The Effect of L-Tryptophan on Daytime Sleep Latency in Normals: Correlation with Blood Levels

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1 Sleep 12(4): , Raven Press, Ltd., New Yrk 1989 Assciatin f Prfessinal Sleep Scieties The Effect f L-Tryptphan n Daytime Sleep Latency in Nrmals: Crrelatin with Bld Levels C. F. P. Gerge, T. W. Millar, P. J. Hanly, and M. H. Kryger Sectin f Respiratry Medicine, University f Manitba, Winnipeg, Manitba, Canada Summary: L-Tryptphan, an essential amin acid, is readily cnverted t sertnin, which is thught t be imprtant fr expressin f slw wave sleep and pssibly rapid eye mvement (REM) sleep. A vast but ften cnfusing literature exists n L-tryptphan effects n inducing, maintaining, r altering sleep. In this study we measured the effects f L-tryptphan n bjective (multiple sleep latency) and subjective [Stanfrd Sleepiness Scale (SSS)] measures f sleepiness and examined their relatinship t bld L-tryptphan levels. Ten healthy vlunteers (eight men and tw wmen; mean ± SD age 34 ± 1 years) received placeb r 1.2 r 2.4 g f L-tryptphan n separate days in randm duble-blind fashin. Sleep latency and SSS were measured initially and at 6 and 12 min after ingestin. Bld and urine were cllected at regular intervals. Cmpared with placeb bth L-tryptphan dses reduced sleep latency at 1 h, with the reductin persisting at 2 h fr the 2.4-g dse nly (p <.5). There was a psitive crrelatin between subjective and bjective sleepiness measures but nly with the 2.4-g dse (rs =.76, p <.1). There was a highly significant crrelatin between bld L-tryptphan and sleep latency at,6, and 12 min in all subjects fr all drug cnditins (r =.276, df = 79, p =.13). Very small amunts f free L-tryptphan r its metablites were fund in the urine, with the exceptin f kynurenic acid. We cnclude that L-tryptphan cnsistently reduced sleep latency in nrmals and that this crrelates with bld levels. Increased urinary excretin f kynurenic acid suggests that bld kynurenic acid was similarly elevated and that kynurenic acid, given its inhibitry effects n excitatry neurtransmissin, may pssibly be invlved with inducing sleep. Key Wrds: L-Tryptphan-Sleep latency Sleepiness-Kynurenic acid. Since Juvet's early wrk, it has been suggested that sertnin and its cngeners are in sme way respnsible fr slw-wave sleep (SWS) and fr the priming f paradxical r rapid eye mvement (REM) sleep (1,2). L-Tryptphan is an essential amin acid that Accepted fr publicatin March Address crrespndence and reprint requests t Dr. C. F. P. Gerge at Victria Hspital, 375 Suth Street, Lndn, Ontari, Canada N6A 4G n 1 February 218

346 C. F. P. GEORGE ET AL. is readily cnverted t 5-hydrxytryptamine r sertnin. Thus, a vast literature has emerged n L-tryptphan effects n sieep inductin, sieep maintenance, and sleep architecture.

