Marijuana intoxication and brain activation in marijuana smokers

Life kicnces, Vol. 60, No. 23, pp. 2075-2~389,1997 Copyight 0 1997 Etsevicr Science Inc. Printed in the USA. All riats resewed 0024-3205/97 $17.00 + .m

PII s0024-3205(97)00195-1

ELSEVIER

MARIJUANA INTOXICATION AND BRAIN ACTIVATION IN MARIJUANA SMOKERS

Roy J. Mathew, William H. Wilson, R. Edward Coleman, Timothy G. Turkington, Timothy R. DeGrado

Department of Psychiatry and Radiology, Duke University Medical Center, Durham, NC, 27710. (Received in final form February 27, 1997)

Objective and Method: The acute effects of delta9 tetrahydrocannabinol (THC) on cerebral blood flow (CBF) were studied in human subjects. Regional CBF was measured with 150-water and Positron Emission Tomography (PET) in 32 volunteers with a history of exposure to marijuana. Scans were performed before and after intravenous (IV) infusion of either of two doses of THC or a placebo, given under double blind conditions. Results: THC but not placebo increased CBF especially in the frontal regions bilaterally, insula and cingulate gyrus and sub-cortical regions with somewhat greater effects in the right hemisphere. While most regions showed significant change at 60 minutes for the lower dose group, the higher dose group had significant change at 30 and 60 minutes. There was a highly significant change in the anterior/posterior ratio for the two THC groups reflecting minimal change in occipital flow but significant increases in frontal flow. Self ratings of THC intoxication showed significant effects, and regression analysis indicated it correlated most markedly with the right frontal region. Conclusion: Behavioral manifestations of marijuana intoxication may be associated with increased functional activity of the brain especially the frontal cortex, insula and cingulate gyrus.

Key Words:

positron emission

tomography,

cerebral blood flow, delta’ tetrabydrocannabinol

Address for Correspondence: Roy J. Mathew, M.D., Department of Psychiatry, Duke University Medical Center, Box 3972, Durham, NC 27710. Telephone: +919 684 6857, Fax: +919 684 3882.

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In spite of a sharp decline in its use over the last decade, marijuana is still the most commonly used illicit drug in the United States (1,2). It continues to be one of the more commonly abused drugs among adolescents. Thus, acute and long-term effects of marijuana smoking and its neurobiologic correlates are of obvious clinical and research significance. Marijuana intoxication is accompanied by a wide variety of behavioral changes including mood changes known as a “High” associated with intoxication, altered time sense and depersonalization (2-4). Since the acute, marijuana-induced behavioral changes are reversible, it would seem safe to assume that such changes may be brought about via alterations in global and/or regional brain function. In the normal brain, cerebral blood flow (CBF) and cerebral metabolism (CMR) are closely coupled with brain function (5,6). We have conducted a number of studies on the acute effects of marijuana smoking on CBF using ‘%enon inhalation (7-11). Marijuana was found to increase CBF globally with most marked changes in the right hemisphere (7-10). Middle cerebral artery blood velocity measured with transcranial Doppler also increased on the right side after marijuana smoking (11). CBF increase after marijuana was dose related, i.e., marijuana cigarettes with a higher delta9 tetrahydrocannabinol (THC) content, which is believed to be the main active ingredient in marijuana, produced more marked CBF increase. CBF increase in both hemispheres significantly correlated with plasma levels of THC, pulse rate, intoxication, altered time sense, depersonalization, somatic symptoms and state anxiety. Volkow et al. (12,13) studied the effects of THC on cerebral metabolism of glucose (CMR ,“). In one study, CMR,,, was measured during baseline and 30-40 minutes after h mg of THC, given intravenously (12). Post THC changes in global CMR ,” were variable, but all subjects showed an increase in normalized cerebellar meta&olism which correlated with intoxication and plasma THC levels. In another report, CMR ,” under resting conditions and 24 hours after an intravenous injection of 2 mg. of TH8 was described (13). Cerebellar CMR showed consistent increase which correlated with plasma THC and intoxication. There were some apparent differences between marijuana users and controls on CMR,,, responses to THC with the marijuana users showing less changes in the cerebellum and more changes in the prefrontal cortex after THC. CBF studies performed with the ‘=xenon inhalation technique yield information only on cortical flow and with low spatial resolution (14). Studies using 150-water and positron emission tomography (PET) provide better spatial resolution than the ‘%enon inhalation technique and measurements of flow to subcortical structures (15). This study of brain activation after intravenous infusions of two doses of delta9 tetrahydrocannabinol (THC) was conducted with 150-water and PET.

