Melia (Melia azedarach L. and Melia toosendan Sieb. et Zucc.): A Comprehensive Reference
1. Identity and Botanical Classification
Among the widely used plants in traditional medicine is Melia azedarach, commonly referred to as melia, chinaberry, or cinamomo. Melia azedarach L., a species of the mahogany family (Meliaceae), has long been used as a folk medicine for various diseases. The genus Melia is closely associated with two principal medicinal species: Melia azedarach L. (common chinaberry, Persian lilac, or Ku Lian Zi) and Melia toosendan Sieb. et Zucc. (Sichuan chinaberry, or Chuan Lian Zi). Melia toosendan Sieb. et Zucc. is a variety of chinaberry (Melia azedarach). In contemporary scientific and traditional medicine literature, the name "Melia" as a supplement or herbal ingredient refers to preparations from one or both of these closely related species, predominantly their fruit, bark, leaves, seeds, or root bark.
1.1 Accepted Botanical and Common Names
- Scientific names: Melia azedarach L.; Melia toosendan Sieb. et Zucc.
- Family: Meliaceae (the mahogany family)
- Common names (English): Chinaberry, Persian lilac, China tree, China berry tree, bitter chinaberry tree, Chinese neem tree, paradise tree, bead tree, white cedar
- Chinese names: Melia azedarach (Ku-lian) is also known as China tree, China berry tree, bitter China berry tree, or Chinese neem tree.
- TCM (Pinyin) names: Chuan Lian Zi (川楝子; fruit of M. toosendan); Ku Lian Zi (苦楝子; fruit of M. azedarach)
- Ayurvedic name: Maha Nimba (Melia azedarach), commonly known as Persian Lilac, is an important medicinal tree described in Ayurvedic texts.
- Other regional names: Azad derakht (Persian/Iranian), Ghoda Neem (Bangladesh), Mahanimba (Sanskrit)
1.2 Morphological Description
Physically, it is a medium-sized deciduous tree reaching 7–12 meters high, with grey-brown bark and a spreading crown of finely divided pinnate leaves. In spring it blooms fragrant lilac-colored flowers in loose panicles. Its fruit are yellowish drupes (1–2 cm in diameter), maturing in late summer. Flowers are arranged in large axillary panicles and have a rich lilac-like fragrance. The fruit consists of a small, round-to-ovoid seedpod or drupe that is approximately 1.5 cm in diameter, initially green and smooth but turning a pale yellow.
The chinaberry is native to Persia, India, and China but has become well established worldwide and naturalized to the temperate regions of North America and coastal areas such as Hawaii and Bermuda. M. azedarach is native to Africa, Asia and Northern Australia, and is conventionally employed as an antiparasitic and antifungal agent with significant free radical scavenging activity.
1.3 Distinction Between the Two Principal Medicinal Species
'Chuan Lian Zi' refers to the fruit of the Chuan Lian tree (Melia toosendan Sieb. et Zucc.), while 'Ku Lian Zi' is the fruit of the Chinaberry tree (Melia azedarach L.). These two species are sometimes confused or used interchangeably, but they differ in phytochemical composition and potency. The two are not interchangeable: Ku Lian Zi has greater toxicity and a lower toosendanin content (approximately 0.48 mg/g versus 0.84 mg/g for Chuan Lian Zi). Key identification differences: Ku Lian Zi is smaller (1–2 cm diameter versus 2–3.2 cm for Chuan Lian Zi), elliptical rather than spherical, with a reddish-brown or grey-brown surface that is more wrinkled.
1.4 Common Preparations and Dosage Forms
The leaves, bark, and fruit are typically used in traditional Ayurvedic formulations. In winter, people gather the ripe fruits of Melia toosendan Sieb. et Zucc., remove impurities, dry them, crush them to use directly, or cut them into thick slices or crush them, stir-fry them, and make them into Chinese herbal medicines. It is harvested in the winter and dried in the sun. It is usually broken before use and used in crude form or after being stir-baked with bran.
