Kava is described in the ethnopharmacology literature as “the
most important psychoactive agent in Oceania” (1). The plant Piper methysticum is
cultivated on most of the islands of Polynesia. It is used both culturally and for medicinal
purposes. It grows as a low evergreen
shrub and is grown on plantations. Roots are harvested, peeled, and chopped and
then extracted with alcohol or other solvents. In the ethnopharmacology literature the active
compounds are referred to as kavapyrones and in the chemistry literature
kavalactones. Structures of the main
kavalactones are illustrated in the above graphic.
Kava has been cultivated and consumed in this area since prehistoric
times when it was brought to the Hawaiian Islands. The effect of consumption described
over time has been that of an intoxicant - euphorigenic and increased
socialization. Consumption is decreased as varying widely (p 446 of Ref 1) –
from 0.5-1 liter per day to 1-2 liters at ceremonies to 4 liters per day. There are some very high consumptions of up
to 13 liters per day. High doses produce
signs of toxicity including rash, hair loss, yellow coloration of the skin,
reddened eyes and decreased appetite. Where it has been studied up to 4 liters
per day does not product this toxicity. The standard prepared beverages contain
about 70 mg of kavalactones per 100 ml, so 4 liters at this concentration is roughly
308 mg of kavalactones. That is slightly
above the upper limit that many countries who regulate kava suggest.
From a psychiatric perspective, the pattern of use suggests
that kava can be a problematic substance for many. Although the specific epidemiology of consumption
is not detailed if most people consume 1 liter a day, toxicity occurs at greater
than 4 liters a day, signs of toxicity occur at higher doses, and some people
are consuming up to 13 liters per day that suggests uncontrolled use and a
potential substance use problem.
From an ethnopharmacology standpoint there have also been
descriptions of hallucinations occurring from kava ingestion. The most famous one was a vision by a chief
that led to the Polynesians colonizing the Easter Islands in the 3rd
or 4th century. More recent
descriptions suggest that additional intoxicants are needed to produce these
effects and kava by itself is not a psychedelic.
Despite the above information, kava remains generally
available as a food or nutritional substance in most states. It can be easily ordered online where it is
sold as a remedy for anxiety and insomnia.
That stands in contrast to kratom that is illegal in 6 states, regulated
in 30, and unregulated in 20 states. In contrast to the reviews that show clear
hepatotoxic and carcinogenic potential there are current papers that question
that research and reference papers with those results. They suggest that the incidence of kava
induced hepatotoxicity is “rare”, but the true epidemiology is unknown
specifically the total population exposed.
That brings me to the recent paper from the Mortality and
Morbidity Weekly Report (MMWR) on the combination of kava and kratom. The
paper uses the same methodology of a recent post just about kratom. It analyzes data from the National Poison
Data System (NPDS) on exposures to kava alone (single substance exposure N=
1,754) or kava and other substances (multiple substance exposures N=1,347) and
the outcomes over a 15-year period to 2025.
The remarkable trend in multiple substance exposures was a
shift from using alcohol and benzodiazepines with kava to kratom. This coincides with an increase in kava use
following an initial fall in use with the 2002 FDA warning on
hepatotoxicity. In addition, even though
kava is not regulated in the US there are regulation limits in other countries
(such as 250 mg of kavalactones per serving) that are not applicable in the US. Some products have multiple 250 mg servings
per container. The lack of US specifications
implies that the hepatotoxicity of kava is considered idiosyncratic rather than
a population wide risk despite the lack of any organized pharmacovigilance and
a recent decline in the quality of regulatory agencies.
Since kava affects the GABAA receptor and kratom is a mu opioid receptor
agonist there is also the pharmacodynamic risk of combining those substances. In
my previous most about kratom’s mu opioid receptor affinity, it seemed that a
lot of the risk
from that compound was attenuated by using preparations with lower
concentrations of the active drug (leaves rather than concentrated
liquid). In the case of kava, it is a
GABAA receptor allosteric modulator that binds to sites other than
the benzodiazepine receptor (the effect is not reversed by flumazenil)
(10). Since kavalactones are active at
multiple sites rather than a single receptor Kis are not available
(see definitions in Supplementary below).
Comparing the EC50 of kavalactones (1.3-150 μM) to benzodiazepines
(25-72 nM) shows a difference of 1,000 fold in potency. The lower potency is reflected in the need
for greater amounts of kavalactones to achieve similar effects of sleep and
anxiety as well as lower abuse and overdose potential.
Despite the decreased potency, the MMWR shows that there are
more hospitalization and serious medical outcomes and they are more likely with
the kava-kratom combination (click to enlarge).
A comparison with acetaminophen is useful. Acetaminophen is widely used and effective
analgesic. 52 million people in the US
take it on a weekly basis. It has a
unique pattern of hepatotoxicity that accounts for the warnings on the bottle
about dose limitations and use with alcohol. There are 500 deaths, 38,000 hospitalizations,
and 100-150 liver transplantations per year from acetaminophen toxicity. General risk benefit considerations include the
need for a better pain medication, reducing the number of combination
medications to reduce the exposure, and the current number of people who safely
take the medication (11). An analysis by
MMWR of acetaminophen using the same technique they used for both kratom and
kava would be useful. The highest level
of kava consumption I could find in US estimate was 21M kava drinkers. It is likely they are not drinking it on a
weekly basis but that is unknown. It is
also unregulated in the US so the dose of kavalactones and warnings about
synergism with alcohol, benzodiazepines, opioids, and other sedative hypnotics
is not available.
