Eur J Clin Pharmacol (1990) 38:371-377 EuropeanJouma,of ( ~ [ ~ ( ~ @ ~

© Springer-Verlag 1990

Effects of adinazolam and diazepam, alone and in combination with ethanol, on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers M. Linnoila, J. M. Stapleton*, R. Lister, H. Moss, E. L a n e , A. G r a n g e r , D. J. G r e e n b l a t t * * , and M. J. E c k a r d t Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA Received: September 5,1989/Accepted in revised form: January 5, 1990

Summary. Effects on psychomotor and cognitive performance of adinazolam (15 or 30 mg), alone and in combination with ethanol (0.8 g/kg), were studied in healthy male volunteers and c o m p a r e d to effects of 10 mg diazepam. Adinazolam 30 mg produced relatively long-lasting impairments on tests of tracking, attention, verbal and nonverbal information processing, and memory. Adinazolam 15 mg resulted in descreased visual information processing. Adinazolam decreased supine m e a n arterial pressure, but only the 15 mg resulted in a tendency for decreased plasma norepinephrine concentrations. After standing for 5 min, 30 mg adinazolam was associated with increased heart rate. Although ethanol consumption produced additive decrements on a continuous p e r f o r m a n c e task, there was little evidence to support a synergistic effect. Adinazolam 30 mg was accompanied by increased self-reports of side effects, especially drowsiness. Key words: ethanol, adinazolam, diazepam; benzodiazepines, psychomotor, cognition

Adinazolam is a triazolobenzodiazepine that, like 1,4benzodiazepines (e. g., diazepam and chlordiazepoxide), has anxiolytic properties. In other ways, however, it appears to differ f r o m 1,4-benzodiazepines [1]. Adinazolam has also b e e n reported to have antidepressant effectiveness similar to classical antidepressants without the typical anticholinergic autonomic side effects [2-5]. The most commonly reported side effect of adinazolam is drowsiness, but there have b e e n some reports of adinazolam-induced mania in bipolar patients [6]. * Current address: National Institute on Drug Abuse, Addiction Research Center, Baltimore, MD 21224 ** Division of Clinical Pharmacology, Tufts University School of Medicine and New England Medical Center Hospital, Boston, Massachusetts

Benzodiazepines have been shown to alter cognitive and psychomotor functioning [7]. Consequently, it is important to determine acute effects of adinazolam on cognitive and psychomotor functions. It is also of considerable practical importance to assess whether adinazolam exacerbates ethanol-induced p e r f o r m a n c e impairments, because a large proportion of patients taking psychotropic drugs have b e e n reported to be at risk for drinking and driving while on medication [8]. It is also of interest to compare the cognitive and p s y c h o m o t o r effects of adinazolam to those of a commonly used reference benzodiazepine such as diazepam.

Methods Subjects Eight male caucasian volunteers aged 21 to 24 (mean age and (SEM): 22.1 (0.5) were paid for their participation in the study as outpatients. The subjects were social drinkers who consumed 2 to 10 g equivalents of ethanol per kg of body weight per week. Medical evaluation revealed blood pressure, pulse, serum liver enzyme values, and respiratory and cardiovascular functioning to be within normal limits, and all subjects were within + / - 15% of the average height to weight ratio for their age group. They were not currently taking any medication and had no operations within the past year. Clinical interview by a research psychiatrist verified that subjects had no history of mental illness and no family history of alcoholism. Subjects were nonsmokers or light smokers (no more than 10 cigarettes per day), and all reported themselves to be right-handed. Subj ects were allowed to consume alcoholic beverages between test days but were asked to abstain for at least 24 h prior to each test day.

Plasma concentrations of adinazolam, diazepam and metabolites Plasma concentrations of adinazolam and desmethyladinazolam were determined with high performance liquid chromatography [10]. Plasma diazepam and nordiazepam concentrations were determined with high performance liquid chromatography using a modification of the method ofRao et al. [11].

M. Linnoila et al.: Adinazolam and diazepam effects

372 70 n~

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30

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20

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2

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Time after ethano[ consumption (h} Fig. 1. Mean blood ethanol concentrations as estimated by breathalyser. P L A C = placebo, D I A Z = 10 mg diazepam, ADIN15 = 15 mg adinazolam, and ADIN30 = 30 mg adinazolam

meat of the bar across the screen horizontally was controlled by a computer and by the subject with a car steering wheel. Two levels of task difficulty were administered. The task was to maintain the position of the bar as close to the middle of the CRT as possible. The root mean square deviation was computed as the dependent variable. This task took approximately 4 min.

