PSYCHIATRY RESEARCH NEUROIMAGING Psychiatry Research: Neuroimaging 67 (1996) 29-38 Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication Nora D. Volkow*avb, Hampton Gillespie”, Nizar Mullanid, Lawrence Tancredic, Cathel Grantc, Allan Valentinec, Leo Hollister” ‘Medical Department, Brookhaven National Laboratory. Upton, NY 11973. USA bDepartment of Psychiatry, State University of New York at Stony Brook, Stony Brook, NY II 794, USA ‘Department of Psychiatry, University of Texas in Houston, Houston, TX 11973. USA ‘Department of Internal Medicine, University of Texas in Houston, Houston, TX 11973. USA Received 4 April 1995; revised 12 July 1995; accepted 8 August 1995 AbSWCt Despite the widespread abuse of marijuana, knowledge about its effects in the human brain is limited. Brain glucose metabolism with and without A’tetrahydrocannabinol (THC) (main psychoactive component of marijuana) was evaluated in eight normal subjects and eight chronic marijuana abusers with positron emission tomography. At baseline, marijuana abusers showed lower relative cerebellar metabolism than normal subjects. THC increased relative cerebellar metabolism in all subjects, but only abusers showed increases in orbitofrontal cortex, prefrontal cortex, and basal ganglia. Cerebellar metabolism during THC intoxication was significantly correlated with the subjective sense of intoxication. The decreased cerebellar metabolism in marijuana abusers at baseline could account for the motor deficits previously reported in these subjects. The activation of orbitofrontal cortex and basal ganglia by THC in the abusers but not in the normal subjects could underlie one of the mechanisms leading to the drive and the compulsion to self-administer the drug observed in addicted individuals. Keywords: Positron emission tomography; ganglia; Substance abuse Delta-9-tetrahydrocannabinol; 1. -00 Marijuana is the most widely used illicit drug of abuse in the United States (National Institute on Drug Abuse, 1991), but its acute and chronic Correspondingauthor, h&dical Department, Building 490, ?? Breokhaven National Laboratory, Upton, NY 11973, USA, Tel: +I 516 282-3335; Fax: +I 516 282-5311. Cerebellum; Orbitofrontal cortex; Basal effects on brain function are not clearly understood (Martin, 1986). Furthermore, whether chronic marijuana use leads to cerebral dysfimction and brain damage is still a matter of debate (Stefanis et al., 1976). Multiple pharmacological actions for A9tetrahydrocannabinol (THC) (the main psychoactive component of marijuana) have been reported, but their involvement in the reinforcing, addicting, and behavior-impairing proper- 0925-4927/9WS15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PM: SO925-4927(96)02817-X 30 N.D. Volkow et al. /Psychiatry Research: Neuroimaging 67 (19%) ties of THC is mostly unknown (reviewed by Martin, 1986). Imaging studies that measure the effects of acute and chronic marijuana administration on regional brain glucose metabolism or cerebral blood flow (CBF) permit the investigation of THC’s actions in the human brain. These measures are useful indicators of brain function because CBF and brain glucose metabolism, under physiologic conditions, are tightly coupled with brain activity (Sokoloff et al., 1977). Although studies of the effects of acute and chronic marijuana use on CBF have been reported (Tunving et al., 1986; Mathew et al., 1989; Mathew and Wilson, 1992), their interpretation with respect to functional brain effects is confounded by the vasoactive properties of THC (Nahas, 1986). We had previously assessed the regional brain metabolic effects of acute THC in normal subjects and reported an increase in cerebellar metabolism (Volkow et al., 1991); however, that study did not address aspects related to chronic THC use such as addiction and toxicity. This study evaluates regional brain metabolism at baseline and during THC intoxication in marijuana-dependent subjects versus normal volunteers. We predicted that acute THC would elicit a different regional brain metabolic