Ethanol-1-C14 metabolism in alcoholics and nonalcoholics.

Metabolism of ethanol-1-C(14) was assessed in a group of alcoholic and nonalcoholic male subjects. All subjects were screened for absence of physical derangement. Subjects were also carefully matched by dietary, social, and environmental criteria. No differences in rate of output of C(l4)CO(2) were detected after ingestion of alcohol which produced concentrations of 50 to 60 milligrams of alcohol per 100 milliliters of blood. These data do not support the hypothesis that alcoholics metabolize ethanol more rapidly than nonalcoholics do.

Blood concentrations of acetaldehyde and ethanol in chronic alcoholics.

Fifteen adult male alcoholic volunteers were studied before, during, and after a 10- to 15-day period of experimentally induced intoxication. Blood acetaldehyde concentrations ranged from 0.11 to 0.15 and from 0.04 to 0.08 milligrams per 100 milliliters when blood ethanol concentrations ranged from 1 to 400 milligrams per 100 milliliters after consumption of bourbon or grain ethanol, respectively. No dose or dose-time relationships were found between blood ethanol concentrations and blood acetaldehyde concentrations during any phase of this study.

Buprenorphine suppresses heroin use by heroin addicts.

Heroin-dependent men were given buprenorphine (a partial opiate agonist-antagonist) or a placebo under duoble-blind conditions on a clinical research ward where they could acquire heroin (21 to 40.5 milligrams per day, intravenously). Buprenorphine significantly (P less than .001) suppressed the self-administration of heroin over 10 days. Control subjects took between 93 and 100 percent of the available heroin. The effects of buprenorphine were dose-dependent; a dose of 8 milligrams per day reduced heroin use by 69 to 98 percent; a dose of 4 milligrams per day reduced heroin use by 45 percent. Termination of buprenorphie maintenance did not result in opiate withdrawal signs or symptoms. The subjects liked buprenorphine and indicated that it was preferable to methadone or naltrexone. Buprenorphine should be a safe and effective new pharmacotherapy for heroin dependence.

Alcohol-induced hyperlipidemia and beta lipoproteins.

Alcohol addicts with a primary type IV hyperlipoproteinemia show a striking elevation of triglycerides in the serum during long periods of alcohol consumption as compared with controls, without an accompanying significant increase in free fatty acids in the serum. These data suggest that this genetically related lipid abnormality may be a significant factor in the pathogenesis of alcohol hyperlipemia and the alcohol-induced fatty liver.

Buprenorphine suppresses cocaine self-administration by rhesus monkeys.

Cocaine abuse has reached epidemic proportions in the United States, and the search for an effective pharmacotherapy continues. Because primates self-administer most of the drugs abused by humans, they can be used to predict the abuse liability of new drugs and for preclinical evaluation of new pharmacotherapies for drug abuse treatment. Daily administration of buprenorphine (an opioid mixed agonist-antagonist) significantly suppressed cocaine self-administration by rhesus monkeys for 30 consecutive days. The effects of buprenorphine were dose-dependent. The suppression of cocaine self-administration by buprenorphine did not reflect a generalized suppression of behavior. These data suggest that buprenorphine would be a useful pharmacotherapy for treatment of cocaine abuse. Because buprenorphine is a safe and effective pharmacotherapy for heroin dependence, buprenorphine treatment may also attenuate dual abuse of cocaine and heroin.

Alcohol self-administration disrupts reproductive function in female macaque monkeys.

Female macaque monkeys self-administered high doses of alcohol (2.9 to 4.4 grams per kilogram per day) for 3 to 6 1/2 months. Amenorrhea, atrophy of the uterus, decreased ovarian mass, and significant depression of luteinizing hormone levels were associated with chronic alcohol intoxication. Reproductive system failure in female primates following self-induced dependence on alcohol parallels the results of clinical studies of alcoholic women.

Marijuana consumption and tolerance to physiological and subjective effects.

The relation between marijuana consumption and the development of tolerance was investigated during a 31-day study. Volunteers with a history of moderate or heavy marijuana use were given access to one-gram (2.1% delta9 tetrahydrocannabinol [THC]) marijuana cigarettes during a 21-day smoking period. Both groups tended to increase consumption during this time. Heavy users averaged 5.7 cigarettes per day and indicated a progressive decline in ratings of intoxication and duration of pulse rate effect. Moderate users averaged 3.2 cigarettes per day but showed no changes in either of these reactions during this time. Results suggested that tolerance does not develop to the two most reliable indexes of marijuana intoxication unless heavy doses of delta9 THC are self-administered repeatedly. Also, the tendency to increase consumption during this time is not necessarily associated with the development of tolerance.