Subjects: Subjects were recruited through local advertising, and signed written informed consent. They were screened by a psychiatrist (RJM) who excluded significant physical or psychiatric disorders, abuse or addiction to any drug other than marijuana during the previous six months, current use of any prescribed or unprescribed medication, current vascular disorders including migraine and heavy alcohol use (more than two drinks per day for men and one drink per day for females).

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Substance abuse was evaluated according to the Structured Clinical Interview for DSMIll-R (16). While all were required to have used marijuana, none met criteria for abuse or dependence for alcohol or other substances. All subjects completed the Beck Depression inventory (17), State-Trait Anxiety Inventory (16), Drug Abuse Screening Test (19), and Brief Michigan Alcoholism Screening Test (20). Participants were predominantly right handed, verified with the Harris Test of Lateral Dominance (21). Medical history, physical examination, electrocardiogram and clinical laboratory tests were obtained on all participants. Pregnancy was excluded with plasma HCG tests. The 32 subjects (20 male and 12 female, mean age of 32.5 years, SD 7.6) included 11 (7M/4F) assigned to placebo infusion, 11 (6M/5F) assigned to 0.15 mg./min. THC infusion, and 10 (7M/3F) assigned to 0.25 mg./min. THC infusion. Participants were assigned to one of the three conditions (Groups) on a random basis, but men and women were randomized separately. Chi square tests and analysis of variance (ANOVA) indicated no differences in the age or sex distributions of the subjects by Group. Only 6 of the 32 subjects were tobacco smokers with all reporting use of less than half pack/day. Assigned randomly, these 6 were distributed 3, 2 and 1 to the three study groups. On average, subjects began using marijuana in their teens (16.6~ 3.6 years). ANOVA indicated no difference in age of onset of marijuana use by group, nor were there differences by sex, although women tended to start somewhat younger than men (15.7~ 2.7 years vs 17.62 4.0 years). All subjects had a high school degree or better. The mean Beck Depression score was 1.6~ 2.1, and the Trait scores of the State-Trait anxiety scale was 30.6 + 6.5. There were no differences among the three groups on BECK or Trait scores by ANOVA. Following the screening visit, subjects came to the PET Laboratory on one day and obtained an MRI scan on a separate day. They were required to abstain from marijuana for two weeks, alcohol for 24 hours, and nicotine and caffeine for four hours before the visit. A urine drug screen was conducted before PET scans which was negative for all participants, indicating compliance with the requirement of no use of drugs. PET Scans: CBF measurements were performed in a semi-dark room with eyes and ears unoccluded. Subjects were instructed not to move. The left radial artery was catheterized under local anesthesia after performing an Allen’s Test (manual occlusion of radial and ulnar arteries followed by release of the ulnar artery and examination of return of color to the hand) to insure adequacy of blood supply to the hand. A venous line was established in the opposite arm for infusion of “O-water and THC or placebo. Beginning simultaneously with each bolus injection of 150-water, 20 arterial blood samples (l-2 ml each) were drawn manually during each scan for determination of the 150-water input function. Arterial levels of CO, (PaCO,) were determined at two minutes post infusion. PET measurements of CBF utilized 150-water and the autoradiographic method (15,22,23). Emission scans were obtained with a General Electric 4096-Plus whole body scanner (24), which acquires data simultaneously from 15 planes with an approximate axial resolution of 6 mm full width half maximum with an axial field of view of 10 cm. A 5 minute transmission scan was obtained for attenuation correction before each emission scan. Approximately 50 mCi 150-water was administered intravenously. At the time of the bolus injection, PET measurements were obtained at five-second

