Agarwood (Aquilaria spp.): A Comprehensive Reference
1. Identity
Botanical and Taxonomic Classification
Agarwood is a resinous portion of Aquilaria trees, a genus belonging to the family Thymelaeaceae. It is more precisely defined as a resin-impregnated heartwood obtained from plants belonging to the genera Aquilaria, Daphne, Gonystylus, Gyrinops, and Wikstroemia. Within the genus Aquilaria, the species most prominent in trade and research include Aquilaria sinensis, A. malaccensis, A. crassna, and A. subintegra. In addition, there are at least 19 species of Aquilaria plants producing agarwood.
Formation and Natural Source
Agarwood is a resinous portion of Aquilaria trees, which is formed in response to environmental stress factors such as physical injury or microbial attack. The sweet-smelling wood and oils that it produces only occur as a result of a fungal infection in the heartwood of the tree; as a defense against the fungus, the tree produces a resin that infuses the heartwood, producing the highly prized agarwood. Sesquiterpene is not found in healthy A. sinensis and can only be formed in stems, branches, or roots subjected to wounding stress. It is thought that this process only occurs in around 2 percent of trees in the wild.
Common Names
Agarwood is known as 'chenxiang' in Chinese and 'aloeswood', 'agalloch', 'eaglewood', 'jinkoh', 'gaharu', and 'kanankoh' in other parts of the world. It is also known as chen xiang in China, jinkoh in Japan, and oud in the Middle East. The word "agar" ultimately comes from one of the Dravidian languages, probably from Tamil அகில் (aghil).
Common Forms and Preparations
It is traditionally used for the production of perfume and incense sticks, and for pharmaceutical applications. Major commercial and medicinal preparations include the raw resinous wood, essential oil (obtained by hydrodistillation or steam distillation), aqueous decoctions (teas), ethanol and organic solvent extracts, powders, and incense. Many manufacturers now use agarwood and agarwood oil to make different kinds of goods like personal care products including shampoo and soap, decorative sculptures, wooden boxes, and beads, as well as paper. The price of essential oils extracted from agarwood can be as high as 30,000 USD/kg, depending on the grade and quality of the agarwood.
2. Traditional and Historical Use
Overview and Antiquity
Agarwood, a highly precious non-timber fragrant wood of Aquilaria spp. (Thymelaeaceae), has been widely used in traditional medicine, religious rites, and cultural activities. It is still used in traditional Chinese herbal medicine, where it goes by the name of Chén Xiāng (沉香), literally meaning "sinking fragrance." Its earliest recorded mention is from the Miscellaneous Records of Famous Physicians (名医别录, Ming Yi Bie Lu), ascribed to the author Táo Hǒng-Jǐng, c. 420–589 CE.
Traditional Chinese Medicine (TCM)
Agarwood from Aquilaria plants, also known as Chen Xiang (沉香), is traditionally used in TCM for the treatment of abdominal pain and as a sedative. It is known for its pungent taste and warming properties, which influence the spleen, stomach, and kidney meridians. This herb is commonly used to treat conditions such as abdominal pain, chest pain, nausea, asthma, and breathing difficulties. It can relieve pain, arrest vomiting, and relieve asthma in traditional Chinese medicine.
Ayurvedic Medicine
It is very sought-after among the natural incenses, as well as for its medicinal properties in traditional Chinese and Ayurvedic medicine. In Ayurvedic practice, agarwood has been used to balance the doshas and as a treatment for digestive conditions. Agarwood has been used as a valuable incense in Buddhist, Hindu, and Islamic practices in Asian countries. In China, it was employed as a traditional medicine in Ayurvedic practices.
Traditional Arabian and Unani Medicine
In traditional Arabian medicine, agarwood has been widely used to treat digestive, neurodegenerative, and sedative diseases. Agarwood is also commonly used in aromatherapy to treat neurodegenerative, digestive, and sedative diseases in traditional Arabian medicine. Traditionally, agarwood is prescribed to treat pleurisy by the Sahih Muslim, relieve pain, arrest vomiting, and asthma.
