The Basics:   

    Safrole is an natural constituent of a number of plant oils and spices from around the world such as nutmeg, mace, cinnamon, anise, black pepper and sweet basil.

    It's density is greater than water so it would generally sit as a fraction (layer) below water apon distillation rather than on top as most other oils will.

Availability:

Traditional Use:

    There are many reports of the worlds native peoples and developed civilizations using safrole containing preparations for therapeutic uses, including both Australian aboriginals and the more relatively recent settlement/immigrating populations.

    Some of the ways both native aboriginals and other cultures have used these plants include making an infusion such as tea, crushing the leaves followed by inhalation, and burning the plant pieces for smoke.

    Australian Aborgnals used some of the plants listed below in preparations for eye, skin and body washes and as a counter irritant while in.the desert among other places.

    It is worth noting here that an infusion or tea/brew may lead to the loss via "distillation" (evaporation) of safrole and other essential oils in the steam if much steam is produced for an extended period in an unsealed/uncovered vessel.. 

    Another issue here with this preparation method could be the possible extraction of plant chemicals, such as alkaloids from the source material. Which in certain cases including some of the plants mentioned here, have a relatively specific enough toxicity which has been reported to lead to side-effects and/or possible health complications. This would generally not be an issue if making a steam distilled oil. 

    Sassafras (an american safrole containing tree) was used by Native Americans for many purposes, primarily for infections, gastrointestinal problems and as a spring blood tonic. It is still used today in many parts of the Appalachian Mountains, where the root is locally gathered.

    Topically, sassafras oil could relieve the pain and inflammation of insect bites. It may have some anti-infective properties, which might also help to prevent infection of bites and minor skin rashes. And has such been used as a topical antiseptic, a pediculicide (head and body lice treatment) and washes used to soothe the eyes.

    It has also been used by alternative medicine for treating high blood pressure, rheumatism, arthritis, gout, menstrual problems, colds, flu, and bronchitis, as a diuretic, for urinary tract disorders and kidney problems. Also as a liniment, and the treatment of bruises, swellings and skin complaints. 

Modern Use:

A Commercial History (of the north American Sassafras albidum):

    How it all is supposed to have happened: Internet sources (which may or may not be accurate but are often cross-derived and, therefore, are often at least mercifully consistent) have it that Europeans exploring North America in the early 1500’s (probably the Spanish in Florida?) observed the medicinal use of (Sassafras albidum) by Native Americans, but thought that the plant was the East Indian cinnamon tree. This is understandable because, at the time, they thought that they were in India. Whatever, Sir Walter Raleigh, a one-time favorite of Queen Elizabeth I who was later executed for treason, is said to have created a major stir when he brought (Sassafras albidum) back to England from the “Virginia Colony”, in the very early 1600’s.

    Europeans got the idea that (Sassafras albidum) was a “wonder drug” that could cure almost anything, even the dreaded “new” disease syphilis which had appeared in Europe shortly after Christopher Columbus’ first return voyage. Even better yet, the belief somehow developed that (Sassafras albidum) would retard old age. (Sassafras albidum) does seem to have antibacterial and antiviral properties that are good, for example, at warding off colds.

    So, by the mid-1600’s, (Sassafras albidum) became the Americas’ number two export to Europe; number one being tobacco, and number three probably being cane sugar products such as molasses and rum. (The sugar cane itself probably originated in Polynesian but was definitely imported to Jamaica by Christopher Columbus in the 1500’s). 

    Following its stunning European debut, various parts of the (Sassafras albidum) tree came to be widely used in food and medicine. Sassafras oil, extracted from the root bark, was used to flavor many things. Root beer was named for the beverage’s major flavoring agents which, you guessed it, were the roots of our friend (Sassafras albidum), combined with fermented molasses (from cane sugar). People also ingested gallons of sassafras tea, believed to be healthful as well as delicious. (Sassafras albidum) leaves were ground up and widely sold as “filè” powder, a major Cajun seasoning and thickening agent.

