Effects of zimeldine,mianserin and amitriptyline on psychomotor skills and their interaction with ethanol a placebo controlled cross-over study

Summary 13 healthy volunteers participated in a double-blind, four-period, cross-over study. In each period, the trial drugs (placebo, zimeldine, amitriptyline and mianserin) were given in fixed dosages for 8 days; amitriptyline 10–50 mg twice daily, mianserin 10–30 mg twice daily and zimeldine 200 mg once daily. Ethanol 1 g/kg bodyweight was drunk 2 hours after drug intake on Days 1 and 8 of each period, the latter being separated by a 2 week wash-out period. Ratings of subjective feelings and side effects, and performance tests were done on Days 1 and 8 of each period before, 1.5, 3 and 4.5 h after drug intake, i.e. 2 of the tests were performed under the influence of ethanol. Mianserin decreased critical flicker frequency, slowed reactions under discriminative stimulation and tended to cause nystagmus, but only on Day 1 (after the first 10 mg dose). Amitriptyline impaired coordination on Days 1 (after the initial 10 mg dose) and 8, and lowered the flicker threshold on Day 8 at steady state (after the 50 mg morning dose). Both these antidepressants were felt to be sedative, especially in the initial phase of the treatment, and they interacted additively with ethanol. No impairment of psychomotor skills was associated with zimeldine, only a subjective sedative effect of the 200 mg dose was seen on Day 1. Zimeldine did not enhance the effects of ethanol; it even showed some antagonism of ethanol-induced body sway in the standing steadiness test. In contrast to amitriptyline and mianserin, zimeldine was regarded as not harming psychomotor skills, and as not having any observable interaction with ethanol.     

The psychopharmacological effects of repeated doses of fluvoxamine,mianserin and placebo in healthy human subjects

Summary The psychopharmacological effects of fluvoxamine, 50 mg twice a day, were compared with those of mianserin, 20 mg twice a day, and placebo, each given for 8 days in a double-blind crossover design to 9 healthy human volunteers.At least one week was left between the 8-day courses of drugs. Testing was carried out before and 3 h after taking the morning dose on Days 1 (predrug), 4, and 8, and comprised EEG, cognitive and psychomotor tasks, and self-ratings of mood and bodily symptoms.Fluvoxamine had no effect on any of the EEG wavebands, but mianserin increased voltages in the slow wavebands as compared with placebo. This effect was particularly pronounced on Days 4 and 8.Mianserin significantly decreased critical flicker fusion frequency and speed of reaction time, and slowed down tapping rate; digit symbol substitution and symbol copying test performances were also impaired by mianserin. These effects were most marked after the first dose and had lessened somewhat later in the week. Symbol copying was the only task impaired by fluvoxamine as compared with placebo.Mianserin caused drowsiness after the first dose but this effect declined by Day 8. By contrast, fluvoxamine induced feelings of anxiety, sweatiness, trembling, nausea, loss of appetite, restlessness, muscle tension, irritability, tiredness, headache, and dizziness; these effects were most evident in the middle of the week and relatively reduced at the end of the week. Mianserin produced a few of these effects but they tended to be maximal on Day 1 or 4 and then to wear off.It was concluded that fluvoxamine is much less likely to produce psychomotor and cognitive impairment on repeated usage than is mianserin, but that some adverse effects, particularly nausea, may be troublesome. Fluvoxamine would seem more appropriate in patients in whom sedation is not required, mianserin in those in whom initial sedation is acceptable.     

Dissociations in the expression of the sedative effects of triazolam

Fifteen normal volunteers were administered 0.250, 0.375, and 0.500 mg of triazolam and placebo in a double-blind repeated measures cross-over design. Subjects demonstrated dose-dependent impairments in free recall, a test of explicit memory requiring awareness and reflection, and sedation as assessed by objective behavioral measures (the digit symbol substitution task) and subjective visual analogue scales. The sedative drug response did not account for the impairment in free recall. Differences in performance of the two tests of sedation indicated that the effect of this drug on reflective processes accounts for impairment in episodic memory and the inability to track the sedative effects of this drug at the higher doses tested in this study.     

