Introduction to Kavalactones — Part 3: Methysticin and Dihydromethysticin
This article provides an examination of the scientific literature concerning kava and kavalactones. It is important to note that this article is not intended to serve as an endorsement for diagnosing, treating, preventing, or curing any disease.
This blog will continue the series about the six major kavalactones, focusing on methysticin and dihydromethysticin.
Similar to the difference in the chemical structures of kavain and dihydrokavain, the only difference between methysticin and dihydromethysticin is a loss of a double bond at the C7 position!
Methysticin, a major kavalactone in kava extract, exerts its pharmacological effects primarily through the modulation of neurotransmitter systems, particularly the gamma-aminobutyric acid (GABA) system. Methysticin acts as a positive allosteric modulator of GABA-A receptors, enhancing the binding of GABA to its receptor site and potentiating inhibitory neurotransmission (1). This mechanism results in anxiolytic and sedative effects akin to those of benzodiazepines but without the associated risks of tolerance and dependence. Additionally, methysticin has been shown to inhibit serotonin and norepinephrine reuptake, leading to increased extracellular levels of these neurotransmitters in certain brain regions (2). This dual mechanism of action on neurotransmitter systems may contribute to the mood-enhancing and cognitive-enhancing effects observed with methysticin administration.
Dihydromethysticin shares similar pharmacological properties and mechanisms of action to methysticin. Like methysticin, dihydromethysticin acts as a positive allosteric modulator of GABA-A receptors, enhancing GABAergic neurotransmission and producing anxiolytic and sedative effects (3). However, the reduced potency of dihydromethysticin may result in a milder sedative effect compared to methysticin.
Both methysticin and dihydromethysticin exhibit dual mechanisms of action on neurotransmitter systems, including the GABAergic, serotonergic, and noradrenergic pathways. By potentiating GABAergic neurotransmission and inhibiting serotonin and norepinephrine reuptake, these compounds modulate synaptic transmission and neuronal excitability, leading to anxiolytic, sedative, and mood-enhancing effects.
Recent research has focused on elucidating the mechanisms underlying the hepatoprotective effects of methysticin and dihydromethysticin. Studies have demonstrated their ability to mitigate liver damage induced by various toxins and oxidative stressors, highlighting their potential as therapeutic agents for liver diseases (4). Additionally, investigations into the synergistic effects of kavalactones with other natural compounds, such as flavonoids and terpenoids, have revealed promising outcomes in preclinical models of inflammation and neurodegeneration (5).
In conclusion, methysticin and dihydromethysticin exert their pharmacological effects by modulating neurotransmitter systems, primarily the GABAergic system. Understanding the mechanisms of action of these kavalactones is crucial for optimizing their use.
References:
1. Kretzschmar R, Meyer FP, Strohmeier B, Gollnhofer O. Kava pyrones exert effects on neuronal transmission and transmembrane cation currents similar to established mood stabilizers – a review. Phytomedicine. 2019;55:18-27.
2. Baum SS, Hill R, Rommelspacher H. Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog Neuropsychopharmacol Biol Psychiatry. 1998;22(7):1105-20.
3. Singh YN. Kava: an overview. J Ethnopharmacol. 2002;80(2-3):85-97.
4. Li, X., Long, J., Wang, H., Fang, L., Lu, X., Zhu, Z., Yu, R., et al. (2020). Methysticin and Dihydromethysticin Mitigate Liver Injury in Acetaminophen-Induced Acute Hepatic Damage in Mice. Frontiers in Pharmacology, 11, 413.
5. Narayan, A. P., Bao, X., McCart Reed, A. E., Smith, R. A., Callen, D. F., Kavallaris, M., Al-Ejeh, F. (2020). A Novel Role for Kava (Piper methysticum) in Mitigating Oxidative Stress in Triple-Negative Breast Cancer Cells. Frontiers in Pharmacology, 11, 481.