Marijuana: Effects on deep and surface electroencephalograms of rhesus monkeys

Neuropharmacology. 1973.12,I-14 Pergamon Press. Printed inGt. Britain.

MARIJUANA:

EFFECTS

ON DEEP AND SURFACE

R. G. HEATH Department

of Psychiatry and Neurology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112 (Accepted 21 April 1972)

Summary-Six rhesus monkeys prepared with electrodes implanted into numerous specific subcortical brain sites and over the brain surface under the skull were exposed to smoke of marijuana containing a significant quantity of deltag-tetrahydrocannabinol. Electroencephalograms were obtained before, during, and after exposure to the marijuana smoke, which was delivered to the monkeys by use of a specially designed head chamber. Control agents for the study were inert marijuana of low deltag-tetrahydrocannabinol content, tobacco, alcohol and methamphetamine. Exposure to smoke of active marijuana consistently induced distinct recording changes in the septal region, occasionally accompanied by changes in recordings from the cerebellum, postero ventral lateral thalamus, hippocampus, and orbital and temporal cortices. Only generalized electroencephalographic changes, consisting of slight shifts in the dominant frequency, were obtained in association with the other agents used in the study.

Studies conducted in lower animals (dogs, rabbits, cats, rats) give some indication that brain recordings from deep nuclear masses are affected more than surface recordings by the active ingredients of marijuana (HOCKMAN, PERRIN and KALANT, 1971; BOYD and MERIIT, 1966; CHRISTENSEN, BEST and HERIN, I97 1; BOSE, SAIFI and BRAGWAT, 1964). HOCKMAN et al. (197 1) reported considerable delta activity and fast high-amplitude spindling from the amygdala, ventromedial hypothalamus, hippocampus, and a number of cortical areas in association with administration of deltal-tetrahydrocannabinol (THC) to cats. CHRISTENSENer al. (1971) reported predominantly hippocampal and septal changes with THC in rats. No studies have been found, however, of the effects of marijuana or its known ingredients on the function of deep brain structures of sub-human primates. The present report concerns the effects of marijuana smoke on deep and surface electroencephalograms (EEGs), as well as on behavior, of rhesus monkeys in which electrodes had been implanted for long-term study. For comparison, the effects of methamphetamine, alcohol and tobacco smoke were also studied. METHOD

Six feral-raised rhesus monkeys (3-6 yr old), obtained through the Tulane Medical School Vivarium, were used for this study. EIectrode implantation The operative procedure, which has previously been described (HEATH, JOHN and FONTANA,1968), was carried out under Nembutal anaesthesia with roentgenographic visualization of the ventricular system after pneumoencephalography. Two types of silver-ball

R. G. HEATH

2

Fig. I. Transparent plastic box apparatus used to pump marijuana and tobacco smoke to monkeys. electrodes (LUS~ICKand HEATH, 1971) were stereotaxically implanted into a variety of deep sites and over the cortex of the brain: a single ball electrode O-025in. in diameter and a bipolar electrode composed of two silver balls0.08 in. apart, each O-015 in. in diameter. The electrodes were soldered to two IO-place plugs which were fixed with Cranioplastic to the skull. All six monkeys had electrodes implanted into the following 8 sites: right septal region, right dentate nucleus of the cerebellum, right fastigius nucleus of the cerebellum, poster0 ventral lateral thalamus, hippocampus bilaterally, mesencephalic reticulum, and over the right temporal cortex. The remaining electrode placements varied: in two monkeys, single (monopolar) silver-ball electrodes were also implanted into the caudate nucleus and the hypothalamus (mammillary bodies) and over the frontal and occipital cortices; two other monkeys had bipolar electrodes into the centromedian thalamus and the orbital cortex; and two had bipolar electrodes over the cerebellar cortex and into the orbital cortex. Each monkey was allowed to rest for 3 weeks after implantation, to permit all recording artifacts consequent to the operation to disappear. At the end of the studies, the monkeys were killed and the brains fixed in 10 % formalin for later sectioning and staining by the KluverBerrara method, to permit histologic study which established the absence of notable brain damage at electrode tips (LUSTICKand HEATH, 1971) and verified accuracy of the electrode placements.