Effects of single and multiple doses of a new reversible MAO-A inhibitor,befloxatone, on psychomotor performance and memory in healthy subjects

The effects on memory, psychomotor performance and mood of two dosage regimens of befloxatone, a new reversible and selective MAO-A inhibitor were assessed in a randomized, double-blind, cross-over, placebo-controlled study involving 12 healthy young male volunteers. Befloxatone and a placebo were orally administered as single (5 and 10 mg) and repeated doses (10 mg once daily and 5 mg twice daily) at one week wash-out intervals. Objective tests evaluated both memory (working memory, immediate and delayed free recall of a word list, dual coding and faces recognition) and vigilance continuous performance task (CPT), and digit symbol substitution (DSST). Subjective mood and sleep were assessed using visual analogue scales and the Leeds Sleep Evaluation Questionnaire. Statistical analysis was conducted using an ANOVA with pairwise comparisons using the Student Newman Keuls procedure. Both dosage regimens of befloxatone (10 mg once daily or 5 mg twice daily) were free of any detrimental effect on vigilance (CPT) and information processing (DSST) and did not significantly disrupt short- and long-term memory (working memory, free recall of words, dual coding and faces recognition). In addition, no subjective sedation or sleep disturbances were recorded. In conclusion, this study gives no evidence to suggest that befloxatone, at a daily dose which shows potent MAO-A inhibition, has any sedative or amnestic properties likely to interfere with the activities of everyday-life in young subjects and therefore may be safely administered in depressed outpatients.     

Effects of diazepam on cognitive processes in normal subjects

The effects of 10 mg orally-administered diazepam on various aspects of cognition were examined in ten male subjects. Diazepam produced a subjective sense of cognitive impairment and impaired auditory vigilence, immediate recognition of twice presented words, and context-dependent free recall. There was a trend for a significant proportion of subjects to show impairment in delayed recognition of twice-presented words. There was no impairment of context-independent semantic memory, or of subjects' ability to judge how well they had performed on the free recall task. In fact, subjects' subjective sense of cognitive impairment was correlated with their performance on context-dependent memory tasks.     

Effects of tiapride on electroencephalograms and cognitive functions in the elderly.

Tiapride is a substituted benzamide with selective dopamine D2 and D3-antagonist properties which appears to have preferential affinity for extra-striatal dopamine receptors. Tiapride is used in the treatment of agitation, aggressiveness and anxiety in the elderly. To define the effects of a single dose of tiapride 100 mg on psychomotor performance and cognitive functions and electroencephalogram (EEG), a randomized, double-blind, three-way crossover, placebo-controlled study using lorazepam 1 mg as a positive control was carried out in 12 elderly individuals (six women and six men, mean age +/- SD: 69 +/- 3 years). A 1-week wash-out interval was allowed between each administration. Psychomotor and cognitive functions were assessed using both objective [EEG, critical flicker fusion, simple reaction time, tapping, body sway, continuous performance task (CPT), digit symbol substitution test, Sternberg memory scanning and a learning memory test using word lists] and subjective (visual analogue scales) measures before and up to 6 h after dosing. Tiapride was devoid of any detrimental or sedative effects on EEG and all of the performance tasks used and did not impair memory compared with-placebo. In contrast, a single dose of lorazepam produced significant deleterious effects on psychomotor performance (decrease in tapping and in sustained attention (CPT) and an increase in reaction time and body sway), and sedative effects on EEG (significant increase in delta and decrease in alpha waves) as well as significant impairment in working memory (Sternberg) and anterograde amnesia (decrease in immediate and delayed free recall) up to 6 h after dosing compared with placebo and tiapride. In conclusion, the present study showed that in contrast to lorazepam 1 mg there is no evidence to suggest that a single dose of tiapride 100 mg has any sedative and amnestic effects in the elderly which may interfere with everyday life activities.     

A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 h before awakening

AIMS: To compare the duration of the residual hypnotic and sedative effects of zaleplon with those of zolpidem and placebo following nocturnal administration at various times before morning awakening. METHODS: Zaleplon 10 mg, zolpidem 10 mg, or placebo was administered double-blind to 36 healthy subjects under standardized conditions in a six-period, incomplete-block, crossover study. Subjects were gently awakened and given medication at predetermined times 5, 4, 3, or 2 h before morning awakening, which occurred 8 h after bedtime. When the subjects awoke in the morning, a battery of subjective and objective assessments of residual effects of hypnotics was administered. RESULTS: No residual effects were demonstrated after zaleplon 10 mg, when administered as little as 2 h before waking, on either subjective or objective assessments, whereas zolpidem 10 mg showed significant residual effects on DSST and memory (immediate and delayed free recall) after administration up to 5 h before waking and choice reaction time, critical flicker fusion threshold and Sternberg memory scanning after administration up to 4 h before waking. Residual effects of zolpidem were apparent in all objective and subjective measurements when the drug was administered later in the night. CONCLUSIONS: The present results demonstrate that zaleplon at the dose of 10 mg is free of residual hypnotic or sedative effects when administered nocturnally as little as 2 h before waking in normal subjects. In contrast, residual effects of zolpidem are still apparent on objective assessments up to 5 h after nocturnal administration, longer than has been reported from studies involving daytime administration.     