Traditional Use Across Asia
Agarwoods have wide uses in traditional medicine, for example, as aphrodisiacs, sedatives, cardiotonics, and carminatives, as well as in the relief of gastric problems, coughs, rheumatism, and high fever. In addition, agarwoods are present in important spices and are also used as incense. In India and China, it is used as a medicine to treat digestive tract diseases such as loss of appetite, vomiting, and diarrhea, as well as respiratory diseases such as asthma and bronchitis, as it has an effect to reduce cough, sleep disorders, and pain relief.
Religious and Ceremonial Use
Agarwood is considered the finest natural incense and has been used in many cultures, such as the Arabian, Chinese, Indian, and Japanese cultures. Agarwood has been used as a valuable incense in Buddhist, Hindu, and Islamic practices in Asian countries. In Japan, during the sixth century CE, in the recordings of the Nihon Shoki (The Chronicles of Japan), the second oldest book of classical Japanese history, mention is made of a large piece of fragrant wood identified as agarwood.
3. Key Constituents and Active Compounds
Primary Phytochemical Classes
The major groups of phytochemicals identified in agarwood extracts are sesquiterpenes, 2-(2-phenylethyl)-4H-chromen-4-one derivatives (PECs), and aromatic compounds. The chemical constituents of agarwood and healthy Aquilaria trees are quite different. Sesquiterpenes and 2-(2-phenethyl)chromones with diverse scaffolds commonly accumulate in agarwood. Similar structures have rarely been reported from the original trees, which mainly contain flavonoids, benzophenones, xanthones, lignans, simple phenolic compounds, megastigmanes, diterpenoids, triterpenoids, steroids, and alkaloids.
Sesquiterpenes
Sesquiterpenes are one of the two dominant chemical classes in agarwood, comprising approximately 35% of newly identified compounds. Agarwood is a dark resinous wood, produced when an Aquilaria tree responds to wounding and microbial infection, resulting in the accumulation of fragrant metabolites. Sesquiterpenoids and 2-(2-phenylethyl) chromones are the major phytochemicals in agarwood, and Cytochrome P450s (CYPs) are one of the important enzymes in the biosynthesis of these fragrant chemicals. Structurally diverse sesquiterpene types identified in agarwood include guaiane-, eudesmane-, eremophilane-, and prezizane-type skeletons, among others.
2-(2-Phenylethyl)chromones (PECs)
Among the 154 new compounds identified from Aquilaria plants, 2-(2-phenylethyl)-4H-chromen-4-one derivatives and sesquiterpenes account for 57% and 35%, respectively, where most of the new compounds (accounting for 89%) were isolated from A. sinensis. PECs are particularly associated with the characteristic aroma and several bioactivities of agarwood. The mediation of these biosynthetic transformations is mainly via the cytochrome P450 monooxygenases (CYPs), of which CYP82G1 is the major chromone-hydroxylating enzyme in A. sinensis. CYP82G1 catalyzes hydroxylation at C-6 of the chromone backbone, producing a key PEC product, 6-hydroxy-2-(2-phenylethyl)chromone — a key agarwood aroma compound and antioxidant.
Additional Phytochemicals in Aquilaria Leaves
Agarwood tree leaves, rich in flavonoids, 2-(2-phenethyl) chromone compounds, and flavonoid compounds, also exhibit significant anti-inflammatory, antioxidant, and immune-modulating effects. A literature survey of agarwood plant materials showed that they contain sesquiterpenes, 2(-2-phenylethyl)-4H-chromen-4-one derivatives, genkwanins, mangiferins, iriflophenones, cucurbitacins, terpenoids, and phenolic acids.
Species-Dependent Variation in Chemistry
Generally, agarwood originating from different Aquilaria plants shares some common compounds, but still has several different compounds. The quality of agarwood was traditionally assessed by the resin content, density, color, scent/aroma, the agarwood-inducing method, formation time, and place of origin. Now, quality assessment of agarwood is performed by chemical analysis, which identifies the constituents in the agarwood.
