The effects of multivitamin supplementation on mood and general well-being in healthy young adults. A laboratory and at-home mobile phone assessment.

Previous research has suggested that multivitamin (MV) supplementation may be associated with beneficial effects for mood and general well-being, although treatment durations have typically been less than 90 days, samples have often been restricted to males only and acute effects have not been adequately differentiated from chronic effects. In the current study a MV supplement containing high levels of B-vitamins was administered daily to 138 healthy young adult participants between the ages of 20 and 50 years over a 16-week period. Chronic mood measures (GHQ-28, POMS, Chalder fatigue, PILL, Bond-Lader and custom visual analogue scales) were administered pre-dose at baseline, 8- and 16-weeks. Changes in Bond-Lader and VAS in response to a multi-tasking framework (MTF) were also assessed at 8- and 16-weeks. For a subset of participants, at-home mobile-phone assessments of mood were assessed on a weekly basis using Bond-Lader and VAS. No significant treatment effects were found for any chronic laboratory mood measures. In response to the MTF, a significant treatment x time interaction was found for STAI-S, with a trend towards a greater increase in stress ratings for male participants in the MV group at 16 weeks. However, this finding may have been attributable to a larger proportion of students in the male MV group. In contrast, at-home mobile-phone assessments, where assessments were conducted post-dose, revealed significantly reduced stress, physical fatigue and anxiety in the MV group in comparison to placebo across a number of time points. Further research using both acute and chronic dosing regimens are required in order to properly differentiate these effects.

Neurocognitive and mood effects of alcohol in a naturalistic setting.

OBJECTIVE: The current pilot study aimed to assess the effects of drinking alcohol in a naturalistic setting on aspects of performance. METHODS: Thirty individuals were approached and tested individually in a university campus bar. They provided details regarding alcoholic drinks consumption. Each was breathalysed before and after completion of a computerised test battery administered on a handheld device. The battery consisted of visual analogue mood scales, a series of alcohol-sensitive psychomotor and cognitive tests. RESULTS: There were highly significant correlations between measured blood alcohol concentrations, estimated units of alcohol consumed and scores on a 'sober-drunk' VAS (p < 0.001 in all cases). For performance, there was a characteristic alcohol-associated shift in the speed/accuracy trade-off (SATO), which was reflected as significantly more errors with less effect on speed across several measures (including maze performance and Serial Sevens). Individuals who were more intoxicated were also significantly less alert. CONCLUSIONS: The data suggest that controlled laboratory tests into the effects of alcohol intoxication may have ecological validity, with SATO shifts amongst the characteristic impairments seen in both controlled and naturalistic settings.

Evaluation of a new method of assessing depth of sedation using two-choice visual reaction time testing on a mobile phone.

The utility of two-choice visual reaction time testing using a specially programmed mobile telephone as a measure of sedation level was investigated in 20 healthy patients sedated with target controlled infusions of propofol. At gradually increasing target concentrations visual reaction time was compared with patient-assessed visual analogue scale sedation scores and an observer-rated scale. Propofol sedation caused dose-dependent increases in visual reaction time and visual analogue scale scores that were statistically significant when the calculated effect-site concentration reached 0.9 microg.ml(-1) (p < 0.05) and 0.5 microg.ml(-1) (p < 0.01) respectively. While visual analogue scale scores were more sensitive at lower levels of sedation than visual reaction time, the latter demonstrated marked increase in values at higher levels of sedation. Visual reaction time may be useful for identifying impending over-sedation.

Comparison of the sedative, cognitive, and analgesic effects of nitrous oxide, sevoflurane, and ethanol.

BACKGROUND: Anaesthetics which work by different mechanisms may have different patterns of effect. Measurement of these patterns thus may elucidate their mechanisms of action and allow therapeutic choices between the agents. METHODS: We compared the effects of ethanol (approximately 80 mg per 100 ml), and different end-tidal concentrations of nitrous oxide (15% and 25%) and sevoflurane (0.3% and 0.5%) in volunteers. We measured speed and accuracy in psychomotor tests, reaction time and memory, touch and pain sensitivity to von Frey filaments, and subjective mood for a range of descriptors. RESULTS: All treatments caused the same degree of overall abnormal feelings, but sevoflurane caused more obtunding (subjective drowsiness, slow reaction times, and loss of memory function) and nitrous oxide was more analgesic. Ethanol caused a marked feeling of drunkenness, but little drowsiness or analgesia. CONCLUSIONS: In the same volunteer subjects, direct comparison of sub-anaesthetic doses of these agents showed a clear and characteristic pattern of effects. These support the possible mechanisms for these disparate agents and may help choose appropriate agents for specific desired anaesthetic outcomes such as sedation or analgesia.