        This all went on for some time until its use was prohibited.

Chemotypes:

    As with many plants containing essential oils, there can exist multiple "chemotypes" within a species. The composition of an oil extracted can vary depending on many factors resulting in plants of the same "cataloged" species and living in that same area having differing levels of constituents.

    The term chemotype is used to refer to a "sub-group" of a species which illustrates similar constitution.

    Apart from variation in chemotypes, essential oil yield and composition and can vary due to factors such as:

        time of day harvested
        climate and rainfall
        growing conditions
        flowering and seeding
        part of plant extracted
        health and age of plant

    When summarising the reports outlined below, generally only the chemotype with the highest levels of safrole is mentioned, so there quite often is results for the same "species"from a differing region for example that yield nearly no safrole.

Toxicity:

    An awfully lot of reports have been released containing results relating towards the toxic properties of safrole.  Mostly supported by grants from various Foundations and Institutes. This has sparked some controversy and debate among various circles, as some of these provided the needed stepping stone to what has become a worldwide outlawing of safrole. These early experiments simply involved exposing various animals and isolated biological cells to enough safrole to give a result that would prove its toxicity. Most compounds both organic and not are "toxic" at high enough levels... even water. And what we may be seeing here in the form of "toxicity" may just be an over-amplified expression of what could have been and may still be an important part of human evolution. And that it could be seen as responsible for such serious and detrimental traits may simply be a result of how far out of context and exaggerated the potential levels of exposure have been taken. The human body and all living things have been seen and commented on as having astounding potential for adaptability and resilience, if not just for their survival amongst such a modernly polluted environment, full of things with well recorded toxicities and dangers that have been recorded on par and beyond that of safrole. Perhaps its banning and disregard came so easily to those responsible under the light that it had no

    Interestingly enough though, allot of the new reports being released, which are  more forward thinking and at home with a "ying yang" perspective on the human multi-verse are those coming out of china. The "some could say" mekka of medicinal herbal practice. Very much connected with a long traditional and possibly still modern day use of safrole containing plants.

Here is some extracts from just a few:

• Firstly here's a concise summary of type: "alarmist research", from a report on the safety of the presence of safrole in food ingredients by the "Scientific Committee on Food" (part of the European Commission):
  

    An oral LD50 has been reported to be 1950 mg/kg bw for rats and 2350 mg/kg bw for mice. Compared with ...

• The following gives a simple summary of the commonly accepted process safrole undergoes inside the body leading to damage:
  

    Safrole is metabolized in the liver mainly by two pathways, one of these producing  1-hydroxysafrole which has been shown to be the preponderant proximate carcinogenic metabolite, which, following a further biotransformation can bind covalently to cellular DNA. -Toxicology Letters 75 (1995) 201-207
   

• Here's an example of some "new wave" research attaining to monitor safrole's presence via subtler internal response's rather than the extreme end case scenario of cancer and death:

    Safrole was an inhibitor of human (cytochrome P450) enzymes primarily responsible for the oxidation (breaking down) of both internal (endogenous) and external (exogenous) chemicals including steroids, drugs, and chemical carcinogens.
    Methylenedioxybenzenes are the substrates, inducers, and inhibitors of P450. These P450 forms are responsive to the inductive and inhibitory effects of xeno-biotics including plant constituents. -Food and Chemical Toxicology 43 (2005) 707-712
 

• This next one is interesting as it points towards evidence of anti-oxidants playing a role in reducing and blocking potential damage, and that the lack of these due to depletion within a bodies natural healing/growth/connection systems, sheer overwhelment and/or non-function may be what then leads to the more serious side of safrole's catalytic potential: (once again, we have the more comprehensive investigation of the subtleties)
  