response in marijuana-dependent subjects since they show poor control over drug intake while nondrugdependent subjects do not. 2. Methods 2.1. S&jects Patients were eight healthy right-handed men (mean age = 31 years, SD = 6) who met D&U-IIIR criteria for cannabis dependence (American Psychiatric Association, 1987). Subjects dependent on other drugs of abuse were excluded (except for caffeine and/or nicotine). A cut limit for exclusion included use of other drugs (except for caffeine and/or nicotine) more than twice a week and abuse of marijuana for < 18 months. Subjects had abused marijuana consistently for an average of 5.5 * 2 years. Two of the subjects reported using the drug on an average of l-3 days a week, one reported using it 2-4 days a week, and five reported using it 4-7 days a week. On days when 29-38 they used the drug, subjects reported using one to five joints a day. The normal comparison group consisted of eight healthy right-handed men (mean age = 35 years, SD = 7). Subjects with a past or present history of drug abuse or dependence (apart from nicotine and/or caffeine), who used marijuana more than twice a year, or who had never used marijuana were excluded. All subjects underwent a complete physical and medical examination to exclude the presence of medical, psychiatric, or neurologic disease, except for marijuana dependence in the patients. None of the subjects were taking regular medication at the time of the study, and subjects were requested not to use any drug 72 h before the PET scan. Blood screens were obtained before the PET scan to ensure absence of psychoactive drug use. Informed consent was obtained from all subjects, and the study was approved by the Human Protection Committee at the University of Texas Health Sciences Center in Houston. Data for four of the normal subjects have been published (Volkow et al., 1991). 2.2. PET scan The studies were done with a TOFPET camera (9 planes, in-plane and axial resolution, respectively, of 1.2 and 1.1 cm full-width half-maximum) (Mullani et al., 1982). Subjects had two catheters implanted, one in the antecubital vein for injection of tracer, and the other in the radial artery for plasma sampling. A transmission scan was obtained before the emission scan to correct for attenuation. Emission scans were performed 35 min after injection of 6-7 mCi of 2deoxy-2-[ ‘*F]-fluoro-Dglucose for a total of 20 min, in a dimly lit room with noise kept to a minimum (the only intervention was the periodic evaluation of subjects). During the study, blood sampling was obtained to qua&ate for F-18, THC, and 11-nor-9-carboxy THC (THC-COOH). Measurements of THC and its metabolite, THC-COOH, in plasma were done using capillary column gas chromatography with negative ion chemical ionization/mass spectrometry before and at 30 and 60 min after THC administration (Foltz et al., 1983). Subjects were scanned twice 24 h apart. The scans were done at the same N. D. Volkow ei al. /Psychiatry time of day with subjects (eyes open and ears unplugged) lying supine in the PET camera. The first scan was done with no intervention and the second was done 30-40 min after THC (2 mg, i.v.). THC was dissolved in a 3-ml solution of 95% ethanol, which was slowly injected into the port of a rapidly running saline solution. The 2-mg i.v. dose of THC was chosen because it consistently induces behavioral effects and is well tolerated by subjects (Volkow et al., 1991). Subjects were told they were given THC. Baseline scans were done before the THC scans to avoid confounding from long-term effects of acute THC. Subjects were asked to rate their subjective experience of intoxication on an analog scale from 0 (no effect) to 10 (maximal effect) every 10 min for the first hour after THC injection and then every 20 min. Before THC administration and at the end of the PET scan (90- 110 min after THC), subjects were questioned about the presence of paranoid symptoms and a test for motor effects was performed. For the motor test, subjects were evaluated from 0 to 10 by scoring (0 = no effect, 1 = moderate effect, 2 = severe effect) the following parameters: gait, tremors, muscular twitches, Research: Neuroimaging 67 (1996) 29- 38 rhythm, and equilibrium as described (Volkow et al., 1991). The motor test was done at the end of the PET procedure to avoid confounding the brain metabolic activity with the motor behavior. 