On the Comparative Ethnopharmacology of Malpighiaceous and Myristicaceous Hallucinogens

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This article discusses comparative ethnographic,ethnobotanical, phytochemical and pharmacological as-pects of two Amazonian hallucinogens. The hallucino-genic drink ayahuasca is prepared from t}le lianaBanisteriopsis caapi (Malpighiaceae) and sundry admix-rure plants, notably Diplopterys cabrerana and variousPsychonia spp. (Schultes 1957). The cambial resin ofcenain members of the genus Virola (Myristicaceae) isthe source of hallucinogenic snuffs and oraliy ingestedhallucinogenic pastes used by some tribes (Schultes197 9).Although derived from entirely different botanicalsources, similar alkaloids - tryptamines and p-carbo-iines - are the active constiruents of both preparations.In the case of ayahuasca and the orally ingested Virolapastes, it has been suggested that monoamine oxidaset.\lAO) inhibition - due to the p-carbolines - protectsthe hallucinogenic tryptamines from oxidadve deamina-tion by peripherai MAO and thus permits their oralactivity (Schultes I972, 1969; Der Marderosian, Pinkley& Dobbins 1968). Experimental investigations of thisposrulated mechanism of oral activity - involving invitro evaluations of the drugs and their constinlents as\1,\O inhibitors (MAOI) - have been reponed in otherrnicles (McKenna, Towers & Abbott 1984a, 1984b).The present article summarizes the results of thesecomparative studies of ayahuasca and rhe Myristicaceous

'Department of Botany, University of British Columbia,\'ancouver, British Columbia, Canada V6T 1W5. Please addressrcprint requests to Dennis J. McKenna, P.O. Box 16942" SanDiego, California 92116.Journal of Psycboactiue Drugs 35 Vol. 17(1) Jan-Mar, 1985

On the CompatatlveEthnopharmacology of

Malpighiaceous andMyristicaceous Hallucinogens

DENNTS J. McKENNA* & G.H.N. TowERS*

hallucinogens. Complete details of these phytochemicaland pharmacologicai investigations may be found inMcKenna, Towers & Abbott (1984a, 1984b).

AYAHUASCAThe contemporary use of ayahuasca in South

America occurs primarily within the context of mestizofolk medicine, which is comprised of an amalgam ofmany tribal traditions. Although most of these tribeshave long since fragmented or disappeared, much oftheir ethnobotanical lore has survived and been adoptedby the mestizos. Ayahuasca is pan of this lore and itoccupies a central and importanr position in mestizofoik medicine. Not only is it employed as a generalcure-all for the treatment of many disorders rangingfrom mental illness to parasites, it is also the ayahuas-quero's or healer's passport to supernatural dimensionswhere the skills intrinsic to the healer's profession can beacquired. It enables the healer to leam the medicinaluses of plants - as well as the songs and chants used inthe healing ceremonies - with which the healer is able todiagnose diseases, divine the supernatural causes ofiliness, predict the furure, and see and communicateacross distances. Whether or not there is a rational basisfor any of these practices, an impressive pharmacopoeiaof plants - many of which do contain highly bio-dynamic constituents - is (or can be) used in conjunc-tion with ayahuasca (McKenna, Luna & Towers 1984).

Phytochemical investigations (McKenna, Towers &Abbott 1984a) have found that most mestizo ayahuascabrews contain substantial amounts of p-carbolines and


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MC KENNA & TOWERSN,N-dimethyltryptamine (DMT). The major p-carbolinesare harmine and tctrahydroharmine, with lesser amountsof harmaline. Only traces of other p-carbolines weredetected. The amounts of p-carbolines in these sampleswere several orders of magniude greater than thosereported in an earlier study of ayahuasca prepared bytribes inhabiting the upper Rio Purus in southwesternPeru (Rivier & Lindgren 1972). A typical 100 ml dose ofmestizo ayahuasca contains between 500 and 800 mgp-carbolines and 40-80 mg DMT. This is well above thehallucinogenic threshold dose for DMT and within therange at which the B-carbolines are effective MAOIs.However, it is still well below the threshold level forhallucinogenic activity of the p-carbolines. Thereforethese data indicate that the hallucinogenic activity ofayahuasca is probably due to DMT, which is orallyactivated by some mechanism, presumably the I{AOinhibition induced by the high concentration of p-carbo-lines. This hypothesis is supponed by the finding thatayahuasca is a very effective inhibitor of MAO in vitroeven when diluted by many orders of magnitude(McKenna, Towers & Abbott 1984a).A number of ayahuasca samples, brewed by differ-ent practitioners in different parts of Peru, were ana-lyzed. Although the same alkaloids were consistentlyfound, the samples differed mainly in the concentrationand proponions of various components. Concentrationdifferences are expected as this is dependent on theamount of plant material extracted and other variablesin the preparation procedure. Proportional differencesmay be attributable to the use of different B. caapicultivars. It is remarkable that, faced with so manyvariables, ayabuasqueros all across Peru manage tomanufacture a drug having a high degree of pharmaco-logical consistency from batch to batch. Except forconcentration and proportional differences, all of theayahuasca samples anzlyzed could have been taken fromthe same pot. Ail of the DMT-containing admixrureplants that were analyzed were similar and DMT was thesingle major base in all of them, while only traces ofother alkaloids were detected. The concentration ofDMT was between 1.0-2.0 mglg dry weight in allsamples. Similar consistenry was not found in the severalB. caapi cultivars that were analyzed. More or less thesame constituents were present, but concentrationsranged from 1.7 mg/g dry weight (total alkaloids) toL3.6 mglg dry weight. These differences probably aredue to environmental factors rather rhan ro geneticallybased biochemical differences between cultivars.

