Nutmeg essential oil

Nutmeg oil is a volatile essential oil from nutmeg (the seed of Myristica fragrans Houtt., family Myristicaceae) ¹⁾. At present, nutmeg still maintains its status as a unique kitchen spice with growing evidence for many of its traditional uses as a natural remedy. The evergreen nutmeg tree can reach 20 m in height and continues to be cultivated in its original location (Indonesian East Indies islands and Srilanka) as well as the West Indies (Caribbean Grenada islands) where the tree was introduced in the 19th century ²⁾. The lemon-like yellowish fruit contains the seed (nutmeg kernel, Figure 1) which is enveloped in a reddish net-like spongy tissue known as the aril or arillus (nutmeg mace, Figure 1). Both nutmeg kernel and nutmeg arillus are rich in essential oil that imparts the characteristic aroma and taste to nutmeg as a unique culinary ingredient. Primary metabolites (carbohydrates, lipids/fatty acids and proteins) constitute up to 80% of the weight of dry nutmeg kernel while the remaining weight comprises secondary metabolites of diverse chemical nature. They include essential oils (terpenes and phenylpropanoids) and phenolic compounds (caffeic, ferulic and protocatechuic acids, lignans/neolignans, and diarylalaknes) as the major constituents ³⁾. Polyphenols and pigments (catechins, epicatechins, falvonoids, and cyanidins) are also present (Table 1). Nutmeg mace is separately processed from nutmeg and has relatively less fats and carbohydrates.

Table 1. Relative chemical composition of nutmeg kernel and methods of preparation of major constituents 

Chemical class	Concentration (w/w, dry)	Main Constituents (abundance within class)	Preparation Method
I) Primary metabolites:
Fixed oil (nutmeg butter)	up to 40%	Myristic acid (~8%) & trimyristin triglyceride (~73%)	Expression
Carbohydrates	up to 30%	Starch	Insoluble residue
Protein	up to 6%		Insoluble residue
II) Secondary metabolites:
Nutmeg Essential oil	2–16%	Terpenes (~88%), Phenylpropanoids (~12%)	Steam distillation
Small phenolic compounds	varies	Phenolic acids, lignans, diarylalkanes, flavonoids	Organic solvent extraction
Resins & pigments	varies	Polyphenolics, polycatechins, tannins, anthocyanins	Variable

[Sources ⁴⁾, ⁵⁾, ⁶⁾]

Figure 1. Nutmeg fruit anatomy

Figure 2. Nutmeg kernel

Figure 3. Nutmeg oil

Chemistry of major secondary metabolites of nutmeg essential oil

The essential oil is obtained by the steam distillation of ground nutmeg and is used heavily in the perfumery and pharmaceutical industries. The nutmeg essential oil is used as a natural food flavoring in baked goods, syrups, beverage and sweets etc. Nutmeg essential oil replaces ground nutmeg as it leaves no particles in the food. The essential oil is also used in the cosmetic and pharmaceutical industries for instance in tooth paste and as a major ingredient in some cough syrups. In traditional medicine nutmeg and nutmeg oil were used for illnesses related to the nervous and digestive systems.

The essential oil constitutes up to 16% of nutmeg (w/w) and is rich in monoterpenes (approximately 90%) and phenylpropanoids ⁷⁾. A number of recent reports listed between 27–37 components present at various concentrations as determined by gas chromatography–mass spectrometry. In two independent studies by Wahab et al. ⁸⁾ and Piaru et al. ⁹⁾, the total number of compounds identified in the nutmeg essential oil was 37. In other studies, Du et al. ¹⁰⁾ reported 27 compounds, Muchtaridi and co-workers ¹¹⁾ listed 32 compounds while Piras et al. ¹²⁾ identified 30 compounds. Based on these most recent reports, the average number of compounds identified in nutmeg essential oil is 34. The monoterpenes -pinene (1, 7.4±3.5 %), 4-terpineol (2, 16.0±10.6 %), -terpinene (3, 5.3±3.3 %), limonene (4, 5.9±2.8 %), sabinene (5, 16.4±4.8 %), -terpineol (6, 2.4±2.2 %), -terpinene (7, 4.4±3.7 %), and -pinene (8, 5.2±3.0 %); and the phenylpropanoids myristicin (9, 12.4±11.7 %), elemicin (10, 1.9±1.7 %), methyleugenol (11, 3.8±7.2 %), safrole (12, 2.6±1.9 %), eugenol (13, 6.8±11.4 %), and methylisoeugenol (14, 5.7±9.6 %) were the most detected constituents in the five reported samples. Interestingly, isoeugenol the propenyl isomer of 13 or the O-demethyl isomer of 14, was present in trace amounts in only one of the five recent reports on the essential oil of nutmeg (Muchtaridi et al. 2010). Mean concentrations shown between parentheses reflects a wide range of variability (chemical structures are shown in Figure 2).