Temazepam impairs effortful but not automatic processing of stimulus elements

The experiment investigated the effects in healthy volunteers of a single dose of temazepam (30 mg, oral) on effortful and automatic processing, by measuring memory for information and its context. Effortful processing was impaired, as shown by significant impairments in free recall of an 18-item list, but automatic processing was spared, as evidenced by no impairments in recall of the frequency of presentation, the colour, size or form of the items. In a second task, temazepam significantly impaired both recognition and recency memory of 30 items, although these scores were not correlated. Temazepam caused significant sedation, measured by an objective test and by subjective ratings, but this did not correlate with the memory impairments. The pattern of results is discussed with reference to the hypothesis that the memory impairments resulting from benzodiazepines are due to a reduction in information processing resources and thus affect effortful processing more than automatic processing.     

Male and female C57BL/6 mice respond differently to diazepam challenge in avoidance learning tasks

Benzodiazepines (BZ) impair learning and memory performance of animals. The goal of this study was to examine sex differences in the effects of diazepam on learning and memory of C57BL/6 mice in avoidance paradigms. Male and female C57BL/6 mice were tested in the one-way active avoidance, step-down passive avoidance, and foot-shock pain threshold tasks, following administration of vehicle or diazepam (1 mg/kg). No substantial sex or drug effects on the threshold of the pain response to shock were found. There were no significant differences in avoidance performance between vehicle-treated male and female mice while 1 mg/kg of diazepam produced opposite effects on performance of males and females in both tasks. Diazepam-treated females learned faster in the active avoidance task and showed stronger retention in the passive avoidance task. In contrast, diazepam impaired learning of males in the active avoidance task and had no effect on their performance in the passive avoidance task. Diazepam-induced impairment in males was not due to higher sensitivity to the sedative effect of diazepam as females were more sedated than males on the first trial of the passive avoidance task. Our data showed that sedative and amnesic effects of BZs are not tightly linked. This study also suggests that cognitive effects of BZs in rodents could be sex dependent and highlight the importance of using both sexes in studies on behavioral effects of psychoactive drugs.     

Acute and subchronic effects of Org 2305 and diazepam on psychomotor performance in man.

Three doses (15, 30 and 60 mg) of Org 2305 (O 15, O 30 and O 60 respectively), a novel anxiolytic drug chemically related to mianserin, were compared with placebo and 15 mg diazepam (DZ) on human psychomotor performance in a double-blind, cross-over study with 15 healthy volunteers. Objective measurements (choice reaction, tracking, flicker fusion, Maddox wing, digit symbol substitution, memory recall) and subjective assessments (visual analogue scales) were done at baseline and 2 and 13 h after the first dose. This testing procedure was repeated on day 7 when administering the seventh consecutive daily night-time dose. After the first dose O 15 did not differ from placebo and O 30 rarely differed from placebo. O 60 impaired various objective functions similarly to, or less than DZ. Subjectively, DZ and O 60 were felt as sedative. During subchronic treatment, DZ caused some impairment of baseline due to accumulation of bioassayable benzodiazepines, but significant responses to the last DZ dose were less than those to the first dose. DZ but not O 60 was reported to have caused lethargy and clumsiness during subchronic treatment. In the doses used Org 2305 impaired psychomotor performance less than diazepam did. A dose of 60 mg Org 2305 may offer some advantage over 15 mg diazepam, provided that their anxiolytic effects are about similar.     