Cocaine-induced erythrocytosis and increase in von Willebrand factor: evidence for drug-related blood doping and prothrombotic effects.

BACKGROUND: Mechanisms that mediate cocaine-induced cardiovascular events following vasoconstriction are incompletely understood. OBJECTIVE: To examine the effects of cocaine in moderate doses on hematologic and hemostatic parameters that influence blood viscosity and thrombotic potential. METHODS: Changes in hemoglobin concentration, hematocrit, and red blood cell counts were measured in human subjects who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for long-term cocaine abuse, before and sequentially after moderate intranasal and intravenous doses of cocaine. Hemostatic parameters, including von Willebrand factor, fibrinolytic activity, fibrinogen, plasminogen activator inhibitor antigen, and tissue-type plasminogen activator antigen, were sequentially measured after intravenous cocaine or saline placebo with cardiac troponin subunits T and I. RESULTS: Hemoglobin level (P= .002), hematocrit (P =.01), and red blood cell counts (P = .04) significantly increased from 4% to 6% over baseline from 10 to 30 minutes after intranasal (n = 14) and intravenous (n = 7) cocaine administration in doses of 0.9 mg/kg and 0.4 mg/kg, respectively, with no change in white blood cell or platelet counts. There was a significant increase (P =.03) in von Willebrand factor from 30 to 240 minutes, peaking at 40% over baseline following intravenous cocaine administration in a dose of 0.4 mg/kg (n = 12), with no change after 0.2 mg/kg (n = 3) or placebo (n = 6). Other hemostatic factors, creatinine, blood urea nitrogen, and cardiac troponin subunits T and I showed no changes. CONCLUSIONS: Cocaine induced a transient erythrocytosis that may increase blood viscosity while maintaining tissue oxygenation during vasoconstriction. An increase in von Willebrand factor without a compensatory change in endogenous fibrinolysis may trigger platelet adhesion, aggregation, and intravascular thrombosis.

Cocaine effects on luteinizing hormone-releasing hormone-stimulated anterior pituitary hormones in female rhesus monkey.

The effects of acute cocaine administration on synthetic LHRH-stimulated anterior pituitary hormones (LH, FSH, and PRL) were studied in 6 female rhesus monkeys during the follicular phase of the menstrual cycle (days 4-7). Integrated plasma samples were collected every 10 min for 40 min before iv administration of cocaine (0.4 or 0.8 mg/kg) or an equal volume of vehicle control solution. Synthetic LHRH (100 micrograms, iv) was administered 10 min after cocaine or placebo-cocaine administration, and 10 plasma samples were collected for an additional 100 min. LHRH stimulated a significant increase in LH within 10 min after placebo-cocaine administration (P less than 0.05) and after each dose of cocaine (P less than 0.0001). Cocaine (0.4 mg/kg) significantly enhanced LHRH stimulation of LH compared to placebo or 0.8 mg/kg cocaine administration (P less than 0.01). FSH increased significantly within 20-30 min after LHRH alone (P less than 0.008) and after 0.4 mg/kg cocaine (P less than 0.0001). LHRH-stimulated FSH levels also were significantly higher after 0.4 mg/kg cocaine than after placebo or 0.8 mg/kg cocaine (P less than 0.01). These data indicate that cocaine does not suppress LHRH stimulation of pituitary gonadotropins, and low doses of cocaine significantly enhance LH and FSH release. Consequently, cocaine does not compromise anterior-pituitary function at the level of the gonadotroph and may stimulate hypothalamic release of endogenous LHRH. PRL levels were unchanged by LHRH and placebo-cocaine administration. After LHRH and cocaine administration, PRL levels decreased significantly (P less than 0.05-0.01) and remained suppressed throughout the 110-min postcocaine sampling period. These data indicate that cocaine's significant suppression of PRL is not blocked by LHRH. These findings are consistent with dopaminergic inhibitory control of PRL and suggest that cocaine's inhibition of dopamine reuptake down-regulates pituitary lactotroph activity in rhesus monkey.

Alcohol effects on naltrexone-induced stimulation of pituitary, adrenal, and gonadal hormones during the early follicular phase of the menstrual cycle.

