Chemistry of Phenethylamines Related to Mescaline ALEXANDER T. SHULGIN, PH.D.* This review will bring together a number of the and "pellotinogenic" to distinguish these two types on a known facts related to the cactus origins of the chemical basis, but he claimed that there was no phenethylamine alkaloids, a comparison of their morphological distinction between them. There is, chemical structures, a listing of several synthetic variants however, a distinct morphological variant called that are known and a description of the psychopharma- Lophophora diffusa which appears to contain largely cologic intoxication that follows their administration to pellotine. With apologies to the morphologists and for normal human subjects. This will be centered upon the simplicity's sake, it would seem to be useful to make a drug mescaline which is the major active alkaloid of the temporary assignment of name primarily on cherno- North American dumpling cactus, known by the taxonomic grounds. common name Peyote. The dozen or so cacti that are associated with Anyone familiar with the mysteries of taxonomic mescaline content are listed in Table 1. The distinction binomial nomenclature must be aware of the confusion between the first two, both commonly known as Peyote, and frequently personal arguments that seem always to has already been commented upon, and the variant be underway amongst botanists. The area of Peyote Lophophora diffusa is arbitrarily placed with Anhalo- assignment is no exception. The Peyote button, which is nium lewinii due to the relative paucity of mescaline accepted as being the major hallucinogenic cactus in this content in both. Of the many Tricbo cereus species area, appears to occur in two variations. Both contain listed, the first two are noteworthy due to their some one to two percent alkaloids, but they differ in the relatively large mescaline content. The first, T. composition of this fraction. In one, mescaline is the peruvianus, on a weight basis probably exceeds peyote as major component accompanied by some 60 other a source of this alkaloid. The remainder of the species alkaloids in lesser amounts, most of them tetrahydro- listed have not been quantitatively determined. Only isoquinolines. In the other, the alkaloids are largely estimates have been made, by mass spectral determi- phenolic in nature and pellotine constitutes approxi- nation or by a combined gas chromatography-mass mately 90 percent of this fraction. Mescaline is present spectral procedure, and all contain unisolatable quanti- in trace amounts at most. Thus when the buttons are ties of mescaline. These are listed as being less than 0.1 collected at random, it is quite reasonable that there percent (the upper limit of assay) and may be should be wide variations in composition reported. considerably below this figure. The last two entries, Heffter , in his seminal studies of various batches of Pelecypbora aselliformis and Opuntia spinosior (com- Peyote buttons, employed the terms "mescalinogenic" monly known as the Hatchet Cactus and Cane Cholla, respectively) contain only microscopic quantities of *1483 Shulgin Road, Lafayette, California 94549. mescaline. It can be calculated that the former, at Journal of Psychedelic Drugs 41 Vol. 11(1-2) [an-jun, 1979 SHULGIN PHENETHYLAMINES TABLE 1 CACTI SOURCES OF MESCALINE Botanical Name Locale Approximate Percent Mescaline Content Lopbopbora williamsii Texas, Chihuahua 1 Anhalonium lewinii (L. diffusa) Queretaro trace (1 % pellotine) Trichocereus peruvianus Peru 1 T. pachanoi (San Pedro) Peru 0.1 T. bridgesii Bolivia < 0.1 T. macrogonus South America < 0.1 T. terscheckii Argentina < 0.1 T. werdermannianus South America < 0.1 T. cuzcoensis Peru < 0.1 T. fulvilanus South America < 0.1 T. taquimbalensis South America < 0.1 T. validus South America < 0.1 Stetsonia coryn e Argentina < 0.1 Pelecypbora asilliformis San Luis Potosi 10-5 Opuntia spinosior Arizona, Chihuahua 10-5 approximately two ounces per plant, would require the commonly found in microorganism and animal biosyn- consumption of some 100,000 plants for central thesis as well as in plant chemistry. This step, step "A," activity. The report of mescaline as a component of is best characterized by the formation of tyrosine from another Opuntia species (0. cylindrica) must be held as phenylalanine, in amino acid chemistry. Step "B," the questionable as there are reports of plant misidenti- introduction of a second oxygen adjacent to the first, is fication. again common to both living kingdoms, and in the The organization of the major alkaloids of Peyote is amino acid analogy represents the formation of dopa simplified by a preliminary consideration of the from tyrosine. At this point the animal and plant probable biosynthetic steps that are employed in the biosynthetic paths diverge. Most animal schemes plant. This is outlined in Figure 1, with a progressive introduce the third oxygen either adjacent to the development of ring oxygenation and ring complexity. aliphatic chain to form the 2,4,5-orientation