2 346 C. F. P. GEORGE ET AL. is readily cnverted t 5-hydrxytryptamine r sertnin. Thus, a vast literature has emerged n L-tryptphan effects n sieep inductin, sieep maintenance, and sleep architecture. A wide range f dsages has been used in a wide variety f subjects, including nrmals, insmniacs, and patients with psychiatric illnesses. Unfrtunately, the results have nt been cnsistent and s it is nt clear hw effective L-tryptphan is fr inducing r maintaining sleep r altering the distributin f sleep stages. Fr sleep architecture changes with L-tryptphan, sme authrs shw n effect n SWS r REM with lw dses «5 g) (3-7), a mdest increase in SWS and/r decrease in REM with an intermediate dse (5-9 g) (8-11), and paradxical results, i.e., decreased SWS and increased REM with higher dsages (1--15 g) (8,9). In examining the effects n sleep latency, the ncturnal administratin f L-tryptphan is cmpunded by the usually shrtened sleep latency at bedtime. It has been suggested that L-tryptphan simply lwers the arusal threshld during the waking state t permit mre rapid sleep nset (7). It is als pssible that the effect f L-tryptphan n sleep is nt related t sertnin at all. Sme ther L-tryptphan metablic byprduct may have an effect n sleep. Fr example, ne f the majr metablic end prducts f L-tryptphan metablism is kynurenic acid. This agent has the effect f brad-spectrum inhibitin f excitatry amin acid neurtransmissin at the N-methyl-D-aspartate (NMDA) and nn-nmda receptrs (12). Mst if nt all studies have measured sleep latency and subsequent sleep architecture after L-tryptphan dsing withut interrupting the sleep. As such, there is little r n infrmatin n L-tryptphan effects n sleepiness as bjectively measured with the Multiple Sleep Latency Test (MSLT). Accrdingly, we wanted t examine the effects f L-tryptphan, if any, n sleepiness as measured by a mdified MSLT during the mrning hurs, when sleepiness is at a minimum. In additin, we measured bld L-tryptphan t examine its relatinship t bjective (sleep latency) and subjective (Stanfrd Sleepiness Scale) (SSS) measures f sleepiness. L-Tryptphan is readily available in many cuntries frm' 'health fd stres. " Since the dsage used is usually lwer than reprted in the literature, we studied dsages likely t be used by patients. METHODS We recruited 1 healthy vlunteers (eight men and tw wmen; mean ± SD age 34 ± 3.3 years) wh gave n histry f sleep disrders. Plysmngraphy r daytime MSLT testing was nt perfrmed prir t the study, but a sleep histry was btained and subjects maintained their usual sleep-wake cycle fr the duratin f the study. One subject reprted his nrmal sleep perid time as nly 5 h. Hwever, he denied any daytime smnlence, s was cnsidered at the utset t be a shrt sleeper. In a randm duble-blind fashin, each subject received placeb r 1.2 r 2.4 g f L-tryptphan in tablet frm n separate days after an vernight fast. Subjects reprted t the sleep labratry at 8 h after their usual night's sleep at hme. The nly intake permitted was water until all samples were btained (16 h). Surface electrdes were applied t measure electrencephalgram (EEG) (C3-A2, C3-2), submental electrmygram (EMG), and electrculgram (EOG) and a heparin-lcked intravenus line was established t allw repeated bld sampling. Measurement f sleep latency time (SLT) was recrded at 9, 1, and 11 h accrding t standard prtcl (13). Sleep was nt permitted t accumulate between nap times. Subjects ingested placeb r drug Sleep, Vl. 12, N.4, 1989 n 1 February 218

3 L-TRYPTOPHAN AND DAYTIME SLEEP LATENCY 347 with water just prir t the first nap and subjective ratings f sleepiness were recrded befre each nap using the shrt SSS (14). T determine the absrptin, distributin, and excretin f nnmetablized L tryptphan, bld and urine were cllected ver the curse f each test day. Bld was cllected just prir t ingestin f placeb r drug (time ) and 3, 6, 8, 95, 15, 12, ISO, 18, 24, and 36 min thereafter. Urine was cllected at 6, 24, and 48 min, the vlumes measured and runded t the nearest 1 ml. Serum and urinary L-tryptphan levels and urinary metablites f L-tryptphan were measured by high pressure liquid chrmatgraphy using a mdificatin f the methd f Pfeifer et al. (15). Serum L tryptphan measurements were btained after filtratin t remve residual prtein. Accrdingly serum measurements are fr free L-tryptphan. Statistical analysis included analysis f variance fr effects f subject, dsage, and time n SLT, while nnparametric crrelatin assessed the relatinship between bld level f L-tryptphan, SLT, and SSS. RESULTS Sleepiness The individual results f the SL Ts and the SSS are shwn in Table 1. One subject had a sleep latency cnsistently <5 min, which is in the pathlgical range, and he was excluded frm the analysis. This subject (a physician) wuld regularly allw himself nly 5 h f sleep per night. While we initially thught he might just be a shrt sleeper, his shrt sleep latencies were attributed t sleep deprivatin. Figure 1 shws the mean SLTs fr placeb and tw dses f tryptphan. Bth dses (1.2 and 2.4 g) prduced a significant reductin in sleep latency cmpared with placeb at 1 h, with the reductin persisting at 2 h fr the 2.4-g dse nly (p <.5). The relatinship between subjective and bjective measures f sleepiness is shwn in Fig. 2. Here we are lking at the change in SL T between naps and the crrespnding change in SSS. Fr SSS, an increasing scre (frm 1 t 7) relates t increasing subjective sleepiness; thus, a negative change in SSS between naps indicates increasing subjective sleepiness. Cnversely, fr SLT a decreasing value (frm 2 t 1) indicates increasing sleepiness and will be reflected by a psitive change in SLT between naps. Gruping all three drug cnditins tgether, there was an verall psitive crrelatin between subjective and bjective measures f sleepiness (rs =.44, p <.5). Hwever, taking each cnditin separately, this was statistically significant nly fr the 2.4-g dse (rs =.76, p <.1) (Fig. 2), despite a similar reductin in sleep latency with the 1.2-g dse (rs =.37, p = NS) (Fig. O. There were n adverse effects frm the tryptphan althugh fur subjects reprted a mild transient headache with the 2.4-g dse. Bld levels Bld levels are shwn in Fig. 3. After ingestin f 1.2 g, peak level was at 6 min. Peak bld level fr the 2.4-g dse was at 15 min. Interestingly, the bld level at 6 min was virtually the same fr bth dsages. Our results are cnsistent with thse f Yuwiler et al. (16) wh used a dse f 5 mg/kg f tryptphan. We examined the crrelatin between L-tryptphan bld level and sleep latency at, 6, and 12 min in all subjects fr all cnditins. This relatinship was highly significant (r = , df = 79, p =.126). Hwever, nly 8% f the variability f SLT was explainable by the variability in abslute tryptphan bld level. Thus, we n 1 February 218 Sleep, Vl, 12, N, 4,1989