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intervals for two minutes. Images were reconstructed with attenuation correction. The first image to show cerebral counts was taken as time zero and the next subsequent scans were summed to obtain a 60-second image, and from this data parametric images of CBF were computed according to the method of Meyer et al. (22). The first PET scan was obtained under resting conditions. Following this baseline scan, subjects received an intravenous infusion for 20 minutes of either THC (0.15 mg./min. or 0.25 mg./min.) or human albumin (placebo condition) as described by Perez-Reyes et al. (25). Infusions were given under double-blind conditions. Pet scans were repeated at 30, 60, 90 and 120 minutes after the start of the THC infusion. Magnetic Resonance Imaging (MRI) with both T2-weighted and Tl-weighted images was performed and used for region identification in PET scans. Transaxial MRI scans were performed with a General Electric 1.5 Tesla Sigma System. Algorithms were used to anatomically align and register PET images with the MRI cross-sectional images using a computer based matching of surfaces. Regions of interest (ROI) were defined on each slice of the MRI which provides greater anatomical information, and then transferred to the PET images which were registered to match the MRI (26,27). Statistical analyses were based on volume weighted mean CBF from the ROI, which consists of summing the CBF for all pixels for an ROI and dividing by the number of pixels. The MRI (proton density) was also utilized to establish segmentation criteria to separate white from grey matter; criteria established on an individual basis. This process consisted of identifying signal levels on the MRI in one area that was predominantly grey matter and one predominantly white, then using the midpoint of these signal levels as the cut criterium. A set of rules for identifying the regions of interest bilaterally (frontal, temporal, parietal and occipital lobes, the insula, cingulate gyrus, basal ganglia, thalamus, amygdala and hippocampus) were determined by use of the Talairach and Tournoux atlas (28) in consultation with a neuroanatomist. These rules were applied for ROI which were traced by hand on a computer screen for each MRI slice. One person, blind to group assignment, did all region identification for all subjects. Several rating scales were administered before the first measurement and repeated after other scans. The rating scales administered consisted of the Analogue Intoxication Scale (29), Temporal Disintegration Inventory (30), Depersonalization Inventory (31), Somatic Sensation scale (32) and the anxiety subscale of the Profile of Mood states (33). The intoxication scale was completed at all time points, and the other scales were completed at baseline, 30 and 120 minutes. This report is focused on the ratings reflecting the perception of “high” or intoxication. Analogue Intoxication Scale uses a line 10 cm. in length with one end of the line marked as “not intoxicated” and the other end, “extremely intoxicated”. The subject is asked to indicate levels of intoxication with a mark along the line. Somatic Sensation Scale developed by Tyrer (32) measures bodily symptoms of arousal. A 10 ml venous blood sample was drawn following each PET emission scan for PaCO, determination and delta9 tetrahydrocannabinol was assayed with radioimmunoassay with a kit supplied by NIDA. Data Analysis: Prior to analysis, post infusion CBF was corrected for change in PaCO, from baseline. The primary model was a multivariate analysis of variance (MANOVA) which compared regions over time between groups in a Group (placebo, 0.15mgJmin. and 0.25 mg./min.) by Hemisphere by ROI (frontal, temporal, parietal,

