Received November 13, 2011; Accepted January 06, 2012; Published January 12, 2012
Citation: Mahoney III JJ, Jackson BJ, Kalechstein AD, Garza II RDL, Shah R, et al. (2012) The Effects of the Benzodiazepine, Temazepam, on Neurocognitive Functioning and Sleep Patterns in Methamphetamine-Dependent Participants. J Addict Res Ther S1:007. doi:10.4172/2155-6105.S1-007
Copyright: © 2012 Mahoney III JJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Objectives: Previous research has shown that methamphetamine users demonstrate poorer sleep quality and daytime sleepiness when compared to healthy controls. It is also well known that long-term methamphetamine use is associated with impaired neurocognitive function and, similarly, sleep deprivation is associated with decreased neurocognitive performance. Temazepam is a potent sedative and is effective for the treatment of insomnia. It was hypothesized that treatment of methamphetamine dependent volunteers with temazepam would improve sleep characteristics resulting in improved cognitive functioning.
Methods: 18 subjects completed a seven-day inpatient study where they completed daily subjective assessments, such as the PSQI, ESS, and VAS. Temazepam or placebo was administered on the evenings of Nights 5 and 6. Sleepiness was objectively assessed using the MSLT on Days 5-7 and neurocognitive testing was performed on Day 5 (prior to drug administration) and on Day 7.
Results: The findings of this study demonstrate that temazepam did not improve quality of sleep, did not decrease sleep onset latency, and did not improve in neurocognition in methamphetamine-dependent participants.
Discussion: Since the chosen dose and duration of temazepam did not improve neurocognitive performance when compared to placebo, further research must be performed to better understand temazepam’s effects and potential utility in this population.
Methamphetamine; Cognition; Temazepam; Sleep
Previous research has shown that methamphetamine users demonstrate poorer sleep quality and daytime sleepiness when compared to healthy controls [1,2]. In a sample of methamphetamine users, Mahoney and colleagues reported average scores on the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were 8.5+5.0 and 9.8+5.5, respectively [1, unpublished findings], which are significantly higher than the average scores in healthy, nondrug using individuals [3,4]. Moreover, acute methamphetamine administration is associated with reduced self-reported fatigue and increased daytime sleepiness , as well as improved performance on measures of information processing speed, attention, and working memory [6,7]. Thus, it is possible that one motivation for continued methamphetamine use is to reduce daytime sleepiness by increasing alertness and attention.
It is also well known that long-term methamphetamine use is associated with impaired neurocognitive function  and, similarly, sleep deprivation is associated with decreased neurocognitive performance [9-13]. Thus, methamphetamine may enhance cognitive functioning in part by counteracting effects of methamphetamineinduced sleep disturbances.
Temazepam is a potent sedative acting at the benzodiazepinebinding site on the gamma-aminobutyric acid receptor and is effective for the treatment of insomnia [14,15]. For instance, in a study comparing temazepam (30 mg per night for 3 nights) to placebo in healthy volunteers, temazepam significantly reduced sleep onset latency and also increased sleep efficiency . In another study, temazepam administration (1 dose of 20 mg) induced quality sleep with less sleepiness after waking when compared to the non-benzodiazepine, zaleplon . Temazepam has a relatively short half-life (half-life of 14 hours) , limiting next-day carryover effects. Consistent with this, some reports indicate that administration of a moderate dose of temazepam (20 mg per night for 5 nights or) before bedtime did not impair next-day performance on neuropsychological tasks, including memory and psychomotor speed .
Based on these considerations, we hypothesized that treatment of methamphetamine dependent volunteers with temazepam would improve sleep characteristics resulting in improved cognitive functioning.
18 subjects were recruited for this seven-day inpatient study through advertisements in the community, and were paid for their participation. All subjects were non-treatment seeking and met DSMAbstract IV-TR criteria for methamphetamine dependence, as assessed by the MINI International Neuropsychiatric Interview (MINI) . Other inclusion criteria included being between 18 and 45 years of age, twiceweekly use of methamphetamine (smoked or i.v.) in 4 out of the 6 previous weeks, positive urine toxicology for Meth prior to admission, and normal vital signs. Exclusion criteria included diagnosis of any other Axis I psychiatric disorder, dependence on any other drugs aside from nicotine, a history of seizure disorder, head trauma, or concomitant use of any psychotropic medication. Additionally, a previous diagnosis with any primary sleep disorder (e.g. narcolepsy, insomnia, REM sleep behavior disorder) or any sleep disordered breathing or apnea was exclusionary. The Institutional Review Board of the University of California Los Angeles approved this study and all subjects gave informed consent after being made aware of the possible risks of participation. Participating individuals were compensated for their enrollment.
