Richard A. Nelson

Imaging brain mu-opioid receptors in abstinent cocaine users: Time course and relation to cocaine craving

BACKGROUND Cocaine treatment upregulates brain mu-opioid receptors (mOR) in animals. Human data regarding this phenomenon are limited. We previously used positron emission tomography (PET) with [11C]-carfentanil to show increased mOR binding in brain regions of 10 cocaine-dependent men after 1 and 28 days of abstinence. METHODS Regional brain mOR binding potential (BP) was measured with [11C]carfentanil PET scanning in 17 cocaine users over 12 weeks of abstinence on a research ward and in 16 healthy control subjects. RESULTS Mu-opioid receptor BP was increased in the frontal, anterior cingulate, and lateral temporal cortex after 1 day of abstinence. Mu-opioid receptor BP remained elevated in the first two regions after 1 week and in the anterior cingulate and anterior frontal cortex after 12 weeks. Increased binding in some regions at 1 day and 1 week was positively correlated with self-reported cocaine craving. Mu-opioid receptor BP was significantly correlated with percentage of days with cocaine use and amount of cocaine used per day of use during the 2 weeks before admission and with urine benzoylecgonine concentration at the first PET scan. CONCLUSIONS These results suggest that chronic cocaine use influences endogenous opioid systems in the human brain and might explain mechanisms of cocaine craving and reinforcement.

Pharmacodynamic effects of new de-nicotinized cigarettes

The effects of cigarette smoking result from the delivery of nicotine, other components of smoke, and sensory stimulation. In the present study, pharmacological effects of new tobacco-derived de-nicotinized cigarettes (controls) were compared with standard cigarettes. The de-nicotinized cigarettes had the appearance, draw and taste of standard cigarettes but contained and delivered virtually no nicotine (< 0.06 mg), but delivered tar and carbon monoxide (CO). They were compared with cigarettes that delivered nicotine, CO and tar. Subjects (n = 20: 10 men, 10 women) participated in four experimental sessions in which they smoked either a standard cigarette or a de-nicotinized cigarette after either 3 or 12 h of tobacco deprivation. Heart rate, blood pressure, and EEG were recorded before, and for 1 h after, ad lib smoking. Plasma nicotine concentrations verified that de-nicotinized cigarettes did not deliver nicotine. The de-nicotinized cigarettes did not increase heart rate or activate the EEG. The subjects preferred the cigarettes that delivered nicotine compared to the de-nicotinized cigarettes. However, both types of cigarettes reduced subjective measures of tobacco craving and withdrawal. These data extend previous research that suggested the process of smoking and components of tobacco smoke other than nicotine mediate some effects of cigarette smoking. The de-nicotinized cigarettes may prove useful in evaluating effects of smoking independent of the delivery of nicotine.

Pharmacokinetics and pharmacodynamics of moist snuff in humans

INTERVENTION Four brands of moist snuff and a non-tobacco mint snuff were tested. Subjects reported to the laboratory for five experimental sessions. After baseline measurement of dependent variables, each subject placed 2 g of one of the brands of snuff (or one Skoal Bandits pouch) between the cheek and gum for 30 minutes. The subjects remained in the experimental laboratory for an additional 60 minutes. SUBJECTS Ten volunteers who were daily users of smokeless tobacco. MAIN OUTCOME MEASURES Plasma nicotine concentration, cardiovascular effects, and subjective effects. RESULTS Large amounts of nicotine were delivered rapidly to the bloodstream. The amount of nicotine absorbed and the rate of absorption were related to the pH of the snuff product in aqueous suspension. Cardiovascular and subjective effects were related to the amount of nicotine absorbed. CONCLUSIONS Snuff products are capable of rapidly delivering high doses of nicotine, which can lead to dependence. Long-term use of snuff can lead to a number of adverse health effects including oral cancers, cardiovascular diseases, and gingival diseases. For these reasons, it is important that the public health community considers oral snuff use as a burden on public health in the same way that cigarette smoking is recognised.

The regulation of cerebral blood flow during intravenous cocaine administration in cocaine abusers.

