Psychomotor,respiratory and neuroendocrinological effects of buprenorphine and amitriptyline in healthy volunteers

Summary Actions and interactions of buprenorphine (BUP) and amitriptyline (AMI) on performance and respiration were studied double-blind and cross-over in 12 healthy volunteers. After one-week pretreatments with AMI or placebo, the subjects received on Day 8 placebo, BUP or AMI so that the final treatments were 1) placebo, 2) acute AMI 50 mg, 3) acute BUP, 4) subchronic AMI + acute BUP and 5) subchronic AMI. The subacute treatments were started at two-week intervals.A Mapleson D rebreathing circuit including a pneumotachograph and an infrared capnograph was employed to study drug effects on respiration. Minute volume and end-tidal carbon dioxide as well as psychomotor performance were measured and the blood samples taken on Day 8 before the drug intake and 2 and 4 h thereafter. The performance tests included tracking, choice reaction, flicker fusion, exophoria, nystagmus, digit symbol substitution and the subjective assessment of mood.BUP depressed respiration, and subchronic AMI increased this depression. Both BUP and acute AMI 50 mg each alone impaired various measures of performance and rendered the subjects drowsy, feeble, mentally slow and muzzy but subchronic AMI did not enhance BUP effects. BUP increased plasma prolactin levels similarly after both pretreatments.The results suggest that both BUP and AMI moderately affect psychomotor performance but the interaction between these agents is mild and restricted mainly to respiration.     

A comparison of the effects of fluvoxamine and amitriptyline on autonomic functions in healthy volunteers

Summary We have compared the effects of single oral doses of fluvoxamine (50 mg and 100 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced, double-blind, crossover design.Amitriptyline significantly reduced salivation, the miosis evoked by locally applied pilocarpine, and the sweat secretion evoked by locally applied carbachol. Fluvoxamine also significantly attenuated carbachol-evoked sweat gland activity, although to a smaller degree than amitriptyline; fluvoxamine did not significantly alter salivation or pilocarpine-evoked miosis.Neither treatment significantly altered the miotic responses evoked by brief light stimuli. Heart rate and blood pressure were not greatly affected by either treatment, although the fall in heart rate (erect posture) with placebo was significantly reduced by amitriptyline (100 mg).The results suggest that fluvoxamine has some antimuscarinic activity in man, but is considerably less potent in this respect than amitriptyline.     

The effects of reboxetine and amitriptyline, with and without alcohol on cognitive function and psychomotor performance

Reboxetine is a novel antidepressant that has been shown to be effective in the treatment of major depressive disorders. The present experiment was designed to assess whether it affects the cognitive and psychomotor skills necessary for optimum function in everyday life. Ten healthy male volunteers received reboxetine 0.5  mg, 1  mg or 4  mg, amitriptyline 25  mg, or matched placebo with and without alcohol (0.6  mg  kg⁻¹) in a double-blind 10-way crossover study. A psychometric test battery was administered at baseline and at 1, 2.25, 3.5, 6 and 9  h post-dose. The results showed that reboxetine had little or no effect on performance at any dose, compared with placebo. Amitriptyline, however, with and without alcohol, lowered critical flicker fusion threshold compared with placebo and/or reboxetine at all test points (e.g. at 3.5  h: 28.51   vs 30.33  Hz; P <0.05); increased reaction time (e.g. 619   vs 540  ms; P <0.05); increased tracking error (e.g. 16.34 vs 8.54 RMS units; P <0.05); and slowed short-term memory scanning (e.g. 742 vs 590  ms; P <0.05). It is concluded that reboxetine at doses of 4  mg and below is free from disruptive effects on cognitive function and psychomotor performance, and that it does not act synergistically with alcohol, in contrast to amitriptyline.     

A comparison of the effects of single doses of amoxapine and amitriptyline on autonomic functions in healthy volunteers

Summary We have studied the effects of single oral doses of amoxapine (100 mg and 200 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced double-blind crossover design.Amitriptyline significantly reduced salivation and it significantly attenuated both miosis evoked by locally applied pilocarpine and sweat secretion evoked by locally applied carbachol. Amoxapine did not significantly alter any of these measures. Neither treatment significantly altered the pupillary light reflex (latency, amplitude, or 75% recovery time). Resting pupil diameter was significantly reduced by the higher dose of amoxapine but was not affected by the other treatments.The higher dose of amoxapine significantly increased supine systolic blood pressure, but did not affect heart rate or diastolic blood pressure; amitriptyline had no effect on any of these cardiovascular measures.These results confirm the antimuscarinic effects of amitriptyline in man, but provide no evidence for antimuscarinic effects of amoxapine.     

