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“( June 21, 1996- . #
: —— ___ “uEcEIvEcI BY rHC OFFICE (IF sp~f~L wR/TK)HA~&-n~..,:$-~.so ~ETAPHARW Natural PreventiveHcahhcare xAmlPluqkc WJCXSCY Ayi)uc, B..Sui@l”. ~u~~i~ New Bnmsvick. Nl W901.3279:.. “( ( June 21, 1996- Dr. Ekabeth; Yetky, Director 0i3ice of Special Nutritional HFS450 Center for Food Safety and Applied Nutrition Food and Drug Administration 200 C StrX N.W. Washington D.C. 20204 . # ● :. Dear Dr. Yetley Notkeis hereby given purmant to the requirements ofSection403(r)(6) (21 U.S.C. 343 (r)(6)) oftheFedeml F@ Drug and Cosmetic Act of Statements of nutritional support which have been made on the label and in the labeling in connection with the marketing of the dietary supplement Melatonin1mgwithViB-61 mg @let Mektonin 1 mg with Vitamin B-6 1 mgtabl~ packagedin blister ptlOkwill be first marketed with these statement of nutritional support on July 1, W96. The statements of nutritional support areas follow . Bliiter Pack ~bel: For restoring normal sleep in individuals whose natural melatonin has been take 1 tablet at bedtimq or as directed by your health care profmsional. DIRECTION& alt- WARNINGS: TAKE ONLY ONE TABLET PER DAY. NOT FOR CHILDREN UNDER 18. DO NOT USE IF PREGNANT OR NURSING, OR IF TRYING TO CONCEIVE (BOTH MEN AND WOMEN). FOR RELIEF OF OCCASIONAL SLEEPLESSNESS. IF SLEEPLESSNESS PERSISTS CONTINUOUSLY FOR MORE THAN 2 WEEKS, CONSULT YOUR DOCTOR DO NOT TAKE THIS PRODUCT IF YOU ARE TAKING SEDATIVES OR TRANQUILIZERS OR UNDER MEDICATION WITHOUT CONSULTING YOUR DOCTOR (SEE ENCLOSED INSERT).* 97s”o/4- .’ - /--=- Dr. Ebabeth Director Oflice of Special Nutritional Page 2 June 21, 1996 & Yetky, . -. . Melatonin helps regulate your sleep cycle resultingin quality sleep. This is espeokdly useiid for travel- and shift workers. This product is also an excellent. source of vii B-6 yhich is needed for your body’s natural abiity to produce mehitonin.* x-~ sTA~ S HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMLNISTIUTION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE, TREAT, CURE, OR PREVENT ANY DISEASE. A Label copy is attached. Labelings: Number 1: Introducing Melatonin with Wamin B-6 Nutritional Supplement* We are pleased to offkr Melatonin - Low Do= containing lmg of Melatonin and lmg of Vkunin B-6. ● ● ● ● Melatouin: Helps to regulate the onset and quality of sleep, especially in those individuals whose natural abiity to produce melatonin has been altered.” I%w-Dosage Because consumer safety is our primary conce~ lmg effective ,. dose. our Melatonin comes in a Vitamin B-6: Maintainsthe body’s mtural abiity to produce Melatonin. For Shift Workers and Travelem: Mdatonin is particularly usefid for those who have their light patterns disrupted-such as shiil workers, travelers across time zon~ and individuals with dficulty ad~sting to seasonal changes in dayh.ight length. .“, - Dr. Ekabeth A Yetky, Mreotor OfEce of Special Nutritional Page 3 ~ June 21, 1996 -. . ● Lower-Dose Option: Tablets are scored for the option of 0.5mg. em s’rA~ . HAVE NOT BEEN EVALUATED BY THE FOOD ANDDRUG ADMINISTRATION. THIS PRODUCT IS NOT INTENDEDTO DIAGNOSQ TREAT, CURIjOR PREVENTANY DISEASE. ● A Labeling copy is attached. 1. Dollins et al. Effkct of inducing nooturmd serum melatonin concentration in daytime sleep, rno@ bodytemperaturej and pdormance. ProcNatl Acad Sci USA 1*,91:1824-1828. 2. Zhdanova et al. Slgep-induc%g eflbots of low doses of melatonin ingested in the evening. ClinPharmacol Ther. 1995;57:5512-S58. Number2and3: - There’s melaton@ and now there’s MeIatonin from XetaPharmTM,IK Melatonin helps regulate your sleep oyclq resulting in quality sleep. This is especially uselid for traveks and shiil workers. Also, as you age your body’s production of melatonin slowly decrm ofbm leadingto sleep dkurbanoes. Soientitic data indioates that supplementing witli melatonin may help prevent th-esesleep disturbances.* This product is also a source of Vi produce melatonin.* B-6, which is needed for your body’s natural ability to Our Melatonin Low Dosage* ● ● Because consumer tiety is our primary condose112. Tablets are scored for the lower-dosage our Melatonin mmes in an effective lmg option of 0.5mg. r . Dr. Ekabeth A Yetley, Director Office of Special Nutritional Page 4 June 21, 1996 .. . Purest Grade* . ● ● ● Pr6duct is prepared with the purest grade of Melatonin and Vi . B-6 av@able. . Fiied products are tested for potency, puxity, weight variatio% disintegration%and dissolution as per Nutritional Supplemen@ Uni&dSt@s Pharmacopoeia(USP). fl Products are manufktured with the same care and quality control necessary for a pharmaceutical product. ~ STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE TREAT, CURE OR PREVENT ANY DISEASE. Labeling copies are attached.’ 1. Dollins et al. E&xx of inducing nocturnal serum melatonin concentration in daytime sleep, mod body temperature and pefiormance. Proc Natl Aoad Sci USA 1994;91: 1824-1828. 2. ZManova et al. Sleep-inducing effkzts of low doses of melatonin ingested in the evening. Clin Pharmacol Ther. 1995;57:5512-558. Very truly yours, Xet.aP~ Inc. A subsidiary of Xeche~ International Inc. ~“ Ramesh ChandraPandey, Ph.D. President and CEO .! ! . . . ...’ ... .. : . .. :. ., .. . . .:”:. : ., :.,:. ... .!. .. .4> .7. ‘.. . .. . ,,. . ... .. . ... ~:, . ...:.i .“. , . .. . ,:’ .. >.. :>. , . .8 :.. . . ...... .. . .. ... .. .. .... .. .. ... .. * ... .) .;- .: “. . . . . L :.” ;. “.. . . . t. . . . . ... . ‘“~~. 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J.‘. .“ . . . . . . . . .. . . . . . . . .. .. . -. ,.. .:. ... ... .. .... . . . . .—. .. —.-. —.- ——— ——— ,-—.— $w--F-E - —- —-- . ... . .. . . * .. “, .. . ... ... . , ✎ ‘... . . ----- ;-. . . . .. ✎ ✎✎ . .. . .. . . . . . .. < -. _. .-_. “.W*W. -.. .-.. . . - .. .... . .. . “. ... ; : - . . . .... >.:. . .. . . ..... . . . .. .. . . mst=lwd Amm@pcrmld %MyvdM wt&dn M *wwaoIo$wktd @kbsnatdxmwckfInl%lq&a@~ steakmdsoawnsaafa 6t#4kk, ,.. Fmrk&awcdofq —---.——. wwmUwsamamy. .. . .. . . . . - . . ---- .... . .. . .. . . . ... . . . . . . ..... . . . . . .. .- .......:.<..: .. .-..— < .. -.. .. ... -.....’---7? ..-. .... ,. ..-. . . .==+.. . . There%mel.atoniq and now therek Melatonin fkomXetaPharnf’,Inc Melatonin helps regulate your sleep cycle, resulting b. quality sleep. This is especidy useful for tmvelem and shift workers. AISO,as you ag%your body%production of mclatonin slowly decmascs, often leading to sleep disturbances. scientific data indicates that supplementing with mclatonin my help p~ellt these Skp disturbances.* . . This product is also a source of Vhnin B-6, which is needed f;r”your body% natural ability to produce melatonin~ # Our MeIatonin ● Low-Dosage* Becauseconsumer safety is our primary concern, our Melatonin comes ● in an effective lmg dosel~. . Tablets are scored for the lowerdosage option of 0.5mg. Grade* Product is prepared with the purest grade of Melatoqin and ~lm B-6 avdable. Purest ● ● Finished products am tested for poten~, pmity, weight variatio~ disintcgratio~ and dissolution as per Nutritional Supplements, United States Phamtacopeia (USP). ● Products am mamdhctured with the same cam and QualitYcontrol ..