Suzette M. Evans

Withdrawal syndrome after the double-blind cessation of caffeine consumption

BACKGROUND People who stop consuming caffeine may have symptoms, but the incidence and severity of caffeine withdrawal are not known. This study was performed to determine the effects in the general population of ending ones dietary intake of caffeine. METHODS We studied 62 normal adults whose intake of caffeine was low to moderate (mean amount, 235 mg--the equivalent of 2.5 cups of coffee--per day). They completed questionnaires about symptoms and tests of their mood and performance when consuming their normal diets (base-line period) and at the end of each of two two-day periods during which they consumed caffeine-free diets and under double-blind conditions received capsules containing placebo (placebo period) or caffeine (caffeine period) in amounts equal to their daily caffeine consumption. RESULTS More subjects had abnormally high Beck Depression Inventory scores (11 percent), high scores on the trait scale of the State-Trait Anxiety Inventory (8 percent), low vigor scores (11 percent) and high fatigue scores (8 percent) on the Profile of Mood States, and moderate or severe headache (52 percent) during the placebo period than during either the base-line period (2, 0, 0, 0, and 2 percent, respectively; P less than 0.05) or the caffeine period (3, 2, 2, 0, and 6 percent; P less than 0.05). More subjects reported unauthorized use of medications during the placebo period (13 percent) than during the caffeine period (2 percent, P = 0.017). Performance of a tapping task was slower during the placebo period than during the base-line and caffeine periods (P less than 0.01). CONCLUSIONS Persons who consume low or moderate amounts of caffeine may have a withdrawal syndrome after their daily consumption of caffeine ceases.

Prevalence of adult attention-deficit hyperactivity disorder among cocaine abusers seeking treatment

In this study, 281 cocaine abusers seeking treatment were assessed for adult attention-deficit hyperactivity disorder (ADHD). Structured assessments included the SCID for DSM-IV, a SCID-like module for ADHD, and a pattern of drug use questionnaire. The sample consisted of 82% men, 67% African-Americans, 19% Hispanics, and 14% Caucasians identified at several treatment sites. Average age was 33.7 +/- .4 years. Twelve percent (n = 34) of the sample met DSM-IV criteria for childhood ADHD. Of the entire sample, 10% (n = 27), or 79% of the patients diagnosed with childhood ADHD, had adult ADHD. A history of conduct disorder and antisocial personality disorder were prevalent among those with adult ADHD (63% and 52%, respectively). This subpopulation of cocaine abusers may be one of the most difficult-to-treat cocaine-abusing groups, particularly if the ADHD remains undetected. To provide effective treatment for cocaine abusers, clinicians may need to identify subpopulations of patients, such as those with ADHD, and target both pharmacologic and nonpharmacologic interventions for these groups.

Exogenous Progesterone Attenuates the Subjective Effects of Smoked Cocaine in Women, but not in Men

In a previous study, we showed that the positive subjective effects of cocaine were higher during the follicular phase compared to the luteal phase of the menstrual cycle. The purpose of the present study was to determine if exogenously administered progesterone during the follicular phase in females would attenuate the response to cocaine compared to the normal follicular phase, thus making the response to cocaine similar to the luteal phase. To address the role of sex differences, males were also administered exogenous progesterone during one inpatient stay. In all, 11 female and 10 male non-treatment-seeking cocaine smokers participated. Females had three inpatient stays: one during a normal follicular phase, one during a normal luteal phase, and one during a follicular phase when exogenous progesterone was administered. Males had two inpatient stays: one when exogenous progesterone was administered and the other when placebo was administered. During each inpatient admission, there were four smoked cocaine administration sessions: participants were administered six doses of cocaine (0, 6, 12, or 25 mg cocaine base) at 14 min intervals. Smoked cocaine increased heart rate, blood pressure and several subjective effects such as ‘good drug effect’ and ‘drug quality’ cluster scores. Administration of progesterone during the follicular phase in women attenuated the positive subjective effects of cocaine, whereas only minimal changes were observed in men. These results indicate that progesterone modulates the response to cocaine in women and suggests that fluctuations in endogenous progesterone levels account for some of the sex differences observed in humans.

Caffeine tolerance and choice in humans

Thirty-two healthy subjects with histories of moderate caffeine consumption abstained from dietary caffeine throughout the study. Subjects were stratified into two groups based on several factors including caffeine preference, which was assessed using a caffeine versus placebo choice procedure. Subsequently, subjects received either caffeine (300 mg t.i.d.) or placebo (placebo t.i.d.) for 18 consecutive days, and thereafter were exposed again to a caffeine versus placebo choice procedure. The study documented tolerance development to the subjective effects of caffeine: after chronic dosing, administration of caffeine produced significant subjective effects in the chronic placebo group but not in the chronic caffeine group. The study also provided indirect evidence for tolerance development: during chronic dosing, the chronic caffeine and placebo groups did not differ meaningfully on ratings of mood and subjective effect. When subjects were categorized into caffeine choosers or nonchoosers, caffeine choosers tended to report positive subjective effects of caffeine and negative subjective effects of placebo. Nonchoosers, in contrast, tended to report negative subjective effects of caffeine. Chronic caffeine did not alter the reinforcing effects of caffeine as assessed by caffeine versus placebo choice, possibly because the relatively short duration of caffeine abstinence in the placebo condition was not sufficient to result in maximal withdrawal effects after termination of the relatively high caffeine dose. This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.

