Green Light Attenuates Melatonin Output and Sleepiness during Sleep Deprivation

Transcription

1 Sleep, 14(3): Assocaton of Professonal Sleep Socetes Green Lght Attenuates Melatonn Output and Sleepness durng Sleep Deprvaton *J. A. Home, *J. Donlon, and tj. Arendt *Department of Human Scences, Loughborough Unversty, Loughborough, Lecestershre LEI 1 3TU, u.k.; and. tdepartment of Bochemstry, Surrey Unversty, Guldford, Surrey GU2 5XH, u.k. Summary: Melatonn output covares wth sleepness, wth both peakng early mornng. Brght whte lght suppresses ths output, but t s not known f such treatment amelorates nghttme sleepness durng sleep deprvaton. However, sleep-deprved subjects fnd such lght rrtatng. Humans are partcularly senstve to green lght, and melatonn output s more readly suppressed by ths hue. A plot study usng dfferent green lght regmens showed that sleep-deprved subjects well tolerated 2,000 lux green lght gven 10 mn hourly, and that ths dose reduced nghttme melatonn output. The man study gave ths lght treatment vs. a low ntensty red/green lght control, from 1900 hr for 11 hr, to two groups of subjects (n = 6 each) sleep deprved for 36 hr. Urne was collected at 6-hr ntervals durng sleep loss and on a baselne day. Vglance performance, subjectve sleepness, and oral temperature were montored durng sleep loss. The expermental condton suppressed urne 6-hydroxymelatonn sulfate (amt6s) output between 0000 hr and 0600 hr, and ncreased t hr; but there was no change n total 24-hr values. The control condton had no such effects. The oral temperature rhythm remaned unchanged. Vglance and subjectve sleepness were mproved sgnfcantly relatve to control values durng hr; these mprovements were mantaned somewhat over the hr perod, contrary to what one mght expect f the delayed melatonn surge at ths tme was ncreasng sleepness. Although the brght green lght helped counteract sleepness, any causal lnk wth changes n melatonn output seem tenuous. Key Words: Sleep deprvaton-melatonn Performance-Body temperature - Lght-Sleepness. Human melatonn output exhbts a clear crcadan rhythm, peakng durng the nght, partcularly durng the early mornng (e.g. 1,2). Durng sleep deprvaton, crcadan levels of the hormone covary wth subjectve sleepness and psychologcal performance detrment (3), wth the hormone's peak concdng wth the tme of greatest sleepness. Although melatonn may be soporfc n pharmacologcal amounts [e.g. 50 mg ntravenous (4); 80 mg orally (5); 240 mg orally (6)], and can cause sleepness n humans when gven n small doses [1. 7 mg by nasal spray (7); 2 mg orally (8)], t s not known to what extent the normal physologcal levels at nght contrbute to the feelngs of sleepness durng sleep deprvaton. Lewy et al. (9) have shown that exposure to brght (2,500 lux) lght of daylght qualty for about 2 hr around the melatonn peak tme wll reduce the hormone's output by about 60% (there Accepted for publcaton December Address correspondence and reprnt requests to Dr. J. A. Horne, Department of Human Scences, Loughborough Unversty, Loughborough, Lecestershre LEI! 3TU, U.K. 233 s a dose-response effect); however, sleepness was not montored. Our orgnal ntenton was to nvestgate whether artfcal lght of a type able to suppress nghttme melatonn output mght also amelorate the crcadan rse n sleepness at ths tme, and mght therefore be of practcal use. However, a problem s that sleep loss often leads to photosenstvty (10), and artfcal lght of the type needed to suppress melatonn output can be dstressng to sleep-deprved subjects; so they avod the full lght (11). Ths rased a major ethcal ssue that prevented us from proceedng n ths partcular drecton. Another avenue (11) was to expose subjects to hgh ntensty lght flashes (around 300,000 lux) of exceedngly short (nanosecond) duraton, so as not to leave retnal after-effects. Most modem studo-qualty professonal photographc flashguns acheve ths, and under bounce-flash cause no dscomfort, especally when people are seated about 3 m away, as n a typcal studo photographc sesson. Home et al. (11) found that 30 flashes/mn for 2 mn each hour durng a nght wthout