Comparative amnesic and sedative effects of lorazepam and oxazepam in healthy volunteers

Oxazepam and its chlorinated derivative, lorazepam, have similar half-lives but differing potencies. This study compared the effects of these two benzodiazepines with a placebo on memory, mood and psychomotor function. Thirty six volunteers took part in a double-blind, independent groups design. Subjects completed a battery of tests before and 2.5 h after drug administration. Lorazepam 2 mg produced more profound subjective and motor sedation than oxazepam 30 mg, and this in turn produced a similar, global pattern of impairments across a wide range of tasks. However, lorazepam produced greater decrements than oxazepam on a task involving episodic memory even when sedative effects were partialled out. We suggest that this finding may reflect either differential task sensitivities or a contribution of priming to performance on the explicit memory task.     

Memory functions, alertness and mood of long-term benzodiazepine users: a preliminary investigation of the effects of a normal daily dose

The effects of a normal daytime dose of a benzodiazepine (BZ) on memory functions and mood were assessed in 20 out-patients who had taken BZs regularly for an average of 10 years. The results implied that these chronic users may have developed tolerance differentially to the sedative, anxiolytic and amnesic effects of one dose of BZ. A daytime dose did not produce subjective sedation. Lack of change in psychomotor performance and certain memory measures may either show tolerance or imply that the drug counteracts a possible practice effect. Anxiety levels decreased markedly after a daily dose, but this does not necessarily imply a purely pharmacological effect. Memory impairments were apparent in terms of increased susceptibility to proactive interference. This impairment was significantly correlated with the dosage of BZ taken.     

Alcohol hangover effects on memory functioning and vigilance performance after an evening of binge drinking.

The impairing effects on memory functioning after acute alcohol intoxication in healthy volunteers and after chronic use in alcoholics are well established. However, research determining the next-morning effects of a single episode of binge drinking on memory functioning is scarce. A total of 48 healthy volunteers participated in a single-blind study comprising an evening (baseline) session, followed by a treatment administration (ethanol 1.4 g/kg or placebo), and a morning session. Memory was tested with a word-learning test (including immediate and delayed recall, and recognition). Further, a 45-min Mackworth clock test for measuring vigilance was included (parameters: number of hits and false alarms) and subjective alertness was assessed, to infer whether word-learning test findings reflect sedation or specific memory impairments. Delayed recall in the morning session was significantly worse in the alcohol group when compared to the placebo group (F(1,42)=6.0, p<0.02). In contrast, immediate recall and recognition were unimpaired in the alcohol group. In the morning session, relative to the placebo group, subjective alertness was significantly reduced in the alcohol group before and after the tests (F(1,44)=8.7, p<0.005; F(1,44)=13.3, p&<0.001, respectively). However, in the Mackworth clock test, the alcohol group and placebo group did not differ significantly in the morning session. The specific findings of impaired delayed recall show that memory retrieval processes are significantly impaired during alcohol hangover. Vigilance performance was not significantly affected, indicating that this memory impairment does not reflect sedation.     

The effects of citalopram in single and repeated doses and with alcohol on physiological and psychological measures in healthy subjects

Summary Citalopram, a selective 5-HT uptake inhibitor with antidepressant properties, was assessed in three studies in 12 healthy subjects using a battery of EEG, psychological, subjective and symptomatic measures.Study A involved the administration of citalopram, 20 mg and 40 mg, amitriptyline 50 mg and placebo in single dose using a balanced cross-over design. The test battery was applied before, and 1 and 3 h after each drug. Citalopram decreased slow-wave EEG activity whereas amitriptyline increased power in most EEG wavebands. Citalopram increased tapping rate and symbol copying whereas amitriptyline impaired these and other psychomotor tasks. Subjectively, amitriptyline was much more sedative than citalopram and produced more complaints of dry mouth.Study B comprised the administration of citalopram in the usual clinical dose of 40 mg, amitriptyline in the low clinical dose of 75 mg and placebo, each given for 9 nights using a balanced cross-over design. The test battery was applied on the first morning (pre-drug) and on the morning after the last nightly dose. None of the physiological tests showed any drug effects. Subjectively, citalopram was associated with feelings of shaking, nausea, loss of appetite and physical tiredness; amitriptyline produced feelings of shaking, nausea, loss of appetite, dryness of mouth, irritability, dizziness and indigestion; in general, amitriptyline effects were more marked than those of citalopram. Plasma samples were taken on the last day and plasma concentrations of both drugs and their metabolites were found to be in the expected range for the regimens used.In the third study (C), 12 healthy subjects took similar courses of citalopram, amitriptyline and placebo. On the morning of the 8th day, a test dose of ethanol was given. The battery of tests was given predrug, on Days 4/5 and on Day 8, before and 1 and 3 h after the ethanol. Amitriptyline increased the 7.5–13.5 Hz waveband. Amitriptyline impaired critical flicker fusion frequency, tapping, DSST and reaction time; citalopram affected DSST and immediate memory recall. The subjective and symptomatic effects of the drugs were similar to those in Study B. Plasma concentrations of citalopram, amitriptyline and their desmethylated metabolites were in the expected range for the regimens used.Ethanol had the expected effects, impairing performance and producing sedation. No evidence for potentiation of ethanol and drug effects were found, most interactions being additive, or even with some symptoms subtractive.It is concluded that in clinical use citalopram should have little or no effect on cognitive and psychomotor performance, produce minimal sedation but some nausea, loss of appetite and insomnia. Interactions with ethanol should be unremarkable.     

