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Toxicity Effects

CAS Registry Number: 607-91-0

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 2.

Names 1

  • 1,3-Benzodioxole, 4-Methoxy-6-(2-Propenyl) (9ci)
  • 6-Allyl-4-Methoxy-1,3-Benzodioxole
  • MYRIS
  • Myristicin

Human Toxicity Excerpts

  • ALTERNATIVE and IN VITRO TESTS: The present study was conducted to assess the cytotoxic and apoptotic effects of myristicin on the human neuroblastoma SK-N-SH cells. ... A dose-dependent reduction in cell viability /was found/ at myristicin concentration >/ =0.5 mM in SK-N-SH cells. Apoptotic cell death was confirmed using DNA fragmentation, terminal deoxyribonucelotidyl transferase-mediated dUTP nick end labeling and by 4,6-diamidino-2-phenylindole staining. Microscopy was used to observe apoptotic cell morphology. Western blotting was used to investigate the protein expression of known apoptotic mediators including cytochrome c, caspase-3, and PARP. The apoptosis triggered by myristicin was accompanied by an accumulation of cytochrome c and by the activation of caspase-3. The results obtained suggest that myristicin induces cytotoxicity in human neuroblastoma SK-N-SH cells by an apoptotic mechanism. ...[Lee BK et al; Toxicol Lett 157 (1): 49-56 (2005)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: ... In the present case, myristicin (4 ug/mL) was detected for the first time in the postmortal serum of a 55-year-old woman. Identification was achieved with the aid of UV-VIS spectroscopy and TLC; for quantification, HPLC was used. Because also flunitrazepam (0.072 ug/mL) was found, death had probably been due to the combined toxic effect of both substances. From 1996 to 1998, in a series of cases, seven poisonings with nutmeg were recorded by the Erfurt Poison Information Centre. Even where higher doses (20-80 g of powder) had been ingested, a life-threatening situation was never observed. In one of these cases, a myristicin blood level of 2 ug/mLwas measured 8hr after ingestion of two to three tablespoonful of nutmeg powder (approx. 14-21 g, or 280-420 mg/kg).[Stein U et al; Forensic Sci Int 118 (1): 87-90 (2001)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: /The authors/ present a case of acute nutmeg poisoning in a 16-year-old youth who had ingested the substance for recreational purposes. He developed a number of neurological symptoms and signs along with non-specific electrocardiographic changes and anti-cholinergic-type symptoms. /The authors/ describe the pharmacology of nutmeg and its constituents, discuss its metabolism, and make recommendations about the management of nutmeg poisoning. Emergency staff should be aware of the effects of nutmeg, which may present in marijuana users who seek alternative substances. /Nutmeg/[McKenna A et al; Eur J Emerg Med 11 (4): 240-1 (2004)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: A 13-year-old female ingested 15-24 g of nutmeg over a 3-hour period and smoked and shared 2 joints of marijuana. To facilitate ingestion, the nutmeg was put into 00-000 gelatin capsules. Bizarre behavior and visual, auditory, and tactile hallucinations developed. She also experienced nausea, gagging, hot/cold sensations, and blurred vision followed by numbness, double, and "triple" vision, headache, and drowsiness. Nystagmus, muscle weakness, and ataxia were present. Her vital signs and laboratory tests were normal. She received 50 g of activated charcoal and except for complaints of dizziness and visual changes, her 2-day admission was uneventful. The central nervous system activity of nutmeg is often postulated to result from biotransformation of its chemical components to amphetamine-like compounds, but this has not been proven. Nutmeg contains several compounds with structural similarities to substances with known central nervous system neuromodulatory activity. /Nutmeg/[Sangalli BC, Chiang W; J Toxicol Clin Toxicol 38 (6): 671-8 (2000)] **PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: Nutmeg is an easily obtainable spice that has been widely used domestically for centuries because of its psychotropic effects. Several cases of nutmeg poisoning, including one fatality, have been published. The active ingredients are volatile oils where myristicin and elemicin are thought to be the most important constituents. These have anticholinergic and psychotropic properties and are metabolised to compounds similar to amphetamine. The first reported case of nutmeg poisoning in Norway /is presented/. /Nutmeg/[Pytte M, Rygnestad T; Tidsskr Not Laegeforen 118 (28): 4346-7 (1998)] **PEER REVIEWED** PubMed Abstract