2 234 J. A. HORNE ET AL. TABLE 1. Plot study Lght condton 5-green lo-green Control Alquot (percentage of 24-hr total output) 1800"{)000 hr 0000"{)600 hr hr hr Base Dep Base Dep Base Dep Base Dep Average urnary 6aMTs levels n 6-hr alquots, gven as perce:ntages of the total 24-hr output, for three groups under baselne (Base) and sleep deprvaton (Dep) condtons: 5 mn green lght (5-Green), 10 mn green lght (IO-Green), and 10 mn red/green lght control (Control) sleep led to mproved vglance performance and l{~ssened sleepness compared to a control condton of r<ed/ green I-Hz alternatng tungsten lghts (300 lux each), gven under smlar condtons. Subjects were blnd to whch treatments were the expermental and control condtons. Nghttme urnary melatonn was reduced by the flash. Although flash s worth pursung further, our unversty's ethcal commttee expressed conce:rn, owng to the large total number of flashes nvolved over the course of sleep loss. The human vsual system s partcularly senstv{~ to lght of about nm wavelength (.e. n the color range of green to green/yellow). Recently; and followng on from earler studes [cf. revew by Wurtmann (12)], Branard et al. (13) have shown that plasma m(~latonn levels are more readly suppressed by such lght than by varous other hues of the same ntensty. For example, the suppresson s about 75% greater than for lght of 600 nm (orange-red). As green lght s more potent n suppressng melatonn output, a more subjectvely acceptable ntensty may have smlar effects on melatonn output compared to, for example, fllllspectrum artfcal whte lght of a somewhat hgher ntensty. The use of green lght for several hours n a skep deprvaton regmen s feasble n a laboratory settng, but t has obvous lmtatons f t s to have any applcaton. The am of the present study was to deltermne: 1) a feasble mnmum dose regmen of gr4~en lght treatment for the nghttme suppresson of melatonn output; 2) whether ths mproves objectve and SUbjectve measures of sleepness. PILOT STUDY Three male and three female healthy volunteers, aged yr, were recruted from the campus populaton. They were nonsmokers of average body sze and physcal ftness. They collected ther urne for 24 hr n 6-hr alquots over a baselne day, startng at 0600 hr. The volumes of each alquot were measured and 15 ml samples were taken and mmedately frozen. Subjects avoded coffee and alcohol ntake. Three days later they were sleep deprved for one nght. They entered the laboratory at 1745 hr, empted ther bladders, and began collectng urne as before. Subjects were dvded nto three groups (one male and one female n each). Group 1 sat for 5 mn each hour at a whte-panted desk facng a whte-panted wall n a lght booth saturated wth green lght from a bank of sx fluorescent tubes [Sylvana (Canada) type F20T 12-G green preheat], behnd a translucent opaque screen over the desk and 50 cm above the subjects' heads. Lght-meter readngs of lght ncdent on the subjects' eyes was 1,900-2,100 lux. Treatment began at 1800 hr and contnued hourly untl and ncludng 0600 hr the next day. Group 2 receved 10 mn of ths treatment hourly, commencng at 1805 hr, for 12 hr. Group 3 receved the alternatng red/green lght (see above-also located behnd the opaque screen), for 10 mn hourly for 12 hr commencng at 1815 hr. Subjects lstened to musc and talked durng the treatments and were nstructed to look at the facng wall and table top as much as possble. Subjects completed the Stanford Sleepness Scale (SSS) (14) 10 mn before each treatment sesson, and then hourly throughout the remander of the sleep deprvaton perod. Between treatments they pursued prvate study, talked, watched TV, and played computer games. Subjects remaned n the laboratory buldng for the 24 hr. Food was suppled at 0330 hr, 0730 hr, and 1230 hr. No coffee was allowed, but they drank soft drnks and weak tea ad lbtum. Melatonn n the urne was assayed as 6-hydroxymelatonn sulfate (amt6s), usng the method descrbed by Arendt et al. (15). The plasma elmnaton halflfe of melatonn s about 45 mn (16,17). The 6-hr levels of amt6s were expressed as percentages of the total 24-hr output (18), owng to the large ndvdual dfferences found wth the excreton of ths hormone. The data for each par of subjects were averaged and the outcome s shown n Table 1. Whereas the 5-mn treatment dd not affect urne 6aMT6s when compared wth control values, the 10- Sleep. Vol. 14, No.3, 1991

