Effect of marihuana on cardiorespiratory responses to submaximal exercise Six male chronic marihuana (MH) users exercised on a bicycle ergometer for 15 min at

~

50%

V(hma.l' under 3 conditions: (1) not smoking (control), (2) after smoking MH containing 7.5 mg (-) delta-9-tetrahydrocannabinol, and (3) after smoking placebo marihuana (PL). The MH was

administered double-blind in a counterbalanced repeated-measures design. Heart rates (HRs), arterial blood pressures (BPs), pulmonary ventilation (V E), and oxygen uptake (VoJ were measured during exercise and 15 min recovery. PL had no effect on any of the physiologic variables. Smoking MH had no effect on systolic blood pressure (SBP) , diastolic blood pressure (DBP) , VE, or V0" but did induce a marked increase in heart rate which persisted throughout exercise and recovery periods, averaging 34% higher than control values at rest, 18% higher during exercise, and up to 50% higher during recovery. MH smoking increased the product of HR

X

SBP in all circumstances.

Edward V. Avakian, Ph.D., Steven M. Horvath, Ph.D., Ernest D. Michael, Ph.D., and Samuel Jacobs, Ph.D.t Santa Barbara, Calif. 1nstitute of Environmental Stress and Department of Ergonomics, University of California, Santa Barbara

The acute pharmacologic effects of smoked marihuana (MH) in resting man have been investigated extensively. Cardiovascular responses include sinus tachycardia 4 • 5, 7, 9, 13 and an increase in limb blood flow. 5, 15 Large doses (> 10 mg delta-9-tetrahydrocannabinol [THe]) administered intravenously or by smoking have been reported to increase resting cardiac output8 , 10 and systolic blood pressure (SBP).7 Effects of MH on ventricular contractility remain unclear, as other studies with large doses report Received for publication June 18, 1979. Accepted for publication Aug. 9, 1979. Reprint requests to: Dr. Edward V. Avakian, Jf., Institute of Environmental Stress, University of California, Santa Barbara, Santa Barbara, CA 93106. tDeceased.

no change in cardiac output, 12, 14 and either a decrease 12 or increase 8 in stroke volume. Few studies have assessed the effects of MH on exercise performance. Aronow 3 reported that after smoking MH, patients with coronary artery disease had a 50% reduction in exercise time before onset of angina pain. It has been suggested that the decrease in exercise tolerance in these patients may be due in part to increased carboxyhemoglobin (HbCO), which has been shown to induce angina during exercise at levels as low as 2%.1 Few data are available on cardiovascular and respiratory responses to standardized exercise and recovery in normal subjects subsequent to MH smoking. Our purpose was to determine the effects of smoking MH and placebo marihuana (PL) on heart rate (HR),

0009-9236/79/120777+05$00.5010 © 1979 The C. V. Mosby Co.

777

778 Avakian et ai.

Clin. Pharmacal. Ther. December 1979

170 R EI s r : - EXERCISE I I I I I I I I I I I I

160 ~

c::

-

E ...... .0

150 140 130

w 120

I

• I ..

I

RECOVERY

..

I I I

• CANNABIS o CONTROL t;,. PLACEBO

I-

oct: 110

a: a: 100

I-

oct:

w

I

90 80 70 60 -1

5

10

15 TIME (min)

Fig. 1. Heart rate responses at rest, during exercise, and recovery for the 3 experimental conditions. Means:±: SEM.

arterial blood pressure (BP), pulmonary ventilation eVE, and oxygen consumption (VoJ in chronic MH users during sub maximal exercise. Method

Subjects. Our subjects were 6 males between the ages of 21 and 27 yr. They were screened by an interview with a clinical psychologist and underwent a complete medical history and physical examination. Mean body weight and height were 74.6 kg and 176 cm. All had used MH on a regular basis for at least 3 yr. None of the subjects was a tobacco smoker, and all stated that they used no drugs other than MH on a regular basis. None of the subjects was involved in an athletic training program. Experimental procedure. An initial familiarization session was held for each subject to review the experimental procedure, meet the laboratory personnel, and to practice exercising on the bicycle ergometer. Each subject then came to the laboratory for 3 separate experimental sessions and was tested once under the following conditions: (1) not smoking (control), (2) after smoking PL, and (3) after smoking MH. The order of the subject rotation through the 3 conditions was counterbalanced; MH was administered double-blind. For each testing session, the subject reported

