Plasma Cocaine Levels Research Articles

Acquisition and maintenance of intravenous cocaine self-administration in Lewis and Fischer inbred rat strains

Lewis and Fischer inbred rat strains differ in behavioral and biochemical responses to psychoactive drugs: Lewis rats show greater behavioral responses to psychoactive drugs than Fischer rats and they fail to show biochemical adaptations in the mesolimbic dopamine system after chronic drug exposure, in contrast to Fischer and outbred rats. This suggests that Fischer and Lewis rats may differ in the initial, reinforcing effects of psychoactive drugs, but not in responses seen after the exposure that occurs with maintenance of drug-reinforced behavior. Thus, the present study tested whether these strains differ in acquisition or maintenance of intravenous cocaine self-administration. Acquisition of cocaine self-administration was examined in separate groups that were allowed 15 days to acquire the operant at one of three cocaine doses (0.25, 0.5, or 1.0 mg/kg/infusion). Compared to Fischer rats, Lewis rats acquired cocaine self-administration after fewer training trials and at lower doses. After maintenance, both strains showed characteristic extinction responding with saline substitution and dose-related responding to cocaine, although Fischer rats tended to show higher response rates. Finally, cocaine plasma levels, obtained after an intravenous cocaine infusion (1.0 mg/kg), showed no strain differences suggesting that the strain difference in acquisition was not due to cocaine pharmacokinetics. These strain differences in acquisition of cocaine self-administration may be related to reported strain differences in the mesolimbic dopamine system. Further, because acquisition of drug self-administration is an animal model of vulnerability to drug addiction, these inbred strains may be useful to study factors underlying such vulnerability.

Cocaine and Benzoylecgonine in Serum Microsamples of Intact and Gonadectomized Male and Female Wistar Rats

VAN HAAREN, F., M. GARCEA, K. G. ANDERSON AND I. R. TEBBETT. Cocaine and benzoylecgonine in serum microsamples of intact and gonadectomized male and female Wistar rats. PHARMACOL BIOCHEM BEHAV 58(2) 421–424, 1997.—Tail-tip plasma samples of intact and gonadectomized male and female Wistar rats were analyzed for cocaine and benzoylecgonine. The samples were obtained from immobilized subjects 10 and 30 min following the 1st and 22nd intraperitoneal injections of 10 mg/kg cocaine hydrochloride. Gender differences in plasma cocaine or benzoylecgonine levels were not observed after the first injection of cocaine because many of the samples were below the detection limit. Cocaine plasma levels were much higher after the 22nd injection, but gender differences were not observed either 10 or 30 min following cocaine administration. Plasma levels of benzoylecgonine were higher 30 min than 10 min after cocaine administration in intact and castrated male rats and ovariectomized female rats but not in intact female rats. These data show that, in rats, gender differences in cocaine metabolism may be observed after repeated cocaine administration, but the exact mechanism remains to be elucidated.

Behavioral Sensitization to Cocaine in the Absence of Altered Brain Cocaine Levels

We conducted experiments investigating the role of altered cocaine distribution in behavioral sensitization. The first was designed to determine whether carry-over from one injection to the next occurs after acute cocaine administration. Female, Sprague–Dawley rats were administered 5 mg/kg 3H-cocaine and 24 h later were challenged with either 5 mg/kg unlabeled cocaine or saline. Animals were sacrificed 15 min after drug administration. There was no difference between groups in cocaine levels in brain, liver, or plasma, thus indicating that carry-over did not occur following acute cocaine administration. The second experiment was designed to determine whether bound cocaine could be released following acute or multiple dose cocaine administration. In the acute dose study, animals were administered either 20 mg/kg cocaine or saline, challenged 24 h later with 5 mg/kg 3H-cocaine, and sacrificed 5 min after drug administration. Animals with previous cocaine experience exhibited a significant increase in the number of rearings. The groups did not differ in brain or plasma cocaine levels. In the multiple dose study, animals were injected daily for 4 days with 20 mg/kg cocaine or saline, challenged with 5 mg/kg 3H-cocaine on day 5, and sacrificed 10 min after drug administration. Animals with previous cocaine experience exhibited significantly greater locomotor activity and number of rearings. There was no difference between groups in cocaine levels in various brain regions, plasma, or liver. Brain cocaine content in various regions was significantly correlated, though heterogeneously distributed within the various regions. The highest cocaine levels were found in hippocampus, striatum, thalamus/hypothalamus, and cortex. These results provide further evidence that behavioral sensitization is not the result of cocaine redistribution following repeated administration.

