Nutmeg: A Review on Basic Source, Traditional Use, Chemical Components, Pharmacological Activities, Mechanism, and Quality Control

Abstract

Myristica fragrans (M. fragrans) is a species within the Myristicaceae family and the Myristica genus. It is an evergreen tree plant native to Maluku and the Banda Islands. Nutmeg (dried kernel of M. fragrans) could be used not only as a spice but also as a valuable medicinal herb used in traditional ethnomedicines, including Ayurvedic medicine, Tibetan medicine, Mongolian medicine, and Chinese medicine. From previous studies, it has been found that its chemical components are lignans, neolignans, volatile oils, and other chemical components. Modern pharmacological studies have shown that nutmeg extract and its chemical constituents possess a wide range of pharmacological activities such as neurological and digestive pharmacological effects, as well as cardioprotective, anti-inflammatory, analgesic, potential anticancer, antimicrobial, antioxidant activities, and other pharmacological effects, which are closely related to its rich ethnomedical uses. There were more studies on the pharmacological activities and chemical constituents of nutmeg, but few studies had been carried out in terms of incorporating the experience of traditional medicine and systematic quality control studies. Based on botanical books, Chinese classic texts, medical monographs, and academic search engines (Pubmed, Web of Science, CNKI, Science Direct, and Wiley Online Library), this paper reviewed various aspects of nutmeg, such as its basic source, traditional use, chemical components, pharmacological activities, and mechanism of action, as well as quality control, with a view to laying a foundation for the study of the potential pharmacological activities and quality control of nutmeg and providing a theoretical basis for the further development of nutmeg.

Keywords

Myristica fragrans - Myristicaceae - traditional use - chemical components - pharmacological activity - quality control

Introduction

Myristica fragrans Houtt. (M. fragrans) is a species within the Myristicaceae family and the Myristica genus. M. fragrans is an evergreen tropical tree [1]. It was first used as a kitchen spice for its fragrant aroma and distinctive flavor [2]. M. fragrans was native to the Maluku and Banda Islands in Indonesia and has been used around the world for centuries as the spice trade developed [3]. It was distributed in Malaysia, Indonesia, India, and Grenada and is also grown in the Pacific and northeastern Australia [4]. For centuries, nutmeg (dried kernel of M. fragrans) has been used not only as a valuable kitchen spice but also as an herbal medicine in a number of traditional ethnomedicines, including Ayurvedic medicine [5], Tibetan medicine [6], Mongolian medicine [7], and Chinese medicine [8]. Nutmeg extract possesses antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, antidiabetic, and potential anticancer properties and also has therapeutic effects on neurological, digestive, and cardiovascular diseases [9]. The chemical composition of nutmeg was found to mainly consist of lignans, neolignans, volatile oils, and polyphenols [10]. Lignans are the main active compounds in nutmeg, and they include dehydrodiisoeugenol, meso-dihydroguaiaretic acid, nectandrin B, macelignan, licarin B, myrisfrageal B, and myrisfrageal A, which has antibacterial, anti-inflammatory, antidiabetic, hepatoprotective, and neuroprotective activities [11], [12], [13]. The volatile oil content of nutmeg is about 16%, mainly monoterpenes such as α-pinene, β-pinene, limonene, and sabinene, and phenylpropanoid compounds such as myristicin, elemicin, safrole, and methylisoeugenol, which have antispasmodic, antioxidant, and cytotoxic activities [14]. In addition, nutmeg extract contains diarylnonanoid compounds with strong antioxidant activity such as malabaricone B and malabaricone C [15]. The literature search for this review was conducted through a comprehensive and systematic approach to ensure the inclusion of relevant and up-to-date information on nutmeg. Academic search engines and databases including Pubmed, Web of Science, CNKI, Science Direct, and Wiley Online Library were utilized. The search terms employed were a combination of the scientific name “Myristica fragrans Houtt.” and common names such as “nutmeg” along with keywords related to its traditional uses, chemical components, pharmacological activities, mechanisms of action, and quality control. The references from the included studies were also manually searched to identify additional relevant studies. This extensive search strategy aimed to provide a comprehensive overview of nutmeg, integrating both traditional wisdom and modern scientific research.

As mentioned above, nutmeg has long been used in different ethnomedicines around the world, and its medicinal value has been recognized by experts and scholars worldwide. On the basis of this, this paper reviewed various aspects of nutmeg, such as its basic source, traditional use, chemical components, pharmacological activities, and mechanism of action, as well as quality control, with a view to laying the foundation for the discovery of the potential pharmacological activities of nutmeg and providing a theoretical basis for the the further development of nutmeg.

Basic Source

Myristicaceae plants are typical tropical rainforest trees. There are about 21 genera and nearly 500 species worldwide. China has four species of nutmeg trees, mainly distributed in Taiwan, Guangdong, Guangxi, and Yunnan [16], [17]. [Table 1] lists some species of the Myristicaceae family and Myristica genus along with their native area [18]. Among them, only M. fragrans was used in traditional medicine with a long history of medicinal use. The application of nutmeg in traditional Chinese medicine was documented in the Compendium of Materia Medica (16th century, Li Shizhen, Ben Cao Gang Mu) [19]. The pharmacological effects and main therapeutic efficacy of nutmeg were recorded in the first Mongolian medicinal classic (18th century, Yixbaljor, Qagan Bolor Tole) [20]. In Tibetan medicine, the use of the nutmeg to treat ailments was documented in The Four Medical Tantras (known as the encyclopedia of Tibetan medicine) [21]. Nutmeg, which is imported from outside, is used in all of the above traditional medicine.

Table 1 Some species of myristica and their geographic distribution.

No.	Species names	Native area
(Excerpts from: https://powo.science.kew.org/)
1	Myristica fragrans Houtt.	Maluku
2	Myristica cagayanensis Merr.	Philippines, Taiwan
3	Myristica simiarum A. DC.	Borneo, Maluku, Philippines, Sulawesi
4	Myristica yunnanensis Y. H. Li	China South-Central, Thailand
5	Myristica glomerata (Blanco) Kudô & Masam.	Borneo, Maluku, Philippines
6	Myristica iners Blume	Borneo, Cambodia, Jawa, Malaya, Philippines, Sumatera, Thailand, Vietnam
7	Myristica ingens (Foreman) W. J. de Wilde	New Guinea
8	Myristica philippensis Lam.	Philippines
9	Myristica quercicarpa (J. Sinclair) W. J. de Wilde	New Guinea
10	Myristica rumphii (Blume) Kosterm.	Lesser Sunda Is.

Nutmeg ([Fig. 1]) was native to the Maluku and Banda Islands in Indonesia and has been used around the world for centuries as the spice trade developed. So far, it was widely distributed in Malaysia, India, Indonesia, and Southeast Asia. In recent years, it has also been cultivated in Guangdong, Taiwan, and Yunnan in China [22]. M. Fragrans grows on fertile, loose, well-drained loamy soils with annual rainfall between 2000 ~ 3000 mm and at an altitude of 0 ~ 700 m [8], [23], [24]. M. Fragrans trees usually grow to 5 ~ 13 m tall and sometimes up to 20 m [25]. M. Fragrans is suitable for growing in a hot and humid environment; the young trees need shade, and mature trees need sunlight. When the mature tree has enough sunlight, the plant grows robustly, has more branches, and produces more flowers and fruits [8]. The leaves are dark green, leathery, glossy above, apex acuminate, base oblong, and glabrous on each side [26]. Flowers are usually dioecious, male inflorescences 1 ~ 3 cm long, glabrous, triangular-ovate, gray-brown tomentose in appearance; female inflorescences are longer than male inflorescences, with a stout peduncle, tomentulose in appearance [8]. The flesh of the ripened fruit splits open automatically, revealing the orange-red reticulated tissue wrapped around the outer layer of the seed, called the aril [27]. When the rind is shattered, the nutmeg is the kernel, and both the nutmeg and aril emit a pungent and slightly bitter scent. The nutmeg is ovoid or ellipsoid, 2 ~ 3 cm long, and 1.5 ~ 2.5 cm in diameter, with light longitudinal grooves and irregular net-like grooves throughout the body. The umbilicus is at the broad end, with a light, rounded projection and a dark depression at the meristem. The ridges are longitudinally furrowed and connect the two ends. The texture is firm, the section shows a yellow, mixed marbling, and the broad end can be seen in the dry, wrinkled, and oily embryo [28].

Fig. 1 a Illustration of nutmeg; b worldwide distribution of M. fragrans with green areas showing areas where nutmeg is native and orange areas where nutmeg has been introduced; c kernel (nutmeg); d powdered nutmeg.

Traditional Use

Nutmeg was originally used primarily as a spice due to its unique flavor, color, or preservative effect. In the course of continuous exploration, a great deal of research and practice has been carried out to discover the medicinal value of nutmeg and its application in different ethnomedicines. In traditional Ayurvedic medicine, nutmeg significantly works on vitiated vatta (air and space components of the body) and kapha (earth and water components of the body) and was used a stomachic, astringent, heart tonic, carminative, stimulant, aphrodisiac, appetizer, and blood purifier, as well as to quench thirst and for intestinal trouble [29]. In traditional Tibetan medicine, nutmeg was used in the treatment of heart and “lung (the driving force of vital activity)” diseases [21], [30]. In the theory of traditional Mongolian medicine, nutmeg has been recognized for the effect of removing “heyi” and of better efficacy in the heart, which is known as Jurhen Sayin (good for the heart) [31]. Nutmeg was a commonly used medicine and food homologous in traditional Chinese medicine, which has the effects of warming the middle and moving “qi”, astringing the intestines, and checking diarrhea [32]. It was often used to treat deficiency diarrhea, cold dysentery, epigastric bloating and pain, inappetence with vomiting, and the indigestion of retained food [8], [19]. The main therapeutic effects of nutmeg in traditional medicine are summarized in [Table 2].

Table 2 Traditional use of nutmeg (dried kernel of M. fragrans).