4 348 C. F. P. GEORGE ET AL. TABLE 1. Results f sleep latency test (SLT) and Stanfrd Sleepiness Scale (SSS) SLTO SLTI SLT2 Subject SSSO SSSI SSS2 (min t sleep nset) Placeb MK IS PH ZP2 I I TMI VSI JLl SR CG3 I CF2 I Mean SO L-Tryptphan 1.2 mg MK PHI ZPI I I I TM2 I VS JL SR CG CF Mean SO L-Tryptphan 2.4 mg MKI PH IS.O IS.O ZP TM3 I VS JL IS.O SRI S CGI CFI Mean SO als examined the relatinship between the change in tryptphan level frm the preceding nap versus the change in sleep latency frm the preceding nap. Thus, fr each subject fr each cnditin, we had the fllwing tw sets f data pints: (a) L tryptphan level (6 min - min) sleep latency (6 min - min) and (b) tryptphan level (12 min - 6 min) sleep latency (12 min - 6 min). The relatinship between the change in tryptphan level was significantly crrelated with the change in sleep latency (r = -.284, df = 54, p =.37). Very large increases in L-tryptphan levels between naps did nt appear t further reduce sleep latency. Indeed, if ne excludes the larger internap tryptphan changes (exceeding 5 mg/l) frm analysis, then a much better crrelatin exists (r = -.434, df = 41, p =.36). Urine levels Very little free tryptphan appeared in the urine in the 8 h after ingestin: 12.9 ± 4.2 mg after placeb, 27. ± 1.1 mg after 1.2 g (representing 2.3% f the ingested dse), Sleep. Vl. 12. N n 1 February 218

