Effects of short-term citicoline treatment on acute cocaine intoxication and cardiovascular effects.

RATIONALE: The majority of pharmacotherapies proposed for cocaine dependence have been marginally effective and frequently have undesirable side effects. We recently demonstrated that short-term treatment with citicoline decreased self-reported desire to use cocaine in crack cocaine users. OBJECTIVE: The present study was conducted to assess the safety of citicoline in combination with cocaine by investigating whether cocaine-induced cardiovascular and behavioral effects and cocaine plasma levels are altered by citicoline pretreatment. METHODS: Eight healthy male and female volunteers who used cocaine on an occasional basis participated in this randomized, placebo-controlled, three-visit study. During all three visits, subjects received an acute intranasal dose of cocaine (0.9 mg/kg) and were continuously monitored for the ensuing 3.5 h. The first visit involved no pretreatment, and visits 2 and 3 were preceded by a 4-day pretreatment period of either citicoline (1 g/day) or placebo. RESULTS: Citicoline pretreatment did not alter the cardiovascular, physiologic, or subjective effects of acute cocaine. CONCLUSIONS: Although citicoline did not block the acute subjective effects of cocaine in a laboratory environment, the combined use of citicoline and a moderate dose of intranasal cocaine presented no added risk of cardiovascular effects. Further study is necessary to determine whether this medication (which is currently used to treat strokes) will be a useful adjunct to treat cocaine dependence.

Nicotine alters some of cocaine's subjective effects in the absence of physiological or pharmacokinetic changes.

Tobacco smoking and cocaine use often co-occurs and the frequency of smoking has been positively correlated with the likelihood of cocaine use. In addition, nicotine pretreatment has been shown to increase the rate of cocaine self-administration in rats and to enhance cue-induced cocaine craving in humans. The present study was conducted to investigate whether nicotine pretreatment via a transdermal patch alters the behavioral, physiological, and pharmacokinetic effects of an acute dose of cocaine in nondependent human volunteers. Seven male tobacco smokers who used cocaine occasionally provided informed consent and participated in this placebo-controlled, four-visit study. Following pretreatment with a transdermal nicotine patch (placebo, 14 mg), subjects were challenged with an acute dose of intranasal cocaine (placebo, 0.9 mg/kg). Nicotine pretreatment attenuated cocaine-induced increases in reports of "high" and "stimulated" and increased the latency to detect cocaine effects and cocaine-induced euphoria. Nicotine did not alter cocaine's effects on heart rate, skin temperature, and blood pressure or plasma cocaine, benzoylecgonine (BE), or ecgonine methylester (EME) concentrations. Our findings indicate that nicotine pretreatment alters some of the positive subjective effects of cocaine in humans without affecting cocaine's effects on physiologic responses or pharmacokinetic profiles.

Impact of family history of alcoholism on cocaine-induced subjective effects and pharmacokinetic profile.

RATIONALE: The importance of genetic factors in the development of alcoholism has been demonstrated repeatedly. However, the impact of a family history of alcoholism on the development of other drug use has been less thoroughly studied. OBJECTIVE: The present study was conducted to investigate whether individuals with a positive family history of alcoholism (FHP) differ from individuals without a history (FHN) in their pharmacokinetic profile, subjective and physiological response to an acute intranasal dose of cocaine (0.9 mg/kg). METHODS: Nine FHP and nine FHN male occasional cocaine users provided informed consent and participated in this double-blind, placebo-controlled, two-visit study. Responses to cocaine were assessed via a joystick device, the Addiction Research Center Inventory, visual analog scales and heart rate. Plasma concentrations of cocaine and its metabolites, benzoylecgonine and ecgonine methylester also were measured. RESULTS: There were no significant differences between FHP and FHN subjects in subjective reports of intoxication, physiologic responses or plasma cocaine and benzoylecgonine concentrations following cocaine administration. Plasma levels of the cocaine metabolite ecgonine methylester were significantly higher in FHP subjects from 50 to 120 min post-cocaine administration compared to FHN subjects. CONCLUSIONS: Our findings indicate that family history of alcoholism does not appear to influence the behavioral and physiological responses to acute cocaine administration, but that some aspects of cocaine metabolism may be different between the two groups.

