The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans
Kristy Lu
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Search for more papers by this authorMarcus A. Gray
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Search for more papers by this authorDavid T. Liley
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Search for more papers by this authorBen J. Harrison
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Search for more papers by this authorCali F. Bartholomeusz
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Search for more papers by this authorK. Luan Phan
Department of Psychiatry and Behavioural Neuroscience, Wayne State University, Detroit, MI, USA
Search for more papers by this authorCorresponding Author
Pradeep J. Nathan
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne University of Technology, Melbourne, Australia.Search for more papers by this authorKristy Lu
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Search for more papers by this authorMarcus A. Gray
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Search for more papers by this authorDavid T. Liley
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Search for more papers by this authorBen J. Harrison
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Search for more papers by this authorCali F. Bartholomeusz
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Search for more papers by this authorK. Luan Phan
Department of Psychiatry and Behavioural Neuroscience, Wayne State University, Detroit, MI, USA
Search for more papers by this authorCorresponding Author
Pradeep J. Nathan
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne, University of Technology, Victoria, Australia
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne University of Technology, Melbourne, Australia.Search for more papers by this authorAbstract
L-Theanine (δ-glutamylethylamide) is one of the predominant amino acids ordinarily found in green tea, and historically has been used as a relaxing agent. The current study examined the acute effects of L-theanine in comparison with a standard benzodiazepine anxiolytic, alprazolam and placebo on behavioural measures of anxiety in healthy human subjects using the model of anticipatory anxiety (AA). Sixteen healthy volunteers received alprazolam (1 mg), L-theanine (200 mg) or placebo in a double-blind placebo-controlled repeated measures design. The acute effects of alprazolam and L-theanine were assessed under a relaxed and experimentally induced anxiety condition. Subjective self-reports of anxiety including BAI, VAMS, STAI state anxiety, were obtained during both task conditions at pre- and post-drug administrations. The results showed some evidence for relaxing effects of L-theanine during the baseline condition on the tranquil–troubled subscale of the VAMS. Alprazolam did not exert any anxiolytic effects in comparison with the placebo on any of the measures during the relaxed state. Neither L-theanine nor alprazalam had any significant anxiolytic effects during the experimentally induced anxiety state. The findings suggest that while L-theanine may have some relaxing effects under resting conditions, neither L-theanine not alprazolam demonstrate any acute anxiolytic effects under conditions of increased anxiety in the AA model. Copyright © 2004 John Wiley & Sons, Ltd.
REFERENCES
- American Psychiatric Association. 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington, DC.
- Baas JM, Grillon C, Brocker KBE, et al. 2002. Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology (Berl) 161: 233–247.
- Barlow DH, Chorpita BF, Turovsky J. 1996. Fear, panic, anxiety, and disorders of emotion. Nebraska Symp Motiv 43: 251–328.
- Beck AT, Steer RA. 1987. Beck Anxiety Inventory: Manual. The Psychological Corporation: San Antonio, TX.
- Beck AT, Steer RA, Brown GK. 1996. Manual for Beck Depression Inventory-II. The Psychological Corporation: San Antonio, TX.
- Bellodi L, Perna G, Caldirola D, Arancio C, Bertani A, Di Bella D. 1998. CO2-induced panic attacks: a twin study. Am J Psychiatry 155: 1184–1188.
- Benkelfat C, Bradwejn J, Meyer E, Ellenbogen M, Milot S. 1995. Functional neuroanatomy of CCK4-induced anxiety in normal healthy volunteers. Am J Psychiatry 152: 1180–1184.
- Bitsios P, Philpott A, Langley RW, Bradshaw CM, Szabadi E. 1999. Comparison of the effects of diazepam on the fear-potentiated startle reflex and the fear-inhibited light reflex in man. J Psychopharmacol 13: 226–234.
- Bond A, Lader M. 1974. The use of analogue scales in rating subjective feelings. Br J Med Psychol 80: 1–46.