Cognitive functioning in polycystic ovary syndrome.

To date there have been no published studies of cognitive functioning in polycystic ovary syndrome (PCOS). This large internet-based study compared neuropsychological functioning in right-handed women with (minimum n=135) and without PCOS (minimum n=322), stratified according to use of anti-androgen medication and level of depression. Women with PCOS are thought to have hyperandrogenism and hyperestrogenism which was hypothesized to differentially influence cognitive function across cognitive domains. Performance did not differ according to diagnosis on mental rotation and spatial location tasks. Hence, no evidence to support the view that women with PCOS display a more masculine cognitive profile due to hyperandrogenism. Despite presumed hyperestrogenism, women with PCOS demonstrated impaired performance in terms of speed and accuracy, on reaction time and word recognition tasks. These findings are intriguing given the well-documented roles of estrogen and testosterone in cognitive function. Overall, these findings suggest that PCOS is not associated with masculinized cognitive functioning, and, although associated with impaired performance on tasks considered to demonstrate female-advantage, such impairments are subtle and are unlikely to affect daily functioning.

The effects of age on the response to caffeine.

Twelve healthy subjects, six young and six elderly, of either sex, took part in this two-period crossover study. In each session, a dose of trial drug--either 200 mg caffeine or a matching placebo--was given orally at 0900 hours. A battery of psychomotor tests and visual analogue scales was administered before treatment and at 1, 2 and 3 h post-treatment. The objective tests showed a significant increase in tapping rate in the young, while the elderly showed improved attention, faster choice-reaction time, and greater body sway on caffeine. The visual analogue scales showed that the young subjects felt more alert, calmer, more interested, and steadier on caffeine, while no significant changes were seen in the elderly. These results show that caffeine produces changes predominantly in the direction of improved performance and feeling of well-being, and suggest that the elderly are more sensitive to the objective effects of the drug, while reporting less subjective effect than the young.

A study of the effects of zimelidine on the pharmacokinetics and pharmacodynamics of temazepam in healthy volunteers.

In this double-blind two-period crossover study, ten healthy volunteers received either 200 mg zimelidine each morning for 5 days, or placebo on the same schedule. On day 5 they received 20 mg temazepam 2 h after zimelidine or placebo. A battery of psychometric tests and subjective measurements was carried out on days 4 and 5. Blood samples were collected on day 5 for pharmacokinetic analysis of temazepam. All the measures of psychomotor performance showed the effects of temazepam, as did two of the subjective measures, the "alert/drowsy" and "steady/dizzy" visual analogue scales. No effect of zimelidine alone on performance or subjective state was seen. Zimelidine showed no discernible interaction with the effects of temazepam as assessed by subjective reports, by psychomotor tests, or by pharmacokinetic analysis.

"First-dose" response to mianserin: effects of age.

The effects of single 10 mg oral doses of the antidepressant mianserin on psychomotor performance, subjective sedation and supine and standing blood pressure were compared in ten young and nine elderly healthy volunteers. Immediate and residual sedation following this subtherapeutic dose was readily detected in both groups. In contrast to previous studies with benzodiazepines, the sedation effect was not accentuated in the older subjects. Subjective awareness of sedation was significant in the young but not, however, in the elderly. "First-dose" postural hypotension, presumably due to post-synaptic alpha-blockade also occurred in young subjects only. Caution may be needed on initial dosage of mianserin in young individuals who drive or undertake skilled tasks and in the elderly who may be unaware of psychomotor impairment. The reported alpha 2 receptor selectivity of mianserin might explain the lack of postural effects in the elderly, and might constitute a potentially useful characteristic in the development of new compounds.

Effects of amitriptyline and zimelidine in combination with ethanol.

Six healthy male volunteers took part in this three-period crossover study. In each session, a dose of trial drug -- either placebo, zimelidine 200 mg, or amitriptyline 75 mg -- was given at 09.00 h. Ethanol (50 g) was taken orally at 1200 h. Blood samples were taken for measurement of drug and ethanol concentrations, and body sway and subjective sedation were determined. No differences in the pharmacokinetics of ethanol were seen between the three treatment sessions. Amitriptyline and ethanol showed marked sedative effects, and the results suggest that these two effects may be additive. The combination of amitriptyline and ethanol results in a particularly marked increase in body sway. No sedative nor alerting effect of zimelidine was seen, nor was any interaction between zimelidine and ethanol apparent.

