Cannabinol During OS

7/28/2019 Cannabinol During OS

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ANESTHESIAND ANALGESIA. . Current Researches VOL. 5, No. 2, MARCH-APRIL,976 203

C a r d i o v a s c u l a r E f f e c ts of C a n n a b i n o l D u r i n g O ra l S u r g e r yJ O H N M. GREGG, DDS, PhD*ROBERT L. CAMPBELL, DDSt

KENNETH J . LEVIN, MS, M D*J AWAHAR GHIA, MDSRILEY A. ELLIOTT, BSII

Fifty-five clinical trials were conducted to de-termine the cardiovascular combined effects ofstressful oral surgery and systemic cannabi-nols. In a first study, A-tetrahydrocannabinol(THC) was given IV as a premedicant andcompared with diazepam and with a placebo.A classic dose-related tachycardia followedTHC injection. Th e peak h eart ra te response apatients prernedicated with 0.044 mg/kg THCwas 24.1% higher ( p < 0 . 0 5 ) tha n th e peak effectfo r a nonsurgerized control group, suggestinga synergistic effect between THC and surgicalstress. A predisposition to syncopal hypoten-sion followed THC premedication, and anti-arrhythmic effects were observed after largedoses. The injection of local anest hetic pre par a-

HE cannabinols, the most heavily usedT sychoactive drugs in the world, areused by an estimated 250,000,000 persons.The 1972 estimates for college-age users was54% (with about 5 to 10% of these usingmarijuana on a daily basis), and 1980 pro-jections for young adults have been set at66%.l Inevitably, more marijuana users willbe approaching elective or emergency sur-gical anesthesia after having premedicatedthemselves with cannabinols.

Marijuana has several properties that sug-gest it might be useful as a surgical pre-medicant: analgesia in subhumans;2 antisi-alosis;3 a moderate amnesic effect;4 a low

tions containing epinephrine did not alt er TH Ccardiovascular response. An apparent drug in-teraction was observed, however, in a secondstudy, in patients given general anesthesiawithin 72 hours after smoking marijuana.These patients demonstrated sustained abnor-mal postoperative tachycardia when comparedwith control nonsmokers, an effect which mayhave resulted from an interaction betweenstored cannabinol metabolites and a tropin e ad-ministered as part of the anesthetic technic.It was concluded that THC had no particularadvan tage over diazepam o r placebo as a pre-medicant. Further, THC altered the patientsadaptivity to stress and interacted undesirablywith other anesthetic medications.

or nonexistent addiction potentia1;s and avery low t~xicity.~eath from cannabinoloverdose has rarely been reported, and mostsevere reactions have occurred followingun-controlled I V injections. Extrapolating fromanimal toxicity studies, a human LD,, ofat least 30 mg/kg is far above the psycho-logically effective range, and much morefavorable than that of alcohol.5 And finally,the extensive use of marijuana as a socialdrug suggests a pleasant psychic experiencewhich could also serve well as a surgicalpain and anxiety sedative.

There is considerable evidence, however,that significant incompatibilities may exist*Associate Professor, Departments of Oral Surgery and Anesthesiology, The University of North Carolina,?Assistant Professor, Department of Oral Surgery, The University of North Carolina.$Associate Professor, Department of Anesthesiology, Th e University of North Carolina.SAssistant Professor, Department of Anesthesiology, The University of North Carolina.//Intern n Dentistry, The University of Vermont.This study was supported in part by NIH Research Grant DE 02668 from the National Institute ofDental Research and by NIH Grant RR 05333 from the Division of Research Facilities and Resources.Paper received: 5/13/75Accepted for publication: 8/7/75

Chapel Hill, North Carolina 27514.


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204 ANESTHESIAND AXAI.GESIA. . C u r r e n t Researches VOL.55, No. 2, MARCH-APRIL,976between cannabinol premedication and sur-gical anesthesia, making this drug of ques-tionable value in this situation. Althoughthe response to marijuana, as to most psy-choactive drugs, is largely determined bydoseGand route of administration,' person-ality factors,Rpsychologic set," and especial-ly the stress of the environmental setting:3.1"appear inordinately significant. For exam-ple, dysphoric "high" responses ("highs")with marijuana are more commonly seen inpatients with chronic depression,ll andparanoid delusional reactions occur morefrequently in hypnotic-suggestiblepatients. 1Marijuana is now looked upon as a mood-intensifying drug rather than as a pureCNS excitant, euphoriant, or depressant perse.13 Thus, it might be anticipated that thepsychophysiologic stress of a surgical exper-ience in the marijuana-premedicated patientcould result in an exaggerated sympatho-adrenal stress response.

