AM. J. DRUG ALCOHOL ABUSE, 17(2), pp. 129-136 (1991)
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Amnestic Effects of Intravenous Diazepam in Healthy Young Men Robert M. Anthenelli, MD Department of Psychiatry School of Medicine University of California- San Diego La Jolla, California 92093
Maristela G. Monteiro, MD, PhD Department of Psychopharmacology Escola Paulista de Medicina Sao Paulo, Brazil
Barbara Blunt, MD School of Medicine University of California- San Diego La Jolla, California 92093
Marc A. Schuckit,' MD Department of Psychiatry School of Medicine University of California- San Diego La Jolla, California 92093 Alcohol Research Center San Diego Veterans Administration Medical Center San Diego, California 92 161
*To whom requests for reprints should be addressed at Veterans Affairs Medical Center (1 16A), 3350 La Jolla Village Drive, San Diego, California 92161.
129
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ABSTRACT Changes in a test of memory performance were evaluated in 103 healthy young men after Challenges with placebo and two different doses of intravenous diazepam (0.12 and 0.20 mg/kg). Both diazepam doses significantly impaired free recall in a dose-dependent manner. Within each dose challenge there was no significant correlation between the average serum diazepam or desmethyldiazepamlevels and the average number of words recalled across the time points. The data expand our current understanding of the amnestic effects of benzodiazepines and suggest that patients abusing these drugs in large doses may develop profound degrees of memory impairment.
INTRODUCTION Benzodiazepines (Bzs) are capable of producing clinically relevant levels of memory impairment [l-71. Considered a side effect in most clinical contexts, this attribute may pose serious problems for patients abusing these drugs, and may contribute to their decline in social and occupational functioning. It is important for clinicians not only to warn patients of this potential consequence [8], but also to gain a better understanding of the nature of the memory impairment produced by these agents. Focusing on diazepam, the drug for which the preponderance of data are available [9-111, acute administrationhas been shown to produce an anterograde amnesia for both verbal and visual information [7, 12-21]. A major effect appears to occur at the acquisition or storage of information, impeding the transfer of factors from short-term to long-term memory [ 14- 181. This hypothesis is supported by the finding that diazepam does not impair immediate memory (sevendigit span) or the retrieval of words learned before drug administration, even in tests of delayed recall [ 191. Despite the information outlined above, relatively little data are available on the relationship between the memory impairment and the drug dose or serum drug levels. This paper describes the effect of challenges with two different doses of diazepam and placebo in 103 healthy young men. Serum diazepam levels were obtained, and the relationship between serum levels and memory effect was explored.
METHODS The 103 men were identified and tested through two stages of work. In the first phase a structured questionnairewas sent to all male students and nonacademic
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Mcgill University on 11/03/14 For personal use only.
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staff aged 18 to 25 years at the University of California, San Diego. Subjects were chosen from approximately 800 men who were paid $3.00 to provide information on demographic characteristics, medical problems, smoking history, drinking and drug use patterns and problems, personal history of psychiatric disorders, and family history of drug abuse, alcoholism, or major psychiatric disorders. Men were excluded from the study if they reported they had serious medical disorders such as diabetes or severe asthma, were taking medications, were total abstainers, or if, following a review of the data by a psychiatrist (MAS), they met DSM-I11 criteria for any major psychiatric or substance abuse problems (all exclusions added up to approximately 10% of the sample). In the second phase, selected individuals were telephoned to corroborate their historical data and then invited to the laboratory for a screening evaluation. Blood was drawn to identify and exclude subjects who were likely to have been drinking heavily as signaled by changes in gamma-glutamyltransferase, mean corpuscular volume, etc. [22]. The men also completed the Michigan Alcoholism Screening Test (MAST) in the presence of the research assistant, with positive results reviewed by a psychiatrist (MAS) [23]. The men then participated in a four-session paradigm with data for the present study gathered after intravenous (IV) challenges with placebo, 0.12 mg/kg of diazepam (“low dose”), and 0.20 mg/kg of diazepam (“high dose”) administered over 7 minutes. The fourth session involved an alcohol challenge and, thus, those results are not reported here. For all test sessions, individuals arrived at 7:OO A.M. after a 10-hour fast. Two 18-gauge scalp-vein needles attached to heparin locks were inserted into two noncontiguousantecubital veins-one for the infusion and the other for subsequent blood samples. AU hfbsions were given through a syringe covered by yellow paper so that the subjects and laboratory personnel could not discern the agent being administered. The subjects underwent baseline testing of predrug performance, and then the IV infusions were administered and reactions monitored for 3 l/i hours. At baseline and at 10, 30, 60,90, 120, and 180 minutes after infusion, the men participated in a test of immediate free recall. At each time point the subjects viewed a list of 15 nouns (word-frequency AA in the Thorndike-Lorge word count) shown twice on a television screen [24, 251. Nouns were presented at a rate of l/second with a 4-second pause before the list was repeated. Immediately following the presentation, the subject then had 1 minute to recall as many nouns as possible in any order. Different word lists were used for each time point, and the order in which subjects received the lists was randomized over the sessions. The computed score was the number of words correctly recalled.