Preparations reported in traditional and research contexts include:
- Crude dried fruit, administered orally
- Bark and root bark decoctions
- Leaf extracts (aqueous, ethanolic, methanolic, ethyl acetate fractions) used in research settings
- Seed kernel extracts studied for antimicrobial and cytotoxic activities
- Topical poultices from leaf or fruit preparations
- Today, it is harvested in winter, dried, and processed into forms like slices or powders.
2. Traditional and Historical Use
2.1 Ayurvedic Tradition (India)
Maha Nimba (Melia azedarach), commonly known as Persian Lilac, is an important medicinal tree described in Ayurvedic texts for its potent Pitta–Kapha pacifying properties. It is traditionally used in the management of skin disorders (Kushta), itching (Kandu), wounds (Vrana), fever (Jwara), and parasitic infestations. The bark, leaves, fruits, and seeds possess detoxifying actions, making the herb effective in inflammatory and infective conditions.
Melia azedarach is used as an Ayurveda and Unani medicine in India and Arab nations, respectively, for its anti-inflammatory, analgesic, insecticidal, rodenticidal, anti-diarrheal, deobstruent, diuretic, antidiabetic, cathartic, emetic, antirheumatic, and antihypertensive properties. Melia azedarach Linn, also known as mahanimba, is a large evergreen tree found throughout India, used for its anthelmintic, antilithic diuretic, emmenagogue, astringent, and stomachic properties.
2.2 Traditional Chinese Medicine (TCM)
Historically, it has been a staple since the days of Shennong's Classic of Materia Medica (around 200 BCE), where it was praised for treating fever, madness, and "three bugs" (likely parasites). In the TCM framework, it is bitter in flavour and cold in nature, whilst also being mildly toxic. Its main function is to promote circulation of Qi. Additionally, it can help to kill parasites and treat tinea. Clinically, Chuan Lian Zi is used for Liver Qi stagnation or Liver Qi attacking the stomach causing chest/rib pain, stomach pain, abdominal pain and distension.
Channels entered in TCM classification: Liver, Stomach, Small Intestine, Bladder. It is one of the few Qi-moving herbs that is cold rather than warm, making it uniquely suited for people with pain accompanied by signs of heat such as irritability, bitter taste in the mouth, or a flushed tongue. According to traditional Chinese medicine records, both fruits (M. toosendan and M. azedarach) have effects such as expelling roundworms, treating abdominal pain, and treating tinea capitis.
Traditionally, Chuan Lian Zi produced in Sichuan is considered to be a Daodi medicinal material — a concept in TCM indicating the highest quality product coming from a specific, historically recognized geographic origin.
A classic TCM formula incorporating Fructus Meliae Toosendan is Jinlingzi San (金铃子散), composed of equal parts of the fruit and Rhizoma Corydalis, traditionally used to relieve pain associated with Qi stagnation and heat.
2.3 Iranian and Middle Eastern Traditional Medicine
Melia azedarach L. is an important medicinal plant that is used for variety of ailments in Iranian traditional medicine. Melia azedarach L. (Meliaceae), commonly known as Persian lilac or chinaberry, has long been recognized in Iran as a medicinal plant with a variety of medicinal effects and mentioned in ancient medical literatures as "Azad derakht."
2.4 Cross-Cultural and Global Folk Use
Over time, European colonists introduced Melia azedarach to the Americas and Africa; by the 19th century, American settlers used it in decoctions against intestinal worms, calling it "Southern chinaberry." Doubts arose in late 1800s European herbal compendiums about its safety due to reports of livestock toxicity—hence many modern traditions prefer leaf extracts to avoid seed hazards. Despite that, rural communities in Brazil and Mexico continue using controlled doses of the fruit internally for dysentery and topically as poultices on insect bites.
