The effect of cholecystokinin antagonism on postprandial lower oesophageal sphincter function in asymptomatic volunteers and patients with reflux disease

BACKGROUND: Postprandial acid reflux is thought to be mediated by the increase in transient lower oesophageal sphincter relaxations (TLOSR) frequency and fall in lower oesophageal sphincter (LOS) pressure seen after ingestion of a meal. Studies in animals and healthy volunteers suggest that cholecystokinin (CCK) may play a role. AIM: To study the role of CCK in postprandial LOS function using the CCK antagonist loxiglumide. SUBJECTS: 10 asymptomatic volunteers (7 male, 20-29 years) and 9 patients with symptomatic gastro-oesophageal reflux (4 male, 33-66 years). METHODS: Oesophageal, LOS and gastric pressure and oesophageal pH readings were recorded for 1 h before and 2 h after intragastric infusion of a 200 kCal, 300 mL long chain triglyceride meal. Each subject underwent two studies and received intravenous loxiglumide or placebo infusion in randomized order. RESULTS: During placebo infusion, postprandial LOS pressure fell [volunteers: 17 (9-31) to 7 (1-19) mmHg (P < 0.01), patients: 15 (6-26) to 9 (2-21) mmHg (P=0.02)] and TLOSR frequency increased [volunteers: 0 (0-1) to 2 (0-7) per hour (P=0.01), patients: 0 (0-3) to 2 (0-10) per hour (P=0.03)]. Loxiglumide infusion attenuated the postprandial fall in LOS pressure and the postprandial increase in TLOSR frequency [volunteers: 0 (0-3) per hour (P=0.04 vs. placebo), patients: 0 (0-2) per hour (P=0.03 vs. placebo)], but it had only modest effects on postprandial acid exposure [volunteers: placebo 45 (0-1725) vs. loxiglumide 0 (0-443) seconds (N.S.), patients: placebo 60 (0-3442) seconds vs. loxiglumide 31 (0-1472) seconds (N.S.)]. CONCLUSIONS: Loxiglumide inhibits TLOSR and attenuates the fall in LOS pressure following a meal, but has only modest effects on postprandial gastro-oesophageal acid reflux.     

A double-blind placebo-controlled trial of BRL 24924 on lower oesophageal sphincter pressure and gastro-oesophageal reflux in healthy volunteers

BRL 24924 is a new gastrointestinal prokinetic agent with properties similar to metoclopramide but with increased potency and devoid of side-effects associated with blockade of dopamine receptors in the central nervous system. A double-blind placebo-controlled trial of the effect of a single oral dose of 2.2 mg BRL 24924 on lower oesophageal sphincter pressure and gastro-oesophageal reflux has been performed in 20 healthy volunteers. BRL 24924 significantly increased mean lower oesophageal sphincter pressure (21.9 cmH2O BRL; 15.9 cmH2O placebo: P less than 0.017) but failed to alter either the frequency or the duration of gastro-oesophageal reflux after provocation following a test meal. BRL 24924 has significant effects on lower oesophageal sphincter pressure but no effect on provoked post-prandial reflux in healthy volunteers. Further studies in patients with gastro-oesophageal reflux and oesophagitis are needed to evaluate the clinical efficacy of this compound.     

The effect of baclofen on gastro-oesophageal reflux,lower oesophageal sphincter function and reflux symptoms in patients with reflux disease

BACKGROUND: Baclofen decreases gastro-oesophageal reflux episodes in healthy subjects by reducing the incidence of transient lower oesophageal sphincter relaxations. AIM: To investigate the effect of baclofen on reflux symptoms, oesophageal pH and lower oesophageal sphincter manometry in patients with gastro-oesophageal reflux disease. METHODS: A double-blind, placebo-controlled, two-way crossover design was used to study the effect of baclofen on heartburn and regurgitation 3 h after a provocation test meal in 37 patients with gastro-oesophageal reflux disease. Additionally, in 20 of these patients, the effect of baclofen on oesophageal pH, transient lower oesophageal sphincter relaxations and basal lower oesophageal sphincter pressure was studied. RESULTS: Baclofen significantly decreased the acid reflux time and the incidence of gastro-oesophageal reflux episodes (8.3 +/- 8.8% vs. 12.4 +/- 12.0%, P = 0.03 and 10.9 +/- 7.3 per 3 h vs. 18.7 +/- 12.4 per 3 h). The incidence of transient lower oesophageal sphincter relaxations was significantly lower with baclofen than with placebo (15.1 +/- 6.4 per 3 h vs. 22.8 +/- 5.4 per 3 h, P < 0.0001). Lower oesophageal sphincter pressure and the percentage of transient lower oesophageal sphincter relaxations associated with reflux were not affected by baclofen. No significant effect on symptom scores was observed. CONCLUSIONS: Baclofen decreases post-prandial acid reflux in patients with gastro-oesophageal reflux disease by reducing the incidence of transient lower oesophageal sphincter relaxations. No effect of a single dose of baclofen on reflux symptoms could be demonstrated in this 3-h post-prandial study.     

