G. A. Starmer

A twin study of ethanol metabolism

Blood alcohol measurements were obtained for 206 pairs of twins who had ingested a standard dose of alcohol (0.75 g/kg body weight) and repeat measurements were obtained for 40 of these pairs on a second occasion. The repeatability of the peak blood alcohol concentration (BAC) was 0.66, that of the rate of elimination was 0.39, and that of the time to peak BAC was 0.27. Only a small portion of the nonrepeatable variance could be explained by measurement error or drinking experience. It is concluded that short-term environmental factors exercise considerable influence on alcohol metabolism, particularly in the absorption phase. All of the repeatable variance in peak BAC and rate of elimination was due to genetic factors. Only a small proportion of any of the genetic variance could be explained by individual differences in weight, adiposity, or lung function. Likewise, these three factors were unable to account for the fact that females had higher BACs than males during both absorption and elimination.

A Twin Study of Psychomotor and Physiological Responses to an Acute Dose of Alcohol

A battery of psychomotor tasks and physiological measures was administered to 206 pairs of twins before alcohol and then three times at hourly intervals after they ingested a standard dose of ethanol (0.75 g/kg body weight). Repeat measurements were obtained for 41 of these pairs on a second occasion. Performance on motor coordination, standing steadiness, pursuit rotor, arithmetic computation, and reaction-time tasks deteriorated after alcohol, but decrements on the five tasks were generally independent of each other. Measurements of blood pressure, pulse rate, and skin temperature were all elevated following alcohol intake, but these responses were also uncorrelated. The variance in many of these measures increased after alcohol. An analysis of covariance structure revealed that most of this additional variance exposed by alcohol was genetic in origin, particularly for standing steadiness, pursuit rotor, arithmetic computation, and pulse rate. Up to 50% of the variance in body sway after alcohol was estimated to be due to genetic factors expressed only under the influence of alcohol. Although significant correlations were found with blood alcohol concentration, previous drinking experience, and the personality trait Extraversion, little of the genetic variance exposed by alcohol could be explained by these predictors. It is concluded that the sources of the considerable genetic variation affecting performance under alcohol must be sought elsewhere.

The effect of caffeine on human performance, alone and in combination with ethanol

The effect of caffeine (300 mg/70 kg) on cognitive, perceptual and motor functions was investigated both alone and in combination with ethanol (0.75 g/kg) in 68 healthy student volunteers of both sexes. A test battery consisting of standing steadiness, simple and complex reaction time, manual dexterity, numerical reasoning, perceptual speed and verbal fluency was used. Placebos for both drugs were included. Caffeine was administered in decaffeinated coffee immediately after finishing drinking the alcoholic beverage. A peak plasma ethanol concentration of 92 ± 4 mg/100 ml occurred at 40 min which was not modified by caffeine. Caffeine did not antagonise the ethanol-induced decrement in performance except in the reaction time tests. Caffeine alone caused a significant increase in body sway at 40 min.

Renal and gastric lesions after phenylbutazone and indomethacin in the rat.

Summary Oral administration of single large doses of phenylbutazone (400 mg/kg) and indomethacin (75 mg/kg) to female Wistar rats resulted in the development of patchy renal papillary necrosis in 19% and 21% of kidneys respectively. The lesions were seen as early as 2 hours after drug administration. The appearances of the necrotic areas suggested a toxic aetiology, although in some animals, some contribution by haemorrhagic shock could not be excluded because with both drugs, many animals developed massive gastro‐intestinal haemorrhage. Most rats receiving phenylbutazone developed acute gastric erosions with a peculiar distribution, similar to that reported in man for this drug. Although many rats receiving indomethacin suffered from gastro‐intestinal haemorrhage, only a few developed gastric ulcers.

The effect of (-) ? 9-tetrahydrocannabinol, alone and in combination with ethanol, on human performance

Twenty five volunteers received (-) Δ9-tetrahydrocannabinol (THC) (320 μg/kg) or placebo (both orally, T0), and, 60 min later, they consumed an ethanolic beverage (0.54 g/kg) or placebo. The effects of this medication were measured at T1 (100 min after THC ingestion), T2 (160 min), T3 (220 min) and T4 (280 min) using a battery of cognitive, perceptual and motor function tests. Factorial analysis indicated that the test procedures could be adequately expressed by four rotated factors: a reaction speed factor (I′), a cognitive factor (II′), a standing steadiness factor (III′) and a psychomotor coordination factor (IV′), The first principal component (I) was used as a measure of general performance across the whole test battery.Both THC and ethanol produced significant decrements in the general performance factor. Ethanol produced significant decrements in standing steadiness and psychomotor coordination, while THC caused a significant deterioration in performance on all the four rotated factors. In all cases the peak effect of ethanol occurred at T1 and by T4 the effect had worn off. The performance decrements induced by THC were slower in onset and lasted longer than those induced by ethanol. In general, the peak effect of THC occurred at T1 and T2. There was no evidence of any interaction between THC and ethanol, and the effects of a combination of THC and ethanol were no more than additive. THC (but not ethanol) produced a significant rise in pulse rate. Prior administration of THC did not significantly affect the blood ethanol levels obtained. The subjects were able to identify correctly which of the treatments they had received.