Chronic alcohol abuse in women is associated with severe derangements of menstrual cycle regularity. However, acute alcohol ingestion has no effect on pituitary-gonadal secretory function. The purpose of this study was to determine whether acute alcohol ingestion altered the effects of naltrexone, a long-acting opioid antagonist, on pituitary, adrenal, and gonadal hormones in normal women. Fourteen women were studied during the early follicular phase (between days 2 and 4) of their menstrual cycle. Plasma LH, PRL, estradiol, progesterone, and cortisol concentrations were measured before and after administration of 50 mg naltrexone, orally, and alcohol or placebo solution given 1 h after naltrexone, under double blind conditions. Naltrexone significantly increased mean plasma LH (P = 0.02), PRL (P = 0.003), E2 (P less than 0.03), and cortisol (P less than 0.001) levels. Alcohol significantly augmented the naltrexone-stimulated increases in plasma LH (P = 0.006), estradiol (P less than 0.004), and cortisol (P less than 0.001) levels and significantly decreased plasma progesterone levels (P = 0.001). Plasma PRL increased (P = 0.001) to the same extent after naltrexone and alcohol ingestion or naltrexone and placebo. We conclude that alcohol enhances naltrexone-induced increases in plasma gonadotropins and adrenal and gonadal steroid hormones in women during the early follicular phase of the menstrual cycle.

Effect of endogenous opioid blockade on the amplitude and frequency of pulsatile luteinizing hormone secretion in normal men.

The role of endogenous opiates in the neuroendocrine regulation of episodic LH secretion in normal men was examined in seven adult males before and after the administration of a potent and specific opiate receptor antagonist, naltrexone. The quantitative pattern of pulsatile LH secretion was analyzed in serum derived by continuous exfusion of blood in 20-min samples over 8-h period. The administration of naltrexone markedly increased the following: 1) total area under the continuous LH secretion curve [22,725 +/- 2,026 (control) vs. 33,442 +/- 2,226 ng/ml . min (after naltrexone); P less than 0.0006]; 2) mean serum concentration of LH, which increased from 47.3 +/- 4.2 to 69.7 +/- 5.0 ng/ml; 3) the absolute amplitude of Lh peaks, which rose from 62.7 +/- 6.2 tp 85.2 +/- 5.8 ng/ml; and 4) the number of LH secretory peaks observed over the 8-h interval (4.3 +/- 0.4 basally and 5.4 +/- 0.6 after the drug; P less than 0.0003). Naltrexone administration did not significantly alter the most rapid component of LH elimination calculated after each pulse or alter the fractional arise in LH above interpulse baseline. These data suggest that endogenous opioids tonically suppress frequency- and amplitude-dependent neuromodulation of LH production, probably through hypothalamic mechanisms that impinge upon gonadotropin-releasing hormone-secreting peptidergic neurons.

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.

Cocaine effects on pulsatile secretion of anterior pituitary, gonadal, and adrenal hormones.

Pulse frequency analysis of LH, PRL, testosterone, and cortisol was carried out with the Cluster Analysis Program in eight male cocaine abusers and eight aged-matched normal men. Four of the eight cocaine abusers had hyperprolactinemia (range, 22.08-44.65 micrograms/L). Cocaine users as a group had significantly higher mean peak height (P less than 0.02) than control subjects. Cocaine users with hyperprolactinemia had higher mean peak height than control subjects or cocaine users with normal PRL levels (P less than 0.01). Cocaine users with hyperprolactinemia also had higher mean amplitude increments than control subjects (P less than 0.02). Cocaine users with hyperprolactinemia had a higher mean valley than controls (P less than 0.01) and cocaine users with normal PRL levels (P less than 0.03). However, there were no significant differences in PRL peak frequency, peak duration, or interpulse intervals between cocaine users with or without hyperprolactinemia and control subjects. There were minimal differences between cocaine users and control subjects in pulse frequency analysis of LH parameters; the small differences in mean LH levels and average interpulse interval were not in the abnormal range and were probably not biologically significant. No differences between cocaine users and controls were detected for pulse frequency analysis of testosterone or cortisol. Cocaine-induced hyperprolactinemia may contribute to disorders of sexual and reproductive function in men who abuse the drug, and recent reports that PRL modulates immune function suggest that cocaine-induced derangements of PRL secretion may also contribute to cocaine-related comorbidity in infectious disease. Since cocaine users with hyperprolactinemia had a higher mean valley as well as a higher peak pulse PRL height than control subjects, but did not have greater PRL pulse frequencies, we conclude that hyperprolactinemia in these men may be due to a cocaine-induced derangement of dopaminergic inhibition of basal PRL secretion.

Pituitary volume in men with concurrent heroin and cocaine dependence.