- necessay for a pharmaceutical product. Gold Leaf EmIldchallenge -~l=w -afthisb&nd LsVawabti These statements have not been evaluated by the Food and Dmg Mmidstmdon. - This productis not inte+d @-&gnosqQeaL~ or pmv~t my disease ● - “-~~ outsidetcsttng kbomtoryintkworId. “Mektonin is available itz.bdes of 90 tublets, and ako in Travder Packs of 10 tubkts. To place your oni.ercdl Customer savice at 1-800-858-58S4 XETAPCIARM NaturalPreventiveHedthcare kc xdaPharm’1 A subsidiary ofxcchun. Intcrnatiod k. 100Jmcy Avenue Buildiig B. Suite 310 NCW Bmnswids NJ 08901-3279 TEL (908) 249-0133 FAX (90S) 2474090 OmmudOn 10dba4EUrxt0(indudng nmumd-aclltOda ~w=+.ti~y—w—m andpdemw% R’OcNdAad Sdum. 19M$M824-1628. zZh&muaal ~dbsdbwcbcaddawdn Thee 19%575S12-593 -b~qaklPlum—al Xud%umka-dxcdumhmzdmd,k Xalumkam@cml IrdemA. mnl XaaPh8mkam&mutiq dXuima Mcnw&xullnc. 1 ‘“ . .. . . .. . ..”. ““”, ‘“”. ‘... ... .. . . . . . . ::“... ... .... .. ....4.. ,., 2’ ,. . ., . .. ,,:.. ,, ..?.~, We are pleased to offer Melatonin-Low D= containing lmg of Melatonin and lmg of vitamin B-d. ● i , ,,, :,.,, ., S;CCC.Z.. ::.:<.: . . . ..., . . . . > . . . .. . .. .. . ... . ... .. , :..... .. ... ...:..,,. . ........ .... ..y.y.. . :!........... . . . ., .W <*.?. . . ... . . . #.. ,.... ... ...................... .,. ., Melatonim Helps to regulatethe onset and quality of sleep, especidy h those indivihls whose naturalability to produce pnelatonin hasbeen ahimd.1~ o ● . .. ● ● LOvv-Dosagc2Becauseconsumer safety is our Mekttonin &mprimary conq 4 . . . . .. .. . . . . . . . .. . . . . .. : ... %9-,. . ..d +. . . . .. . . . . and manufkcturhtg nutritional supplements as go into our phmmaceutial product% We measure quality w$h only one yardstick . .“ . ...”” Maintainsthe bodyk natural ability to produce Melatonin. ) We folIowastrictcode ofethicstnmgards to label Ch’CCtiOIIS, declarations of identity strength and purity, daily intake valu~ conditions of usq and warnings ● Purest Grade productis prepared with thepuxestgrade of Mekmoninand Vitamin B-6 avaitabk ● Potency, Puriw Pinished products are tested for potelq Pm’@ weight Vatiatioq disintegration and dissolution as per Nutritional Supplements, UMtedStates Phmmuc@a (usP). . For Shift Workersand Tkavelers ● hb T~e& Mommy control and test proeedurea are designed to assure that the componexmqin-process matetials, label% and finished products conform to appypiate Standatdaof identiq, stren~ quality, and purity . Fnmtx&Phann”, hlc & . . XetaPharnrdemands that the same rigid quality standards must go into developing Vitankt B-& Mehorh is particularly useful for those who have thetr light patterns dismptedsuch as shift workem, travelersacross time zones, and indMdds with diflkmlty adjusting to seasonal changes in Ck#nig,htlength. ,.,.,. .;.:. ● Low&Dose optioru .,,K, I, J!!? .*=fl oTablti are scored for the option of 0.5mg. A . . ...... .... .,, , . . NutritionalSu pkments, Hlarnlaceuticl standards. comes in a lmg effectivedose. . ,., .. .. . .. . . . . . . . .,.., IntroducingMelatoni.n with ~ltiilllh B-6 NutritionalSupplement* . ...... ... . ,,. .. ., when? Hfglmstanaank tm stunafmiFr- ) .-= n . . # ● 1. Dolhs et al. Effit of inducing nocturnal serum melatonin concentrations in daytime sleep, mood body temperature and performance. Proc. Natl. Acad. Sci. 91,1824-1828,1994. . pmt. Nad. Acad. Set USA Vd. 91, PP. 1824-1828.March 1994 physiology 3 Effect of inducing nocturnal serum melatonin concentrations in daytime on sIeep, mood, body temperature, and performance (ddi-df8@4vwW*dti) ANDREW B. DOLLINS*, IRINA V. ZHDANOVA,RtCHARDJ. WURTMANt, HARRY-J.LYNCH, AND M= H. DENG tkpmsn@ai Camnsu Bdsand Gxmisiw SdCGUS. MBSsdsussm tssstituteof Tedmotow. Cambsi@. MA tlZ139 tsicatedby Walk J. H. Nauta, November 23,1993 {received for review July 20, lk3) # We’examined effects of very kJW doses of ABsrRAcr mdatonin (0.1-10 mg,.oraiiy)or placebo, admiaktcrcd at1145 h, on sleep latency and duration, mood, performance, oral temperatuset and changes IISserum mcktonin kveis in 20 doubie-btiad healthy mate ~oluntecrs. A repeated—measure a bate of Latin square design was used. SubjectsCQmPiCtCKi tests designedWasstss moodand pClfO~CC between 0930 and 1730 h. The sedative-likeeffectsofmeiatonin wereascssed by a $impIedeep test at 1330 h subjectswere asked to bold a positive pressure switch ineachhand andtoreiaxwitbeyes dosed while recliningin ● qukt darkeaedroan Latencyand dumtion of switch release+indicatorsofskep, were measured. Areas under the timenwlatonin concentrationcurve varied in proportion to the different meiatoniadosrs ingested, and the 0.1- and 0.3-mg doses generatedpeak serum meiatonk kveis kveis that werewkhin the normalrangeofnocturd mdsstoaill b untreatedpcopk.M mektoaia doses tested s@iik@ly kcmascdskp duratioq as Wdiassdf-repod akepincasaad fdigq diltk to @ilCdIO.Moswwx, d of the doses s@ifand kallt!y &crcasd Skepousct latenq, oral tenlpcmm wiikboo ●dkory thcmsmbcrofco mcctrcsponsesoothe TigiMce task. Tbescdata ildicsStcthat oratiydmIukmd mclatoain an bcabighly pokothypaotic agcnqthcyako auggcstthatthepbsidogkdbcreas eimserum mdatodn kve&whkho ccumaround2100h daily,mayamstitutc Signal initiating normal Skcp ollseL ● serum mdat(min levels in normal humans ale Vuy low during most ofthc day but incmaacSignitlcantlyto a mean of 80 pg/ml (range,*MO) between0200and 0400h (1 pg/ml = 4.31 pmol/liter) and remaincl-~cd duringthe normaIhours Skal@y to daytime dues around ()$@ h (l). l%e physiologicalsi@kancc of the nocwmal incmasc in Of SkCf.), fai@ serum mdatonin could derive tim acute effects of the hormone [e.g., its ability to reduce core body temperature Q). ~ter tie~o~htion (3), modiiy brain kveis of m- 1 amine neurotmnsmittcrs (4), stimulate prolactin accretion (S), or induce skcpincss (6, 7)]. . Altcmativcly, the nocturnal increase-in serum mdatonin could constitute a time sig@, affecting the temporal characteristics of other circadian rhythms. Oscillations in the concentmtion of circulating mdatonin could directly affect ckadian rhythms (8, 9) or could provide humorai coinmunication of information about environmental lighting (and thus about time of day), which entrains endogenous physiological and behavioral rhythms (e.g., those associated with photopcriodism or scasonaiity; ref. 10). some studies also suggest a role for mciatonin in human development. The decrease in amplitude of the melatonin rhythm, which occurs late in the 1st decade of life, has been proposed as a factor contributing to pubescence (11), while further decrease, of this suticlc The poblicdon COSIS payment. This tick ;- .-,-,.4 .--* w:,h were dcfsaycd in pas-sby page charge must tlwcfore bc hcsrby marked.