Caffeine and diazepam: Separate and combined effects on mood,memory, and psychomotor performance

The effects of caffeine and diazepam on several mood, cognitive, learning, memory, and psychomotor tasks were investigated in a double-blind study of 108 young healthy adults who were randomly assigned to nine treatments; oral administration of caffeine (0, 3 and 6 mg/kg), diazepam (0, 0.15, and 0.30 mg/kg) and their combinations. Subjects completed a battery of tasks once before and twice after administration of the drugs. Caffeine alone showed no effects on cognitive, learning, and memory performance, but impaired fine motor coordination and increased anxiety and tenseness. Diazepam alone produced sedation, lowered other ratings of subjective moods, and impaired cognitive, learning, and memory performance. The two drugs did not antagonize the effects of each other, except in the symbol cancellation task.     

The behavioral actions of diazepam and oxazepam are similar

In a double-blind and randomized study, we assessed the comparative pharmacodynamic profiles and behavioral effects of diazepam and oxazepam administered to young healthy volunteers. Diazepm 0.3 mg/kg or oxazepam 1.2 mg/kg or placebo were each administered orally to 13 subjects who were tested with tasks which measured learning and memory, cognition, psychomotor performance and mood before and for 9 h after treatment. The two drugs had similar actions, although subjective effects were milder after oxazepam, which also had a slower onset of action. There was no evidence of rebound behavioral impairment.     

Dose-response analysis of the behavioral effects of diazepam: I. Learning and memory

A total of 120 healthy volunteers were randomly assigned to four treatments (placebo, 0.1, 0.2, and 0.3 mg/kg) and three testing times (7 AM, 1 PM and 7 PM). Immediate and delayed free recall of word lists revealed consistent decreases in performance as oral diazepam dose increased from 0.1, 0.2, to 0.3 mg/kg. Paradoxically, as the dose increased, the number of predrug list words recalled also increased. A serial number-learning task displayed a pattern of delayed improvement of acquisition as the dose increased. Response times in a semantic-categories task were prolonged as the dose increased. Parallel recovery functions were observed for all doses and tasks. Full recovery after a single administration of 0.1, 0.2, and 0.3 mg/kg doses was estimated to occur after 3.5, 4.5, and 5.5 h, respectively. Several analyses were consistent with the view that acquisition and not retrieval was impaired by diazepam. There were no circadian interactions with the effects of the drug.     

Behavioral effects of oral versus intravenous administration of diazepam

The behavioral effects of oral versus intravenous administration of diazepam were studied in 50 volunteers using a battery of memory, cognitive, mood and psychomotor tests repeated over a 4.5 hr period. Subjects received diazepam 0.2 mg/kg or placebo as capsules, commercial tablets or intravenous solution in a randomized double blind manner. While a quick onset of effects occurred with intravenous administration followed by the capsule and tablet oral administrations in that order, the recovery rate was similar for the 3 methods of administration. Contrary to many claims in the literature the effects of oral administration were substantial. Behavioral impairment was directly related to the magnitude of the memory component of the task. On many of the tasks the pattern of diazepam impairment was one of delayed improvement of performance, a pattern which would only be apparent with repeated testing. Subjects who received diazepam showed a paradoxical enhancement of recall for material learned before the drug.     

Absence of reinforcing,mood and psychomotor performance effects of caffeine in habitual non-consumers of caffeine

Rationale. The extent to which the measured (and felt) psychostimulant effects of caffeine represent a real benefit of caffeine consumption or merely withdrawal reversal is unclear. Results showing positive psychostimulant effects of acute caffeine administration in habitual non-consumers of caffeine would provide evidence for a net benefit of caffeine unconfounded by withdrawal. Objectives. To compare the mood, alerting, psychomotor and reinforcing effects of caffeine in caffeine non-consumers and acutely (overnight) withdrawn caffeine consumers. Methods. In experiment 1, these participants consumed two differently flavoured dinks, one containing 100 mg caffeine and the other containing no caffeine. Each drink was consumed on 4 separate days in semi-random order, and self-ratings of mood and alertness were completed before and after drink consumption. On day 9, both drinks contained 50 mg caffeine and drink preference (choice) and intake were assessed. In experiment 2, mood, alertness and performance on a long-duration simple reaction time task were assessed before and after administration of 100 mg or placebo in a single test session. Results. Prior to receiving caffeine, the (overnight withdrawn) caffeine consumers were less alert and more tense than the non-consumers. Caffeine only had significant reinforcing, mood and psychomotor performance effects in the caffeine consumers. The reinforcing effect of caffeine was evident from an effect on drink intake, but drink choice was unaffected. Caffeine increased self-rated alertness of both caffeine consumers and non-consumers; however, for some of the non-consumers this was associated with a worsening of performance. Conclusions. These results support the hypothesis that the psychostimulant and related effects of caffeine are due largely to withdrawal reversal. Electronic Publication     

