Dihydromyricetin

Pharmacological Actions
DHM exhibits a broad spectrum of pharmacological effects, primarily observed in preclinical studies. These include:

Cardioprotection: DHM demonstrates anti-atherosclerotic properties by reducing pyroptosis in human umbilical vein endothelial cells (HUVECs) at concentrations of 0.5–1 μM via the Nrf2 pathway, and enhances cholesterol efflux in THP-1 macrophages at 1–100 μM through LXRα, ABCA1, and ABCG1 upregulation (source). It also protects against myocardial ischemia/reperfusion injury with 7-day pre-treatment, and reduces adriamycin-induced cardiotoxicity at 125–500 mg/kg in mice, suppressing apoptosis and ROS.
Anti-diabetes: DHM improves insulin sensitivity via AMPK, Akt, and AS160 phosphorylation, with an 8-week treatment reducing blood glucose and plasma insulin in high-fat diet (HFD) rats, and 50 mg/kg/day for 12 weeks enhancing sensitivity in mice, involving the AMPK-PGC-1α-SIRT3 pathway (source).
Hepatoprotection: DHM protects against liver ischemia/reperfusion injury at 100 mg/kg/d for 7 days, activating autophagy via FOXO3a, Atg5, Atg12, beclin 1, and LC3. It ameliorates alcoholic liver disease at 75–150 mg/kg/d for 6 weeks, activating Nrf2 and inhibiting NF-κB, and improves non-alcoholic fatty liver disease (NAFLD) by enhancing mitochondrial function, with a clinical trial using 150 mg twice daily showing benefits (source).
Neuroprotection: DHM inhibits catechol-O-methyltransferase (COMT) activity in a dose-dependent manner, protecting dopaminergic neurons in Parkinson's models, and shows antidepressant effects at 10–20 mg/kg for 3–7 days, enhancing BDNF and reducing TNF-α, IL-6 (source).
Anti-tumor: It induces apoptosis in hepatocellular carcinoma cells via Akt/Bad and G2/M arrest via Chk2, with autophagy mediated by mTOR, ERK1/2, and AMPK, and shows effects against melanoma at 1.25–10 μM, suppressing proliferation and inducing G1/S arrest (source).
Dermatoprotection: DHM protects against UVA-induced damage and inhibits melanoma proliferation, with mechanisms involving ROS-NF-κB signaling and tyrosinase inhibition.

These actions are supported by mechanisms involving AMPK, MAPK, Akt, NF-κB, Nrf2, and other pathways, as detailed in supplementary materials .
Pharmacokinetic Parameters
DHM's pharmacokinetics have been studied primarily in rats, with the following parameters:

Half-life: Approximately 2.05 hours for intravenous administration at 2 mg/kg and 3.70 hours for oral administration at 20 mg/kg, based on LC-MS/MS analysis.
Bioavailability: Oral bioavailability is low, at 4.02% in rats, due to poor absorption via passive diffusion and efflux by transporters like MRP2 and BCRP, with rapid distribution and elimination mostly in feces within 12 hours (source).

Efforts to improve bioavailability include solid dispersions, nanocapsules, and phospholipid complexes, which have shown promise in enhancing absorption in animal models.
Dosage and Administration
Human dosage data is limited but includes:

A clinical trial for NAFLD used 150 mg twice daily (300 mg/day) for three months, showing improvements in glucose and lipid metabolism without reported adverse effects (source).
Suggested dosages for other uses, such as hangover prevention, range from 300 mg per drink to 2000–4000 mg for reducing alcohol intoxication, based on commercial recommendations and extrapolations from animal studies (source).

Animal studies suggest dosages like 1.8–11.8 mg/kg in rats for behavioral effects, translating to approximately 126–824 mg for a 70 kg human, aligning with clinical trial doses.
Safety and Toxicity
DHM is generally considered safe, with traditional use in Asia for centuries and minimal adverse effects reported:

LD50: Greater than 5 g/kg in mice, indicating low acute toxicity (source).
Acute Toxicity: No significant side effects at 150 mg/kg to 1.5 g/kg in mice, with a human equivalent dose (HED) suggesting safety up to 15.68 g for a 70 kg person, based on a 22 g/kg no-effect level in mice (source).
Chronic Toxicity: No negative effects on development, hematology, or pathology in long-term rat studies, with enhanced immunologic function observed (source).

However, some controversy exists, with studies suggesting potential pro-oxidant and mutagenic effects, though these are not well-supported in human contexts (source).