Acute gestational cocaine exposure alone or in combination with low-dose ethanol does not influence prenatal mortality or fetal weight in mice.

The teratogenic effects of cocaine and ethanol were investigated using an acute treatment model of C57BL/6J mice treated on gestation day 15 (GD15) with evaluation on GD17. Females were intubated once with a subteratogenic dose of ethanol (0 or 4 g/kg) and injected subcutaneously twice, 1 h apart, with equal doses of cocaine HCl (0 or 60 mg/kg), for a final daily dose of 120 mg/kg. The first cocaine injection followed ethanol by 10 min. Blood ethanol levels (BEL) and plasma cocaine levels were determined, and pair-feeding was employed. The results revealed no group differences on pregnancy outcome. That is, maternal weight gain, total number of implants, prenatal mortality, and fetal body weight were not statistically different. No significant differences in BEL or plasma cocaine levels were found among the various treatment groups. These results suggest that, under these conditions, relatively high levels of cocaine (120 mg/kg, SC), given alone or in combination with subteratogenic doses of ethanol late in pregnancy, are not teratogenic in mice.

Effects of cocaine and corticotropin-releasing factor on pulsatile ACTH and cortisol release in ovariectomized rhesus monkeys.

Cocaine stimulates ACTH secretion by a corticotropin-releasing factor (CRF)-dependent mechanism in male rats, rhesus monkeys, and humans. To determine the generality of this effect, we examined the effects of acute cocaine administration on the pulsatile release of ACTH and cortisol in three ovariectomized (OVX) rhesus monkeys and compared its effects to stimulation with CRF. Venous blood samples were collected at 2-min intervals for 60 min before and after iv administration of cocaine (0.4 and 0.8 mg/kg) and CRF (1.0 and 10 micrograms/kg). Cluster analysis procedures were used to evaluate the pulsatile characteristics of ACTH and cortisol release. After placebo administration, an ACTH pulse frequency of 3 peaks/h was detected. After cocaine administration, plasma cocaine levels peaked at 92 +/- 3.0 and 201 +/- 60 ng/mL within 2 min. However, in contrast to normal intact males, cocaine did not stimulate the pulsatile release of ACTH in OVX females. Cocaine (0.4 mg/kg) decreased ACTH incremental peak height and valley levels compared with pre-cocaine values, and a higher dose of cocaine produced no changes in ACTH release. Bolus injection of a low dose of CRF (1.0 micrograms/kg, iv) significantly increased ACTH incremental peak height (P < 0.05), and a higher dose of CRF (10 micrograms/kg) increased ACTH peak amplitude, percentage increase in peak amplitude, area under the peaks, and incremental peak heights as well as ACTH valley level and nadir (10 micrograms/kg, iv) (P < 0.05). ACTH pulse frequency did not change after CRF or cocaine administration. Pulsatile release of cortisol was 2.7 peaks/h under placebo conditions and did not change after cocaine or CRF administration. Cortisol pulse amplitude was increased after low and high doses of CRF. High doses of CRF (10 micrograms/kg) also increased the mean level of cortisol valleys. In summary, we found that CRF but not cocaine stimulated pulsatile ACTH and cortisol release in OVX rhesus monkeys. The profound ACTH response to CRF challenge suggests that the CRF sensitivity and the ACTH release capacity of the anterior pituitary corticotroph cells were intact. The lack of stimulatory effects of cocaine on the hypothalamic-pituitary-adrenal axis in OVX monkeys, in contrast to normal male monkeys, may reflect the absence of gonadal steroids.

Marihuana smoking increases plasma cocaine levels and subjective reports of euphoria in male volunteers

The reasons why individuals use this combination are not entirely clear, however, it has been speculated that marihuana may potentiate cocaine's subjective effects. Five male recreational drug users provided informed consent and volunteered to participate in this study. Each subject participated on 3 different days, separated by at least 1 week. Subjects sat in an isolated chamber and were prepared with electrocardiographic (ECG) electrodes for heart rate monitoring and an IV catheter for blood withdrawal. After adapting to the experimental chamber, they smoked a marihuana cigarette containing either 0.004% (placebo), 1.24%, or 2.64% Δ 9-tetrahydrocannabinol (THC). Thirty minutes later they received an intranasal dose of 0.9 mg/kg cocaine. On subsequent visits, the marihuana dose was varied on a random basis. Subjects continuously reported changes in their mood state via an instrumental joystick device and filled out visual analog scales. Marihuana-induced tachycardia was increased even more after cocaine. The duration of all marihuana- and cocaine-related positive subjective effects was unchanged when both drugs were given, but marihuana pretreatment significantly reduced the latency to cocaine effects, from 1.87 to 0.53 min, and decreased the duration of dysphoric or bad effects, from 2.1 to 0.5 min. Peak plasma cocaine levels were 122.8 ± 26.6 ng/ml after placebo marihuana, but pretreatment with the high-dose marihuana resulted in a significant increase in peak cocaine levels (233.8 ± 19.2 ng/ml) and the apparent bioavailability as determined by area under the curve (AUC) analysis. We conclude that marihuana-induced vasodilation of the nasal mucosa attenuates the vasoconstrictive effects of cocaine and thus increases its absorption.