Abstinence symptoms during withdrawal from chronic marijuana use.

Although marijuana is the most commonly used illicit drug in the United States, it is not established whether withdrawal from chronic use results in a clinically significant abstinence syndrome. The present study was conducted to characterize symptoms associated with marijuana withdrawal following chronic use during a supervised 28-day abstinence period. Three groups of participants were studied: (a) current chronic marijuana users, (b) former chronic marijuana users who had not used marijuana for at least 6 months prior to the study, and (c) marijuana nonusers. Current users experienced significant increases in anxiety, irritability, physical tension, and physical symptoms and decreases in mood and appetite during marijuana withdrawal. These symptoms were most pronounced during the initial 10 days of abstinence, but some were present for the entire 28-day withdrawal period. These findings support the notion of a marijuana withdrawal syndrome in humans.

Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial.

BACKGROUND: Field studies of illicit anabolic-androgenic steroid users suggest that some develop manic or aggressive reactions to these drugs-a potential public health problem. However, controlled laboratory evaluations of these effects remain limited. METHODS: In a randomized, placebo-controlled, crossover trial, we administered testosterone cypionate for 6 weeks in doses rising to 600 mg/wk and placebo for 6 weeks, separated by 6 weeks of no treatment, to 56 men aged 20 to 50 years. Psychiatric outcome measures included the Young Mania Rating Scale (YMRS), the Point Subtraction Aggression Paradigm (a computerized provocation test of aggression), the Aggression Questionnaire of Buss and Perry, the Symptom Checklist-90-R, daily diaries of manic and depressive symptoms, and similar weekly diaries completed by a "significant other" who knew the participant well. RESULTS: Testosterone treatment significantly increased manic scores on the YMRS (P = .002), manic scores on daily diaries (P = .003), visual analog ratings of liking the drug effect (P = .008), and aggressive responses on the Point Subtraction Aggression Paradigm (P = .03). Drug response was highly variable: of 50 participants who received 600 mg/wk of testosterone cypionate, 42 (84%) exhibited minimal psychiatric effects (maximum YMRS score, <10), 6 (12%) became mildly hypomanic (YMRS score, 10-19), and 2 (4%) became markedly hypomanic (YMRS score, > or =20). The 8 "responders" and 42 "nonresponders" did not differ significantly on baseline demographic, psychological, laboratory, or physiological measures. CONCLUSIONS: Testosterone administration, 600 mg/wk increased ratings of manic symptoms in normal men. This effect, however, was not uniform across individuals; most showed little psychological change, whereas a few developed prominent effects. The mechanism of these variable reactions remains unclear.

Changes in aggressive behavior during withdrawal from long-term marijuana use.

RATIONALE: Even though marijuana is the most commonly abused illicit drug in the United States, it is still undetermined whether withdrawal after chronic use results in changes in aggressive behavior in humans. OBJECTIVE: The present study investigated the pattern and duration of changes in aggressive behavior in long-term marijuana users during a 28-day abstinence period verified by daily urines. METHOD: Chronic marijuana users who had smoked marijuana on at least 5000 occasions (the equivalent of smoking daily for approximately 14 years) and who were smoking regularly when recruited were studied on days 0 (when they were still smoking), 1 (during acute withdrawal), 3, 7 and 28 of a 28-day detoxification period. Aggressive behavior was measured using the Point Subtraction Aggression Paradigm. RESULTS: Compared to controls and to the pre-withdrawal data, chronic marijuana users displayed more aggressive behavior on days 3 and 7 of marijuana abstinence. These increases in aggressive responding returned to pre-withdrawal levels after 28 days and were paralleled by small, non-significant changes in depression and anxiety scores. CONCLUSIONS: Our findings confirm previous reports of an abstinence syndrome associated with chronic marijuana use and suggest that aggressive behavior should be an additional component of this syndrome.

Effects of alcohol and other drugs in women of reproductive age: hormonal interactions.