2.3. Analysis A template that identified a total of 41 regions was projected directly onto the metabolic images and was manually fitted into the individual images (Fig. 1). The 41 regions were grouped into 12 the ‘composite’ regions which represented weighted average of regions of interest (ROIs) from different planes corresponding to the same anatomical structure. In addition, a ‘global brain’ region was obtained by averaging the activity in the six sequential planes that followed the uppermost plane. Due to calibration errors in the counter used to measure F-18 in the arterial samples, we did not quantify absolute metabolism. Instead ‘relative measures’ were obtained using the ratio of radiotracer concentration in a given region to that of the ‘global brain’ region. Differences in ‘relative’ metabolism between subjects and abusers were tested using a repeated measures analysis of variance (ANOVA) with PR L LP RF RP LP OFC I 31 OFC 0 Fig. 1. Template for the lo&ion of regions of interest used in the analysis of metabolic images. PR, prefrontal; LF, left frontal; RF, right frontal;OFC, orbitofrontal cortex; LP, left parietal; RP, right parietal; LT, left temporal; RT, right temporal; OC, occipital; BGL, basal ganglia; TH, thalamus; CBL, cerebellum. 32 N.D. Volkow et al. /Psychiatry Research: Neuroimaging 67 (19% ) group (normal subjects vs. marijuana abusers) as a between-subjects factor and condition (baseline vs. THC intoxication) as a within-subjects factor. A separate factorial ANOVA was performed on the regional brain metabolic changes with THC quantified as percent change from baseline. Post hoc t tests were then performed on significant measures to assess differences between the groups in baseline measures and in their response to THC assessed as percent change from baseline. The relations between plasma concentrations of THC and THC-COOH and THC-induced behavioral and metabolic changes (percent change from baseline) were evaluated using Pearson productmoment correlation analysis. Evaluation of the relation between regional metabolism and behavioral effects of THC used the metabolic measures during intoxication, rather than percent change, since a drug-induced state is likely to be the resultant of the unique pattern of brain metabolism at the time of intoxication. Levels of significance were set at P < 0.01 for ANOVA and correlation analysis, and at P < 0.05 for post hoc t tests (Volkow et al., 1986). 3. Results 3.1. Plasma THC levels There w ere no between-group differences in plasma THC concentration. Plasma levels of THC-COOH were higher in marijuana abusers than in normal subjects, but the difference was not significant (Table 1). 29- 38 3.2. Behavioral response to THC subjects showed a more intense subjecNor14 tive response to the action of THC than the marijuana abusers (Table 1) (F= 33.41, df= 1,14, P s 0.0001) (Table 2). Although the motor impairing effects of marijuana were more accentuated in normal subjects than in marijuana abusers, the difference was not significant (P = 0.11). The groups did not differ in THCinduced paranoid symptoms. 3.3. Baseline brain metabolism Table 3 shows the relative metabolic values at baseline and during THC intoxication for the normal subjects and the marijuana abusers. The twoway repeated measures ANOVA revealed a group effect for regional metabolism in frontal and cerebellar regions, but the post hoc t tests for baseline measures were only significant for the cerebellum (t = 2.8, df = 14, P < 0.02). Marijuana abusers had signifkantly lower baseline cerebellar metabolic values than normal subjects (see Fig. 2). 