Ayahuasca In The Early Twentieth Century

(1900-1950)

The early decades of the twentieth century witnessed the publication of Spruce's detailed accounts of his Amazonian explorations and his observations of the use of the narcotic beverage among several tribes that he contacted. Although brief reports had been published earlier by Spruce and others, it was Spruce's account of his travels in a volume edited by the famed naturalist and codiscoverer of evolution A. R. Wallace in 1908 that may have rescued the knowledge of ayahuasca from the depths of academic obscurity and brought it to the attention of educated lay people.

During this early twentieth-century period, progress in the understanding of ayahuasca took place mainly on two fronts: taxonomic, and chemical. With some notable exceptions, pharmacological investigations of the properties of ayahuasca were relatively quiescent during this period.

The botanical history of ayahuasca during this period is an amusing combination of excellent taxonomic detective work by some, and egregious errors compounded upon errors by others. Safford, in 1917, asserted his belief that ayahuasca and the beverage known as caapi were identical and derived from the same plant. The French anthropologist Reinberg (1921) compounded the confusion by his assertion that ayahuasca was referable to Banisteriopsis caapi, but that yagé was prepared from an Apocyanaceous genus, Haemadictyon amazonicum, now correctly classified as Prestonia amazónica. This error, which apparently originated from an uncritical reading of Spruce's original field notes, was to persist and propagate through the literature on ayahuasca for the next forty years. It was finally put to rest when Schultes and Raffauf published a paper specifically refuting this misidentifica-tion (Schultes and Raffauf 1960), however, it still crops up occasionally in technical literature.

Among the investigators who helped to clarify, rather than clot the taxonomic understanding of ayahuasca botany must be mentioned the works of Rusby and White in Bolivia in 1922 (White 1922) and the publication by Morton in 1930 of the field notes made by the botanist Klug in the Colombian Putumayo. From Klug's collections, Morton described a new species of Banisteriopsis, B. inebriens, used as a hallucinogen, but he also asserted that at least three species, B. caapi, B. inebriens, and B. quitensis, were used similarly and that two other species, Banisteria longialata, and Banisteriopsis rusbyana may have been used as admixtures to the preparation. Curiously, it was two chemists, Chen and Chen (1939), who did the most to clarify the early taxonomic confusion about the identity of the ayahuasca source plants. These investigators, working on the isolation of the active principles of yage and ayahuasca, supported their investigations with authentic botanical voucher specimens (a rare practice at that time) and, after a review of the literature, concluded that caapi, yage, and ayahuasca were all different names for the same beverage, and that their source plant was identical: Banisteriopsis caapi. Subsequent work by Schultes and others in the 1950s would establish that, in fact, Malpighiaceous species other than B. caapi were implicated in the preparation of the beverage, but considering the reigning confusion of the time, Chen and Chen's contribution was a rare light in the forest of prevailing darkness. From subsequent fieldwork, it is now quite clear that the two main botanical sources of the beverage variously known as caapi, ayahuasca, yage, natema, and pinde are the barks of B. caapi and B. inebriens.

The first half of the twentieth century was also the period in which the first serious chemical investigations of the active principles of ayahuasca were carried out. Like much of the initial taxonomic work taking place during this same period, scientific progress on this front was marked at first by confusion arising from the simultaneous investigations of several independent groups of investigators. Gradually, as these investigations found their way into the scientific literature, clarity began to emerge from a fairly murky picture.

Harmine, which consensus would eventually establish as the major S-carboline alkaloid of Banisteriopsis species, had been isolated from the seeds of Peganum barmala in 1847 by the German chemist Fritsch. Its unequivocal identification was still several decades in the future when an alkaloid named "telepathine" was obtained from unvouchered botanical material called "yaje" by Zerda and Bayon in 1905 (quoted in Perrot and Hamet 1927). In 1923, an alkaloid was again isolated from unvouchered botanical materials by the Colombian chemist Fisher

Cardenas (1923) and was also named telepathine; at the same time, another Colombian team, chemists Barriga-Villalba and Albarracin (1925) isolated an alkaloid, yageine. This may also have been harmine in an impure form, but the formula assigned at the time and the melting point were inconsistent for a iS-carboline structure. To compound the confusion, the vine with which Barriga-Villalba worked had been "identified" as Prestonia amazonica, but he later revised this identification to Banisteriopsis caapi. In all of these instances, the lack of botanical reference specimens rendered the work of dubious value.

