This rat study (n=54) investigated the acute effects of ibogaine (12mg/0.3kg) with intracranial electroencephalography and computational assessment of brain states related to sleep and wakefulness. Results indicated that ibogaine induces REM sleep traits during wakefulness and NREM sleep, which are driven by local power increases of gamma oscillations. This provides evidence that ibogaine’s effects are psychedelic in so far that it enhances dream-like states of waking consciousness.
Abstract
“Introduction: Ibogaine is a psychedelic alkaloid that has attracted large scientific interest because of its antiaddictive properties in observational studies in humans as well as in animal models. Its subjective effect has been described as intense, vivid dream-like experiences occurring while awake; hence, ibogaine is often referred to as an oneirogenic psychedelic. While this unique dream-like profile has been hypothesized to aid the antiaddictive effects, the electrophysiological signatures of this psychedelic state remain unknown. We previously showed in rats that ibogaine promotes a waking state with abnormal motor behavior along with a decrease in NREM and REM sleep.
Methods: Here, we performed an in-depth analysis of the intracranial electroencephalogram during “ibogaine wakefulness”.
Results: We found that ibogaine induces gamma oscillations that, despite having larger power than control levels, are less coherent and less complex. Further analysis revealed that this profile of gamma activity compares to that of natural REM sleep.
Discussion: Thus, our results provide novel biological evidence for the association between the psychedelic state and REM sleep, contributing to the understanding of the brain mechanisms associated with the oneirogenic psychedelic effect of ibogaine.”
Authors: Joaquín González, Matias Cavelli, Santiago Castro-Zaballa, Alejandra Mondino, Adriano BL Tort, Nicolás Rubido, Ignacio Carrera & Pablo Torterolo
Summary
Abstract
Ibogaine is a psychedelic alkaloid that promotes a waking state with abnormal motor behavior, accompanied by a decrease in NREM and REM sleep. The electrophysiological signatures of the ibogaine psychedelic state remain unknown.
INTRODUCTION
Ibogaine is a potent psychedelic alkaloid that produces an intense dream-like episode while awake, without producing the typical interferences in thinking, identity distortions, and space – time alterations produced by classical psychedelics.
The biological substrate of ibogaine’s unique oneiric effects remains elusive, but it has been hypothesized that the oneirogenic effects could aid its antiaddictive properties through an increase in neural plasticity and memory reconsolidation.
In our previous work, we showed that ibogaine promotes a wakefulness state with abnormal motor behaviors in rats. However, we were not able to answer which features characterize the waking state induced by ibogaine.
Ibogaine
Ibogaine was obtained from T. Iboga extracts and used in this work at a dose of 40 mg/kg.
Experimental Animals
Six Wistar adult rats were maintained on a 12-h light/dark cycle. The animals were in good health and all experimental procedures were conducted in agreement with the National Animal Care Law.
Surgical Procedures
Animals were chronically implanted with electrodes to monitor the states of sleep and wakefulness. The electrodes were placed in the skull above motor, somatosensory, visual cortices, the right olfactory bulb, and cerebellum, and fixed onto the skull with acrylic cement.
Experimental Sessions and Sleep Scoring
Rats were housed individually in transparent cages with wood shaving material in a temperature-controlled room with water and food ad libitum. Polysomnographic data were acquired and stored in a computer using the Dasy Lab Software.
The states of sleep and wakefulness were determined by 10-s epochs. NREM sleep was defined as high-voltage slow cortical waves together with sleep spindles in frontal, parietal, and occipital cortices associated with a reduced EMG amplitude.
Data Analysis
To evaluate the ibogaine effect on iEEG activity, we selected the first two hours following the ibogaine i.p. administration and examined only artifact-free wake epochs, NREM sleep epochs, and REM sleep epochs.
Power spectra were obtained by means of the pwelch built-in function in Matlab, and time-frequency spectrograms were obtained using the function mtspecgramc from the Chronux toolbox 23. All spectra were whitened by multiplying the power at each frequency by the frequency itself.
We measured spectral coherence between electrodes using the magnitude squared coherence built-in function in Matlab, and the time-frequency coherograms were obtained using the cohgramc function.
We employed a data-driven approach to compare empirical clusters of frequencies instead of comparing traditionally defined frequency bands. We obtained statistical thresholds for group comparisons of power and coherence by comparing empirical clusters of frequencies to a null hypothesis distribution of cluster statistics.
The permutation entropy was quantified by dividing the time-series into non-overlapping vectors and classifying each vector according to the relative magnitude of its D elements. The Shannon entropy was used to quantify the average randomness of the OP distribution.
We used a multi-layer perceptron (10 hidden layers) to distinguish between the states of wakefulness and REM sleep. The network was trained using the scaled conjugate gradient backpropagation algorithm.
