Effects of triazolam on brain activity during episodic memory encoding: a PET study.

It is well documented that acute administration of the benzodiazepine hypnotic drug triazolam (Halcion) impairs episodic memory encoding. We examined the neuroanatomical substrates of this effect in healthy adult volunteers using a double-blind, within-subject design. Following oral capsule administration (0.25 mg/70 kg triazolam or placebo), regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) with 15O-H(2)O during the performance of semantic categorization, orthographic categorization, and visual fixation (resting) tasks. rCBF associated with episodic memory encoding was measured by the difference in rCBF during the orthographic categorization task relative to that during the semantic categorization task. Results in the placebo condition (n = 9) replicated those of previous nonpharmacological encoding studies (activation in the left prefrontal cortex, cerebellum, anterior cingulate cortex, temporal cortex, and occipital cortex). Relative to placebo, results in the triazolam condition (n = 6) revealed significantly impaired memory performance, and deactivation during encoding in a subset of areas shown previously to be associated with encoding (anterior cingulate cortex, cerebellum, and precuneus). Results are discussed in relation to triazolam's effects on mnemonic versus attentional processes.

Alcohol and false recognition: a dose-effect study.

RATIONALE: The pattern of acute memory impairment produced by alcohol is similar to that produced by the benzodiazepines. However, in contrast to demonstrations that benzodiazepines decrease false recognition rates, results of a recent study suggest that a low dose of alcohol increases false recognition rates; false recognition refers to the phenomenon of mistakenly claiming that one has been exposed previously to a novel item. OBJECTIVE: This study was designed to examine the acute dose-effects of alcohol on false recognition. METHODS: Effects of alcohol (0.27 and 0.60 g/kg) on performance in the Deese/Roediger-McDermott false recognition paradigm were examined in a repeated measures placebo-controlled double-blind design in 18 healthy volunteers. RESULTS: The 0.60 g/kg dose of alcohol significantly reduced true recognition rates (measured by hit rate) and induced a more conservative response bias (measured by C) relative to placebo; however, neither alcohol dose significantly impaired participants' sensitivity in discriminating between old and new words (d'). Neither alcohol dose affected false recognition rates. CONCLUSIONS: Effects of alcohol on false recognition and on response bias may differ from those observed previously with benzodiazepines. A direct comparison at equivalent doses will be necessary to draw conclusions about qualitative differences between alcohol and benzodiazepines.

Acute dose-effects of scopolamine on false recognition.

RATIONALE: Recently, there has been increased research interest in the phenomenon of false recognition, in which participants claim to recognize words that had not been presented during an initial study phase but that are associatively related to presented words. Acute administration of the benzodiazepine hypnotic triazolam has been shown to decrease false recognition rates. However, no false recognition studies have examined the effects of scopolamine, an anticholinergic drug that might produce a different profile of memory-impairing effects than the benzodiazepines due to its distinct neurochemical profile. OBJECTIVE: This study was designed to examine the acute dose-effects of scopolamine on false recognition. METHODS: The effects of subcutaneously administered scopolamine (0.3 and 0.6 mg/70 kg) on performance in the Deese/Roediger-McDermott false recognition paradigm were examined in a repeated-measures placebo-controlled double-blind design in 18 healthy volunteers. RESULTS: Scopolamine produced dose-related reductions in both true and false recognition rates, and induced a more conservative response bias relative to placebo for recollection-based ("remember") responses to studied words. CONCLUSIONS: While scopolamine's effects on false recognition are similar to those observed previously with triazolam, its effects on response bias may differ from those of triazolam.

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.

A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users.

