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The Heffter Review of Psychedelic Research, Volume 1, 1998
 
1
Heffter Research Institute, Santa Fe, NM
2
Department of Pharmaceutical Chemistry, University of Kuopio, Finland
3
Heffter Research Institute, Santa Fe, NM, and Department of Psychiatry, Harbor/UCLA Medical CenterTorrance, CA65
10. The Scientific Investigation of Ayahuasca: A Review of Past and Current Research
Dennis J. McKenna,
1
Ph.D., J. C. Callaway, Ph.D.,
2
and Charles S. Grob. M.D.
3
Introduction
Of the numerous plant hallucinogens utilized byindigenous populations of the Amazon Basin,perhaps none is as interesting or complex,botanically, chemically, or ethnographically, as thehallucinogenic beverage known variously as
ayahuasca
,
caapi
, or
 yage
. The beverage is mostwidely known as
ayahuasca
, a Quechua termmeaning "vine of the souls," which is applied both tothe beverage itself and to one of the source-plantsused in its preparation, the Malpighiaceous jungleliana,
 Banisteriopsis caapi
(Schultes, 1957). InBrazil, transliteration of this Quechua word intoPortuguese results in the name,
 Hoasca
.
 Hoasca,
or
ayahuasca
, occupies a central position in Mestizoethnomedicine, and the chemical nature of its activeconstituents and the manner of its use makes itsstudy relevant to contemporary issues inneuropharmacology, neurophysiology, andpsychiatry.
Traditional and Indigenous Uses of Ayahuasca
The use of 
ayahuasca
under a variety of namesis a widespread practice among various indigenousaboriginal tribes endemic to the Amazon Basin(Schultes, 1957). Such practices undoubtedly werewell established in pre-Columbian times, and in factmay have been known to the earliest humaninhabitants of the region. Iconographic depictions onceramics and other artifacts from Ecuador haveprovided evidence that the practice dates to at least2000 B.C. (Naranjo, 1986). Its widespreaddistribution among numerous Amazonian tribes alsoargues for its relative antiquity.Considerable genetic intermingling and adoptionof local customs followed in the wake of Europeancontact, and
ayahuasca
, along with a virtualpharmacopoeia of other medicinal plants, graduallybecame integrated into the ethnomedical traditions of these mixed populations. Today the drug forms animportant element of ethnomedicine and shamanismas it is practiced among indigenous Mestizopopulations in Peru, Colombia, and Ecuador. Thesociology and ethnography of the contemporary use of 
ayahuasca
(as it is most commonly termed) inMestizo ethnomedicine has been extensivelydescribed (Dobkin de Rios, 1972, 1973; Luna, 1984,1986)
Syncretic Religious Use of Ayahuasca
From the perspective of the sociologist or theethnographer, discussion of the use of 
ayahuasca
or
ayahuasca
can conveniently be divided into aconsideration of its use among indigenous aboriginaland mestizo populations, and its more recentadoption by contemporary syncretic religiousmovements such as the União do Vegetal (UDV),Barquena, and Santo Daime sects in Brazil. It iswithin the context of acculturated groups such asthese that questions regarding the psychological,medical, and legal aspects of the use of 
ayahuasca
become most relevant, and also, most accessible tostudy.The use of 
ayahuasca
in the context of mestizofolk medicine closely resembles the shamanic uses of the drug as practiced among aboriginal peoples. Inboth instances, the brew is used for curing, fordivination, as a diagnostic tool and a magicalpipeline to the supernatural realm. This traditionalmode of use contrasts from the contemporary use of 
ayahuasca
tea within the context of Braziliansyncretic religious movements. Within these cults,the members consume
ayahuasca
tea at regularintervals in group rituals in a manner that moreclosely resembles the Christian Eucharist than thetraditional aboriginal use. The individual groups of the UDV, termed
nucleos
, are similar to a ChristianHutterite sect, in that each group has a limitedmembership, which then splits to form a new grouponce the membership expands beyond the set limit.The
nucleo
consists of the congregation, a groupleader or mestre, various acolytes undergoing a courseof study and training in order to become mestres, anda temple, an actual physical structure where thesacrament is prepared and consumed at prescribedtimes, usually the first and third Saturday of eachmonth. The membership of these newer syncreticgroups spans a broad socio-economic range andincludes many educated, middle-class, urbanprofessionals (including a number of physicians andother health professionals). Some older membershave engaged in the practice for 30 or more yearswithout apparent adverse health effects. The UDV andthe Santo Daime sects are the largest and mostvisible of several syncretic religious movements inBrazil that have incorporated the use of 
ayahuasca
into their ritual practices. Of the two larger sects, itis the UDV that possesses the strongestorganizational structure as well as the most highlydisciplined membership. Of all the
ayahuasca
churches in Brazil, the UDV has also been the mostpivotal in convincing the government to remove
ayahuasca
from its list of banned drugs. In 1987, thegovernment of Brazil approved the ritual use of 
 
 McKenna et al., Investigation of ayahuasca
66
hoasca
tea in the context of group religiousceremonies. This ruling has potentially significantimplications, not only for Brazil, but for global drugpolicy, as it marks the first time in over 1600 yearsthat a government has granted permission to its non-indigenous citizens to use a psychedelic in thecontext of religious practices.