At admission, participants were randomized to receive either temazepam (Mallinckrodt, Hazelwood MO; 30 mg) or placebo on Nights 5 and 6 of the study. Temazepam was encapsulated to match placebo in appearance. Temazepam was administered at 10 PM, as peak plasma levels are reached at about one hour , and bedtime for each enrolled subject was 11 PM every evening of the study.
Daytime sleep assessment
We objectively assessed sleepiness using the multiple sleep latency test (MSLT), consisting of a series of 4 nap opportunities offered at set times throughout the day. Sleep onset latency is measured during this time, and this test is believed to measure the physiological sleep tendency in the absence of alerting stimuli . The MSLT was performed on Days 5-6 of the inpatient stay at 9 AM, 11 AM, 1 PM, and 3 PM. Standard electroencephalography (EEG) electrodes were attached to the scalp and face according to the international 10-20 system. Five minutes prior to each test, subjects were asked to get into bed, and were led through a standardized diagnostic series of movements (eyes left, eyes right, eyes up, eyes down, blink) to ensure correct electrode functioning. Participants then completed the Stanford Sleepiness Scale (SSS) to assess self-perceived somnolence levels. Following completion of the SSS, lights in the room were turned off, shades and curtains were drawn, and the subjects were asked to try to fall asleep. As per clinical research standards for the MSLT, subjects were given 20 minutes to fall asleep, indexed by typical changes in the EEG. If they did not fall asleep after 20 minutes the test was concluded and the lights were turned back on.
Between test sessions, subjects were instructed to remain out of bed, and napping was not permitted on those days. To prevent confounds due to the arousing effects of nicotine, exercise, and caffeine, each was restricted during the inpatient stay . Specifically, exercise and caffeine were not allowed during the duration of the inpatient stay, and participants were not allowed to smoke for 1 hour before each nap session.
Hopkins verbal learning test – revised (HVLT – R) : The HVLT is an assessment of verbal learning and memory. Participants were read a list of 12 words, and asked to recall as many as they could. This procedure was repeated two times (for a total of 3 learning trials). Following a 20-25 minute delay, participants were asked to recall the words without the aid of cues (Delayed Recall). After delayed recall, participants were then read a list of 24 words, and had to identify the 12 words from the original list (Recognition). The dependent variables of interest for the HVLT – R were total words recalled during the three learning trials and number of words remembered on the delayed recall subtest.
Simple reaction time task (SRT): The SRT is an assessment of attention. The SRT involves pseudo-random presentation of a series of letters (from the set A, a, G, g, T, t, H, h), one at a time, at the center of a computer screen. Participants were instructed to press a red button on the response box with their dominant forefinger as quickly as possible following presentation of the letter. Letters were black on a white background, subtended approximately 1.9° x 1.6°. Each letter was presented for 500 ms, with a subsequent letter presented 2500 ms later. A total of 32 trials were presented. The dependent variable was difference in reaction time (msec) between the second and first administrations of the task (SRT2 – SRT1).
Choice reaction time task (CRT): The CRT is an assessment of attention and working memory. The CRT involves presentation of the same set of letters seen during the SRT. In this task, however, participants are instructed to press a red button on the response box with their dominant forefinger upon presentation of G, g, H, or h. Upon presentation of A, a, T, or t, participants were instructed to press a blue button on the response box. Letters were black on a white background, subtended approximately 1.9 x 1.6° Each letter was presented for 500 ms, with a subsequent letter presented 2500 ms later. A total of 32 trials were presented. The dependent variables were reaction time (msec) and response accuracy, indexed as the ratio of actual accurate responses to total possible responses.
Brief visuospacial memory test – revised (BVMT-R; ): The BVMT is an assessment of visual learning and episodic memory. Participants were shown a sheet containing 6 simple objects for 10 seconds, and then asked to draw, as accurately as possible, the objects they were shown. This procedure was repeated two additional times (for a total of 3 learning trials). Following a 20-25 minute delay, participants were asked to draw the objects from memory, without being shown the sheet again (Delayed Recall). A maximum of two points were awarded per object (based on likeness to the original), for a total of 12 per trial. After the delayed recall trial, participants were shown 12 objects, and had to identify the original 6. The dependent variables of interest for the BVMT – R were total points, learning slope (number of points on the third learning trial minus the number of points on the first learning trial), and points recalled on the delayed recall trial.