4. Mechanisms of Action
Anti-inflammatory Mechanisms
Modern research has shown that the beneficial pharmacological properties of agarwood oil, including its anti-inflammatory properties, can be attributed to the presence of a wide range of bioactive compounds, such as flavonoids, terpenoids, chromones, phenolic acids, steroids, and alkanes. Several chromones detected in agarwood have been shown to inhibit NF-κB activation, LPS-induced NO production, and superoxide anion generation. Some studies indicate that agarwood extracts may inhibit enzymes like cyclooxygenase (COX) and lipoxygenase (LOX) involved in the generation of inflammatory mediators including prostaglandins and leukotrienes. By inhibiting these enzymes, agarwood could potentially suppress the inflammatory cascade. Recent innovative research has highlighted new compounds such as 2-(2-phenylethyl) chromone derivatives from agarwood that possess significant anti-inflammatory activity through inhibition of nitric oxide production from mice macrophage cells (RAW264.7) and protection against acid-induced apoptosis of gastric cells.
Sedative / Anxiolytic Mechanisms
Agarwood essential oil displays sedative-hypnotic effects through the GABAergic system (Molecules, 2017). Results from animal studies demonstrate that agarwood essential oil (AEO) exerts anxiolytic and antidepressant effects which are related to the inhibition of CRF and hyperactivity of the HPA axis. Additionally, it lowers hypothalamic–pituitary–adrenal (HPA) axis activity, which reduces stress-mediated neural damage and promotes neurite outgrowth in neurotoxic cells.
Antidiabetic Mechanisms
α-Amylase breaks down digestive starches into simpler sugars to be absorbed into the bloodstream, causing blood glucose levels to increase. It is thus a therapeutic strategy to lower complex sugar breakdown by inhibiting α-amylase activity to aid in the gradual release of glucose into the blood. Screening for anti-α-amylase properties is common in testing natural products' anti-diabetic potential. In kinetic studies, specific sesquiterpene and chromone compounds from agarwood were found to act as uncompetitive inhibitors for α-glucosidase and mixed-type inhibitors for tyrosinase, respectively. Molecular docking simulations revealed the binding sites and interactions of the most active compounds with α-glucosidase and tyrosinase.
Neuroprotective Mechanisms
For a long time, Asians have considered the plant as a priceless natural product with anxiolytic, sedative, and anti-inflammatory effects. Recently, various Aquilaria species have been scientifically shown to possess anti-oxidative, anti-inflammatory, and anxiolytic properties. Preliminary in vitro study demonstrated that agarwood extracts have significantly protected HT-22 hippocampal neuronal cell lines from glutamate excitotoxicity, which implies its neuropharmacological action in stress-related brain disorders.
5. Scientific Evidence by Area of Use
5.1 Anti-inflammatory Activity
Agarwood (Aquilaria spp.) is a resinous wood traditionally used in various medicinal systems across Asia for treating inflammation-related ailments. Despite its longstanding ethnopharmacological use, scientific validation of its anti-inflammatory effects remains fragmented. Studies have shown that agarwood leaf extracts can markedly alleviate ear edema induced by dimethyl benzene, paw edema caused by carrageenan, and leukocyte migration triggered by CMC-Na, exhibiting pronounced anti-inflammatory and analgesic properties.
A 2024 scoping review (searching PubMed, Scopus, and Google Scholar for original papers from 2013 to 2023) revealed that, despite the absence of clinical trials, agarwood exhibits antimicrobial and anti-inflammatory properties. The evidence base at the time of that review was confined entirely to in vitro and animal models. PEC compounds 9, 37, 47, and 75 were shown to reduce the release of TNF-α in LPS-activated RAW264.7 cells, while PECs 6, 26, 52, 60, 66, and 146 suppressed superoxide anion generation in fMLP-activated human neutrophils. Overall, anti-inflammatory evidence is preliminary and lacks human clinical trials.