Words. Verbal information processing was measured by a choice reaction time task with a one- to three-seconds random intertrial interval (ITI). A three-letter word was displayed vertically on a CRT at 5 degrees to either side of a fixation point for 100 ms. This brief stimulus exposure duration was used to minimize eye movements so as to ensure primary presentation of the stimulus to only one hemisphere. The subject responded by switching two levers, one with each hand, up for the words " H A M " or "WAX," down for the words "HAY" or "TAX." The task consisted of 48 trials, 24 on each side of the fixation point. Response accuracy and reaction time were recorded. This task took approximately 4 min. Angles. Nonverbal information processing was measured using the same apparatus and time parameters as for words. Forty-eight angles were the stimuli, and the task was to press up for angles of 15 or 55 °, down for angles of 30 or 75 °. This task took approximately 4 min.

Lying-standing norepinephrine concentrations Plasma levels of norepinephrine were measured with the subject lying supine and again at 5 min after the subject rose to a standing position. The catheter was inserted 30 min before the first blood sample was drawn, and blood pressure and heart rate were also measured. Norepinephrine concentration was determined using a modification of the method of Mefford et al. [12].

Questionnaires Spielberger anxiety rating. A self-evaluation questionnaire which consisted of 20 statements was administered to measure the level of state anxiety [13]. To each statement, the subject responded by checking a box for "not at all," "somewhat," "moderately so," or "very much so."

Mood scale. To measure mood, the subject was asked to circle the number that best expressed his present mood on a visual analog scale marked with equally spaced numbers from 0 to 10 (0 = "I feel more depressed than ever,", 5 = "I feel normal," 10 = "I feel more elated than ever").

Side effects questionnaire. A self-evaluation questionnaire was administered consisting of 14symptoms (e.g., drowsiness, nausea, blurred vision) with the subject checking "not at all," "mild," "moderate," or "severe" for each symptom.

Hopkins symptom checklist. A self-report inventory was administered which is comprised of items representative of symptom configurations commonly observed among outpatients [14]. Items measuring fatique, dry mouth, and blurred vision were added to the standard inventory since they have been reported to accompany administration of antidepressant drugs. For each symptom, the subject checked "not at all," "a little," "quite a bit," or "extremely."

Tasks Tracking. Tracking ability was measured with a continuous tracking task [15]. The target (illuminated bar, 2.5 high x 0.2 cm wide) was displayed on a 36-cm diagonal cathode ray tube (CRT). The move-

Continuous Performance Task (CPT). The digits 0 through 9 were presented randomly in the center of a CRT, at a fixed one-second ISI (interstimulus interval) for a total of 1190 stimuli during a 20 min period. The subject's task was to respond when a 6 followed immediately by a 4 was presented. Numbers of hits, false alarms and reaction times were recorded. Verbal memory. Subjects were presented a list of 12 words belonging to a single category, six of which were presented twice (giving a total of 18 words) in random order [16]. Words were presented at a rate of one every 2 s. Subjects were asked to raise their right hand when they heard a word repeated. Sixteen different lists were compiled for use on the eight test days (two tests per day). Following a distracting task lasting 1 min, subjects were asked to recall as many of the items as possible. Recognition memory was tested by asking patients to identify the 12 previously presented words from an equal number of semantically equivalent distractors. This task took approximately 5 min.

Table 1. Experimental procedures as a function of time after the oral administration of placebo, 10 mg diazepam, 15 mg adinazolam, or 30 mg adinazolam Time (h)