N-back task : The N-Back is an assessment of working memory and was a variation of an N-back that has been used previously . Participants were presented with a series of letters from the same set as seen on the SRT and CRT. In the 1-back condition, participants were to signal a ‘yes’ response (pressing a blue button with the dominant forefinger) if the presented letter matched the letter presented immediately beforehand. If the two letters did not match, a ‘no’ response (pressing a red button with the dominant forefinger) was required. In the 2-back condition, a ‘yes’ response was required if the presented letter matched the letter two trials previous. Otherwise, a ‘no’ response was required. Case of the letter was not relevant to matching verbal identity. Letters were black on a white background, subtended approximately 1.9° x 1.6°. Each letter was presented for 500 ms, with a subsequent letter presented 2500 ms later. After completing at least 20 trials of practice, participants completed a total of 32 trials for each condition. The dependent variables were reaction time (msec) and response accuracy, indexed as the ratio of actual accurate responses to total possible accurate responses.
Stroop interference task : The Stroop is an assessment of selective attention and ability to inhibit a prepotent verbal response. In this task, individuals are given 3 separate sheets containing 100 words (Red, Blue, Green; Word List), a series of 100 sets of ‘XXXX’ printed in either red, green, or blue (Color List), and finally 100 words printed in incongruent colors (‘Red’ printed in blue ink, for example; Color Word List). For the first two lists, participants read the word, and the color of the ‘XXXX’ sequences respectively. For the final list, participants must read the color that the word is printed in, not the verbal identity of the word (if ‘Red’ is printed in blue ink, participants must respond by saying “blue”). Individuals were given 45 seconds to read each list. The dependent variables of interest for the Stroop Interference Task are number of items read for each of the three lists, and interference score (calculated as number of Color Words actually read correctly minus the number that should have been read correctly based on performance on the first two trials).
Stop-signal task (SST; ): The SST is an assessment of response inhibition and was performed according to the method outlined by Logan and colleagues . Briefly, participants were presented with a target (either ‘X’ or ‘O’) following presentation of a fixation dot. The target remained on the screen for 2000 ms, and participants were instructed to respond as fast as they could with a left key-press for ‘O’, or right key-press for ‘X’ (Go trials). They were also instructed to try to stop themselves from completing a response if a target was followed by a “stop-signal” tone. This signal occurred during 25% of the 256 trials (64 times), at a variable delay (Stop-Signal Delay, SSD) after presentation of the target stimulus. After a successful stop-trial, the SSD (initial presentation 200 ms after the stimulus) was increased by 50 ms, and after a failed stop-trial, it was decreased by 50 ms, thereby converging on a SSD resulting in approximately 50% successful inhibition rate. The dependent variables for this task were reaction time on Go trials, accuracy, and stop-signal reaction time (SSRT). SSRT was computed as the difference between mean reaction time on Go trials, and the averaged SSD.
Controlled oral word association test (COWAT): COWAT is an assessment of verbal fluency (for review see: ). The purpose of the test is to evaluate the spontaneous production of words within a limited amount of time. Specifically, participants were asked to orally produce as many words as possible, in 60 seconds, beginning with a given letter of the alphabet. Three trials were administered, each employing a different letter (in this case, FAS). For the purposes of this study, only one letter was given on each of the three testing days (‘F’ on Day 5, ‘A’ on Day 6, and ‘S’ on Day 7). During this task, participants were prohibited from saying proper nouns (e.g., Frankfurt, Sarah) or saying the same word using a different ending (e.g., sit, sitting, sits). Scoring was conducted according to standardized published norms . Errors were tracked and were not included in the final total. Errors included correct words that had been repeated, words that began with the wrong letter, proper nouns, or words that differ from a previous response by tense or plurality. Homonyms were accepted if the participant could verbalize the separate meanings clearly. Slang and commonly used foreign words were also scored as acceptable responses. The dependent variable of interest on the COWAT was the total number of acceptable words produced for each letter trial.
Verbal intelligence measurement: The American National Adult Reading Test (AMNART) was administered on Day 5 (baseline) for assessment of pre-morbid verbal intelligence . Subjects were given a list of 46 words and were asked to read them aloud. Incorrect pronunciations were scored as misses, and through the use of a simple formula, pre-morbid verbal IQ was calculated.
