164
BIOL PSYCHIATRY 1992;32:164-169
Changes in Middle Cerebral Artery Velocity After Marijuana Roy J. Mathew, William H. Wilson, Diane F. Humphreys, Joe V. Lowe, and Kathryn E. Wiethe
Velocity of blood flow in the middle cerebral artery was measured with transcranial Doppler flowmeter before, during, and I hr after smoking a marijuana cigarette and a placebo cigarette during two separate visits to the laboratory. Ten healthy, right-handed male volunteers with a history of marijuana smoking took part in the study. The participants were drug.freefor a minimum of 3 mo before the project. During the experiment, blood pressure, pulse rate, and end tidal levels of carbon dioxide were continually monitored. Marijuana smoking was associated with a significant increase in middle cerebral artery velocity. Although marijuana smoking was associated with increased pulse rate, the changes in blood velocity and pulse rate followed different time courses. Marijuana smoking was not associated with significant changes in blood pressure or end tidal carbon dioxide.
Marijuana is one of the most commonly abused drugs in the United States. In addition, marijuana abuse is associated with a number of psychiatric complications, and therefore its effects on the brain are of considerable psychiatric significance (Gold 1989). Marijuana smoking has been reported to produce increase in cerebral blood flow (CBF) to both hemispheres in experienced marijuana smokers (Mathew et al 1989; Mathew and Wilson Mathew et al 1992a). Changes in CBF are accompanied by changes in the flow velocity in the intracranial artery supplying that region (Aaslid and Lindegaard 1986). The middle cerebral artery carries 80% of the flow to the hemisphere, the highest volume of flow of all the branches of the circle of Willis (Aaslid and Lindegaard, 1986). Because marijuana smoking was found to alter hemispheric CBF, it seemed highly likely that it would have a similar effect of middle cerebral artery flow. The present study evaluated the effects of marijuana on the right middle cerebral artery blood velocity in experienced marijuana smokers with transcranial Doppler (TCD) ultrasonography (Aaslid et al 1982).
Subjects and Methods S~,bjects Ten healthy, right handed male volunteers (mean age 25.9 yr, SD ± 6) participated in this study after signing informed consent forms. None was found to suffer from any
From the Depart~aie.ntof Psychiatry, Duke University Medical Center, Durham, North Carolina. Address reprint requests to Roy J. Mathew M.D., Box 3972, Duke University Medical Center, Durham, NC 27710. Received December 19, 199f; revised March 14, 1992.
© 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
CerebralArteryVelocityafterMarijuana
BIOL PSYCHIATRY
165
1992;32:164-169
DSM-III-R diagnoses (includingalcoholism)other than marijuana use. None had abused any drugs other than marijuana during the previous year. Physical examination did not show any significantabnormalities.They reported not to have consumed marijuana or any other drugs or medication for 3 months before the project. They were required to avoid alcoholfor 24 hr and nicotineand caffeinefor 4 hr beforeeach visitto the laboratory (Mathew and Wilson 1986; Mathew and Wilson 1985; Skinhoj et al 1973). Subjects visitedthe laboratorytwo times. A urine drug screen was performed during both visits.
Cerebral Blood Velocity Measurement The shift in frequency of a wave when either the transmitter or receiver is moving with respect to the propagating medium was first described by Doppler (Eden 1986). In transcranial Doppler (TCD) ultrasonography, the same transducer is used for transmitting and detecting pulsed ultrasound waves. The effect detected by this configuration is that of a frequency shift caused by the moving reflector, namely blood. Bursts of ultrasound are transmitted at regular intervals with a burst or pulse repetition. Some of the reflected energy travels back and is picked up by the receiver. The Doppler shift is filtered to remove artifacts, and fast Fourier analysis is used to display the spectral content of the signal. The technique provides quantitative information on flow velocity through various intracerebral arteries (Aaslid 1989; Arnolds and VonReuteru 1986). The volunteers rested on a couch during the entire experiment, which took 1 hr. Blood pressure from the right arm was taken every minute with an automated blood pressure apparatus, which also provided pulse rate measurements. End tidal levels of carbon dioxide (PECO2) were also continuously monitored during this period. Right hemisphere middle cerebral artery velocity was measured with TCD ultrasonography at l-min intervals through a temporal window with a 2 MHz flat ultrasonic probe. Ultrasonic gel was applied on the patient's skin in the temporal region. Ille probe was configured to a depth setting of 50 ram, placed on the gel-coated area, and then moved by a few millimeters over the surface at various angles until a good signal (CBV more than 50 cm/sec) was received. It was held in place by a headband (Aaslid and Lindegaard 1986; Aaslid 1989; Arnolds and VonReuteru 1986). The subject remained still and in a reclining position for 5 min. While still reclining, the subject then smoked a marijuana cigarette (THC = 3.55%) or a placebo for l0 rain. During one visit, the subject received marijuana, and the other, a placebo. Recording continued for the next 50 minutes with the subject still reclining. The laboratory staff knew about the identity of the cigarette but the subjects did not. The same subjects also participated in another study evaluating the effects of marijuana (THC = 3.55%) on mood, intoxication levels, and CBF (Mathew and Wilson 1992; Mathew et al ~992a).
