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.
