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Original Paper
Neuropsychobiology 2017;75:46–51
DOI: 10.1159/000480053
Valeriana officinalis Root Extract
Modulates Cortical Excitatory Circuits
in Humans
Ludovico Mineo a Carmen Concerto a Dhaval Patel b Tyrone Mayorga b
Michael Paula b Eileen Chusid b Eugenio Aguglia c Fortunato Battaglia a
a Department of Interprofessional Health Science and Health Administration, Seton Hall University,
South Orange, NJ , and
b Department of Preclinical Sciences, New York College of Podiatric Medicine,
New York, NY , USA;
c Department of Clinical and Molecular Biomedicine, Psychiatry Unit, University of
Catania, Catania , Italy
parameters: resting motor threshold, motor-evoked poten-
tial amplitude, cortical silent period, short-interval intracorti-
cal inhibition, and intracortical facilitation. Furthermore, we
assessed sensorimotor integration by short-latency and
long-latency afferent inhibition. Results: We found a signifi-
cant reduction in ICF, without any significant changes in oth-
er 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.
© 2017 S. Karger AG, Basel
Introduction
Despite the availability of effective pharmacological
and psychotherapy strategies, up to 50% of cases of de-
pression, anxiety, and insomnia are nonresponders and
Keywords
Valerian · Transcranial magnetic stimulation · Short-interval
intracortical inhibition · Intracortical facilitation · Cortical
excitability
Abstract
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 transmis-
sion, the mechanism of action has not been fully investigat-
ed in humans. Noninvasive brain stimulation protocols can
be used to elucidate the mechanisms of action of psychoac-
tive 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 stimula-
tion (TMS). Methods: Fifteen healthy volunteers participated
in a double-blind, randomized, cross-over, placebo-con-
trolled study. Subjects were required to take either 900 mg
of VE (valerenic acid 0.8%) or placebo (an equal dose of vita-
min E). Motor cortex excitability was studied by single and
paired TMS before and at 1 h and 6 h after the oral adminis-
tration. Cortical excitability was assessed using different TMS
Received: June 6, 2017
Accepted after revision: August 7, 2017
Published online: October 17, 2017
Dr. Fortunato Battaglia
Seton Hall University
400 South Orange Avenue
South Orange, NJ 07079 (USA)
E-Mail fortunato.battaglia @ shu.edu
© 2017 S. Karger AG, Basel
www.karger.com/nps
Ludovico Mineo and Carmen Concerto contributed equally to this
work.
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Valerian and Cortical Circuits Neuropsychobiology 2017;75:46–51
DOI: 10.1159/000480053
47
show relapses [1] . Indeed, there is well-documented evi-
dence that individuals who have found little or no im-
provement through standard interventions often use
herbal remedies for the treatment of these conditions. It
has been reported that 50% of patients suffering from de-
pression, anxiety, and insomnia use complementary and
alternative medicine
[2] .
Although herbal therapies have been used for centu-
ries as remedies for psychiatric conditions, research fo-
cusing on assessing the effectiveness of botanical psycho-
active plants used in psychiatry and their psychopharma-
cological properties in humans is still inconclusive for
many compounds
[3] . Among herbal medications for in-
somnia and anxiety, Valeriana officinalis root extract
(VE) is one of the most popular
[4] . A previous survey
study reported that 1.1% of the adult population in the
USA (approx. 2 million adults) had used valerian in the
past week
[5] . Other studies indicate that VE has antioxi-
dant and neuroprotective effects
[6–9] . Furthermore, VE
modulates brain neurotransmitters
[10–14] , and shows
antianxiety, antidepressant, and antiepileptic activity in
animal models
[15, 16] .