Table 1. Chemical composition of nutmeg essential oil from nutmeg seeds

No.	Compounds	Percentage %
1	α-thujene	0.78
2	α-pinene	10.23
3	Camphene	0.16
4	Sabinene	21.38
5	α-myrcena	2.38
6	α-terpinene	2.72
7	Limonene	5.57
8	β-ocimene	0.03
9	γ-terpinene	3.98
10	trans-sabinene hydrate	0.03
11	Terpinolene	1.62
12	Linalool	0.75
13	Fenchyl alcohol	0.05
14	cis-sabinene hydrate	0.06
15	4-terpineol	13.92
16	α-terpineol	3.11
17	Citronellol	0.77
18	Linalyl acetate	0.06
19	Bornyl acetate	0.24
20	Safrole	4.28
21	Methyl eugeunol	0.77
22	Isoeugeunol	1.74
23	Myristicin	13.57
24	Elimicin	1.42
25	Metoxyeugeunol	0.1
26	β-asaron	0.03
27	Myristic acid	0.11
28	Ethyl miristate	0.04
29	Palmitic acid	0.03
30	Ethyl palmitate	0.07
31	Stearic acid	0.01
32	Ethyl oleate	0.01

[Source ¹³⁾]

Figure 4. Nutmeg essential oil major secondary metabolites – monoterpenes (90% approx.) and phenylpropanoids

[Source ¹⁴⁾]

Lignans and neolignans

Based on the number of identified compounds, lignans and neolignans constitute the most abundant class of secondary metabolites present in nutmeg kernel and mace ¹⁵⁾. A lignan can be loosely identified as a product of tail-to-tail dimerization of two phenylpropanoids while neolignans are formed mainly via head-to-tail coupling, with other possible non-C-2/C-2 couplings. Thus, the basic skeleton of a lignan usually comprises a dibenzyl-substituted tetrahydrofuran, a hexahydrofurofuran or a butane moiety while that of a neolignan may be an ether, a benzofuran, a benzodioxane, or a biphenyl (head-to-head coupling). Due to the abundance of phenylpropanoids (see Figure 4 above number 9-14) in nutmeg, all identified lignans and neolignans represent various dimerization patterns between these five phenylpropanoids.

Diphenylalkanes

In addition to lignans, which can be chemically classified as diphenylbutanes, two types of diphenylalkanes have been identified in nutmeg. The diphenylnonanoid malabaricones A-D were originally isolated Myristica malabarica (wild nutmeg), and, of these malabaricone B and C (59 & 60, respectively, Figure 5) are among common constituents later isolated from the kernel and mace of nutmeg as well as the bark of another Myristica species, Myristica cinnamomea (compound 60) ¹⁶⁾. Another -terpineol ether of malabaricone C (61) was isolated and reported as a new compound by Duan et al ¹⁷⁾. 1,3-Diphenylpropanes constitute a number of less common diphenylalkanes that were recently reported by Cuong et al. in the course of a bioassay-directed isolation project. Three compounds were isolated and identified as 5-¹⁸⁾. It is noteworthy that diarylpropanoids reported by Forrest et al. in 1974 ¹⁹⁾ are more appropriately classified as neolignans based on their benzofuranoid and 8,4’-oxyneolignan core structures.

Figure 5. Nutmeg essential oil major secondary metabolites – Diphenylalkanes

It seems that most promising biologically active secondary metabolites of nutmeg are either lignans/neolignans or diarylnonanoids.