Botanical, Chemical, and PharmacologicalAspects of 
 Ayahuasca
 Ayahuasca
is unique in that its pharmacologicalactivity is dependent on a synergistic interactionbetween the active alkaloids in the plants. One of thecomponents, the bark of 
 Banisteriopsis caapi
,contains ß-carboline alkaloids, which are potentMAO-A inhibitors; the other component, the leavesof 
Psychotria viridis
or related species, contains thepotent short-acting psychoactive agent N,N-dimethyltryptamine (DMT). DMT is not orallyactive when ingested by itself, but can be renderedorally active in the presence of a peripheral MAOinhibitor - and this interaction is the basis of thepsychotropic action of 
ayahuasca
tea (McKenna,Towers, & Abbott, 1984).
1. Botanical sources of ayahuasca
In a traditional context,
Ayahuasca
is a beverageprepared by boiling - or soaking - the bark and stemsof 
 Banisteriopsis caapi
together with variousadmixture plants. The admixture employed mostcommonly is the Rubiaceous genus
Psychotria
,(Rubiaceae), particularly
P. viridis.
The leaves of 
P.viridis
contains alkaloids which are necessary for thepsychoactive effect (see the sections on chemistry andpharmacology, below). There are also reports(Schultes, 1972) that other
Psychotria
species,
especially P. leiocarpa
or
P. carthaginensis
, are usedinstead of 
P. viridis
, but such reports may be due to abotanical misidentification; in any case, use of 
Psychotria
species other
than P. viridis
is rare. Inthe Northwest Amazon, particularly in theColombian Putumayo and Ecuador, the leaves of 
 Diplopterys cabrerana
, a jungle liana in the samefamily as
 Banisteriopsis
, are added to the brew inlieu of the leaves of 
Psychotria
. The alkaloid presentin
 Diplopterys
, however, is identical to that in the
Psychotria
admixtures, and pharmacologically, theeffect is the same. In Peru, various admixtures inaddition to
Psychotria
or
 Dipolopterys
are frequentlyadded, depending on the magical, medical, orreligious purposes for which the drug is beingconsumed. Although a virtual pharmacopoeia of admixtures are occasionally added, the mostcommonly employed admixtures (other than
Psychotria
, which is a constant component of thepreparation) are various Solanaceous genera,including tobacco (
 Nicotiana
sp.),
 Brugmansia
sp.,and
 Brunfelsia
sp. (Schultes, 1972; McKenna, et al.,1995). These Solanaceous genera are known tocontain alkaloids, such as nicotine, scopalamine, andatropine, which effect both central and peripheraladrenergic and cholinergic neurotransmission. Theinteractions of such agents with serotonergic agonistsand MAO inhibitors are essentially unknown inmodern medicine.
 2. Chemistry of Ayahuasca and its source plants
The chemical constituents of 
ayahuasca
and thesource-plants used in its preparation have been wellcharacterized (McKenna, et al., 1984; Rivier &Lindgren, 1972).
