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Biomedical subjects

P B Dews

Publications and source records attributed to P B Dews.

At least 19 recordsLinked to original sources

Caffeine: behavioral effects of withdrawal and related issues.

Acquired tolerance to some behavioral effects of caffeine in humans is widely assumed to occur but is poorly documented and appears, at most, to be of low magnitude. Withdrawal from regular consumption of caffeine has been reported to result in a variety of symptoms, including: irritability, sleepiness, dysphoria, delerium, nausea, vomiting, rhinorrhea, nervousness, restlessness, anxiety, muscle tension, muscle pains and flushed face. Some of these same symptoms have been reported following excess intake of caffeine. The prevalence of symptoms reported on withdrawal in different studies also covers a wide range from 11% or less to 100%. It is suggested that the evidence leads to the conclusion that non pharmacological factors related to knowledge and expectation are the prime determinants of symptoms and their reported prevalence on withdrawal of caffeine after regular consumption.

Behavior↗

The frequency of caffeine withdrawal in a population-based survey and in a controlled, blinded pilot experiment.

Reports of symptoms when regular caffeine consumption is stopped have appeared in the medical literature, but the frequency and significance of this phenomenon have remained controversial. The objective of this study was to collect information on the prevalence and severity of caffeine withdrawal in the general population and determine the incidence and type of symptoms reported on blind abrupt and gradual caffeine cessation among coffee drinkers reporting past episodes of caffeine-withdrawal symptoms. A community-based telephone survey was followed by a stratified, randomized, double-blind controlled study. Participants included 11,112 persons spontaneously calling to inquire about studies not related to caffeine and 57 regular caffeine users selected from among the callers because of self-reported caffeine-withdrawal symptoms. Gradual or abrupt withdrawal from caffeine was compared to continuation of the same caffeine level. In a survey of 11,112 persons, 61% reported daily caffeine consumption, and 11% of the caffeine consumers reported symptoms upon stopping caffeine. Among the regular caffeine users, only 0.9% of males and 5.5% of females reported symptoms significant enough to interfere with normal activities when they abruptly stopped caffeine. A group of those reporting withdrawal symptoms were randomly assigned to three subsamples. In the group subjected to abrupt withdrawal (N = 18), 6 (33.3%) reported symptoms (e.g., headaches and tiredness). Including decreases in functional ratings, a total of 7 of the 18 (38.8%) could be considered to have experienced caffeine withdrawal. The gradual withdrawal group (N = 20) reported minimal if any caffeine withdrawal symptoms. A third group (N = 18) was kept on a level dose of caffeine for comparison. When participants are unaware of the caffeine-withdrawal focus of the study, these results suggest that both the frequency and severity of caffeine-withdrawal symptoms are much lower than found in some previous reports and that clinically significant symptoms may be uncommon events among the general population.

Adult↗

Stereotypy and asymmetry in mice.

Mice ran in a circular runway. Number and direction of circuits were recorded. Most control mice ran about the same number of circuits in each direction. After 100 mumols/kg cocaine there were 3.5 times as many circuits and most mice ran most circuits in one direction. Some mice ran strongly in one direction after a first dose of cocaine and strongly in the other direction after a second dose. Hence, the primary influence toward unidirectional running is stereotypy rather than asymmetry.

Animals↗

Extrapolation by proximate inference.

Scientific extrapolation, as in astronomy, is different from legal or regulatory extrapolation, as in arriving at acceptably safe levels of agents. Scientific and technological information is required in the latter process, but scientists fail to contribute when they respond to legal and regulatory questions by attempting purely scientific extrapolation.

Animals↗

Directional running in mice: effects of cocaine and chlorpromazine.

Mice ran in a circular runway. Some received milk at every third circuit in a designated direction, clockwise or counterclockwise, in daily 1000-s sessions. Under control conditions, about 10 times as many circuits were made in the reinforced direction as in the non-reinforced direction. Cocaine (10, 30, 100 microM/kg) had little effect on the total number of circuits, but progressively increased the number in the non-reinforced direction. Chlorpromazine (1, 3, 10, 30 microM/kg) caused a monotonic decrease in total number of circuits and in number in non-reinforced direction. At the highest doses the proportion in the non-reinforced direction was increased. Mice, untrained in the runway and with no reinforcement of circuits in either direction, made many fewer total circuits than when running was reinforced and about equal numbers were in clockwise and in counterclockwise directions. Cocaine greatly increased the total number of circuits. As in the subjects whose running was reinforced, cocaine led to a much higher tendency for mice to run in a single direction. The similarities between the tendency to run in one direction after cocaine and the rotational behavior of rodents seen after cocaine and amphetamine suggest a common mechanism.

Animals↗

Behavioral effects of caffeine, (-)N-((R)-1-methyl-2-phenylethyl)-adenosine (PIA), and their combination in the mouse.