Response of the Newborn Cerebral Circulation to Cocaine

Cocaine abuse by pregnant women is often associated with neurological injury in the newborn. To explore a vascular-related mechanism of injury, we investigated the effect of cocaine on the cerebral circulation in newborn pigs. During normoxic conditions, cocaine administration (1.5 mg/kg i.v.), resulting in peak plasma cocaine levels on the order of 10(-6) M, decreased cerebral blood flow (CBF) by 14%, as measured by the tracer microsphere method. To elicit the mechanisms by which cocaine decreased CBF, closed cranial windows were placed and the diameter of pial arterioles was measured by intravital microscopy while cocaine (10(-6) M) was applied onto the cortical surface. Topically applied cocaine decreased pial arteriolar diameter by 9%. Vasoconstriction induced by topically applied cocaine was blocked by tetrodotoxin (10(-7) M, Na+ channel blocker), whereas phentolamine (10(-5) M, noradrenergic receptor blocker) had no effect on the arteriolar response to cocaine, which suggested that cocaine effected constriction by an anesthetic and not a sympathomimetic mechanism. To evaluate this hypothesis further, cerebral vessels in the right hemibrain were sympathetically denervated while those in the left hemibrain remained innervated. During normoxia, cocaine (1.5 mg/kg i.v.) decreased CBF equally in both hemibrains, confirming the non-sympathomimetic mechanism. During asphyxia, cocaine administration attenuated cerebral hyperemia in both hemibrains, but in innervated more than in denervated, indicating that anesthetic and sympathomimetic vasoconstriction occurred during asphyxia. We conclude that cocaine constricts the immature cerebrovasculature and decreases CBF by an anesthetic mechanism during normoxic conditions and by both sympathomimetic and anesthetic mechanisms during asphyxia.

Monoamine uptake inhibitors alter cocaine pharmacokinetics.

The time course of change in plasma levels of cocaine and its major metabolite benzoylecgonine following 3 mg/kg IV cocaine and the pharmacokinetic interaction between cocaine and several monoamine uptake inhibitors were investigated in conscious rats implanted with arterial and venous cannulae. The IV bolus administration of 3 mg/kg cocaine resulted in plasma levels of 1276 +/- 53 ng/ml cocaine at 0.5 min following its injection and the levels then rapidly declined to 768 +/- 110 ng/ml by 2 min. Thereafter, the decline of plasma cocaine levels was relatively slow. Plasma benzoylecgonine levels were similar at 0.5 and 2 min following cocaine injection but increased gradually over the next 25 min. Pretreatment with the norepinephrine-selective uptake inhibitors desipramine and nisoxetine, the serotonin-selective uptake inhibitor fluoxetine or the dopamine-selective uptake inhibitor GBR 12909 all enhanced plasma levels of cocaine after a 3 mg/kg IV bolus injection at 0.5, but not at 5 min after injection. The enhancement of plasma cocaine levels by GBR 12909 was of greater magnitude than that produced by desipramine, nisoxetine or fluoxetine. These agents, with the exception of the high dose (10 mg/kg) of GBR 12909, did not significantly alter plasma levels of benzoylecgonine measured at either 0.5 or 5 min following cocaine injection. These results indicate that monoamine uptake inhibitors can alter or interfere with the pharmacokinetics of cocaine and that this interaction is not due to a change in the biotransformation of cocaine. It is suggested that the central monoamine uptake sites serving as rapid distribution sites for cocaine may play a role in this pharmacokinetic interaction.