Traditional medicine	Another name	Medicinal properties	Therapeutic use	References
Ayurvedic medicine (traditional Indian medicine)	Jatiphala	Works on vitiated vatta (air and space components of the body) and kapha (earth and water components of the body)	A stomachic, astringent, heart tonic, carminative, stimulant, aphrodisiac, appetizer, and blood purifier; quenches thirst and treats intestinal trouble and melasma	[29]
Tibetan medicine	Zadi	Treats “lung (the driving force of vital activity)” disease, aids digestion, regulating stomach fire	To treat “lung” disease, various heart diseases, and indigestion	[21], [30]
Mongolian medicine	Jurhen Sayin	Removing “heyi”, regulating stomach fire, eliminating food, and appetizing	Chest fullness, sighing, panic, dizziness, insomnia, delirium, angina pectoris caused by “heyi” abnormal	[31]
Chinese medicine	Roudoukou (Semen Myristicae)	Warming the middle and moving “qi”, astringing the intestines, and checking diarrhea	To treat deficiency diarrhea, cold dysentery, epigastric bloating and pain, inappetence with vomiting, indigestion of retained food	[8], [19], [32]

Chemical Components

Nutmeg is a tropical spice widely used as a spice and medicinal plant. It contains high levels of fat, protein, carbohydrates, and fiber. In addition, it contains essential minerals and vitamins for the human body, such as calcium (Ca²⁺), potassium (K⁺), phosphorus (PO₄³⁻), magnesium (Mg²⁺), iron (Fe²⁺), zinc (Zn²⁺), ascorbic acid, thiamine, niacin, and riboflavin [33]. In addition to these nutritional components, nutmeg contains a wide range of complex chemical compounds, including lignans, neolignans, volatile oils, flavonoids, and phenols. These chemical constituents of nutmeg give it its distinctive aroma and flavor and also provide the basis for its many traditional and modern medicinal uses. Currently, global research on nutmeg is primarily focused on lignin and volatile oil. When it comes to the extraction methods of these components, organic solvent extraction is often used for lignans and neolignans, with solvents such as methanol, ethanol, acetone, or chloroform. Steam distillation is commonly used to extract volatile oils due to its simplicity and low cost, and supercritical fluid extraction, such as with CO₂, can also be applied.

Lignans

Among the many methods of lignin extraction, Organic solvents (such as methanol, ethanol, acetone, chloroform, etc.) were often used to extract the lignan components of nutmeg at home and abroad. The study found that more than 20 lignans had been identified in nutmeg ([Table 3], [Fig. 2]) [34], [35], [36], [37], [38], [39], [40], [41], [42]. These lignans had been categorized into three structural classes including 2,3-dimethyl-1,4-diaryl-butane-type lignans (1 ~ 9), aryltetralin lignans (10 ~ 14), and tetrahydrofuran lignans (15 ~ 23).

Table 3 Lignan constituent of nutmeg (M. fragrans).

Phytochemical type	No.	Chemical component	PubChem CID/SID	Molecular weight	Molecular formula	References
2,3-Dimethyl-1,4-diaryl-butane lignans	1	Macelignan	10 404 245	328.4 g/moL	C20H24O4	[34]
	2	Meso-dihydroguaiaretic acid	476 856	330.4 g/moL	C20H26O4	[34]
	3	Machilin A	10 359 012	326.4 g/moL	C20H22O4	[34]
	4	Myristargenol	–	344.4 g/moL	C20H24O5	[34]
	5	7-(4-Hydroxy-3-methoxyphenyl)-7-(3,4-methylenedioxyphenyl)-8,8-lignan-7-methyl Ether	–	358.47 g/moL	C21H26O5	[34]
	6	Meso-monomethyldihydroguaiaretic acid	11 725 068	344.4 g/moL	C21H28O4	[35]
	7	(8R,8′S)-7′-(3′,4′-Methylenedioxyphenyl)-8,8′-dimethyl-7-(3,4- dihydroxyphenyl)-butane	–	314.4 g/moL	C19H22O4	[35]
	v8	(8R,8′S)-7-(3,4-Methylenedioxyphenyl)-8-methyl-8′-hydroxymethyl-7′-(3′,4′-methylenedioxyphenyl)-butanol	–	343.15 g/moL	C20H22O5	[35]
	9	Threo-Austrobailignan-5	–	326.4 g/moL	C20H22O4	[36]
Aryltetralin lignans	10	Otobaphenol	14 704 575	326.4 g/moL	C20H22O4	[37]
	11	(+)-Guaiacin	11 724 027	328.4 g/moL	C20H24O4	[35]
	12	(+)-Myrisfragransin	14 655 081	326.4 g/moL	C20H22O4	[38]
	13	(+)-Dimethyl myrisfragransin	–	356.5 g/moL	C22H28O4	[38]
	14	Isootobaphenol	44 447 181	326.4 g/moL	C20H22O4	[36]
Tetrahydrofuran lignans	15	Nectandrin A	156 516	358.4 g/moL	C21H26O5	[39]
	16	Nectandrin B	156 517	344.4 g/moL	C20H24O5	[39]
	17	Machilin F	13 844 301	342.4 g/moL	C20H22O5	[40]
	18	Fragransin A2	16 069 561	344.4 g/moL	C20H24O5	[34]
	19	Saucernetindiol	–	344.4 g/moL	C20H24O5	[39]
	20	Tetrahydrofuroguaiacin B	13 870 572	344.4 g/moL	C20H24O5	[39]
	21	Galbacin	234 441	340.4 g/moL	C20H20O5	[39]
	22	Jusaho G	–	340.4 g/moL	C20H20O5	[41]
	23	(7S,8′R,7′R)-4,4′-Dihydroxy-3,3′-dimethoxy-7′,9-epoxylignan	–	356.5 g/moL	C21H24O5	[42]

Fig. 2 Structure of the lignans from nutmeg (M. fragrans).

Neolignans

Neolignan compounds were also one of the most important chemical constituents of nutmeg. The extraction method for the neolignan of nutmeg was the same as that for lignans. Currently, about 30 neolignans have been isolated from nutmeg by researchers, some of which include benzofuranoid neolignans (24 ~ 35) and 8.O.4′ neolignans (36 ~ 53) ([Table 4], [Fig. 3]) [44], [45], [46], [47], [48], [49], [50], [51]. Among them, dehydrodiisoeugenol had a variety of pharmacological activities and was an indicator component of nutmeg (the 2020 edition of the Pharmacopoeia of the Peopleʼs Republic of China), which was used to assess the quality of nutmeg [43].

Table 4 Neolignan constituent of nutmeg (M. fragrans).

Phytochemical type	No.	Chemical component	PubChem CID/SID	Molecular weight	Molecular formula	References
Benzofuranoid neolignans	24	Myrisfrageal A	101 663 168	312.3 g/moL	C18H16O5	[44]
	25	Myrisfrageal B	102 225 414	342.3 g/moL	C19H18O6	[44]
	26	Isodihydrocarinatidin	–	–	–	[44]
	27	Licarin B	6 441 061	324.4 g/moL	C20H20O4	[44]
	28	3′-Methoxy-licarin B	–	–	–	[44]
	29	Dehydrodiisoeugenol	5 379 033	326.4 g/moL	C20H22O4	[44]
	28a	Licarin A	5 281 836	326.4 g/moL	C20H22O4	[45]
	30	3′-Methoxy-licarin A	11 703 153	356.4 g/moL	C21H24O5	[45]
	31	Licarin C	131 751 410	370.4 g/moL	C22H26O5	[45], [46]
	32	3-(4-Allyl-2,6-dimethoxy-phenyloxy)-2-methyl-5-methoxy-2,3-dihydrobenzofuran	154 827 488	356.4 g/moL	C21H24O5	[46]
	33	Myticaganal A	–	328.3 g/moL	C18H16O6	[47]
	34	Myticaganal B	–	312.3 g/moL	C18H16O5	[47]
	35	Myticaganal C	–	328.4 g/moL	C19H20O5	[47]
8.O.4′ Neolignans (8-O-4′type diarylpropanoid ethers)	36	Myrifralignan A	101 902 714	372.4 g/moL	C21H24O6	[48]
	37	Myrifralignan B	101 902 715	444.5 g/moL	C24H28O8	[48]
	38	Myrifralignan C	21 770 239	374.4 g/moL	C21H26O6	[48]
	39	Myrifralignan D	25 751 146	404.5 g/moL	C22H28O7	[48]
	40	Myrifralignan E	101 902 716	418.4 g/moL	C22H26O8	[48]
	41	Surinamensin	5 281 868	388.5 g/moL	C22H28O6	[48]
	42	Myrisisolignan	–	–	–	[49]
	43	Machilin D	16 397 289	344.4 g/moL	C20H24O5	[48]
	44	Erythro-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4-methylenedio-xyphenyl) propan-1-ol	10 067 873	372.4 g/moL	C21H24O6	[50]
	45	Erythro-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethoxy-phenyl) propan-1-ol	10 477 119	418.5 g/moL	C23H30O7	[50]
	46	Erythro-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(4-hydroxy-3-met-hoxyphenyl) propan-1-ol	23 872 112	374.4 g/moL	C21H26O6	[50]
	47	Erythro-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4-methylenedio-xyphenyl) propan-1-ol acetate	137 321 415	446.5 g/moL	C24H30O8	[50]
	48	Erythro-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(5-acetoxy-3,4-di-methoxyphenyl) propan-1-ol acetate	–	–	–	[50]
	49	2-(4-Allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethoxyphenyl) propane	–	–	–	[50]
	50	Erythro-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4-dimethoxyph-enyl) propan-1-ol	137 321 415	446.5 g/moL	C24H30O8	[49]
	51	Erythro-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4-dimethoxyph-enyl) propan-1-ol acetate	137 321 415	446.5 g/moL	C24H30O8	[49]
	52	2-(4-Allyl-2,6-dimethoxyphenoxy)-1-(3,4-dimethoxyphenyl) propane	–	–	–	[49]
	53	2-(4-Allyl-2,6-dimethoxyphenoxy)-1-(4-hydroxy-3-me-thoxyphenyl) propan-1-ol acetate	–	–	–	[51]

Fig. 3 Structure of the neolignans from nutmeg (M. fragrans).

Volatile oils

Nutmeg was rich in oil and pleasantly fragrant, and its distinctive aroma was mainly derived from in its volatile oils [3]. Studies on the extraction methods of volatile oils from nutmeg involved steam distillation, solvent extraction, assisted extraction methods, and supercritical and subcritical fluid extraction techniques. Of these, steam distillation was the more commonly used method for extracting the volatile oil components of nutmeg, which was a simple and low-cost method for extracting the volatile components. This method used steam to bring out the volatile components within nutmeg from the raw material and obtains the volatile oil after condensation [52]. Studies have shown that nutmeg had a large amount of volatile oils, which consist of phenylpropanoids (54 ~ 63), monoterpenes (64 ~ 100), sesquiterpenes (101 ~ 129), fatty acids and fatty acid esters (130 ~ 149), alkanes (150 ~ 154), and other components (155 ~ 161) [27], [46], [51], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67]. Among them, the volatile oil was dominated by phenylpropanoids, monoterpenoids, and sesquiterpenoids ([Table 5], [Fig. 4 a] and [b]).