Alprazolam and lorazepam effects on memory acquisition and retrieval processes

A double-blind study involving healthy young adult males examined acute effects of two benzodiazepines (alprazolam 1 mg and lorazepam 2 mg) on long-term memory acquisition and retrieval, using Buschke's "selective reminding" task and a free recall task. Subjects learned lists consisting of high and low imagery nouns. The assessments, done at baseline and hourly for 4 hours after drug ingestion, also included two psychomotor tests and subjective ratings by subjects. Both benzodiazepines produced marked memory impairment. Contrary to the prevailing view that benzodiazepines primarily impair long-term memory acquisition rather than retrieval, results from Buschke's task indicated impairment of retrieval as well. This finding may be related to the procedures and assumptions of Buschke's task. The benzodiazepine-induced impairments increased over the course of successive trials on the same list. Both drugs decreased the normal superiority in recall of high imagery words relative to low imagery words, impaired psychomotor performance, and increased subjective sedation. Alprazolam and lorazepam produced equally intense impairments. Alprazolam tended to produce earlier impairment and earlier recovery.     

Triazolam-amphetamine interaction: dissociation of effects on memory versus arousal

It is well-documented that benzodiazepine sedative/hypnotics produce robust dose-dependent memory-impairing effects. However, benzodiazepines also induce marked sedation, as reflected in changes in observer and subjective ratings of arousal and impaired psychomotor performance. Thus, it is possible that the observed amnestic effects are secondary to more global sedative effects, and do not reflect a specific, primary, benzodiazepine effect on memory mechanisms. This study was designed to use the non-specific stimulant d-amphetamine to dissociate the sedative and memory-impairing effects of the benzodiazepine triazolam. Across four sessions, 20 healthy adult volunteers received via oral capsule administration placebo, 0.25 mg/70 kg triazolam alone, 20 mg/70 kg d-amphetamine sulfate alone, and triazolam (0.25 mg/ 70 kg) and d-amphetamine (20 mg/70 kg) conjointly, in a double-blind, staggered dosing, cross-over design. d-Amphetamine significantly reversed the effects of triazolam on all participant rating and psychomotor performance-based measures of sedative effects, and selectively reversed the memory-impairing effects of triazolam on some measures (e.g. working memory assessed by a 2-back task, episodic memory assessed by free recall, metamemory), but not others (e.g. working memory assessed by a digit recall task, episodic memory assessed by recognition memory). Results suggest that benzodiazepines do have specific effects on memory that are not merely a by-product of the drugs' sedative effects, and that the degree to which sedative effects contribute to the amnestic effects may vary as a function of the particular memory process being assessed. In addition to enhancing the understanding of the mechanisms underlying benzodiazepine-induced amnesia, these results may also contribute to a better understanding of the complex relationship between specific memory processes and level of arousal.     

Comparative pharmacodynamics of Ro 41-3696, a new hypnotic,and zolpidem after night-time administration to healthy subjects

In a double-blind, six-way crossover study the effects on psychomotor performance and memory of single doses of Ro 41-3696 (1, 3, 5 and 10 mg), a novel non-benzodiazepine partial agonist at the benzodiazepine receptor, zolpidem (10 mg) and placebo were compared after night-time administration to 12 healthy young male subjects. Psychomotor performance tests (tracking and attention as part of a standardized task battery) were conducted just before and at 1.5 and 8 h after drug intake. The memory test consisted of the recall of a list of 15 words at 8 h after drug intake which had been learned at 1.5 h after intake. At 1.5 h after drug intake 10 mg zolpidem induced markedly larger psychomotor effects than any dose of Ro 41-3696. The effects of 5 and 10 mg Ro 41-3696 and zolpidem were significantly greater than those of placebo (P < 0.05). The following morning, 8 h after drug intake, the slight residual effects of 5 and 10 mg Ro 41-3696 were statistically significantly greater than placebo, whereas zolpidem effects did not differ from placebo. The results of the memory test showed that learning as well as recall were most clearly impaired by zolpidem. An influence of Ro 41-3696 on these variables was not observed for doses up to 5 mg. In conclusion, Ro 41-3696 at all doses tested induced less effects on psychomotor performance and memory than 10 mg zolpidem at 1.5 h after intake. However, the effects of Ro 41-3696 appeared to be of longer duration.     