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occipital, insula, cingulate, basal ganglia, thalamus, amygdala and hippocampus) by Time (baseline, 30 and 60 minutes). In this model hemisphere, region and time were treated as multiple (or repeated) dependent measures. Significant MANOVA effects are reported as the approximate F statistic derived from the Pillais multivariate statistic. Significant MANOVA analyses were followed by ANOVA analyses when appropriate. Post hoc contrasts between means were carried out with the Least Significant Difference test (LSD-test) which makes use of the error term from the over all analysis (34), and keeps the alpha probability rate constant for all pairwise contrasts. Because of the small number of women in each of the three Groups, sex was not included as a factor in these analyses. To examine the relationship of CBF to measures of intoxication we performed multiple regression analyses using a hierarchical model that included measures of global CBF, plasma levels and ratings of intoxication over time (baseline, 30 and 60 minutes). This model includes all of the measurements of each subject over time. Global effects were removed because there was a significant global change over time in CBF. The subject was treated as a dummy variable and forced with global flow, then logged plasma level and logged intoxication ratings were permitted to enter stepwise. Global CBF was based on a volume weighted mean of the ten ROI from each hemisphere. These analyses allow us to examine the partial correlations (p,) which are the unique relationship between two variables when other effects are removed. Results Analyses of baseline scores on rating scale and physiological variables indicated that men had a significantly higher mean_+sd baseline systolic blood pressure (men = 129.7_+12;women = 113.6~12) but there were no other differences in these variables between the sexes or among the 3 study conditions at baseline. CBF: All 32 subjects completed scans at baseline, 30 and 60 minutes, but for a variety of reasons data were not collected on 6 subjects at the 90 and 120 min. scans. Therefore, we have focused our analysis on the first three scans. A Group by hemisphere repeated measures ANOVA determined there were no significant differences in global CBF at baseline between the groups. The primary MANOVA model indicated a significant Group by Region by Time interaction (Pillais F=2.00, df=36,26; ~5.035). Figure 1 presents the mean CBF at baseline, 30 and 60 min. for the three groups for three regions that showed the greatest change. Post hoc analyses of the interaction were carried out on the 30 and 60 minutes change scores, and the results of these analyses at 60 minutes are presented in Table I. THC produced increased CBF in most regions at 30 min. for the 0.25 mg./min. group, but not for the 0.15 mg./min. group. At 60 minutes, post infusion areas of change included both the left and right frontal, temporal, parietal lobes, the cingulate gyrus, insula, basal ganglia and thalamus. While the right amygdala and hippocampus were significant at 30 minutes, they were no longer significant at 60 minutes. For the 0.15 mg./min. group the frontal lobe and cingulate in the right hemisphere and the insula on the left showed significant increase in CBF at 30 min., but by 60 min. all cortical areas except the occipital ROI were increased from baseline in both hemispheres. Thus, it appears that the maximal effects were at 30 minutes for the 0.25 mg./min. group and at 60 minutes for the 0.15 mg./min. group. The placebo group showed a slight decrease from baseline in most regions, a finding that is consistent with many previous reports (35).

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EFFECTS OF DELTA-9 THC ON RCBF IN LEFT AND RIGHT HEMISPHERES ML/lOC_GM/MIN

MEAN*1srJ

80

0.25

mg/min

70 60

0.15 mg/min

70 60

30

.

B 30 60

-LEFT nn.

B 30 60

B 30 60

.

HEMISPHERE MEAN*l:

SD

“”

FRONTAL

Placebo

ANTERIOR CINGULATE

INSULA

70

60

30

B 30 60

TIME

FROM

6

B 30 60

Figure BASELINE

30 60

.

1 (B) IN MINUTES

Mean CBF for three regions that showed significant change following THC compared to placebo.

While the area weighted mean of the cingulate showed significant effects, inspection of the scans suggested that the greatest area of change for the cingulate was in the anterior portion on both sides. An exploratory analysis of this sub-region indicated a significant group by time interaction (MANOVA F=4.43, df=4,!%, pC .003).

