Using LORETA on EEG from 18 volunteers given encapsulated ayahuasca (0.85 mg DMT/kg), the study found significant decreases in alpha‑2, delta, theta and beta‑1 power 60–90 minutes after dosing versus placebo. These reductions were localised to the temporo‑parieto‑occipital junction and temporomedial/frontomedial regions, paralleled increased Hallucinogen Rating Scale scores, and implicate unimodal/heteromodal association cortices and limbic structures in ayahuasca’s psychological effects.
<i>Ayahuasca,</i> a South American psychotropic plant tea obtained from <i>Banisteriopsis caapi</i> and <i>Psychotria viridis</i>, combines monoamine oxidase-inhibiting β-carboline alkaloids with N,N-dimethyltryptamine (DMT), a psychedelic agent showing 5-HT<sub>2A</sub> agonist activity. In a clinical research setting, <i>ayahuasca</i> has demonstrated a combined stimulatory and psychedelic effect profile, as measured by subjective effect self-assessment instruments and dose-dependent changes in spontaneous brain electrical activity, which parallel the time course of subjective effects. In the present study, the spatial distribution of <i>ayahuasca</i>-induced changes in brain electrical activity was investigated by means of low-resolution electromagnetic tomography (LORETA). Electroencephalography recordings were obtained from 18 volunteers after the administration of a dose of encapsulated freeze-dried <i>ayahuasca</i> containing 0.85 mg DMT/kg body weight and placebo. The intracerebral power density distribution was computed with LORETA from spectrally analyzed data, and subjective effects were measured by means of the Hallucinogen Rating Scale (HRS). Statistically significant differences compared to placebo were observed for LORETA power 60 and 90 min after dosing, together with increases in all six scales of the HRS. <i>Ayahuasca</i> decreased power density in the alpha-2, delta, theta and beta-1 frequency bands. Power decreases in the delta, alpha-2 and beta-1 bands were found predominantly over the temporo-parieto-occipital junction, whereas theta power was reduced in the temporomedial cortex and in frontomedial regions. The present results suggest the involvement of unimodal and heteromodal association cortex and limbic structures in the psychological effects elicited by <i>ayahuasca</i>.
Papers cited by this study that are also in Blossom
Riba, J., Urbano, G., Morte, A. et al. · Psychopharmacology (2001)
Riba, J., Valle, M., Urbano, G. et al. · Journal of Pharmacology and Experimental Therapeutics (2003)
Riba, J., Anderer, P., Morte, A. et al. · British Journal of Clinical Pharmacology (2002)
Vollenweider, F. X., Leenders, K. L., Maguire, P. et al. · Neuropsychopharmacology (1997)
Riba and colleagues introduce ayahuasca as a traditional South American plant tea combining Banisteriopsis caapi, which supplies monoamine oxidase (MAO)–inhibiting ß-carbolines, with Psychotria viridis, a source of the short-acting psychedelic N,N-dimethyltryptamine (DMT). Because the ß-carbolines inhibit MAO, orally ingested DMT becomes bioavailable and produces acute perceptual, cognitive and mood effects that have been documented subjectively and in scalp electroencephalography (EEG) as dose-dependent reductions in spectral power and acceleration of centre-of-gravity frequency. Previous functional imaging work with related indoleamine psychedelics (for example, psilocybin) has shown metabolic increases in prefrontal regions, but the regional cortical generators of ayahuasca-induced EEG changes had not been assessed using source-localisation techniques available at the time. The present study therefore set out to map the intracerebral sources of ayahuasca-induced changes in spontaneous EEG using low-resolution electromagnetic tomography (LORETA). The authors aimed to identify which cortical and paralimbic regions show altered current density across classical EEG frequency bands after a single oral dose of encapsulated, freeze-dried ayahuasca, and to relate those regional effects to concurrently measured subjective psychedelic effects.