ANTHENELLI ET AL.
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Mcgill University on 11/03/14 For personal use only.
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Blood drug values were monitored in the subjects every 30 minutes during the experiment. Serum diazepam and desmethyldiazepam levels were measured by the electron-capture gas-liquid chromatography approach [26]. Theflrst step in the data analysis was to evaluate the consistency of baseline memory performance across the three sessions by using a one-way analysis of variance (ANOVA) for the mean and standard deviations for the baseline scores on the number of words recalled for the 103 men. Second, to determine if there was a placebo effect, we carried out an ANOVA for changes in performance (number of words recalled) across time following placebo. Ihird, in order to determine if there was a dose-dependent relationship between the diazepam challenges and the degree of memory impairment, we carried out a 3 (dose: placebo, low, high) x 7 (number of words recalled at each time point) analysis of variance. However, this type of analysis does not allow us to address whether the results following the two active doses differed significantly without numerous post-hoc evaluations that carry heavy statistical penalties and a resultant loss of power. Thus, we also carried out a 2 (dose: low and high) x 7 (time points) analysis of covariance (ANOCOVA) for the number of words remembered, using placebo results as a covariate. Finally, to better understand the relationship between Bz blood levels and memory, for each session we determined the correlation between the grand mean of the number of words recalled across the time points and the grand mean across all the time points of the diazepam and desmethyldiazepam blood levels using Pearson’s correlation coefficient.
RESULTS The sample of 103 men had a mean age of 21.8 f 1.8 years, with 15.4 f 1.1 years of completed education. None of the subjects had ever used Bzs regularly, and all were free of major psychiatric disorders. For the 3-month period prior to testing, subjects had consumed alcoholic beverages on an average of 8.4 f 4.9 days per month with a mean consumption of 3.4 f 1.6 drinks per drinking day (a drink was defined as 12 oz of beer, 4 oz of nonfortified wine, or 1.5 oz of 80-proof distilled spirits). Data on blood levels of diazepam and desmethyldiazepamwere available for only 79 of the 103 subjects (77%). The overall mean serum levels for the low dose and high dose challenges were 235.4 f 53.2 ng/mL and 379 f 62.0 ng/mL for diazepam, and 19.39 f 16.44 ng/mL and 23.44 f 12.27 ng/mL for desmethyldiazepam, respectively.
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0
m--+
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---
0 . 2 0 m g I k g DIAZEPAM I V
. 0
I
0c
- _____-----
-
-_-------I
w 2 -
5
Fig. 1. Mean number of words recalled over 180 minutes in the three test conditions for 103 men.