Table 5 Volatile oil of nutmeg (M. fragrans).

Phytochemical type	No.	Chemical component	PubChem CID/SID	Molecular weight	Molecular formula	References
Phenylpropanoids	54	Myristicin	4276	192.21 g/moL	C11H12O3	[46]
	55	Elemicin	10 248	208.25 g/moL	C12H16O3	[46]
	56	Isoelemicin	5 318 557	208.25 g/moL	C12H16O3	[46]
	57	2,3-Dimethoxy-5-(1-propenyl)-phenol	85 361 106	194.23 g/moL	C11H14O3	[51]
	58	Methoxyeugenol	226 486	194.23 g/moL	C11H14O3	[51]
	59	Isoeugenol	853 433	164.2 g/moL	C10H12O2	[53]
	60	Methylisoeugenol	637 776	178.23 g/moL	C11H14O2	[54]
	61	Eugenol	3314	164.20 g/moL	C10H12O2	[54]
	62	Methyleugenol	7127	178.23 g/moL	C11H14O2	[54]
	63	Safrole	5144	162.18 g/moL	C10H10O2	[54]
Monoterpenes	64	α-Pinene	11 240 513	136.23 g/moL	C10H16	[27]
	65	β-Pinene	14 896	136.23 g/moL	C10H16	[27]
	66	Terpinen-4-ol	11 230	154.25 g/moL	C10H18O	[27]
	67	Sabinene	18 818	136.23 g/moL	C10H16	[27]
	68	α-Phellandrene	7460	136.23 g/moL	C10H16	[27]
	69	3-Carene	26 049	136.23 g/moL	C10H16	[27]
	70	Camphene	6616	136.23 g/moL	C10H16	[27]
	71	β-thujene	520 384	136.23 g/moL	C10H16	[55]
	72	Myrcene	31 253	136.23 g/moL	C10H16	[55]
	73	α-Terpinene	7462	136.23 g/moL	C10H16	[55]
	74	β-Phellandrene	11 142	136.23 g/moL	C10H16	[55]
	75	γ-Terpinene	7461	136.23 g/moL	C10H16	[56]
	76	p-Cymene	7463	134.22 g/moL	C10H14	[56]
	77	ThymoL	6989	150.22 g/moL	C10H14O	[56]
	78	Linalool	6549	154.25 g/moL	C10H18O	[55]
	79	Limonene	22 311	136.23 g/moL	C10H16	[57]
	80	1,8-Cineole	2758	154.25 g/moL	C10H18O	[57]
	81	Trans-β-ocimene	5 281 553	136.23 g/moL	C10H16	[57]
	82	α-Terpinolene	11 463	136.23 g/moL	C10H16	[57]
	83	Cis-sabinene hydrate	20 055 523	154.25 g/moL	C10H18O	[58]
	84	Trans-Sabinene hydrate	12 315 151	154.25 g/moL	C10H18O	[58]
	85	α-Terpineol	17 100	154.25 g/moL	C10H18O	[58]
	86	β-Terpineol	8748	154.25 g/moL	C10H18O	[59]
	87	o-Cymene	10 703	134.22 g/moL	C10H14	[60]
	88	Trans-4-isopropyl-1-Methyl-2-cyclohexen-1-ol	5 319 367	154.25 g/moL	C10H18O	[60]
	89	Cis-4-isopropyl-1-Methyl-2-cyclohexen-1-ol	13 918 681	154.25 g/moL	C10H18O	[60]
	90	Borneol	1 201 518	154.25 g/moL	C10H18O	[60]
	91	3-Methyl-6-isopropyl-2-cyclohexen-1-ol	10 282	154.25 g/moL	C10H18O	[60]
	92	Nerol	643 820	154.25 g/moL	C10H18O	[60]
Monoterpenes	93	Trans-α-ocimene	5 320 249	136.23 g/moL	C10H16	[53]
	94	1,3,8-p-Menthatriene	176 983	134.22 g/moL	C10H14	[53]
	95	m-Cymene	10 812	134.22 g/moL	C10H14	[53]
	96	p-Menth-2-en-1-ol	526 657	154.25 g/moL	C10H18O	[53]
	97	Cosmene	5 368 451	134.22 g/moL	C10H14	[53]
	98	Methylcamphenilol	101 680	154.25 g/moL	C10H18O	[53]
	99	d-Citronellol	8842	156.26 g/moL	C10H20O	[53]
	100	Sylvestrene	12 304 570	136.23 g/moL	C10H16	[61]
Sesquiterpene	101	α-Copaene	19 725	204.35 g/moL	C15H24	[62]
	102	(E)-Caryophylene	5 281 515	204.35 g/moL	C15H24	[62]
	103	α-Cubebene	442 359	204.35 g/moL	C15H24	[62]
	104	β-Copaene	57 339 298	204.35 g/moL	C15H24	[62]
	105	β-Elemene	6 918 391	204.35 g/moL	C15H24	[62]
	106	Aromandendrene	91 354	204.35 g/moL	C15H24	[62]
	107	β-Farnesene	5 281 517	204.35 g/moL	C15H24	[62]
	108	γ-Muurolene	6 432 308	204.35 g/moL	C15H24	[62]
	109	Germacrene D	5 373 727	204.35 g/moL	C15H24	[62]
	110	β-Bisabolene	10 104 370	204.35 g/moL	C15H24	[62]
	111	β-Gurjunene	6 432 176	204.35 g/moL	C15H24	[62]
	112	Spathulenol	92 231	220.35 g/moL	C15H24O	[62]
	113	ElemoL	92 138	222.37 g/moL	C15H26O	[62]
	114	α-Elemene	80 048	204.35 g/moL	C15H24	[61]
	115	β-Cadinene	10 657	204.35 g/moL	C15H24	[61]
	116	Viridiflorene	10 910 653	204.35 g/moL	C15H24	[61]
	117	β-Cubebene	93 081	204.35 g/moL	C15H24	[61]
	118	α-Bergamotene	86 608	204.35 g/moL	C15H24	[61]
	119	Bicyclogermacrene	13 894 537	204.35 g/moL	C15H24	[61]
	120	α-Farnesene	5 281 516	204.35 g/moL	C15H24	[61]
	121	α-Gurjunene	15 560 276	204.35 g/moL	C15H24	[61]
	122	α-Bisabolene	86 597	204.35 g/moL	C15H24	[61]
	123	γ-Gurjunene	90 805	204.35 g/moL	C15H24	[61]
	124	Alloaromadendren	91 746 537	204.35 g/moL	C15H24	[61]
	125	β-Humulene	5 318 102	204.35 g/moL	C15H24	[61]
	126	Valencene	9 855 795	204.35 g/moL	C15H24	[61]
	127	Tau-cadinol	160 799	222.37 g/moL	C15H26O	[61]
	128	δ-Cadinene	441 005	204.35 g/moL	C15H24	[61]
	129	1-Ene,2-isopropyl-5 methyl-9-methylene	595 137	204.35 g/moL	C15H24	[61]
Fatty acid and fatty acid esters	130	Trimyristin	11 148	723.2 g/moL	C45H86O6	[63]
	131	Palmitic acid (hexadecanoic acid)	985	256.42 g/moL	C16H32O2	[64]
	132	Linoleic acid	5 280 450	280.4 g/moL	C18H32O2	[64]
	133	Oleic acid (9-octadecenoic acid)	445 639	282.5 g/moL	C18H34O2	[64]
	134	Oleic acid methyl ester	5 364 509	296.5 g/moL	C19H36O2	[64]
	135	Stearic acid	5281	284.5 g/moL	C18H36O2	[65]
	136	Tetradecanoic acid (myristic acid)	11 005	228.37 g/moL	C14H28O2	[65]
	137	Dodecanoic acid	3893	200.32 g/moL	C12H24O2	[65]
	138	Ethyl laurate	7800	228.37 g/moL	C14H28O2	[65]
	139	Citronellyl acetate	9017	198.3 g/moL	C12H22O2	[66]
	140	Geranyl acetate	1 549 026	196.29 g/moL	C12H20O2	[66]
	141	α-Terpinyl acetate	111 037	196.29 g/moL	C12H20O2	[55]
	142	Isoamyl isovalerate	12 613	172.26 g/moL	C10H20O2	[61]
	143	Bornyl acetate	6448	196.29 g/moL	C12H20O2	[61]
	144	Isobomyl acetate	61 061	196.29 g/moL	C12H20O2	[61]
	145	Methylgeranate	22 565 016	181.25 g/moL	C11H17O2-	[61]
	146	Trans-β-terpinyl acetate	88 693	196.29 g/moL	C12H20O2	[53]
	147	Ethyl myristate	31 283	256.42 g/moL	C16H32O2	[53]
	148	Fenchyl acetate	107 217	196.29 g/moL	C12H20O2	[67]
	149	Linalyl acetate	8294	196.29 g/moL	C12H20O2	[67]
Alkanes	150	N-decane	15 600	142.28 g/moL	C10H22	[67]
	151	N-hendecane	14 257	156.31 g/moL	C11H24	[67]
	152	N-tridecane	12 388	184.36 g/moL	C13H28	[67]
	153	N-tetradecane	12 389	198.39 g/moL	C14H30	[67]
	154	N-hexadecane-d34	12 302 799	260.65 g/moL	C16H34	[67]
Other constituents	155	Heptaldehyde	8130	114.19 g/moL	C7H14O	[67]
	156	5-Methyl furfural	12 097	110.11 g/moL	C6H6O2	[67]
	157	Acetophenone	7410	120.15 g/moL	C8H8O	[67]
	158	2′-Methylacetophenone	11 340	134.17 g/moL	C9H10O	[67]
	159	1-Methylnaphthalene	7002	142.2 g/moL	C11H10	[67]
	160	4-Hydroxy-3-methoxystyrene	332	150.17 g/moL	C9H10O2	[67]
	161	Vanillin	1183	152.15 g/moL	C8H8O3	[67]

Fig. 4 a Structure of volatile oil from nutmeg (M. fragrans).

b Structure of volatile oil from nutmeg (M. fragrans).

Other chemical components

In addition to the components mentioned above, nutmeg has diarylnonanoids (162, 163), phytosterols (164), steroidal saponins (165, 166), organic acid (167, 173), polyphenols (174, 175), and flavonoids (176 ~ 181) ([Table 6], [Fig. 5]) [15], [41], [63], [68], [69], [70], [71], [72].