Eighteen healthy volunteers (15 males, 3 females; mean age 25.7 years) took part in a double-blind, placebo-controlled, randomised crossover trial. Eligibility required prior experience with psychedelic drugs on at least five occasions and absence of current or past neurological or psychiatric disorder; volunteers underwent a structured psychiatric interview (DSM-III-R), trait anxiety screening and a physical examination including ECG, laboratory tests and urinalysis. Two of the participants had prior exposure to ayahuasca; all reported prior cannabis and cocaine use. Experimental sessions were at least one week apart and volunteers abstained from medications, illicit drugs and from alcohol, tobacco and caffeine before sessions. The active intervention was a lyophilised ayahuasca preparation characterised by HPLC analysis: the freeze-dried powder contained 8.33 mg DMT, 14.13 mg harmine, 0.96 mg harmaline and 11.36 mg tetrahydroharmine per gram. Individual doses were administered to deliver 0.85 mg DMT per kg body weight, encapsulated in gelatin capsules; placebo capsules contained lactose. Capsules were given around 10:00 a.m. with 250 ml water, and the number of capsules was balanced between sessions so volunteers ingested identical numbers on active and placebo days. EEG was recorded with 19 scalp electrodes positioned according to the international 10/20 system, referenced to averaged mastoids, together with vertical and horizontal electrooculograms. Vigilance-controlled, eyes-closed three-minute recordings were obtained at baseline (including -15 min) and at 30, 60, 90, 120, 180, 360 and 480 min after dosing. Signals were band-pass filtered (0.3–30 Hz), digitised at 100 Hz, and subjected to a two-step artefact correction (ocular regression and automatic time/frequency rejection), followed by visual inspection. Spectral analysis was performed on six 5-second artefact-free epochs per recording; data were filtered into seven frequency bands: delta (1.5–6 Hz), theta (6–8 Hz), alpha-1 (8–10 Hz), alpha-2 (10–12 Hz), beta-1 (12–18 Hz), beta-2 (18–21 Hz) and beta-3. LORETA was used to estimate three-dimensional intracerebral current density (power) from the scalp cross-spectral matrix. The solution space was constrained to cortical gray matter and hippocampus using a digitised Talairach-based atlas; voxels with >33% probability of being gray matter were included, yielding 2,394 voxels at 0.343 cm3 resolution. Statistical analysis of LORETA power used paired-sample t tests on log-transformed data at each voxel and frequency band, with a nonparametric single-threshold permutation correction (Holmes method) based on 5,000 randomizations to control for multiple comparisons. The omnibus test identified time points with maximal suprathreshold voxels (used to select main analysis times), and anatomical distributions of suprathreshold voxels were tabulated by lobe, gyrus and Brodmann area. Subjective effects were measured with a Spanish version of the Hallucinogen Rating Scale (HRS), with six subscales (somaesthesia, affect, volition, cognition, perception and intensity); HRS scores after ayahuasca and placebo were compared using paired t tests.
The omnibus voxel-wise analysis across time showed a steep rise in suprathreshold voxels at 60 min after dosing and a pharmacodynamic peak at 90 min; LORETA comparisons versus placebo were therefore computed at those two time points. At 60 min, statistically significant decreases in intracerebral power were most prominent in the alpha-2 band, with 459 suprathreshold voxels. These alpha-2 reductions were distributed across parietal (135 voxels), temporal (170), occipital (79) and limbic (69) lobes, with only minimal involvement of left frontal and sublobar regions. The spatial pattern at 60 min concentrated around the temporo-parieto-occipital junction, notably the angular and supramarginal gyri, precuneus, superior and middle temporal gyri and fusiform gyrus; limbic suprathreshold voxels were mainly in the cingulate and parahippocampal gyrus. Smaller delta-band decreases at 60 min were detected in a left occipito-temporal border region (15 voxels, BA 19/37/21). Theta decreases at 60 min narrowly missed significance (lowest t = -3.58, p = 0.0522), localising to BA 24 in medial frontal cortex. At the 90-min peak, significant power reductions extended to the delta, theta and beta-1 bands. Delta-band decreases comprised 471 suprathreshold voxels located in parietal (135), temporal (263), occipital (70) and limbic (3) lobes, again centred on the temporo-parieto-occipital junction (BA 37, BA 19, BA 39). Theta-band decreases (128 suprathreshold voxels) formed three non-confluent regions: medial and superior frontal gyri (BA 6, 8), the anterior cingulate, and a left temporomedial cluster including fusiform and parahippocampal gyri and the uncus. Beta-1 reductions (139 suprathreshold voxels) were mainly parietal (122 voxels), occurring in two non-contiguous regions that included posterior cingulate/precuneus/superior parietal lobule and right supramarginal/angular gyri (BA 39). Alpha-2 power was reduced at 90 min relative to placebo but did not reach statistical significance at that time point. Subjective effects followed a time course that paralleled the LORETA findings: volunteers reported initial effects by 15 min, greater effects between 30 and 45 min, a steep rise at 60 min and maximal subjective intensity between 90 and 120 min, with effects subsiding and disappearing by 360 min. The HRS, administered at 240 min, nevertheless showed statistically significant increases in all six subscales after ayahuasca compared with placebo. Reported phenomena included somatic sensations (pins and needles, increased skin sensitivity, physical comfort), a range of visual and auditory experiences including synesthetic reports by five subjects, altered time sense, accelerated thought, reduced ability to sustain focussed attention and positive mood changes; none of the participants experienced full psychosis-like symptoms or loss of awareness that effects were drug-induced.
