A Pharmacological Study of Ayahuasca in Healthy VolunteersJordi Riba and
Manel J. Barbanoj, M.D., Ph.D.
This study aims to be the first controlled pharmacological study of ayahuasca in humans undertaken in a Western country and with local volunteers who are familiar with its consumption.
THERE CAN BE few natural psychoactive preparations whose consumption has increased so spectacularly as has that of ayahuasca in Europe over the last decade. The Amazonian inebriant par excellence, whose Quechuan name means "vine of the souls" or "vine of the dead" enjoys great prestige among several intellectual circles and in certain religious practices of Brazilian origin as a medium facilitating introspection and self knowledge. The fact that it is natural is highly valued in these spheres, to the detriment of synthetic drugs with analogous properties to which, in contrast, inferior qualities or clearly harmful properties are attributed. Although ayahuasca is not as widely used by the general public as amphetamine derivatives of the MDMA type are, it has a achieved a certain popularity and is beginning to attract media attention in Spain; in Summer 1997 a weekly general interest magazine labelled it a "fashionable drug" on the Spanish island of Ibiza.
Our study aims to be the first controlled pharmacological study of ayahuasca in humans undertaken in a Western country and with local volunteers who are familiar with its consumption. In this first phase we do not intend to discuss the possible adverse psychopathological effects derived from repeated consumption, nor to study the hypothetical therapeutic qualities suggested by some. In addition to collecting information about the preparation's pharmacokinetics and tolerability after the administration of different single doses we also aim to place special emphasis on its neurophysiological and subjective effects; quantitative pharmaco- electroencephalography and an evaluation scale of the subjective effects of hallucinogens, whose validation in Spanish will be undertaken in the course of the project, will be used respectively. We also aim to model pharmacokinetic-pharmacodynamic relationships using N,N-dimethyltryptamine (DMT) plasma levels and the modifications observed in the electroencephalogram.
In addition to the study's pharmacological aspects we propose to collect information regarding phenomenological aspects of the experience through interviews with the volunteers after the experimental sessions. This is a very ambitious project indeed and our group is therefore in contact with Rick J. Strassman, a psychiatrist who consulted, and James C. Callaway, a neurochemist who participated in the 1993 Hoasca Project and who have kindly made valuable suggestions for the carrying out of this study.
We shall now take a brief look at the recognised pharmacological aspects of ayahuasca and comment on the objectives and methodological issues of this study.
The pharmacology of ayahuasca
Of the four main alkaloids which the drink contains it is DMT which is chiefly responsible for its hallucinogenic effects. DMT is a potent ultra-short acting hallucinogen present in numerous species of plant growing in temperate and tropical regions. Before its presence in ayahuasca was discovered it had in fact been identified, along with other indole derivatives in Anadenanthera hallucinogenic snuffs which had been used in South America since before Columbus. The compound is remarkable within the hallucinogen family because of its pharmacological characteristics; when administered parenterally it produces extremely strong effects which are felt almost immediately (intravenously) or within around ten minutes (intramuscularly), to disappear within the space of about half an hour or forty-five minutes. Surprisingly, when the drug is administered orally it provokes no psychoactive effects whatsoever, even in doses as high as a gram, appearing to be entirely destroyed in the intestines and at hepatic level by monoamine oxidase (MAO), an enzyme which is widely distributed throughout the body, and thus prevented from reaching systemic circulation and the brain. Because of DMT's inactivity when taken orally several other methods of parenteral administration have been used; Anadenanthera and Virola snuffs are taken through the nose and synthetic DMT has circulated in a free base form for smoking.
On a molecular level DMT interacts equally with serotonin 5- HT1a and 5-HT2a/2c receptor sites, just like LSD does. Unlike LSD, however, repeated administration of DMT does not lead to tolerance of the subjective effects, or at least it has not done so in studies carried out to date. Furthermore, DMT does not show cross tolerance with this classic hallucinogen; that is, an individual who has developed tolerance to the effects of LSD through repeatedly taking the drug will experience full hallucinogenic effects if administered a dose of DMT.
What is truly extraordinary about ayahuasca is that in a single preparation it combines DMT which is inactive when taken orally with the ß-carbolines referred to above. These tricyclic compounds, to which proserotonergic and prodopaminergic properties are attributed, lack hallucinogenic activity but in vitro they display a potent inhibiting activity with respect to the MAO enzyme, or to be more precise, the isoenzyme MAO-A. In line with the generally accepted hypothesis the ß-carbolines' inhibiting of this enzyme would prevent the oxidative deamination of the DMT, which could then reach and exercise its effects on the central nervous system. The experience which follows the ingestion of ayahuasca differs from the effects of parenterally administered DMT by being less intense and of greater duration; the onset of its effects is not instantaneous but occurs approximately an hour after ingestion and the effects usually last for a maximum of two hours, to disappear altogether after around three or four hours. In addition, adverse events such as nausea and vomiting, which are not observed in the parenteral administration of DMT and which are attributable to the action of the ß-carbolines, frequently occur. The inhibiting of the MAO brings with it an increase in endogenous catecholamine and serotonin levels which would modulate the effects of the DMT, either reinforcing them or, as has also been postulated, reducing them given that the DMT now has to compete for the 5-HT2 receptor with higher serotonin levels.
