Elemicin
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Elemicin is an allylbenzene essential oil found in large quantities in Zingiber niveum and an elemicin chemotype of Cinnamon myrtle essential oil, and also found in the essential oils of nutmeg, ginger grass, elemi and many other plants. It's believed to be partially responsible for the hallucinogenic effects of nutmeg.


Psychoactivity

Both elemicin and myristicin are often quoted as having "anticholinergic effects in humans". This appears to be very popular misinformation based on the study of the ingestion of nutmeg nuts in humans, not the study of elemicin and myristicin. This anticholinergic effect is likely attributed to the large content in nutmeg of the anxiogenic depressant trimyristin1. A vast search of several databases found absolutely no evidence of elemicin and myristicin being anticholinergic in humans. As of June 2015, there have been absolutely no studies published that evaluated the psychoactivity of elemicin in humans available on PubMed, or anywhere else that could be easily verified. All verifiable studies have been only animal studies, and they show that elemicin acts as a 5-HT2A agonist, a hallucinogen, just like LSD and mescaline[23].

In humans elemicin is metabolized to a wide array of mostly inactive metabolites. Elemicin is structurally similar to mescaline and under certain circumstances in animals it was proven to produce 3 different mescaline-like alkaloid metabolites in vivo after ingestion (proven by analyzing urine using gas-liquid chromatography and chemical ionization mass spectrometry).[9] One or more of these metabolites might occasionally occur in humans, and could potentially produce effects similar to those of mescaline.[9]

Elemicin itself is believed to be inactive. Activity is possibly caused by one of its alkaloid metabolites created in vivo in humans. In order to coerce the human metabolism of elemicin in favor of creating possible active alkaloid metabolites, specific enzymes may need to be inhibited and induced. The theory behind this process of enzyme manipulation is known as oilahuasca. In many people mescaline-like effects are not possible without the use of oilahuasca activation techniques. However some people are able to experience mescaline-like effects from ingesting elemicin without enzyme manipulation. Elemicin appears to be one of the most difficult allylbenzenes to achieve psychedelic effects from. Many people are unable to experience mescaline-like effects from elemicin even when using proper oilahuasca activation techniques (the reason for this is currently unknown).


5-HT2A Activation

Tests performed on rats administered elemicin intraperitoneally at 80mg/kg concluded that elemicin had distinct agonist effects on 5-HT2A showing symptoms in rats that are typical of psychedelics like LSD and mescaline.[23] This essentially proves that elemicin or one or more of it's metabolites can cause psychedelic effects, at least in rats. 5-HT2A is the main site responsible for psychedelic activity from drugs such as LSD and mescaline.

However, the study did not determine that elemicin itself caused the agonist effects on 5-HT2A. Because it is known that rats specifically metabolize elemicin into 3 known mescaline-like alkaloids[9], the actual agonist effects of elemicin on 5-HT2A could have been caused by one or more of the three mescaline-like alkaloid metabolites of elemicin, and not by elemicin itself.


Natural Sources

Plant Origin Part Contents of Essential Oil
Asarum insigne ? ? 5.38%[18]
Backhousia myrtifolia Hook (Cinnamon myrtle, elemicin chemotype) Eastern Australia leaf 91% [22]
Cinnamomum cecidodaphne Wood Unspecified [14]2
Cinnamomum cecidodaphne Fruit Rind 6.8% [14]
Cinnamomum cordatum Bark 2.5% [14]
Cinnamomum glanduliferum Unspecified [14]3
Cinnamomum glaucescens (Nees) Meissn Northeast India leaf 92.9%[24]
Collinsonia canadensis L. Plant 3.6% [13]
Cymbopogon martini var. sofia (Ginger Grass) India Grass 17.77% [6]
Cymbopogon microstachys (Hook.f.) Soenarko Grass 25.3% [7]
Cymbopogon pendulus (Nees ex Steud) Wats India Grass 53.7% [8]
Cymbopogon travancorensis Bor (Poaceae) Grass 17% [7]
Danish Tarragon Denmark Plant 1.23-10.31% [2]
Daucus carota L. subsp. carota Tunis, Tunisia ? 31.5 - 35.3%[17]4
Daucus glaber Forssk Northern Nile Delta stem 6.04%[19]
Daucus glaber Forssk Northern Nile Delta fruit 32.69%[19]
Daucus glaber Forssk Northern Nile Delta leaves 18.16%[19]
Daucus gracilis ? aerial parts 35.3%[25]
Elemi Philippines Resin 10.60% [3]
Etlingera brevilabrum Borneo Rhizomes 35.6%[21]
Mosla dianthera ? ? 16.51% [15]
Nutmeg India Nuts 2.4% [4]
Parsley Seed 2.64% [5]
Peucedanum pastinacifolium Golpaygan mountain air-dried aerial parts 31.1%[26]
Piper krukoffii North Brazil leaves 2.8% [16]
Piper krukoffii North Brazil twigs 3.0% [16]
Tarragon (Russian/Siberian) Latvia Plant 16.1-57.21% [2]
Zingiber niveum Mood & Theilade Laos Root and rhizome 60.97% [20]