Riba and colleagues interpret the LORETA findings as evidence that ayahuasca produces time-dependent reductions in intracerebral EEG power that implicate posterior association cortices and medial paralimbic regions. The principal effects were decreases in slow rhythms (delta and theta) and reductions in alpha-2 and beta-1 power, with maximal spatial extent around the temporo-parieto-occipital junction and with theta decreases in medial frontal and temporomedial areas. These electrophysiological changes accompanied a constellation of perceptual, cognitive and mood effects typical of psychedelics, and the temporal alignment between EEG source changes and subjective peak effects supports a pharmacodynamic relationship. The authors relate the spectral pattern to proposed neuropharmacology: diminished delta and theta power is seen with psychostimulants and psychedelics and is broadly compatible with an arousing or excitatory action, whereas the alpha-2 suppression observed here is a feature shared with several perception-altering drugs and distinguishes ayahuasca from prototypical stimulants that often enhance alpha. Comparisons with PET and SPECT studies of psilocybin and mescaline reveal partial concordance, notably in temporomedial and cingulate involvement, but the present EEG-source results did not show the same degree of frontal metabolic increases reported in some metabolic imaging studies; the authors suggest this divergence could arise from differences in the physiological variables measured (electrical current density versus blood flow or glucose metabolism) and from differences in subjective response profiles. Given the exploratory design, the investigators propose hypotheses about functional implications: decreases in unimodal sensory association cortices may underlie modality-specific perceptual alterations, while effects in heteromodal association cortex, cingulate and temporomedial structures could account for higher-order changes in attention, emotion and memory. The authors acknowledge the exploratory nature of the work and note that the volunteers' prior psychedelic experience may have influenced the predominantly positive character of subjective reports. They conclude by recommending further studies that directly examine ayahuasca effects on the cognitive and emotional domains implicated by the present source-localisation results, to better characterise the neural basis of its complex psychological effects.
The psychoactive plant tea known as ayahuasca, a Quechua name meaning vine of the souls or vine of the dead, is a traditional shamanic inebriant used in the Upper Amazon since pre-Columbian times for religious and medicinal purposes. In the second half of the last century, the use of ayahuasca reached the urban areas of Amazonian countries, where it is used by mestizo 'ayahuasqueros' for healing and divination. However, modern nonindigenous use of ayahuasca mainly takes place within the context of syncretic religious groups, particularly the Brazilian 'Santo Daime' and 'Unia ˜o do Vegetal', which have combined Old World religious beliefs with the sacramental use of the beverage. In recent years, groups of followers of these Brazilian religions have become established in the United States and in several European countries. Botanical research into the plant sources of ayahuasca has shown that the main ingredient of the tea is the woody vine Banisteriopsis caapi (Malpighiaceae). Ayahuasca is obtained by infusing the pounded stems of the vine either alone or more frequently in combination with the leaves of Psychotria viridis (Rubiaceae) or Diplopterys cabrerana (Malpighiaceae). B. caapi contains notable amounts of ßcarboline alkaloids, mainly harmine and tetrahydroharmine, and to a lesser extent harmaline and traces of harmol and harmalol. P. viridis and D. cabrerana also contain indole alkaloids, mainly the potent short-acting psychedelic agent N,N-dimethyltryptamine (DMT). DMT is structurally related to the neurotransmitter serotonin, and like better-characterized psychedelics such as LSD and mescaline (a phenethylamine), binds to the 5-HT 2A receptor sites in the central nervous system (CNS), where it acts as an agonist. The combination of DMT from P. viridis with the ßcarboline alkaloids from B. caapi in a single oral preparation is most remarkable from the pharmacological point of view. It takes advantage of the pharmacodynamic properties of the ß-carbolines, which allow access to the system of the otherwise orally inactive tryptamine component. Indeed, DMT is known for its lack of psychoactivity when orally ingested, probably due to metabolism by the enzyme monoamine oxidase. On the other hand, the ß-carbolines present in ayahuasca, particularly harmine and harmaline, are potent natural monoamine oxidase inhibitors, apparently preventing the extensive gut and liver first-pass effect on DMT, which is subsequently able to reach the systemic circulation and the CNS unaltered. In a clinical research setting, ayahuasca has been found to induce transient modifications in perception, thought processes and mood that fit a combined stimulatory and psychedelic effect profile, as measured by subjective effect self-assessment instruments. Furthermore, the central effects of ayahuasca have also been evidenced by means of objective