Myrica nagi tree

Myrica nagi (Kaphal / Katphala): A Comprehensive Reference Article

1. Identity, Nomenclature, and Natural Source

1.1 Botanical and Taxonomic Identity

Myrica nagi is also known as Myrica esculenta (family Myricaceae), with common names including katphala, boxberry, and kaphal. The species sits within the order Fagales. The accepted botanical authority citation is Myrica esculenta Buch.-Ham. ex D. Don, with Myrica nagi Thunb. (syn. M. nagi Hook. f.) treated as a synonym in most contemporary phytochemical and pharmacological literature. In multiple languages the plant carries distinct names: Kaiphula or Kayaphal in Sanskrit and Hindi, Box Myrtle or Bayberry in English, Azuri or Kandool in Arabic, Kayachal in Bengali, Kirishivani in Kannada, Maruth in Malayalam, and Kaidarayamu in Telugu.

M. esculenta Buch.-Ham. ex D. Don is a multipurpose, economically important plant belonging to the family Myricaceae, well recognized for its medicinally therapeutic utilization in ancient Ayurveda and Unani systems of medicine. It is also known as box myrtle and is indigenous to India, widely distributed across various regions of the Himalayas, Nepal, and China.

1.2 Morphology and Distribution

Commonly known as Kaiphala or Katphala, it is an evergreen dioecious tree distributed in the subtropical Himalayas, found in India, Nepal, China, Pakistan, and the Malaysian Islands. The plant is commonly found in the outer Himalayan region at an altitude starting from about 900 m up to 2,100 m, and is a medium to large woody, evergreen, dioecious tree attaining a height of 12 to 15 meters. Leaves are lanceolate, 9 cm long and 3 cm broad, with a pale-green lower surface and dark-green upper surface, generally crowded towards the end of branches. High tannin content in the woody tissues provides longevity to the timber, and the commercial name 'boxberry' derives from the tree's edible berries.

It is a slow-growing species that has become endangered in the Himalayan region due to loss of natural habitat and anthropogenic activities. M. esculenta is found to grow naturally in the wild and is not cultivated for commercial purposes.

1.3 Plant Parts Used and Common Preparations

Ethnobotanical reports indicate that the fruits and bark are the most widely used parts, traditionally employed for managing cardiac debility, respiratory ailments, gastrointestinal disorders, and wound healing. The utilization of leaves and fruits of the tree as medicine is a highly sustainable source of natural medicines, and the utilization of roots and stem barks for different remedies is also in practice. Preparations encountered in the literature include aqueous decoctions, ethanolic extracts, methanolic extracts, and essential oils derived from the bark, leaves, and fruit. Fruit is edible and natives of the region use its fruits to prepare pickle, jam, and refreshing drinks. Fruits and roots are also used to prepare Ayurvedic formulations such as Chyawanprash and Brahmarasayan to enhance digestion, memory, intelligence, concentration, and physical strength.

The bark of Myrica nagi is listed as a raw material in the Ayurvedic Pharmacopoeia of India, Part I, Volume III, issued by the Ministry of Health and Family Welfare, Department of Indian System of Medicine and Homeopathy. With its recognition in the Ayurvedic Pharmacopoeia and its widespread use in folk medicine, M. esculenta has significant ethnopharmacological value.

2. Traditional and Historical Use

2.1 Ayurvedic System (India)

Ayurveda literatures have reported the bark to be acrid, bitter, and pungent. It is stated to be beneficial in fever, asthma, bronchitis and other respiratory conditions, infection, urinary discharges, piles, constipation, throat complaints, tumours, anaemia, depression, chronic dysentery, and ulcers. In the classical Ayurvedic system, the plant is referred to as Katphala or Kaiphala, and features in compound formulations as well as in its raw form.

2.2 Unani System of Medicine

Myrica nagi is a well-recognized medicinal plant distributed in sub-Himalayan regions; in the Unani System of Medicine (USM), it is known as Kaiphal and is used in the prevention and management of several common disorders including Amraz-i-Riya (respiratory disease), Amraz-i-Hazam (gastrointestinal disease), Amraz-i-Aasab (nervine disease), and Amraz-i-Bawl (genitourinary disease).