Recording procedures

Electroencephalographic (EEG) recordings were obtained on a 1Zchannel Grass Model VI electroencephalograph. A 7-channel Ampex FR 1300 recorder was used to record samples

Effectof marijuanaon monkeyEEG

3

of significant recordings simultaneously on magnetic tape. The EEGs and the magnetic tape recordings were synchronized with an EECO (Electronics Engineering Co. of California) 858-A time code generator/reader with one EEG channel used as a marker for the generator. Another EEG channel was used to record activity from over the heart to indicate pulse rate. Activity of the right temporal cortex and of the right anterior septal region during both baseline recordings and at intervals after exposure to both marijuana and tobacco smoke were analyzed to determine brain activity in the canonical delta, theta and alpha bandwidths. The measure of activity was the average of the absolute amplitude. For this analysis an Electrophysiological Monitor and Event Detector (EMED) was used which integrates energy at predetermined frequencies (HEATH, 1972a). Significance of the activity in each of the canonical delta, theta, and alpha bandwidths at these sites was obtained with a two sample t-test. Test materials and mode of administration Marijuana. Marijuana was obtained by court order from federal narcotics agents. For

this study, two different batches of marijuana were used. Assay by gas chromatography of the crude petroleum ether extract from the dried leaves showed that one batch contained 2.29 % THC (referred to hereafter as active marijuana). The other batch, in contrast, contained a barely detectable quantity (0.1 %) of THC (referred to hereafter as inert marijuana). Marijuana smoke was delivered to the monkeys by use of a specially fabricated transparent plastic box placed over the animal’s head (Fig. 1). A pipe was fixed to the box, and by means of a rubber bulb, the smoke was pumped from the pipe into the plastic box; it was mixed sufficiently with air or with oxygen pumped through another opening to prevent anoxia. It was not possible by this procedure of delivering smoke to the monkeys (both marijuana and tobacco) to estimate the quantity of active material absorbed by inhalation. Since the period of exposure to smoke for each test reported here was the same (5 min), it was assumed that about the same amount of smoke was inhaled on each occasion. During the exposure of one monkey to marijuana smoke and to tobacco smoke, air samples were obtained of both the room air and the air within the smoke box and blood-gas analyses were made on an Instrumentation Laboratory I.L.-313 blood-gas analyzer. Blood samples were obtained before exposure, during 5-min exposures (to both marijuana and tobacco smoke on separate occasions), and at lo,30 and 60 min after exposure to smoke. Each of the 6 monkeys studied was exposed to marijuana smoke 2-5 times. Tobacco. The smoke from a standard brand of pipe tobacco was delivered to the monkeys by use of the same apparatus that was used for delivery of marijuana smoke. Alcohol. Each monkey received 5 ml of a solution consisting of 2.5 ml U.S.P. absolute ethyl alcohol diluted with 2.5 ml water and injected iv. at a rate of 1*Oml/min. Methamphetamine. Each monkey received 0.25 mg/kg of body weight of methamphetamine injected i.v. RESULTS

Active marijuana (2.29 % deltag-tetrahydrocannabinol)

The behavioral responses of the 6 monkeys to the active marijuana smoke were consistent, as were the responses of individual monkeys to repeated exposure to the smoke, although the intensity of the responses varied. All displayed dilated pupils and sharp reduction in level of awareness. The monkeys would stare blankly into space, sometimes displaying spontaneous