Results The data were plotted for every S min for 60 min. On each measure, paired t-tests were used to compare change from baseline for the postmarijuana condition at 5, 10, 15, 20, 30, 40, and 60 min. Figure I shows the effects of marijuana and placebo on CBV measured as a percent change from resting values. During the 10-min smoking period there was an increase in CBV, which was then maintained for the rest of the 60-min recording. The effect of the placebo cigarette was negligible and CBV remained approximately at
166
BIOLPSYCHIATRY 1992;32:164-169
R.J. Mathew et al
% CHANGE FROM BASELINE 25 20 15 10
$ ALL TIME PLACEBO-11.7 r M~RIJUANA=15 9
/
5 0 -5 SMOKING -10 0
10
20
30
40
50
60
MINUTES •I
3.55% THC
*
p'==O.05
]
Figure 1. Cerebral blood velocity while reclining following marijuana and placebo.
baseline throughout the 60-min period. Paired t-tests indicated statistically significant increases in CBV at most of the time points. Figtlres 2 and 3 show summaries of the effects of marijuana on pulse rate and blood pressure, respectively. Consistent with many published reports, marijuana substantially inc'~'eased pulse rate (Ohlsson et ai 1980; Perez-Reyes et al 1982) during the lO-min of smoking, and it gradually dropped during the next 50 rain; the placebo had essentially no effect. All t-tests indicated significant differences from baseline during the marijuana session. Comparisons of change in mean arterial blood pressure after marijuana from baseline (t-tests) indicated no statistically signit~eant changes. End tidal CO2 did not change significantly after marijuana or placebo.
Discussion Marijuana smoking was followed by increase in CBV for the entire period of recording. The differences between postmarijuana CBV and baseline (resting) CBV were statistically significant during most time points. There were no significant changes in PECO2 after marijuana and placebo smoking when compared with presmoking values. The physiological basis for the marijuana-induced "high" may be an increase in global cerebral activity as evidenced by the postrnarijuana increases in cerebral blood flow (CBF) and cerebral metabolism (CMR) (Mathew and Wilson 1991; Mathew et al 1989; Mathew and Wilson 1991; Mathew et al 1992; Volkow et al 1991). In the normal brain, CBF and CMR are closely coupled with brain function (Mathew et al 1986). Because increases in CBF (and consequent increased cerebral capillary perfusion) to the hemisphere supplied by the middle cerebral artery will reduce resistance to flow, there should be a parallel increase in flow velocity.
Cerebral Artery Velocity after Marijuana
BIOL PSYCHIATRY
167
1992;32:!64-169
RATE 100
~
AVERAGE
SD
ACROSS
ALL
POINTS
90
80
70 SMOKING 60
i 5
0
i 10
-
15
I
I
20
25
PLACEBO
-
t
t
I
30 85 MINUTES
MARIJUANA
I
I
I
I
40
45
50
55
~
60
t - t e s t s (pC~.C Press; in press. Mathew RJ, Wilson WH, Humphreys DF, Lowe JV, Weithe KE (1992a): Regional cerebral blood flow after marijuana smoking. J Cereb Blood Flow Metab in press. Mathew RJ, Wilson WH, Tant SR (1989): Acute changes in cerebral blood flow associated with marijuana smoking. A cta P sychiatr Scand 79:118-128. Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK (1980): Plasma delta9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Therap 28:409-416. Perez-Reyes M, DiGuiseppi S, Davis KH, Schindler VH, Cook CE (1982): Comparison of effects of marijuana cigarettes of three different potencies. Clin Pharmacoi Ther 31:617-624. Skinhoj E, Olesen J, Paulson OB (1973): Influence of smoking and nicotine on cerebral blood flow and metabolic rate for oxygen. J Appl Physiol 35:820-822. Thomas DJ (1982): Whole blood viscosity and cerebral blood flow. Stroke 13:285-287. Volkow ND, Gillespi H, Mullani N, Tancredi L, Hollister L, Ivanovic M, Grant C (1991): Use of positron emission tomography to investigate the action of marijuana in the human brain. In Nahas GG, Latour C (eds): Physiopathology of Illicit Drugs. Oxford, Pergamon Press. Weiss JL, Watanabe AM, Lemberger L, Tamarkin NR, Cardon PV (1972): Cardiovascular effects of delta9 tetrahydrocannabinol in man. Clinical Pharmacol Therap 13:671-684.
