Diazepam and triazolam self-administration in sedative abusers: concordance of subject ratings,performance and drug self-administration

The reinforcing effects of diazepam (DZ), triazolam (TZ) and placebo were examined in eight male subjects with histories of sedative abuse. DZ (40 or 80 mg), TZ (1.0 or 2.0 mg) and placebo were each individually available for oral self-administration using a double-blind within-subject design. After an initial sampling exposure, subjects could self-administer a single dose of drug on each of 6 days by completing a progressively increasing bicycle riding requirement. All subjects initially self-administered DZ and TZ but a decreasing number of subjects continued to self-administer drugs on the remaining days; there was no difference between DZ and TZ in the total number of self-administrations. Placebo was self-administered only by one subject on two occasions. Performance measures showed that TZ produced greater memory impairment than DZ and that DZ produced residual psychomotor impairment on the next day. With repeated dosing, evidence of tolerance was seen for both drugs on psychomotor and memory performance and subject ratings of drug liking. A few modest correlations of drug self-administration and subject-ratings were obtained, suggesting some correspondence of subject verbal and drug self-administration behaviors, but these measures did not covary in a completely consistent manner.     

Retrograde facilitation of memory by triazolam: effects on automatic processes

RATIONALE: Retrieval processes have been implicated as a potential mechanism by which benzodiazepines can produce retrograde memory facilitation. OBJECTIVES: This study tested the degree to which benzodiazepine-induced retrograde facilitation of memory was due to an enhancement of automatic retrieval processes. METHODS: Forty healthy adults were randomly assigned to one of three dose conditions (double-blind), under which they received 0.0 mg (placebo), 0.125 mg, or 0.25 mg of the short-acting benzodiazepine triazolam (Halcion). Subjects studied a list of words just prior to dose administration. One hour after dose administration, subjects performed a word-stem completion task which tested their retrieval of the studied words. A process-dissociation procedure was used to estimate the degree to which retrieval was under the influence of memory processes that were automatic (i.e., unintentional) versus controlled (i.e., intentional). RESULTS: Subjects who received active doses of triazolam displayed a greater probability of using studied words as stem completions. Estimates of memory processes showed a greater influence of automatic influences during memory retrieval under triazolam doses. CONCLUSIONS: The findings indicate that retrograde memory facilitation following benzodiazepine administration does not necessarily reflect an improved ability to intentionally retrieve information but could instead reflect increased responsiveness to cues that automatically elicit retrieval of pre-drug information.     

Trazodone and triazolam: acute subject-rated and performance-impairing effects in healthy volunteers

The present study compared the acute subject-rated and performance-impairing effects of trazodone and triazolam in seven healthy humans. Trazodone (50, 100 and 200 mg), triazolam (0.125, 0.25, 0.50 mg) and placebo were administered orally in a double-blind, crossover design. Drug effects were measured approximately 30 min before drug administration and repeatedly afterwards for 6 h. Trazodone and triazolam produced dose-related increases in subject-ratings of drug effect and sedation. The absolute magnitude of trazodone”s and triazolam”s effects was comparable across these measures, which suggests the doses tested were equivalent on some behavioral dimension. By contrast, triazolam, but not trazodone, increased subject ratings of “dizzy”, “excited”, “nervous”, “restless”, “stomach turning” and “itchy skin”. Triazolam, but not trazodone, significantly impaired learning, recall and performance. The present findings suggest trazodone may be a viable alternative to benzodiazepine hypnotics like triazolam, especially when needing to minimize drug-induced impairment. Future research could extend the present findings by replicating them in a clinically relevant population such as individuals with histories of drug abuse. Received: 9 May 1996 / Final version: 15 September 1996     

The effects of flurazepam,lorazepam, and triazolam on sleep and memory

This study evaluated the effects of flurazepam 30 mg, lorazepam 4 mg, triazolam 0.5 mg, and placebo upon sleep and memory in eleven normal male subjects continuously monitored for nighttime EEG, EOG, and EMG recording. Subjects received each drug or placebo for two consecutive nights per week for 4 weeks in a repeated measures, double-blind, Latin Square design. Three hours post-administration, subjects were awakened and presented with a series of tasks. Recall was assessed immediately following task presentation and after the final morning awakening. The results showed that every drug significantly decreased stage 1, increased stage 2, and produced no change in stage 3–4 sleep in comparison to placebo. Only lorazepam significantly decreased REM percent. Post-drug recall was significantly decreased in comparison to placebo at night and was further decreased in the morning. Morning recall was significantly poorer when the return to sleep was 2.5 min or less than when the return to sleep was greater than 5 min following the nighttime awakening in all drug conditions. These results indicate that 1. failure of memory consolidation rather than failure of retrieval is the most likely explanation for the morning memory loss and 2. hypnotic drug properties, measured by latency to fall back asleep, affect memory consolidation.     

