Clinical investigations of the therapeutic potential of ayahuasca: rationale and regulatory challenges

This study (2004) discusses ayahuasca as a possible therapeutic agent and details the challenges that need to be overcome for clinical studies utilizing ayahuasca in the United States to become viable.

Abstract

“Ayahuasca is a hallucinogenic beverage that is prominent in the ethnomedicine and shamanism of indigenous Amazonian tribes. Its unique pharmacology depends on the oral activity of the hallucinogen, N,N-dimethyltryptamine (DMT), which results from inhibition of monoamine oxidase (MAO) by h-carboline alkaloids. MAO is the enzyme that normally degrades DMT in the liver and gut. Ayahuasca has long been integrated into mestizo folk medicine in the northwest Amazon. In Brazil, it is used as a sacrament by several syncretic churches. Some of these organizations have incorporated in the United States. The recreational and religious use of ayahuasca in the United States, as well as ‘‘ayahuasca tourism’’ in the Amazon, is increasing. The current legal status of ayahuasca or its source plants in the United States is unclear, although DMT is a Schedule I-controlled substance. One ayahuasca church has received favorable rulings in 2 federal courts in response to its petition to the Department of Justice for the right to use ayahuasca under the Religious Freedom Restoration Act. A biomedical study of one of the churches, the Uñiao do Vegetal (UDV), indicated that ayahuasca may have therapeutic applications for the treatment of alcoholism, substance abuse, and possibly other disorders. Clinical studies conducted in Spain have demonstrated that ayahuasca can be used safely in normal healthy adults, but have done little to clarify its potential therapeutic uses. Because of ayahuasca’s ill-defined legal status and variable botanical and chemical composition, clinical investigations in the United States, ideally under an approved Investigational New Drug (IND) protocol, are complicated by both regulatory and methodological issues. This article provides an overview of ayahuasca and discusses some of the challenges that must be overcome before it can be clinically investigated in the United States.”

Author: Dennis J. McKenna

Summary

Ayahuasca is a hallucinogenic beverage that is prominent in the ethnomedicine and shamanism of indigenous Amazonian tribes. It has been used for religious and recreational purposes in the United States, but its legal status is unclear and it has not been clinically investigated in the United States.

1. Introduction

The beverage known variously as ayahuasca, caapi, or yage, is a plant psychotropic utilized by indigenous populations of the Amazon Basin. Its chemical nature and use make it relevant to contemporary issues in neuropharmacology, neurophysiology, and psychiatry.

2. What is ayahuasca?

Ayahuasca is a beverage prepared by boiling the bark and stems of B. caapi together with various admixture plants. The leaves of Psychotria viridis contain alkaloids that act synergistically with the h-carboline alkaloids in the bark to produce the psychoactive effect. There are reports that other Psychotria species are similarly utilized in other parts of the Amazon. In Peru, various admixtures are frequently added, including tobacco, Brugmansia sp., and Brunfelsia sp., which contain alkaloids that affect adrenergic and cholinergic neurotransmission.

3. Prehistorical origin of ayahuasca

The origins of ayahuasca use in the Amazon Basin are unknown, but it was already widespread among numerous indigenous tribes by the time Western ethnographers discovered it in the mid-19th century.

The use of psychoactive plants in the Ecuadorian Amazon was well established by 1500 – 2000 BC, and there is evidence that preColombian cultures were also familiar with ayahuasca and its preparation. However, there is no evidence that prehistoric humans consumed ayahuasca.

Ayahuasca is unique among plant hallucinogens in that it is prepared from a combination of 2 plants. It is believed that this combination was discovered at some point in prehistory, and that King Solomon imparted the knowledge to the Inca king during a little publicized visit to the New World.

4. Traditional and indigenous use of ayahuasca

The use of ayahuasca among indigenous tribes in the Amazon Basin dates back to pre-Columbian times, and has become an important element of ethnomedicine and shamanism among mestizo populations in Peru, Colombia, and Ecuador.