The chemical groups, lignans and neolignans seem to be among the most studied. Nguyen et al. ²⁰⁾, in search of novel AMP-protein kinase (5’-adenosine monophosphate-activated protein kinase, AMPK) activators, isolated 2,5-bis-aryl-3,4-dimethyltetarhydrofuran lignans 15-20 & 22 from nutmeg. AMPK enzyme system plays a crucial role in regulating lipid and glucose homeostasis in a various tissue types. Studies have emphasized its role in obesity, diabetes, and cardiovascular diseases. Activation of AMPK has recently emerged as a therapeutic target for the aforementioned disease states ²¹⁾. Because of antihyperlipidemic and anti-atheroscelorotic activities reported for nutmeg extract ²²⁾, Nguyen et al. ²³⁾ screened the seed extract of AMPK activator activity, followed by isolation of pure lignan compounds. Out of the seven isolated compounds, tetrahydrofuroguaiacin, nectandrin A, and nectandrin B exerted strong activation of AMPK in differentiated C2C12 muscle cells, at 5 M concentration ²⁴⁾. The study also examined the effect of administration of a nectandrin B-rich active fraction in a high fat-induced animal model of obesity. The results showed a protective effect of the fraction against weight gain and blood glucose elevation caused by the high fat diet, suggesting potential application for nutmeg and its compounds in obesity, type 2 diabetes mellitus, and metabolic syndrome. A follow up study reported that nectandrin B activated AMPK in vascular smooth muscle cells and inhibited vascular smooth muscle cells proliferation and neointima formation, events that are critical in the development of vascular occlusive diseases. An elaborate study of the mechanism of vascular smooth muscle cells anti-proliferative effect revealed that AMPK activation resulted in P53 and P21 induction, that in turn downregulated retinoblastoma (Rb) phosphorylation, E2 transcription factor 1 (E2F1) resulting in inhibition of pin1 gene expression. The cascade of events results in inhibition of intimal hyperplasia ²⁵⁾. These results support a therapeutic potential for nectandrin B in the treatment or prevention of various occlusive vascular diseases, however further studies, particularly clinical studies are still needed.

Reviewing the literature reveals that lignans have received wide attention for their potential role in prevention of osteoporosis. Lignans are classified as phytoestrogens that exert estrogenic activity through binding to the estrogen receptor. Various phytoestrogens, especially isoflavones, have demonstrated beneficial clinical effects against bone loss in both preclinical and clinical studies ²⁶⁾. Machilin A, one of the lignan components of nutmeg, was reported to stimulate osteoblast differentiation through activation of the p38 mitogen activated protein kinase pathway ²⁷⁾. In early stage osteoblast differentiation, machilin A significantly increase alkaline phosphatase (ALP) activity, a commonly used marker for stimulating differentiation. Similarly, machilin A activated late stage differentiation and significant bone mineralization. The observed bone anabolic activity occurred in a dose-dependent manner. Other activities for machilin A include inhibition of proliferation of blood lymphocytes, human leukemia HL-60 cells, and topoisomerase I and II inhibition, suggesting potential anticancer properties ²⁸⁾. Follow-up studies and proper clinical evaluation of these properties remain uninvestigated.