2.3 Ethnobotanical Use Across Himalayan Peoples

Traditionally, the bark has been used for the treatment of cough, asthma, fever, chronic bronchitis, diarrhoea, rheumatism, and inflammation. Roots have been used in bronchitis, asthma, and cholera, while flowers have been claimed to treat earache, diarrhoea, and paralysis. The plant is found in foothill tracts of the Eastern Himalayas, Meghalaya, Nepal, China, and Pakistan, and local tribes mainly use its fruits to prepare pickles and refreshing drinks.

Ethnobotanical surveys highlighted the traditional use of M. esculenta in treating cough, fever, digestive issues, and skin diseases. In the Khasi traditional healing system of Meghalaya, northeast India, the plant (locally known as Sohphie) is also in traditional use for various ailments and has been reviewed from an Ayurvedic perspective. Flower oil has been found useful in earache, diarrhoea, paralysis, and inflammation, while roots are used in bronchitis, asthma, cholera, and cough.

3. Key Constituents and Active Compounds

3.1 Phytochemical Overview

Phytochemical investigations have identified over 80 bioactive compounds, including flavonoids (notably myricetin), tannins, terpenoids, diarylheptanoids, phenolic acids, and volatile constituents. The plant is found to be a rich source of phenolic compounds, flavonoids, and flavonols. Other bioactive compounds reported in the plant belong to the class of alkaloids, glycosides, diarylheptanoids, ionones, steroids, saponins, triterpenoids, and volatile compounds.

Preliminary phytochemical analysis has confirmed the presence of alkaloids, carbohydrates, flavonoids, saponins, sterols, tannins, and triterpenoids. Chemical analysis of Myrica esculenta fruit shows the presence of ascorbic acids (0.071 mg/100 g DW), phenolics (34.95 mg/g FW), flavonoids (30.16 to 44.55 mg/100 g FW), saponins (8.27% FW), and alkaloids (7.48% FW).

3.2 Flavonoids

Key phytochemicals include diarylheptanoids, flavonoids, terpenoids, and glycosides, including myricetin (1), quercetin (2), myricitrin — myricetin 3-O-rhamnoside (3), kaempferol (4), isoquercetin (5), and rutin (6), all identified and validated by chromatographic methods.

Myricetin is the principal bioactive flavonol of the plant. First isolated from the bark of Myrica nagi, myricetin is a common flavonol occurring in both free and glycosylated forms, with anti-inflammatory activity and cardioprotective effect that prevents myocarditis by reducing apoptosis. Myricitrin (the 3-O-rhamnoside of myricetin) is its most abundant glycoside form.

3.3 Diarylheptanoids

Myricanol and myricanone are cyclic diarylheptanoids characteristic of the Myrica genus. As a natural cyclic diarylheptanoid, myricanol is attracting increasing attention as a potential drug candidate for various diseases. Myricanol has a seven-carbon skeleton linked to two phenyl rings; one ring contains two methoxyl groups and one phenolic hydroxyl group, whereas the other ring has only one phenolic hydroxyl group. Tree roots, bark, and foliage of M. esculenta contain diarylheptanoids; identified in the foliage and bark are myricanol and myricanone.

3.4 Tannins and Phenolic Acids

M. nagi bark contains gallic acid, myricanol, myricanone, epigallocatechin 3-O-gallate, two prodelphinidin dimers — epigallocatechin-(4β→8)-epigallocatechin 3-O-gallate and 3-O-galloyl epigallocatechin-(4β→8)-epigallocatechin 3-O-gallate — and the hydrolyzable tannin castalagin. Main compounds found in the fruit include hydroxybenzoic acid, gallic acid, p-coumaric acid, caffeic acid, catechin, ellagic acid, trans-cinnamic acid, chlorogenic acid, and myricetin.

3.5 Terpenoids and Sterols

β-rosasterol, daucosterol, and β-sitosterol-β-D-glucopyranoside were identified in the leaves, whereas taraxerol and stigmasterol were found in the bark. β-sitosterol was identified in both leaves and bark. Taraxerane-type triterpenoids — a class characterized by the taraxerane pentacyclic skeleton — have been isolated from the stem bark.

