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Based on its unique pharmacological profile, buprenorphine may produce less impairment in psychomotor and cognitive performance than methadone. However, the few studies that have investigated the performance effects of buprenorphine in opioid-abusing volunteers examined effects of single acute doses rather than effects of repeated dosing and included a very limited range of measures. The present inpatient study evaluated dose-related effects of repeated administration of the buprenorphine/naloxone combination product (8/2, 16/4, 32/8 mg, sublingual tablets) in eight opioid-dependent volunteers on performance of a broad range of tasks, following a period of 7-10 days of dosing at each level, in a double-blind, within-subject, crossover design. The testing battery included measures of psychomotor speed, time perception, conceptual flexibility, focused attention, working memory, long-term/episodic memory, and metamemory. Supporting the hypothesis of limited impairment with buprenorphine, results revealed minimal impairment in performance as buprenorphine/naloxone dose was increased four-fold. The only significant effect of dose was an impairment in episodic/long-term memory (recognition memory) performance at the highest dose (32/8 mg) relative to the two lower doses. Future studies incorporating larger sample sizes and non-drug controls, as well as directly comparing buprenorphine to methadone and LAAM are needed to further test the hypothesis of limited impairment with buprenorphine. [ABSTRACT FROM AUTHOR]

Acute administration of the benzodiazepine hypnotic drug triazolam induces temporary amnesia. The present double-blind, placebo-controlled, repeated-measures experiment used triazolam-induced amnesia to test predictions of the dual process account of the word frequency effect in recognition memory (the reliably observed finding that low frequency words have higher hit rates and lower false alarm rates than high frequency words) in 28 healthy adult volunteers. According to the dual process account (Joordens & Hockley, 2000; Reder et al., 2000), the hit rate component of the word frequency effect is driven by recollection, whereas the false alarm rate component is driven by familiarity. Based on evidence that triazolam produces relatively greater impairment in recollection-based recognition than in familiarity-based recognition, the dual process account would predict that the hit rate effect should be eliminated or reversed in the triazolam condition, but that the false alarm rate effect should be relatively unaffected by drug condition. These predictions were confirmed. Copyright © 2003 by Elsevier Science (USA). [ABSTRACT FROM AUTHOR]

Few well-controlled studies have examined psychomotor and cognitive performance in methadone maintenance patients (MMP). In the present study, performance of 18 opioid-dependent MMP was evaluated relative to that of 21 control participants without substance abuse histories. The MMP and control groups were balanced with respect to gender, race, age, years of education, current employment status, current reading level, and estimated IQ score. Recent drug abstinence was verified by urine testing. Participants with a urine screen positive for benzodiazepines or a breathalyzer test positive for alcohol prior to performance testing were excluded. To avoid testing under conditions of acute heroin or cocaine intoxication, but without testing under conditions of acute withdrawal, participants with current use of heroin or cocaine were only required to abstain for 24 h prior to performance testing. MMP exhibited impairment relative to controls in psychomotor speed (digit symbol substitution and trail-making tests), working memory (two-back task), decision making (gambling task), and metamemory (confidence ratings on a recognition memory test); results also suggested possible impairment in inhibitory mechanisms (Stroop color-word paradigm). MMP did not exhibit impairment in time estimation, conceptual flexibility or long-term memory. The wide range of impaired functions is striking, and may have important implications for daily functioning in MMP. Further research is necessary to determine the clinical significance of the impairments in laboratory-based tests for daily performance in the natural environment, as well as to differentiate impairments due to acute methadone dosing, chronic methadone maintenance, chronic poly-drug abuse, and other factors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Adolescent cannabis use is associated with working memory impairment. The present randomized controlled trial assigned adolescents ages 14 to 21 enrolled in cannabis use treatment to receive either working memory training (experimental group) or a control training (control group) as an adjunctive treatment. Cognitive function, drug use, and other outcomes were assessed before and after training. We observed few differences in cognitive, functional, or self-reported drug use outcomes as a function of training group, although tetrahydrocannabinol (THC) urinalysis results favored the experimental group. These findings are similar to previous studies in substance users, which have shown limited transfer effects for working memory training., Competing Interests: Conflicts of Interest MJ Fishman is the Medical Director of Mountain Manor Treatment Center (MMTC) where the patients enrolled in the study described in this article were treated. He is a part-time faculty member of Johns Hopkins University. He is a beneficiary of the trust which owns MMTC. He also serves on the governing board of the trust and the Board of Directors of MMTC. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. The authors have no other conflicts of interest.