In traditional Chinese medicine, Melia azedarach (Ku-lian) is used orally and topically as an antiparasitic and antifungal agent. Melia azedarach L. has been widely used in traditional Chinese and Ayurvedic prescriptions to control various infections.
3. Key Constituents and Active Compounds
A diverse range of organic compounds has been isolated from this species, such as triterpenoids, limonoids, degraded limonoids, steroids, lignans, flavonoids, and phenolics. The phytochemistry of Melia is dominated by a structurally complex class of tetranortriterpenoids known as limonoids, which are responsible for the majority of its documented pharmacological activities.
3.1 Limonoids
Limonoids are the most pharmacologically significant and thoroughly studied class of compounds in the genus Melia. These compounds can be classified into two categories: the ring-intact group and the ring-C-seco group. Benefiting from the development of separation and analysis technology, more than 200 limonoids have been isolated and identified from this genus. There is growing evidence that limonoids from genus Melia possess diverse pharmacological activities, especially anti-cancer effects, insecticidal activities, and anti-botulism effects.
Key limonoids identified from Melia azedarach and Melia toosendan include:
- Toosendanin (TSN): Toosendanin, as a characteristic compound in the trichilin class, has been confirmed to be a potential bioactive component in the field of anti-tumor, insecticide, and anti-botulism. Notably, toosendanin can only be isolated from two plant species, M. toosendan and M. azedarach. The first isolation and identification of toosendanin can be traced back to 1975. In 1980, Chinese researchers corrected its chemical structure due to the occurrence of two tautomers found by paper chromatography and silica gel plate method.
- Meliatoxins A1, A2, B1, B2: Tetranortriterpenes such as meliatoxin A1, A2, B1, and B2 are the most relevant toxic compounds identified in the fruits of this plant.
- Meliacarpinins and derivatives: The phytochemicals content of an active fraction included steroids and triterpene saponin, limonoid (toosendanin, meliarachin, salannin, salannal, 12-hydroxyamoorastatin, meliacarpinin and its derivatives), and flavonoids (quercetin glycoside).
- Azedarachins (A, B, C): Members of the trichilin class identified in both leaves and fruits, with documented antifeedant and insecticidal properties.
- Additional limonoids: Chuan Lian Zi contains toosendanal, 2-O-methylvolkensin, meliatoxin B1, trichilin H, toosendanin, meliasenins I–R, methyl kulonate, kulinone, toosendansins E–I, meliatoosenins E–S, and others.
3.2 Flavonoids and Phenolic Acids
Research has revealed the presence of phenolic acids and flavonoids such as gallic acid, chlorogenic acid, caffeic acid, hyperoside, isoquercetin, quercetin, and isorhamnetin in both Algerian and Tunisian leaf samples, with an abundance of phenolic acids compared to flavonoids. Flavonols are abundant in the leaves of M. azedarach and these compounds seem to be responsible for many of the medicinal effects exploited in the traditional uses.
Other identified phenolic compounds include rutin, morin, homoeriodictyol, daidzein, kaempferol, clematine, quercetin, and isoquercitrin.
3.3 Triterpenoids
A new tirucallane triterpenoid, 3-α-tigloylmelianol, was isolated along with three known tirucallanes from the dichloromethane-soluble part of the methanol extract obtained from the fruits of Melia azedarach. 21-β-acetoxy-melianone, 3-α-tigoylmelianol, and melianone were cytotoxic, while 21-β-acetoxymelianone and 3-α-tigloylmelianol showed an additional moderate antiproliferative effect against the human lung adenocarcinoma epithelial cell line A549.
3.4 Steroids and Lignans
A comprehensive review found 147 phenolic compounds from 17 genera within the Meliaceae family. Lignans are the predominant class of phenolic compounds, representing 46.3% of total isolates. Steroids identified include β-sitosterol, stigmasterol, and daucosterol. The present findings showed the presence of phytochemicals such as steroids, alkaloids, phenols, flavonoids, saponins, tannins, anthraquinone, and amino acids in M. azedarach extracts.
