The present study compared the acute dose effects of triazolam and alcohol in healthy volunteers across a variety of cognitive performance outcomes using a repeated measures, placebo-controlled, double-dummy, double-blind design. As discussed below, at doses that produced similar levels of impairment on psychomotor and choice reaction time (see and ), triazolam and alcohol had differing effects on other outcomes.
The finding that triazolam and not alcohol impaired divided attention in the present study (see and ) is consistent with previous research showing that triazolam had more robust impairing effects on a similar type of divided attention task relative to alcohol (
Roehrs et al., 1993). Nevertheless, the absence of alcohol-related impairment on divided attention is striking given that several previous reports suggest that alcohol impairs divided attention performance (
Hamilton & Copeman, 1970;
Leigh, Tong, & Campbell, 1977;
Maylor, Rabbitt, James, & Kerr, 1990;
Schulte, Muller-Oehring, Strasburger, Warzel, & Savel, 2001,
Wilkinson, 1995). However, all of the above studies included tasks that incorporated two sensory modalities into the design (e.g., auditory and visual) or tasks that included auditory stimuli only. In contrast, the present study (and
Roehrs et al, 1993) utilized visual stimuli only. Thus, the absence of an alcohol effect on divided attention in the present study may be related to sensory modality, although a previous review of the effects of alcohol on divided attention suggests that sensory modality does not mediate alcohol’s impairing effects (
Moskowitz, 1984).
Triazolam and alcohol also had differing effects across measures of memory in the present study (see and ). First, the high dose of alcohol and not triazolam significantly impaired semantic memory performance. This finding is consistent with previous research showing alcohol-related impairment on a similar measure of semantic memory (i.e., general information task;
Nelson et al., 1986). The finding that triazolam did not impair semantic memory replicates results of another study in our laboratory that examined triazolam using the same task (
Mintzer, Kleykamp, & Griffiths, 2008). However, it should be noted that Bacon and colleagues have found impairment with the benzodiazepine lorazepam in several studies with a similar general information task (
Bacon et al., 1998,
2007;
Massin-Krauss et al., 2002).
In contrast to the pattern of effects on semantic memory, only high dose triazolam but not alcohol increased working memory response time after controlling for a non-memory control condition. More robust effects of triazolam on working memory were reported previously in a study directly comparing these drugs (i.e., number recall task;
Roache et al., 1993). In addition, some studies examining alcohol alone have reported minimal to no effects on working memory (
Finn, Justus, Mazas, & Steinmetz, 1999;
Paulus, Tapert, Pulido, & Schuckit, 2006;
Schweizer et al., 2006; but see also
Grattan-Miscio & Vogel-Sprott, 2005). Lastly, triazolam produced relatively greater effects on episodic memory measures. That is, both doses of triazolam but only the high dose of alcohol impaired hits and d′ on the recognition memory task and number correct on the free recall task. This finding is consistent with previous reports suggesting more robust effects of benzodiazepines relative to alcohol on episodic memory outcomes (
Matilla et al., 1998;
Mintzer & Griffiths, 2002;
Roache et al., 1993;
Schuckit et al., 1991). The finding of differences between triazolam and alcohol in dose effects on episodic memory is interesting in conjunction with results of a study in our laboratory examining the dose effects of the NMDA antagonist ketamine (
Lofwall, Griffiths, & Mintzer, 2006), which suggest that ketamine may also produce less robust effects on episodic memory than benzodiazepines. Robust subjective ratings of drug effect and impaired psychomotor performance were observed at a ketamine dose (0.2 mg/kg) that did not produce significant episodic memory or working memory impairment. Although the effects of a benzodiazepine were not examined in that study, this pattern of effects appears to differ from that observed with benzodiazepines, which produce memory impairment even at relatively low doses.
More robust effects of triazolam relative to alcohol were also observed for the number of attempted trials on the DSST. Similar to the pattern observed with episodic memory, both doses of triazolam but only high dose alcohol decreased the number of attempted trials on the DSST suggesting that this speed of processing measure is more sensitive to triazolam. However, only high dose alcohol and not triazolam impaired accuracy (proportion correct) on the DSST. Taken together, these DSST findings are in agreement with a previously proposed hypothesis that benzodiazepines are more likely to slow performance relative to alcohol, whereas alcohol is more likely to impair accuracy relative to benzodiazepines (a pattern of effects that might reflect a speed/accuracy tradeoff;
Tiplady et al., 1998;
2003). The findings that triazolam and not alcohol increased the number of timeouts in the 2-sec response interval condition of the choice reaction time task and increased response time on the working memory task lend additional support to the idea that benzodiazepines are more slowing than alcohol (although the pattern of effects on these measures does not indicate a speed/accuracy tradeoff)/Interestingly, research suggests that benzodiazepines are also more slowing relative to the anticholinergic drug scopolamine (
Curran, Schifano, & Lader, 1991;
Mintzer & Griffiths, 2003a;
2007).
