# Evodiamine (Evodia rutaecarpa)

**Canonical URL:** https://ingredients.hermeticasuperfoods.com/ingredients/evodiamine-evodia-rutaecarpa
**Data Source:** Hermetica Superfoods Ingredient Encyclopedia
**Updated:** 2026-04-03
**Evidence Score:** 1 / 10
**Category:** Compound
**Also Known As:** Evodia rutaecarpa alkaloid, EVO, Wu-Zhu-Yu alkaloid, Rhetsinine, Evodiae fructus biomarker

## Overview

Evodiamine is a quinazolinocarboline alkaloid that exerts anti-tumor, analgesic, and thermogenic effects by inhibiting Cdc2/cyclin B complex activation, modulating vanilloid (TRPV1) receptors, and suppressing NF-κB-mediated [inflammatory](/ingredients/condition/inflammation) signaling. All documented efficacy data originate from preclinical in vitro and animal models—including oral bioavailability as low as 0.1% in rats at 500 mg/kg—and no controlled human clinical trials have established effective or safe doses in humans.

## Health Benefits

- **Anti-Cancer Activity (Preclinical)**: Evodiamine blocks cell cycle progression at the G2/M checkpoint by inhibiting Cdc2 phosphorylation at Thr14, Tyr15, and Thr161 through Wee-1/Myt-1 modulation and Cdc25C phosphatase regulation, inducing apoptosis in multiple tumor cell lines in vitro.
- **Thermogenic and Anti-Obesity Effects**: Animal studies suggest evodiamine activates vanilloid TRPV1 receptors and increases catecholamine release, raising core body temperature and resting energy expenditure, mimicking effects seen with capsaicin in rodent obesity models.
- **Anti-Inflammatory Properties**: Evodiamine suppresses NF-κB nuclear translocation and downregulates [pro-inflammatory cytokine](/ingredients/condition/inflammation)s including TNF-α and IL-6, reducing inflammatory markers in lipopolysaccharide-stimulated macrophage cell cultures.
- **Analgesic Effects**: By interacting with TRPV1 receptors and modulating central pain pathways, evodiamine demonstrates dose-dependent antinociceptive effects in rodent hot-plate and acetic acid writhing assays, paralleling traditional Wu-Zhu-Yu use for pain relief.
- **Cardioprotective Signaling (Context-Dependent)**: At low concentrations in specific preclinical models, evodiamine has shown protection against ischemia-reperfusion injury via antioxidant enzyme upregulation, though cardiotoxicity is documented at higher concentrations, indicating a narrow therapeutic index.
- **[Antimicrobial](/ingredients/condition/immune-support) Activity**: In vitro studies demonstrate evodiamine inhibits growth of several bacterial strains and fungi by disrupting membrane integrity and inhibiting topoisomerase activity, though minimum inhibitory concentrations have not been translated to clinical applications.
- **[Neuroprotective](/ingredients/condition/cognitive) Potential**: Evodiamine has been shown in cell-based models to reduce amyloid-beta aggregation and [oxidative stress](/ingredients/condition/antioxidant) in neuronal cells, suggesting exploratory relevance to neurodegenerative disease research, though evidence remains at the earliest preclinical stage.

## Mechanism of Action

Evodiamine's primary anti-proliferative mechanism involves inhibition of Cdc2 kinase phosphorylation at regulatory residues Thr14, Tyr15, and Thr161, achieved by suppressing Wee-1 and Myt-1 kinase activity while modulating Cdc25C phosphatase, ultimately preventing assembly of the active Cdc2/cyclin B complex and arresting cells in G2/M phase. It also acts as a partial agonist at transient receptor potential vanilloid-1 (TRPV1) channels, triggering intracellular calcium influx and downstream catecholamine release, which underlies its thermogenic and analgesic properties. Additionally, evodiamine inhibits topoisomerase I and II activity—intercalating into DNA similarly to camptothecin analogs—and suppresses NF-κB signaling by preventing IκB phosphorylation and degradation, collectively reducing transcription of pro-survival and pro-[inflammatory](/ingredients/condition/inflammation) genes. Metabolically, evodiamine undergoes hepatic oxidation, N-demethylation, dehydrogenation, glucuronidation, and [glutathione](/ingredients/condition/detox) conjugation, with the primary metabolite 18-hydroxyevodiamine achieving a peak plasma concentration of 302.09 ng/mL and an AUC of 3279.39 ng·h/mL in rats, suggesting active metabolite contributions to overall pharmacodynamics.

## Clinical Summary

No human clinical trials evaluating evodiamine's efficacy or safety have been identified in the published literature, making it impossible to summarize clinical outcomes, effect sizes, or confidence intervals for any therapeutic application in humans. Preclinical data in rodents and cell lines support biological plausibility for anti-cancer, analgesic, and thermogenic properties, but translation to human physiology is unestablished. The compound's documented inhibition of CYP1A2, CYP2C9, and CYP2D6 enzymes raises significant pharmacokinetic interaction concerns that would need rigorous clinical pharmacology studies before safe human dosing protocols could be designed. Regulatory bodies including the FDA have not reviewed evodiamine as a drug or approved any supplemental dose, and the current evidence does not support efficacy claims in humans.