“udvcrrismwsf*’ Ifl ! T < P $1774 .oTe Iv ,n ;mA;ea, C ,h;< far, which occurs after the 6th decade, &y contributeto dq tions in circadian rhythmkity reportedby the ddcrly (12). The acute cffbctsof exogenousmektonin on human k havior have &en studied onlYsporadiiy and have used mciatonin doses that rake scmm mdatonin levels well be- yond their normal nocturnalrange.IIXIS,LAu7nanetd “ (13) found that a dose (240 mg over a 2-h period) that raised serum meiatonin kvds several thousandfoldimpairedmood and pCIfOMWCC. More r’eccdy, wCfOUtId SiMiiWbdtatiorai changes after a cmnsidcrablylower dose of the hormone (10 mg),whii still raisedserumkveisto4050timcs thenormai noctumai kvci (i.e., 4072 pg/mi; ref. 14). The present study was designed to dctcrminc whether much lower daythne doses, which elevate serum mdatonin but keep these kvcla within the normal kvds Si@fkdy nocturnal range, arc @so Suflkient to produce abort-term bchavioraici%cts.Ifso,thiswouIdsuggcstaaitnikrrokfm thcnormalnoctumd iWrCaWinsctltmlWIxOOhkv& gave the mektodn atmidday (9amoreb noctumd=mcrcasc)andmcasmcdmpccf~ incss, and (indirectly) skcp onset. before the skcp M33THODS m MA’mRxUs TWcnty hcaithy male volunteers [mean age, 23.05 = 4.22 (SEM) .y~, range, 18-24 yCIU%] participate k)cfote admission to the study, each subjcctgavc his htformcdco~ hadaphyskai examination tocnsurc that bcwasitt~ to become health, and contpktui tWO M-b _acsskns fawithtcst.ing procedtues andtheperfortnaw testbattery. subjects Wre also screened f- depressive sytnptoms by using the -ton p@lktdC rat@ acak fm depression (M) with a special addendumfor seasonal affGctive disorder; any with a histo~ orfe of dcpmsskn were excluded. Ail subjects were paid for thdr participation in the experiment. The study was double blind and pIaccbo controU&. A rcpcatcd-mcasttrcs,within-subjects, 5 x 5 Latin square design w& used. TiIc subjects paticipatcd in five 8-h (093& 1730 h) testing sessions. At least 5 days elapsed between successive test sessions. Capsules containing 0.1,0.3,1.0, or 10mgof mciatonin orpiacebo wcm adtniniitcrcd odiy (p.o.) at 1145 h each test &y. Treatmentorder m determinedby the balanced Ixitin square design. Orai temperatures were measured hourly and biood was sampIed at rcgukr intervals via an indwdiii”venous catheter for subsequent serum melatonin measurement. Serum sampies were separated by centrifugation and stored at -WC Abbreviations: P.O., Odfi RT, SCSW+OO time; POMS, proiik of mocd sfaks; SSS. Stanford slccpincssscale. %-cscnt address: DoD Polygraph Institute, Bufi@ 3~5. FLMc~Cbn. AL 36205. -f’To whom rcpsint requests should bc ackksscd ac Massachusct~“lnstit,!te of Technolow. E2S-604. Cambridte. MA 02139. Physiology Dollins et af. ) Ptvc. NatL Acad. Sci. USA 91 (199$) undi thCYCOUMbc SSSSyCCt by radioinununoasaayfor melatanln (In. ‘fltroughout~est SCssions,aubjccts were requ”d to sit at wOfk*tiOtl with CYCSOpCSt.~C task _* qtm ordcrand time oftcsting WCrCheldconstant across test days. N instru@ons, performance tasks, and mood questionnaires were automated to rcducc the possttity of expcrilIWItCdtldUCCd bk. lk @WttWtCC tasks used WCf’C in-house and included rncasyrcs of (i) auditory vigilsncc(18), (ii) four-choi~ SCSC~On time (RT)(~)t (fi9 simPk RT. and(iv) symbol digit(modalities)substitution(20). Mood questknnaircs included the profde of mood states (POMS; rd. 21) am! the Stanford slqincss scale (SSS; ref. 22). &tails of the tasks and th+r administrationarc published clscwhcrc (24). The mood questionnaireswere compkted at 1030hand at hourlyintervalsbeginningat 1200h. The simple andfdur-choiceRTs andsymbol digitsubstitution tasks were compktcd at 1030,2300 MOO,1600,and 1700h. Theauditoty vigbcc task was adAtcrcd at 1200and 1400 h. Subjects were allowed to kave their workstations during lunch (a standardlunch was scnfcd bctwccn 1100 and 1130 h), toilet breaks (- rein), and duringthe half-hour skcp tcsc subjects participatedin a sleep test bctwccn 2330and 1400 h ‘Ilwy were asked to recline(oneither a bed or a nxlining coded . chair)and relax with their eyes closed in a quiet, darkened mom In each handthey held a l-in (254 cm) plastic tube that hose apositiveprcssurc switch. ‘fltcy were asked to test their hands, palm up, aIongside their body and to depress the awkchcs with the last segmentof their index f~ers. Rekasc oftiac swkch on cithcrtubc was nxordcd as a pca dcfkction oaan event rccdcr. An investigatorremainedin attendance that they followedinstructions. with the subjects to Cnsurc ~ Aa CVatt-tintersoknoid wss randomlyactivated to dUCC wotddbc thepossiiility thatthc aoftdkkof thesw itch mkonstmcd by the subjectsas a s“@dfkantevcnL After 30 m& the subjects were asked to stop relaxing and/or were awakened. They were then asked (i) if they f~ askep. (iin if m,ti@htakti Md=p, md(m@~W@wti SSS. Latency to switch rckasc was measured from the ~-of i~ction~cn~tionto the firatfidl minute of switch rclcasc. Total switchrckasc time was measuredas the total kngth of time a recording pcn was dcfkctcd (the atnallcat intctval of pcn deflection measured was 1 ttdn; WXWWY.OX rein). Onc subject med to rckasc a switch dudaga sleep test session butwas identified as asleep by his -d snofins. skp onset for WE subjcctwas rccotxkd as occwring afkcr 2 min of continuous snoring. When questioned later, the sub~ repotted that he had indeed fden *. The after-trcatmentdepcndcnt measures were each assessed by using a repeated-tncasurcs, Witiln-subjects. 5 x 5 Latinsquareanalysis. Orthogonalplannedcomparisons (23) west! used to evaluate dticrenccs among the melatonin/ treatment conditions when a significant (P c 0.0S) pbbo tmattnent effkct was found. The comparisons chosen were(i) placebo vs. all mclatonin treatments,(ii) 0.1 vs. 0.3.1.0, and 10 tngof mclatonin. (iii) 0.3 vs. 1.0 and 10 mg of melatonin, and (iv) 1.0 vs. 10 mg of melatonin. Pairwisc comparisons WCresubsequently calculated for these measures (rcpcatedmcasures t tests for the sleep test and melatonin data and ANOVAS for the other measures) because inspection of the daa suggested tha( the planned comparisons provided an insufiicien[ basis for interpreting results. Only main effects I that resulted in significant contrasts and interaction effects zuc reported. TI-JCm were some missing data due (o dficuhies with equipmen(. croup means were therefore subs(inned for the 1700-h (0.1 mg). 1300-h (1.0 mg), 1700-h (1.0 mg). and l~h (10 mg) Measures for subjects 15.03.16. ~d 15. ttspcctivc[y, on most pcrforrnancc measures. Blood samples WcrC not drown durina nlaccbo [cstin~ of subicct 01 due to -1825 difficulties with cathctcrization, and groupmeans were sub- stituted for the data. Group means of serummclatoninlevels were also substituted for six other mussingdata points. The Gteek syt@ol A ~ used to indicate “an avemge change of.,” . REsuLm-” , Suum Mctatosdn Levels. Mean serum melatonin levels arc ihstratcd in Fii. 1. The man (SEM) areas under the tirnmlatonitt conccntmtion curve (AUC) bctwccn 1000 and 1730 h for the placebo and 0.1-, 0.3-, 1.0-, and ltl-mg treatment conditions wcm 87.7 (5.11), 213.2 (2S.02), 4S99 (62.7), 2S99.0 (141.7), and 21,000.4 (37523), I’CSpCCtiV~y. Serum melatcminAUC differed significandyamong the five = 34.34; P C 0.001) and all treatment conditions (J74* planned contrasts were signKcant (P < 0.001). All painvisc comparisonswere also significant(P c 0.001).The order and treatment-by-ordercfkcts were not signikant. Mctatonin TYcatmcnt EffcctQ Sign&ant mclatonin treatment cffccta were found for otzdtcmpcratqm(Fw40 = 7.S0; P< O.UU);skcp test skcp-onset Iatency (F’(im = 6.6S; P < 0.001);skcp duration(F(fm = 7.80;P < 0.001);self-icportcd skc~nsct latency (F(f~ = 10.52;P C 0.(01): postskcp test SSS responses (Fwm = 3.11; P < 0.05) @ii. 2k ~MS vigor-activity (Fwa = 4.16; P < 0.01) and fatigue+crtia U?(4XOI = 3.M J’ < 0.0S) (F%. 