Things began to get slightly better from 1926 into the 1950s. Michaels and Clinquart (1926) isolated an alkaloid that they called yageine from unvouchered materials. Shortly afterward, Perrot and Hamet (1927) isolated a substance that they called telepathine and suggested that it was identical to yageine. Lewin, in 1928, isolated an alkaloid that he named banisterine; this was shown to be identical with harmine, previously known from the Syrian rue, by chemists from E. Merck and Co. (Elger 1928; Wolfes and Rumpf 1928). Elger worked from vouchered botanical materials that had been identified at Kew Gardens as Banisteriopsis caapi. At Lewin's urging, based on his own animal studies, the pharmacologist Kurt Beringer (1928) used samples of "banisterine" donated by Lewin in a clinical study of fifteen postencephalitic Parkinson's patients and reported dramatic positive effects (Beringer 1928). This was the first time that a reversible MAO inhibitor had been evaluated for the treatment of Parkinson's disease, though harmine's activity as a reversible MAOI was not discovered until nearly thirty years later. It also represents one of the few instances where a hallucinogenic drug has been clinically evaluated for the treatment of any disease (Sanchez-Ramos 1991).

Working from vouchered botanical materials supplied by Llewellyn Williams of the Chicago Field Museum, Chen and Chen (1939) succeeded in confirming the work of Elger and Wolfes and Rumpf; these workers isolated harmine from the stems, leaves, and roots of B. caa and confirmed its identity with banisterine, previously isolated by Lewin. In 1957 Hochstein and Paradies analyzed vouchered material of ayahuasca collected in Peru and isolated harmine, harmaline, and tetrahydroharmine. The investigations of the constituents of other

Banisteriopsis species was not undertaken until 1953, when O'Connell and Lynn (1953) confirmed the presence of harmine in the stems and leaves of vouchered specimens of B. inebriens supplied by Schultes. Subsequently Poisson (1965) confirmed these results by isolating harmine and a small amount of harmaline from "natema" from Peru, identified by Cuatrecasas as B. inebriens.

MID-TWENTIETH CENTURY (1950-1980)

The first half of the twentieth century witnessed the initial scientific studies of ayahuasca and began to shed some light on the botanical sources of this curious hallucinogen and the nature of its active constituents. During the three decades from 1950 to 1980, botanical and chemical studies continued apace, and new discoveries laid the groundwork for an eventual explanation of the unique pharmacological actions of ayahuasca.

On the chemical front, the work of Hochstein and Paradies (1957) confirmed and extended the previous work of Chen and Chen (1939) and others. The active alkaloids of Banisteriopsis caapi and related species were now firmly established as harmine, tetrahydroharmine, and harmaline. In the late 1960s however, the first detailed reports of the use of admixtures as a regular, if not invariant, component of the ayahuasca brew began to emerge (Pinkley 1969), and it soon became apparent that at least two of these admixtures, Banisteriopsis rusbyana (later reclassified by Bronwen Gates as Diplopterys cabre-rana) and Psychotria species, particularly P. viridis, (Schultes 1967) were added to the brew to "strengthen and extend" the visions. A further surprise came when the alkaloid fractions obtained from these species proved to be the potent short-acting (but orally inactive) hallucinogen N,N-dimethyltryptamine (DMT) (Der Marderosian et al. 1968). This compound had been known as a synthetic for some decades following Manske's initial synthesis; but its occurrence in nature and its hallucinogenic properties had only come to light a few years earlier, when Fish, Johnson, and Horning (1955) had isolated it as the putative active principle in Piptadenia peregrina (later reclassified as Anadenanthera peregrina), the source of a hallucinogenic snuff used by Indians of the Carribean, as well as the Orinoco basin of South America.

The pharmacological rationale for the discovery by Schultes, Pinkley, and others in the late 1960s that ayahuasca depended for its activity on a synergistic interaction between the MAO-inhibiting l?-carbolines in Banisteriopsis with the psychoactive but peripherally inactivated tryptamine DMT had already been provided in 1958 by Udenfriend and coworkers (Udenfriend et al. 1958). These researchers in the Laboratory of Clinical Pharmacology at NIH were the first to demonstrate that 13-carbolines were potent, reversible inhibitors of MAO. During this same period, clinical work and self-experimentation by the Hungarian psychiatrist and pharmacologist Stephen Szara (1957) with the newly synthesized DMT lead to the publication of the first reports of its profound, though short-lasting, hallucinogenic actions in humans. Szara's experiments also lead to the first recognition that the compound is not orally active, though the mechanisms of its inactivation on oral administration were not fully understood. Ironically, several decades later, the DMT pioneer Szara would be appointed as the head of NIDA (National Institute on Drug Abuse).