Several pharmacological activities have been attributed to macelignan the main bioactive component identified in nutmeg mace. The activities range from anti-microbial, anti-inflammatory, anti-cancer, to antidiabetic, hepato- and neuro-protective ²⁹⁾. The anti-inflammatory effects of macelignan have been extensively studied. Shin et al. ³⁰⁾ reported that treatment with macelignan prevents the development of allergen-induced asthma in experimental animal models. The protective effect was coupled to a reduction in CD4+ T cells production of interleukin-4 (IL-4), but with no apparent effect on IL-17 or interferon-cells. Animals administered macelignan showed lower expression of the type-2 T helper cell (Th2) transcription factor, GATA3, an effect that needs might contribute to the protective anti-asthma activity, but requires further mechanistic studies. An earlier study demonstrated that macelignan inhibits the activation of mast cells in response to allergen exposure. Macelignan inhibited the release of histamine, calcium influx, degranulation, as well as various inflammatory mediators’ release ³¹⁾. The protective effect of macelignan has been tested in a variety of models of neurological dysfunction. Cui et al. ³²⁾ reported a protective effect of oral administration of macelignan against lipopolysaccharide-induced hippocampus microglial cells in rats. It also protected against impaired spatial learning induced by chronic lipopolysaccharide administration, implying potential therapeutic benefit for Alzheimer’s Disease patients. The mechanism of anti-inflammatory effect was investigated by Ma et al. ³³⁾. The study reported that macelignan suppressed lipopolysaccharide-induced activation of the Toll-like receptor 4 pathway, as evidenced by suppression of the nuclear factor NF-κB, reduction in cyclooxygenase type-2 (COX-2) expression, and inhibition of reactive oxygen species (ROS) generation. The results were in agreement with anti-inflammatory and protective effects of macelignan observed in animal models of diabetes and hepatotoxicity ³⁴⁾. A recent study corroborated the neuroprotective effect of macelignan. Using midbrain slice cultures, macelignan treatment protected dopaminergic neurons against the interferon (IFN)-γ and lipopolysaccharide-induced degeneration ³⁵⁾. Mechanistic studies revealed the protective neuroprotective effect observed was mediated by macelignan activation of the peroxisome proliferator activated receptor (PPAR-γ), which in turns activated arginase 1 enzyme expression. The result of the study implicates probable protective role of maceliganan against Parkinson’s Disease and other neurodegenerative disorders. The use of macelignan as an antiphotoaging agent stems from its antioxidant, antionflammtory, as well as its documented ability to protect human skin fibroblasts against damaging effects of UVB irradiation. The observed protective effect is mediated by suppression of two cellular responses involved in premature skin aging: the upregulation of matrix metalloproteinases and reduced collagen synthesis ³⁶⁾. Another potential skin application for macelignan was reported by Choi et al. ³⁷⁾ whereby the authors suggested the use of macelignan as a natural depigmenting agent based on its ability, at 10 M concentration, to inhibit melanosome transfer and dendrite formation in B16F10 melanoma cells. In addition to its earlier documented anti-diabetic effect, macelignan, isolated from Schisandra grandiflora, was recently reported to possess an inhibitory action against advanced glycation end products, an effect that adds to its potential role in the management of diabetes and metabolic syndrome ³⁸⁾.

Nutmeg essential oil uses and potential benefits

In folkloric medicine, nutmeg has long been used as a remedy for gastrointestinal problems, such as flatulence, colic, indigestion and diarrhea ³⁹⁾. The traditional use of nutmeg to treat tumors and infectious diseases, such as parasites and plague, has also been reported ⁴⁰⁾. Nutmeg has been used externally to treat skin infections, rheumatism and paralysis ⁴¹⁾. Other interesting uses for nutmeg include the treatment of psychological disorders ⁴²⁾, and as a cheap substitute for marijuana especially among teenagers, sailors and prison inmates ⁴³⁾.

Despite the myriad of folkloric uses of nutmeg, preclinical and clinical studies supporting such uses are relatively limited. Pharmacological studies have confirmed a few activities of nutmeg extracts, including antidiarrheal, antimicrobial, antioxidant, and different central nervous system (CNS) activities. Gorver et al. ⁴⁴⁾ examined the effects of crude nutmeg suspension, aqueous, as well as petroleum ether extracts in a variety of activities. The study ⁴⁵⁾ revealed a significant antidiarrheal effect exerted by both the crude suspension and petroleum ether nutmeg extract. However, only the petroleum ether extract had a significant sedative effect. None of the extracts showed significant cardiovascular effects as measured by blood pressure and ECG changes. On the other hand, a cardioprotective effect against myocardial infarction (heart attack) has been reported. Abdul Kareem et al. ⁴⁶⁾ examined the effect of daily administration of aqueous nutmeg extract (100 mg/kg, orally) for 30 days on isoproterenol-induced heart attack in adult male rats. Data collected show that pretreatment with nutmeg extract offered protection against isoproterenol effects on blood glucose, plasma lipids, as well as histological myocardiac changes, suggesting a potential cardiovascular protective role of nutmeg consumption.

