Background:Valeriana officinalis extract (VE) is a popular herbal medicine used for the treatment of anxiety and sleep disorders. Although the anxiolytic and sedative effects are mainly attributed to the modulation of GABA-ergic transmission, the mechanism of action has not been fully investigated in humans. Noninvasive brain stimulation protocols can be used to elucidate the mechanisms of action of psychoactive substances at the cortical level in humans. In this study, we investigated the effects of a single dose of VE on cortical excitability as assessed with transcranial magnetic stimulation (TMS). Methods: Fifteen healthy volunteers participated in a double-blind, randomized, cross-over, placebo-controlled study. Subjects were required to take either 900 mg of VE (valerenic acid 0.8%) or placebo (an equal dose of vitamin E). Motor cortex excitability was studied by single and paired TMS before and at 1 h and 6 h after the oral administration. Cortical excitability was assessed using different TMS parameters: resting motor threshold, motor-evoked potential amplitude, cortical silent period, short-interval intracortical inhibition, and intracortical facilitation. Furthermore, we assessed sensorimotor integration by short-latency and long-latency afferent inhibition. Results: We found a significant reduction in ICF, without any significant changes in other TMS measures of motor cortex excitability. The amount of ICF returned to baseline value 6 h after the intake of the VE. Conclusion: A single oral dose of VE modulates intracortical facilitatory circuits. Our results in healthy subjects could be predictive markers of treatment response in patients and further support the use of pharmaco-TMS to investigate the neuropsychiatric effects of herbal therapies in humans.

Keywords:
Intracortical facilitation, Cortical excitability, Valerian, Transcranial magnetic stimulation, Short-interval intracortical inhibition
1.
Nelson JC, Portera L, Leon AC: Residual symptoms in depressed patients after treatment with fluoxetine or reboxetine. J Clin Psychiatry 2005;66:1409-1414.
2.
Kessler RC, Soukup J, Davis RB, Foster DF, Wilkey SA, Van Rompay MI, Eisenberg DM: The use of complementary and alternative therapies to treat anxiety and depression in the United States. Am J Psychiatry 2001;158:289-294.
3.
Thirthalli J, Zhou L, Kumar K, Gao J, Vaid H, Liu H, Hankey A, Wang G, Gangadhar BN, Nie JB, Nichter M: Traditional, complementary, and alternative medicine approaches to mental health care and psychological wellbeing in India and China. Lancet Psychiatry 2016;3:660-672.
4.
Hadley S, Petry JJ: Valerian. Am Fam Physician 2003;67:1755-1758.
5.
Bruno JJ, Ellis JJ: Herbal use among US elderly: 2002 National Health Interview Survey. Ann Pharmacother 2005;39:643-648.
6.
Sudati JH, Fachinetto R, Pereira RP, Boligon AA, Athayde ML, Soares FA, de Vargas Barbosa NB, Rocha JB: In vitro antioxidant activity of Valeriana officinalis against different neurotoxic agents. Neurochem Res 2009;34:1372-1379.
7.
Yoo DY, Jung HY, Nam SM, Kim JW, Choi JH, Kwak YG, Yoo M, Lee S, Yoon YS, Hwang IK: Valeriana officinalis extracts ameliorate neuronal damage by suppressing lipid peroxidation in the gerbil hippocampus following transient cerebral ischemia. J Med Food 2015;18:642-647.
8.
de Oliveria DM, Barreto G, De Andrade DV, Saraceno E, Aon-Bertolino L, Capani F, Dos Santos El Bacha R, Giraldez LD: Cytoprotective effect of Valeriana officinalis extract on an in vitro experimental model of Parkinson disease. Neurochem Res 2009;34:215-220.
9.
Malva JO, Santos S, Macedo T: Neuroprotective properties of Valeriana officinalis extracts. Neurotox Res 2004;6:131-140.
10.
Awad R, Levac D, Cybulska P, Merali Z, Trudeau VL, Arnason JT: Effects of traditionally used anxiolytic botanicals on enzymes of the gamma-aminobutyric acid (GABA) system. Can J Physiol Pharmacol 2007;85:933-942.
11.
Cavadas C, Araujo I, Cotrim MD, Amaral T, Cunha AP, Macedo T, Ribeiro CF: In vitro study on the interaction of Valeriana officinalis L. extracts and their amino acids on GABAA receptor in rat brain. Arzneimittelforschung 1995;45:753-755.
12.