 Banisteriopsis caapi
contains theß-carboline derivatives harmine, tetrahydroharmine,and harmaline as the major alkaloids (Callaway, etal., 1996). Trace amounts of other ß-carbolines havealso been reported (McKenna, et al., 1984; Rivier &Lindgren, 1972; Hashimoto and Kawanishi, 1975,1976) as well as the pyrrolidine alkaloids shihunineand dihydroshihunine (Kawanishi et al. 1982). Theadmixture plant,
Psychotria viridis
, contains a singlemajor alkaloid, N,N-dimethyltryptamine (DMT),while N-methyl tryptamine and methyl-tetrahydro-ß-carboline have been reported as trace constituents(McKenna, et al., 1984; Rivier & Lindgren, 1972).The admixture plant
Psychotria carthagenensis
hasbeen reported to contain the same alkaloids (Rivier &Lindgren, 1972) but a subsequent investigation couldnot confirm the presence of DMT in the singlecollection examined (McKenna, et al., 1984). Theconcentrations of alkaloids reported in
 Banisteriopsiscaapi
range from 0.05 % dry weight to 1.95 % dryweight; in
Psychotria,
the concentration of alkaloidsranged from 0.1 to 0.66 % dry weight (McKenna, etal., 1984; Rivier & Lindgren, 1972). Similar rangesand values were reported by both groups of investigators.The concentrations of alkaloids in the
ayahuasca
beverages are, not surprisingly, several times greaterthan in the source plants from which they areprepared. Based on a quantitative analysis of themajor alkaloids in several samples of 
ayahuasca
collected on the upper Rio Purús, Rivier & Lindgren(1972) calculated that a 200 ml dose of 
ayahuasca
contained an average of 30 mg of harmine, 10 mgtetrahydroharmine, and 25 mg DMT. Callaway, etal., determined the following concentrations of alkaloids in the
hoasca
tea utilized in the biomedicalstudy with the UDV (mg/ml): DMT, 0.24; THH,1.07; harmaline, 0.20; and harmine 1.70. A typical100 ml dose of hoasca thus contains in mg: DMT,24; THH, 107; harmaline, 20; harmine, 170.Interestingly, these concentrations are above thethreshold of activity for i.v. administration of DMT(Strassman & Qualls, 1994).McKenna et al. (1984) reported somewhat highervalues for the alkaloid content of several samples of Peruvian ayahausca. These investigators calculatedthat a 100 ml dose of these preparations contained atotal of 728 mg total alkaloid, of which 467 mg isharmine, 160 mg is tetrahydroharmine, 41 mg isharmaline, and 60 mg is DMT. This is well withinthe range of activity for DMT administered i.m.(Szara, 1956) or i.v. (Strassman & Qualls, 1994) andis also well within the range for harmine to acteffectively as a monoamine oxidase inhibitor (MAOI).
 
The Heffter Review of Psychedelic Research, Volume 1, 1998
67In vitro, these ß-carbolines function as MAOI atapproximately 10 nM (e.g., harmine's IC
50
for MAOIis ~1.25 x 10
-8
M; cf. McKenna, et al., 1984;Buckholtz & Boggan, 1977). In mice, harmalineadministered i.p. at 5 mg/kg causes 100% inhibitionby 2 hours post-injection, the activity falling off rapidly thereafter (Udenfriend et al. 1958) This dosecorresponds to approximately 375 mg in a 75 kgadult, but, based on the measured concentration of harmine in the liver, it is likely that one half thisdose or less would also be effective. The reasons forthe discrepancy in alkaloid concentrations betweenthe samples examined by Rivier & Lindgren (1972)and those examined by McKenna, et al. (1984) arereadily explained by the differences in the methods of preparation. The method employed in preparing
ayahuasca
in Pucallpa, Peru, where the samplesanalyzed by McKenna et al. (1984) were collected,results in a much more concentrated brew than themethod employed on the upper Rio Purús, the regionwhich was the source of the samples examined byRivier & Lindgren. The concentrations and propor-tions of alkaloids can vary significantly in differentbatches of 
ayahuasca
, depending on the method of preparation, as well as the amounts and proportionsof the source-plants.The notion that the ß-carbolines, by themselves,are hallucinogenic and thus contribute to the overallhallucinogenic activity of the ayahuasca beverage, wasbased on flawed earlier research (Naranjo, 1967) andhas been discredited (Callaway, et al., 1997). AsMAO inhibitors, ß-carbolines can increase brainlevels of serotonin, and the primarily sedative effectsof high doses of ß-carbolines are thought to resultfrom their blockade of serotonin deamination. Theprimary action of ß-carbolines in the ayahuascabeverage is their inhibition of peripheral MAO-A,which protects the DMT in the brew from peripheraldegradation and thus renders it orally active. Thereis some evidence, however, that tetrahydroharmine(THH), the second most abundant ß-carboline in thebeverage, acts as a weak 5-HT uptake inhibitor andMAOI. Thus, THH may prolong the half-life of DMT by blocking its intraneuronal uptake, andhence, its inactivation by MAO, localized inmitochondria within the neuron. On the other hand,THH may block serotonin uptake into the neuron,resulting in higher levels of 5HT in the synaptic cleft;this 5-HT, in turn, may attenuate the subjectiveeffects of orally ingested DMT by competing with itat post-synaptic receptor sites (Callaway, et al.,1997).
