Life Sciences, Vol. Printed in the USA
51, pp.
553-563
Pergamon
Press
ETHANOL/COCAINE INTERACTION: COCAINEAND COCAETHYLENE PLASMACONCENTRATIONS AND THEIR RELATIONSHIP TO SUBJECTIVE AND CARDIOVASCULAR EFFECTS Mario Perez-Reyes and A. Robert Jeffcoat* Department of Psychiatry, School of Medicine University of North Carolina at Chapel H i l l , U.S.A. and *Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, N.C.U.S.A. (Received
in final
form June i0,
1992)
Summary To investigate the pharmacologic effects of the interaction between ethanol and cocaine, eleven male, paid volunteers familiar with the use of both ethanol and cocaine were tested in a doseresponse, placebo-controlled, single-blind, randomly-assigned, cross-over design. Ethanol (0.85 g/kg) or placebo was administered in divided doses over a t h i r t y minute period. Fifteen minutes after the termination of ethanol ingestion, cocaine HCI (1.25 and 1.9 mk/kg) or placebo (lidocaine and mannitol) was given by nasal insufflation (snorting). Cocaine and cocaethylene plasma concentrations, blood ethanol levels, subjective ratings of drug effects, and cardiovascular parameters were measured. Statistical analysis of the results indicate that: i) cocaine administration did not alter blood ethanol concentrations nor the ratings of ethanol intoxication; 2) ethanol caused a significant increase in cocaine plasma concentrations, ratings of cocaine "high", and heart rate; 3) acute tolerance to the subjective and heart rate effects of cocaine was observed; 4) when combined with cocaine, ethanol led to the slow formation of cocaethylene in amounts much lower than those of i t s parent compound; and 5) the appearance of cocaethylene in plasma did not alter cocaine's subjective and cardiovascular effects. Epidemiological investigation of the combined use of ethanol and cocaine, using as data base the 1985 National Household Survey on Drug Abuse, indicated that approximately 5 million Americans had used this drug combination during the past month and 12 million during the past year ( I ) . Although the 1990 National Household Survey on Drug Abuse reported a decline in the prevalence of cocaine use (2), the combined use of ethanol and cocaine continues to be a major public health problem. Thus, the 1990 Drug Abuse Warning Network (DAWN) reported that in emergency room episodes, ethanol and cocaine were frequently mentioned in combination with another drug (69.2% and 41.6%, respectively) (3). Hence, i t is l i k e l y that the combination of these two drugs was the most frequent reason for emergency room treatment. In addition to morbidity, there was also mortality associated with this drug combination, e.g., the DAWN Medical Examiner data showed the occurrence of 1,005 f a t a l i t i e s due to the ethanol/cocaine combination in 1990 (4). Because of the c l i n i c a l and public health importance of the combined use of ethanol and commonly used recreational drugs, we have studied the interaction between ethanol and marihuana (5), and between ethanol and
Copyright
0024-3205/92 $5.00 + .00 © 1992 Pergamon Press Ltd All rights
reserved.
554
Ethanol/Cocaine
Interaction
Vol.
51, No. 8, 1992
dextroamphetamine (6). In this communication, we report the results of a single-blind, placebo-controlled, dose-response, randomly-assigned, crossover study of the effects of the interaction between ethanol and cocaine. In this study, the following variables were measured: blood ethanol levels, plasma concentrations of cocaine and cocaethylene, subjective ratings of cocaine "high" and ethanol intoxication, and parameters of cardiovascular function. METHODS Subjects: Twelve male, healthy, paid volunteers familiar with the recreational use of ethanol and cocaine participated in the study. Unfortunately, one of the subjects moved out of the country and failed to complete the study. Therefore, only the results obtained in eleven subjects are reported. The volunteers were f u l l y informed of the purpose, experimental procedures, and potential risks of the study. All signed a consent form approved by the Committee on the Protection of the Rights of Human Subjects of the University of North Carolina at Chapel H i l l . Demographic characteristics were age 23.8 ± 1.3 years, weight 76.7 ± 3.4 kg, and height 181.3 ± 2.0 cm. The subjects had previously used cocaine (snorting) an average of 11.4 ± 2.8 times (range 2 - 35), and their current ethanol consumption was 15.8 ± 2.8 g/kg of ethanol per month (range 4.7 - 29.0 g/kg). Quantity-frequency estimates of ethanol consumption were derived from a six-item questionnaire adapted from Khavari and Farber (7), in which a nine-point scale was used to assess the usual quantities of beer, wine, fortified wine, and d i s t i l l e d spirits consumed by the subject during the month prior to the study. Experimental Desiqn: Subjects were tested in a single-blind, placebocontrolled, dose-response, randomly assigned, latin-square, crossover paradigm. The six treatment conditions were placebo ethanol/placebo cocaine, placebo ethanol/low dose cocaine, placebo ethanol/high dose cocaine, ethanol/placebo cocaine, ethanol/low dose cocaine, and ethanol/high dose cocaine. The subjects were tested at weekly intervals to ensure that plasma concentrations of cocaine and its metabolites reached undetectable