Del Valle-Mojica LM, Ayala-Marin YM, Ortiz-Sanchez CM, Torres-Hernandez BA, Abdalla-Mukhaimer S, Ortiz JG: Selective interactions of Valeriana officinalis extracts and valerenic acid with Hglutamate binding to rat synaptic membranes. Evid Based Complement Alternat Med 2011;2011:403591.
13.
Del Valle-Mojica LM, Cordero-Hernandez JM, Gonzalez-Medina G, Ramos-Velez I, Berrios-Cartagena N, Torres-Hernandez BA, Ortiz JG: Aqueous and ethanolic Valeriana officinalis extracts change the binding of ligands to glutamate receptors. Evid Based Complement Alternat Med 2011;2011:891819.
14.
Jung HY, Yoo DY, Kim W, Nam SM, Kim JW, Choi JH, Kwak YG, Yoon YS, Hwang IK: Valeriana officinalis root extract suppresses physical stress by electric shock and psychological stress by nociceptive stimulation-evoked responses by decreasing the ratio of monoamine neurotransmitters to their metabolites. BMC Complement Alternat Med 2014;14:476.
15.
Muller LG, Salles LA, Stein AC, Betti AH, Sakamoto S, Cassel E, Vargas RF, von Poser GL, Rates SM: Antidepressant-like effect of Valeriana glechomifolia Meyer (Valerianaceae) in mice. Progr Neuropsychopharmacol Biol Psychiatry 2012;36:101-109.
16.
Torres-Hernandez BA, Del Valle-Mojica LM, Ortiz JG: Valerenic acid and Valeriana officinalis extracts delay onset of pentylenetetrazole (PTZ)-induced seizures in adult Danio rerio (Zebrafish). BMC Complement Alternat Med 2015;15:228.
17.
Ziemann U: TMS and drugs. Clin Neurophysiol 2004;115:1717-1729.
18.
Ziemann U, Reis J, Schwenkreis P, Rosanova M, Strafella A, Badawy R, Muller-Dahlhaus F: TMS and drugs revisited 2014. Clin Neurophysiol 2015;126:1847-1868.
19.
Oldfield RC: The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 1971;9:97-113.
20.
Anderson GD, Elmer GW, Kantor ED, Templeton IE, Vitiello MV: Pharmacokinetics of valerenic acid after administration of valerian in healthy subjects. Phytother Res 2005;19:801-803.
21.
Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD: Corticocortical inhibition in human motor cortex. J Physiol 1993;471:501-519.
22.
Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, Di Lazzaro V, Ferreri F, Fitzgerald PB, George MS, Hallett M, Lefaucheur JP, Langguth B, Matsumoto H, Miniussi C, Nitsche MA, Pascual-Leone A, Paulus W, Rossi S, Rothwell JC, Siebner HR, Ugawa Y, Walsh V, Ziemann U: Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol 2015;126:1071-1107.
23.
Connors BW, Malenka RC, Silva LR: Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat. J Physiol 1988;406:443-468.
24.
Hwa GG, Avoli M: Excitatory synaptic transmission mediated by NMDA and non-NMDA receptors in the superficial/middle layers of the epileptogenic human neocortex maintained in vitro. Neurosci Lett 1992;143:83-86.
25.
Ziemann U, Chen R, Cohen LG, Hallett M: Dextromethorphan decreases the excitability of the human motor cortex. Neurology 1998;51:1320-1324.
26.
Schwenkreis P, Liepert J, Witscher K, Fischer W, Weiller C, Malin JP, Tegenthoff M: Riluzole suppresses motor cortex facilitation in correlation to its plasma level. A study using transcranial magnetic stimulation. Exp Brain Res 2000;135:293-299.
27.
Liepert J, Schwenkreis P, Tegenthoff M, Malin JP: The glutamate antagonist riluzole suppresses intracortical facilitation. J Neural Transm (Vienna) 1997;104:1207-1214.
28.
Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W: The effect of lorazepam on the motor cortical excitability in man. Exp Brain Res 1996;109:127-135.
29.
Mohammadi B, Krampfl K, Petri S, Bogdanova D, Kossev A, Bufler J, Dengler R: Selective and nonselective benzodiazepine agonists have different effects on motor cortex excitability. Muscle Nerve 2006;33:778-784.
30.
Boroojerdi B, Battaglia F, Muellbacher W, Cohen LG: Mechanisms influencing stimulus-response properties of the human corticospinal system. Clin Neurophysiol 2001;112:931-937.
31.
