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Cited by 112Psychedelics and Drug StudiesAlkaloids: synthesis and pharmacologySynthesis and bioactivity of alkaloids

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Acute biphasic effects of ayahuasca.

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Schenberg, Eduardo Ekman, Alexandre, João Felipe Morel, Filev, Renato, Cravo, Andre Mascioli, Sato, João Ricardo, Muthukumaraswamy, Suresh D., Yonamine, Maurício, Waguespack, Marian, Lomnicka, Izabela, Barker, Steven A., da Silveira, Dartiu Xavier·2015·PLoS ONE
DOI 10.1371/journal.pone.0137202PMC PMC4589238
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Abstract

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. 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. 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.

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Figures

Fig 1 Plasma data. Time-concentration curves for DMT, NMT and DMT-NO (A), IAA (B), THH and THH-OH (C), harmine and harmol (D), harmaline and harmalol (E) and correlation between hamaline Tmax with time for emesis. All concentration data is expressed as mean ± SD in ng/ml. All times expressed in minutes.
Fig 1 Plasma data. Time-concentration curves for DMT, NMT and DMT-NO (A), IAA (B), THH and THH-OH (C), harmine and harmol (D), harmaline and harmalol (E) and correlation between hamaline Tmax with time for emesis. All concentration data is expressed as mean ± SD in ng/ml. All times expressed in minutes.CC BY · PubMed Central
Fig 2 HRS subjective ratings. Subjective results as measured with the Hallucinogen Rating Scale–Brazilian Version. Int = Intensity, Som = Somaesthesia, Aff = Affect, Per = Perception, Cog = Cognition and Vol = Volition. For all six sub scales four is the maximum score possible.
Fig 2 HRS subjective ratings. Subjective results as measured with the Hallucinogen Rating Scale–Brazilian Version. Int = Intensity, Som = Somaesthesia, Aff = Affect, Per = Perception, Cog = Cognition and Vol = Volition. For all six sub scales four is the maximum score possible.CC BY · PubMed Central
Fig 3 Alpha rhythm cluster. Changes in alpha frequency band power spectrum over the 2 hours since ayahuasca ingestion. A) F statistics in the entire scalp revealed a significant cluster at left parieto-occipital electrodes (P7, PO7, O1 and Oz, p = 0.0398, highlighted by white *). B) Post-hoc analysis revealed decreases in the cluster depicted at left to be significant after 50 minutes from ingestion of ayahuasca (*p<0.05, corrected). Inset highlights the electrodes averaged for the post-hoc analysis, in correspondence with A. Data in B is expressed as mean and standard error.
Fig 3 Alpha rhythm cluster. Changes in alpha frequency band power spectrum over the 2 hours since ayahuasca ingestion. A) F statistics in the entire scalp revealed a significant cluster at left parieto-occipital electrodes (P7, PO7, O1 and Oz, p = 0.0398, highlighted by white *). B) Post-hoc analysis revealed decreases in the cluster depicted at left to be significant after 50 minutes from ingestion of ayahuasca (*p<0.05, corrected). Inset highlights the electrodes averaged for the post-hoc analysis, in correspondence with A. Data in B is expressed as mean and standard error.CC BY · PubMed Central
Fig 4 Beta rhythm cluster. Changes in beta frequency band power spectrum over the 2 hours since ayahuasca ingestion. A) F statistics in the entire scalp revealed a significant cluster at left fronto-temporal electrodes (FT9, AF7, F7, FT7 and T7, p = 0.0260, highlighted by white *). B) Beta band increases did not survive post-hoc analysis. Inset highlights the electrodes averaged for the post-hoc analysis, in correspondence with A. Data in B is expressed as mean and standard error.
Fig 4 Beta rhythm cluster. Changes in beta frequency band power spectrum over the 2 hours since ayahuasca ingestion. A) F statistics in the entire scalp revealed a significant cluster at left fronto-temporal electrodes (FT9, AF7, F7, FT7 and T7, p = 0.0260, highlighted by white *). B) Beta band increases did not survive post-hoc analysis. Inset highlights the electrodes averaged for the post-hoc analysis, in correspondence with A. Data in B is expressed as mean and standard error.CC BY · PubMed Central