3.5 Fatty Acids and Other Metabolites
Leaves of M. azedarach are rich in important fatty acids and oleamide. Water deficit increases the radical scavenging capacity, total phenol, flavonoids, and catechol pools, and the accumulation of β-sitosterol, myo-inositol, succinic acid, sucrose, d-glucose and derivatives, and the fatty acids stearic, α-linolenic, linoleic, and palmitic acids.
4. Mechanisms of Action
4.1 Insecticidal and Antifeedant Mechanisms
It is believed that toosendanin and its derivatives are formed by the loss of four carbons from the side chain of the euphane (20R) or tirucallane (20S) skeleton, which then cyclize to form the 17β-furan ring. Toosendanin and its derivatives demonstrate high insecticidal activity and are important insecticidal molecules derived from plants. The main targeted compounds, limonoids (terpenes), have higher solubility in polar solvents and alcohol.
4.2 Anticancer Mechanisms
TSN (toosendanin) exerts an anticancer effect via mechanisms including proliferation inhibition, apoptosis induction, migration suppression, and angiogenesis inhibition. To elucidate the mechanism underlying the anticancer effects of M. azedarach leaf extract (MLE), MLE-treated MKN1 cells were observed using an electron microscope; MLE treatment induced autophagy.
Key signaling pathways screened via cell transcriptomics show that the MAPK pathway was identified as the core pathway involved in isotoosendanin (ITSN)-mediated therapy against hepatocellular carcinoma (HCC). Following findings that the ethyl acetate fraction was the most active cytotoxic fraction against T47D cells, researchers aimed to isolate the cytotoxic compounds and further elucidate their apoptotic mechanisms.
4.3 Antibacterial Mechanisms
The antibacterial efficacy and mechanisms of action against Gram-positive and Gram-negative pathogenic microorganisms were evaluated; findings revealed a presence of phenolic acids and flavonoids such as gallic acid, chlorogenic acid, caffeic acid, hyperoside, isoquercetin, quercetin, and isorhamnetin, with an abundance of phenolic acids compared to flavonoids. Phenolic acids are established to disrupt bacterial cell membranes and inhibit cell wall biosynthesis.
4.4 Antidiabetic Mechanisms
Effects were examined on stimulation of glucose uptake by C2C12 cultured cell line, inhibitory effect on human recombinant Protein tyrosine phosphatase-1B (PTP-1B), and hypoglycaemic activity of extracts in Streptozotocin (STZ)-induced diabetic rats. This is likely due to its stimulatory impact on insulin production, improving insulin-dependent gene expression, lipid profile, oxidative stress, and antioxidant defense systems.
4.5 Anti-inflammatory Mechanisms
Limonoids from Melia toosendan have demonstrated inhibitory effects on macrophage activation pathways. All new meliacarpinin-type compounds were evaluated for their inhibitory activity on LPS-activated RAW 264.7 macrophages; limonoids 2 and 3 showed moderate inhibitory effects with IC50 values of 21.3 ± 1.5 μM and 20.7 ± 2.3 μM, respectively.
4.6 Hepatotoxic Mechanisms (Toosendanin)
The lipid droplets were significantly decreased, accompanied by a decrease in fatty acid transporter CD36 and crucial enzymes in the lipogenesis including ACC and FAS after treatment of TSN. It was suggested that TSN caused lipid metabolism disorder in hepatocytes. The metabolism of TSN can produce reactive metabolites, which can interact with proteins to induce the formation of reactive metabolites-protein adducts of TSN, thereby causing liver injury. Several studies have explored the potential mechanisms underlying TSN-induced hepatotoxicity, including oxidative stress, autophagic disruption, and impaired lipid metabolism.
5. Scientific Evidence by Area of Use
5.1 Antimicrobial Activity
Evidence level: Preclinical only (in vitro). No controlled human trials identified.
