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Electrocncephalography and Clinical Neurophysiology, 1976, 4 1 : 4 0 8 - - 4 1 3 © Elsevier Scientific Publishing Company, Amsterdam -- Printed in The Netherlands

Clinical note HUMAN SLEEP AND 5-HTP. EFFECTS OF REPEATED HIGH DOSES AND OF ASSOCIATION WITH BENSERAZIDE (RO.04.4602) A. AUTRET, M. MINZ, B. BUSSEL, H.P. CATHALA and P. CASTAIGNE

Clinique des Maladies du Syst~me Nerveux, 4 7, boulevard de 1'HSpital, 75634 Paris Cedex 13 (France) (Accepted for publication: February 19, 1976)

According to Jouvet's monoaminergic theory, sleep mechanisms may involve a serotoninergic link (Jouvet 1967). The improvement of some insomnias after administration of the direct precursor of serotonin 5-hydroxy-tryptophan (5-HTP) (Guilleminault et al. 1973; Fischer-Perroudon et al. 1974) suggests the intervention of a serotoninergic mediation in human sleep. Another indication is given by the increase of CSF 5.hydroxyindol acetic acid, a serotonin metabolite, after administration of probenecide in some hypersomniac patients (Mouret et al. 1972). However, the effect of tryptophan on several groups of insomnias seems to be variable (Griffiths et al. 1972). Tryptophan, 1--12 g/day (Oswald et al. 1966; Williams et al. 1969; Hartmann et al. 1971; Griffiths et al. 1972) and of 5-HTP, up to 2500 rag/day (Mandell et al. 1965; Oswald et al. 1966; Wyatt et al. 1971; Zarcone et al. 1972), administered to normal subjects, have quite constantly elicited a decrease in sleep and paradoxical sleep latencies. Some conflicting results emerge from these studies: the duration of paradoxical sleep (PS) was usually found to be increased, except by Zarcone et al. (1973) who found no change after large amounts of 1. 5-HTP; and the duration of slow wave sleep (SWS) (stages III and IV) was only increased in 3 studies (Williams et al. 1969; Griffiths et al. 1972; Zarcone et al. 1973). These findings, suggesting that an increase in serotonin metabolism may favour the dura-

tion of PS, are confirmed by similar observations from two psychotic children (Zarcone et al. 1973). The decrease in PS observed after administration of parachlorophenylalanine (PCPA) (Wyatt et al. 1969) and after a synthetic diet free of phenylalanine and tyrosine (Williams et al. 1969} could also uphold this view. Because of the apparent contradiction in the results noted after administration of precursors of serotonin in human and animal studies, we attempted to test the effects on sleep of normal human subjects of large doses of d.1. 5-HTP administered orally, either alone and for a prolonged period, or together with RO.04.4602, an inhibitor of the decarboxylase.

Method

Three male medical students (21--26 years old) volunteered and were remunerated. Their psychological profiles, estimated by an MMPI test, showed no dramatic deviation. During the whole trial, they were asked to lead a regular life and, on the recording days, to avoid an afternoon nap and to refrain from taking coffee or alcohol. It was a single blind study, such that only one of us was aware of the nature of the treatment. Three times a day the subjects took a capsule of either placebo or 300 mg of 5-HTP. An urine sample was collected daily to check the extent of ingestion. Placebo was given for

HUMAN SLEEP AND 5-HTP

409

were grouped for all three patients and the averages were calculated. The results of each period were compared by a t test.

the first week, 5-HTP for the next 2 weeks and placebo again for 9 days. Three 125 mg capsules of RO.04.4602 were taken together with d.1. 5-HTP each day during 2 consecutive days by two of the three subjects, 3 weeks after the end of the previous test period.

Psychological study Each subject performed 4 tests each week during the trial with 5-HTP alone and on the second day of the 5-HTP + RO.04.4602 administration: an anxiety scale extracted from the MMPI test, including 21 items; a '%hymic variation" scale, including the items of the "depressive" and "mania" MMPI scales (44 items); Murphy's scale: evaluation of the subjects' behaviour by the psychologist; a thymic disorder scale, including 28 items.

Polygraphic study Night recording began between 8.30 and 11 p.m. in separate partially sound proof rooms. Subjects had to be out of bed at 8.15 a.m. Continuous polygraphic recording was performed: EEG with fronto-parietal, parietooccipital, bioccipital and 3 vertex deviations, EMG activity of the chin and submental muscles, horizontal eye movements, ECG. The records were analysed in 1 min epochs and classified according to the international classification (Rechtschaffen and Kales 1968) by two independent scorers. After each night, each subject was asked to rate the comfort of his sleep from 1 to l 0 . Records were made during 5 consecutive weeks and the data were grouped in periods (see Fig. 1). The results of each night corresponding to the same period

Placebo

Adaptation

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treatment

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During each of the first 3 periods, the subjects' mono- and polysynaptic reflexes were studied by various techniques: recruitment curves of the H reflex, excitability cycle of the H reflex, determination of the liminar intensity necessary to obtain a polysynaptic reflex (RA III type).

Short term I treat=ent l

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Study of medullary reflexes

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Fig. 1. Design of the trial. * L a b o r a t o r y night. ° H o m e night.

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A. A U T R E T ET AL.

410 P.S.

TABLE I Variation of duration of stage III. Number of recordings indicated in parentheses.

Subject 1

Reference

Short term treatment

44.5 + 10 (3)

56

MiN ....5

+ 4.7 (3)

(m -+so)

HTP

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Subject 2

40.5 + 15 (3)

59.5 +

6

(3)

Subject 3

46.3 + 10 (2)

51.3 +

2.8 (2)

(m -+SO) Mean-+SO

42.7+12

56

(m -+SO)

*P