Discriminative stimulus and subjective effects of theobromine and caffeine in humans

Theobromine versus placebo discrimination and caffeine versus placebo discrimination were studied in two consecutive experiments in seven volunteers who abstained from methylxanthines. Daily sessions involved PO double-blind ingestion of two sets of capsules sequentially, one of which contained drug and the other placebo. Subjects attempted to identify, and were later informed, which set of capsules contained the drug. In each experiment subjects were exposed to progressively lower doses. Five subjects acquired the theobromine discrimination; the lowest dose discriminated ranged from 100 to 560 mg. All seven subjects acquired the caffeine discrimination; the lowest dose discriminated ranged from 1.8 to 178 mg. A final experiment evaluated subjective effect ratings following 560 mg theobromine, 178 mg caffeine and placebo, which were administered double-blind in capsules once daily, five times each in mixed sequence. Caffeine produced changes in both group and individual ratings (e.g. increased well-being, energy, social disposition and alert). Theobromine did not produce changes in group ratings but changed ratings in some subjects. Across subjects, sensitivity to caffeine discriminative effects in the discrimination experiment correlated significantly with the number and magnitude of caffeine subjective effects in the final experiment. This study documents modest discriminative effects of theobromine in humans, but the basis of the discrimination is unclear. This study suggests that commonly consumed cocoa products contain behaviorally active doses of caffeine and possibly theobromine.

Changes in mood, cognitive performance and appetite in the late luteal and follicular phases of the menstrual cycle in women with and without PMDD (premenstrual dysphoric disorder)

Although its been reported that women with premenstrual dysphoric disorder (PMDD) have increased negative mood, appetite (food cravings and food intake), alcohol intake and cognitive deficits premenstrually, few studies have examined these changes concurrently within the same group of women or compared to women without PMDD. Thus, to date, there is not a clear understanding of the full range of PMDD symptoms. The present study concurrently assessed mood and performance tasks in 29 normally cycling women (14 women who met DSM-IV criteria for PMDD and 15 women without PMDD). Women had a total of ten sessions: two practice sessions, 4 sessions during the follicular phase and 4 sessions during the late luteal phase of the menstrual cycle. Each session, participants completed mood and food-related questionnaires, a motor coordination task, performed various cognitive tasks and ate lunch. There was a significant increase in dysphoric mood during the luteal phase in women with PMDD compared to their follicular phase and compared to Control women. Further, during the luteal phase, women with PMDD showed impaired performance on the Immediate and Delayed Word Recall Task, the Immediate and Delayed Digit Recall Task and the Digit Symbol Substitution Test compared to Control women. Women with PMDD, but not Control women, also showed increased desire for food items high in fat during the luteal phase compared to the follicular phase and correspondingly, women with PMDD consumed more calories during the luteal phase (mostly derived from fat) compared to the follicular phase. In summary, women with PMDD experience dysphoric mood, a greater desire and actual intake of certain foods and show impaired cognitive performance during the luteal phase. An altered serotonergic system in women with PMDD may be the underlying mechanism for the observed symptoms; correspondingly, treatment with specific serotonin reuptake inhibitors (SSRIs) remains the preferred treatment at this time.

Bupropion Treatment for Cocaine Abuse and Adult Attention-Deficit/Hyperactivity Disorder

Abstract There are few published studies assessing the efficacy of pharmacologic treatments for attention-deficit hyperactivity disorder (ADHD) among substance abusers seeking treatment. Eleven patients who met DSM-IV diagnostic criteria for cocaine dependence and adult ADHD were entered into a 12-week single-blind trial of divided daily doses of bupropion (BPR). All patients received weekly individual standardized relapse prevention therapy. Treatment compliance and retention were good. Patients reported significant reductions in attention difficulties, hyperactivity and impulsivity. Self-reported cocaine use, cocaine craving, and cocaine positive toxicologies, also decreased significantly. In a previously published trial, 12 patients who met similar diagnostic criteria for adult ADHD and cocaine dependence were entered into a 12-week trial of divided daily doses of sustained-release methylphenidate (MPH). Improvements observed on BPR were similar to, and did not differ from those previously observed with MPH. These preliminary data suggest that BPR may be as effective as sustained-release MPH, when combined with relapse prevention therapy, for cocaine abusers with adult ADHD. However, a future study directly comparing BPR to MPH in a double-blind placebo-controlled trial is needed.

Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates?

Stimulant abuse continues to be a growing problem among women. Over the last 10-15 years, an increasing number of studies have focused on factors that may be implicated in stimulant abuse in women as compared to men, including the role of hormonal fluctuations across the menstrual cycle. Numerous preclinical studies have documented that female rodents are more sensitive than male rodents to the behavioral effects of stimulant administration and the hormone estradiol is involved in the enhanced response to stimulants observed in females. In contrast, fewer studies have been conducted in humans and non-human primates addressing the role of sex and gonadal hormones on the effects of cocaine. This review paper presents a recent update on data collected in our Human Cocaine Challenge Laboratory and our Non-human Primate Laboratory, including analysis of cocaine pharmacokinetics, sex differences, the menstrual cycle, and the role of progesterone in modulating the response to cocaine. Our studies indicate that there is minimal evidence that the response to intranasal cocaine varies across the menstrual cycle or between men and women. In contrast, the response to smoked cocaine is greater in the follicular phase than the luteal phase and differences between men and women generally only emerge when men are compared to women in the luteal phase. In terms of potential hormonal mechanisms for these differences, the hormone progesterone attenuates the subjective response to cocaine. With respect to cocaine self-administration, there are minimal changes across the menstrual cycle in both humans and non-human primates. Thus, there is converging evidence across a range of species that the behavioral effects of cocaine (1) differ between males and females, (2) differ in relation to hormonal fluctuations, (3) can be attenuated by progesterone (at least in females), and (4) do not appear to be related to differences in cocaine pharmacokinetics.

Absorption rate of methylxanthines following capsules, cola and chocolate

Objective:To compare caffeine and theobromine absorption after oral administration of capsules, cola beverage and chocolate candy.Methods:Three males and four females who abstained from methylxanthines received five methylxanthine-containing treatments: caffeine in capsules (72 mg), administered twice; theobromine in capsules (370 mg); cola beverage (72 mg caffeine) and chocolate candy (72 mg caffeine and 370 mg theobromine). Plasma methylxanthine levels were assayed from samples collected before and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, and 3.0 h after caffeine capsule and cola treatments and, additionally, at 4.0 and 6.0 h after theobromine capsule and chocolate treatments.Results:Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min following both capsule treatments 1 (Cmax: 1.93 μg ⋅ ml−1); and 2 (Cmax: 2.05 μg ⋅ ml−1). Relative to capsules, caffeine absorption from cola and chocolate was delayed and produced lower maximum caffeine plasma concentrations which peaked 1.5–2.0 h after treatment (For cola, Cmax: 1.57 μg ⋅ ml−1); and for chocolate, Cmax: 1.50 μg ⋅ ml−1. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (Cmax: 6.72 μg ⋅ ml−1). Relative to capsules, theobromine absorption from chocolate was more rapid and produced higher maximum theobromine plasma concentrations which peaked approximately 2 h after treatment (Cmax: 8.05 μg ⋅ ml−1).Conclusions:The results suggest that a usual dietary portion of the cola or chocolate used in this study would produce behaviorally discriminable plasma levels of caffeine in most subjects and of theobromine in at least one subject.

Acute Interaction of Baclofen in Combination with Alcohol in Heavy Social Drinkers

BACKGROUND There is growing evidence that gamma-amino butyric acid-B receptor agonists may be effective in the treatment of alcohol abuse or dependence. The primary goal of this study was to determine the safety of baclofen in combination with alcohol consumption in heavy drinkers. In addition, the effects of baclofen alone, and in combination with alcohol, on subjective effects, cognitive performance effects, as well as alcohol craving, were assessed. METHODS Eighteen non-treatment-seeking heavy social drinkers (mean of 28 drinks per week), who did not meet the criteria for alcohol dependence participated. All individuals were tested using a double-blind double-dummy design with six 2-day inpatient phases. Baclofen (0, 40, and 80 mg) was administered 2.5 hours before alcohol (1.5 g/l body water or approximately 0.75 g/kg) or placebo beverages, given in 4 divided doses every 20 minutes. RESULTS Baclofen, either alone or in combination with alcohol, produced only modest increases in heart rate and blood pressure and no adverse effects were reported. Baclofen did not increase positive subjective effects (e.g., Stimulant effects, Drug Liking) but did increase sedation and impair performance. Even though both baclofen and alcohol impaired performance, for the most part performance was not impaired to a greater extent when baclofen was combined with alcohol. Among this population of nondependent drinkers, baclofen did not alter alcohol craving or alcohol-induced positive subjective effects. CONCLUSIONS Baclofen alone has minimal abuse liability in heavy social drinkers, and baclofen is relatively well tolerated and safe when given in combination with intoxicating doses of alcohol.