Discriminating the effects of triazolam on stimulus and response processing by means of reaction time and P300 latency

The benzodiazepines slow information processing and the sites of this slowing were mapped using the Additive Factors Method in combination with the P300 component of the event-related brain potential. It was assumed that P300 largely reflects the time to evaluate a stimulus while reaction time (RT) reflects this time plus the time to select and execute a response. Twelve subjects were administered 0.25 mg triazolam in a repeated measures single-blind design. A visual 80–20% oddball task was used in which stimulus intensity and signal quality were manipulated with accuracy of responding held constant at a high level. RT and EEG data were collected simultaneously and the P300 elicited by the low probability stimuli was measured on a single trial basis. Triazolam slowed RT (172 ms,P<0.0003) more than P300 (88 ms,P<0.0007), but both measures exhibited a drug × stimulus intensity interaction. RT also exhibited a drug × signal quality interaction but P300 did not. These results suggest that triazolam has selective effects on perceptual processing by slowing an early preprocessing stage but not a later feature extraction stage. In addition, the drug appears to slow some aspect of response processing. This evidence is taken as support for a multiple process rather than a general sedation view of benzodiazepine effects on stages of processing.     

A comparison of the effects of flurazepam 30 mg and triazolam 0.5 mg on the sleep of insomniacs

The effects of oral, bedtime triazolam 0.5 mg and flurazepam 30 mg, on the laboratory sleep of 12 insomniacs were compared in a double blind, crossover study. A 22 consecutive night schedule was used: Nts. 1–2 placebo; 3–6 first drug; 7–8 placebo; 9–14 no drugs; 15–16 placebo; 17–20 second drug; 21–22 placebo. In 6 Ss first drug was triazolam and second drug was flurazepam. In the other 6 Ss the drug order was reversed. Effects on sleep were assessed objectively by conventional EEG/EOG/EMG sleep recordings and subjectively by questionnaires administered each morning. Side or toxic effects were assessed by physical exams, clinical lab tests, and twice daily questionnaires. During their administration the two drugs were practically indistinguishable in their effects. Both significantly reduced objective and subjective measures of insomnia, such as total wake time and sleep latency. On discontinuation the drugs differentially affected sleep, e.g., on the first post flurazepam night total sleep time was significantly more than baseline whereas on first post triazolam night, total sleep time was significantly less than baseline. There were no remarkable side or toxic effects with either drug.     

Triazolam and zolpidem: effects on human memory and attentional processes

Rationale: The imidazopyridine hypnotic zolpidem may produce less memory and cognitive impairment than classic benzodiazepines, due to its relatively low binding affinity for the benzodiazepine receptor subtypes found in areas of the brain which are involved in learning and memory. Objectives: The study was designed to compare the acute effects of single oral doses of zolpidem (5, 10, 20 mg/70 kg) and the benzodiazepine hypnotic triazolam (0.125, 0.25, and 0.5 mg/70 kg) on specific memory and attentional processes. Methods: Drug effects on memory for target (i.e., focal) information and contextual information (i.e., peripheral details surrounding a target stimulus presentation) were evaluated using a source monitoring paradigm, and drug effects on selective attention mechanisms were evaluated using a negative priming paradigm, in 18 healthy volunteers in a double-blind, placebo-controlled, crossover design. Results: Triazolam and zolpidem produced strikingly similar dose-related effects on memory for target information. Both triazolam and zolpidem impaired subjects’ ability to remember whether a word stimulus had been presented to them on the computer screen or whether they had been asked to generate the stimulus based on an antonym cue (memory for the origin of a stimulus, which is one type of contextual information). The results suggested that triazolam, but not zolpidem, impaired memory for the screen location of picture stimuli (spatial contextual information). Although both triazolam and zolpidem increased overall reaction time in the negative priming task, only triazolam increased the magnitude of negative priming relative to placebo. Conclusions: The observed differences between triazolam and zolpidem have implications for the cognitive and pharmacological mechanisms underlying drug-induced deficits in specific memory and attentional processes, as well for the cognitive and brain mechanisms underlying these processes. Received: 8 June 1998/Final version: 15 December 1998     