Table 6 Other chemical components of nutmeg (M. fragrans).

Phytochemical type	No.	Chemical component	PubChem CID/SID	Molecular weight	Molecular formula	References
Diarylnonanoids	162	Malabaricone B	163 001	342.4 g/moL	C21H26O4	[68]
	163	Malabaricone C	100 313	358.4 g/moL	C21H26O5	[68]
Phytosterols	164	β-Sitosterol	222 284	414.7 g/moL	C29H50O	[15]
Steroidal saponins	165	Daucosterol	5 742 590	576.8 g/moL	C35H60O6	[15]
	166	Sitosterol 3-O-[β-d-glucopyranos-6′-yl tetradecanoate	–	772.08 g/moL	C45H76O9	[69]
Organic acid	167	Succinic acid	1110	118.09 g/moL	C4H6O4	[69]
	168	Fumaric acid	444 972	116.07 g/moL	C4H4O4	[69]
	169	Jusaho B	–	259.13 g/moL	C14H20O3	[41]
	170	Jusaho C	–	259.13 g/moL	C14H20O3	[41]
	171	Jusaho D	–	275.13 g/moL	C14H20O4	[41]
	172	Jusaho E	–	259.13 g/moL	C14H20O3	[41]
	173	Jusaho F	–	245.11 g/moL	C₁₃H₁₈O₃	[41]
Polyphenols	174	Phthalic acid	1017	166.13 g/moL	C8H6O4	[70]
	175	Protocatechuic acid	72	154.12 g/moL	C7H6O4	[71]
Flavonoids	176	Isoliquiritigenin	638 278	256.25 g/moL	C15H12O4	[71]
	177	Butein	5 281 222	272.25 g/moL	C15H12O5	[72]
	178	Sulphuretin	5 281 295	270.24 g/moL	C15H10O5	[72]
	179	7,3′,4′-Trihydroxyflavone	5 322 065	270.24 g/moL	C15H10O5	[72]
	180	7-Hydroxy-4-benzopyrone	5 409 279	162.14 g/moL	C9H6O3	[72]
	181	5,7-diacetyl chrysin	–	354.35 g/mol	C₂₀H₁₈O₆	[63]

Fig. 5 Structure of other chemical components from nutmeg (M. fragrans).

Pharmacological Activities and Mechanism of Action

Neuropharmacologic effects

In recent years, scientific studies have begun to reveal the protective effects of nutmeg on the nervous system and its potential application in neurodegenerative diseases. Neurodegenerative disorders were characterized by a gradual deterioration of neurons within the central nervous system (CNS), resulting in impairments of specific brain functions (such as memory, mobility, and cognition) that are associated with the affected areas of the CNS. Common neurological disorders such as Alzheimerʼs disease (AD), Parkinsonʼs disease (PD), and Huntingtonʼs disease (HD) are all neurodegenerative diseases [73]. Studies have shown that co-treatment with myristic acid (136) and heptadecanoic acid downregulated the expression of interleukin IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in the LPS-mediated BV-2 microglial cells. Moreover, myristic acid and heptadecanoic acid inhibited the phosphorylation of the p65, IκB, and IκB kinase proteins in the NF-κB pathway and suppressed the LPS-induced inflammatory response in BV-2 microglial cells, which provides a potential pathway and a new research strategy for the treatment of PD [74]. Macelignan (1) was a compound derived from nutmeg that shows potential therapeutic value in inflammation-induced neurodegenerative diseases, particularly PD. PD was characterized by degenerative injuries of midbrain dopaminergic neurons. Macelignan provided neuroprotective effects on dopaminergic neurons through activation of PPARγ and expression of arginase-1 [13]. It was found that macelignan acts through the MAPK pathway in LPS-stimulated BV-2 microglia, as well as in the downregulation of NF-κB activation by the regulation of IκBa [75]. In addition, macelignan could pass through the blood–brain barrier, reduce chronic LPS-induced hippocampal inflammatory responses, and improve the spatial learning impairments caused by chronic LPS infusions [76]. Notably, Jusaho C (a newly discovered furan acid in nutmeg) demonstrated significant neuroprotective and anti-neuroinflammatory effects in BV2 and HT22 cells by modulating the MAPK/NF-κB signaling pathway [41]. Research has shown that the TLC-bioautography showed the five anticholinesterase-active metabolites of eugenol (61), methyleugenol (62), myristic acid (136), galbacin (21), and β-sitosterol (164) in nutmeg extract, which inhibited in vivo and in vitro acetylcholinesterase activity in rats with scopolamine-induced amnesia, with potential therapeutic effects in dementia and AD [77]. There was a potential link between nutmeg extract and monoamine neurotransmitter levels (norepinephrine, serotonin, and dopamine). It was found that nutmeg could target and regulate the expression levels of GFAP, PDIA3, DPYSL2, and p-DPYSL2 and increase the levels of 5-hydroxytryptamine (5-HT), norepinephrine, and dopamine in the hippocampus of rats to exert neuroprotective effects, which are therapeutically useful in the prevention and treatment of neurodegenerative disorders [78]. Additionally, nutmeg n-hexane extract possessed an antidepressant-like effect through various serotonergic and noradrenergic nervous systems [79]. Ethanolic extract of nutmeg reduced seizure behavior in pentylenetetrazol (PTZ)-induced mice through its attenuation of neuronal loss and glial activation [80]. A randomized, double-blind, placebo-controlled trial assessed the clinical efficacy of topical nutmeg extracts for painful diabetic neuropathy (PDN). Seventy-four diabetic subjects with PDN were recruited and randomized to receive either topical nutmeg extracts (NEMM) or placebo (MM). After 4 weeks of treatment, both groups showed significant reductions in worst and average pain scores, as well as improvements in interference with walking, sleep, and mood scores. However, there were no statistically significant differences between the two groups for any outcome measure. The study concluded that topical nutmeg extracts did not add to the improvements observed in PDN symptoms during the 4-week treatment with preparations containing menthol and methyl salicylate [81]. [Table 7] shows the mechanism of neuropharmacological effects of different components and extracts of nutmeg.

Table 7 Neuropharmacological effect and mechanism of nutmeg extracts.

Type of extract	React with particular disease	Mechanism of action	References
Myristic acid and heptadecanoic acid	These two components can inhibit the LPS-induced inflammatory response in BV-2 microglial cells, reduce the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in BV-2 cells, and significantly suppress the LPS-induced inflammatory response, showing potenzial for Parkinsonʼs disease treatment.	Myristic acid and heptadecanoic acid exert anti-inflammatory effects by inhibiting the nuclear factor-κB (NF-κB) pathway, specifically by suppressing the phosphorylation of p65, IκB, and IκB kinase proteins in the NF-κB pathway, thereby reducing the secretion of inflammatory cytokines and potenzially delaying disease progression in the early stage of Parkinsonʼs disease.	[74]
Macelignan	Macelignan may benefit Parkinsonʼs disease. In rat midbrain slice cultures exposed to IFN-γ and LPS, it caused inflammatory degeneration of dopaminergic neurons and increased NO production. Macelignan (10 µM) prevented the loss of dopaminergic neurons.	The neuroprotective effect of macelignan was mediated by arginase-1 expression in microglia. Macelignan activates the PPARγ signaling pathway, promoting arginase-1 expression in microglia. Notably, macelignanʼs action was independent of nitric oxide (NO) regulation, as it did not affect parameters like iNOS protein expression and nitrite accumulation.	[13]
Macelignan	Oral administration of macelignan reduces hippocampal microglial activation and spatial memory impairments caused by chronic LPS infusion.	Macelignan exerts anti-inflammatory effects by inhibiting the MAPK signaling pathway (including the phosphorylation of p38, ERK, and JNK) and blocking NF-κB activation (through preventing IκBα degradation and NF-κB nuclear translocation). This mechanism reduces microglial activation and neuroinflammation, highlighting its therapeutic potenzial against neurodegenerative diseases like Alzheimerʼs disease.	[75]
Macelignan	Macelignan can alleviate LPS-induced inflammation and spatial learning impairments in rats. Oral administration of macelignan reduces microglial activation in the hippocampus and improves the performance of rats in the Morris water maze.	Although the exact mechanism is not fully elucidated, studies have found that macelignan is a peroxisome proliferator-activated receptor-γ/α (PPAR-γ/α) agonist and is involved in the mitogen-activated protein kinase (MAPK) signaling pathway. PPARγ agonists have anti-inflammatory and anti-amyloidogenic effects, and MAPK plays a key role in the regulation of Tau and β-amyloid precursor proteins.	[76]
Jusaho C (a newly discovered furan acid in nutmeg)	Jusaho C suppresses the activation of BV2 microglial cells induced by LPS, reducing the production of pro-inflammatory mediators such as NO, PGE2, IL-6, and TNF-α. It showed significant antineuroinfammatory and neuroprotective effects.	Jusaho C exerts its neuroprotective effects primarily through its anti-inflammatory properties. Jusaho C inhibits the phosphorylation of MAPKs (including p38, ERK, and JNK) and consequently affects NF-κB activation, leading to decreased expression of inflammatory factors. Molecular docking experiments also indicate that jusaho C has a high binding affinity for MAPK14 (p38), suggesting that it may inhibit the activity of MAPK14 to exert its anti-inflammatory and neuroprotective effects. Furthermore, jusaho C demonstrates a direct protective effect on HT22 hippocampal neuronal cells against inflammation-induced damage, which may be related to the activation of antioxidant mechanisms.	[41]
Hexane extract	Nutmeg hexane extract likely benefits cognitive disorders by lowering acetylcholinesterase activity in mice brains, countering the elevated enzyme activity and reduced acetylcholine in cognitive disorders.	Nutmeg hexane extract inhibits acetylcholinesterase, prolonging acetylcholine duration and increasing its concentration in the brain, enhancing cholinergic transmission and promoting cognition.	[77]
Volatile oil	Nutmeg volatile oil shows potential preventive and therapeutic effects on neurodegenerative diseases like Alzheimerʼs disease and Parkinsonʼs disease.	Nutmeg volatile oil increases rat hippocampal monoamine neurotransmitter levels, modulates the proteomic profile (affects proteins like GFAP, PDIA3, DPYSL2, and p-DPYSL2), and has antioxidant effects (boosts SOD2 and glutathione S-transferase levels) by metabolizing components that influence the serotonin system, suggesting potential therapeutic effects on depression and other diseases.	[78]
N-hexane extract	In the tail suspension test, nutmeg n-hexane extract (10 mg/kg, p. o.) significantly reduced the immobility time of mice in a dose-dependent manner. In the open field test (OFT), nutmeg n-hexane extract (5 and 10 mg/kg) did not significantly alter the spontaneous locomotor activity of mice, indicating that its antidepressant-like effect was not due to a simple enhancement of motor activity.	The antidepressant-like effect of nutmeg n-hexane extract mainly occurs via multiple neurotransmitter receptor systems, including 5-HT2A/2C, 5-HT3 receptors, and noradrenergic α2 receptors, with some involvement of 5-HT1A receptors. Myristicin in n-hexane extract may inhibit monoamine oxidase, raising monoamine neurotransmitter (e. g., 5-HT, noradrenaline) levels to combat depression.	[79]
Ethanolic extract	Pretreatment with nutmeg extract effectively reduced seizure behavior in mice, decreased neuronal loss, and alleviated glial activation. Specifically, mice pretreated with nutmeg extract exhibited lower seizure stages, shorter seizure durations, increased neuronal density in the hippocampus, and reduced glial cell activation following PTZ induction.	The potenzial mechanisms involve the anti-inflammatory properties of nutmeg extract. Myristic acid exerts anti-inflammatory effects by inhibiting phospholipase A2 enzyme. Myristicin reduces inflammation by inhibiting the production of nitric oxide (NO), cytokines, chemokines, and growth factors. Elemicin and myristicin can suppress the production of interleukin-1β (IL-1β) and interleukin-6 (IL-6). Additionally, eugenol, another component, inhibits pro-inflammatory cytokines and redox signaling pathways. These anti-inflammatory actions may mitigate PTZ-induced neuroinflammation, thereby reducing seizure severity and neuronal damage.	[80]