5. Syncretic religious use of ayahuasca

The use of ayahuasca can be divided into indigenous aboriginal and mestizo populations, and contemporary syncretic religious movements. The psychological, medical, and legal aspects of the use of ayahuasca are most relevant.

The use of ayahuasca in mestizo folk medicine closely resembles the shamanic uses of the drug as practiced among aboriginal peoples. The use of ayahuasca tea in Brazilian syncretic religious movements is more similar to the Christian Eucharist than the traditional aboriginal use.

The UDV and Santo Daime sects are the largest and most visible syncretic religious movements in Brazil that use ayahuasca in their ritual practices. The UDV was the most successful in convincing the government to remove ayahuasca from its list of banned drugs.

6. Chemistry of ayahuasca and its source plants

The chemical constituents of ayahuasca and the source plants used in its preparation have been well characterized. The concentrations of alkaloids in B. caapi and Psychotria carthagenensis range from 0.05% dry weight to 1.95% dry weight, respectively.

Ayahuasca and hoasca are both plants that contain alkaloids that can cause hallucinations. They contain concentrations of DMT, THH, harmaline, and harmine that are above the threshold of activity for intravenous administration of DMT.

McKenna et al. (1984) reported that a 100-mL dose of Peruvian ayahuasca contained 728 mg total alkaloid, of which 467 mg was harmine, 160 mg was THH, 41 mg was harmaline, and 60 mg was DMT. This dose is well within the range of activity for DMT administered intramuscularly. The differences in the methods of preparation of ayahuasca between Rivier and Lindgren (1972) and McKenna et al. (1984) can be explained by the different concentrations of alkaloids in the samples collected from different regions.

h-Carbolines may have some psychoactivity, but it is probably inaccurate to characterize them as ”hallucinogenic” or ”psychedelic”. They may protect DMT from peripheral degradation, but they may also attenuate the effects of DMT by competing with serotonin at postsynaptic receptor sites.

7. Pharmacological actions of ayahuasca and its active alkaloids

Ayahuasca’s psychotropic activity is due to the inhibition of peripheral MAO by the h-carboline alkaloids, which enable the DMT to reach the central nervous system in an intact form.

DMT is active by itself following parenteral administration starting at around 25 mg, and the effects of ayahuasca are different from those of parenterally administered synthetic DMT because the enzyme-inhibiting principles in one plant (h-carbolines) are used to facilitate the oral activity of the psychoactive principles in another plant (DMT).

Ayahuasca causes phosphene imagery, dream-like reveries, and a feeling of alertness and stimulation. Some individuals experience transient nausea and episodes of vomiting, while others are rarely affected in this respect.

The main contribution of h-carbolines to the acute effects of ayahuasca may be their facilitation of the oral activity of DMT, through their action as MAOI at peripheral sites. Tyramine, on the other hand, has a greater affinity for MAO-B, and may displace any residual h-carbolines.

DMT and its derivatives are widespread in the plant kingdom and are also found in mammals, including man. The possible neuroregulatory functions of DMT and h-carbolines are incompletely understood, but Callaway (1988) has presented an interesting hypothesis regarding the possible role of endogenous DMT and h-carbolines in regulating sleep cycles and rapid eye movement states.

h-Carbolines are tricyclic indole alkaloids that are closely related to tryptamines, both biosynthetically and pharmacologically. They have been detected in human plasma, platelets, brain, and adrenal glands, and may be related to the etiology of alcoholism.

h-Carbolines are selective, reversible, competitive inhibitors of MAO-A and exert a variety of neurophysiological and biological effects, including inhibition of Na+-dependent membrane ATPases, interference with biosynthesis of biogenic amines, and vasopressin-like effects on sodium and water transport in isolated toad skin.

h-Carbolines exhibit other biological activities in addition to their effects on neurophysiological systems, such as anti-trypanosomal activity, mutagenic or co-mutagenic effects, and UV light-activated photocytotoxic and photogenotoxic activity.

