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 sassa- fras 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 ad- dition 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 ail- ments 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. al- bidum. 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
486 Journal of Chemical Education a) Acz0, pyridine b) CH~COZH,ThOz, combustion tube c) CH~CHZNOZ,mBuNHz d) Fe(O), HCI e) CH~COZCHZCH~,CH3CHzO- f) HzS04 g) CHZ(COZCHZCH~)Z,Mg(O), CH~CHZOH h) H30+
Figure 6. Methods used in illicit P2P production.
Attempts to attack the substance abuse problem in the raided labs (Fig. 6) (13).Four of these routes involve one United States by legal proscriptionbegan in earnest with omni- carbon homoloeations of uhenvlacetic acid or an eauiva- bus drug legislation, the Comprehensive Drug Abuse Control lent. The otherrelies on aAKno&enagel condensatio; with Act of 1970 (16). Included amongits many provisions wereregu- benzaldehvde and subseauent dissolvine metal reduction lations for controlling the possession, manufacture, and distri- of the vinGlnitro compound so obtained. >eon the ranks of bution of controlled substances. AclassiIication scheme consist- scheduled substances exvanded as precursors of Drecur- ing of five schedules was established and populated with sors were added. ~ethamihetamineproduction viareduc- rouddv 150 comwunds and mixtures (Table 1).Provision was tion of ephedrine extracted from commercial cold medica- made allow the Attorney General to amend the list through tions also gained in favor. Law enforcement was further addition, deletion. or rescheddiw. Scheddiw a previously un- daunted by the movement of production facilities into ru- cuntrnlld compound would wqu& tmth a publichea~~gand a ral northern border states. ~kmotelocales, meager DEA findiw hy the Sccretan ofHealth, Education, and \Velfaw\now resources, and access to precursor materials smuggled ~caltl,Ad Human ~e-mces,qounded upon a .ioentific review across the border from Canada, where chemical control that spoke to the need ~IJre~wlatr: rht: suhstancf and the appm measures are less mature thanin the United States, create oriettn(,.siof the xheduline level. msw,as toensur~that clini- an ideal environment for this criminal enterorise (17).. . hinvestigationof potentia?ly wf%lpsychoactive agents would Another option once available to the illegal producer not be impeded unnecessarily seeking to remain a step ahead of the law is the synthesis It also was apparent that an effective national drug control of "deiigner drugs", 'term that probably suggests a policy would have to limit access to chemicals utilized in the greater degree of chemical and pharmacological prowess synthesis or processing of drum of abuse. Accordingly, so- on the Dart of the criminal than is merited and one that called immediate che&cals, those that by simple glamo&es potentially deadly substances. Designer drugs chemical conversion could be transformed into controlled sub- are svnthesized comoounds. at one time exemut from DEA stances, could be scheduled at or aho\.e the level of rhr psy- control because of their unique chemical structures, that choactwe substance itself: tbxulntions werc r;ubwquently im- are often marketed aggressively. They closely resemble oosed on commerce involvine two additional cateeories- of previously popular and scheduled drugs (controlled sub- chemicals. Precursor chemical;. are initial starting materials stance analom. CSA's) (18) and are seldom. if ever, novel for multi-steu svntheses of controlled substances (an examule compounds. ~r;:~aratiwmutes and biologic& activity pro- is anthranilik ahd, used in methaqualone synthesis).~sseniial files normally are to be found in the medicinal chemistw chemicals are defined as solvents. reacenta... . or catalvsts re- literature. potential target compounds have been identi- quired for the production of schedulrd drugs iex:im&s in- fied in reviews such as "Drugs of Abuse in the Future" (19) clude acetic anhvdridr nnd 2-hut anon(!