neurophysiological measures such as topographic pharmaco-electroencephalography (EEG). The effects of ayahuasca on the human EEG are characterized by an overall reduction in absolute power in the classical frequency bands (more pronounced in the slow delta and theta bands), and also by an acceleration of the center-of-gravity frequency. These actions on the spontaneous EEG follow a dose-response pattern and closely parallel the time course of subjective effects. The aim of the present study was to assess the differential involvement of cortical brain regions in the acute central effects of ayahuasca by means of a recently developed neuroimaging technique: low-resolution electromagnetic tomography (LORETA). Based on the scalp electrical potential distribution obtained by means of classical EEG measures, LORETA provides three-dimensional information regarding the cortical neural generators of brain electrical activity. Furthermore, LORETA computes a unique three-dimensional intracerebral power density distribution for the different EEG frequency bands, allowing their separate analysis. Unlike dipole modeling, LORETA makes no a priori assumptions about the number of sources involved. The only constraint implemented is that of maximal smoothness of the solution, based on the assumption that neighboring neuronal sources are likely to be similarly active (i.e. have similar orientations and strengths). The distribution obtained is thus the smoothest of all possible inverse solutions, as it is considered the most plausible. In a new implementation of LORETA, an additional neuroanatomical constraint restricts the solution space to cortical gray matter volume. The technique has previously been used in the evaluation of acute effects of psychoactive drugs. To our knowledge, regional brain electrical activity has not been evaluated previously by means of LORETA following the administration of ayahuasca or other psychedelics with 5-HT 2A agonist activity. It is consequently difficult to establish an a priori hypothesis regarding the brain areas involved in the effects of ayahuasca on the EEG. However, PET and SPECT investigations of blood flow and glucose metabolism after acute psilocybin (an indoleamine structurally similar to DMT) and mescaline administration have evidenced increased activation in the prefrontal cortex. Consequently, we postulated that changes in electrical activity would be identified at least in these regions.
Eighteen healthy volunteers (15 males and 3 females) participated in the study. Eligibility criteria included prior experience with psychedelic drugs on at least five occasions without sequelae derived therefrom, no current or previous history of a neurological or psychiatric disorder, and no family history of an Axis-I psychiatric disorder in first-degree relatives. Volunteers were given a structured psychiatric interview (DSM-III-R) and completed the trait anxiety scale from the State-Trait Anxiety Inventory. Exclusion criteria included alcohol or other substance dependence, and high scores on the trait anxiety scale (over 1 standard deviation above the normative mean). Each participant underwent a complete physical examination that included a medical history, laboratory tests, ECG and urinalysis. Their mean age was 25.7 years (range 19-38 years), mean weight was 66.47 kg (range 50.7-79.5 kg) and mean height was 175.11 cm (range 158-188 cm). In addition to their prior intake of psychedelics, all volunteers had previous experience with cannabis and cocaine. Although prior exposure specifically to ayahuasca was not required for participation, two of the volunteers had ingested the drug before inclusion in this study. The study was conducted in accordance with the Declarations of Helsinki and Tokyo concerning experimentation on humans, and was approved by the hospital's ethics committee and the Spanish Ministry of Health. The volunteers received detailed information on the nature of ayahuasca, the general psychological effects of psychedelics and their possible adverse effects, as reported in the psychiatric literature. Written informed consent was obtained from all participants.
The ayahuasca employed in the present study was not administered in its original liquid form, but as a lyophilizate. The freeze-dried homogenized material had been obtained from a 9.6-liter batch of ayahuasca. The DMT content in the lyophilizate had been determined by HPLC, as described by Callaway et al., and the ß-carboline constituents were determined following a modification of the method described in that study. The 9.6-liter batch yielded 611 g of freeze-dried powder, containing 8.33 mg of DMT, 14.13 mg of harmine, 0.96 mg of harmaline and 11.36 mg of tetrahydroharmine per gram. Based on tolerability and subjective effects assessed previously, an ayahuasca dose containing 0.85 mg DMT/kg body weight was administered to the volunteers. The calculated individual dose for each volunteer was administered by combining 00 gelatin capsules containing 0.5, 0.25 or 0.125 g of freeze-dried ayahuasca. Placebo capsules were 00 gelatin capsules containing 0.75 g of lactose. These were administered on the placebo day, and were also combined with active ayahuasca capsules when necessary, so that all volunteers took the same number of capsules on each experimental day.