Individuals with substance use disorders have shown deficits in the ability to implement future intentions, called prospective memory. Deficits in prospective memory and working memory, a critical underlying component of prospective memory, likely contribute to substance use treatment failures. Thus, improvement of prospective memory and working memory in substance use patients is an innovative target for intervention. We sought to develop a feasible and valid prospective memory training program that incorporates working memory training and may serve as a useful adjunct to substance use disorder treatment. We administered a single session of the novel prospective memory and working memory training program to participants (n = 22; 13 men, 9 women) enrolled in outpatient substance use disorder treatment and correlated performance to existing measures of prospective memory and working memory. Generally accurate prospective memory performance in a single session suggests feasibility in a substance use treatment population. However, training difficulty should be increased to avoid ceiling effects across repeated sessions. Consistent with existing literature, we observed superior performance on event-based relative to time-based prospective memory tasks. Performance on the prospective memory and working memory training components correlated with validated assessments of prospective memory and working memory, respectively. Correlations between novel memory training program performance and established measures suggest that our training engages appropriate cognitive processes. Further, differential event- and time-based prospective memory task performance suggests internal validity of our training. These data support the development of this intervention as an adjunctive therapy for substance use disorders. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Objective: Working memory impairment in individuals with chronic opioid dependence can play a major role in cognitive and treatment outcomes. Cognitive training targeting working memory shows promise for improved function in substance use disorders. To date, cognitive training has not been incorporated as an adjunctive treatment for opioid dependence., Methods: Methadone maintenance patients were randomly assigned to experimental (n=28) or active control (n=28) 25-session computerized training and run in parallel. Cognitive and drug use outcomes were assessed before and after training., Results: Participants in the experimental condition showed performance improvements on two of four working memory measures, and both groups improved on a third measure of working memory performance. Less frequent drug use was found in the experimental group than in the control group post-training. In contrast to previous findings with stimulant users, no significant effect of working memory training on delay discounting was found using either hypothetical or real rewards. There were no group differences on working memory outcome measures that were dissimilar from the training tasks, suggesting that another mechanism (e.g., increased distress tolerance) may have driven drug use results., Conclusions: Working memory training improves performance on some measures of working memory in methadone maintenance patients, and may impact drug use outcomes. Working memory training shows promise in patients with substance use disorders; however, further research is needed to understand the mechanisms through which performance is improved and drug use outcomes are impacted., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Methadone maintenance patients (MMP) often abuse other drugs, including alcohol. The combined use of methadone and alcohol could impair performance and daily functioning., Objective: To examine the effects of methadone in combination with alcohol, as well as acute increases in methadone, on performance outcomes., Methods: This double-blind, double-dummy, crossover study included eight opioid-dependent participants stabilized on methadone. Participants completed six inpatient sessions corresponding to methadone (100% or 150% of daily dose) and beverage (placebo, 0.25 or 0.50 g/kg alcohol). Performance tasks were completed before and after drug administration. Area under the time-course values were analyzed by a 2 (methadone dose) by 3 (alcohol dose) repeated measures analysis of variance., Results: Main effects of methadone were observed for two attention outcomes, suggesting reduced accuracy and slowed responding at an elevated methadone dose. In addition, main effects of alcohol were observed for episodic memory (false alarms and response bias) suggesting more impulsive responding as alcohol dose increased. No robust interactions of methadone and alcohol were observed for any outcome., Conclusions: Study findings indicate that an acute increase in methadone (150%) and a moderate dose of alcohol (2-3 drinks) can impair distinct aspects of performance, although no significant interactive effect between methadone and alcohol was found. Future studies with larger sample sizes, larger doses, and more clinically informative tasks could expand on the present findings and further explore the cognitive consequences of concurrent opioid and alcohol use.

Topiramate is being investigated as a potential pharmacotherapy for the treatment of addictive disorders. However, its cognitive side effects raise concerns about its use, especially in populations with cognitive impairment, such as persons with chronic substance use disorders. This study investigated topiramate's cognitive effects in individuals dually dependent on cocaine and opioids as part of a double-blind, randomized, controlled trial of topiramate for cocaine dependence treatment. After 5 weeks of stabilization on daily oral methadone (M = 96 mg), participants were randomized to topiramate (n = 18) or placebo (n = 22). Cognitive testing took place at 2 time points: study weeks 4 through 5 to assess baseline performance and 10 to 13 weeks later to assess performance during stable dosing (300 mg topiramate or placebo). All participants were maintained on methadone at both testing times, and testing occurred 2 hours after the daily methadone plus topiramate/placebo administration. The topiramate and placebo groups did not differ on sex, level of education, premorbid intelligence, methadone dose, or illicit drug use. Topiramate slowed psychomotor and information processing speed, worsened divided attention, reduced n-back working memory accuracy, and increased the false alarm rate in recognition memory. Topiramate had no effects on visual processing, other measures of psychomotor function, risk-taking, self-control, Sternberg working memory, free recall, and metamemory. These findings indicate that topiramate may cause cognitive impairment in this population. This effect may limit its acceptability and use as a treatment in individuals with chronic opioid and cocaine use disorders, among whom preexisting cognitive impairments are common. (PsycINFO Database Record, ((c) 2015 APA, all rights reserved).)