5.2 Anxiolytic, Sedative, and Antidepressant Activity
In previous investigations, agarwood essential oil (AEO) was found to have a sedative-hypnotic effect. Sedative-hypnotic drugs usually have an anxiolytic effect, where concomitant anxiety and depression are common comorbidities. Animal studies using a restrained-stress mouse model found that AEO significantly reduced anxiety- and depression-related behaviors. A study evaluated the neuroprotective effect of a 30% ethanol extract of Aquilariae Lignum (ALE) in repeated stress-induced hippocampal oxidative injury. Fifty BALB/c male mice (12 weeks old) were randomly divided into five groups (n = 10). For 11 consecutive days, each group was orally administered with distilled water, ALE (20 or 80 mg/kg), or N-acetylcysteine (NAC; 100 mg/kg), and then all mice (except the unstressed group) were subjected to restraint stress for 6 hours.
Positive outcomes of aromatherapy with agarwood in clinical evidence (Lei et al.) include better sleep quality and decreased insomnia duration, thus adding to its anxiolytic effectiveness. Network pharmacology analysis performed by Pang et al. further identified anxiolytic-related bioactive compounds found in Aquilaria spp. These studies confirm the ability of agarwood as a natural modality with an antidepressant effect on anxiety, depression, and stress-related disorders. Human clinical evidence in this area is limited to a single aromatherapy study and requires further replication.
5.3 Gastrointestinal Effects
Agarwood possesses exceptional gastrointestinal protective and regulatory properties, mainly due to antioxidant, anti-inflammatory, and microbiota-modulating effects. These effects have indicated that it can be used to prevent and treat gastrointestinal diseases related to oxidative stress, inflammation, and microbial imbalance. Agarwood has been traditionally used for treating many abnormal physical conditions, including gastrointestinal disorders, asthma, and pain. Evidence in this area remains principally from traditional use descriptions and preliminary animal models; clinical trials are absent.
5.4 Antidiabetic Activity
The findings from studies elucidated the antidiabetic potentials of various Aquilaria extracts, including A. sinensis, A. crassna, and A. malaccensis, as well as the bark of A. agallocha, also called A. lignum. Considering the results from these studies, the agarwood dosage range of 200–1,000 mg/kg appears to be effective for achieving significant hypoglycaemic effects and improving insulin sensitivity in mice models. A specific ethyl ether extract of agarwood showed an inhibition rate of 44.13 ± 1.92% against α-glucosidase at a concentration of 50 µg/mL (compared to 62.06 ± 4.77% for acarbose, the reference drug). All antidiabetic evidence to date derives from in vitro and animal studies; no human clinical trials have been published.
5.5 Antimicrobial Activity
Agarwood has demonstrated antimicrobial activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Candida albicans, and Bacillus subtilis. Some studies have shown its potential application as a potent inhibitor of fungi, including Lasiodiplodia theobromae, Fusarium oxysporum, and Candida albicans. Moreover, it is capable of inhibiting Bacillus subtilis and Staphylococcus aureus activities. These findings are based on in vitro microbiological assays; no clinical trials have examined the antimicrobial effects of agarwood in humans.
5.6 Anticancer / Cytotoxic Activity
There have been no reports on traditional use of agarwood toward cancer treatment. However, this is most probably due to the fact that cancer nomenclature is used in modern medicine to describe the diseases associated with unregulated cell growth, in which inflammation and body pain are involved. The agarwood essential oil exhibited anticancer activity which supports the traditional use against inflammatory-associated diseases. This warrants further investigation toward the development of alternative remedies toward cancer. In vitro evidence indicates activity against the MCF-7 breast cancer cell line, and animal studies have demonstrated anti-colorectal-cancer activity, but no human trials exist.