The combination of kava and kratom is giving a clear early
signal that it can potentially lead to serious medical outcomes. Despite the reputation of being a benign
herbal medication kava is associated with deaths and rare but very serious
hepatic complications. Like most of
these situations unless there is a different regulatory environment or people
decide to stop experimenting it is likely that these complications will
increase. There is no reason to use
either kava or kratom.
George Dawson, MD DFAPA
References:
1: Food and Drug
Administration. Consumer advisory: kava containing dietary supplements may be
associated with severe liver injury. Silver Spring, MD: US Department of Health
and Human Services, Food and Drug Administration; 2002.
https://wayback.archive-it.org/7993/20170722144010/https:/www.fda.gov/Food/RecallsOutbreaksEmergencies/SafetyAlertsAdvisories/ucm085482.htm.
2. Food and Drug Administration. Scientific memorandum: kava
(review of the published literature pertaining to the safety of kava for use in
conventional foods). Silver Spring, MD: US Department of Health and Human
Services, Food and Drug Administration; 2020. https://www.fda.gov/media/169556/download
3: LiverTox: Clinical
and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda
(MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.
Adverse Drug Reaction Probability Scale (Naranjo) in Drug Induced Liver Injury.
[Updated 2019 May 4].
Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/
4: Teschke R, Wolff
A. Regulatory causality evaluation methods applied in kava hepatotoxicity: are
they appropriate? Regul Toxicol Pharmacol. 2011 Feb;59(1):1-7. doi:
10.1016/j.yrtph.2010.09.006. Epub 2010 Sep 18. PMID: 20854865.
5: Stickel F, Shouval
D. Hepatotoxicity of herbal and dietary supplements: an update. Archives of
toxicology. 2015 Jun;89(6):851-65.
Over 100 cases of liver damage attributed to kava – many
resulting in death or liver transplantation as of 2015. Mechanism unknown. Durg induced liver disease typically reverses
by stopping kava.
6: Teschke R, Frenzel
C, Schulze J, Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of
causality assessment methods. World J Gastroenterol. 2013 May
21;19(19):2864-82. doi: 10.3748/wjg.v19.i19.2864. PMID: 23704820; PMCID:
PMC3660812.
7: Pantano F,
Tittarelli R, Mannocchi G, Zaami S, Ricci S, Giorgetti R, Terranova D, Busardò
FP, Marinelli E. Hepatotoxicity Induced by "the 3Ks": Kava, Kratom
and Khat. Int J Mol Sci. 2016 Apr 16;17(4):580. doi: 10.3390/ijms17040580.
PMID: 27092496; PMCID: PMC4849036.
“On the one hand, growing controversial data have been
reported about the hepatotoxicity of kratom, while, on the other hand, even
though kava and khat hepatotoxicity has been investigated, the hepatotoxic
effects are still not clear. Chronic recreational use of kratom has been
associated with rare instances of acute liver injury.”
8: Bleifuss W, Boley S, Bardwell J, Goebel C, Wilkinson J.
Severe kava withdrawal managed with phenobarbital. Am J Emerg Med. 2025
Oct;96:298.e5-298.e7. doi: 10.1016/j.ajem.2025.06.016. Epub 2025 Jun 16. PMID:
40541460.
9: Towers EB,
Williams IL, Holstege CP, Farah R. Increase in Poison Center Reports Linked to
Kratom-Containing Kava Products - National Poison Data System, United States,
2000-2025. MMWR Morb Mortal Wkly Rep. 2026 Apr 2;75(12):157-163. doi:
10.15585/mmwr.mm7512a1. PMID: 41926333; PMCID: PMC13046178.
10: Chua HC,
Christensen ET, Hoestgaard-Jensen K, Hartiadi LY, Ramzan I, Jensen AA, Absalom
NL, Chebib M. Kavain, the Major Constituent of the Anxiolytic Kava Extract,
Potentiates GABAA Receptors: Functional Characteristics and Molecular
Mechanism. PLoS One. 2016 Jun 22;11(6):e0157700. doi:
10.1371/journal.pone.0157700. PMID: 27332705; PMCID: PMC4917254.
11: Lee WM. Acetaminophen (APAP) hepatotoxicity-Isn't it
time for APAP to go away? J Hepatol. 2017 Dec;67(6):1324-1331. doi:
10.1016/j.jhep.2017.07.005. Epub 2017 Jul 20. PMID: 28734939; PMCID:
PMC5696016.
Supplementary 1: Some definitions of receptor
kinetics:
Ki (inhibition constant) is the equilibrium
dissociation constant for an inhibitor binding to its target, representing the
concentration at which 50% of the target is bound by the inhibitor at
equilibrium in the absence of competing substrate. A fundamental constant independent of
experimental conditions.
EC50 (half-maximal effective concentration) is the
concentration of a compound that produces 50% of its maximal response in a
functional assay.
IC50 (half-maximal inhibitory concentration) is the
concentration that produces 50% inhibition of a measured activity.
Both EC50 and IC50 can vary with experimental conditions.