Order of Neurocognitive Test Administration
Order of Neurocognitive Test Administration The battery of neurocognitive tests was administered on Days 5 and 6 at 11:45 AM (following the written daily assessments mentioned above) in the following order: The HVLT – R learning recall trials, BVMT – R learning recall trials, SRT, CRT, the N-back tests, delayed recall and recognition trials of the HVLT - R, delayed recall and recognition trials of the BVMT – R, the stop-signal task, re-administration of the SRT, the Stroop Interference Task, and the COWAT. Difference scores between the two SRT administrations was used as a measure of psychomotor fatigue. The reaction time tests were programmed on a laptop computer using SuperLab (SuperLab, 1997). All responses for computerized tasks (other than the SST) were administered using a RB-730 response box (Cedrus, Phoenix AZ). A standardized set of written and oral instructions was given to the participants prior to administration of each task, and participants were always reminded to respond as quickly and accurately as possible.
Paired sample t-tests were used to determine differences between temazepam and placebo groups. Reaction time cutoffs of shorter than 100 ms and longer than 1500 ms for each computerized task were established to eliminate the possibility of anticipating the appearance of the stimuli, as well as the possibility of a delayed response intruding on the presentation of the subsequent stimulus. Repeated measures ANOVA (temazepam dose x rday) were used to investigate the effects of temazepam on daytime sleep latency, MSLT latencies on the baseline day (Day 5) and the post-temazepam day. In addition, within-subjects, repeated measures analysis of variance (ANOVA) was performed to evaluate the effects of temazepam versus placebo on test performance pre- and post-temazepam/placebo exposure. Significance for all analyses was set at p < 0.05 .
|8 (89%)||8 (89%)|
|1 (11%)||1 (11%)|
|4 (44%)||4 (44%)|
|4 (44%)||4 (44%)|
|1 (6%)||0 (0%)|
|0 (0%)||1 (6%)|
|METH Drug Use|
|Years of use||12.67±8.57||12.22±6.57|
|^ Recent use||20.00±9.30||16.67±8.63|
|Nicotine Use||8 (89%)||7 (78%)|
1 Same subject population as reported in Mahoney, 2011
^ Recent use indicates number of days of use of primary drug in the 30 days preceding interview.
*p < 0.05Age, Education, Years of use, and Recent use, Grams/week, Amount Spent/week, Days Abstinent, PSQI, ESS reflect mean ± S. D.
Table 1: Demographic Characteristics1
A note on full study design
The subjects described in the current report were also randomized to receive modafinil on either Day 6 or 7 and completed neurocognitive assessments following modafinil administration. Modafinil had no impact on neurocognitive functioning and those null findings will be published in a separate manuscript.
Effects of treatment with temazepam on sleep and craving
Demographic information for the 18 methamphetamine users are detailed in Table 1. Nine individuals were randomized into each group and the groups were statistically similar in for all baseline subjective and objective sleep variables except for Day 1 PSQI score (F1,16 = 4.83, p < 0.05) and baseline (Day 5) daytime sleep latency (F1,16 = 14.46, p < 0.01). Day 1 PSQI score did not correlate with any of the objective daytime sleep latency or neurocognitive measures, so it was not included as a covariate in subsequent analyses.
The data show that sleep latency for individuals who received temazepam increased from 9.41 ± 2.48 minutes at baseline to 11.07 ± 3.96 minutes the morning after temazepam administration, thought this did not reach statistical significance (F1,14 = 1.03, p = 0.33). In addition, there were no differences between placebo and temazepam groups after treatment on self-reported nighttime sleep onset latency (F1,15 = 0.00, p = 0.98), self-reported rating of how well participants slept (F1,15 = 0.21, p = 0.65), how “deep” their sleep was (F1,15 = 0.08, p = 0.78), how “refreshed” they were (F1,15 = 0.24, p = 0.63), how “energetic” they felt (F1,15 = 0.19, p = 0.66), how likely they would be to take a nap (F1,15 = 1.92, p = 0.19). In addition, there were no significant differences between treatment groups in how much “better” methamphetamine would make them feel (F1,15 = 0.23, p = 0.64), how likely they would be to use methamphetamine (F1,15 = 2.92, p = 0.11), craving for methamphetamine (F1,15 = 0.17, p = 0.68), desire for methamphetamine (F1,15= 0.54, p = 0.47),or BDI-II score (F1,14 = 0.04, p = 0.86).
