Judith J. Wurtman

Drugs that enhance central serotoninergic transmission diminish elective carbohydrate consumption by rats.

Abstract We previously showed (Science 198:1178, 1977) that fenfluramine or fluoxetine, drugs thought to enhance serotoninergic transmission, selectively decrease the rats consumption of carbohydrates, without affecting protein intake, when animals are given simultaneous access to diets differing in protein (5% vs 45%) and carbohydrate contents; in contrast, d-amphetamine lacks this selective effect. Present studies affirm this relationship using another serotoninergic drug, MK-212, and show that the suppression of carbohydrate intake occurs whether the test diets contain variable amounts of protein, or carbohydrates, or of both nutrients. Evidence is presented that rats given diet mixtures containing various proportions of carbohydrates have the ability to regulate their carbohydrate intakes (i.e., to choose to eat amounts of each diet that, taken together, will give them a desired proportion of carbohydrate), and that this ability is independent of whether or not the carbohydrate consumed has a sweet taste. It is proposed that serotoninergic neurons comprise part of a behavioral feedback loop, whereby the consumption of carbohydrate (which, by altering plasma amino acid patterns, accelerates serotonin synthesis in brain neurons) diminishes the rats subsequent tendency to consume additional carbohydrates. Drugs that enhance central serotoninergic transmission can probably be substituted for dietry carbohydrate to activate this behavioral loop.

Effects of protein and carbohydrate meals on mood and performance: Interactions with sex and age

Normal adult subjects (n = 184) consumed a high-protein or high-carbohydrate meal. Two hours later their mood and performance were tested. The effects of meal composition on mood were different for men and women, and for older and younger subjects. Females, but not males, reported greater sleepiness after a carbohydrate as opposed to a protein meal. Male subjects, but not females, reported greater calmness after a carbohydrate as opposed to a protein meal. Older subjects responded differently to meals depending upon the time of day when these were consumed. When meals were eaten for breakfast (but not for lunch) individuals 40 yr of age or older felt more tense and less calm after a protein than after a carbohydrate meal. Although older subjects reported subjective discomfort after a morning protein meal, they displayed objective performance impairments after a carbohydrate lunch. Subjects 40 yr of age or older were impaired on a test of sustained selective attention (dichotic shadowing) after consuming a high-carbohydrate lunch. The shadowing impairment after carbohydrate consumption was as pronounced without distraction as with distraction and resulted mostly from increased omission errors. Our findings suggest negative effects on concentration when older subjects consume a high-carbohydrate, low-protein lunch. These negative effects of carbohydrate consumption appear to arise predominantly from lapses of attention rather than from intrusion of distractors.

Carbohydrate craving in obese people: Suppression by treatments affecting serotoninergic transmission

We examined the existence of carbohydrate cravings, and the effects on such cravings of treatments that enhance serotonin release, among 24 obese subjects who claimed to have excessive appetites for carbohydrates. Subjects living in a college dormitory for four weeks were given three fixed meals daily and allowed to choose at will among five protein-rich or five carbohydrate-rich isocaloric snack foods, provided via a vending machine. For two weeks, they received no treatment (study 1) or a placebo (study 2); for the next two weeks, they received placebo, d-1 fenfluramine or 1-tryptophan. All but one of the subjects exhibited a marked preference for carbohydrate-rich over protein-rich snacks during the first two weeks of the study. The average daily intake of carbohydrate-rich snacks was 4.1 ± 0.4 and of protein-rich snacks 0.8 ± 0.3. Seventeen of the subjects failed to consume any protein snacks on most days during the baseline or test periods, thus it was not possible for us to examine the effect of test treatments on protein snack intake. Fenfluramine administration significantly reduced carbohydrate snacking in six of nine test subjects, as well as in the group as a whole (2.4 ± 0.6 snacks/day vs 4.2 ± 0.6 during the two-week baseline period). Tryptophan significantly diminished carbohydrate intake in three of the eight treated subjects, and increased it in one subject; it did not significantly modify snacking patterns in the group as a whole. Placebo administration did not affect carbohydrate intake in any of the seven test subjects. These observations show that some obese people do consume carbohydrate-rich snacks frequently and preferentially, and that this behavior can sometimes be diminished by treatments thought to enhance serotonins release (fenfluramine) or synthesis (tryptophan).