Comparison of the effects of binodaline and amitriptyline on peripheral autonomic functions in healthy volunteers.

Twelve healthy male volunteers participated in five experimental sessions separated by weekly intervals. At the beginning of each session the subjects received one single oral dose of the following drugs, according to a double-blind, balanced cross-over design: binodaline hydrochloride (50 mg or 100 mg); amitriptyline hydrochloride (50 mg or 100 mg); lactose placebo. Salivation and resting pupil diameter were assessed before and 2 h after the ingestion of the drugs; baseline sweating, carbachol- or phenylephrine-evoked sweating were measured 2 h following drug taking. Binodaline, like placebo, had little effect on salivary output, whereas amitriptyline caused a dose-dependent decrease in salivation. None of the drugs caused any significant change in resting pupil diameter or in baseline sweating. Carbachol-evoked sweating did not differ significantly following the ingestion of binodaline or placebo; on the other hand responses to carbachol were significantly reduced following amitriptyline. Phenylephrine-evoked sweating was reduced by both binodaline and amitriptyline. The lack of effect of binodaline on salivation, resting pupil diameter, baseline and carbachol-evoked sweating is in agreement with the results of animal experiments indicating the lack of an interaction of this drug with cholinergic mechanisms. The reduction in phenylephrine-evoked sweating would be indicative of an alpha-adrenoceptor blocking property of this drug.     

The effects of cimetidine and ranitidine on psychomotor function in healthy volunteers

Summary

Single oral doses of cimetidine (400?mg), ranitidine (150?mg), promethazine (25?mg) or placebo were administered to 8 healthy volunteers in a double-blind study. Cimetidine and ranitidine did not cause any significant change in critical flicker frequency (c.f.f.), reaction time, pursuit rotor or the visual analogue scale scores for sedation. Promethazine significantly lowered c.f.f., prolonged reaction time and increased sedation when compared with placebo. It is concluded that in this study cimetidine and ranitidine had little, if any, effect on psychomotor function.     

Dose-effect study of levomepromazine on psychomotor and memory tasks in healthy volunteers

The effects of single doses of levomepromazine (3, 6 and 12 mg) on psychomotor skills and memory tasks, as well as haemodynamic and pupil diameter parameters, were assessed in 12 normal volunteers. Each subject was given three of the four treatments, at a weekly interval in a double-blind crossover randomized balanced incomplete-block design. The three doses and a placebo were monitored using a battery of tests including critical flicker fusion (CFF), choice reaction time (CRT), subjective ratings and memory tasks before, 3 and 6 hours after drug intake. Supine standing blood pressure and pupil diameter were recorded at the same times. Compared to placebo, levomepromazine impaired both subjective and objective vigilance measures in a dose-related manner, with 3 mg affecting only some subjective ratings, while 12 mg impaired most objective and subjective vigilance evaluations with a moderate effect on memory tasks (i.e. anterograde amnesia). Pupil diameter was reduced by the evaluations with a moderate effect on memory tasks (i.e. anterograde amnesia). Pupil diameter was reduced by the three doses. In conclusion, levomepromazine at low doses induced a sedative effect the intensity and duration of which are compatible with its use as an hypnotic.     

Double-blind placebo-controlled study of the autonomic effects of clovoxamine,imipramine, and amitriptyline in normal volunteers

The autonomic effects of clovoxamine, a possible new antidepressant, were compared with placebo, imipramine, and amitriptyline in a double-blind, repeated-measures, latin-square study design, using 16 healthy volunteers. Salivary flow, pupillary response, near-point accommodation, and pilocarpine-evoked miosis were assessed before and 1, 2, and 3 hours after each treatment condition. Dose-related autonomic effects were seen with all three active drugs. Clovoxamine at a 50-mg dose was not distinguishable from placebo. For salivary flow, perhaps the most reliable index of anticholinergic activity, the effects of 100-mg and 150-mg doses of clovoxamine were comparable to those of 50-mg and 75-mg doses of imipramine but were less than those of 50- and 75-mg doses of amitriptyline at 3 hours postdosing.     