3 MELATONIN AND SLEEPINESS 235 mn sessons produced about a 50% suppresson between 0000 hr and 0600 hr, and an approxmately doublng of output durng hr. Thus, the daly peak appeared durng the hr alquot. SSS ratngs ndcated that the 1 O-mn brght green lght had an alertng effect throughout the nght, whch seemed to persst well beyond the termnaton of the treatment. A longer treatment, say 20 mn/hr, or a more ntense green lght mght have been more effectve. However, as the presented lght ntensty was well tolerated by the subjects, and as 10 mn of treatment began to nduce boredom, whch may have been counterproductve, the 1 O-mn green lght regmen was retaned. Also, we wshed to keep the lght treatment to a feasble mnmum. Subjects MAIN STUDY Twelve healthy volunteers (eght females, four males; yr), lean, of average physcal ftness, and nonsmokers, were recruted from the same populaton as that of the plot study. They were also selected on the bass of a mornngnes~venngness nventory (19), wth defnte mornng and defnte evenng types beng excluded. They were pad 25 (approx. US $45) for completng the study. Wth regard to the women subjects, t should be noted that: 1) all happened to be on combned oral contraceptves (so, for example, there would not be any luteal phase of the menstrual cycle-there s evdence that general alertness s greater then than durng the precedng prolferatve phase); 2) urnary levels of amt6s are farly stable across the menstrual cycle (20). Desgn and procedure Ths was smlar to that of the plot study, that s, two 24-hr perods (desgnated baselne and total sleep loss), commencng at 1900 hr (after the frst performance test-see below), wth 6-hr urne collectons. As all the subjects could not be run at once, duplcate sessons were held. Subjects were dvded randomly nto two sets (wth the provso that the men were equally dvded), wth one set tested 2 wk after the other. The frst set underwent baselne followed 7 days later by sleep loss, and the second set, the reverse order. Wthn each set the subjects were randomly dvded nto two equal groups (n = 3 each-one man per set), desgnated brght green lght (expermental), and red! green lght (control). It was necessary to dvde the men up as body temperature was to be montored (see below), and there seem to be sex dfferences n ths parameter (21,22). Subjects were blnd to whch condtons were really expermental and control, and they were led to beleve that both condtons would have smlar effects on ther behavor. The lght booth could accommodate three people, and each subgroup was treated together. Durng sleep loss the lght treatments were gven n a smlar manner as n the plot study, that s, 10-mn sessons of ether the expermental or control lght condtons, gven hourly, commencng at 1900 hr and contnung for 12 hr to nclude 0600 hr the next mornng. The study was conducted between md-february and md-march, wth sunset and sunrse beng approxmately 1740 hr and 0700 hr, respectvely. Thus, the treatment was largely confned to the dark hours of the day. Indoor lghtng conssted of standard daylght qualty fluorescent tubes mounted n the celng. These were on contnuously throughout the study (day and nght), and produced about 500 lux of lght at table level. Both groups of subjects experenced these same general lght condtons. Indoor llumnaton by daylght was poor, partcularly as the weather was generally overcast on all occasons. Startng at 1800 hr, then 10 mn before each lght treatment, and then hourly after 0600 hr, subjects had ther oral temperatures taken (dgtal thermometer), and they completed the SSS. They could not eat or drnk for 15 mn beforehand. Subjects underwent 30 mn of the Wlknson Audtory Vglance Test (W A VT - see below) on fve successve occasons, n the perods: hr (before commencement of treatment), hr, hr, hr, and hr. Subjects had an addtonal 2- mn ntal warm up each tme. They had undergone two 30-mn practce sessons the day before. On the expermental day, subjects came to the laboratory at 1700 hr, and remaned n ts envrons throughout deprvaton. Subjects were under the constant observaton of expermenters who ensured wakefulness. In ther spare tme subjects read, talked, watched TV, and played computer games. Food was avalable at 1730 hr, 0330 hr, 0730 hr, and J230 hr. They drank soft drnks (dluted frut cordal) and weak (neglgble caffene) tea ad lbtum. Coffee, cola, and other substances contanng unwanted levels of caffene or alcohol were excluded. For three nghts precedng the sleep loss day, lghts out was no later than 2345 hr, and arsng tme no later than 0800 hr. Subjects kept sleep logs over ths perod. Vglance testng The W A VT s very senstve to sleepness, and beng a smple task s free of practce effects beyond one or two tranng sessons (23). Subjects were tested n groups Sleep, Vol. 14, No.3, 1991