    Safrole is a weak hepatocarcinogen, and its carcinogenic effect has been linked to the formation of stable safrole-DNA adducts. Results demonstrate that safrole has the potential to induce oxidative damage in vivo, and this damage may be blocked by antioxidant detoxification systems. This safrole induced oxidative damage may be involved in the hepatocarcinogenic effects of safrole. The most effective antioxidant tested was the precursor of glutathione, NAC (N-acetylcysteine)  which acts as a cysteine prodrug and can enhance GSH synthesis, a molecule which plays a central role in the elimination of electrophilic xenobiotics and in the defense of the cell against oxidative stress. The generation of oxidative stress has been linked to chemical carcinogenis.
     In vitro, safrole can be biotransformed to a redox-active o-quinone which may generate ROS (reactive oxygen species) and forms the basis of safrole-induced oxidative damage. This may explain why NAC was most efficient in reducing both of the safrole-induced oxidative markers in vivo since o-quinone is scavenged efficiently by GSH.
    Two other antioxidants tested which reduced the safrole-induced formation of biomarkers LHP(representative of either a less sever injury, or an early step in ROS-mediated safrole-induced hepatic injury.) but not 8-OH-dG (correlated to cyctotoxicity) where: vitamin E and deferoxamine, yet for a shorter time than NAC could.
      This study suggested that safrole caused lipid per-oxidation and oxidation DNA damages in rat liver. In addition, this study also demonstrated that this damage was rapidly repaired within 15 days after safrole treatment. -Food and Chemical Toxicology 37 (1999) 697-702
     

• The following is an inspiring illustration of the bodies dynamicity, such that we have catalytic cell transformation into neurons rather than self-destruction if the levels of in this case "safrole oxide" are low enough. (safrole oxide has piperonyl and epoxy structures, which are important in many compounds with physiological activity.)
  

    Low concentrations of safrole oxide have been shown to induce HUVEC (human umbilical vein vascular endothelial cell) to phenomenonly make an irreversible switch from one type of already differentiated cell to another type of normal differentiated cell in postnatal life.
    In this case a transdifferentiation to neuron-like cells via the depression of intracellular ROS (reactive oxygen species) levels, which act as a intracellular messengers in signal transduction pathways.
    Recent studies show that productions of ROS lead to cell death or promote dysfunction. And that elevating ROS levels triggered apoptosis (natural self destruction) in HUVEC's.
    Thus illustrating a critical balance between the synthesis and destruction of ROS is likely to regulate the balance among the cellular process of proliferation , differentiation, and apoptosis.
    In addition, recently, ROS was suggested as inducers of neuronal differentiation, and some findings indicate that HUVEC's have the potential to differentiate into smooth muscle-like cells.
    It has also been reported that some antioxidants can induce MSC's (marrow stromal cells) and HUVEC's to differentiate into neurons too. -Biochimica et Biophysica Acta 1763 (2006) 247-253

    (L. S. Gold, et.al., Science, vol. 258, pg 261, 9 Oct 92, "Rodent Carcinogens: Setting Priorities");

    Comparing instances of the cancer development response levels in rats to a life time of daily being fed synthetic or/vs natural carcinogens found from various sources, (including safrole in root beer). 

    A relative likely-hood of carcinogenicity can be illustrated such that 1 bottle (375ml) of traditional root beer containing 6.6mg of safrole has the equivalence to:

Plant Sources:

Atherosperma moschatum

Cinnamomum baileyanum

Cinnamomum camphora

 
Cinnamomum laubatii

 
Cinnamomum oliveri

 “The bark gave 0.4% oil, of which 25% was safrole.”
 Identification by fractional distillation followed by b.p. , m.p. and density tests.
(Hargreaves, J.Chem.Soc. 1916, 109, 751)

Doryphora aromatica

 “The bark gave 0.3% of oil, consisting chiefly of safrole at 95%.”
 Identification by fractional distillation followed by b.p. , m.p. and density tests.
(Jones and Smith, Proc.Roy.Soc.Queensland, 1923, 35, 61-3 via P.E.O.R., 16, 179)  - (This abstract was read from a scan of a book quoting the original report)

Doryphora sassafras

 “The leaves yielded from 0.1 to 0.85% oil, of one district had 60-65% safrole and the other district had 30% safrole.”
 Identification by fractional distillation followed by b.p. , m.p. and density tests.
(J and Proc. Roy. Soc. N.S.W. 1921, 55, 270) 