Figure 1 shows the free recall test results after placebo, low dose, and high dose diazepam. There were no significant differences in predrug performance on the 3 days of testing (F = 1.12; 2,204 df;p = .328). During the placebo trial, there was a small decrease in the mean number of words recalled at the 10-minute time point, with a significant time effect for this session (F = 3.83; 6,612 df;p < .001). In contrast, there was a marked decrease in test performance during both diazepam challenges which reached a nadir at 10 minutes and then gradually returned to baseline. The high dose condition showed a greater decrement during the 3-hour test period. The 3 x 7 repeated measures ANOVA revealed significant dose (F = 350.61; 2,204 df;p < .OO01) and time effects (F = 283.05; 6,612 df;p < .OO01), and a dose by time interaction (F = 76.64; 12,1224 df;p < .OO01). In light of the small but significant time effect after placebo, the 2 X 7 analysis was performed as an ANOCOVA (covarying for placebo), and revealed significant dose (F = 139.93; 1,102 df;p < .OO01) and time effects (F = 334.53; 6,612 df;p < .OOOl), and a dose by time interaction (F = 11.92; 6,612 df; p < .OO01). This demonstrates that even after controlling for changes during the placebo session, the effects of the two active doses on memory performance were significantly different.
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Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Mcgill University on 11/03/14 For personal use only.
To better understand the effect of diazepam on the memory task, we looked at the relationship between the subjects’ performance on the test of free recall and the blood levels of diazepam and desmethyldiazepamobtained following the low and high dose challenges. Within each dose challenge there was no significant correlation between the average number of words recalled over the 180 minutes and the average blood level of either diazepam or desmethyldiazepam measured over the 180-minute test session.
DISCUSSION The present study was established to address two questions about the effects of IV diazepam on a memory task in healthy young men. First, there was a significant effect of IV diazepam across doses on the immediate free recall of a list of common nouns. This finding expands the results of Ghonheim et al. who found consistent decreases in performance as the dose of orally administered diazepam increased [20]. Taken together, these results have clinical relevance in that patients taking higher doses of benzodiazepines may exhibit more profound degrees of memory impairment, and clinicians should warn their patients of this potential side effect. Second, despite the different effects across doses, within each dose challenge there was no significant correlation between the score on the test of immediate free recall and the serum levels of either diazepam or desmethyldiazepam. This is probably a consequence of the fairly narrow range of these diazepam parameters within a specific milligram/kilogram dose. It is also possible that the degree of impairment is related to the rate of change in blood levels rather than the actual values per se, a hypothesis not tested in the present study [27, 281. In interpreting our results, it is important to recognize some of the caveats inherent in our design. While our sample was large, it was limited to healthy, educated, young, Caucasian men who were chosen from respondents to a questionnaire and our results may not generalize to women, older subjects, or persons who take benzodiazepines on a regular basis. Although two different doses of diazepam were tested, we did not sample the entire spectrum of clinically relevant doses which might be administered. Finally, the major limitation of our study is that we used only one test of memory performance and while word lists were constructed from the Thorndike-hrge word count, no independent index of comparability was established. As a result, while the degree of memory impairment observed in this study was relatively marked, we are unable to comment on how other components of memory may have been affected.
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135
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In conclusion, our findings confirm previous studies indicating that diazepam significantly impairs memory performance and that this effect appears to be dosedependent. Clinicians prescribing benzodiazepines may do well to inform their patients of this potential clinical effect, and patients abusing these agents may exhibit signs of marked memory impairment.
ACKNOWLEDGMENTS This work was supported by the Veterans Affairs Research Service, NIAAA Grant 05526, the Alcohol Beverage Medical Research Foundation, and a FAPESP Fellowship from Sao Paulo, Brazil. The authors are grateful to David Greenblatt without whose help this project could not have been carried out.