Effect of non-selective gamma-aminobutyric acid receptor stimulation on motor function of the lower oesophageal sphincter and gastro-oesophageal reflux in healthy human subjects

BACKGROUND: Transient lower oesophageal sphincter relaxation and low lower oesophageal sphincter pressure are the main mechanisms of reflux. It has recently been shown that the stimulation of gamma-aminobutyric acid type B (GABAB) receptors by baclofen decreases the rate of transient lower oesophageal sphincter relaxation and increases the lower oesophageal sphincter pressure in healthy humans. Valproic acid increases synaptosomal GABA concentrations, thus affecting all types of GABA receptors. AIM: To evaluate the effect of valproic acid on transient lower oesophageal sphincter relaxation, lower oesophageal sphincter pressure and gastro-oesophageal reflux. METHODS: Thirteen healthy subjects underwent 2-h post-prandial oesophageal motility and pH monitoring on two separate occasions after the oral administration of 1 g valproic acid or placebo. RESULTS: Valproic acid increased the lower oesophageal sphincter pressure by 41% (14.0 +/- 2.1 mmHg vs. 9.9 +/- 2.0 mmHg after placebo, P<0.02), but did not affect the rate of transient lower oesophageal sphincter relaxation (7.9 +/- 1.0/h vs. 8.2 +/- 0.9/h after placebo), the number of reflux episodes or gastro-oesophageal reflux. CONCLUSIONS: Non-selective GABA receptor stimulation may be beneficial to reflux patients with low lower oesophageal sphincter pressure, but exerts a different modulation of transient lower oesophageal sphincter relaxation than the selective stimulation of GABAB receptors.     

Lack of effect of a 5-HT3 antagonist, pancopride, on lower oesophageal sphincter pressure in volunteers.

Effects of pancopride (5 and 10 mg, intravenously), on lower oesophageal sphincter pressure (LOESP), were assessed in healthy volunteers by means of oesophageal manometry. After pancopride 10 mg, the LOESP was higher than placebo and 5 mg pancopride but there were no differences among the three treatments (P = 0.42). The areas under the curve were similar without differences, neither with absolute measurements (P = 0.53) nor after a baseline correction (P = 0.16). In conclusion, pancopride has no clinically relevant effect on lower oesophageal sphincter pressure.     

Effect of caloric density of a meal on lower oesophageal sphincter motility and gastro-oesophageal reflux in healthy subjects

BACKGROUND: Patients with gastro-oesophageal reflux disease are advised to avoid the ingestion of large meals. In healthy volunteers, a relationship between the amount of postprandial gastro-oesophageal reflux and the volume of a liquid meal has been demonstrated. AIM: To evaluate whether the amount of postprandial gastro-oesophageal reflux is also related to the calorie content of a meal, a second parameter that will be reduced by avoidance of the ingestion of large meals. METHODS: Twelve healthy volunteers (six female, 19-31 years) received two solid-liquid meals with either 842 kcal (solid 582 kcal, liquid 260 kcal) or 582 kcal (31% reduction) in a randomized order. The nutritional components (10% fat, 76% carbohydrates, 14% protein) and the volume of the meals were identical in both meals. The lower oesophageal sphincter pressure was measured continuously in the first postprandial hour with a Dent sleeve, and pH-metry was performed for 3 h postprandially with a glass electrode in the distal oesophagus. Blinded to the type of ingested meal, we calculated the mean lower oesophageal sphincter pressure, the frequency of transient lower oesophageal sphincter relaxations, the number of reflux episodes, and the fraction of time for which pH < 4. RESULTS: A similar decrease in lower oesophageal sphincter pressure was observed after ingestion of the high calorie meal (median 10.9 mmHg, range 4.8-16.7 mmHg) and low calorie meal (median 9.9 mmHg, range 3.9-18.4 mmHg). No difference in the number of transient lower oesophageal sphincter relaxations (high calorie: median 9 per hour, range 5-13 per hour; low calorie: median 7 per hour, range 0-14 per hour) and of reflux episodes (high calorie: median 12 in 3 h, range 3-22 in 3 h; low calorie: median 12 in 3 h, range 3-30 in 3 h) was registered after intake of both types of meal. Additionally, no difference was identified regarding the fraction of time for which pH < 4 between the high calorie (mean 2.3%, 0.2-23.7%) and low calorie meal (3.3%, 0.5-17.8%). CONCLUSION: Reducing the caloric density of a meal neither influences postprandial lower oesophageal sphincter pressure nor decreases gastro-oesophageal reflux in healthy volunteers. Thus, the amount of gastro-oesophageal reflux induced by ingestion of a meal seems to depend on the volume but not on the caloric density of a meal.     