3.6 Novel Compound: Myresculoside

One new monoterpenoid glycoside, myresculoside (1), and eleven known compounds were isolated from a methanol extract of Myrica esculenta leaves by repeated column chromatography. The effects of these compounds on angiotensin I-converting enzyme (ACE) inhibition were investigated. Compounds 3 and 4 showed the most potent ACE inhibition with rates of 29.97% and 25.63% at a concentration of 100 µM, respectively.

4. Mechanisms of Action

4.1 Antioxidant Activity

A number of the chemical constituents of M. nagi have been identified as strong antioxidants. The primary mechanism involves scavenging of free radicals and reactive oxygen species, attributed predominantly to the polyphenolic content (myricetin, gallic acid, epigallocatechin gallate, and proanthocyanidins). Myricanol demonstrates antioxidant actions primarily by scavenging free radicals and interacting with Peroxiredoxin 5.

4.2 Anti-inflammatory Mechanisms

The anti-inflammatory action is primarily driven by inhibition of key enzymes such as 5-LOX (IC₅₀: 11.26 µg/mL) and hyaluronidase (IC₅₀: 21.61 µg/mL), alongside suppression of inflammatory signaling cascades including TNF-α, IL-6, COX-2, and NF-κB. Myricanol inhibits iNOS expression as part of its anti-inflammatory action.

4.3 Anticancer Mechanisms

Myricanol demonstrates anticancer actions primarily by regulating Caspase and BCL-2 family proteins, inhibiting iNOS expression, and scavenging free radicals. Myricetin has been found to be a significant inhibitor of migration, invasion, and adhesion and could reduce matrix metalloproteinase (MMP-2/9) activities and mRNA levels of ST6GALNAC5 genes in MDA-MB-231Br cells in a concentration-dependent manner, and in animal models when treated with 50 mg/kg dose.

4.4 Antidiabetic Mechanisms

In patients with type 2 diabetes (T2DM), myricetin has been observed to reduce plasma glucose levels, protect pancreatic β-cells, and restore islet function. It also has protective effects on diabetic cardiomyopathy. The essential mechanism of myricetin for improving insulin sensitivity might be the amelioration of impaired signaling intermediates downstream of insulin receptors through enhancing the secretion of β-endorphin (BER), which in turn leads to activation of peripheral µ-opioid receptors. Additionally, myricetin has been identified as an agonist of glucagon-like peptide 1 (GLP-1) receptor. Myricetin also increased GLP-1 due to inhibition of the degrading enzyme dipeptidyl peptidase-4 (DPP-4) at a higher dose in rats.

Myricitrin, a natural compound from the bark of Myrica esculenta, exhibits a potential role in the hypoglycemic effect and improves glucose uptake by the muscles of rats with type 2 diabetes.

4.5 Anti-obesity Mechanisms

Molecular docking analysis has shown that myricanol could act as an AMPK activator that inhibits lipid accumulation by suppressing adipogenic factors like leptin and adiponectin. Accordingly, M. nagi extract could serve for the treatment of obesity via various anorexigenic pathways. Myricanol improves metabolic abnormalities in mice by activating the AMPK/SIRT1/PGC-1α signaling pathway.

4.6 Antihypertensive Mechanism (ACE Inhibition)

Myresculoside, a monoterpenoid glycoside isolated from the methanolic extract of Myrica esculenta leaves, has exhibited ACE inhibition. Recent studies have shown the presence of this new compound from the methanolic leaf extract that had potent ACE-I inhibitory property.

5. Scientific Evidence by Area of Use

5.1 Anti-inflammatory Activity

Study type: In vivo (animal model). The anti-inflammatory activity of ethyl acetate and aqueous extracts of the bark of M. nagi was evaluated using carrageenan- and histamine-induced rat paw edema. Adult Wistar albino rats were subjected to carrageenan and histamine induced rat paw edema tests. In carrageenan-induced rat paw edema, the effects of ethyl acetate and aqueous extract at 100 and 200 mg/kg showed % inhibition of edema of 27% and 22%, respectively, compared to the standard drug aspirin (28%). These extracts also showed % inhibition of edema of 25% and 18%, respectively, compared to the standard drug (27%) when rats were challenged with histamine-induced rat paw edema.

