:Myristicin

Isolated myristicin has proven an effective insecticide against many agricultural pests, including Aedes aegypti mosquito larvae, Spilosoma obliqua (hairy caterpillars), 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.

The chemical structure of myristicin is similar to some amphetamine compounds, and it may be capable of producing psychotropic effects. Normal levels of intake of myristicin from spices in food is unlikely to cause these effects. Myristicin can be used in the chemical synthesis of amphetamine derivatives such as the designer drug MMDMA that is similar in structure and effect to MDMA. Out of the common spices that contain myristicin, nutmeg has a high relative concentration of the compound, and therefore is used to exploit the effects of myristicin.

Furthermore, myristicin interferes with multiple signaling pathways and enzyme processes in the body.

Myristicin can be found in the essential oil of nutmeg, black pepper, kawakawa,{{cite q|Q118646408|pp=24-27}} and many members of the Umbelliferae family, including anise, carrots, parsley, celery, dill,{{cite journal| vauthors = Rahman NA, Fazilah A, Effarizah ME | date=2015 |title=Toxicity of Nutmeg (Myristicin): A Review |journal=International Journal on Advanced Science, Engineering and Information Technology |volume=5 |issue=3 |pages=212–215 |doi=10.18517/ijaseit.5.3.518 |doi-access=free |citeseerx=10.1.1.920.6379 }} and parsnip.

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),{{cite journal | vauthors = Shulgin AT | title = Possible implication of myristicin as a psychotropic substance | journal = Nature | volume = 210 | issue = 5034 | pages = 380–384 | date = April 1966 | pmid = 5336379 | doi = 10.1038/210380a0 | bibcode = 1966Natur.210..380S | s2cid = 4189608 }} and Piper mullesua ("Hill Pepper").{{cite journal| vauthors = Srivastava S, Gupta MM, Prajapati V, Tripathi AK, Kumar S |date=2001|title=Insecticidal Activity of Myristicin from Piper mullesua |journal=Pharmaceutical Biology|language=en|volume=39|issue=3|pages=226–229|doi=10.1076/phbi.39.3.226.5933 |s2cid=83947896}}

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.{{cite journal| vauthors = Nowak J, Woźniakiewicz M, Gładysz M, Sowa A, Kościelniak P |date=2015|title=Development of Advance Extraction Methods for the Extraction of Myristicin from Myristica fragrans |journal=Food Analytical Methods|language=en|volume=9|issue=5|pages=1246–1253|doi=10.1007/s12161-015-0300-x |doi-access=free}}

At a minimum dose of about 5 grams of nutmeg powder, symptoms of nutmeg intoxication can begin to emerge. 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.{{cite journal | vauthors = Roeters van Lennep JE, Schuit SC, van Bruchem-Visser RL, Özcan B | title = Unintentional nutmeg autointoxication | journal = The Netherlands Journal of Medicine | volume = 73 | issue = 1 | pages = 46–48 | date = January 2015 | pmid = 26219944 }}

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 monoamine oxidase inhibitors (MAOIs), potentially explaining a weaker inhibitory effect.{{cite journal | vauthors = Truitt EB, Duritz G, Ebersberger EM | title = Evidence of monoamine oxidase inhibition by myristicin and nutmeg | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 112 | issue = 3 | pages = 647–650 | date = March 1963 | pmid = 13994372 | doi = 10.3181/00379727-112-28128 | s2cid = 44996415 }}

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{{cite web |title=Monoamine oxidase inhibitors (MAOIs) |url=https://www.mayoclinic.org/diseases-conditions/depression/in-depth/maois/art-20043992 |website=Mayo Clinic |date=12 September 2019 }}) or taking selective serotonin reuptake inhibiting (SSRI) antidepressants should avoid essential oils rich in myristicin, such as that of nutmeg and anise.{{cite book |doi=10.1016/b978-0-443-06241-4.00004-7 |chapter=Kinetics and dosing |title=Essential Oil Safety |year=2014 | vauthors = Tisserand R, Young R |pages=39–67 |isbn=978-0-443-06241-4 |chapter-url=https://books.google.com/books?id=DbEKAQAAQBAJ&pg=PA39 }}

Metabolism of myristicin yields 3-methoxycatechol and enzymatically forms 5-allyl-1-methoxy-2,3-dihydroxybenzene (oxidation of the methylenedioxy group). Myristicin is also transformed into demethylenylmyristicin, dihydroxymyristicin, and elemicin is transformed into O-demethylelemicin, O-demethyldihydroxyelemicin, and safrole.{{cn|date=May 2023}}