The effects of caffeine (1-100 mg/kg, IP), (-)N-((R)-1-methyl-2-phenylethyl)-adenosine (PIA) (0.01-1 mg/kg, IP), and of the two drugs in combination were studied in mice responding under a mult FR30 FI600 s schedule of food presentation. The lowest dose of caffeine, 1 mg/kg, had no effect on responding under either component of the mult schedule. Intermediate doses of caffeine (3 and 10 mg/kg) slightly increased responding under the FI component, while higher doses decreased responding. Caffeine only decreased responding, at doses above 30 mg/kg, under the FR component. PIA decreased responding under both components of the mult schedule in a dose-dependent, and similar, manner. In most cases, the rate-increasing effect of caffeine on FI responding was diminished when combined with a rate-decreasing dose of PIA. However, when 0.01 mg/kg PIA, a dose that had no effect alone, was combined with 3 mg/kg caffeine, the increase in rate exceeded that of caffeine alone. Rate-decreasing effects of PIA were antagonized by caffeine; with larger doses of PIA, larger doses of caffeine were required for antagonism. Thus, while the rate-increasing effects of caffeine can be either enhanced or diminished, when combined with different doses of PIA, the rate-decreasing effects of PIA are clearly antagonized by caffeine in a dose-dependent manner.

Adenosine↗

Effects of drugs on schedule-controlled running of mice in a circular runway.

Partially food deprived mice ran in a 1-m circular runway. Every 30 circuits, diluted evaporated milk was delivered. Under control conditions mice averaged 0.18 circuits/s for 1 h. The rate was reduced to 0.11 circuits/s 1 h after gavage of Tylose (cellulose derivative) vehicle. Amphetamine, chlordiazepoxide and pentobarbital increased the rate of responding over some dose range, but chlorpromazine, clozapine, imipramine and morphine caused only decreases in responding at effective dose levels. The results are generally similar to reports of effects of the drugs on responses of much briefer duration occurring at similar rates.

Amphetamine↗

Caffeine.

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Adult↗

Cannabinoids. I. Behavioral effects.

The effects of two new cannabinoids, nabilone and canbisol, have been compared to delta 9-tetrahydrocannabinol (delta 9-THC) and chlordiazepoxide in behavioral tests in mice, rats, dogs and rhesus monkeys. Activity of mice was measured in a photocell device. Oral doses of 5 and 10 mg/kg of delta 9-THC and 200 mg/kg of chlordiazepoxide caused only a decrease in the initial high activity. Doses of 5 and 10 mg/kg of nabilone and 2.5, 5.0 and 10 mg/kg of canbisol decreased the initial high activity but increased the subsequent low activity. In rats delta 9-THC, nabilone and canbisol, but not chlordiazepoxide, slowed muricide and intracranial self-stimulation. Chlordiazepoxide, nabilone and canbisol, but not delta 9-THC, reduced reactivity of septal-lesioned rats. At ehe dosages studied only nabilone and canbisol reduced food consumption by rats. Ataxia in dogs was detected following as little as 0.062 mg/kg of delta 9-THC, 0.032 mg/kg of nabilone and 0.004 mg/kg of canbisol when given intravenously; orally, doses of more than 0.25 mg/kg of delta 9-THC, and 0.1 mg/kg of nabilone or canbisol were necessary. Rhesus monkeys working under multiple fixed-ratio fixed-interval schedules showed an increase in rate at some dose of all three cannabinoids but higher doses reduced responding, and responding was abolished following 3.0 mg/kg of delta 9-THC or nabilone or 0.3 mg/kg of canbisol. Chlordiazepoxide increased responding at all doses studied, 3.0 to 30.0 mg/kg. Nabilone and canbisol resemble chlordiazepoxide in som tests and delta 9-THC in other tests.

Animals↗

Testing for behavioral effects of agents.

In the present state of science no morphological or chemical changes may be detectable at a time when behavior is profoundly disturbed, as in schizophrenia. Until we are reassured to the contrary, we must assume that exogenetic intoxication can produce changes detectable only as behavioral changes. Therefore behavioral toxicology must be studied. In contrast to toxic manifestations such as lethality or carcinogenicity, which tend to be unequivocal and irreversible, behavioral changes are like physiological changes in that they are quantitative, changing in time, and relate to variables with a considerable range of normal variability. An experiment on behavioral teratology in mice is described and the results used to illustrate the limits of the possible in behavioral toxicology. From reported and observed variability it is surmised that changes that occur in as many as 1 per 100 of the population or average as large as a 10% decrement will still be too small to be detected by direct experiment. Such risks are frequently unacceptable. Reasons are given for hoping that epidemiological studies may be able to supplement experimental toxicological studies to provide a better assessment of risk of small impairments or rare susceptibility.

Animals↗