Fig 5 Slow-gamma rhythm clusters. Changes in slow-gamma frequency band power spectrum over the 2 hours since ayahuasca ingestion. A) F statistics in the entire scalp revealed three significant clusters at the right frontal (Fp2, AF4 and F2, p = 0.0046, highlighted by white *), left centro-parieto-occipital (C3,CP3, P5, P3, P1, PO7 and O1, p = 0.0152, highlighted by white x) and left fronto-temporal (FT9, AF7, F7, FT7, T7 and C5, p = 0.0026, highlighted by white +). B) Slow-gamma band power increases at right frontal cluster were significant only after 100 min from ayahuasca ingestion (*p<0.05, corrected). C) Slow-gamma band power increases at left centro-parieto-occipital cluster were significant only after 100 min from ayahuasca ingestion (*p<0.05, corrected). D) Slow-gamma band power increases at left fronto-temporal cluster were significant after 75, 100 and 125 min from ayahuasca ingestion (*p<0.05, corrected). Insets in B, C and D highlight the electrodes averaged for each post-hoc analysis, in correspondence with A. Data in B, C and D is expressed as mean and standard error.
Fig 5 Slow-gamma rhythm clusters. Changes in slow-gamma frequency band power spectrum over the 2 hours since ayahuasca ingestion. A) F statistics in the entire scalp revealed three significant clusters at the right frontal (Fp2, AF4 and F2, p = 0.0046, highlighted by white *), left centro-parieto-occipital (C3,CP3, P5, P3, P1, PO7 and O1, p = 0.0152, highlighted by white x) and left fronto-temporal (FT9, AF7, F7, FT7, T7 and C5, p = 0.0026, highlighted by white +). B) Slow-gamma band power increases at right frontal cluster were significant only after 100 min from ayahuasca ingestion (*p<0.05, corrected). C) Slow-gamma band power increases at left centro-parieto-occipital cluster were significant only after 100 min from ayahuasca ingestion (*p<0.05, corrected). D) Slow-gamma band power increases at left fronto-temporal cluster were significant after 75, 100 and 125 min from ayahuasca ingestion (*p<0.05, corrected). Insets in B, C and D highlight the electrodes averaged for each post-hoc analysis, in correspondence with A. Data in B, C and D is expressed as mean and standard error.CC BY · PubMed Central
Fig 6 Fast-gamma rhythm clusters. Changes in fast-gamma frequency band power spectrum over the 2 hours since ayahuasca ingestion. A) F statistics in the entire scalp revealed four significant clusters at right-frontal (Fp2, AF4, F2 and F6, p = 0.0016, highlighted by white +), right parieto-occipital (P4, PO4, O2 and PO8, p = 0.0088, highlighted by white $), left fronto-temporal (FT9, F7, FT7, FC5 and T7, p = 0.0098, highlighted by white *) and left centro-parieto-occipital region (C3, CP3, CP1, P5, P3, PO7 and O1, p = 0.0132, highlighted by white x). B) Fast-gamma band power increases at left fronto-temporal cluster were significant after 75, 100 and 125 min from ayahuasca ingestion (*p<0.05, corrected). C) Fast-gamma band power increases at right frontal cluster were significant after 75, 100 and 125 min from ayahuasca ingestion (*p<0.05, corrected). D) Fast-gamma band power increases at left centro-parieto-occipital cluster were significant only after 75 min from ayahuasca ingestion (*p<0.05, corrected). E) Fast-gamma band power increases at right parieto-occipital cluster were significant after 75, 100 and 125 min from ayahuasca ingestion (*p<0.05, corrected). Insets in B, C, D and E highlight the electrodes averaged for each post-hoc analysis, in correspondence with A. Data in B, C, D and E is expressed as mean and standard error.
Fig 6 Fast-gamma rhythm clusters. Changes in fast-gamma frequency band power spectrum over the 2 hours since ayahuasca ingestion. A) F statistics in the entire scalp revealed four significant clusters at right-frontal (Fp2, AF4, F2 and F6, p = 0.0016, highlighted by white +), right parieto-occipital (P4, PO4, O2 and PO8, p = 0.0088, highlighted by white $), left fronto-temporal (FT9, F7, FT7, FC5 and T7, p = 0.0098, highlighted by white *) and left centro-parieto-occipital region (C3, CP3, CP1, P5, P3, PO7 and O1, p = 0.0132, highlighted by white x). B) Fast-gamma band power increases at left fronto-temporal cluster were significant after 75, 100 and 125 min from ayahuasca ingestion (*p<0.05, corrected). C) Fast-gamma