EEG recordings were obtained in a double-blind placebo-controlled randomized crossover clinical trial. Two weeks prior to the beginning of the experimental procedure, volunteers were requested to abstain from any medication or illicit drug use until the completion of the study. Volunteers also abstained from alcohol, tobacco and caffeinated drinks 24 h prior to each experimental day. Urine was screened for illicit drug use on each experimental day. Experimental days were at least 1 week apart. On each experimental day, volunteers remained in the clinical research unit for a period of approximately 10 h. Following arrival in the morning under fasting conditions, EEG electrodes were placed on the scalp, and drug/placebo capsules were administered at approximately 10.00 a.m. with 250 ml of tap water. EEG recordings were obtained at baseline and at regular intervals after treatment administration. For the first 4 h, volunteers remained seated in a reclining chair in a quiet and dimly lit room. The experimenter remained outside the room during the EEG recordings. The last recording was performed at 8 h, and volunteers were discharged approximately 9 h after drug administration.
Nineteen-lead EEG recordings were obtained by means of scalp electrodes placed according to the international 10/20 system: Fp1, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1 and O2, referenced to averaged mastoids. Additionally, vertical and horizontal electrooculograms were recorded. The signal was acquired through a Neuroscan SYNAMPS amplifier. Three-minute vigilancecontrolled EEG with eyes closed was recorded at baseline, prior to drug administration and at different time points after dosing. During the vigilance-controlled EEG recordings, the experimenter tried to keep the volunteers alert; as soon as drowsiness patterns appeared in the EEG, they were aroused by acoustic stimulation. The EEG signal was band-pass filtered at 0.3-30 Hz, and digitized on-line with a sampling frequency of 100 Hz. EEG recordings were obtained prior to drug administration (-15 min and baseline), and 30, 60, 90, 120, 180, 360 and 480 min after dosing. A two-step artifact processing procedure was used. It included ocular artifact minimization based on regression analysis in the time domain, as described by Semlitsch et al., and automatic artifact rejection based on a time and frequency domain approach as described by Anderer et al.. Validity of the artifact processing procedure was visually assessed. After recomputation to average reference, spectral analysis was performed for artifact-free 5-second epochs. For each recording, the spectral power of six 5-second epochs of artifact-free, vigilance-controlled EEG was averaged. Data were digitally filtered into seven frequency bands according to Kubicki et al.: delta (1.5-6 Hz), theta (6-8 Hz), alpha-1 (8-10 Hz), alpha-2 (10-12 Hz), beta-1 (12-18 Hz), beta-2 (18-21 Hz) and beta-3. Subsequently, LORETA was used to estimate the three-dimensional intracerebral current density distribution from the voltage values recorded at the scalp electrodes. The LORETA version employed implements a three-shell spherical head modelregistered to the human brain atlas of Talairach and Tournouxavailable as a digitized MRI from the Brain Imaging Centre, Montréal Neurological Institute. The EEG electrode coordinates reported by Towle et al.were used for registration between spherical and realistic head geometry. The LORETA solution space was restricted to the cortical gray matter and hippocampus, based on the Digitized Probability Atlas corresponding to the Talairach atlas and also available from the Brain Imaging Centre, Montréal Neurological Institute. A voxel was included in the solution space if its probability of being gray matter was higher than 33%, and higher than its probability of being either white matter or cerebrospinal fluid. The final solution space consisted of 2,394 voxels with a spatial resolution of 0.343 cm 3. The EEG lead field was computed numerically with the boundary element method. LORETA images represent the power (i.e. squared magnitude of computed intracerebral current density) in each of the 2,394 voxels. 'LORETA power', synonymous to 'EEG power', refers to the spectral power of current density as estimated by Riba/Anderer/Jané/Saletu/Barbanoj Omnibus significance test LORETA. Thus, in a first step, current density values were estimated based on the EEG cross-spectral matrix and then squared for each voxel and frequency band.