levels before retesting. The subjects contracted to abstain from the use of ethanol, cocaine and amphetamines for three days before each experimental session, as well as abstaining from marihuana use for seven days before each session. Druq Administration: In drug interaction studies, the time of administration of the companion drug with respect to the reference drug can be varied, e.g., the companion drug can be administered before, simultaneously, or after administration of the reference drug. In this study, the companion drug (cocaine) was snorted 15 minutes after the consumption of the reference drug (ethanol). Placebo (diluted orange juice sprayed with 100-proof vodka to mimic the aroma of a mixed drink) or 0.85 g/kg of ethanol (two ml/kg of 100 proof vodka) diluted to a volume of 300 ml with orange juice were administered in 50-ml portions every five minutes; therefore, the total period of placebo or ethanol ingestion was 30 minutes. Fifteen minutes after the end of the period of ethanol ingestion, the subjects snorted placebo (a mixture of lidocaine and mannitol), 1.25 or 1.9 mg/kg of cocaine HCI. Drug administration followed an over night fast in order to facilitate the absorption of ethanol from the gastrointestinal tract. Experimental Variables: Subjective Ratinqs of Intoxication: To measure these effects, subjects were asked to rate both their degree of "drunkenness" and of cocaine "high"
Vol.
51, No. 8, 1992
Ethanol/Cocaine
Interaction
555
independently at frequent intervals during the experiment. They were instructed to use a scale of 0 to 100, in which 0 represented no perceivable drug effects and 100 represented either the "highest" they had ever been under the influence of cocaine or the drunkest t h e y had ever been under the influence of ethanol. Each time ratings were to be made, subjects were given their previous ratings for comparison. This technique allowed the subjects to rate themselves as experiencing relatively more, less, or the same effects as those rated in the previous interval. This method of evaluating the magnitude of subjective drug effects over time has been found to be efficient, informative, and to generate curves that parallel physiologic effects, e.g. the cardiovascular effects of psychoactive drugs (8). Cardiovascular Effects: Because of its sympathomimetic activity, cocaine produces acceleration of the heart rate and elevation of the blood pressure. To obtain more complete knowledge of the cardiovascular effects produced by the interaction between ethanol and cocaine, the cardiac output and systemic vascular resistance were a l s o measured. To determine these parameters unobtrusively and non-invasively, two instruments were used. Blood pressure was recorded with an Accutracker (Suntech Medical Instruments, Inc.). This instrument is portable and measures the blood pressure at any desired time interval, e.g., every 2 minutes or longer. Heart rate and cardiac output were measured using impedance cardiography, adopting a tetrapolar spot electrode configuration (9) with a Hutcheson Impedance Cardiograph and specialized computer software (COP, Instrumentation for Medicine, Inc.). T h i s instrument measures, at pre-determined intervals, heart rate and cardiac output (10). The systemic vascular resistance was calculated f r o m simultaneous determinations of the cardiac output and the blood pressure. Cardiovascular parameters were recorded prior to ethanol or placebo ingestion (baseline) and, thereafter, at frequent intervals (usually five minutes). Determination of Blood Ethanol Concentration: For this purpose, an Alcosensor I l l (Intoximeters, Inc.) breath analyzer was used. T h i s instrument was calibrated at appropriate intervals with standards provided by the manufacturer to assure accuracy. Breath ethanol readings were taken at baseline, at 45 and 60 minutes after the beginning of ethanol consumption, and at 30-minute intervals for the next 5 hours. Determination of Druq Plasma Concentrations: Cocaine and cocaethylene plasma concentrations were measured in blood samples collected at baseline and at 15, 30, 45, 60, 75, 90, and 120 minutes after cocaine administration. As we have found in a previous study (11), these sampling times permit determination of the rate of cocaine absorption from the nasal mucosa and of the peak plasma concentrations obtained. A specific assay for cocaine and cocaethylene determinations was was used. Plasma samples (5.0 ml) were placed on a pre-wet C18 SPE cartridge (Waters Corp.) followed by 5.0 ml of water. Cocaine and cocaethylene were eluted with 5.0 ml of methanol (Recoveries of t r i t i a t e d cocaine spiked into human plasma as part of a previous study (11) were 98 + 6 [SD]% by this method o v e r five cocaine concentrations ranging from 3 to 500 ng/ml). Propylbenzoylecgonine (500 ng) was added to each methanol eluant as an internal standard. The solvent was evaporated and the residue reconstituted in 2.0 ml of butyl chloride. Cocaine and cocaethylene were extracted with 1.0 ml of 0.07 N sulfuric acid. The aqueous phase was then adjusted to pH 8-10 with 0.1 N sodium hydroxide and extracted with 2.5 ml of butyl chloride. The butyl chloride layer was concentrated in a 4-ml vial to approximately 1.0 ml. The concentrate was transferred to a low volume autosampler insert.