Most of the adverse effects reported formarijuana have been on cardiovascular func-tions and related drug interactions. As in thepresent study, the most consistently report-ed pharmacologic response is a dose-relatedtachycardia.14.l; Both hypotensive and hy-pertensive effects have been described.1"The combination of increased cardiac de-mand from tachycardia with sustained cate-cholamine elevation has led some authorsto warn tha t the use of cannabinols inelderly or in cardiac patients may be haz-ardous.z.12 Studies of patients with anginapectoris support this warning, for it hasbeen shown that smoking marijuana signifi-cantly decreases exercise tolerance whencompared to placebo smoking.IH

Studies of long-term hashish users havedemonstrated elevated hemoglobin andpacked-cell volumes, which have been attrib-uted to chronic hypoxia.1 1:) There are alsoreports of increased potential for cardiacarrhythmias,18 and ECG studies have dem-onstrated shortening of the S-T interval anddepression of T-wave amplitude.?O Otherstudies, however, have indicated that can-nibinols may actually have a therapeutic orprotective effect against cardiac arrhyth-mias." Nevertheless, because the incidenceof arrhythmia during oral surgery withlocal anesthesia alone has been reported asgreater than 45%,'2 our investigations ofcannabinol effects appear warranted.

There have been other warnings of dan-gerous drug interactions between marijuanaand anesthetic medications. Cannabinols

have been shown to double ketamine sleep-ing time and to quadruple thiopental dura-t i ~ n . ' ~entobarbital sleeping time in ratswas doubled after a single cannabinol dose.'-'Marijuana is also known to potentiate thedepressant effects of alcohol'" and to sum-mate with amphetamines. .6 Beaconsfield'sgroup1-' predicted dangerous cardiovasculardrug interactions between marijuana andsuch common agents as atropine or local-anesthetic preparations containing epineph-rine.

Our studies were designed to determinethe cardiovascular effects of cannabinols (1)by comparing the cardiovascular effects ofpremedicant I V doses of THC, diazepam,and placebo, and ( 2 ) by a retrospectivestudy of the cardiovascular effects of out-patient general anesthesia in patients knownto have smoked marijuana within 72 hoursbefore anesthesia.

STUDY 1: METHODSTen healthy male patients between 19and28 years of age (mean 26 + 2.8 yr SD) wereselected for study, without regard to priormarijuana experience, from a populationrequiring elective surgical removal of 4 im-pacted 3rd molars. All 10 subjects hadsmoked marijuana, and 2 admitted to pre-

vious experiences with LSD-25 and mesca-line. After explanation of the procedure andthe risks involved, informed consent wasobtained. A complete physical examination,including ECG, chest x-ray, and laboratorytests, showed all subjects to be healthy andfree of cardiovascular or respiratory abnor-malities. Each subject participated in 4separate weekly clinical trials, at which timea single 3rd molar was removed, and duringwhich time he was prernedicated with oneof the following 4 agents:1. THC: 0.044 mg/kg* ("larger dose")2. TH C: 0.022 mg/kg" ("smaller dose")3. Diazepam: 0.157 mg/kg4. Placebo (dextrose 5%, NaC1): 0.2%These were given in random order on 4consecutive weeks, double-blind with re -spect to patient and surgeon. This allowedeach patient to serve as his own control formeasuring cardiovascular changes. Th e THCsolutions were prepared by dissolving the

*These 2 dosages were selected from a pilot studyin which 0.02 mg/kg was found to consistentlyproduce minimal subjective "highs"and 0.04 mg/kgconsistently produced near-100% "highs." Subjectsreported that IV "highs" were equal to or beyondthe usual effects from smoking marijuana.


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Cardiovascular Effects of Cannabinol . . .Gregg, et a1 205dose of active THC in 0.5 ml of ethyl alco-hol and adding 25 ml of human serum albu-min.

On the morning of each clinical trial,patients, who had fasted since midnight andhad recently voided, were brought to theclinical research unit. All had been askedto avoid smoking in any form for at least24 hours before each clinical trial. Patientsreclined in an approximately 30" sittingposition throughout the test period. TheECG was continuously recorded from amodified lead I1 placed entirely on thethoracic cage, and heart rate was monitoredelectronically from the ECG. Indirect sys-tolic and diastolic blood pressures were re-corded at 2-minute intervals with a Littonphonosensor. All transducer signals werepreamplified and oscilloscope-displayedthrough the Litton Product Basic BedsideUnit. Continuous recording of output wasmade on a 12-channel Honeywell 5600 elec-tromagnetic tape recorder and subsequentlyprinted out on the Siemens Mingograph@polygraph.

Simultaneously with the cardiovascularmonitoring, subjective psychologic drug ef-fects were studied, using the State-TraitAnxiety Inventory (STAI) 2 7 a modifiedSubjective Drug Effects Questionnaire(SDEQ) 28 and the measure of subjective"high" described by Perez-Reyes and co-workers.2C' Details of these tests are con-tained in another report.30Baseline resting physiologic functionswere monitored for a 30-minute period, andthe injection procedure was isolated andshielded from the patient's view. Patientswere told that the injection was to begin,and the premedicant was injected evenlyover a 5-minute period through an indwell-

ing venous catheter, after which the surgeonand nurse entered the operatory, where theyadministered the local anesthetic. Appro-priate peripheral trigeminal blocks were per-formed by standard aspiration technic, usingan average of 2 to 4 ml (40 o 80 mg) of2% lidocaine containing 40 to 60 mcg of1:100,000 epinephrine. The surgeon then re-moved the molar by ordinary surgical tech-nics, pacing the procedure to be completedexactly 30 minutes after drug injection. Fol-lowing a 30-minute surgical test period, thepatient remained in the operating chair foran additional 60 minutes of monitoring andthen was escorted to a recovery room, wheremonitoring continued for a minimum of 60minutes until discharge.