Very few studies examined the antimicrobial activity of nutmeg extracts. Methanolic extracts possess potent antifungal activity against various plant pathogenic fungi, with three lignans (erythro-austrobailignan-6 [macelignan, 23], meso-dihydroguaiaretic acid [30] and nectandrin B [19]) identified as the primary constituents responsible for the reported antifungal activity ⁴⁷⁾. Similar antimicrobial activity was reported for nutmeg against the pathogenic Escherichia coli O157 and O111. The activity proved to be selective against the pathogenic versus the non-pathogenic E. coli strains ⁴⁸⁾. On the other hand, evaluation of nutmeg ethanolic extract against clinical isolates of Staphylococcus aureus, E. coli, and Streptococcus pyogenes resulted in lack of antimicrobial activity against all tested bacteria ⁴⁹⁾. Ethyl acetate and ethanolic extracts of the seed, mace, and flesh of nutmeg demonstrated high bactericidal activity against several Gram positive and Gram negative oral pathogens ⁵⁰⁾. In vitro evaluation of antimalarial activity of 27 herbal extracts and 5 formulations proved nutmeg to be among the identified eight extracts that exhibited potent antimalarial activity with IC50 value less than 10 mg/mL. In addition, the activity showed a selectivity index of >10 against multidrug resistant Plasmodium falciparum versus human renal epithelial cells ⁵¹⁾. Chemical investigation of nutmeg resulted in the isolation of a wide range of phenolic compounds belonging to the lignan group. With such compounds identified, research efforts intensified at evaluating the antioxidant potential of nutmeg. A study conducted by Assa et al. ⁵²⁾ examined the antioxidant capacity of methanolic extracts of nutmeg mace, seed, and flesh. Results attributed the highest free radical scavenging antioxidant activity to the seed extract based on the 1,1-diphneyl-2-picrylhydrazyl (DPPH) and ferric-reducing antioxidant power assays. Phytochemical evaluation correlated the high antioxidant capacity of the seed extract to its tannin, terpenoid, and flavonoid components. Lack of antioxidant activity of mace was also reported by Yadav and Bhatnagar ⁵³⁾ and was attributed to the relatively low polyphenolic content. The antioxidant properties of the aqueous extract of nutmeg seem to be responsible for its observed antimuatgenic and antimitotic actions against the cyclophosphamide-induced carcinogenic effects in the Allium cepa test ⁵⁴⁾.

Unlike the plethora of preclinical studies evaluating the nutmeg extracts, very few studies examined the potential activities of nutmeg oil. Wahab et al. ⁵⁵⁾ reported a dose-dependent activity of nutmeg oil in various animal seizure models. The oil exerted significant anticonvulsant effect against seizures induced by maximal electroshock, pentylenetetrazole, and strychnine, at doses that did not impair locomotor activity. Higher doses of the nutmeg essential oil seem to possess a weak proconvulsant effect, potentiating the clonic seizures induced by both pentylenetetrazole and bicuculline. Administration of nutmeg essential oil to experimental animals via the inhalation route showed a dose-dependent depressant effect on locomotor activity, with potential sedative effect attributed to myristicin, safrole, and 4-terpineol oil constituents ⁵⁶⁾. Using the DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging assay, Piaru et al. ⁵⁷⁾ reported a significant antioxidant activity of nutmeg oil. The oil also showed strong cytotoxic action against colorectal cancer carcinoma cell line and breast carcinoma cell line.

Limited studies focused on preclinical pharmacological evaluation of myristicin. Leiter et al. ⁵⁸⁾ examined the anxiolytic effect of myristicin (see Figure 4 above – phenylpropanoids of nutmeg essential oil – number 9) in the experimental elevated plus maze animal model. In line with a previous report by Sonvane and co-workers ⁵⁹⁾, myristicin failed to show anxiolytic action in the Leiter et al. study. The results demonstrated that myristicin may actually have some anxiogenic effect and may antagonize the actions of benzodiazepine, the GABAA receptors allosteric potentiators. In addition the CNS activity, antihelmintic ⁶⁰⁾, insecticidal ⁶¹⁾, apoptotic, and protection against DNA damage ⁶²⁾ effects were reported to myristicin ⁶³⁾. However, most of these activities are scattered in the literature, with no systematic follow up studies that further corroborate the findings or carry them further to application.