In spite of this preclinical evidence and the large em-
pirical use of VE, there is an ongoing debate in the scien-
tific literature regarding the magnitude of its effects and,
to date, no studies have investigated the acute effect of VE
administration on cortical excitability in humans. Tran-
scranial magnetic stimulation (TMS), a noninvasive tech-
nique widely used to investigate cortical physiology in
humans, has been a valid tool to probe the acute pharma-
cological effects of central nervous system active drugs
[17] . Indeed, pharmaco-TMS experiments offer the op-
portunity of investigating the mechanism of action of
psychoactive molecules by analyzing their effects on well-
characterized single-and paired-pulse TMS parameters
such as resting motor threshold (RMT), motor-evoked
potential (MEP) amplitude, cortical silent period (CSP),
short-interval intracortical inhibition (SICI), intracorti-
cal facilitation (ICF), and short-latency and long-latency
afferent inhibition (SAI and LAI)
[18] . Indeed, the modu-
lation of the physiological mechanisms underlying these
parameters after drug intake offers the possibility to
translate the preclinical results to human use, and to
probe, noninvasively, the activity on specific cortical
functions like membrane excitability (RMT), corticospi-
nal excitability (MEP size), GABA
B -dependent inhibition
(CSP), intracortical inhibitory and excitatory circuits
(SICI and ICF), and sensorimotor integration (SAI and
LAI)
[18] .
Hence, to elucidate the mechanism of action and the
neuroactive properties of VE, we sought to investigate the
acute effect of a recommended dose in a randomized,
double-blind, cross-over study employing a broad array
of TMS measures of human motor cortex excitability. In
view of the extensive preclinical literature, we hypothe-
sized that compared to placebo VE would induce a mod-
ulation of intracortical inhibitory and excitatory circuits.
Methods
Subjects
Fifteen healthy, right-handed college students
[19] (9 males
and 6 females; mean age 30.2 ± 5.8 years) participated in this study.
We excluded subjects who had a history of neurological or psychi-
atric diseases, metal implants, brain trauma, psychoactive medica-
tion use, drug addiction, a family history of epilepsy, or were preg-
nant. The study conformed to the Declaration of Helsinki and was
approved by the Institutional Review Board at the New York Col-
lege of Podiatric Medicine. All subjects signed a written consent
form. None of the subjects took herbal extracts before this study.
Study Design
This was a randomized, double-blind, cross-over study; sub-
jects were required to take 3 capsules (900 mg in total) of VE (the
active arm) or placebo. Commercial VE capsules (300 mg each)
contained a standardized amount of valerenic acid (0.8%). The
“dummy” capsules contained an equal amount of vitamin E; these
were prepared by a pharmacist and put into an empty bottle of the
commercial product. In this way, the placebo preparation assimi-
lated the typical valerian root odor. The order of drug conditions
was pseudorandomized and balanced between subjects. All sub-
jects participated in 2 drug conditions, separated by 3 weeks. In
accordance with a previous pharmacokinetic study
[20] , the sub-
jects were assessed at T0 (before the intake), and at 1 h (T1) and
6 h (T2) after the intake of the capsules.
Cortical Excitability
TMS experiments were performed during the morning hours.
Ag-AgCl surface electrodes were positioned over the muscle belly
and the tendon of the right abductor pollicis brevis (APB) muscle.
Signals were amplified, band-pass-filtered, and sampled using a
micro 1401 AD converter (Cambridge Electronic Design, Cam-
bridge, UK) controlled by Signal software (Cambridge Electronic
Design v3) and stored on a PC for off-line analysis. TMS was de-
livered through a focal figure of eight-shaped magnetic coil (diam-
eter of external loop: 90 mm) connected to 2 Magstim 200 mag-
netic stimulators via a “Y” cable (The Magstim Co., Dyfed, UK).
Several parameters of corticospinal excitability were investigated.
RMT, a parameter that depends upon neuronal membrane excit-
ability as it is modulated by voltage-gated sodium or calcium-
channel blockers, was determined as the minimum stimulator in-
tensity to the nearest 1% to produce an MEP of 50 μV in 5 of 10
trials. We then assessed mean peak-to-peak MEP amplitudes, a
parameter that reflects changes in the excitability of the corticospi-
nal tract, using a stimulus intensity of 120% of the RMT (an aver-
age of 20 MEPs). CSP was tested by delivering TMS of the motor
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48
cortex during tonic APB contraction (50% of the maximal volun-
tary contraction, assessed and monitored with a visual electromyo-
graphic [EMG] feedback). The duration of 15 CSPs was measured
from the end of the MEP until the restart of constant EMG activ-
ity. EMG traces were rectified but not averaged. CSP is modulated
by GABA-ergic and dopaminergic drugs. If a subthreshold (con-
ditioning) stimulus precedes a suprathreshold (test) stimulus at
short and long interstimulus intervals (ISI), the MEP generated by
the test stimulus is either inhibited (by SICI) or facilitated (by ICF).