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 daytime administration of zolpidem versus triazolam on memory

To determine whether zolpidem (an imidazopyridine hypnotic) produces amnestic effects which are similar to those produced by triazolam (a benzodiazepine hypnotic), 70 subjects were administered either triazolam (0.125, 0.25, or 0.5 mg), zolpidem (5, 10 or 15 mg) or placebo, then tested on Simulated Escape, Restricted Reminding, and Paired-Associates memory tests at 1.5 hours post-dosing (i.e., near the time of estimated peak blood concentration for both drugs) and again at 6 hours post-dosing. Triazolam 0.5 mg produced the greatest memory impairment at both test times, and also produced the greatest degree of sedation during intervening daytime naps in a non-sleep-conducive environment. Other doses of triazolam and zolpidem produced less memory impairment, but also failed to significantly enhance sleep. The results are consistent with the view that the amnestic and hypnotic effects of these sleep-inducing medications are functionally coupled.     

An evaluation of a caffeinated taurine drink on mood, memory and information processing in healthy volunteers without caffeine abstinence

RATIONALE: Caffeine is present in a wide variety of beverages, often together with a number of other ingredients, such as sugars, taurine, glucuronolactone and vitamins. However, the majority of psychopharmacological studies have used pure caffeine tablets or drinks with doses in excess of those normally consumed in daily life. In addition, all the participants are usually deprived of caffeine for 10 h or more before the study. Consequently, it has been argued that any improvement in performance is only due to a reversal of caffeine withdrawal. OBJECTIVE: The present two studies tested participants who had minimal deprivation from caffeine (an hour or less) with an 80-mg caffeinated (80 mg/250 ml), taurine-containing beverage (commercially available) verum, which also contained sugars, glucuronolactone and vitamins. The placebos in the two studies were a sugar-free and a sugar-containing drink, in order to examine the effects of the sugar. METHODS: In total, 42 participants were tested with a rapid visual information test, a verbal reasoning test, a verbal and non-verbal memory test and a set of mood measures. Prior to testing, they were allowed ad libitum caffeinated beverages until 1 h before testing (study 1) and unrestricted caffeine use before testing (study 2). RESULTS: In both studies, the caffeinated, taurine-containing beverage produced improved attention and verbal reasoning, in comparison with a sugar-free and the sugar-containing drinks. The improvement with the verum drink was manifested in terms of both the mean number correct and the reaction times. Another important finding was the reduction in the variability of attentional performance between participants. No effects on memory were found. There were no differences in performance between the glucose and sugar-free drinks. CONCLUSIONS: Moderate doses of caffeine and taurine can improve information processing in individuals who could not have been in caffeine withdrawal.     

The effect of triazolam on the sleep of insomniacs

The effects of three oral doses of bedtime triazolam (0.25 mg, 0.5 mg, and 1.0 mg) a new benzodiazepine, on the laboratory sleep of insomniacs were studied in a double blind design which used the following 14 consecutive night schedule: 1–4 placebo; 5–11 drug; 12–14 placebo. Effects on sleep were measured objectively by conventional EEG/EOG/EMG sleep recordings and subjectively by questionnaires administered each morning. Side or toxic effects were assessed by screening physicals and questionnaires administered each morning and each evening and by a comparison of the prestudy vs. end-study physical exams and clinical lab tests. At the 0.5 mg dose triazolam significantly reduced several objective and subjective measures of insomnia. It had lesser effects at the 0.25 mg dose and equal or greater effects at 1.0 mg dose. There were no remarkable side or toxic effects at any dose.     

Zolpidem and triazolam do not affect the nocturnal sleep-induced memory improvement

