Pharmacokinetics of Hoasca alkaloids in healthy humans

This open-label field study (n=15) investigated the pharmacokinetics, subjective, neuroendocrine, autonomic, and cardiovascular effects of ayahuasca (35.5 mg DMT, 158.5 mg THH, 29.7 mg Harmaline, 252.3 mg Harmine), providing a time-course of these parameters in a 24-hour period in the context of a religious ceremony.

Abstract

“Introduction: N,N-Dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine (THH) are the characteristic alkaloids found in Amazonian sacraments known as hoasca, ayahuasca, and yajè. Such beverages are characterized by the presence of these three harmala alkaloids, where harmine and harmaline reversibly inhibit monoamine oxidase A (MAO-A) while tetrahydroharmine weakly inhibits the uptake of serotonin. Together, both actions increase central and peripheral serotonergic activity while facilitating the psychoactivity of DMT. Though the use of such ‘teas’ has be known to western science for over 100 years, little is known of their pharmacokinetics.

Methods: In this study, hoasca was prepared and administered in a ceremonial context. All four alkaloids were measured in the tea and in the plasma of 15 volunteers, subsequent to the ingestion of 2 ml hoasca/kg body weight, using gas (GC) and high pressure liquid chromatographic (HPLC) methods.

Results: Pharmacokinetic parameters were calculated and peak times of psychoactivity coincided with high alkaloid concentrations, particularly DMT which had an average T_max of 107.5±32.5 min.

Discussion: While DMT parameters correlated with those of harmine, THH showed a pharmacokinetic profile relatively independent of harmine’s.”

Authors: J.C. Callaway, Dennis J. McKenna, Charles S. Grob, G. S. Brito, L. P. Raymon, R. E. Poland, E. N. Andrade, E. O. Andrade & D. C. Mash

Summary

Three harmala alkaloids were found in Amazonian sacraments known as hoasca, ayahuasca, and yaje. The pharmacokinetics of these alkaloids was studied in 15 volunteers, and the peak times of psychoactivity coincided with high alkaloid concentrations, particularly DMT.

Ayahuasca, also known as caapi, daime, yage, natem, and by many other local names, is a beverage made from the leaves of Psy chotria 6iridis. It is used for medicinal and ceremonial purposes throughout the extensive river regions of Brazil, Bolivia, Ecuador and Peru.

Harmine and harmaline allow the oral activity of DMT, a potent psychedelic agent obtained from the leaves of P. 6iridis, by temporarily inhibiting the activity of MAO. The resulting visionary effects are a hallmark of this unique plant combination.

MAO inhibition may also contribute to the effects of other psychoactive alkaloids found in these beverages, such as nicotine, cocaine, caffeine, atropine, scopolamine and other tropane alkaloids from members of the Solanaceae family.

In South America, over 15 000 individuals use hoasca on a regular basis, excluding users from the indigenous population. It is not physically addictive nor has psychological dependence been demonstrated for these beverages.

During the summer of 1993, a clinical study was initiated to investigate the psychopharmacologic properties of hoasca. The results showed that hoasca has some pharmacodynamic effects, but not enough to warrant its use in modern medicine.

2.2. The Hoasca

Sufficient amounts of B. caapi and Psychotria 6iridis were gathered on site at the Nucleo Caupur to prepare 120 l of hoasca for the purpose of this study. The tea was tested for quality and potency, and its alkaloid content was quantified by HPLC.

Each of the 15 volunteers consumed 2 ml:kg of hoasca, rounded up to the nearest power of 10, and consumed the entire amount within 10 seconds.

A group of 24 volunteers who had used hoasca as part of their regular religious practice for at least 10 years were randomly selected, and a group of 15 males who had never consumed hoasca were subjected to the same medical evaluation.

2.4. Subjective Effects

The hallucinogenic rating scale (HRS) was developed to measure the psychotropic effects of injected DMT.

2.7. Pharmacokinetic Calculations

GH and prolactin were measured in plasma against standards obtained from the National Pituitary Agency, and cortisol was determined by radio-immuno assay. All samples were analyzed in duplicate.

3.1. The Hoasca

A standard dose of 2ml:kg body weight was used throughout the study, and the alkaloid content was revealed to be: harmine 1.70 mg:ml, harmaline 0.20 mg:ml, THH 1.07 mg:ml and DMT 0.24 mg:ml.

3.2. The Volunteers

In the preclinical study, no significant differences were found between the experimental and control groups. One volunteer vomited during the study, and his data were not included in the final analyses.

3.3. The Subjective Sffects

The duration of psychoactivity from the tea was coincidental with alkaloid plasma levels, and all 15 volunteers experienced these subjective effects.

3.4. Pharmacokinetics

DMT, harmine, THH and harmaline were determined in all volunteers, but only 12 had sufficient concentrations for all pharmacokinetic calculations. The Cmax and Tmax for DMT were 15.8 ng:ml and 107.5 ng:ml, respectively, and for harmine they were 114.8 ng:ml and 102.0 ng:ml, respectively.

3.5. Neuroendocrine Effects

All measures of neuroendocrine response showed sharp increases over basal levels for each volunteer. Plasma growth hormone, prolactin, and cortisol levels increased to maximum levels after 20 min and then returned to basal levels by 360 min.

Each volunteer’s pupil size increased over basal values after 40 min, and remained dilated after the last measurement at 240 min. Their respiration rate increased slightly over basal values, and their oral temperature increased slightly over basal measures.

All measures increased over basal levels for each volunteer, with the heart rate reaching a maximum of 79.3 9 0.3 bpm by 20 min, and the systolic pressure reaching a maximum of 123.9 9 3.2 mmHg by 180 min.

4. Discussion

This study examined the pharmacokinetic effects of hoasca in healthy humans. The alkaloid content of the tea used in this study was in agreement with published reports of tea dosages from other sources, and the beverage itself was considered typical of hoasca by experienced volunteers.

The intensity and duration of subjective effects differ considerably between hoasca and intravenous DMT. The latter has a faster onset, singular effect, and shorter duration than hoasca, which is probably due to its route of administration.

Hoasca can cause nausea, vomiting, tremors, and nystagmus, which are probably caused by increased levels of unmetabolized 5-HT. These effects are attenuated by increasing levels of central 5-HT, which decreases cardiac response through vagal stimulation.

Periodic increases in levels of 5-HT may signal an upregulation of 5-HT uptake sites on blood platelets, which could actually stimulate 5-HT production.

A mechanism for the oral activity of DMT was suggested over 30 years ago, and gastrointestinal absorption and subsequent MAO inhibition lengthened Tmax to 108 9 32.5 min and increased Cmax to 90.0 ng:ml.

The oral activity of DMT in hoasca is facilitated by the presence of harmala alkaloids. DMT is primarily metabolized by MAO, but 5-methoxy-DMT is also metabolized by MAO, and 5-HT could compete with DMT for any of these reactions, and effectively slow its eventual metabolism.

Increased cortisol and prolactin levels were observed after the neuroendocrine challenge by hoasca, which was comparable to previously reported values after injected DMT. Increased pupillary diameter, oral temperature and cardiac effects were also observed after this sudden surge in neurochemical activity.

5. Conclusions

A long and continuous history of regular use indicates the utility of hoasca. It seems to increase one’s ability to psychologically adapt to the larger process of life.

Acknowledgements

This study was made possible by the support of the Unia o do Vegetal and INPA, and by funding from The Heffter Institute.