## Nutritional Profile

Evodiamine is a trace alkaloid constituent of Evodiae fructus and does not contribute meaningfully to macronutrient or micronutrient intake in any supplemental form. The whole fruit contains additional bioactive classes including quinolone alkaloids (rutaecarpine, hydroxyevodiamine), limonoid compounds (limonin, evodol), essential oils (ocimene, β-phellandrene), flavonoids (quercetin glycosides), and carboxylic acids (evodinone), which collectively constitute the phytochemical matrix of Wu-Zhu-Yu preparations. Evodiamine itself, as an isolated compound, exhibits extremely poor aqueous solubility and oral bioavailability (~0.1% in rats), which is a critical pharmacokinetic limitation governing any potential biological effect. Bioavailability is influenced by formulation technology (HP-β-CD complexation increases it 2.56-fold), co-administration with other fruit constituents, and metabolic activation to 18-hydroxyevodiamine, which achieves substantially higher systemic exposure than the parent compound.

## Dosage & Preparation

- **Traditional Decoction (Wu-Zhu-Yu)**: Whole dried Evodiae fructus boiled in water; standardized modern extracts purify evodiamine to 16–80% purity and are reported to improve bioavailability compared to crude herb preparations.
- **Capsule Form**: Commercial dietary supplements typically encapsulate Evodiae fructus standardized extract; no clinically validated human dose exists—animal studies used 100–500 mg/kg oral doses, which are not directly translatable to humans.
- **Solid Dispersion Technology**: Pharmaceutical research preparations improve aqueous solubility and dissolution rate; these are experimental and not commercially available as standardized consumer products.
- **Hydroxypropyl-β-Cyclodextrin (HP-β-CD) Complex**: Inclusion complexes with HP-β-CD demonstrated a 2.56-fold increase in oral bioavailability, a 1.57-fold increase in Cmax, and near-identical Tmax (1.01-fold) compared to raw evodiamine in rat models—still preclinical.
- **Standardization Note**: Quality control guidelines use evodiamine content as the primary biomarker for Evodiae fructus; users should verify standardization percentage on supplement labels.
- **No Established Human Dose**: Due to the complete absence of human pharmacokinetic or clinical trial data, no recommended supplemental dose can be responsibly stated.

## Safety & Drug Interactions

Evodiamine demonstrates cardiotoxicity in preclinical models: in vitro assays in cardiomyocytes show an IC50 of 28.44 µg/mL at 24 hours with significantly reduced cell viability above 62.5 µg/mL, increased lactate dehydrogenase and malondialdehyde, and decreased superoxide dismutase activity, while zebrafish embryo studies establish an LC10 of 354 ng/mL associated with pericardial malformations and circulatory disruption via [oxidative stress](/ingredients/condition/antioxidant) mechanisms. Evodiamine inhibits CYP1A2, CYP2C9, and CYP2D6 cytochrome P450 enzymes, creating clinically significant drug interaction potential with substrates such as warfarin (CYP2C9), codeine and tamoxifen (CYP2D6), and theophylline or caffeine (CYP1A2), by elevating substrate Cmax and AUC while reducing clearance. No safety data in pregnant or lactating humans exist, and given the embryotoxic signals observed in zebrafish, use during pregnancy is strongly inadvisable; no maximum tolerated dose has been established in any human population. Due to the complete absence of human safety studies and the documented cardiotoxic and drug-interaction profile, evodiamine supplementation should be approached with significant caution and ideally only within supervised research settings.

## Scientific Research

The entire body of evidence for evodiamine consists of in vitro cell culture studies and in vivo animal experiments, predominantly conducted in rodents and zebrafish; no peer-reviewed human clinical trials have been published as of the available literature. Pharmacokinetic studies in rats report an oral bioavailability of approximately 0.1% at 500 mg/kg (Cmax 49.0 ± 19.0 ng/mL, Tmax 3.38 h), rising slightly to 5.3 ng/mL Cmax at 100 mg/kg intragastric dosing, while beagle dog studies at 10 mg/kg capsule doses recorded an AUC0–24h of 45.85 ± 29.17 ng·h/mL and Cmax of 30.94 ± 12.16 ng/mL, underscoring species-variable and universally poor oral absorption. Cardiotoxicity studies in zebrafish embryos established an LC10 of 354 ng/mL with observable pericardial malformations and circulatory disruption, while in vitro cardiomyocyte assays identified an IC50 of 28.44 µg/mL at 24 hours with significant LDH release and [oxidative stress](/ingredients/condition/antioxidant) markers above 62.5 µg/mL. The total evidence base is classified as preliminary; the absence of dose-finding Phase I trials, pharmacodynamic studies in humans, or randomized controlled trials means that no benefit claim can be substantiated for human supplementation at this time.