Effects of nitrous oxide on psychological performance. A dose-response study using inhalation of concentrations up to 15%.

In this six-period randomised double-blind study, 12 healthy volunteers inhaled mixtures of nitrous oxide at concentrations of 0% (placebo); 3%, 5%, 7%, 10%, and 15% in oxygen. Each concentration was inhaled for 55 min, each period being on a separate day. The order of treatments was randomised using a Latin-Square design. The effects of nitrous oxide were assessed using a battery of performance tests which included measures of attention, psychomotor function, memory and cognition. Mood was assessed using visual analogue scales. Measures of attention and psychomotor performance showed impairment at 15% nitrous oxide, and subjective measures showed sedation at this dose. The Buschke Selective Reminding Task showed impairment to long-term recall at all doses of nitrous oxide compared to placebo, while short-term recall was impaired only at 15%. These results suggest that consolidation of memory may be particularly sensitive to disruption as a result of CNS depression.

Effects of remoxipride on measures of psychological performance in healthy volunteers.

The acute psychomotor effects after oral doses of 30, 60 and 120 mg remoxipride, a new selective D2 receptor blocker, and placebo were investigated in a double-blind crossover study in 11 healthy male volunteers. Two out of the first three subjects given 120 mg remoxipride experienced marked akathisia, and therefore no subsequent subjects were given this dose. There were no other clearly drug-related adverse effects reported below 120 mg, although restlessness was reported at 60 mg. Remoxipride was associated with increases in error scores on a continuous attention task and on auditory vigilance, and with a reduction in critical flicker frequency, suggesting a decrease in arousal level. There were no significant changes in psychomotor measures such as choice reaction time, decision making time, or body sway. Subjective assessments using visual analogue scales showed a slight dose-related increase in drowsiness, while the calm-excited scale showed a small change in the excited direction with 30 mg only. The peak effects were at 4-6 h after drug intake, which was later than expected from previous pharmacokinetic data. These results indicate that remoxipride may have a slight depressant effect in the dose-range used. The pattern of changes is consistent with current theories on the role of dopamine in attention and arousal, and with the effects of other neuroleptics. It differs, however, from tranquilisers such as the benzodiazepines, which show a more global pattern of effects.

A dose-response study of the effects of inhaled nitrous oxide on psychological performance and mood.

In this five-period randomised double-blind crossover study, 12 healthy volunteers inhaled mixtures of nitrous oxide at concentrations of 0% (placebo); 5%, 10%; 20% and 40% in oxygen. Each concentration was inhaled for about 1 h, each period being on a separate day. The effects of nitrous oxide were measured using a comprehensive battery of performance tests including measures of attention, psychomotor function, memory and cognition. Mood was assessed with visual analogue scales. All tests except critical flicker fusion showed substantial effects at the highest does (40%). No measure showed evidence of change at the lowest concentration (5%). Several measures showed significant impairment at 10%, viz: digit-symbol substitution, choice reaction time (latency and total), tapping, and continuous attention. Subjects felt dizzy and muzzy on nitrous oxide, but no significant effect was seen on the Alert-Drowsy VAS. The dose-response profiles of the various tests showed substantial differences. Thus tapping was virtually linear, while choice reaction motor time and body sway showed steeply accelerating impairment with increasing dose. These results indicate that comparisons of profiles of drug-induced change must take into account the variable effects of dose before interpretations in terms of specific drug effects can be made.

Validity and sensitivity of a pen computer battery of performance tests.