Evidence strength: This is preclinical (animal model) evidence only. No controlled human clinical trials of M. nagi specifically for inflammation have been identified in the published literature.

5.2 Antioxidant Activity

In vitro assays demonstrated significant antioxidant activity in the methanolic extract of M. esculenta. The chemical constituents of Myrica esculenta are known for their potent antioxidant properties and reported pharmacological effects. One study used methanol extract to assess antioxidant activity (DPPH assay), anthelmintic effects, anti-inflammatory properties (human red blood cell membrane stabilization), and cytotoxicity (brine shrimp lethality bioassay).

Evidence strength: Predominantly in vitro (DPPH, FRAP, and related assays). No human clinical trials evaluating antioxidant biomarkers specifically for Myrica nagi have been identified.

5.3 Antimicrobial Activity

In vitro assays demonstrated effective antimicrobial action against common pathogens. The essential oil shows an average antimicrobial inhibition zone of 17.9 mm against various pathogens, particularly effective against foodborne bacteria. The extract demonstrates antibacterial properties against common pathogens like Staphylococcus aureus and Pseudomonas aeruginosa.

Evidence strength: In vitro only. No controlled human clinical trials for antimicrobial applications of M. nagi have been published.

5.4 Antiasthmatic and Anti-allergic Activity

It was discovered that Myrica nagi polar extract of bark (PEB) at 200 mg/kg has an antiasthmatic effect that was virtually identical to that of Ketotifen (1 mg/kg) in a preclinical study. Mast cell stabilization by M. nagi bark extracts has also been reported in preclinical work (Patel et al., J Pharmacognosy Phytother 2011), suggesting a mechanism for both anti-allergic and antiasthmatic properties. Pharmacological studies have confirmed the therapeutic potential of M. esculenta and demonstrated its antiasthmatic, antiulcerative, anxiolytic, hepatoprotective, and wound healing properties.

Evidence strength: Preclinical animal model and in vitro data. No human clinical trials have been found in the indexed literature.

5.5 Antidiabetic Activity

The methanolic extract of Myrica esculenta leaves shows antidiabetic activity against type 2 diabetes. The extract exhibited antidiabetic properties in alloxan-induced diabetic mice, showing a dose-dependent decrease in blood glucose levels and a simultaneous increase in body weight, especially at 400 mg/kg, closely resembling the conventional medication glibenclamide. Myricetin possesses interesting pharmacological potentials such as anticancer, antidiabetic, and anti-inflammatory activities.

Evidence strength: Primarily in vivo animal models and in vitro mechanistic studies. Few clinical trials have been performed using myricetin as a nutraceutical. No dedicated human trials using whole Myrica nagi extract for diabetes management have been identified in peer-reviewed literature.

5.6 Anti-obesity Activity

A study aimed to elucidate the anti-obesity effect of the methanolic extract of M. nagi (MEMN) using in vivo animal models of obesity induced by gold thioglucose or a high-fat diet. The obese mice were treated or untreated with MEMN for 8 weeks. Thereafter, feed intake, Lee index, and BMI; biochemical parameters such as lipid profile, liver enzymes, and specific biomarkers of obesity — including insulin, leptin, adiponectin, free fatty acids (FFA), monocyte chemoattractant protein (MCP)-1, and resistin — were recorded. The weight and histopathology of organs and fat tissue were examined to validate the effectiveness of the extract.

Evidence strength: In vivo animal model only. No human clinical trials have been identified.

5.7 Anticancer Activity

Myrica esculenta is an evergreen tree species found in the Himalayan region that has been traditionally used for medicinal purposes. The plant contains various bioactive compounds, such as flavonoids, phenolic acids, and triterpenoids, which have been reported to possess various pharmacological properties. In recent years, Myrica esculenta has gained attention for its potential anticancer properties. Summarized in vitro and in vivo studies have evaluated the anticancer properties of Myrica esculenta. Evidence shows that myricanol has multiple bioactive properties, including antioxidant, anticancer, anti-inflammatory, antimicrobial, antidiabetic, and antihyperlipidemic effects.