^ lhnsactims involv- and "Future Synthetic Drugs of Abuse" (20).Additional pa- ing these categories of chemicals are subject to strict pers are available that include surveys of published proce- record-keeping provisions, restricted in sale to clearly identi- dures for the synthesis of controlled substances and poten- fied and authorized parties and subject to volume limitations. tial CSA's, some of which include evaluation of their In February 1980, P2P was classified as a schedule I1 relative merits as well as adantations to simolifv. "" svnthetic substance due to its status as a immediate precursor routes, eliminate special equipment requirements or sub- chemical in amphetamine syntheses. Not surprisingly, the stitute vet unreeulated startine.. materials. In manv cases combination of a large profit motive and ethical shortfall detaild t,xpt!rimt:ntal infurmation is prnided. The hallu- bred meat in~enuitvon the part of clandestine drue lab cinogen. ohencvclidine (14) sneel dust,. functioned as a opera'tors. In Volume 72 Number 6 June 1995 487 tanyl (lW, potent synthetic heroin surrogates (an- algesics) (Fig. 7), as well as on derivatives of the stimulant and hallucinogenic amphetamines. MDMA (ll), a designer amphetamine, initially noted in the recreational drug-using population in 1970, saw a surge of popularity in the mid 1980's (21). Certainly not a new compound, MDMA had first been described in the German patent litera- ture in 1912 where its synthesis from safrole and evaluation as an anoretic agent are described (22). In the mid 1980's, a small group of psychothera- pists became intrigued with this compound's seemingly unique psychopharmacological profile and began to make it available to their patients. Supplies of the compound came exclusively from underground sources. Although scientifically sound, controlled experiments were not conducted (nor were relevant toxicological studies), a body of anecdotal evidence accumulated that suggested to some that this agent might be a singularly effec- tive chemical adjunct in psychotherapy and repre- sent the first example of a new class of drugs dubbed entactogens (23). Subjective effects re- ported by users included a sense of euphoria, in- creased empathy and communicativeness, and heightened alertness and self-awareness. Unde- sirable side effects, evident the day after use, were also noted by some. These included drowsiness, muscle aches, and a diminished ability to coucen- trate (24). A small circle of proponents was con- vinced that the compound was worthy of further study to determine its efficacy in promoting inter- action in the psychotherapeutic setting. An MDMA conference was held in Oakland, California, in 1986 where papers were presented by private practitioners who were dispensing MDMA to their patients as well as by faculty from schools of medi- cine, pharmacy, and public health. Others were ir- responsibly touting it as a social lubricant (alcohol Fioure 7. Hallucinogenic and analgesic drugs of abuse and some encountered without a hangover), a mind-expanding agent (an innocuous LSD substitute), and a New Age soma.' Some were reaping huge financial rewards. Structurelactivity relationships in the phenylisopropy- The Drug Enforcement Agency first responded to the lamine series for both CNS stimulatory and hallucinogenic emergence of MDMAas a widely used recreational drug in properties have been well defined (26). The substitution of July 1984, with a proposal that it be categorized as a hydroxy, alkoxy, and methylenedioxy functionality in the schedule I substance, the classification reserved for drugs aromatic ring is associated w~ththeaddition of hallucino- with significant abuse potential and no accepted medical utility (29). A legal basis for emergency scheduling was eenic- activitv, The Dotencv of this effect ii dctcrmincd bv provided two months later by the Dangerous Drug Diver- the number, type,-. and relative substitution pattern. 3,4,5- sion Control Act of 1984 (30) that enables temporary Trisubstitution confers the maximum hallucinogenic prop- scheduling of drugs where an immediate threat to the pub- erties (mr~calinc(121). N~trogenalkylation is associated lic health exists. Such emergency scheduling can be initi- with a diminution of hallucinoamecitv. The anuloaous ~n- ated by the Attorney General with publication in the Fed- mary amine, 3,4-methylenedioxyamphetamine(MDA) eral Register of the intent to regulate and a supporting (10)is a moderately potent hallucinog~;whereas, ecstasy rationale. It comes into effect 30 days thereafter. Schedul- amearss. to be non-hallucino~.enic.