8. Recent biomedical investigations of ayahuasca

Although ayahuasca has achieved some notoriety in North American literature, it has received little rigorous study. Various travelers to the Amazon have reported their own first hand experiences with ayahuasca, while both formal and informal ethnographic narratives have excited the public imagination.

The individuals who join the UDV seem to belong to a more educated socioeconomic class than those who join the Santo Daime. The medically educated members of the UDV have a genuine spiritual reverence for the hoasca tea and the experiences it evokes.

8.1. The ‘‘Hoasca Project’’

A consortium of scientists from Brazil, the United States, and Finland conducted a biomedical investigation of long-term hoasca drinkers. The study was financed by private donations to various nonprofit sponsoring groups, including Botanical Dimensions, the Heffter Research Institute, and the Multidisciplinary Association for Psychedelic Studies.

Long-term psychological effects of hoasca teas

A group of 15 healthy, male volunteers who had been members of the UDV for a minimum of 10 years consumed hoasca once every 2 weeks. A control group of 15 age-matched males was also used.

The psychological assessments administered to both groups consisted of structured psychiatric diagnostic interviews, personality tests, and neuropsychological evaluations. The hoasca drinkers also completed semistructured and open-ended life story interviews.

UDV volunteers showed significant differences from hoasca-naive subjects in the Tridimensional Personality Questionnaire and the WHO-UCLA Auditory Verbal Learning Test. They had greater confidence versus fear of uncertainty and greater gregariousness versus shyness.

The 15 UDV volunteers performed significantly better than the control subjects on word recall tests.

The Hallucinogen Rating Scale, developed by Strassman et al. (1994), was administered to UDV volunteers only. The clinical clusters were in the mild end of the spectrum compared to intravenous DMT.

The psychological assessment found that none of the UDV subjects had a current psychiatric diagnosis, whereas 2 of the control subjects had an active diagnosis of alcohol misuse and hypochondriasis. All of the UDV subjects reported improved mental and physical health and significant improvements in interpersonal, work, and family interactions.

Physiological effects of hoasca tea

The major focus of the biochemical and physiological measurements carried out for the study was on the acute effects subsequent to consuming hoasca tea. The results showed that heart rate, blood pressure, and pupillary diameter increased following ingestion, and then returned to baseline values by 180 min. We measured the neuroendocrine response to oral DMT and found that the response was delayed by a factor of 4 or 5 compared with the almost immediate response to injected DMT.

The fourth objective of the study was to measure the pharmacokinetic parameters of the hoasca alkaloids in plasma following ingestion of hoasca tea. The average dose of tea consumed by each subject was 148.4 mL, containing 35.5 mg DMT, 158.8 mg THH, 29.7 mg harmaline, and 252.3 mg harmine.

Only 12 of 15 volunteers had sufficient plasma levels of DMT to permit pharmacokinetic measurements, and the half-life of THH was 259 min. The Cmax of harmine was 114.8 ng/mL and the Tmax was 145 min.

This study was conceived because of the need to collect basic data on the physiological and pharmacokinetic characteristics of hoasca, since none had existed previously. The results indicate that the highest plasma concentrations of DMT correlated with the most intense subjective effects.

Functions in long-term users of hoasca

A study was conducted to determine if long-term use of hoasca resulted in any identifiable biochemical marker that was correlated with hoasca consumption. The study used platelet-binding assays to determine if any kind of long-term biochemical marker existed.

We conducted assays on platelets collected from 15 volunteers and 15 age-matched controls after they had abstained from consuming hoasca for a week. We found that the density of the citalopram binding sites in the hoasca drinkers was significantly higher than in the control subjects, although their affinity for the labeled citalopram binding site was not changed. This finding is unclear, but may be related to the natural course of neuronal decline. Although our sample size was limited, we found no correlation between age and serotonergic up-regulation. The subjects showed exceptionally healthy psychological profiles.