M YRISTICACEOUS HALLUCIN OGEN SUniike ayahuasca, the use of hallucinogenic prepara-

Journal of Psycboactiae Drugs

HALLUCINOGENStions derived from Virola spp. or other Myristicaceousgenera is a practice confined to a few indigenousAmazonian tribes and has never become integrated intomestizo folk medicine (Schultes 1979). As a result, theuse of these Myristicaceous drugs has diminished or insome cases disappeared as the tribal societies havefragmented due to outside influenccs. This is particularlytrue of the orally ingested Myristicaceous pastes. Use ofVirola spp. as an oral hallucinogen is more ethnologicallyrestricted than its use as a snuff. It has been reportedamong the Bora, Witoto, Muinane and possibly theMaku, but apparently does not occur outside thesegroups. Even within these tribes, the source plants,methods of preparation and modes of usage of the oralVirola drug are the specialized knowledge of the healersand are not known to most members of the uibe.Another complicating factor is that the Bora and Witotopopulations inhabiting the Rio Ampiyacu region, wherethe fieldwork for this study was carried out, are notindigenous to that area but migrated there from north ofthe Rio Putumayo in the early decades of this centuiy,as a result of the dislocations produced by the rubberindustry. This has not contributed to the preservation oftheir ethnomedical traditions nor any other rribalinstitutions. The result is that local knowiedge of theoral Myristicaceous drugs has become, in some cases,ra!her inexact.Work reported elsewhere (McKenna, Towers &Abbott 1984b) has shown that there is a high degree ofvariability in the type and amount of alkaloid constiru-ents, not only among different Virola spp., but evenamong different collections of the same species. Thecomposition of the orally ingested paste samples thatwere analyzed was similarly variable, both qualitativelyand quantitatively. Prezumably this is a reflection of thechemical variabiliry of the source plants. Thus, while allof the ayahuasca samples had essentially the sameconstituents (with DMT being present or absent, depend-ing on which Psychotria sp. was used as admixture), zorone of the oral Virola pastes had the same basecomposition as any other one. Large differences in theconcentration of alkaloids in various samples were alsofound. Either this high degree of chemical variability hasalways been a fearure of these orally ingested pastes orthe criteria that were formerly used to select ttrestrongest Virola species to prepare the paste (e.g., taste,smell and/or visual appearance of the resin) have beenlaryely forgotten and the selection now has become afairly haphazard process. If the former possibility is true,this may explain why the paste was restricted to thehealers and why they usually consumed it alone. If onlyone out of every three or four samples actually rs orally