Verbal memory performance during subchronic challenge with a selective serotonergic and a mixed action antidepressant

OBJECTIVES: Effects of escitalopram 10-20 mg/day and mirtazapine 30-45 mg/day on verbal memory of 18 healthy participants were assessed in a randomized, double-blind, placebo-controlled, three-way crossover trial. METHOD: Each treatment period lasted for 15 days and was separated from the next period by a washout period of at least 13 days. Participants received an evening dose of escitalopram 10 mg, mirtazapine 30 mg, or placebo from days 1 to 7 and an evening dose of escitalopram 20 mg, mirtazapine 45 mg, or placebo from days 8 to 15. On days 2, 9, and 16 a visual verbal memory task was performed measuring drug effects during the acute phase, after dose increase and at steady state. RESULTS: Escitalopram did not affect immediate or delayed verbal memory score throughout treatment. During mirtazapine treatment, participants performed less well in the overall immediate recall score compared to placebo. This impairment was most pronounced in the final trial of the visual verbal learning task. CONCLUSION: Verbal memory was not affected by acute and subchronic escitalopram treatment in healthy participants. Overall immediate verbal memory was slightly but significantly impaired throughout mirtazapine treatment, probably due to a general reduction in overall arousal caused by H1 blockade.     

Does tolerance develop to the sedative and amnesic effects of antidepressants?

Summary The psychomotor, sedative and memory effects of a sedative, anticholinergic antidepressant (amitriptyline), a sedative antidepressant (trazodone) and placebo were compared in a double-blind, cross-over study with 12 healthy volunteers. Amitriptyline (37.5 mg) and trazodone (100 mg) were administered for the first 7 days of treatment and in double-dosage for the next 7 days of treatment. Subjects completed a battery of tests before and 2 h after drug administration on days 1, 8 and 14.Over the 2 weeks of treatment, there was no accumulation of effects but subjects experienced marked sedation and psychomotor impairments following a daily dose of both active drugs. Although both amitriptyline and trazodone produced impairments on memory tasks, the effect of amitriptyline was significantly greater and may reflect its anticholinergic action over and above global sedative effects. Tolerance to the effects of amitriptyline built up differentially over measures of sedation, psychomotor function and memory.     

Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults

The effects of cannabis extracts on nocturnal sleep, early-morning performance, memory, and sleepiness were studied in 8 healthy volunteers (4 males, 4 females; 21 to 34 years). The study was double-blind and placebo-controlled with a 4-way crossover design. The 4 treatments were placebo, 15 mg Delta-9-tetrahydrocannabinol (THC), 5 mg THC combined with 5 mg cannabidiol (CBD), and 15 mg THC combined with 15 mg CBD. These were formulated in 50:50 ethanol to propylene glycol and administered using an oromucosal spray during a 30-minute period from 10 pm. The electroencephalogram was recorded during the sleep period (11 pm to 7 am). Performance, sleep latency, and subjective assessments of sleepiness and mood were measured from 8:30 am (10 hours after drug administration). There were no effects of 15 mg THC on nocturnal sleep. With the concomitant administration of the drugs (5 mg THC and 5 mg CBD to 15 mg THC and 15 mg CBD), there was a decrease in stage 3 sleep, and with the higher dose combination, wakefulness was increased. The next day, with 15 mg THC, memory was impaired, sleep latency was reduced, and the subjects reported increased sleepiness and changes in mood. With the lower dose combination, reaction time was faster on the digit recall task, and with the higher dose combination, subjects reported increased sleepiness and changes in mood. Fifteen milligrams THC would appear to be sedative, while 15 mg CBD appears to have alerting properties as it increased awake activity during sleep and counteracted the residual sedative activity of 15 mg THC.