EBM Consult

How can kava (Piper methysticum) increase the risk for CNS depression and/or coma in patients taking alprazolam (Xanax)?

Summary:

  • Kava (Piper methysticum) is a member of the pepper family that is native to the South Pacific.  It is used to treat anxiety, insomnia and symptoms related to menopause.        
  • The active ingredients found in kava supplements include a group of chemicals called alpha-pyrones which appear to modulate the activity of the same GABA receptor complex used by the benzodiazepines (such as alprazolam).
  • The main mechanisms for kava induced CNS depression include 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 for GABA agonists to interact with., thereby resulting in synergistic suppression the CNS.
  • There are no data regarding the long-term effects of kava as it relates to safety, physical dependency, or development of signs and symptoms of withdrawal as seen with benzodiazepines.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed:
February 2018

Explanation

  • Kava (Piper methysticum) is a member of the pepper family that is native to the South Pacific.  It is used to treat anxiety, insomnia and symptoms related to menopause.(1)  Data from the United States National Comorbidity Survey showed the one year prevalence of anxiety to be approximately 17% and the lifetime prevalence to be up to 25%.(2)  While many of these patients will be treated with benzodiazepines initially by a general practitioner, others may seek treatment with a homeopathic or natural medicine/supplement such as kava extract.(1,3,4)  The problem occurs when patients choose to treat their anxiety with both a kava supplement and a benzodiazepine, such as alprazolam (Xanax), that was prescribed by their physician or when the prescribing physician initiates standard doses of alprazolam without the knowledge that the patient is also taking a kava extract.3,4 For example, one case report describes a patient who required hospitalization after taking a combination of kava and alprazolam for 3 days that caused the patient to enter a semicomatose state.(3)  

    How does kava interact with benzodiazepines (e.g., alprazolam) to cause a degree of central nervous system (CNS) depression that may result in a coma?

    • The active ingredients found in kava supplements include a group of chemicals called, alpha-pyrones.(5,6)  The alpha-pyrones include dihydro-kawain, dihydroyangonin, kawain, methysticine and yangonin.  These compounds are known to augment or facilitate gamma-aminobutyric acid (GABA) receptors mainly in the amygdala, hippocampus, medulla of the central nervous system (CNS) and to a lesser extent in the frontal cortex and cerebellum.(5,6)  They do this through at least one known main mechanism. 
    • The presence of the alpha-pyrone is known 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.(6)  The GABA-A receptor is also the main receptor whereby benzodiazepines exert their CNS depressive effects.  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).(7) 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.(7)  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 makes the neuron less responsive to stimulation by excitatory postsynaptic potentials (EPSPs), thus suppressing the CNS.  The presence of alpha-pyrones at concentrations achieved with standard doses of kava will facilitate further suppression of the CNS by increasing binding sites available to GABA agonists on the GABA-A receptor. 
    • The exact reason for how kava increases the density of binding sites 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.  Interestingly, this is also an effect seen with other medications, in particular anesthetics.(8,9)   

    Regardless of the exact mechanism, kava is known to enhance suppression of the CNS in the presence of a benzodiazepine through the modulation of the GABA-A receptor in various regions in the brain and brainstem.  This is likely why the patient who took both kava and alprazolam for 3 days declined to a near comatose state.  Unfortunately, there are no data regarding the long-term effects of kava as it relates to safety, physical dependency, or development of signs and symptoms of withdrawal as seen with benzodiazepines.  Until further evidence becomes available, it would be prudent for clinicians to consider these factors in patients who desire to or have been taking kava long-term.

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. 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.
    6. 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.
    7. 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.
    8. 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.
    9. Miller KW.  The nature of the site of general anesthesia.  Int Rev Neurobiol  1985;27:1-61.
    10. Busti AJ, Lehew DS, Nuzum DS, Daves BJ, McKeever GC.  How does the herb valerian (Valeriana officinalis) work to treat insomnia? 
    11. 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.
    12. 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.  
    13. 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.

Keywords

  • Kava, Piper methysticum, Kava Benzodiazepine, Alprazolam, Xanax