The drug dilemma: manipulating the demand.

Drug abuse in the United States has posed a dilemma during most of this century. Intemperate use of reinforcing drugs is hazardous to health and safety, but strict prohibition fosters an illicit market with criminal effects that may be equally harmful. The crux of the problem is the willingness of millions of people to risk toxicity and arrest to gain psychopharmacological rewards. Cocaine is the present source of most concern. Recommendations for reducing demand and abuse are given, including the implementation of preventive techniques, the investigation of various treatments, the use of modern chemical and electronic technology, and the development of new pharmacological alternatives.

Amnesic effects of small bilateral brain puncture in the mouse.

A small acute brain puncture produced retrograde amnesia in a passive avoidance learning situation in mice. If injury to the hippocampus was inflicted either immediately, 1 hour after the learning, or 1 hour before the learning, the animals showed a retention deficit; the degree of this deficit was related to the time interval. No effect of this injury was observed on retest performance when the animals were treated as long as 6 hours before or after the learning trial.

Deficits in passive avoidance and fear conditioning in mice with septal lesions.

By means of a simple activity measure, mice with lesions of the septal forebrain were tested for passive avoidance (response inhibition) and fear conditioning. In two separate experiments animals with septal lesions showed little or no conditioning, as evidenced by lack of suppression of activity during and following activitycontingent foot shock. Results support and extend thehypothesis that these deficits in passive avoidance derive from the removal of normal inhibitory influences mediated by the septal area.

Long temporal gradient of retrograde amnesia for a well-discriminated stimulus.

This experiment tested the general validity of recent findings that retrograde amnesia can be produced by electroconvulsive shock only if the shock is administered within 10 to 30 seconds after the learning trial. Precautions were taken to avoid confusion of other shock effects with retrograde amnesia. A temporal gradient of elec- troconvulsive shock-produced retrograde amnesia, extending up to at least 1 hour, for a well-discriminated stimulus, was demonstrated in mice in a one-trial learning passive avoidance situation.

Memory: modification of anisomycin-induced amnesia by stimulants and depressants.

Mice were trained in a passive (foot shock)avoidance task. When administered after training, the stimulants caffeine or nicotine blocked amnesia for the task that had been produced by injections of the protein synthesis inhibitor anisomycin given prior to training. With foot shock at a higher intensity, anisomycin did not produce amnesia by itself, but the administration of the depressants chloral hydrate or sodium phenobarbital after training did cause amnesia. Stimulants and depressants did not have an appreciable influence on the overall degree of protein synthesis inhibition produced by anisomycin. The results support the hypothesis that arousal after training is an important factor in the conversion of short-term to long-term memory.

Memory functions in depression.

In an attempt to elucidate the memory deficit in depression, short-term memory and long-term memory were examined by means of a memory test battery in 26 hospitalized depressed patients. Their performance was compared with a matched control group and with the performance of those 20 patients who improved after 26 days of treatment with antidepressants. Results indicate that depressed patients show marked impairment in short-term memory without an impairment in long-term memory. The greater the improvement of the clinical state, the greater the improvement in short-term memory, whereas long-term memory was not influenced by the therapeutic success.

Physiological and psychological effects of methadone in man.

Methadone hydrochloride-maintenance outpatients were compared to abstinent exaddicts on physiological and psychological measures, and to normal subjects on physiological measures. The battery of psychological tests measure cognitive abilities and mental state. Methadone depressed respiration rate below other groups; abstinent subjects had higher heart rates than methadone or control subjects. No other physiological differences appeared. Electroencephalographic spectral analysis disclosed that the location of the alpha peak was at the lowest frequency in the methadone group, next lowest being the abstinent group. Discriminant functions based on a weighted combination of variables (frequencies) successfully distinguished the EEGs of the three groups. Both discriminant analysis and multiple regression analysis indicated that EEG changes were dose-dependent. Methadone subjects performed significantly poorer on several tests of learning and immediate recall compared to absitinent subjects.

Titration of nicotine intake with full-length and half-length cigarettes.

Titration, the self-regulation of nicotine intake, was studied in 12 smokers by gas chromatograph assays of urinary nicotine levels. Results demonstrated that excretion of urinary nicotine in the proximal condition (half cigarette close to the filter) did not differ significantly from the whole cigarette condition; however, less nicotine was excreted in the distal condition (half cigarette farther from the filter) because of a rod filtration effect. Subjects extracted proportionately more nicotine from the half than from the whole cigarettes; titration was approximately the same in both half-cigarette conditions. On scales of strength and satisfaction, full-length cigarettes were given the highest rating, followed by proximal and then distal cigarettes.

Reactions to cigarettes as a function of nicotine and "tar".