Jace Callaway, who had access to single photon emission computerized tomography scanning facilities in the Department of Pharmacology at the University of Kuopio, found that his own brain 5-HT uptake transporters had increased after taking THH, and that they gradually returned to previous levels after discontinuing THH. This study found that those who used hoasca tea in the UDV rituals had a long-term change in serotonin levels, which argues that biochemical factors may also play a role.

9. Current legal and regulatory status of ayahuasca

In recent decades, ayahuasca has been integrated into the religious practices of several syncretic religions in Brazil, including the UDV, the Santo Daime, and the Barquinia. These religions are sanctioned and legally permitted to use ayahuasca.

Ayahuasca and its source plants are not prohibited under the 1971 Convention on Psychotropic Substances, although one of them contains a Schedule I controlled substance, DMT. The controversy centers around the occurrence of DMT in the admixture plant, P. viridis, or other DMT-containing admixtures that may occasionally be substituted for P. viridis.

The US chapter of the UDV, which uses ayahuasca in religious ceremonies, petitioned the Department of Justice for the return of 30 gal of its sacramental hoasca, but the government filed an emergency stay, and the favorable ruling was temporarily contravened. The US Supreme Court may eventually review the UDV case. A complete chronology of the case can be found on the Center for Cognitive Liberty and Ethics web site.

Although the use of ayahuasca for religious purposes is growing in the United States, the legal status of ayahuasca under US law is uncertain, and this may pose challenges for future clinical investigations.

10. The rationale for clinical studies of ayahuasca

Ayahuasca is becoming increasingly popular in the United States for both religious and recreational purposes. Although a long history of safe use is indicated, very little actual clinical data have been accumulated, which provides a scientific basis for the notion that ayahuasca is safe for human use. Ayahuasca may have therapeutic applications, and should be investigated in well-designed clinical studies with approval from the FDA and DEA.

11. Ayahuasca clinical research to date

11.1. Key findings from the ‘‘Hoasca Project’’

In the Brazilian UDV, hoasca is consumed regularly by men and women ranging in age from 13 to 90. There is no evidence of long-term toxicity or other adverse health effects, and most members perform slightly better than control subjects on psychological tests. The study included 15 long-term UDV members utilizing hoasca as a legal, psychoactive sacrament, as well as 15 matched controls with no prior history of hoasca ingestion. Overall assessment revealed high functional status.

12. Potential therapeutic applications of ayahuasca

Two kinds of evidence argue that ayahuasca may have therapeutic applications. Anecdotal evidence and a 1993 biomedical study indicate that ayahuasca may be useful for the treatment of abuse disorders and physical maladies.

12.1. Treatment of alcoholism and substance abuse

Regular and long-term hoasca use may result in profound, lasting, and positive behavioral and lifestyle changes, including the resolution of histories of alcoholism, substance abuse, domestic violence, and other maladaptive behaviors.

Dr. Micheal Winkelman coined the term psychointegrator plants to describe the psychological benefits of ayahuasca administration. A recent report on BBC radio discusses the successful use of ayahuasca to treat cocaine addition.

12.2. Treatment of serotonergic deficits

The study found that regular ayahuasca use results in a long-term modulation of serotonin systems in the brain, possibly due to one of the h-carbolines in the ayahuasca mixture. The serotonin transporter, which manages the reuptake of serotonin from the synapse, is intimately involved with syndromes such as depression and other mood disorders, suicidal behavior, etc. The elevation of 5-HT transporters seen with long-term ayahuasca use may be linked to the positive behavioral changes.

Serotonergic deficits have been linked to a variety of functional, behavioral, and neurodegenerative disorders, including alcoholism, depression, autism, schizophrenia, attention deficit hyperactivity disorder, and senile dementias. The results from the UDV study indicate that ayahuasca may be able to modulate serotonin transporter expression and regulation.