REFERENCES [I] Scharf, M. B., Fletcher, K., and Graham, J. P., Comparative amnestic effects of benzodiazepine
hypnotic agents, J. Clin. Psychiatry 49: 134-137 (1988). [2] Taylor, J . L., and Tinklenberg, J. R., Cognitive impairment and benzodiapines, in Psychophurmacology: The Third Generdon of Progress (H. Y. Meltzer, ed.), Raven Press, New York, 1987. [3] Scharf, M. B., Saskin, P., and Fletcher, K., Benzodiazepine-induced amnesia: Clinical and laboratory findings, J . Clin. Psychiarry (Suppl.) 5 :14-17 (1987). [4] Gamzu, E. R., The role of benzcdiazpines in amnesia: Laboratory predictors, J. Clin. Psychiatry (Suppl.) 5:8-13 (1987). [5] Block, R. I . , and Berchou, R., Alprazolam and lorazepam effects on memory acquisition and retrieval processes, P h u m c o l . Biochem. Behuv. 20:233-241 (1984). [6] Roth, T., Hartse, K. M., Saab, P. G., et al., The effects of flurazepam, lorazepam, and uiazolam on sleep and memory, Psychophamcology 70:231-237 (1980). [7] Brown, J . , Lewis, V., Brown, M. W., er al., Amnesic effects of intravenous diazepam and lorazepam, Erperienria 34501-502 (1978). [8] Scharf, M. B., Clinical commentary: Benzodiazepine-induced amnesia, J. Clin. Psychiarry (Suppl.) 5:3-7 (1987). [9] Romney, D. M., and Angus, W. R., A brief review of the effects of diazepam on memory, P S y C h o ~ h a ~ C O Bull. l. 20:313-316 (1984). [ 101 Wittenborn, J . R., Effects of benzodiazepines on psychomotor performance, Br. J . Clin. Phurmac01. 7~615-675(1979). [ l l ] Kleinknecht, R. A., and Donaldson, D., A review of the effects of diazepam on cognitive and psychomotor performance, J. New. Ment. Dis. 161:399-411 (1975). [12] Clarke, P. R., Eccersley, P. S., Frisby, J. P., eral., The amnesic effect ofdiazepam (Valium), Br. J. Anaesrh. 42:690-697 (1970). [I31 Ghonheim, M. M., Mewaldt, S. P., and Thatcher, J . W., The effect of diazepam and fentanyl on mental, psychomotor and electroencephalographic functions and their rate of recovery, Psychophamcologia 44:61-66 (1975). [ 141 Ghonheim, M. M., and Mewaldt, S.P., Effects of diazepam and scopolamine on storage, retrieval and organizational processes im memory, Psychophamcologia 44:257-262 (1975).
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[15] Ghonheim, M. M., and Mewaldt, S. P., The interactions of diazepam, scopolamine, and physostigmine, Psychophurmocology 52: 1-6 (1977). [16] Clark, E. O., Glanzer, M., and Turndorf, H., The pattern of memory loss resulting from intravenously administered diazepam, Arch. Neurol. 35296-300 (1979). [17] Petersen, R. C., and Ghonheim, M. M., Diazepam and human memory: Influence on acquistion, retrieval, and statedependent learning, Prog. Neuro-Psychophurmacol.4231-89 (1980). [18] Hinrichs, I . V., Mewaldt, S. P.,Ghonheim, M. M., et ul., Diazepam and learning: Assessment of acquisition deficits, Pharmucol.. Biochem. Behuv. 17: 165-170 (1982). [19] Mewaldt, S. P.,Hinrichs, I. V., and Ghonheim, M. M., Diazepam and memory: Support for a duplex model of memory, Mem. Cognit. 11557-564 (1983). [20] Ghonheim, M. M., Hinrichs, J. V.,and Mewaldt, S. P., Lkw-nsponse analysisof the behavioral effects of diazepam: I. Learning and memory, Psychophurmacology 82:291-295 (1984). [21] Angus, W. R., and Romney, D. M., The effect of diazepam on patients’ memory, J. Clin. P ~ c h o p h a ~ c o l4:203-206 . (1984). [22] Schuckit, M. A,, and Irwii, M., Diagnosis of alcoholism, Med. Clin. N. Am. :D z f l d Diagnoses 7211133-1 153 (1988). [23] Selzer, M. L., The Michigan alcoholism screening test: The quest for a new diagnostic instrument, Am. J. Psychiatry 127:1653-1658 (1971). [24] Becker, J. T., Butters, N., Hexmanu, A., et al.,A comparison of the effects of long-term alcohol abuse and aging on the performance of verbal and nonverbal divided attention tasks, Alcoholism: Clin. Exp. Res. 7:213-219 (1983). 1251 Thorndike, E. L., and Lorge, L., 7he Teacher’s WordBook o f 3 0 . Words, ~ Columbia University Press, New York, 1944. [26] Greenblatt. D. J., Ochs, H.R., and Lloyd, B. L., Entry of diazepam and its major metablite into cerebralspinal fluid, Psychophumcology 70:89-93 (1980). [27] Greenblatt, D. J., Shader, R. I., Hannatz, J. S., et ul., Absorption rate, blood concentrations and uuly responses to oral chlordiazepoxide, Am. J. Psychiatry 134559-562 (1977). [28] Komila, K.,Manila, M. J., and Linnoila, M., Prolonged recovery after diazepam sedation: The influence of food, charcoal ingestion and injection rate on the effects of intravenous diazepam, Br. J. Anuesrh. 48:333-340 (1976).