Effect of cannabinoids on the abdominal constriction response in mice: within cannabinoid interactions

After oral administration to mice, δ9-tetrahydrocannabinol (THC) and cannabinol (CBN) caused a dosedependent suppression of the abdominal constriction response to formic acid. Cannabinol was 50 times less active than THC and cannabidiol (CBD) was without effect. The effects of THC and CBN were additive. CBD antagonised the antinociceptive effects of both THC and CBN in a dose-dependent manner.

The effects of orally administered Δ9-tetrahydrocannabinol in man on mood and performance measures : a dose-response study

Abstract A dose-response study of the effect of orally administered Δ9-tetrahydrocannabinol (THC) on human mood and skills performance was conducted. Using five dose levels of THC (0, 5, 10, 15, 20 mg) with 16 volunteers per dosage group, mood and performance measures were recorded at five testing occasions, one before and four after drug administration. The slope of the linear regression of performance on the test battery was significant for up to 200 minutes after dosage. That is to say, oral THC, at the doses used, produced significant dose-dependent impairment of performance for a period in excess of three hours. A similar time course for the effect of THC on the subjective assessment of intoxication (‘stone’) suggested a correlation between drug-induced impairment skills and the effects on mood.

Interactions among the cannabinoids in the antagonism of the abdominal constriction response in the mouse

The ability of Δ9-tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD), 11-OH THC and 8α,11-diOH THC to antagonise the abdominal constriction response in the mouse induced by formic acid, phenylquinone, 5-hydroxytryptamine, prostaglandin E1 (PGE1) and bradykinin was tested. THC was an effective antagonist against all nociceptive agents with an ED50 in all cases between 1.0 and 2.6 mg/kg. CBN, while also effective against all nociceptive agents, was less potent than THC, with an ED50 range between 46.2 and 112.5 mg/kg. CBD in doses as high as 200 mg/kg was without effect. Using PGE1 as the nociceptive agent, 11-OH THC was equipotent to THC while 8α,11-diOH THC was inactive. Naloxone, while able to antagonise the antinociceptive effect of morphine against formic acid-induced writhing, did not reverse the antinociceptive effects of THC. There were no pharmacological interactions between THC, CBD and CBN.

The effect of cannabidiol, alone and in combination with ethanol, on human performance

Fifteen volunteers received cannabidiol (CBD) (320 μg/kg) or placebo (both orally, T0), and 60 min later they consumed an ethanolic beverage (0.54 g/kg) or placebo. The effects were measured at T1 (100 min after CBD ingestion), T2 (160 min) and T3 (220 min) using cognitive, perceptual and motor function tests. Factorial analysis indicated that test procedures could be adequately expressed by three rotated factors: A reaction speed factor (I), a standing steadiness factor (II) and a psychomotor coordination/cognitive factor (III). Ethanol produced a significant decrement in factor III. There was no demonstrable effect of CBD, either alone or in combination with ethanol. Neither CBD nor ethanol produced any significant effect on pulse rate. Prior administration of CBD did not significantly affect the blood ethanol levels. Whilst the subjects were able to identify correctly when they were given ethanol, they did not report any subjective effects of CBD.

Antihistamines and highway safety.

Available evidence that antihistamine-induced impairment of human psychomotor performance constitutes a traffic hazard is reviewed against a set of criteria which could theoretically be applied to any drug or group of drugs. Two distinct classes of histamine antagonists, which act at different receptors (H1 and H2) are now available and they should be considered separately. H1-Antagonists are freely available to the public and are consumed in enormous quantities. They are a rather heterogeneous group of drugs which share the common property of antagonising some of the effects of histamine. Other effects, particularly sedation, are prominent with many of the older members of the group and these drugs can be shown to impair performance in laboratory tasks and to interact additively with alcohol and other central nervous system depressant drugs. Despite this potential for impairment of driving ability, they are seldom suggested as causative factors in traffic crashes. This may, of course, be due to inadequacy of reportage. A number of new histamine H1-antagonists have been developed recently which only gain limited access to the central nervous system and appear to be less likely to cause impairment of performance skills. Histamine H2-antagonists have a much more restricted and closely supervised use in medicine and of the two agents currently available (cimetidine and ranitidine), only cimetidine appears to pose traffic safety problems largely because of its ability to interfere with the metabolism of other drugs which depress the central nervous system. Appropriate prescribing should eliminate this problem.(ABSTRACT TRUNCATED AT 250 WORDS)