12.3. Immune modulation

Ayahuasca may have significant immunomodulatory effects. Ayahuasca users in North America have reported remissions of cancers and other serious illnesses in conjunction with regular use of the tea, and ayahuasca users in Peru appear to live long, healthy lives. Ayahuasca is a popular medicine in mestizo folk medicine and indigenous shamanic practice, and may have immune-potentiating properties. This hypothesis can be resolved empirically, if the effects are found to exist.

12.4. Clinical studies by Spanish investigators

After the completion of the ”Hoasca Project” and the publication of its results, a group of investigators at the Universitat Autonoma de Barcelona in Spain conducted clinical investigations examining various aspects of the pharmacology of ayahuasca in healthy volunteers. They found that ayahuasca was well tolerated and presented an acceptable side-effect profile.

13. The pathway to clinical studies

There is a need for more rigorous scientific investigations into the safety and efficacy of ayahuasca, and the American medical community will insist on more rigorous investigations in the form of controlled clinical trials before any possible therapeutic investigations can proceed.

Ayahuasca is not internationally regulated, and the legal status of the preparation and the source plants remains in limbo. A favorable resolution of the UDV’s case will simplify the regulatory challenges to biomedical studies of ayahuasca.

study—phytochemistry and pharmacology

Although the clinical studies of Riba et al. (2001a, 2001b, 2002a, 2003) and Yritia et al. (2002) have shown that ayahuasca can be used safely in a clinical setting, the FDA may insist on generating preclinical data within the United States.

Ayahuasca is a complex combination of hundreds of biologically active compounds, many of which have not been investigated thoroughly. Ayahuasca is likely to contain flavonoids, tannins, lignans, saponins, volatile oils, and many other classes of secondary metabolites.

Much of the early phytochemical work and preclinical pharmacology on Banisteriopsis extracts was conducted over 30 years ago. There is a need to revisit these questions using more current methodologies, and to make a standardized preparation for eventual use in IND-authorized clinical studies.

Preclinical studies will enable investigators to examine aspects of ayahuasca’s pharmacology that may be relevant to its suspected therapeutic activity, such as the effects of ayahuasca on serotonin transporter and other neurobiological functions, and the possible immune-potentiating effects of ayahuasca.

13.2. Step II: investigational new drug application

The FDA has issued a draft of guidelines for the development of botanical drugs. These guidelines are still under review.

The ayahuasca preparation recommended under the IND protocol differs from the traditional preparation in that it will be a freeze-dried, aqueous extract made from fresh plant materials and administered in capsules. This preparation will be more easily standardized and will have longer term stability. In the present study, we suggest that freeze-dried decoctions of each plant be prepared separately and quantitatively analyzed. The combined extracts can then be adjusted for volume and alkaloid concentrations using inert excipient materials such as lactose.

Advances in phytopharmaceutical technology have made it possible to prepare a standardized version of ayahuasca, in which the levels of active constituents are well-characterized. However, range-finding work is needed to determine the appropriate extraction parameters prior to scaling up to produce the test batch.

13.3. Step III: initial clinical studies—safety assessment

Once IND and IRB approvals have been obtained, an open-label dose escalation study will be conducted in healthy volunteers to establish the safety and tolerability of the standardized ayahuasca preparation. This study will consist of 6 doses administered at 2-week intervals.

We propose to administer 6 doses at 2-week intervals over the course of 12 weeks in a single-blind design in an initial Phase I safety study.

13.4. Step IV: subsequent clinical studies—efficacy of ayahuasca therapy for alcoholism

If the safety and tolerability of ayahuasca is confirmed in the initial study, then an efficacy trial should focus on a clear therapeutic objective. Candidates with a history of alcohol dependence should be selected for the study, and neuroimaging technologies should be applied to prescreen for central serotonin transporter deficits.

Conclusion

Ayahuasca is a legendary jungle medicine, but scientific investigations have revealed much of its botany, chemistry, pharmacology, and ethnography. Clinical investigations of its potential as a medicine have been few, but preliminary studies in Brazil and Spain indicate promising results.