Background: Dual dependence on opiate and cocaine occurs in about 60% of patients admitted to methadone maintenance and negatively impacts prognosis (Kosten et al. 2003. Drug Alcohol Depend. 70, 315). Topiramate (TOP) is an antiepileptic drug that may have utility in the treatment of cocaine dependence because it enhances the GABAergic system, antagonizes the glutamatergic system, and has been identified by NIDA as one of only a few medications providing a "positive signal" warranting further clinical investigation. (Vocci and Ling, 2005. Pharmacol. Ther. 108, 94)., Method: In this double-blind controlled clinical trial, cocaine dependent methadone maintenance patients (N=171) were randomly assigned to one of four groups. Under a factorial design, participants received either TOP or placebo, and monetary voucher incentives that were either contingent (CM) or non-contingent (Non-CM) on drug abstinence. TOP participants were inducted onto TOP over 7 weeks, stabilized for 8 weeks at 300 mg daily then tapered over 3 weeks. Voucher incentives were supplied for 12 weeks, starting during the fourth week of TOP induction. Primary outcome measures were cocaine abstinence (Y/N) as measured by thrice weekly urinalysis and analyzed using Generalized Estimating Equations (GEE) and treatment retention. All analyses were intent to treat and included the 12-week evaluation phase of combined TOP/P treatment and voucher intervention period., Results: There was no significant difference in cocaine abstinence between the TOP vs. P conditions nor between the CM vs. Non-CM conditions. There was no significant TOP/CM interaction. Retention was not significantly different between the groups., Conclusion: Topiramate is not efficacious for increasing cocaine abstinence in methadone patients., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Given the long-term nature of methadone maintenance treatment, it is important to assess the extent of cognitive side effects. This study investigated cognitive and psychomotor performance in 51 methadone maintenance patients (MMP) as a function of time since last methadone dose and maintenance dose level. MMP maintained on doses ranging from 40 to 200 mg (mean = 97 mg) completed a battery of psychomotor and cognitive measures across 2 sessions, during peak and trough states, in a double-blind crossover design. Peak sessions were associated with worse performance on measures of sensory processing, psychomotor speed, divided attention, and working memory, compared with trough sessions. The effects of maintenance dose were mixed, with higher dose resulting in worse performance on aspects of attention and working memory, improved performance on executive function, and no effects on several measures. Longer treatment duration was associated with better performance on some measures, but was also associated with increased sensitivity to time since last dose (i.e., worse performance at peak vs. trough) on some measures. The results suggest that cognitive functioning can fluctuate as a function of time since last dose even in MMP who have been maintained on stable doses for an extended time (mean duration in treatment = 4 years), but worsened performance at peak is limited to a subset of functions and may not be clinically significant at these modest levels of behavioral effect. For patients on stable methadone maintenance doses, maintenance at higher doses may not significantly increase the risk of performance impairment., (PsycINFO Database Record (c) 2014 APA, all rights reserved.)

Preliminary evidence suggests that there is minimal withdrawal after the cessation of chronically administered buprenorphine and that opioid withdrawal symptoms are delayed compared with those of other opioids. The present study compared the time course and magnitude of buprenorphine withdrawal with a prototypical μ-opioid agonist, morphine. Healthy, out-of-treatment opioid-dependent residential volunteers (N = 7) were stabilized on either buprenorphine (32 mg/day i.m.) or morphine (120 mg/day i.m.) administered in four divided doses for 9 days. They then underwent an 18-day period of spontaneous withdrawal, during which four double-blind i.m. placebo injections were administered daily. Stabilization and spontaneous withdrawal were assessed for the second opioid using the same time course. Opioid withdrawal measures were collected eight times daily. Morphine withdrawal symptoms were significantly (P < 0.05) greater than those of buprenorphine withdrawal as measured by mean peak ratings of Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Scale (SOWS), all subscales of the Profile of Mood States (POMS), sick and pain (0-100) Visual Analog Scales, systolic and diastolic blood pressure, heart rate, respiratory rate, and pupil dilation. Peak ratings on COWS and SOWS occurred on day 2 of morphine withdrawal and were significantly greater than on day 2 of buprenorphine withdrawal. Subjective reports of morphine withdrawal resolved on average by day 7. There was minimal evidence of buprenorphine withdrawal on any measure. In conclusion, spontaneous withdrawal from high-dose buprenorphine appears subjectively and objectively milder compared with that of morphine for at least 18 days after drug cessation.

Rationale: Several studies have documented impairments in memory processes as a result of ketamine administration; however, few studies have compared the profile of cognitive effects of ketamine to other drugs., Objectives: The aim of this study was to compare the cognitive effects of ketamine with those of triazolam in healthy volunteers., Methods: Doses of ketamine (0.2, 0.4 mg/kg intramuscular (i.m.)), triazolam (0.2, 0.4 mg/70 kg p.o.), and double-dummy placebos were administered to 20 volunteers under repeated measures, counterbalanced, double-blind conditions. Peak physiological, psychomotor, subjective, and cognitive effects were examined., Results: Ketamine impaired balance when balance was assessed early in the task order, whereas triazolam impaired psychomotor coordination and divided attention irrespective of task order. Triazolam also tended to produce greater effects on working memory and episodic memory tasks than ketamine at doses that produced lower subjective effects and higher estimates of performance., Conclusions: Ketamine produces less cognitive impairment than triazolam at doses that produced greater subjective effects. Thus ketamine does not produce the underestimation of cognitive impairment typically seen with triazolam.