4 236 J. A. HORNE ET AL..s:.....J 70 - EXPERIMENTAL DIEP. 1) percentage of target sgnals correctly dentfed (hts); - EXPERIMENTAL B'~SE 2) percentage of background sgnals wrongly dentfed CONTROL DEP. as target sgnals (false responses); and ""'''''''' CONTROL BASE 3) average reacton tme to hts and false responses. 50 ~ ~ 30 2G TIME OF DAY 6h. ALQUOTS FIG. 1. Average urnary 6aMTs levels n 6-hr alquots, gven as percentages of the total 24-hr output, under baselne and sleep deprvaton condtons, for the two groups. See Table 2 for standard devatons and sgnfcance levels. ofthree, wth each person sttng n an ndvdual soundproof cubcle at a termnal. For 30 mn they lstened to monotonc sgnals generated at 30/mn. There were 75% background sgnals of 0.5 sec duraton, wth the remander beng randomly nterspersed target sgnals of just perceptbly shorter duraton (0.45 sec). Subjects had to respond by depressng one of two keys dentfed as background or target. Data were computed as DATA ANALYSIS Melatonn. For each subject the melatonn levels n the 6-hr alquots were converted to a percentage of the 24-hr total. The four values for sleep deprvaton were subtracted (wthn subjects) from the relevant baselnes, and a one-way multvarate analyss of varance (MANOVA) was performed on repeated measures (24) usng the "MacSS" statstcal system (25). Lght was the between-group factor, and the alquots were four dependent varables. Oral temperature. Data wthn each group were averaged for each hourly pont (ths procedure reduced nose and smoothed the data). As t was clear from the resultant graphs (see Fg. 2) that there were no dfferences n the phase or ampltude of the temperature cycle, no further analyses were performed. SSS scores. Prelght treatment values at 1800 hr and 1900 hr (.e. a form of baselne) were averaged wthn subjects and groups. The resultant values were very smlar (green lght SSS mean = 2.2, SD 0.7; control = 2.3, SD 0.8). Each of the remanng hourly SSS values ( hr = 23 ponts) were averaged wthn groups and the 23 ponts compared between the groups, usng a sgn test (df, 22). Ths had a hghly sgnfcant - EXPERIMENTAL CONTROL O c 5 4 ' FIG. 2. TIME OF DAY (Hours) Average 24-hr oral temperature trends (and standard error bars) durng sleep deprvaton for the two groups. Sleep, Vol. 14, No.3, 1991

5 MELATONIN AND SLEEPINESS 237 TABLE 2. Average urnary amt6s n 6-hr alquotsfor brght green lght and red/green lght a Alquot (percentage of 24-hr total output) IS0O-D000 hr 000O-D600 hr hr hr Base Dep Base Dep Base Dep Base Dep Expermental b b 9.S 6.4 (6.0) (7.5) (S.7) (4.S) (11.6) (S.3) (7.1) (3.5) Control (7.8) (3.7) (11.9) (10.9) (10.9) (9.8) (5.4) (11.1) a All values are averages wth standard devatons n parentheses, expressed as percentages of the total 24-hr output under baselne (Base) and sleep deprvaton (Dep) condtons for brght green lght (Expermental) and red/green lght (Control) groups. Statstcal analyss by MANOVA. b Sgnfcant dfference (p < 0.01) between Expermental and Control. outcome (see below), and post hoc unrelated t tests were performed between the two groups for those hourly ponts showng a potentally sgnfcant dfference. WA VT data. The 1900-hr prelght treatment data were averaged wthn groups and compared. These values were very smlar (see Table 4). The 0200-hr, hr, 1100-hr, and 1800-hr data for hts, and reacton tmes (not false responses-see below) were then tested for homogenety of varance and sphercty (acceptable n all cases), and one-way MANOV As performed, usng a repeated measures desgn (lght condton = between-group factor, four tmes of day = dependent varables). For comparson, ANOVA (two-factor repeated measures) values wll also be gven. RESULTS Fgure 1 and Table 2 show the 6-hr melatonn values relatve to the total 24-hr amount. These fndngs are smlar to those of the plot study. Whereas the baselne and sleep loss levels for the control condton were very smlar, those for the expermental treatment showed a suppresson of melatonn output n the hr perod, and an elevaton n the subsequent hr perod. MANOVA revealed sgnfcant dfferences between condton effects for the hr