Design of the study and objectives
During the course of the investigation two doses of ayahuasca (0.5 and 0.8 mg/kg of DMT) and one placebo will be administered. The study has been designed as a double blind, that is, neither the subject nor the researcher will know whether the drug administered is ayahuasca or a placebo, and if it should be ayahuasca they will not know the size of the dose. The double blind condition will be maintained until the information gathered is analyzed. The investigation will be cross-over and randomized, which is to say that the 18 participant subjects will receive the three preparations in totally random order, and a washout period of two weeks between experimental sessions will also be established.
Given the study's double blind nature the ayahuasca used will not be administered in its normal liquid form, as the preparation's appearance, color and flavor would prevent its being administered without the subject's knowledge. To achieve efficient masking the following process will be carried out: the ayahuasca will undergo a lyophilization process in which the water in the infusion is eliminated in a high vacuum chamber at low temperature, after which the solid obtained will be homogenised and analyzed. In this way the different alkaloid concentrations per gram of lyophilized product can be determined and the doses adjusted according to the main active element, DMT. Finally, a quantity of the lyophilized substance corresponding to 0.5 mg/kg and 0.8 mg/kg of DMT will be encapsulated for each subject; the quantity of ß-carbolines administered in each dose will also inevitably vary. Instead of obtaining natural ayahuasca, lyophilizing and encapsulating it, we initially considered the option of administering a synthetic analogue which combined variable quantities of DMT with fixed quantities of ß-carbolines. This would have permitted the elimination of the "background noise" of increasing levels of ß-carbolines and other undesirable effects predominantly attributable to these compounds, but would have yielded results that could not have been applied to the natural preparation, which is ultimately the subject of the study. So, the study's objectives are as follows: 1. Description of the pharmacokinetics of N,N-dimethyltrypt-amine and ß-carbolines, the main alkaloids in ayahuasca, after the oral administration of increasing doses of the preparation. 2. In vivo determination of MAO inhibition provoked by ayahuasca. 3. Quantification of ayahuasca's pharmacological effects on the central nervous system: neurophysiological and subjective effects. 4. General tolerability of the preparation. 5. Study of the concentration-response relationships (PK/PD).
The MAOI effect
Effects on the Central Nervous System
These tests and scales have been used with numerous psychoactive drugs which, although potent, do not completely prevent the subject from performing tasks nor from interacting with the evaluator. However, given the profound alteration of consciousness experienced by the subject after a hallucinogen has been administered and the overwhelming nature per se of the effects of hallucinogens, asking the subject to actively collaborate by completing these scales is not feasible. Certain Visual Analogic Scales (VAS) which require minimal cooperation from the subject, and questionnaires which may be completed once the drugs' effects have worn off, are perhaps an exception.
Subjective effects study
This scale does not permit the time sequence of the drug's effects to be followed and it will not therefore be possible to establish correlations with plasma levels, but it does allow the overall quantification of these effects to obtain numerical values which in principle will be in relation to the dose of the drug administered. One of the study's objectives, therefore, is to verify the validity of a scale which, despite being designed for a specific compound (DMT) and a specific means of administration (intravenous) also aims to be of use with other hallucinogenic drugs and other methods of administration.
The relative simplicity of registering this electrical activity allows information to be obtained continuously throughout the experimental session. This permits the subsequent correlation of the plasma levels of the drug administered (pharmacokinetic variable), in this case DMT, with the effect it sets in motion on the cortex's electrical activity (pharmacodynamic variable) in an integrated pharmacokinetic-pharmacodynamic model.
In addition, electrocardiograms and clinical analyses will be carried out between the experimental sessions to check whether these parameters have been affected by the administration of the ayahuasca.
Pharmacokinetic- pharmacodynamic modelling
Conclusion and acknowledgements
Authors from left: Jordi Riba and Manel J. Barbanoj, M.D., Ph.D.
Questions relating to this study should be addressed to:
Area d'Investigació Farmacològica
Institut de Recerca, Hospital de Sant Pau
Sant Antoni Maria Claret 167
Barcelona 08024 SPAIN
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