Neuroendocrine control of the menstrual cycle is very complex, and the pulsatile hormonal secretory patterns characteristic of the follicular, ovulatory and luteal phases can interact, under certain conditions, with alcohol and other drugs to modulate their effects. The presence of the premenstrual syndrome, with its characteristic symptoms of depression and anxiety, appears to be a critical factor in determining whether alcohol and drug use patterns increase during the premenstruum.

Hormonal treatments for premenstrual syndrome.

Ovarian function appears to play a fundamental role in premenstrual syndrome (PMS). Accordingly, treatment strategies designed to suppress ovulation have generally been found to be effective for treatment of menstrually related syndromes and symptoms. GnRH agonists and Danazol(R) are probably inferior to estrogen, due to their unfavorable side effects profile. In addition, it is worthwhile to emphasize that in spite of the publicity of progesterone treatment for PMS, in most well-controlled studies it has not been shown to be more effective than placebo for the treatment of these syndromes. The efficacy of hormonal treatments that do not suppress ovulation is still controversial.

Psychotropic effects of hormonal replacement therapy.

Estrogens have been shown to have a positive effect on mood and cognition. The effect on mood is probably by modulation of other processes, but estrogen probably is not an effective antidepressant when given alone. The effect on cognitive function is mostly favorable and direct, but might vary according to the specific task involved. Some progestins counteract the effects of estrogen and especially when administered in a sequential dosing might cause dysphoria. The mood effects of mixed estrogen-like compounds are not yet established. It may be predicted that eventually the cognitive effects of estrogen replacement therapy for postmenopausal women will be recognized as an additional indication for that hormone.

Drug use history and criminal behavior among 133 incarcerated men.

The present study investigated the relationship between crime and substance abuse in a sample of 133 consecutively evaluated male prisoners. Using the Structured Clinical Interview for DSM-III-R, we assessed the prevalence of various forms of substance abuse in this population and attempted to judge whether substance abuse played a role in the index crime which has led to the present incarceration. In addition, we assessed whether there was a relationship between the nature of substance dependence and the type of crime committed, whether sexual, violent, or non-violent. Among the 133 prisoners, 95% obtained a diagnosis of dependence on one or more substances. Fifty-eight percent of the inmates reported that they were acutely intoxicated with one or more substances at the time they committed the index crime and an additional 6% were withdrawing from a substance at the time of the crime. There was no significant correlation between the type of substance abuse diagnosis and the type of crime committed. Similarly, there was no significant correlation between the number of individuals who reported they were intoxicated at the time of the offense and the type of crime committed.

State and trait serotonergic abnormalities in women with dysphoric premenstrual syndromes.

Three to eight percent of women of reproductive age suffer from dysphoric premenstrual disorder (PMS). Although the exact pathophysiology of this disorder is not known, serotonergic dysregulation appears to be involved. In this article, we review and summarize the current data on changes in serotonergic parameters in women with dysphoric PMS and emphasize the distinction between state-related abnormalities which are present only during the symptomatic late-luteal phase and trait abnormalities which are present even during non-symptomatic phases of the menstrual cycle. The notion of diversified serotonergic systems that are selectively affected by fluctuations in gonadal hormones is discussed in the context of PMS as well as other dysphorias.

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.

Anabolic-androgenic steroid use among 133 prisoners.

We performed a forensic evaluation of a 16-year-old boy convicted of murdering his 14-year-old girlfriend while he was taking anabolic steroids. Prior to steroid use, he had displayed no features of antisocial personality disorder and no criminal record. Prompted by this index case, we interviewed 133 consecutive male convicts at the same facility where this boy was incarcerated to assess whether steroid use frequently contributed to criminal acts. Two other cases of apparent steroid-induced crimes were found in this cohort, suggesting that steroid use is an uncommon, though occasionally significant, factor in criminal behavior.

Changes in lipoprotein-lipid levels in normal men following administration of increasing doses of testosterone cypionate.