This study compared administration of performance tests and visual analogue scales (VAS) using a newly developed pen computer (PenC) battery with established tests using either pencil-and-paper (PP) or conventional computer. The performance of 47 subjects (23 male, age 18-45 years, weight 51-112 kg) was compared on the two systems after a dose of ethanol (0.8 g/kg up to a maximum of 60 g for males, 50 g for females) or placebo in a double-blind two-period randomized crossover study. Mean (SD) blood ethanol concentrations (breathalyser) were 94.5 mg/100 ml (21.9) at the start of the test battery (30 min post-drink) and 80.2 (13.0) at the end of the battery (75 min post-drink). Ethanol effects were found in all tests, with most outcome measures showing significant slowing or loss of accuracy. Results from the Rapid Visual Information Processing, Sentence Verification and Continuous Attention tasks show that the ethanol-placebo difference and the statistical significance of this difference are in close correspondence for the two modes of administration. The pen computer versions of these tasks may therefore be used as direct replacements for the previous versions. Digit-Symbol and maze tasks did not correspond so closely both showing differences in the speed-accuracy trade-off between the two modes. These tests, however, are sensitive to the effects of ethanol, and may be useful in their own right. Principal component analysis suggested that VAS may be grouped into two factors: (1) 'functional integrity', including measures of alertness and perceived proficiency, and (2) 'mood', including happiness and sociability. Factor 1 showed substantial effects of ethanol, while factor 2 was unchanged. There was close agreement between the results from PP and PenC for both factors as well as for the Sober-Drunk scale, which showed the expected effects of ethanol. Thus pen computer VAS perform in a similar way to the PP versions.

Effects of ethanol on psychomotor performance under steady-state conditions.

Ethanol was administered to eight male volunteers using an oral loading dose followed by repeated small oral doses to achieve approximate steady-state drug concentrations in a double-blind placebo controlled cross over design. Ethanol or placebo were administered over a 5-h period in two sessions at least 7 days apart. The effects of ethanol were assessed using a short battery of psychomotor tests and visual analogue scales which was administered repeatedly during the steady-state period, and a long battery administered once before and once during the steady-state period. The concentrations of ethanol in plasma and breath were determined at 20-min intervals. Mean plasma concentrations of 94 mg/100 ml were obtained. Ethanol produced a clear impairment to psychomotor performance, with a 41% increase in body sway, a 61% increase in errors on a maze task, a 6.5% reduction in digit-symbol substitution and an 8% slowing in tapping. Subjective feelings of drunkenness and sedation were noted. No measure showed evidence for acute tolerance, as assessed by comparison of the slopes fitted to the performance measures in the short battery.

Effects of chlormethiazole on psychological performance under conditions of constant plasma concentrations.

Chlormethiazole was administered intravenously to six healthy volunteers (four male, two female, aged 20-33 years) using a loading dose followed by a maintenance infusion lasting ∼ 90 min. Doses were individually calculated from previous pharmacokinetic investigations in these subjects to produce a target steady-state plasma concentration of 1.5 µg ml(-1). Effects of chlormethiazole were determined using a short battery consisting of digit-symbol substitution, body sway and visual analogue scales, which was performed repeatedly before, during and after the active infusion. A more comprehensive battery of performance tests was performed once before and once during the active infusion. The mean plasma concentration of chlormethiazole obtained was 1.33 µg ml(-1). This produced marked sedation, with subjects scoring themselves as much more drowsy on chlormethiazole than on placebo, and global impairment to performance. An analysis of the slopes of scores on the performance tests in the short battery showed no evidence of a diminution of the effects of chlormethiazole over the infusion period. The same was true of the majority of the visual analogue scales, but two scales, rating eye symptoms and nose symptoms, did decline over the period of the infusion. Recovery was rapid, subjects returning to approximately baseline levels of performance within 30 min of discontinuation of the infusion. These results suggest that acute tolerance to the CNS effects of chlormethiazole does not occur over this time scale, but is found for peripheral effects such as eye and nose symptoms.

Effects of caffeine on vigilance and other performance tests in normal subjects.

In two randomized double-blind crossover studies, 8 and 10 healthy volunteers took either 200 mg caffeine or placebo. Objective and subjective measures of caffeine effects were carried out over the following 1-3.5 h. Auditory vigilance, a test lasting 1 h, showed significantly better performance on caffeine than on placebo. In the second study, this effect was only apparent in the second half of the test. Of the shorter objective tests used, only finger tapping showed a significant effect of caffeine, the rate of tapping over 1 min being increased. The subjective assessments showed increased interest and alertness in the caffeine session. Reliable detection of the effects of mild stimulant drugs using objective measures may require the use of tests of long duration.

Errors in performance testing: a comparison of ethanol and temazepam.