- Also of note is the rever- ing in this manner is for one year with the possibility of a sal of normal stereochemical correlates with bioactivity In six-month extension and is not subject to judicial review. the hallucinogenic amphetamines, greater sensory distort- This authority was invoked on five occasions to deal with ing activity resides in the (R)-enantiomer; whereas, the 13drugs in the first year after coming into force. As ofApril more potent entactogenic properties of MDMAare found in 1993, the ranks of controlled substances permanently or the (S)-enantiomer. Parasympathetic stimulatory activity temporarily scheduled had swollen from the original 150 is stronger in the (S)-form. This obsenration has led to the to more than 300 (31). This mowth can be attributed ~ri- suggestion that a novel mode of action through which ec- marily to the introduction O~:CSA'S and the recogn~tionof the problem of anabolic steroid abuse that led to the sched- stasy alters perception may exist. Evidence suggests that ule 111 regulation of these compounds. some of MDMKs subjectively desirable effects may be as- sociated with stimulation of serotonin release in the brain In early 1985, DEA officers in Dallas were estimating that 50,000-100,000 tablet-form MDMA doses were arriv- (27). Studies with baboons and rhesus monkeys show that these species will self-administer this substance by injec- 'S~cnclalrns were reporteo n bolh tne pow ar press and a ralher tion-a result that suggests abuse potential in humans extens ve undergroLno press tnal deve oped arobnd In's sLbstance. (28). A substantial compilation of such references can be found in ref. 25. 488 Journal of Chemical Education that these provisions did not unconstitutionally delegate legislative powers to the Attorney General nor did the temporary preclusion of judicial review violate nondele- gation doctrine. At the time emereencv.. . scheduling came into force. hearmgi were underway that would determine .MI)M,Ys Figure 8. Reductive amination route to MDMA ultimntr schrdulinc l(w(!l. Proooncnt.i nrzwd for xhed- ule I11 classification that wohd have Gabled clinical testing to proceed. This position was endorsed by the DEA's administrative law judge. However, nearly two years later, in November 1986, MDMAwas permanently placed into schedule I (35).A subsequent appeals court t decision invalidated this assignment and MDMA again HCOzH became unregulated. Re-review and reclassification into schedule I soon followed and has not been successfully challenged. Stepping out of the courtroom and back into the ga- CH~rage, trailer or kitchen, the stories ofsassafras albidum and ecstasy now merge. As in the synthesis of the pure reductive amination of an imine produced from the ap- propriately substituted phenyl-2-propanone (Fig. 8) Fiaure" 9. Preoaration of 3.4-methvlenedioxv~henvl-2-propane...... (36). Althoueh P2P had been controlled ureviouslv, a siz- able numb& of ring substituted derivatives remained commerciallv available. 3.4-Methvlenedioxv~henvl-2- propanone was-not regulatedhntil arch 1989: A As had previously been demonstrated, the control of a required precursor had not usually been sufficient to cur- tail synthesis of high demand drugs, and underground labs again turned to in-house synthesis of the needed starting materials. One such route was based on oxidation of isosa- frole to the key ketone via epoxidation/rearrangement with hydrogen peroxide in formic acid (Fig. 9) (37). As part of the 1990 Anti-Crime Act, isosafrole, safrole, and methy- lamine were deemed precursor chemicals and controlled (38). Figure 10. Synthesis of MDMAfrom safrole. Sassafras root bark is not readilv controllable and those ine uer month and selling on the street and in the dance who cannot coll(.ct their own run siill p~rchascthe pmduct cl;bs for $15425 a dose. Authorities were actually receiv- at health and natural foods storcs The root bark contam; ine-. hone calls from citizens beine- recruited as distrihu- up to 8% by weight of safrole rich essential oil. It was not tors inquiring into the legality of the enterprise (at the surprising that a clandestine producer would seek to ex- time, MDMA was not controlled). Meanwhile, a darker ploit this natural source of starting material. In fact, the side of MDMA use was emer~ng.