3) rcspon-, SSS responses (Fa~ = 2.7%P< 0.0S); numberofcorrcct rcapottscson the WMnson auditoty vigilance task (F(f@j = 3.4Z P <0.0$, and four-choke RT response latency (F(fm) = 3.84; P < 0.01). Table 1 summarizes the planned compsrkoa results and Table 2 contains the mean (SEM) Iev+ measured. TIM treatment-by-order interaction effects were nonsignificant for alI mcasums”except the Sss (F(4#3 “ 4.68; P < 0.001). ‘nHc were no significant diffksencca among the baseline (1000h)otaltcmpcrature, SSSOorFOMs mcasm AttOtdCr cffcctwaa found among the four-choi~ RTrcsponac latency baadinc mcasuma (FH~ = 2S.23; P < 0.001), but the treatment and tmatmcnt-by+xdcr intctaclion effects were nons”-L As Table 2 indicates, response kvcls for some measures did not consktcmly incteasc or dcaease dative to serum mclatoninkvets. For cxampk, self-rcportqdSSS responses weregreatestandPOMSvigor-activityscaletesponscawere stnakst tics ingesting0.3 mg, rather than higherdosca, of mclatonin. Pahisc comparisonswere caktdatcd to aid in intcrp~tion ofthesedata. Meanoral tcmpcmtturcmcasurca werestgnifkantlykss, relativeto placebo,afteringesting1.0 and 10 mg of mc[atonin[A -0.24°F and -0.37F, rcspcc10000 E H = E > a. A 0.0 mg 0.1 mg p A o.s : mg 1.0 mg + 10.0 mg I I 1000 1 1200 ...“.* . . ...* ..”””+. -+ ; 0 1000 ---- ; I 1 1400 1600 Clock +iOUf FIG. 1. Mcari (SEM) serum mclatonin profiles of 20 subjects sampled at in(emtals after ingesting 0.1. 0.3, 1.0, and 10 mg of mclatonin or placctm at 1145 h. . ● .-. Physiology 1826 n Dollins et uJ. Pr~ A m 4.5 25 [A 15 t . A .B :’20 10 Nut!. Acad. SCL USA 91 (1994) f 4.0 15 r/\\\, ts l.klh 3.5 10 o LELb .0 0.1 0.s 1.0 10.0 0.0 0.1 S.o 2.5 .010.0 B 14 Molatodnc w FIG. 2. Mcaw(SEM)sleep-on=t ~tcti$ (A). $Ieepd~tin$ (B). adf-rqxtcd sleep-onsetMc* (C). and posttcst SSS responses(D) aftcria.gcsdonof melatoidnorplaccbo at 1145 h (n - 20). 12 tivelfi 1°F = CC x 9/5) + 321.H temwmmms m~ after ingesting LO (A -0.16Y7 and 10 (A -0.2Y~ mg of mclatonin wcte also less thanthose measuredafter ingestion of O.1mg of tnelatortin.Ingestionof 10mgof melatottinaIso 10 dccmascd oral temperaturerelative to the 03- and l.o-mg doses (A -0.21T and -0.13”F, rCS~tiV~y). SSS responses ) . indicated greater feelings of slccpincss, relative to placebo, after ingesting 0.3, 1.0, and 10 mg of meIatonin (A +0.S1, +0.47, and +0.46, respectively). POMS responses showed a decrease insclf-reported fedngs of vigor+wtivity, rclativeto pbCCbO,after Ittgcst@ 0.3, LO, and 10 mg ofutclatonitt (A -N7. -190. and -1.95, t’CSpd@y). Fcclinga of @oractivi&ywcrcalso dccmascdaftcriagcsting03 mgtdativeto 1.0 tng ofmclatottin (A -1.33). POMS.ms_.indi!i~e~ &crcasc ittscff%cportcdfeuttgs of~ -, a ht8c$tig 0.3,1.0, and 10 mg of melatonist (A +214, +1.S6, and +2.28, -Vdy). Skcp test dq onset latenck-s were Shottcr, relative to placebo, * itt-7.4S, -9.03, g@@ O.LO.3, 1.0, ~d 10m80f mhti(A -11.02, and -10.32 tnin, respectively). The duration ofslccp (i.e., switch rclcasc) cxpcdcnccd dusing the sleep test was greater, relative to placebo, forthc 0.1-,03-,1.0-, and lo-mg mclatotdtt doses (A +8.20, +10.04, +22.09, and +10.47 ndn, respectively). Sleep test sclf%cportcddeep latencics were smaller, relative to phwcbo, forthe 0.1-,0.3-, LO-,and lo-mg mclatonittdoses (A -7.60,-10.60,-23.27, and -10.65 mist). Subjects also indicated that they slept more quickly after ingesting 1.0 trig,relative to 0.1 mg, ofmdatonitt (A -5.67). Responses to thepostsleep test SSS indbte that subjects felt sleepier after ingesting 1.0 and 10 tngof mclatonin than after ingesting pklCCbO (A +0.70 and +0.95, respectively). Wstslecp test SSS responses also inditite that LO mg of mclatonin caused greater feelings of sleepiness than 0.1 mg (A +0.70). Fewer Wdkinson auditow vigilance task correct responses were recorded, relative to placebo, after subjects ingested 1.0 and 10 mg of tnelatonin (A -4.75 and -S.67, respectively). Correct four-choice RT response latencica were greater (i.e., longer) after ingesting 10 mg, relative to placebo, and 0.1 mg of melatonin (A +17.21 and +14.46 ma, respectively). All of the painvkc comparison. results reported above were signifxant at the P <0.05 level. Order and Tic Effects. Sign&ant order effects wem found on the Wilkinson auditory vigilance, simple RT, fourchoice RT, and symbol digit substitution tasks. Thcsc rcstdts indicate that subjects tended to respond mot-c accumtely (symbol digit substitution responses and RT response latcncics) with practice and ICSSfrequently (WiWinson auditory B . . 8 1 c ..●. $-u. ,~ 1000 1200 Clock 1400 1600 ~OUC 3. Mean response scores on-the .Sss (A), ~~ V&OCl%. activity scale (B), and POMS tkti@Hnma Scslcs(c) throughout testing.Mctatordnor @XCbO was in&stcd at 1145h (n = 20). breascd feelingsof stccpincss,vigor,and fatiguearc indicatedby higher scores. Wanc@on subsequent test days. ‘Ike changes arc oflittlc interest because (i) significant treatment-by-order intcfactions were not fwnd on these tncas~ (h? the Latin square is balanced to compensate for order effcds, and (iii) similar rc$wh.shave been observed previously (14). There WC= consistent patterns of VariiinCCover time among the mood scale measures. Subjects’ SSS (Fo.m = 17.50; p < 0.001) ~d ~MS fatigue-inc& (F(s.73 = 8.04; P < O.(Ktl)NSpOnSCSindi~te hat they felt sleepiest d most fatigued and that they felt the least vigorous mMS vigoractivity scale (5379 = 12.79; P < 0.001)] at 1400 h. 2.25 h after mekitonin hgcstion @ii. 3). Oral temperatures WCrC consistently ]OW at H(l(j md 1400 h (mCans, %.8YF and PhydoIow Dolhs et UL ProG NatL Acad Tabk L McstI diffuenccs ofptanncdcompakM f-s-t M vs. 0.1,03, 1.0,and10 -Q~** Orat tcmpcratum,●F 0.42”” s!xPrOfiks)fmood states .=.. vii-activity scale 1.75”” Fat@c-kstss“ scste stsxp test Steqwwt latency,miss SCL VSA 91 (1994) ovaan F-ts 0.1 vs. 0.3:1.0. o.3v&l.oandlo and10 -0.14”” -0.28”” “ 0.25’” -0.0s”” -. -0.77’” 0.97”” 0.84”” -o.22””- 1827 . 14 vs. 10 -0.33 -0.01 -0.0s 0.72 -9,4** 1020”” -10.s3”” 0.61”” -2.67”” ‘ -1.64”” 0.70 2.67”” ~ 1.24”” , -1.62 tip dmin -1.36”” -3.91”” 2.62 sctf~stccp tatcncy,min 0.0s”” ,-0.40” 0.48”” . =~. WikmsOn●ditOry Vi@ncc. -3.33* -3.03 -219” -0.92” Corrcu Iespomics Four-choiceRT 10.06”” U.25 7.s7” 2.62* cOITcctresponselatcsscy,MS vd~btimaav mdtiwbmtm~t ib(dtiub--=bti-a comnadsonawwe Ftcstscalculatd wW5and15dc8secsofkd XSGn =20(scc kxtfordctailaofsnksin8 value ● subskutiona). ●. P < O.@,●c, P <0.001. 97.@T, rcspdvcly). Meanfour+At&c RTresponselatcncics were the greatest at 2300h (i.e., 377.77MS)and dccrcascdto 360.2SMSat 1700h. Significanttreatment-by-time hlteradons Werefoundin Od tunpclaturc (F(’S4.%S) = 1.60; P< O.OS)and numbcrofcorrcctsespo~ onthefw-choice RT task (Z@soj = 1.92; P < 0.0S). DISCUSSION -n ?f snclatottin(0.1-10 mg) at 1145 h dtd in cmqmnd@y kreascd circulating tnclatonin kvcls. scSum melatottin Concctttnltions Obaclwd after the 0.1- and O.%ngdoscs wcrcwithin thettormaldyttdc rangcfm nodurnd snclatonin concentrations (1). Sleep test results hdicatc that acute adminktratiostof mclatdn (0.1-10 mg, pa) at midday krcascd objective and Sclfwcpmtcdsleep ostsct latcnoks by an averageof 9.46 and 10.S3mist,rcspccti@y, relative to P&do. SIccpduration was krcascd by an average of 10.2 mistduringthe 30-tninsleep test, teladve toplaccbo,byingcstionof mclatottin.Paitwkccotnparisonof SSS scores, stftcrthe skcp tcs~ indicates that the 0.3- and LO-mgdosca oftnclatonin incnmcd self-reportedfcdings of akcplncsa, rclrstivcto placebo, and that feelingsof slccphtcss afterthc l.