Volunteers were requested to answer the Hallucinogen Rating Scale (HRS), a self-report questionnaire measuring psychedelicinduced subjective effects. The HRS includes six subscales: 'somaesthesia', reflecting somatic effects; 'affect', sensitive to emotional and affective responses; 'volition', indicating the volunteer's capacity to willfully interact with his/her 'self' and/or the environment; 'cognition', describing modifications in thought processes or content; 'perception', measuring visual, auditory, gustatory and olfactory experiences, and finally 'intensity', which reflects the strength of the overall experience. In the present study, a Spanish version of the questionnaire was used. The HRS was administered 240 min after administration of ayahuasca and placebo. Statistical Analysis LORETA Data. In a first step, in order to explore the time course of ayahuasca effects, paired-sample t tests were computed for log-transformed LORETA power at each voxel and frequency band for the different time points. To correct for multiple comparisons, a nonparametric single-threshold test was applied on the basis of the theory for randomization and permutation tests developed by Holmes et al.. The omnibus null hypothesis of no activation anywhere in the brain was rejected if at least one t value (i.e. voxel, t MAX ) was above the critical threshold (t CRIT ) for p = 0.05 determined by 5,000 randomizations. The total number of suprathreshold voxels was plotted versus time in order to select the time points with the largest effects. Subsequently, LORETA images were computed for log-transformed normalized data for each separate frequency band at the selected time points and following the same statistical approach. On the basis of the Structure-Probability Maps Atlas, the number of significant vox-els in each lobe (frontal, parietal, occipital, temporal, limbic and sublobar), gyrus and Brodmann area (BA) of the left and the right hemisphere was computed separately for each suprathreshold region. Subjective Effects. Scores on the HRS questionnaire after ayahuasca administration were compared with those after placebo by means of paired-sample Student's t tests.
Figureshows the results for the omnibus significance test performed for all voxels and frequency bands at the different time points in order to explore the time course of effects. A steep rise in the number of suprathreshold voxels was observed 60 min following drug administration, and the pharmacodynamic peak occurred 90 min after dosing. LORETA images were thus computed for the ayahuascaversus placebo-induced changes at these two time points. The voxel-by-voxel statistical comparison of ayahuasca-induced versus placebo-induced effects 60 min after drug administration (0.85 mg DMT/kg body weight dose), followed by Holmes correction, showed statistically significant decreases mainly in the alpha-2 frequency band (459 suprathreshold voxels). As listed in table 1, power density decreases were found in the parietal (135), occipital (79), temporal (170) and limbic (69) lobes in both hemispheres, and at the left frontal (3) and sublobar level The number of significant voxels (N sig ), the total number of voxels (N total ) and the percentage of significant voxels (%) for each gyrus and hemisphere are given (n = 18). The number of significant voxels (N sig ), the total number of voxels (N total ) and the percentage of significant voxels (%) for each gyrus and hemisphere are given (n = 18). (3). Suprathreshold voxels were thus found over extensive cortical areas around the temporo-parieto-occipital junction predominantly in the angular gyrus, supramarginal gyrus, precuneus, superior and middle temporal gyri and fusiform gyrus. In the limbic lobe, suprathreshold voxels covered mainly the cingulate and the parahippocampal gyrus. The BAs showing the highest percentage of suprathreshold voxels were BA 7 in the parietal lobe, BA 19 in the occipital lobe, BA 39 and BA 37 in the temporal lobe, and BA 36 and BA 35 in the limbic lobe. Figureshows LORETA axial brain slices as statistical nonparametric maps corresponding to the suprathreshold regions found for the alpha-2 frequency band, 60 min after drug administration. In addition to the above results, power decreases were observed for the delta frequency band in a small area covering 15 suprathreshold voxels in the border between the left occipital and temporal lobes in BA 19, BA 37 and BA 21. Finally, decreases in the theta band fell short of statistical significance, with the lowest t value equal to -3.58 (p = 0.0522; cutoff t value = 3.61). This local minimum was located in BA 24 in the medial frontal cortex. As shown in figure, the largest number of suprathreshold voxels, i.e. the pharmacodynamic peak, was observed 90 min after administration of ayahuasca. At this time point, statistically significant decreases were found for the delta, theta and beta-1 frequency bands. Alpha-2 power density was also reduced relative to placebo, but contrary to what was observed 60 min after Riba/Anderer/Jané/Saletu/Barbanoj administration, these decreaseswere not statistically significant. Tablelists the anatomical distribution of the power decreases observed for the delta frequency band. Thus, 471 suprathreshold voxels were located in the parietal (135), occipital (70), temporal (263) and limbic (3) lobes in both hemispheres. Suprathreshold voxels were found over extensive cortical areas around the temporo-parietooccipital junction predominantly in the angular gyrus, superior occipital gyrus, middle temporal gyrus and fusiform gyrus. The BAs showing the highest percentage of suprathreshold voxels were BA 37, BA 19 and BA 39. Figureshows LORETA