In 1967, during the height of the Summer of Love in Haight-Ashbury, a unique symposium was held in San Francisco under the sponsorship of what was at the time the U.S. Department of Health, Education, and Welfare. Entitled Ethnopharmacologic Search for Psychoactive Drugs (the proceedings were later published under that title as U.S. Public Health Service Publication No. 1645, issued by the U.S. Government Printing Office) (Efron et al. 1967) this conference brought together the leading lights of the day in the emerging field of psychedelic eth-nopharmacology. Participants included toxicologist Bo Holmstedt of the Karolinska Institute in Stockholm, ethnobotanist Richard Evans Schultes, chemist Alexander Shulgin, newly credentialed M.D. and marijuana researcher Andrew Weil, and others. It was the first time that a conference on the botany, chemistry, and pharmacology of psychedel-ics had been held, and as it happened, it was certainly the last time ths such a conference would be held under government sponsorship. This landmark conference, and the publication issuing from it, which was to become a classic of psychedelic literature, was the first forum where the state of the art at the time regarding ayahuasca in its multidisciplinary aspects was revealed to the world. The symposium volume included chapters on the chemistry of ayahuasca (Deulofeu 1967), the ethnography of its use and preparation (Taylor 1967), and the human psychopharmacology of the S-carbolines of ayahuasca (Naranjo 1967). It is an ironic commentary on the paucity of knowledge of ayahuasca at the time that the uses of tryptamine-containing admixtures, and their activation via MAO-inhibition, did not even surface for discussion at the symposium; the prevailing assumption was that the psychoactivity of ayahuasca was due primarily if not entirely to the l?-carbolines.

In the five years following this conference, progress was made in understanding ayahausca pharmacology and chemistry. Schultes and his students Pinkley and der Marderosian published their initial findings on the DMT-containing admixture plants (Der Marderosian et al. 1968; Pinkley 1969), fueling speculation that DMT, orally activated by i?-carbolines, was responsible for much of the activity of the brew. This notion, although plausible, would not be scientifically confirmed for another decade.

In 1972, Rivier and Lindgren (1972) published one of the first interdisciplinary papers on ayahuasca, reporting on the alkaloid profiles of ayahuasca brews and source plants collected among the Shuar people of the upper Rio Purus in Peru. At the time, their paper was one of the most thorough chemical investigations of the composition of ayahuasca brews and source plants that referenced vouchered botanical collections. It also discussed numerous admixture plants other than the Psychotria species and Diplopterys cabrerana, and for the first time provided evidence indicating that ayahuasca admixture technology was complex, and that many species were on occasion used as admixtures.

In the later 1970s a team of Japanese phytochemists became interested in the chemistry of Banisteriopsis and reported the isolation of a number of new i3-carbolines and the pyrrolidine alkaloids shihunine and dihydroshihunine (Hashimoto and Kawanishi 1975, 1976; Kawanishi et al. 1982). Most of the newly reported 6-carbolines were isolated in extreme trace amounts, however, and the possibility was later raised that they might be artifacts resulting from the isolation procedures (McKenna et al. 1984).

LATE TWENTIETH CENTURY (1980-PRESENT)

Following publication of Rivier and Lindgren's paper, there was little further progress on the scientific front for the remainder of the 1970s. There was no comparable follow-up to Rivier and Lindgren's work until Terence McKenna et al. (1984) published the results of their chemical, ethnobotanical, and pharmacological investigations of ayahuasca and its admixtures, based on vouchered botanical specimens and samples of brews used by mestizo ayahuasqueros in Peru. This paper was significant because it represented the first time that the theory proposed to explain the oral activity of the beverage was experimentally confirmed. The active principal was shown to be DMT, rendered orally active by S-carboline-mediated blockade of peripheral MAO. Assays of ayahuasca fractions in rat-liver MAO systems showed that the brews were extremely potent MAO inhibitors even when diluted many orders of magnitude. A further important discovery was the finding that the levels of alkaloids typically found in the mestizo ayahuasca brews exceeded the levels found in the upper Rio Purus ayahuasca by Rivier and Lindgren, sometimes by an order of a magnitude or more. Based on the known human pharmacology of DMT and l?-carbolines, Terence McKenna and coworkers showed that a typical dose (100 ml) of the mestizo ayahuasca samples contained enough DMT to constitute an active dose. The investigators suggested that the lower levels of alkaloids found in the Shuar samples of Rivier and Lindgren (1972) may have resulted from the different methods used in preparation. The Shuar typically soak the Banisteriopsis and admixture plants in cold water; they do not boil the plants, nor do they reduce the volume of the final extract, as is typically done in mestizo practice. These factors explained the discrepancies in alkaloid concentration found in the two different studies or at least provided a plausible rationale to explain the differences.

The decade of the 1980s also witnessed the early contributions of the anthropologist, Luis Eduardo Luna. Working among mestizo ay* huasqueros near the cities of Iquitos and Pucallpa in Peru, Luna's work was the first to articulate the importance of the strict diet followed by apprentice shamans, as well as the specific uses of some of the more unusual admixture plants (Luna 1984a; 1984b; 1986). He was also the first to report on the concept of "plant teachers" (plantas que enseiian), which is how many of the admixture plants are viewed by the mestizo ayahuasqueros. In 1986, McKenna, Luna, and Towers published the first comprehensive tabulation of the species used as admixtures and the biodynamic constituents contained in them, pointing out that these relatively uninvestigated species comprise an extensive folk pharmacopoeia worthy of closer scrutiny as potential sources of new therapeutic agents (McKenna et al. 1995).