- - The report of five ec- Table 2. Some Components of the Sassafras Oil stasy-related fatalities in Dallas county in a nine-month Bromination Mixture oeriod a~oeared(32). Neuro~harmacoloeicalstudies in .A . . - rats and primates suggested moderate neurotoxicity asso- ciated with the administration of the drug. A deleterious Compound Source impact on serotonergic neural systems involving depletion camphor impurity in starting material of the neurotransmitter, 5-hydroxytryptamine, and its me- tabolites was noted (33). safrole unreacted starling material Prompted by reports of escalating usage (primarily in cis-isosafrole H+ catalyzed alkene isomerizatlon of California, Texas, and Florida) and the new toxicity data safrole and perhaps sensitized by the recent tragedy experienced trans-isosafrole by abusers of the demerol analog, MPPP (15aLZDEA tem- 2-methoxysafrole solvoiysis of 2-bromosafrole porarily placed MDMA into schedule I on May 31, 1985. The emergency scheduling of MDMA generated much liti- 2-hydroxysafrole gation in the ensuing five years. The constitutionality of 2-bromosafrole Markovnikov ionic addition of HBr to the emergency scheduling provision was challenged on safrole separation of powers grounds. A series of conflicting court anti-Markovnikov radical addition of HBr to decisions followed. Ultimately, the Federal Courts ruled safrole -. - Markovnikov ionic addition of HBr to '1n !he early 1980's a n~mberof abLsers of tne meper 0 ne analog. eugenol 1.metny -4-pneny-4-prop onoxy-p per 0 ne (MPPP (15a)) exper - enced a rapid onset of profound Parkinson's disease symptoms. It 4-(2-oromopropy1)-t.2-Marnovn kov onlc add ton of hBr to 4. was soon discovered that an impurity present in amounts up to 3.2% d melhoxyoenzene a1 y .t,2-o~metnoxybenzene l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine (MPTP), which can 4-(3-bromopropy1)-l,2-anti-Markovnikov radical addition of HBr to form via dehydration of the benzylic alcohol utilized in the final acyla- dimethoxybenzene 4-allyl-1,2-dimethoxybenzene tion step in the MPPP synthesis, was responsible for the potent neurotoxicity. See ref. 14 and 34. safrole dimer ? Volume 72 Number 6 June 1995 489 first synthesis of MDMAreported in the chemical lit- erature involves treatment of safrole with aqueous hydrobromic acid followed by displacement with ("-(33-cH3 - methylamine (Fig. 10) (22). Although access to the original patent (in German) or a later paper in the Polish pharmaceutical literature (39) (in Polish) is certainly not convenient, the Chemical Abstract of the Acta Polon. Pharm. paper contains the required experimental details in English. In 1991, a paper appeared in the Journal of Chmma- tographic Science describing the forensic analysis of samples seized from a raided laboratory This analysis revealed a process in development for ecstasy manufac- tnre based on steam distillation of sassafras root bark (40). Capillary GC-MS analysis of the essential oil starting material revealed the presence of camphor, methylenedioxystyrene, eugenol, 4-allyl-12-di- methoxybenzene, and a trimethoxy substituted allyl- benzene in addition to the major component, safrole. Hydrobmmination of the crude extract with KBr had been carried out to afford a complex product mixture. GC-MS analysis of this highly impure material re- vealed more than two dozen compounds about half of which could identified unequivocally via comparison be 17s 17b with standards and/or fragmentation pattern analysis (Table 2). the pmduct composition Figure 11. Possible identity and mechanism of formation of safrole dimer. constitutes an excellent review exercise for the intro- dudory organic group. Two of the three most abun- dant products were identified as 2-bromosafrole, the product of Markovnikov ionic addition to the allyl benzene and 3-bromosafrole that presumably arises via the com- petitive radical addition pathway. It is probably safe to as- sume that the lab operator did not take steps to prevent this side reaction. (=:H:CH~ 18 cm::19 Conspicuous in its absence is the isomeric l-bmmosa- frole that one would expect to form via carbocationic rear- rangement to the relatively stable secondary benzylic car- bocation. However, the investigators observed a third major product of high retention time that yielded a mo- lecular ion at mlz 324 and a base peak resulting from the loss of 29 amu and suggested an unspecified safrole dimer. &:20 ~::21 A speculative rationale that accounts for the high molecu- lar weight product and the lack of any rearranged bro- mosafrole follows (Fig. 11). It is possible that either the H2N&N 1-bromosafrole or the carbocation intermediate leading to 0 it is intercepted in a Friedel-Crafts alkylation with safrole affording 17 a or 17b.Loss of the ethyl group during frag- mentation would afford the exceptionally stable dibenzhy- dry1 cation with mlz 295. 