alquot (F = 16.1, df = 1,10, p < 0.003) and for the hralquot(F= 13.0,df= 1,IO,p < 0.005). There were no sgnfcant dfferences n the total 24- hr absolute levels (Table 3). The crcadan varaton n oral temperature was unaffected (Fg. 2). For the SSS scores the sgn test revealed a sgnfcant dfference between the two groups (p < 0.002). Fgure 3 ndcates that obvous dfferences began to appear after 0200 hr. Post hoc unrelated t tests showed sgnfcant dfferences from 0500 hr to 0800 hr nclusve (respectvely: t = 2.45, df = 11, p < 0.05; t = 2.8, df = 11, p < 0.02; t = 6.1, df= 11, p < 0.001; t = 2.3, df = 11, p < 0.05), declnng thereafter to apparent but nonsgnfcant dfferences untl about mdday. The W A VT fndngs (Fgs. 4-6) seem to bear out the SSS reports. The MANOV A for reacton tme showed sgnfcant effects for the 0200-hr and 0600-hr values (respectvely: F= 5.56, df= 1,10, p < 0.04; F= 18.97, df = 1,10, p < 0.002). ANOV A produced a sgnfcant dfference for between condtons (F = 6.33, df = 1,10, p < 0.03). ANOV A gave no sgnfcant dfference between tmes but produced a sgnfcant condton x tme nteracton effect (F = 2.93, df = 3,30, p < 0.05). For ht rate MANOV A revealed sgnfcant dfferences between the groups for 0200, 0600 and 1100 hr (respectvely: F = 11.03, df = 1,10, p < 0.008; F = 28.72, df= 1,10, p < 0.005; F = 8.3, df= 1,10, p < 0.02). The between-condtons ANOV A value was sgnfcant (F = 8.44, df = 1,10, p < 0.02). ANOV A gave no sgnfcant dfferences for between tmes. False responses gave no sgnfcant changes for MANOV A or ANOVA. DISCUSSION The brght green lght treatment depressed the nghttme urnary melatonn peak, appearng to shft t from the hr to the hr alquot perod. Total 24-hr melatonn output was unchanged, and there was no evdence of ths treatment affectng the crcadan temperature rhythm. The control lght condton had no effect on melatonn output, whch was comparable to baselne values. Commensurate wth the melatonn changes under the brght green lght regmen TABLE 3. Total 24-hr means (and standard devatons) of urnary amt6s for the two groups under baselne and sleep deprvaton condtons 24-hr totals of amt6s (ng) Baselne Deprvaton Expermental 11,916 11,574 (9,560) (8,171) Control 10,591 9,996 (7,139) (6;513) There were no sgnfcant dfferences. \ Sleep. Vol. 14. No

6 238 J. A: HORNE ET AL. ALERT 1 - EXPERIMENTAL 2 - CONTROL 3 UJ a: 4 0 (/) (/) (/) (/) 6 5 Sgnf Icantly dfferent 7 SLEEPY TIME OF DAY (Hours) FIG. 3. Average 24-hr sleepness ratngs (and standard error bars) durng sleep deprvaton for expermental and control groups. See text for statstcal analyss. s the sgnfcantly mproved W A VT performance at 0200 hr and 0600 hr (hts and reacton tme), together wth the more alert ratngs on the SSS. However, whether the lower hormone levels at ths tme were the cause of the mproved performance s another matter. If such a relatonshp was true, then one mght exp,ect performance and sleepness to have deterorated n the hr perod, n accordance wth the relatlve rse n melatonn followng the expermental condton. Ths was not evdent, but rather, performance and alertness remaned mproved relatve to the control condton (e.g. the sgnfcantly better ht scores at 1100 hr). Thus, t seems that melatonn secreton per se s not causally lnked to subjectve sleepness. It should be remembered that ambent lght levels for the subjects durng the second half of the mornng after sleep loss were about 500 lux-that s, not suffcent to suppress any melatonn surge. There may be a problem n ths study wth the lag tme between melatonn secreton by the pneal, ts excreton n the urne, and the 6-hr spacng of alquots. However, as the plasma elmnaton half-lfe s relatvely short [about 45 mn (16,17)] then most of the melatonn found n an alquot of urne 'Would have been released by the pneal n that perod. So, for example, the sustaned and relatve mprovement n sleepness between 0600 and 1200 hr n the exper- mental group would have been largely concurrent wth tbe rse n plasma melatonn levels. Oral temperature s senstve to unwanted ntervenng varables that can affect the phase and ampltude of the underlyng rhythm. The averagng together of the data from sx subjects wthn each group mproves the sgnal-to-nose rato. Although ths may lead to ampltude attenuaton of the rhythm, a reasonable estmate can stll be made of the rhythm's characterstcs, and especally, whether