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, 0.5mg/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 6h., 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 0.5mg/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., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Prior studies have separately examined the effects of dronabinol (oral THC) on cannabis withdrawal, cognitive performance, and the acute effects of smoked cannabis. A single study examining these clinically relevant domains would benefit the continued evaluation of dronabinol as a potential medication for the treatment of cannabis use disorders., Methods: Thirteen daily cannabis smokers completed a within-subject crossover study and received 0, 30, 60 and 120mg dronabinol per day for 5 consecutive days. Vital signs and subjective ratings of cannabis withdrawal, craving and sleep were obtained daily; outcomes under active dose conditions were compared to those obtained under placebo dosing. On the 5th day of medication maintenance, participants completed a comprehensive cognitive performance battery and then smoked five puffs of cannabis for subjective effects evaluation. Each dronabinol maintenance period occurred in a counterbalanced order and was separated by 9 days of ad libitum cannabis use., Results: Dronabinol dose-dependently attenuated cannabis withdrawal and resulted in few adverse side effects or decrements in cognitive performance. Surprisingly, dronabinol did not alter the subjective effects of smoked cannabis, but cannabis-induced increases in heart rate were attenuated by the 60 and 120mg doses., Conclusions: Dronabinol's ability to dose-dependently suppress cannabis withdrawal may be therapeutically beneficial to individuals trying to stop cannabis use. The absence of gross cognitive impairment or side effects in this study supports safety of doses up to 120mg/day. Continued evaluation of dronabinol in targeted clinical studies of cannabis treatment, using an expanded range of doses, is warranted., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Rationale: Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM., Objective: This study in humans evaluated the effects of supratherapeutic doses of DXM and triazolam., Methods: Single, acute oral doses of DXM (100, 200, 300, 400, 500, 600, 700, and 800 mg/70 kg), triazolam (0.25 and 0.5 mg/70 kg), and placebo were administered to 12 healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Subjective, behavioral, and physiological effects were assessed repeatedly after drug administration for 6 h., Results: Triazolam produced dose-related increases in subject-rated sedation, observer-rated sedation, and behavioral impairment. DXM produced a profile of dose-related physiological and subjective effects differing from triazolam. DXM effects included increases in blood pressure, heart rate, and emesis; increases in observer-rated effects typical of classic hallucinogens (e.g., distance from reality, visual effects with eyes open and closed, joy, anxiety); and participant ratings of stimulation (e.g., jittery, nervous), somatic effects (e.g., tingling, headache), perceptual changes, end-of-session drug liking, and mystical-type experience. After 400 mg/70 kg DXM, 11 of 12 participants indicated on a pharmacological class questionnaire that they thought they had received a classic hallucinogen (e.g., psilocybin). Drug effects resolved without significant adverse effects by the end of the session. In a 1-month follow-up, volunteers attributed increased spirituality and positive changes in attitudes, moods, and behavior to the session experiences., Conclusions: High doses of DXM produced effects distinct from triazolam and had characteristics that were similar to the classic hallucinogen psilocybin.

Background: There is evidence for psychomotor and cognitive performance impairment in methadone maintenance patients (MMP), as well as in individuals with current cocaine dependence. It is unknown whether MMP with concurrent cocaine dependence perform worse on tests of cognitive function than MMP without cocaine dependence., Methods: Performance was compared between MMP with and without current cocaine dependence (MMP/CD+; N = 53 and MMP/CD-; N = 24) on a standard battery of tasks designed to measure psychomotor performance, attention, episodic and working memory, and executive function., Results: Participant characteristics were mostly similar across groups. However, the MMP/CD+ group had a shorter duration of methadone treatment, and a larger percentage of participants with self-reported 30-day poly-substance abuse and positive urine drug tests on the day of cognitive testing. There were no differences between the groups on measures of balance, psychomotor coordination, divided attention, working memory, most measures of episodic memory, or executive function. Relative to MMP/CD-, MMP/CD+ showed significant impairment on select measures of psychomotor performance/attention (simple reaction time and trail-making test A) and episodic memory (higher false alarm rates on recognition memory)., Conclusions: The absence of differences between MMP/CD+ and MMP/CD- on measures of higher order cognitive functions, and the relatively small magnitude between-group differences on other measures suggest that current cocaine dependence, in the absence of cocaine intoxication, is unlikely to be associated with clinically meaningful increases in performance impairment in MMP., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Working memory is impaired in opioid-dependent individuals, yet the neural underpinnings of working memory in this population are largely unknown. Previous studies in healthy adults have demonstrated that working memory is supported by a network of brain regions that includes a cerebro-cerebellar circuit. The cerebellum, in particular, may be important for inner speech mechanisms that assist verbal working memory. This study used functional magnetic resonance imaging to examine brain activity associated with working memory in five opioid-dependent, methadone-maintained patients and five matched, healthy controls. An item recognition task was administered in two conditions: (1) a low working memory load "match" condition in which participants determined whether target letters presented at the beginning of the trial matched a probe item, and (2) a high working memory load "manipulation" condition in which participants counted two alphabetical letters forward of each of the targets and determined whether either of these new items matched a probe item. Response times and accuracy scores were not significantly different between the groups. FMRI analyses indicated that, in association with higher working memory load ("manipulation" condition), the patient group exhibited hyperactivity in the superior and inferior cerebellum and amygdala relative to that of controls. At a more liberal statistical threshold, patients exhibited hypoactivity in the left prefrontal and medial frontal/pre-SMA regions. These results indicate that verbal working memory in opioid-dependent individuals involves a disrupted cerebro-cerebellar circuit and shed light on the neuroanatomical basis of working memory impairments in this population.