3.4. M etabolic response to THC The condition effect (baseline vs. THC) was significant and showed that THC intoxication increased relative metabolism in prefrontal cortex, left and right frontal cortices, and right temporal cortex and cerebellum (Table 3). The group (normal subjects vs. abusers) x condition (baseline vs. THC) effect was significant for prefrontal cortex, orbitofrontal cortex, and basal ganglia (Table 3). A separate ANOVA on the mea- Table 1 Plasma levels of A9tetrahydrocamabinol (THC) and its metabolite, 1I-nor-9-carboxy THC (THC-COOH). in normal subjects and marijuana abusers at 30 and 60 min after THC administratioo Subjects 3omin 6OOliO THC Normal subjects Marijuana abusers THC-COOH THC THC-COOH Meao SD Mean SD Mean SD Mean SD 18.42 11.13 9 5 26.3 63 8 59 7.2 6.1 1 2 30.9 57.14 10 13 between-group diffaencesin plasmaTHC concentm.ioo. Although plasma levels of THC-COOH were higher in the marijuana abusers than in the oomml subjects, this difhncc was not statistically signifiit. Plasma values are expressed as Note. There wcm no aghal. 'So'0 > de :SJW'lq8W8l@?lUpU8Sl# qns ~s~uou ucml3q 3u!lmq 18 wnl8A 3p?q8l?rujo ‘~Oplp~03 ‘dnofi :swgp lua~?~~!pa~ JOJ umoqs9~8 zx18y8~~0 S!S&U8?qlJoJ(1~0 800-O > d ‘5’6 = d SN 10’0 > d ‘8’8 =Ll SN SN SN SN SN 100’0 > d ‘25’81 =d SN SN SN SN SN SN SN 100’0 > d ‘L’81 =d SN MIO’O > d > dnoJ%)uop38.mu! pm, @to WON ‘SZI =d EO’O ZI’I Lo’0 Lo’1 90’1 62’1 So’0 Lo’0 80’0 80’1 60’1 EE’I PO’0 Lo’0 80’0 01’1 50’1 WI PO’0 zwo so’0 90’0 Cl’1 SO’I LI’I 80’1 PO.0 wo EO’O SO’0 LI’I Lo’1 61’1 60’1 w’o 10’0 ‘30 So’0 PI.1 so’1 81’1 80’1 PI’1 SO’0 LO’1 co’0 60’1 90’0 21’1 CO.0 91’1 20’0 11’1 20’0 ZI’I ZO’O 01’1 ZI’I 20’0 Lo’1 wo 90’1 PO.0 so‘1 PO’0 60'1 tco 01'1 so'0 60'1 Lo’0 EO’I Lo’0 *86’0 SN SN SN PO’0 60’0 80’0 ZI’I 80’1 8Z’I 90’0 Lo’0 90’0 SN SN SN SN HJO Sl’l EO’O 80’1 80’0 61’1 80’0 11’1 SN so’0 80’1 “1119aw ‘J!@d lBFBB mmlsKL wdm l=duu, wdutn l%!X WI wa!Jd Is%!ll wa!Jd WI ~8luoJ~-ol!qJ~ ‘5’1 I =d I8lUO JJ I@ !U d ‘S’ZI =d SN PO’0 d 'I'SZ =d SN SO'0 91’1 w”oJJ WI 100’0 > ‘Z'ZI =J as -kv 3H.L la?gJ uoymaxq uo!WW uoyqxolu! x S00'0>d ‘L’OZ = d SO O ’O '(UOpyKM > d‘PI‘I =&)SS4+tW83g!U@S 500'0 > d SN 100'0>d SN uospudum isaw 3oq lsod JO 13myyx8!s as u8w as u-i4 as 3H.L VU!l=H I~UOJPJd uwt4 =nn?wa =w dnoa (8 = u) gu8nqB =“bJ’W (3HJ+) ~U!q8UU83O~@W$$7 Pupnp put? aqamq (8 = “) Q=f‘lns 18 SJVSllq88U8dIJBul pun sp a fq ns suo@ax twuoN lwuJo u Iq lm 3~ a q 8lm a A !ie la x E 998.L Z t’l E 6’1 Z P SE P 6’P I as rre3yy stuo,dtis P!oumd as u8W WIJIJ~UI! Jolofl SJ?snqU 8U8d+?UJ pU8 SldqtIS PUUOU as uoyqxo~u! *L’P Z’6 s.mnqs =%ns 8U8n[~Uyy I-ON u8W JO 1~113s=Awfqns U! ~OU!q8UU830Jpr(q8J~CQ6~J0UO!l8JlS!tqUJpU 1lZl3801 modS3J w?qns I8JO!ASqw z 1IQ8.L EE N. D. Volkow et al. /Psychiatry Research: Neuroimaging 67 (19%) 29-38 Fig. 2. Baseline brain metabolic images in a normal subject and a marijuana abuser. The four images represent different levels of the brain; two were obtained at basal ganglia levels and two at cerebellar levels. Colors represent different levels of metabolism with red > yellow > green > blue > purple. The images were scaled to the maximum value for the two studies. trend toward a correlation with subjective sense of intoxication (r = 0.53, df = 15,P < 0.05). There were no significant correlations between percent change in metabolism and THC concentration in plasma. None of the correlations with plasma THC-COOH were significant. Correlations between the subjective sense of THC intoxication and regional brain metabolism during THC intoxication were only significant for the cerebellum (r = 0.79, df = 15, P < 0.001). The larger the cerebellar metabolism during THC intoxication, the larger the subjective sense of intoxication (Fig. 4). 