  • OTHER TOXICITY INFORMATION: Each nutmeg is composed of 5 to 15% volatile oil. Myristicin was initially thought to be the psychoactive agent; however, ingestion of pure myristicin does not produce the same results obtained from ingestion of the entire nutmeg. The other volatile oils may be responsible for the psychoactive effect noted.[Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 767] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Chronic poisoning by oral administration has caused temporary (up to six months) psychosis in prison inmates. /Myristica fragrans/[International Programme on Chemical Safety (IPCS); Poisons Information Monograph: Myristica Fragrans Houtt (PIM 355) (1991) Available from, as of June 14, 2007: http://www.inchem.org/pages/pims.html] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: In the toxic state /after ingestion/, the patient first feels excited and may have psychedelic hallucinations. This is followed by a period of drowsiness, delirium and, possibly, unconsciousness. Thirst has been reported. Mental concentration may either be impaired or enhanced; delirium with agitation, disorientation and incoherence may develop. Prison inmates taking nutmeg "trips" have compared it to alcohol, heroin and marihuana and referred to it as making them feel "high", relaxed and drowsy. Some reported a sleepy feeling, others, restlessness and tense. Most patients with accidental nutmeg intoxication experience an impending sense of doom after the initial excitation. The effects of nutmeg are most often compared to those of marihuana. Although the hallucinogenic effects of nutmeg are satisfactory, the side effects often discourage its use as such an agent. One reported case of nutmeg intoxication after drinking nutmeg tea, states that the reaction is immediate. /Myristica fragrans/[International Programme on Chemical Safety (IPCS); Poisons Information Monograph: Myristica Fragrans Houtt (PIM 355) (1991) Available from, as of June 14, 2007: http://www.inchem.org/pages/pims.html] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Ingestion of five or more grams of nutmeg causes acute nutmeg poisoning, which includes giddiness, hallucinations, and feelings of depersonalization. Symptoms usually appear three to six hours after ingestion of 1-3 whole nutmegs or 5-15 gm of the grated spice. Recovery usually occurs within 24 hours. Nevertheless, duration of action may extend beyond several days and even include death. /Nutmeg/[Green RC, Jr; JAMA 171 (10): 1342-4 (1959); Painter JC et al; Clin Toxicol 4 (1): 1-4 (1971)] **PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Myristicin, or methoxysafrole, is the principal aromatic constituent of the volatile oil of nutmeg, the dried ripe seed of Myristica fragrans. Myristicin is also found in several members of the carrot family (Umbelliferae). Several intoxications have been reported after an ingestion of approximately 5 g of nutmeg, corresponding to 1-2 mg myristicin/kg body weight (b.w.). Although these intoxications may be ascribed to the actions of myristicin, it is likely that other components of nutmeg may also be involved. ...[Hallstrom H, Thuvander A; Nat Toxins 5 (5): 186-92 (1997)] **PEER REVIEWED** PubMed Abstract