there has has been any obvous phase-shftng, whch was not the case. (For ths lght to have sgnfcantly affected the phase of the temperature rhythm, an exposure over several crcadan cycles would probably have been necessary). The brght green lght seems to have been ndependently affectng melatonn output and subjectve/objectve measures of sleepness, wth the hormone not drectly nfluencng the latter. It s lkely that the expermental condton was the cause ofthe altered output of the hormone, but why such lght should also affect sleepness s a matter for debate, especally as t s unlkely that physologcal changes n melatonn affect sleepness. One possble explanaton relates to fndngs that brght lght can attenuate sleep length n the short term (e.g. 26), and, n the long term, may be responsble for any shortenng of sleep n the summer and for seasonal Sleep. Vol. 14. No

7 MELATONIN AND SLEEPINESS ~ ~ * o TIME OF DAY 10~ ~ o TIME OF DAY 500., , TIME OF DAY COKTROL II EXPTL COKTROL IIJ,IEXPTL CONTROL FIGS Wlknson Audtory Vglance Test: percent hts and percent false responses and reacton tme (msec) for the fve sessons. Means (and standard error bars) for brght green lght (EXPTL) and red/green lght (CONTROL) groups. Statstcal analyss by MAN OVA-see text. t = sgnfcant dfference at p < 0.05 between expermental and control; * = sgnfcant dfference at p < 0.0 I between expermental and control. changes n the phase of the crcadan temperature rhythm (22). All these sleep reductons would be at the expense of optonal sleep (10). The corollary, whch s more approprate to the present fndngs, s that brght lght also allevates the sleepness accompanyng the shortened sleep. That s, brght lght attenuates optonal sleepness (10,27). Thus, the mproved alertness followng the green lght treatment s resultant of the attenuaton of the optonal sleepness component of the gross sleepness followng the total sleep loss. Of course, there may have been unwanted behavoral factors n our study. We endeavored not to bas the subjects about any antcpated outcome. Nevertheless, there was the possblty of a Hawthorne effect (28), whereby unusual and subjectvely nterestng stmulaton n an otherwse monotonous envronment wll ncrease motvaton and mprove performance. The expermental condton could have been more potent n ths respect. But reports from the subjects showed that they were equally dvded about whch treatment they thought was the more stmulatng and nterestng. A Hawthorne effect could account for the carry-over wth mproved alertness beyond the treatment perod. However, had such a response been present, then an mproved alertness from 1800 to 0000 hr mght also have been expected, whch was not the case. Unless, there was a celng effect present at ths tme, whereby alertness was already too hgh to be boosted further. REFERENCES 1. Arendt J, Wetterberg L, Heyden T, Szonenk PC, Panner L. Radommunoassay of melatonn n human serum and cere" brospnal flud. Horm Res 1977;8: Wetzman ED, Wenberg U, D'Eletto R, Lynch H, Wurtmann RJ, Czesler C, Erlch S. Studes of the 24 hour rhythm of me I a tonn n man. J Neural Transm I 978;Suppl 13: Akl1rstedt T, Froberg 1, Frberg Y, Wetterberg L. Melatonn excreton, body temperature and subjectve arousal durng 64 hours of sleep deprvaton. Psychoneuroendocrnology 1979;4: Cramer H. Melatonn and sleep. In: Popovcu L, Asg:ln.13, Badu G, eds. Sleep 78. Basel: Karger, 1980: Waldhauser F, Saletu B, Trnchard-Lugan L. Sleep laboratory nvestgatons on hypnotc propertes of melatonn. Psychopharmacology 1990; 1 00: Leberman HR. Behavor, sleep and melatonn. J Neural Tttnsm I 986;Suppl 21: Vollrath L, Semm P, Gammel G. Sleep nducton by ntranasal. applcaton of melatonn. Boscences1981 ;29: Arendt J, Borbely AA, Franey C, Wrght J. The effects of chronc small doses of melatonn gven n the late afternoon on fatgue n man: a prelmnary study. Neurosc Lett 1984;45:3IT Lewy AJ, Wehr TA, Goodwn FK, Newsome DA, Markey SP. Lght suppresses melatonn secreton n humans. Scence 1980; 210: Horne JA. Why we sleep; the functons of sleep n humans and other mammals. Oxford: Oxford Unversty Press, II. Horne JA, Burns F, Arendt J. Effects of hgh ntensty lght flash on melatonn output, sleepness, and vglance performance durng 36 h sleep deprvaton. Abstracts of the 8th European Con- Sleep, Vol. 14, No.3, 1991

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