Cocaine effects on pulsatile secretion of ACTH in men.

The effects of cocaine on pulsatile secretion of adrenocorticotropic hormone (ACTH) in men were studied under controlled clinical research ward conditions. Eight men with a Diagnostic and Statistical Manual of the American Psychiatric Association Version III, revised, diagnosis of concurrent cocaine and opioid dependence provided their informed consent for participation in this study. After an overnight fast, a challenge dose of cocaine (30 mg i.v.) or placebo was administered under single-blind conditions in a randomized order on 2 study days. Blood samples were collected at 2-min intervals for 76 min during base line and for an additional 76 min after i.v. administration of the challenge dose. Peak plasma cocaine levels of 313.8 +/- 46.5 ng/ml were detected within 2 min after cocaine administration. The cluster analysis program originally described by Veldhuis and Johnson (1986) was used to characterize ACTH pulsatile secretion (Iranmanesh et al., 1990). Acute cocaine administration (30 mg i.v.) significantly increased ACTH mean peak amplitude (P < .05), mean percent increase in peak amplitude, (P < .05), mean peak area (P < .04), total peak area (P < .04) and incremental peak height (P < .04). Mean ACTH valley levels (P < .02) and mean valley nadir (P < .02) were also significantly increased after cocaine administration. We postulate that cocaine stimulates the release of corticotropin releasing factor and that the cocaine-induced secretion of corticotropin releasing factor increases the amplitude of ACTH pulses, because ACTH pulse frequency was not altered by cocaine.

Parallel increases in sister-chromatid exchanges at base level and with UV treatment in human opiate users.

The SCE base level frequency and SCE levels induced by far-UV (254 nm) treatment of cells in early G1 and early S phases of the cell cycle were significantly higher in leukocytes from heroin addicts as compared to controls. The increased SCE levels in addicts was greatest at base level and smallest after UV irradiation of cells in S phase. These results corroborate and extend our previous findings of increased chromosome damage and reduced DNA-repair synthesis in heroin users. Since opiates do not directly damage DNA, the elevated cytogenetic effects associated with opiate use probably arise from secondary promotional effects related to opiate-mediated alterations in leukocyte metabolism.

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.

Operant analysis of human heroin self-administration and the effects of naltrexone.

The effects of maintenance on a narcotic antagonist, naltrexone (50 mg/day p.o.), or placebo on patterns of operant acquisition and use of heroin were studied under double-blind conditions. Twelve male heroin addict volunteers lived on a clinical research ward for 34 days. After a 9 day drug-free period, naltrexone or placebo were given and heroin) 40 mg/day) was available for 10 days. Subjects could earn money ($1.50) or heroin (10 mg i.v.) by responding on a second-order schedule of reinforcement [FR 300 (FI 1 sec: S)] for approximately 90 min. The three naltrexone-maintained subjects took only 2 to 7.5% of the total heroin available. Two naltrexone subjects stopped heroin self-administration after the 1st or 2nd heroin injection; the third subject took a 3rd heroin injection on the 8th day of heroin availability. Naltrexone maintenance for 25 consecutive days did not produce adverse side effects. In contrast, the nine placebo naltrexone subjects used 57.5 to 100% of the total heroin available. Five placebo subjects used all or all but one of the 40 injections available; four placebo subjects often used less heroin than was available each day. Heroin intoxication did not impair operant performance. Heroin users worked longer hours and earned more purchase points (P < .05) during heroin self-administration and subsequent methadone detoxification than during the drug-free period. Subjects precisely titrated operant work to acquire the desired amount of heroin, then resumed working for money. These data demonstrate the feasibility of using direct measures of drug self-administration behavior to evaluate new pharmacotherapies for heroin abuse and indicate the effectiveness of naltrexone in suppressing heroin self-administration.

Alteration of T and null lymphocyte frequencies in the peripheral blood of human opiate addicts: in vivo evidence for opiate receptor sites on T lymphocytes.

Street opiate addiction produces a significant depression in the absolute number of total T lymphocytes in peripheral blood as measured by the ability of the lymphocytes to rosette sheep red blood cells (SRBC). Associated with the decrease in T cells, there is an increase in the absolute number of null lymphocytes but no significant changes in B lymphocytes or total white blood cell count. The T cell values for 2 different populations of addicts (n = 12 and 32) are 31.8% and 23.1%, whereas the null cell values are 51.1% and 57.6%, respectively. The values for comparable control populations (n = 18 and 10) are: T% = 70.7% and 67.4%, and null % = 9.2% and 14.5%. Self-reported use of marihuana does not significantly alter the distribution of cell populations. A 1- to 3-hr incubation of addicted-derived lymphocytes with 10(-6) to 10(-7) M Naloxone reverses both T cell depression and null cell increase by allowing the null cells to express SRBC receptors. Cyclic AMP and dibutyryl cyclic AMP can also convert the null cells to T cells. The conversion of null to T lymphocytes has additionally been measured by monitoring the increase in PHA-stimulated growth in 72-hr cultures as determined by tritiated thymidine incorporation into DNA. These results support the hypothesis that opiates can alter T lymphocyte number and function in vivo, and that this alteration may produce a significant degeneration in the immune competence of street opiate addicts.

Heroin and naltrexone effects on pituitary-gonadal hormones in man: interaction of steroid feedback effects, tolerance and supersensitivity.