R. G. HEATH

4

nystagmus, and would become much less attentive or completely unresponsive to environmental stimuli. When their hands or feet were grasped, the clasping response, which was consistently elicited on baseline examinations, was absent. Responses to pain (pinprick) and to sound (hand claps) were minimal to absent. Although the monkeys were not particularly drowsy, spontaneous motor movements were notably slowed, and passive tests of muscle tone suggested a degree of catatonia, although true waxy flexibility never developed. Eiectroencephaiographic changes, which always accompanied the behavioral changes, consistently began within i-3 min after the monkey’s initial exposure to a high concentration of active marijuana smoke. They became increasingly pronounced over a period of the next 5 min and then remained distinct for at least 30 min. At that point the recording usually began a return toward baseline, and generally in another hour the recording again resembled the baseline EEG. With each exposure, the pulse rates of the monkeys increased from 50 to 100 %. Although there were similarities in the EEGs of the 6 monkeys, there were variations as well. A consistent feature was the profound change that occurred in recordings from the septai leads. On occasion only this site was affected, but usually other sites showed changes as well. When only the septai region was affected, a delta wave at a frequency of 3-4 Hz characteristically appeared (Figs. 2 and 3). Occasionally, a sharp wave was interspersed with this focal delta activity. This slow wave and occasional sharp wave activity was intermittent, bursts lasting 5-10 set appearing every 20-30 sec. Sometimes the slow wave in recordings from the septai region was accompanied by a similar wave (frequency of 2-4 Hz) recorded from the mesencephaiic reticulum or the poster0 ventral lateral thaiamus, or both, while no

MARIJUANA BASELINE RTCX-\

M--w L P V L THAL

I MONK

XG

5Op

lsec

Fig. 2. Baseline deep and surface EEGs obtained from Monkey XG. R T CX: right temporal cortex; ORB CX: orbital cortex; L HIP: left hippocampus; R HIP: right hippocampus; R SEP: right septal region; R C M THAL: right centromedian thalamus; R MAMM: right mammilary body; L P V LTHAL: left postero-ventral lateral thalamus; R CBL FAS: right cerebellum fastigius; R RET or R MES RET: right mesencephalic reticulum; R HYP: right hypothalamus; R A SEP: right anterior septal region; EKG or PULSE: EEG channel indicating pulse rate; TCG: EEG channel used as marker for time code generator. (These abbreviations also apply to the other EEG figures in this paper.)

Effect

marijuana on monkey EEG

5

signi~cant changes appeared in recordings from other deep structures or from the surface (Figs. 4 and 5). Another frequent recording change was the appearance of bursts of high-amplitude spindles (approximating 16 Hz), most pronounced in the septal leads but occasionally present in other deep leads and over the temporal cortex (Figs. 6-8). The presence of spindles at other MARIJUANA

5 MIN POST

KG-L

EXPOSURE

KA’ ) \Ipflp ‘, [imr7~w~qqr\l&~; 11

, qqqq~#.~ MONK

5opv

XG

&&

Fig. 3. Deep and surface EEGs obtained from Monkey XG 5 min after exposure to marijuana smoke. Note focal delta activity in the septal lead. Artifact caused by eye-blinking is seen in the right temporaf cortex lead.

MARI JUANA BASELINE

R. G.

HEATH

MARIJUANA 5 MIN

MONK

POST

EXPOSURE

XH

5opv

_&&

Fig. 5. EEGs obtained from Monkey XH 5 min after exposure to marijuana smoke. Note delta activity in the right mesencephalic reticular (R RET) and left postero-ventral lateral thalamic leads along with focal slowing in the septal lead.

MARtJUANA BASELINE R T CX ORB

CXp

L HIP

R A SEP-____-_

R CBL

DEN-

L P V L THAL EKG TCG

198_

_ ’

f

.J7nmmm~““I”T MONK

r,y ~~rp”“I”~~.‘?“I”“““‘“““““‘~~,~~.~~.~~l”” r XL

1,,,,,,,l,.,,~II:F;~iT;i: ” I 2opv

,

,c

I SW

6. Typical baseline EEG obtained from Monkey XL. The pulse rate ofthe animal was rapid when this recording was made. Post-marijuana recordings (Figs. 7 and 8) do not show the monkey’s maximal pulse rate increase which did occur. Fig.