The GABAB receptor agonist AZD9343 inhibits transient lower oesophageal sphincter relaxations and acid reflux in healthy volunteers: a phase I study

Background  Transient lower oesophageal sphincter relaxations (TLESRs) represent an interesting target for the treatment of gastro-oesophageal reflux. Baclofen reduces TLESRs and reflux episodes, but is not optimal for clinical application because of its central side effects. Therefore, new agents are required.
Aim  To study the effect of AZD9343, a new selective GABA_B receptor agonist, in healthy volunteers.
Methods  A total of 27 subjects participated in a placebo-controlled, randomized, two-centre phase I study. Subjects underwent oesophageal manometry and pH-metry for 3 h postprandially. Before meal ingestion, a single oral dose of placebo, 60 and 320 mg AZD9343 or 40 mg baclofen was given on four separate days.
Results  Somnolence was reported after 320 mg AZD9343 and baclofen. Reversible short-lasting paraesthesia was reported after AZD9343. AZD9343 320 mg and baclofen significantly reduced the number of TLESRs with 32% and 40% respectively. Acid reflux was significantly decreased by AZD9343 and baclofen. Like baclofen, AZD9343 increased LES pressure before meal intake. AZD9343 320 mg and baclofen significantly reduced the swallowing rate.
Conclusions  Like baclofen, AZD9343 dose-dependently decreases the number of TLESRs and acid reflux episodes, increases LES pressure and reduces swallowing, extending the concept that GABA_B agonists are potent reflux inhibitors. However, discovery of analogues with an improved side effect profile is warranted.     

A double-blind dose ranging study of BRL 24924 and metoclopramide on lower oesophageal sphincter pressure in healthy volunteers.

1. A double-blind placebo controlled dose ranging study of the effect of single oral doses of 1 and 2 mg BRL 24924 and 10 mg metoclopramide on lower oesophageal sphincter pressure has been performed in 20 healthy volunteers. 2. The 2 mg dose of BRL 24924 caused a statistically significant increase in mean lower oesophageal sphincter pressure (P less than 0.05) at 30-45 min post-dose (20.8 +/- 7.1 cm H2O BRL 24924; 16.4 +/- 5.7 cm H2O placebo). BRL 24924 1 mg and metoclopramide 10 mg failed to increase lower oesophageal sphincter pressure at any time. However, eight volunteers with a hypotensive resting lower oesophageal sphincter pressure (less than 15 cm H2O) showed a statistically significant rise in pressure at 120 min for both 1 mg, 2 mg (P less than 0.01; P less than 0.001) BRL 24924 and 10 mg metoclopramide (P less than 0.01). No other significant effect was detected on oesophageal manometry. 3. BRL 24924 (2 mg) has statistically significant effects on lower oesophageal sphincter pressure. However, further studies in patients with gastro-oesophageal reflux disease and oesophagitis are needed to evaluate its clinical efficacy, especially where a hypotensive lower oesophageal sphincter pressure predominates.     