556
Ethanol/Cocaine
Interaction
Vol.
51, No.
8,
1992
Analysis was carried out on a 30 m x 0.32 mm DB-5 column (J&W) housed in a Hewlett Packard Model 5890 gas chromatograph with nitrogen-phosphorus selective detector. Helium was used as the carrier g a s . Samples were introduced from the autoinjector using splitless injection at an oven temperature of 90°C. After one minute this temperature was rapidly raised to 250°C. Constituents of interest were eluted during a gentle temperature ramp between 250°C and 270°C (Figure I). Analytes were quantitated using a Hewlett Packard Model 3396 integrator. Standard curves relating peak area with concentrations of analytes in plasma were constructed from plasma containing known amounts of cocaine and cocaethylene. A linear regression analysis was performed for cocaine concentrations between 10 and 500 ng/ml (r=0.9995) and for cocaethylene between 4 and 154 ng/ml (r=0.9998). Control plasma samples spiked with 30 or 154 ng/ml of cocaine and with 29 or 148 ng/ml of cocaethylene (11 for each concentration) were analyzed along with subject samples. The measured concentrations were 32 + 2 and 150 + 10 ng/ml for cocaine and 28 + I and 138 + 7 ng/ml for cocaethylene.
l,i O0 Z
o
a. o0 n" nO
o
C
IU l-IU a
PB
a. Z
1
2
,3
'4
5
(~
-l
8
9
1'0 11
12 13
TIME (min)
FIGURE I Capillary gas chromatogram of cocaine (c, 78 ng/mL), cocaethylene (CE, 22 ng/mL) and the internal standard, propylbenzoylecgonine (PB, 50 ng/mL) from a 2.75 h plasma sample from a subject in the EtOH/low cocaine group. The large peak at 7.3 min is present in blank plasma and is not related to the administered drugs.
Statistical Analysis: For comparison, the means of the data ± SEM were calculated and are reported as such throughout the test. Areas under the curve (AUCs) were calculated by the trapezoidal rule method. The experimental design used in this study permitted within-subjects comparisons of the effects of ethanol, cocaine or their combination for each of the variables measured. The results were analyzed by ANOVAand MANOVA.
Vol. 51, No. 8, 1992
Ethanol/Cocaine Interaction
557
RESULTS Blood Ethanol: Mean peak blood ethanol levels occurred approximately 50 minutes after the beginning of ethanol ingestion, and were 0.094 g/dl, 0.092 g/dl, and 0.090 g/dl for the ethanol/placebo, ethanol/low dose cocaine, and ethanol/high dose cocaine, respectively. Mean blood ethanol levels across time of observation (0-300 minutes), mean peak values, and mean area under the curve (AUC) were unchanged by the administration of cocaine. Subjective Ratinqs of Ethanol Intoxication: Ethanol but not placebo produced ratings of drunkenness that increased progressively, reaching peak values approximately 45 minutes after the beginning of ethanol consumption. Mean maximal ratings of drunkenness were of moderate magnitude (approximately 40%). Cocaine administration did not alter the ratings of drunkenness over time, the mean peak ratings or the mean AUC (0-300'). Plasma Cocaine: Mean cocaine plasma concentrations reached maximal values approximately one hour after the drug was snorted and then progressively declined (Figure 2). The magnitude of the plasma concentrations of cocaine measured over the time of observation (0-120 minutes) were doserelated for both the placebo-ethanol conditions [F(I,10)=25.32, ~
51, pp.