RATIONALE: Preclinical studies of the benzodiazepine antagonist flumazenil (Romazicon) have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use; when administered to animals chronically pretreated with benzodiazepines, flumazenil precipitates a withdrawal syndrome. However, few controlled clinical studies have been conducted. OBJECTIVES: The objective was to characterize the effects of flumazenil in long-term users of therapeutic doses of benzodiazepines. METHODS: The acute physiological, participant-rated, and observer-rated effects of intravenously administered flumazenil (1 mg/70 kg) and caffeine (300 mg/70 kg; active drug control) were evaluated in an experimental group of 13 long-term users (mean 4.6 years) of low therapeutic doses (mean 11.2 mg/day diazepam equivalent) relative to a matched group of 13 volunteers without prior exposure to benzodiazepines in a double-blind, placebo-controlled, mixed design. RESULTS: Whereas the experimental group did not differ from the control group with respect to the effects of placebo, and both groups showed some changes in response to caffeine (e.g., increased blood pressure and anxiety scores), only the experimental group showed considerable changes in physiological measures, participant ratings (e.g., increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch), and observer ratings in response to flumazenil; in addition, four participants developed panic attacks. CONCLUSIONS: This study clearly demonstrates that flumazenil can precipitate symptoms commonly associated with benzodiazepine withdrawal in chronic low-dose benzodiazepine users.

Buspirone is differentiated from diazepam in humans using a three-response drug discrimination procedure.

The discriminative stimulus effects of buspirone and diazepam were examined in 12 healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 15 mg/70 kg buspirone, and 10 mg/70 kg diazepam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made two hours after drug administration. Ten out of 12 subjects acquired the three-response discrimination. When lower doses of buspirone (3.75 and 7.5 mg/70 kg) and diazepam (2.5 and 5.0 mg/70 kg) were tested in a subsequent generalization testing phase, both buspirone and diazepam produced dose-related increases in appropriate drug identifications, without significant cross-generalization. Analyses of standardized and unstructured self report questionnaires revealed that buspirone and diazepam produced different profiles of effects, and that buspirone was associated with a number of "negative" subject-rated effects including tension, nausea, and dizziness. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for buspirone relative to diazepam which is consistent with its distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure.

Flunitrazepam and triazolam: a comparison of behavioral effects and abuse liability.

The performance, observer-rated, and participant-rated effects of orally administered placebo, and two benzodiazepines, flunitrazepam (2, 4 and 8 mg/70 kg) and triazolam (0.25, 0.5 and 1 mg/70 kg), were compared in 14 sedative drug abusers using a double-blind crossover design. Both flunitrazepam and triazolam produced dose-related decrements in memory and psychomotor/cognitive performance, and increases in many participant- and observer-rated measures. Effects of flunitrazepam had an earlier onset and a longer duration than those of triazolam. Although there was evidence that the flunitrazepam doses selected for study were somewhat higher overall relative to the selected triazolam doses, analysis of the participant-rated measures collected 24 h after drug administration (next-day) suggests that flunitrazepam may have a greater abuse liability than triazolam when abuse liability is assessed 24 h after drug administration. The highest flunitrazepam dose produced effects that were significantly greater than those of the highest triazolam dose on next-day ratings of good effects, take again, and worth; all tested flunitrazepam doses produced effects greater than any triazolam dose on next-day ratings of liking and take again. The highest flunitrazepam dose, but no triazolam dose, significantly increased the maximum dollar value at which participants chose drug over money in a Drug versus Money Choice Procedure.

Selective effects of zolpidem on human memory functions.

Zolpidem is an imidazopyridine hypnotic with preferential binding affinity for the omega1-benzodiazepine (BZD) receptor. The present double-blind, placebo-controlled study evaluated the effects of orally administered zolpidem (15mg/70kg) on specific memory functions in 16 healthy volunteers using a battery of word and picture memory tasks. Relative to placebo, zolpidem significantly impaired memory for material presented after drug administration when memory was assessed directly by referring subjects back to the prior study episode (explicit memory: recall and recognition) but not when memory was assessed indirectly by evaluating subjects' ability to identify degraded versions of studied stimuli (implicit memory: fragment completion). Zolpidem did not impair explicit memory for material presented before drug administration or memory for previously acquired knowledge (semantic memory: categorization). There was evidence suggesting that zolpidem enhanced explicit and implicit memory for material presented before drug administration and that zolpidem produced a specific deficit in the acquisition of contextual information about material presented after drug administration. Despite zolpidem's unique pharmacological profile, the observed selectivity of zolpidem's memory-impairing effects for particular functions appears qualitatively similar to the selectivity observed with classic BZDs in previous studies.

Investigation of preference for nightly triazolam versus placebo in moderate social alcohol drinkers.

