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Effects of Melatonin on Human Mood and Performance

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Effects of Melatonin on Human Mood and Performance .. ... .. ... ... - Brain Research. 323 (1984) 201-207 201 Elsevier BRE 10404 Research Reports Effectsof Melatonin on Human Mood and Performance HARRIS R. LlEBERMANI.2, FRANZ WALDHAUSERz*, GAIL GARFIELDI, HARRY J. LYNCH2 andRICHARDJ. WURTMANZ IDepartment 0/ Psychology £10-130 and 2Department 0/ Nutrilion £15-604, Massachusetts InstilUte o/Technology, CAmbridge, MA 02139 (U.S.A.) (Accepted March 20th, 1984) Key words: melatonin - pineal- sleepiness- performance- human The function of melatonin, a hormone secreted by the pineal gland primarily at night, has not been definitively established in hu- 'mans. To determine if pharmacologic doses of melatonin had any behavioral effects it was administered acutely to 14 healthy men. Their mood, performance, memory and visual sensitivity were assessed. Plasma melatonin concentration was assayed as well. Melato- nin significantly decreased self-reported alertness and increased sleepiness as measured by the Profile of Mood States and the Stanford Sleepiness Scale self-report mood questionnaires. The effects were brief. Melatonin also affected performance, slowing choice-reac- tion time but concurrently decreasing errors of commission. Sustained fine motor performance was not impaired after melatonin ad- ministration nor were the tests of memory and visual sensitivity that were administered. It is concluded that melatonin, administered orally in pharmacological quantities, has significant but short acting sedative-like properties. INTRODUCTION known to participate in the regulation of sleep and on the ability of melatonin to reduce anxiety-like behav- Little definitive information is available concern- iors in animals. For example, melatonin has been ing the function of the hormone melatQnin in hu- 'shown to'decrease saccharin neophobia, increase ex- mans32.Evidence from a variety of sources does how- ploratory activity and decrease postural freezing in ~ver suggest that this hormone could affect certain rats7,8.A few studies have also described induction of behavioral functions. In both man and other species, sleep among human subjects receiving melato- melatonin is secreted by the pineal organ primarily nin2,s.26. during the night. This nocturnal release of melatonin We have examined the ability of oral melatonin, can be suppressed by sufficiently intense Iight16.18.It given during the daylight hours in pharmacological can be hypothesized that the physiological role of quantities, to modify various aspects of behavior in melatonin in humans might thus have some relation- healthy young males, and have rel~ted such effects to ,ship to behaviors, like sleep, that are associated in plasma melatonin levels sampled concurrently. We humans with darkness. That endogenous melatonin selected a battery of behavioral tests including many might influence human behavior is also suggested by that have been shown to be sensitive to substances reports describing effects of this endogenous indole acting as sedatives. on brain levels of serotonin1, a neurotransmitter * Present address: Univ. -Kinderklinik, Waehringer Geurtel 74-76 A-1090 Vienna, Austria. Correspondence: H. R. Lieberman, Dept. of Psychology E10-130, MassachusetU Institute of Technology, Cambridge, MA 02139, U.S.A. 0006-8993/84/$03.00@1984ElsevierSciencePublishers B.V. 202 MATERIALS AND METHODS stages of the alertness-sleepiness continuuml1. It has been used in a number of psychopharmacological Subjects studies and is sensitive to the effects of hypnotics24. Fourteen paid male volunteers between the ages of 18 and 45 participated in this crossover study. Prior Performance, visualsensitivity and memory tests to enrollment in the study each subject had a physical We selected a battery of tasks that sampled a vari- examination and gave his informed consent to the ety of perceptual and motor capabilities as well as vis- protocol. ual sensitivity and memory. Each test or similar tests have previously been shown to be sensitive to the be- Procedures havioral effects of various drugs. Melatonin and placebo were administered to each Simple auditory reaction time. In this microcom- subject in a double blind, counterbalanced manner. puter administered test, the subject responded, as Each subject received a total of 240 mg of oral mela- rapidly as possible, to the onset of a 75 dB (SPL), tonin or placebo (divided into three 80 mg doses) 1900Hz tone. After 5 warm-up trials, 125 test trials over a 2-h period (at 12.00, 13.00 and 14.00 h). The were presented in rapid succession. A visual cue, dose selected was based on pilot studies conducted in presented on a cathode-ray tube (CRT), indicated our laboratory and previously published studies of the start of a trial. Both commission errors (respond- melatonin's behavioral effects in humans2.5and other ing prior to the termination of the stimulus tone) and species7.8. Since melatonin is rapidly metabo- errors of omission (response latency greater than lized14,27,it