The most studied pharmacological activity attributed to nutmeg is its effects on the central nervous system (CNS). As early as the 12th century, nutmeg has been used and known for its central nervous system activity. Available literature has recognized a variety of nervous system effects of nutmeg and its major constituents. Earlier anecdotes report psychoactive and hallucinogenic properties of nutmeg ⁶⁴⁾. These reports were the basis of Shulgin’s hypothesis that attributed nutmeg’s psychoactivity to metabolic conversion of its main phenylpropanoid constituents to amphetamine-like metabolites ⁶⁵⁾. So far, the hypothesis has not been experimentally supported. Inconsistent animal findings and lack of detection of the amphetamine-like metabolites in biological fluids of nutmeg abusers led to reevaluation of the validity of the hypothesis ⁶⁶⁾. Further experimental data have ascribed several additional nervous system effects to nutmeg. Hayfaa et al. ⁶⁷⁾ reported analgesic activity of acidulated ethanolic extract of nutmeg (1 g/kg dose) in acetic acid-induced writhing animal model in support of earlier reports of the analgesic activity of the n-hexane nutmeg extract ⁶⁸⁾. Neurobehavioral effects exerted by nutmeg have been documented in various animal models, with numerous activities reported. Sonavane et al. ⁶⁹⁾ reported an anxiogenic activity exerted by the n-hexane extract of nutmeg, at doses of 10 and 30 mg/kg, i.p., as well by trimyristin (10, 30, and 100 mg/kg, intra-peritoneal). On the other hand, Ayurvedic literature reports the use of aqueous nutmeg extract as an anxiolytic agent ⁷⁰⁾. Such claim has not been substantiated by experimental dependent anxiolytic activity of aqueous nutmeg extract in the open field test experimental model. Similar to reported results for its effect on anxiety, conflicting data have been documented for nutmeg’s (and its components) effect on depression. Dhingra et al. ⁷¹⁾ and Moinuddin et al. ⁷²⁾ reported antidepressant activity of nutmeg extracts in both models of behavioral despair as well in reserpine reversal test paradigms, respectively. The studies also suggested the involvement of adrenergic, serotonergic, and dopaminergic systems in the observed antidepressant effect, since it was inhibited by 1 and dopaminergic receptor antagonists as well as a serotonin synthesis inhibitor. On the other hand, tryimyristin exerted a depressant effect when tested in behavioral despair animal models and potentiated hypothermia induced by reserpine. The observed effects were blocked by pre-administration of a serotonin 5-HT2A receptor antagonist ⁷³⁾. A previous study in a laboratory ⁷⁴⁾ evaluated the neurobehavioral effects of nutmeg in the four-point tetrad assay as compared to common drugs of abuse, Δ9-tetrahydrocannabinol (Δ9-THC), morphine, and amphetamine. The results of the study showed that nutmeg extracts have various activities in the assay, depending on the nature of the extract, as well as the route of administration. The study demonstrated that the dichloromethane nutmeg extract, when injected at 100 and 300 mg/kg doses, intra-peritoneal, exerted some cannabimimetic activity in the tetrad assay at ⁷⁵⁾.

Maity and co-workers reported a significant healing effect of malabaricone B against indomethacin-induced stomach ulcer ⁷⁶⁾. Administration of malabaricone B attenuated the increased nitric oxide synthesis induced by indomethacin, while enhancing the arginase pathway, thus favoring an anti / pro inflammatory cytokine ratio. Malabaricone C has potential pharmacological benefits in vascular disease ⁷⁷⁾, promotion of healing, anti-inflammation and angiogenesis caused by stomach ulcers ⁷⁸⁾, antioxidant activity ⁷⁹⁾ and cytotoxic activity against certain cancers ⁸⁰⁾. Malabaricone C also has anti-anaerobic, antifungal, and antibacterial properties ⁸¹⁾ as well as anti-parasitic, leishmanicidal and nematocidal activity ⁸²⁾.