Effects of a controlled-release formulation of trazodone on psychomotor and autonomic functions in healthy volunteers: Comparison with trazodone (conventional formulation), amitriptyline and placebo

Summary The gastrointestinal absorption of lactitol has been studied in 6 healthy volunteers and 8 patients with cirrhosis.Following administration of lactitol 0.5 g/kg, no lactitol was found in serum. The urinary excretion of lactitol over 24 h ranged from 0.1 to 1.4% of the administered dose (0.46% in cirrhotics and 0.35% in healthy volunteers). Blood D- and L-lactate and plasma glucose did not increase following lactitol.The data indicate that lactitol was poorly absorbed from the gastrointestinal tract in healthy volunteers and patients with cirrhosis, and that the disaccharide did not disturb glucose or lactate homeostasis.     

Comparison of the effects of ranitidine, cimetidine and thioridazine on psychomotor functions in healthy volunteers

Eight healthy male volunteers participated in four experimental sessions in which they ingested one of the following drugs: ranitidine hydrochloride (150 mg), cimetidine hydrochloride (400 mg), thioridazine hydrochloride (50 mg), placebo (lactose). Drugs were allocated to subjects and sessions in a double-blind fashion, according to a balanced cross-over design. The subjects' mood state and psychomotor performance were assessed 1 and 3 h after drug taking. Mood state was measured using a battery of visual analogue scales, and psychomotor performance using pencil-and-paper tests, critical flicker fusion frequency, wire-maze tracing and tapping. Ranitidine and cimetidine had no significant effect on subjectively rated alertness, whereas thioridazine caused a significant decrease in alertness. Ranitidine and cimetidine had no significant effect on performance on the pencil-and-paper tests (digit cancellation, digit symbol substitution, symbol copying), whereas thioridazine caused a significant decrement on these tests. Ranitidine and cimetidine had no significant effect on critical flicker fusion frequency, wire-maze tracing, and tapping rate. Thioridazine caused a significant impairment of psychomotor performance as evidenced by all the instrumental tests. It is concluded that, in contrast to thioridazine and similarly to cimetidine, ranitidine has little effect on subjectively rated alertness and psychomotor performance in healthy volunteers.     

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

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 compared 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 mean 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 performance task, there was little evidence to support a synergistic effect.Adinazolam 30 mg was accompanied by increased self-reports of side effects, especially drowsiness.     

Acute effects of amitriptyline on human performance and interactions with diazepam

Summary The effects on psychomotor performance and attention of amitriptyline 75 mg administered without and with diazepam 10 mg have been investigated in 12 healthy subjects.The effects of the compounds were evaluated by objective tests (measurement of body sway, critical flicker fusion, visual reaction time, tachistoscopy, short term visual memory, tapping test, arithmetical calculation and Clement's code) and subjective measurements (visual analogue scales and side effects questionnaire). Measurements were taken before treatment and after 1, 3, 6, 8 and 24 h.Placebo did not affect either the objective or the subjective measurements. Diazepam caused a reduction in attention and performance after 1 h which had disappeared at 3 h.Amitriptyline caused a marked reduction in attention and performance, reaching a peak 3 hours after drug administration and persisting until 8 h. the deterioration in vigilance induced by amitriptyline was potentiated by concomitant diazepam.     

Electroencephalographic and psychomotor effects of chlorpromazine and risperidone relative to placebo in normal healthy volunteers