(kssgdoscwcrc gmatcrthan those aftertheO.l+ng “Tksc results indicatethatingestion of anacutedose of mclatonitt, sufficient to imxcasc circulating mciatonin to within the normal nocturnal physiologic range, has lCVCIS hypnotic effects. The acute nature of the hypnotic cfkt of mclatoninsuggests that it may constitute a directphysiologic cfikct of the honnonc independent of its actionas a circadm by zcit@scrtime Si#lid (2426). ‘ThiS hypothesis is SUpWItCd the rcccnt independent observation that rnclatonin(S trig, p.o.) administeredat 1200,1700, or 1900 h cxatcd a direct hypnotic effccG isicmdng sleep propensity withii 90-220 min of ingestion (27). The phase shifts in ckadian rhythms its sleep (27) or cndogcnous mclatottin sccmtion (28, 29) -Y scco after a single acute dose ofthc hormone, as used ~ w~ of iasttfficieat magnitude to support the hypothds thattbc hypnotic cfkctsfd inthccttrrcnt study cotUdbcatttscdby mclatonittactingas aze@cbcrtimc signaI.Suchahypothcsia would suggcstthata9-h phascahift in slccponsctcanoccuraftcra sis@eacutcdoscofmclatonht at m“ddafi this scents MgMyitnptvbable The obsctvcd signiit dccmasca iaotaltcmpcratum ttftcringestion of 1.0 and 10 tng of mclatonin arc cott!dstcnt with previous reports (’2, 14). Alterations in ntood and pcrrntancc mcasurca after mclatottin ingestion, relative to kbo (C.g., incmasc in fdngs of slwpincas and fatigue; dcacasc in fangs of incrcaw in four-tltoid RT latc~ vigor, dccrcasc in number of correct responses on the Wilkistson auditoty vi@ancc task), arc also consistent with previous reports in both dwction and magnitudeofsncasurc (13, 14).The direction and magnitude of response change, relative to p[accbo, among the melatonin doses administered Table 2. hkan (SEM)measuredresponses Mctatoniningested,mg W tcsnpcrwm, “F 0.0 97*5 (0.06) 3.IS (0.10) 0.1 97.47(0.06) 3.38 (0.10) 0.3 97.39(0.0s) 3.66(0.10) 1.0 97.31(0.05) 3.62 (0.12) 10.0 97.18(0.0S) 3.61(0.13) 12.73(0.S9) 11.29 (0.64) 9.% (0.57) 10.83(0.65) 10.78(0.63) 3.83 (0.40) 4.85 (0.42) 5.97 (0.44) 5.39(0.49) 6.11 (0.53) R&k. of moodstates Vlgor+ctivity scale Fatigue-inertia scale sleep test Sleep-onset Is4ency. min Sleep duration. min Scif-reported sleep lalcncy, min SSS rcspomes Wilkinson auditory vigilance, comcct responses Four-choice RT corrcc[ rcspmssc Iatcncy. ms 17.06(2.43) 9.61 (1.84) 8.03 (1.60) 6.04 (1-65) 6.74 (1.24) 11.36 (2.34) 19.56 (1.79) 21.40 (1.63) 23.45 (1.67) 21.83 (1.41) 20.55 (2.23) 3.80 (0.22) 12.95 (2.07) 4.05 (0.26) 9.95 (1.69) 4.s0 (0.22) 7.28 (1.33) 4.75 (0.25) 9.90 (2.07) 4.35 (0.26) 27.30 (1.48) 25.85 (1.32) 24.28(1.53) 22.55(1.66) 21.63 (1.56) 359.41 (8.2S) 359S4(7.36) 367.74(7.65) 374.03(9.08) 376.62 (9.86) .=- 1828 were consistent on both the mood and pcrformattcc tncasurcs. [t thus seems likely that failure to fti si.gnifiit differences in mood or pcrfbsmanccbetween placebo andthe lower mctatonin doses (0.1 and 0.3 mg) is due to the limited sensitivity of the measures used rather than an abscncc of Ctrect. The results of thk study arc consistent with the observations of Vollrath et aL (6). who rcpon a decrease in daytime. latency of sleep onset in subjects given 1.7 w of melatonin nasally and with those of Lavie and COkgWX WI dcscrii above. Nickelscn etd. (30)rcpomd W m m Ofmelatonin, administered p.o. at 0900 or 1900 h, caused nonsignifkant decreases in sleep latency but increased feelings ofslccpincss only after the administration at 0900 h. Others (31, 32) reported that evening ingestionof mchtonh(1 and S W) did not influence sleep onset or duration but did csusc an incmasc in rapideye movement (REM) sleep-onset latency. These studies suggest that the magnkude of mclatonin’s sedative-like effects may be significantly influenced by the time of its administration. Alternatively, the cxpctimental designs used itf the negative studies might have precluded observing the hypnotic effect seen here (e.g., by not allowing subjects to modify thcii sleep times or by forbiddingafternoon napping; rcfs. 28 and 29). It should bc noted that the pattern of physiologic and performance responses observed here resembles that obsemd fordrugsin the bcnzodiazcpine family (33-3s). In summary, administration of a small mclatonin dose (0.1-0.3 mg, p.o.) during the daytime, which raises serum tttclatonin concentrations to within the normal nocturnal range, or of sliitly highcrdoscs (LO-1OW, p.o.) was shown to cause hypnotic effects KhltivC tO pkCbO. _ effects include adccrcasc in objective andself-cstimt cd slq-onset latency. an incmasc in sleep duration, and skcpincss upon waking. Sclfwcportcd feelings of sleepiness and fatigue were increased and fcdings of vigor diminished.Od tcmpcratum and the number of correct responses on the W-n ttuditoty vigilancetask wcm found to decrease signifiidy after ingestionof 1.0 and 10tng of melatonin.These results arc similar to those repotted after ingestion of bcnzodiazcpittcs and suggestthat tttclatonintnayfindusc as a hypnotic dtug. TINYalsosuggestthat the normalphysiologicsecretion of melatoninmaybean importantand direct-actingfactorin bringingabout skcp onset. Thcauthors wish toexprcss special thsnksto thesubjects who participated in the study, ths Massachusetts InstituteofTdmalogy Clinical Rcscamh center nursing staff, and Ms. Yilun I% for assistsmxthroughoutthedatacoktion. This study was suppastcd in part by grants from the U.S. Air Force (AFOSR90-012Sand AFOSR 90-0326), the Nahnai Aeronauticsand Space AdtnWtration (NAG 9-14). the Center for Brain Scicrsccs and Mctabolisrn ChasitabteTrust,the Nationalhssthte of MentalHoakh(MHS114$ 01), and the National Institutesof Hcatth to the Clinical Research center at Massachusetts Instituteof Tcchnotogy (MO1-RROO088). Lynch, H. J., Brzczkiski. A.. Dcng, M. H.& Licbcrmaa, H. (1987) in Advances in Pineal Research. ed$. Frsschini, F. & Reitcr. R J. (Liibcy, London). Vet. 2, pp. 181-189. 2. Cagnacci, A.. Eltiott, J. A. & Yen, S. S. C. (1992) J. Clin. L Endocrinol. Metab. 75,447-452. 3. vkvanathsn, M.. Laitinen, J. T. & Saavcdm, J. M. (1990) Proc. lVatl. Acad. Sci. USA 87, 62CQ-6203. 4. 5. . Physiology Dollirtset U; Anton-Tay. F.. Chou. C.. Anton. S. & Wurunan.R. J. (1968) Science 162,277-278. WaJdhauscr, F., Lick-man, H. R., Lynch, H. J., Watdhauscr, PrO-A>atL Acad. Sci. USA 91 (1994] M.. Hcskna. K.. FsischiH...vii. R. J. &-s Schctnpcr.M.. Wum. 6. 7. 8. 9. 10. 11. H.. Wddhaust, W., W. F. (19S7)Nae rocn&rinology 46.125-130. vothth. L., Scmm.P. & Gamsnct.G. (1981)Adv. Biosri. ~, . 327-329. wtwman. R. L & LicbcrsnsmH. (1987)hucgr. Psychiix~ q 13-14. J. M.(1991)Adv.pineal LewY. A. J.. sack. R. L. A ~~. Res. S, 285-293. ‘J. M. L. & sSCtG R. L LCWY.A. J., Ahtncd.S.. J*-. (1992) Chronobw. InI. 9,380-392. Rcitcr. R. J. (1988) ia Melistonin:CCnlcalPerspectives. eds. Mica. A., Phiibti% D. R S. &Thompson,C. (Oxfbrdhif. New York). pp. 1-42. bss, Watdhauscr, F.. Wciszcnhscha. G., Frisch, H., tith~, U.. Watdhbcr. M. & W&tman. R. J. (1984) Lancer L 362- J. W.. 12. ?%islcr. C. A., Durnont. M.. Dfsffy, J. F., Stein~ Richardson;G. S., Brown, E. N.. Sanchez R. Rios, C. D. & Rod& J. M. (1992) ti~ct 340.933-936. 13. Licbaman, H. R.. Watdtsauscr.F., GarfickI,G..LynckH.J. &Wurtman,R. J. (1984)Erath Rcs. 323,201-207. 14. Doltins, A. B., Lynch, H. J., Wumnam R. J.. Dcng. M. H., Kjschk K. U.. Gleason, R. E. & Licbamart, H. R (1993) Psychophysiology 11% 490-4%. 2s. Hamilton, M. (1%7) Br. J. Sot. Clin. PsychoL ~ 278-296. 16. Roscnthat, N. E., Gcnhsrt, M.. Sack, D. A., skewer,R G.& Wehr, T. A. (1987) in 271ePsychobiology ~ Bulimia, ok Hudson, J. L& POPC,H. G., Jr. (Am. Psychiatr.Press, Wdsington, DC), pp. 265-228. 17. Brzezinski, A.. sciil, M. M.. Lync& H. J., Dcng,M.H.& Wurtrnan.R J. f2987)J. Cfin.Endachol. Merab. 