Myristicin

Myristicin is a naturally occurring compound found in common herbs and spices, the most well known being nutmeg. It is an insecticide, and has been shown to enhance the effectiveness of other insecticides in combination.[1] Myristicin is also a precursor for substituted amphetamine derivative compounds structurally related to MMDA and MDMA; it is believed to be metabolized in the liver into MMDA, but unlikely since no MMDA was found in urine, in the body it produces hallucinogenic effects,[2] and can be converted to MMDMA in controlled chemical synthesis.[3] It interacts with many enzymes and signaling pathways in the body,[4][5] is cytotoxic to living cells,[4] and may also have chemoprotective properties.[6]

Myristicin
Clinical data
Other names3-methoxy-4,5-methylenedioxy-allylbenzene; 5-methoxy-3,4-methylenedioxy-allylbenzene
Routes of
administration		Oral
Legal status
Legal status
  • In General Unscheduled
Identifiers
IUPAC name
  • 7-Allyl-5-methoxy-1,3-benzodioxole
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.009.225
Chemical and physical data
FormulaC11H12O3
Molar mass192.214 g·mol−1
3D model (JSmol)
SMILES
  • O1c2cc(cc(OC)c2OC1)C\C=C
InChI
  • 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 Y
  • Key:BNWJOHGLIBDBOB-UHFFFAOYSA-N Y
  (verify)

Uses

Isolated myristicin has proven an effective insecticide against many agricultural pests, including Aedes aegypti mosquito larvae, Spilosoma obliqua (hairy caterpillars),[7] Epilachna varivestis (Mexican bean beetles), Acyrthosiphon pisum (pea aphids), mites, and Drosophila melanogaster (fruit flies). Myristicin was shown to be an effective repellant, and to cause mortality via direct and systemic exposure. It also displayed a synergistic effect when administered to insects in combination with existing insecticides.[1]

The structure of myristicin closely resembles that of amphetamine compounds, and it is capable of producing psychotropic effects similar to MDMA compounds. 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.[3] Out of the common spices that contain myristicin, nutmeg has the highest relative concentration of the compound. Therefore, it is used most frequently to isolate myristicin or exploit its effects.

Structural Comparison of Amphetamine and Derivatives

Furthermore, myristicin interferes with multiple signaling pathways and enzyme processes in the body.[4][5] It is toxic to cells and also may have chemoprotective properties, making it an interesting topic for further pharmacological or therapeutic research.[6] [See Pharmacology, Toxicity]

Sources

Myristicin can be found in nutmeg, black pepper, and many members of the Umbelliferae family including anise, carrots, parsley, celery, dill,[8] and parsnip.[1]

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),[9] and Piper mullesua ("Hill Pepper").[7]

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,[10] or 1.3%. In the isolated essential oils, myristicin constitutes on average 13.24% of nutmeg oil, 6.32% of parsley leaf oil, 7.63% of dill herb oil, and 0.18% of celery seed oil.[6]

Physiological effects

Psychoactive effects

The psychotropic potential of myristicin is believed to emerge when it is metabolized into MMDA, an amphetamine derivative that is reported to have a more potent hallucinogenic effect than mescaline.[2] There is more research needed on the exact mechanism of action of myristicin in the body.

Brief overview of chemical synthesis: myristicin to MMDMA[3]

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.[3] A 400 mg dose of myristicin has been shown to produce “mild cerebral stimulation” in 4 out of 10 human subjects. Myristicin is most commonly consumed in nutmeg, and 400 mg would be contained in approximately 15 g of nutmeg powder. However, at a minimum dose of about 5 g of nutmeg powder, symptoms of nutmeg intoxication can begin to emerge, indicating the interaction of other compounds contained in nutmeg.[8] elemicin and safrole are also components of nutmeg that, while at lower concentrations than myristicin, are thought to contribute to the hallucinogenic and physiological symptoms of nutmeg intoxication.[11]

Toxicity

Myristicin has been proven to be cytotoxic, or toxic to living cells. Specifically, it stimulates cytochrome c release, which activates caspase cascades and induces early apoptosis in the cells.[4]

In human neuroblastoma SK-N-SH cells, myristicin led to apoptosis and observable morphological changes, as well as chromatin condensation and DNA fragmentation.[4] This indicates a definite cytotoxic effect, and a potential neurotoxic effect that requires further investigation.