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Amnestic Effects of Intravenous Diazepam in Healthy Young Men Robert M. Anthenelli, MD Department of Psychiatry School of Medicine University of California- San Diego La Jolla, California 92093
Maristela G. Monteiro, MD, PhD Department of Psychopharmacology Escola Paulista de Medicina Sao Paulo, Brazil
Barbara Blunt, MD School of Medicine University of California- San Diego La Jolla, California 92093
Marc A. Schuckit,' MD Department of Psychiatry School of Medicine University of California- San Diego La Jolla, California 92093 Alcohol Research Center San Diego Veterans Administration Medical Center San Diego, California 92 161
*To whom requests for reprints should be addressed at Veterans Affairs Medical Center (1 16A), 3350 La Jolla Village Drive, San Diego, California 92161.
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Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Mcgill University on 11/03/14 For personal use only.
ABSTRACT Changes in a test of memory performance were evaluated in 103 healthy young men after Challenges with placebo and two different doses of intravenous diazepam (0.12 and 0.20 mg/kg). Both diazepam doses significantly impaired free recall in a dose-dependent manner. Within each dose challenge there was no significant correlation between the average serum diazepam or desmethyldiazepamlevels and the average number of words recalled across the time points. The data expand our current understanding of the amnestic effects of benzodiazepines and suggest that patients abusing these drugs in large doses may develop profound degrees of memory impairment.
INTRODUCTION Benzodiazepines (Bzs) are capable of producing clinically relevant levels of memory impairment [l-71. Considered a side effect in most clinical contexts, this attribute may pose serious problems for patients abusing these drugs, and may contribute to their decline in social and occupational functioning. It is important for clinicians not only to warn patients of this potential consequence [8], but also to gain a better understanding of the nature of the memory impairment produced by these agents. Focusing on diazepam, the drug for which the preponderance of data are available [9-111, acute administrationhas been shown to produce an anterograde amnesia for both verbal and visual information [7, 12-21]. A major effect appears to occur at the acquisition or storage of information, impeding the transfer of factors from short-term to long-term memory [ 14- 181. This hypothesis is supported by the finding that diazepam does not impair immediate memory (sevendigit span) or the retrieval of words learned before drug administration, even in tests of delayed recall [ 191. Despite the information outlined above, relatively little data are available on the relationship between the memory impairment and the drug dose or serum drug levels. This paper describes the effect of challenges with two different doses of diazepam and placebo in 103 healthy young men. Serum diazepam levels were obtained, and the relationship between serum levels and memory effect was explored.
METHODS The 103 men were identified and tested through two stages of work. In the first phase a structured questionnairewas sent to all male students and nonacademic
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Mcgill University on 11/03/14 For personal use only.
