The Sassafras Tree and Designer Drugs: from Herbal Tea to Ecstasy

The Sassafras Tree and Designer Drugs From Herbal Tea to Ecstasy Larry G. French St. Lawrence University, Canton, NY 13617 The following account reviews some aspects of the phyto- The sassafras tree ranges from Maine across southeast- chemistry of Sassafras albidum. Its origin is found in a ern Ontario to Michigan and south to Florida and Texas. special topic lecture that I insert into the presentation of Its preferred habitat is thickets, roadsides, and old fields amine chemistry in the introductory organic course. Adis- where it typically attains heights of 20-50 feet. Perhaps its cussion of clandestine drug synthesis provides a far more most unusual characteristic is its multivariate foliage. Un- interesting venue for presenting methodology for amine lobed, single- and triple-lobed leaves grow concurrently on synthesis than the catalog approach that prevails in most the same twig. All tissue from the plant (most notably the textbooks. In the course of gathering material for this pres- root bark) emits a pronounced aromatic aroma. entation, I became aware of the significance of the sassafras tree in the underground production of methylenedi- Of the Tree that Is Brought from the Florida, Whlche Is oxymethamphetamine (MDMA, ecstasy, XTC, Adam) (11) Called Sassafras a controversial designer drug. After presenting some basic So begins an extensive treatise on the remarkable curative botanical information, a brief historical overview of me- powers associated with this materia medica in Joyfull Newes dicinal interest in material from the sassafras tree will be out of the Newe Founde World, the 1577 translation of the given. This will be followed by a discussion of the chemical first European pharmacopeia to catalog materials from the composition and utilization of the derived essential oil. The second portion of the paper. examines the chemistry of amphetamines and their rl:inrlestint, production. Finr~lly, the desicner- drue.-, F'cstasv.", will be discussed in detail rind its link with oil of sassafras explored. Interwoven into this story will be a look at the mechanisms through which the federal government designs, enforces, and interprets legis- lation for chemical substance regulation. Botanical Considerations Taxonomically, Sassafms albidum is a member of the fam- ily Lauraceae, the laurels, which comprises approximately 40 penera and is represented bv more than 2000 species. Num- bered among this group arethe camphor laureiand the cin- namon trees of the Orient and the West Indian avocado pear. Distribution of the Lauraceae is primarily throughout tmpi- cal southeastern Asia and Central and South America. In addition to sassafras, the California laurel, Umbellularia cali- fomica, the spicebush, Lindem benzoin, and redbay, Persea borbonia, are native to North America. Figure 1. Sassafras oil principal cornponenfs. 484 Journal of Chemical Education piperonal (6) (heliotropin), widely employed in fine per- fumes, can be prepared most economically from safrole via ~~5yJ-base-catalyzed alkene isomerization to isosafrole (5) followed 0 ' by oxidative cleavage (Fig. 2). Prior to 1942, the United States 5 relied primarily on oil of camphor, available from the Asian camphur laurel, to meet its requirements (br safrole With the 101 ,O./yCHO entrnnn! of thc I:niwd Stater into tht, Stwnd \i'orld War a a) 1)HBrZ) aniline new source had to be secured. At this point, "Brazilian sassa- b) KOHIC2H50H fras oil" emerged as an important commodity Originally, the [O] 1) HCQHIH202 2) H5106 some of this oil was incorrectly identified as Ocotea cymbar- or ~02if.CdHgOHN205inter alia 6 ium. The actual source is Ocotea ~retiosawhile the oil from the previously mentioned specie is devoid of safrole (4). Figure 2. Heliotropin synthesis. Food and Drug Administration studies conducted in 1960 indicated that safrole is a weak liver carcinogen in rats. The Americas authored eight years earlier by the Span- ish physician, Nicholas Monardes (I).Withamedical practice established in the coastal city of Seville, Mon- ardes had access to herbal materials carried back to Soain bv the Conauistadors. and he freelv. exoeri-. P-450 mented with them in the treament ol'his patients. In NADPH il hook dcscribine the utditv ol'such exotic and dutrious therapeutic age& as ''oyle of the fig tree of hell", '%load stone", and "dragon's blood", the sassafras tree is afforded substantial attention; (only the chapter on tobacco is longer). The litany of infirmities and ailments said to respond to treatment with aqueous infu- sions of the root bark includes fever, liver discomfort, * headache, bronchial congestion, stomach ailments, sulfotransferase kidney stones, gout, toothache, arthritis, constipation, and infertility Early accounts of New World explorers unfailingly cite enormous populations of the tree all along the eastern seaboard. Second only to tobacco, sassafras root bark became a principal export to England com- mencing with the first permanent British settle- ment at Jamestown. Vireinia. Alexander Brown in TI,? GWIZSISoffhe i/n~ttv?.