Nutmeg extracts and their compounds may be novel therapies for the treatment of neurodegenerative diseases, especially for those involving an inflammatory response. Current research is focused on determining the specific mechanism of action of these compounds and how they cross the blood-brain barrier and affect specific neural signaling pathways. Future clinical studies will also need to explore the efficacy and safety of nutmeg extracts in human patients and whether they could be a complementary or alternative therapy to traditional neurodegenerative disease treatments.

Effects on the digestive system

Myristicin (54), isolated from nutmeg, exhibited significant hepatoprotective effects, including the inhibition of increased serum tumor necrosis factor receptor (TNF-R) concentrations and hepatic DNA fragmentation [82]. Nectandrin B (16) enhanced the antioxidant capacity of hepatocytes and protected against oxidative stress-induced liver cell injury by activating the Nrf2/ARE signaling pathway [12]. Nutmeg extract mitigated paracetamol (APAP)-induced hepatotoxicity in rats by reducing oxidative stress, inflammation, and apoptosis, possibly through activating the Nrf2/ARE pathway, showing potential as a liver protectant against APAP-induced liver injury [83]. Oral administration of nutmeg aqueous extract effectively inhibited the isoproterenol-induced changes in hepatic marker enzymes and antioxidant enzyme activities in plasma and heart tissue, along with lipid peroxidation levels. The findings suggest that nutmeg aqueous extract possessed significant potential as a hepatoprotective and antioxidative agent against ISO-induced damage in rats [84]. Nutmeg extract effectively alleviated inflammation and lipid metabolism disorders in non-alcoholic fatty liver disease mice by regulating the gut microbiota and metabolites, particularly the tryptophan metabolic pathway, activating the aryl hydrocarbon receptor (AhR) and inhibiting the nuclear factor kappa B (NF-κB) signaling pathway [85]. However, it is important to note that high doses of nutmeg can lead to significant increases in CYP450s, depletion of antioxidants, and consequent oxidative stress-induced liver damage in male Kunming mice [86].

Recent pharmacological studies have shown that the ethanolic extract of nutmeg might be gastroprotective against ethanolic gastric ulcer rat model, through the anti-oxidative and anti-inflammatory properties of its flavonoids [87]. Eugenol (61) reduced gastric mucosal damage induced by the platelet-activating factor (PAF) and ethanol in a dose-dependent manner. It not only reduced the number of ulcers but also the severity of lesions and was more effective than other known antiulcer drugs in preventing ethanol-induced gastric injury [88]. Malabaricone B (162) and malabaricone C (163) significantly enhanced gastric ulcer healing in mice by promoting angiogenesis and modulating key angiogenic factors, with malabaricone C demonstrating superior efficacy. These compounds were non-toxic in mice at doses up to 500 mg/kg, suggesting that they may have no potential side effects in the treatment of gastric ulcers [89]. In addition, malabaricone B and C exhibit significant anti-ulcer activity by modulating antioxidant activity, mucin secretion, prostaglandin synthesis, and EGF receptor expression, thereby facilitating gastric ulcer healing [90].

Water extract of nutmeg ameliorated dextran sulfate sodium (DSS)-induced colitis in mice by inhibiting inflammatory cytokines [91]. Myristicin (54) positively affected the treatment of ulcerative colitis (UC) by affecting three important target effectors molecules for UC development, including downregulation of the endoplasmic reticulum stress ERS mediator GRP78 and CHOP genes expression and apoptosis, upregulation of the expression of the transcription factor Nrf-2 and its downstream antioxidant signaling pathway, and downregulation of the NF-κB pro-inflammatory cascades [92].

Overall, the uses of nutmeg in the digestive system have been confirmed in a number of scientific studies ([Fig. 6]). The future of nutmeg as a therapeutic agent for gastrointestinal health is promising. If these effects are validated in humans, nutmeg could offer a natural alternative to conventional medications with fewer side effects. Further research is essential to translate these findings into clinical applications.

Fig. 6 Pharmacological Mechanisms of Nutmeg on the Digestive System.

Cardioprotective effects

Nutmeg is widely used in traditional medicine to treat chronic cardiovascular diseases such as coronary heart disease and angina pectoris. In recent years, researchers have determined through network pharmacology that nutmeg treatment for ischemic heart disease involved multiple signaling pathways, including the prolactin signaling pathway, estrogen signaling pathway, inflammatory signaling pathway, and cancer signaling pathway [93]. The aqueous extract of nutmeg has antiarrhythmic effects by directly or indirectly acting on calcium or sodium channels in cardiomyocytes to significantly reduce the incidence of ventricular fibrillation, the duration of arrhythmia, and the mortality rate induced by calcium chloride in rats [94]. The volatile oil of nutmeg showed protective effects against myocardial ischemia-reperfusion injury in rats. This was achieved by slowing the heart rate, decreasing the incidence of arrhythmia, decreasing the release of cardiac enzymes, increasing the activity of superoxide dismutase (SOD), and decreasing the malondialdehyde (MDA) content, suggesting that it may protect cardiomyocytes, attenuate the injury, and maintain cardiac function by inhibiting the production of free radicals and the lipid peroxidation reaction [95]. Malabaricone C (163), one of the chemical components of nutmeg, acts as a natural antioxidant. It has a significant antihypertensive effect by reducing systolic blood pressure in deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats, alleviating organ hypertrophy, decreasing cardiovascular collagen deposition and inflammation, enhancing plasma total antioxidant capacity, and improving endothelial and smooth muscle function. Moreover, it reversed the harm that DOCA-salt caused to the liver and kidneys and enhanced vasodilation function by controlling vasoconstrictor factors and nitric oxide levels [96]. Nutmeg extract has the potential to ameliorate caffeine-induced cardiac damage by reducing lactate dehydrogenase (LD) activity and improving cardiac tissue structure [97]. The above discusses the cardioprotective effects of nutmeg as a single drug. In addition, the traditional Mongolian medicine formula (nutmeg-5), which uses nutmeg as the main ingredient, also has significant cardioprotective effects.

Nutmeg-5, which consists of Myristica fragrans Houtt., Aucklandia lappa Decne., Inula helenium L., Choerospondias axillaris (Boxb.) Burtt et Hill., and Piper longum L., is traditional formula in traditional Mongolian medicine that is widely used in clinical practice for the treatment of heart disease [31]. Nutmeg-5 alleviated cardiac fibrosis after myocardial infarction in rats by inhibiting the myocardial the extracellular matrix- receptor interaction pathway and transforming growth factor TGF-β1/Smad2 signaling, which was achieved by regulating plasma metabolites [98]. In addition, nutmeg-5 attenuates cardiac remodeling after myocardial infarction by improving heart metabolism and preserving mitochondrial dysfunction by inhibiting (hypoxia inducible factor 1, alpha subunit) HIF-1α expression in the mouse heart after myocardial infarction [99]. Fructus Choerospondiatis and nutmeg significantly reduced the levels of creatine kinase MB (CK-MB) and lactate dehydrogenase in the serum of rats with ISO-induced myocardial injury, indicating that they has a protective effect on myocardial injury [100].

In summary, the cardioprotective effects of nutmeg have been confirmed through research ([Fig. 7]). However, it is important to note that while these properties are supported by the scientific research, further studies are needed to fully understand the mechanisms and to establish the safest and most effective ways to utilize the cardioprotective effects of nutmeg for heart health. The promise of nutmeg in cardiac protection warrants deeper exploration.

Fig. 7 Cardioprotective effects and mechanism of nutmeg and its traditional prescription.

Anti-inflammatory and analgesic activity

Both nutmeg oil (volatile oil) and nutmeg chloroform extract showed significant anti-inflammatory effects in the carrageenan-induced paw oedema model rats. Furthermore, in the acetic-acid-induced writhing model in mice, nutmeg oil and nutmeg chloroform extract exhibited superior analgesic activity [101], [102]. Nutmeg oil could potentially alleviate the CFA-injection-induced joint swelling, mechanical allodynia, and heat hyperanalgesia of rats through inhibition of cyclooxygenase-2 (COX-2) expression and blood substance P level, which made it possible for nutmeg oil to be a potential chronic pain reliever [103]. Lignans and phenolic compounds (malabaricone C) in nutmeg significantly suppressed the inflammatory response induced by LPS by inhibiting COX-2 and inducible nitric oxide synthase (iNOS) expression [104]. In addition, (8R,8′S)-7′-(3′,4′-Methylenedioxyphenyl)-8,8′-dimethyl-7-(3,4-dihydroxyphenyl)-butane (7) not only reduced NO production but also showed inhibitory effects on COX-2 and iNOS mRNA expression, suggesting that it suppresses the inflammatory response at the transcriptional level [105]. [Table 8] shows the mechanism of anti-inflammatory and analgesic activities of different components and extracts of nutmeg.

Table 8 Anti-inflammatory and analgesic activity and mechanism of nutmeg extracts.