4. Discussion This study shows significantly lower baseline cerebellar metabolism in marijuana abusers than in normal subjects. Because the cerebellum has a high concentration of cannabinoid receptors (Herkenham et al., 1990), the decreases in cerebellar metabolism in the marijuana abusers could reflect changes in cannabinoid receptors attributable to chronic marijuana use. Abnormal cerebellar metabolism in the marijuana abusers could account for the impairments in motor performance reported in these subjects (Dombush N. D. Volkow et al. /Psychiatry -7 ! Research: Neuroimaging 67 (19%) 35 29-38 b PR LF RF OFC’ LP RP LT RT OC TH BGL’ CBL Fig. 3. Percent change in relative metabolic activity during A’tetrahydrocannabinol intoxication in normal subjects and marijuana abusers. See note to Fig. 1 for abbreviations of brain regions. Comparisons representdifferences in response between normal subjects (hatched) and marijuana abusers (black). ‘P < 0.01; bP < 0.005; ‘P < 0.001. lot 5 ‘g 2 g c 6.0 - 6.0 - 6 ~ 4.0 - ,r t $ 2.0 - Fig. 4. Correlation between the subjective sense of A’tetrahydrocannabinol (THC) intoxication and cenbellar metabolism during THC intoxication (r = 0.79, df= 15, P C 0.001). and Kokkevi, 1976; Mendhiratta et al., 1978; Varma et al., 1988) as well as the high frequency of accidents associated with THC intoxication (Yesavage et al., 1985; Kirby et al., 1992). The cerebellum also appears to play a role in learning (Decety et al., l!SO), and its disruption by chronic THC could contribute to the learning impairment in chronic marijuana users (Rickles et al., 1973; Schwartz et al., 1989) as well as the impairment during THC intoxication (Abel, 1970; Tinkle&erg et al., 1970; Dombush et al., 1971; Rickles et al., 1973; Reautris and Marks, 1976; Schwartz et al., 1989). Cannabinoid receptors are also localized in other discrete brain areas - namely, hippocampus, substantia nigra pars reticulata, and globus pallidus (Herkenham et al., 1990) - but those 36 N. D. Volkow et al. /Psychiatry Research: Neuroimaging 67 (1996) 29-38 areas are too small to be measured with the spatial resolution of the PET instrument used The cerebellum was also an area in which significant increases in metabolism were observed during THC intoxication in normal subjects and marijuana abusers. These results replicate in marijuana abusers our previous findings of increased cerebellar metabolism during THC intoxication in normal healthy volunteers (Volkow et al., 1991). Cerebellar metabolism during THC intoxication was significantly correlated with the subjective sense of THC-induced intoxication. Although there is not much information about the role that the cerebellum plays in the intoxicating properties of drugs in humans, animal studies have shown that it may contribute to drug self-administration (McDonald, 1953) and that animals will selfstimulate into this brain region (Plotnik et al., 1972; Ball et al., 1974). The cerebellum has connections with the limbic system (Heath and Harper, 1974) and with the prefrontal cortex (Leiner et al., 1989), so that cerebellar activation could lead via its neuroanatomic connections to activation of brain areas directly involved with reward processes. During THC intoxication, there were also increases in metabolism in prefrontal cortex, frontal co&es, and right temporal cortex. Increases in metabolism in prefrontal cortex were significantly higher in abusers than in normal subjects, a tinding that is in agreement with previous findings documenting prefrontal activation during THC intoxication in regular but not in infrequent marijuana abusers (Mathew and Wilson, 1992). In addition, abusers, but not normal subjects, showed significant increases in metabolism in orbitofrontal cortex and in basal ganglia. The unique pattern of activation observed in the marijuana abusers is particularly interesting in that previous imaging studies found metabolic abnormalities in orbitofrontal cortex and basal ganglia in cocaine abusers (Volkow et al., 1990) and alcoholics (Volkow et al., 1993b). Because the orbitofrontal cortex and the basal ganglia form part of a cerebral circuit involved in the regulation of the initiation and termination of behaviors (Model1 et al., 1990), disruption of these regions in the addicted subject has been postulated to lead to the loss of control and the compulsion to selfadminister cocaine (Volkow et al., 1990, 1993a) and alcohol (Model1 et al., 1990; Volkow