While conducting fieldwork together in the Peruvian Amazon in 1985, McKenna and Luna first began discussing the possibility of conducting a biomedical investigation of ayahuasca. The superior health of the ayahuasqueros, even at advanced ages, seemed remarkable and something that could be amenable to scientific study. The logistical challenges of carrying out such work in Peru, however, seemed daunting, since access to storage facilities for plasma samples was limited and local concepts of witchcraft made it unlikely that ayahuasqueros would submit to medical procedures such as collection of blood and urine samples. The workers wrote a preliminary proposal for the project following their return from the field but did not pursue funding.

In 1991, however, a fresh opportunity to initiate such a study presented itself in Brazil. McKenna and Luna were among several foreigners invited to participate in a conference in Sao Paulo by the Medical Studies section of the Uniao do Vegetal (UDV), a Brazilian syncretic religion that used ayahuasca in their ceremonies. The group's use of ayahuasca in a ritual context (under the names boasca, vegetal, or simply cha, "tea"), while permitted by the Brazilian regulatory authorities, was subject to provisional review. Many members of the UDV were themselves physicians, psychiatrists, or had other kinds of medical expertise and so were most receptive to the notion of conducting a biomedical study of ayahuasca when it was proposed to them by Luna and McKenna. It turns out that this had been a part of their own unspoken agenda all along and was part of the reason for inviting the foreign investigators to the first Medical Studies Conference on Hoasca. Besides the opportunity to satisfy scientific curiousity about the human pharmacology of hoasca, the UDV had a political motive for carrying out such a study; they wanted to be able to demonstrate to the Brazilian health authorities that the long-term use of hoasca tea was safe, and did not cause addiction or other adverse reactions. The UDV physicians were hoping to enlist foreign scientists to collaborate in the study. The question of how the study was to be funded had yet to be answered.

Following the 1991 conference, McKenna returned to the United States and drafted a proposal describing the objectives of the study that was to become known as the Hoasca Project. Initially, the objective was to submit the proposal to the National Institute on Drug Abuse, but as the proposal took shape it became clear that funding for the study would be unlikely to originate from any government agency. Not only were there legal, logistical, and political problems with securing NIH funds for a study to be carried out in Brazil, it was also clear that given the nature of government drug policy, the NIH would not look favorably on a proposal that was not aimed at demonstrating serious harmful consequences resulting from the use of a psychedelic drug. Fortunately, McKenna had affiliations with Botanical Dimensions, a nonprofit organization dedicated to the investigation of ethnomedically important plants, and through this venue he was able to solicit generous grants from several private individuals.

With sufficient funding assured for at least a modest pilot study, McKenna enlisted the collaborative talents of various colleagues in the medical and academic communities. Eventually, a truly international, interdisciplinary study team was formed, consisting of scientists from UCLA, the University of Miami, the University of Kuopio in Finland, the University of Rio de Janeiro, University of Campinas near Sao Paulo, and the Hospital Amazonico in Manaus.

The team returned to Manaus in the summer of 1993 to begin the field phase of the research, which was conducted using volunteers who were members of the Nucleo Caupari in Manaus, one of the oldest and largest UDV congregations in Brazil. The team spent five weeks in Brazil administering test doses of hoasca tea to the volunteers, collecting plasma and urine samples for later analysis, and carrying out a variety of physiological and psychological measurements.

The result was one of the most comprehensive multifaceted investigations of the chemistry, psychological effects, and psychopharmacol-ogy of a psychedelic drug to be carried out in this century. Both the

acute and the long-term effects of regular ingestion of hoasca tea were measured and characterized; extensive psychological evaluations, and in-depth structured psychiatric interviews were conducted with all volunteers; the nature of the serotonergic response to ayahuasca was measured and characterized; and the pharmacokinetics of the major hoasca alkaloids were measured for the first time in human plasma. Since completion of the field phase of the study, the results have been published in a number of peer-reviewed papers (Grob et al. 1996; Callaway et al. 1994, 1996, 1998) and have recently been summarized in a comprehensive review (McKenna et al. 1998). Among the key findings were that long-time members of the UDV commonly underwent experiences that changed their lives and behavior in positive and profound ways; and that there was a persistent elevation in serotonin uptake receptors in platelets, possibly indicative of similar long-term serotonergic modulation occurring in the central nervous system that may reflect long-term adaptive changes in brain functions. The study did establish that the regular use of hoasca, at least within the ritual context and supportive social environment that exists within the UDV, is safe and without adverse long-term toxicity, and, moreover, apparently has lasting, positive influences on physical and mental health.

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