OBJECTIVE: The objective of this study was to examine the relationship between anabolic--androgenic steroids and lipoprotein levels in men receiving weekly injections of gradually escalating doses of up to 600 mg/week of testosterone cypionate. DESIGN: The design was a placebo-controlled, double-blind, 24-week cross-over design in which subjects were randomized to one of two treatment sequences: (a) weekly testosterone cypionate injections for 6 weeks, no treatment for 6 weeks, weekly placebo injections for 6 weeks, and then again no treatment for 6 weeks; or (b) placebo, no treatment, testosterone, and then no treatment, with each interval also lasting 6 weeks as in the first sequence. SETTING: The setting was a private hospital. PARTICIPANTS: Participants were normal male volunteers. INTERVENTIONS: Testosterone cypionate injections were given in gradually increasing doses of 150 mg/week for 2 weeks, 300 mg/week for 2 weeks, and 600 mg/week for 2 weeks. Eight subjects received testosterone injections during the first injection phase and placebo during the second injection phase, and the remaining eight subjects received placebo first and testosterone second. RESULTS: We found a 21% depression of high-density lipoprotein cholesterol (HDL-C) levels following the first 300-mg testosterone dose. This depression remained unchanged after the two 600-mg doses. In contrast, we did not find any changes in low-density lipoprotein or total cholesterol levels at any of the time points studied. Subjects' total cholesterol/HDL-C ratios were significantly elevated during testosterone administration and even 4 weeks following the last injection. CONCLUSION: Our findings suggest that testosterone cypionate adversely affects cholesterol fractions, that this effect reaches its full magnitude even at very modestly supraphysiologic doses, and that this effect persists for several weeks after discontinuation of the drug.

Increased aggressive responding in male volunteers following the administration of gradually increasing doses of testosterone cypionate.

The present study assessed the effects of supraphysiologic doses of testosterone on aggressive responding in a controlled laboratory setting. Eight male subjects received gradually increasing doses of testosterone cypionate (150 mg/week for two weeks, 300 mg/week for two weeks, and 600 mg/week for two weeks) or placebo using a double-blind, randomized, cross-over design. Subjects were tested both before and after the series of injections. During the experimental session subjects could press a button to accumulate points exchangeable for money (non-aggressive response) or press another button to subtract points from a fictitious opponent (aggressive response). Aggressive responding was instigated by subtracting points from the subject which was attributable to the fictitious opponent. Testosterone administration resulted in a significantly higher number of aggressive responding compared to placebo.

Fat-free mass index in users and nonusers of anabolic-androgenic steroids.

We calculated fat-free mass index (FFMI) in a sample of 157 male athletes, comprising 83 users of anabolic-androgenic steroids and 74 nonusers. FFMI is defined by the formula (fat-free body mass in kg) x (height in meters)-2. We then added a slight correction of 6.3 x (1.80 m - height) to normalize these values to the height of a 1.8-m man. The normalized FFMI values of athletes who had not used steroids extended up to a well-defined limit of 25.0. Similarly, a sample of 20 Mr. America winners from the presteroid era (1939-1959), for whom we estimated the normalized FFMI, had a mean FFMI of 25.4. By contrast, the FFMI of many of the steroid users in our sample easily exceeded 25.0, and that of some even exceeded 30. Thus, although these findings must be regarded as preliminary, it appears that FFMI may represent a useful initial measure to screen for possible steroid abuse, especially in athletic, medical, or forensic situations in which individuals may attempt to deny such behavior.

Determination of chromium and caesium in human cataractous lenses.

The concentration of chromium and caesium in totally opaque (mature) cataractous lenses has been determined by instrumental neutron activation analysis and gamma spectrometry. The presence of these trace-elements in the human lens has to our knowledge not been investigated so far. Both elements under study are of known biological importance. Chromium is an essential trace-element necessary for the maintenance of normal glucose metabolism. Moreover it is considered to rank among those elements, the increased level of which contributes to environmental pollution. Caesium is a biologically important trace-element due to its relationship with potassium, as has been demonstrated in a variety of biochemical and physiological processes. The concentration of these elements was determined in cataractous lenses from fifty-one patients with senile cataract and has been correlated with age and sex.