The acute and chronic effects of heroin, and the opiate antagonist naltrexone, on integrated plasma samples analyzed for luteinizing hormone (LH) and testosterone (T) levels were studied in six adult males with a history of heroin addiction. Acute doses of heroin (10 mg i.v.) significantly suppressed LH levels. Chronic heroin use was also associated with a significant decrease in plasma T levels. LH levels after chronic heroin use were lower than control levels but the degree of LH suppression was approximately the same as after the acute doses of heroin. Acute naltrexone administration did not alter T levels appreciably but was associated with a significant elevation in LH levels. After 22 days of chronic naltrexone maintenance, T levels were in the high normal range and LH levels were in the low normal range. These data suggest the development of tolerance and supersensitivity to opiate agonist and antagonist effects on pituitary-gonadal hormones involves interaction between the direct effects of these drugs on LH followed by steroid feedback effects of T on gonadotrophin secretory activity.

Effect of alcohol and marihuana on tobacco smoking.

Tobacco smoking covaried with alcohol consumption in male social drinkers over 15 days of unrestricted alcohol availability. Increased tobacco smoking was associated with alcohol consumption in occasional, moderate, and heavy smokers. Tobacco smoking was not systematically related to marihuana smoking even though both drugs were often smoked at the same time. During ten days of concurrent access to tobacco, alcohol, and marihuana, tobacco smoking continued to covary with alcohol consumption rather than with marihuana smoking. Marihuana smoking appeared to be independent of alcohol consumption patterns.

Effect of acute ethanol ingestion on integrated plasma prolactin levels in normal men.

Healthy male subjects ingested 1.0 g ethanol/kg (Alcohol Day) and caloric equivalents of sucrose (Control Day). Plasma prolactin was determined on samples collected at 20-min intervals by serial constant blood exfusion, from 2 hr before to 4 hr after the drink. In 14 of the 15 men studied, plasma prolactin levels during the 2-hr period after alcohol administration were elevated an average of 31% above values for the preceding 2-hr period. Data pooled for all subjects revealed a small but statistically significant increase in prolactin coinciding with ascending and peak concentrations of blood alcohol. A significant increment in prolactin was associated with peak blood alcohol levels when values were compared between control and alcohol treatment days. Although of statistical significance, these transient and variable increases were within the normal range of basal prolactin levels for most subjects and are unlikely to be physiologically meaningful.

Effects of heroin self-administration on cigarette smoking.

Cigarette smoking increased during heroin self-administration in comparison to drug-free and methadone detoxification conditions in eight heroin addicts given naltrexone placebo (P less than 0.01) and three heroin addicts given buprenorphine placebo. Cigarette smoking was stable across conditions for one subject who did not use heroin during naltrexone blockade of heroin effects. Five subjects smoked significantly more (P less than 0.01) during the hour following a heroin injection than during the preceding hour, and two subjects in the same group smoked significantly less following a heroin injection (P less than 0.05). Subjects smoked significantly more during the evening and night when self-administering heroin than during baseline conditions (P less than 0.05), but subjects did not sleep significantly less during heroin self-administration. The peak of the intercigarette interval distribution remained between 16-30 min during baseline and heroin conditions. However, the increased smoking during heroin use appeared to reflect a higher rate of smoking rather than a generalized increase across intercigarette intervals. These data extend previous findings, that alcohol consumption is associated with increased cigarette smoking, to IV heroin self-administration.

Effects of heroin and naltrexone on plasma prolactin levels in man.

Plasma levels of prolactin were increased following intravenous self-administration of heroin by young men with a history of heroin addiction. Following 10 days of controlled heroin usage, tolerance could be demonstrated to the acute prolactin-releasing effect of heroin. There was no evidence that a single dose of naltrexone affected basal prolactin levels.

Effects of chronic marihuana use on integrated plasma testosterone and luteinizing hormone levels.

Integrated plasma testosterone and luteinizing hormone levels were determined for 13 healthy adult males before, during and after a 21-day period of marihuana use. No significant relationships were found between antecedent or concurrent marihuana smoking and integrated plasma testosterone and luteinizing hormone levels. All values for all subjects obtained during the entire study were within normal limits for healthy adult males.

Social effects of marijuana use in a recreational setting.

Adult male volunteers with a prior history of either moderate (N = 12) or heavy (N = 14) marijuana use were systematically observed before, during, and after a 21-day period of free access to marijuana cigarettes. Data relevant to social interaction and recreational preferences were collected at hourly intervals. Moderate users consumed an average of 2.6 cigarettes per day and showed both acute and persistent (21-day) decrements in social interaction. Heavy users consumed 5.7 cigarettes per day but indicated fewer social reactions. The results suggested that marijuana inhibits social interaction in moderate users but behavioral tolerance in heavy users may mitigate this effect.

Marihuana and mood in human volunteers.

Fifteen adult male marihuana smokers volunteered to live on a hospital research ward for a 31-day study which included a five-day baseline, a 21-day marihuana smoking period and a concluding five-day baseline. Subjects rated their moods and level of intoxication each day at scheduled occasions. Analyses of variance indicated a significant trend in the mood ratings which increased slightly in the euphoric direction just before smoking marihuana (compared to routine ratings) and further increased slightly after smoking marihuana. Level of intoxication ratings and mood ratings were not significantly correlated, but an intoxicated subject's mood ratings were significantly correlated with the average mood ratings of other subjects intoxicated or not. The results suggest that marihuana may increase a person's susceptibility to the moods of others and the feeling of being in harmony with others may be a positive reinforcer.