band power increases at right frontal cluster were significant after 75, 100 and 125 min from ayahuasca ingestion (*p<0.05, corrected). D) Fast-gamma band power increases at left centro-parieto-occipital cluster were significant only after 75 min from ayahuasca ingestion (*p<0.05, corrected). E) Fast-gamma band power increases at right parieto-occipital cluster were significant after 75, 100 and 125 min from ayahuasca ingestion (*p<0.05, corrected). Insets in B, C, D and E highlight the electrodes averaged for each post-hoc analysis, in correspondence with A. Data in B, C, D and E is expressed as mean and standard error.CC BY · PubMed Central
Fig 7 Tryptamine’s concentration and EEG effects. Statistical associations between plasma levels of DMT (first column from left), DMT-NO (second column), NMT (third column) and IAA (fourth column) with the delta, alpha, beta, slow- and fast-gamma frequency bands. No significant effects were found with the theta band. A) DMT and delta frequency band. B) DMT and alpha frequency band. C) DMT-NO and alpha frequency band. D) IAA and alpha frequency band. E) DMT and beta frequency band. F) NMT and beta frequency band. G) DMT and slow-gamma frequency band. H) DMT-NO and slow-gamma frequency band. I) NMT and slow-gamma frequency band. J) IAA and slow-gamma frequency band. K) DMT and fast-gamma frequency band. L) DMT-NO and fast-gamma frequency band. M) NMT and fast-gamma frequency band. N) IAA and fast-gamma frequency band. Corresponding p values and Cohen’s d for each cluster are shown in the main text.
Fig 7 Tryptamine’s concentration and EEG effects. Statistical associations between plasma levels of DMT (first column from left), DMT-NO (second column), NMT (third column) and IAA (fourth column) with the delta, alpha, beta, slow- and fast-gamma frequency bands. No significant effects were found with the theta band. A) DMT and delta frequency band. B) DMT and alpha frequency band. C) DMT-NO and alpha frequency band. D) IAA and alpha frequency band. E) DMT and beta frequency band. F) NMT and beta frequency band. G) DMT and slow-gamma frequency band. H) DMT-NO and slow-gamma frequency band. I) NMT and slow-gamma frequency band. J) IAA and slow-gamma frequency band. K) DMT and fast-gamma frequency band. L) DMT-NO and fast-gamma frequency band. M) NMT and fast-gamma frequency band. N) IAA and fast-gamma frequency band. Corresponding p values and Cohen’s d for each cluster are shown in the main text.CC BY · PubMed Central
Fig 8 Beta-carboline’s concentration and EEG effects. Statistical associations between plasma levels of the beta-carbolines harmine (first column from left), harmol (second column), harmaline (third column), harmalol (fourth column), THH (fifth column) and THH-OH (last column) with delta, theta (only for THH-OH) and alpha, slow- and fast-gamma frequency bands (not significant for THH-OH). A) Harmine and alpha. B) Harmol and alpha. C) Harmaline and alpha. D) Harmalol and alpha. E) THH and alpha. F) Harmine and slow-gamma. G) Harmol and slow-gamma. H) Harmaline and slow-gamma. I) Harmalol and slow-gamma. J) THH and slow-gamma. K) Harmine and fast-gamma. L) Harmol and fast-gamma. M) Harmaline and fast-gamma. N) Harmalol and fast-gamma. O) THH and fast-gamma. P) THH-OH and delta. Q) THH-OH and theta. Corresponding p values and Cohen’s d for each cluster are shown in the main text.
Fig 8 Beta-carboline’s concentration and EEG effects. Statistical associations between plasma levels of the beta-carbolines harmine (first column from left), harmol (second column), harmaline (third column), harmalol (fourth column), THH (fifth column) and THH-OH (last column) with delta, theta (only for THH-OH) and alpha, slow- and fast-gamma frequency bands (not significant for THH-OH). A) Harmine and alpha. B) Harmol and alpha. C) Harmaline and alpha. D) Harmalol and alpha. E) THH and alpha. F) Harmine and slow-gamma. G) Harmol and slow-gamma. H) Harmaline and slow-gamma. I) Harmalol and slow-gamma. J) THH and slow-gamma. K) Harmine and fast-gamma. L) Harmol and fast-gamma. M) Harmaline and fast-gamma. N) Harmalol and fast-gamma. O) THH and fast-gamma. P) THH-OH and delta. Q) THH-OH and theta. Corresponding p values and Cohen’s d for each cluster are shown in the main text.CC BY · PubMed Central

