Acute Biphasic Effects of Ayahuasca

This double-blind placebo-controlled study (n=20) examines the effects of ayahuasca on brain activity with respect to the temporal metabolism of its active compounds and found that DMT (97.3mg/70kg) and harmine (320.6mg/70kg) are related to the early phase of the experience, measured as reduced power in the alpha band after 50 minutes, while harmaline (52.5mg/70kg) and tetrahydroharmine (380.1mg/70kg) are more strongly associated with the later phase of the experience, measured as gamma-band increases after 75 minutes from ingestion. The present results reveal acute biphasic effects of ayahuasca in the brain.

Abstract

Introduction: Ritual use of ayahuasca, an amazonian Amerindian medicine turned sacrament in syncretic religions in Brazil, is rapidly growing around the world. Because of this internationalization, a comprehensive understanding of the pharmacological mechanisms of action of the brew and the neural correlates of the modified states of consciousness it induces is important.

Methods/Results: Employing a combination of electroencephalogram (EEG) recordings and quantification of ayahuasca’s compounds and their metabolites in the systemic circulation we found ayahuasca to induce a biphasic effect in the brain. This effect was composed of reduced power in the alpha band (8–13 Hz) after 50 minutes from ingestion of the brew and increased slow- and fast-gamma power (30–50 and 50–100 Hz, respectively) between 75 and 125 minutes. Alpha power reductions were mostly located at left parieto-occipital cortex, slow-gamma power increase was observed at left centro-parieto-occipital, left fronto-temporal and right frontal cortices while fast-gamma increases were significant at left centro-parieto-occipital, left fronto-temporal, right frontal and right parieto-occipital cortices. These effects were significantly associated with circulating levels of ayahuasca’s chemical compounds, mostly N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine and some of their metabolites.

Discussion: An interpretation based on a cognitive and emotional framework relevant to the ritual use of ayahuasca, as well as it’s potential therapeutic effects is offered.

Authors: Eduardo Ekman Schenberg, João Felipe Morel Alexandre, Renato Filev, Andre Mascioli Cravo, João Ricardo Sato, Suresh D. Muthukumaraswamy, Maurício Yonamine, Marian Waguespack, Izabela Lomnicka, Steven A. Barker & Dartiu Xavier da Silveira

Summary

RESEARCH ARTICLE

Ritual use of ayahuasca, an amazonian Amerindian medicine turned sacrament in syncretic religions in Brazil, induces a biphasic effect in the brain. This effect is accompanied by increases in slow-and fast-gamma power, and is significantly associated with circulating levels of ayahuasca’s chemical compounds.

Introduction

Ayahuasca is a powerful psychoactive brew made from an amazonian vine, Banisteriopsis caapi, and other plants. It is used by Amerindian cultures for healing, divination and community bonding.

Ayahuasca contains beta-carbolines harmine, harmaline and tetrahydroharmine, which inhibit monoamine oxidase (MAO) and allow DMT to access the brain, rendering it orally psychoactive. DMT acts mostly as a 5HT-2A receptor agonist, but may also be the endogenous ligand for sigma-1 receptors and the trace amine receptor.

Most studies to date have employed the electroencephalogram (EEG) to record brain oscillatory activity after ayahuasca intake. These studies have revealed increased alpha in the occipital lobes and increased theta in the frontal regions. The third study aimed to control for the placebo effect through the use of a lyophilized ayahuasca administered in double-blind design in a laboratory environment. The study revealed decreases in alpha, delta and theta frequencies and increases in the beta band at central and parieto-temporal locations.

We invited experienced individuals to participate in an EEG recording session with liquid ayahuasca ingestion in a laboratory setting to better understand the effects of ayahuasca on brain rhythms.

Subjects

Twenty healthy volunteers gave informed consent to participate in the study and disclosed their previous drug use histories. Exclusion criteria were as follows: ages 21, personal history of psychiatric illness, current use of any psychiatric medication, cardiovascular disease and any neurologic disorder or brain injury in the past.