- Boshuisen ML, Ter Horst GJ, Paans AM, Reinders AA, den Boer JA. 2002. rCBF differences between panic disorder patients and control subjects during anticipatory anxiety and rest. Biol Psychiatry 52: 126–135.
- Bradwejn J, Koszycki D, Paradis M, Reece P, Hinton J, Sedman A. 1995. Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers. Biol Psychiatry 38: 742–746.
- Casimir J, Jadot J, Renard M. 1960. Separation and characterisation of N-ethyl-δ-glutamine in Xerocomus badius (Boletus ladius). Biochem Biophys Acta 39: 462–468.
- Charney DS. 2003. Neuroanatomical circuits modulating fear and anxiety behaviors. Acta Psychiatr Scand 108(Suppl. 417): 38–50.
- Chua P, Kram M, Toni I, Passingham R, Dolan R. 1999. A functional anatomy of anticipatory anxiety. Neuroimage 9: 563–571.
- Davis M. 1984. The mammalian startle response. In Neural Mechanisms of Startle Behaviour, RC Eaton (ed.). Plenum Press: New York; 287–351.
10.1007/978-1-4899-2286-1_10 Google Scholar
- de Montigny C. 1989. Cholecystokinin tetrapeptide induces panic like attacks in healthy volunteers. Preliminary findings. Arch Gen Psychiat 46: 511–517.
- Deakin JFW, Graeff FB. 1991. 5-HT and mechanisms of defense. J Psychopharmacol 5: 305–315.
- Fawcett JA, Kravitz HM. 1982. Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action. Pharmacotherapy 2: 243–254.
- Graeff FG. 2002. On serotonin and experimental anxiety. Psychopharmacology 157: 256–262.
- Graeff FG. 2003. Pharmacology of human experimental anxiety. Braz J Med Biol Res 36: 421–432.
- Graeff FG, Zuardi AW, Giglio JS, Lima Filho EC, Karniol IG. 1985. Effect of metergoline on human anxiety. Psychopharmacology 86: 334–338.
- Gray M, Kemp AH, Silberstein RB, Nathan PJ. 2002. Neurophysiology and psychopharmacology of anticipatory anxiety. Program No. 472.4. 2002 Abstract Viewer/Itinerary Planner. Society for Neuroscience: Washington, DC.
- Gray MA, Kemp AH, Silberstein RB, Nathan PJ. 2003. Cortical neurophysiology of anticipatory anxiety: an investigation utilizing steady state probe topography (SSPT). Neuroimage 20: 975–986.
- Grillon C, Ameli R. 2001. Conditioned inhibition of fear-potentiated startle and skin conductance in humans. Psychopharmacology 38: 807–815.
- Grillon C, Ameli R, Foot M, Davis M. 1993a. Fear-potentiated startle: relationship to the level of state/trait anxiety in healthy subjects. Biol Psychiatry 33: 566–574.
- Grillon C, Ameli R, Merikangas K, Woods SW, Davis M. 1993b. Measuring the time course of anticipatory anxiety using the fear-potentiated startle reflex. Psychophysiology 30: 340–346.
- Grillon C, Ameli R, Woods SW, Merikangas K, Davis M. 1991. Fear-potentiated startle in humans: effects of anticipatory anxiety on the acoustic blink reflex. Psychophysiology 26: 588–594.
- Guimaraes FS, Kohem CL, Gus G, et al. 1989. A simple simulated public speaking test for evaluating anxiolytic drugs. Braz J Med Biol Res 22: 1083–1089.
- Hellewell JS, Guimaraes FS, Wang M, Deakin JF. 1999. Comparison of buspirone with diazepam and fluvoxamine on aversive classical conditioning in humans. J Psychopharmacol 13: 122–127.
- Hetem LA, De Souza CJ, Guimaraes AW, Graeff FG. 1996. Effect of D-fenfluramine on human experimental anxiety. Psychopharmacology 127: 276–282.