AMNESTIC EFFECTS OF INTRAVENOUS DIAZEPAM
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staff aged 18 to 25 years at the University of California, San Diego. Subjects were chosen from approximately 800 men who were paid $3.00 to provide information on demographic characteristics, medical problems, smoking history, drinking and drug use patterns and problems, personal history of psychiatric disorders, and family history of drug abuse, alcoholism, or major psychiatric disorders. Men were excluded from the study if they reported they had serious medical disorders such as diabetes or severe asthma, were taking medications, were total abstainers, or if, following a review of the data by a psychiatrist (MAS), they met DSM-I11 criteria for any major psychiatric or substance abuse problems (all exclusions added up to approximately 10% of the sample). In the second phase, selected individuals were telephoned to corroborate their historical data and then invited to the laboratory for a screening evaluation. Blood was drawn to identify and exclude subjects who were likely to have been drinking heavily as signaled by changes in gamma-glutamyltransferase, mean corpuscular volume, etc. [22]. The men also completed the Michigan Alcoholism Screening Test (MAST) in the presence of the research assistant, with positive results reviewed by a psychiatrist (MAS) [23]. The men then participated in a four-session paradigm with data for the present study gathered after intravenous (IV) challenges with placebo, 0.12 mg/kg of diazepam (“low dose”), and 0.20 mg/kg of diazepam (“high dose”) administered over 7 minutes. The fourth session involved an alcohol challenge and, thus, those results are not reported here. For all test sessions, individuals arrived at 7:OO A.M. after a 10-hour fast. Two 18-gauge scalp-vein needles attached to heparin locks were inserted into two noncontiguousantecubital veins-one for the infusion and the other for subsequent blood samples. AU hfbsions were given through a syringe covered by yellow paper so that the subjects and laboratory personnel could not discern the agent being administered. The subjects underwent baseline testing of predrug performance, and then the IV infusions were administered and reactions monitored for 3 l/i hours. At baseline and at 10, 30, 60,90, 120, and 180 minutes after infusion, the men participated in a test of immediate free recall. At each time point the subjects viewed a list of 15 nouns (word-frequency AA in the Thorndike-Lorge word count) shown twice on a television screen [24, 251. Nouns were presented at a rate of l/second with a 4-second pause before the list was repeated. Immediately following the presentation, the subject then had 1 minute to recall as many nouns as possible in any order. Different word lists were used for each time point, and the order in which subjects received the lists was randomized over the sessions. The computed score was the number of words correctly recalled.
ANTHENELLI ET AL.
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Mcgill University on 11/03/14 For personal use only.
132
Blood drug values were monitored in the subjects every 30 minutes during the experiment. Serum diazepam and desmethyldiazepam levels were measured by the electron-capture gas-liquid chromatography approach [26]. Theflrst step in the data analysis was to evaluate the consistency of baseline memory performance across the three sessions by using a one-way analysis of variance (ANOVA) for the mean and standard deviations for the baseline scores on the number of words recalled for the 103 men. Second, to determine if there was a placebo effect, we carried out an ANOVA for changes in performance (number of words recalled) across time following placebo. Ihird, in order to determine if there was a dose-dependent relationship between the diazepam challenges and the degree of memory impairment, we carried out a 3 (dose: placebo, low, high) x 7 (number of words recalled at each time point) analysis of variance. However, this type of analysis does not allow us to address whether the results following the two active doses differed significantly without numerous post-hoc evaluations that carry heavy statistical penalties and a resultant loss of power. Thus, we also carried out a 2 (dose: low and high) x 7 (time points) analysis of covariance (ANOCOVA) for the number of words remembered, using placebo results as a covariate. Finally, to better understand the relationship between Bz blood levels and memory, for each session we determined the correlation between the grand mean of the number of words recalled across the time points and the grand mean across all the time points of the diazepam and desmethyldiazepam blood levels using Pearson’s correlation coefficient.
RESULTS The sample of 103 men had a mean age of 21.8 f 1.8 years, with 15.4 f 1.1 years of completed education. None of the subjects had ever used Bzs regularly, and all were free of major psychiatric disorders. For the 3-month period prior to testing, subjects had consumed alcoholic beverages on an average of 8.4 f 4.9 days per month with a mean consumption of 3.4 f 1.6 drinks per drinking day (a drink was defined as 12 oz of beer, 4 oz of nonfortified wine, or 1.5 oz of 80-proof distilled spirits). Data on blood levels of diazepam and desmethyldiazepamwere available for only 79 of the 103 subjects (77%). The overall mean serum levels for the low dose and high dose challenges were 235.4 f 53.2 ng/mL and 379 f 62.0 ng/mL for diazepam, and 19.39 f 16.44 ng/mL and 23.44 f 12.27 ng/mL for desmethyldiazepam, respectively.
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0
m--+
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---
0 . 2 0 m g I k g DIAZEPAM I V
. 0
I
0c
- _____-----
-
-_-------I
w 2 -
5
Fig. 1. Mean number of words recalled over 180 minutes in the three test conditions for 103 men.