M E A N B L OOD P R E S S UR E R E S P ON S E TOSURGICAL PREMEDICATION WIT H A9 TE TR A H Y D R OC A N N A B I N OL ,DIAZ EPAM , AND PLACEBO ( n = 0 s u b I r c t s 1

A 9 T H C i 0 0 4 4 m q / h q l -A' TH C i O . 0 2 2 rng / hq IPlacebo .D i a z c o a m ( 0157rnp/hql ----

~."1 r ' , ' " I20 40 6 0Surgery Surgerybegun en d

D ru gbegunT i m e ( m i n u t e s )

Ib P 'FIG 1. Measures of blood pressure response tosurgical premedication with 'THC revealed a peaksystolic hypertension 25 minutes after injection. Amild gradual hypotensive trend followed the end ofsurgery with the larger THC dose.The additional control group of 5 nonsur-gerized volunteers consisted of healthy men,aged 21 to 34 (mean 26 k3.2 SD), who

underwent a single trial in which they weregiven a single dose of THC (0.044 mg/kg)from the batch used in the main experimentdescribed above. Cardiovascular monitoring,subjective measurements, and experimentalsetting were identical, but no operationswere performed. When cardiovascular datafrom this group were compared with datafrom the main experiment, influences thatcould be attributed solely to drug effectcould be separated from those due to drug-surgical stress interactions.STUDY 1: RESULTS

Blood Pressure.-The average blood pres-sure response to surgical premedication withTHC changed little from average preopera-tive baselines and placebo levels (fig 1 ) .Amild elevation of systolic pressure was ob-served, with the peak effect at the 25-min-Ute postinjection interval; the larger dose ofTHC produced an average elevation of 8torr, and a 9-torr elevation followed thesmaller dose. In the Iarger-dosage THCgroup, a gradual hypotensive trend was ob-served, beginning approximately at the timeof completion of the operative procedureand reaching an average maximum depres-sion of 12 tom below preoperative baseline


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206 ANESTHESIA N D AXALGESIA . . C u r r e n t Re s e a r c he s Vor,. 55, No. 2 , MARCH-APRIL,976and 14 torr below placebo levels at the 55-minute postinjection time period. Bloodpressures following larger doses of THCreturned gradually to placebo levels an aver-age of 70 minutes after initial drug injec-tion.

The blood pressure effects of diazepamwere dissimilar to those of THC: Diazepamconsistently induced a mild systolic hypo-tension, ranging from 7 to 15 torr through-out the entire trial. However, average dia-stolic responses to both dosages of THCwere statistically and clinically similar toplacebo responses throughout.Transient moderate hypotension of 20 to45 torr systolic and diastolic in the intervalof 4 to 8 minutes after THC injection oc-

curred in 3/10 subjects. These episodesappeared to be typical syncope, associatedwith nausea, dizziness, anxiety complaints,and, in 2 instances, loss of consciousness ac-companied by carpopedal spasm for up to25 seconds. No similar syncopal responsesor transient hypotension was observed withany of the patients given placebo or diaze-pam.Blood pressure response in the periodduring and immediately after administra-tion of the local anesthetic (lidocaine withepinephrine) was not significantly different

from placebo responses with either dose ofTHC or diazepam.Heart Rate.-Comparison between bothdosages of THC, which induced tachycardiain all surgical patients, and response todiazepam and placebo premedicants (fig 2)showed the average peak heart rate increasewith 0.044 mg/kg THC to be 69% abovepreoperative baseline and 36% above place-bo peak. The greatest elevation occurred

5 18 minutes after the start of drug injec-tion. Peak heart rate increases after 0.022mg/kg THC occurred typically at the 15-minute postinjection interval, with 53%above preoperative baseline and 26% aboveplacebo peak. Although heart rate peak timewas similar with both doses of THC, theduration of tachycardia differed. Whereasaverage heart rate had returned t o placebolevels 75 minutes after injection of 0.022mg/kg THC, heart rate after 0.044 mg/kgTHC had not returned to placebo levelsuntil after the 100-minute postinjectiontime.

Local-anesthetic administration in pa-tients premedicated with THC had no sig-nificant effect on heart rate during or afterthe injection process. "Highs" experiencedafter TH C premedication did not coincidewith peak heart rates, peak tachycardia OC-curring typically 12 minutes before peak

MEAN HEART RATE RESPONSES TOSURGICAL PREMEDICA TION WITH A' TETRAHYDROCANNABINOL,DIAZEPAM, AND PLACEBO ( n =10 subjects 11401 A'TCIC ( 0 . 0 4 4 m q / k g ) -

A THC ( 0 . 0 2 2 m g / k g )Placebo .....Diazepam (0.157 g/kg)

L ' I # ' I ' ' 1 " ' 1 " ' 1 ' " 1 " ' 1-20 0 20 40 60 80 100 120

Surge ry S u r g e r ybegun end

begun T i m e ( m i n u t e s )Drug'

FIG2. Peak T H C tachycardias significantly above placebo and diazepam levels occurred at the 15-18post-injection interval. Heart rate returned to placebo levels approximately 100 minutes after injection ofTHC, .044 mg/kg.


