Safrole
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Safrole is the main component of sassafras essential oil and a minor component of nutmeg essential oil. It is an allylbenzene. Used without proper Oilahuasca Activation techniques it only produces mild sedative effects. It has produced psychedelic effects in a few individuals when used with proper Oilahuasca Activation techniques.


Natural Sources

Plant Origin Part Contents of Essential Oil
Piper auritum Panama Leaves 70% [9]
Sassafras albidum Root Bark 80-85%

Effects on Cytochrome P450 Enzymes

In vitro tests determined that safrole potently inhibited human CYP1A2, CYP2A6, and CYP2E1 with IC50 values less than 20 microM. CYP2D6 and CYP3A4 were moderately inhibited.[11]


The Carcinogenicity Myth

No evidence exists for sassafras tea or safrole ingestion causing cancer in humans.

In humans, the close amphetamine relative of safrole, MDMA has been shown to protect against cancer formation.[6]

The very closely related allylbenzene myristicin has also shown anti-cancer properties. A 65% inhibition of the tumor multiplicity in the lung was observed as the result of treatment of myristicin in rats.[5]

Animal in vitro tests determined safrole to act as a possibly weak carcinogen, but human tests have not shown this to be the case. Animal tests showing potential carcinogenicity were enough for it to be banned for use in food in the USA, despite no evidence of human carcinogenicity.

The main metabolite of safrole leading to possibly carcinogenicity in rats is 1-hydroxysafrole after SULT metabolism to its sulfate conjugate. However, this metabolite has not been detected in humans after the oral ingestion of safrole using the same tests that found it occurred in rats.[7]

Its believed that the banning of safrole, despite a total lack of evidence of it being carcinogenic in humans, and it's close relatives actually showing anti-cancer effects in vivo, was a move to prevent the sale of safrole because of its use in the manufacture of the illegal drug MDMA.


Non-Alkaloid Metabolites Found in Humans

These metabolites are created in vivo by humans after ingestion of safrole. Human P450 enzymes are responsible for their creation.

Hydroxychavicol

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Hydroxychavicol (also known as 1,2-dihydroxy-4-allylbenzene) is the main metabolite of safrole found in human urine (up to 65%) after the ingestion of pure safrole.[7]

This metabolite is an allylbenzene and could potentially be converted to an alkaloid in vivo in humans producing possible activity. The predicted action of this compound as an alkaloid is stimulation without psychedelic activity because it lacks a methoxy group on the benzene ring.

Eugenol

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The allylbenzene eugenol occurs as a very minor metabolite in human urine after ingestion of pure safrole.[7]

Chavibetol

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The allylbenzene chavibetol (also known as 1-methoxy-2-hydroxy-4-allylbenzene) occurs as a very minor metabolite in human urine after ingestion of pure safrole.[7]

Non-Alkaloid Metabolites Found in Rats

1'-Oxosafrole

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1'-Oxosafrole is a metabolite made from safrole's metabolite 1'-hydroxysafrole.

This metabolite, although not yet found to occur in human urine, is presumed to be created in humans, but rapidly metabolized.

Human liver produces 1'-oxosafrole as a primary detoxification route of 1'-hydroxysafrole in vitro. On the contrary, in rats this is a minor metabolite of 1'-hydroxysafrole.[12]

1'-Oxosafrole is believed to produce adducts with primary amines leading to alkaloids with possible psychedelic activity.[8]

Hydroxychavicol

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Hydroxychavicol is the main metabolite of safrole found in rat urine after the ingestion of pure safrole.[7]

Eugenol

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The allylbenzene eugenol occurs as a very minor metabolite in rat urine after ingestion of pure safrole.[7]

Chavibetol

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The allylbenzene chavibetol (also known as 1-methoxy-2-hydroxy-4-allylbenzene) occurs as a very minor metabolite in rat urine after ingestion of pure safrole.[7]

1'-Hydroxysafrole

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Tests performed in rats found this metabolite occurred in urine after oral ingestion of safrole as a minor metabolite.[7] This metabolite could not be detected in urine samples of human test subjects after the ingestion of pure safrole.[7]

According to one human in vitro study the P450 enzymes CYP2C9 and CYP2E1, and to a lesser degree CYP2A6 and CYP2D6, play a role in oxidizing the allylbenzene safrole into 1'-hydroxysafrole.[10] It's possible that this metabolite is created in humans but metabolized completely shortly after creation.