Setting

EEG recordings were conducted in a standardized private room in a psychiatric facility of the Universidade Federal de S. Paulo. Volunteers were accompanied by two researchers and a nurse, and remained in a “resting-state”, i.e. quiet and introspective, with eyes closed.

Ayahuasca and plasma samples

A sample of six liters of “Hoasca” was donated by the Unio do Vegetal (UDV) church in Brazil for the specific purpose of use in this study. The main compounds were quantified using liquid chromatography-electrospray ionization-tandem mass spectrometry.

Blood was collected in sterile EDTA containing tubes, centrifuged at 2000 rpm for 10 min at 4°C, and stored at -80°C until shipped on dry ice to USA for analysis.

Electroencephalography (EEG)

Electroencephalogram recordings were made using a Brain Vision ActiCHamp with 64 channels using the standard ActiCap with PyCorder software. The recordings were referenced to Cz and re-referenced offline to the common average.

Two subjects had their whole EEG data discarded due to excess movement during the whole recording period. The remaining subjects’ data was divided in ten minute windows immediately preceding each blood sample collection and preprocessed using EEGLab v.13.3.2b. Bad channels were removed, the remaining data was segmented into 3 s consecutive epochs, and the infomax independent component analysis algorithm was used to remove components with characteristics of line noise, muscle artifacts, or eye blinks and eye movements.

Ayahuasca effects were studied using EEGLab and Fieldtrip. The power spectrum was calculated for six frequency bands: delta, theta, alpha, beta, slow-gamma, and fast-gamma.

Statistical analysis

Spectral changes in each frequency band were evaluated using permuted F statistic, and relationships between plasma concentration of identified compounds and spectral changes in the six frequency bands evaluated were calculated using generalized linear models.

Previous experience with ayahuasca and other psychoactive substances

The patients’ lifetime experience with ayahuasca and psychoactive substances, especially psychedelics, varied greatly. The most frequent reason for the first ayahuasca use was curiosity, followed by self-knowledge, contact with the divine, going with friends and consciousness expansion.

Ayahuasca composition

The concentration of the main active ingredients in the ayahuasca used in this study were 0.328 (DMT), 1.08 (Harmine), 0.18 (Harmaline) and 1.28 (THH) mg/l, and the dose was 1.39 mg/kg.

Blood levels

Two volunteers opted out of blood collection, and one volunteer’s blood samples were discarded due to high hemolysis. No significant differences were found between men and women for any of the identified compounds in blood, and no correlations were found between concentrations in blood and age.

Subjective effects

Participants reported increased imagination, introspection and emotional arousal after ingesting ayahuasca.

Spectral Analysis

Ayahuasca ingestion caused significant decreases in alpha power at left parieto-occipital electrodes, significant increases in beta power at left fronto-temporal electrodes, and significant increases in slow-gamma power at right frontal, left fronto-temporal, and left centro-parieto-occipital electrodes. Four clusters were identified in the fast-gamma range in the right-frontal, right parieto-occipital, left fronto-temporal and left centro-parieto-occipital regions, with the exception of the left centro-parieto-occipital region, where it was significant only after 75 min.

Plasma concentration and EEG spectra

Two significant clusters were found between concentration of DMT and increases in the delta band, and another significant cluster was found between concentration of DMT-NO and alpha band power decrease. No significant effects were found between the tryptamines and the theta frequency band.

Localized clusters were found between DMT and beta power increase at left fronto-central electrodes and between NMT and beta power increase at left frontal electrodes.

Slow-gamma power increases were found to be associated with DMT plasma concentration, DMT-NO and right frontal electrodes. Four significant clusters were found to be associated with NMT and left fronto-temporal, left centro-parieto-occipital, right parietal and occipital electrodes.

Fast-gamma power increases and DMT concentration yielded three significant clusters at left fronto-temporal electrodes, right frontal electrodes, and bilateral temporo-parieto-occipital electrodes. Fast gamma increases were found to be associated with increased DMT-NO concentrations at left centro-frontal electrodes, right centro-temporo-frontal electrodes and bilateral parietooccipital electrodes. Two significant clusters were found to be associated with increased IAA concentrations at right frontal electrodes and bilateral parieto-occipital electrodes.

