the number in the general driving population; and 8) That the impaired drivers are causing a disproportionate number of traffic crashes and/or deaths.. There is general agreement that the above criteria have been met for one drug, alcohol, but practically no others. Some drugs can calm the overly aggressive driver, whereas others can make tired drivers more alert. Practically none of the criteria offered above has been met by marihuana researchers. The drug has been shown to affect short-term memory, to lessen aggressiveness, and to produce elation ("high"). It has a subtle effect on some complex testing procedures. Unfortunately, in most instances blood or plasma concentrations were not reported in these studies. What is the present status of relating tissue concentrations to behavioral effects and hopefully to driving behavior? Urine: Urine can be rather easily and inexpensively screened for cannabinoids. Two of the available immunoassays used to screen urine cross-react with delta-9-tetranydrocannabinol (THC) and many of its metabolites, but otherwise have good specificity. Urine has been found to contain practically no THC, but contains mostly ll-nor-delta-9-tetrahydrocannibinol -9-carboxylic acid (THC-COOH), "pclar acids," and many other metabolites of the THC in small quantities (Haildin et al. 1982, a & b; Haildin & Widman, 1982; Wall & Perez-Reyes, 1981). Immunoassays should be confirmed by alternate chemical analyses (McBay et al. 1983). Regardless of the certainty of the determination of the concentration of the cannabinoids in the urine, it is impossible to relate any concentration with behavior. Cannabinoids are detectable in urine after about 1 hour after exposure to marihuana and can be detected for days to weeks depending on the sensitivity of the method (Hawks, 1982; McBay et al., 1983). Therefore, urine testing is not helpful in relating cannabinoid 950

3 concentrations to effects. A person could smoke marihuana, have his urine tested within the next hour, and not have detectable concentrations of cannabinoids present in the specimen, yet experience the euphoric effects associated with marihuana use. Urine specimens may continue to be positive for cannabinoids for many days after only a single use, long after any effects are gone (Hawks, 1982). Saliva: Cannabinoids do not appear in the saliva following intravenous injection of THC (Hawks, 1982). Cannabinoids which can be detected in saliva appear to be present because of direct exposure to marihuana smoke. They appear to persist in the saliva for several hours (Gross & Soares, 1978; Hawkes, 1982). By using mouth swabs it appears that cannabinoids can be detected for up to 12 hours after smoking (Norton & Garriott, 1983). Therefore, saliva cannabinoid concentrations do not correlate with drug effects. At the most, they indicate recent smoking. Some preliminary work on trapped breath specimens has been reported but the data are too scanty to allow for evaluation (Soares et al., 1982). How cannabinoids, if they are present, get into the breath is not explained adequately. Blood and Plasma: Practically all of the THC and THC-COOH present in a blood specimen are bound to proteins in the plasma fraction. Thus, THC and THC-COOH concentrations will be twice as high in plasma compared to the same volume of blood (Cook, 1983; Owens et al., 1981). The THC concentrations peak about 7 minutes after smoking starts, and drop while smoking continues (Owens et a., 1981; PSrez-Reyes, 1982). After smoking marihuana cigarettes containing 1.3 and 2.5% THC, the peak THC plasma concentrations are 94 and 155 ng/ml, respectively (P^rez-Reyes et al., 1982). At about 20 minutes after starting to smoke, THC concentrations will be about h that of the peak; at about 1 hour 1/6; and at 2 hours less than 1/10 of the peak concentration. The THC-COOH concentrations rise slowly and peak in about 20 to 30 minutes at 31 and 45 ng/ml, respectively, for the 2 cigarettes (PSrez-Reyes et al., 1982). The THC and THC-COOH concentrations will crossover at about 20 to 30 minutes after starting to smoke. At 1 hour after starting to smoke, plasma contained the following proportions of cannabinoids: 17% THC; 40% THC-COOH; 25% "polar acids;" and 9% different hydroxy metabolites (Wall & P6rez-Reyes, 1981). One of these, the 11-hydroxy THC, is psychoactive and is detected 951