553-563
Pergamon
Press
ETHANOL/COCAINE INTERACTION: COCAINEAND COCAETHYLENE PLASMACONCENTRATIONS AND THEIR RELATIONSHIP TO SUBJECTIVE AND CARDIOVASCULAR EFFECTS Mario Perez-Reyes and A. Robert Jeffcoat* Department of Psychiatry, School of Medicine University of North Carolina at Chapel H i l l , U.S.A. and *Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, N.C.U.S.A. (Received
in final
form June i0,
1992)
Summary To investigate the pharmacologic effects of the interaction between ethanol and cocaine, eleven male, paid volunteers familiar with the use of both ethanol and cocaine were tested in a doseresponse, placebo-controlled, single-blind, randomly-assigned, cross-over design. Ethanol (0.85 g/kg) or placebo was administered in divided doses over a t h i r t y minute period. Fifteen minutes after the termination of ethanol ingestion, cocaine HCI (1.25 and 1.9 mk/kg) or placebo (lidocaine and mannitol) was given by nasal insufflation (snorting). Cocaine and cocaethylene plasma concentrations, blood ethanol levels, subjective ratings of drug effects, and cardiovascular parameters were measured. Statistical analysis of the results indicate that: i) cocaine administration did not alter blood ethanol concentrations nor the ratings of ethanol intoxication; 2) ethanol caused a significant increase in cocaine plasma concentrations, ratings of cocaine "high", and heart rate; 3) acute tolerance to the subjective and heart rate effects of cocaine was observed; 4) when combined with cocaine, ethanol led to the slow formation of cocaethylene in amounts much lower than those of i t s parent compound; and 5) the appearance of cocaethylene in plasma did not alter cocaine's subjective and cardiovascular effects. Epidemiological investigation of the combined use of ethanol and cocaine, using as data base the 1985 National Household Survey on Drug Abuse, indicated that approximately 5 million Americans had used this drug combination during the past month and 12 million during the past year ( I ) . Although the 1990 National Household Survey on Drug Abuse reported a decline in the prevalence of cocaine use (2), the combined use of ethanol and cocaine continues to be a major public health problem. Thus, the 1990 Drug Abuse Warning Network (DAWN) reported that in emergency room episodes, ethanol and cocaine were frequently mentioned in combination with another drug (69.2% and 41.6%, respectively) (3). Hence, i t is l i k e l y that the combination of these two drugs was the most frequent reason for emergency room treatment. In addition to morbidity, there was also mortality associated with this drug combination, e.g., the DAWN Medical Examiner data showed the occurrence of 1,005 f a t a l i t i e s due to the ethanol/cocaine combination in 1990 (4). Because of the c l i n i c a l and public health importance of the combined use of ethanol and commonly used recreational drugs, we have studied the interaction between ethanol and marihuana (5), and between ethanol and
Copyright
0024-3205/92 $5.00 + .00 © 1992 Pergamon Press Ltd All rights
reserved.
554
Ethanol/Cocaine
Interaction
Vol.
51, No. 8, 1992
dextroamphetamine (6). In this communication, we report the results of a single-blind, placebo-controlled, dose-response, randomly-assigned, crossover study of the effects of the interaction between ethanol and cocaine. In this study, the following variables were measured: blood ethanol levels, plasma concentrations of cocaine and cocaethylene, subjective ratings of cocaine "high" and ethanol intoxication, and parameters of cardiovascular function. METHODS Subjects: Twelve male, healthy, paid volunteers familiar with the recreational use of ethanol and cocaine participated in the study. Unfortunately, one of the subjects moved out of the country and failed to complete the study. Therefore, only the results obtained in eleven subjects are reported. The volunteers were f u l l y informed of the purpose, experimental procedures, and potential risks of the study. All signed a consent form approved by the Committee on the Protection of the Rights of Human Subjects of the University of North Carolina at Chapel H i l l . Demographic characteristics were age 23.8 ± 1.3 years, weight 76.7 ± 3.4 kg, and height 181.3 ± 2.0 cm. The subjects had previously used cocaine (snorting) an average of 11.4 ± 2.8 times (range 2 - 35), and their current ethanol consumption was 15.8 ± 2.8 g/kg of ethanol per month (range 4.7 - 29.0 g/kg). Quantity-frequency estimates of ethanol consumption were derived from a six-item questionnaire adapted from Khavari and Farber (7), in which a nine-point scale was used to assess the usual quantities of beer, wine, fortified wine, and d i s t i l l e d spirits consumed by the subject during the month prior to the study. Experimental Desiqn: Subjects were tested in a single-blind, placebocontrolled, dose-response, randomly assigned, latin-square, crossover paradigm. The six treatment conditions were placebo ethanol/placebo cocaine, placebo ethanol/low dose cocaine, placebo ethanol/high dose cocaine, ethanol/placebo cocaine, ethanol/low dose cocaine, and ethanol/high dose cocaine. The subjects were tested at weekly intervals to ensure that plasma concentrations of cocaine and its metabolites reached undetectable levels before retesting. The