Alkaloid Metabolites Created In Vivo

By analizing urine of animals using gas-liquid chromatography and chemical ionization mass spectrometry, these alkaloid metabolites have been detected in urine after ingesting elemicin.[9]

Similar corresponding alkaloids have also been detected after the ingestion of safrole.[10]

The exact mechanism that produces these alkaloids in vivo is current unknown.

Dimethylamine Metabolite

The dimethylamine metabolite created in vivo is known as 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)propan-1-one or 1'-oxoelemicin-DMA.

This alkaloid has an XLogP3-AA of 1.5.
3-%28dimethylamino%29-1-%283%2C4%2C5-trimethoxyphenyl%29propan-1-one-UP.gif

Piperidine Metabolite

The piperidine metabolite created in vivo is known as 3-piperidin-1-yl-1-(3,4,5-trimethoxyphenyl)propan-1-one or 1'-oxoelemicin-piperidine.

This alkaloid has an XLogP3-AA value of 2.3 allowing it to more easily cross the blood brain barrier compared to the dimethylamine form.

3-piperidin-1-yl-1-%283%2C4%2C5-trimethoxyphenyl%29propan-1-one.gif

Pyrrolidine Metabolite

The pyrrolidine metabolite created in vivo is known as 3-Pyrrolidin-1-yl-1-(3,4,5-trimethoxyphenyl)propan-1-one or 1'-oxoelemicin-pyrrolidine.

Elemicin-pyrrolidine-metabolite.gif

Non-Alkaloid Metabolites Found in Humans

In humans elemicin is completely metabolized. After the ingestion of elemicin, no quantity of elemicin is detectable in human urine.[1]

O-Demethyl dihydroxy elemicin

O-Demethyl_dihydroxy_elemicin.png

O-demethyl dihydroxy elemicin is detectable in human urine as the primary metabolite of elemicin following the ingestion of nutmeg.[1] This compound has no known route to alkaloid formation in animals or humans. It's not currently known for certain how this metabolite forms. It is likely a metabolite created directly after elemicin forms the metabolite methoxyeugenol.

Methoxyeugenol

Methoxyeugenol.gif

Methoxyeugenol (also known as O-demethyl elemicin) is detectable in human urine as a metabolite of elemicin.[1]

Because this metabolite is still an allylbenzene it might possibly be further metabolized in vivo into alkaloid metabolites, as has been proven for other allylbenzenes. The alkaloid forms of methoxyeugenol are theorized to produce stimulant effects similar to those of the presumed effects of alkaloid metabolites of eugenol. The predicted effects are possibly stimulation and strong tingling sensations, with no psychedelic action.

It's theorized that CYP3A4 or CYP2D6 might be responsible for creating this metabolite in humans.

1'-Hydroxyelemicin

1-Hydroxyelemicin.gif
1'-Hydroxyelemicin us usually found in it's conjugated form as 1'-hydroxyelemicin glucuronide created by glucuronosyltransferase (UGT) and as 1'-sulfoxyelemicin created by sulfotransferase (SULT).

1'-Hydroxyelemicin glucuronide

1-Hydroxyelemicin_Glucuronide.png

1'-Sulfoxyelemicin

1-sulfoxyelemicin.png

Elemicin's metabolite 1'-hydroxyelemicin is often reported to be created by CYP1A2 and CYP2A6 primarily, but there are other enzymes said to cause this metabolite to form, with some reports giving very conflicting information. It's possible that many other enzymes can produce this metabolite under certain conditions.

