I Letter to the Editor

Journal of Analytical Toxicology, Vol. 29, November/December 2005

I

THC Can Be Detected in Brain While Absent in Blood*

To the Editor:

Cannabis use produces dose-related impairments in cognitive and behavioral functions that may induce serious consequences in a number of circumstances such as driving (1,2). Ag-Tetrahydrocannabinol (THC) and its primary metabolite, 11-hydroxy-Ag-tetrahydrocannabinol (11-OH-THC) are the active constituents responsible for the occurrence of these adverse effects. An important forensic issue is to know how long impairment persists. Some studies indicate that the effects of cannabis may still be present after THC blood concentrations have dropped to a few nanograms per milliliter (3), but this has never been confirmed by biological data. In order to answer this question, a new approach could consist of analyzing cannabinoids in brain and comparing the results obtained with those in the corresponding blood. To date only one paper has reported THC concentrations in brain, however this study was performed in only one case. In addition, metabolites were not analyzed, and the precise location of brain sample was not defined (4).

In this study, paired samples (blood and brain) were provided from 12 postmortem cases in which cannabinoids were detected in blood. THC, 11-OH-THC, and 11 nor-9- carboxy-THC (THC-COOH) were determined by gas chromatography-mass spectrometry (4). Brain samples (about 200 mg) were homogenized in pH 7.4 Tris buffer, and then extracted as blood samples were.

In the first step, 10 cases were analyzed for THC only, and the precise location of brain sampling was not defined. These results, expressed in nanograms per gram, are indicated in Table I. No correlation was observed between blood and brain concentrations of THC. In all cases, THC was found in brain at significant concentrations as compared with those reported by Kudo et al. (5). THC concentrations in brain were higher than THC concentrations in blood in all cases. In three cases (8-10) THC was still present in brain, whereas it was not detected in blood (limit of detection, 0.2 ng/mL). These results could explain the recent findings of Herning et al. (6), revealing that cerebrovascular resistance and systolic velocity are significantly increased in marijuana users after a month of monitored abstinence.

Taking into account these results, 11-OH-THC and THC-COOH were also analyzed in two cases where the location of brain samples were defined. The mean concentration (n = 3) obtained in blood and in several brain areas are presented (Table II). These results indicate that THC was present at significant concentrations in all brain

Table I. Cannabinoids Concentrations in Human Brain and Blood Samples

Case THC Blood THC.COOH Blood THC Brain No. (ng/mL) (ng/mL) (ng/g)

1 0.5 2.8 0.9 2 0.6 13.0 1.1 3 1.8 3.6 2,5 4 2.3 6.0 2.9 5 3.0 28.7 12.4 6 4.4 11.0 19.4 7 11.5 66.0 20.8 8 <0,2 8.9 1.6 9 <0.2 1.8 2.2

10 < 0.2 6.1 29.9

Table II. Cannabinoids in Blood and in Different Brain Areas from Two Regular Cannabis Smokers

THC 11-OH-THC THC-COOH

Case 11 Blood (ng/mL) 5.4 2.8 38.3

Locus niger (ng/g) 35.6 16.6 28.8

H ippocampus (ng/g) 17.9 11.1 17.9

Occipital lobe (ng/g) 16.6 11.7 27.8

Striatum-putamen- pallidum (ng/g) 20.0 14.7 26.1

Frontal lobe (ng/g) 12.6 12.5 12.5

Spinal cord (ng/g) 27.0 12.0 28.7

Corpus callosum (ng/g) 38.6 15.8 16.8

Case 12 Blood (ng/mL) 8.3 2.7 22

Cortex (ng/g) 10.2 10 18.1

White matter (ng/g) 10.4 4.9 16.6

* This study was carried out with financial support from the French Ministry of Health, in the framework of a clinical research regional program.

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Journal of Analytical Toxicology, Vol, 29, November/December 2005

regions assayed. These brain regions are where cannabis CB1 receptors are present in high densities (7), consistent with the postulated consequences of cannabis use on behavioral and cognitive functions. The very high THC concentration found in locus niger is interesting because it could be related to a potential role of cannabinoids in Parkinson's disease as described by some authors (8). Such findings could be of great interest for further studies. In brain, THC concentrations were always higher than 11-OH-THC concentrations and carboxy-THC concentrations generally were equivalent or greater than THC concentrations. Although the mechanisms of action of THC are now well documented, little data exist about the role of 11-OH-THC. The possible consequences of THC-COOH's presence in brain needs to be determined.

As a conclusion, our observations demonstrate that active constituents of cannabis may be present in brain when they are no longer detectable in blood. Moreover, the identification of metabolites such as 11-OH-THC and THC-COOH in brain suggests the need for further research.

Patrick Mura 1, Pascal Kintz 2, V6ronique Dumestre 3, S~bastien Raui 4, and Thierry Hauet 1

1Laboratoire de Biochimie et Toxicologie, Centre Hospitalier Universitaire, BP 577, 86021, Poitiers, France; 2Laboratoire ChemTox, X'pertise Consulting, Strasbourg, France; aLaboratoire Toxgen, Bordeaux, France; and 4Institut de M~decine L~gale, Strasbourg, France

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Coartet, and O. Pourrat. Comparison of the prevalence of alcohol, cannabis and other drugs between 900 injured drivers and 900 control sub- jects: results of a French collaborative study. Forensic Sci. Int. 133:79-85 (2003).

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4. P. Kintz and V. Cirimele. Testing human blood for cannabis. Biomed. Chromatogr. 11:371-373 (1997). 5. K. Kudo, T. Nagata, K. Kimura, T. Imamura, and N. Jitsufuchi. Sensitive determination of Ag-tetrahydrocannabinol in human tissues by GC-MS.

J. Anal ToxicoL 19:87-90 (1995). 6. R.I. Herning, W.E. Better, K. Tate, and J.L. Cadet. Cerebrovascular peffusion in marijuana users during a month of monitored abstinence. Neu-

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