In addition to objective measures of performance, the present study revealed that triazolam and alcohol significantly impaired subjective ratings of performance, or metacognition. Across most performance estimates, both drugs were associated with an over-estimation of performance impairment, regardless of whether volunteers were asked to rate performance before or after the task, and the magnitude of this over-estimation effect was generally larger for alcohol. For example, for DSST accuracy, the performance estimate difference score value was 4.24 for high dose triazolam and 27.46 for high dose alcohol (see ). The tendency for participants to estimate performance as less impaired in the triazolam condition relative to the alcohol condition is consistent with results of a previous study that showed triazolam was associated with under-estimation of performance impairment, while alcohol had no effect on performance estimates (
Roache et al., 1993). Interestingly, participants tend to estimate performance as less impaired under benzodiazepine conditions when compared to other performance-impairing drugs as well (e.g., pentobarbital, scopolamine;
Mintzer & Grifiths, 2003a;
Roache & Griffiths, 1985).
While the tendency to estimate performance as less impaired for triazolam relative to alcohol is consistent with previous work, the finding that both drugs produced over-estimation of impairment relative to placebo is in contrast to reports that triazolam produces under-estimation of impairment (
Bacon et al., 1998;
Massin-Krauss, et al., 2002;
Mintzer & Griffiths, 2003b;
Roache et al., 1985,
1987,
1993) and alcohol generally produces no effects on performance estimates (
Acons et al., 2006;
Harrison & Filmore, 2005;
Mintzer, Frey, Yingling, & Griffiths, 1997a;
Nelson et al., 1986;
Roache et al., 1993). One explanation for the present findings is that participants might have been sensitized to their level of performance because they were asked to rate their performance before and after completing multiple tasks and these tasks were administered at multiple time points in each study session. Thus, over-estimation of performance impairments might have been driven by hyper vigilance to performance. Indeed, previous research suggests an “under-confidence-with-practice (UWP)” effect for learning new information such that the more volunteers completed a task, such as word recollection, the less confident they were with regards to their performance (
Koriat, 1997;
Koriat, Ma’ayan, Sheffer, & Bjork, 2006,
Koriat, Sheffer, Ma’ayan, 2002). One explanation for this UWP effect suggests that memory for past task performance increases under-confidence (
Finn & Metcalfe, 2008). Therefore, volunteers in the present study might have remembered their performance on a task earlier in the session and this memory could have increased their under-confidence or over-estimation of performance impairment. Further, this UWP effect might have been enhanced in active drug conditions because volunteers experienced disorienting drug effects (e.g., dizziness) and thus were even more conservative when rating their performance.
Interestingly, a significant time by drug interaction for the working memory task suggests that practice with the task, at least for this measure, has differing effects on estimates of performance depending on drug type. That is, ratings of accuracy on the working memory task revealed that, prior to completing the task, volunteers significantly over-estimated impairment in the high dose alcohol condition relative to high dose triazolam and placebo conditions. In contrast, after completing the task, volunteers significantly over-estimated impairment in the high dose triazolam condition relative to high dose alcohol and placebo. This finding suggests that in the high dose alcohol condition volunteers were able to use their experience with the task to adjust their ratings such that they more accurately estimated actual performance. In contrast, in the triazolam condition experience with the task contributed to an impairment of metacognition such that individuals were no longer accurate in their ratings and were more likely to over-estimate impairment. More research on task practice and drug effects would be helpful in clarifying whether the UWP effect varies as a function of performance measure and drug type.
A further point to consider is the role that drug experience played in the effects of triazolam and alcohol on metacognition in the present study. Notably, volunteers were not benzodiazepine users, but were regular users of alcohol. Previous research suggests that experience with a drug influences the subjective effects of that drug (
Brumback, Cao, & King, 2007;
Marczinski, Harrison, & Fillmore, 2008) and perhaps our metacognitive findings might have differed had the participants also been regular users of benzodiazepines.