The extended-release formulation of zolpidem (Ambien CR) is approved for the treatment of insomnia without a treatment duration limit. Acutely zolpidem impairs performance, and no research to date has examined whether tolerance develops to these performance impairments during nighttime awakening. The present double-blind, placebo-controlled study examined whether tolerance develops to zolpidem-induced acute performance impairment after repeated (22-30 days) nightly use. Effects of bedtime administration of zolpidem extended-release (ZOL; 12.5 mg) were tested on a battery of performance measures assessed during a forced nighttime awakening in 15 healthy male volunteers who completed overnight polysomnographic recording sessions in our laboratory at baseline and after approximately a month of at-home ZOL. As expected, bedtime ZOL administration was associated with changes in sleep architecture and impairments across all performance domains during nighttime testing (psychomotor function, attention, working memory, episodic memory, metacognition) with no residual next morning impairment. Tolerance did not develop to the observed ZOL-related impairments on any outcome. Possible evidence of acute abstinence effects after discontinuation of ZOL was observed on some performance and sleep outcomes. Overall, these findings suggest that performance is significantly impaired during nighttime awakening even after a month of nightly ZOL administration, and these impairments could significantly impact safety should nighttime awakening require unimpaired functioning (e.g., driving; combat-related activities in the military).

Tramadol is an atypical, mixed mechanism analgesic used to treat moderate to severe pain. Based on evidence that tramadol has relatively low abuse potential and can relieve opioid withdrawal, tramadol may be useful for treating opioid dependence. The purpose of this study was to assess the performance side-effect profile of tramadol. Nine opioid-dependent volunteers completed a performance battery following 5-7 days of subcutaneous morphine (15 mg, 4 times/day) and two doses of oral tramadol (50, 200 mg, 4 times/day) in a within subject cross-over design. Morphine was always the first condition, and the order of the two tramadol doses was randomized and double blind. Performance was significantly worse in the morphine condition relative to one or both tramadol doses on measures of psychomotor speed/coordination (circular lights task), psychomotor speed/pattern recognition (DSST speed measure) and psychomotor speed/set shifting (trail-making tasks). There were no significant differences among conditions in DSST accuracy, simple reaction time, divided attention, working memory, episodic memory, metamemory, or time estimation. Neither tramadol dose was associated with worse performance than morphine on any measure. Although practice sessions were conducted prior to the first session to reduce order effects, the possibility that residual practice effects contributed to the differences between tramadol and morphine cannot be ruled out. The high tramadol dose produced worse performance than the low dose only on the balance measure. These findings suggest that tramadol is generally a safe medication with respect to cognitive and psychomotor measures and support tramadol's further evaluation as an opioid-dependence treatment., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Rationale: Tramadol is an atypical, mixed-mechanism analgesic involving both opioid and catecholamine processes that appears to have low abuse potential and may be useful as a treatment for opioid dependence., Objectives: The current study assessed the level of physical dependence and opioid blockade efficacy produced by daily maintenance on oral tramadol., Methods: Nine residential opioid-dependent adults were maintained on two doses of daily oral tramadol (200 and 800 mg) for approximately 4-week intervals in a randomized, double-blind, crossover design. The acute effects of intramuscular placebo, naloxone (0.25, 0.5, and 1.0 mg), and hydromorphone (1.5, 3.0, and 6.0 mg) were tested under double-blind, randomized conditions. Outcomes included observer- and subject-rated measures and physiologic indices., Results: Challenge doses of naloxone resulted in significantly higher mean peak withdrawal scores compared to placebo. Withdrawal intensity from naloxone was generally greater during 800 versus 200 mg/day tramadol maintenance. Mean peak ratings of agonist effects were elevated at higher hydromorphone challenge doses, but did not differ significantly between tramadol doses. Physiologic measures were generally affected by challenge conditions in a dose-dependent manner, with few differences between tramadol maintenance dose conditions., Conclusions: Chronic tramadol administration produces dose-related opioid physical dependence, without producing dose-related attenuation of agonist challenge effects. Tramadol may be a useful treatment for patients with low levels of opioid dependence or as a treatment for withdrawal during opioid detoxification, but does not appear to be effective as a maintenance medication due to a lack of opioid cross-tolerance.