BIOL PSYCHIATRY 1992;32:164-169
Changes in Middle Cerebral Artery Velocity After Marijuana Roy J. Mathew, William H. Wilson, Diane F. Humphreys, Joe V. Lowe, and Kathryn E. Wiethe
Velocity of blood flow in the middle cerebral artery was measured with transcranial Doppler flowmeter before, during, and I hr after smoking a marijuana cigarette and a placebo cigarette during two separate visits to the laboratory. Ten healthy, right-handed male volunteers with a history of marijuana smoking took part in the study. The participants were drug.freefor a minimum of 3 mo before the project. During the experiment, blood pressure, pulse rate, and end tidal levels of carbon dioxide were continually monitored. Marijuana smoking was associated with a significant increase in middle cerebral artery velocity. Although marijuana smoking was associated with increased pulse rate, the changes in blood velocity and pulse rate followed different time courses. Marijuana smoking was not associated with significant changes in blood pressure or end tidal carbon dioxide.
Marijuana is one of the most commonly abused drugs in the United States. In addition, marijuana abuse is associated with a number of psychiatric complications, and therefore its effects on the brain are of considerable psychiatric significance (Gold 1989). Marijuana smoking has been reported to produce increase in cerebral blood flow (CBF) to both hemispheres in experienced marijuana smokers (Mathew et al 1989; Mathew and Wilson Mathew et al 1992a). Changes in CBF are accompanied by changes in the flow velocity in the intracranial artery supplying that region (Aaslid and Lindegaard 1986). The middle cerebral artery carries 80% of the flow to the hemisphere, the highest volume of flow of all the branches of the circle of Willis (Aaslid and Lindegaard, 1986). Because marijuana smoking was found to alter hemispheric CBF, it seemed highly likely that it would have a similar effect of middle cerebral artery flow. The present study evaluated the effects of marijuana on the right middle cerebral artery blood velocity in experienced marijuana smokers with transcranial Doppler (TCD) ultrasonography (Aaslid et al 1982).
Subjects and Methods S~,bjects Ten healthy, right handed male volunteers (mean age 25.9 yr, SD ± 6) participated in this study after signing informed consent forms. None was found to suffer from any
From the Depart~aie.ntof Psychiatry, Duke University Medical Center, Durham, North Carolina. Address reprint requests to Roy J. Mathew M.D., Box 3972, Duke University Medical Center, Durham, NC 27710. Received December 19, 199f; revised March 14, 1992.
© 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
CerebralArteryVelocityafterMarijuana
BIOL PSYCHIATRY
165
1992;32:164-169
DSM-III-R diagnoses (includingalcoholism)other than marijuana use. None had abused any drugs other than marijuana during the previous year. Physical examination did not show any significantabnormalities.They reported not to have consumed marijuana or any other drugs or medication for 3 months before the project. They were required to avoid alcoholfor 24 hr and nicotineand caffeinefor 4 hr beforeeach visitto the laboratory (Mathew and Wilson 1986; Mathew and Wilson 1985; Skinhoj et al 1973). Subjects visitedthe laboratorytwo times. A urine drug screen was performed during both visits.
Cerebral Blood Velocity Measurement The shift in frequency of a wave when either the transmitter or receiver is moving with respect to the propagating medium was first described by Doppler (Eden 1986). In transcranial Doppler (TCD) ultrasonography, the same transducer is used for transmitting and detecting pulsed ultrasound waves. The effect detected by this configuration is that of a frequency shift caused by the moving reflector, namely blood. Bursts of ultrasound are transmitted at regular intervals with a burst or pulse repetition. Some of the reflected energy travels back and is picked up by the receiver. The Doppler shift is filtered to remove artifacts, and fast Fourier analysis is used to display the spectral content of the signal. The technique provides quantitative information on flow velocity through various intracerebral arteries (Aaslid 1989; Arnolds and VonReuteru 1986). The volunteers rested on a couch during the entire experiment, which took 1 hr. Blood pressure from the right arm was taken every minute with an automated blood pressure apparatus, which also provided pulse rate measurements. End tidal levels of carbon dioxide (PECO2) were also continuously monitored during this period. Right hemisphere middle cerebral artery velocity was measured with TCD ultrasonography at l-min intervals through a temporal window with a 2 MHz flat ultrasonic probe. Ultrasonic gel was applied on the patient's skin in the temporal region. Ille probe was configured to a depth setting of 50 ram, placed on the gel-coated area, and then moved by a few millimeters over the surface at various angles until a good signal (CBV more than 50 cm/sec) was received. It was held in place by a headband (Aaslid and Lindegaard 1986; Aaslid 1989; Arnolds and VonReuteru 1986). The subject remained still and in a reclining position for 5 min. While still reclining, the subject then smoked a marijuana cigarette (THC = 3.55%) or a placebo for l0 rain. During one visit, the subject received marijuana, and the other, a placebo. Recording continued for the next 50 minutes with the subject still reclining. The laboratory staff knew about the identity of the cigarette but the subjects did not. The same subjects also participated in another study evaluating the effects of marijuana (THC = 3.55%) on mood, intoxication levels, and CBF (Mathew and Wilson 1992; Mathew et al ~992a).