Pituitary gland volume was measured in 16 men between the ages of 26-33 with magnetic resonance imaging. Eight male patients had a Diagnostic and Statistical Manual III-Revised, American Psychiatric Association Axis I diagnosis of concurrent opioid and cocaine dependence. The average duration of opioid and cocaine abuse was 7.8 +/- 2.0 and 6.9 +/- 1.4 yr, respectively. All patients were in good physical health as determined by physical examination, blood chemistry, hemogram and hormone analysis, and all tested negatively for the HIV antibody. No patient had any other Diagnostic and Statistical Manual III-Revised Axis I diagnosis or neurological disorder. Eight healthy males served as age-matched control subjects. None of the control subjects had any past or current history of substance abuse or any clinical indication for magnetic resonance imaging. Opioid and cocaine dependent men had significantly larger pituitary gland volumes (730.0 +/- 24.4 mm3) than control subjects (540.0 +/- 26.6 mm3) (P < 0.01). The significant increase in pituitary gland volume in men who abuse opiates and cocaine may be antecedent to detection of abnormal anterior pituitary hormone function.

The concordance of pulsatile ultradian release of adrenocorticotropin and cortisol in male rhesus monkeys.

The ultradian release of ACTH and cortisol was investigated in six male rhesus monkeys (Macaca mulatta) with an intensive (2-min) blood-sampling procedure to investigate micropulsatile hormone secretory patterns. A sensitive and specific immunoradiometric assay was used to measure plasma ACTH concentrations. An objective pulse detection algorithm (Cluster) was used to assess the pulsatility of ACTH and cortisol release. The temporally coincident release of ACTH and cortisol was also examined. Venous blood samples were collected (over < 15 s) every 2 min for 120 min beginning at 1300 h. The number of ACTH peaks (3.2 peaks/h), interpulse intervals (19 +/- 2.4 min), and pulse amplitudes (9.7 +/- 1.6 pmol/L) in rhesus monkey were similar to corresponding measures of ACTH release in humans (3.3 peaks/h, 18 +/- 0.8 min, and 4.7 +/- 1.0 pmol/L, respectively). The number of cortisol peaks (2.3 peaks/h), interpulse interval (26 +/- 8.6 min), and other characteristics of pulsatile cortisol release were also determined. There was a 32.4% exact concordance of ACTH with cortisol peaks (11 of 34; P < 0.001). Fifty-six percent of ACTH peaks (19 of 34) were followed by a cortisol peak within 10 min (P < 0.02). There was a significant correlation between the ACTH and coincident cortisol pulse amplitudes (P < 0.0001). The amplitudes of ACTH peaks coincident with cortisol peaks at 0 min time lag were significantly higher than ACTH peaks not temporally coupled with cortisol peaks. Our data indicate that 1) high frequency, low amplitude micropulsatile ACTH secretion in rhesus monkeys is very similar to the high frequency ACTH rhythm in humans; 2) temporally concordant ACTH and cortisol release episodes may be amplitude coupled; and 3) an adequate incremental ACTH pulse amplitude may elicit a concurrent cortisol release episode from the adrenal cortex. These data suggest that the rhesus monkey is a potentially useful model for the study of neuroendocrine control of ACTH release.

Concurrent pharmacokinetic analysis of plasma cocaine and adrenocorticotropic hormone in men.

The purpose of this study was to determine the covariance between plasma cocaine and ACTH pharmacokinetics. Twelve healthy male occasional cocaine users participated in a double blind study. Intravenous cocaine (0.2 mg/kg) or placebo was infused over 1 min, and samples for cocaine, ACTH and cortisol analysis were collected at 2, 4, 8, 12, 16, 20, 30, 40, 60, 80, 120, 180, and 240 min. Peak cocaine plasma levels averaged 101.2 +/- 14.6 ng/mL. ACTH increases were significantly correlated (P < 0.0001) with increases in plasma cocaine levels (r = 0.67; r2 = 0.44). Pharmacokinetic analysis showed that the t(max) (observed time to maximum concentration) values for cocaine (6.0 +/- 1.4 min) and ACTH (7.3 +/- 1.2 min) were almost identical. The area under the curve was calculated using the trapezoidal rule. The area under the curve for plasma cocaine was 6463 +/- 1070 ng/min x mL, and the area under the curve for ACTH was 1873 +/- 188 pmol/min x L. The mean half-life for plasma cocaine was 46.7 +/- 4.0 min, and that for ACTH was 35.8 +/- 5.1 min. Cardiovascular and subjective effect measures were correlated with concurrent increases in plasma cocaine and ACTH levels.

Electroencephalographic activity and plasma ACTH during ethanol-induced euphoria.