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TABLE REGIONAL DIFFERENCES FROM PLACEBO MEAN

CEREBRAL BLOOD FLOW BASELINE AT 60 MINUTES 0.15 mg/min’

SD

MEAN 80 min

60 min LEFT

I

POST

INFUSION 0.25 mg/min*

SD

MEAN

SD

80 min

HEMISPHERE

FRONTAL

-0.4

5.4

c

5.4

5.8

c

5.0

9.3

TEMPORAL

-1.1

8.1

B

4.0

5.4

B

3.3

8.7

PARIETAL

-0.7

5.8

B

3.4

5.2

B

3.4

8.1

OCCIPITAL

-1.3

8.7

1.8

8.1

2.1

8.9

ClNGUlATE

-0.7

7.8

c

4.5

8.3

c

5.4

7.8

INSULA

-2.0

7.7

c

8.3

9.4

C

8.8

13.8

-0.7

7.0

C

4.3

8.6

c

4.4

9.8

THALAMUS

-0.2

5.0

2.3

8.2

B

3.8

13.3

AMYGDALA

-0.7

9.4

3.7

7.2

2.2

10.9

HIPPOCAMPUS

-1.8

8.5

1.4

8.7

0.5

8.7

RIGHT HEMISPHERE FRONTAL

-0.6

5.8

C

5.7

8.9

c

6.0

10.3

TEMPORAL

-0.2

5.7

B

3.8

5.7

c

4.5

9.1

PARIETAL

-0.1

5.7

A

2.7

5.1

B

3.7

a.0

OCCIPITAL

0.2

5.8

1.3

8.1

2.0

10.0

CINGULATE

-0.2

8.2

6

5.1

7.7

0.7

8.0

G

4.4

8.6

-0.9

5.4

2.5

8.4

2.2

7.5

2.6

7.1

A

.2.8

7.8

-0.2

-2.4

8.7

1.1

BASAL

GANGLIA

lNSUL4 BASAL

GANGLIA

THALAMUS AMYGDALA

A

HIPPOCAMPUS (‘) THC

Infusion

Tukey’s

Least

6

A

4.2

9.4

c

7.0

14.8

C

5.2

10.7

3.0

11.1

8.1

0.8

7.5

7.2

1.3

7.4

C

Rate

Significance

Test:

A = p < = 0.05,

B = p < = .Oi, C = p < = .I-JJ~.

We computed the anterior/posterior (AP) ratio by dividing the mean frontal flow for the two hemispheres by the mean of the occipital flow. A MANOVA indicated a Group by Time interaction (Pillais F = 3.75; df=4,58; ps.009). The LSD-test showed the two THC groups had significant increases in this ratio. The mean AP-ratio for the low dose group changed from 95& 6.0 at baseline to 108.2_+8.0at 60 min., and high dose group went from 95.6L6.3 to 106.1~8.6. This change reflected the increase in the frontal flow with essentially no change in the occipital flow. There was no significant change for the placebo control group. We computed the blood flow to the cerebellum and entered this data into a similar model, but there was no significant difference. While there appeared to be a trend for increased cerebellar blood flow following THC, there was considerable variation. The mean cerebellar blood flow changes at 30 min. as a percent of baseline

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were: placebo 1.5% + 11.7, low 5.3% + 16.6, high 15.9% + 16.5. Neither rank nor log,, transformation of the change score from baseline resultedin a significant group difference. Rating Scales: Similar analyses were carried out for the Analogue Intoxication, Depersonalization, Temporal Disintegration and Somatic Sensation scales. Ratings of intoxication did not meet the equality of variance assumption and was log transformed. There was a highly significant group by time interaction for intoxication (F=21.4, df=4,58; pi .OOl) and Depersonalization (F=6.63, pi .004), but temporal disintegration showed only a significant time effect (F=6.14, ph .019). The somatic sensation scale did not show significant effects (p < .09). While there appeared to be a trend for increased anxiety with the THC infusion there was no significant difference between the groups in change in anxiety. Changes from baseline at 30 minutes are presented in Table II.