Procedure

0.0

Drug administration

0.5

Tracking, Words, Angles

1.0

Spielberger, Mood, Side Effects, Tracking, Words, Angles

1.5

Spielberger, Mood

2.0

Memory, Lying/Standing Norepinephrine

3.0

Spielberger, Mood, Ethanol or Placebo Drink

4.0

Spielberger, Mood, Side Effects, Tracking, Words, Angles, CPT

5.0

Spielberger, Mood

6.0

Spielberger, Mood, Side Effects, Memory

7.0

Tracking, Words, Angles, CPT

8.0 24.0

Side Effects Hopkins Symptom Checklist

M. Linnoila et al.: Adinazolam and diazepam effects

373

Procedures This study used a double-blind, crossover design. Each subject was tested on eight separate days with ethanol (0.8 g/kg) or placebo drink crossed with the following 4 drug treatments in random order: placebo, 10 mg diazepam, 15 mg adinazolam, or 30 mg adinazolam. Time between testing days for an individual subject was usually i week, with a minimum of 5 days and a maximum of 14 days. All drugs were administered orally at 8 am, with the drink consumed 3 h later. Ethanol was administered mixed with a 360 ml volume of ginger ale and crushed ice, and the placebo drink was the iced ginger ale with a drop of ethanol floated on top to produce the odor of ethanol. Before the first test day, subjects were trained on the Words and Angles tasks to a criterion of less than 10% error rate, and on the easy Tracking task close to an asymptote on their learning curve. During each test day, blood samples were obtained by venipuncture before and at 30, 60, and 90 min, and 4, 6, and 8 h after drug administration. Breathalyser readings to estimate blood ethanol concentrations were taken before drug administration and at half-hour intervals beginning 30 min after the drink, using a portable Alco Sensor II from Intoximeter, Inc., St. Louis, MO. Testing was accomplished according to the schedule shown in Table 1. The Hopkins Symptom Checklist was taken home by the subject and filled out 24 h after drug administration. Data were analyzed using Multivariate Analysis of Variance (BMDP 4V), and results are reported at a significance level of P < 0.05. Subjects with missing data for some tasks or sessions due to equipment malfunction were deleted from the relevant analyses.

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Blood Ethanol Concentrations (BECs) T h e b l o o d e t h a n o l c o n c e n t r a t i o n s a r e s h o w n in Fig. 1. It can b e s e e n t h a t B E C s d e c r e a s e d o v e r time. H i g h e r B E C s w e r e o b s e r v e d a f t e r r e c e i v i n g 30 m g a d i n a z o l a m t h a n p l a c e b o at 3 h o u r s a f t e r e t h a n o l c o n s u m p t i o n a n d at all time points thereafter.

Plasma concentrations of adinazolam, diazepam and metabolites T h e p l a s m a c o n c e n t r a t i o n s of a d i n a z o l a m a n d its m e t a b o lite d e s m e t h y l a d i n a z o l a m a r e s h o w n in Fig. 2. It c a n b e s e e n t h a t p l a s m a c o n c e n t r a t i o n s of b o t h c o m p o u n d s w e r e initially h i g h e r after t h e 30 m g dose. L e v e l s of d e s m e t h yladinazolam were higher overall after ethanol consumption, p a r t i c u l a r l y at i h. S h o w n in F i g . 3 are the p l a s m a levels of d i a z e p a m a n d n o r d i a z e p a m . T h e r e w e r e no significant effects o f e t h a n o l c o n s u m p t i o n on d i a z e p a m o r n o r d i a z e p a m c o n c e n t r a t i o n s at a n y t i m e point.

Lying-standing norepinephrine concentrations W i t h t h e s u b j e c t lying supine, 15 m g a d i n a z o l a m r e d u c e d m e a n a r t e r i a l p r e s s u r e , b u t this effect was n o t s e e n with the h i g h e r d o s e of a d i n a z o l a m . D i a z e p a m r e d u c e d systolic b l o o d p r e s s u r e , a n d t h e r e was a t e n d e n c y for 30 m g a d i n a z o l a m to r e d u c e d i a s t o l i c b l o o d p r e s s u r e . T h e r e w e r e n o d r u g effects on pulse. T h e r e was a t e n d e n c y for 15 m g adi-

I

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2

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10 b Fig.2a, b. Mean and SEM plasma levels of (a) adinazolam and (b) desmethyladinazolam. ADIN15-EtOH=15mg adinazolam and ethanol drink and ADIN30-PLAC = 30 mg adinazolam and placebo drink 6 8 Time affer adinazolam adminisfrafion (h)

n a z o l a m to r e d u c e p l a s m a c o n c e n t r a t i o n s o f n o r e p i nephrine. A f t e r 5 m i n of standing, the o n l y effect o b s e r v e d was t h a t 30 m g a d i n a z o l a m i n c r e a s e d h e a r t rate.

Questionnaires Spielberger state anxiety. S u b j e c t s r a t e d t h e m s e l v e s as more anxious 1 h after being administered either diazep a m o r 30 m g a d i n a z o l a m . T h e r e w e r e n o significant diff e r e n c e s at a n y o t h e r t i m e points. T h e r e w e r e n o signific a n t effects of e t h a n o l o r i n t e r a c t i o n s b e t w e e n e t h a n o l a n d d r u g t r e a t m e n t s on ratings of anxiety.