The concentrations of harmine, harmol, harmaline, harmalol and THH with EEG spectra did not show any significant clusters in the delta, theta and beta frequency bands. Alpha band power decreases and harmine concentration formed one significant cluster at left centro-parieto-occipital electrodes. Alpha band power decrease and THH concentration formed significant clusters at left centro-parietal and left parieto-occipital electrodes, and THH concentration and alpha band power decrease formed significant clusters at right fronto-centro-parieto-occipital electrodes.

The power increase in the slow-gamma frequency band and harmaline concentration formed four significant clusters, one at left frontocentral electrodes (F7 and FC5), one at right frontal electrodes (AFz, AF4, F4, F6 and F7) and one at right parieto-occipital electrodes (P5, P3, PO7, O1 and Oz). Slow-gamma power increase and harmalol concentration formed three localized clusters at left fronto-central electrodes, right frontal electrodes, left fronto-temporo-central electrodes, and left parieto-occipital electrodes. No significant clusters were found for THH-OH and slow-gamma frequency band.

Fast-gamma power increases were widespread, forming one large bilateral cluster. Harmalol concentration increased in a similar manner, forming two significant clusters, one at left fronto-temporal electrodes and the other at right frontal electrodes. Fast-gamma frequency band power increase and THH concentration formed one widespread large cluster in both hemispheres, with THH-OH forming two marginally significant clusters with delta band power increase.

Discussion

We found ayahuasca to induce a biphasic effect with changes in neural oscillations composed of decreases in alpha (8 – 13 Hz) power after 50 minutes and increases in the power of fast oscillatory activity after 75 to 125 minutes, especially in the slow- and fast-gamma frequency bands. Ayahuasca ingestion results in alpha decreases and gamma increases in the EEG, which are in agreement with previous studies. No significant correlations were found between EEG and HRS results.

Alpha power decreases

Alpha band power reductions at left parieto-occipital electrodes were located 50 minutes after ayahuasca ingestion, and are consistent with increased visual cortex BOLD signal during ayahuasca visions.

Alpha reductions in posterior regions of the brain were also observed after psilocybin, another 5HT-2A receptor agonist. These alpha decreases are likely due to activation of cortical 5HT-2A receptors in the parieto-occipital cortex.

Gamma power increases

After 75 minutes from ayahuasca ingestion, there were significant increases in slow- and fast-gamma power at left fronto-temporal, left centro-parieto-occipital and right frontal cortices, as well as right occipito-temporal electrodes. However, the current results in the gamma range do not seem to be due to muscle artifacts. We used visual inspection to remove components with a spectrum typical of muscle activity, and observed traces with high frequency activity but low amplitude while subjects were very still. The observed power increases in the gamma range after ayahuasca ingestion can be considered neural in origin. These increases are also found during other introspective states such as meditation.

Meditation or lucid dreaming can induce self-awareness, which may be related to increased awareness of memories and intentions.

Relevant alpha-gamma interactions

The changes in alpha and gamma power at frontal and parieto-occipital electrodes observed during ayahuasca use closely match the results obtained during emotional regulation by cognitive reappraisal. This may have great implications for the understanding of ayahuasca’s effect as related to increased awareness of one’s emotions and how to deal with them.

Plasma levels

The detected IAA can be attributed to ayahuasca intake because the method does not have significant matrix effects. The positive correlation of IAA Cmax and AUC with age might suggest decreased inhibition of MAO activity in older subjects, although this was not statistically significant.

When using plasma concentrations as predictors of EEG spectral changes, the effects appear to be more widespread in the scalp and include decreases in the alpha, slow- and fast-gamma bands as well as in the delta, theta and beta bands.

Tryptamines and the EEG

DMT reduces alpha power and extends the cluster from left posterior parietooccipital electrodes to more broad parieto-central regions. DMT may also contribute to effects beyond alpha decreases at 50 minutes.

