tyrosine humans benefit 1

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(0RAPID COMMUNICATION OTIC0 S ELECTETreatment with Tyrosine, DEC 0 1989a Neurotransmitter Precursor,

Reduces Environmental Stress in HumansLOUIS E. BANDERET* AN D HARRIS R. LIEBERMAN-

*U.S. Army Research Institute of Environmental Medicine, Natick, MA 01760-5007iDepartmentof Brain and Cogaitive Sciences, Massachusetts Institute ol Technotog , Camibridge, MA 02139

Received 7 February 1989

BANDERET, L. E. AND H. R. LIEBERMAN. Treatment with tvro.sine. a neurotrantxijtter precursor, redu(e,%envirnomental stre.s.in humans. BRAIN RES BULL 22(4) 759-762, 1989.-Acutely stressful situations can disrupt behavior and deplete brainnorepinephrine and dopamine. catecholaminergic neurotransmitters. In animals, administration of tyrosine, a food constituent andprecursor of the catecholamines, reduces these behavioral and neurochemical deficits, Using a double-blind, placebo-controlledcrossoverdesign we investigated whether tyrosine (100 mg/kg) would protect humans from some of the adverse consequences of a 4.5hour exposure to cold and hypoxia. Tyrosine significantly decreased sympboms. adverse moods, and performance impairments insubjects who exhibited average or greater responses to these environmental conditions. These results suggest that tyrosine should beevaluated in a variety of acutely stressful situations. -.Tyrosine Environmental stressors Behavioral effects Mood Performance

ANIMALS that are acutely stressed exhibit characteristic neuro- exposure to high altitude and the resulting hypoxia cause symp-chemical and behavioral changes (26,27). In certain brain regions toins and adverse changes in performance and mood soon afterturnover of norepinephrine increases and its absolute level de- ascent to altitude (I. 3. 22. 24). To our knowledge tyrosine'sclines. When these changes occur animals explore less, interact effects have not been previously evaluated in experimentallyless with their environment, and seem debilitated (26,27). Ty- stressed humans. In studies of normal subjects, not exposed torosine. given acutely or in the diet, protects rodents from both the experimental stress. its administration resulted in small improve-reu: chemical and the behavioral effects of acute stressors such as ments in mood and reaction time 114.17).tail shock or cold exposure (5, 15, 16).Tyrosine is a large neutral amino acid found in dietary proteins ETI4ODand is the precursor of norepinephrine. dopamine. and epinephrine(29). During stressful situations, highly active catecholaminergic Twenty-three male U.S. Army personnel, aged 18-20 yearsneurons may require additional precursor so that catecholamine (median =21). participated in this experiment. All were volunteersNynthesis can keep pace with the increaed amounts of neurotrans- and gave their informed consent after they were fully apprised ofmitters being released (20.29). Some of the behavioral deficits the potential risks and benefits of the study. The protocol wascaused by acute stress may result from depletion of norepineph- reviewed and approved by the appropriate institutional human userine. and perhaps dopamine, in catecholaminergic neurons (10, review committees. All volunteers were exposed twice to two21. 26, 27). Specifically. noradrenergic neurons within the locus levels of environmental stressors: I) 15'C and 4200 m (450 torr)coeruleus are thought to influence attention, alertness, motor simulated altitude: and 2) 15'C and 4700 in (421 torr) simulatedactivity, and anxiety (10,21). This, tyrosine may protect against altitude. These conditions were generated in an altitude chamberthe adverse behavioral effects of acute stress by preventing by reducing atmospheric pressure. The relative humidity wasdepletion of norepinephrine in such neurons. 30-50c,; ventilation was 0.71 m/min. Such environments resem-To determine whether tyrosine might have beneficial effects on ble conditions encountered by travelers to mountainous regions;humans who are exposed to acutely stressful conditions we the altitudes we selected were slightly lower and higher than Pikesemployed a combination of environmental stressors-cold and Peak. Colorado. A control condition with normal temperature andhypoxia. In rodents, acute cold exposure depletes central cate- pressure conditions [22C and 550 m (710 torr altitudel was alsocholamines and impairs various behaviors (26,27). In humans included. All subjects were tested with both placebo and tyrosine