Mood scale. T h e r e was no significant m a i n effect o f d r u g t r e a t m e n t o r e t h a n o l at a n y t i m e p o i n t a n d n o d r u g / e t h a nol i n t e r a c t i o n .

Side effects questionnaire. A n a l y s i s of t h e t o t a l n u m b e r o f s e l f - r e p o r t e d side effects r e v e a l e d a significant effect of d r u g t r e a t m e n t a n d a significant effect of e t h a n o l t r e a t -

374

M. Linnoila et al.: Adinazolam and diazepam effects

Tasks

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Tracking. T h e r e was a significant effect of task difficulty at all time points, with subjects performing worse on the m o r e difficult tracking task (Table 2). T h e r e were no differences a m o n g drug treatments at 30 min. Subjects m a d e m o r e tracking errors with 30 mg adinazolam than placebo or any other drug condition at 1 and 4 h after administration. T h e r e were m o r e errors under diazepam than placebo at i h after administration. T h e r e was no significant main effect of ethanol or interaction of ethanol with drug treatment at any time point. However, ethanol impaired p e r f o r m a n c e c o m p a r e d to placebo drink in the difficult task condition 1 hour after consumption.

Time after diazepamadministration (h) 5O --

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EfOH PLAC

EtOH

E ro

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30

Angles. There were fewer correct responses with 30 mg

m o

20 10

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Words. A d i n a z o l a m 30 mg decreased the n u m b e r of correct responses at i h. A t all other time points, there were no significant effects of drug t r e a t m e n t on n u m b e r of correct responses. T h e r e were no significant effects of ethanol or interactions of ethanol with drug treatment at any time point. There were no effects of ethanol consumption or drug administration on reaction times.

I

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2 4 6 8 Time affer diazepam administration (h)

Fig.3a, h. Mean and SEM plasma levels of (a) diazepam and (b) nordiazepam. PLAC = placebo drink and EtOH = ethanol drink

ment with no additive interaction between t h e m (Fig. 4). Adinazolam 30 mg and diazepam produced higher total side effect scores than placebo, but 15 mg adinazolam was not different f r o m placebo. The effect on total score was due primarily to items measuring drowsiness and faintness. D i a z e p a m produced significantly increased selfratings of drowsiness at 30 min, 1 and 6 h, but not at 4 h. Adinazolam 30 mg increased drowsiness at 1, 4, and 6 h after administration, and 15 mg adinazolam produced significantly m o r e drowsiness than placebo at 30 rain and 6 h, and a borderline (P = 0.06) effect at 1 h. T h e r e was a tendency for increased drowsiness 3 h after consuming ethanol, but this failed to reach statistical significance (P = 0.08). There were no effects of ethanol or drug treatment at 8 h after drug administration (5 h post ethanol consumption).

Hopkins Symptom Checklist. On the Hopkins S y m p t o m Checklist, there were no significant effects on the total score of drug treatment, ethanol consumption or their interaction. Moreover, there were no main effects on individual items nor were there any significant interactions between ethanol and drug treatments.

adinazolam at 1 and 4 h. There were fewer correct responses with either dose of adinazolam than with placebo or diazepam. There were no significant effects of drug treatment at 7 h. T h e r e was no effect of ethanol or interactions involving ethanol at any time point. T h e r e were no effects of ethanol consumption or drug administration on reaction times.

CPT. Fewer correct responses were observed 4 h after either dose of adinazolam, and there were fewer correct

6 5

4

0

Post-drug • [] [] []

PLA[-PLAC PLAC-EtOH DIAZ-PLAC DIAS-EfOH

Post-EtOH [] [] [] []

ADINIS-PLAC ADIN15-EtOH ADIN30-PLA[ ADIN30-EfOH

Fig.4. Mean and SEM total number of self-reported side effects during the 8 h after drug administration. PLAC-PLAC = placebo drug and placebo drink, PLAC-EtOH = placebo drug and ethanol drink, DIAZ = diazepam, ADIN15 = 15 mg adinazolam and ADIN30= 30 mg adinazolam

375

M. Linnoila et al.:Adin azolam and diazepam effects 5O o ..~

either dose of adinazolam than with placebo. T h r e e hours after consuming ethanol, recall and recognition of related words were impaired.