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MC KENNA & TOWER5active, this information was probably kept from thepeople at large, in order to preserve their faith in theefficacy of the healer and the medicines.Another objective of these investigations was toexamine the mechanism for the (presumed) oral activityof rhese Myristicaceous pasres: Is it due, like ayahuasca,ro rhe oral activation of the tryptamine constituentsthrough the inhibition of visceral MAO by p-carbolines?In the process of answering some of these questions,these investigations have created new and even morepuzzling ones. In the first instance, p-carbolines were norconsistently found as constituents of all of the pastesamples. Even in the two samples containing p-carbo-lines, only traces were detected. Those p-carbolines that-^ere fould belong ro the rerrahydro-p-carboline type,rvhich are poor MAOIs compared to the dihydro- andfully aromatic p-carbolines. A further point is that thepresence or absence of p-carbolines in the past samplesapparently had litrle or nothing to do with their oralactivity or inactiviry as derermined by self-experimenrs(,\lcKenna, Towers & Abbott 1984b). The paste samplethat contained rhe highest levels of p-carbolines wasc ompletely inactive in repeated self-experiments.Another sample that contained only high concentrationsof 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) inthe base fraction was highly orally acrive, although theactivity was nor rypical of hallucinogens. Although theIl;-risticaceous paste samples did exhibit some degree ofIiAO inhibirion, this was shown to be primarily, if notentirely, due to the tryptamine constituents, whilenonalkaloidal constituents from the samples showedonll a slight degree of nonspecific inhibition (McKenna,Towers & Abbott 1994b). Most of rhe synthetictryptamine derivatives rhat were assayed as MAOIs didexhibit some activiry, but the 156 values were usuallyseveral orders of magnitude iower than those for theficarboline derivatives. Interestingly, DMT showed themost MAOI activity of dl the typtamine derivativestested: Irs I5s was comparable to tetrahydroharmine(THH), one of the least acrive of the p-carbolines. Ail ofthis evidence considered togelher suggesrs that rhe^\tvristicaceous pastes, when they are oraally active, mustorve their acrivity to some mechanism otber than MAOinhibition, wherher due to p-carbolines or other con-

s ti ru en ts.What alternative mechanism might account for oralrclivity of some samples? There are basically twopossibilitie s worrh considerarion and both would requireiurther experimental investigations to confirm them.Thc first is thar the oral acriviry of the Myristicaceousp.tstes is not due to the tryptamines at all, but rather toIttme other biologically active constituents, such asJrttrnol of psycboactiue Dntgs 37

HALLUCINOGENSlignans (phenylpropanoid dimers). Certainly this wouldhelp to explain why the oral activiry observed inself-experiments was atyptical for hallucinogens. It isequaliy possible, however, that tryptamines taken orallydiffer significanrly in their effects from tryptaminesadministered parenterally. Thar Virola resin (includingthe sample assayed) does contain biologically activelignans has been established (MacRae & Towers l9g4a),but whether or not these lignans are capable of elicitingthe spectrum of biological responses observed in thebioassay is not known. The second possibility, whichalso calls for much funher experimental investigation, isthar the oral inactivation of DMT, 5-MeO-DMT andrelated derivatives is zot due to oxidative deaminationby peripheral MAO. Alternative metabolic parhwaysmay be relatively more significant in rhe degradation ofthese compounds in peripheral tissues.Both in vitro and in vivo studies of DMT metab-olism (Barker, Monti & Christian 19gO; Szara & Axelrod1959) suggest that 6-hydroxylation and/or N-oxidationof DMT occurs more readily in peripheral tissues thandeamination by MAO. 6-Hydroxylation has been shownto occur in peripheral rissues, but apparently not in thebrain (Barker, Monti & Christian 1980; Szara & Axelrod1959). Significantly, 6-hydroxy derivatives of DMT andrelated compounds are inactive as hallucinogens (Shulgin1976). Little is known of the hallucinogenic aclion ofN,N-dimethyltryptamine-N-oxide (DMT-NO), but if itfollows the general pattern for tertiary amine N-oxides(Bickel 1969), it would either be completely inactive or1O to 100 times less acrive rhan DMT. Other studies ofin vivo DMT metabolism in the presence of MAOIs andmicrosomal mixed function oxidase (MFO) inhibitors(Shah & Hedden L977) have found that while the MAOIiproniazid prolongs plasma and tissue halflife of DMT,the MFO inhibitor SKF-525,4. does not. The authorsinterpret these results as supporr for the hypothesis thatDMT is metabolized mainly by MAO in vivo.A problem with most in vivo studies of the fypereported by Shah and Hedden is that the DMT isadministered to rhe animal intraperitoneally rather thanorally, thus the compound reaches the circulationdirectly and avoids intestinal/heparic-portal shunr me-tabolism. It is possible that the metabolism of DMT viathe intestinal/hepatic-portal shunt may differ in impor-tant respects from its metabolism when introduceddirectly into the bloodstream or body cavity. In thehepatic shunt, 6-hydroxylation and/or N-oxidation maybe more important than MAO as a catabolic route forthe compound. In any evenr, in vivo metabolic studiesinvolving intraperitoneal or other parenteral routes ofadministration acrually shed little light on DMT metabo-