The effects on memory of pipequaline,alone or in combination with diazepam

Pipequaline (PK 8165) is a putative mixed agonist/antagonist at benzodiazepine receptors. The effects of pipequaline and diazepam on memory were assessed in 12 normal volunteers. Diazepam 10 mg or placebo was added to two doses of pipequaline, 50 and 150 mg, or to placebo in a double-blind crossover design. Diazepam produced impairments of episodic memory. In contrast, the effects of pipequaline were minor. Addition of diazepam to pipequaline increased drowsiness and general lethargy, with a less marked effect occurring for the higher dose of pipequaline alone. Pipequaline did not antagonise any of the effects of diazepam.     

Effects of caffeine,sleep loss,and stress on cognitive performance and mood during U.S. Navy SEAL training

Abstract Rationale. When humans are acutely exposed to multiple stressors, cognitive performance is substantially degraded. Few practical strategies are available to sustain performance under such conditions. Objective. This study examined whether moderate doses of caffeine would reduce adverse effects of sleep deprivation and exposure to severe environmental and operational stress on cognitive performance. Methods. Volunteers were 68 U.S. Navy Sea-Air-Land (SEAL) trainees, randomly assigned to receive either 100, 200, or 300 mg caffeine or placebo in capsule form after 72 h of sleep deprivation and continuous exposure to other stressors. Cognitive tests administered included scanning visual vigilance, four-choice visual reaction time, a matching-to-sample working memory task and a repeated acquisition test of motor learning and memory. Mood state, marksmanship, and saliva caffeine were also assessed. Testing was conducted 1 and 8 h after treatment. Results. Sleep deprivation and environmental stress adversely affected performance and mood. Caffeine, in a dose-dependent manner, mitigated many adverse effects of exposure to multiple stressors. Caffeine (200 and 300 mg) significantly improved visual vigilance, choice reaction time, repeated acquisition, self-reported fatigue and sleepiness with the greatest effects on tests of vigilance, reaction time, and alertness. Marksmanship, a task that requires fine motor coordination and steadiness, was not affected by caffeine. The greatest effects of caffeine were present 1 h post-administration, but significant effects persisted for 8 h. Conclusions. Even in the most adverse circumstances, moderate doses of caffeine can improve cognitive function, including vigilance, learning, memory, and mood state. When cognitive performance is critical and must be maintained during exposure to severe stress, administration of caffeine may provide a significant advantage. A dose of 200 mg appears to be optimal under such conditions. Electronic Publication     

Chronic MDMA (ecstasy) use, cognition and mood

Rationale It has been suggested that 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) causes damage to the serotonergic system, and that this damage results in cognitive and mood impairments.Objectives To examine the effect of chronic MDMA usage on a wide battery of cognitive tests and psychological abilities and processes.Methods In the present study, the performance of 17 participants with a history of MDMA use was compared to the performance of 15 control subjects on a battery of neuropsychological tests. This battery included tests for depression, immediate word recall, delayed recall, attention and working memory.Results Results indicated that the MDMA group had significantly higher scores for depression than the control group, and displayed poorer delayed recall and verbal learning than controls after accounting statistically for the effects of cannabis and depression.Conclusions These results suggest that MDMA users exhibit difficulties in coding information into long-term memory, display impaired verbal learning, are more easily distracted, and are less efficient at focusing attention on complex tasks.     

Effect of diazepam on the speed of mental rotation

The effect of diazepam on spatial visualization was studied using a double-blind crossover design. Diazepam 10 mg (or placebo) was given orally to 12 healthy young men at bedtime, followed again by 10 mg (or placebo) the next morning. One hour after the administration of the morning dose, the subjects performed a mental rotation task. Diazepam effects were analyzed in terms of an information processing model previously constructed to account for performance of the task. Using this method, the slope and intercept parameters of a linear function relating reaction time to task condition (i.e., angular difference in orientation between two identical stimulus figures) were computed for diazepam and placebo conditions. Diazepam significantly increased the slope and intercept of the mental rotation function (P<0.05). These results suggest that diazepam impairs spatial visualization ability. Present address: Psychiatry Service (116A3), Veterans Administration Medical Center, 3801 Miranda Avenue, Palo Alto, CA 94304, USA     

Mood effects of diazepam and caffeine

Changes in mood after administration of Diazepam and Caffeine were analyzed. Six aspects were studied: pleasantness, activation, extraversion, calmness, social orientation and control. In addition to this check list, mood ratings using magnitude estimation of selected adjectives were obtained. It was found that Diazepam decreased feelings of activation and extraversion and increased calmness. Caffeine had no clear effects on the check list, but on the magnitude estimation scale some effects opposite to those of Diazepam were observed. Men reported a higher degree of pleasantness than women after administration of Diazepam. No differences in heart rate were found. Few distinct scale values were utilized on the magnitude estimation scale and the discriminative power was found to be larger for the check list than for the magnitude estimation scale.     