SICI and ICF were studied with a paired-stimulation paradigm
[21] . ISIs of 2 ms (for SICI) and 10 ms (for ICF) were used. Each
study consisted of 20 trials for each ISI, and the test stimuli alone
were delivered in random order controlled by a laboratory com-
puter. These parameters assess the excitability of intracortical in-
hibitory and excitatory circuits modulated by GABA-ergic and
glutamatergic drugs.
To probe afferent inhibition, the medial nerve was stimulated
at the wrist using a Digitimer D-160 stimulator (Digitimer Ltd.,
Welwyn Garden City, UK) using electrodes with the cathode po-
sitioned proximally. Stimulus intensity was adjusted to produce a
slight thumb twitch. SAI and LAI were tested at ISIs of 25 and 200
ms. Forty stimuli were delivered at each ISI, and randomly inter-
mingled with 20 trials in which MEPs were elicited by the test stim-
ulus alone. SAI and LAI are modulated by cholinergic and GABA-
ergic drugs. For a comprehensive review of the pharmacological
modulation of TMS parameters, see Ziemann et al. 2015
[18] . For
SICI, ICF, SAI, and LAI, the mean amplitude of the conditioned
MEP was expressed as a percentage of the unconditioned (test)
MEP mean amplitude.
F-wave amplitude and M
max (supramaximal electrical stimula-
tion of the median nerve at the wrist) were tested to investigate
changes in spinal motorneuron and neuromuscular excitability.
TMS parameters were tested according to the published guidelines
for the use of TMS in clinical neurophysiology
[22] .
Statistical Analysis
Data were analyzed using SPSS software v22.0 (SPSS Inc., Chi-
cago, IL, USA). All the tested parameter of cortical excitability,
spinal excitability, and sensorimotor integration (RMT, MEP,
CSP, SICI, ICF, SAI, LAI, F-wave, and M
max ) were analyzed using
a 2-way repeated-measures ANOVA with the main effects “Group”
(VE or placebo) and “Time” (T0, T1, and T2). We used the Mauch-
ly test to assess the sphericity and applied the Greenhouse-Geisser
correction when appropriate. The repeated-measure analyses were
followed by pair-wise comparison with the Bonferroni correction.
Data are means ± SE. An α value of <0.05 was considered signifi-
cant.
Results
The study was well-tolerated without adverse events.
RMT, MEP amplitude, CSP duration, sensorimotor inte-
gration assessed with SAI and LAI, and neuromuscular
and motorneurons and excitability assessed with M
max
and F-wave did not differ between groups ( Table1 ). We
then tested intracortical excitability with the paired-pulse
paradigm. SICI was not affected by valerian intake (VE:
T0 38.54 ± 4.2%, T1 34.1 ± 4.9%, and T2 39.68 ± 3.7%;
placebo: T0 43.17 ± 4.3%, T1 41.1 ± 4.3%, and T2 42.04 ±
4.5% [Group: F
1, 56 = 0.71, p = 0.4; Time: F
2, 56 = 1.3, p =
0.2; Group × Time interaction: F
2, 56 = 0.52, p = 0.5]).
However, VE intake decreased the amount of ICF (VE:
T0 150.9 ± 7%, T1 114.8 ± 6.9%, and T2 155.7 ± 7.6%;
placebo: T0 153.4 ± 6.1%, T1 155.5 ± 5.7%, and T2 159.4
± 6.3% [Group: F
1, 56 = 3.5, p = 0.06; Time: F
2, 56 = 17.4,
p ≤ 0.0001; Group × Time interaction: F
2, 56 = 15, p ≤
0.0001]). Post hoc analysis indicated that there was a sta-
tistically significant difference between T0 and T1 ( p ≤
0.0001) but no difference between T0 and T2 ( p = 0.1).