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760 BANDERET AND LIEBERMAN

in counterbalanced orders for each of the three environmental SYMPTOMS ANDconditions. Each environmental exposure (control condition, les- CATECHOLAMINERGIC EFFECTSsor stressor. or greater stressor) was 4.5 hr per day. At least 48 hr PLACEBO TYROSINEseparated test sessions. Order of exposure to the envirunmentalconditions was counterbalanced across the three groups of subjects 2.5 HEADACHEwh o were studied, to control for order effects and adaptation 1.9 0across exposures. In addition, to further reduce order effects all 1.3 1subjects were briefly exposed to cold and hypobaric hypoxia a few COLDNESSdays before testing began. 3.2 CLNSTyrosine or placebo was administered double-blind, in gelatin > 2.7capsules, in two equal doses. On a given test day about half of the 2.2subjects received tyrosine: the others received placebo. Each U 1.7 DISTRESScapsule contained 300 mg of tyrosine. Test sessions began at 7:00 Za.m. The first dose of tyrosine (50 mg/kg) was given at 7:20 a.m.. i 1.3just before we exposed subjects to the environmental condition, Z 0.9the second dose (50 mg/kg). 40 min later. The total dose was about 1.8 MUSCULAR DISCOMFORT80 % of an adult's daily dietary intake. The subjects had no O 1.4difficulty ingesting the capsules. Blood samples (


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TYROSINE REDUCES ENVIRONMENTAL STRESS 761

MOOD STATES COGNITIVE, REACTION TIME,PLACEBO 0 TYROSINE AND VIGILANCE PERFORMANCE

'CEAR -PLACEBO Q TYROSINE N

39 T

75 DIZZINESS ,L 5.2 MAP COMPASSW a 4.6 *Ir 67 X 4.0

0o 5 0 3.4Oi (3 -- -- 03 22 NUMBER COMPARISON(Ci 16 HOSTILITY 18 1O 12 w0 114O28 19 PATTERN RECOGNITIONa 10 CONFUSION z 168 13

41 0 620 CHOICE RT (LATENCY)KxLU 560

14 FATIGUE 50e i lmC HOICE RTERRORS)

18 TENSION 314 W U12 DUAL TASK (HITS)10 21 9- *- i m:*- :)n:15"C + 4200M 15"C + 4700M Z1 +M-7ENVIRONMENTAL STRESSORS l5*C + 4200M 15*C + 4700MENVIRONMENTAL STRESSORS

FIG. 2. Tyrosine treatment effects (meant sem) as measured by factorsfrom the Clyde Mood Scale. Multiple Affect Adjective Check loist, and the FIG. 3. Tyrosine treatment effects (mean sem) as measured by cognitive.Profil of Mood States (151. An asterisk(s) indicates the level of statistical reaction time. and vigilance tests. An asterisks) indicates e level ofsignificance (*pS0.05" **p


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762 BANDERET AND LIEBERMAN

stress-induced impairments in behavior are present in individuals G. Garfield, Dr. R. P. Francesconi. Dr. R. F. Goldman, Major T. M.with the greatest central deficits in catecholaminergic functioning. Rauch, Colonel D. D. Schnakenberg, Lt. Colonel G. F. Meadors Ill, theAdditional research will be necessary to determine whether ty- Altitude Research Division of USARIEM and the 23 test subjects. NASArosine's beneficial effects will be present in other stressful circum- grant NAG 2-210 and NIH grant 5R01-AG 04591 supported the Massa-stances. chusetts Institute of Technology efforts. A report describing the initialresults of this project was presented at a NATO conference, "BiochemicalEnhancement of Performance," Lisbon. September 1986. The investiga-

tors adhered to AR 70-25 and USAMRDC Regulation 70-25 on the use ofACKNOWLEDGEMENTS Volunteers in Research. The views, opinions, and/or findings contained inthis report are those of the authors and should not be construed as an

We acknowledge the statistical assistance of Mr. R. V. Spring and Dr. official Department of the Army position, policy, or decision, unless soB. Chew. We also recognize the contributions of Ms. B. L. Shukit, Ms. designated by other official documentation.REFERENCES