Myristicin has also been shown to inhibit cytochrome P450 enzymes in humans, which is responsible for metabolizing a variety of substrates including hormones and toxins, allowing these substrates to accumulate.[5] This can compound its own toxicity and/or lead to increased bioavailability of other substances, which can lower the threshold for overdose from other drugs that may be in the body.

The effects of nutmeg consumed in large doses are attributed mostly to myristicin, where 1–7 hours following ingestion symptoms include disorientation, giddiness, stupor, and/or stimulation of the central nervous system leading to euphoria, intense hallucinations that alter one's orientation to time and surroundings, feelings of levitation, loss of consciousness, tachycardia, weak pulse, anxiety, and hypertension. Symptoms of nutmeg intoxication further include nausea, abdominal pain, vomiting, dryness of mouth, mydriasis or miosis, hypotension, shock, and potentially death.[2]

Myristicin poisoning can be detected by testing levels of myristicin in the blood.[12] There are currently no known antidotes for myristicin poisoning, and treatment focuses on symptom management and potential sedation in cases of extreme delirium or aggravation.[13]

Pharmacology

Myristicin is soluble in ethanol and acetone, but insoluble in water[14]

Myristicin is additionally known to be a weak inhibitor of monoamine oxidase (MAO), a liver enzyme in humans that metabolizes neurotransmitters (e.g., serotonin, dopamine, epinephrine, and norepinephrine). It lacks the basic nitrogen atom that is typical of MAO inhibitors (MAOIs), potentially explaining a weaker inhibitory effect.[15]

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[16]) or taking selective serotonin re-uptake inhibiting (SSRI) antidepressants should avoid essential oils rich in myristicin, such as that of nutmeg or anise.[17]

Myristicin also has potential chemoprotective properties. In mouse liver and small intestine mucosa, myristicin induced higher levels of glutathione S-transferase (GST), which catalyzes a reaction that detoxifies activated carcinogens. This indicates that myristicin may act as an inhibitor of tumorigenesis.[6] It is still unknown how much the tendency of myristicin to induce apoptosis in cells contributes to its chemoprotective abilities.

References
  1. 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. doi:10.1021/jf60129a017.
  2. 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.
  3. Clark CR, DeRuiter J, Noggle FT (1996-01-01). "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.
  4. 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.
  5. 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. doi:10.1016/j.cbi.2015.06.018. PMID 26091900.
  6. Zheng GQ, Kenney PM, Lam LK (1992). "Myristicin: a potential cancer chemopreventive agent from parsley leaf oil". Journal of Agricultural and Food Chemistry. 40 (1): 107–110. doi:10.1021/jf00013a020.
  7. 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.
  8. 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.
  9. Shulgin AT (April 1966). "Possible implication of myristicin as a psychotropic substance". Nature. 210 (5034): 380–4. Bibcode:1966Natur.210..380S. doi:10.1038/210380a0. PMID 5336379. S2CID 4189608.
  10. 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.
  11. Gunaydin, Mucahit; Tatli, Ozgur; Altuntas, Gurkan; Uslu, Zakire; Ozsahin, Faruk; Beslioglu, Necla (29 June 2017). "Nutmeg Intoxication Associated with Consumption as a Stupefacient". Journal of Emergency Medicine Case Reports. 8 (3): 64–65. doi:10.5152/jemcr.2017.1820.
  12. 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.
  13. Demetriades AK, Wallman PD, McGuiness A, Gavalas MC (March 2005). "Low cost, high risk: accidental nutmeg intoxication". Emergency Medicine Journal. 22 (3): 223–5. doi:10.1136/emj.2002.004168. PMC 1726685. PMID 15735280.
  14. "Myristicin - LKT Laboratories, Inc". 2012-03-28. Archived from the original on 2012-03-28. Retrieved 2020-05-05.
  15. 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): 647–50. doi:10.3181/00379727-112-28128. PMID 13994372. S2CID 44996415.
  16. "Monoamine oxidase inhibitors (MAOIs)". Mayo Clinic. 12 September 2019.
  17. Tisserand, Robert; Young, Rodney (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.
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