RUNNING HEAD: Lorazepam and Memory

Lorazepam and its Effects on Memory

Melissa Branco

Carleton College

Abstract

            Much of the human way of life depends on one’s ability to remember the events that occur in our everyday lives. When a medication has the potential to impair memory, close monitoring of the patient is necessary to insure his or her safety. When taken at the correct dosage for short periods of time, lorazepam effectively treats acute stress and anxiety. However, as with any drug, the side effects must be considered before using the drug. Lorazepam shares similar side effects with other benzodiazepines including sedation and impaired memory function. File, Fluck, & Joyce (1999) explain that there are three stages of memory: acquisition, consolidation, and retrieval. Benzodiazepines like lorazepam impair the acquisition of new memory process, which essentially causes anterograde amnesia; memory acquired prior to exposure to the drug remains intact. The following paper outlines the different effects on memory that lorazepam has been known to cause, and offers a personal example of what can happen when a patient taking a drug like lorazepam is not closely monitored by a doctor.

Lorazepam and its Effects on Memory

Lorazepam belongs to a class of drugs known as the benzodiazepines. Benzodiazepines were introduced in the United States in the 1960s and have anxiolytic, sedative, anticonvulsant, amnestic, and muscle-relaxant effects on humans. As GABA-benzodiazepine-chloride receptor complex agonists, the benzodiazepines work by facilitating binding of GABA. This action, in turn, assists the influx of chloride, which hyperpolarizes the postsynaptic neuron, thus depressing excitability in the cell. The drugs’ anxiolytic properties, for which they are most commonly used, stem from such action at limbic centers (Julien, 2001).

Though they are increasingly displaced by antidepressant drugs in the treatment of anxiety disorders the benzodiazepines are still widely used in medicine. Benzodiazepines in general are easy to use and have low toxicity, and are very effective for treatment of short term stress-related anxiety and insomnia. Because of the side effects of long term use of benzodiazepines, however, they are usually only prescribed for a couple of weeks at a time. Side effects include mental confusion, anterograde amnesia, sedation, decreased psychomotor function and academic performance, and a potential for dependency if taken for long (Julien, 2001).

            Lorazepam is an intermediate-acting agent generally taken in oral form. It does not have an active metabolite and its elimination half life is approximately 10-24 hours (Julien, 2001). As with many benzodiazepines, it is used primarily for its stress-related anxiety reducing properties. Also like many benzodiazepines, it is generally only used for a couple of weeks at a time due to its side effects. Research over the last decade has revealed in particular very specific memory side effects connected to use of the drug. Specifically, lorazepam is known to affect several types of memory including semantic, episodic, explicit, and implicit memory (priming in particular) in a large portion of patients.

            In a study by Bacon, et al. (1998), 26 healthy volunteers were given a dosage (either 0.026 or 0.038mg/kg) of lorazepam and asked to perform a series of tests to gage the effects the drug had on metamemory, confidence level, and feeling of knowing. They found that lorazepam did indeed impair episodic memory and confidence accuracy in higher doses, but not feeling of knowing or, at first glance, semantic memory. However, subjects tended to selectively overestimate confidence level for incorrect answers, and had impaired performance in both recall and recognition for semantic memory. Subjects also experienced a decreased ability to distinguish between correct and incorrect information. Bacon and his colleagues therefore conclude that lorazepam does indeed affect metamemory for episodic and semantic memory.

            While the effects of lorazepam on explicit memory were initially well documented, its effects on implicit memory and on priming were harder to prove. After overcoming several limitations in a prior study, Buffett-Jerrott, Stewart, & Teeham (1998) found that the effects on episodic memory of lorazepam and other benzodiazepines are time-dependent even when involving everyday memory demands. They administered either 2mg lorazepam, 30mg oxazepam (another benzodiazepine), or placebo to thirty subjects and then administered two tests 170 minutes later to see the effects of the drugs on memory. Subjects were tested at 170 minutes in order to rule out “explicit memory contamination” – a limitation of their previous research. One test involved a word-stem completion task to test implicit memory and the other involved a cued recall task to test explicit memory. Results ultimately indicated that lorazepam and oxazepam, as well as benzodiazepines in general, affect explicit and implicit memory in subjects tested during the peak concentrations of the administered drug. The implications of this study are that, due to the memory impairments common with these drugs, concurrent cognitive and behavioral therapy may not be very effective. Further, even those people who become dependent and tolerant to these drugs still suffer from memory impairment, so everyday functioning will likely suffer as a result (Buffett-Jerrott, Stewart, & Teeham 1998).