This study was designed to examine whether the widely prescribed benzodiazepine hypnotic triazolam has reinforcing effects in moderate social alcohol drinkers, without histories of drug abuse or insomnia, in the context of its use as a hypnotic. Eleven healthy adult volunteers who met criteria for 'good sleepers' participated in a 60-session double-blind choice study which was conducted on an outpatient basis with participants sleeping at home. Twenty three-session sampling/choice tests were conducted sequentially to provide 20 evaluations of the reinforcing effects of 0.25 mg/70 kg triazolam versus placebo, ingested orally 30 min before bedtime. Each three-session test consisted of two sampling sessions, in which participants received exposure to each of the two drug conditions in different colored capsules, followed by one choice session, in which participants were asked to choose one of the two colour-coded capsules for self-administration. Four participants exhibited a significant choice of triazolam, three, a significant choice of placebo (i.e. triazolam avoidance), and four, a random (i.e. non-significant) choice between triazolam and placebo. The reasons provided by participants were consistent with their choices and with the expected effects of triazolam versus placebo. Analyses of post-sleep questionnaires indicated that triazolam did not produce a clinically meaningful improvement in sleep. The finding that triazolam functioned as a reinforcer in participants without insomnia suggests that triazolam has reinforcing effects in some individuals for which hypnotic treatment is not clinically indicated, and that health care professionals must continue to assess the risk/benefit ratio of benzodiazepine hypnotic prescription.

Ethanol and pentobarbital: comparison of behavioral and subjective effects in sedative drug abusers.

The behavioral and subjective effects of acute oral doses of placebo, ethanol (0.5, 1.0, and 2.0 g/kg), and pentobarbital (150, 300, 600, and 750 mg/70 kg) were compared in 8 male volunteers with histories of sedative drug abuse using a double-blind, double-dummy, cross-over design. Ethanol and pentobarbital produced similar dose-related decrements in psychomotor and cognitive performance and exhibited a similar profile of effects on staff- and participant-rated measures. There was some evidence indicating that, at the highest dose, pentobarbital was perceived by participants as being more sedating than ethanol and that pentobarbital has a greater abuse liability than ethanol. In conjunction with the results of previous human laboratory studies comparing the effects of different types of sedative-hypnotic drugs, these results support a mostly barbiturate-like rather than benzodiazepine-like profile of effects for ethanol.

The picture superiority effect: support for the distinctiveness model.

The form change paradigm was used to explore the basis for the picture superiority effect. Recognition memory for studied pictures and words was tested in their study form or the alternate form. Form change cost was defined as the difference between recognition performance for same and different form items. Based on the results of Experiment 1 and previous studies, it was difficult to determine the relative cost for studied pictures and words due to a reversal of the mirror effect. We hypothesized that the reversed mirror effect results from subjects' basing their recognition decisions on their assumptions about the study form. Experiments 2 and 3 confirmed this hypothesis and generated a method for evaluating the relative cost for pictures and words despite the reversed mirror effect. More cost was observed for pictures than words, supporting the distinctiveness model of the picture superiority effect.

An abuse liability comparison of flunitrazepam and triazolam in sedative drug abusers.

The present double-blind, placebo-controlled study compared the acute effects of oral administration of the benzodiazepine hypnotics flunitrazepam (6 mg/70 kg) and triazolam (1 and 2 mg/70 kg) on measures relevant to abuse liability as well as on psychomotor performance and observer- and participant-rated measures of drug effects in nine sedative drug abusers. Analysis of participant-rated measures collected 24 h after drug administration (next-day; assessing the overall effects of the drug received 24 h earlier) indicated that flunitrazepam, but neither triazolam dose, produced significant increases relative to placebo in next-day ratings of drug liking, the amount of money the drug would be worth on the street, and the amount of money the participant would be willing to pay for the drug on the street. Importantly, these abuse liability differences between flunitrazepam and triazolam were present at a dose of flunitrazepam (6 mg/70 kg) that produced overall drug effects that were comparable to, or significantly less than, those of a high triazolam dose (2 mg/70 kg). Consistent with results of a previous study in our laboratory, these results suggest that flunitrazepam may have a greater abuse liability than triazolam, and that this abuse liability difference emerges on measures taken 24 h after drug administration but not on same-day measures.