The studied methanolic leaf extracts of M. azedarach exhibit a broad spectrum of antibacterial activities, with MIC values ranging from 31.25 mg/mL to 125 mg/mL against Gram-positive and Gram-negative pathogenic bacteria. In a serial agar dilution method, hexanic and ethanolic extracts from fruit, seed kernels, and senescent leaves exhibited fungistatic activity against Aspergillus flavus, Diaporthe phaseolorum var. meridionales, Fusarium oxysporum, Fusarium solani, Fusarium verticillioides, and Sclerotinia sclerotiorum. Both hexanic extract from senescent leaves and ethanolic extract from seed kernel were highly effective on all tested fungi, with MIC values ranging from 0.5 to 25 mg/mL and 0.5 to 5 mg/mL, respectively. All extracts showed fungicidal activity on these fungi, with ethanolic seed kernel extract being the most active.
Active antifungal compounds isolated from the ethanolic seed kernel extract were characterized as vanillin, 4-hydroxy-3-methoxycinnamaldehyde, and (+/−)-pinoresinol, with MICs of 0.6, 0.4, and 1.0 mg/mL, respectively. These compounds also showed a synergistic effect when combined in different concentrations, needing four times less concentration to reach complete inhibition in the growth of F. verticillioides.
All antimicrobial findings to date are from cell culture or agar diffusion assays. No published randomized controlled trials or prospective clinical studies in humans have established clinical efficacy for any antimicrobial application.
5.2 Antiviral Activity
Evidence level: In vitro only. No human clinical trials identified.
By assessing the in vitro antiviral activities of both total leaves extracts against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), it was found that A. indica L. and M. azedarach L. have robust anti-SARS-CoV-2 activities at low half-maximal inhibitory concentrations (IC50) of 8.451 and 6.922 μg/mL, respectively. These results are preliminary and limited to cell-line models. No human data exist on the antiviral efficacy of Melia extracts.
5.3 Anticancer Activity
Evidence level: In vitro and animal models. No human clinical trials identified.
By conducting an initial screening of several subtropical plants, one study evaluated the anticancer activities of Melia azedarach L. The extract from M. azedarach L. leaves (MLE) showed high cytotoxic effects on cancer cells and in vivo mouse and dog tumor models. During the initial screening, MLE showed strong antiproliferative activity against HT-29 colon, A549 lung, and MKN1 gastric cancer cells. In subsequent tests, using 39 human tumor cell lines, the potent anticancer activities of MLE were confirmed.
The anticancer activity of MLE was also confirmed in vivo. MLE markedly inhibited the growth of transplanted gastric MKN1 cancer xenografts in mice.
Five new compounds, including two limonoids, one triterpenoid, one steroid, and one sesquiterpenoid, along with nine known limonoids, were isolated from the bark of Melia azedarach. The isolated compounds were evaluated for their cytotoxicities against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480) by an MTT assay. Seven limonoids showed significant inhibitory activities against tested cell lines with IC50 values ranging from 0.003 to 0.555 µM.
Three limonoids, including trichilinin B, 3-deacetyl-4′-demethyl-28-oxosalannin, and 23-hydroxyohchininolide, were cytotoxic to gastric cancer cell line of AZ521 with IC50 values of 58.2, 3.2, and 78.5 µM, respectively. In another study, 31 limonoids were isolated and identified from the fruits of M. azedarach; among them, 12-dehydroneoazedarachin D showed the most potent cytotoxicity with an IC50 value of 11.8 µM.
Seven limonoids were isolated from the bark of Melia azedarach, including two new compounds; compounds 1–7 exhibited varying degrees of inhibitory effects on Hep3B cells. Among these, isotoosendanin (ITSN), displayed the most potent activity, with an IC50 value of 15.06 μg/mL. Mechanism studies have shown that ITSN inhibits cell proliferation and promotes apoptosis in Hep3B cells.