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Cardiovascular Effects of Cannabinol . . .Gregg, et a1 207M E A N H E A R T R A T E . SYSTO L IC 8L00D

FOLLOWING SURGICAL PREMEDICATIONW I T H A9 TETRAHYDROCANNABINOL ,P R E S S U R E A N D SUBJECTIVE HIGH RESPONSES

( 0 04 4 mg / g ( n=IO s u b j e c t s I1307

70 -

6 0 - 1 . . , 7 1 7 , I , , # , , , --10 0 1 20 / 40 60 80 100Surgery S u r g e r y1 b e g u n e n d

70

60

50ch40z

30 9bs

20

10

0

Drugb e g u n

FIG3. Simultaneous plotting of heart rate, bloodpressure and subjective high responses to THC dur-ing surgery showed that peak tachycardia precededboth the peak hypertensive and subjective higheffect, and that the heart rate and blood pressuresreturned to placebo baselines an average of 30minutes before subjective high was reported asnormal.

highs. Heart rates also returned to place-bo levels an average of 30 minutes beforesubjects reported a normal psychic state

ECG Responses.-There was a dose-re-lated shortening of P-R interval greater than33% in all subjects given THC (table 1).T-wave amplitude reduction of greater than33% during peak drug effect was observed

(fig 3 ) .

in 70% of subjects after the smaller dosesof THC and in 60% of subjects after thelarger THC dose, as compared to a 30%depression with diazepam and 10% depres-sion with placebo. ECG changes in THC-premedicated patients were the same withlocal anesthetic injection as with placebo.Arrhythmias, interpreted as functionalpremature ventricular contractions (PVCs),were observed in 11/40 clinical trials duringbaseline preoperative recording and in 2/10subjects during intraoperative trial withplacebo premedication. After injection of0.022 mglkg THC, arrhythmias seen preop-eratively in 2 subjects increased slightly infrequency intraoperatively, and PVCs wereobserved in 2 other subjects who had notdisplayed arrhythmias during preoperativebaseline recording. After injecting the largerdose of THC, arrhythmias observed in asingle subject during baseline preoperativerecording disappeared for an hour after drugadministration and intraoperative recording(fig 4).No other instances of arrhythmiawere observed after giving the larger doseof THC.

Surgical and Nonsurgical THC GroupsCompared.-A significant difference ( p


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208 ANESTHESIAN D ANALGESIA. .C u r r e n t Researches VOL. 55, No. 2, MARCH-APRIL,976R A T E OF C A RD IA C A R R H Y T H M I A S F OL L O W IN GSURGICAL PREMEDlCATlON WITH A9 TETRAHYDROCANNABINOL,D I A Z E P A M , A N D P L A C E B O

P l a c e b o . . ...Diazepam ( 0 . 1 5 7 m g I k g )---THC (0.022m g / kg l -.-THC (0.044 g/ kgl-

Surgery Surgery1 begun endDrugbegu n T i m e ( m i n u t e s )

FIG4. Preoperative rate of arrhythmias significantly reduced following premedication with THCcompared to diazepam and placebo. when

TABLE 2Comparison of Mea n Cardiovascu lar Responses to 0.044 mg/kgIV A'-THC in Surgical an d in Nons urgi cal Subjects

Sur g i c a l pa t i en t s ( N=101 N ons ur g i c a l s ub i ec t s (N =5 )(2 E) (f SE )Yo change change

Heart r a t e R a t e b a s e l i n e R a t e b a s e l i n eBaseline 71.7 - 70.8 -

&4 .5 k 4 . 2D r u g given ( 5 m i n ) 96.8 35.0* 80.6 13.8*

rt5.l k 2 . 8Peak effect 117.8 64.3* 102.0 44.1*

k 7 . 1 2 4 . 6Trial end ( 9 0 m i n ) 80.9 12. 8t 73.0 3.lf

k 7 . 0 & 2 . 5Sy r to l i c /d i as to l i c c hange Sy s to l i c /d i o r to l i c yoc h a n g e

B l o o d pressure pressure S/D basel ine pressure S/ D b a s e l i n eBaseline 117.6176.2 - 128.6168.8 -

i 5 . 7 4 / & 4 . 6 24.52/14.2Drug g ivenPeak effect

117.2/7 2.0 -0.3/-5.5? 131.8/70.8 2.4/2..9?"5 .31k3 .8 k5 .3 /&3 .5122.9168.1 4.5/-10.6? 142/73.2 10.4/6.4+k 7 . 3 1 k 4 . 1 1 1 2 . 5 / & 4 . 1

Trial end (9 0 min) 111.8 /69.6 -4.91-8.6* 133 .8/68 4.0/-1.2*c4.21k3.6 ?7.0 /&6.4* p


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Cardiovascular Effects of Cannabinol .. .Gregg, et a1 209subjects. Dysphoria, as measured by SDEQanalysis, and low moods predominated atthe periods of syncopal hypotension afterTHC.

