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Natural Substances Nutmeg
Natural Substances Nutmeg
NUTMEG
(Myristica fragrans Houtt.)
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PART 1 FOODBORNE and MICROBIAL TOXINS
and processed separately. Mace is also a spice, and this fraction, and miscellaneous compounds.7 The aromatic
spice has been used as an aphrodisiac by physicians in fraction contains myristicin, elemicin, safrole, and minor
the Near East. There are relatively few reports of poi- constituents (methyleugenol, eugenol, isoeugenol,
soning following the ingestion of mace. toluene). The essential oil of nutmeg contains variable
amounts (0.1–18%) of methyleugenol, which is a poten-
PRINCIPAL TOXINS tially genotoxic compound with DNA-binding potency
similar to safrole.8 Myristicin, elemicin, and safrole
Structure and Properties account for the majority (85–95%) of the compounds in
the aromatic fraction, and myristicin represents about
The concentration of active components depends on the 4–12% of the compounds present in the essential oil.9
botanical source, environmental conditions, storage, and Myristicin is present in plants from the carrot (Umbel-
analytical methods. The two oils of nutmeg are fixed oil liferae) family including dill, celery, parsnip, parsley, and
(expressed oil, nutmeg butter) and essential oil. The carrot. This compound is also a minor constituent of oil
fixed oil is an orange, butter-like material obtained by of black pepper (Piper nigrum). The estimated intake of
applying heat and hydraulic pressure to nutmeg. This oil myristicin from these sources by the general population
contains primarily trimyristin, and the product has no is a few mg daily.10
culinary value. Essential oil of nutmeg is a steam distil-
late that appears as a pale-yellow, nearly colorless liquid Mechanism of Toxicity
with the characteristic odor of spice. Table 9.1 lists some
properties of myristicin, which is the main psychoactive Structural similarities of myristicin to classical halluci-
constituent of nutmeg. This compound is structurally nogenic compounds (e.g., mescaline) suggest that myris-
similar to kawain and related psychoactive constituents ticin may act as a serotonin receptor agonist and
of kava (Piper methysticum Forst.). Myristicin is also the hallucinogenic compound. However, the acute toxicity
major component of the aromatic ether fraction of of myristicin is relatively low. Although myristicin com-
essential oil of mace.7 Figure 9.1 displays the chemical prises the largest fraction (i.e., about 4–8%) of com-
structure of myristicin. pounds in the aromatic fraction of nutmeg, human
studies with myristicin have not duplicated the effects
Poisonous Parts of nutmeg intoxication on the central nervous system.17
In rodent studies, myristicin and elemicin impair coor-
This essential oil contains from 5–15% volatile oils com- dination and decreased motor activity.11 Safrole, eugenol,
prised of about 80% monoterpenes (α-pinene, sabinene, and isoeugenol do not have similar behavioral effects is
1,8-p-methadiene, β-pinene, 1,4-p-menthadiene, cam- these animal studies.
phene), 5% monoterpene alcohols, an aromatic ether
DOSE RESPONSE
TABLE 9.1. Identifying Characteristics and Properties of
Myristicin
One grated nutmeg is approximately one tablespoon
and weighs about 6–7 g with typical recreational doses
Property Value ranging from 5–30 g.7 The administration of 6 g nutmeg
CAS Number 607-91-0 to students did not significantly alter performance on
Chemical name 1-allyl-5-methoxy-3,4- neuropsychological tests.12 Symptoms do not usually
methylenedioxybenzene develop following the ingestion of <10 g nutmeg.7 The
Synonyms Myristicin, methoxysafrole ingestion of two whole nutmegs caused moderate toxic-
Empirical formula C11H12O3 ity;1 the ingestion of an estimated dose of 18 g of finely
Molecular weight 192.22 ground nutmeg powder resulted in prolonged periods
Appearance Colorless oil
of obtundation.13 The ingestion of 25–28 g of nutmeg
powder produced tachycardia, anxiety, miosis, paresthe-
sias, palpitations, anticholinergic signs (mydriasis, diffi-
O CH2 culty voiding, tachycardia), and paranoid behavior
without hallucinations.14,15 The ingestion of an estimated
dose of 37 g nutmeg blended in a milkshake was associ-
O ated with tachycardia, palpitations, drowsiness, nausea,
dry mouth, anxiety, restlessness, and agitation without
OCH3 hallucinations.16 Variation in toxicity may result from
FIGURE 9.1. Chemical structure of myristicin. the loss of essential oils from the ground nutmeg.