The present study compared the acute dose effects of the benzodiazepine triazolam and the anticholinergic scopolamine on metamemory (knowledge and awareness of one's own memory) in a two-phase paradigm designed to assess effects on both monitoring and control components of metamemory in both semantic (general knowledge) and episodic memory (cued-recall) tasks. Placebo and 2 doses each of triazolam (0.125, 0.25 mg/70 kg, oral) and scopolamine (0.25, 0.50 mg/70 kg, subcutaneous) were administered to 80 healthy volunteers (16 per group) in a double-blind, double-dummy, independent groups design. Both triazolam and scopolamine impaired episodic memory (quantity and accuracy) but not semantic memory. Results suggested that both drugs impaired monitoring as reflected in absolute accuracy measures (impaired calibration in the direction of overconfidence) and control sensitivity (the relationship between confidence and behavior). Overall, the results did not provide evidence for differences between triazolam and scopolamine in memory or metamemory. In addition to the clinical relevance of the observed effects, this study adds to the accumulating body of cognitive psychopharmacological research illustrating the usefulness of drug-induced amnesia as a vehicle to explore memory and metamemory., ((PsycINFO Database Record (c) 2010 APA, all rights reserved).)

Benzodiazepines and alcohol are widely used psychoactive substances that have performance-impairing effects. Research suggests that the impairment profiles for benzodiazepines and alcohol differ, although few cognitive psychopharmacological studies have directly compared these drugs. This double-blind, double-dummy, placebo-controlled, repeated measures study directly compared the acute dose effects of triazolam (0.125, 0.25 mg/70 kg) and alcohol (0.40, 0.80 g/kg) in 20 social drinkers. At doses that produced comparable psychomotor impairment, triazolam was more likely to impair several objective measures of cognitive performance (e.g., episodic memory, divided attention) and to slow performance across several measures. However, only alcohol impaired accuracy on the digit symbol substitution and semantic memory tasks. In addition to objective measures, both drugs impaired awareness of performance impairments (i.e., metacognition) such that participants overestimated impairment, and the magnitude of this effect was generally larger for alcohol. Only triazolam impaired other measures of metacognition (e.g., error detection on a choice reaction time task). Future research might examine the clinical implications of the performance impairments reported here given the widespread use of benzodiazepines and alcohol., ((PsycINFO Database Record (c) 2010 APA, all rights reserved).)

Rationale: Illicit gamma-hydroxybutyrate (GHB) has received attention as a "date rape drug" that produces robust amnesia; however, there is little experimental evidence in support of GHB's amnestic effects., Objectives: This study compared the cognitive effects of GHB (sodium oxybate) with those of triazolam in healthy volunteers., Materials and Methods: Doses of sodium oxybate (1.125, 2.25, and 4.5 g/70 kg), triazolam (0.125, 0.25, and 0.5 mg/70 kg), and placebo were administered to 15 volunteers under repeated measures, counterbalanced, double-blind, double-dummy conditions. The time course and peak physiological, psychomotor, subjective, and cognitive effects were examined., Results: Sodium oxybate and triazolam produced similar increases in participant ratings of drug effects. Performance on psychomotor, working memory, and episodic memory tasks was impaired to a greater extent after triazolam than sodium oxybate., Conclusions: Together, these data suggest that sodium oxybate produces less psychomotor and cognitive impairment than triazolam at doses that produce equivalent participant-rated subjective effects in healthy volunteers.

Rationale: In addition to producing robust memory impairment, benzodiazepines also induce marked sedation. 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., Objective: The objective was to use the nonspecific stimulant d-amphetamine to dissociate the sedative and memory-impairing effects of the benzodiazepine triazolam., Materials and Methods: Single oral doses of placebo, triazolam alone (0.25, 0.50 mg/70 kg), d-amphetamine sulfate alone (20, 30 mg/70 kg), and triazolam (0.25, 0.50 mg/70 kg) and d-amphetamine sulfate (20, 30 mg/70 kg) conjointly (at all dose combinations) were administered to 18 healthy adult participants across nine sessions in a double-blind, staggered-dosing, crossover design. In addition to standard data analyses, analyses were also conducted on z-score standardized data, enabling effects to be directly compared across measures., Results: Relative to the sedative measures, the memory measures generally exhibited a pattern of less reversal of triazolam's effects by d-amphetamine. The memory measures ranged in degree of reversal such that the most reversal was observed for reaction time on the n-back working memory task, and the least reversal was observed for accuracy on the Sternberg working memory task, with most measures showing an overall pattern of partial reversal., Conclusions: Benzodiazepines have specific effects on memory that are not merely a by-product of the drugs' sedative effects, and the degree to which sedative effects contribute to the amnestic effects varies as a function of the particular memory process being assessed.