to the laboratory at the same time of day (approximately 2 P.M.). He was instructed not to use MH for 24 hr before experimental sessions. The subject sat resting quietly for 20 min, after which resting baseline measurements were recorded. The subject then exercised on a Quinton-Monark bicycle ergometer for 15 min at a work load of 750 kgm/min, pedaling at 50 rpm. Physiologic measurements were taken throughout the exercise period and up to 15 min recovery still in the seated position. When MH or PL was smoked, the resting preexercise period was lengthened by 20 min to allow 10 min for smoking and 10 min for onset of drug action. Measurements. Heart rates were monitored continuously by electrocardiogram (ECG) (modified Vs position). The ECG was recorded during the last 10 sec of each min during the entire session. Arterial BPs were measured by the Riva-Rocci method during rest (before and 10 min after smoking), during the last minute of exercise, and at 1 and 5 min of recovery. Fifthphase diastolic pressure was recorded. Expired gas was collected into meterologic balloons in 3-min samples at rest and during exercise, and in I-min samples during the first, third, and sixth minutes of recovery. One-liter aliquots were drawn from each balloon for FEeo2 and FEo2

Volume 26 Number 6

Marihuana effect on response to submaximal stress

779

Table I. Systolic and diastolic blood pressures at rest, during exercise, and recovery

Rest

Rest (10 min after smoking)

Recovery

I

Exercise 1/5 min) (X ± SEM)

1 min (X ± SEM)

145 ± 6 73 ± 4

132 ± 4 80 ± 2

116 ± 2 80 ± 2

5 min (X ± SEM)

Control SBP DBP

120 ± 2 79 ± 3

Marihuana SBP DBP

122 ± 3 80 ± 2

126 ± 4 80 ± 3

145 ± 7 72 ± 3

129 ± 5 81 ± 2

116 ± 3 80 ± 3

120 ± 3

120 ± 2 78 ± 2

148 ± 7 76 ± 4

134 ± 4 80 ± 3

120 ± 4 81 ± 3

Placebo SBP DBP

78 ± I

Table II. Systolic index* during rest, exercise, and recovery

Control Marihuana Placebo

Recovery

Rest (before smoking)

Rest (10 min after smoking)

Exercise IJ5 min) (X ± SEM)

- 1 min (X ± SEM)

7,802 ± 104 7,882 ± 122 7,615 ± 130

7,802 ± l04t 10,614 ± 181t 7,920 ± 190

18,980 ± 320t 22,348 ± 302t 19,536 ± 214

11,712 ± 216t 14,880 ± 262t 12,760 ± 243

I

5 min (X ± SEM)

8,030 ± 192t 12,600 ± 175:j: 8,850 ± 215

'Heart rate x systolic blood pressure. tp < 0.05. < 0.01.

*p

analysis using a Godart capnograph and Beckman E2 oxygen analyzer. Minute ventilation was measured in a 3S0-L Collins spirometer and corrected to BTl'S. Statistical analysis of data. The data were analyzed by a single-factor analysis of variance (ANOV A) with repeated measures. Planned comparisons were conducted between MH smoking and control conditions, between PL smoking and control conditions at rest, and during exercise and recovery. Statistical significance was accepted at p ~ O.OS. Drug administration. The MH, supplied by the National Institute on Drug Abuse, was Mexican female Cannabis sativa (Food and Drug Administration No. IND IOS06, California State Research Advisory Panel, Application No. 7446) containing 1.S4% (-) delta-9-THC. PL was Cannabis sativa that had been exhaustively extracted with 9S% ethanol to a cannabinoid content near zero. Both MH and PL were rolled into identical SOO-mg cigarettes.

This gave a deIta-9-THC content of 7. S mg per cigarette. A standard smoking technique was used by all subjects, consisting of inhaling 4 sec and holding the smoke from each inhalation in the lungs for 15 sec, until the entire cigarette was smoked. Ten minutes was allowed for smoking the cigarette, followed by 10 min quiet rest to allow for maximum onset of drug action before starting exercise. Results

All of the subjects were able to distinguish whether they were smoking MH after and often before finishing the cigarette. It also became apparent to the investigators when a subject had smoked MH, based on conjunctival vascular congestion and behavior typical of MH intoxication. Thus, the double-blind condition is difficult if not impossible to maintain in a study involving experienced MH smokers, The heart rate response in the nonsmoking condition was in the same range as that after

780

Clin. Pharmacal. Ther. December 1979

Avakian et al.