The effect of motilin agonist ABT-229 on gastro-oesophageal reflux, oesophageal motility and lower oesophageal sphincter characteristics in GERD patients

BACKGROUND: ABT-229, a motilin agonist without antibacterial activity, has been shown to enhance both lower oesophageal sphincter pressure in cats and gastric emptying in humans. AIM: To investigate the effect of oral treatment with ABT-229 10 mg b.d., ABT-229 5 mg b. d. and cisapride 10 mg q.d.s. on gastro-oesophageal reflux, lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxations and symptoms in GERD patients. METHODS: Twenty-four GERD patients completed the study. A randomized, double-blind, placebo-controlled, three-period incomplete crossover design was used with three dosing periods of 7 days. All patients received ABT-229 10 mg b.d. and placebo during two of the three periods. In the remaining period 12 patients were given ABT-229 5 mg b.d. and 12 received cisapride 10 mg q.d.s. Ambulatory 24 h recordings of oesophageal pH and pharyngeal, oesophageal, lower oesophageal sphincter and gastric pressures were performed on day 7 using an assembly incorporating a Dent sleeve connected to a portable water-perfused manometric system. RESULTS: Oesophageal acid exposure was not affected by ABT-229 or cisapride, but the incidence of reflux episodes was reduced by cisapride. None of the drugs affected oesophageal motility, lower oesophageal sphincter pressure or the incidence of transient lower oesophageal sphincter relaxations. Both ABT-229 10 mg b.d. and cisapride reduced the severity of daytime heartburn. CONCLUSION: The value of ABT-229 in the treatment of GERD appears to be limited.     

The effects of itopride on oesophageal motility and lower oesophageal sphincter function in man

Aliment Pharmacol Ther 2011; 33: 99–105

Summary

Background Itopride is a new prokinetic agent that combines antidopaminergic and cholinesterase inhibitory actions. Previous studies suggested that itopride improves heartburn in functional dyspepsia, and decreases oesophageal acid exposure in gastro‐oesophageal reflux disease. It remains unclear whether this effect is due to effects of itopride on the lower oesophageal sphincter (LES). Aims To study the effects of itopride on fasting and postprandial LES function in healthy subjects. Methods Twelve healthy volunteers (five men; 32.6 ± 2.0 years) underwent three oesophageal sleeve manometry studies after 3 days premedication with itopride 50 mg, itopride 100 mg or placebo t.d.s. Drug was administered after 30 min and a standardized meal was administered after 90 min, with measurements continuing to 120 min postprandially. Throughout the study, 10 wet swallows were administered at 30‐min intervals, and gastrointestinal symptoms were scored on 100 mm visual analogue scales at 15‐min intervals. Results Lower oesophageal sphincter resting pressures, swallow‐induced relaxations and the amplitude or duration of peristaltic contractions were not altered by both doses of itopride, at all time points. Itopride pre‐treatment inhibited the meal‐induced rise of transient LES relaxations (TLESRs). Conclusions Itopride inhibits TLESRs without significantly affecting oesophageal peristaltic function or LES pressure. These observations support further studies with itopride in gastro‐oesophageal reflux disease.     

Review article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastro-oesophageal reflux disease

Aliment Pharmacol Ther 2011; 33: 650–661

Summary

Background Transient lower oesophageal sphincter relaxations (TLOSR) are considered the physiological mechanism that enables venting of gas from the stomach and appear as sphincter relaxations that are not induced by swallowing. It has become increasingly clear that most reflux episodes occur during TLOSRs and therefore play a key role in gastro‐oesophageal reflux disease (GERD). Aim To describe the current knowledge about TLOSRs and its clinical implications. Methods Search of the literature published in English using the PubMed database and relevant abstracts presented at international conventions. Results Several factors influence the rate of TLOSRs including anti‐reflux surgery, meal, body position, nutrition, lifestyle and a wide array of neurotransmitters. Ongoing insights in the neurotransmitters responsible for the modulation of TLOSRs, as well as the neural pathways involved in TLOSR induction, have lead to novel therapeutic targets. These therapeutic targets can serve as an add‐on therapy in patients with an unsatisfactory response to proton pump inhibitor by inhibiting TLOSRs and its associated reflux events. However, the TLOSR‐inhibiting drugs that are currently available still have significant side effects. Conclusion It is likely that in the future, selected GERD patients may benefit from transient lower oesophageal sphincter relaxation inhibition when compounds are found without significant side effects.     

Effect of propranolol on the lower oesophageal sphincter in man

Summary

The effect of an intravenous dose (2?mg) of propranolol on the lower oesophageal sphincter was studied in 10 human volunteers. A hydraulic-capillary infusion manometric technique was used to measure the lower oesophageal sphincter pressure. A significant increase in sphincter pressure was recorded, together with increased amplitude and duration of oesophageal peristaltic activity. This study confirms the presence of specific beta-receptors in the lower oesophageal sphincter.     

