Brit. 3. Psychiat. (ig66), 112, 391—399

Some Experiments in the Chemistry of Normal Sleep

By IAN OSWALD, G. W. ASHCROFT, R. J. BERGER, D. ECCLESTON, J. I. EVANS andV. R. THACORE

Sleep is essential for physical and nientalhealth. In the last 15 years there has grown upthe concept of the brain stem reticular activatingsystem. Electroencephalographic studies haveshown two qualitatively different and alternating kinds of sleep, the orthodox (“slowwave―,or “¿�fore-brain―)and the paradoxical (“hindbrain―, “¿�rapideye movement―, “¿�activated―,or “¿�dreaming―)phases (Akert et at., 1965).It may be predicted that in the next decadeattention will turn increasingly to the chemical

basis of sleep. If a man is deprived of sleepfor 100 hours, it is extremely difficult tokeep him awake and one may suppose that anabnormal biochemical state exists within hiscentral nervous system.

It has been shown that selective deprivationof either the paradoxical phase (Dement, 1960;Kales ci at., 1964; Jouvet ci at., 1964) or themore profound stages of the orthodox phase(Agnew ci a!., 1964) is followed when subsequent sleep is undisturbed by an increasedproportion of the kind of sleep that was lost.This may be compensatory, there being a needfor each kind of sleep, with a different neurochemical substratum for each. There is generallyan abrupt switch from one to the other. Whatcontrols the switching? At the beginning of thenight, orthodox sleep predominates and, as ifwith high priority, will often momentarilyobtrude into the first periodof paradoxical sleep.The converse occurs when there is an increased“¿�pressure―towards paradoxical sleep, createdby, for example, amphetamine withdrawal.Can one therefore conceive of a delicatebalance between two competing systems? Somesubstances having sedative properties, such asbarbiturates (Oswald ci at., 1963) and alcohol(Gresham ci a!., 1963), suppress paradoxicalsleep, as also, curiously enough, do amphetamine (Rechtschaffen and Maron, 1964) and

tranylcypromine (Le Gassicke et at., 1965).Shift of the balance in favour of paradoxicalsleep by the administration of 4-butyrolactoneand sodium 4-hydroxybutyrate to certain catbrain stem preparations was reported by Jouvetet at. (1961). A means of producing such a shiftin intact man is described below.

Our study has involved the oral administration of L-tryptophan (Oswald, 1963; Oswaldet at., 1964) and of intravenous DL-5-hydroxytryptophan (5HTP). These are precursors of5-hydroxytryptamme (5HT or serotonin), asubstance increasingly considered to play amajor role in brain function. 5-HT givenperipherally is unsuitable for investigation of itscentral action because it passes the blood brainbarrier with difficulty. Tryptophan, however, israpidly absorbed from gut (see, for example,Table I) and, like 5-HTP, quickly reaches thebrain, bringing about a rapid rise in the 5-HTcontent of the parts where it is normally found(Costa and Rinaldi, 1958; Bogdanski, ci a!.,1957; Hess and Doepfner, 1961). Oral trypto

phan has been administered experimentally toschizophrenics by Pollin ci at. (1961) and todepressed patients by Coppen et at. (1963) todetermine whether changes in central 5-HTresult in changes in observable symptoms.Drowsiness was reported as one side-effe@ct bythese authors, and also by Smith and Prockop(1962) and was noted by ourselves in experiments with normal people. A subjective feelingof being slightly drunk and some euphoria wasapparent within 20 minutes after ingestion uponan empty stomach.

PHYSIOLOGICAL INDEx STUDIED

It is usual for indices of physiological functions to show a scatter about a mean. One canattempt to demonstrate that a function isaltered by some externally applied variable in

391

SubjectHMWLohours7.36.99@27.5,,8.817.829.242I

,,3832.27576.52

,,67.530.8io867.36,,67.535.445.352.9

SubjectTime5-HIAAIAA5-HTTryptamineH9

a.m.—i2 noon12 —¿�6 p.m.6oo 4,150i

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a.m.—12noon12 —¿�6p.m.440 3,200495 5,10017.2 3106.5 215