Between-study comparisons of benzodiazepine and anticholinergic drugs on working memory suggest that anticholinergics may produce greater impairment in maintenance processes, whereas benzodiazepines may produce greater impairment in manipulation processes. This study directly compared acute effects ofthe benzodiazepine lorazepam (1.0 and 2.0 mg/70 kg, orally administered) and the anticholinergic scopolamine (0.25 and 0.50 mg/70 kg, subcutaneously administered) on working memory maintenance (storage and rehearsal) and manipulation processes in a placebo-controlled, double-dummy, double-blind, crossover design in 20 healthy volunteers. Using a modified Sternberg paradigm, storage, rehearsal, and manipulation processes were parametrically manipulated by varying memory load, delay between stimulus presentation and test, and number of operations performed on the letter strings, respectively, while controlling for drug effects on nonmemory processes. As predicted, the results suggested greater impairment in maintenance processes (rehearsal) with scopolamine than with lorazepam and greater impairment in manipulation processes with lorazepam than with scopolamine. In addition, the results suggested greater overall slowing of working memory processes with lorazepam.

Although preclinical studies suggest that GHB has low likelihood for abuse, case reports indicate that GHB is abused. This study evaluated the relative abuse liability of GHB in 14 volunteers with histories of drug abuse. Psychomotor, subjective, and cognitive effects of a broad range of GHB doses (2-18 g/70 kg), up to a dose that produced severe behavioral impairment in each participant, were compared to placebo and two abused sedative/hypnotic drugs, triazolam (0.5 and 1 mg/70 kg) and pentobarbital (200 and 400 mg/70 kg), under double-blind, double-dummy conditions at a residential research facility. In general, GHB produced effects similar to triazolam and pentobarbital, although GHB was not identified as a benzodiazepine or barbiturate by participants that correctly identified triazolam and pentobarbital as such. On most measures of likelihood of abuse (eg ratings of liking, reinforcing effects), effects of pentobarbital were significantly greater than those of triazolam, with GHB being intermediate. GHB produced significantly greater negative subjective effects, including nausea, than the other drugs. Memory impairment after GHB was less than that after triazolam and pentobarbital. Within participants, the dose-effect function for sedation was steeper for GHB than for triazolam and pentobarbital. Also, at higher doses, GHB was associated with greater sedation and more variability across participants in sedation. Taken together, these data suggest that the profile of effects of GHB only partially overlaps with that of triazolam and pentobarbital. Although the likelihood for GHB to be abused is intermediate to triazolam and pentobarbital, the possibility of accidental overdose (ie greater sedation than intended) with GHB appears to be greater.

Rationale: Although it is well established that acute benzodiazepine administration impairs episodic memory encoding, little is known about the neuroanatomical substrates of this effect., Objective: The objective was to examine the acute dose effects of the benzodiazepine hypnotic triazolam on brain activity during episodic memory encoding., Methods: After oral capsule administration (placebo, 0.1, 0.2, and 0.4 mg/70 kg triazolam), regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) with 15O-H2O during performance of semantic categorization and orthographic categorization tasks in a double-blind, within-subject design in 12 healthy volunteers. The rCBF associated with episodic memory encoding was measured by subtracting the rCBF during orthographic categorization from that during semantic categorization and by examining correlations between brain activity during encoding and subsequent recognition memory performance., Results: Results in the placebo condition replicated those of nonpharmacological encoding studies, including activation in left ventrolateral prefrontal cortex. Correlations between brain activity and subsequent memory performance additionally showed medial temporal activation. Triazolam produced dose-related impairment in memory performance and dose-related deactivation in encoding-associated areas including right prefrontal cortex, left parahippocampal gyrus, and left anterior cingulate cortex., Conclusions: Results are consistent with behavioral evidence that benzodiazepines impair prefrontal control processes as well as contextual memory and episodic binding processes thought to be controlled by the medial temporal lobe. In addition to elucidating the brain mechanisms underlying these benzodiazepine-induced behavioral deficits, results of this study also help validate hypotheses generated in nonpharmacological neuroimaging studies regarding the processes controlled by these brain regions.

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) antagonist. Given the purported role of the NMDA receptor in long-term potentiation, the primary purpose of the present study was to further understand the dose-related effects of ketamine on memory. The study was also designed to provide information about the relative effects of ketamine on memory versus nonmemory effects and to more fully characterize ketamine's overall pattern and time course of effects. Single intramuscular injections of ketamine (0.2 mg/kg, 0.4 mg/kg) were administered to 18 healthy adult volunteers using a double-blind, placebo-controlled, crossover design. Word lists were used to evaluate episodic memory (free recall, recognition memory, source memory) and metamemory. Working memory, time estimation, psychomotor performance, and subjective effects were assessed repeatedly for 5 hours after drug administration. Ketamine selectively impaired encoding (as measured by free recall) while sparing retrieval, working memory while sparing attention, and digit symbol substitution task speed while sparing accuracy. Ketamine did not significantly impair recognition or source memory, metamemory, or time estimation. There were no hallucinations or increases in mystical experiences with ketamine. Memory measures were less sensitive to ketamine effects than subjective or psychomotor measures. Subjective effects lasted longer than memory and most psychomotor impairments. Ketamine produces selective, transient, dose- and time-related effects. In conjunction with previous studies of drugs with different mechanisms of actions, the observed selectivity of effects enhances the understanding of the pharmacological mechanisms underlying memory, attention, psychomotor performance, and subjective experience.