22 Although no MDMA was found on the premises it was $ anticipated that a successful synthesis would conclude with treatment of the crude bromination mixture with Figure 12, Some recentlyencountered amphetamine CSAs, methylamine. The AuhudAlabama Department of Foren- sic Sciences team bas found that this reaction is viable, although a highly impure product results. logical disturbances, including psychosis, depression, and panic disorders, also have been documented. Epilogue A significant number of structurally creative ampheta- Interest in the recreational use of MDMA has not corn- mines have been introduced by the underground pharma- pletely subsided. Asmall group of psychiatrists and thera- ceutical industry since the emergence of ecstasy (Fig. 12). pists continue to call for clinical evaluation of the com- These include derivatives of MDMA (18, 19) (441, cathi- pound (41). The youth rave culture that originated in none and analogs (20,21) (45) as well as the oxazoline in- Britain and has since spread into some major US. metro- corporating 4-methylaminorex (22) (46).Legislative meas- politan centers (42) has adopted ecstasy as the drug of ures to combat the designer drug ~roblemevolved rapidly. choice to complement its grueling dance parties. Recent When it became apparent that even the emergency sched- papers in the British medical literature have spoken to uling provision was insufficient in keeping pace with the this phenomenon and chronicled a disturbing number of problem, a remedy not based on the regulation of specific adverse, sometimes fatal, complications associated with chemical substances was crafted. The Controlled Sub- MDMA abuse (43). Renal failure, liver toxicity, and hyper- stance Analogue Enforcement Act of 1986 (47) imposes pyrexia have been observed in users. More severe psycho- criminal penalties on non-exempted individuals engaged 490 Journal of Chemical Education in the manufacture or sale of compounds intended for hu- I9 [email protected]. T. Clin Tor. 1975.8.405456. no. coopsr,D. AP~Chi. symposium on ihp~orrnsic~spectsof~ontm~~pd~ubstonces. man consumption that have chemical structures substan- Drug Enforcement Administration, Federal Bureau of Inverligil6on, Quantieo, tially similar to those of controlled substances in schedules Vtrplnia. (19881:oo 79-103. I or-11 or have, or are represented as having, stimulant, depressant, or hallucinogenic effects substantially similar to or uaeater than those of schedule I or I1 drues.- Thus. escaping criminal penalties has been effectively removed as a motivation for the uroduction and distribution of novel drugs of abuse. 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Lancet L991.638.1335. 14. Soine, W. H. Mdeinoi Res. Rev. 1986.6.41-74. 44. Noggle, F. T.Jr: DeRuiiel J.: Iang. M. J. J. Assm OK And Chem. 1988, fi9, 531- 15. Mdhamphdmnine Ahin the Unzlsd Stales: NIDA, Sept. 1988; U. S. Department 686. ofHeslth and Human SaMces Pub. No. iADMl89-1608: p 13. 45. aFdwolRegishi 1993,5S.25788. b. Glastns. P. US.Ne~sond WorldRmorl April. 16. Public Law 91.513. 1970. 26. 1993, 114,20-21. 17. Dlugsin the 199vs: New Penlr.New Promise; Heanng Before the Committee on the 46. 181 Federal Register 1992. 57. 43399. Ihl Glennon. R. A.: Miseilheimer, B. Phnrm. Judiciaw, United States Senate. I0lsf Conpess. 1st Session, Aug. 31,1988; Serial Biochem. Behavior 199O,35.517-521. No. 5~101-40.U. S. Government Pnnting OWee. Washington. DC. 1991; pp 103- 47. 1a)Public Law 99-570. ntle I. SubiitleE. 1986. lhl Designer Drugs; HearingBefore 7 ?A the Suhmmmittee on crime of ,he committee on the Judieian: House or Repre- 18. Church. A. C.; Sapienza. F. L. EdsProc. ofConfmlled SubstoneeAnologkademhip sentatives, 99th Congress, IstSesaion on H.R. 2014, H.R. 2977, H. R. 3936. and S. Cmfmnce, U. S. Dept, of.lurtiee. Drng Enforcement Agency. OWce of Diversion 1437. May 1. 1986: Soda1 No. 73. U. S. Goverment Printing OWce. Washington. Control. San Fmncisco, 11986l. DC, 1986. Volume 72 Number 6 June 1995 491