Ethnic variation in lower oesophageal sphincter pressure and length

Background  Oesophageal manometry (OM) is used to diagnose oesophageal motor disorders. Normal values of OM among United States ethnic groups are only available for Hispanic Americans (HA).
Aim  To obtain normal values of OM in adult African American (AA) volunteers, compare these with those obtained in HA and non-Hispanic white (nHw) volunteers to determine if ethnic variation in normal oesophageal motor function exists.
Methods  Healthy AA, HA and nHw were recruited from the Jacksonville metropolitan area. Ethnicity was self-reported. Exclusion criteria were symptoms suggestive of oesophageal disease, medication use or concurrent illness affecting OM. All underwent OM using a solid-state system with wet swallows. Resting lower oesophageal sphincter (LOS) pressure and LOS length were measured at mid-expiration, while per cent peristaltic contractions, distal oesophageal contraction velocity, amplitude and duration were measured after 5 cc water swallows.
Results  Fifty-six AA, 20 HA and 48 nHw were enrolled. All completed OM. AA had significantly higher resting LOS pressure, LOS length and distal oesophageal contraction duration than nHw ( P  < 0.05).
Conclusions  Significant ethnic exist in OM findings between AA and nHw. These underscore the need for ethnic specific reference values for OM to allow for correct diagnosis of oesophageal motor disorders in AA.     

Sublingual nitroglycerine: effects on contractile activity of the distal oesophagus and lower oesophageal sphincter in healthy men

Background and Aims : Nitric oxide plays an important role in the control of gastrointestinal motility. This study assessed the effects of graded doses of the nitric oxide-releasing agent, nitroglycerine, on distal oesophageal motor activity and lower oesophageal sphincter resting pressure.
Methods : Eight healthy young men received at 1-week intervals placebo, 0.2 mg, 0.4 mg or 0.8 mg nitroglycerine sublingually under random double-blind conditions. Sphincter pressure was recorded using a Dent sleeve and oesophageal motility using sensors 1, 4, 7 and 10 cm orad the sleeve during two 15-min periods before and four 15-min periods after drug administration. In minutes 4 to 6 of each period, subjects swallowed 5 mL water at 30 s intervals.
Results : After 0.2 mg and 0.4 mg nitroglycerine, amplitude, duration and area under curve of swallow-initiated contractions were smaller than after placebo. After 0.8 mg nitroglycerine, amplitude, duration and area under curve were slightly greater than after placebo and significantly greater than after the lower nitroglycerine doses. No effects were discernible on onset latency and propagation velocity of contractions as well as on lower oesophageal sphincter resting pressure.
Conclusions : Sublingual nitroglycerine had modest, dose-dependent effects on oesophageal peristaltic amplitude and duration, but did not affect the tone of the lower oesophageal sphincter.     

Lack of effect of flunarizine on the pharmacokinetics and pharmacodynamics of sumatriptan in healthy volunteers.

Twenty-four healthy subjects completed a double-blind, placebo controlled, parallel group study to evaluate the effect of treatment with flunarizine on the pharmacokinetics and pharmacodynamics of sumatriptan, a 5HT1-like agonist. Subjects received a single oral 200 mg dose of sumatriptan on the eighth day of a once daily treatment with either flunarizine 10 mg or matching placebo. There were no significant differences between treatments in relation to Cmax (82.3 ng ml-1 in the absence and 81.4 ng ml-1 in the presence of flunarizine), AUC (368 ng ml-1 h in the absence and 360 ng ml-1 in the presence) and elimination half-life (2.2 h in the absence and 2.4 h in the presence of flunarizine) of sumatriptan. Similarly pretreatment with flunarizine was not found to have any clinically significant effect on the pharmacodynamics of sumatriptan as measured by pulse rate, blood pressure and ECG.     