For breast cancer cell lines specifically, the EtOAc fraction of Melia azedarach L. leaves and the isolated 5-pregnene-16-one steroids were identified as promising reagents for breast cancer treatment by introducing apoptosis to tumor cells. All findings remain preclinical. No human oncology trials have been conducted.
5.4 Antidiabetic Activity
Evidence level: In vitro and animal model studies. No robust human clinical trials identified.
In a study investigating the antidiabetic effect of Himalayan medicinal plants, effects were examined on stimulation of glucose uptake by C2C12 cultured cell line, inhibitory effect on human recombinant PTP-1B, and the hypoglycaemic activity of extracts in Streptozotocin-induced diabetic rats. A significant decrease in blood glucose level was observed in the ethanol extract of Melia azedarach-treated group. This study demonstrated that these plants have a significant therapeutic value in type-2 diabetes mellitus and related complications, thus supporting their traditional uses in the Indian traditional system of medicine.
Melia azedarach fruit's methanol extract (MEMA) has been found to have stronger antidiabetic action than its aqueous extract (AEMA). This is likely due to its stimulatory impact on insulin production, improving insulin-dependent gene expression, lipid profile, oxidative stress, and antioxidant defense systems. All results are from preclinical models; no published human clinical trials have evaluated Melia extracts for diabetes management.
5.5 Anti-inflammatory and Analgesic Activity
Evidence level: In vitro and animal studies. No human clinical trials identified.
Animal studies reveal that root and bark preparations reduce pain and inflammation, corroborating traditional use in inflammatory and painful conditions. Mechanistically, the inhibition of LPS-activated macrophage inflammatory pathways by meliacarpinin-type limonoids has been demonstrated in cell culture, as noted in Section 4.5 above.
5.6 Insecticidal and Antiparasitic Activity
Evidence level: Well-established in laboratory and agricultural contexts; traditional antiparasitic use for humans supported by bioactive compound identification.
The repellence bioassay indicated that Melia azedarach extracts exhibited the highest repellence percentage against S. frugiperda (95%) and P. xylostella (90%). The feeding deterrence bioassay showed that M. azedarach and Trichilia dregeana extracts displayed excellent antifeeding activity against the S. frugiperda. The minimum inhibitory concentrations reflecting antifeeding activity of trichilin-type limonoids against different insects ranged from 200–400 μg/mL against S. exigua in 6–24 h.
In the 1950s, Chinese scientists isolated toosendanin (TSN), which, like azadirachtin, is also a triterpenoid compound. Toosendanin has subsequently been developed as an antiparasitic agent in China. Toosendanin extracted from Melia toosendan and Melia azedarach has been developed into an ascaris repellent in China.
5.7 Hepatoprotective Activity
Evidence level: Animal studies only. No human clinical trials identified.
The hepatoprotective effects of Melia azedarach were investigated against the liver injury induced by carbon tetrachloride (CCl4). Researchers measured parameters such as ALP, SGPT, SGOT, and serum bilirubin, and conducted pathological evaluations. They found that the biochemical markers improved after treatment, and the histological changes, like changes in fatty liver cells and fibrosis in the CCl4-treated group, returned to normal levels. This research is underway for identification of the specific compounds responsible for the hepatoprotective effects.
It is important to note that these hepatoprotective findings stand in tension with the well-documented hepatotoxicity of toosendanin (see Section 6.2). The net effect on the liver may depend on dose, extract type, plant part used, and species.
6. Body Systems and Health Areas Associated with Melia
- Digestive / gastrointestinal system: Used traditionally for abdominal pain, dysentery, digestive parasites, and Qi stagnation-related gastric complaints.
- Integumentary system (skin): Traditionally used in the management of skin disorders (Kushta), itching (Kandu), and wounds (Vrana).
- Immune/infectious disease: Traditionally applied to fever, parasitic infestations, and fungal infections.