Alcohol and triazolam: differential effects on memory, psychomotor performance and subjective ratings of effects.

The effects of alcohol (0.80 g/kg) and the benzodiazepine hypnotic triazolam (0.25 mg/70 kg) were compared directly in a double-dummy, double-blind, placebo-controlled, repeated-measures design in 18 healthy volunteers. While alcohol (0.80 g/kg) and triazolam (0.25 mg/70 kg) produced comparable levels of psychomotor performance impairment, a dissociation was observed, such that the magnitude of memory impairment (measured by d', participants' sensitivity in discriminating between old and new words in the recognition memory paradigm) was greater with triazolam than with alcohol, whereas subjective ratings of the overall strength of drug effect were higher with alcohol than with triazolam. Participants also adopted a more conservative response bias in the recognition memory paradigm in the alcohol (0.80 g/kg) condition relative to both placebo and triazolam (0.25 mg/70 kg). In addition to characterizing the adverse effects of two widely used psychoactive substances, the present results may also contribute to the understanding of underlying neurochemical mechanisms.

Acute effects of triazolam on false recognition.

Neuropsychological, neuroimaging, and electrophysiological techniques have been applied to the study of false recognition; however, psychopharmacological techniques have not been applied. Benzodiazepine sedative/anxiolytic drugs produce memory deficits similar to those observed in organic amnesia and may be useful tools for studying normal and abnormal memory mechanisms. The present double-blind, placebo-controlled repeated measures study examined the acute effects of orally administered triazolam (Halcion; 0.125 and 0.25 mg/70 kg), a benzodiazepine hypnotic, on performance in the Deese (1959)/Roediger-McDermott (1995) false recognition paradigm in 24 healthy volunteers. Paralleling previous demonstrations in amnesic patients, triazolam produced significant dose-related reductions in false recognition rates to nonstudied words associatively related to studied words, suggesting that false recognition relies on normal memory mechanisms impaired in benzodiazepine-induced amnesia. The results also suggested that relative to placebo, triazolam reduced participants' reliance on memory for item-specific versus list-common semantic information and reduced participants' use of remember versus know responses.

Zolpidem is differentiated from triazolam in humans using a three-response drug discrimination procedure.

The discriminative stimulus effects of the imidazopyridine hypnotic zolpidem and the classic benzodiazepine hypnotic triazolam were examined in seven healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 20 mg/70 kg zolpidem, and 0.5 mg/70 kg triazolam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made 3.75 h after drug administration. Five out of seven subjects acquired the three-response discrimination. Analyses of standardized and unstructured self-report questionnaires revealed that zolpidem and triazolam produced different profiles of effects; zolpidem was associated with a number of negative somatic symptoms including nausea, blurred vision, visual images/hallucinations, and heavy limbs, whereas triazolam was associated with greater sedative effects. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for zolpidem, relative to triazolam, which is consistent with its somewhat distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure for detecting between-drug differences.

Triazolam and zolpidem: a comparison of their psychomotor, cognitive, and subjective effects in healthy volunteers.

The psychomotor/cognitive performance, subject-rated, and observer-rated effects of single oral doses of the benzodiazepine hypnotic triazolam (0.125, 0.25, and 0.5 mg/70 kg) and the imidazopyridine hypnotic zolpidem (5, 10, and 20 mg/70 kg) were compared in 11 volunteers, in a double-blind, placebo-controlled, crossover design. Triazolam and zolpidem produced similar dose-related decrements on several performance measures, and similar dose-related increases on most observer-rated and several subject-rated measures. The drugs differed in the time course of their effects on these measures; the effects of zolpidem typically peaked 30 min earlier (1-1.5 h postdrug) than the effects of triazolam (1.5-2 h postdrug). Triazolam and zolpidem produced a different profile of effects on other performance measures which could not be attributed to time course differences. Triazolam produced significantly more impairment than zolpidem in time estimation. Triazolam, but not zolpidem, produced significant impairment on a short-term memory task. Zolpidem produced significantly more impairment than triazolam on several novel measures of performance on a computerized trail-making test. The observed differences between triazolam and zolpidem may be related to zolpidem's reported binding selectivity for the omega 1 receptor subtype.