  • SIGNS AND SYMPTOMS: The effects by inhalation are generally similar to those experienced via oral administration with the exception that onset is faster by 15 minutes. /Myristica fragrans/[International Programme on Chemical Safety (IPCS); Poisons Information Monograph: Myristica Fragrans Houtt (PIM 355) (1991) Available from, as of June 14, 2007: http://www.inchem.org/pages/pims.html] **PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • ALTERNATIVE and IN VITRO TESTS: Mice given one of several widely consumed cola drinks in place of drinking water for up to 8 wk developed significant levels of covalent liver DNA adducts in a time dependent manner, as measured by (32)P-postlabeling. These adducts were not detected in mice given tap water or one of 3 non-cola beverages. Adducts chromatographically identical to those induced by cola drinks were detected in mice treated with extracts of nutmeg or mace, spices from the nutmeg tree (Myristicia fragrans), or with myristicin, the major spice constituent of nutmeg. In addition, small amounts of adducts derived from the hepatocarcinogen safrole, a minor constituent of nutmeg, were observed. Liver DNA adducts were also detected in fetal liver when pregnant mice were intubated with myristicin. ...[Randerath K et al; Biochem Biophys Res Commun 192 (1): 61-8 (1993)] **PEER REVIEWED** PubMed Abstract
  • GENOTOXICITY: ... The data on the ability of the /alkylbenzenes/ ... to induce unscheduled DNA synthesis (UDS) in hepatocytes derived from male Fischer 344 rats are presented ... Cytotoxicity was assessed by lactate dehydrogenase leakage. Elimicin and alpha- and beta-asarone are genotoxic in the UDS assay but myristicin is not. ...[Hasheminejad G, Caldwell J; Food Chem Toxicol 32 (3): 223-31 (1994)] **PEER REVIEWED** PubMed Abstract
  • GENOTOXICITY: A detailed exam was made of myristicin for in vitro mutagenicity using the Salmonella/mammalian (rat) microsome mutagenicity assay. Myristicin displayed no significant mutagenicity over a wide range of concn.[BUCHANAN RL ET AL; J FOOD SCI 47 (1): 330 (1982)] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Cats are especially sensitive to myristicin and exhibit central excitation followed by coma. /Myristica/[Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976., p. II-148] **PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Myristicin showed high activity as an inducer of the detoxifying enzyme glutathione S-transferase (GST) in the liver and small intestinal mucosa of female A/J mice. Reduction of myristicin yielded dihydromyristicin that retained the GST-inducing activity. Myristicin and dihydromyristicin were tested for their capacity to inhibit benzo[a]pyrene (B[a]P)-induced tumor formation in female A/J mice. A 65% inhibition of the tumor multiplicity in the lung was observed as the result of treatment of myristicin. Dihydromyristicin produced small or insignificant reduction of lung tumor formation. In the forestomach, myristicin showed a 31% inhibition of tumor formation; while dihydromyristicin exhibited a 27% inhibition. Comparison of the structures and activities indicated that the saturation of the isolated double bond in myristicin resulted in a significant decrease in the inhibitory activity against B[a]P-induced tumorigenesis. The present results showed that myristicin, an active inducer of GST activity, is an effective inhibitor of B[a]P-induced tumorigenesis in mice. Stimulation of GST activity by myristicin could be a major mechanism for its inhibition of B[a]P or other carcinogens that may be detoxified in the same manner. ...[Zheng GQ et al; Carcinogenesis 13 (10): 1921-3 (1992)] **PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Neurotoxicity: Myristicin impaired the rope-climbing and bar-pressing performance of rats, and caused catatonia and decr motor activity in mice. Rats developed a tolerance.[CESARIO DE MELLO A ET AL; PSYCHOPHARMACOLOGIA 31 (4): 349 (1973)] **PEER REVIEWED** PubMed Abstract
  • OTHER TOXICITY INFORMATION: Freshly prepd ground nutmeg and synthetic myristicin given orally to mice inhibited monoamine oxidase activity both in vivo and in vitro.[TRUITT EB JR; ETHNOPHARMACOL SEARCH PSYCHOACT DRUGS (PROC SYMP) 215 (1979)] **PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • None found