Effect of marijuana on monkey EEG

MARI JUANA IO

MIN

POST

EXPOSURE

RTCXORB CX‘a+%fwpwh

L HIP R HIP R A SEPCBL ANT LOBE_._

c~--+++-+*~~v”-“-.-“~~

R CBL OEN-

~m~mwwM*wkvwe!*~

v

R CBL FAS R RET LPVLTHALEKE

ZOO-

t

TCG

‘m~p.m”“‘;r~,m MONK

XL

““1”

”

Ii:: %

2opv - ISOC

Fig. 7. EEG from Monkey XL 10 min after exposure

to marijuana

smoke. Note spindling at certain sites.

MARI JUANA 50

MIN

POST

EXPOSURE

RTCX_ ORB cx_ L HIP R HIP R A SEPCBL ANT

LOBE-

R CBL DEN_ R CBI. FASR RET LPYLTHALEKG

IEO-

TCG

“~~~~~~~~~~~~,(~~~~~~~~~~~~~~~~,~~ MONK

XL

Fig. 8. EEG from Monkey XL 50 min after

2opv

isec

exposureto marijuanasmoke.

sites was sometimes synchronous with their appearance in the septal region and sometimes independent of it. Other sites frequently involved were the postero-ventral lateral thalamus, both deep cerebellar nuclei, orbital cortex and hippocampus. In Figures 9 and 10 spindling was constant in the cerebeliar nuclei when the characteristic slow-wave was most prominent in the poster0 ventral lateral thalamus and orbital cortex and was less obvious in the septal region and the temporal cortex. Scalp leads, by visual inspection,

R. G. HEATH

PULSE - IBO-

TCGMonkey XQ

Fig. 9. Baseline EEC obtained from Monkey XQ.

did not reflect the slow-wave activity present at deep sites. Spindling in cerebellar nuclei of the type shown in Figure 10 occasionally appeared in baseline recordings when the monkeys were relaxed, but was present more often (for a much higher percentage of recording time) after exposure to marijuana smoke. When spindles appeared in recordings from the temporal cortex, they were visible but less apparent in scalp recordings over the temporal region. MARi JUANA 20 LF-Lf

MIN POST

EXPOSURE

SC-;

RF-RTSC-

c

RTCX.-__._

~~~

$+J+fL+w+

R HIP

-r R ORB CX

ht

-~~

R A SW_ LPYLTHALR CBt OENR CBL FAS_ R HYP_ R MES RETPULSE - ZIQ103 ~~~~~n~!~l~~~~,~~~~~

~~~~1~~ Monkey XQ Fig.

10. EEG from Monkey XQ 20 min after exposure to marijuana smoke.

Effect of marijuana on monkey EEG

9

Results of the air samples obtained with marijuana smoke and with tobacco smoke are shown in Table 1. Results of the blood-gas analyses are summarized in Table 2. With exposure to smoke of marijuana mixed with oxygen, the partial pressure of oxygen remained above baseline values while partial pressure of carbon dioxide remained below baseline values. The values remained within the normal limits after the smoke inhalation, indicating that there was no hypoxia. Table 1. Marijuana smoke* and tobacco smoke* air samDIes ptCOz

(mm Hg)

~tOe (mm Hg)

Marijuana Sample taken inside smoke box: Room air sample

11.5 6.4

258.1 146.7

Tobacco SampIe taken inside smoke box: Room air sample

9-2 5.2

162.1 149.2

*Supplementary oxygen mixed with smoke. fPartia1 pressure (of COz or Oz in mm Hg). :Smoke at highest density inside box when sample was taken.

Table 2. Marijuana smoke* and tobacco smoke* 5 min exposure to each blood-gas analysis ptCOs (mm Hg):

PWZ (mm H&B

PH

Marijuana Before exposure During exposure 10 min post 30 min post 60 min post

41.1 39-5 29.2 32.3 29.0

106.4 258.1 122.3 121.8 142.0

7.419 7412 7.431 7.429 7.414

Tobacco Before During 10 min 30 min 60 min

30.5 32.4 24.1 35.7 34.9

132.4 162.1 137.5 94.0 94.0

7.422 7.450 7.429 7.450 7470

exposure exposure post post post

*Supplementary oxygen mixed with smoke. tPartial pressure (of COZ or Oz in mm Hg). $Normal p CO2 values in man at sea level=41.0 mm Hg (and below). JNormaI p 02 values in man at sea level==94*0 mm Hg (and above).