Effect of nutrient intake on premenstrual depression

We examined the occurrence and coincidence of depressed mood and excessive carbohydrate intake in 19 patients who claimed to suffer from severe premenstrual syndrome and in nine control subjects, all as inpatients, during the early follicular and late luteal phases of their menstrual cycles. Mood was assessed with the Hamilton Depression Scale and an addendum that evaluated fatigue, sociability, appetite, and carbohydrate craving. Calorie and nutrient intakes were measured directly. The subjects with premenstrual syndrome significantly increased calorie intake during the late luteal phase (from 1892 +/- 104 to 2395 +/- 93 kcal, mean +/- SEM); carbohydrate intake increased by 24% from meals and by 43% from snacks. Protein intake failed to change, whereas intake of fat, a fixed constituent of all of the test foods, rose in proportion to calorie intake. The Hamilton Depression Scale and addendum scores rose from 2.0 +/- 0.5 to 21.2 +/- 0.8 (Hamilton Scale) and from 0.5 +/- 0.5 to 10.2 +/- 0.6 (addendum) among subjects with premenstrual syndrome during the luteal phase but failed to change among the controls (2.1 +/- 0.8 to 2.4 +/- 0.8, and 0.4 +/- 0.3 to 0.6 +/- 0.3). Consumption of a carbohydrate-rich, protein-poor evening test meal during the late luteal phase of the menstrual cycle improved depression, tension, anger, confusion, sadness, fatigue, alertness, and calmness scores (p less than 0.01) among patients with premenstrual syndrome. No effect of the meal was observed during the follicular phase or among the control subjects during either phase. Because synthesis of brain serotonin, which is known to be involved in mood and appetite, increases after carbohydrate intake, premenstrual syndrome subjects may overconsume carbohydrates in an attempt to improve their dysphoric mood state.

Effects of hormone replacement therapy on weight, body composition, fat distribution, and food intake in early postmenopausal women: a prospective study.

OBJECTIVE To evaluate the effects of hormone replacement therapy (HRT) on body weight and composition, fat distribution, and food intake in women entering the climacteric. DESIGN Prospective clinical study. SETTING Outpatient menopause clinic at a tertiary medical center. PARTICIPANTS Sixty-three early postmenopausal women (44 to 54 years old) were prospectively studied for 1 year. They consisted of two groups: group A, 34 subjects who initiated continuous estrogen and progestin treatment (daily oral conjugated estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg), and group B, 29 women who refused hormonal therapy and served as controls. The age, menopausal status, initial anthropometric measurements (weight, body mass index [BMI], fat mass, and waist-to-hip girth ratio), and daily food intake (total caloric intake and food composition) were similar in both groups. INTERVENTIONS Anthropometric measurements were performed before commencement of HRT use and after 12 months. MAIN OUTCOME MEASURES Anthropometric measurements included BMI, waist-to-hip girth ratio, and body composition (the percentage of body fat and water) estimated by means of infrared interactance. Daily food intake was also recorded. RESULTS The body weight and fat mass increased significantly in both the treatment (73.22 +/- 2.01 [mean +/- SE] to 75.57 +/- 1.12 kg) and the control group (71.45 +/- 3.11 to 73.51 +/- 1.23 kg). However, a significant shift from gynoid to android fat distribution was observed only in the control group (waist-to-hip ratio shifted from 0.80 +/- 0.01 to 0.85 +/- 0.01), whereas no significant change was observed in the treatment group (0.81 +/- 0.01 to 0.82 +/- 0.01). Caloric and macronutrient intake did not change in either group. CONCLUSIONS These results indicate that continuous daily estrogen and progestin replacement therapy neither prevents nor increases early postmenopausal weight gain and fat accumulation. However, it does minimize the shift from gynoid to android fat distribution.

Depression and weight gain: the serotonin connection

The inability to control food intake and to engage in consistent exercise may account for repetitive episodes of weight gain. Many individuals who fail to maintain a normal weight may be susceptible to daily, monthly or seasonal perturbations in mood which result in an excessive intake of carbohydrate-rich foods and resistance to engaging in physical activity. Brain serotonin appears to be involved in these disturbances of mood and appetite; recent studies have shown that dietary and pharmacological interventions which increase serotoninergic activity normalize food intake and diminish depressed mood. Preventing recurrent weight gain may require periodic or sustained interventions that maintain mood and control over food intake.