Plasma cocaine and tetracaine levels following application of topical anesthesia in children

To measure plasma cocaine and tetracaine levels in children after standardized application of a solution of tetracaine 0.5%, epinephrine 0.05%, and cocaine 11.8% (TAC) to lacerations requiring suture repair. Nonrandomized, controlled trial over a five-month period. University hospital emergency department. Stable children less than 16 years of age with uncomplicated lacerations. Blood was obtained at either 15 or 20 minutes (early; 32) or 45 or 60 minutes (late; 45) for measurement of plasma cocaine and tetracaine levels. Analysis for cocaine and tetracaine concentrations was performed using gas chromatography-mass spectroscopy with a limit of detection for both assays of 0.5 ng/mL. Serum cocaine levels were low but measurable at both times in 75% of children. No tetracaine was measurable. Median cocaine levels were 1 ng/mL (range, 0 to 112 ng/mL) for the early group and 2 ng/mL (range, 0 to 274 ng/mL) for the late group (P = NS). Only two children had levels of more than 100 ng/mL. No significant correlation between patient or laceration characteristics and cocaine levels was detected. No significant change in heart rate or blood pressure was detected. Children who required additional local anesthesia had nonfacial lacerations and lower cocaine levels than children with facial lacerations. Application of 3 mL of standard TAC solution for 15 minutes results in low but measurable plasma cocaine levels in 75% of children.

Cocaine use and withdrawal: the effect on sleep and mood.

Three recreational cocaine users (age, 26.7 years), after one adaptation night, spent 5 days and nights in the laboratory where their EEG, EOG, and submental EMG were recorded during all of their sleep. On the second afternoon and evening of the study, subjects used an estimated 1 to 2 g cocaine intranasally. They all slept between 2:00 A.M. and 9:00 A.M. that night. Blood samples were drawn each evening and morning. Absolute plasma cocaine levels and patterns of elimination were consistent with subjects report of dose and time of administration. Mood ratings were made repeatedly throughout the study. There was suppression of REM sleep during the use of cocaine followed by a rebound which is specific to REM sleep and is not seen in other stages of sleep. REM variables subsided to normal levels on the third recovery night following cocaine use.

Plasma cocaine and tetracaine levels following application of topical anesthesia in a swine laceration model

Standard TAC (0.5% tetracaine, 0.05% epinephrine, and 11.8% cocaine) solution is finding increased use as a topical anesthetic for lacerations. The extent of systemic absorption of TAC components and their resultant physiologic effects are unclear. Absorption of cocaine or tetracaine may result in serious toxicity. The investigators hypothesized that there are no measurable plasma cocaine or tetracaine levels after application of TAC in a swine laceration model. After an overnight fast 10 domestic swine underwent tracheostomy, mechanical ventilation, femoral venous, and arterial cannulation. Maintenance anesthesia with intermittent thiopental and pancuronium was provided to maintain stage III anesthesia. Heart rate (HR), arterial pressure (BP), plasma cocaine, and tetracaine levels were measured at intervals for 180 minutes. Five milliters of TAC was applied for 15 minutes to a standardized facial laceration in experimental swine (n = 5). Randomly labeled plasma samples were placed in vials containing 2% sodium fluoride and 1% potassium oxalate, immediately refrigerated, and analyzed for cocaine and tetracaine using gas chromatography and mass spectroscopy. Significant changes in HR and mean BP, compared with baseline values, were analyzed using Dunnett's multiple range test. Plasma cocaine levels were measurable in all experimental swine after 10 minutes, while no tetracaine was detectable. No significant differences in HR or BP changes were observed between experimental and control subjects. Application of standard TAC solution results in measurable plasma cocaine levels, but not tetracaine. Further studies into anesthetic formulation, as well as timing and technique of application, are required before consensus on optimal emergency departmental use of topical anesthesia can be achieved.

Cocaine inhibits baroreflex control of blood pressure by actions at arterial baroreceptors

Blood pressure and heart rate often increase during cocaine intoxication, but the mechanisms of these cardiovascular responses are poorly understood. The most often suggested theories are central nervous system mechanisms involving the blockade of neuronal transmitter uptake. Cocaine also has potent local anesthetic properties, and in this study we tested the possible role of peripheral actions of cocaine at baroreceptor afferents. Single fiber baroreceptors were recorded using an in vitro preparation of the rat aortic arch. Diameter, pressure, and baroreceptor discharge were recorded. Cocaine perfused through the lumen of the aortic arch at a suprathreshold pressure reduced baroreceptor discharge within 90 s of entering the lumen of the aorta. Slow ramps of pressure elicited complete pressure- and diameter-discharge curves every 5 min. Beginning at about 1 microM, cocaine inhibited baroreceptor function; threshold increased, the maximum discharge decreased, and at 100 microM cocaine, all discharge ceased. The vasodilator nitroprusside or the alpha 1-adrenoreceptor antagonist prazosin did not affect baroreceptor responses to cocaine. In in vivo tests in rabbits, cocaine that perfused through a vascularly isolated carotid sinus reduced the slope of the baroreflex relationship between carotid sinus pressure and systemic mean arterial pressure. Significant depression of baroreceptor function was found at concentrations similar to the plasma cocaine levels measured in clinical studies. The local anesthetic properties of cocaine may be involved in baroreceptor effects. Our studies suggest a possible contributing role of a new site of action of cocaine outside the central nervous system. Compromise of baroreceptor reflexes could facilitate the development of serious cardiovascular complications associated with cocaine abuse.