axial brain slices as statistical nonparametric maps corresponding to the suprathreshold regions found for the delta frequency band. Note the marked overlap between these brain areas and those found at 60 min for the alpha-2 frequency band. Areas of power density decrease in the theta frequency band are indicated in table. One hundred and twentyeight voxels showed t values below the statistical threshold. These suprathreshold voxels were found in the frontal lobe, in the temporal lobe (58) and in the limbic lobe (57). Suprathreshold voxels were found distributed in three nonconfluent areas, i.e. in the medial and superior frontal gyri (BA 6, 8), in the anterior cingulateand in the left temporomedial cortex comprising mainly the fusiform and parahippocampal gyri and the uncus. Riba/Anderer/Jané/Saletu/Barbanoj The number of significant voxels (N sig ), the total number of voxels (N total ) and the percentage of significant voxels (%) for each gyrus and hemisphere are given (n = 18). Figureshows LORETA orthogonal slices (axial, sagittal and coronal views) as statistical nonparametric maps corresponding to the three nonconfluent suprathreshold regions found for the theta frequency band, through the voxel of the extreme t value. Areas of beta-1 power density decrease are shown in table. These comprised 139 suprathreshold voxels, located in the parietal lobe (122), occipital lobe (3), temporal lobe (5) and limbic lobe. Suprathreshold voxels were found on two nonconfluent areas. The first area comprised voxels in the parietal lobe, extending medially and bilaterally from the posterior cingulate gyrus (BAto the precuneus and superior parietal lobule. The second area comprised voxels in the right supramarginal and angular gyri (BA 39). Figureshows LORETA orthogonal slices (axial, sagittal and coronal views) as statistical nonparametric maps corresponding to the two nonconfluent suprathreshold regions found for the beta-1 frequency band, through the voxel of the extreme t value.
Ayahuasca induced a series of perceptual, mood and cognitive modifications with a characteristic psychedelic pattern, as measured by the HRS questionnaire. Tableshows the mean values obtained after placebo and ayahuasca for the HRS scores, and the results of the statistical analyses performed. Drug-induced subjective effects were first noted as early as 15 min, became more marked between 30 and 45 min, showed a steep rise at 60 min, reached a maximum between 90 and 120 min, and decreased thereafter, disappearing entirely at 360 min. All volunteers experienced somatic modifications, which included altered bodily sensations, pins and needles, increased skin sensitivity and physical comfort. Visual and auditory phenomena were also frequently reported but varied greatly in quality and intensity between volunteers, ranging from distortions of objects and sounds to elaborate visions with eyes closed and perception of nonexistent noises. Five subjects reported experiencing auditory and visual synesthesia. In the cognitive sphere, the sense of time was altered, thought speed increased and the ability to focus attention was subjectively perceived to be reduced. Mood modifications were also present, the experience being globally regarded as satisfactory, with most volunteers reporting having experienced happiness, excitation and a 'high'. It is important to note that, at the doses administered, ayahuasca did not induce full-blown psychotic symptoms and none of the participants lost awareness of the druginduced nature of the psychological effects experienced.
The analysis of brain electrical activity by means of LORETA identified significant drug-induced changes in the intracerebral power density distribution 60 and 90 min following ayahuasca administration. At the peak of the pharmacodynamic effects, the slow delta rhythm was decreased in posterior brain regions. Additionally, decreases in theta were observed in the medial frontal and medial temporal cortices. Similar effects, although less intense (delta) or bordering on statistical significance (theta), were also observed in analogous brain regions 60 min after dosing. At this time point, however, a widespread power reduction in the alpha-2 band was observed in pos-terior areas, showing considerable overlap with those demonstrating significant decreases in delta power 90 min after administration. These modifications of the EEG power spectrum were accompanied by a constellation of perceptual, cognitive and mood modifications typical of the psychedelics, as evidenced by significant increases in all subscales of the HRS. The pattern of subjectively reported effects corresponded qualitatively and The number of significant voxels (N sig ), the total number of voxels (N total ) and the percentage of significant voxels (%) for each gyrus and hemisphere are given (n = 18). with respect to the time course with previous results obtained in a smaller sample of volunteers. It is of particular interest that these effects involving perceptive and cognitive modifications were regarded by the majority of volunteers as positive and desirable, in contrast with the more psychosis-like profile, including paranoid thoughts and fear of control loss, reported in studies in which other psychedelics, such as psilocybin, have been administered to drug-naive subjects. The fact that the volunteers who enrolled in the present study had prior experience with psychedelics may account for these differences. The effects of ayahuasca on the EEG power spectrum are compatible with its proposed neurochemical mechanism of action. Decreases in slow activity, i.e. delta and theta power, are a general feature of psychostimulants, such as