392 SOME EXPERIMENTS IN THE CHEMISTRY OF NORMAL SLEEP

T@suc I

Concentration of Tryptophan in Whole Blood (ug./ml.) Following a Loading Dose of 5 g. Tryptophan

Cone. Tryptophan ug./ml.

either of two ways. Most commonly, with theuse of mathematical techniques and using alarge number of individuals, one attempts toshow that the applied variable causes a shift inthe value of the mean so large that chance isan improbable explanation. Or one can arbitrarily select for that function a value whichoccurs so rarely in the normal population that itcan be used as a limit of normal, and then makeattempts deliberately to cause the functionconcerned to be abnormal (outside the chosenlimit). The Second method has here been usedas the first would have been uneconomic oflabour.

The normal human who falls asleep at nightpasses first into orthodox sleep. After about anhour the first period of paradoxical sleep withrapid eye movements begins. The delay betweenfalling asleep (onset of sleep spindles) and thefirst rapid eye movement is not less than 45minutes in normal persons (Dement andKleitman, 1957; Oswald and Thacore, 1963;

Rechtschaffen and Verdone, 1964). This delayperiod has been the criterion used in this study.Apart from its use in an arbitrary manner, thesubjects served as their own controls in experiments which have been essentially exploratoryin nature. Fig. i indicates how the delay periodis observed and measured, techniques similarto those previously reported (Oswald andThacore, 1963) being used.

THE EXPERIMENTS

It was first observed that rats looked sleepyafter intraperitoneal L-tryptophan. A pilotstudy over 12 nights of sleep, using 2 humanvolunteers given 5 grams of L-tryptophan orallyupon retiring, revealed nothing to suggest aneffect upon the amounts of the different phasesof sleep over the night as a whole. In all, 16normal young adult males received 5 to JOgrams of oral tryptophan before sleep on 1—3pilot nights each. Five gave delay periods ofunder 45 minutes at least once. Two, Subjects

TABLE II

Concentration of 5-Hydroxyindol-3-ylacetic Acid (5-HIAA), Indole Acetic Acid (IAA), Indole Lactic Acid (ILA),5-Hyd@oxyt7yptamine (5-HT) and Ttyptamine in Urine During Control Period (@ hours) and Following the Oral

Administration of 5 g. Tryptophan (6 hours)

Reactors H and M Non-reactors W and L

BY IAN OSWALD et al.

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I 2.14 2

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12.ISj

\,‘\J@ .@_ .- -‘--@@@.j'N,-.....‘/-,@ ,. “¿�--I',N

1240

@@@ 7j@

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SUBJECT M 75G OF L-TPYPTOPHAN AT IL 5Op@ ON 27063 (CONTINUED)

247

REM 1249

REM REM

393

Fic. i—Afour channel recording from Subject M. Theupper excerpt is that ofdrowsiness with irregular lowvoltage EEG activity and rolling eye movements. Arrowspoint to what looks likebeginnings of spindle activityon the original record. At12.15 well-developed spindlesbegin to appear, showingthemselves strongly in theanterior derivations, principally intended to show eyemovement potentials.

The lower excerpt shows thehigh voltage slow wave patternof profound orthodox sleep at12.40. Seven minutes later theEEG is of lower voltage, andthen, after a series of slow wavecomplexes, rapid eye movements (REMs) begin at 12.49.

SHIP 3

394 SOME EXPERIMENTS IN THE CHEMISTRY OF NORMAL SLEEP

SLEEP CI.IRAI!ON PRIOR TO REMS. (MINUTES)

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FIG. 3.

FIGs. 2 and 3.—The scale across the top indicates the number of minutes between falling asleep (EEG spindleonset) and first rapid eye movements (REMs) of the first period of paradoxical sleep.

The horizontal bars indicate the duration of the delay period on the various dates in *963—5shown on the left.Where no tryptophan was given the horizontal bars show that the delay period was always normal, in that it

exceeded 45 minutes. Where tryptophan alone was given prior to sleep the delay period was always abnormal, under45 minutes.

Methysergide in particular, given for three prior days, prevented the tryptophan effect.

BY IAN OSWALD et al. 395

M and H, did so consistently and have beenstudied over a two year period. The experiments with these subjects are portrayed in Figs.numbered 2 and 3. Lengthy intervals betweenexperimental nightswere used deliberatelytominimize carry over effects between treatments.