~fnfcsdocuments a letter sent from the Councd in Virginia to Enghnd in dun+! 1607, in which a potentiallydetrimental preoccupa- Figure . Mechanism of chemical carcinogenesis by safrole. tion with root gathering is noted. The letter relates "our easiest and richest commodity being saxifrax roots were gathered up by the sailors with loss and spoil of many of our tools and with drawing our men from our labor" (2). By the 1820's, scientific scrutiny had voided the majority of the therapeutic claims indicated earlier. However, the dried root bark remained official in the US. Pharmacopeia through 1926 where it is indicated that the material has useful antiseptic properties, can induce a beneficial in- crease in sweating or be used to mask the taste or odor of other unpalatable medicines. Even today, sassafras tea produced by steeping the young roots remains a fixture in Appalachian folk culture where it enjoys repute as a "spring tonic" and "blood thinner" (3). Sassafras Oil North American sassafras oil consists of the volatile, steam distillable components of the roots and mot bark of S. albidum. It is a yellow to amber liquid with a melting point of P6 "C. Its olfactory quality has been described as sweet- spicy, fresh, slightly campboraceous and woody-floral with a fresh-peppery topnote. It possesses a unique sweet, woody flavor and was widely employed to flavor toothpastes and soft drinks, particularly root beer, prior to 1961. The principal chemical constituent of the oil (~80%)is safrole (1)(4-allyl-1,2-methylenedioxybenzene). Other sig- nificant components that have been identified include eugenol(2), camphor (3),and a-pinene (4) (Fig. 1). Enormous quantities of safrole are used in technical per- Figure 4. Some phenethyl- and phenyl isopropylene incorporating fuming to scent soaps and commercial cleansers. In addition, drugs of abuse. Volume 72 Number 6 June 1995 485 Food Additives Amendment (1958) to Table 1. Controlled Substance Scheduling Criteria the Federal Food, Drug and Cosmetic Act includes the much discussed De- Schedule Abuse Accepted Medical Dependence Creation Examples laney Clause (51, which stipulates that Potential Use in the (current level) no known carcinogenic substance can be United States utilized as a food additive. In another FDA study, safiole levels in the range of I high no heroin, LSD, C26.7 ppm were detected in various root marihuana, mescaline beer samples (6).The use of safrole and II high yes severe psychological cocaine, methadone, sassafras oil as flavoring agents was pro- or physical amphetamine scribed on December 2,1960. Dihydrosa- 111 <I&II yes modllow psych. or barbiturates, anabolic &ole and isosafrol were also banned (71. P~YS. steroids Further regulation was promulgated to IV < 111 address the commercial sale of herbal yes limited psych. or phys. diazepine, tranquilizers teas containing ground sassafras root v < IV yes limited psych. or phys. pharmaceutical bark (8)and a 1976 article in The Journal mixtures with narcotic Dain killers of the American Medical Association ~ointedto the daneers associated with sa- Bole exposure th_fough the ingestion of sassafras tea (9). Safrole is also present in lower concentra- cleosides have resulted in the isolation and charac- tions in many spices includim- anise, basil, nutmeg,- mace, and terization of N-alkylated guanosine and adenosine ad- black ' ducts whose formation can be rationalized in terms of SN1 Evidence for the mechanism of safrole carcinogenicity (Fig. and SN~-reactions(11). 3) has accumulated that im~licatesa two-step metabolic acti- vation of safrole, the precakinogen, into a highly electrophilic Ecstasy--Sassafras Oil in the Clandestine Drug Lab sulfuric acid mouoester ultimate carcinogen (10). The pro- Compounds incorporating the phenethylamine pharma- posed bioactivation pathway. proceeds. by. way. of enzymatic cophore have been popular drugs of abuse and targets for bxidltion at the wadily oxidized secondary benzylieall~licprr underground synthetic chemists for over 50 years (Fig. 4). sition. Sulfate donation affords the mtrnt rlwtm~hii~!.1-sul- The prototypical representatives of this class, metham- fooxvsafrole (7),a compound that can be viewed asa biokemi- phetamine (8) and amphetamine (9), are central uewous cal equivalent of the &fonate esters employed by synthetic system psychomotor stimulants. Current legitimate medi- oreanic chemists to activate alcohol substrates toward substi- cal utilization of amphetamines is limited

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