64,865-867. 18. Wilkinson, R T. (l%!l) Psycho/. Bull. 72s 260-272. 19. wilkinsom R. T. & Houghton, D. 097S) Behav. Res. Me&a% Instrum. 7,441-446. 20. Smith,A. (2967)E&c. Psywhol. Mess. 27,1077-1083. L F. (1~) J%@ 21. McNair,P. M., Lorr,M. & DroPPkmsII, of MoodStates Manual(Educationsad IndssstWTcstiog 22. sciviCc.San Diego). Haddcs,E., DemcnGW. & ~ Ob?gy10,431-436. V. (2973)Psyc@hysi- 23. W=, B. J. (2971) Staddical Ptiacipks in Espdnetud sign (McGraw-HilL New York), 2std Ed. pp. 384-388. 24. 2s. Asendt, L & Broadway. J. (2987)ChIVnobiaf.ht. 4, 2734D. De Pcuic, K., Conagl&I,J. VqlWnpsom L&*_K (2989)Br. Med. J. 29& W-707. 26. Ctaustrat, B.. Brun, J., David, M., Sassotas,G. & Chat. G. (1992)Biol. Psychiaoy 3% 70S-711. 27. Tzischinski. Q.. bvle. P. & Pal. I. (2992) J. Sleep Ra. 1, Suppl. 1, m.. 28. Lcwy. A. J. & sack R L (2993)in Me&toninapdthe@netd Gkand. ji-om Bask S&tce 10 Clinical Appkariam cds.. Tiitou. Y.. Arm&. J.& Pcvct. Y. fElscvi~Scicncc. Amsta-). PP. =210. 29. Zaidart,R.. GeofMau, M.. ClaustsaLB., BruinJ.. Taillar&J.. Bureau, C. & ChaZ@ G. (2993) in Mdatonits and the ~al Gland, jktn Basic Science to Clinical Applicatk eds. Tiiitou, Y., Amndt. J. & PCVCLY. (EIscvicr Scicncc Pub fishers B.V.. Amsterdam), pp. 23%339. 30. Nickctscn, T.. Dcmisch, L., Dcmisch, K.. Radermacha. B. & Schoffting,K. (1989) J. PineaJ Res. 6, 32S-334. 31. James, S. P.. Mcndelson. W. B., Sack. D. A., Rosenthal, 1, N. E. & Wehr, T. A. (2987) NeUrop$ychoPti~off 41-44. 32. kUllCS, S. P., Sack. D. A.. Rosenthal, N. E. & Mcssdctsao. W. B. (1990) Neuropsychaphamtocology 3, 19-23. 33. Koelcga, H. S. (1989) Psychopharmacology 98, 145-2%. 34. Grecnblau, D. J.. Harmatz. J. S., Engelhardt, N. & Sbada. R. L (1989) Arch. Gen. J%ycitiufry 46, 32&332. 35. Watsh.J. K.. Schweitzer. P. K. & Parwstikcr. S. (1983)Ciin. Pharmacol. Ther. 34,496-500. ‘ n --- . -. . . # . ● 2. .) Zhdanova et al. Sleep-inducing effixts of low doses of melatonin ingested in the evening. Clin. Pharmacol. ‘l%erap.57,552-558, 1995. . ? PHARMA CODYNAMICS DRUG ACTION AND . . Sleep-inducing effects of low-dosti of melatonin ingested in the evening ‘ W4previouslyobsenwd that low oral doses of rnelatonin given at noon in~ b[ood melatonin connoeturdyand fkilitateslcep o~a$assessdtd.ng aninvolcentrations to dmsc normdy _ sethe induction of po~pthisstudyweaamined unczymuscle relaxation -In corded sleep bysimilar ”dosesgiven later inthccvcrdng, dosetothe times ofdogenma mdatoado release and habitual sleep onset Vohmtcas received the hormooe (oral doses of 0.3 or 1.0 mg) or bat~8,0r9r~ ~tiAmsIqo~ ~~2d~4timpid ~mo~t~d~ were measured polyxmnogm pMy.B&*~atayof&c&tiph@~* 2 $kq. Melatonin did not SUPPreSS~ S!eCp or tiy its OnSeC OllSCtkncy and iatcncy to ~ Most volunteers could clearly dkingukh betwan the effkaa of mch.onin and those of pla- placebo when tictim- tiat60r8~~&tia m&*~~~~~q=~ tests ahinistdon Withmoodandpafknallce thceafkrtreamwn&l hcSedat2pvkktlew scauionmay beinvolvcd inphysiologic slecponslx 2ndthstcx0ge. nousmelatonin may beasefid intrcatiaghsomms. “-(G.Q4 PaUwUxm k 199$57:552-8.) evidence that nocturnal melatoti. Irina V. ~&llO~ I?hl), Richard J; W~ MD, Harry J. Lyn4 PhD, J&n IL Iv-B% Andrew B. Doll& PhD, Claudia Morabitq BS, . ad-Mm. Jean K Matheso& MD, and Donald L Schema, MD -c In the initial description of mdatocin (S-mcthoxyMcetyltxyptatnine) as the mclanophore lightening agent present in bovine pineaI glands, the hormone’s Fmmthc Clii Rcscard Gntrrand2kparmuof Braioaod Mxs@mem Ins&weof Tcchnotogy,CamW* -. bridge,and he Dcpamnm[of Neumtogy.Beth fsrad Hospkd, HamsrdMcdicd Sehoot,h“ Suppmtcdbymscuchgnntsfmmthe Nstioaaltnsti~of&aftb, Becbcs4 Md. (MH-5114S) aod.* Centerfor Bnio seimces Cambridge, kss. Stud”ks sod Maabotiim Charitabk T- waecoo&ckd a(ttKGmenf ~useasImtimtcofT~M Clinii RcseamhCeatcrat&c by agrant (RRO008S)hO(bCNXiOOd thUXfWRti RcsouKe. Nationallnsriwcsof HcatIIL Raxivcd fw pubticatiooAug. 29, l% xcepted Nov. 15.1994. ReprintGXJUCS& RiCfWId J. Wurunan, MD, Cd H- GmcnDistin~ of Braind CO@tivc scknccs, g@hcd Pmfti. Masxbuwu fnstiNtcof Tcchno!ogy.E&604, 45 (3rtemn St.. CUnhidgc. MA 02142. Copy@N Q 1995by Mosby-Year Boo&. tnc. M39-92349SfS3.CO+ O 13/(/620s3 552 - 1 sedative effect on humans ti noted.’ Although melatoain was subsequently shown to k seeRtcd primaruy at night, when people sleep,2 its mle in physiologic sleep remained uncertain.3PbrmaeOlogic doses of the hormone, Which inemase serum melatonin levels far beyond theii normal noeturmdrange, eotdd be shown to produce hypnti”c cffeets in humans*: however, Sllli3kf doses WXii@’ tcSed and yielded inconsistent results when examined.’~ We started by testing the midday administration of a phmnaeologic dose (240 mg, administered orally) of mclatonin and, on the basii of perfomlanee tests and SeIf-rcpom, obsenfed hypnotic-like cffeets. ‘0 We next tested four much lower (but still pharmacologic) doses of the hormone (10, 20, 40, or 80 mg) or placebo, given at noon. Although the resulting mean serum melatonin mncentrations were ~ugtiy proportionalto the do= administered, all doses wem equally effective, Axive to placebo, in induckg subjdvc sleepiness. ‘1’hcsc in decreasing oral doses wem aISO equd]y cffw(ive “ “ . ) ~, ~ the number of correct responses in audi- Self.rcporud Vigor.11Because the cffbcts were not dated to dose, we concluded that the . . btockmd moehaniims that mediate the behavioral (and temperature)effects of melatoninhad been saturated by tdl of the doses tested. In further pursuit of this line of investigation, we examined the effects of much lower oml doses (i.e., 1.0, 0.3, and 0.1 mg of me!atonin or p[acdxx compafcd with a 10.0 mg refercncc dose) administereda} noqn. Sleep onw and duration wetc studied beginning 1V4hours after the addnistration of melatonin ok placebo by means of a ~gflancc,and positive pressure switch technique.iz serum melatonin concentrations wete,~again, ioughly proportional to dose, but the peak amplitudes Obsetwd after the 0.1 0.3 mg doses (mean a SEM, 48.4 * 37.1 and 121.45 “a 24.21, respectively)wem withh the nomud (noetud) range for human serum melatonin levels. Sleep onset Iatencics *; ingestion of any of the doses tested were significantlyshorter than those after ingestionof pladw peak effects were observed with the 0.3 mg and 1.0 mg doses. Thii study was designed to determinewhethersuch doses also facilitate skcp onset when given in the evening, close to the hour that most people elect to skcp, and whether the hypnoticeffect of the hormonecao be detected @yand ) somnogmphkauy. METHODS Six healthy male volunteers (mean age * SEM, 26.5 * 1.3 years) WE paid to participated in the study after each gave informed consent. The cxperimctttal protocol and the Subject’s Consent Form was ,by the MassachusettsInstitute of Tcchnoi~ (MIT) Co~ttee oti the Use of Humans as Expcnmentd Subpxs. All vohtnteersreported that they were free of habitual sleep disturbancesand thazthey were dntg-fmc. Self-report questionnaires completed by volunteerson each test day mgardhg thcii previous nights’ sleep ‘htdkated that their mean bedtime wcurredat 1240 AM&22 minutes, mean sleep duration was 7.2 A 0.32 hours, and mean estimated sleep onset latencyat the habitualsleep time was 21.6 Y 4.26 minutes.Subjectswere nonsmokersand were asked to not consume alcohol or caffeine for 24 hours before each test session. Meals (providedby the MIT