For a long time studies have focused on lignans as the main active components of nutmeg. Recent research efforts explored the activities of neolignan-type compounds. Kang et al. reported an antiplatelet activity to erythro-(7S,8R)-7-acetoxy-3,4,3’,5’-tetramethoxy-8-O-4’-neolignan (EATN) ⁸³⁾. Results of the study showed that erythro-(7S,8R)-7-acetoxy-3,4,3’,5’-tetramethoxy-8-O-4’-neolignan (EATN), exerted a concentration dependent inhibition of platelet aggregation induced by platelet activating-factor and thrombin, and arachidonic acid. EATN had IC50 values of 3.2 ± 0.4 and 3.4 ± 0.4 M against platelet activating factor and thrombin-induced platelet aggregation, respectively. Further mechanistic investigation delineated the mechanism of anti-platelet activity. EATN regulates the level of cAMP, a crucial second messenger in the activation of platelet aggregation. EATN elevates intracellular cAMP levels inhibiting the Ca2+-induced mobilization of platelets activated by thrombin. Though these results are promising and elude to potential therapeutic application of EATN in atherothrombotic diseases, in vivo and clinical studies are still in demand. Licarin E, another neolignan, proved to protect against UVB irradiation damage to human skin fibroblasts ⁸⁴⁾. It reversed the two events induced by UVB: elevation of matrix metalloproteinase-1 and reduction of procollagen expression. The molecular mechanism of these effects proved to be via stimulation of transforming growth factor (TGF )/Smad signaling pathway. Similar to macelignan, licarin E could offer a novel therapeutic agent for photoaging. Using rat basophilic leukemia cells, stimulated by dinitrophenyl-human serum albumin, the effect of the neolignan licarin A on histamine release and mast cell activation was examined ⁸⁵⁾. The results demonstrated that licarin A inhibited mast cell activation, as evidenced by inhibiting tumor necrosis factor (TNF ), COX-2, and prostaglandin production. Further studies are needed to corroborate the role of licarin A in the treatment of immediate hypersensitivity cases. In vitro studies have elucidated that licarin A, isolated from Machilus thunbergii, may possess neuroprotective value against glutamate-induced toxicity of rat cortical cells ⁸⁶⁾. The protective effect was also evident against kainic acid-induced neurotoxicity, though more selective protection was observed for glutamate toxicity. The neuroprotective effect was attributed to the potent antioxidant properties of licarin A, evidenced by reduction of NO (nitric oxide), peroxide, free radical production as well as enhancing the activity of antioxidant enzyme systems. In addition, licarin A effectively suppressed Ca2+ influx that is typically induced by glutamate. Synthetic (−)-licarin A was reported to possess concentration-dependent anti-parasitic activity ⁸⁷⁾. In vitro studies reported potent inhibition of growth Leishmania promastigotes, suggesting promising application as a leishmanicidal agent. Using a tuberculosis murine animal model, Leon-Diaz et al. ⁸⁸⁾ demonstrated that licarin A possesses a significant suppressant action of the pulmonary burden and pneumonia in animals infected with both drug sensitive as well as drug-resistant tuberculosis strains. Animals administered licarin A (5mg/kg for 30 days) showed significant reduction in lung bacilli and pneumonia incidence. The anti-parasitic effect of licarin A was further corroborated against both Schistosoma mansoni and Trypanosoma cruzi ⁸⁹⁾. It is evident that the potential anti-parasitic activity of licarin A is worth further investigation in the hope of future development of effective medications.

Nutmeg essential oil side effects

Myristicin (see Figure 4 above – phenylpropanoids of nutmeg essential oil – number 9) is the major phenylpropanoid constituent of nutmeg essential oil. Various toxicological reports have attributed adverse effects associated with nutmeg ingestion to myristicin ⁹⁰⁾. These adverse effects include gastrointestinal; vomiting, and paralytic ileus, nervous system; drowsiness, paresthesia, numbness, reality detachment, and cardiovascular; hypotension, tachycardia, symptoms ⁹¹⁾, ⁹²⁾.