Table III. Pulmonary ventilation (V EBTPS) and oxygen uptake (V(12) during rest, exercise, and recovery

VE BTPS (I' min-I)

Control Marihuana Placebo Yo, (I . min-I) Control Marihuana Placebo

Exercise *

Rest (before smoking)

Rest (after smoking)

2-5 min

10.5 ± 0.9 ll.l±0.7 11.3 ± 0.8

12.4 ± 0.4 11.4 ± 0.7

4l.9 ± l.3 42.0 ± 2.1 42.0 ± 2.0

50.0 ± 1.0 43.4 ± 1.3 48.7 ± 1.2

47.2 ± l.0 47.6 ± 2.0 48.9 ± l.9

0.342 ± 0.02 0.400 ± 0.02 0.375 ± 0.06

0.425 ± 0.08 0.370 ± 0.08

1.88 ± 0.12 l.96 ± 0.04 l.93 ± 0.12

1.86 ± 0.09 2.02 ± 0.22 1.97 ± 0.15

1.72 ± 0.08 1.85 ± 0.07 l.90 ± 0.08

I

7-10 min

I

12-15 min

'x± SEM. smoking PL (Fig. 1). MH smoking resulted in a pronounced tachycardia for all subjects. Ten minutes after smoking, the mean resting heart rate had increased 26 beats/min above control values, a 34% difference (p < 0.01). During exercise, heart rate was significantly elevated above values obtained during either the control or placebo exercise bouts by 16% to 18% (p < 0.05). During the recovery period, the tachycardia became even more pronounced. At 1, 5, 10, and 15 min after exercise, the mean heart rates were 28%, 51%, 48%, and 37% higher, respectively, than control and placebo values (p < 0.01). There were no significant differences in blood pressure responses between the 3 experimental conditions at any time throughout the study (Table I). Systolic index values (HR x SBP) are given in Table II. Nonsmoking and PL-smoking values were of the same order at all phases of rest, exercise, and recovery. MH smoking increased the systolic index above control values 26% at rest (p < 0.05), 15% during the last minute of exercise (p < 0.05), 21% during the first minute of recovery (p < 0.05), and 36% during the fifth minute of recovery (p < 0.01). Pulmonary ventilation and oxygen uptake responses are shown in Table III. There were no differences in these measures. The respiratory rates during the 3 experimental conditions were also unchanged. Discussion

The exercise required approximately 40% to 50% of the subjects' maximal aerobic capacity.

All subjects perceived the work effort to be most strenuous while under the influence of MH but all reported that they felt fully recovered from the work by 10 min after exercise during the smoking and nonsmoking sessions. It is apparent from our results that the tachycardia induced by MH smoking at rest is maintained throughout 15 min of submaximal exercise. The elevation of heart rate above control and placebo values is even greater during the early postexercise period. MH severely retarded the return of the heart rate to resting levels. Although smoking MH containing 7.5 mg of delta-9-THC induced no change in BPs in our study, the product of HR and SBP (systolic index) was elevated. This measurement correlates with myocardial oxygen consumption and coronary blood flow, 11 and therefore our results suggest that after MH there is increased myocardial work during exercise. The MH-induced tachycardia alters the functional relationship of cardiac rate to oxygen transport, indicating that substantially less oxygen is delivered to the working muscles per stroke volume. Since none of these effects was evident after smoking PL, it is unlikely that the chronotropic and associated cardiovascular alterations resulting from MH smoking are related to increased HbCO levels. Real and placebo MH are known to induce equal amounts of HbCO when pyrolyzed. 2 The decrement in exercise tolerance observed in patients with coronary artery disease after smoking MH is believed to be in part due to HbCO. Other studies on normal subjects with HbCO levels up to 5% have not shown any

Volume 26 Number 6

Marihuana effect on response to submaximal stress

3.