“The fresh leaves had yields of 0.8 - 2% (14.71% safrole), 0.3% for the bark (14.88% safrole), and seed oil containing 13.04% safrole.”
Analysis by GC and GC/MS.
(J. Essent. Oil. Res. 5, 581-586, 1993)

 
Eremophila longifolia

"Steam distillation of the leaves gave an aromatic oil in 5.8 % yield. Various levels of safrole content between collection groups where recorded via fractional distillation and gas chromatography at (i) 72%, (ii) 90% mean / 93% best, (iii) 37%, and (iv) 0%."
(Australian Journal of Chemistry. 1961;14:663-664)
 

Zieria (Rutaceae)

•  Essential Oil constituents of the genus Zieria:

Analysis by GC and GC/MS.
(Phytochemistry, vol. 26, no. 6, 1673-1686, 1987.)

 
“Essential oil yields from the genus Zieria showed wide inter- and infraspecific variation (Fig. 1). Yields ranged from 0.1% and less for Z. involucrata and Z. oeronicea to 8.3 and 9.1% for Z. smithii sens. strict. and Z. grantdata, respectively. Variation within the one form was as great as 0.5-8.3 % for Z. smithii sens. strict. Some correlations between oil yield and chemistry were evident.”

 


Subgroup 3.2: species yielding safrole-rich oils (% safrole fraction)

species (# samples analysed)	mean	range	s.d.
Z. arborescens sens. strict. (2)	14.1	13.1-15.1	1.4
Z. arborescens “c” form (3)	80.8	56.8-94.1	20.8
Z. smithii sens. strict. (5)	71.3	65.8-81.2	6.1
Z. smithii “c” form (4)	56.6	52.5-59.1	2.8
Z. smithii “f” form (1)	41.4	n/a	n/a
Z. sp.aff. smithii (5)	92.3	90.0-95.5	2.3

 

•   Zieria (Rutaceae): a systematic and evolutionary study:

 “Steam-distillation of the foliage of subsp. Smithii resulted in high oil yields (0.5-8.3%, mean 3.1%), rich in either methyl eugenol, elemicin or safrole. The methyl eugenol rich samples occur throughout the species distribution in NSW; the elemicin rich samples occur in the coastal ranges from the Blue Mountains to south-eastern Queensland and the safrole rich samples are known from the coastal ranges in the south of NSW and from the south-eastern and central Queensland (South and Armstrong 1982, 1987).”

• The Essential Oils of Zieria Smithii (Andrews) and its varias forms, Part II, 1950:

(reprinted from the Proc. Roy. Soc. N.S.W., vol. LXXXIV, 196-201.)
Identification by fractional distillation followed by b.p. , m.p. and density tests.

“The yields of oils varied from 0.5% to 1.2%, calculated on the freshly cut leaves and terminal branchlets.”

• In relation to an anonymous addition to the online article titled "the safrole faq" :

>>
It would seem this person most likely collected a chemo-type containing little or no safrole... :)

Further Resources:

The Australian Virtual Herbarium

A searchable database of recorded botanical plant collections'.

Ideal for getting approximate locations of where certain plants may be growing.
Though alot of the coordinates are very old and have low resolution of definity.
Not much work to download search results to a gps, but more involved in actually getting there to find nothing but a bare paddock or an airport...

Australian Tropical Rain Forest Plants (cdrom)

http://www.publish.csiro.au/nid/18/pid/3400.htm

An interactive identification and information system for 2154 species of trees, shrubs and vines of northern Australian rain forests.

Internet Forums

Information disseminates, finding's posted and general discussion.


Library's: Public, TAFE, University, Institute 

Access journals online or via inter-library loans, as well as read books.

Herbarium, Nurseries and Gardens 

Get yourself a fresh oxygen fix, while checkin' out actual specimens both alive and dried, or having your own collections/photos identified.

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