The pair-wise comparison also indicated that in the VE
Table 1. Comparison of cortical excitability, sensorimotor integration, and neuromuscular and notorneuronal excitability before (T0)
and 1 h (T1) and 6 h (T2) after VE and placebo intake
VE Placebo Group × Time
interaction
T0 T1 T2 T 0 T1 T2
RMT, % 43.2 ± 1.9 43 ± 1.4 43.2 ± 1.9 43.4 ± 1.8 43.3 ± 2 43.5 ± 1.8 F2, 56 = 0.01, p = 0.9
MEP, mV 0.67 ± 0.08 0.69 ± 0.07 0.73 ± 0.08 0.75 ± 0.07 0.76 ± 0.1 0.71 ± 0.08 F2, 56 = 0.8, p = 0.4
CSP, ms 139.6 ± 3.6 139.5 ± 3.7 140.2 ± 3.7 143.3 ± 3.7 144.7 ± 2.9 142.8 ± 2.9 F2, 56 = 1.1, p = 0.3
SAI, % 85.5 ± 4.1 82.7 ± 4 84.4 ± 4.1 82.3 ± 4.4 81.7 ± 4.7 82.2 ± 3.6 F2, 56 = 0.03, p = 0.9
LAI, % 73.4 ± 5 74.3 ± 4.6 75 ± 5.1 88.7 ± 5.5 81.5 ± 3.6 82.5 ± 4.8 F2, 56 = 0.03, p = 0.9
Mmax, mV 16 ± 1.1 16.4 ± 1 16.4 ± 1 15.6 ± 1.2 15.4 ± 1.1 15.7 ± 1.3 F2, 56 = 0.7, p = 0.9
F-wave
amplitude, μV 311.1 ± 19.7 310.4 ± 13.1 304.9 ± 12.9 280.8 ± 17.9 284.6 ± 17.9 296.8 ± 19.2 F2, 56 = 0.47, p = 0.69
Error bars indicate standard errors. RMT, resting motor threshold; MEP, motor-evoked potential; CSP, cortical silent period; SAI,
short-latency afferent inhibition; LAI, long-latency afferent inhibition; Mmax, maximum M wave; VE, Valeriana officinalis extract.
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49
group, there was a difference between T0 and T1 ( p =
0.001) but not between T0 and T2 ( p = 0.5). The amount
of ICF did not change in the placebo group (T0 vs. T1:
p = 0.2; T0 vs. T2: p = 0.7) ( Fig.1 ).
Discussion
The results of this study provide evidence that acute
administration of VE in healthy humans affects motor
cortex excitability with a specific effect on the ICF. The
decrease in the amount of ICF is reversible.
Mechanistically, the impact of acute VE intake on cor-
tical excitability can be explained by taking the physiol-
ogy of ICF into consideration. In cortical brain slices, a
single electrical stimulus to the deep cortical layers evokes
a sequence of postsynaptic potentials (PSPs) in the resting
neuron: first, a brief excitation, then a short-latency fast
inhibition, and then long-latency, more prolonged inhi-
bition
[23] . It has been suggested that ICF relates to slow
excitatory PSPs induced by activation of the N-methyl-
D -
aspartate (NMDA) receptor
[24] , and indexes GABA
A re-
ceptor activity (the fast-inhibition PSP)
[18] . Previous
pharmaco-TMS studies demonstrated that ICF is de-
creased by the NMDAR antagonists, dextromethorphan
[25] , memantine [26] , and riluzole [27] . In addition, the
contribution of GABA
A inhibition to ICF is supported by
the decrease in ICF induced by a single dose of lorazepam
[28] , zolpidem, and diazepam [29] , indicating that GA-
BA
A agonists contribute to the net facilitation represent-
ed by ICF. In contrast, NE system modulators enhance
ICF
[30] . These mechanisms are remarkably consistent
with the premise that VE, and, particularly valerenic acid,
the main component of VE, allosterically modulate GA-
BA
A receptors and, in this way, are thought to induce anx-
iolytic activity
[31–34] . A similar modulatory effect on
the GABA
A channel was demonstrated for other compo-
nents of the VE such as alerenol, 6-methylapigenin, and
linarin
[35, 36] . To this extent, our findings provide sup-
port for a similar modulation in humans. The lack of ef-
fect on SICI might be explained by the fact that valerenic
acid is a subunit-specific (β
3 ) allosteric modulator of GA-
BA
A receptors [34, 37] . Furthermore, a point mutation in
the β
3 GABA A receptor subunit prevents the ability of
valerenic acid to display anxiolytic-like activity in vivo
while the administration of diazepam still maintains the
anxiolytic-like activity, as tested with the elevated plus
maze and the light/dark choice tests
[32] . These data in-
dicate that VE targets neuronal circuits expressing β
3 -
containing GABA
A receptors, while the anxiolytic activ-
ity of benzodiazepines has been shown to be mediated via
α
2 GABA A receptors [38] . This specific inhibitory effect
might explain the lack of activity on SICI and the net ef-
fect on ICF.