5 L-TRYPTOPHAN AND DAYTIME SLEEP LATENCY I/) c: -"e > Z w I- <t..j 8 a.. W W..J C/) 4 * 6 12 TIME AFTER INGESTION (mins) FIG. 1. Sleep latency at baseline (time ) and 6 and 12 min after ingestin f placeb r tryptphan (TRYPT). **p <.5 fr bth dses cmpared with placeb; *p <.5 fr 2.4-g dse (e) cmpared with 1.2-g dse (6) r placeb (). and 27.5 mg after 2.4 g (representing 1.1% f the ingested dse). With the exceptin f kynurenic acid, there were very small amunts f ther L-tryptphan metablites in the urine (Table 2). Urinary 5-hydrxyindleacetic acid increased with dse f L tryptphan, but the levels were all lw and within the accepted nrmal range f 1-5 mg/24 h. We fund a marked increase in urinary excretin f kynurenic acid in the 8 h after ingestin f L-tryptphan (ttal excretin: 1.89 ± 2.96 mg after placeb, ± mg after 1.2 g, and 37.8 ± mg after 2.4 g). The ttal urinary excretin f bth L-tryptphan and kynurenic acid was highly significantly crrelated with peak bld L-tryptphan during the study perid (r =.5865, df = 28, p =.6 fr tryptphan; r =.5476, df = 28, p =.17 fr kynurenic acid). There was als a very high crrelatin between urinary excretin f tryptphan and kynurenic acid (r =.5568, df = 28, P =.14). Urinary 5-hydrxyindleacetic acid, the main final metablic byprduct f sertnin, was nt crrelated with either peak L-tryptphan bld level (r =.27, df = 28, P = NS) r ttal urinary excretin f L-tryptphan (r =.18, df = 28, p = NS). A detailed examinatin f the pharmackinetics f the L-tryptphan metablic prducts is being cnducted. DISCUSSION Daytime sleepiness is nrmally minimal during the mrning hurs. By administering L-tryptphan in the mrning and subsequently measuring sleep latency, we felt that any effect f L-tryptphan wuld be easily discernible at that time. The results shw that sleep latency was cnsistently reduced with L-tryptphan in this shrt-term experiment. This reductin cincides with a rise in serum tryptphan, and as the serum level n 1 February 218 Sleep. Vl. 12. N

6 35 C. F. P. GEORGE ET AL. PLACEBO TnvnT 4 " Inlr I I.' TRYPT U) 6 16 «>- Q, D Z r=o.22 r=o.37 r=o.76 iii Z 8 p=ns 8 P-Os 8 p<o.5 W [, [ W == E [ [ [ W [ [ [ 6...I >- [ Q, [ [ U) Z iii [ I/) -8-8 [ W.!! [ Z I/) [ «::I: I I, I, I, I less sleepy mre sleepy less sleepy mre sleepy less sleepy mre sleepy CHANGE IN SSS BETWEEN NAPS FIG. 2. Relatinship between bjective (sleep latency time; SL T) and subjective (Stanfrd Sleepiness Scale; SSS) measures f sleepiness fr the three cnditins (symbls same as in Fig. I). Changes in SSS and SL T are the differences between successive tests fr each: i.e., (SSSO - SSS1), (SSS1 - SSS2), (SLTO - SLTl), (SLTI - SLT2). An increase in sleepiness is indicated by a negative SSS and a psitive SLT. r, Spearman rank crrelatin; TRYPT, tryptphan. falls, the sleep latency returns tward baseline. These results are cnsistent with the hypthesis that L-tryptphan mediates increases in sertnin and thus facilitates sleep nset. If this were the case, the previus vast literature shuld all be cnsistent. Hwever, mst previus studies with L-tryptphan have nt measured serum r plasma levels and nly a few have measured urinary excretin f metablites. Accrdingly, variatins in absrptin and metablism f L-tryptphan might give widely varying bld levels and accunt fr a gd deal f the variatin in the previus literature. By measuring bld levels frequently between naps, we culd establish a relatinship between serum L-tryptphan and sleep latency. As well, mst studies with ingestin f L-tryptphan at bedtime have nt been cnducted after 8 h f fasting. L-Tryptphan ingestin in the fasting state, as in ur case, may well be imprtant in determining the amunt f tryptphan available fr metablism and neurtransmitter synthesis in the brain. Extensive wrk by Wurtman and clleagues (17-2) has shwn that the cmpsitin f fd intake influences amin acid transprt acrss the bld-brain barrier. Fr large neutral amin acids (such as tryptphan, tyrsine, phenylalanine, leucine, isleucine, and valine), there is a single carrier mlecule fr which each amin acid must cmpete. Since there is much less tryptphan in mst prteins than the ther large neutral amin acids, a high-prtein meal will reduce the rati f try;jtphan t cmpeting amin acids and less tryptphan will crss t the brain fr subsequent metablism. Cnversely, a Sleep, Vl. 12, N.4, 1989 n 1 February 218

