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The Mechanism and Rationale for the Avoidance of Taking Benzodiazepines Along with Kava (Piper methysticum) and/or Valerian (Valeriana officinalis) Supplements

Summary:

  • Kava (Piper methysticum) and valerian (Valeriana officinalis) are well known natural medicines used to treat anxiety and insomnia.
  • Both are known to influence or modulate gamma-aminobutyric acid-A (GABA-A) receptor activity that can result in CNS depression, as are benzodiazepines.
  • The main mechanism for kava induced CNS depression is the alpha-pyrone'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.
  • The two mechanisms for valerian to induce CNS depression are, first, its similar action to benzodiazepines; however, instead of binding to the gamma subunit like a benzodiazepine, it appears to bind to the beta subunit on the GABA-A receptor instead.  Secondly, valerian has also been shown to decrease the removal or metabolism of GABA, thereby allowing GABA to stay around longer.
  • There are no data regarding the long-term effects of kava as it relates to safety, physical dependency, and/or development of signs and symptoms of withdrawal as seen with benzodiazepines.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed:
November 2015

Explanation

  • Kava (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. 

    Why would the coadministration of kava and valerian be of potential concern for some patients?
    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.

    Benzodiazepines 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.

                 

    How 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 

    As 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 hyperpolarized state.    

    Therefore, 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.

    References:

    1. National Institutes of Health: National Center for Complimentary and Alternative Medicine.  Herbs at a glance: kava.  June 2008.  Last accessed on June 9, 2009.
    2. Kessler RC, McGonagle KA, Zhao S et al.  Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States.  Results from the National Comorbidity Survey.  Arch Gen Psychiatry  1994;51:8-19.
    3. Almeida JC, Grimsley EW.  Coma from the health food store: interaction between kava and alprazolam.  Ann Intern Med  1996;125:940-1.
    4. Kessler 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 Psychiatry  2001;158:289-94.
    5. National Center for Complementary and Alternative Medicine: National Institutes of Health.  Herbs at a glance: Valerian.  Last accessed on 2-14-2009: 
    6. National Institutes of Health: Office of Dietary Supplements.   Valerian.  Bethesda, Maryland.  Version: 1/16/2008.  Last accessed on 2/14/09.
    7. Health Canada.  Natural Health Products.  Valerian.  March 30, 2007.  Last accessed on 2-14-2009.
    8. Donath F, Quispe S, Diefenbach K et al.  Critical evaluation of the effect of valerian extract on sleep structure and sleep quality.  Pharmacopsychiatry  2000;33:47-53.
    9. Stevinson C, Ernst E.  Valerian for insomnia: a systematic review of randomized clinical trials.  Sleep Med  2000;1:91-9.
    10. Ziegler 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.
    11. Miyasaka LS, Atallah AN, Soares BG.  Valerian for anxiety disorders.  Cochrane Database Syst Rev  2006;18:CD004515.
    12. Ebadi M.  Valerian.  In:  Pharmacodynamic basis of herbal medicine. 2nd Ed.  Taylor & Francis Group.  Boca Raton, FL. 2007:599-609.
    13. Therapeutic Goods Administration. Department of Health and Ageing: Australian Government.  Substances that may be used in listed medicines in Australia.  Version 12/2007.  Last accessed on 2/14/2009.
    14. World Health Organization.  Traditional medicine fact sheet.  Revised last on December 2008.  Last accessed on 2/14/2009.
    15. National Center for Complementary and Alternative Medicine: National Institutes of Health.  The Use of complementary and alternative medicine in the United States: 2007 National Health Interview Survey Report.  Last accessed on 2/14/2009.
    16. Health Canada.  Natural Health Products.  Baseline natural health products survey among consumers, March 2005.  Last accessed on 2-14-2009.
    17. Davies 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.  
    18. Jussofie A, Schmiz A, Hiemke C.  Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain.  Psychopharmacology (Berl)  1994;116:469-74.  
    19. 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. 
    20. Hirst A, Sloan R.  Benzodiazepines and related drugs for insomnia in palliative care.  Cochrane Database Syst Rev  2002;4:CD003346.  
    21. Mennini 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  1993;64:291. 
    22. 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.  Neuropharmacology  2009;56:174-81.  
    23. Riedel E, Hansel R, Ehrke G.  Inhibition of gamma-aminobutyric acid catabolism by valerenic acid derivatives.  Planta Med  1982;46:219-20. 
    24. Wheatley D.  Stress-induced insomnia treated with kava and valerian: singly and in combination.  Hum Psychopharmacol  2001;16:353-356.  
    25. Wheatley D.  Kava and valerian in the treatment of stress-induced insomnia.  Phytother Res  2001;15:549-51.  
    26. 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. 
    27. United States Food and Drug Administration.  Consumer advisory: kava-containing dietary supplements may be associated with severe liver injury.  March 25, 2002.  Last accessed on June 9, 2009.  
    28. National Institutes of Health: National Center for Complimentary and Alternative Medicine.  Consumer advisory: Kava linked to liver damage.  July 23, 2002.  Last accessed on June 9, 2009.

MESH Terms & Keywords

  • Kava, Piper methysticum, Valerian, Valeriana officinalis, Benzodiazepines, GABA receptor, GABA Channel