Kavalactones and the endocannabinoid system: The plant-derived yangonin is a novel CB1 receptor ligand

Ligresti, Alessia; Villano, Rosaria; Allarà, Marco; Ujváry, István; Marzo, Vincenzo Di

doi:10.1016/j.phrs.2012.04.003

Cited by 44 publications

(25 citation statements)

References 40 publications

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“…Yangonin, a kavalactone extracted from kava, Piper methysticum , exhibits affinity for CB 1 with a K i = 0.72 µM [164]. Curcumin, extracted from curry powders, elevates eCB levels and brain nerve growth factor (NGF) in a brain region-specific fashion, and pretreatment with CB 1 antagonist AM4113 blocks this effect [165].…”

Section: Resultsmentioning

confidence: 99%

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

2014

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BackgroundThe “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.Methodology/Principal FindingsWe searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulate the eCB system.Conclusions/SignificanceFew clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

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Section: Resultsmentioning

confidence: 99%

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

2014

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Section: Discussionmentioning

confidence: 99%

“…The former model is also plausible, since plant odorants, endogenous lipids and cyclic peptides have variously been described to ligate GPCR. Recent descriptions of a kavalactone cannabinoid receptor (the GPCR CB1) ligand and the overlap between the cannabinoid receptor ligands and TRP pharmacology are intriguing and worthy of further study (De Petrocellis et al, 2008;Ligresti et al, 2012). Calcium mobilizing activity is, of course, not only a convenient assay system in which to compare fractions, cultivars and extraction methods: as a fundamental second messenger, it is a critical mediator of cellular responses including growth, differentiation, motility and extensive transcriptional and functional responses.…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Calcium Signalling Pathways by Components of Piper methysticum ('Awa)

Shimoda

Showman

Baker

et al. 2015

Phytotherapy Research

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Kava is a soporific, anxiolytic and relaxant in widespread ritual and recreational use throughout the Pacific. Traditional uses of kava by indigenous Pacific Island peoples reflect a complex pharmacopeia, centered on GABA-ergic effects of the well-characterized kavalactones. However, peripheral effects of kava suggest active components other than the CNS-targeted kavalactones. We have previously shown that immunocytes exhibit calcium mobilization in response to traditionally-prepared kava extracts, and that the kavalactones do not induce these calcium responses. Here, we characterize the complex calcium-mobilizing activity of traditionally-prepared and partially HPLC-purified kava extracts, noting induction of both calcium entry and store release pathways. Kava components activate intracellular store depletion of thapsigargin-sensitive and –insensitive stores that are coupled to the calcium release activated (CRAC) current, and cause calcium entry through non-store-operated pathways. Together with the pepper-like potency reported by kava users, these studies lead us to hypothesize that kava extracts contain one or more ligands for the transient receptor potential (TRP) family of ion channels. Indeed, TRP-like conductances are observed in kava-treated cells under patch clamp. Thus TRP-mediated cellular effects may be responsible for some of the reported pharmacology of kava.

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“…There are 18 kavalactones present in the kava root, six of which account for a majority of the pharmacological activity: yangonin, methysticin, kavain, 7,8‐dihydrokavain, 7,8‐dihydromethysiticin, and desmethoxyyangonin (Fig. ) . Studies have shown that the kavalactones have several different mechanisms of action.…”

mentioning

confidence: 99%

“…Kavain, 7,8‐dihydrokavain, yangonin, methysticin, and 7,8‐dihydromethysticin interact with GABA A receptors and potentiate GABA binding response . Yangonin is an agonist to the cannabinoid type‐1 receptor . Kavain and methysticin block voltage‐gated sodium and calcium ion channels .…”

mentioning

confidence: 99%

Cases of Kava Impairment in Iowa Drivers

Berry

Gilbert

Grodnitzky

2019

Journal of Forensic Sciences

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Kava is an Oceanic plant in which the root is consumed as a beverage and is becoming increasingly popular. The effects of kava consumption may include sedation, euphoria, and impairment of motor coordination. This article demonstrates kava impairment through four cases of self‐reported kava use supported with Drug Recognition Expert (DRE) evaluations of each subject. Subject's urines screened negative for common drugs of abuse by immunoassay analysis. Urine from cases 3 and 4 were analyzed by liquid chromatography–tandem mass spectrometry, and gas chromatography–mass spectrometry, which yielded the presence of kavalactones. Subjects exhibited poor driving behavior and signs of intoxication. Indicators of impairment from multiple drug categories, central nervous system (CNS) depressants, CNS stimulants, and cannabis were observed, which may be consistent with the presence of multiple kavalactones and their diverse array of mechanisms of action. The consumption of kava can hinder one's ability to operate a vehicle safely.

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Kavalactones and the endocannabinoid system: The plant-derived yangonin is a novel CB1 receptor ligand

Cited by 44 publications

References 40 publications

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

Differential Regulation of Calcium Signalling Pathways by Components of Piper methysticum ('Awa)

Cases of Kava Impairment in Iowa Drivers

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