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PLAC-PLAC PLAC-EtOH DIAZ-PLAC DIAS-EfOH

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Fig.5. Mean and SEM number correct on a Continuous Performance Task. Ethanol consumption occurred 3 h after drug administration. PLAC-PLAC = placebo drug and placebo drink, PLACEtOH = placebo drug and ethanol consumption, DIAZ : 10 mg diazepam, ADIN15 = 15 nag adinazolam, and ADIN30 = 30 mg adinazolam

responses after 30 mg adinazolam than after diazepam (Fig. 5). T h e r e were fewer correct responses and m o r e errors of commission 7 hours after being administered 30 mg adinazolam than any other drug condition. There were no treatment effects on reaction times in this task. There was no main effect of ethanol or interactions between ethanol and the benzodiazepines at either time point. There was, however, a tendency (P = 0.09) for ethanol to reduce the n u m b e r of correct responses 1 h after consumption.

Verbal memory. A d i n a z o l a m 30 mg reduced the n u m b e r of words correctly identified as being repeated during presentation 2 h after administration. Although there were no effects of drug t r e a t m e n t on free recall or recognition, there was a tendency (P < 0.10) for lower scores with

During the 4.5 h of evaluation after ethanol consumption, estimated B E C s decreased from approximately 5075 mg. dl- 1 to 10-20 rag- dl- 1 (see Fig. 1). Tracking was impaired at B E C s of 40-50 mg. d1-1 on only the difficult task. Performance on the spatial information-processing task (Angles) was not impaired, and there was no effect on the verbal-information processing task (Words). H o w ever, a B E C of 20-35 mg. dl-1 was associated with decreased recall and recognition of related words. T h e r e was a marginal reduction in performance on a Continuous Performance Task, appearing to be m o r e p r o n o u n c e d at B E C s of 40-50 rag- dl- 1 that at 10-20 mg. dl- 1. This relatively reduced attention at 40-50 mg.d1-1 was not reflected in the ability to recognize 6 words that were repeated twice in a list of 18 total words at B E C s of 20-35 mg. d1-1. Similar findings have b e e n reported f r o m this laboratory previously [17, 18]. Although the oral administration of 30 mg adinazolam increased B E C s some 6 h later, there were no demonstrable effects on mood, cognition or psychomotor performance. T h e r e were no obvious effects of ethanol consumption on state anxiety, mood, side effects or symptoms reported the following day that might explain the above results. During the 8 h of evaluation after the administration of 10 mg diazepam, plasma levels ranged f r o m peaks of 225-275 ng- m l - ~ at 1.5 h to lows of 125 ng. dl- ~ at 4-8 h (see Fig.3) and increasing n o r d i a z e p a m levels f r o m 510 ng. dl- 1 at 30 min to 20-25 ng- m l - 1 at 8 h. Although ethanol consumption has been associated with increased plasma diazepam levels [19], this effect was not observed in the present experiment nor in other studies [20]. Tracking was impaired at diazepam levels approximating 200 ng. ml 1 in combination with nordiazepam levels of 10 n g . m l - 1 ( l h post-administration). Increased state anxiety and drowsiness were self-reported at 1 h also and might be related to decreased tracking performance. In that increased drowsiness was also self-reported at 30 min

Table 2. Mean error score as a function of time after the oral administration of placebo (PLAC), 10 mg diazepam (DIAZ), 15 mg adinazolam (ADIN15) or 30 mg adinazolam (ADIN30) Time (h)

Task Difficulty

Placebo Drink PLAC DIAZ ~

ADIN15

ADIN30a

0.5 0.5 1.0 1.0 4.0 4.0

easy hard easy hard easy hard

1782 3160 1012 2357 1751 3036

2626 4904 3009 5137 2427 3832

1734 4144 2246 4496 3007 5134

2338 4854 3600 6712 4655 6714

7.0 7.0

easy hard

841 2105

1800 3586

1164 2667

1944 3733

a Significant drug effect - see text b Significant effect of ethanol consumption- see text