Evidence strength: In vitro and limited animal model data. The available evidence suggests that Myrica esculenta may possess significant anticancer properties and can be explored as a potential candidate for the development of novel anticancer agents. No human clinical trials for cancer outcomes have been published.

5.8 Anxiolytic and Antidepressant Activity

In vivo studies revealed that the ethanolic extract had significant antidepressant effects, as evidenced by decreased immobility durations in both the forced swim and tail suspension tests, similar to normal desipramine therapy. Anxiolytic properties of Myrica nagi bark extract were reported by Khan et al. using animal behavior models.

Evidence strength: Preclinical (rodent behavioral pharmacology models) only. No human data available.

5.9 Hepatoprotective Activity

Important pharmacological activities such as hepatoprotective, antioxidant, antibacterial, antifungal, anthelmintic, anti-inflammatory, and antiasthmatic properties were demonstrated by researchers. Demonstrating notable antioxidant, anti-inflammatory, and hepatoprotective effects, Myrica esculenta's rich bioactive profile supports its therapeutic promise and bridges folk remedies with modern pharmacological insights.

Evidence strength: Animal model and in vitro evidence only. No human clinical trial evidence for hepatoprotection by M. nagi per se has been identified.

5.10 Neuroprotective Activity

One of the beneficial biological effects of myricetin — the principal flavonol of M. nagi — is the neuroprotective activity, showing preclinical activities on Alzheimer, Parkinson, and Huntington diseases, and even in amyotrophic lateral sclerosis. Health benefits of myricetin are related to its impact on different cell processes, such as apoptosis, glycolysis, cell cycle, energy balance, lipid level, serum protein concentrations, and osteoclastogenesis.

Evidence strength: Preclinical. These findings are for the isolated compound myricetin, not for whole-plant M. nagi extracts, and no human clinical trial evidence is available.

5.11 Antihypertensive Activity

One new monoterpenoid glycoside, myresculoside, and eleven known compounds were isolated from a methanol extract of Myrica esculenta leaves. Their effects on angiotensin I-converting enzyme (ACE) inhibition were investigated. Compounds 3 and 4 showed the most potent ACE inhibition with rates of 29.97% and 25.63% at a concentration of 100 µM, respectively.

Evidence strength: In vitro (isolated enzyme assay). No animal or human studies specifically examining blood pressure endpoints for M. nagi extracts have been identified in the published record.

6. Body Systems and Health Areas of Association

• Respiratory system: Conventionally, different parts of Kaiphal are used in asthma and allergic disorders. Traditional bark use for cough, bronchitis, and asthma is reinforced by preclinical mast-cell stabilization and antiasthmatic animal data.
• Gastrointestinal system: Traditionally used for the treatment of liver diseases, fever, asthma, anaemia, chronic dysentery, ulcer, and inflammation.
• Cardiovascular and metabolic system: Chemical constituents like myricetin isolated from its fruit have been shown to exert beneficial effects against cardiovascular disease, cancer, inflammatory conditions, and metabolic disorders.
• Endocrine/metabolic system (diabetes and obesity): Preclinical evidence for antidiabetic activity via glucose-lowering, GLP-1 agonism, and insulin sensitization; anti-obesity activity via AMPK/SIRT1 pathway activation.
• Nervous system: Myricetin shows neuroprotective preclinical activities and has also revealed antidiabetic, anticancer, immunomodulatory, cardiovascular, analgesic, and antihypertensive biological activities.
• Immune/allergic system: Mast cell stabilization and anti-allergic activity demonstrated in preclinical studies.
• Liver (hepatoprotective): Activity observed in animal and in vitro models.
• Kidney (nephroprotective): Nephroprotective activity is listed among the pharmacological actions attributed to the phytoconstituents of Kaiphal.
• Skin/wound healing: Myricetin, predominantly present in the bark, has been extensively studied for its anticancer, anti-inflammatory, antidiabetic, and wound-healing properties.