STUDY 2 : METHODSThis retrospective study included 10 con-secutive patients, 7 women and 3 men (ages21 to 30, mean 25 k 3.1) undergoing outpa-tient general anesthesia for routine removalof from 2 to 4 third molars in one clinicalprocedure. Each patient was healthy andfree of cardiovascular or respiratory abnor-malities and gave informed consent.At each clinical triaI, patients were seatedin the operating chair in an approximately30 upright position with legs parallel tothe floor. A venous catheter was inserted inthe forearm. Physiologic monitoring con-sisted of continuous ECG, heart rate, in-direct blood pressure, and respiratory rate,by a technic similar to that described forstudy 1. In addition, serial blood-gas meas-urements (IL Blood Gas Analyzer) weremade through radial-artery puncture, pre-operatively and at selected intervaIs duringoperation,After baseline blood pressure, ECG, heartrate, respiratory rate, and blood gases had

been recorded, all 10 patients received thesame form of general anesthetic manage-Instrumentation Laboratories.

ment. First, 0.4 mg of atropine sulfate wasadministered IV, followed by 0.1 mg offentanyl. Ten to 15 mg of diazepam wasthen infused over a 6 to 8-minute period toan endpoint of hypnosis with Verrills sign(lid lag over pupils). After adequate seda-tion, N,O-0, (70:30) was administeredthrough a McKesson nasal inhaler by aMcKesson Analor@ as machine. After 15 to30 seconds, 1% sodium methohexital wasgiven at a rate of 20 mgl30 sec until voicecontact with the patient was lost.

Following induction, respirations weregently assisted with nasal insufflation, andadditional increments of methohexital wereinfused as needed. Tooth extraction thenproceeded according to standard technic, in-cluding mouth gauze packing and the P R Nadministration of local anesthetic blocks.The total usual dose of local anestheticranged from 4 o 6 ml of 2% lidocaine (80to 120 mg) with 40 to 60 mcg of 1:100,000epinephrine.

Surgical anesthesia ranged from 25 to 45minutes in duration. No major complica-tions were encountered. Following awaken-ing, patients were monitored for a minimumof 1 hour before discharge.

STUDY 2 : RESULTSOf the 10 patients studied, 5 admitted tohaving smoked marijuana within 72 hoursTABLE 3

Comparison of Mean Cardiovascu lar Responses to OutpatientGeneral Anesthesia in Mar ij uan a Smokers and in Nonsmokers(N=10subjects)

Blood gasB lood pressure Heart rate Po a Pcoa

Preoperative baselineSmokersNonsmokers

PostinductionSmokersNonsmokers

Peak anestheticSmokersNonsmokers

Peak postanestheticSmokersNonsmokers

10,1.6/68.2106.0/66.4

1(14.8/66.0106.3/68.1

102.0/64.8105.6/65.2

115.2/89.6ll6.0d91.2

83.0 90.0 35.274.8 90.6 36.0

104.0 97.6 39.090.3 98.1 44.0

98.6 160.2 40.293.6 158.4 40.4

136.8*104.6*

* p


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210 ASFSTHESIASD ASALCESIA Current Researches VOL.55, No. 2, MARCH-APRIL,976ME AN HEART RATE RESPONSES TOMAR I U A NA SMOKERS COMPAREDGENERAL ANESTHESIA IN] TO N O N - S M O K E R S (n : lO )I40

nSmokersLbaseline anesthesla 10 20 30 40 50Pre-op ' Surgicol Post -surgical anesthesiaMcnutes

FIG5. Tachycardia following general anesthesiawas markedly elevated and lengthened in marijuanasmokers as compared to non-smokers.

of operation. A comparison of cardiovascu-lar responses between marijuana-smoker andnonsmoker groups revealed similar preoper-ative baselines of blood pressure, heart rate,ECG, and blood gases (table 3 ) . In addi-tion, blood pressure responses and bloodgases were found similar and within ex-pected limits for both groups throughout theduration of anesthesia and the postoperativeperiod.

A major difference between the 2 groupswas observed, however, in heart rate re-sponse during the postanesthetic interval(fig 5) . In the marijuana group, a peaktachycardia averaging 64.8% above baselineoccurred, which did not return to baselinelevels until an average of 38 minutes afterthe end of anesthesia. In the nonsmokergroup, postoperative heart rate peaked at39% above baseline at the 7-minute markafter anesthesia and returned to baselinelevels by the 19-minute mark after anesthe-sia.

