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Myristicin

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Myristicin
Clinical data
Other names3-methoxy-4,5-methylenedioxy-allylbenzene; 5-methoxy-3,4-methylenedioxy-allylbenzene
Dependence
liability		None
Addiction
liability		Low
Routes of
administration		Oral (nutmeg); Insufflated (pure myristicin)
Legal status
Legal status
Identifiers
  • 7-Allyl-5-methoxy-1,3-benzodioxole
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.009.225 Edit this at Wikidata
Chemical and physical data
FormulaC11H12O3
Molar mass192.214 g·mol−1
3D model (JSmol)
  • O1c2cc(cc(OC)c2OC1)C\C=C
  • InChI=1S/C11H12O3/c1-3-4-8-5-9(12-2)11-10(6-8)13-7-14-11/h3,5-6H,1,4,7H2,2H3 checkY
  • Key:BNWJOHGLIBDBOB-UHFFFAOYSA-N checkY
  (verify)

Myristicin is a naturally occurring compound (a benzodioxole) found in common herbs and spices, such as nutmeg.[1][2] It is an insecticide, and has been shown to enhance the effectiveness of other insecticides.[1][3]

When ingested, myristicin may produce hallucinogenic effects,[1][4] and can be converted to MMDMA in controlled chemical synthesis.[5] It interacts with many enzymes and signaling pathways in the body,[6][7] and may have dose-dependent cytotoxicity in living cells.[6] Myristicin is listed in the Hazardous Substances Data Bank.[1]

Uses

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Isolated myristicin has proven an effective insecticide against many agricultural pests, including Aedes aegypti mosquito larvae, Spilosoma obliqua (hairy caterpillars),[8] Epilachna varivestis (Mexican bean beetles), Acyrthosiphon pisum (pea aphids), mites, and Drosophila melanogaster (fruit flies). Myristicin was shown to be an effective repellent, and to cause mortality via direct and systemic exposure. It also displayed a synergistic effect when administered to insects in combination with existing insecticides.[3]

The structure of myristicin closely resembles that of amphetamine compounds, and it is capable of producing psychotropic effects similar to MDMA compounds.[1] Because of this, it can be used in synthetic synthesis to create amphetamine derivatives, and create designer drugs like MMDMA that are similar in structure and effect to MDMA.[5] Out of the common spices that contain myristicin, nutmeg has a high relative concentration of the compound,[2] and therefore is used to exploit the effects of myristicin.[1][2]

Furthermore, myristicin interferes with multiple signaling pathways and enzyme processes in the body.[1][6][7]

Sources of myristicin

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Myristicin can be found in the essential oil of nutmeg, black pepper, kawakawa,[9] and many members of the Umbelliferae family, including anise, carrots, parsley, celery, dill,[10] and parsnip.[3]

Trace amounts have also been isolated from a variety of plant species including Ridolfia segetum (harvest fennel), species of the Oenanthe genus (water dropworts), species of the Lamiaceae family (mint, sage, or deadnettle families), Cinnamomum glanduliferum (Nepal camphor tree),[11] and Piper mullesua ("Hill Pepper").[8]

Depending on the conditions of growth and storage of the plant, a high quality nutmeg (Myristica fragrans) seed can contain up to 13 mg of myristicin per 1 gram.[12]

Physiological effects

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Psychoactive effects

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At a minimum dose of about 5 grams of nutmeg powder, symptoms of nutmeg intoxication can begin to emerge.[10] Nutmeg intoxication may produce dizziness, drowsiness, and confusion, although in higher amounts, it may have effects similar to other deliriants due to its hallucinogenic effects.[1][13]

Pharmacology

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Myristicin is additionally known to be a weak inhibitor of monoamine oxidase (MAO), an enzyme in humans that metabolizes neurotransmitters (for example, serotonin, dopamine, epinephrine, and norepinephrine). It lacks the basic nitrogen atom that is typical of MAO inhibitors (MAOIs), potentially explaining a weaker inhibitory effect.[14]