We employed the modulation index method to measure coupling between frequencies within a same region. The co-modulation maps were obtained by plotting the modulation index values of slow-fast frequency combinations and then assessing the statistical significance between conditions.
Ibogaine alters iEEG oscillatory components
To understand the acute effects of ibogaine on the rat brain, we recorded iEEG signals following its intraperitoneal administration (40 mg/Kg). We found that ibogaine increased gamma oscillations, decreased theta power and decreased the peak frequency of high-frequency oscillations in the olfactory bulb, primary motor, primary somatosensory and secondary visual cortex.
Ibogaine decreases inter-regional synchronization
Ibogaine significantly decreased inter-regional gamma synchronization, as opposed to its effect on oscillatory power content.
Ibogaine decreased phase coherence at the sigma-beta, gamma, and high-frequency bands in multiple cortical areas, including the OB, M1, and S1. This decrease was especially pronounced in the inter-regional gamma coherence between the right OB and right S1 cortex.
Ibogaine decreases iEEG temporal complexity
We showed that ibogaine promoted local gamma oscillations which were uncoupled between areas. This activity resembled gamma oscillations that naturally occur during REM sleep.
We down-sampled the original signals to 128 Hz and measured the permutation entropy of the time-series to assess the temporal complexity of the iEEG. Ibogaine wakefulness displayed significantly lower levels of dynamical complexity in OB, M1 and S1 cortex.
Ibogaine wakefulness and REM sleep have similar iEEG gamma activity
The previous section showed that ibogaine wakefulness differs from normal wakefulness, and that theta, sigma and beta power were lower during ibogaine wakefulness than in REM sleep. However, the high-frequency component had significantly higher power, likely due to muscular activity.
We found that ibogaine wakefulness had similar temporal complexity to REM sleep, and that gamma oscillations were comparable in power, complexity and interregional synchronization.
We trained an artificial neural network to automatically classify the states of wakefulness and REM sleep, and then tested whether the ibogaine wakefulness was closer to a REM-like state or to physiological wakefulness. The results show that the ibogaine wakefulness has convincing REM sleep-like features.
DISCUSSION
We found that intraperitoneal administration of ibogaine to rats induces a waking brain state that has electrocortical REM sleep traits. These traits were dragged into NREM sleep and were similar to the ones present during REM sleep.
When comparing our results to previous literature in human beings, we found that ibogaine reduced the connectivity at sigma and beta bands and increased the power at alpha and beta bands. Additionally, the gamma coupling to other frequencies was not affected by ibogaine in any of the cortical locations.
Ibogaine induces a state of consciousness similar to dreams, and the type of cognition elicited by this state is similar to the one present during REM sleep.
Although human subjective reports indicate differences between the experience elicited by ibogaine and classic psychedelics, pharmacological and behavioural data in rodents also support these differences. Additionally, ibogaine may produce some of its effect via 5-HT 2A activation, but this does not appear to be essential to the ibogaine-appropriate stimulus.
Ibogaine is rapidly metabolized to produce noribogaine, which has its own pharmacological and pharmacokinetic profiles. Noncompetitive antagonism at N-methyl-D-aspartate receptors (NMDA-R) by ibogaine and in a less extent by noribogaine should be considered as a key factor to explain the effects on the gamma band found on this study.
Ibogaine and noribogaine inhibit serotonin re-uptake by modulating SERT activity, and this could explain some of the similarities found in the electrocorticographical activity between ibogaine and classic psychedelics.
REM sleep is considered a natural model of psychosis, and psychedelics are studied as pharmacological models of psychosis. Hence, REM sleep, psychosis and psychedelia are qualitatively and quantitatively similar brain states.
Author contributions
J.G., M.C., I.C and P.T. designed the experiments, J.G., M.C. and A.M. conducted the experiments, J.G., N,R. wrote analysis software, J.G. analyzed the data, J.G. wrote the manuscript.
Data and code availability
Data are available under request to the authors, and the codes to obtain power and coherence spectra are freely available.
Figure S1 shows that ibogaine slows down theta peak frequency in the right hemisphere and increases theta peak frequency in the left hemisphere during wakefulness.
Figure S4 shows the power spectrum and coherence spectra of the gamma band during physiological wakefulness and REM sleep.
Figure S5 shows that permutation entropy can be used to quantify the temporal complexity of iEEG during REM sleep and ibogaine wakefulness.
Figure S6 shows that ibogaine decreases inter-regional synchronization during NREM sleep. No significant differences were found between physiological NREM sleep and ibogaine NREM sleep, paired t-test.
Ibogaine administration did not affect gamma band cross-frequency coupling, as indicated by the fact that theta-gamma and theta-high frequency oscillation coupling remained unaltered.