5.7 Neuroprotective and Cognitive Effects
The primary active compounds of agarwood, which have been researched for neuroprotective, sedative, antibacterial, and anti-inflammatory uses, have been observed in recent pharmacological and chemical studies. A deeper understanding of the neuropharmacological potential of agarwood-derived compounds could facilitate the development of novel therapeutic strategies for cognitive enhancement, neurogenesis, and the prevention of neurodegenerative disorders. Evidence is confined to in vitro cell-line studies and rodent models; human clinical evidence is lacking.
5.8 Summary of Evidence Strength
The crude extracts and some of the isolated compounds exhibit anti-allergic, anti-inflammatory, anti-diabetic, anti-cancer, anti-oxidant, anti-ischemic, anti-microbial, hepatoprotective, laxative, and mosquitocidal properties and effects on the central nervous system. Agarwood plant materials are considered to be safe based on the doses tested. The traditional medicinal use of agarwood plant materials has provided clues to their pharmacological properties. Indeed, agarwood contains a plethora of bioactive compounds that now elegantly support their use in traditional medicine. Nevertheless, with the exception of a single clinical aromatherapy study on insomnia, the entire evidence base rests on in vitro cell assays and animal pharmacology. Randomized controlled human trials are absent across all therapeutic areas.
6. Body Systems and Health Areas of Association
- Central Nervous System: Neuronal activity includes sedative, anxiolytic, and antidepressant effects.
- Gastrointestinal System: Used to treat digestive tract diseases such as loss of appetite, vomiting, and diarrhea.
- Respiratory System: Used for respiratory diseases such as asthma and bronchitis, and to reduce cough.
- Immune and Inflammatory System: The main bioactive components of agarwood, derived from Aquilaria sinensis, include sesquiterpenes, 2-(2-phenethyl) chromone derivatives, aromatic compounds, and fatty acids, which typically exert anti-inflammatory, antioxidant, immune-modulating, hypoglycemic, and antitumor pharmacological effects in the form of essential oils.
- Endocrine / Metabolic System: Antidiabetic effects via α-glucosidase and α-amylase inhibition demonstrated in preclinical models.
- Musculoskeletal System: Used in traditional medicine for the relief of rheumatism.
- Cardiovascular System: Used in traditional medicine as a cardiotonic.
7. Dosage Forms and Reported Dosages
No standardized or pharmacopoeia-approved dosage for agarwood as a dietary supplement exists as of the time of this writing. The following dosages are reported only as cited in the listed experimental sources and should not be interpreted as clinical recommendations.
- Animal (in vivo) anti-inflammatory and analgesic: Leaf extracts tested to produce significant anti-inflammatory effects at various concentrations in rodent models.
- Animal (in vivo) antidiabetic: The agarwood dosage range of 200–1,000 mg/kg appears to be effective for achieving significant hypoglycaemic effects and improving insulin sensitivity in mice models.
- Animal (in vivo) neuroprotective (ethanol extract, ALE): Oral administration of ALE at 20 or 80 mg/kg for 11 consecutive days, followed by restraint stress for 6 hours, was used to evaluate neuroprotective effects in a mouse model.
- Animal (acute oral toxicity, essential oil): Swiss female mice were given a single dose of the essential oil extract at 2,000 mg/kg/day orally and screened for two weeks after administration.
- Animal (sub-chronic, essential oil): In the sub-chronic study, two different doses (100 and 500 mg/kg) of the extract were administered for 28 days.
- In vitro (α-glucosidase inhibition): An ethyl ether extract showed an inhibition rate of 44.13 ± 1.92% at a concentration of 50 µg/mL.
The low solubility and poor bioavailability of essential oils present challenges that necessitate the development of improved active formulations.
8. Safety Considerations and Drug Interactions
General Safety Profile
Agarwood plant materials are considered to be safe based on the doses tested. However, the toxicity and safety of the materials, including the smoke from agarwood incense burning, should be further investigated. Collectively, data obtained indicated that essential oil extract from agarwood might be a safe material, and this essential oil is suggested as a potential anti-colon cancer candidate. No side effects were found on the usual biomarkers of liver and kidney toxicity, suggesting that the essential oils did not cause adverse effects to these organs.