Covariance of brain electrical activity (EEG), plasma adrenocorticotrophic hormone (ACTH) and cortisol levels, and mood states were determined for healthy adult men during the first 2 hr after ingestion of ethanol or ethanol placebo under controlled double-blind conditions. Analysis of integrated plasma ACTH and cortisol levels at 5-min intervals, EEG power spectral analysis during consecutive 2-min epochs, and continuous assessment of mood states with a nonverbal instrumental device were carried out during the ascending phase of the blood ethanol curve. Ethanol induced rapid changes in brain electrical activity and plasma ACTH levels that were significantly correlated with subjective perception of changes in mood. The paroxysmal short epochs of euphoria associated with electroencephalographic and ACTH responses during the ascending phase of the blood ethanol curve may reflect physiological concomitants of pharmacological and behavioral reinforcers that enhance risk for perpetuation of drinking and alcohol abuse.

P300 assessment of opiate and cocaine users: effects of detoxification and buprenorphine treatment.

We assessed cognitive function following heroin and cocaine detoxification and investigated whether buprenorphine treatment improves the disruptive effects of detoxification. Three groups of male volunteers meeting DSM-III-R criteria for concurrent opiate and cocaine dependence were tested using an auditory oddball paradigm before and after detoxification, and again on the 15th day of either buprenorphine or placebo treatment. There were no significant differences in P300 amplitude, latency, or topographic distribution between drug-dependent subjects and controls on admission day. Following detoxification there was a significant decrease in P300 amplitude in the drug-dependent group at a time when self-reported signs of withdrawal were minimal. Buprenorphine treatment significantly reversed the P300 amplitude decrement following detoxification, whereas placebo-treated subjects continued to show depressed P300 amplitudes. These data demonstrate that buprenorphine treatment is effective in eliminating detoxification-induced impairments in one measure of cognitive ability.

Proton magnetic resonance spectroscopy of human basal ganglia: response to cocaine administration.

BACKGROUND: Proton magnetic resonance spectroscopy was used to determine the effects of intravenous cocaine or placebo administration on human basal ganglia water and metabolite resonances. METHODS: Long echo time, proton magnetic resonance spectra of water and intracellular metabolites were continuously acquired from an 8-cm(3) voxel centered on the left caudate and putamen nuclei before, during, and after the intravenous administration of cocaine or a placebo in a double-blind manner. RESULTS: Cocaine, at both 0.2 and 0.4 mg/kg, did not alter the peak area for water. Cocaine at 0.2 mg/kg induced small and reversible increases in choline-containing compounds and N-acetylaspartate peak areas. Cocaine at 0.4 mg/kg induced larger and more sustained increases in choline-containing compounds and N-acetylaspartate peak areas. No changes in either water or metabolite resonances were noted following placebo administration. CONCLUSIONS: These increases in choline-containing compounds and N-acetylaspartate peak areas may reflect increases in metabolite T2 relaxation times secondary to osmotic stress and/or increased phospholipid signaling within the basal ganglia following cocaine administration. This is the first report of acute, drug-induced changes in the intensity of human brain proton magnetic resonance spectroscopy resonance areas.

Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual cycle phase.

BACKGROUND: Chronic cocaine abusing women experience fewer cerebral perfusion defects and less neuronal injury than men with comparable drug use histories. This study assessed whether a basis for this discrepancy is a sex difference in cocaine's acute cerebrovascular effects. METHODS: The subjects in this study were 13 healthy and neurologically normal women, reporting occasional cocaine (mean 13, range 1-40 lifetime cocaine exposures). All subjects were administered cocaine (0.4 mg/kg) intravenously, during both the follicular (days 3-8) and luteal (days 18-24) menstrual cycle phases. Dynamic susceptibility contrast magnetic resonance imaging assessments of relative global cerebral blood volume (CBV) changes were conducted on both study days, 10 min after cocaine administration. RESULTS: Cocaine did not alter CBV in follicular phase women, but reduced luteal phase CBV by 10%, indicative of vasoconstriction (analysis of variance [ANOVA], F = 5.1, p <.05). Postcocaine CBV was lower in men administered the drug via an identical protocol relative to follicular phase women (ANOVA, F = 5.4, p <.04). Postcocaine CBV was also lower in the male referent group relative to luteal phase women, but this difference did not achieve statistical significance. No measurable sex or menstrual cycle phase differences in cocaine's cardiovascular effects were noted. CONCLUSIONS: These findings suggest both menstrual cycle phase and sex differences in cocaine's acute cerebrovascular effects, which may contribute to sex differences in the severity of brain dysfunction found in chronic cocaine abusers. These findings imply that gonadal steroids or the factors they modulate merit study as possible therapeutic agents for reducing cocaine-induced cerebrovascular disorders.