Inert marijuana (0.1% deltaQetrahydrocannabino1) Behavioral responses of the monkeys to smoke of inert marijuana were minimal to absent. When the concentration of smoke in the chamber was high, the monkeys showed some irritability but settled down promptly when the smoke cleared. Pulse rates increased from 10 to 20 %. By visual inspection, EEG changes were absent or limited to slight shifts in the dominant frequency.

10

R. G. HEATH

Tobacco No notable changes were observed in behavior of the 6 monkeys as a result of exposure to tobacco smoke. Pulse rates rose from 10 to 19 %. Visual inspection of recordings indicated the possibility of a slight increase in low-voltage beta activity at a frequency of 18 Hz. Alcohol In response to i.v. injections of alcohol, all 6 monkeys retched and one vomited. All displayed rolling of the eyes and fleeting lateral nystagmus, and all showed severely depressed awareness, tending to stare into space and responding less to stimulation. Their behavior in response to the alcohol was in some ways similar to that after exposure to marijuana smoke, but it was also qualitatively different. Like their responses to active marijuana, the monkeys showed reduction in level of awareness, stared blankly into space, and were less responsive to sensory stimuli. Qualitatively, however, impairment was less marked; catatonic features, for example, were less apparent. Behavioral effects gradually subsided within l-2 hr. Pulse rates increased from 5-20 “/ Recording changes in association with the alcohol were insignificant. Visual inspection of the EEGs suggested only that high frequencies (I 6-20 Hz) persisted longer. Methamphetamine More consistent alerting and increased restlessness were the only behavioral changes observable in the monkeys after administration of methamphetamine. Pulse rates rose from 10 to 35%. Their EEGs showed more consistent low-voltage fast activity than baseline recordings (Fig. 11). Recordings of two of the monkeys showed intermittent bursts of high-amplitude fast spindles (16-18 Hz), most pronounced in the septal region. This change resembled those seen in the EEGs of some of the monkeys when exposed to the marijuana smoke, but it was present a much shorter time. METHEDRINE

Effect of marijuana on monkey EEG

11

Analyses of recordings The typical results obtained with the EMED device when the monkeys were exposed to marijuana smoke and to tobacco smoke are shown in Table 3. The activity (average absolute amplitude) during a pre-test epoch (baseline) is compared with that during the 2 periods after exposure. Table 3. Effect of marijuana and of tobacco on EEG activity EMED analyses Marijuana Bandwidth Delta Baseline mean* Post mean* Significance level Theta Baseline mean* Post mean* Significance level Alpha Baseline mean* Post mean* Significance level *Determined

Tobacco

Rt. Tern. Cortex

Rt. Ant. Septal

Rt. Tern. Cortex

Rt. Ant. Septal

0.146 O-207 < 1% 0.096 0.126 < 1% 0.083 0.113
0.101 0,222

0.083 0.069

0.095 0.066



< 10%

0.049 0.088 cl% 0.020 0.041 < 1%

0.045 0.031
0.049 0.030 cl% 0.026 0.016
from IO-min of continuous data.

There was a significant increase in activity in each bandwidth and at both the anterior septal region and over the temporal cortex in association with the marijuana smoke. This increased activity did not, however, seem to be specific in location, and it was not confined to a particular frequency band. With exposure to tobacco smoke, the EMED analysis showed a notable decrease in activity at all sites and at all frequencies. DISCUSSION