et al., 1993b). Metabolic abnormalities in orbitofrontal cortex and basal ganglia have also been reported in patients with obsessive-compulsive disorders, for whom they have been linked to compulsive behaviors and obsessive thoughts (Baxter et al., 1987). The orbitofrontal cortex receives direct projections from the dopamine pathway in the ventral tegmental area (reviewed by Model1 et al., 1990), which is implicated in the reinforcing properties of drugs of abuse (Di Chiara and Imperato, 1988; Koob and Bloom, 1988). Furthermore, THC has been shown to increase dopamine concentrations in prefrontal cortex (Chen et al., 1990). Thus, one could postulate that chronic use of drugs, which directly or indirectly stimulate the mesocortical dopamine pathway, could lead to disruptions in the orbitofrontal cortex and associated striatal pathways. These pathways could become hyperactive when the drug is taken or with associated drug cues, leading to loss of control and compulsive drug use. Because the orbitofrontal cortex is regulated by multiple neurotransmitters (reviewed by Model1 et al., 1990), it is likely that nondopaminergic pathways also contribute to the increased sensitivity to activation in the addicted individual. In general, most studies evaluating the effects of acute single drug administration on regional brain metabolism have demonstrated decreases after cocaine (London et al., 199Ob), heroin (London et al., 199Oa), amphetamines (Wolkin et al., 1987), alcohol (DeWit et al., 1990; Volkow et al., 1990), and benzodiazepines (DeWit et al., 1991; Volkow et al., 1995) To our knowledge, marijuana is the only drug of abuse that does not show a reduction in absolute metabolism after a single acute administration (Volkow et al., 1991). Unfortunately, in the current investigation, absolute measures could not be obtained to determine if THC, as previously shown in normal subjects, failed to decrease absolute metabolic measures (Volkow et al., 1991). Because of the relatively long half-life of THC in tissue, the possibility needs to be entertained that there may have been residual effects from the drug in the baseline scans in the abusers. Although plas- N. D. Volkow et al. /Psychiatry ma screens were done before the PET scans, their sensitivity is limited. Alternatively, the baseline scans in the abusers could also have been influenced by the effects of THC withdrawal. Other limitations of this study relate to the multiple uncertainties surrounding the pattern of drug use among the abusers as well as the accuracy of the information that they supplied. For example, an accurate quantification of THC use was not possible in these subjects nor was it possible to estimate their exact use of alcohol or other drugs such as nicotine and caffeine that have also been shown to affect CBF and glucose metabolism. Because of this limitation, it is not possible to address the specificity of the current results with respect to THC use rather than ‘drug use’ or to rule out the possibility that cerebellar abnormalities preceded THC abuse. This study reports decreased baseline cerebellar metabolism in chronic marijuana abusers and documents activation of orbitofrontal cortex and basal ganglia during THC intoxication in marijuana abusers but not in normal subjects. Acknowledgme~~ts Research: Neuroimaging 67 (1996) 29- 38 37 eBlux in medial prefrontal cortex. Eur J Pharmacol 190, 259-262. Decety, J., SjBhohn, H., Ryding, E., Stenberg, G. and Ingvar, D. (1990) The cerebellum participates in mental activity: tomographic measurements of regional cerebral blood flow. Brain Res 535, 313-317. DeWit, H., Metx, J., Wagner, N. and Cooper, M. (1990) Behavioral and subjective effects of ethanol: relationship to cerebral metabolism using PET. Alcohol CIin Exp Res 14, 482-489. DeWit, H., Metx, J., Wagner, N. and Cooper, M. (1991) Effects of diaxepam on cerebral metabolism and mood in normal volunteers. Neuropsychopharmacology 5, 33- 41. Di Chiara, G. and Imperato, A. (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesoliibic system of freely moving rats. Proc Nat1 Acad Sci USA 85, 5274- 5278. Dombush, R.L., Fink, M. and Freedman, A.M. (1971) Marijuana, memory and perception. Am J Psychiatry 128, 194- 197. Dombush, R.L. and Kokkevi, A. (1976) The acute effects of various cannabis substances on cognitive, perceptual and motor performance in very long term hashish users. In: Braude, M.C. and Sxara, S. (Eds.), Pharmacology of M arihuana. Raven Press, New York, pp. 421-427. Foltx, R.L., McGinnis, K.M. and Chime, D.M. (1983) Quantitative measurement of 9delta-tetrahydrocannabinol and two major metabolites in physiological specimens using capillary column gas chromatography negative ion chemical ionization mass spectrometry. Biomed M ass Spect IO, 316- 323. This research was supported in part by the U.S. Department of Energy under Contract DE-ACO*76CHOOO16and National Institute on Drug Abuse Grant No. 5ROl-DA-06278. References Abel, E.L. (1970) Marijuana and memory. Nature 227, 1151-1152. American Psychiatric Association. (1987) DSM -III-R: Dingnwtic and Statistical M anual of M ental Disorders. 3rd rev. edn. American Psychiatric Press, Washington, DC. Ball, G.G., I&co, D.J. and Bemtson, G.G. (1974) Cerebellar metabolism in the rat: complex stimulation-bound oral behavior and self-stimulation. Phy siof Rehav 13, 123- 127. Baxter, L.R., Phelpa, M.E., Maxxiotta, J., Guxe, B.H., Schwartz, J.M. and Selin, C.E. (1987) Local cerebral ghicase metabolic rates in obsessive compulsive disorder: a comparison with rates in unipolar depression and normal controls. Arch Gen Psychtatry 44, 21 l-218. Beautris, A.L. and Marks, D.F. (1976) A test of state dependency effects in marihuana intoxication for the learning of psychomotor tasks. Psychophannacologia 46, 37- 40. Chen, J., Paredes, W., Lowinson, J. and Gardner, E.L. (1990) A%‘etrahydrocannabinol enhances presynaptic dopamine , Heath, R.G. and Harper, J.W. (1974) Ascending projection of the cerebellar fastigial nucleus to the hippocampus, amygdaIa and other temporal lobe sites: evoked potential and histological studies in monkeys and cats. Exp Neurol 45, 268-287. Herkenham, M., Lynn, A.B., Little, M.D., Ross Johnson, M., Melvin, L.S., DeCosta, B.R. and Rice, K.C. (1990) Cannabinoid receptor localization in brain. Proc Nat1 Acad Sci USA 87, 1932- 1936. Kirby, J.M., Maull, K.I. and Fain, W. (1992) Comparability of alcohol and drug use in injured drivers. South M ed J 85, 300- 302. Koob, G.F. and Bloom, F.E. (1988) Cellular and molecular mechanisms of drug dependence. Science 242, 715-723. Leiner, H.C., Leiner, A.L. and Dow, R. (1989) Reappraising the cerebellum: what does the hindbrain contribute to the forebrain? B&v Neurosci 103, 998-1008. London, E.D., Broussolle, E.P.M., Links, J.M., Wong D.F., Cascella, N.G., Dannals, R.F., Sano, M., Heming, R., Snyder, F.R., Rippetoe, L.R., Toung, T.J.K., Jaffe, J.H. and Wagner, H.N. (1990a) Morphine induced metabolic changes in human brain: studies with positron emission tomography and fluorine-18 fluorodeoxyglucose. Arch Gen Psychiatry 47, 73- 82. London, E.D., Cascella, N.G., Wong, D.F., Phillips, R.L., Dannals, R.F., Links, J.M., Heming, R., Grayson, R., 38 N. D. Volkow et al. /Psychiatry Research: Neuroimaging 67 (19% ) Jaffe, J.H. and Wagner, H.N. (1990b) Cocaine-induced reduction of ghtcose utilization in human brain: a study using positron emission tomography and [fluorine-18]fluorodeoxyglucose. Arch Gen Psychiatry 41, 567- 574. Martin, B.R. Cellular effects of cannabinoids. (1986) Pharmacol Rev 38, 45-74. Mathew, R.J. and Wilson, W.H. (1992) The effects of marijuana on cerebral blood flow and metabolism. In: Murphy, L. and Bartke, A. (Eds.), M arijuana&znnabinoi& Neurobiology and Neurophy siology . CRC Press, Boca Raton, FL, pp. 337-386. Mathew, R.J., Wilson, W.H. and Tant, S.R. (1989) Acute changes in cerebral blood flow associated with marijuana smoking. Acta Psych&r Stand 79, 118-128. McDonald, J.V. (1953) Responses following electrical stimulation of anterior lobe of cerebellum in rat. J Neurophy sioll6, 64- 