Elena M. Kouri

Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers

Gender differences after acute cocaine administration have received little attention in spite of the fact that males and females respond differently to many drugs. Seven male and seven female occasional cocaine users received both an intranasal dose of cocaine hydrochloride (0.9 mg/kg) and placebo powder in a randomized order and reported subjective effects via an instrumental joystick device and various questionnaires. Blood samples were withdrawn at 5-min intervals to assess pharmacokinetic differences. Male subjects achieved the highest peak plasma cocaine levels (144.4 ± 17.5 ng/ml), detected cocaine effects significantly faster than females and also experienced a greater number of episodes of intense good and bad effects. Women studied during the follicular phase of their menstrual cycle had peak plasma cocaine levels of 73.2 ± 9.9 ng/ml, which was significantly higher than when they were studied during their luteal phase (54.7 ± 8.7 ng/ml), but there were no differences in their subjective reports of cocaine effects. In spite of the different cocaine blood levels and subjective effects, peak heart rate increases did not differ between males and females suggesting that women may be more sensitive than males to the cardiovascular effects of cocaine. These data suggest that there are significant gender and menstrual cycle differences in the response to acute intranasal cocaine administration and these differences may have implications for the differential abuse of this 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.

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.

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. Methods: 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.

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.

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.

Racial Differences in Definitive Breast Cancer Therapy in Older Women: Are They Explained by the Hospitals where Patients Undergo Surgery?

Background:Prior research has documented racial disparities in patterns of care and outcomes for women with breast cancer. Objectives:To assess whether black women receive care from lower-quality or lower-volume hospitals and if such differences explain disparities in receipt of definitive primary breast cancer therapy. Research Design:Observational study of a population-based sample of breast cancer patients included in the SEER-Medicare database. Subjects:Fifty five thousand four hundred seventy white or black women aged >65 diagnosed with stage I/II breast cancer during 1992–2002. Measures:Surgery at a high-quality hospital (top quartile rates of radiation after breast-conserving surgery) or high volume (top quartile) hospital and receipt of definitive primary therapy (mastectomy or breast-conserving surgery with radiation). Results:Black women were significantly less likely than white women to be treated at high-quality hospitals (adjusted odds ratio [OR] 0.60; 95% confidence interval [CI]: 0.40–0.87) but not high-volume hospitals (adjusted OR 0.85; 95% CI: 0.54–1.34). Black women were less likely than white women to receive definitive primary therapy, a finding partially explained by having surgery at a high-quality hospital but not by having surgery at a high-volume hospital. Conclusions:Older black women were more likely than white women to undergo breast cancer surgery at hospitals with lower rates of radiation following breast-conserving surgery, and this explains some of the reported racial disparities previously observed in receipt of definitive therapy for early-stage breast cancer. Interventions to help hospitals treating large numbers of black women improve rates of radiation after breast-conserving surgery may help to decrease racial disparities in care.

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 cocaines 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% delta 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.

Ethanol-induced alterations in EEG alpha activity and apparent source of the auditory P300 evoked response potential

The relationship among topographic brain electrical activity mapping, auditory-evoked response potentials (ERPs), plasma ethanol levels and subjective reports of intoxication was examined in 4 male volunteers. The source of the auditory P300 ERP (a measure of selective attention and memory encoding) was estimated using a recently developed computer program. The effect of ethanol on the P300 wave was studied using a standard oddball paradigm both with and without a concomitant divided attention task. Ethanol (0.7 g/kg) administration produced marked increases in EEG alpha activity during the ascending limb of the blood ethanol curve. Acute ethanol administration caused a delay in the latency and a reduction in the amplitude of the auditory P300 ERP. A similar effect on P300 topography was noted in waves that were affected by the tones while the subjects also listened to a story (divided attention). After ethanol, the source of the P300 wave appeared to have shifted to a position posterior and inferior to its original location. P300 ERPs generated during the divided attention task were also disrupted and shifted to positions inferior to their original. However, the variability of the dipole vector was much greater during the divided attention task than after ethanol administration. These data demonstrate that ethanols effects on cognitive processing skills may be similar to those produced when individuals experience distractions while concentrating on a task.