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Absorption, Distribution And Excretion

  • None found

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Metabolism/Metabolites

  • ... From in vitro and in vivo metabolism of myristicin, the two metabolites 5-allyl-1-methoxy-2,3-dihydroxybenzene and 1'-hydroxymyristicin were identified using GC-MS after derivatization of sample matrices with a mixture of BSTFA-TMCS. Those metabolites from in vitro study were also confirmed in urine after an oral administration of myrisitcin to rats, and enzymatic hydrolysis of urine suggested that these metabolites were excreted as conjugated forms as well.[Lee HS et al; J Chromatogr B: Biomed Sci Appl 705 (2): 367-72 (1998)] **PEER REVIEWED** PubMed Abstract
  • 2 N-containing metabolites of myristicin were excreted in the urine of rats and guinea pigs following oral or ip admin. In the rats the metabolite was 3-piperidyl-1,3-methoxy-4,5-mehtylenedioxyphenyl)-1-propanone while the major metabolite in the guinea pig was 3-pyrrolidinyl-1(3-methoxy-4,5-methylenedioxy-phenyl)-1-propanone.[OSWALD ED ET AL; BIOCHIM BIOPHYS ACTA 244 (2): 322 (1971)] **PEER REVIEWED** PubMed Abstract
  • In mice, the major metabolic pathway for ... myristicin includes cleavage of the methylenedioxyphenol residue and exhalation of the methylene carbon atom as carbon dioxide.[The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 304] **PEER REVIEWED**
  • Myristicin was converted into 3-methoxy-4,5-methylenedioxyamphetamine during perfusion of isolated rat liver or incubation with rat liver homogenates.[BRAUN U, KALBHEN DA; PHARMACOLOGY 9 (5): 312 (1973)] **PEER REVIEWED** PubMed Abstract
  • Myristicin yields 3-methoxycatechol probably in mouse, housefly; yields 1-(3-methoxy-4,5-methylenedioxyphenyl)-3-piperidyl-1-propanone in rat, guinea pig; yields 1-(3-methoxy-4,5-methylenedioxyphenyl)-3-pyrrolidinyl-1-propanone in rat, guinea pig. /From table/[Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. M-48] **PEER REVIEWED**
  • Seeds of nutmeg are used as spice, but they are also abused because of psychotropic effects described after ingestion of large doses. It was postulated that these effects could be attributable to metabolic formation of amphetamine derivatives from the main nutmeg ingredients elemicin (EL), myristicin (MY), and safrole (SA). In a case of a suspected nutmeg abuse, neither such amphetamine derivatives nor the main nutmeg ingredients could be detected in urine. The metabolites of EL, MY, and SA were identified using gas chromatography-mass spectrometry in rat urine and their presence in human urine of the nutmeg abuser was confirmed. The identified metabolites indicated that EL, MY, and SA were once and twice hydroxylated at the side chain. ... MY and SA were demethylenated and subsequently methylated. In the human urine sample, the following metabolites could be identified: O-demethyl elemicin, O-demethyl dihydroxy elemicin, demethylenyl myristicin, dihydroxy myristicin, and demethylenyl safrole. As in the human urine sample, neither amphetamine derivatives nor the main nutmeg ingredients could be detected in the rat urine samples.[Beyer J et al; Ther Drug Monit 28 (4): 568-75 (2006)] **PEER REVIEWED** PubMed Abstract
  • The aim of this work was to identify the form(s) of human liver cytochrome P450 (CYP) involved in the hepatic transformation of myristicin to its major metabolite, 5-allyl-1-methoxy-2,3-dihydroxybenzene. When microsomes prepared from different human liver samples were compared, the activity of 5-allyl-1-methoxy-2,3-dihydroxybenzene formation was well correlated (r(2)=0.87) with nifedipine oxidation (a marker of CYP3A4). With a microsomal sample having high CYP3A4 activity, microsomal oxidation of myristicin to the major metabolite (5-allyl-1-methoxy-2,3-dihydroxybenzene) was markedly inhibited by gestodene and ketoconazole, selective inhibitors of CYP3A enzymes, but not by any of several other P450 inhibitors. Antibodies raised against CYPs 3A4 and 1A2 could also inhibit the oxidation of myristicin, but antibodies recognizing other CYPs had no effect. The oxidation of myristicin to 5-allyl-1-methoxy-2,3-dihydroxybenzene was catalyzed by purified bacterial recombinant CYPs 3A4 and 1A2. These results provide evidence that CYP3A4 (and possibly other CYP3A enzymes) and CYP1A2 play roles in the formation of the major metabolite, 5-allyl-1-methoxy-2,3-dihydroxybenzene.[Yun CH et al; Toxicol Lett 137 (3): 143-50 (2003)] **PEER REVIEWED** PubMed Abstract
  • The effect of myristicin on the expression of liver cytochrome P450s and its mRNA levels was examined in rats. Treatment of rats with myristicin (i.p., 500 umol/kg) caused 2-20 fold increases in liver P450 1A1/2, 2B1/2, and 2E1 enzyme activities relative to controls. Immunoblot analysis using anti-rat liver P450 1A, 2B, and 2E1 showed that the increases in each of P450 protein levels by myristicin were consistent with those in enzyme activity levels. When increased levels of P450 mRNA by myristicin were examined by Northern blot analysis, levels of mRNA of P450 1A1/2 and 2B1/2 also increased. However, the level of P4502E1 mRNA did not increase. The total amount of spectrally detectable P450, also increased about 1.5-fold following treatment of myristicin. ...[Jeong HG, Yun CH; Biochem Biophys Res Commun 217 (3): 966-71 (1995)] **PEER REVIEWED** PubMed Abstract

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Tsca Test Submissions

  • None found

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Footnotes

1 Source: the NTP's CEBS database.

2 Source: the National Library of Medicine's Hazardous Substance Database, 02/28/2017.

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