4 at far greater concentrations following oral ingestion of marihuana than after marihuana smoking. At present, it appears that blood and plasma contain a far less complex spectrum of metabolites than does urine. However, it is important to remember that the specificity or lack of specificity of common immunoassays may have great influence on quantitative analytical results obtained from examination of blood of urine specimens. Interpretation of Blood and Plasma Concentrations; The finding of 10 ng/ml of THC in plasma (5 ng/ml in blood) probably indicates that marihuana was smoked within about 2 hours and with 20 ng/ml in plasma, within an hour. The THC plasma concentrations greater than 50 ng/ml indicate smoking within about 20 minutes; they increase very rapidly after starting to smoke and will peak within about 7 minutes; they will decline rapidly for the next 20 to 25 minutes then will decline more slowly. Concentrations of THC-COOH of 10 ng/ml are attained in less than 10 minutes after beginning smoking and will remain over 10 ng/ml for about 6 hours. They will be greater than THC concentrations in 20 to 30 minutes. Little is known about very high THC-COOH concentrations (100 ng/ml or more). It could be expected that these might be present in heavy chronic smokers but reports of this have not been found. Although no relationship has been reported between the subjects rating his "high" and possible effects on driving, it is interesting to relate the high to THC and THC-COOH concentrations. The intensity of the high increases rapidly for the first 10 minutes of smoking, peaks in the next 20 minutes, and is reported to last for up to 4 hours after smoking started (Hollister et al., 1981; P6rez-Reyes et al., 1982). This is much different from the way that THC peaks and rapidly declines. It more closely resembles the curve of THC-COOH (non-psychoactive) concentrations vs time. Little is known about the possibility of elevated concentrations of THC and THC-COOH remaining in chronic heavy smokers. A group of smokers was reported to have serum concentrations of 2 to 8 ng/ml of THC and 27 to 93 ng/ml of THC-COOH despite the fact that they were instructed to refrain from marihuana usage for a period of at least 24 hours prior to testing (Hanson et al., 1983). Concentrations of 5 ng/ml of THC were found in serum in 1 to 9 hours after different subjects smoked the same strength marihuana cigarettes. Opinions concerning concentrations and behaviors at some prior time (retrograde extrapolation) based solely on cannabinoid concentrations are unsupportable at the present time. 952

5 It appears that whatever affects marihuana may have, they will have to be interpreted based on plasma concentrations of THC greater than 10 ng/ml (5 ng/ml blood). Further, THC-COOH concentrations are probably too dependent on prior smoking habits to be used as a sole basis of effects interpretation. Reports correlating concentrations of plasma cannabinoids and driving and other performance have not been found. REFERENCES Cook, C. E. (1983). Personal communication. Gross, S. J., and Soares, J. R. (1978). Validated direct blood THC radioimmune quantitation. Journal of Analytical Toxicology, 2 : Halldin, M. M., Anderson, L. K. R., Widman, M., and Hollister, L. E. (1982 a). Further urinary metabolites of THC in man. Arzneimittel Forschung, 32: Halldin, M. M., Carlsson, S., Kanter, S. L., Widman, M., and Agurell, S. (1982 b). Urinary metabolites of THC in man. Arzneimittel Forschung, 32; Halldin, M. M., and Widman, M. (1983). Glucuronic acid conjugate of THC identified in urine of man. Arzneimittel Forschung, 33: Hanson, V. W., Buonarati, M. H., Baselt, R. C., Wade, N. A. Yep, C., Biasotti, A. A., Reeve, V. C., Wong, A. S., and Orbanowsky, M. W. (1983). Comparison of 3H- and 1251-Radioimmunoassay and gas chromatography/mass spectrometry for the determination of THC and cannabinoids in blood and serum. Journal of Analytical Toxicology, 7: Hawks, R. L. (1982). The constituents of cannabis, and the disposition and metabolism of cannabinoids. In Hawks, R. (ed.), Analysis of Cannabinoids. Research Monograph 42. Washington, D.C.: National Institute for Drug Abuse. Pp Hollister, L. E., Gillespie, H. K., Ohlsson, A., Lindgren, J. E., Wahlen, A., and Agurell, S. (1981). Do plasma concentrations of THC reflect the degree of intoxication? Journal of Clinical Pharmacology, 21: 171S-177S. 953

6 McBay, A. J., Dubowski, K. M., and Finkle, B. S. (1983). Urine testing for marihuana use. Journal of American Medical Association, 249; 881. Norton, L. E., and Garriott, J. C. (1983). Detection of marihuana by GC/MS analysis of mouth swabs. American Journal of Forensic Medicine and Pathology, 4^: Owens, S. M., McBay, A. J., Reissner, H. M., and P rez-reyes, M. (1981). 125 I-Radioimmunoassay of THC in blood and plasma with a solid-phase second-antibody separation method. Clinical Chemistry, 27: PSrez-Reyes, M., DiGuiseppi, S., Davis, K. H., Schindler, V. H., and Cook, C. E. (1982). Comparison of effects of marihuana cigarettes of three different potencies. Clinical Pharmacology and Therapy, 31; Soares, J. R., Grant, J. D., and Gross, S. J. (1982). Significant developments in radioimmune methods applied to THC and its 9-substituted metabolites in analysis of cannabinoids. Research Monograph 42. Washington, D.C.: National Institute for Drug Abuse. Pp Wall, M. E., and Perez-Reyes, M. (1981). The metabolism of THC and related cannabinoids in man. Journal of Clinical Pharmacology, 21; 178S-189S. 954