- Endocrine (metabolic): Antidiabetic activity demonstrated in preclinical models via PTP-1B inhibition and stimulation of glucose uptake.
- Hepatic (liver): Both hepatoprotective (in CCl4 animal models) and hepatotoxic (via toosendanin at higher doses) effects have been reported.
- Oncology: Broad-spectrum in vitro cytotoxicity against multiple human cancer cell lines (colon, lung, gastric, breast, liver); in vivo animal model efficacy demonstrated for gastric cancer.
- Musculoskeletal / neurological: Animal data suggest analgesic and anti-inflammatory effects; toosendanin has documented neurotoxic effects at toxic doses.
- Reproductive: Do not use if pregnant or nursing — a precaution noted in traditional-use literature, reflecting emmenagogue properties historically attributed to the plant.
7. Dosage Forms and Reported Dosages
No standardized clinically validated dosage exists for any preparation of Melia in Western or regulatory contexts. The dosages below are those reported in traditional use systems and/or research literature.
- Toosendanin content as quality marker: Toosendanin (TSN) has been identified as the main toxic ingredient in Fructus Meliae Toosendan and is designated as a quality control marker according to the Chinese Pharmacopoeia (2020 edition).
- Human poisoning thresholds (Chinese pharmacopoeial literature): In the Chinese medical literature, human M. azedarach poisoning is said to occur if six to nine fruits, 30–40 seeds, or 400 g of bark is consumed.
- Antibacterial study extract concentrations: Methanolic leaf extracts exhibited antibacterial activities with MIC values ranging from 31.25 mg/mL to 125 mg/mL.
- Antidiabetic research dose (in vitro): Petrol, benzene, ethyl acetate, methanol, and aqueous seed extracts were evaluated at five different concentrations (1, 2, 5, 10 and 15 mg/mL).
- Cytotoxic limonoid IC50 values: Seven limonoids showed significant inhibitory activities against tested human tumor cell lines with IC50 values ranging from 0.003 to 0.555 µM.
- Toosendanin oral LD50 (mice): The LD50 of toosendanin varies between animals and routes; in mice the oral LD50 ranges between 250 and 500 mg/kg.
- Toosendanin content comparison: Ku Lian Zi (M. azedarach) has a lower toosendanin content (approximately 0.48 mg/g versus 0.84 mg/g for Chuan Lian Zi from M. toosendan).
8. Safety Considerations and Toxicology
8.1 Fruit Toxicity in Humans
The fruit of M. azedarach is highly toxic to warm-blooded animals; the consumption of 6–8 fruit can cause nausea, spasms, and in children, even death. According to Chinese medical literature, human poisoning can occur if 6–9 fruits, 30–40 seeds, or 400 grams of bark are eaten. The toxins include neurotoxins and unidentified resins, found mainly in the fruits. The first symptoms of poisoning appear a few hours after ingestion. They may include loss of appetite, vomiting, constipation or diarrhea, bloody faeces, stomach pain, pulmonary congestion, cardiac arrest, rigidity, lack of coordination and general weakness. Death may take place after about 24 hours.
8.2 Clinical Case Series of Human Poisoning
Onset of symptoms typically occurs within 4–6 hours, but as short as 0.5 hour had been documented. In patients reviewed at the Taiwan National Poison Center, the onset of M. azedarach poisoning was variable, ranging from a few hours to up to 3 weeks after consumption of the herb. Neurological symptoms were the major manifestation in four cases: weakness, myalgia, numbness, and ptosis. Treatment was symptomatic and supportive; all patients recovered without sequelae. M. azedarach poisoning may result in gastrointestinal, cardiovascular, respiratory, or neurological effects, and death in severe cases.