There were no significant differences be-tween smoker and nonsmoker groups fortotal required methohexital (193 versus 194mg). Nor were there differences betweenmean "sleep time" induced by these con-centrations (32.4 versus 31.8 min) or inrecovery rate.DISCUSSION

In the current studies, which involvedhealthy young adults, there was no signifi-cant deterioration in cardiovascular func-tions. However, certain changes were ob-

served that might hold significance for otherpatient populations.Transient syncopal hypotension followedTHC premedication. (Psychologic measuresduring these periods demonstrated above-average levels of dysphoria and anxiety.)These patients did not demonstrate syncopewhcm premedicated with placebo or diaze-pam. Orthostatic hypotension and presynco-pal responses to table tilt have been de-scribed as common with THC .31J2 Con-trolled animal experiments have shown thatstress exaggerates an already elevated sym-pathoadrenal response to parenteral can-nabinols, manifest as marked elevations inserum dopamine hydroxylase levels.2"Beaconsfield first warned that under

stressful or emergency conditions, the vaso-motor reflex mechanisms may be significant-ly impaired in marijuana-pretreated sub-jects.' 4 . u He demonstrated that peripheralblood flow increases concomitantly withpulse rates following cannabinol administra-tion, and that peripheral flow adjustmentsto mild psychogenic stress (mental arith-metic and ice placed on a limb) are mark-edly slowed or absent. Careful cardiovascu-lar monitoring, therefore, is mandatory fol-lowing THC premedication.After the initial tendency to syncopalhypotension from THC during operation,the blood-pressure response displayed a bi-phasic pat tern of mild hypertension, whichpeaked at the 25-minute postinjection in-terval, followed by a gradual hypotensivetrend which reached its peak depression at55 minutes postinjection. Surgical stimula-tion probably had a strong influence onblood-pressure response. However, similararousal-depression patterns have been ob-served in nonsurgical experiments with can-nabinols, and there may be pharmacologicreasons for this pattern:]' As A9-THC un-dergoes biotransformation to the more polarform, ll-O H-ng-T HC, within 10 to 15 min-utes after injection, it has been suggestedthat n!'-THC exerts a generalized CNS andcardiovascular arousal effect, and that 11-OH-n!I-THC has a longer-acting depressanteffect."4In our study, combining T H C premedica-tion with the stress of oral surgery appearedto have a synergistic effect on heart rate,since subjects who had received 0.044 mg/kgof T HC before operation reached peak heartrates averaging 24.1% higher than the peaksfor the nonsurgerized controls. These obser-vations are consistent with current theories


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Cardiovascular Effects of Cannabinol . . .Gregg, e t a1 211of the mechanism of THC cardiovascularaction. Studies have suggested that vago-lytic action by the cannabinols is unlikelybecause cannabinol tachycardia is inducibleeven in atropinized patients.14 Most evi-dence points to a CNS-activated sympatho-adrenal response to cannabinol. Beta-adren-ergic receptors appear to be the final com-mon pathway for this response, since pro-pranolol, a beta blocker, reduces the effectsof cannabinol.35

Even though THC tachycardia appearedto be heightened by the stress of operationin this study, it is of interest that the ini-tiation and duration of heart rate changesappeared to precede psychic effects. Onsetof heart rate elevation consistently precededthe onset of highs by a few minutes, andthe peaks of heart rate and subjective high,as well as the duration curves, were gen-erally out of phase by a matter of manyseconds to a few minutes. This finding isconsistent with those of Lows group,13 whoobserved that subjective THC effects maypersist even though heart rate has returnedto normal.

It may be speculated that the inevitableTHC tachycardia acts as a partial triggerfor the psychic effect of cannabinols, andthat the surgically stressed patient reactsto tachycardia in a manner different fromthe nonstressed THC subject. Whereas thenonstressed subject interprets THC tachy-cardia as an expected and nonthreateningaspect of his drug experience, the stressedpatient considers it a signal that is part ofan overall harmful situation (the operation)which is out of his control. This activatesthe hypothalamo-pituitary complex andeventually a classic sympathoadrenal stressresponse, which then potentiates the pre-existing THC tachycardia.In pursuing one of the goals of the cur-rent study, the detection of significant druginteractions between cannabinols and a localanesthetic agent, it was observed that usualsurgical levels of 2% lidocaine and 1 :100,000epinephrine had no measurable effect on anycardiovascular parameter. Bea~onsfield~~has shown that TH C potentiates the pressoreffects of I V epinephrine in humans, whirelaboratory studies32J6 have shown elevationof circulating epinephrine for periods of 6hours following THC administration. Itwould appear, however, that the doses oflidocaine and epinephrine used in our stud-ies with surgery patients and with routineanesthetic block were insufficient to inter-

act significantly with cannabinol premedi-cation.An apparent drug interaction was ob-served, however, in study 2 of this investi-gation, where a prolonged postoperativetachycardia was observed in a series of pa-tients who had smoked marijuana within72 hours before undergoing outpatient gen-eral anesthesia. Not only is this a poten-tially dangerous problem, but when the eti-ology of the tachycardia is not appreciated,errors in medical management may occur.Previous studie d4 have demonstratedsynergistic cardiovascular effects betweencannabinols and vagolytic agents. This sug-gests that atropine, used in the current anes-thetic technic, was the drug most likely to