Table II

MEAN CHANGE FROM BASELINE AT 30 MINUTES POST INFUSION RATING SCALES PLACEBO MEAN

SD

.15 MG/MIN

.25 MG/MIN

MEAN

MEAN

SD

SD

INTOXICATION

0.4

1.2

76.5

24.3

70.4

18.9

DEPERSONALIZATION

0.4

3.9

5.9

11.1

8.1

9.8

ALTERED TIME SENSE

-0.2

6.9

7.4

11.4

6.3

11.9

Multiple regression analyses of each ROI examined the relationship of change over time between CBF, plasma levels and ratings of intoxication. Presented in Table Ill are the partial correlations for intoxication and plasma levels for those regions where there was a significant relationship between intoxication and CBF. The frontal ROI showed significant positive partial-r, with a stronger correlation on the right hemisphere, and the left anterior cingulate also had a significant positive partial-r. The left parietal lobe and left and right hippocampi all showed significant negative relationships with intoxication ratings (Table Ill). Some regions (e.g., insula) had significant positive pr with plasma level, but no significant covariation with ratings of intoxication. Neither plasma level nor intoxication ratings were significantly related to cerebellar blood flow in the regression models. Physiological measures: Analysis of blood pressure, pulse rate and PaCO, over time (Group by Time model) indicated the expected significant increase in pulse rate (Group by Time interaction F=l5.6, pi .OOl), but there were no significant changes in the other measures.

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TABLE III PARTIAL CORRELATIONS WITH RCBF REGIONS WITH SIGNIFICANT CORRELATIONS WITH INTOXICATION RIGHT

LEFT INTOX(*)

PLASMA

rp

rp

Ps

PLASMA

INTOX(*)

PS

rp

P<

rp

PS

FRONTAL

0.40

.ool

-.18

NS

0.54

,001

0.15

NS

PARIETAL

0.03

NS

-.32

,002

-.37

.003

-.08

NS

A.CINGUlATE

0.29

,019

-.05

NS

-.Oi

NS

0.36

,004

-.44

.GQl

0.22

NS

-.32

,011

0.13

NS

HIPPOCAMPUS

(*) Intoxication ratings

Mean plasma levels at baseline 30, and 60 minutes are presented in Table IV. We compared the 30 and 60 min levels between the two THC groups with t-tests. These were both significant (30 min: t=2.63, df = 19, pi .02; and 60 min: t=3.48, df = 19, P-I. 603) indicating higher plasma levels for the higher infusion group. Table IV PLASMA LEVELS OF THC 0.15 MG/MIN

PLACEBO MEAN(*)

SD

MEAN

0

2.94

2.06

1.20

30

2.33

60

2.30

SD

0.25 MG/MIN MEAN

SD

Time 1.24

2.92

1.05

1.66

26.29

10.03

2.04

15.70

6.57

Discussion This study demonstrated that after THC, levels of intoxication reached a peak 30 minutes after the drug. CBF to both hemispheres showed significant increase after THC but not placebo with somewhat more marked changes in the right hemisphere. Anterior brain regions showed more marked CBF increase than posterior regions. Post hoc analyses found cortical regional differences reached significance for the 0.25 mg./min. group in the right and left hemispheres for the frontal, temporal, parietal, occipital, cingulate and insula. These results are similar to our previous experiments involving marijuana smoking (7-11). In the four subcortical regions there was significant change for the basal ganglia, thalamus, amygdala and hippocampus after the high dose of THC at 30 min., but only the basal ganglia and thalamus at 60 min. Pulse increased significantly as expected. There were no significant changes in blood pressure. Intoxication showed significant correlations with global CBF. Among the various regions studied, frontal lobe and cingulate gyrus (especially the anterior part) showed the largest correlations with intoxication.