The distinct changes recorded from specific subcortical structures of the rhesus monkeys exposed to smoke of marijuana with high THC content lends support to previous reports of studies in lower animals showing changes in brain recordings from deep nuclear masses (HOCKMAN etal., 1971; BOYD and MERITT, 1966; CHRISTENSENet al., 1971; BOSE etal., 1964). The scalp EEGs of the monkeys only minimally reflected the profound activity occurring at deep sites. This finding corresponds with data obtained from a study of marijuana in a severely ill psychiatric patient in whom deep and surface electrodes were implanted for diagnostic and therapeutic purposes (HEATH, 1972a). On the several occasions when the patient smoked a cigarette of marijuana with high THC content from the same batch that was given to the 6 monkeys described here, there was a notable absence of surface EEG changes, by visual inspection, in contrast to the distinct changes recorded from septal leads. These findings agree with previous reports of negligible scalp EEG changes in human subjects in association with smoking of marijuana (GIBBS, 1970; WIKLER and LLOYD, 1945; RODIN, DOMINO and PORZAK, 1970; DELIYANNAKIS,PANAGOPOULOSand HUO~T, 1970). The extent of involvement of subcortical sites in the monkeys was greater than in the human subject we studied. Other reports indicate that animals lower on the phylogenetic scale than the subhuman primates display even more widespread brain involvement. More diffuse effects on brains of cats and rats with administration of THC were, for example, reported by HOCK&IANet al. (197 1) and by CHRISTENSENet al. (197 l), suggesting that marijuana asserts a more localized effect as one moves up phylogenetically.

12

R.G.

HEATH

None of the control substances used in this study induced the notable EEGs from subcortical neural sites that have been identified with emotional expression (HEATH, 1972b). Since smoke of tobacco and inert marijuana failed to induce marked, focal subcortical recording changes, it is assumed that the EEG alterations seen with active marijuana were a consequence of inhalation of active materials-probably THC-rather than the smokeper se. Administration of alcohol and amphetamine, used as control materials because they induce some behavioral changes similar to those seen in association with marijuana, resulted in less dramatic recording changes. Alcohol induced only generalized effects. Amphetamine induced some minimal spindling in septal recordings along with generalized low-amplitude fast activity. These findings suggest that active constituents of marijuana exert a unique effect on activity of brain cells identified with pleasure feelings (HEATH, 1964; HEATH and GALLANT, 1964; HEATH etal., 1968; HEATH, 1972~). The septal region (HEATH, 1954a), from which the distinct recording changes consistently occurred in the monkeys after inhalation of smoke of active marijuana, is rostra1 to the anterior commissure at the base of the anterior horn of the lateral ventricles. As we defined the region, its rostra1 caudal extent is 6-9 mm rostra1 to the anterior commissure and its lateral extent is 3 mm from the midline. Dorsoventrally, it extends from the base of the ventricle to the orbital cortex. Principal structures included within this region are the nucleus accumbens septi and the nucleus of-the diagonal band of Brocha. Electrodes in the brains of these monkeys from which we recorded the most significant EEG changes were at the stereotaxic AP coordinate of A-25. Studies in our laboratories during the past 22 years have consistently identified activity of the septal region with pleasure, levels of awareness, and emotional expression (HEATH, 1964; HEATH and GALLANT, 1964; HEATHet al., 1968; HEATH, 1972~). When function of this region is impaired, level of awareness decreases, ability to experience pleasure is reduced, and emotionality is damaged. Lesions in the septal region ofcats and rhesus monkeys, for example, have induced gross impairment in emotional expression and levels of awareness (HEATH, 1954b; HEATH, 1959). Psychotomimetic chemicals that grossly impair behavior of monkeys, such that it resembles the psychotic state of humans, have induced abnormal spiking and slow-wave activity in the septal region like that recorded from the septal region of psychotic patients (HEATH and MICKLE, 1960; HEATH and DEBALBIANVERSTER, 1961; HEATH, 1966, HEATH, 1970). Further, in a recent study in our laboratories, a consistent finding in the EEGs of isolation-raised monkeys whose behavior was severely disturbed was sharp spiking in the anterior septal leads (HEATH, 1972d). Activation of the septal region, on the other hand, heightens awareness and induces pleasure. Such responses have been elicited with electrical and chemical stimulation of the brains of patients (HEATH, 1964; HEATH, et al., 1968). Activity of the septal region has been shown to be profoundly affected during pleasurable behavior states (HEATH, 1972~). Other subcortical sites of these rhesus monkeys most often affected by smoke of active marijuana have been shown, by evoked potential studies, to be directly connected to the septal region and to be involved in the phenomenon of emotional expression (HEATH, 1972b). Involvement of the sensory relay nuclei (cerebellar nuclei for proprioception and poster0 ventral lateral thalamus for somatosensory functions) provides a physiological basis for the clinical observation that distortions of body image and unusual somatic sensations often accompany the mood changes that occur with marijuana smoking. It may be that the pleasurable feelings associated with marijuana are related to activation of the septal region and other neural sites implicated in emotional expression. As our studies of