have interacted with the previously smokedcannabinol.Potential drug interactions occurring manyhours, or even days, after marijuana smok-ing appear quite possible, in light of theknown distribution, catabolism, and excre-tion patterns of the cannabinols. Plasmalevels of Ag-THC decrease rapidly afterinjection, probably because of a great affin-ity for fat stores.3i TH C may also be storedin significant quantities in the enterohepatictissues and be secreted along with bile in

response to food ingestion.9 Although thisappears to be the primary means of can-nabinol excretion, with 70 to 80% elimi-nated in the feces and 20 to 30% in theurine, the enterohepatic secretion, with sub-sequent plasma resorption from the gut, mayalso account for the frequently observedmaintenance of sustained and episodic THCplasma levels.38The plasma half-life of AS-THC is 36hours; that of the active liver metabolite,ll-OH-ny-THC, is 40 hours. The release

of active THC compounds has been shownto continue for 8 days after a single humandose.7~34 herefore, 20 to 35% of active can-nabinols may remain in the tissues for long-er than 72 hours after a single administra-tion. This time course is quite compatiblewith the sequence of drug interactions sug-gested by our study 2.An acute dose-related antiarrhythmic ef-fect was observed during oral surgery withTHC premedication. The smaller doses ofAS-THC were associated with intraopera-tive PVC activity at levels similar to thoseof placebo, whereas the larger doses werecorrelated with the disappearance of ar-rhythmias after injection. Although some


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212 AXESTHESIAXD AXALGESIA. .Current Researches VOL.55, No. 2, MARCH-APRIL,976report possible induction ofarrhythmias by cannabinols, other observ-ers?1,RD have shown possible antiarrhythmiceffects. In our study, arrhythmias were ofthe benign variety, consisting mainly oftransitory ectopic foci. It would be unwise

to assume that a similar therapeutic effectwould have occurred in a group of patientswith chronic cardiopathy.We conclude that @g-THC has no par-ticular advantage over diazepam or placeboas a premedicant; although potentially ther-apeutic antiarrhythmic effects were seen,THC appeared to compromise to some de-gree the surgical patients adaptivity tostress and to interact undesirably with otheranesthetic medications.

REFERENCES1. Marijuana and Health. Washington. DC,Third Annual Keport to Congress, DHEW Pub #(ADMI 74-50, 19742. Parker JS , Dubas TC: Automatic determina-tion of the pain threshold to electroshock and theeffects of a-THC. In t J Clin Phaimacol 7:75-81,19733 . Jones RT : Marijuan a-induced high: in-fluence of expectation, setting and previous drugexperience. Pharmacol Rev 23:359-369, 19714. Klonoff H, Low M, Marcus A: Neurapsy-chological effects of mar ijuana. Ca n Me d Assoc J108:150-165, 19735. Nah as GG: Toxicology and pharmacology ofCannabis S Q ~ ~ L W ith special reference to n-THC.Bull Narc 24:l l-29 , 19726. Hill SY , Goodwin DW, Schwin R. Powell B:Marijuana: CNS depressant or excitant? Am JPsychiatry 131~313-315, 9747. Lemberger L, Weiss JL, Watanabe AM. et al:Delta-9-tetrahydrocannabinol. Temporal correlationof t he psychologic effects and blood levels aftervarious routes of administration. N Engl J Med286: 685-688, 19728. Klapper JA, McCollach MA, Side11 FR: Theeffect of personality on reactivity to 1,2-dimethyl-heptyl tetrahydrocannabinol. Arch Gen Psychiatry26:483-485, 19729. Mills L, Brawley P: Th e psychopharmacologyof Cannabis sativ a: a review. Agents Actions 2:201-215, 1972

10. Carlin AS, Bakkar CB, Halpern L, et a l:Social facilitation of mar iju ana intoxication: impactof social set. J Abnorm Psycho1 80:132-140, 197211. Ablon SL, Goodwin FK: High frequency ofdysphoric reactions to tetrahydrocannabinol among

depressed patients. Am J Psychiatry 132:448-453,197412. Bilash IS, Arnold M, Zell C: Marijuana andsuggestibility. Can Psychiatr Assoc J 17 :327-329,1972

13. Low MD, Klonoff J , Marcus A: The neuro-physiological basis of the marijuana experience.Can Med Assoc J 108:157-165, 197314. Beaconsfield P, Ginsburg J , Rainsbury R:Mar.ijuana smoking: cardiovascular effects in manand possible mechanisms. N Engl J Med 287:209-212. 197215. Renault PF, Schuster CK, Heinrich R, et al:Marijuana: standardized smoke administration anddose effect cuives on heart rate in humans. Science174:589-591. 197111;. VlilIiams RB, Ng LK, Lamprecht F, et al:~T etra hyd roca nna bin ol: a hypotensive effect inrats. Isychopharmacology 28:269-274, 197317 . Johnson S, Domino E F : Some cardiovascularefferts of marijuan a smo king in normal volunteers.Clin Pharmacol Ther 12 :762-768, 197118. Aronow WS, Cassidy J : Effect of mari juanaand placebo-marijuana smoking on angina pectoris.