was administered in multiple doses to one s) were recorded. maintain high plasma levels throughout the testing Four-choice visual reaction time. This test closely period. For every subject a minimum washout period resembles the Wilkinson four-choice RT task30and is of two weeks separated the first from the second ses- a measure of sustained visual vigilance. Subjects are sion. presented a series of visual stimuli at one of four dif- On each testing day for 2 h before (10~00-12.oo) ferent spatial locations on a CRT screen. The subject and 2 h after (14.00-16.00 h) treatment, the subjects must correctly indicate, by striking one of four adja- were tested on a battery of behavioral tests that cent keys on a microcomputer keyboard, the correct measured various aspects of performance, memory location of each stimulus. Four hundred trials were and visual sensitivity. In addition, two self-report administered and errors of omission (response laten- mood questionnaires were administered at hourly in- cy greater than 1s) and commission wer~recorded. tervals. Groovedpegboardtest. This modified version of Also, 10ml blood samples were drawn hourly from the grooved pegboard test (Lafayette Inst., La- an intravenous line and used for the determination of fayette, IN) was designed to measure sustained, plasma melatonin concentration. complex motor performance. In the standard version of the test the subject is required to insert, as.rapidly Mood scalesadministered as possible, a series of 25 pegs into randomly oriented Profile of mood states (POMS). The POMS is a holes on a board. Since both the pegs and board are self-report mood questionnaire which, when ana- grooved, each peg must be properly oriented to be in- lyzed, yields 6 factors: Tension-Anxiety, Depression- serted. To measure sustained performance, the task Dejection, Anger-Hostility, Vigor-Activity, Fatigue- was repeated 8 times in rapid succession. Inertia, and Confusion-Bewilderment21. The test Digit symbol substitution test (DSST). This test, consists of 65 adjectives each of which is rated on a 5- taken from the Weschler IQ test28,has been reported point scale. The POMS has been employed in many to be sensitive to drug-induced decrements in per- psychopharmacological studies and is sensitive to the formance20.The subject is presented with a series of effects of many different classes of psychoactive digits and a code which identifies 'each digit with a drugs, includinghypnotics12and stimulants4. particular symbol. The subject must correctly copy, Stanford Sleepiness Scale (SSS). This self-rated 7- in boxes directly below the digits, as many of the ap- point scale was designed to quantify the progressive propriate symbols as possible in the 90-s time period 203 allotted. of 10 words selected from a single category such as Critical flicker fusion (CFF). CFF is the visual 'animals', Each list was presented by tape recorder at threshold at which a flickering light is perceived to be a rate of one item per second and succeeded by a list steadily on. This test wasselected to indicate whether of 6 digits. Six different lists were presented on melatonin altered temporal visual sensitivity, It has the two testing days at 10.10, 14.10 and 15.40 h. also been reported that this simple sensory task is Immediately after the presentation of each list and sensitive to drugs that impair brain function13.CFF the accompanying digits, the subject was asked to re- was measured with two yellow (585 nm dominant call the digits in order of presentation and the word wavelength) light emitting diodes (LED) as the light list in any order. At 16.20 h, recognition memory for source. The light from the LEOs was diffused and each word list presented during the day was tested. presented through a circular opening which sub- At that time, for each list, the subject was sequential- 'tended 40 of visual angle. A parameter estimation ly presented' with 20 cards in randomized order; 10 staircase technique17was used to rapidly determine with the words from that list and 10 with new words each observer's threshold. selected from the same category. The subject rated Recall and recognition memory. Since benzodiaze- each word on a four point scale. pines impair certain memory functions, and melato- nin has been rePorted to have some benzodiazepine- Melatonin assay like properties7.8.19, we selected a memory test Melatonin in serum was measured by radioimmu- known to be sensitive to the effects of these drugs. noassay (RIA) using anti-melatonin serum provided The test, adapted from Brown et aJ.3, presented lists by Dr. L. Levine of Brandeis University, Waltham, MA15.One ml samples of serum were extracted in chloroform. The organic extract was evaporated to POMSVIGORSCALE dryness under a stream of nitrogen and the residue redissolved in 0.5 ml of Tris buffer (pH 7). The buffer extract was then combined with 100.ul of antiserum (IMELATONIN solution (diluted 1:5(00) and 100J.d(1750 CPM) of oPLACEBO pH]melatonin (New England Nuclear, Boston, 201- T T MA). After the mixture was incubated for 1 h at p<O.05 1",1 ...........1\(\1;.
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