Type of extract	React with particular disease	Mechanism of action	References
Chloroform extract	Inhibited carrageenan-induced rat paw oedema and reduced writhing induced by acetic acid in mice.	Not detailed	[101]
Nutmeg oil	Exhibited anti-inflammatory effect on acute inflammation by inhibiting carrageenan-induced rat paw oedema. Produced analgesic effect in the acetic-acid-induced writhing model and in the late phase of the formalin-induced licking in mice.	Nutmeg oil may act similarly to non-steroidal anti-inflammatory drugs (NSAIDs), possibly by inhibiting prostaglandin synthesis.	[102]
Nutmeg oil	Alleviated CFA-injection induced joint swelling, mechanical allodynia, and heat hyperanalgesia in rats.	Through inhibition of COX-2 expression and blood substance P level	[103]
Lignans, phenolic, and malabaricone C	Showed anti-inflammatory activity by inhibiting LPS-induced NO production in macrophage RAW264.7 cells.	Not detailed	[104]
Lignans isolated from nutmeg	Demonstrated anti-inflammatory activity by inhibiting LPS-induced NO production in RAW264.7 cells.	Dose-dependently reduced LPS-induced COX-2 and iNOS expressions and inhibited iNOS and COX-2 mRNA expressions, as well as iNOS and COX-2 promoter activities in LPS-stimulated RAW264.7 cells, suggesting suppression at the transcription level.	[105]

Potential anticancer activity

In recent years, researchers have discovered through studies of the pharmacological activity of nutmeg that it also has potential anticancer activity. Macelignan (1) reduced secretion of IL-1β from M2 macrophages, which in turn blocked NF-κB p65 nuclear translocation and inhibited metastasis. Furthermore, macelignan suppressed macrophage M2 polarization via the ROS-mediated PI3K/AKT signaling pathway, thus preventing IL-1β/NF-κB-dependent CRC metastasis [106]. Myristicin (54), a compound found in nutmeg, exhibited dose-dependent cytotoxicity against breast cancer cells MCF-7 cells, which not only significantly induced apoptosis, but also activated cellular anti-migration, promoted intracellular reactive oxygen species (ROS) generation, and blocked the cell cycle in G1/S phase. In addition, it regulated the apoptotic signaling pathway in MCF-7 cells by affecting the expression of apoptosis- and cell-cycle-related genes (e.g., Caspases8, Bax, Bid, Bcl2, PARP, p53, and Cdk1). It is shown that Myristicin was able to induce apoptosis in MCF-7 breast cancer cells by regulating the apoptotic signaling pathway, which has the potential to act as an anticancer agent and provides a new strategy for breast cancer treatment [107]. Dehydrodiisoeugenol (29), a lignan derived from nutmeg, significantly inhibited the proliferation of colorectal cancer cells by arresting the cell cycle at the G1/S phase and inducing autophagy through endoplasmic reticulum (ER) stress. This led to the activation of the PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways, which in turn suppresses tumor growth both in vitro and in vivo, suggesting its potential as an effective anticancer agent against colorectal cancer [108]. Both the essential and fixed oils of nutmeg demonstrated significant in vitro inhibitory effects on the growth of undifferentiated human intestinal epithelial (Caco-2) cells, with myristicin (54), a major component of the essential oil, showing notable antiproliferative activity [55]. In conclusion, these studies indicate that the chemical composition of nutmeg may possess potential anticancer properties, but more research is needed to fully understand their mechanisms and clinical applications.

Antimicrobial activity

Studies have shown that nutmeg stops the growth of a wide range of bacteria with powerful antimicrobial properties. [Table 9] displays the results of extensive research on the antimicrobial activity of nutmeg extract using various solvents and assays.

Table 9 Antimicrobial activity of nutmeg extracts.

Type of extract	Methods	Strains	Findings	References
Methanol extracts	Agar diffusion method	15 strains of H. pylori	Methanol extracts of nutmeg had a minimum inhibitory concentration MIC of 12.5 µg/mL; nutmeg extracts inhibit the growth of H. pylori.	[109]
Crude extract, essential oil	Agar diffusion method	Methicillin-resistant Staphylococcus aureus and Staphylococcus aureus	Crude extract and essential oil obtained from nutmeg were applied as efflux pump inhibitors (EPIs), thereby enhancing the antimicrobial activity of the drugs they were used in.	[110]
Essential oil	Serial tube dilution method	Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, Streptococcus mutans, Candida albicans, Lactobacillus casei, Actinomyces viscosus, Prevotella intermedia, and Porphyromonas gingivalis	Essential oil of M. fragrans was effective against all tested endodontic microorganisms.	[111]
Essential oil, essential oil with an excipient	Serial dilution method	Klebsiella pneumoniae, Salmonella enterica 24 SPn06, Pseudomonas aeruginosa 17 – 331, Acinetobacter baumanni 17 – 380, Proteus mirabilis, Methicillin-resistant Staphylococcus aureus, Enterococcus faecalis 86, Enterococcus faecium 103, Bacillus cereus 1801, Streptococcus mutans (referent), Enterobacter cloacae, Citrobacter freundii, Staphylococcus epidermidis, Staphylococcus haemoLyticus, and Pasteurella multocida	Nutmeg essential oil with aluminometasilicate has extended antibacterial properties compared to the pure oil without additions. Both preparations prevent growth of Pasteurella multocida, but the oil with aluminometasilicate also inhibits Enterococcus faecalis and Streptococcus mutans.	[112]
N-hexane extract	Microdilution method	Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi, and Staphylococcus aureus	Elemicin (55) showed MIC of 31.25 µg/mL against Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhi, and 62.5 µg/mL against Klebsiella pneumonia and Staphylococcus aureus. It exhibited better antifungal activity against Candida tropicalis and Aspergillus flavus than Aspergillus niger, Penicillium chrysogenum, and Trichophyton rubrum.	[113]
Methanol extract, fractions, and 3′,4′,7-trihydroxyflavone (172)	Colorimetric assay method	Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae, Providencia stuartii, and Pseudomonas aeruginosa	The study demonstrated significant antibacterial activity of methanol extract and the derived compound 3′,4′,7-trihydroxyflavone from Myristica fragrans against multi-drug resistant Gram-negative bacteria	[114]
Essential oil	A disc diffusion method	Staphylococcus aureus, Bacillus cereus, B. luteus, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus vulgaris, and Candida albicans	The essential oil showed significant activity against most of the tested microorganisms. The tested Gram-negative bacteria showed lower sensitivity.	[115]
Essential oil	Microdilution method	Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, Methicillin-Resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli	The essential oil of nutmeg showed antibacterial activity against both Gram-positive and Gram-negative bacteria. MIC of essential oils range from 0.313% to 10%.	[116]
Macelignan	Microdilution method	Streptococcus sobrinus, Streptococcus salivarius, Streptococcus sanguis, Lactobacillus acidophilus and Lactobacillus casei	MIC of macelignan against Streptococcus mutans was 3.9 mg/mL. Macelignan also exhibited preferential activity against other oral microorganisms with MIC values ranging from 2 to 31.3 mg/mL. Notably, macelignan at a concentration of 20 mg/mL completely inactivated Streptococcus mutans in just 1 min.	[117]

Antioxidant activity

The antioxidant activity tests such as DPPH, ABTS, superoxide anion, and hydroxyl radical scavenging assay revealed that methanolic, ethanolic, and acetone extracts of nutmeg showed strong antioxidant activity, and its methanolic extract also showed significant anti-α-glucosidase activity. Furthermore, three major compounds, dehydrodiisoeugenol (29), malabaricone B (162), and malabaricone C (163), were identified as the major antioxidant constituents in nutmeg seeds by HPLC analysis [118]. Dibenzylbutane lignans from nutmeg effectively inhibit soybean lipoxygenase-1 with IC50 values of 25.7 µM and 0.46 µM, respectively, showing significant antioxidant potential [119]. Eugenol (61) had the strongest DPPH scavenging capacity compared to other volatile oil constituents with antioxidant activity, surpassing BHT and α-tocopherol, while all three were relatively weaker than standard antioxidants in the β-carotene-linoleic acid assay [120]. It is noteworthy that the acetone extract of nutmeg has strong antioxidant properties compared to other extracts of nutmeg. The acetone extract had the highest total phenolic content and showed significant DPPH radical scavenging, iron chelating, and β-carotene bleaching inhibition activities [121]. [Table 10] shows the mechanism of antioxidant activity of different components and extracts of nutmeg.

Table 10 Antioxidant activity and mechanism of nutmeg extracts.

Type of extract	React with particular disease	Mechanism of action	References
Methanol extract of nutmeg dehydrodiisoeugenol, malabaricone B, and malabaricone C	The antioxidant activities of nutmeg extracts suggest potential in preventing and treating diseases related to oxidative stress.	The antioxidant activity of the compounds is attributed to their ability to scavenge free radicals (DPPH, ABTS+, hydroxyl radicals). Malabaricone C showed the strongest DPPH radical scavenging activity.	[118]
Seven kinds of lignans from nutmeg such as meso- dihydroguaiaretic acid (MDGA) and demethyldihydroguaiaretic acid (DDGA)	The lipoxygenase inhibitory activity of these compounds suggests their potential use in preventing and treating diseases associated with lipid peroxidation.	MDGA and DDGA act as competitive inhibitors of lipoxygenase. DDGA, with its free phenolic hydroxyl group, can ligate to the Fe atom in the enzymeʼs active site, forming the 6th coordination sphere. This interaction hinders the enzymeʼs catalytic activity, while the methoxy group in MDGA reduces its ability to interact with the Fe atom, leading to lower inhibitory activity.	[119]
Eugenol, isoeugenol, and methoxyeugenol isolated from nutmeg oil	The antioxidant activity of nutmeg oil is comparable to that of BHT and α-tocopherol, making it potenzially useful in preventing diseases related to oxidative stress.	In the DPPH• free radical scavenging assay, eugenol and methoxyeugenol showed stronger scavenging activities than BHT and α-tocopherol. In the β-carotene-linoleic acid assay, α-tocopherol > BHT > isoeugenol > methoxyeugenol > eugenol. The antioxidant activities are attributed to the ability of these compounds to donate hydrogen atoms or electrons to neutralize free radicals.	[120]
Acetone extract	Prevent or slow down various oxidative stress-related diseases.	These compounds render their effects via different mechanisms such as radical scavenging, metal chelation, inhibition of lipid peroxidation and quenching of singlet oxygen to act as antioxidants.	[121]