3'-Hydroxyisosafrole

Tests performed in rats found this metabolite occurred in urine after oral ingestion of safrole as a minor metabolite, but not in human urine.[7]


Alkaloid Metabolites

Safrole is proven to produce dimethylamine, piperidine, and pyrrolidine alkaloids as very minor metabolites after oral or topical use. They are believed to be adducts that form from 1'-oxosafrole. They are presumed to be psychoactive, and to contribute to the effects of nutmeg as sassafras.[8]

Dimethylamine Adduct

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3-N,N-Dimethylamino-1-(3,4-methylenedioxyphenyl)-1-propanone is the dimethylamine adduct of 1'-oxosafrole.

Piperidine Adduct

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3-Piperidino-1-(3,4-methylenedioxyphenyl)-1-propanone is the piperidine adduct of 1'-oxosafrole.

Pyrrolidine Adduct

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3-Pyrrolidino-1-(3,4-methylenedioxyphenyl)-1-propanone is the pyrrolidine adduct of 1'-oxosafrole.

Chemical Properties

Compound ID: 5144
Molecular Weight: 162.1852 [g/mol]
Molecular Formula: C10H10O2
Appearance: Colorless or pale yellow oil[4]; colorless liquid, prisms, or crystals[3]
Boiling Point: 234.5 deg C[2]
Melting Point: 11.2 deg C[2]
Solubility: Soluble in alcohol; slightly soluble in propylene glycol; insoluble in water, glycerol[4]; Miscible with chloroform, ether[1]
XLogP3: 3
IUPAC Name: 5-prop-2-enyl-1,3-benzodioxole
InChI: InChI=1S/C10H10O2/c1-2-3-8-4-5-9-10(6-8)12-7-11-9/h2,4-6H,1,3,7H2
InChIKey: ZMQAAUBTXCXRIC-UHFFFAOYSA-N
Canonical SMILES: C=CCC1=CC2=C(C=C1)OCO2


See Also


Bibliography
1. O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1493
2. Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000, p. 3-67
3. Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 10th ed. Volumes 1-3 New York, NY
John Wiley & Sons Inc., 1999., p. 3175
4. Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY
John Wiley & Sons, Inc. 1997., p. 980
5. Carcinogenesis. 1992 Oct;13(10):1921-3.
Inhibition of benzo[a]pyrene-induced tumorigenesis by myristicin, a volatile aroma constituent of parsley leaf oil; Zheng GQ, Kenney PM, Zhang J, Lam LK; LKT Laboratories, Inc., Minneapolis, MN 55413. PubMed PMID: 1423855
6. Chem Biol Drug Des. 2010 Nov;76(5):425-32. doi: 10.1111/j.1747-0285.2010.01027.x. Epub 2010 Sep 28.
Computational studies on effects of MDMA as an anticancer drug on DNA. Riahi S, Eynollahi S, Ganjali MR; Institute of Petroleum Engineering, University of Tehran, Iran. PubMed PMID: 20880019
7. Toxicology. 1977 Feb;7(1):69-83.
Absorption, metabolism and excretion of safrole in the rat and man. Benedetti MS, Malnoë A, Broillet AL; PubMed PMID: 14422
8. E.O. Oswald, L. Fishbein, B.J. Corbett, M.P. Walker. Identification of tertiary aminomethylenedioxy-propiophenones as urinary metabolites of safrole in the rat and guinea pig. Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 230, Issue 2, 23 February 1971, Pages 237-247 (web link)
9. Mahabir P. Gupta , Tomás D. Arias , Norris H. Williams , R. Bos , D. H. E. Tattje;
Safrole, the Main Component of the Essential Oil from Piper auritum of Panama; J. Nat. Prod., 1985, 48 (2), pp 330–330 DOI: 10.1021/np50038a026 Publication Date: March 1985
10. Safety evaluation of certain food additives; Prepared by the Sixty-ninth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA); World Health Organization, Geneva, 2009; ISBN: 978-92-4-166060-0
11. Inhibition of human cytochrome P450 enzymes by the natural hepatotoxin safrole.
Ueng YF, Hsieh CH, Don MJ. PubMed PMID: 15778010
12. Physiologically based biokinetic (PBBK) modeling of safrole bioactivation and detoxification in humans as compared with rats.
Martati E, Boersma MG, Spenkelink A, Khadka DB, van Bladeren PJ, Rietjens IM, Punt A. PubMed PMID: 22588462
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