- Ito K, Nagato Y, Aoi N, et al. 1998. Effects of L-theanine on the release of alpha-brain waves in human volunteers. Nippon Nogeikagaku Kaishi 72: 153–157.
10.1271/nogeikagaku1924.72.153 Google Scholar
- Javanmard M, Shlik J, Kennedy SH, Vaccarino FJ, Houle S, Bradwejn J. 1999. Neuroanatomic correlates of CCK-4-induced panic attacks in healthy humans: a comparison of two time points. Biol Psychiatry 45: 872–882.
- Juneja LR, Chu D, Okubo T, Nagato Y, Yokogoshi H. 1999. L-Theanine, a unique amino acid of green tea and its relaxation effect in humans. Trends Food Sci Technol 10: 199–204.
- Kakuda T. 2002. Neuroprotective effects of the green tea compounds theanine and catechins. Biol Pharm Bull 25: 1513–1518.
- Kakuda T, Yanase H, Utsunomiya K, Nozawa A, Unno T, Kataoka K. 2000. Protective effect of δ-glutamylethylamide (theanine) on ischemic delayed neural death in gerbils. Neurosci Lett 289: 189–192.
- Kent JM, Mathew SJ, Gorman JM. 2002. Molecular targets in the treatment of anxiety. Biol Psychiatry 52: 1008–1030.
- Kimura R, Murata T. 1971. Influence of alkylamides of glutamic acid and related compounds on the central nervous system I. Central depressant effect of theanine. Chem Pharm Bull 19: 1257–1261.
- Laakmann G, Schule C, Lorkowski G, Baghai T, Kuhn K, Ehrentraut S. 1998. Buspirone and lorazepam in the treatment of generalized anxiety disorder in outpatients. Psychopharmacology 136: 357–366.
- Leite JR, Seabra M de L, Sartori VA, Andreatini R. 1999. The video recorded Stroop colour-word test as a new model of experimentally induced anxiety. Prog Neuropsychopharmacol Biol Psychiatry 23: 809–822.
- Lu K, Gray M, Oliver C, Nathan PJ. 2004. The neuropharmacology of L-theanine. J Herbal Pharmacotherapy. (in press).
- Lydiard RB, Ballenger JC, Rickels K. 1997. A double-blind evaluation of the safety and efficacy of abecarnil, alprazolam, and placebo in outpatients with generalized anxiety disorder. Abecarnil Work Group. J Clin Psychiatry 58(Suppl.): 11–18.
- McNair DM, Frankenthaler LM, Czerlinsky T, White TW, Sasson S, Fisher S. 1982. Simulated public speaking as a model of clinical anxiety. Psychopharmacology 77: 7–10.
- Millan MJ. 2003. The neurobiology and control of anxious states. Prog Neurobiol 70: 83–244.
- Nakano S, Gillespie HK, Hollister LE. 1978. A model for evaluation of antianxiety drugs with the use of experimentally induced stress: comparison of nabilone and diazepam. Clin Pharmacol Ther 23: 54–62.
- Palma SM, Guimaraes FS, Zuardi AW. 1994. Anxiety induced by simulated public speaking and stroop colour word test in healthy subjects: effects of different trait-anxiety levels. Braz J Med Biol Res 27: 2895–2902.
- Patrick CJ, Berthot BD, Moore JD. 1996. Diazepam blocks fear-potentiated startle in humans. J Abnorm Psychol 105: 89–96.
- Ponto LL, Kathol RG, Kettelkamp R, et al. 2002. Global cerebral blood flow after CO2 inhalation in normal subjects and patients with panic disorder determined with [15O] water and PET. J Anxiety Disord 16: 247–258.
- Reiman EM, Fusselman MJ, Fox PT, Raichle ME. 1989. Neuroanatomical correlates of anticipatory anxiety. Science 243: 1071–1074.