84. Mendhiratta, S.S., Wig, N.N. and Varma, V.K. (1978) Some psychological correlates of long-term heavy cannabis users. Br J Psychiatry 132, 482-486. Modell, J.G., Mountx, J.M. and Beresford, TP. (1990) Basal ganglia/Iiibic striatal and thalamocortical involvement in craving and loss of control in alcoholism. J Neuropsychiatry 2, 123- M . Mullani, N., Wang, W.H. and Hartz, R.H. (1982) Design of TOFPET: a high resolution time of flight positron camera. IEEE Trans Nucl Sci 29, 31- 39. Nahas, G.G. (1986) Toxicology and pharmacology, In: Nahas, G.G. (Ed.), Mar&ana in Science and M edicine. Raven Press, New York, p. 109. National Institute on Drug Abuse. National Household Survey on Drug Abuse. (1991) Superintendent of Documents, U.S. Government Printing Office, Washington, DC. Plotnik, R., Mir, D. and Delgado J.M.R. (1972) Map of reinforcing sites in the rhesus monkey brain. Int J Psy chobiol2, l- 21. Rickles, W.H., Jr., Cohen, M.J., Whitaker, C.A. and McIntyre, K.E. (1973) Marijuana-induced state-dependent verbal learning. Psychopharmacologia 30, 349-354. Schwartz, R.H., Gruenewald, P.J., Khtxner, P. and Fedio, P. (1989) Short term memory impairment in cannabisdependent adolescents. Am J Dis Child 143, 1214-1219. Sokoloff, L., Reivich, M., Kennedy, C., Des Rosiers, M.H., Patlak, C.S., Pettigrew, K.D., Sakurada, 0. and Shinohara, M. (1977) The ttC deoxyghtcose method for the measurement of local cerebral glucose utilization: the conscious and anesthetized albino rat. J Neurochem 28, 897- 916. Stefanis, C., Boulougouris, J. and Liakos, A. (1976) Clinical and psychophysiological effects of cannabis in long-term 29- 38 users. In: Braude, M.C. and Sxara, S. @is.), Pharmacology ofMarihuana. Raven Press, New York, pp. 659-665. Tinklenberg, J.R., Melges, F.T., Hollister, L.E. and Gillespie, H.K. (1970) Marijuana and immediate memory. Nature 226, 1171- 1172. Tunving, K., Thulin, SD. and Risberg, J. (1986) Regional cerebral blood flow in long-term heavy cannabis use. Psychiatry Res 17, 15- 21. Varma, V.K., Malhotra, A.K., Dang, R., Das, K. and Nehra, R. (1988) Cannabis and cognitive functions: a prospective study. Drug Alcohol Depend 21, 147- 152. Volkow, N.D., Brodie, J.D., Wolf, A.P., Gomez-Mont, F., Cancro, R., Van Gelder, P., Russell, J.A.G. and Overall, J. (1986) Brain organization of schiiophrenics. J Cereb Blood Flow Metab 6,.441-446. Volkow, N.D., Fowler, J.S., Wang, G.-J., Hitzemann, R., Logan, J., Schlyer, D., Dewey, S. and Wolf, A.P. (1993a) Dopaminergic dysregulation of frontal metabolism may contribute to cocaine addiction. Synapse 14, 169-177. Volkow, N.D., Gillespie, H., Mullani, N., Tancredi, L., Grant, C., Ivanovic, M. and Hollister, L. (1991) Cerebellar metabolic activation by delta-9-tetrahydrocannabinol in human brains: a study with positron emission tomography and tsF-2-fluoro-2deoxyglucose. Psychiatry Res Neuroimaging 40, 69- 78. Volkow, N.D., Him, R., Wolf, A.P., Logan, J., Fowler, J.S., Christman, D., Dewey, S.L., Schlyer, D., Burr, G., Vitkun, S. and Hirschowitx, J. (1990) Acute effects of ethanol on regional brain glucose metabolism and transport. Psychiatry Res Neuroimaging 35, 39- 48. Volkow, N.D., Wang, G.J., Hitxemann, R., Fowler, J.S., Pappas, N., Loremier, P., Burr, G., Pascani, K. and Wolf, A.P. (1995) Depression of thalamic metabolism by loraxepam is associated with sleepiness. J Neuropsycharmacol 12, 123-132. Volkow, N.D., Wang, G.-J., Hitxemann, R., Fowler, J.S., Wolf, A.P., Pappas, N., Biegon, A. and Dewey, S.L. (1993b) Decreased cerebral response to inhibitory neurotransmiesion in alcoholics. Am J Psychiatry 150, 417- 422. Wolkin, A.B., Angrist, B., Wolf, A.P., Brodie, J.D., Wolkin, B., Jaeger, J. and Cancro, R. (1987) Effects of amphetamine on local cerebral metabolism in normal and schizophrenic subjects as determined by positron emission tomography. Psychophamtacology 92, 241-246. Yesavage, J.A., Leirer, V.O., Denari, M. and Hollister, L.E. (1985) Carry-over effects of marijuana intoxication on aircraft pilot performance: a preliminary report. Am J Psychiatry 142, 1325- 1329.