Effect of marijuana on monkey EEG

13

human subjects have indicated, however, characteristically different recordings have been obtained from these same brain sites during episodes of psychotic behavior. It is provocative that an increasing number of reports indicate that chronic marijuana smoking can induce distinct personality changes and even psychotic behavior (TINKLENBERG,MELGES, HOLLISTER and GILLESPIE, 1970; MELGES, TINKLENBERG,HOLLISTERand GILLESPIE, 1970; KOLANSKYand MOORE, 1971). Further, pneumoencephalographic evidence suggests that marijuana can cause organic brain change (CAMPBELL, EVANS, THOMSON and WILLIAMS, 1971). Since the data presented in this study correspond with those obtained from a studyin a patient prepared with deep and surface electrodes (HEA~.H, 1972a), chronic exposure to marijuana smoke of the rhesus monkey preparation could conceivably shed light on some of these current issues. author is grateful to C. J. FONTANA,J. P. WUST, JR. and H. J. DAIGLE for their technical assistance with the study, and to L. S. LUSTICK,M.S., who conducted the analyses of the recordings using the Electrophysiological Monitor and Event Detector. Supported in part by the Behavioral Science Research Foundation, Inc., New Orleans, Louisiana, and the Institute of Mental Hygiene of the City of New Orleans, Louisiana.

Acknowledgements-The

REFERENCES BOSE,B. C., SAIFI,A. Q. and BHAGWAT,A. W. (1964). Observations on the pharmacological action of Cannabis indica, II. Archs int. Pharmacodyn. T/A. 147: 285-290. BOYD, E. S. and MERITT,D. A. (1966). Effects of barbiturates and a tetrahydrocannabinol derivative on recovery cycles of medial lemniscus, thalamus, and reticular formation in the cat. J. Pharmac. exp. Ther. 151:

376-384.

CAMPBELL,A. M. G., EVANS,M., THOMSON,J. L. G. and WILLIAMS,M. J. (1971). Cerebral atrophy in young cannabis smokers. Lancer 2: 1219-1224. CHRISTENSEN, C. W., BEST,J. B. and HERIN,R. A. (1971). Changes seenin theelectroencephalograms and heart rate in the rat after administration of marihuana intravenously. Fedn Proc. Fedn Am. Sots. exp. Biol. 30: abs: 375 (abs. #1017). DELIYANNAKIS, E., PANAGOPOULOS, C. and HUOTT, A. D. (1970). The influence of hashish on human EEG. Clin. Electroenceph. 1: 128-140. GIBBS,F. A. (1970). Editorial. Clin. Elecrroenceph. 1: 127. HEATH, R. G. (1954a). Definition of the Septal Region. In: Studies in Schizophrenia. (HEATH, R. G. and the Tulane University Department of Psychiatry and Neurology, Eds.), pp. 3-5. Harvard University Press, Cambridge. HEATH,R. G. (l954b). Behavioral Changes Following Destructive Lesions in the Subcortical Structures of the Forebrain in Cats. In: Studies in Schizophrenia. (HEATH,R. G., and the Tulane University Department of Psychiatry and Neurology, Eds.), pp. 83-84, Harvard University Press, Cambridge. HEATH, R. G. (1959). Physiological and biochemical studies in schizophrenia with particular emphasis on mind-brain relationships. Int. Rev. Neurobiol. 1: 299-331. HEATH,R. G. (1964). Pleasure Response of Human Subjects to Direct Stimulation of the Brain: Physiologic and Psychodynamic Considerations. In: The Role of Pleasure in Behavior (HEATH, R. G., Ed.), pp. 219-243, Hoeber Medical Division, Harper & Row, New York. HEATH, R. G. (1966). Schizophrenia: Biochemical and physiologic aberrations. Inr. J. Neuropsychiut. 2: 597-610.