Trauner G, Khom S, Baburin I, Benedek B, Hering S, Kopp B: Modulation of GABAA receptors by valerian extracts is related to the content of valerenic acid. Planta Med 2008;74:19-24.
32.
Benke D, Barberis A, Kopp S, Altmann KH, Schubiger M, Vogt KE, Rudolph U, Mohler H: GABAA receptors as in vivo substrate for the anxiolytic action of valerenic acid, a major constituent of valerian root extracts. Neuropharmacology 2009;56:174-181.
33.
Murphy K, Kubin ZJ, Shepherd JN, Ettinger RH: Valeriana officinalis root extracts have potent anxiolytic effects in laboratory rats. Phytomedicine 2010;17:674-678.
34.
Khom S, Strommer B, Ramharter J, Schwarz T, Schwarzer C, Erker T, Ecker GF, Mulzer J, Hering S: Valerenic acid derivatives as novel subunit-selective GABAA receptor ligands - in vitro and in vivo characterization. Br J Pharmacol 2010;161:65-78.
35.
Fernandez S, Wasowski C, Paladini AC, Marder M: Sedative and sleep-enhancing properties of linarin, a flavonoid-isolated from Valeriana officinalis. Pharmacol Biochem Behav 2004;77:399-404.
36.
Marder M, Viola H, Wasowski C, Fernandez S, Medina JH, Paladini AC: 6-Methylapigenin and hesperidin: new valeriana flavonoids with activity on the CNS. Pharmacol Biochem Behav 2003;75:537-545.
37.
Khom S, Baburin I, Timin E, Hohaus A, Trauner G, Kopp B, Hering S: Valerenic acid potentiates and inhibits GABAA receptors: molecular mechanism and subunit specificity. Neuropharmacology 2007;53:178-187.
38.
Low K, Crestani F, Keist R, Benke D, Brunig I, Benson JA, Fritschy JM, Rulicke T, Bluethmann H, Mohler H, Rudolph U: Molecular and neuronal substrate for the selective attenuation of anxiety. Science 2000;290:131-134.
39.
Del Valle-Mojica LM, Ortiz JG: Anxiolytic properties of Valeriana officinalis in the zebrafish: a possible role for metabotropic glutamate receptors. Planta Med 2012;78:1719-1724.
40.
Ortiz JG, Rassi N, Maldonado PM, Gonzalez-Cabrera S, Ramos I: Commercial valerian interactions with 3Hflunitrazepam and 3HMK-801 binding to rat synaptic membranes. Phytother Res 2006;20:794-798.
41.
Sahu S, Ray K, Yogendra Kumar MS, Gupta S, Kauser H, Kumar S, Mishra K, Panjwani U: Valeriana wallichii root extract improves sleep quality and modulates brain monoamine level in rats. Phytomedicine 2012;19:924-929.
42.
Bella R, Ferri R, Pennisi M, Cantone M, Lanza G, Malaguarnera G, Spampinato C, Giordano D, Alagona G, Pennisi G: Enhanced motor cortex facilitation in patients with vascular cognitive impairment-no dementia. Neurosci Lett 2011;503:171-175.
43.
Lanza G, Bramanti P, Cantone M, Pennisi M, Pennisi G, Bella R: Vascular cognitive impairment through the looking glass of transcranial magnetic stimulation. Behav Neurol 2017;2017:1421326.
44.
Pennisi M, Lanza G, Cantone M, Ricceri R, Ferri R, D'Agate CC, Pennisi G, Di Lazzaro V, Bella R: Cortical involvement in celiac disease before and after long-term gluten-free diet: a transcranial magnetic stimulation study. PLoS One 2017;12:e0177560.
45.
Cantone M, Lanza G, Pennisi M, Bella R, Schepis C, Siragusa M, Barone R, Ferri R: Prominent neurological involvement in Dercum disease. J Neurol 2017;264:796-798.
46.
Pennisi M, Lanza G, Cantone M, Ricceri R, Spampinato C, Pennisi G, Di Lazzaro V, Bella R: Correlation between motor cortex excitability changes and cognitive impairment in vascular depression: pathophysiological insights from a longitudinal TMS Study. Neural Plast 2016;2016:8154969.
47.
Bella R, Lanza G, Cantone M, Giuffrida S, Puglisi V, Vinciguerra L, Pennisi M, Ricceri R, D'Agate CC, Malaguarnera G, Ferri R, Pennisi G: Effect of a gluten-free diet on cortical excitability in adults with celiac disease. PLoS One 2015;10:e0129218.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.