            Vidailhet, Danion, Chemin, & Kazès (1999) decided to build on prior research with perceptual (visual) priming and investigate whether the effects of lorazepam on auditory priming are similar to those seen in perceptual priming. They randomly assigned 32 healthy volunteers to either experimental or placebo group following a double-blind process. Subjects were informed to refrain from caffeine and alcohol use for 24 hours prior to experiment, and were tested in the morning before breakfast. Subjects from the experimental group received 0.038mg/kg of lorazepam orally while the subjects from the placebo group received a standard sugar pill. Each subject was administered similar word-stem completion tasks involving auditory and perceptual priming. They also tested explicit memory using a free recall test, and explored auditory perception by an auditory word-identification task. Each subject completed each test and rated their alertness with visual analogue scales; throughout the tests, no subject experienced substantial sedation side effects. The results of these tests indicated that lorazepam distinctly reduced performance in visually and auditorily presented words in the free-recall task. In the placebo group, auditory priming facilitated perception of the stem-completion task, but did not in the experimental group. Thus, Vidailhet, et al. (1999) determined that lorazepam does not only affect visual priming, but auditory priming as well.

            There were very few limitations of the Vidailhet, et al. study in 1999. One main factor is the potential for explicit memory contamination, which was accounted for in the Buffett-Jerrott, et al. study of 1998, but not in this present study. Essentially, the placebo group was given a slight advantage by being able to use explicit memory to aid in their priming performance. However, the researchers did try to minimize this effect by tweaking the test instructions in order to minimize the effect of explicit contamination. Further, since there was no significant correlation between performance on the free-recall test and the auditory priming tests, the experimenters concluded that the effect of explicit contamination, if any, did not significantly alter results of their study.

            File, Fluck, & Joyce (1999) used lorazepam to show how in some cases benzodiazepines can facilitate the retrieval of memory traces acquired prior to exposure of the drug. They first investigated the effect of lorazepam on explicit memory using doses of 0.5mg, 1.0mg, and 2.5mg. Results showed that 1.0mg of lorazepam improved the recall of items studied prior to drug exposure, and did not cause impairment of items studied after drug exposure. Armed with this information, they next explored the conditions under which 1.0mg lorazepam could facilitate retrieval. As lorazepam facilitated the recall of two lists of semantically related words, these experiments suggest that lorazepam does not affect the consolidation stage of memory. Further, since 1.0mg lorazepam is sufficient to produce anxiolytic effects, it may in fact be possible to combine doses of lorazepam and cognitive therapy. One limitation with this study, however, is that the subjects (while all young and healthy) were all given a set amount of the drug; the researchers did not vary the dosage according to weight. However small, this may have contributed (positively or negatively) to their results.

            Two more recent studies build on much of this prior research and revisit the effects of lorazepam on different types of memory in slightly new ways. The first was a study by Martin et al. (2002) on the effects of lorazepam and oxazepam on perceptual and procedural memory functions. This study revisits a lot of the work from the Buffett-Jerrott, et al. study from 1998. In this recent study, Martin and his colleagues decided to compare the “time-dependent effects of lorazepam and oxazepam on implicit memory tasks, specifically perceptual priming and procedural learning” (Martin, et al., 2002, p 262). Thirty-three healthy female volunteers, all undergraduate students, were randomly assigned to one of three time groups and then administered either 2.5mg lorazepam, 30mg oxazepam, or placebo (100mg of vitamin B₁) in counterbalanced order at one-week intervals. The first group was tested prior to the peak concentration of the drugs, the second group was tested during peak concentration, and the third group was tested after peak concentration. Testing materials included perceptual priming tasks and procedural learning tasks (in the form of rotary pursuit).

            Results from the Martin et al. (2002) study show that while lorazepam impaired perceptual priming at each time interval, oxazepam did not. Further, procedural learning was not affected by either drug. These results call to question the notion that all benzodiazepines exert time-dependent effects on implicit memory, in particular the results offered by Buffett-Jerrott, et al. (1998). Martin and his colleagues offer several reasons for the inconsistency, among them differences in methodologies. Further, Martin, et al. (2002) found significant interactions between the sedative side effects of the two drugs and impairment of memory. In all likelihood, it was probably the combination of the two which caused the difference in results. Also, since drugs affect all people differently, there is a chance that the samples from which these two experiments drew from were significantly different.

Another recent work combines the efforts of Massin-Krauss, Bacon, and Danion (2002) on the effects of lorazepam on monitoring and control processes in semantic memory. Thirty subjects, divided equally between experimental and control groups, participated in a semantic memory task involving several different conditions including forced and free report and incentive and no-incentive. Subjects were all healthy individuals with no mental illness or history of drug, alcohol, or severe tobacco abuse; each subject was paid for his or her participation and asked to avoid caffeine and alcohol for 24 hours prior to the start of the experiment. The subjects were given either 0.038mg/kg lorazepam or placebo in double-blind procedure.