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C KENNA & TOWERSlism following oral administration.The fact is that current understanding of theperipheral metabolism of DMT and related compounds isfar from complete. All that is known for certain is thatmore than one type of oxidative reaction is involved.MAO may be partiaily responsible for the degradation oftryptamines in the periphery, but microsomai MFOs,which are involved in both the 6-hydroxyl and N-oxidepathways, are possibly even more important. Interest-ingly, if orally administered DMT ls a substrate formicrosomal oxidases, then a mechanism can be proposedto explain the oral activity of some Tirola pastes, eventhough they lack p-carbolines and are not significantiveffective'as MAOIs, This alternative mechanism posru-lates that some of the nonalkaloidal constiruents in thepastes may possess antioxidant activity and/or exhibiractivity as specific inhibitors of microsomal MFOs. Inthe former case, presence of high concenuations ofnonspecific antioxidants could scavenge a high propor-tion of the molecular oxygen in the viciniry, thusmaking less of it available as cosubsrrate for themicrosomal enzymes catalyzing DMT N-oxidation and6-hydroxylation. In the latter cas, constituents in theVirola resin may specifically inhibit hepatic microsomalMFOs and thus block the oxidation(s) of DMT causedby these enzymes. In either case, the compound couldbe protected from oxidative transformation in theintestinal/hepatic shunr and thus be taken up into thecentral nervous sysrem (CNS) in the form of theunchanged tertiary amine.A number of Iignans have been characterized thatexhibit protective activiry against hepatotoxins (MacRae& Towers 1984b); inhibition of hepatic MFO has beenproposed as the probable mechanism. All of the activecompounds possessed a methyienedioxyphenyl moiery,but analogues lacking this configuration did not havehepatoprotective properties. The methylenedioxyphenylgroup has been implicated in other studies as the mainpharmacophore responsible for MFO inhibition (Brart-sten 1977). The Myristicaceous genera Viroh andIryantbera are both rich in constituents incorporatingthe methylenedioxyphenyl group, including fatty acidderivatives, neolignans, flavones and diarylpropanoids(Gottleib 1979).

Several novel lignans having this substitution werecharacterized in the bark of DMK-59 (V. elongata),which was the source plant for the paste sample thatshowed the greatest degree of oral activiry in self-ex-periments (MacRae & Towers L984a; McKenna, Towers& Abbott 1984b). A number of other phenolic com-pounds, including flavones, flavonoids, isoflavonoids,diarylpropanoids and neolignans, have been isolatedJournal of Psycboactiue Drugs

HA LLUCINOGENSfrom a number of Virola and, Iryantha.d spp. Some ofthese compounds could act as antioxidants and couldcontribute to the inactivation of MFOs via this non-specific mechanism. In any case, rhe peripheral merabo.lism of DMT and relared compounds, foliowing oraladministration, may be significantly altered in thepresence of antioxidants and/or specific MFO inhibitors.Under these conditions, the compound might well reachthe CNS in the form of the unchanged tertiary amine.Further in vivo and in viuo experiments would berequired to confirm or disprove this alternative mecha-nism of oral activiry. In view of the phytochemical andpharmacological data accumulated in the presenr study,it appean that this alternative hypothesis is at least asprobable - if not more probable than MAO inhibi-tion - as the mechanism responsible for the oral activityof the Myristicaceous pasres. .

CONCLUSIONPhytochemical and pharmacological informationcollected in the course of these authors' srudies has beeninsufficient to definitely establish the mechanism of oralactivity in two Amazonian hallucinogens. However, irhas provided phytochemical data and in viuo pharmaco-logical evidence that indicates, in the case of ayahuasca,that the original hypothesis proposed to explain the oralactivity has not been disproved. Certainly ayahuascacontains high enough concentrarions of p-carbolines toeffectively inhibit MAO and by this mechanism rheactive hallucinogenic consrituent DMT may be protectedfrom peripheral degradative metabolism. The alternativemechanism proposed in the above discusion may also be

implicated in the pharmacology of ayahuasca, but atleast it is not zecessary to invoke this mechanism forayahuasca. In the case of the orally ingested Myrisri-caceous preparations, however, these investigations indi-cate that MAO inhibition - whether due to p-carbolinesor some other constiruents - is almost certainly not themechanism responsibie for their oral activity. The pastesdo not contain more than traces of p-carbolines, theyshow poor activity as MAOIs and their oral activiry,when present, is not correlated with the presence ofp-carbolines. Some alternative mechanism musr thereforebe invoked to explain the oral acrivity of these Myristi-caceous pastes. Two such alternatives have been dis-cussed above. One is that the oral activity is due tobiologically active consrituents other than trypramines.The other possibiiity is that the active trypramines areprotected from peripheral degradation by constituentsthat inhibit hepatic MFOs, the enzymes responsible for6-hydroxylation and N-oxidation of tryptamine deriva-tives. MFO inhibitors require rhe presence of a methyl-