There has been speculation that myristicin might be converted into the psychedelic MMDA, but this has not been demonstrated in humans.{{CitePiHKAL}}{{cite journal | vauthors = Al-Rawi SS, Ibrahim AH, Ahmed HJ, Khudhur ZO | title = Therapeutic, and pharmacological prospects of nutmeg seed: A comprehensive review for novel drug potential insights | journal = Saudi Pharm J | volume = 32 | issue = 6 | pages = 102067 | date = June 2024 | pmid = 38690209 | pmc = 11059288 | doi = 10.1016/j.jsps.2024.102067 | url = }}{{cite journal | vauthors = Braun U, Kalbhen DA | title = Evidence for the biogenic formation of amphetamine derivatives from components of nutmeg | journal = Pharmacology | volume = 9 | issue = 5 | pages = 312–316 | date = 1973 | pmid = 4737998 | doi = 10.1159/000136402 | url = }}{{cite journal | vauthors = Beyer J, Ehlers D, Maurer HH | title = Abuse of nutmeg (Myristica fragrans Houtt.): studies on the metabolism and the toxicologic detection of its ingredients elemicin, myristicin, and safrole in rat and human urine using gas chromatography/mass spectrometry | journal = Ther Drug Monit | volume = 28 | issue = 4 | pages = 568–575 | date = August 2006 | pmid = 16885726 | doi = 10.1097/00007691-200608000-00013 | url = }}

However, two nitrogen-containing metabolites of myristicin have been identified in the urine of rats and guinea pigs following oral or intraperitoneal administration. The major basic ninhydrin-positive urinary metabolite of myristicin in the rat is 3-piperidyl-1-(3′methoxy-4′,5′-methylenedioxyphenyl)-1-propanone, while the major basic ninhydrin-positive urinary metabolite of the guinea pig is 3-pyrrolidinyl-1-(3′methoxy-4′,5′-methylenedioxyphenyl)-1-propanone.{{cite journal | vauthors = Oswald, Fishbein, Corbett, Walker | title = Urinary excretion of tertiary amino methoxy methylenedioxy propiophenones as metabolites of myristicin in the rat and guinea pig | journal = Pharmacology | volume = 244 | issue = 2 | pages = 322-328 | date = 1971 | pmid = 5125615 | doi = 10.1016/0304-4165(71)90233-9 | url = }} Equivalent nitrogen-containing metabolites have also been identified for safrole{{cite journal | vauthors = Oswald, Fishbein, Corbett, Walker | title = Identification of tertiary aminomethylenedioxy-propiophenones as urinary metabolites of safrole in the rat and guinea pig | journal = Pharmacology | volume = | issue = 2 | pages = | date = 1971 | pmid = | doi = 10.1016/0304-4165(71)90208-X | url = }} and elemicin,{{cite journal | vauthors = Oswald, Fishbein, Corbett, Walker | title = Metabolism of naturally occuring propenylbenzene derivatives: II. Separation and identification of tertiary aminopropiophenones by combines gas—liquid chromatography and chemical ionization mass spectrometry. | journal = Pharmacology | volume = | issue = 2 | pages = | date = 1971 | pmid = 5081654 | doi = | url = }} including the dimethylamine, piperidine and pyrrolidine forms.

File:Myristicin to MMDMA Synthesis.svg

File:Amphetamine_derivative_and_myristicin_structures.svg

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.

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

In laboratory studies, myristicin is cytotoxic. Specifically, it stimulates cytochrome c release, which activates caspase cascades and induces early apoptosis in the cells. 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.

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. 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. 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.

Myristicin poisoning can be detected by testing levels of myristicin in the blood.{{cite book| vauthors = Baselt RC |title=Disposition of toxic drugs and chemicals in man|date=2008|publisher=Biomedical Publications|isbn=978-0-9626523-7-0|edition=8th|location=Foster City, CA|oclc=243548756}}{{pn|date=September 2021}} There are no known antidotes for myristicin poisoning, and treatment focuses on symptom management and potential sedation in cases of extreme delirium or aggravation.{{cite journal | vauthors = Demetriades AK, Wallman PD, McGuiness A, Gavalas MC | title = Low cost, high risk: accidental nutmeg intoxication | journal = Emergency Medicine Journal | volume = 22 | issue = 3 | pages = 223–225 | date = March 2005 | pmid = 15735280 | pmc = 1726685 | doi = 10.1136/emj.2002.004168 }}

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Category:Plant toxin insecticides

Category:Monoamine oxidase inhibitors

Category:Phenylpropenes

Category:O-methylated phenylpropanoids

Category:O-methylated natural phenols

Category:Benzodioxoles

Category:Allyl compounds

Category:Pyrogallol ethers

Category:Plant toxins