While smaller concentrations of MAOIs may not cause problems, there are additional warnings regarding drug interactions. Those taking antidepressants that are MAOIs (such as phenelzine, isocarboxazid, tranylcypromine or selegiline[15]) or taking selective serotonin reuptake inhibiting (SSRI) antidepressants should avoid essential oils rich in myristicin, such as that of nutmeg or anise.[16]

Metabolites

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Brief overview of synthesis and metabolism[5]

Metabolism of myristicin yields 3-methoxycatechol[1] and enzymatically forms 5-allyl-1-methoxy-2,3-dihydroxybenzene (oxidation of the methylenedioxy group). Myristicin is also formed into demethylenylmyristicin, dihydroxymyristicin, and elemicin is formed into O-demethylelemicin, O-demethyldihydroxyelemicin, and safrole.[1][citation needed]

Chemistry

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Structural comparison of myristicin, amphetamine and derivatives

With a chemical structure resembling amphetamines and other precursors, myristicin can also be used to synthesize illicit hallucinogenic drugs. Under controlled conditions, myristicin isolated from nutmeg oil can be converted into MMDMA, a synthetic "designer drug" amphetamine derivative that is less potent than MDMA but produces comparable stimulant and hallucinogenic effects.[5]

Myristicin is insoluble in water, and soluble in ethanol, ether, and benzene.[1]

Toxicity

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In laboratory studies, myristicin is cytotoxic. Specifically, it stimulates cytochrome c release, which activates caspase cascades and induces early apoptosis in the cells.[6] Myristicin has also been shown to inhibit cytochrome P450 enzymes, which are responsible for metabolizing a variety of substrates including hormones and toxins, allowing these substrates to accumulate.[1][7]

The effects of nutmeg consumed in large doses are attributed mostly to myristicin: 1–7 hours following ingestion, symptoms include disorientation, giddiness, stupor, and stimulation of the central nervous system leading to euphoria.[1][2] Also occurring are mild to intense hallucinations (similar to those induced by deliriants: walls and ceiling glitching or breathing), disorientation to time and surroundings, dissociation, feelings of levitation, loss of consciousness, tachycardia, weak pulse, anxiety, and hypertension.[1] Symptoms of nutmeg intoxication further include nausea, abdominal pain, vomiting, minor to severe muscle spasms (severe in extreme overdose), headache, dryness of mouth, mydriasis or miosis, hypotension, shock, and potentially death.[1][2][4]

Myristicin poisoning can be detected by testing levels of myristicin in the blood.[17] There are no known antidotes for myristicin poisoning, and treatment focuses on symptom management and potential sedation in cases of extreme delirium or aggravation.[1][18]

