The acute stress response is regulated by the catecholamine hormones norepinephrine (NE) and epinephrine, which bind to adrenergic receptors (ARs) and induce calcium influx and cyclic AMP (cAMP) production. However, psychosocial stress leads to increased adrenergic signaling and prolonged elevation of systemic cAMP. This accumulation is linked to various mental disorders and found in cancerous tissues. Kava (Piper methysticum) is a plant of South Pacific origin that gained popularity as a drink due to its relaxing effects. Kavalactones, kava’s main chemicals, are proposed to contribute to its relaxing properties. Mechanistically, kavalactones have been shown to inhibit NE-induced calcium influx. Dihydromethysticin, in particular, has been demonstrated to suppress NNK- and NNAL-induced signaling, potentially through the β-AR pathway. Yet, structure-activity relationships (SARs) for the major kavalactones have never been fully characterized. The mechanism(s) by which kava exhibits its stress-reducing properties have not been rigorously elucidated as well. In this study, we first demonstrate via LC-MS/MS that systemic cAMP may be elevated in lung cancer patients. Kava intake decreases systemic cAMP in healthy smokers, indicating cAMP as a potential readout for the stress response in vitro. Using the non-small cell lung cancer cell line H1299, we then demonstrate that extracellular cAMP quantification via LC-MS/MS is more sensitive than that of intracellular cAMP. Using this method, we evaluated and demonstrate that the six major kavalactones inhibit NE-induced cAMP production, and yangonin exhibits the greatest potency. Yangonin selectively antagonizes β-ARs, potentially β2-ARs, with preliminary SARs suggesting its aromatic substituent and unsaturation contribute to its potency. Our data indicate that kava’s use could benefit individuals with high psychosocial stress, including lung cancer patients, by lowering systemic cAMP levels via β-AR antagonism. This could prevent downstream stress- and other cAMP-related oncogenic signaling. Future studies entail binding site characterization, performing systematic SARs, and evaluating the translational potential in appropriate animal models.

Antagonism of the β-adrenergic receptor as a potential anti-stress mechanism of kava and its kavalactones characterized via a cell-based cAMP assay

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