 3. Pharmacological actions of Ayahuasca and its Active Alkaloids
The hallucinogenic activity of 
ayahuasca
is afunction of the peripheral inactivation of MAO by theß-carboline alkaloids in the mixture. This actionprevents the peripheral oxidative deamination of theDMT, which is the primary hallucinogeniccomponent, rendering it orally active and enabling itto reach its site of action in the CNS in an intactform. (McKenna, et al 1984; Schultes, 1972). DMTalone is inactive following oral administration atdoses up to 1000 mg (Shulgin, 1982; Nichols, et al.1991). DMT is active by itself following parenteraladministration starting at around 25 mg (Szara, 1956;Strassman & Qualls, 1994). Because of its oralinactivity, various methods of parenteraladministration are employed by users. For example,synthetic DMT is commonly smoked as the freebase; in this form, the alkaloid volatilizes readily andproduces an immediate, intense psychedelic episodeof short duration (5 -15 min), usually characterized bymulticolored, rapidly moving visual patterns behindthe closed eyelids (Stafford, 1977). The YanomamoIndians and other Amazonian tribes prepare a snuff from the sap of various trees in the genus
Virola
,which contain large amounts of DMT and the relatedcompound, 5-methoxy-DMT, which is also orallyinactive (McKenna, et al. 1985; Schultes andHofmann, 1980). The effects of the botanical snuffscontaining DMT, while not as intense as smokingDMT free base, are similarly rapid in onset and of limited duration [unpublished data]. The
ayahuasca
beverage is unique in that it is the only traditionallyused psychedelic where the enzyme-inhibitingprinciples in one plant (ß-carbolines) are used tofacilitate the oral activity of the psychoactiveprinciples in another plant (DMT). The psychedelicexperience that follows ingestion of 
ayahuasca
differsmarkedly from the effects of parenterally ingestedDMT; the time of onset is approximately 35-40minutes after ingestion, and the effects, which are lessintense than parenterally administered syntheticDMT, last approximately four hours. The subjectiveeffects of 
ayahuasca
include phosphene imagery seenwith the eyes closed, dream-like reveries, and afeeling of alertness and stimulation. Peripheral auto-nomic changes in blood pressure, heart-rate, etc., arealso less pronounced in
ayahuasca
than parenteralDMT. In some individuals, transient nausea andepisodes of vomiting occur, while others are rarelyaffected in this respect. When
ayahuasca
is taken ina group setting, vomiting is considered a normal partof the experience and allowances are made toaccommodate this behavior (Callaway, et al., 1997).The amounts of ß-carbolines present in a typicaldose of 
ayahuasca
are well above the threshold foractivity as MAOI. It is likely that the maincontribution of the ß-carbolines to the acute effects of 
ayahuasca
results from their action as peripheralMAO inhibitors, rendering DMT orally active. It isworthy of note that ß-carbolines are highly selectiveinhibitors of MAO-A, the form of the enzyme forwhich serotonin, and presumably other tryptamines,including DMT, are the preferred substrates(Yasuhara, et al., 1972; Yasuhara, 1974). Thisselectivity of ß-carbolines for MAO-A over MAO-B,combined with their relatively low affinity for liverMAO compared to brain MAO, may explain whyreports of hypertensive crises following the ingestionof 
ayahuasca
have not been documented. On theother hand, Suzuki et al. (1981) has reported thatDMT is primarily oxidized by MAO-B; it is
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