Recovery * 0-1 min

19.8 ± l.l 20.9 ± 1.3 20.4 ± !.7 1.14 ± 0.04 1.20 ± 0.04 1.15 ± 0.05

2-3 min

5-6 min

12.5 ± 0.9 13.6 ± 1.0 13.4 ± 1.3

10.6 ± 1.0 9.9 ± 0.9 10.2 ± 1.0

0.688 ± 0.04 0.720 ± 0.10 0.678 ± 0.10

0.335 ± 0.02 0.400 ± 0.09 0.342 ± 0.03

4. 5.

6.

7.

influence on submaximal performance. 6 In our study, MH had no effect on minute pulmonary ventilation, respiratory rate, or oxygen consumption. Our observations do not agree with those of Zwillich et aI., 16 who recently reported that MH smoking increased resting pulmonary ventilation 29% and oxygen consumption 22% over control and placebo values in chronic MH users. They concluded that MH was both a respiratory and metabolic stimulant. We observed neither of these responses. The discrepancy may be related to dosage. Our subjects received a total dose of 7.5 mg of delta-9-THC, while the dose Zwillich used was II mg. In conclusion, sustained tachycardia appears to be the most prominent physiologic response to smoking MH during sub maximal exercise as it is at rest. It is not known whether the tachycardia induced by MH would be maintained during work of longer duration or of greater intensity. Although our results indicate that a physiologic price may be paid by those who exercise after smoking MH, the significance of the observation is not established. We wish to express our appreciation to Caroline Ellis and Mary Hernandez for technical assistance.

References 1. Aronow WS: Effect of passive smoking on angina pectoris. N Engl J Med 299:21-24, 1978. 2. Aronow WS, Cassidy J: Effects of marijuana

8.

9.

10.

11.

12.

13.

14.

15.

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and placebo marijuana smoking on angina pectoris. N Engl 1 Med 291:65-67, 1974. Aronow WS, Cassidy J: Effects of smoking marijuana and of a high-nicotine cigarette on angina pectoris. CUN PHARMACOL THER 17: 549-554, 1975. Beaconsfield P: Some cardiovascular effects of cannabis. Am Heart J 87:143-146, 1974. Beaconsfield P, Ginsberg J, Rainsbury R: Marijuana smoking: Cardiovascular effects in man and possible mechanisms. N Engl J Med 287:209-212, 1972. Gliner JA, Raven PB, Horvath SM, Drinkwater BL, Sutton JC: Man's physiologic response to long-term work during thermal and pollutant stress. J Appl Physiol 39:628-632, 1975. Johnson S, Domino EF: Some cardiovascular effects of marijuana smoking in normal volunteers. CUN PHARMACOL THER 12:762-768, 1971. Kanakis C, Pouget 1M, Rosen KM: The effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac performance with and without beta blockade. Circulation 53:703-707, 1976. Linyton PH, Kuechenmeister CA, White HB, Travis RP: Marijuana: Heart rate and EEG response. Res Commun Chern Pathol Pharmacol 10:201-213, 1975. Malit LA, Johnston RE, Bourke DJ, Kulp RA, Klein V, Smith TC: Intravenous delta-9-THC: Effects on ventilatory control and cardiovascular dynamics. Anesthesiology 42:666-671, 1975. Nelson RR, Gobel FL, Jorgenson CR, Wang K, Wang Y, Taylor HL: Hemodynamic predictors of myocardial oxygen consumption during static and dynamic exercise. Circulation 50: 1179, 1974. Prakash R, Aronow WS, Warren M, Laverty W, Gottschalk L: Effects of marijuana and placebo marijuana smoking on hemodynamics in coronary disease. CUN PHARMACOL THER 18:90-95, 1975. Renault PF, Shuster CR, Heinrich R, Freeman DX: Marijuana: Standardized smoke administration and dose-effect curves on heart rate in humans. Science 174:589-591, 1971. Tashkin DP, Levisman JA, Abbasi AS, Shapiro Bl, Ellis NM: Short-term effects of smoked marijuana on left ventricular function in man. Chest 72: 20-26, 1977. Weiss JL, Watanabe AM, Lemburger L, Tamarkin NR: Cardiovascular effects of delta-9THC in man. CUN PHARMACOL THER 13: 671684, 1972. Zwillich CW, Doekel E, Hammill S, Weil JV: The effects of smoked marijuana on metabolism and respiratory control. Am Rev Respir Dis 118:885-891, 1978.