CIinical ResearchCenter)reflecteda typicalAmericandiet: 15% protein, 35% fat, 50% carbohydrates; 3000 to 4000 calories per day. lle study consisted of three double-blind and placebo-controlled exprimcnts. Treatment order for each experiment was determined with use of a 3 X 3 Latin- / square dcs@ to counterbalance for order effects. Each volunteer pa@ipatcd in a total of nine test sessions, with at kast 5 days elapsing betweensuczcssive sessions. In the first cxperitnent, subjects undcnvcnt three test sessions in whkh they received placebo or mclatonin (0.3 .or 1.0 m~ NCQE Co., VCVCY, SwiCAand) in gelatia capsules, orally at 6 PM.In the second and third expdncnts they received the same doses of melatoninor placeboat 8 or 9 PM.In the first two ex@ments, the sleep test consisted of2.hours of polysornnogmphicallyreeordcdsleep that began when the lights were turned off 2 hours after administration of mclatonin or placebo (i.e., at 8 or 10 PM).In the thii experiment, subjects spent the night before the test session in the Cliiical Research Center, and their sleep was mordcd polysomnographicallytiom 11 PM to 7 AM.On the following night they retired in darkness at 10 PM,1 hour after ingestion of melatonin or p!~ 9 PM,and tkii SkCP W= ~fded POlj’somnographicallyfrom 10 mt until 7 M the folIowing motning. For polysomnographic~rdings, ekctroenccphalographic electrodes. placed accordiig to the International l(Y20 System (with tecmdings from C4-AI, C3A2, U-01, and @-02), and elcctr@od -* ~ submental ckctromyographicektrodes were used fw sleep staging. SignaIs from the cktz0de5 and transducers were amplified by lkhanncl prcamplifier/multipkxor uttiw they were then digitized and mootded (DigiTraccCarcSdccs Inc.; B6stdn,Mass.). ‘fMrtysccondcpocbs wercstaged according tothccritcriaof Rcchtschaffimand Kalcs13:~, stages 1,2,3, or ~ and rapid eye movement(REM) sleep. Skcp onset latency was definedas the timeelapsing betwekttthe time that lights were turned off and the appearanceof three consecutiveepochsof stage 1 sleep: or of one epoch of any other skef) stage. Latency to REM SkCP was defined as the time elapsingbetween sleep onset and the appeamnccof one epoch of REM sleep. timpkte sets of polysontnographicxecxmdings were obtainedfromall six of the subjects, except as noted below, after txeatment at 8 and 9 PM and from two of the subjects afler treatmentat 6 PM.(No polysomnographicrecordingwas obtained for subject6 after he received 1.0 mg mclatonin at 9 tw.) To test the subjectiveresponsesof the voluntcm to treatment, subjects given me!atoninor placebo at 6 or 8 PMwereaskedat the end of eachsleep test whetherthey thoughtthat theday’s treatmenthad been a placebo or a hypnotic, and their answers were recorded. On the morning after trea[ment, subjects completed a battery of computerized performance tasks and 554 ZkiJwJw a al. A 80 Table I. Effects of melatonin, ingested at 9 PM,on DaSe” 60 40 ‘4 Sub~ct No. * Sleep onset fatenq 1 - 20 0.0 . 60 40 20 0 1.0 B 0.3 1.0 Fii. 1. Effects of melatonin (iigested at 8 PM)on average (SEZvf)latency to skq oosel (A) aid SkfI $ta& 2 @). ● p < O.tx)l. mood inventories that previous studies have shown to be adequate fOr evaluating Of the kvcl of Skp-. Four C&kc Reaction Tii, Siile Auditoty Rcactiott Tii, Rofik of Mood States, and Stanford SIccphcsaScale (for details see Dollinaet al.lJ). Becausc ofthchigh variabili~ ofchamctm “ tic akcp patterns among subjects, the JJOtJ_C ~a~ ~t14 Wasuscd tocvahtatcdiffcmmccaasSociated with the three tnmtment conditions. Group mean VaIues Wcte substituted fw tile Jnissiig data points Iiotn subject 6 (1.0 sttg at 9 M). RC@OtJ analysis wssusedtocvaluatc tbercktionship b@iccu the sleep onset latency after Imatmeat and halhal sleep onset Iatency. . R.IXULTS Both doses of melatoningivca at 8 PM~lg. 1) or at 9 W (Table 1) significantlydccmscd sleep onset k+ tency and latencyto stage 2 sleep (p < 0.001) dative to placebo, as assessed polysonmographically.The hormone was qually effective in the two subjects studied at 6 m. llus, latency to sleep onset after tseatmentat 6 PMdecreawd h 57.3 ~“17.88 (SEM) minutes (placebo) to 10.8 A 0.13 tninuta (0.3 mg dose) or 8.5 A 1.50 minutes (1.0 mg dosek at 8 w, latency decmscd from 29.4 A 10.77 minutes (placebo) to 6.4 & 1.88 minutes (0.3 mg dose) or 7.2 & 1.13 minutes (1.0 mg dose); and at 9 PM, latency 03 mg Latency-to stage 2 (rein) 1 214 2.5 : 28 4 35 5 6. 6 59 17 6 13 10 2 12 : 4. 5 6 ] mg (mitt) 12 4 6 8 2 10 ** L_m F 0.0 . 0.3 Placebo 187 23 23 34 5 56~ 0 k 80 I deep patterns* Latency to REM sleep {min~ 1 163 2 80 3103 4 63 41 : 141 8: 7 6 7 t’ 95 : 70 48 106 dcmased from 54.8 A 27.39 minutes (placebo) to 7.1 A 1.61 JJJiJJUk5 (03mgdose)or6.0* I.07miJJutcs(l.O mgdosc). Latencyt0sIeepqe2& a more sensitive index of the hypnoticCf%ctof melatonia. At 6 PM,Iatency kreased fiotn 65.3 & 1438 minutes (placebo) to 19.0 A 125 JtdnUtcs (0.3 Jng dose) or 14.0A 3.75 minutes.(1.Omg dosch at 8 JIM, it decrcad from 33.8 a 10.O6JJ@teS @l&) [O 7.2 & 1.% JJJiJIUte$ (0.3 mg dose) or 11.4 A 3.23 minutes (l.0mgdose~at9Wit~ from 61.25 x 3134 MifNJkS (placebo)to 10.1 A 2.17 minutes (0.3 mg dose) or 11.3 A 3.7 minutes (1.0 mg dose). l-he effects of tbc physiologic(0.3 J@ and low -logic (1.0 mg) doses of mclatonin did not ddhr significantly with mpect to any of tbe parametersmcasu@ thcmfotetbcbighcrh didnotcnhiincethe hypnotic effect. We did not findstatistically significant differences in latency to REM sleep ~ mclatonin or placebo dminimw .00 at 9 m, Jdtbough in three of the siX subjects this intend .dccmased ~mcwhat afier administrationof the IOWCX dose. ~able l). The abtity of mclatonin to dcuwsc the sleep onset latengy of any subja varied in proportion to his sleep Zba%z?wiw a d. 555 8 . 200 ) 150 100 50 0.0 .0 50 Sleep F&2.’1herdadon sesicy* ?00 150 0.3 1.0 200 latency bpenthcrcductiofti nskponsctla- the ingesoott of 0.3 mg dose of mcktonia at 9 ru aod the sleep latency in the untreatedcondition. Iatency after placebo administration(r= 0.99 for the 0.3 tngdose andr = 0.94 for the 1.0 mgdosq Fig. 2). and in propordonto his sdf-seportedsleep onset latcacy at his usual bedtime (r = 0.86). ‘fbus, subjects who required more than 20 minutes to fdl asleep after placebo t2eattnuttexhibited the more robust* sponscs to the exogenous hormone(Table I). Analysis of subjective slecpimas and of scaction times in se_@*Wtil@tYstitionti_~= matmutt (at 730 Or 93 AM)rcveakd no hangover effects of melatotdntreatment(Fig. 3). None of the volunteersmistook the placebof~ melamtdnintheir aelf-tqmsts. At8w, fourofthesubjecta seceiviog the 0.3 mg dose and five of the subjectsteceiving thel.Omgdosc mct@zedthatthey had been tmatcd with a hypnotic. Most subjects perceived the hypnoticeffectwithinan hour of mchttonht ingestion. DISCUSSION These data show that low era! doses of mclatonin, which were previouslyshown to increasesuum mclatotdrt concentrations to kvels normally ocauring at stighc’z produce acutehypnoticeffects when given in the evening (Fig. 1, Table I’).Moreover,.theseeffects am discernibleboth subjcctkly and by stattdatdpolySOtlU)O~phiC m!thods. ThCSC obsctvations COtttpkmcttt our carlkr findingthat simi!ar small melatonin doses given at noon dccmase sleep latency, as tncasumd electromcchanically,12and support the idea that the physiologicincreasein blowt melatoninlevels that occurs late in the evening, 1 to 2 bouts bcfote habitual bedtime, is involvedin the mechanisms that normally trigger sleep onset. Normally. the daily alternation of environmental 0.0 0.3 1-0 0.0 0.3 1.0 350 300 250 Melatonin. Dose. (rn.9) Fig. 3. Moodandpufonnanceon the-g aftermclatonht tmtmetm Simpk RcacdenT- (A~”IMile of Mood Statc5(fdgucdi scale)(B~ andFourChoii Reaction Tii, lllMWrdat731m (open& @m9Nti(~d hers). lightand darkness, ~latcd throughthe eycs,ls adap tivcly harmonizesthe rhythmicsex-don of melatonin from the pine-algland with other cimdiatt rhythms. l%e noctutd lekasc of mclatonin fi-om the pined gIand is coincidentwith the habitual hours of sleep in PCOpk With entrained 24-hour SkCp-WSkC rhythms.2 In bhd persons, deprived of thk cnvimmncntalzeitgebcr, endogenouslydsivcn circadian rhythms tend to fmc-rutt and become, to wuying degrees, dissociated; deep LWXUTRSdisrupted, and dafiime alertness is diminished. 