This inactive metabolite is detected in human and rat urine when pure elemicin is ingested. Curiously, 1'-hydroxyelemicin was found to be absent from urine samples when humans or rats ingested nutmeg containing elemicin. The reason for this is unknown but assumed to be related to possible enzyme inhibitors present in nutmeg which prevent the formation of this inactive metabolite of elemicin. [11]


Non-Alkaloid Metabolites Found In Animals

Small amounts of the epoxide of the 3-O-demethylated derivative of elemicin were identified in the urine.[12]

3-(3,4,5-Trimethoxyphenyl)propionic acid

3-(3,4,5-Trimethoxyphenyl)propionic_acid.png
The major metabolic reactions in rats of elemicin follow the cinnamoyl pathway or the epoxide-diol pathway. The cinnamoyl pathway gives 3-(3,4,5-Trimethoxyphenyl)propionic acid and its glycine conjugate as major metabolites.[12]

3-(3,4,5-trimethoxyphenyl)propane-1,2-diol

3-(3,4,5-Trimethoxyphenyl)propane-1,2-diol.png

The epixide-diol pathway gives 3-(3,4,5-trimethoxyphenyl)propane-1,2-diol as a major metabolite.[12]


Chemical Properties

PubChem Compound ID: 10248
Molecular Weight: 208.25364 [g/mol]
Molecular Formula: C12H16O3
XLogP3: 2.5
H-Bond Donor: 0
H-Bond Acceptor: 3
IUPAC Name: 1,2,3-trimethoxy-5-prop-2-enylbenzene
InChIKey: BPLQKQKXWHCZSS-UHFFFAOYSA-N
Canonical SMILES: COC1=CC(=CC(=C1OC)OC)CC=C
InChI: InChI=1S/C12H16O3/c1-5-6-9-7-10(13-2)12(15-4)11(8-9)14-3/h5,7-8H,1,6H2,2-4H3
Solubility: Several vendors state its soluble in chloroform and ethyl acetate, without giving references to these details.