Psychomotor performance: investigating the dose-response relationship for caffeine and theophylline in elderly volunteers

Objective: The aim of this study was to investigate the dose-response relationship for psychomotor performance, caffeine and theophylline in healthy elderly volunteers. Methods: In a randomized, double-blind, placebo-controlled, six-period cross-over study we compared the effect of three doses of theophylline (predicted peak concentrations of 3, 6 mg · l⁻¹ and 12 mg · l⁻¹), two doses of caffeine (predicted peak concentrations of 4.5 mg · l⁻¹ and 9 mg · l⁻¹) and placebo on ten healthy elderly volunteers. Psychomotor performance was measured using a continuous attention task, symbol digit substitution test and choice reaction time. Subjective effects were assessed using visual analogue scales. Following drug administration, subjects received the test battery at 30-min intervals, up to 150 min. Maximum and mean effects from baseline on each variable were included in the analysis. Results: Significant improvement on the continuous attention task was seen at the lowest concentration of caffeine and theophylline used, while at higher concentrations there was a non-significant trend towards placebo scores. There was little effect of either drug on the subjective effects measured by visual analogue scales. Conclusion: Caffeine and theophylline increase psychomotor performance measures of attention at low plasma concentrations in healthy elderly volunteers. This effect is not increased by higher drug concentrations and there is trend towards a return to placebo scores. The lack of effect of both caffeine and theophylline on subjective measures is consistent with previous studies of caffeine in the elderly. Received: 11 December 1997 / Accepted in revised form: 18 March 1998     

Adverse effects of single therapeutic doses of diazepam on performance in normal geriatric subjects: Relationship to plasma concentrations

Elderly normal volunteers (N=12, mean age 70.4 years) were administered placebo or diazepam 2.5, 5, 10 mg in four consecutive sessions separated by at least a 1-week interval. Memory and psychomotor performance and plasma diazepam concentrations were assessed at baseline and at 1 and 3 h following drug administration. Significant impairments were found in response to all doses of diazepam. The maximum impairment occurred at 1 h, which coincided with the highest plasma concentration of the drug.     

Tofisopam,a novel 3,4,-benzodiazepine: Multiple-dose effects on psychomotor skills and memory. Comparison with diazepam and interactions with ethanol

Twelve healthy male volunteers were treated (double-blind crossover design) with tofisopam (a new 3,4-benzodiazepine), diazepam, or placebo, on 2 consecutive days each. Psychomotor skills were impaired after a single dose of diazepam (10 mg) given on day 1. Measurements on day 2 showed that some tolerance had developed to the diazepam-induced impairment of reactive and coordinative skills, but not to its effects on flicker fusion or on the extraocular muscle balance. Tofisopam failed to impair performance both as a single dose (100 mg) and after repeated doses (100+50+50+100 mg). The subjects felt more fatigue, dizziness, calmness, and passiveness after diazepam than after tofisopam. When either drug was given together with 0.8 g/kg ethanol on day 2, the breath ethanol concentrations were 0.7–1.0 mg/ml and all psychomotor skills were impaired. Diazepam+ethanol particularly impaired memory and learning as well. After this combination the subjects were classified (time anticipation test) as disqualified drivers more often than after placebo. It is concluded that diazepam,as well as either benzodiazepine with ethanol, may reduce the ability to drive vehicles or operate machinery.     

Memory and performance effects of single and 3-week administration of diazepam

The effects of diazepam on several cognitive and performance tasks were investigated in 30 healthy volunteers randomly assigned to three groups: A chronic group received diazepam for 21 days; an acute group received placebo during the same period, except at session 4 when they received diazepam; and a third group received placebo only at the sessions. Diazepam was given orally in a dose of about 0.2 mg/kg. Behavioral sessions were conducted before treatment (practice), after one administration (session 2), after 19 days (session 3), after 20 days (session 4), and 7 days following withdrawal (session 5). A single administration of diazepam produced significant memory impairment in both immediate and delayed free recall. Reduced memory performance was the result of impaired acquisition rather than reduced retention. Comparison of the chronic and acute groups in sessions 3 and 4 and analysis of the performance of the chronic group over sessions indicated the development of some tolerance to the memory impairment with continued administration. No residual memory effects were apparent following withdrawal. No other cognitive or psychomotor functions differed among the three treatment groups.     