Dose-Dependent and Extract-Specific Toxicity
Negative effects could be caused by some chemical constituents that are naturally safe but may exhibit toxic effects at a certain dose or prolonged exposure. Consistent with this, methanol extract of A. malaccensis has shown cytotoxicity and genotoxicity effects in lymphocytes at higher concentrations. Generally, the boundary between toxic and non-toxic extracts depends on several aspects, such as the strength of secondary metabolites, the quantity consumed, part of the plant, and the extraction method. Aqueous extracts seem overall to be less toxic than organic extracts, as the relatively low toxicity in aqueous extracts relies on the fact that they contain a wide class of phytochemical components in a similar way to their existence in natural form, and hence exhibit less risk of side effects.
Drug–Herb Interactions: CYP Enzyme Inhibition
Agarwood tea derived from Aquilaria malaccensis is becoming an increasingly popular herbal drink. Co-administration of this tea and clinically used drugs is possible, but it increases the risk of drug-herb interactions. An in vitro study found that agarwood aqueous extract potently inhibited CYP2C9, CYP2D6, and CYP3A4 activities with Ki values of 5.1, 34.5, and 20.3 µg/mL, respectively. The most likely inhibition mode responsible for these inhibitions was non-competitive inhibition. At 1,000 µg/mL, the agarwood tea aqueous extract negligibly inhibited CYP1A2, CYP2B6, CYP2C19, CYP2E1, and CYP3A5 activities. CYP2C9, CYP2D6, and CYP3A4 are among the most important drug-metabolizing enzymes in humans; their inhibition could potentially increase plasma concentrations of coadministered drugs that rely on these enzymes for clearance. These findings are from in vitro studies only, and in vivo relevance has not yet been established.
Incense Smoke: Respiratory and Oxidative Concerns
Incense burning has been reported to trigger Phase I xenobiotic-metabolizing enzymes, such as the cytochrome P450 (CYP) system, which is known for catalytic action for the generation of reactive metabolites from PAHs (polycyclic aromatic hydrocarbons) and other chemicals. Incense particles were reported to alter mitochondrial function and NADPH oxidase activity, leading to a second wave of ROS production. A broad spectrum of oxygenates including polar organic compounds, highly reactive carbonyls, and redox-cycling quinones have been identified in whole incense smoke. The specific toxicological profile of agarwood incense smoke, as distinct from incense smoke in general, requires further dedicated research.
Conservation Status and Regulatory Context
The high price that agarwood and the oils can command has led to unsustainable harvesting and illegal logging, so much so that the global wild population of Aquilaria trees has dropped around 80% in little more than a century. Many species of Aquilaria are now critically endangered and listed in CITES Appendix II, which strictly regulates their trade. Although CITES lists 62 agarwood-producing species belonging to three genera (Aquilaria, Gyrinops, and Gonystylus), most agarwood trade is based on products derived from just three species: A. filaria, A. crassna, and A. malaccensis. These three species are categorized as Vulnerable (A. filaria) or Critically Endangered (A. crassna and A. malaccensis) in the IUCN Red List, with almost 97% of traded A. filaria and 57% of traded A. malaccensis being sourced from the wild. As wild agarwood trees are critically endangered and vulnerable, sustainable agricultural and forestry practices are necessary for the further development and utilization of agarwood as a source of health beneficial compounds.
Research Gaps
The toxicity and safety of the materials, including the smoke from agarwood incense burning, should be further investigated. Future research should be directed toward the bio-guided isolation of bioactive compounds with proper chemical characterisation and investigations of the underlying mechanisms toward drug discovery. Research on the toxicity of agarwood does not yet provide accurate information on agarwood toxicity due to the lack of adverse reactions and mortality among treated subjects after extracts were administered.
References
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