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MC KENNA & TOWERSenedioxyphenyl configuration as the active pharma-cophore, and Virola spp. are excellent sources ofcompounds possessing this moiety. Unfortunately,neither alternative mechanism can be proven or dis-proven until more has been learned about the in vivo

Barker, S.A.; Monti, J.A. & Christian, S.T. 198O' Metabolisrn ofthe hallucinogen N,N-dimethyltryptamine in rat brain homog'enrtes. B io c b e m i c al P h arm a c ol o gt Y ol. 29 t |04.*lO 57'Bickel, I!'|"H. 1969. The pharmacologr and biochemistry ofN-oxides. Pbarmacological Revieus Vol. 21: t2+358'Brxnster\ L.B. 1977, Biochemical defense mechanisrns in herbi-vores against Plant allelochemicals. In: Rosenthal, G.A. &Janzeq D.H. (Eds.). Herbiuorcs: Tbeir Interactions uitbSecondary Metabolites. New York: Academic Press.Der Marderosiar\ A.H.; Pinkley, H.V. & Dobbins, Ivt F., IV.1968. Native use and occurrence of N,N-dimethyltryptaminein the leaves of. Banisteriopsis rusbyana. Ameican Journal ofPbarmacy Vol.' 14o: L37'147.Gotdieb, O.R. 1979. Chemical studies on medicinal Myristicaceae from Amazonia Journal of Etbnophannacologl,r YoLl: 3O*323.MacRae, W.D. & Towerg G.H.N. 1984a- An etinopharmaco-logicd examination of Virola elongata bark: A SouthAmerican anow poison. Journal of Etbnopbarmacologgt Yol.12:7j92.MacRae, W.D. & Towerg G.H.N. 1984b. Biologicd activities oflign:r,s. Phytocbemistry In press,McKenna, D.J.; Luna, L.E. &Towers, G.H.N. 1984. Biodynamicconstiruents in ayahuasca admixrure plants: An uninvesti-gated fol k pharmacopoeia Unpubl ished manuscripcMcKenn4 D.J.; Towers, G.H.N. & Abbott, F.S. 1984a- Monoamine oxidase inhibitors in South American hallucinogenicplants: Tryptamine and p-carboline constituents of aya'huasca. Jouraal of Etbnopbarmacolopt Vol. 1O: 79r22t.IlcKenna- D.J.; Towers, c.H.N. & Abboa, F.S. 1984b. Mone

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HALLUCINOGENSmetabolism of DMT end related compounds. An obviousplace to start would be to study tlre metabolism oforally administered DMT in the presence of known MFOinhibitors.

REFERENCESamine oxidase inhibitors in South American hallucinogenicplants Part 2: Constiruents of orally'active Myristicaceoushallucinogens. Journal of Etbnopbarmacologit Vol. 12:179-211.Rivier, L & Lindgrer\ l. 1972. Ayahuasca, the Soutl Americanhallucinogenic drink: Ethnobotanical and chemical investi-gations. Economic Botany Yol.29t l0l'129.Schultes, R.E. 1979. Evolution of the identification of theMyristicaceous hallucinogens of South America. Journal ofE thno pbarmac o Io gt Y ol. I r 271-239.

Schultes, R.E. 1972. Ethnotoxicological significance of additivesto New World hallucinogens. Plant Science Bulletin Vol. 18:3+41.Schultes, RE. 1969. Virola zs an orally administered hallucine

gen. Botanical Museum Leaflets, Harvard University Yol. 22t22*240.Schultes, RE. 1957. The identity of the Malipighiaceousnarcotics of South America- Botanical Museum Leaflets,Harvard Universiry Vol. 18: 1-56.Shah, N.S. & Hedderl M.P. 1977. Behaviord effects endmetabolic fate of N,N-dimethyltryptamine in mice pretreatedwith p-diethylaminoethyl-diphenylpropylacetate (SKF-52iA), iproniazid and chlorpromazine. Pbarmacolog5t, Bio-chemistry and Bebatsior Vol. 8: 351-356.Shulgin, A.T. t976. Psychotomimetic agents. In, Gordon, M.(Ed.r. Psycbopharmacological Agents Yol. IV. New York:Academic Press.

Szara, S. & Axelrod, J. 1959. Hydroxylation and N-demethyl-etion of N,N-dimethyltryptamine. Experientia Vol. 15:2LG2l7.

On the Comparative Ethnopharmacology of Malpighiaceous and Myristicaceous Hallucinogens

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