Figure 1 shows the free recall test results after placebo, low dose, and high dose diazepam. There were no significant differences in predrug performance on the 3 days of testing (F = 1.12; 2,204 df;p = .328). During the placebo trial, there was a small decrease in the mean number of words recalled at the 10-minute time point, with a significant time effect for this session (F = 3.83; 6,612 df;p < .001). In contrast, there was a marked decrease in test performance during both diazepam challenges which reached a nadir at 10 minutes and then gradually returned to baseline. The high dose condition showed a greater decrement during the 3-hour test period. The 3 x 7 repeated measures ANOVA revealed significant dose (F = 350.61; 2,204 df;p < .OO01) and time effects (F = 283.05; 6,612 df;p < .OO01), and a dose by time interaction (F = 76.64; 12,1224 df;p < .OO01). In light of the small but significant time effect after placebo, the 2 X 7 analysis was performed as an ANOCOVA (covarying for placebo), and revealed significant dose (F = 139.93; 1,102 df;p < .OO01) and time effects (F = 334.53; 6,612 df;p < .OOOl), and a dose by time interaction (F = 11.92; 6,612 df; p < .OO01). This demonstrates that even after controlling for changes during the placebo session, the effects of the two active doses on memory performance were significantly different.
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134
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Mcgill University on 11/03/14 For personal use only.
To better understand the effect of diazepam on the memory task, we looked at the relationship between the subjects’ performance on the test of free recall and the blood levels of diazepam and desmethyldiazepamobtained following the low and high dose challenges. Within each dose challenge there was no significant correlation between the average number of words recalled over the 180 minutes and the average blood level of either diazepam or desmethyldiazepam measured over the 180-minute test session.
DISCUSSION The present study was established to address two questions about the effects of IV diazepam on a memory task in healthy young men. First, there was a significant effect of IV diazepam across doses on the immediate free recall of a list of common nouns. This finding expands the results of Ghonheim et al. who found consistent decreases in performance as the dose of orally administered diazepam increased [20]. Taken together, these results have clinical relevance in that patients taking higher doses of benzodiazepines may exhibit more profound degrees of memory impairment, and clinicians should warn their patients of this potential side effect. Second, despite the different effects across doses, within each dose challenge there was no significant correlation between the score on the test of immediate free recall and the serum levels of either diazepam or desmethyldiazepam. This is probably a consequence of the fairly narrow range of these diazepam parameters within a specific milligram/kilogram dose. It is also possible that the degree of impairment is related to the rate of change in blood levels rather than the actual values per se, a hypothesis not tested in the present study [27, 281. In interpreting our results, it is important to recognize some of the caveats inherent in our design. While our sample was large, it was limited to healthy, educated, young, Caucasian men who were chosen from respondents to a questionnaire and our results may not generalize to women, older subjects, or persons who take benzodiazepines on a regular basis. Although two different doses of diazepam were tested, we did not sample the entire spectrum of clinically relevant doses which might be administered. Finally, the major limitation of our study is that we used only one test of memory performance and while word lists were constructed from the Thorndike-hrge word count, no independent index of comparability was established. As a result, while the degree of memory impairment observed in this study was relatively marked, we are unable to comment on how other components of memory may have been affected.
AMNESTIC EFFECTS OF INTRAVENOUS DIAZEPAM
135
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by Mcgill University on 11/03/14 For personal use only.
In conclusion, our findings confirm previous studies indicating that diazepam significantly impairs memory performance and that this effect appears to be dosedependent. Clinicians prescribing benzodiazepines may do well to inform their patients of this potential clinical effect, and patients abusing these agents may exhibit signs of marked memory impairment.
ACKNOWLEDGMENTS This work was supported by the Veterans Affairs Research Service, NIAAA Grant 05526, the Alcohol Beverage Medical Research Foundation, and a FAPESP Fellowship from Sao Paulo, Brazil. The authors are grateful to David Greenblatt without whose help this project could not have been carried out.
REFERENCES [I] Scharf, M. B., Fletcher, K., and Graham, J. P., Comparative amnestic effects of benzodiazepine
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