D-Fenfluramine selectively suppresses carbohydrate snacking by obese subjects

Twenty obese inpatients who claimed to crave carbohydrate-rich foods were given d-fenfluramine (15 mg p.o., twice daily) or its placebo, double-blind, for two consecutive eight-day periods. Food choices were measured on treatment days 1, 7, and 8 by giving the subjects access to unlimited portions of six isocaloric meal foods (three high in carbohydrate and three high in protein) and of 10 isocaloric snack foods (five high in protein and five high in carbohydrate) available 24 hours a day in a computerized vending machine. d-fenfluramine reduced mealtime calorie intake by only 16% (from 1940 +/- 94 to 1630 +/- 92; p < .001), mealtime carbohydrate by 22%, and had no significant effect on mealtime protein consumption; in contrast, snack calorie intake was reduced by 41% (from 707 +/- 97 to 414 +/- 46; p < .001), and snack carbohydrate intake by the same proportion. The mean number of carbohydrate-rich snacks consumed per day decreased from 5.8 +/- 0.8 to 3.4 +/- 0.4 (p < .01), while that of protein-rich snacks failed to change signficantly (i.e., from 0.7 +/- 0.2 to 0.5 +/- 0.2).

Circadian rhythms of activity in healthy young and elderly humans

Patterns of activity of healthy adult humans were monitored in a controlled environment for several days using a wrist-mounted ambulatory activity meter. Subjects were 15 young males, 14 young females, 17 elderly males and 23 elderly females. Substantial differences in the absolute levels and patterns of daily rest and activity across age groups were observed. The elderly subjects were somewhat more active than the young subjects overall, especially in the early morning. Consistent with their increased levels of daytime activity the elderly subjects reported less sleepiness, especially in the morning, than the young volunteers. The age groups also differed significantly on all circadian parameters. The mean acrophase (peak of a sinusoid fitted to the activity rhythms) of the elderly group occurred at 1326 hr, significantly earlier than in the young group (1513 hr). The amplitude and the mesor (mean level) of the rhythms were both greater in the elderly group. It is uncertain whether these differences reflect changes in behavior that occur as a consequence of the aging process, previously-established differences in the life styles of the different populations studied, or some other factor. These findings suggest that levels and rhythms of daily activity in healthy elderly people are often well preserved and may not deteriorate as readily as had been assumed.

Weight Gain and Withdrawal Symptoms After Smoking Cessation: A Preventive Intervention Using d-Fenfluramine

Directly measured food intake in 31 overweight female smokers to test whether (a) calorie and carbohydrate intakes increase after smoking cessation and (b) double-blind d-fenfluramine (30 mg), a serotonin-releasing drug, suppresses weight gain, overeating, and dysphoric mood associated with stopping smoking. Placebo-treated patients grew dysphoric after smoking withdrawal and ate 300 kcal/day more from 2 to 28 days after, showing a 3.5-lb weight gain. Fat and protein intakes did not change, but carbohydrate intake increased (30% to 40%). D-fenfluramine prevented postcessation dysphoria. Although drug-treated patients ate more carbohydrate snacks just after quitting, they returned to baseline by 4 weeks, showing a 1.8-lb weight loss. Agents that enhance brain serotonin-mediated neurotransmission may help prevent weight gain, overeating, and dysphoric mood after smoking withdrawal.

Fenfluramine suppresses snack intake among carbohydrate cravers but not among noncarbohydrate cravers

Two groups of obese individuals who consume excessive calories primarily as snack foods have been distinguished: carbohydrate cravers and noncarbohydrate cravers. Both groups consume about 800 calories from snacks (860 kcal vs 879 kcal) and about 2000 calories from meals (1906 kcal vs 2080 kcal) daily. The carbohydrate-cravers consume almost all of their snacks as carbohydrate-rich foods (7 ± 0.4 CHO snacks/day vs 0.9 ± 0.12 protein snacks/day) whereas the noncarbohydrate cravers consume approximately equal numbers of protein and carbohydrate snacks (4.5 ± 0.6 carbohydrate snacks/day vs 3.5 ± 0.5 protein snacks/day). D-fenfluramine significantly reduced the intakes of calories (range 24–44%) and carbohydrates (range 28–41%) from snacks among the carbohydrate cravers over a three month treatment period. The drug did not affect snack intake by the noncarbohydrate cravers until the third month of treatment when the consumption of both types of snacks decreased significantly. D-fenfluramine decreased mealtime carbohydrate intake among the carbohydrate cravers throughout the treatment period (range 16–23%); mealtime protein intake declined comparably (range 14–18%) during the first and third treatment months. The drug had no effect on mealtime carbohydrate nor protein intake by noncarbohydrate cravers.