AIMS: To investigate the effects of single oral doses of chlorpromazine (50 mg) and risperidone (2 mg) relative to placebo on topographical electroencephalometry (CATEEMTM ) and psychomotor tests in 12 healthy male volunteers. METHODS: A double-blind, placebo-controlled, three-way crossover design using a double dummy blinding technique was utilized. Chlorpromazine was selected as representative of the 'typical' neuroleptics, being also highly sedative. Risperidone has been suggested as representative of the newer 'atypical' neuroleptics and is claimed to be only minimally sedative. Volunteers were dosed on 3 separate days with a minimum of 7 days interval between trial days. On each trial day volunteers were dosed twice. Dose 1 consisting of either chlorpromazine 50 mg or placebo to chlorpromazine, and dose 2 either risperidone 2 mg or placebo to risperidone. The volunteers were randomized so that each received either chlorpromazine or risperidone (or neither), but not both on an individual trial day. A 17 electrode quantitative topographical electroencephalograph (EEG) recording was taken for each volunteer before and after each dosing period. Seven psychomotor function tests were used to determine the effects of each treatment on psychomotor performance. RESULTS: The data confirm the cited reports of sedation following single oral doses of chlorpromazine 50 mg. However, 7 of the 12 volunteers dosed with risperidone 2 mg also reported drowsiness/lethargy which was of greater severity and duration than 5 of the 12 volunteers who reported somnolence following dosing with chlorpromazine 50 mg. Objective assessment of psychomotor impairment using a short battery of psychomotor function tests mirrored the subjective reports of somnolence in that the impairment in volunteers dosed with risperidone 2 mg was greater in extent and magnitude than in volunteers dosed with chlorpromazine 50 mg. With respect to the cortical quantitative electroencephalogram, both chlorpromazine (50 mg) and risperidone (2 mg) increased power (4.75-6.75 Hz) in keeping with cited effects of other neuroleptics on the quantitative EEG. In addition, there was a statistically significant increase (P<0.05) in alpha1 (7.0-9.5 Hz) and beta1 (12.75-18.5 Hz) wavebands in volunteers dosed with risperidone 2 mg. Furthermore, based on estimates of variability, we propose that a 3 min eyes open and 3 min eyes closed quantitative EEG recording is sufficient to maintain adequate power for this technique, whilst allowing its application to early volunteer trials of novel neuroleptic agents. CONCLUSIONS: This study demonstrates that quantitative EEG can be utilized in the profiling of neuroleptic agents, and could be readily applied to the early profiling of novel neuroleptics in limited numbers of volunteers, early in drug development. The chosen battery of psychomotor tests has clearly demonstrable sensitivity to the quantification of the subjective reports of somnolence secondary to both chlorpromazine and risperidone.     

Lack of effect of single and repeated doses of levocetirizine,a new antihistamine drug,on cognitive and psychomotor functions in healthy volunteers

Aims  Levocetirizine (R-cetirizine), is the active enantiomer of cetirizine, an antihistamine indicated in the treatment of allergic rhinitis and chronic idiopathic urticaria. The purpose of this trial was to analyse the effects of levocetirizine single and multiple doses on CNS using integrated measures of cognitive and psychometric performance.
Methods  A battery of psychometric tests was used: critical flicker fusion (CFF), choice reaction time (CRT), body sway (BS), learning memory test (LMT) and subjective assessments of alertness compared with placebo. Nineteen (19) healthy male volunteers received either levocetirizine 5 mg (therapeutic dose), diphenhydramine 50 mg or placebo once daily for 5 consecutive days (3-way cross-over). Diphenhydramine was used as a positive control. CFF tests were performed on days 1 and 5 at baseline and up to 24 h following drug intake. Subjects used the Bond-Lader visual analogue scales (VAS) to assess their mood and vigilance.
Results  In contrast to diphenhydramine, when compared with placebo, levocetirizine did not modify the CFF (primary endpoint), regardless of the dosing scheme (−1.62 Hz [−2.61, −0.64] and −0.81 Hz [−1.80, 0.19], respectively, 3 h after dosing on day 1). CRT was decreased with both levocetirizine and placebo up to 5 h after dosing on day 1 and up to 3 h after dosing on day 5. Body sway data were similar with levocetirizine and placebo but increased with diphenhydramine. LMT was similar in all three groups. No relevant difference between placebo and levocetirizine was recorded by the subjects on their assessment of alertness using the VAS, whilst decreased alertness was reported following diphenhydramine 50 mg.
Conclusions  This study showed that levocetirizine does not produce any deleterious effect on cognitive and psychometric functions compared with placebo in healthy male volunteers.     