References

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  1. ^ a b c d e f g h i j k l m n o p "Myristicin". PubChem, US National Library of Medicine. 13 May 2023. Retrieved 14 May 2023.
  2. ^ a b c d e "Nutmeg". Drugs.com. 21 November 2022. Retrieved 14 May 2023.
  3. ^ a b c Lichtenstein EP, Casida JE (1963). "Naturally Occurring Insecticides, Myristicin, an Insecticide and Synergist Occurring Naturally in the Edible Parts of Parsnips". Journal of Agricultural and Food Chemistry. 11 (5): 410–415. Bibcode:1963JAFC...11..410L. doi:10.1021/jf60129a017.
  4. ^ a b Stein U, Greyer H, Hentschel H (April 2001). "Nutmeg (myristicin) poisoning—report on a fatal case and a series of cases recorded by a poison information centre". Forensic Science International. 118 (1): 87–90. doi:10.1016/s0379-0738(00)00369-8. PMID 11343860.
  5. ^ a b c d Clark CR, DeRuiter J, Noggle FT (1 January 1996). "Analysis of 1-(3-Methoxy-4,5-Methylenedioxyphenyl)-2-Propanamine (MMDA) Derivatives Synthesized from Nutmeg Oil and 3-Methoxy-4,5-Methylenedioxybenzaldehyde". Journal of Chromatographic Science. 34 (1): 34–42. doi:10.1093/chromsci/34.1.34.
  6. ^ a b c d Lee BK, Kim JH, Jung JW, Choi JW, Han ES, Lee SH, et al. (May 2005). "Myristicin-induced neurotoxicity in human neuroblastoma SK-N-SH cells". Toxicology Letters. 157 (1): 49–56. doi:10.1016/j.toxlet.2005.01.012. PMID 15795093.
  7. ^ a b c Yang AH, He X, Chen JX, He LN, Jin CH, Wang LL, et al. (July 2015). "Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2". Chemico-Biological Interactions. 237: 133–40. Bibcode:2015CBI...237..133Y. doi:10.1016/j.cbi.2015.06.018. PMID 26091900.
  8. ^ a b Srivastava S, Gupta MM, Prajapati V, Tripathi AK, Kumar S (2001). "Insecticidal Activity of Myristicin from Piper mullesua". Pharmaceutical Biology. 39 (3): 226–229. doi:10.1076/phbi.39.3.226.5933. S2CID 83947896.
  9. ^ Vennell, Robert (2019). The Meaning of Trees. Auckland: HarperCollins Publishers. pp. 24–27. ISBN 978-1-77554-130-1. LCCN 2019403535. OCLC 1088638115. Wikidata Q118646408.
  10. ^ a b Rahman NA, Fazilah A, Effarizah ME (2015). "Toxicity of Nutmeg (Myristicin): A Review". International Journal on Advanced Science, Engineering and Information Technology. 5 (3): 212–215. CiteSeerX 10.1.1.920.6379. doi:10.18517/ijaseit.5.3.518.
  11. ^ Shulgin AT (April 1966). "Possible implication of myristicin as a psychotropic substance". Nature. 210 (5034): 380–384. Bibcode:1966Natur.210..380S. doi:10.1038/210380a0. PMID 5336379. S2CID 4189608.
  12. ^ Nowak J, Woźniakiewicz M, Gładysz M, Sowa A, Kościelniak P (2015). "Development of Advance Extraction Methods for the Extraction of Myristicin from Myristica fragrans". Food Analytical Methods. 9 (5): 1246–1253. doi:10.1007/s12161-015-0300-x.
  13. ^ Roeters van Lennep JE, Schuit SC, van Bruchem-Visser RL, Özcan B (January 2015). "Unintentional nutmeg autointoxication". The Netherlands Journal of Medicine. 73 (1): 46–48. PMID 26219944.
  14. ^ Truitt EB, Duritz G, Ebersberger EM (March 1963). "Evidence of monoamine oxidase inhibition by myristicin and nutmeg". Proceedings of the Society for Experimental Biology and Medicine. 112 (3): 647–650. doi:10.3181/00379727-112-28128. PMID 13994372. S2CID 44996415.
  15. ^ "Monoamine oxidase inhibitors (MAOIs)". Mayo Clinic. 12 September 2019.
  16. ^ Tisserand R, Young R (2014). "Kinetics and dosing". Essential Oil Safety. pp. 39–67. doi:10.1016/b978-0-443-06241-4.00004-7. ISBN 978-0-443-06241-4.
  17. ^ Baselt RC (2008). Disposition of toxic drugs and chemicals in man (8th ed.). Foster City, CA: Biomedical Publications. ISBN 978-0-9626523-7-0. OCLC 243548756.[page needed]
  18. ^ Demetriades AK, Wallman PD, McGuiness A, Gavalas MC (March 2005). "Low cost, high risk: accidental nutmeg intoxication". Emergency Medicine Journal. 22 (3): 223–225. doi:10.1136/emj.2002.004168. PMC 1726685. PMID 15735280.

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