Ethanol Drink b

PLAC

DIAZ

ADIN15

ADIN30

2267 4338 2266 3730

2521 4716 2029 3874

2383 5198 1313 3776

5422 7315 1549 3838

M. Linnoila et al.: Adinazolam and diazepam effects

376 and 6 h with no accompanying decrement in tracking performance, the relationships among state anxiety, drowsiness and tracking are complex and deserving of further study. Diazepam administration had no significant effects on visual information processing, verbal information processing, verbal memory, or on the Continuous Performance Task. Reduced systolic blood pressure was observed in supine individuals with diazepam levels approximating 225 ng.ml ~ in combination with nordiazepam levels of 15 ng. ml z. There were no effects of diazepam on plasma norepinephrine concentrations or heart rate, and there were no demonstrable effects after standing for 5 min. Diazepam, alone and in combination with ethanol, did not alter self-reported mood or symptoms reported the following day. The findings of diazepam increasing reported side effects and decreasing performance on a tracking task are consonant with the literature [7, 21]. Although the ability of diazepam to impair memory is well documented [22], no significant effects on memory were found. Diazepam has also been reported to reduce blood pressure and plasma norepinephrine levels [23-25]. Previous studies that have reported memory and sympathetic nervous system effects have usually evaluated effects of diazepam within the first hour after drug administration. Perhaps these effects are no longer measurable at 2 h after administration. The finding that both diazepam and adinazolam increased anxiety was somewhat surprising, but other investigators have suggested that psychomotor-impairing agents which are anxiolytic in certain circumstances may also increase anxiety in laboratory settings wherein subjects' performance is to be evaluated [26, 27]. Different doses of adinazolam resulted in different plasma levels (see Fig. 2) until approximately 4 h. In contrast, the metabolite desmethyladinazolam reflected the different doses of adinazolam throughout the experiment. Adinazolam, alone and in combination with ethanol, did not alter self-reported mood or symptoms reported the following day. Adinazolam 15 mg had no effect on state anxiety and resulted in increased drowsiness at only 30 min and 6 h after administration. Decreased performance accompanied administration of 15 mg on visual information-processing at plasma levels of 25 ng. dl- 1 adinazolam and 100 ng- ml 1 desmethyladinazolam. These same plasma levels were also associated with reduced performance on the Continuous Performance Task. Administration of 15 mg also resulted in decreased arterial pressure and a tendency for lower plasma norepinephrine concentrations with individuals in the supine position at concentrations of 50 ng. ml- 1 adinazolam in combination with 100-150 ng. ml-~ desmethyladinazolam. The 30 mg dose of adinazolam was much more pervasive in its effects, producing impairment on all cognitive and psychomotor tasks. Verbal and visual information processing and tracking were impaired I h after administration (125-150ng.m1-1 adinazolam in combination with 175-200 ng. ml 1 desmethyladinazolam). Increased, self-reported state anxiety and drowsiness were also associated with these plasma levels and might therefore explain some of the observed deficits in performance. Defi-

cits in performance on visual tracking, visual information processing and Continuous Performance Task were apparent 4 hours after administration (adinazolam levels of 50 ng. ml-1 and desmethyladinazolam levels of 175 ng. ml ~); increased drowsiness, but not state anxiety, was reported at this time also. Performance on the Continuous Performance Task was impaired 7 h after administration. Although adinazolam 30 mg (adinazolam levels of 25 ng. ml- ~in combination with desmethyladinazolam levels of 120 ng. ml-1) was associated with a reduction in the number of words recognized as being said twice, there was only a marginal effect on subsequent free recall or recognition. Adinazolam 30 mg marginally lowered diastolic blood pressure while supine and increased heart rate after 5 min standing; there was no significant effect on norepinephrine concentration. The higher dose of adinazolam produced impairment on all the psychomotor tasks of a magnitude equal to or greater than that produced by diazepam, while the lower dose was generally less disruptive of performance. Similarly, the higher dose yielded substantial self-reports of side effects with no more effects for the lower dose than for placebo. This suggests that in clinical treatment, care should be taken to use the minimal dose compatible with therapeutic effectiveness. The higher dose of adinazolam increased blood ethanol concentrations but there was little evidence for interaction between ethanol and adinazolam on performance. Interactions between ethanol and benzodiazepines have been previously reported [28-31], but these interactions are highly variable and dependent on study design [32, 33]. Additive effects were observed, however, between ethanol consumption and 30 mg adinazolam on the Continuous Performance Task. In that ethanol was consumed 3 hours after the benzodiazepines were administered, stronger interactive effects might have been observed if the temporal proximity of administration was closer. It has been suggested that acute tolerance to benzodiazepines seems to occur rapidly [7]. Since benzodiazepines and ethanol may act partly on the same receptor complex [34], the lack of interaction may be due in part to acute cross tolerance when ethanol is given after sufficient time so that acute tolerance to the benzodiazepine has developed [35].

Acknowledgements. We are grateful for the assistance of Ann Locniskar in performing plasma adinazolam and desmethyladinazotam determinations.

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M. Linnoila, M. D., Ph.D. Laboratory of Clinical Studies National Institute on Alcohol Abuse and Alcoholism Building 10, Room 3 B-19, 9000 Rockville Pike Bethesda, MD 20892, USA