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Research works printed but not linked: 4

  1. B Holmstedt, 1967, Chemical constituents and pharmacology of South American snuffs, Psychopharmacol Bull, 4, 16
  2. J Ott, 1997, Pharmahuasca, Anahuasca and Vinho da Jurema: Human Pharmacology of Oral DMT Plus Harmine, yearbook for Ethnomedicine, 1
  3. P Naranjo, 1959, Estudio comparativo de la harmina, la dietilamida del ácido lisérgico (LSD-25) y la mescalina, Revista de la Confederación Médica Panamericana, 6, 1
  4. AT Shulgin, 1977, Profile of Psychedelic Drugs. 4. Harmaline, Journal of Psychedelic drugs, 9, 79

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Metadata

Authors
Schenberg, E. E., Alexandre, J. F. M., Filev, R., Cravo, A. M., Sato, J. R., Muthukumaraswamy, S. D., Yonamine, M., Waguespack, M., Lomnicka, I., Barker, S. A., & da Silveira, D. X.
Affiliations
  • Universidade Federal de São Paulo (BR)
  • Universidade Federal do ABC (BR)
  • University of Auckland (NZ)
  • Louisiana State University (US)
Corresponding author
Schenberg, Eduardo Ekman
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2015-09-30
Volume
10
Issue
9
Pages
e0137202
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0137202
PMC
PMC4589238
OpenAlex
W1914275515
Cited by
111
References
95
Citations by year
2026: 5 · 2025: 12 · 2024: 8 · 2023: 12 · 2022: 14 · 2021: 13 · 2020: 15 · 2019: 5 · 2018: 11 · 2017: 7 · 2016: 7 · 2015: 1
FWCI
10.75
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • ResearchSpace (University of Auckland) (submittedVersion, cc-by)
Funders
Fundação de Amparo à Pesquisa do Estado de São Paulo (12/07699-7, 2014/, 2015/, 2011/, 15/13536-1)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and bioactivity of alkaloids
Keywords
ayahuasca, N,N-dimethyltryptamine, harmine, harmaline, tetrahydroharmine, gamma power, syncretic religion
MeSH terms
Adult, Brain, Electroencephalography, Female, Humans, Male, Middle Aged, Plant Extracts, Psychometrics, Banisteriopsis, Young Adult, Brain Waves

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