Comparison of clozapine and haloperidol on some autonomic and psychomotor functions, and on serum prolactin concentration, in healthy subjects

AIMS: To compare the autonomic, neuroendocrine and psychomotor effects of single doses of the 'atypical' antipsychotic clozapine and the 'classical' antipsychotic haloperidol, in healthy male volunteers. METHODS: Clozapine (50 mg), haloperidol (3 mg) and placebo were administered to 12 healthy male volunteers at weekly intervals, according to a balanced double-blind design. Resting pupil diameter, salivary output, heart rate, blood pressure, plasma prolactin concentration, critical flicker fusion frequency and subjective 'alertness', 'contentedness' and 'anxiety' were measured at baseline and 2, 3, 4 and 5 h after drug ingestion. Data were analysed by analysis of variance with individual comparisons (Dunnett's test) with a significance criterion of P < 0.05. RESULTS: Significant treatment effects (difference from placebo [mean, 95% CI] 5 h after drug ingestion) were as follows: clozapine reduced pupil diameter (mm; -3.02 [-3.56, -2.47]), salivary output (g; -0.34 [-0.60, -0.08]), mean arterial blood pressure (mm Hg; -8.7 [-14.3, -3.1]), critical flicker fusion frequency (Hz; -3.26 [-3.94, -2.58]), and subjectively-rated 'alertness' (mm; -20.94 [-29.21, -12.67]) and 'contentedness' (mm; -12.98 [-17.90, -8.06]), whereas haloperidol increased prolactin concentration (mU l(-1); 301.3 [196.7, 405.8]) and caused small reductions in pupil diameter (mm; -0.68 [-1.23, -0.14]), mean arterial blood pressure (mm Hg; -7.0 [-12.6, -1.4]) and critical flicker fusion frequency (Hz; -1.15 [-1.83, -0.47]). CONCLUSIONS: The effects of the antipsychotics are in agreement with their receptor binding profiles: alpha(1)-adrenoceptor blockade by clozapine may contribute to reductions in pupil diameter, salivation, mean arterial blood pressure and sedation, and muscarinic cholinoceptor blockade by the drug may underlie the reduction in salivation. Conversely, D(2) dopamine receptor blockade by haloperidol is likely to be responsible for the increase in prolactin secretion evoked by the drug.     

Effects of zimeldine,mianserin and amitriptyline on psychomotor skills and their interaction with ethanol a placebo controlled cross-over study

Summary 13 healthy volunteers participated in a double-blind, four-period, cross-over study. In each period, the trial drugs (placebo, zimeldine, amitriptyline and mianserin) were given in fixed dosages for 8 days; amitriptyline 10–50 mg twice daily, mianserin 10–30 mg twice daily and zimeldine 200 mg once daily. Ethanol 1 g/kg bodyweight was drunk 2 hours after drug intake on Days 1 and 8 of each period, the latter being separated by a 2 week wash-out period. Ratings of subjective feelings and side effects, and performance tests were done on Days 1 and 8 of each period before, 1.5, 3 and 4.5 h after drug intake, i.e. 2 of the tests were performed under the influence of ethanol. Mianserin decreased critical flicker frequency, slowed reactions under discriminative stimulation and tended to cause nystagmus, but only on Day 1 (after the first 10 mg dose). Amitriptyline impaired coordination on Days 1 (after the initial 10 mg dose) and 8, and lowered the flicker threshold on Day 8 at steady state (after the 50 mg morning dose). Both these antidepressants were felt to be sedative, especially in the initial phase of the treatment, and they interacted additively with ethanol. No impairment of psychomotor skills was associated with zimeldine, only a subjective sedative effect of the 200 mg dose was seen on Day 1. Zimeldine did not enhance the effects of ethanol; it even showed some antagonism of ethanol-induced body sway in the standing steadiness test. In contrast to amitriptyline and mianserin, zimeldine was regarded as not harming psychomotor skills, and as not having any observable interaction with ethanol.     

The effects of brofaromine alone and in conjunction with alcohol on cognitive function,psychomotor performance,mood and sleep in healthy volunteers

Brofaromine is a novel antidepressant that functions by the inhibition of the A form of monoamine oxidase (MAO). This inhibition is reversible, making brofaromine both pharmacologically and structurally different from most of the currently available MAO inhibitors. The drug has been shown to be clinically effective and to have significantly fewer problems than other MAO inhibitors in terms of hepatic toxicity and interaction with tyramine and coadministered tricyclic antidepressants. The present experiment was designed to assess the behavioural toxicity of the drug. Seventeen normal volunteers received brofaromine 50 mg or 75 mg, amitriptyline 50 mg or placebo with and without alcohol in a double blind eight-way crossover study. A psychometric test battery was administered at 3, 6 and 12 h post-dose. The results show that brofaromine had little or no effect on the measures employed, compared to placebo. The amitriptyline verum (with and without alcohol) however lowered critical flicker fusion threshold compared to placebo at all test points, increased reaction time, increased tracking error, and slowed memory scanning. It is concluded that, in volunteers, acute doses of brofaromine are free from disruptive effects on cognitive function and psychomotor performance, in contrast to both amitriptyline and alcohol which showed debilitating effects on most of the measures employed.     