Other activity

Tetrahydrofuroguaiacin B (20), nectandrin B (16), and nectandrin A (15) demonstrated the strongest AMPK stimulation at a concentration of 5 µM in differentiated C₂C₁₂ cells. A tetrahydrofuran mixture from nutmeg showed a preventive effect on weight gain in a diet-induced obesity animal model, significantly reducing body weight and adipose tissue mass compared to the high-fat diet group [39]. The application of a 3% nutmeg cream led to a reduction in burn wound diameter and promoted wound healing, suggesting that nutmeg cream could potentially enhance burn wound healing in rats with second-degree burns [122]. The M. fragrans extract protected mice from thrombosis induced by a mixture of adrenaline and ADP at all tested doses, indicating its antithrombotic activity [102]. Macelignan (1) could treat PCOS through the TGF-β3/Smad/Cyp19a1 signaling pathway to regulate the secretion ability of ovarian granulosa cells [123]. A 50% ethanol extract of nutmeg stimulated mounting behavior, which significantly enhanced sexual behavior and mating ability in male mice without significant short-term toxicity [124]. Lignans isolated from nutmegs such as machilin A (3), macelignan (1), machilin F (17), and nectandrin B (16) stimulated osteoblast differentiation and exhibited anabolic activity in bone metabolism [34]. Nutmeg extract effectively alleviated atopic dermatitis-like symptoms in NC/Nga mice by reducing IgE levels, improving skin barrier function, decreasing inflammatory cell infiltration, and modulating the differentiation of T helper cells [125]. Additionally, a study on Macelignan from nutmeg revealed it could suppress MMP-1 expression and promote type I procollagen synthesis by inhibiting ROS production and regulating MAPK and TGF-β/Smad signaling pathways in UVB-irradiated human skin fibroblasts, suggesting its potential for preventing and treating skin photoaging [126]. [Table 11] shows the mechanism of other activity of different components and extracts of nutmeg. The broad spectrum of these activities underscores the complex biological potential of nutmeg. Expanding on this, [Table 12] provides an in-depth summary of the key secondary metabolites found in nutmeg and their specific pharmacological activities, further illustrating the extent of nutmegʼs therapeutic potential that continues to be explored. In summary, nutmeg has a large number of potential pharmacological activities still to be explored.

Table 11 Other activity and mechanism of nutmeg extracts.

Type of extract	React with particular disease	Mechanism of action	References
Seven tetrahydrofuran lignans and a tetrahydrofuran mixture (THF) extracted from nutmeg, namely tetrahydrofuroguaiacin B, saucernetindiol, verrucosin, nectandrin B, nectandrin A, fragransin C1 and galbacin, as well as a tetrahydrofuran mixture	In vitro, tetrahydrofuroguaiacin B, nectandrin B, and nectandrin A at a concentration of 5 µM showed significant stimulation of AMPK activation. In animal models, THF demonstrated a protective effect against weight gain in HFD-induced obese mice, effectively lowering body weight, fat content, blood glucose, and blood lipid levels and reducing liver damage.	The tetrahydrofuran lignans and THF work by activating AMPK. The activation of AMPK by THF in mice may have involved the phosphorylation of its downstream substrate ACC (acyl-CoA carboxylase), reducing fat synthesis and promoting fatty acid oxidation, thereby achieving anti-obesity and metabolic disorder improvement effects.	[39]
Nutmeg cream	Nutmeg cream could promote burn wound healing in rats with second-degree burns.	The antioxidant properties of nutmeg essential oils can inhibit lipid peroxidation and reduce metal ions, which may modulate wound contraction and enhance the speed of epithelialization.	[122]
The chloroform extract of nutmeg	The extract could protect mice from thrombosis induced by a mixture of adrenaline and ADP. It showed antithrombotic effects at all studied doses.	Its antithrombotic effect may be linked to its previously reported antiaggregatory activity.	[102]
Macelignan	Macelignan can improve the typical symptoms of polycystic ovary syndrome, including restoring the reproductive cycle and ovarian morphology, alleviating depression and anxiety symptoms induced by PCOS, recovering hormone levels, and balancing ovarian inflammation and antioxidant levels.	Macelignan may influence hormonal regulation by modulating estrogen secretion, potenzially via the TGF-β3/Smad/Cyp19a1 signaling pathway. It may inhibit granulosa cell apoptosis caused by high androgen levels, promoting granulosa cell proliferation, thereby contributing to the improvement of ovarian function and the restoration of the reproductive cycle in PCOS models.	[123]
The 50% ethanolic extract of nutmeg	It was found to significantly enhance the sexual behavior of male mice, including mounting behavior and mating performance.	The exact mechanism of action is not explicitly detailed in the text. However, it is speculated that the aphrodisiac effect may be attributed to their nervous stimulating properties. Nutmeg has been traditionally recognized as nervine stimulants, which may enhance libido and sexual performance.	[124]
Some lignans isolated from nutmeg, such as machilin A macelignan, machilin F, nectandrin B, safrole, licarin A, licarin B, myristargenol, and meso-dihydroguaiaretic acid	They can stimulate osteoblast differentiation, helping to correct imbalances between bone resorption by osteoclasts and bone formation by osteoblasts.	Machilin A stimulates osteoblast differentiation via activation of p38 MAP kinase. It induces MAP kinase activation in a dose-dependent manner, with p38 being activated more strongly than JNK. The p38 inhibitor SB203580 can inhibit machilin A-induced ALP expression and mineralization, confirming the critical role of p38 in this process. Furthermore, machilin A increases the mRNA expression levels of osteoblast differentiation/mineralization-related genes such as ALP, osteopontin (OPN), osteocalcin (OCN), and type I collagen (COLI) in a dose-dependent manner.	[34]
Ethanolic extract of nutmeg	Nutmeg extract can improve Dermatophagoides farina–extract-induced atopic dermatitis-like skin lesions in NC/Nga mice.	Nutmeg extract regulates the Th1/Th2 balance, inhibits Th2 cell activation and cytokine secretion, reducing Th2-related cytokines and serum IgE levels. It also suppresses the mRNA expression of pro-inflammatory cytokines like IL-13 and TNF-α, alleviating skin inflammation and inflammatory cell infiltration.	[125]
Macelignan	Macelignan has an impact on the photoaging-related responses of human skin fibroblasts induced by UVB irradiation. It can alleviate the upregulation of MMP-1 expression and the downregulation of type I procollagen expression and secretion induced by UVB, showing potential anti-photoaging effects and can be used for the prevention and treatment of skin photoaging.	Macelignan exerts anti-photoaging effects by inhibiting UVB-induced intracellular ROS production, reducing the phosphorylation of ERK, JNK, and p38 in the MAPK signaling pathway to decrease c-Jun phosphorylation and modulating the TGF-β/Smad signaling pathway through increasing Smad3 and reducing Smad7 protein levels, which in turn suppresses MMP-1 expression and promotes type I procollagen synthesis.	[126]

Table 12 Secondary metabolites of nutmeg and their pharmacological activities.

Secondary metabolites	Pharmacological activities
Macelignan	Anti-inflammatory by inhibiting NF-κB and MAPK pathways; neuroprotective in Parkinsonʼs and Alzheimerʼs diseases; activates PPARγ, promoting microglial rginase-1 expression; reduces LPS-induced inflammation and spatial memory impairments; possesses antimicrobial properties against various bacteria; it may inhibit granulosa cell apoptosis caused by high androgen levels, promoting granulosa cell proliferation, thereby contributing to the improvement of ovarian function and the restoration of the reproductive cycle in PCOS models; exerts anti-photoaging effects
Myristic acid and heptadecanoic acid	Anti-inflammatory effects by inhibiting the LPS-induced inflammatory response in BV-2 microglial cells; downregulates the expression of interleukin IL-1β, IL-6, and TNF-α; suppresses NF-κB pathway activation
Volatile oil (essential oil or nutmeg oil)	Exhibits anti-inflammatory and analgesic effects; alleviates joint swelling and pain in rats; demonstrates anti-inflammatory activity by inhibiting NO production; suppresses NO production and COX-2/iNOS expression; shows potential neuroprotective effects against neurodegenerative diseases; possesses antimicrobial properties against various bacteria; exhibits antioxidant activity
Myristicin	Anti-inflammatory by inhibiting NF-κB pathway and COX-2 expression; neuroprotective effects by modulating monoamine neurotransmitters and proteomic profiles; anticancer potenzial by inducing apoptosis and cell cycle arrest in breast cancer cells; anti-inflammatory effects by downregulating pro-inflammatory cytokines; exhibited significant hepatoprotective effects; antiproliferative activity
Malabaricone B and Malabaricone C	Anti-ulcer activity by promoting angiogenesis and modulating key angiogenic factors; significant anti-ulcer activity by enhancing gastric ulcer healing; antioxidant and anti-inflammatory effects
Flavonoids	Antioxidant and anti-inflammatory properties; gastroprotective effects against ethanol-induced gastric ulcers
Nectandrin B	Hepatoprotective effects by enhancing the antioxidant capacity of hepatocytes and protecting against oxidative stress-induced liver cell injury via activating the Nrf2/ARE signaling pathway
Eugenol	Reduces gastric mucosal damage induced by platelet-activating factor (PAF) and ethanol in a dose-dependent manner; more effective than other known antiulcer drugs in preventing ethanol-induced gastric injury

Toxicological effect

The phenylpropanoid components in nutmeg, such as myristicin (54), elemicin (55), safrole (63), and methyleugenol (62), were found to be toxic. The metabolic activation product of myristicin, 1′-hydroxymyristicin, forms a conjugate with N-acetylcysteine (NAC) that is closely associated with the cytotoxicity of myristicin. In primary mouse hepatocytes, myristicin exhibits significant cytotoxicity at 250 µM, while 1′-hydroxy myristicin shows cytotoxicity at 62.5 µM, with IC50 values of 356.4 ± 1.06 µM and 132.90 ± 1.07 µM, respectively, indicating that metabolic activation enhances the toxicity of myristicin [127]. Elemicin at a high dose (400 mg/kg bw/day) exhibits significant hepatotoxicity in rats, which includes increased liver weight, hepatocyte hypertrophy, and elevated serum hepatotoxic parameters, as well as genotoxicity and carcinogenicity [128]. Safrole and methyleugenol (62) are classified by the International Agency for Research on Cancer (IARC) as “possibly carcinogenic to humans” (Group 2B) and have been confirmed as hepatocarcinogens in experimental animals. Their metabolites, particularly the 1′-hydroxylated products, are considered the proximate cause of their carcinogenicity. Their toxicity is primarily attributed to metabolic activation on the allylic side chain, specifically 1′-hydroxylation followed by sulfonation, leading to the formation of reactive and unstable intermediates that may react with DNA and proteins [129]. Recent research indicates that the oral LD50 of nutmeg powder is over 5000 mg/kg body weight. This suggests that short-term use of nutmeg powder is safe. Yet sub-chronic exposure reveals certain toxicity, implying long-term use may involve risks. Thus, when employed as a food ingredient or traditional medicine, the potential safety concerns of nutmeg powder must be carefully weighed [130].