The central nervous system depressant effect of trimyristin, the main triglyceride constituent of nutmeg butter, was documented in mice ⁹³⁾. Trimyristin significantly increased immobility time in both forced swim and tail suspension murine tests, indicating a depressant-like action, when administered intraperitoneal injection (abdominal cavity injection) at 10 and 30 mg/kg doses. Furthermore the activity was inhibited by various antidepressant medications including the selective serotonin reuptake inhibitor fluoxetine, the tricyclic antidepressants imipramine, and the atypical antidepressant mianserin. However, the mechanism of such depressant action remains unclear.

Summary of nutmeg essential oil uses and benefits

Nutmeg kernel and mace have a long history of use as a spice and traditional remedy that goes back to the 12th century. Traditional uses of nutmeg in alleviating gastrointestinal disorders, managing rheumatic pain, healing skin wounds and infections as well as its use as a calming agent resulted in massive contemporary efforts to evaluate its different extracts, fractions. Despite the traditional uses and activities reported for nutmeg, the mechanisms underlying its effects remain unclear and further pharmacological studies are certainly needed to properly assess the therapeutic potential of this natural product ⁹⁴⁾, ⁹⁵⁾.

One of the most commonly evaluated activities of nutmeg essential oil and extracts is their effect on the CNS. In addition to the essential oil which is rich in terpenes and phenylpropanoids, nutmeg has significant levels of non-volatile secondary metabolites of the lignan/neolignan-type as well as diarylalkanes that have been isolated and identified. Preclinical studies to evaluate such compounds as myristicin, macelignan, nectandrin A & B, licarin A-E, and malabaricone B & C are abundant in recent literature with focus on anxiolytic, antioxidant/chemopreventive, anti-inflammatory, anti-infective effects of individual compounds. On the other hand, clinical trials are not as abundant in the current literature. They are limited in size, design and focus (topical application of nutmeg or use of a mixed herbal product containing nutmeg among other extracts) with no individual pure compounds included.

While phytochemical studies have supported some of the folkloric uses of nutmeg, very few clinical studies systematically investigated the clinical efficacy of nutmeg uses. A thorough literature search revealed merely two small clinical studies. A randomized, placebo-controlled, double blind trial examined the clinical effects of using topical nutmeg extract in patients with painful diabetic neuropathy ⁹⁶⁾. The study included 74 diabetic neuropathy patients (males and females, ages 30–85 years) who were randomized to receive the different topical treatment: nutmeg extract, mace oil, nutmeg oil, coconut oil, methyl salicylate, menthol, or placebo. The study used a validated Brief Pain Inventory that has been modified for painful diabetic neuropathy in addition to the Neuropathic Pain Symptom Inventory. Following four weeks of treatment, patients showed within group significant improvement of pain, mood scores, and daily functions. However no statistically significant effect was reported between the nutmeg treated and placebo groups. Being the only study that assessed the clinical analgesic effect of nutmeg, it is hard to draw conclusions because of the study limitations. The small sample size, short duration of the study, lack of inert placebo, poor patient compliance, and use of non-standardized nutmeg preparations are all limitations that hinder proper evaluation of the therapeutic role of nutmeg in pain disorders. The other study retrieved describes an open, uncontrolled trial that examined the effect of administration of a nutmeg-containing herbal product in a total of 251 patients ⁹⁷⁾. The product used, Revivin, contained a mixture of various plant extracts including nutmeg in addition to carbohydrate molecules, and is commonly used to enhance performance, improve appetite, and reduce weakness and fatigue. Patients (average age 44 years, males and females) received the capsule daily for 4 weeks. Outcomes were assessed by self-filled patients’ questionnaire. Patients reported improvement in mood, insomnia, and overall weakness, and no adverse effects were reported by the patient. The study suffers from several limitations: subjectivity of outcome evaluation, short duration, and lack of placebo control. In addition, since the study used a product where nutmeg constituted only one component of the mixture, the clinical nutmeg effect cannot be isolated. As evident, there is a lack of well-designed controlled clinical trials that evaluate the potential therapeutic place of nutmeg and its components.