Electrocardiographic and hemodynamic effects of intravenous cocaine in awake and anesthetized dogs

Graded bolus and infusion doses of cocaine were given to 18 dogs, 6 under general anesthesia and 12 awake, to determine the range of hemodynamic and electrocardiographic effects. Blood pressure, electrocardiographic measurements, cocaine plasma levels, temperature, electrolytes, and arterial blood gases were measured before and after the initial bolus and/or infusion at 10 minutes and each 30 minutes up to a maximum of 180 minutes. At the end of the infusion, a single large intravenous terminal bolus of cocaine was given. The hemodynamic and electrocardiographic changes occurred by 10 minutes after the bolus and resolved by 30 minutes, independent of the infusion rate and dose. Only anesthetized dogs could tolerate the highest cocaine doses. Three ranges of bolus doses were given: the lowest range was the average initial bolus dose received by the awake group; the intermediate range was the average initial bolus dose received by the anesthetized group; and the highest range was the average terminal bolus dose. The heart rate changes were unpredictable and did not change significantly at any dose range. The blood pressure increased in the lowest dose range, remained unchanged at intermediate doses, and fell at the highest doses in four of six dogs. Electrocardiographic intervals increased as the dose range increased. Only at the highest doses did potentially lethal ventricular arrhythmia (ventricular tachycardia and an idioventricular escape rhythm) occur. Intravenous cocaine causes hemodynamic and electrocardiographic effects that are related to the dose and rate of administration. At high doses, hypotension, arrhythmia, and electrocardiographic changes consistent with infranodal and/or intraventricular conduction slowing can occur.

Electrophysiologic Effects of Cocaine on the Canine Ventricle

To evaluate the electrophysiologic effects of cocaine on the ventricle, 12 conscious dogs were studied before and after a bolus and infusion of cocaine titrated to maximum tolerance or to an increase in the mean blood pressure by at least 15%. Plasma cocaine levels, blood pressure, and surface and intracardiac electrograms were recorded. Programmed electrical stimulation was performed from the right ventricle at drive cycle lengths of 400 and 350 ms with introduction of up to three extrastimuli. The right ventricular effective refractory period decreased by 10% (p less than or equal to 0.01) and the mean blood pressure increased by 19% (p less than or equal to 0.01). No sustained spontaneous or induced ventricular arrhythmias were recorded after cocaine administration. There were no significant changes in pacing threshold, intraventricular conduction, heart rate, QRS or QTc intervals. The cocaine dose infused was 2.1 +/- 1.0 mg/kg; cocaine plasma levels were 1969 +/- 959 ng/ml immediately after the bolus and 508 +/- 234 ng/ml at the end of the study. It is concluded that in a presumably normal canine heart and at the doses given that cocaine decreases right ventricular effective refractory period, does not change intraventricular conduction, and does not result in sustained spontaneous or induced ventricular arrhythmias.

Acute tolerance to cocaine in humans.

There is controversy as to whether acute tolerance develops to the principal effects of cocaine in humans. The studies described here demonstrate the phenomenon of acute tolerance to cocaine chronotropic and subjective effects and the rate and extent of tolerance development. Stable plasma cocaine concentrations were produced and then maintained in volunteer cocaine users by administering an intravenous cocaine injection followed by a cocaine infusion designed to compensate for the plasma clearance of cocaine. The euphoric effect (high) intensified to a peak at about 1 hour and then declined toward baseline at 4 hours despite the presence of constant plasma cocaine levels. The chronotropic effect reached a peak within 10 minutes and then declined, with a half-life of 31 +/- 13 (mean +/- SD) minutes toward a plateau at 33% +/- 21% of its peak intensity. Tolerance development was quantified as an exponential process, with a rate constant (tolerance factor) accounting for the progressive alteration of the cocaine concentration-effect relationship.