Effects of treatment with temazepam on neurocognitive function
A comparison of neurocognitive performance between treatment groups at baseline (Day 5) revealed no significant difference on any measure. As a result, the analyses centered on post-randomization outcomes (Table 2) which reveal no significant differences between groups on any neurocognitive task (all p values > 0.05). A secondary analysis, utilizing a within- (pre- versus post-temazepam/placebo exposure) and between- (temazepam versus placebo) subjects design, also yielded no significant differences.
The results suggest that temazepam did not improve either sleep or neurocognitive functioning in methamphetamine-dependent participants. It was originally hypothesized that if the amount and quality of sleep was increased/improved, participants would perform at a higher level when administered the neurocognitive assessments. However, since sleep characteristics were not improved, we could not test the hypothesis that sleep abnormalities contributed to neurocognitive functioning in this population
Using a benzodiazepine to ameliorate neurocognitive dysfunction by improving sleep patterns in methamphetamine-dependent individuals is distinct from compounds that have been tested in the past. For example, cognitive enhancers, such as modafinil [31,32], are typically used since they have demonstrated efficacy in increasing attention and alertness. In addition, acetylcholinesterase inhibitors, such as rivastigmine, have been investigated due to their cognitive enhancing effects . While these medications are intended to directly impact cognition by improving memory and increasing alertness, the rationale for using a benzodiazepine is that neurocognition will be indirectly improved by alleviating deficits in sleeping disturbances.
|Temazepam 0 mg (Placebo)||Temazapam 30 mg||p^|
|Reaction Time (ms)||-1.86±43.13||8.14±25.48||24.89±37.52||10.78±29.71||0.85|
|Reaction time (ms)||886.43±55.66||888.11± 38.36||890.61±86.54||865.00±64.45||0.42|
|Reaction time (ms)||795.21±77.31||837.64±61.46||871.11±156.21||853.17±82.23||0.68|
|Correct (%)||93.56±8.15||94.9±5.67||92.60 ±6.97||95.60±5.13||0.80|
|Reaction time (ms)||920.36±69.33||960.43±189.42||1052.83±202.44||923.72±176.79||0.70|
|Total words recalled (#)||21.14±7.52||21.86±5.24||21.33±4.92||21.11±3.86||0.75|
|Delayed Recall (%)||78.91±13.69||61.29±26.79||77.50±20.57||66.89±27.50||0.69|
|Total objects recalled (%)||13.57±4.20||11.57±4.16||15.67±5.50||13.44±3.54||0.35|
|Delayed Recall (%)||87.14±20.58||94.0±21.26||91.78±37.67||94.11±20.65||0.99|
|Words Read (#)||84.86±18.88||88.57±14.68||86.89±15.19||88.11±13.59||0.95|
|Colors Read (#)||62.00±9.24||62.29±9.76||59.89±9.52||66.89±8.15||0.32|
|Color-Words Read (#)||36.43±11.66||38.57±10.28||35.89±7.39||39.89±7.64||0.77|
|Words Pronounced (#)||12.57±4.20||14.86±5.27||10.33±2.50||12.78±5.14||0.44|
|RT – Go Trials (ms)||584.74±97.80||586.02±124.38||650.96±128.42||573.73±183.88||0.40|
|Baseline Accuracy (%)||98.90±1.20||98.53±1.50||93.95±8.47||95.40±5.13||0.24|
^ p values indicate differences between post-treatment groups.
Table 2 : Baseline and post-treatment (post—tx) performance on neurocognitive functioning.
There are several limitations to this study that must be taken into account. First, while Glass et al. (2003) reported the efficacy of a single dose of temazepam in sedating elderly insomniacs , one 30 mg dose might not be enough to observe the desired effects methamphetaminedependent individuals. In addition, the study by Glass et al. investigated individuals with insomnia, while participants with any previous sleep disorder diagnosis were immediately excluded from the current study. Thus, individuals who have never been diagnosed with a sleeping disorder may require an increased dosage or a more frequent dosing schedule. Second, the relatively small sample size (n=18) may also contribute to the negative findings in this report. Third, on the mornings of either Day 6 or Day 7, participants also received modafanil and the counter condition on the other day (findings published separately). While there were no statistically significant interactions found between the modafinil and temazepam, nor statistical differences between the individuals that received modafinil in combination with temazepam versus modafinil in combination with placebo, this is still worth mentioning as a study limitation.
In conclusion, the findings of this study demonstrate that temazepam did not improve quality of sleep, did not decrease sleep onset latency, and did not improve in neurocognition in methamphetamine-dependent participants. Further research must be performed to better understand temazepam’s effects and it’s potential utility in this population.
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