subjects contracted to abstain from the use of ethanol, cocaine and amphetamines for three days before each experimental session, as well as abstaining from marihuana use for seven days before each session. Druq Administration: In drug interaction studies, the time of administration of the companion drug with respect to the reference drug can be varied, e.g., the companion drug can be administered before, simultaneously, or after administration of the reference drug. In this study, the companion drug (cocaine) was snorted 15 minutes after the consumption of the reference drug (ethanol). Placebo (diluted orange juice sprayed with 100-proof vodka to mimic the aroma of a mixed drink) or 0.85 g/kg of ethanol (two ml/kg of 100 proof vodka) diluted to a volume of 300 ml with orange juice were administered in 50-ml portions every five minutes; therefore, the total period of placebo or ethanol ingestion was 30 minutes. Fifteen minutes after the end of the period of ethanol ingestion, the subjects snorted placebo (a mixture of lidocaine and mannitol), 1.25 or 1.9 mg/kg of cocaine HCI. Drug administration followed an over night fast in order to facilitate the absorption of ethanol from the gastrointestinal tract. Experimental Variables: Subjective Ratinqs of Intoxication: To measure these effects, subjects were asked to rate both their degree of "drunkenness" and of cocaine "high"
Vol.
51, No. 8, 1992
Ethanol/Cocaine
Interaction
555
independently at frequent intervals during the experiment. They were instructed to use a scale of 0 to 100, in which 0 represented no perceivable drug effects and 100 represented either the "highest" they had ever been under the influence of cocaine or the drunkest t h e y had ever been under the influence of ethanol. Each time ratings were to be made, subjects were given their previous ratings for comparison. This technique allowed the subjects to rate themselves as experiencing relatively more, less, or the same effects as those rated in the previous interval. This method of evaluating the magnitude of subjective drug effects over time has been found to be efficient, informative, and to generate curves that parallel physiologic effects, e.g. the cardiovascular effects of psychoactive drugs (8). Cardiovascular Effects: Because of its sympathomimetic activity, cocaine produces acceleration of the heart rate and elevation of the blood pressure. To obtain more complete knowledge of the cardiovascular effects produced by the interaction between ethanol and cocaine, the cardiac output and systemic vascular resistance were a l s o measured. To determine these parameters unobtrusively and non-invasively, two instruments were used. Blood pressure was recorded with an Accutracker (Suntech Medical Instruments, Inc.). This instrument is portable and measures the blood pressure at any desired time interval, e.g., every 2 minutes or longer. Heart rate and cardiac output were measured using impedance cardiography, adopting a tetrapolar spot electrode configuration (9) with a Hutcheson Impedance Cardiograph and specialized computer software (COP, Instrumentation for Medicine, Inc.). T h i s instrument measures, at pre-determined intervals, heart rate and cardiac output (10). The systemic vascular resistance was calculated f r o m simultaneous determinations of the cardiac output and the blood pressure. Cardiovascular parameters were recorded prior to ethanol or placebo ingestion (baseline) and, thereafter, at frequent intervals (usually five minutes). Determination of Blood Ethanol Concentration: For this purpose, an Alcosensor I l l (Intoximeters, Inc.) breath analyzer was used. T h i s instrument was calibrated at appropriate intervals with standards provided by the manufacturer to assure accuracy. Breath ethanol readings were taken at baseline, at 45 and 60 minutes after the beginning of ethanol consumption, and at 30-minute intervals for the next 5 hours. Determination of Druq Plasma Concentrations: Cocaine and cocaethylene plasma concentrations were measured in blood samples collected at baseline and at 15, 30, 45, 60, 75, 90, and 120 minutes after cocaine administration. As we have found in a previous study (11), these sampling times permit determination of the rate of cocaine absorption from the nasal mucosa and of the peak plasma concentrations obtained. A specific assay for cocaine and cocaethylene determinations was was used. Plasma samples (5.0 ml) were placed on a pre-wet C18 SPE cartridge (Waters Corp.) followed by 5.0 ml of water. Cocaine and cocaethylene were eluted with 5.0 ml of methanol (Recoveries of t r i t i a t e d cocaine spiked into human plasma as part of a previous study (11) were 98 + 6 [SD]% by this method o v e r five cocaine concentrations ranging from 3 to 500 ng/ml). Propylbenzoylecgonine (500 ng) was added to each methanol eluant as an internal standard. The solvent was evaporated and the residue reconstituted in 2.0 ml of butyl chloride. Cocaine and cocaethylene were extracted with 1.0 ml of 0.07 N sulfuric acid. The aqueous phase was then adjusted to pH 8-10 with 0.1 N sodium hydroxide and extracted with 2.5 ml of butyl chloride. The butyl chloride layer was concentrated in a 4-ml vial to approximately 1.0 ml. The concentrate was transferred to a low volume autosampler insert.