Cocaine absorption from the nasal mucosa.

The absorption of cocaine from the nasal mucosa was measured by serial plasma analysis in patients who received nasal cocaine for routine nasal surgery using the modified Moffett's method. Two groups were compared: one received cocaine alone and one with adrenaline 1:1000 added. Changes in pulse rate and blood pressure were recorded in each group. The group that received intranasal cocaine and adrenaline solution had significantly lower plasma cocaine levels. There was no significant difference in cardiovascular parameters between the two groups.

Confirmation of Cocaine in Human Saliva After Intravenous Use

The presence of cocaine was confirmed in the saliva of two male human subjects who had received intravenous doses of cocaine. For one subject, the saliva:plasma concentration ratios varied from 2.96 to 0.5 over time following drug administration. Correlations of saliva to plasma cocaine levels were highly significant (p less than 0.001) across doses of 15, 20, and 40 mg of intravenously administered cocaine. These findings are important in that they allow monitoring blood levels of cocaine after intravenous infusion in a non-invasive manner, and could form the basis for development of a non-invasive screen for active cocaine levels in saliva.

Hemodynamic effects of intravenous cocaine on the pregnant ewe and fetus

Cocaine is a potent vasoconstrictive agent that is currently the subject of widespread drug abuse. Because little is known of the physiologic responses to cocaine in pregnancy, the effects of intravenous cocaine on uterine blood flow and other maternal and fetal cardiovascular parameters were studied. Eight ewes in late pregnancy were equipped with electromagnetic flow probes around both uterine arteries and catheters were placed in the maternal and fetal inferior vena cavae and aortas. Bolus intravenous infusion of 0.5 and 1.0 mg/kg of maternal body weight achieved peak plasma cocaine levels similar to those observed in human subjects after abuse of the drug (mean level = 229 to 400 ng/ml, n = 8). After bolus infusion of 0.5 or 1.0 mg/kg of cocaine, mean maternal arterial pressure increased 32% and 37%, respectively (p less than 0.005). Fetal blood pressure rose 12.6% after a dosage of 0.5 mg/kg of cocaine. These cocaine infusions significantly decreased uterine blood flow by 36% and 42% for a duration of 15 minutes (p less than 0.005). Analysis of maternal catecholamine responses demonstrated a significant (210%) rise in plasma norepinephrine levels after cocaine infusion. These studies demonstrate that cocaine, when administered in doses that produce plasma levels observed in humans, significantly decreases uterine blood flow for a duration of greater than or equal to 15 minutes while inducing a hypertensive response in the pregnant ewe and fetus.

The urinary excretion of cocaine and metabolites in humans: a kinetic analysis of published data.

Cocaine plasma levels and urinary excretion data from the literature were subjected to kinetic analysis. The objective was to present the available empirical data in a more useful form and provide a basis for interpretation of cocaine and/or metabolite concentrations in isolated urine samples. Cocaine disposition was modeled as a one-compartment open kinetic system exhibiting linearity within the usually encountered dose range. Model-predicted urine concentrations of cocaine, benzoylecgonine, and ecgonine methyl ester after a 100-mg cocaine dose were compared with literature values to test the validity of the model, and to indicate the use of ratios of concentrations in isolated urine samples to estimate the time since the dose of cocaine. A nomogram relating BZ urine concentrations to cocaine doses was constructed.

Interactions of acetylmethadol or methadone with other drugs in rhesus monkeys

Behavioral effects and blood or plasma levels of d-amphetamine, ethanol, cocaine, and diazepam were examined in rhesus monkeys treated chronically with α- l-acetylmethadol (LAAM), methadone, or vehicle. Chronic treatment with the opiates failed to alter blood or plasma levels and behavioral effects of d-amphetamine or ethanol. LAAM-maintained monkeys were somewhat less sensitive to rate-decreasing effects of cocaine on schedule-controlled responding, but cocaine plasma levels and half-lives generally did not differ across the chronic treatment conditions. Behavioral depression after diazepam was prolonged substantially in LAAM- and methadone-maintained monkeys, but blood levels of diazepam and metabolites were not increased or prolonged in those animals. Naloxone partially antagonized the residual depression in LAAM- and methadone-maintained monkeys 24 hr after diazepam, but had no effect on the weaker residual depression in vehicle-maintained animals. Thus, diazepam appeared to interfere with the metabolic inactivation of the opiates. One LAAM-maintained monkey showed recurrent episodes of LAAM overdose and eventually died during the course of the study.