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9 NUTMEG
The ingestion of a single dose 400 mg myristicin by 30 weeks gestation, delivered a healthy infant at
10 subjects was associated with alertness, a feeling of term.22
irresponsibility, and euphoria in 2 subjects as well as an The processing of nutmeg does not usually produce
unpleasant reaction (anxiety, fear, tremor, nausea, tachy- irritative symptoms in spice workers.26 However, aller-
cardia) in 2 subjects.17 Onset of symptoms occurred gic contact dermatitis may develop in workers sensi-
about 1–2 hours after ingestion and resolved within 24 tized to allergens (e.g., isoprenyl myristate) in nutmeg.27
hours. This dose of myristicin is equivalent to the amount Occupational asthma may also occur in workers sensi-
of myristicin present in 40 g of nutmeg. tized to spices including mace.28
In the 1970s, an in vitro study suggested that psychoac- Chromatographic methods easily separate marijuana
tive amphetamine derivatives (e.g., 3-methoxy-4,5- and the components of nutmeg and mace.29 Human
methylenedioxyamphetamine, MMDA) are potential metabolites of the constituents in nutmeg are detect-
metabolites of myristicin.18 Although the alkeneben- able by the use of gas chromatography mass spectrom-
zene derivatives, myristicin, elemicin, safrole, are exten- etry after acid hydrolysis, liquid-liquid extraction of
sively metabolized following ingestion, subsequent analytes, and microwave-assisted acetylation of
studies have not confirmed the presence of amphet- extracted analytes.19 These metabolites include O-
amine metabolites. Limited toxicokinetic studies indi- demethyl elemicin, O-demethyl dihydroxy elemicin,
cate that these alkenebenzene undergo hydroxylation demethylenyl myristicin, dihydroxy myristicin, and
of the side chain, and elemicin undergoes O-demethyl- demethylenyl safrole. Developing biomarkers for
ation prior to hydroxylation. Metabolites detected in nutmeg intoxication is complicated by limited data on
the urine of rats fed these compounds include O- the toxic constituents of nutmeg. Six hours after inges-
demethyl elemicin, O-demethyl dihydroxy elemicin, tion 14–21 g nutmeg powder, a 16-year-old adolescent
demethylenyl myristicin, dihydroxy myristicin, and developed tachycardia, drowsiness, dry mouth, warm
demethylenyl safrole.19 In vivo animal studies suggest skin, and mydriasis.30 The myristicin concentration in a
that enzymatic hydrolysis of myristicin produces at least blood sample drawn 8 hours after ingestion was 2 μg/
two metabolites (5-allyl-1-methoxy-2,3-dihydroxyben- mL. The postmortem blood from a 55-year-old woman
zene, 1′-hydroxymyristicin) that are conjugated and contained 4 μg/mL of myristicin and 0.072 μg/mL of
excreted in the urine.20,21 Amphetamine derivatives were flunitrazepam.30 Death was attributed to the combina-
not detected in these two studies. tion of the two substances. However, myristicin does
not necessarily account for the toxic effects of nutmeg,
CLINICAL RESPONSE and the contribution of myristicin and nutmeg to this
death remains speculative. Routine laboratory tests
The clinical features of nutmeg intoxication resemble during nutmeg intoxication are usually normal.24 The
belladonna (anticholinergic) toxicity manifest by facial ingestion of nutmeg does not produce positive urine
flushing, tachycardia, hypertension, dry mouth, blurred drug screens.14
vision, and delirium.22,23 However, mydriasis is uncom-
mon. Symptoms usually begin about 3–6 hours after TREATMENT
ingestion and resolve by 24–36 hours.6,7 Initially, these
symptoms include nausea, vomiting, abdominal pain, Management is usually supportive. The presence of
chest pain, restlessness, agitation, tremor, ataxia, nystag- hemodynamic instability suggests the presence of other
mus, vertigo, and a feeling of doom. These symptoms toxins or illnesses. Decontamination measures are
occur with alternating periods of lethargy and delir- usually unnecessary because of the presence of vomit-
ium.13,24 Other effects of nutmeg intoxication docu- ing or delayed contact (i.e., >1–2 hours after ingestion)
mented in case reports include the sensation of warmth with the health care facility. There are no clinical data
and coldness of the extremities, distortion of space and to guide management of nutmeg intoxication. The use
colors, auditory and tactile hallucinations, headache, and of standard antiemetics (prochlorperazine, trimetho-
generalized weakness.25 Patients usually recover without benzamide, odansetron, metoclopramide) and intrave-
sequelae.1 The medical literature does not contain any nous fluids may be required to treat protracted nausea
fatalities solely related to nutmeg intoxication since the and vomiting. Sedatives (diazepam, haloperidol)
first decade of the 20th century.2 There are few data on should be used with caution because of alternating
the reproductive effects of nutmeg. A 29-year old periods of delirium and obtundation during nutmeg
woman, who developed signs of nutmeg intoxication at intoxication.
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PART 1 FOODBORNE and MICROBIAL TOXINS
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