In these two subjects, it will be observed thaton the combined total of 20 nights, whensubstances other than tryptophan were given(lactose, amino acids, saline), the delay periodwas always normal (over 45 minutes). It wasalways under 45 minutes on each of the 11 nightswhen tryptophan alone was given. Lactosecapsules, similar to the tryptophan capsules,were used as a control to determine whether theresults obtained were not specific to tryptophan.Other amino-acids, L-tyrosine 10 grams, andDL-methionine 16 grams, each as a suspensionin a quantity of water similar to that used forswallowing the tryptophan capsules, wereadministered.

Prior to October i 963, Subject M receivedtryptophan in 5 gram quantities, thereafter in7.5 quantities. Subject H received 5 grams oftryptophan on his first night, JO grams on thenext occasion, 28th June 1963 (when he tookabout 20 minutes to .fall asleep and had thevery short delay period before paradoxical

sleep of 5 minutes); thereafter he received 7@5gram doses. Another Subject (5), studied overi 8 months, produced delay periods of under 45

minutes on 7 out of i i occasions after tryptophan alone; on none of 6 occasions when lactosewas administered; on none of 3 occasions afterboth methysergide and tryptophan; and on iof 2 occasions after both alpha methyl dopa andtryptophan. The results showing the effect oftryptophan on the onset of REM sleep arecombined for the 3 subjects in Table III.x2 (with Yates' correction) = 21@7(p<O.001).

The other two tryptophan reactors amongst theoriginal total of 16 volunteers were not subjectedto further study.

Alpha methyl dopa, 500 mg., 150 minutesbefore the tryptophan appeared only irregularlyto prevent the action of tryptophan; indeed,Subject H revealed his shortest delay periodunder these circumstances when, on March 7,1965, only 19 minutes after swallowing thetryptophan, he passed into paradoxical sleep,

after less than a minute of orthodox sleep withEEG spindles, and continued therein for 15minutes. Analysis of the combined results of theseexperiments (Table IV) showed no significantdifference between the effect of administrationof tryptophan alone and pretreatment withalpha methyl dopa, x2 = 0@33.

Methysergide (“Deseril―,Sandoz), a specific5-HT blocking agent (Doepfner and Cerletti,1958), 3 mg. daily for three days prior totryptophan, prevented the action of tryptophanon 10 out of 10 occasions. These results areshown in Table V and the difference betweentreatment with tryptophan alone and pretreatment with Deseril is significant, x2 =p<O @OOlIt was noted that the onset of REMsleep, following pretreatment with Deseril,appeared to be occurring even later than oncontrol nights. Taking an arbitrary division of6o minutes, the results of these two groups areshown in Table VI. The difference is notsignificant, x2 = 2@32. The possibility that theeffect is mediated by Deseril alone and not by itscombination with tryptophan was not investigated further in this series of studies.

Intravenous saline injections prior to sleepwere without effect, but 40 mg. of 5-HTPintravenously in 10 ml. of saline caused SubjectM to have his shortest delay period of i6minutes. The injection procedure may havebeen more anxiety-provoking than capsulesand each subject took over 30 minutes to fallasleep on these nights, which may have provideda long enough interval for most of the 5-HTPto be metabolized prior to sleep, the extremeresponse of i6 minutes by Subject M being theonly presumed response among the 6 observations.

WAKING OBSERVATIONS

An investigation carried out with six subjectshaving lactose on two occasions and tryptophan,5 grams, on two occasions (through the kindco-operationof Dr. J. Laidlaw and Miss J.Catlin) failed to reveal any clear effect oftryptophan upon either waking EEG rhythms(an automatic frequency analyser being used)or upon performance in various simple tasksrequiring attention.