Rationale It is widely accepted that sleep facilitates memory consolidation. Hypnotics (e.g., benzodiazepines), which reportedly increase sleep efficiency but also modify sleep architecture, could affect memory improvement that occurs during sleep. Objectives The present study examined the effects of single doses of two short half-life hypnotics, zolpidem and triazolam, on sleep-induced improvement of memory. Methods Twenty-two healthy volunteers participated in this randomized, double-blind, crossover study. All subjects received a single oral dose of zolpidem (10 mg), triazolam (0.25 mg) or placebo at 9 p.m. and slept for 7.5±0.2 h. The effect of sleep on memory was investigated by comparing the performance of this group of volunteers with a group of 21 subjects in wakefulness condition. Declarative memory was evaluated by using a free-recall test of ten standard word and seven nonword lists. Subjects memorized the word and nonword lists 1 h before dosing and they were asked to recall the memorized lists 10 h after dosing. Digit symbol substitution test (DSST) and forward and backward digit tests were also given 1 h before and 10 h after dosing. Results Subjects who slept remembered more nonwords than those in wakefulness condition, but they did not recall significantly more standard words. Neither zolpidem nor triazolam affected the enhanced nonword recall observed after sleep. Finally, none of the hypnotics affected the improvement in the DSST performance of subjects who slept. Conclusions The hypnotics tested did not interfere with the nocturnal sleep-induced improvement of memory.     

Comparison of the daytime sleep and performance effects of zolpidem versus triazolam

Fifty healthy male subjects were administered zolpidem (5, 10, or 20 mg), triazolam (0.5 mg) or placebo, then attempted to sleep in a non-sleep-conductive environment. Subjects were awakened at 90 min post-drug (near peak blood concentration for both drugs) and tested on several cognitive tasks, including Two Column Addition, Logical Reasoning, and a Simulated Escape Task. This was followed by a second, 3.5-h sleep period. Hypnotic efficacy of the 20 mg zolpidem (Z-20) dose was similar to that of the 0.5 mg triazolam (TRIAZ) dose, as indicated by comparably shortened sleep latencies and lengthened total sleep times. Though accuracy on most performance measures was not affected by either drug, a reduction in speed of responding on logical reasoning and addition tasks was evident for the TRIAZ group at 90 min post-drug (Ps<0.05). On the simulated escape task, only triazolam significantly increased the mean number of errors, and interfered with subsequent memory of the task. Thus, zolpidem had milder effects on performance than triazolam. However, 60% of the Z-20 subjects experienced mild, adverse physical reactions. Performance differences between somnogenically comparable doses of zolpidem and triazolam may be due to their differential affinities for the BZ1 and BZ2 receptor subtypes.This material has been reviewed by the Walter Reed Army Institute of Research, and there is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the position of the Department of the Army or the Department of Defense.     

Effects of triazolam (0.5 mg) on sleep,performance, memory,and arousal threshold

The effects of a short-acting benzodiazepine hypnotic, triazolam (0.5 mg), on sleep, performance, and arousal threshold were assessed in 20 male poor sleepers (age 21±2.37 years). Following a laboratory screening night, all subjects received placebo for 3 nights (single-blind), ten received triazolam and ten placebo for 6 nights (double-blind), and all received placebo on 2 withdrawal nights (single-blind). All effects described below were statistically significant. Triazolam reduced sleep latency and increased total sleep time and sleep efficiency. Percent Stage 2 was increased and percent Stage 4 was reduced during treatment. Morning performance, measured 8.25 h post-drug, showed no decrements. Acute effects were assessed on treatment night 6 during arousals from sleep at 1.5, 3, and 5 h post-administration: performance was impaired in triazolam subjects on the Wilkinson 4-Choice Reaction Time Test, Digit Symbol Substitution Test, Williams Word Memory Test, and Card Sorting Task. In the morning following treatment night 6, long-term memory was tested using a recognition task requiring subjects to identify words presented during night-time test batteries: triazolam subjects correctly identified fewer target words. Triazolam administration produced anterograde amnesic effects. However, in a Paired Associates Test learned prior to drug ingestion on the previous evening, triazolam did not impair morning recall of word pairs. Threshold for arousal from slow wave sleep was elevated during treatment, and triazolam subjects did not show increased sensitivity to the arousing tone over nights as did placebo subjects.     

An acute effect of triazolam on muscarinic cholinergic receptor binding in the human brain measured by positron emission tomography

An acute effect of triazolam, a potent benzodiazepine agonist, on cholinergic receptor binding in the human brain was measured by PET (positron emission tomography) using [¹¹C]N-methyl-4-piperidylbenzilate ([¹¹C]NMPB), a potent muscarinic cholinergic receptor antagonist. Two PET scans were performed in each subject: (1) control scan; (2) after oral administration of 0.5 mg triazolam or placebo. The previously discussed amnestic effect of triazolam was measured by immediate and delayed recall of meaningful and meaningless syllables. A compartment model employing the radioactivity in the cerebellum as an input function was used for the quantification of receptor binding. The binding parameter,k ₃, was decreased after triazolam administration in all measured regions, whereas no change was observed after placebo treatment. The reduction compared to the control study varied from 8.6±3.7% in the temporal cortex to 16.3±6.3% in the thalamus. Triazolam administration impaired both immediate and delayed recall of syllables, whereas placebo administration had no effects. Benzodiazepine agonists are reported to decrease the cortical acetylcholine release. The decrease of acetylcholine release in the synaptic cleft might be the explanation for the decreased binding of [¹¹C]NMPB.     

Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans

Background

Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo.

Methods

Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg/70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6 h.

Results

Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100–300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5 mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10–30 times the therapeutic dose of DXM.

Conclusion

The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100–300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse.     

Dose level effects of triazolam on sleep and response to a smoke detector alarm

Thirty-six young adult, male subjects with sleep-onset insomnia were equally divided into placebo, 0.25 mg, and 0.5 mg triazolam groups to examine the effects of the hypnotic, with particular attention to dose level on efficacy, sleep stages, and awakening to a smoke detector alarm. On nights 1 and 4 of a five-consecutive-night protocol, a standard home smoke detector alarm was sounded during stage 2, 5 min after sleep onset, in slow wave sleep (SWS), and at the time of the early morning awakening. The alarm registered 78 dB SPL at the pillow. EEG arousal latency and reaction time to a button press were studied. Failure to awaken to three 1-min alarm presentations was scored as no response. Both dose levels produced similar reductions in sleep latency, decreases in SWS, increases in stage 2, and increases in sleep efficiency. Both dose levels showed similar sedative effects to the smoke alarm. Fifty percent of triazolam subjects failed to awaken on night 1 during SWS, and EEG arousal and response latencies were significantly slowed. Some drug tolerance or sensitization to the alarm was seen by night 4. By morning, all subjects were easily awakened on both nights. The 0.25 mg dose is clearly an effective dose level for both sleep efficacy and sedative effects to outside noise, which in some instances could pose potantial problems.     

d-Amphetamine effects on attention and memory in the albino and hooded rat

Albino and hooded rats were injected with either d-amp or physiological saline and tested on acquisition, reversal, and recall of a brightness discrimination. Hooded rats acquired and reversed the discrimination more quickly than albino rats. D-amp retarded both acquisition and reversal while enhancing recall. The results indicated that d-amp disrupts attention while enhancing memory. The systems which may mediate this behavioral fractionation are discussed.     

Effects of lorazepam on memory,attention and sedation in man

The effects of three doses of lorazepam (0.5, 1.0 and 2.0 mg PO) on various aspects of memory, attention and sedation are described. Lorazepam produced dose-related deficits in verbal secondary memory, choice reaction time and a novel vigilance task. It also produced a dose-dependent increase in subjective sedation, and an enhancement of visual contrast sensitivity. These results are compared with those reported earlier using the muscarinic antagonist scopolamine, and discussed in relation to models of Alzheimer's disease.     

Effects of triazolam on drinking in baboons with and without an oral self-administration history: a reinstatement phenomenon

In a test of the reinforcing efficacy of triazolam under an oral drug self-administration procedure, three baboons consumed higher volumes of triazolam than of vehicle. Although these results suggested that triazolam was serving as a reinforcer, the unconditioned effect of triazolam itself on drinking remained unclear. Therefore, the effect of pretreatment with triazolam on consumption of a nondrug fluid was assessed in sessions that were otherwise identical to oral drug self-administration sessions. Following oral pretreatment with triazolam (0.6–19.2 mg total dose), there was a dose-dependent increase in drinking, suggesting that triazolam increased fluid consumption per se. However, subsequent manipulations showed that following pretreatment with triazolam, there was no systematic change in tap water consumption from the regular drinking spout and that the dipsogenic effect of pretreatment with triazolam was not specific to a particular fluid; however, the effect was specific to prior experience with the oral self-administration procedure. Thus, the dose-related increase in consumption from the drinkometer spout following triazolam pretreatment most likely is explained as the priming or reinstatement of an operant that previously had produced drug reinforcement, even though extinction (i.e., substitution of the drug vehicle) was in effect.This research was supported, in part, by National Institute on Drug Abuse Contract 271-92-7204 and Grant DA-04133. Portions of these data were presented at the meetings of the College on Problems of Drug Dependence, Palm Beach, Fla., 1994.