See Also


References
1. Ther Drug Monit. 2006 Aug;28(4):568-75.
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. Beyer J, Ehlers D, Maurer HH; Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Saarland, Homburg (Saar), Germany; PubMed PMID: 16885726
2. Flavour Science: Recent Developments, edited by A. J. Taylor and D. S. Mottram, The Royal Society of Chemistry, Cambridge, 1996. Special Publication No. 197. Pages 50-51, Tables 2-3 . ISBN 0–85404–702–6.
3. B. M. Lawrence. P&F 9, No. 4, 35, (1984) Allured Publishing Corporation, Carol Stream, IL.
4. G. R. Mallavarapu and S. Ramesh, Composition of essential oils of nutmeg and mace. J. Med. Arom. Plant Sci., 20, 746-748 (1998). P&F 23, No. 5, 52, (2000) Allured Publishing Corporation, Carol Stream, IL.
5. Y.H. Kim, K. S. Kim and C. K. Hong, Volatile Components of Parsley Leaf and Seed (Petrselinum crispum). J. Korean Agric. Chem. Soc., 33, 62-67 (1990). P&F 16, No. 5, 75, (1991) Allured Publishing Corporation, Carol Stream, IL.
6. 2010 Product CG data from www.aromaticsinternational.com
7. Essential Oil-Bearing Grasses. The genus Cymbopogon. Edited by Anand Akhila. CRC Press 2009. ISBN: 978-0-8493-7857-7
8. Composition of Cymbopogon pendulus (Nees ex Steud) Wats, an Elemicin-rich Oil Grass Grown in Jammu Region of India. Journal of Essential Oil Research. Volume 9, Issue 5, 1997.
9. E.O. Oswald, L. Fishbein, B.J. Corbett, M.P. Walker. Metabolism of naturally occuring propenylbenzene derivatives : II. Separation and identification of tertiary aminopropiophenones by combines gas—liquid chromatography and chemical ionization mass spectrometry. Journal of Chromatography A, Volume 73, Issue 1, 8 November 1972, Pages 43-57 (web link)
PubMed PMID 5081654 (Download Attached PDF Document)
11. Safety evaluation of certain food additives, World Health Organization, 2009, Page 370.
12. Xenobiotica. 1980 May;10(5):371-80.
Metabolism of alkenebenzene derivatives in the rat. III. Elemicin and isoelemicin. Solheim E, Scheline RR; PubMed PMID 7415220
13. Shakhnoza S. Azimova, Anna I. Glushenkova, Valentina I. Vinogradova;
Lipids, Lipophilic Components and Essential Oils from Plant Sources; Yunusov Institute of Plant Substances, Tashkent, Uzbekistan; Springer, 2012; ISBN 0857293230, 9780857293237
14. Cinnamon and Cassia: The Genus Cinnamomum
K . Nirmal Babu , P . N . Ravindran , and M . Shylaja; CRC Press 2003; Print ISBN: 978-0-415-31755-9; eBook ISBN: 978-0-203-59087-4
15. Chemical compositions and anti-influenza activities of essential oils from Mosla dianthera.
Wu QF, Wang W, Dai XY, Wang ZY, Shen ZH, Ying HZ, Yu CH. PubMed PMID 22193174
16. Antioxidant capacity and larvicidal and antifungal activities of essential oils and extracts from Piper krukoffii.
da Silva JK, Andrade EH, Kato MJ, Carreira LM, Guimarães EF, Maia JG. PubMed PMID 21941916
17. Essential oils of Daucus carota subsp. carota of Tunisia obtained by supercritical carbon dioxide extraction.
Marzouki H, Khaldi A, Falconieri D, Piras A, Marongiu B, Molicotti P, Zanetti S. PubMed PMID 21299130
18. [Analysis of the chemical constituents of volatile oil from Asarum insigne by GC-MS].
[Article in Chinese] Qu WY, Tan ZW, Yu AN, Quan JP. PubMed PMID 21137366
19. Essential oil of Daucus glaber Forssk.
Mansour el-SS, Maatooq GT, Khalil AT, Marwan el-SM, Sallam AA. PubMed PMID 18998404
20. Essential Oil Compositions from Root and Rhizome of Zingiber niveum Mood & Theilade from Laos
Orawan Theanphong, Thaya Jenjittikul and Withawat Mingvanish; Biological and Chemical Research, Volume 2015, 157-160; Science Signpost Publishing; April 25, 2015 (Download PDF)
21. Essential Oil Composition, Cytotoxic and Antibacterial Activities of Five Etlingera Species from Borneo
Charles Santhanaraju Vairappan, Thilahgavani Nagappan and Kishneth Palaniveloo; Laboratory of Natural Products Chemistry, Institute for Tropical Biology and Conservation, Universiti Malaysia Sabah, Jalan UMS, 88400 Kota Kinabalu, Sabah, Malaysia; Natural Product Communications; 2012 Vol. 7 No. 2 239 -242
22. Food Safety of Australian Plant Bushfoods
M.P. Hegarty, E.E. Hegarty; Plantchem Pty Ltd and R.B.H. Wills; Centre for Advancement of Food Technology and Nutrition, University of Newcastle; 2001; ISBN 0 642 58250 5, ISSN 1440-6845
23. Evaluation of 5-HT2A Receptor Agonistic Property of Elemicin
Maria Gracia N. Cervantes, Sharmane Corina C. Co, Edward Bryan P. King, Mark Kevin L. Lacro, Sean Jose Manuel G. Lansang, Kimberly An Y. Lim, Jovencio G. Apostol; Journal of the Philippine Pharmacists Association; April 24, 2014; Volume 3, Number 1; SMX Convention Center Davao (Download PDF)
24. Leaf Essential Oils of Cinnamomum glanduliferum (Wall) Meissn and Cinnamomum glaucescens (Nees) Meissn
Akhil Baruah & Subhan C. Nath; Journal of Essential Oil Research; Volume 18, 2006 - Issue 2
25. Chemical analysis, antimicrobial and anti-oxidative properties of Daucus gracilis essential oil and its mechanism of action
Meriem El Kolli, Hocine Laouer, Hayet El Kolli, Salah Akkal, Farida Sahli; Asian Pacific Journal of Tropical Biomedicine; Volume 6, Issue 1, January 2016, Pages 8–15
26. Evaluation of anti-spasmodic effect of Peucedanum pastinacifolium extracts on rat's ileum
Hassan Sadraei, Gholam Reza Asghari, and Monireh Motaqedi; Res Pharm Sci. 2015 Nov-Dec; 10(6): 497–503.; PMCID: PMC4698860

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