I. Banderet, L. E. Self-rated moods of humans at 4300 m pretreated with stress: Effects of dietary tyrosine. Brain Res. 303:215-223: 1984.placebo or acetazolamide plus staging. Aviat. Space Environ. Med. 16 . Lehneri, H.; Reinstein. D. K.; Wurtman, R. J. yrosine reverses the48:19-22; 1977. depletion of brain norepinephrine and the behavioral deficits caused2. Banderet, L. E.: Benson, K. P.: MacDougall, D. M.; Kennedy. R. S.: by tail-shock stress in rats. In: Stress: The role of the catecholaminesSmith, M. Development of cognitive tests for repeated performance and other neurotransmitters. New York: Gordon and Beach- 1984:assessment. In: Proceedings of the 26th annual meeting of the Military 81-91.Testing Absociation. vol. 1. Munich, Federal Republic of Germany: 17. Lieberman, H. R.; orkin, S.; pring, B. J.. urtman, R. J.:Psychological Service of the Federal Armed Forces: 1984:375-380. Growdon, J. H. The effects of dietary neurotransmitter precursors on3. Banderet, L. E.; Shukitt, B. L.: Crohn. E. A.: Burse, R. L.: Robert, human behavior. Am. J. lin. Nutr. 42:366-370: 1985.D. E.: Cymerman, A. Effects of various environmental stressors on 18. Lieberman, H. R.; Spring, B. J.: arfield, G. S. The behavioralcognitive performance. In: Proceedings of the 28th annual conference effects of food constituents: Strategies used in studies of amino acids,of the Military Testing Association. Mystic, CT: U.S. Coast Guard protein, carbohydrate and caffeine. Nutr. Rev. 44(Suppl.):61-68:Academy: 1986:592-597. 1986.4. Bittner. A. C., Jr.; Carter, R. C.; Kennedy, R. S.; arbtson, M. M.; 19, McNair. D. .; Lorr, M.: Droppleman, L. F. Profile of Mood StatesKrause, M. Performance evaluation tests for environmental research: Manual. San Diego, CA: Educational and Industrial Testing Service:Evaluation of 114 measures. Percept. Mot. Skills 63:683-708; 1986. 1971.5. Brady. K.; Brown, J. W.; Thurmond, J. B. Behavioral and neuro- 20. Milner, J. .: Wurtman, R. J. ommentary: Catecholamine synthesis:chemical effects of dietary tyrosine in young and aged mice following Physiological coupling to precursor supply. Biochem. Pharmacol.cold swim stress. Pharmacol. Biochem. Behav. 12:667-674; 1980. 35:875-881: 1986.6. Burse. R. L.: Forte, V. A. Acute mountain sickness at 4500 m s not 21. Murphy, D. L.; edmond, D. . The catecholamines: Possible role inaltered by repeated eight-hour exposures to 3200-3500 m nor obaric affect, mood and emotional behavior in min and animals. In:hypoxic exposures. Aviat. Space Fnviron. Med. 59(?):942-949 Freidhoff, A. J., d. Catecholamines and behavior. New York:1988. Plenum Press: 1975:73-117.7. Carter, R. C.: Sbisa, H. Human performance tests for repeated 22. Sampson. J. B.: Cynerman. A.: Burse, R. L.: Maher, J. .: Rock, P.measurements: Alternate forms of eight tests by computer. Report B. Procedures for the measurement of acute mountain sickness, Aviat.NBDL8213003. New Orleans, LA: Naval Biodynamics Laboratory: Space Environ. Med. 54:1063-1073: 1983.1982. 23. Shen, R. S.: Abell. C. W. Phenylketonuria: a new method for the8. Clyde, D. J. Manual for the Clyde Mood Scale. Coral Gables, FL: simultaneous determination of plasma phenylalanine and tyrosine.Biometric Laboratory. University of Miami; 1963. Science 197:665-667: 1977.9. Conlay. L. A.: Maher, T. J.; urtman. R. J. yrosine's pressor effect 24. Shukitt. B. L.: Banderet. L. E. Mood states at 1600 and 4300 metersin hypotensive rats is not mediated by tyramine. Life Sci. 35: terrestrial altitude. Aviat. Space Environ. Med. 59:530-532: 1988.1207-1212; 1984. 25. Spring, B.: Mailer, 0.; Wurtman, J.; igman. L.: Cozolino. L.

10. Gray, J. A. Neuropsychology of anxiety. Oxford: Clarendon Press; Effects of protein and carbohydrate meals on mood and performance:1982:459-462. interactions with sex and age. J. sychiatr. Res. 17:155-167: 1983.11. oddes, E.; emeut. W.; Zarcone, V. The history and use of the 26. Stone, E. A. Stress and catecholamines. In: Freidhoff. A. J.,d.Stanford Sleepiness Scale. Psychophysiology 9:150; 1972. Catecholamines and behavior. New York: Plenm Press: 1975:31-72.12. Jobe, J. B.; Banderet, L. E. Cognitive testing in ilitary performance 27. Stone. E. A. Brain noradrenergic mechanisms in models of depres-research. In: Proceedings of the Workshop on Cognitive Testing sion. In: Halbreich, U., ed. Hormones and depression. New York:Methodologies. Washington. DC: National Academy Press; 1984: Raven Press; 1987:263-277.

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627-634; 1979. 29. Wurtman, R. J.; Hefti. F.;Melamed, E. Precursor control of14. Leathwood. P. D.; Pollet. P. Diet-induced mood changes in nornal neurotransmitter synthesis. Pharmacol. Rev. 32:315-335; 1981.

populations. J. Psychiatr. Res. 17.147-154; 1983. 30. Zuckerman. M.: Lubin, B. Manual for the Multiple Affect Adiective15. ehnert, H.; Reinstein, D. K.; Strowbridge, B. W.; Wurtman, R. J. Check List. San Diego, CA: Educational and Industrial TestingNeurochemical and behavioral consequences of acute uncontrollable Service Publishers; 1965.

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tyrosine humans benefit 1

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