amphetamine and methylphenidate, serotonin releasers such as fenfluramine, and psychedelics displaying 5-HT 2 agonist activity. Early pharmaco-EEG research on LSD, a 5-HT 2A agonist like DMT -the main psychotropic principle found in ayahuasca -had also shown decreases in slow activity after acute drug administration. Delta activity has traditionally been thought to reflect inhibitory activity, and increases in theta have been observed in relaxed and meditative states. Thus, the present results would rather suggest an excitatory or arousing effect for ayahuasca. This assumption is further supported by the fact that major tranquilizers with D 2 or mixed D 2 /5-HT 2 antagonist activity, such as chlorpromazine and risperidone, are characterized by their delta-and theta-promoting effects. An important difference between ayahuasca and psychostimulants is the alpha-2decreasing properties of the former found in the present study. In addition to slow wave-dampening effects, amphetamine is known to enhance alpha power, a feature not shared by ayahuasca. As mentioned above, Itil and Finkfound that LSD had inhibitory effects on slow waves, but also reduced alpha. Interestingly, other drugs, such as scopolamine or ketamine, with various mechanisms of action and different overall EEG profiles but able to elicit hallucinatory states, also display an alpha-suppressing effect. Thus, ayahuasca would combine alpha-dampening effects, a feature shown by other perception-altering drugs, with slow wave reduction properties, in an overall profile which would bring it closer to drugs such as LSD rather than to pure psychostimulants. Given the exploratory nature of the present study, it is the authors' view that some hypotheses should be postulated regarding the brain networks and processes targeted by ayahuasca, based on the spatial information provided by the LORETA analysis. The changes in intracerebral electrical source distribution showed considerable overlapping between frequency bands, mainly between alpha-2 and delta, although these effects were observed at different time points. Delta and alpha-2 power decreases were located bilaterally over somatosensory, auditory and visual association cortices and over the temporo-parietal heteromodal association cortex. Power decreases in Riba/Anderer/Jané/Saletu/Barbanoj the beta-1 frequency band were predominantly found in the somatosensory and visual association cortex, and also in the heteromodal association cortex. Areas showing a theta power decrease, however, did not predominate in the association cortex, but in paralimbic structures with relevant roles in emotion and memory processes. Thus, it can be hypothesized that drug-induced bioelectrical changes in the unimodal sensory association cortex may have played a role in the modality-specific modifications in the visual, somatic and auditory perception reported. Additionally, it appears reasonable to assume that effects on transmodal brain areas could account for more complex cognitive modifications which also characterize the subjective experience elicited by ayahuasca. In this respect, the temporo-parietal and frontomedial heteromodal association cortex, the cingulate and the temporomedial cortices play relevant roles in the neurobiology of attention, emotion and memory. The results obtained in the present study show interesting similarities to, but also differences from, previous SPECT and PET studies involving psychedelics. A recent PET investigation revealed that the most important metabolic increases after psilocybin administration to humans occur predominantly in the temporomedial, frontomedial, frontolateral and anterior cingulate cortices. These areas largely coincide with those showing theta decreases after ayahuasca administration. Nevertheless, PET and SPECT studies following psilocybin and mescaline have revealed a hyperfrontality pattern, i.e. increased blood perfusion or glucose metabolism in frontal regions. Metabolic increases in frontomedial regions, and more specifically in the anterior cingulate cortex, appear to be a common feature of psychedelic drug effects, as these have been observed after psilocybinand after subanesthetic doses of ketamine. In the present study, however, only small areas within the frontal lobes were found to show drug-induced changes in the power density distribution. Besides the obvious differences in the drugs being administered, a possible explanation for this divergence could be the different nature of the variables under study (regional brain electrical activity vs. glucose metabolism or blood perfusion). Also, the aforementioned differences in the reported pattern of subjective effects should be taken into consideration. In conclusion, the effects of ayahuasca on the EEG power spectrum involved mainly reductions in the slow delta and theta activity together with decreases in beta-1 and in the alpha-2 frequency band. The assessment of the spatial distribution of intracerebral power density changes singled out the temporo-parieto-occipital junction, and temporomedial and frontomedial areas as target regions of ayahuasca in the CNS. These areas comprise the unimodal association cortex in the somatosensory, auditory and visual perception modalities, the heteromodal association cortex, and also key regions within the limbic neural network involved in the integration of multimodal sensory information, and in emotion and memory processes. Future studies specifically addressing drug effects on these aspects of human cognition are needed in order to further our understanding of the complex psychological modifications elicited by ayahuasca.
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