In contrast to performance estimate outcomes, triazolam and not alcohol impaired other measures of metacognition relative to placebo. First, error detection was significantly impaired by triazolam and not alcohol suggesting that volunteers were less aware of their errors in the high dose triazolam condition (see ). Similarly, a previous study that utilized a similar choice reaction time found that alcohol (0.8 g/kg) did not impair participants’ detection of errors relative to placebo (
Acons et al., 2006). In addition, benzodiazepine-induced impairment of error detection has been reported elsewhere using behavioral measures and/or electrophysiological correlates of error detection (
deBruijn, Hulstijn, Verkes, Ruigt, & Sabbe, 2004;
Johannes, Wieringa, Nager, Dengler, & Munte, 2001;
Riba, Rodriguez-Fornells, Munte, & Barbanoj, 2005). Second, the effect of drug condition on metamemory on the episodic memory task, as measured by the correspondence between confidence ratings and accuracy (i.e., gamma correlations), was marginally significant (
p < 0.06) in the present study (see ). A closer inspection of the means suggests that high dose triazolam impaired the volunteers’ ability to distinguish between correct and incorrect responses relative to placebo. A similar triazolam-induced impairment of metamemory accuracy has been reported elsewhere suggesting that this effect is reliable (
Mintzer & Griffiths, 2003b).
Lastly, of note is the absence of any effects of either drug on the metamemory outcomes associated with the semantic memory (general information) task in the present study (data not shown). The lack of triazolam-related effects on these outcomes is particularly surprising given that previous reports suggest that the benzodiazepine lorazepam impairs some metamemory outcomes on a similar semantic memory task (
Bacon et al., 1998;
Massin-Krauss et al., 2002). However, results from a separate study in our laboratory confirmed that triazolam had no effects on the same metamemory outcomes included in the present study suggesting that the present findings are reliable (
Mintzer et al., 2008). One important distinction to be made among the above studies as noted above is that those from our laboratory did not observe benzodiazepine-related impairment of actual performance (i.e., semantic memory accuracy) on the general information task, whereas the other studies that reported drug-related impairment of metamemory outcomes also found drug-related impairment of actual performance. Therefore, one possibility is that the presence of actual performance impairment may be related to the detection of metamemory impairments. Further research is needed to explore the inconsistencies among the above studies, as well as to further examine alcohol’s effects on metamemory outcomes considering little research has been dedicated to this topic.
In summary, the present study provides insight into the effects of triazolam and alcohol on specific cognitive processes. Overall, the results suggest that triazolam is a more potent disruptor of objective measures of cognitive performance especially with regards to measures of speed. However, only alcohol impaired accuracy on the DSST and semantic memory task. In addition to objective measures, both drugs impaired subjective awareness of performance decrements, though the magnitude of these effects was generally larger for alcohol (i.e., greater over-estimation of impairment), whereas triazolam had greater effects on other measures of metacognition (i.e., error detection and episodic memory gamma). Importantly, the differential effects of triazolam and alcohol across performance outcomes cannot be accounted for by differences in the time course of drug effects because time course analyses did not reveal differences between active drug conditions. In addition, breath alcohol levels (BALs; see ) confirm that the doses of alcohol chosen for this study produced dose-dependent increases in BALs across the duration of the study sessions. Furthermore, as predicted participant ratings of overall strength of drug effect were higher for alcohol relative to triazolam at corresponding doses. Therefore, an absence of alcohol-related effects on particular measures cannot be accounted for by insufficient alcohol dosing. It is also unlikely that differences between drugs in effects on performance were related to differential effects of alcohol on ascending versus descending limbs of the breath alcohol curve given that most tasks were administered at multiple time points throughout each session. Thus, the absence of an effect of alcohol, for instance on the divided attention outcomes (see and ), cannot be tied to isolated testing on one limb.
Overall, despite the fact that the effects of triazolam and alcohol are both at least partially mediated through the GABAA receptor site, the findings reported here suggest that these drugs have distinct cognitive impairment profiles. In conjunction with an accumulating body of cognitive psychopharmacological research examining these and other drugs (e.g., ketamine, scopolamine, pentobarbital), the observed differences between triazolam and alcohol contribute to a more complete understanding of the neurochemical mechanisms underlying different cognitive processes. In addition, performance impairments observed in the present study could have important clinical implications given the widespread use of benzodiazepines and alcohol. In particular, the triazolam-induced slowing of performance and impairment of divided attention might have detrimental effects on driving performance, and the episodic memory impairments associated with both drugs could impact work-related performance, such as remembering standard operating procedures.
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