A double-blind, placebo-controlled investigation of the residual psychomotor and cognitive effects of zolpidem-MR in healthy elderly volunteers

AIM: To assess residual psychomotor and cognitive effects of a modified-release formulation of zolpidem (zolpidem-MR), developed to provide sustained hypnotic efficacy during the whole night, compared with placebo and flurazepam. METHODS: Twenty-four healthy elderly volunteers received four study treatments (zolpidem-MR 6.25 mg and 12.5 mg, placebo and flurazepam 30 mg) using a randomized, cross-over, double-blind design. Residual psychomotor and cognitive effects were assessed with a psychometric test battery. Quality of sleep and residual effects were evaluated subjectively with the Leeds Sleep Evaluation Questionnaire. RESULTS: Psychometric performance was significantly impaired with flurazepam but not with zolpidem-MR at either dose. Ease of falling asleep and sleep quality were significantly improved with both doses of zolpidem-MR and with flurazepam. Neither active drug modified perception of well-being on awakening. CONCLUSION: In elderly subjects, zolpidem-MR showed no residual functional impairment in psychometric or cognitive tests sensitive to flurazepam.     

Acute and subacute effects on psychomotor performance of femoxetine alone and with alcohol

Summary The effects on human psychomotor performance of femoxetine (FEMO), a 5-hydroxytryptamine-selective antidepressant, alone and in combination with alcohol (EtOH) were compared with those of amitriptyline (AMI) and placebo in a controlled double-blind crossover trial in 11 student volunteers. Objective measurements (body sway, choice reaction, flicker fusion, tracking, nystagmus, digit symbol substitution, backwards recall) and subjective self-assessment (visual analogue scales, reporting of side-effects) were done after single doses of FEMO, AMI and placebo, and subacute administration of FEMO and placebo. Single doses of 200 mg FEMO did not impair psychomotor performance, but 50 mg AMI did so in several respects. AMI but not FEMO increased the objective and subjective effects of EtOH. After FEMO 600 mg/d for 10 days almost no objective difference from placebo was noted, although mild sedation at home was reported as a side-effect. FEMO either did not increase or slightly decreased the effect of EtOH on reactive and co-ordination skills. The plasma concentrations of FEMO varied widely from 0 to 156 ng/ml, as in previous clinical trials but reduced a blood 5-hydroxytryptamine concentration in each subject indicating an effect of FEMO on serotoninergic mechanisms.     

The effects of venlafaxine on autonomic functions in healthy volunteers

Antidepressants that block norepinephrine uptake may cause unwanted effects on autonomic functions such as reduction of heart rate variability. This randomized, double-blind, placebo-controlled study examined the effects of venlafaxine on heart rate variability, vasoconstrictory responses (VRs) of cutaneous blood vessels, and pupillary light reflex in humans. Twelve healthy male subjects aged 23 to 32 years (mean +/- SD, 26 +/- 3 years) orally received 37.5 mg of venlafaxine BID for 7 days and subsequently 75 mg BID for another 7 days. After a 14-day washout phase, placebo was administered to the subjects for 14 days under randomized double-blind crossover conditions. Heart rate variability was diminished, and the dilation phase of VR was prolonged during multiple dosing with venlafaxine (P < 0.05). A significant increase in resting pupil diameter, a decrease in amplitude, an increase in latency, and a shortening of the 33% recovery time of the pupillary light reflex were noted with the drug, whereas no changes were observed under placebo condition. Sustained VR and shortening of the recovery time of the pupillary light reflex are consistent with sympathetic potentiation resulting from noradrenaline reuptake blockade in cutaneous blood vessels and iris. The decrease in amplitude and increase in latency of the pupillary light reflex could be indicative of centrally mediated parasympathetic inhibition.