In addition, there is in vitro and in vivo evidence that
VE modulates glutamatergic neurotransmission. For in-
stance, valerian and valerenic acid have anxiolytic prop-
erties as tested with the dark/light preference task with
zebrafish. This anxiolytic effect of valerian and valerenic
acid is abolished after the administration of LAP3 (an
mGluR I antagonist) and EGLU (an mGluR II antagonist)
[39] . Furthermore, VE has a modest inhibitory effect on
3H dizocilpine (MK-801) binding, an indicator of NMDA-
valerian interactions
[40] . In light of the modest effect on
the NMDA receptor, it is likely that the modulation of
glutamatergic neurotransmission does not play a pivotal
role in inducing the decrease in ICF that we observed in
our study.
There is evidence that VE can reduce the turnover of
5-hydroxytryptamine and norepinephrine (NE) in the
hippocampus and amygdala, reducing, in this way, the
negative effect of stress in mice
[14] . In addition, VE ad-
ministration in rats decreased NE, dopamine, and 5-hy-
droxytryptamine concentrations in the frontal cortex
[41] . A similar effect at the cortical level in humans could
be capable of influencing the amount of ICF
[18] . We
should acknowledge that calcium-channel agonists con-
sistently increase ICF
[30] ; nonetheless, the assumption
of a top-down regulation of ICF induced by the NE brain
170
160
150
140
130
120
110
100
ICF, % of the unconditioned MEP
T0 T1 T2
**
Ve
ଶ Placebo
Fig. 1. VE intake induced a reversible decrease in the amount of
ICF. Error bars represent standard error of the mean. * * p < 0.01.
VE, Valeriana officinalis extract; ICF, intracortical facilitation;
MEP, motor-evoked potential. T0, before the intake; T1, 1 h after
the intake; T2, 6 h after the intake.
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concentration is speculative at the moment. Further-
more, previous TMS studies carried out in a clinical con-
text highlighted the electrophysiological role of ICF
changes as potential markers of a glutamate-mediated
adaptive response or compensatory neuroplastic phe-
nomena
[42–47] . Thus, we cannot rule out an indirect
(adaptive) modulatory effect on ICF.
This study has limitations. First we tested only the rec-
ommended therapeutic dose. Future studies should ad-
dress dose-dependent effects on cortical excitability. In
addition, we tested only 1 commercially available, stan-
dardized VE that contained a high concentration of
valerenic acid. Different VE formulations should be in-
vestigated to assess the contribution of different active
molecules. In our study, an acute dose of α-tocoferol did
not affect cortical excitability in humans, but we cannot
exclude a possible modulation of TMS parameters not in-
vestigated in the study. Lastly, the results need to be rep-
licated in larger studies measuring the overall significance
of the explanatory variables and the way they are com-
bined, not just the individual variables by themselves.
In conclusion, these findings provide the first evidence
that VE affects excitatory intracortical circuits in humans.
We expect that these results will encourage pharmaco-
TMS research aimed at advancing our understanding of
the mechanism of action of complementary and alterna-
tive medicine currently used as a treatment for a variety
of neurological and psychiatric disorders. It remains to be
determined whether the VE neuromodulatory effects are
present in depressed patients and correlate with disease
severity and clinical outcome.
Disclosure Statement
The authors declare no conflict of interest.
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