Lack of multiple dosing effect of sertindole on the pharmacokinetics of alprazolam in healthy volunteers

 The effect of sertindole (a new selective antipsychotic compound) on the pharmacokinetic disposition of alprazolam was investigated. Fourteen subjects who completed the study received a single 1 mg dose of alprazolam without or with concomitant sertindole 12 mg daily. Coadministration of sertindole and alprazolam led to a half-hour decrease (P < 0.05) in mean T_max value (alone: 1.2 h, in combination: 0.7 h) and a 1.6-h increase in the mean t_1/2value (12.5 ± 3.2 versus 14.3 ± 3.4 h, P < 0.05) of alprazolam. The mean C_max (18.5 ± 4.9 versus 18.5 ± 4.8 ng/ml) and AUC (266 ± 68 versus 275 ± 57 ng⋅h/ml) values of alprazolam did not change statistically significantly in the presence of sertindole (P > 0.05). These pharmacokinetic changes are minor and not considered to be of clinical significance. Although both sertindole and alprazolam are substrate for CYP3A4 (cytochrome P-450 3A4), the results in this study suggest that sertindole is not an inhibitor of the metabolism of alprazolam. Received: 5 March 1997/Final version: 28 July 1997     

Lack of effect of rosiglitazone on the pharmacokinetics of oral contraceptives in healthy female volunteers

The effect of rosiglitazone (Avandia [BRL 49653C]) on the pharmacokinetics of ethinylestradiol and norethindrone was evaluated after repeat dosing of rosiglitazone with an oral contraceptive (OC; Ortho-Novum 1/35 containing norethindrone 1 mg and ethinylestradiol 0.035 mg) in a randomized, double-blind, placebo-controlled crossover study. Thirty-four healthy female volunteers received oral rosiglitazone (RSG) 8 mg + OC or matched placebo (P) + OC daily on days 1 to 14 of a 28-day OC dosing cycle; the alternate regimen was administered during a second cycle. Ethinylestradiol and norethindrone pharmacokinetics were determined from plasma concentrations on day 14. Lack of pharmacokinetic effect was prospectively defined as 90% CI for the point estimate (PE) of the ratio (RSG + OC):(P + OC) contained within a 20% equivalence range for both ethinylestradiol and norethindrone (analyzed by ANOVA). For RSG + OC and P + OC, respectively, mean ethinylestradiol AUC(0-24) was 1126 and 1208 pg.h/mL (PE: 0.92; 90% CI: 0.88-0.97), and mean norethindrone AUC(0-24) was 178 and 171 ng.h/mL (PE: 1.04; 90% CI: 1.00-1.07). Thus, rosiglitazone had no significant effects on the pharmacokinetics of ethinylestradiol or norethindrone. Coadministration of rosiglitazone with OCs does not induce metabolism of these synthetic sex steroids and is not expected to impair the efficacy of OCs or hormone replacement therapy.     

Mexiletine inhibits nonadrenergic noncholinergic lower oesophageal sphincter relaxation in rabbits

Nonadrenergic noncholinergic (NANC) nerves are known to be nitrergic and to have an important role in the regulation of gastrointestinal motility and function. Cardiac antiarrhythmic therapy in humans is accompanied by a high incidence of gastrointestinal side-effects. We investigated the effect of mexiletine, a class Ib antiarrhythmic drug, on NANC lower oesophageal sphincter relaxation. Mexiletine concentration dependently inhibited the NANC relaxation induced by 30 mM KCl (EC(50)=4.4 x 10(-6) M); the production of 3',5'-cyclic guanosine monophosphate (cGMP) after KCl stimulation was concentration dependently decreased. The relaxation induced by the exogenous nitric oxide (NO) donor, diethylamine NONOate (10(-5) M), was not inhibited by mexiletine, and the cGMP production after diethylamine NONOate application was not altered. Mexiletine did not alter the activity of NO synthase. These findings suggest that mexiletine inhibits NANC relaxation via NO-cGMP pathway modulation, possibly by inhibiting myenteric nitrergic neurotransmission in the lower oesophageal sphincter in rabbits.     

The effect of sleep deprivation on memory and psychomotor function in healthy volunteers

Benzodiazepines and other psychotropic drugs have been implicated in the production of memory deficits. The mechanism is unclear, but both a distinct pharmacological action and a non-specific sedative effect have been suggested as being causal or contributory. These two postulated mechanisms of action may be examined separately by using sleep deprivation as a method of non-pharmacological sedation. We measured psychomotor and memory functions in eight sleep-deprived healthy volunteers and eight controls. There was both subjective and objective evidence of sedation, but memory function was not affected. These findings support the view that the effect on memory of psychotropic drugs is principally caused by a direct amnestic effect rather than by drug-induced sedation. Copyright 2000 John Wiley & Sons, Ltd.