7 L-TRYPTOPHAN AND DAYTIME SLEEP LATENCY ::::::: m E -Z <t :E:.... > a:: c..j rn TIME AFTER INGESTION (mins) FIG. 3. Mean bld tryptphan (TRYPT) level changes with time fr placeb and bth dses f L-tryptphan (symbls same as in Fig. I). high carbhydrate meal has the ppsite effect because the insulin secreted in respnse t carbhydrate reduces the plasma level f cmpeting amin acids mre than it des tryptphan. While we did nt measure the serum cncentratins f the cmpeting large neutral amin acids, it is quite pssible that the rati ftryptphan t ther amin acids was increased by ingesting L-tryptphan in the fasting state. This wuld have facilitated increased bld-brain transprt and increased metablism t sertnin and ther neurtransmitters. Besides being readily metablized t sertnin, L-tryptphan can underg cmplete TABLE 2. Urinary L-tryptphan metablites 8 h after ingestin Cnditin Cmpund 5-Hydrxy tryptphan Aminhippuric acid Indle-3-lactic acid Indle-3-acetic acid Indle-3-prprinic acid 3-Hydrxyacetic acid 5-Hydrxyindleacetic acid 3-Hydrxykynurenine Kynurenic acid Kynurenine Xanthuric acid Placeb.8 (1.).3 (.5).2 (.6) 1.9 (2.9).1 (.2).3 (.5) L-Tryptphan 1.2 mg 4.6 (7.5).4 (1.2) 2.3 (3.3).3 (.2).5 (.5) 6.1 (.2) 17.9 (15.7).2 (.4).9 (1.1) L-Tryptphan 2.4 mg.1 (.3) 2.6 (3.9) 3.5 (6.6) 2.9 (5.9).7 (1.4).7 (.7) 2.3 (3.5) 37.1 (15.2) 2.8 (3.3) 4.1 (3.9) Values are means (SD). n 1 February 218 Sleep. Vl. 12. N

8 352 C. F. P. GEORGE ET AL. catablism via the enzyme tryptphan pyrrlase and the kynurenine pathway. In peripheral tissues, the metablism f tryptphan by this pathway is abut half as much as the rate f tryptphan t sertnin (21), while in the pineal gland, kynurenine accunts fr 32% f all tryptphan metablites (22). Althugh at the utset we did nt think t measure serum kynurenine levels (r ther serum intermediate metablites f the kynurenine pathway), we did nte a marked increase in urinary kynurenic acid with L-tryptphan ingestin. This suggests that the bld kynurenine levels were similarly increased and we might expect brain levels t shw an increase. A brain kynurenine increase is pssible either by directly crssing the bld-brain barrier (as it des in animals) (21) r by increased metablism f tryptphan since cerebral tryptphan pyrrlase can be induced by a tryptphan lad. Since kynurenic acid is a brad-spectrum inhibitr f excitatry amin acid neurtransmissin, it might pssibly be having an effect n sleep. We acknwledge, hwever, that this is speculatin since we d nt have any serum r brain kynurenine levels. Our gal was nt t address the cmplex neurtransmitter interractin invlved in sleep nset and the expressin f sleep stages. Instead we chse t examine shrt-term effects n sleep latency and cncmitant changes in serum L-tryptphan. Subjective measures f sleepiness (SSS) paralleled the bjective measures (SLT), but nly with the 2.4-g L-tryptphan dse. Despite similar bld levels and reductins in sleep latency at 6 min pst L-tryptphan, nly fur subjects rated themselves mre sleepy with 1.2 g L-tryptphan while eight subjects gave a higher SSS at 6 min with 2.4 g L-tryptphan. Althugh there was a highly significant relatinship between abslute L-tryptphan bld level and sleep latency, nly 8% f the variability in sleep latency was explainable by the variability in abslute L-tryptphan level. This suggests that factrs ther than abslute L-tryptphan bld level are imprtant cntributrs t sleepiness. The design f the experiment des nt permit identificatin f these factrs. In summary, L-tryptphan given t nrmals cnsistently reduces sleep latency and this crrelates with the bld level at the time. Change in subjective sleepiness mirrrs the reductin in sleep latency but cnsistently nly with the larger dse despite similar bld levels. Increased urinary excretin f kynurenic acid suggests that bld levels were similarly elevated. Given the knwn inhibitry effects f kynurenic acid n excitatry amin acid neurtransmissin, it is pssible that it is invlved in sleep nset. Further wrk is necessary t determine if kynurenic acid is invlved in any way with sleep. In nrmals, L-tryptphan may be useful fr sleep inductin. REFERENCES 1. Juvet M. Mechanisms f the states f sleep. A neurpharmaclgical apprach. In: Kety SS, Evarts EF, Williams HL, eds. Sleep and altered states f cnsciusness. Baltimre: Williams & Wilkins, 1967: Juvet M. Bigenic amines and the states f sleep. Science 1968;163: Hartmann E, Cravens J, List S. Hypntic effects f L-tryptphan. Arch Gen Psychiatry 1974;31: Oswald I, Ashcrft GW, Berger RJ, Ecclestn D, Evans n, Thacre YR. Sme experiments in the chemistry f nrmal sleep. Br J Psychiatry 1966;112: Adam K, Oswald 1. One gram f L-tryptphan fails t alter the time taken t fall asleep. Neurpharmaclgy 1979;18: Nichlsn AN, Stne BM. L-Tryptphan and sleep in healthy man. Electrencephalgr Clin Neurphysil 1979;47: Spinweber CL, Ursin R, Hilbert RP, Hilderbrand RL. L-Tryptphan: effects n daytime sleep latency and the waking EEG. Electrencephalgr Clin Neurphysil 1983;55:652...Q1. 8. Wyatt RJ, Engelman K, Kupfer DJ, Fram DH, Sjerdsma A, Snyder F. Effects f L-tryptphan (a natural sedative) On human sleep. Lancet 197;2:842...Q. Sleep, Vl. 12, N.4, 1989 n 1 February 218