In conclusion, understanding the toxicity of nutmeg is essential for quality control and the development of new drugs. Therefore, further research should focus on the isolation and purification of the chemical constituents of nutmeg, as well as an in-depth understanding of its toxicity and side effects to ensure safety and efficacy.

Quality Control

In China, nutmeg prices are influenced by factors such as origin, quality, purpose, and place of purchase and typically range from several dozen to hundreds of yuan per kilogram. Medicinal nutmeg, which demands higher volatile oil content, is generally more expensive than nutmeg used for spices. In the field of traditional medicine, nutmeg holds a significant position in compound formulations of traditional Chinese medicine, Mongolian medicine, and Tibetan medicine. In the Chinese pharmaceutical market, nutmeg is commonly processed into medicinal preparations. Pharmaceutical factories and hospital preparation rooms usually follow local standards and their own established quality criteria during the preparation process, which are often in line with the quality requirements for nutmeg specified in the 2020 edition of the Chinese Pharmacopoeia to ensure the quality and efficacy of the medicinal preparations. To control the quality of nutmeg, it is necessary to consider multiple aspects. Appearance, physical form, and taste are preliminary criteria for judgment. The content of volatile oil, components, and active ingredients are key indicators for assessing its quality. In addition, the preparation process, harvest timing, and safety testing are also critical aspects that require strict control to ensure the quality and safety of nutmeg.

Quality control of herbs is the process of ensuring that the quality of herbs meets the established standards, it plays a vital role in ensuring the safety, efficacy, and stability of herbs and in promoting the healthy development of the whole herb industry. The quality standards of nutmeg in the 2020 edition of the Chinese Pharmacopoeia stipulated that the content of volatile oil should not be less than 6.0% (mL/g) and that the content of dehydrodiisoeugenol (29) should not be less than 0.10% [43]. Meng et al. showed that the volatile oil and dehydrodiisoeugenol contents of nutmeg were 8.0% (mL/g) and 0.13%, respectively, which were higher than the standards of the 2020 edition of the Chinese Pharmacopoeia, indicating that the nutmeg herbs were of good quality [131]. To understand the specific volatile oil constituents of nutmeg, the researcher used gas chromatography–mass spectrometry (GC-MS) to identify 38 compounds of its volatile oil and found monoterpenes (59.6%), oxygenated monoterpenes (22.2%), sesquiterpenes (1.4%), phenolic ether (6.8%), and phenylpropanoids (0.9%) [132]. The volatile fractions of nutmeg extracted by supercritical fractionation with carbon dioxide were mainly composed of myristicin (32.8%), sabinene (16.1%), α-pinene (9.8%), β-pinene (9.4%), β-phellandrene (4.9%), safrole (4.1%), and terpinen-4-ol (3.6%) [55]. In addition, the nutmeg was found to have high contents of fat (26.7%), protein (18.7%), carbohydrate (28.9%), energy (3938.3 Kcal/Kg), and fiber (9.4%) and was rich in Ca²⁺, K⁺, Po₄ ³⁻, Mg²⁺, Fe²⁺, and ascorbic acid, with low levels of Zn²⁺, thiamine, niacin, and riboflavin [33].

Zhao et al. used gas chromatography–mass spectrometry (GC-MS) to quantitatively analyze 9 major active compounds in nutmeg from 15 different origins and found that there were significant variations in the content of the compounds. The findings demonstrated that nutmeg from Malaysia had relatively higher levels of the nine compounds than that from Indonesia, India, and Hainan in China [133]. Researchers determined the contents of macelignan (1), dehydrodiisoeugenol (29), and licarin-B (26) in 11 batches of nutmeg of different origins using ultra-high-performance liquid chromatography (UHPLC) and found that the contents of these three constituents varied significantly among the different origins of nutmeg [134]. From the above studies, it is not difficult to find that the chemical content of nutmeg may be influenced by a variety of factors such as the climate and soil conditions of the place of origin and the method of cultivation.

In recent years, more studies had been conducted on the volatile oil and lignan components of nutmeg, but fewer studies had been conducted on its quality control and comparative studies in different origins. The detection of a single active ingredient was not a reliable indicator of overall efficacy. Therefore, it is important to adopt a multifaceted quality control approach to the study of quality control of nutmeg. We need to further investigate the potential quality markers of M. fragrans as a reference for its quality evaluation.

Discussion

M. fragrans is an evergreen spice tree that grows in the tropics, and the seed kernels, called nutmeg, were traded as are exported as a spice commodity all over the world. Over time, it has been discovered that nutmeg is not only a valuable kitchen spice but also an herb used in many traditional ethnomedicines, including Ayurvedic, Tibetan, Mongolian, and Chinese medicines. Nutmeg contains a variety of chemical components, mainly including lignans, neolignans, volatile oils, and other chemical components. Nutmeg extract and its chemical constituents possess a wide range of pharmacological activities such as neurological and digestive pharmacological effects, as well as cardioprotective, anti-inflammatory, analgesic, antimicrobial, potential anticancer, antioxidant activities, and other pharmacological effects.

Nutmeg has a long history of neurological effects in Ayurveda, Tibetan, and Mongolian medicine [29], [135], [136]. At the same time, modern pharmacological studies have revealed more pharmacological effects of nutmeg on the nervous system. In this regard, it is possible to combine the results of modern research with the experience of traditional medicine to study the potential role of nutmeg in the treatment of neurological diseases and its adverse effects, providing a holistic approach to understanding and utilizing this spice for neurological health. The efficacy of nutmeg in warming the middle and moving “qi”, astringing the intestines, and checking diarrhea was recorded in the Compendium of Materia Medica [8], [19]. This corresponds to the pharmacological effects of nutmeg on the digestive system in modern pharmacological studies worldwide. However, it is clear that there is a paucity of research in this area, and there is a need for further comprehensive and systematic studies on the mechanism of action of nutmeg in the digestive system, with a view to a more complete understanding of its nature and therapeutic versatility in digestive disorders. Nutmeg is known as Jurhen Sayin (good for the heart) in Mongolian medicine [31] and has long been used in traditional Ayurvedic [29], Tibetan [21], [135], and Mongolian medicine for the treatment of various heart conditions. Its cardioprotective effects and mechanism of action have been confirmed by modern scientific research. Current research is still focused on the preliminary exploration of the cardioprotective effects of nutmeg with unclear specific mechanisms of action, limited depth and breadth of research, and a lack of clinical studies. Although some progress has been made in the study of the cardioprotective effects of nutmeg, there is still much work to be done, especially in combining the basic theories and applications of traditional medicine with a deeper understanding of the mechanisms of action and clinical applications. Moreover, nutmeg has been found to possess anti-inflammatory, antioxidant, antimicrobial, potential anticancer, antiviral, and insecticidal activities. The anti-inflammatory properties of nutmeg can be attributed to its ability to modulate various inflammatory pathways. For example, it may inhibit the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which play crucial roles in the initiation and progression of inflammatory responses. Additionally, nutmeg may interfere with the activation of nuclear factor-kappa B (NF-κB); by suppressing these inflammatory mediators, nutmeg can help alleviate inflammation and associated symptoms in conditions. The antioxidant properties of nutmeg may contribute to its protective effects against various diseases by scavenging free radicals and reducing oxidative stress. Its antimicrobial activity suggests potential applications in combating bacterial, fungal, and viral infections, which aligns with its traditional use in preventing and treating infectious diseases. The potential anticancer activity of nutmeg indicates that certain compounds in nutmeg may have the ability to inhibit the growth of cancer cells or induce apoptosis, providing a new direction for cancer treatment research.

To enhance the quality assessment and pharmaceutical development of nutmeg, it is essential to conduct comprehensive research and efforts based on the predicted quality markers (Q-markers). The researchers did Q-marker predictive analyses of the constituents of nutmeg, such as dehydrodiisoeugenol (29), myristicin (54), macelinan (1), methoxyeugenol (57), elemicin (55), eugenol (61), and α-pinene (64), to provide references for their quality evaluation and drug development [32]. Following the prediction of Q-markers for nutmeg, subsequent research should focus on validating their biological activities, establishing quality control standards, conducting pharmacological and toxicological studies, and advancing through preclinical and clinical trials to ensure safety and efficacy. This comprehensive approach will facilitate the translation of Q-markers from prediction to practical application in medicine and quality control.

Moving forward, there is a need to integrate traditional medical experiences, to study nutmeg in depth, and to conduct more systematic quality control studies on its extracts and its chemical constituents. With the deeper and deeper research on nutmeg, its deeper pharmacodynamic material basis and mechanism of action against diseases will continue to be elucidated and discovered. It is believed that through multi-dimensional and more in-depth research, people will have new understanding of and discoveries about nutmeg.

Conclusion

This review synthesizes current knowledge on nutmeg, encompassing traditional uses, chemical composition, pharmacological activities, mechanisms of action, and quality control. Research confirms its bioactive potential in neurological (e.g., anti-inflammatory and cognitive benefits), digestive (e.g., hepatoprotective and anti-ulcer effects), and cardiovascular areas, aligning with its historical applications in traditional medicines. However, significant gaps remain. Future research should focus on mechanistic elucidation using advanced techniques like proteomics and metabolomics to clarify the effects of compounds such as macelignan and myristicin. Additionally, there is a need to establish multi-component quality control protocols to address variability in volatile oil and lignan content across different regions, ensuring consistent efficacy and safety. Detailed toxicological studies on bioactive compounds, particularly the long-term and dose-dependent risks of phenylpropanoids like myristicin, are also essential. Finally, well-designed clinical trials are necessary to validate nutmegʼs therapeutic effects in human. By addressing these areas, future research can effectively bridge traditional uses with modern applications, maximizing nutmegʼs potential in therapeutics.

Contributorsʼ Statement

J. Qi: Conception and design of the review, drafting of the manuscript. Y. Bai, Q. Mu, J. Wu: Data collection (literature review), analysis and interpretation of the data. C. Sa: Critical revision of the manuscript for important intellectual content.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 01 January 2025

Accepted after revision: 28 August 2025

Accepted Manuscript online:
13 October 2025

Article published online:
27 November 2025