- Riba J, Rodriguez-Fornells A, Urbano G, Monte A, Antonijoan R, Barbanoj MJ. 2001. Differential effects of alprazolam on the baseline and fear-potentiated startle reflex in humans: a dose-response study. Psychopharmacology 157: 358–367.
- Sadzuka Y, Sugiyama T, Suzuki T, Sonobe T. 2001. Enhancement of the activity of doxorubicin by inhibition of glutamate transporter. Toxicol Lett 123: 159–167.
- Sakato Y. 1949. The chemical constituents of tea; III. A new amide theanine. Nippon Nogeikagaku Kaishi 23: 262–267.
10.1271/nogeikagaku1924.23.262 Google Scholar
- Sheikh JI, Swales PJ. 1999. Treatment of panic disorder in older adults: a pilot study comparison of alprazolam, imipramine and placebo. Int J Psychiatry Med 29: 91–95.
- Silva M, Hetem LB, Guimaraes FS, Graeff FG. 2001. Opposite effects of nefazodone in two human models of anxiety. Psychopharmacology (Berl) 156: 454–460.
- Simpson JR, Drevets WC, Snyder AZ, et al. 2001. Emotion-induced changes in human medial prefrontal cortex: II. During anticipatory anxiety. PNAS 98: 688–693.
- Somogyi P, Hodgson AJ, Smith AD, Nunzi MG, Gorio A, Wu JY. 1984. Different populations of GABA-ergic neurons in the visual cortex and hippocampus of cat contain somatostatin or cholecystokinin-immunoreactive material. J Neurosci 4: 2590–2603.
- Spielberger CD, Gorsuch RL, Lushene RE. 1970. Manual for the State-Trait Anxiety Inventory. Consulting Psychologist Press: Palo Alto, CA.
10.1037/013734 Google Scholar
- Stewart R, Devous MD, Rush AJ, et al. 1988. Cerebral blood flow changes during sodium lactate induced panic attacks. Am J Psychiatry 145: 442–449.
- Terashima T, Takido J, Yokogoshi H. 1999. Time-dependent changes of amino acids in the serum, liver, brain and urine of rats administered with theanine. Biosci Biotech Biochem 63: 615–618.
- Tillfors M, Furmark T, Marteinsdottir I, Fredrikson M. 2002. Cerebral blood flow during anticipatory of public speaking in social phobia: a PET study. Biol Psychiatry 52: 1113–1119.
- Tulen JH, Moleman P, Boomsma F, van Steenis HG, van den Heuij VJ. 1991. Dose-dependent effects of intravenous lorazepam on cardiovascular activity, plasma catecholamines and psychological function during rest and mental stress. Psychopharmacology 105: 77–83.
- Yokogoshi H, Kobayashi M, Mochizuki M, Terashima T. 1998a. Effect of theanine, r-glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats. Neurochem Res 23: 667–673.
- Yokogoshi H, Mochizuki M, Saitoh K. 1998b. Theanine-induced reduction of brain serotonin concentration in rats. Biosci Biotech Biochem 62: 816–817.
- Zedkova L, Coupland NJ, Man GC, Dinsa G, Sanghera G. 2003. Panic-related responses to pentagastrin, flumazenil, and thyrotropin-releasing hormone in healthy volunteers. Depress Anxiety 17: 78–87.
- Zuardi AW, Cosme RA, Graeff FG, Duimaraes FS. 1993. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol 7: 82–88.
- Zwanzger P, Eser D, Aicher S, et al. 2003a. Effects of alprazolam on cholecystokinin-tetrapeptide (CCK-4) induced panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study. Neuropsychopharmacology 28: 979–984.
- Zwanzger P, Jarry H, Eser D, et al. 2003b. Plasma gamma-amino-butyric-acid (GABA) levels in cholecystokinin-tetrapeptide (CCK-4) induced anxiety. J Neural Transm 110: 313–316.