16 However, in a blind patient who exhibited free-running C“madianrhythms, the ddy pattern of skcp propensity and the onset of mcdatonin scctetion were found to exhibit a normal relationship. 17This as- a. alrwx. $S6 zbdanuvaa d. sociation supports the hypahcsis that melatonin is in- ) volved in normal nocturnal sleeponset. Becauserepeated daily doses of melatonincan shift the phasing of the daily thythm in human mclatonin kvcls,:* it has been suggested that this trcattncnt can also, as a consequence, shVt the sleep rhythml*zi (i.e., that the effect of exogenousmelatoninon skcp is regulated by induced changes in the cndogcnous rhythms). Thk does not seem to be a likely cxpkmation for-the changes in sleep latency observed hem (Fig: 1; TabIq I) or in our previousstudy]2 in which tnelatonin was administered at noon and sleep onset measuredat 2 PM.l%e extent to whicha single dose of mclatonin can shift the daily rnelatonin rhythm has been mqsurcd with usc of repeateddaily administration of the hormone at various time points,2t or melatonin infusions over 3-hour intervals,= and found to be less than 1 hour per by of treatment,regardless of the time of day that melatonin was administered. Our present and previous findings ‘2 show that a single physiologic (0.3 mg) dose of melatonin can ~vokc J sleep onset 5 to 11 hours catiier than skep would otherwise occur. Similarly, Tzischinskyand Lavie,” using a pharmacologicdose of tndatonin (5 mg), found that the hormone facilitated skcp onset and sleep propensity 2 hours after it was administaed at noon or at S m. Such cffdcts arc clearly unrektcd to a gcncd shiiincircadian rhythms. our6ndings andthoscof the Israeli groups suggest that tbc induced ckvation of circulating tndatonin concentrations triggas the omW of sleep, rcgardks of the pmliling phase of CndogeuousCiKadii rhythms. This acute Cffkct of melatoninon skep, considered in view of the reported increasein plasma melatonin kvels24and the incmasc in urinary tnclatonin duting sleep &privation,Z sup ports the idea that endogenous mclatottinmay scnm as a link between circadian rhjthmicity and tk homcostatic mcchankms of skcp. This may account for the obsenwd reduction of sleep latency as a finction of sleep deficiencyreported by Catskadonand Demcnt.M Thus a critical serum melatonin level maybe b@c to normal nocturnalsleep inductionin humans. In our studies, the extent to which mclatonin accelerated sleep onset in any subject varied with hii characteristic sleep latency in the untmawxl state. The sources of intersubject variability in sleep onset latency are unknown but could be related.in part to dif- ferences in subjects” characteristic 24-hour serum melatonin patterns, which were not documented in this study. A similar relationship could also underlie the well-known increase of sleep patho]ogy among older People,z’ inasmuch as nocturnal mclatonin production mmMhmmGi & lllsMrwncs MN Iws also declines with advancing age.=s Becauseon[y. young volunteerswere involvedin our studks, wc do not have data on possible agc-mlatcddifferencesin the skepindueing eff~-of mclatonin. However. H& mov et al.n fwnd that older peopk with insotia have lower nocturnal melatonin kvels than thOSCof young peopk and of older subjects withoutinsomnia. Available && SUggCSt tbt tk SkC@dUCing p~ of rne~atoninmay differ horn thoseof the bcnzodiazepincs. Bcnzodiazcpinesdectcasc the duration of REM sleep after the singk ad-ministrationof a high dose31 or ‘of longer-term administration of low dos+~’; tky dSO ltXhlCC SIOW WVC SkCp,n thus influencingskep quality. In our study, usnegatively ing a single low mclatonindose, We obscivcd no sup pression of REM skcp, and ,mme of the subjectsunde.rwcntREM sleep sooner after mclatortintmatmcnt than after placebo (Table I). It is interestingto oote that the bcnmdkepines reportedly also suppress the nocturnal increase in plasma rnelatoninand may incrwsc daytime plasma melatotiht kvck.x= Such effects could account for the residual daytimesedation that frequentlyoccurs * benzodiazcpinetreatment, as well as for the rebound insomnia that can follow the terminationof qch treatment. hfusion of L-tryp tophan3’-39or of Delta-skcpxnducing Pcptidc,@ whit% can provoke SkCp OtlSCt, abo KCpOttdy inJn contrast, crease cumulatingtnclatonin kv&4’4 dies &dtWtC@C blocking agatts””a or nmateroidal ~. inflammatory dregs (e.g., aip”irin),-” whichdisturb sleep, dccmasc blood melatoninkvck. h the dcdgn of our Cxpcrinmts. the objective “sleep tests” were Misted only I or 2 hoursafk ingestion of mclatoti, thus we lack data on the minimum latency of the hormone’s effect. However,selftepotts of the. volunteers indicated that their usual latency to its hypnoticeffect was 25 to 60 minutes.In previous polysomnographic studies of the Cff” of melatonin on sleep latency positive results were obtained when melatonin was given 1 to 2 hotus bcfom the cffkct was observed (80 mg6 and 5 mgz), and negative results were obtained when it was administered 15 minutes before bedtime(1 or 5 mgs’~. Further studies am needed to determinethe timecourseof the effect of physiologic melatonindoses on sleep latency. One of the major problems with existing hypnotic agents (e.g., the benzodiazcpines) is a hangover effect; that is, on the morning after treatment, patients experience inappropriate sleepiness, changes in mood, and diminished perforrnarm. In thk study, we used a tests previously shown to bC battery of computerized .-. Zhibwva et cd. 557 ● changes inScnsk.iwtobmoodandpcrfbtm— tto hangover ducedby hypnotic agents. ‘fky SCVCSkd cffkcts the morning after evening admittiktrrdonof t mclatonin. Our findmgst1 (Table I; Fig. 1) strongly suggest that the sleep onset, which is provoked by a single dose of melatonitk tesu!ts not from its effect on biological t-hnistgmechanisms, but fmtn a dti action of the elevated ci@ating mclatonin per SC. ? .. We thankJoseph McCarthy&r tcchnicat assistance,the auning staff of the MIT aiikal RescamhCustcs for assistmce in experiments, and Digiiracc Cam Scrvkcs, Inc., Boston, Mass., for loan of the recording equipment. Rqfemuzs L Lcmu AB, Case JD. Me!atonin. Fcd Proc 196%19: 590-2. 2. Lynch HJ. WuqmanRJ, MoskowirzMA, ArcherMC, Ho MH. DaiIy rhythm in human urinasy snclamnin. science 197%181169-71. 3. w~ RI, Li~.HR. Melatonin secretionas a mcdhitor of ciscadii variationsin sleep and SIcepincss. J Pined Rcs 198S?301-3. 4. Anton-Tay F. DiazL Fcrnandez-GuardiolaA. 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