556
Ethanol/Cocaine
Interaction
Vol.
51, No.
8,
1992
Analysis was carried out on a 30 m x 0.32 mm DB-5 column (J&W) housed in a Hewlett Packard Model 5890 gas chromatograph with nitrogen-phosphorus selective detector. Helium was used as the carrier g a s . Samples were introduced from the autoinjector using splitless injection at an oven temperature of 90°C. After one minute this temperature was rapidly raised to 250°C. Constituents of interest were eluted during a gentle temperature ramp between 250°C and 270°C (Figure I). Analytes were quantitated using a Hewlett Packard Model 3396 integrator. Standard curves relating peak area with concentrations of analytes in plasma were constructed from plasma containing known amounts of cocaine and cocaethylene. A linear regression analysis was performed for cocaine concentrations between 10 and 500 ng/ml (r=0.9995) and for cocaethylene between 4 and 154 ng/ml (r=0.9998). Control plasma samples spiked with 30 or 154 ng/ml of cocaine and with 29 or 148 ng/ml of cocaethylene (11 for each concentration) were analyzed along with subject samples. The measured concentrations were 32 + 2 and 150 + 10 ng/ml for cocaine and 28 + I and 138 + 7 ng/ml for cocaethylene.
l,i O0 Z
o
a. o0 n" nO
o
C
IU l-IU a
PB
a. Z
1
2
,3
'4
5
(~
-l
8
9
1'0 11
12 13
TIME (min)
FIGURE I Capillary gas chromatogram of cocaine (c, 78 ng/mL), cocaethylene (CE, 22 ng/mL) and the internal standard, propylbenzoylecgonine (PB, 50 ng/mL) from a 2.75 h plasma sample from a subject in the EtOH/low cocaine group. The large peak at 7.3 min is present in blank plasma and is not related to the administered drugs.
Statistical Analysis: For comparison, the means of the data ± SEM were calculated and are reported as such throughout the test. Areas under the curve (AUCs) were calculated by the trapezoidal rule method. The experimental design used in this study permitted within-subjects comparisons of the effects of ethanol, cocaine or their combination for each of the variables measured. The results were analyzed by ANOVAand MANOVA.
Vol. 51, No. 8, 1992
Ethanol/Cocaine Interaction
557
RESULTS Blood Ethanol: Mean peak blood ethanol levels occurred approximately 50 minutes after the beginning of ethanol ingestion, and were 0.094 g/dl, 0.092 g/dl, and 0.090 g/dl for the ethanol/placebo, ethanol/low dose cocaine, and ethanol/high dose cocaine, respectively. Mean blood ethanol levels across time of observation (0-300 minutes), mean peak values, and mean area under the curve (AUC) were unchanged by the administration of cocaine. Subjective Ratinqs of Ethanol Intoxication: Ethanol but not placebo produced ratings of drunkenness that increased progressively, reaching peak values approximately 45 minutes after the beginning of ethanol consumption. Mean maximal ratings of drunkenness were of moderate magnitude (approximately 40%). Cocaine administration did not alter the ratings of drunkenness over time, the mean peak ratings or the mean AUC (0-300'). Plasma Cocaine: Mean cocaine plasma concentrations reached maximal values approximately one hour after the drug was snorted and then progressively declined (Figure 2). The magnitude of the plasma concentrations of cocaine measured over the time of observation (0-120 minutes) were doserelated for both the placebo-ethanol conditions [F(I,10)=25.32, ~