Both ethanol and benzodiazepines impair psychomotor function. Previous work has suggested that ethanol may have a greater effect on errors while benzodiazepines may cause greater slowing, but this has not been tested in a direct comparison. We assessed the effects of ethanol, at blood concentrations of approximately 80-100 mg/100 ml, compared to two doses of temazepam (20 mg and 30 mg) on psychomotor speed and accuracy and on long-term memory. Sixteen healthy volunteers (eight male, aged 20-25 years) took part in a four-period, placebo-controlled cross-over study. Performance was evaluated using analysis of covariance (critical significance level, p = 0.05) comparing the areas under the response-time curves. Performance on a psychomotor maze showed an almost complete dissociation, with ethanol leading to a substantial and significant increase in errors with little effect on speed, while temazepam slowed performance with no significant change in accuracy. Other tasks showed a similar pattern, but the dissociation was less complete. Handwriting size was substantially increased by ethanol, but not by temazepam. Information processing capacity and long-term memory formation were reduced by a similar amount both for ethanol and 30 mg temazepam. The faster, more error-prone, behaviour on ethanol than with a similarly impairing dose of temazepam has clear implications for the relative potential of the two drugs to contribute to accidents. The results are also important in understanding the differential effects of drugs with different mechanisms of action on human performance.

Effect of ethanol on psychomotor performance and on risk taking behaviour.

Ethanol may increase the willingness to take risks, but this issue remains controversial. We used a risk-taking paradigm in which volunteers answered a series of general knowledge questions with numerical answers and were asked to judge the length of a line that would just fit into a given gap. A maximum score was given for an exactly correct answer. For answers that were less than the correct value, the score was reduced gradually to zero, while answers even slightly over the correct value were penalized considerably. Total points were rewarded by cash payments, so volunteers were taking real risks when making their responses. Performance was assessed in a two-period, double-blind crossover study, comparing ethanol (0.7 g/kg) with placebo in 20 female volunteers aged 19-20 years. Tests were carried out before and at 45 min after dosing. Mean (SD) ethanol blood alcohol concentrations were 65 (10.5) mg/100 ml. Ethanol impaired the skill/ability measure of the length estimation test (SD of difference between length of line and gap), which increased from 5.9 to 6.6 (p < 0.05), indicating a reduced accuracy of estimation. The risk measures in both tasks were not significantly affected. The skill/ability measure in the general knowledge task was not significantly affected. Other performance tests showed that ethanol produced the expected impairment of both speed and accuracy. These results suggest that risk-taking is not increased by ethanol at doses approaching the UK legal limit for driving.

The effects of inhaled nitrous oxide on some measures of attention.

This study compared the sensitivity of various measures of attention to the effects of CNS depression, using a randomised single-blind two-period cross-over study. Nineteen healthy volunteers, 10 males and nine females, aged 20-49 took part in a single session in which they inhaled 15% nitrous oxide in oxygen or 100% oxygen (placebo) through a face-mask for 45 min, followed by a 10-min interval after which they received the other treatment in counterbalanced order. They performed a battery of five attention tasks and completed visual analogue scales starting 10 min after the beginning of each inhalation period. The most sensitive measures of the effects of this dose of nitrous oxide were letter cancellation, which had three target letters to cancel, and an auditory attention task with different stimuli to the two ears. Measures of concentrated attention without distractors (continuous attention task and continuous performance task) were less sensitive, though clear effects were seen at these doses. Tests of differing complexities may involve distinct functions which could be differentially affected by different classes of drug. Thus both simple and more complex tasks should be represented in studies assessing attentional function in detail.

Single dose pharmacodynamics of thioridazine and remoxipride in healthy younger and older volunteers.

Phenothiazines are widely used in older patients, but little experimental work has been carried out in this age group. Two groups of healthy volunteers, a younger group (Y: six males and six females, aged 20-42 years) and an older group (O: six males and eight females, aged 65-77 years) took part in a randomized double-blind three-period crossover study in which they received by mouth single doses of thioridazine (Y: 50 mg; O: 25 mg) remoxipride (Y: 100 mg; O: 50 mg) or placebo. Measures of central nervous system (CNS) and haemodynamic function were carried out before drug administration and at 1.5-h intervals up to 9 h post-dose, and blood samples were collected over a 24-h period. No significant differences in dose-corrected pharmacokinetic variables were found between the two groups. There was evidence of marked CNS depressant effects of thioridazine from both objective and subjective measures. The effects for remoxipride were similar, though generally less marked. After allowance was made for dose, there was little indication of any difference in degree of CNS depression between the two age groups. Haemodynamic measures showed orthostatic reductions in blood pressure with thioridazine which were particularly marked in the older group, who also showed lower compensatory increases in pulse rate. These results indicate potential problems with orthostatic hypotension with thioridazine in older patients. CNS depression may also be a problem, especially in patients with compromised cholinergic function.