ABSTRACT: Cocaine abuse is associated with heightened risk of life‐threatening neurological complications such as strokes, seizures, and transient ischemic attacks. We used transcranial Doppler (TCD) sonography, a continuous measure of cerebral blood flow velocity, to better understand the changes in cerebral hemodynamics produced by cocaine administration, which may lead to an increased risk for stroke in cocaine abusers. Heart rate and blood pressure were also measured. Blood flow velocity of seven cocaine abusers was studied during placebo, 10‐, 25‐, and 50‐mg intravenous (i.v.) injections of cocaine. A significant increase in mean and systolic velocity which lasted for about two minutes was observed with all doses of cocaine, with no change in the placebo condition. This increase in systolic velocity indicates that cocaine produces an immediate and brief period of vasoconstriction in large arteries of the brain. The present results elucidate the time course of cocaines acute cerebrovascular effects and provide a better understanding of etiology of cocaine‐related stroke and transient ischemic attacks.

Effects of cigarette smoking through a partially occluded filter

The effects of a commercially available corn syrup solution that is applied to the filter end of a cigarette causing an occlusive barrier to cigarette smoke were evaluated. The manufacturer claims that the solution reduces exposure to nicotine, carbon monoxide (CO), and other constituents of tobacco smoke and may aid in smoking cessation by providing a means of gradual nicotine dose reduction. Nineteen volunteers (10 men) smoked commercial cigarettes treated with 0, 1, 2, or 3 drops of the corn syrup solution in a double-blind, crossover experiment. Increases in plasma nicotine after smoking averaged 13.3, 10.5, 9.7, and 6.0 ng/ml in the 0, 1, 2, and 3 drop conditions, respectively. In the 3 drop condition, there was a significant reduction in exhaled CO levels. Subjects reported increased difficulty in cigarette draw and a trend toward decreased strength as a function of the number of drops applied. Cardiovascular and EEG measures of smoking were not significantly affected by the application of the drops. Cigarettes treated with 0, 1, 2, or 3 drops of the solution were machine smoked using methods of the Federal Trade Commission (FTC); nicotine yields were 1.0, 1.0, 0.78, and 0.73 mg of nicotine. These results indicate that Take Out drops reduce exposure to nicotine and other constituents of tobacco smoke from a single cigarette.

Exercise stress testing in recently abstinent chronic cocaine abusers

We compared treadmill exercise stress testing (EST) in 28 medically screened, chronic cocaine users with the cardiovascular effects of an IV cocaine challenge (25 mg or 50 mg). All subjects had a clinically normal EST and echocardiography (except 2 subjects had septal wall hypokinesis). The EST produced significantly greater increases in heart rate and rate-pressure product than did the cocaine challenges. These findings suggest that EST may not provide additional diagnostic information in medically screened cocaine users. EST may cause more cardiac work (indicated by heart rate and blood pressure) than intravenous cocaine (at the doses in this study).

Signal-averaged electrocardiogram in physically healthy, recently abstinent chronic cocaine users.

Objectives:Cocaine use is associated with cardiac arrhythmias. Markers of ventricular late potentials, which may be a precursor to malignant ventricular arrhythmias, can be detected by signal-averaged electrocardiography (SA-ECG) but not by standard ECG. Methods:We evaluated SA-ECG parameters in 60 medically screened, physically healthy, recently abstinent cocaine users (53 males, mean [SD] age, 34.0 [4.6] years; 10.1 [6.0] years of use) and 54 nondrug-using controls (21 males, mean [SD] age 28.4 [7.8] years). SA-ECGs were done periodically for ≤12 weeks of monitored abstinence in 25 cocaine users. We analyzed 3 SA-ECG parameters considered markers of ventricular late potentials: duration of filtered QRS complex, duration of low-amplitude potentials during terminal 40 ms of QRS complex (LAS40), and root mean square voltage during terminal 40 ms of QRS complex (RMS40). Results:Cocaine users differed significantly from controls in filtered QRS complex (118.5 [11.2] ms versus 111.9 [11.4] ms; P = 0.03) but not in LAS40 (28.9 [8.2] ms versus 30.8 [8.3] ms; P = 0.40) or RMS40 (40.0 [19.8] &mgr;V versus 30.2 [20.1] &mgr;V; P = 0.06) values. The proportion of subjects with abnormal SA-ECG parameters did not differ significantly between male cocaine users and male controls. There were no significant changes over time in either the mean values or proportion of subjects with abnormal values for any SA-ECG parameter. There were significant gender differences among controls but not among cocaine users. Conclusion:These findings suggest that chronic cocaine use is not associated with a higher prevalence of abnormal SA-ECG parameters in physically healthy users.