Development of acute tolerance after oral doses of diazepam and flunitrazepam

Flunitrazepam (1 and 2 mg), diazepam (10 and 20 mg) or placebo was administered to healthy, male volunteers, and the time course of psychomotor impairment, as indicated by simple and complex choice reaction time and movement time, was studied during a period of 6 h after drug intake. To examine whether acute tolerance developed, the observed performance during decreasing drug plasma concentration was compared to the predicted performance based on kinetic-dynamic modelling of the observed performance during the first 1.5 h after intake when the drug plasma concentrations were increasing or at peak level. Placebo corrections of the test scores were accomplished to adjust for diurnal variation and the possible influence of learning during the test day. After the flunitrazepam treatments, the predictions overestimated the actual performance significantly with respect to simple and choice reaction time at the 6-h session after intake. After the diazepam treatments, however, no significant deviation was detected between predicted and observed performance. The results indicate that acute tolerance develops with respect to impairment of attention demanding performance after medium to large doses of flunitrazepam, and that tolerance is expressed after approximately 4–6 h following intake.     

Ecstasy (MDMA) effects upon mood and cognition: before, during and after a Saturday night dance

Three groups of young people (aged 19–30 years) were compared: 15 regular ecstasy users who had taken MDMA (3,4-methylenedioxymethamphetamine) on ten or more occasions; 15 novice ecstasy users who had taken MDMA on fewer than ten previous occasions; and 15 controls who had never taken MDMA. Each subject completed a cognitive test and mood scale battery four times: an initial drug-free baseline, at a Saturday night dance/club (on-drug), then 2 days later, and 7 days later. On the Saturday night, regular ecstasy users took an average of 1.80 MDMA tablets, novice users took 1.45 MDMA tablets, while controls mostly drank alcohol. The consumption of cannabis and cocaine at the club was similar across groups. All three groups reported positive moods at the dance club (on-drug), although there were borderline trends (P < 0.10) for less sadness/depression in the MDMA subgroups. However 2 days afterwards, the ecstasy users felt significantly more depressed, abnormal, unsociable, unpleasant, and less good tempered, than the controls. Cognitive performance on both tasks (verbal recall, visual scanning) was significantly reduced on-MDMA. Memory recall was also significantly impaired in drug-free MDMA users, with regular ecstasy users displaying the worst memory scores at every test session. This agrees with previous findings of memory impairments in drug-free ecstasy users. Animal data have shown that MDMA can generate long-term serotonergic neurodegereration in various brain areas, including the hippocampus. The cognitive deficits in drug-free recreational ecstasy users, suggest that MDMA may also be neurotoxic in humans. Received: 3 November 1997/Final version: 27 February 1998     

Psychomotor performance in smokers following single and repeated doses of nicotine gum

The psychomotor effects of single and repeated doses of 2 mg nicotine gum were investigated in 13 regular smokers who had abstained from tobacco overnight. In comparison to baseline, a first dose of nicotine led to significantly raised critical flicker fusion thresholds, faster motor reaction times, improved compensatory tracking performance, and faster short-term memory reaction times. Performance after a second and third dose of nicotine remained significantly improved on all measures in comparison to baseline, and absolutely improved when comparing first and third nicotine doses on measures of sensorimotor performance. Throughout, comparisons with a placebo gum condition confirmed that these effects were genuine and not subject to the development of acute nicotine tolerance, suggesting that the enhancement of psychomotor performance experienced by smokers after a first cigarette may be maintained by repeated smoking.     

Models of memory dysfunction? A comparison of the effects of scopolamine and lorazepam on memory,psychomotor performance and mood

The effects on memory, psychomotor functions and mood of intramuscular scopolamine (0.3 mg, 0.6 mg) were compared with those of oral lorazepam (2 mg) and placebo. Thirty-six volunteers took part in a doubleblind, independent groups design. Subjects completed a battery of tests 1 and 3 h after drug administration. Both doses of scopolamine produced levels of sedation comparable to that produced by lorazepam. The time course of effects of scopolamine and lorazepam differed but the pattern of psychomotor impairments and amnestic effects produced was very similar. In terms of mood, lorazepam had an anxiolytic effect whereas scopolamine increased ratings of anxiety. Levels of sedation, indexed by either subjective ratings or motor retardation (tapping speed), were related more to psychomotor performance than to performance on memory tasks. The results suggest that benzodiazepines and scopolamine have similar amnestic and sedative effects and as such may not offer distinct models of memory dysfunction.