Experiments carried out to examine the effects of nicotine and "tar" on the extent of and subjective reactions to cigarette smoking. It was confirmed that smokers rate commercial, low-nicotine cigarettes as less "strong" and less "satisfying" than their usual brands. Since such cigarettes deliver reduced amounts of tar as well as of nicotine, an experiment to distinguish between the two was carried out with special cigarettes. Ratings of "strength" were directly related to nicotine but were not affected by tar. The numbers of cigarettes smoked fell slightly as their estimated delivery of nicotine increased, but tar had no effect on this index. The urinary excretion of nicotine was correlated with the rated yields of nicotine for the different cigarettes, but there was also evidence that subjects tended to adjust their manner of smoking so as to titrate their doses of nicotine. The results are interpreted as indicating a role for nicotine, but not for tar, in the maintenance of cigarette smoking behavior, and as support for the view that less harmful cigarettes should have a high yield of nicotine relative to tar.

Transdermal nicotine reduces cigarette craving and nicotine preference.

The effects of transdermal nicotine in 10 cigarette smokers were studied in a within-subjects, double-blind design. Either 8 mg nicotine base in a 30% aqueous solution or an inactive placebo solution was applied to intact skin under a polyethylene patch. Subjective reports of cigarette craving were collected every 30 minutes during a 90-minute smoking abstinence period. Immediately before and after this abstinence period subjects smoked through a smoke mixing device that allowed them to select their desired nicotine intake with each puff. Transdermal nicotine significantly increased saliva nicotine levels within 30 minutes after application. Cigarette craving was significantly lower in the nicotine condition than in the placebo condition. Nicotine preference during the initial puffs of the smoke mixer test at the end of 90 minutes of deprivation was also decreased by transdermal nicotine. In contrast, measures of cumulative smoke intake were not affected by the nicotine dose used. Our results suggest that transdermal nicotine may enhance success in smoking cessation by preventing the rise in cigarette craving usually observed after cessation. Transdermal nicotine may be preferable to other routes of nicotine administration because of the relative absence of adverse side effects.

Nicotine regulation and cigarette smoking.

A study was conducted to determine whether there is nicotine regulation in cigarette smoking. Tar levels, which often covary with nicotine manipulations, were controlled for by the use of nicotine in chewing gums. Nicotine in cigarettes was also used for preloading. High nicotine cigarette preloads were followed by longer latencies to the next cigarette than were the low nicotine cigarette preloads. High nicotine gum preloads were followed by less puffing on the subsequent cigarettes than were the low nicotine gum preloads.

Plasma nicotine and cotinine concentrations in habitual smokeless tobacco users.

Plasma nicotine and cotinine levels were measured in habitual users of smokeless tobacco. The subjects were 12 male college students who regularly used smokeless tobacco (11 dipped snuff and one chewed tobacco) and did not smoke cigarettes. Subjects abstained from tobacco use overnight and blood was drawn at 8 A.M. and again after a single day of ad libitum consumption of their own tobacco product. Subjects recorded the times at which tobacco was used and the remainder product was weighed. Plasma samples were analyzed by both gas-liquid chromatography (GLC) and radioimmunoassay (RIA) techniques. Subjects consumed about one third of a can of moist ground snuff (10.8 gm) in eight dips spaced throughout the day. Nicotine absorption was observed and an increase in mean plasma concentration fro 2.9 ng/ml after overnight abstinence to 21.6 ng/ml after 6 to 8 hr ad libitum consumption was recorded. Plasma cotinine concentrations rose from a morning mean of 137.3 ng/ml to an afternoon mean of 197.2 ng/ml, concentrations that are typical of those reached in regular cigarette smokers. Subjects fell into two subgroups by post hoc analysis: two-thirds absorbed substantial amounts of nicotine and one-third appeared to have almost no absorption. Subjective effects of tobacco use were not marked; there was little perception of physiologic changes, stimulation, or feelings of relaxation/satisfaction. Results are discussed in terms of pharmacologic effects, comparison of results from GLC and RIA methodologies, and implications for health behaviors.

Naltrexone: physiological and psychological effects of single doses.

An ascending series of single doses of the narcotic antagonist naltrexone, ranging from 20 to 160 mg, was administered to 8 abstinent former addicts in order to assess agonistic activity and any toxic side effects. There was little alteration of normal body function. Significant, but small, changes in sublingual temperature (0.4 degrees F decrease), and diastolic blood pressure (1.7 mm Hg increase) were induced. Among the battery of tests assessing behavioral or mood-feeling variables, only 2 showed significant between-condition effects: facilitated performance on the Cross-out Test (attention and perception), and a dose-related decrease in Morphine-Benzedrine Group (MBG) scores of the Addiction Research Center Inventory (ARCI) (mild euphoria). On the whole, subjects had few subjective reactions or unpleasant side effects. Naltrexone appears to be a safe, nontoxic medication in the dosage range examined.

Effects of cigarette smoking and oral nicotine on hand tremor.