TreatmentNumber

ofNights(a)

With Onset REMunder 45 mm.(b)With

Onset REMat 45 mm. or

laterTotalControls—No

treatment:(Salineor LactoseCapsules)....0i6i6Tryptophan

(5—10grams)......i8422Total

.. ......182038

TreatmentNumber

ofNights(a)With

Onset REM (b) With Onset REMunder 45 mm. at 45 mm. or

laterTotalTryptophan

(5—10 grams.) ....i8422Alpha

Methyl Dopa (500mg.)150 mm. prior to Tryptophan (5—10 gr.)8412Total

.. .. ....26 834TABLE

VTreatmentNumber

ofNights(a)With

Onset REM (b) With Onset REMunder45 mm. at45 mm. or

laterTotalTryptophan

(@—iogram) .. ....*8422“Deseril―

(@ mg. daily for 3 days)Tryptophan (5—10gram) .. ....01010Total

.. .. .. ....18 1432TABLE

VITreatmentNumber

ofNights(a)With

Onset REM (b) With Onset REMunder 6o mm. at 6o mm. or

laterTotalControls—No

Treatment:(Saline or Lactose Capsules) ....II5i6“Deseril―

(@ mg. daily for 3 days)

Tryptophan (5—10gram) .. ....37*0Total

.. .. .. ....14 1226

396 SOMEEXPERIMENTSIN THE CHEMiSTRYOF NORMALSLEEP

TArn@ III

Effect of Ttyptophan on onset of paradoxical (REM) sleep in@ subjects

TArn@z IV

Effect of administration of Alpha Methyl Dopa, 500 mg., 150 mm. prior to T@yptophanon onset REM sleep in 3 subjects

BY IAN OSWALD et al. 397

Some normal volunteers had responded to thetryptophan by having delay periods of under45 minutes, while others did not do so. It wasthought probable that this merely reflecteddifferences in degree of responsiveness ratherthan a sharp division between two categories ofperson, but in order to determine whether therewas a difference in the whole body metabolismof tryptophan along the tryptamine and 5-hydroxytryptamine pathways between the“¿�reactors―and “¿�non-reactors―,Subjects H. andM. were investigated in a metabolic unit, andcompared with Subjects W. and L. who hadnot shown response to tryptophan. Having fastedin the previous 12 hours, urine was collectedover a 3 hour control period. A 5 g. dose of Ltryptophan was administred in gelatin capsulesand urine collected over a subsequent 6 hourperiod. Blood samples were withdrawn at @,i,2, 3 and 6 hours. Subjects H. and W. experi

enced some nausea.Blood tryptophan was estimated by the

method of Hess and Udenfriend (z@@@) asapplied by Guroff and Udenfriend (1962).5-Hydroxylndol-3-ylacetic acid (@-HIAA),indol-3-ylacetic acid (IAA), tryptamine and 5-hydroxytryptamine (5-HT) were determinedas enumerated in the paper ofLe Gassickeetal.

(1965).The resultsobtained (Tables I and II)

show no noteworthy difference between“¿�reactors―and “¿�non-reactors―in the excretionof 5-HIAA, IAA, 5-HT and tryptaminefollowing this loading dose of tryptophan. Theconcentration of these metabolites was ratherhigh in all these young subjects.

When these waking subjects had receivedtryptophan upon an empty stomach theynoticed a slight euphoria, a mild feeling ofdrunkenness and drowsiness after about 20minutes, persisting about one hour. It wasnoticeable on these occasions (and also whenanother normal subject received intravenous5HTP) that their conversation tended to becomelewd. Only subsequently did we discover Smithand Prockop's description (1962) of similarbehaviour after tryptophan leading to complaints from nursing staff. Tryptophan given todogs can provoke spontaneous orgasms (Himwich and Costa, 1960). These observations are

consistent with the penile erections that regularly accompany human paradoxical sleep(Fisher et al., *965) and the other links betweenthat phase of sleep and sexual behaviour(Faure and Bensch, 1962).

DiscussioN

Jouvet (1962) located a pontine centre

controlling the release of paradoxical sleep.The biogenic amine, 5-HT, is distributedthroughout the central regions of brain (Aminel al., 1954; Costa and Rinaldi, 1958; Bogdanskiet al., 1957; Price and West, 1960). The administration of L-tryptophan has been shown to increase the absolute amount (Hess and Doepfner,

1961) and turnover (Ashcroft et al., 1965) of the

amine in the brain. We may reasonablypostulate that the action of tryptophan in thepresent experiments has been an action in thebrain, as opposed to, for example, some unknown reflex arising from an action on the gut.A non-specific effect of amino acid administration has been ruled out by the failure of tyrosineor methionine to produce the effect.