9 L-TRYPTOPHAN AND DAYTIME SLEEP LATENCY Griffiths WI, Lester BK, Culter ID, Williams HL. Tryptphan and sleep in yung adults. Psychphysilgy 1972;9: Kmer E, Bertha G, Flh E, Reinhart B, Wlf R, Lechner H. Sleep-inducing effect f L-tryptphan. Eur Neurl 1986;25(suppl 2): Williams HL, Lester BK, Culter JB. Mnamines and the EEG stages f sleep. Act Nerv Super (Praha) 1969;11 : German IM, Pitts LH, Meldrum BS, et al. Kynurenate inhibitin f cell excitatin decreases strke size and deficits. Ann Neurl 1987;22: Carscadn MA, Dement WC, Mitler MM, Rth T, Westbrk PR, Keenan S. Guidelines fr the Multiple Sleep Latency Test (MSLT): a standard measure f sleepiness. Sleep 1986;9: Hddes E, Zarcne V, Smythe H, Phillips R, Dement WC. Quantificatin f sleepiness: a new apprach. Psychphysilgy 1973;1: Pfeifer R, Karl R, Krpi I, Burgyne R, McCurt D. Practical applicatin f HPLC t amin acid analysis. Am Lab 1983;15: Yuwiler A, Brammer GL, Mrley IE, Raleigh MJ, Flannery IW, Geller E. Shrt-term and repetitive administratin f ral tryptphan in nrmal men. Arch Gen Psychiatry 1981 ;38: Fernstrm JD, Wurtman RI. Brain sertnin cntent: physilgical dependence n plasma tryptphan levels. Science 1971;173: Fernstrm JD, Wurtman RI. Brain sertnin cntent: increase fllwing ingestin f carbhydrate diet. Science 1972;174: Fernstrm JD, Wurtman RJ. Brain sertnin cntent: physilgical regulatin by plasma neutral amin acids. Science 1972;178: Wurtman RI. Precursr cntrl f transmitter synthesis. In: Barbeau A, Grwdn JH, Wurtman RJ, eds. Nutritin and the brain. New Yrk: Raven Press, 1979: Gal EM, Sherman AD. L-Kynurenine: its synthesis and pssible regulatry functin in brain. Neurchem Res 198;5: Fujiwara M, Shibata M, Watanabe Y, et al. Indleamine 2, 3-dixygenase. Frmatin f L-kynurenine frm L-tryptphan in cultured rabbit pineal gland. J Bii Chem 1978;253: n 1 February 218 Sleep, Vl. 12, N.4, 1989

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M.R.C.Path. causes to the raised plasma urea in patients admitted Pstgradcuate Medical Jurnal (January 1979) 55, 1-14 The cause f the raised plasma urea f acute heart failure R D THOMAS MRCP D B MORGAN MRCPath ALISON NWILL AIMLS Departments f Cardilgy and Chemical Pathlgy,