HEATH,R. G. (1970). An Antibrain Globulin in Schizophrenia. In: Biochemistry, SchizophreniusundAfictive Illnesses(H~~~~~~. H. E.. Ed.). vv. 171-197. Williams&Wilkins. Baltimore. HEATH, R. G: (1972a). ‘Marihuana_‘l%fects on deep and surface electroencephalograms of man. Archs gen. Psychiat.

26: 577-584.

HEATH,R. G. (1972b). Physiologic basis of emotional expression: evoked potential and mirror focus studies in rhesus monkeys. Biolog. Psychiut. 5: 15-31. Heath, R. G. (1972~). Pleasure and brain activity in man: Deep and surface electroencephalograms during orgasm. J. nerv. ment. Dis. 154: 3-18. HEATH,R. G. (1972d). Electroencephalographic studies in isolation-raised monkeys with behavioral impairment. Dis. nerv. Syste. 33: 15?-163.HEATH,R. G. and DEBALBIAN VERSTER,F. (1961). Effects of chemical stimulation to discrete brain areas. Am. J. Psychiuf.

117: 980-990.

HEATH, R. G. and GALLANT,D. M. (1964). Activity of the Human Brain During Emotional Thought. In: The Role of Pleasure in Behavior (HEATH.R. G.. Ed.). vv. 83-106. Hoeber Medical Division. Harper & Row, New York.

NP

Vol.12 No.l-B

14

R. G. HEATH

HEATH,R. G., JOHN, S. B. and FONTANA,C. J. (1968). The Pleasure Response: Studies by StereotaxicTechnics in Patients. In: Computers and Electronic Devices in Psychiatry (KLINE, N. and LASKA, E., Eds.), pp. 178-189. Grune &Stratton, New York. HEATH,R. G. and MICKLE,W. A. (1960). Evaluation of Seven Years Experience with Depth Electrode Studies in Human Patients. In: Electrical Studies on the Unanesthetized Brain (RAMEY,E. R. and O’DOHERTY, D. S., Eds.), pp. 214247. Paul B. Hoeber, New York. HOCKMAN,C. H., PERRIN,R. G. and KALANT,H. (1971). Electroencephalographic and behavioral alterations produced by A’-tetrahydrocannabinol. Science 172: 968-970. KOLANSKY,H. and MOORE,W. T. (1971). Effects of marihuana on adolescents and young adults. J. Am. med. Ass. 216: 486-492.

LUSTICK,L. S. and HEATH, R. G. (1971). Comparative study of intracranial electrodes for stimulation and recording. Biophysical Society Abstracts. 11: 165a. MELGES,F. T., TINKLENBERG, J. R., HOLLISTER,L. E. and GILLESPIE,H. K. (1970). Temporal disintegration and depersonalization during marihuana intoxication. Archsgen. Psychiaf. 23: 204210. RODIN,E. A., DOMINO,E. F. and PORZAK,J. P. (1970) The marihuana-induced “social high”. Neurological and electroencephalographic concomitants. J. Am. med. Ass. 213: 1300-l 302. TINKLENBERG, J. R., MELGES,F. T., HOLLISTER,L. E. and GILLESPIE,H. K. (1970). Marijuana and immediate memory. Nature, Land. 226: 1171-1172. WIKLER,A. and LLOYD,B. J. JR. (1945). Effect of smoking marihuana cigarettes on cortical electrical activity. Fedn Proc. Fedn Am. Sots. exp. Biol. 4: 141-142.