Results indicate that memory accuracy was significantly lower in the experimental group and that lorazepam did indeed impair control sensitivity, which is “the extent to which volunteering of answers is affected by the confidence judgments” (Massin Krauss, et al., 2002, p 123). However, the ability to distinguish correct from incorrect answers and the confidence necessary to volunteer an answer were not significantly affected. The researchers therefore conclude that “the pharmacological dissociation between monitoring effectiveness and control sensitivity indicates that these two components involve distinct processes” (Massin-Krauss, et al., 2002, p 123). These results are in slight contrast with the Bacon, et al. (1998) study in which lorazepam impaired confidence accuracy. However, the two studies were testing slightly different aspects of confidence. While Massin-Krauss, et al., (2002) was studying the confidence threshold for making an answer, Bacon, et al., (1998) was studying confidence in an answer already volunteered. The slight difference in what these two researchers were studying suggests that either these two processes are separate, or that methodological differences accounted for the discrepancy.

When used properly and for a short period of time, lorazepam can greatly improve the quality of life for people suffering from periods of acute anxiety. However, lorazepam comes with its own set of side effects that must be considered before prescribing or taking the medication. In addition to its sedative effects, lorazepam has been shown in countless studies to impair memory function including metamemory for episodic and semantic memory (Bacon, et al., 1998), time-dependent explicit and implicit memory (Buffett-Jerrott, et al, 1998), visual and auditory priming (Vidailhet, et al., 1999), perceptual priming (Martin et al., 2002), and even control sensitivity (Massin-Krauss, et al., 2002) in a large portion of patients who take the medication. Explicit memory seems to be the most commonly affected type of memory across studies. While some studies have found the ability to facilitate certain types of memory under very discrete circumstances (see File, et al., 1999), lorazepam has a detrimental effect on every-day memory function that must be considered and constantly monitored when taking the medication.

             It has now been over a year since my mother died from a broken neck caused by a fall down four steps in our home. The accident occurred in the middle of the night, while she was alone, and still there remains some inconsistencies, mostly concerning why a reasonably healthy woman in her fifties would fall down four stairs and break her neck. One thing that is for certain is that, at least partly due to the lorazepam she was taking, my mother was suffering from memory impairment, especially short term explicit memory. In addition to lorazepam, which she claimed she took “only when she really needed it”, my mother was taking Paxil® (paroxetine HCl) on a regular basis. Both drugs were prescribed by different doctors for treatment of acute (lorazepam) and chronic (paroxetine HCl) stress and anxiety.

The major problem was that my mother would take her recommended dose of these medications, forget that she had taken them, and then take more. It was a cycle that culminated about every month or so with her having what she called a “spell” in which she would experience heavy sedation and confusion, profound memory loss, an increased need to sleep, and a “drunk” like stupor the following day. Occasionally my mother would fall during one of her spells, leading her to believe she had a brain tumor when she would wake up with a bump on her head. When MRI scans showed no tumor, my mother was furious that no one could tell her why she had a bump on her head. She refused to believe that it was the result of a fall because she could not remember falling. She could not remember falling because the medications she was taking all affect memory. She further refused to believe that she was unintentionally overmedicating herself.

I do not blame my mother, nor the medication she was taking, for her death. I do blame the doctors for not assessing her individual situation more closely and following up on her status more carefully. This problem is not uncommon today’s world of “tell me your problems but make sure it doesn’t take more than 15 minutes”. The medications we have today are only as good as the doctors prescribing them, and no drug treatment should go without some form of patient monitoring, if only to ensure that the patent is taking his or her medication property and is managing the side effects in a reasonable matter. My mother’s case is just one more example of the adverse affects on memory that lorazepam causes, and how side effects that go unmonitored can escalate to something worse.

References

Bacon, E., Danion, J.M., Kauffmann-Muller, F., Schelstraete, M.A., Bruant, A., Sellal, F., & Grange, D. (1998). Confidence level and feeling of knowing for episodic and semantic memory: an investigation of lorazepam effects on metamemory. Psychopharmacology, 138, 318-325.

Buffett-Jerrott, S., Stewart, S.H., & Teehan, M.D. (1998). A further examination of the time-dependent effects of oxazepam and lorazepam on implicit and explicit memory. Psychopharmacology, 138, 344-353.

File, S.E., Fluck, E., & Joyce, E.M. (1999). Conditions under which lorazepam can facilitate retrieval. Journal of Clinical Psychopharmacology, 19, 349-353.

Julien, R.M. (2001). A Primer of Drug Action, 9^th Ed. New York: Worth Publishers.

Martin, J., Matthews, A., Martin, F., Kirkby, K.C., Alexander, J., & Daniels, B. (2002). Effects of lorazepam and oxazepam on perceptual and procedural memory functions. Psychopharmacology, 164, 262-267.

Massin-Krauss, M., Bacon, E., & Danion, J.M. (2002). Effects of the benzodiazepine lorazepam on monitoring and control processes in semantic memory. Consciousness and Cognition, 11, 123-137.

Vidailhet, P., Danion, J.M., Chemin, C., & Kazès, M. (1999). Lorazepam impairs both visual and auditory perceptual priming. Psychopharmacology, 147, 226-273.