## Historical & Cultural Context

Evodiae fructus, known in Traditional Chinese Medicine as Wu-Zhu-Yu, has been documented in Chinese pharmacopeias for over 2,000 years, with references appearing in the Shennong Bencao Jing (Divine Farmer's Materia Medica), one of the foundational texts of Chinese herbal medicine. It was classically indicated for dispersing cold, relieving pain, descending rebellious qi, and stopping vomiting—applications now understood to partially reflect the TRPV1 agonist and thermogenic properties of its alkaloid constituents including evodiamine and rutaecarpine. Traditional preparation involved decocting the dried unripe fruit, often combined with ginger or licorice to moderate perceived harshness, and the formula Wu-Zhu-Yu Tang remains a canonical prescription in contemporary TCM clinical practice. The isolation and structural characterization of evodiamine as the principal alkaloid in the 20th century bridged classical ethnobotanical knowledge with modern pharmacological investigation, spurring interest in its anti-cancer and metabolic properties.

## Synergistic Combinations

Within Evodiae fructus whole-fruit extracts, co-present alkaloids such as rutaecarpine and hydroxyevodiamine may complement evodiamine's TRPV1 activation and thermogenic effects through additive receptor engagement, and the fruit matrix has been reported to enhance evodiamine's bioavailability compared to isolated compound administration. Hydroxypropyl-β-cyclodextrin inclusion complexation serves as a pharmaceutical synergist by improving solubility and achieving a 2.56-fold increase in bioavailability, representing a formulation-level enhancement rather than a pharmacodynamic one. Combinations with other thermogenic compounds such as capsaicin or piperine are theorized to produce additive TRPV1-mediated energy expenditure effects based on receptor pharmacology, but no controlled combination studies in humans or animals have validated this stack.

## Frequently Asked Questions

### Does evodiamine actually work for weight loss in humans?

There are currently no human clinical trials demonstrating that evodiamine causes weight loss in people. Animal studies show it activates TRPV1 receptors and increases catecholamine-driven thermogenesis in rodents, but these results have not been replicated in controlled human research. Until dose-finding and efficacy trials in humans are completed, any weight loss claims for evodiamine supplements remain scientifically unsubstantiated.

### What is the recommended dose of evodiamine?

No clinically validated human dose for evodiamine has been established because no human pharmacokinetic or clinical efficacy trials have been published. Animal studies used doses of 100–500 mg/kg orally, which are not directly convertible to human equivalents without safety and dose-escalation data. Commercial supplements exist but lack regulatory-approved dosing guidelines, and self-supplementation carries unknown risk.

### Is evodiamine safe to take as a supplement?

Evodiamine's safety in humans is unknown due to the complete absence of human clinical data. Preclinical studies document cardiotoxicity at an in vitro IC50 of 28.44 µg/mL in cardiomyocytes and an LC10 of 354 ng/mL in zebrafish embryos, along with pericardial malformations. It also inhibits CYP1A2, CYP2C9, and CYP2D6 enzymes, raising significant concern for drug interactions with warfarin, codeine, and theophylline.

### What drugs interact with evodiamine?

Evodiamine inhibits three major cytochrome P450 enzymes—CYP1A2, CYP2C9, and CYP2D6—which metabolize a wide range of prescription medications. This means co-administration with warfarin (CYP2C9 substrate), tamoxifen or codeine (CYP2D6 substrates), or theophylline and certain antidepressants (CYP1A2 substrates) could increase those drugs' plasma concentrations and risk of toxicity. Anyone taking prescription medications should consult a healthcare provider before using any product containing evodiamine or Evodiae fructus extract.

### What plant is evodiamine derived from and how is it traditionally used?

Evodiamine is the principal alkaloid isolated from Evodiae fructus, the dried unripe fruit of Evodia rutaecarpa, a tree native to China, Korea, and Japan. In Traditional Chinese Medicine, the fruit is called Wu-Zhu-Yu and has been used for over 2,000 years in classical formulas to relieve cold-type abdominal pain, nausea, and headache. Traditional preparation involves decocting the dried fruit, sometimes combined with ginger or licorice, and the formula Wu-Zhu-Yu Tang remains a standard prescription in contemporary TCM practice.

### How does evodiamine's mechanism of action differ from other thermogenic supplements?

Unlike caffeine or synephrine which act primarily through sympathomimetic pathways, evodiamine activates TRPV1 (vanilloid) receptors to increase thermogenesis and metabolic heat production. This distinct mechanism may offer a complementary approach to traditional stimulant-based fat burners, though human clinical data on its thermogenic efficacy remains limited compared to well-established thermogenics.

### What does current research reveal about evodiamine's anti-cancer potential in humans?

While preclinical studies demonstrate that evodiamine induces apoptosis and blocks cell cycle progression in multiple tumor cell lines through Cdc2 phosphorylation inhibition, these findings are restricted to laboratory and animal models. No clinical trials have been conducted in human cancer patients, so anti-cancer claims cannot be made for supplement use at this time.

### Is evodiamine bioavailability affected by food intake or stomach pH?

Limited pharmacokinetic data exists on evodiamine's absorption in humans, though as a lipophilic alkaloid it may benefit from fat-containing meals to enhance bioavailability. Most animal studies administered evodiamine in controlled dosing conditions, but specific guidance on optimal timing with food or conditions affecting human absorption is not well-established in published research.

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