The effect of nicotine on hand tremor was assessed by measuring the current induced in a coil by a magnet attached to the finger. Experiment 1 assessed the amplitude of tremor induced by smoking two cigarettes in a group of 33 subjects drawn from two age groups. Smoking increased tremor significantly. Age, sex, and anxiety levels had no effect. Experiment 2 assessed the effect of smoking on tremor frequency. Analog recordings of tremor in 10 subjects were processed to yield the total power in 20 1-Hz bands from 1 to 20 Hz. The log amplitude showed a strong linear relationship to the log frequency, but this relationship was not affected by smoking. Smoking also had no effect on peak frequency in the frequency spectrum. Experiment 3 confirmed that the effects of smoking on tremor were attributable to nicotine. Twelve subjects were tested before and after smoking a cigarette and before and after chewing gum containing 4 mg nicotine. The two conditions induced comparable increases in tremor. A 2-mg nicotine preparation tested in eight subjects had no effect on tremor. Tremor may be a useful index of the central activity of nicotine and may help illuminate its mechanism of action.

Degree of addiction and effectiveness of nicotine gum therapy for smoking.

In a double-blind trial, 48 smokers completed a nicotine tolerance questionnaire and then received nicotine gum or placebo during smoking cessation. Subjects given active gum were more likely to remain abstinent if their questionnaire responses indicated high nicotine dependence.

Effects of smoking on free recall and organization.

Habitual smokers smoked either nicotine-free cigarettes or cigarettes containing a known amount of nicotine and then engaged in a free-recall task. Nicotine subjects recalled significantly fewer words on a 75-item list during three successive trials of immediate recall than did nicotine-free subjects. Contrary to expectations, the superiority of the nonnicotine group persisted over two days. The two groups displayed comparable organizational activity (indexed by category clustering).

The use of nicotine gum during cessation of smoking.

The authors present three case studies which suggest that smoking withdrawal symptoms in certain individuals may be due to removal of nicotine per se, implying that smokers may develop a true physical dependence on cigarettes. Nicotine replacement by use of an experimental chewing gum containing nicotine in various dosages successfully prevented or alleviated the abstinence symptoms of the subjects studied.

Transdermal nicotine and smoking behavior in psychiatric patients.

The authors used a double-blind crossover design to observe the effect of transdermally administered nicotine on the smoking behavior of 13 psychiatric patients who were not trying to stop smoking. The patients smoked significantly fewer cigarettes while receiving nicotine than while receiving placebo. These data suggest that transdermally administered nicotine can be a useful adjunct in treating nicotine-addicted psychiatric patients in a non-smoking environment.

Mentholated cigarette smoking and lung-cancer risk.

PURPOSE: Menthol smoking may lead to a greater increase in lung-cancer risk than smoking of nonmentholated cigarettes. Mentholation of cigarettes adds additional carcinogenic components to cigarette smoke and increases retention times for cigarette smoke in the lungs. Only two epidemiologic studies have been conducted on menthol smoking and lung cancer, and their results are conflicting. Of note, African American males have much higher rates of lung cancer than Caucasian males despite smoking fewer cigarettes per day. Because the consumption of menthol cigarettes is much more frequent among African Americans, it is of interest to examine the possible association between menthol smoking and lung-cancer risk in this population. METHODS: We examined the association between menthol cigarette smoking and lung-cancer risk among smokers by comparing 337 incident cases of lung cancer with 478 population controls enrolled in a case-control study of lung cancer. Information on smoking history and other known and potential risk factors for lung cancer, including dietary intake, was obtained by in-person interviews. RESULTS: The adjusted odds ratios did not differ appreciably between smokers of mentholated cigarettes versus exclusive nonmentholated cigarette smokers in the overall study group of smokers. The odds ratio (OR) for 32 pack-years or more of mentholated vs. nonmentholated cigarettes was 0.90 (95% confidence interval (CI) = 0.38-2.12) in African Americans and 1.06 (95% CI = 0.47-2.36) in Caucasians, and did not differ for either ethnic group (p = 0.98). CONCLUSIONS: Our results suggest that the lung-cancer risk from smoking mentholated cigarettes resembles the risk from smoking non-mentholated cigarettes. Our data do not support the hypothesis that the increased risk of lung cancer among African Americans is due to the increased prevalence of menthol smoking.

The effect of nicotine on the delay of gastric emptying.

The effect of cigarette smoking and its active component, nicotine, on the gastric emptying of solid food was assessed in a randomized double-blind crossover design. Ten regular smokers were studied after a 6 h fast and least 18 h after their last cigarette. Subjects smoked a total of three high (1.91 mg) or low (0.17 mg) nicotine cigarettes, before and after a technetium-labelled solid meal and were scanned by gamma camera periodically over a 2-h period. All calculations of gastric emptying revealed a significant delay after smoking high versus low nicotine cigarettes in: mean per cent isotope remaining in the stomach at each measurement point from 90-120 min; amount of meal remaining in the stomach at 2 h; and mean time at which 50% of the meal had emptied (T1/2). Delay in gastric emptying was significantly correlated with increase in serum nicotine concentration on the high nicotine day.