Results The data were plotted for every S min for 60 min. On each measure, paired t-tests were used to compare change from baseline for the postmarijuana condition at 5, 10, 15, 20, 30, 40, and 60 min. Figure I shows the effects of marijuana and placebo on CBV measured as a percent change from resting values. During the 10-min smoking period there was an increase in CBV, which was then maintained for the rest of the 60-min recording. The effect of the placebo cigarette was negligible and CBV remained approximately at
166
BIOLPSYCHIATRY 1992;32:164-169
R.J. Mathew et al
% CHANGE FROM BASELINE 25 20 15 10
$ ALL TIME PLACEBO-11.7 r M~RIJUANA=15 9
/
5 0 -5 SMOKING -10 0
10
20
30
40
50
60
MINUTES •I
3.55% THC
*
p'==O.05
]
Figure 1. Cerebral blood velocity while reclining following marijuana and placebo.
baseline throughout the 60-min period. Paired t-tests indicated statistically significant increases in CBV at most of the time points. Figtlres 2 and 3 show summaries of the effects of marijuana on pulse rate and blood pressure, respectively. Consistent with many published reports, marijuana substantially inc'~'eased pulse rate (Ohlsson et ai 1980; Perez-Reyes et al 1982) during the lO-min of smoking, and it gradually dropped during the next 50 rain; the placebo had essentially no effect. All t-tests indicated significant differences from baseline during the marijuana session. Comparisons of change in mean arterial blood pressure after marijuana from baseline (t-tests) indicated no statistically signit~eant changes. End tidal CO2 did not change significantly after marijuana or placebo.
Discussion Marijuana smoking was followed by increase in CBV for the entire period of recording. The differences between postmarijuana CBV and baseline (resting) CBV were statistically significant during most time points. There were no significant changes in PECO2 after marijuana and placebo smoking when compared with presmoking values. The physiological basis for the marijuana-induced "high" may be an increase in global cerebral activity as evidenced by the postrnarijuana increases in cerebral blood flow (CBF) and cerebral metabolism (CMR) (Mathew and Wilson 1991; Mathew et al 1989; Mathew and Wilson 1991; Mathew et al 1992; Volkow et al 1991). In the normal brain, CBF and CMR are closely coupled with brain function (Mathew et al 1986). Because increases in CBF (and consequent increased cerebral capillary perfusion) to the hemisphere supplied by the middle cerebral artery will reduce resistance to flow, there should be a parallel increase in flow velocity.
Cerebral Artery Velocity after Marijuana
BIOL PSYCHIATRY
167
1992;32:!64-169
RATE 100
~
AVERAGE
SD
ACROSS
ALL
POINTS
90
80
70 SMOKING 60
i 5
0
i 10
-
15
I
I
20
25
PLACEBO
-
t
t
I
30 85 MINUTES
MARIJUANA
I
I
I
I
40
45
50
55
~
60
t - t e s t s (pC~.C Press; in press. Mathew RJ, Wilson WH, Humphreys DF, Lowe JV, Weithe KE (1992a): Regional cerebral blood flow after marijuana smoking. J Cereb Blood Flow Metab in press. Mathew RJ, Wilson WH, Tant SR (1989): Acute changes in cerebral blood flow associated with marijuana smoking. A cta P sychiatr Scand 79:118-128. Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK (1980): Plasma delta9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Therap 28:409-416. Perez-Reyes M, DiGuiseppi S, Davis KH, Schindler VH, Cook CE (1982): Comparison of effects of marijuana cigarettes of three different potencies. Clin Pharmacoi Ther 31:617-624. Skinhoj E, Olesen J, Paulson OB (1973): Influence of smoking and nicotine on cerebral blood flow and metabolic rate for oxygen. J Appl Physiol 35:820-822. Thomas DJ (1982): Whole blood viscosity and cerebral blood flow. Stroke 13:285-287. Volkow ND, Gillespi H, Mullani N, Tancredi L, Hollister L, Ivanovic M, Grant C (1991): Use of positron emission tomography to investigate the action of marijuana in the human brain. In Nahas GG, Latour C (eds): Physiopathology of Illicit Drugs. Oxford, Pergamon Press. Weiss JL, Watanabe AM, Lemberger L, Tamarkin NR, Cardon PV (1972): Cardiovascular effects of delta9 tetrahydrocannabinol in man. Clinical Pharmacol Therap 13:671-684.