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.

This experiment was designed to use the graded dose-related amnesia produced by the benzodiazepine lorazepam (1.0, 2.0 mg/70 kg, oral) and the anticholinergic scopolamine (0.3, 0.6 mg/70 kg, subcutaneous) as a tool to explore the cognitive and neurochemical mechanisms underlying metamemory in the judgment of learning paradigm, with a placebo-controlled independent groups design in healthy volunteers (n = 12/group). Results provide evidence for a pharmacological dissociation between effects on memory versus metamemory (relative accuracy of item-by-item monitoring) across a range of levels of memory performance and suggest that the drugs selectively impair those aspects of metamnemonic monitoring that require participants' awareness of their overall current state of functioning (absolute accuracy of prospective item-by-item monitoring, prospective global monitoring) but not those that rely solely on assessment of individual item characteristics (relative accuracy of item-by-item monitoring)., (Copyright 2005 APA, all rights reserved.)

A few recent studies provide evidence for performance impairment in dependent opioid abusers enrolled in methadone maintenance programs. However, it is difficult to differentiate the effects of a history of long-term opioid (or polydrug) abuse from the effects of methadone maintenance itself. The purpose of the present study was to address this issue by comparing the performance of a newly recruited group of 20 currently abstinent former opioid abusers retrospectively to two groups (18 methadone maintenance patients (MMP); 21 matched non-drug abusing controls) reported on previously in our laboratory [Mintzer, M.Z., Stitzer, M.L., 2002. Cognitive impairment in methadone maintenance patients. Drug Alcohol Depend. 67, 41-51], using the same performance testing battery. The abstinent abusers were demographically similar to the MMP and matched controls, and reported histories of drug use similar to those of the MMP. Although conclusions are somewhat limited by the small sample size, performance of the abstinent abusers fell between that of the MMP and controls on many measures, suggesting that methadone maintenance may be associated with additional impairment over and above that associated with long-term abuse, and that recovery of functioning may occur during abstinence. Further research is necessary to explore the factors underlying performance impairment in MMP and to determine the clinical significance of the observed impairments for daily performance in the natural environment.

Rationale: Parametric preclinical studies of the benzodiazepine antagonist flumazenil have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use. However, few parametric studies have been conducted in human participants., Objective: This study was designed to assess the effect of duration of benzodiazepine exposure on the intensity of flumazenil-precipitated withdrawal in healthy volunteers., Method: Participants were randomly assigned to receive either oral diazepam (15 mg/70 kg; n=10) or placebo (n=8) capsules nightly for 28 days. Effects of flumazenil (1 mg/70 kg, intravenously administered) were assessed in challenge sessions conducted before capsule ingestion, and after 1, 7, 14, and 28 days of capsule ingestion., Results: Flumazenil produced a profile of participant-rated effects consistent with benzodiazepine withdrawal that peaked immediately after completion of the 5-min flumazenil injection and rapidly dissipated thereafter. The magnitude of these effects was comparable after 7, 14, and 28 days of diazepam. Flumazenil also produced modest elevations in blood pressure and decreases in skin temperature in the diazepam group, both of which were sustained throughout the approximate 60-min session., Conclusions: These findings support previous human research studies indicating that flumazenil precipitates withdrawal after short chronic exposure to benzodiazepines and suggests that duration of exposure does not influence the intensity of withdrawal beyond the first week of exposure.

This study used midazolam-induced amnesia to explore the plausibility of the estimates provided by the process dissociation procedure (PDP), which is designed to estimate the contributions of recollection (R) and automatic (A) processes to implicit memory performance. In a double-blind, placebo-controlled, within-subject design with 24 participants, single midazolam doses were administered intravenously, and word stem completion performance was used to calculate PDP estimates. A dissociation was observed such that midazolam decreased R but increased A estimates relative to placebo. Given that a manipulation that induces amnesia would not be expected to facilitate a memory process, these results add to the accumulating body of evidence suggesting that PDP estimates are not always theoretically plausible. Such evidence raises important questions about the use of the PDP.

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.

This placebo-controlled, double-blind, double-dummy, independent groups study directly compared effects of the benzodiazepine, lorazepam (2.0 mg/70 kg orally administered), and the anticholinergic scopolamine (0.6 mg/70 kg subcutaneously administered) on memory and attentional measures hypothesized to differentiate the drugs. At the studied doses, lorazepam and scopolamine produced similar decrements in psychomotor performance, free recall, and overall sensitivity in distinguishing between studied and nonstudied items on a recognition memory test. However, the drugs differed with respect to effects on working memory, response bias, metacognition, subjective awareness, and selective attention. In addition to providing information about the cognitive psychopharmacological profiles of drugs with distinct neurochemical and pharmacological mechanisms of action, this study also informs the understanding of memory and attentional processes.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.