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Animal experiments on the effects of THC and related compounds on CBF have yielded mixed results. Goldman and associates (36) found reduced blood flow to dorsal hippocampus, hypothalamus, cerebellum and basal ganglia after intravenous injection in rats. Ellis and associates (37) examined the effects of anandamide, an endogenous ligand on cerebral circulation. With the use of the closed cranial window anandamide and delta 9 THC were applied to rabbit cerebral arterioles and effects on diameter were measured with a microscope. Both drugs similarly induced a dosedependent dilation. Margulies and Hammer (38) reported increased cerebral glucose metabolism with low doses and decreased values with high doses of delta 9 THC in rats. Marijuana can bring about CBF changes through a variety of mechanisms including altered brain functional activity (6,7). This would include relaxation of vascular smooth muscle, alterations in PaCO,, and sympathetic stimulation (39). In the present project, CBF values were corrected for individual variation of PaCO, even though the mean change in PaCO, was not significant. Sympathetic stimulation decreases CBF (39) and does not increase it. In the present experiment, in spite of the increased pulse rate, CBF increased after THC infusions. The role played by effects of THC on blood vessel smooth muscle is difficult to evaluate. It needs to be pointed out that in our previous study, marijuana had no direct effect on forehead skin perfusion (7,lO). Marijuana induced red-eye has been found to last for several hours (40). In our previous study involving marijuana smoking, although plasma levels of THC and CBF correlated, the two followed different time courses, (7,ll). Time course of the CBF changes resembled that of mood changes more closely than plasma THC levels. Significant correlations between CBF and behavioral phenomena suggest that post-marijuana CBF change is caused at least in part by concomitant changes in brain functional activity. In the normal brain, CBF is tightly coupled with brain functional activity. While most ROI had significant correlations with intoxication, when the global effects and covariation with plasma level was removed there were still significant positive partial correlations with the frontal and anterior cingulate. Global CBF is closely related to levels of arousal (41,42). Conditions associated with high levels of activation show CBF increase, while low arousal states show CBF decrease. The right hemisphere has been implicated in the mediation of emotions (43,44), and in the present experiment, right hemispheric flow increased more substantially after marijuana intoxication than the left. THC increased CBF to most brain regions, cortical as well as sub-cortical. Of the cortical regions examined, the frontal region showed most marked post-THC CBF increase. Similar post marijuana EEG changes have been reported (45,46). Frontal lobes are believed to be responsible for maintaining wakefulness. In addition to arousal, more complicated functions closely related to wakefulness such as abstract thought, synthetic reasoning and organization of independent behavior in time and space towards future goals have been attributed to the frontal lobes (47). Increased frontal activity during wakefulness is supported by a wide variety of clinical and experimental evidence. Subcortical regions believed to mediate arousal are known to have dense connections with the frontal lobe (41, 48, 49). Frontal lobes are also involved in sensory data processing, cognition, volition and initiation of motor activity (50,51). The well-known electroencephalographic (EEG) pattern of dominate wave forms of higher frequency over the frontal lobes during wakefulness provide additional

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support for its role in maintaining arousal. Thus, increase in frontal CBF after marijuana

would seem to suggest increased levels of non-specific brain activation. However,