N Engl J Med 291: 65-67, 197419. Rubin V, Comitas L: Effects of Cannabis inanother culture. Scotch Plains, NJ , Mo uton/McFar-land Publications, 197520. Kochar MS, Hosko M J : Electrocardiographiceffevts of marijuan a. JA MA 225: 25-27, 197321. Roth WT , Tinklenberg JR , Kopell BS, et al:Continuaus electrocardiographic monitoring duringmarijuana intoxication. Clin Pharmacol Ther 14:533-540, 197322. Driscoll EJ , Smilack ZH , Lightbody P M , etal: Sedation with intravenous diazepam. J Oral

Surg 30: 332-343, 197223. Sofia RD, Knobloch LC : The effect ofa-tetrahydroca nnabinol pretreatment on ketaminethiopental or CT-1341-induced loss of righting reflexin mice. Arch Int Phaimacodyn Ther 207:270-281,197424. Siemens AJ , Kalan t H, Khanna JM, et al :Effect of cannabis on pentobarbital-induced sleep-ing time and pentobarbital metabolism in the rat.Biochem Pharmacol 23:447-488, 197425. Ng LK , Lamprec ht F, Williams RE, et al :A! tetrahyd rocannabi nol an d ethanol: differentialeffects on sympathetic activity in differing environ-

mental settings. Science 180:1368-1369, 197326. Zalcman S, Liskow B, Cadoret R, et al: Mari-juana and amphetamine: the question of inter-action. Am J Psychiatry 130:707-708, 197327. Spielberger CK, Gorsuch RL, Lushene RE:State-Trait Anxiety Inventory. Palo Alto, Consult-ing Psychologists Press, 197028. Waskow IE , Olsson JE , Salzman C, et al:Psychological effects of tet rahydrocann abinol. ArchGen Psychiatry 22:97-105, 197029. Perez-Reyes M, Timm ons MC, Lopton MA,

et al: Intravenous injection in man of nS-tetra-hydrocannabinol a n d 11-OH-A-tetrahydrocanna-binol. Science 117:633-635, 197230. Gregg JM, Small EW, Moore R, e t al:Emotional responses to intravenous Atetrahydro-


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Cardiovascular Effects of Cannabinol ...Gregg, et a1 213cannabinol during oral surgery. J Oral Surg (inpress)

31. Hardman HF , Domino EF , Seevers MG:General nharmacoloaical actions of some svnthetictetrahyd&cannabinor derivatives. Pharmacol Rev23:295-316, 197132. Weiss JL, Watanabe AM, Lemberger L, etal: Cardiovascular effects of delta-g-tetrahydrocan-nabinol in man. Clin Pharmacol Ther 13:671-684,197233. Beaconsfield P: Some cardiovascular effectsof cannabis. Am Heart J 87:143-146, 197434. Lemberger L, Axelrod J, Kopin IJ: Metab-olism and disposition of A9-tetrahydrocannabinol

in man. Pharmacol Rev 23:371-380, 197135. Drew WG, Kiplinger GF, Miller LL, et al:Effects of propranolol on marijuana-induced cogni-

tive dysfunctioning. Clin Pharmacol Ther 13:526-533, 197236. Hollister LE, Moore F, Kanter S, et al:~g-tetrahydrocannabinol, ynhexyl and marijuanaextract administered orally in man: catecholamineexcretion, plasma cortisol levels and platelet sero-tonin content. Psychopharmacologia 17:351-360,197037. Kreuz DS, Axelrod J: Delta-g-tetrahvdro-cannabinol: localization in body fat. Science 179:391-392, 197338. Lemberger L, Martz R, Rodda B, et al:Comparative pharmacology of n9-tetrahydrocan-nabinol and its metabolite, ll-OH-A9-tetrahydro-cannabinol. J Clin Invest 52: 2411-2417, 197339. Schaefer JF , Loetzer R, Sofia RD: Effect ofA-tetrahydrocannabinol and propranolol on oua-bain induced arrhythmias. Arch Int PharmacodynTher 205: 5-10, 1973

TEM PERATURE AND d- TUBOCURARI NE The influence of temperature (28-41C)on d-tubocurarine (dTc) neuromuscular blockade and antagonism with neostigminewas studied in anesthetized cats. dTc infusion rate required to maintain 90 per centtwitch depression wa s directly related to temperature . Althoug h the mechanism isnot known, reduced renal and biliary excretion of dTc, may account for the decreaseddTc needs during hypothermia. Hypother mia did not affect th e magnitude b ut pro-longed the on set and then dura tion of dTc antagonism by neostigmine. Since hypo-ther mia reduces skelet al muscle blood flow the delayed upt ake and elimination ofneostigmine should not be unexpected. (Miller R D , Van Nyhuis LS, Eger E I : Theeffect of temperature on a d-tubocurarine neuromuscular blockade and its antagonismb y neostigmine. J Pharm Exp Ther 195:237-241, 1975)

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