(Piper methysticum) and valerian (Valeriana officinalis) are two
natural or herbal medicines available over-the-counter and on the internet that
are used separately for the treatment of a number of ailments, but in
particular anxiety and insomnia.1-13 Since patients may not consider
these to be medications, it is possible that they may seek out natural
treatments for their conditions, especially if one or more natural medicines
and/or prescription medications are not providing the level of control desired.14-16
As such, it is plausible that coadministration of kava and valerian could
likely occur with the use of two separate supplements or where a supplement may
mix the two agents together into one dosage formulation. Either way,
their concomitant use could result in unwanted central nervous system (CNS)
side effects. This would be especially true for patients who may
already be taking benzodiazepines, such as alprazolam, diazepam, lorazepam,
oxazepam, or triazolam to name a few.
would the coadministration of kava and valerian be of potential concern for
In short, both kava and valerian are known to influence
gamma-aminobutyric acid-A (GABA-A) receptor activity that can result in CNS
depression similarities as with the use of a benzodiazepine.3,17-23 This
is why each of the agents are used for treatment of anxiety and insomnia.
While they both influence the GABA-A receptor activity, they do so through
different mechanisms.17,18,21-23 In order to understand their potential
synergistic interaction on the GABA-A receptor it is important to understand
how GABA-A receptor activation causes CNS depression.
work by potentiating the binding of the major inhibitory neurotransmitter, GABA
to the GABA-A receptor (see figure 1).19 GABA-A receptors, found in the
CNS, are most commonly made up of a combination of 5 protein subunits (2-alpha,
2-beta, and 1-gamma).19 In the absence of a benzodiazepine, GABA will
weakly bind to the alpha subunit on the GABA-A receptor and allow the
negatively charged chloride to diffuse into the neuron. However, in the
presence of a benzodiazepine, the benzodiazepine will allosterically bind to
the gamma subunit on the GABA-A receptor, which causes GABA to bind to the
alpha subunit more effectively than before.19 This causes a greater
movement of chloride into the neuron, thereby causing the neuron to be
hyperpolarized (more negatively charged inside the cell as compared to outside
the neuron; from -70 mV to about -80 mV). This now makes the neuron less
responsive to stimulation by excitatory postsynaptic potentials (EPSPs), thus
suppressing the CNS.
does kava and valerian influence GABA-A function?
As it relates to kava's influence, the proposed mechanism is
kava's ability to potentiate the binding affinity of GABA agonists to GABA-A
receptors by increasing the density of binding sites exposed on the GABA-A
receptor.18 The exact mechanism for how this increase binding sites
occurs is not known but it is possible that kava interacts with membrane lipids
in the microenvironment of the GABA-A receptor complex. This influence
would result in an indirect effect on the GABA-A receptor activity.18
it relates to valerian, the mechanism of action of valerian is similar to that
of a benzodiazepine; however, instead of binding to the gamma subunit like a
benzodiazepine, it appears to bind to the beta subunit on the GABA-A receptor
(see figure 1).22 In addition, valerian has also been shown to decrease
the removal or metabolism of GABA, thereby increasing the likelihood that GABA
will bind to its receptor and elicit the effects described above.23 Regardless,
it has the same effect on chloride movement into the neuron resulting in a
since both of these natural substances influence GABA receptor activity towards
causing CNS depression, their concomitant use could result in synergistic
activity. It is plausible that this would be even more likely to occur in
a patient already taking a benzodiazepine and/or a barbiturate.
Unfortunately, there is no meaningful data regarding the safety and efficacy of
coadministering kava and valerian together for anxiety or insomnia.
The one study published with their concomitant use in stress-induced insomnia,
was a single center, single investigator, non-randomized, non-blinded,
non-double dummy, open label study of only 24 patients, of which 5 did not
complete the study for reasons that were not made known.24,25 In
addition, this trial made no reference that it was institutional review board
(IRB) approved or provided appropriate informed consent to the patients, and
was published using the same data in a very similar format to two different
journals indexed in PubMed.24,25 As such, no objective conclusions can be
made from this study. As it relates to their concomitant use along with a
benzodiazepine or barbiturate, there are no safety or efficacy data to our
knowledge and should be avoided until such data exists.
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Alternative Medicine. Herbs at a glance: kava. June 2008. Last
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RC, Soukup J, Davis RB et al. The use of complementary and alternative
therapies to treat anxiety and depression in the United States. Am J
Center for Complementary and Alternative Medicine: National Institutes
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Institutes of Health: Office of Dietary Supplements. Valerian.
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- Health Canada. Natural Health Products. Valerian. March 30, 2007. Last accessed on 2-14-2009.
F, Quispe S, Diefenbach K et al. Critical evaluation of the effect of
valerian extract on sleep structure and sleep quality.
- Stevinson C, Ernst E. Valerian for insomnia: a systematic review of randomized clinical trials. Sleep Med 2000;1:91-9.
G, Ploch M, Miettinen-Baumann A et al. Efficacy and tolerability of
valerian extract LI 156 compared with oxazepam in the treatment of
non-organic insomnia - a randomized, double-blind, comparative clinical
study. Eur J Med Res 2002;7:480-6.
- Miyasaka LS, Atallah AN, Soares BG. Valerian for anxiety disorders. Cochrane Database Syst Rev 2006;18:CD004515.
- Ebadi M. Valerian. In: Pharmacodynamic basis of herbal medicine. 2nd Ed. Taylor & Francis Group. Boca Raton, FL. 2007:599-609.
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LP, Drew CA, Duffield P et al. Kava pyrones and resin: studies on
GABAA, GABAB and benzodiazepine binding sites in rodent brain.
Pharmacol Toxicol 1992;71:120-6.
A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper
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of rat brain. Psychopharmacology (Berl) 1994;116:469-74.
- Raffa RB, Rawls SM, Beyzarov EP. Chapter 3: Drugs Used in Disorders of the Central Nervous System and Treatment of Pain. In: Netter's Illustrated Pharmacology. Elsevier Inc. Philadelphia, PA. 2005:57-67.
A, Sloan R. Benzodiazepines and related drugs for insomnia in
palliative care. Cochrane Database Syst Rev 2002;4:CD003346.
T, Bernasconi P, Bombardelli E et al. In vitro study on the
interaction of extracts and pure compounds from Valeriana officinalis
roots with GABA, benzodiazepine and barbiturate receptors. Fitoterapia
- Benke D, Barberis A, Kopp S
et al. GABA(A) receptors as in vivo substrate for the anxiolytic action
of valerenic acid, a major constituent of valerian root extracts.
E, Hansel R, Ehrke G. Inhibition of gamma-aminobutyric acid catabolism
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D. Stress-induced insomnia treated with kava and valerian: singly and
in combination. Hum Psychopharmacol 2001;16:353-356.
- Wheatley D. Kava and valerian in the treatment of stress-induced insomnia. Phytother Res 2001;15:549-51.
- Patterson RM, Hoyle PC, Editorial Staff of the Publishers of Lawyers' Medical Cyclopedia eds. Drugs in Litigation: Damage Awards Involving Prescription and Nonprescription Drugs. 2008 Edition. LexisNexis. San Francisco, CA.
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