subjective reports of marijuana intoxication do not support this possibility entirely. Most marijuana smokers report “mellowing out” during marijuana intoxication associated with relaxation and tranquility. Objectively, they seem to become more introverted and withdrawn. Yet, their sensitivity to sensory stimulation has been found to be increased. In the present study, THC was found to increase the non-dominate hemispheric activity more markedly. Conscious awareness has been reported to be predominantly a function of the dominant hemisphere. It is conceivable that THC-induced activation of the non-dominant hemisphere is associated with increased arousal qualitatively distinct from that associated with the dominant hemispheric activation (5253). The inverse relationship between right and left hippocampi and intoxication may also be related to the short-term memory loss which accompanies marijuana intoxication. The other brain regions which showed increased CBF after marijuana included insula, thalamus, amygdala and hippocampus. lnsula has multiple connections with the olfactory cortex, amygdala, entorhinal cortex, cingulate and hippocampus (54). lnsula has also been found to be involved in sensory perception (55-57). lnsula also has intimate connections with limbic, paralimbic and brain-stem autonomic centers (58). Insular cortex is also believed to mediate stress-induced cardiovascular responses which probably is related to its involvement in autonomic activity (59). Anterior insula is also considered to contain the primary gustatory center (60). THC produces anxiety and autonomic changes mainly characterized by increased pulse rate. It also produces a variety of somatic sensations both somatic and visceral. It is conceivable that increased insular activity is related to any one of the above. Increase in thalamic blood flow may also be related to increased sensations. PET scan does not have the necessary spatial resolution to pinpoint the thalamic nuclei activated during THC intoxication. Significant correlations between intoxication with cingulate flow are intriguing. It needs to be pointed out that the cingulate gyrus is an important component of the Papez circuit which has been implicated in emotions and short-term memory (61). Electrical stimulation of the anterior cingulate was found to alter emotions and anxiety in human subjects (62). Meyer and associates found altered states of awareness after electrical stimulation of the anterior cingulate in 60% of psychosurgical patients (63). Short-term memory impairment is known to occur after marijuana smoking (2). The anterior cingulate is an important component of the cortico-limbic system, and it is intimately related to motivation, selective attention, social interactiveness and logical processing. Because the anterior cingulate connections with multiple important brain structures including the amygdala, septal nuclei, periaqueductal grey, lower brain stem and spinal cord, pre-frontal cortex and inferior parietal lobule, it is believed to integrate affective experience with cognitive activity (64-66). Volkow et al. (1516) studied the effects of THC on CMRglu. In one study, CMR,,, was measured during baseline and 30-40 minutes after 2 mg. of THC, given intravenously (15). Post THC changes in CMR,,, were variable; three subjects showed increase, three showed decrease and two showed no change. All subjects showed an increase in normalized cerebellar metabolism which correlated with intoxication and plasma THC levels. In another report, CMR,,, under resting conditions and 24 hours after an intravenous injection of 2 mg. of THC was described (16). CMR,,, response

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to THC showed considerable variation among subjects. Seven of the 18 subjects studied showed an increase of more than 10% in global CMF& five showed more than a 10% decrease and six showed changes of less than 16%. CMR,,, also correlated with the THC induced intoxication. Cerebellar CMR showed consistent increase which correlated with plasma THC and intoxication. There were some apparent differences between marijuana users and controls on CMR,,, responses to THC with the marijuana users showing less changes in the cerebellum and more changes in the prefrontal cortex after THC. We did not find a significant effect in the cerebellum, although there was a trend for increase in CBF. This may have been due to large variation. The discrepancy between the findings reported by Volkow and Associates and the present experiment can be attributed to several factors. First of all, Volkow and Associates measured cerebral glucose metabolism while our study was on cerebral blood flow. Although both brain metabolism and brain capillary profusion are indices of brain function, the relationship between cerebral blood flow and metabolism is not as tight as might be expected. For example, somatosensory stimulation increased cerebral blood flow by an average of 29%, while the concomitant local increase in tissue metabolism for oxygen increased by an average of 5% only (66). In the present study, CBF measurements were made over a period of one minute while CMR,,, was averaged over 90 minutes. We measured CBF before and immediately after THC infusions multiple times, while Volkow and associates obtained resting and postmarijuana CMR+ on separate days. Thus, the results of the two experiments cannot be compared directly. Acknowledaementq The project was supported by a grant from National Institute on Drug Abuse, (DA 04985). We wish to thank Sharon Hamblen, Thomas C. Hawk, Joe V. Lowe and Diane F. Wright for their considerable efforts in conducting this study. We wish to express our thanks to John Hoffman, M.D. who provided valuable assistance in the initial implementation of this study. We also wish to thank James Provenzale, M.D. who provided guidance in establishing the criteria for the ROI identification from the MRI. References 1. 2. 3. 4. 5. 6. 7. 8.

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