7. Dosage Forms and Dosages Reported in Studies

No standardized human clinical dosing has been established for Myrica nagi. The following doses appear in the preclinical literature:

• Anti-inflammatory study (rats): Ethyl acetate and aqueous extract of M. nagi at 100 and 200 mg/kg p.o. showed significant % inhibition against carrageenan-induced rat paw edema. The extract at 200 mg/kg showed % inhibition similar to those of the standard group.
• Antiasthmatic study (animal): Polar extract of bark (PEB) at 200 mg/kg was found to have an antiasthmatic effect virtually identical to that of Ketotifen at 1 mg/kg.
• Antidiabetic study (mice): Antidiabetic properties were evaluated in alloxan-induced diabetic mice with a dose-dependent decrease in blood glucose levels, especially at 400 mg/kg, closely resembling glibenclamide.
• Anti-obesity study (mice): The anti-obesity effect was studied using the methanolic extract of M. nagi (MEMN); obese mice were treated or untreated with MEMN for 8 weeks.
• ACE-inhibitory study (in vitro): The most potent ACE inhibition was observed at a concentration of 100 µM.
• Anti-cancer compound dose (in vivo): Myricetin reduced MMP-2/9 activities in animal models when treated with 50 mg/kg dose.

The physicians of the Unani System of Medicine described the properties and therapeutic uses of Kaiphal, but data on safety and efficacy are limited, and there is also a lack of attraction of researchers toward preclinical and clinical trials.

8. Safety Considerations

8.1 Acute Toxicity

Acute toxicity studies showed that the LD₅₀ of the ethyl acetate and aqueous extracts in mice was 1,000 mg/kg by the intraperitoneal (i.p.) route. The lack of acute toxicity at doses of up to 700 mg/kg further substantiates its safety for therapeutic use in the preclinical context.

8.2 Dose-Dependent Cytotoxicity

Although Myrica esculenta has many potentials such as anticancer and anti-inflammatory effects, it shows a degree of toxic effect on overdosing. According to the study of Smit et al. (2013), the dose of 300 mg/kg was nontoxic, and the dosage of 2,000 mg/kg was found to be toxic in some animals. However, this is the only study that shows cytotoxicity of the leaves in a dose-dependent manner, and the plant needs further attention regarding its cytotoxic effects.

8.3 Data Gaps and Regulatory Status

The physicians of the Unani System of Medicine described the properties and therapeutic uses of Kaiphal, but data on safety and efficacy are limited, with a lack of attraction of researchers toward preclinical and clinical trials. Clinical trials on the toxicity of this plant and its pharmacological effects must be carried out to assess its more desirable and undesirable effects. Comprehensive formal safety assessments for systemic human use by major regulatory bodies such as the U.S. FDA, EFSA, or EMA have not been published in the accessible peer-reviewed record.

8.4 Conservation and Sustainable Supply

Pharmacological studies on extracts from fruits, bark, and leaves provide experimental support for many traditional claims, demonstrating analgesic, hepatoprotective, and antimicrobial effects with relatively low toxicity. However, unsustainable harvesting, limited cultivation, and habitat loss have placed this species under threat, necessitating urgent conservation interventions.

9. Overall Evidence Assessment

The body of scientific literature on Myrica nagi / Myrica esculenta is substantial in breadth but low in clinical depth. During the last decade, considerable progress has been achieved regarding the biological activity and medicinal applications of Myrica nagi compounds. Nevertheless, the overwhelming majority of evidence remains at the in vitro and preclinical animal-model level. Further studies and clinical trials are recommended to substantiate these results. The individual compound myricetin has slightly more clinical attention than the whole plant, but few clinical trials have been performed using myricetin as a nutraceutical. The traditional record across Ayurvedic and Unani medicine is extensive and internally consistent, and a growing body of preclinical pharmacology supports biological plausibility for many traditional claims. However, none of the pharmacological endpoints studied to date has been validated in well-designed randomized human trials, and no dose-effect data from human studies are available.

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