pattern, or Although most of these pathways have been determined on the chain immediately adjacent to the aromatic ring, in Peyote itself, the general classes of alkaloids that are as in the enzymatic synthesis of norepinephrine. Cactus known to be in other cacti make it probable that these alkaloids such as macromerine (from Corypantba schemes are quite general. The first stage of oxidation is macromeris) indicate that examples of chain oxidation FIGURE 1 N N N o A B •• o o N o o •• o o o Journal of Psychedelic Drugs 42 Vol. 11(1-2) j an-j un, 1979 -------------------------~--------------- SHULGIN PHENETHYLAMINES some being quite complex and having structures that have not been confirmed by synthesis but merely deduced by studies of physical properties. All of the compounds shown bear some family resemblance, showing varying degrees of a-methylation, N-methyla- tion (in one case N-ethylation), N-acylation and macromerine quaternization. The mono- and dioxygenated phenethyl- can occur In plants, but such products are completely amine alkaloids that are established as being in Peyote unknown in Peyote. The indicated step "C," with the are shown in Table 2. The oxygen function and the introduction of the third oxygen adjacent to the first nitrogen function are given beneath the arrows from two and the formation of the 3,4,5-orientation pattern, those atoms, and only when trivial names are commonly is unique to the plant kingdom. The mechanism of step used are these names given. "D" is variable. There is the necessary introduction of Most of these simpler compounds are found not additional carbon to form the second ring of the only throughout the cactus world, but widely tetrahydroquinoline system. An example of possible distributed in both the plant and animal kingdoms. biosynthetic pathways is shown in Figure 2, for the Three of these alkaloids, tyramine, hordenine and synthesis of anhalonidine, employing compounds all of epinine, are known adrenergic agents and have been well which are known to be present in Peyote. The study of explored pharmacologically. Epinine is also known as such in vivo transformations is both difficult and deoxyepinephrine. Hordenine may also occur in Peyote, inherently uncertain: difficult in that radioactively although a confirming search for it independently has labeled precursors must be synthesized and employed, failed to show it to be present. The compound dopamine and the label in the product must be established as to its represents an interesting component: it is a normal position; and uncertain in that the distinction between a neurotransmitter in humans along with being well plant's native synthetic process and its synthetic established as a natural alkaloid of Peyote. A legal capabilities can only be inferred from the efficiency of paradox might well exist here; in the current code of the observed conversion. Federal regulations, under Title 21, Section 1308.11, Several of the some 60 known alkaloids present in there is an entry immediately following the listing of Peyote are arranged in Tables 2-4 in increasing Peyote as a Schedule I drug. It defines Peyote as: complexity, in agreement with the biosynthetic scheme ... meaning all parts of the plant presently presented. Not all of the known components are given, classified as Lo phophora unlltamsii Lemaire, FIGURE 2 pyruViC acid • COOH OH CH3 3-demethylmescaline peyoruvic acid acetic I acid 1~O, •• NH CH30 / CO OH I CH3 N-acetyl- 3-hydroxy-4, 5- anhalonidine dimethoxyphenethylamine ] ournal of Psychedelic Drugs 43 Vol. 11(1-2) j an-j un , 1979 SHULGIN PHENETHYLAMINES TABLE 2 PEYOTE ALKALOIDS (1) MONO- AND DIOXYGENATED PHENETHYLAMINES N o N o o NH2 Dopamine HO NH2 Tyramine [:JHO NHCH3 Epinine CH30 NH2 HO NHCH3 N-Methyltyramine \ HOi NHCH3 N(CH3h HO N(CH3h Hordenine CH3O NH2 DMPEA iCH30 \ whether growing or not; the seeds thereof; any possible precursor to the several methylenedioxy extract from any part of such plant, and every alkaloids that are mentioned shortly. The in vivo compound, manufacture, salt, derivative, mix- coupling of this compound with formaldehyde would ture or preparation of such plant, its seeds or give rise to homomyristylamine. This is a most logical extracts. compound to be found in Peyote; it would be a logical As the phrase "and every compound of such plant" is precursor to several of the known methylenedioxytetra- used, it is conceivable that a natural neurotransmitter hydroisoquinolines, and is centrally active in humans. essential to brain function could be argued in court as And yet there is no report of its ever having been found being a Schedule I drug! in the natural cactus. In the second group, the Another noteworthy compound in Table 1 is monohydroxy-dimethoxy series, the first compound DMPEA (3,4-dimethoxyphenethylamine). Although it is with the primary amino group serves as a prototypic present as a trace component in Peyote, it has achieved precursor to some of the tetrahydroisoquinolines to be broad notoriety as a component found in the urine of mentioned shortly.