Although the injected 5-HTP reproduced thetryptophan effect only once out of six times, itcaused the shortest delay period in Subject M,of i 6 minutes. Delay-periods of that order donot normally occur. One may suppose the5-HTP to have been responsible, suggestingthat the observed action of tryptophan depended upon its metabolism to 5-HTP andthence to 5-HT. This would seem a reasonableinference,in view of the blockingof the tryptophan effect by a specific 5-HT antagonist,methysergide. It is known from animal experiments that methysergide reaches the brain(Doepfner, 1962) and that it can inhibit thecentral action of 5-HT (Karfa et al., 1961).

Alpha methyl dopa has been shown to blockthe synthesis of 5-HT from tryptophan in brain(Eccieston et al., 1965) and was therefore triedout in the present experiments. The inconsistentresults therefrom may have arisen because alphamethyl dopa also reduces the cerebralconcentration of other biogenic amines, whichmay play a role in cerebral function (Sourks,

1965).Recording only the first hour of sleep, as

was the case on most of the nights, had obvious

398 SOME EXPERIMENTS IN THE CHEMISTRY OF NORMAL SLEEP

practical advantages. It meant, however, that a

record of the duration of each first period ofparadoxical sleep was not regularly kept,though durations of a few seconds to as long as17 minutes were seen—a normal range. It has

now been shown by Rechtschaffen and Verdone(*964) that in a normal night's sleep a shorterdelay period is correlated with a shorter durationof the first period of paradoxical sleep. Dement(personal communication) points out that if the

early, tryptophan-induced initial period ofparadoxical sleep is as long, on average, as thenormal, then a factor making for increase ofduration as well as early onset should be

postulated.The effect of L-tryptophan upon normal sleep

prompted a study of its effect in idiopathic

narcolepsy, where it is found to double the

duration of the period of paradoxical sleep

into which such patients, unlike normal persons,will at once pass upon falling asleep (Evans andOswald, 1965). Faure (1965) has reported thattryptophan enhances paradoxical sleep in therabbit.

SUMMARY

Upon falling asleep there is normally at least45 minutes of orthodox (“slowwave―)sleepbefore the onset of paradoxical sleep (rapid eyemovement phase). Laevo-tryptophan, 5 to 10grams orally upon retiring to bed resulted indelaysoflessthan 45 minutes in 5 of i6 normalyoung male adults,ofwhom threewere studiedin detail and among whom no evidence ofunusual tryptophan absorption or metabolismwas found.

Control amino-acids, tyrosine and methioninedid not produce the response. It is postulatedthat the effect on sleep results from the metabolism of tryptophan to 5-hydroxytryptamine(serotonin). Further results described supportthis hypothesis, particularly the fact that thespecific anti-serotonin agent, methysergide,prevented the effect of tryptophan.

ACKNOWLEDGMENTS

We are much indebted to Messrs. Sandoz Ltd. forgenerous supplies of tryptophan, 5HTP and methysergide(Deseril).Messrs.I.C.I.(Pharmaceuticals)Ltd.alsokindlygave some tryptophan. The Medical Research Councilgave financial aid.

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G. W. Ashcroft, M.B., M.R.C.P.E., D.P.M., Medical Research Council Unit for the Study of Brain Metabolis,n,Department of Pharmacology, University of Edinburgh

R. J. Berger, M.A., Ph.D., Brain ResearchInstitute, Universityof California, Los Angeles, California

D. Eccieston, M.B., Ch.B., D.P.M., Medical Research Council Unit for the Study of Brain Metabolism,Department of Pharmacology, University of Edinburgh

J. I. Evans, * M.B., Ch.B., D.P.M., Lecturer, Department of Psychiatry, University of Edinburgh

V. R. Thacore, B.5c., M.B., B.S., Registrar, Mapperly Hospital, Xottingham

* From whom reprints may be obtained.

(Received ‘¿�5july, 1965)

10.1192/bjp.112.485.391Access the most recent version at DOI: 1966, 112:391-399.BJP 

IAN OSWALD, G. W. ASHCROFT, R. J. BERGER, D. ECCLESTON, J. I. EVANS and V. R. THACORESome Experiments in the Chemistry of Normal Sleep

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