The interaction between IAA and the alpha and gamma frequency bands revealed some degree of nonspecificity in the current analysis, but the effects were considerably less intense than those found for DMT.

The alpha power decreases estimated with the concentration of DMT-NO as a predictor variable reached left- and right-frontal electrodes, differentiating DMT-NO from DMT. DMT-NO also formed larger clusters than DMT in the gamma bands, further differentiating it from DMT.

Beta-carbolines and the EEG

Beta-carbolines, which are peripheral MAO-A inhibitors, may contribute to the central effects of ayahuasca, as suggested by the presence of these compounds in many different psychoactive plants.

Harmine and the EEG

When harmine was used as a predictor of EEG power spectral changes, the alpha cluster was virtually identical to that of DMT, but harmine formed a significant cluster in the right-parietal cortex whereas DMT did not, and harmine predicted significant power changes in almost all the cortex surface.

Harmine has been shown to be psychoactive in i.v. doses of 200 mg or more, and to induce “barely-perceptible sedative effects” at doses of 120 mg orally. It may contribute to the overall psychoactive effects of ayahuasca.

THH and the EEG

THH plasma levels were associated with changes in alpha, slow- and fast-gamma bands, but not with delta and theta bands. THH-OH had marginally significant effects in delta and theta bands, but not with alpha and gamma bands.

The only available report about the psychoactive properties of pure THH was done with only one subject. The subjective effects were rated as similar to 100 mg harmaline, and the possible effects of THH in the brain remain unknown.

Harmaline and the EEG

The effects of harmaline were stronger in the fast-gamma range than the effects of harmine or DMT, suggesting harmaline contributes to the effects of ayahuasca in the brain. Harmaline can substitute the psychedelic DOM, which fully cross-substitutes with DMT.

DMT, THH and harmine did not correlate with the time for emesis, while harmaline did. This is in agreement with previous reports of strong nausea and vomiting after ingestion of Peganum harmala.

Emesis

Although vomiting has been reported to be uncommon when using ayahuasca lyophilized, it can be a challenging side-effect in palliative care. We found no correlations between the time to vomit and the Cmax or AUC of any of the 10 compounds analyzed in blood.

Indigenous cultures who use ayahuasca consider nausea and vomiting to be an important part of the cleansing process and claim it helps them to emotionally heal. Phenomenological studies suggest that nausea and vomiting can be psychogenic in origin and thus can be involved in the emotional experience induced by ayahuasca ingestion.

Ayahuasca may alter the sensation of self and bodily location by increasing activation in the amygdala, regions of the frontal cortex and anterior insula. This may lead to increased bodily awareness and conscious perception of one’s own emotional and affective state.

Placebo effects

The present study has limitations, including the absence of blinding to control for placebo effects. Furthermore, the onset of EEG effects was faster than those reported with lyophilized ayahuasca, suggesting slower absorption dynamics when using the lyophilizate.

The present design of the study makes feasible a more ecologically valid approach to the neuroscientific study of ayahuasca, but it is limited to ignoring many important elements of ritual ayahuasca use.

Conclusion

The present results reveal acute biphasic effects of ayahuasca in the brain, including alpha decreases in the left centro-parieto-occipital cortex after 50 minutes and gamma band increases in frontal, parietal and temporal areas 75 to 125 minutes after ingestion. These effects are associated with concentrations of tryptamines and beta-carbolines in the blood.

Study details

Compounds studied
Ayahuasca DMT

Topics studied
Neuroscience

Study characteristics
Placebo-Controlled Double-Blind

Participants
20

Authors

Authors associated with this publication with profiles on Blossom

Eduardo Schenberg
Eduardo Ekman Schenberg is an entrepreneur and a neuroscientist who works to bring radical and disruptive innovations in psychiatry, developing safer and better treatments than currently available, focusing on severe cases of drug addiction, depression, and trauma, among others. After more than ten years treading a solid academic trajectory in the interface between psychology, neuroscience, and psychiatry, Eduardo is now developing initiatives to provide new psychiatric treatments. He also studies the many facets of the amazonian medicine ayahuasca, bridging science and traditional knowledge and practices.

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