8.3 Toxic Principles Identified
Tetranortriterpenes such as meliatoxin A1, A2, B1, and B2 are the most relevant toxic compounds identified in the fruits of this plant. Multiple limonoid tetranortriterpenes have been isolated from various parts of this plant. Well-characterized limonoids include toosendanin from the bark and meliatoxin from the fruit. Tetranortriterpenoids constitute an important toxic principle, as in related species.
However, it is still not known which specific limonoids are responsible for human toxicities.
8.4 Hepatotoxicity of Toosendanin
TSN exerts an anticancer effect via mechanisms including proliferation inhibition, apoptosis induction, migration suppression, and angiogenesis inhibition. However, TSN's toxicity, particularly its hepatotoxicity, significantly limits its therapeutic application. As the main bioactive component in Fructus Toosendan, toosendanin (TSN) could cause liver injury by inducing hepatocyte energy metabolism disorder and impairing DNA damage responses and autophagy.
8.5 Herb-Herb Interactions and Pharmacokinetics
Fructus Meliae Toosendan (CLZ)–Fructus Foeniculi (XHX) is a typical traditional Chinese herb pair that decreases the toxicity and increases the efficiency of the herbs. Fructus Meliae Toosendan has significant liver toxicity. However, it has been widely used in combination with Fructus Foeniculi (XHX, hot-natured) for thousands of years in TCM, in which form it shows no hepatotoxicity, indicating that the combined use of XHX and CLZ can reduce the hepatotoxicity of CLZ. The pharmacokinetic results indicate that XHX can significantly decrease the absorption and bioavailability and accelerate the elimination process of toosendanin in CLZ. XHX could decrease the risk of in vivo accumulation of the toxic constituent of CLZ, toosendanin, thus decreasing its toxicity.
8.6 Animal Toxicology Findings
In animal studies, toosendanin caused abdominal distension, anorexia, and respiratory depression in rats; severe vomiting and shock in dogs; and transaminitis and muscle weakness in monkeys. In mice, cats, dogs, and monkeys, muscle weakness, respiratory depression, and seizures were also observed.
8.7 Variability in Plant Toxicity
Although only the bark of M. azedarach is listed as the medicinal part in some sources, leaves or other parts may be used and cause toxicity. It seems possible that the entire plant is toxic. Prior investigations had further suggested that the toxicity of this plant can vary depending on the growing conditions. Tetranortriterpenes known as meliatoxins have been reported as toxic principles of the fruit. In contrast to the limitation in fruit consumption, leaves of the plant have been prescribed for a variety of indications.
8.8 Contraindications Noted in Traditional Systems
According to the Chinese Pharmacopoeia, the medicinal nature of Chuan Lian Zi is relatively cold, with slight toxicity, and a bitter taste. This herb has mild toxicity and should only be used under professional guidance. Traditional TCM systems do not recommend use during pregnancy, and the emmenagogue actions historically attributed to the plant support this caution.
9. Current Research Gaps and Evidence Appraisal
Further pharmacological and clinical investigations are recommended to validate the efficacy and safety of Meliaceae-derived compounds. The scientific literature on Melia is characterized by a large and growing body of in vitro and animal model data, without transition to controlled human clinical trials. Key research gaps include:
- No published randomized controlled trials in humans for any therapeutic application of Melia preparations
- No established safe and effective therapeutic dose for oral use in humans
- It is not known which limonoids are responsible for human toxicity.
- Lack of standardized extracts or defined quality specifications across research preparations
- The dual hepatoprotective/hepatotoxic character of different preparations requires further elucidation
- Similar cytotoxic activity was previously reported for the extracts from the bark, roots, and seeds of M. azedarach L.; however, their underlying mechanism of activity remains elusive.
Researchers have investigated the incorporation of TSN into novel therapeutic strategies, such as Proteolysis-targeting chimeras (PROTAC) technology and nanotechnology-based drug delivery systems (DDS), which enhance treatment efficacy while mitigating toxicity. These approaches are investigational and have not yet resulted in approved therapeutic applications.
References
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