Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile

This animal study (n=26) investigated the effects of ibogaine (20 and 40 mg/kg) on the states of sleep and wakefulness in rats and found that it promotes a waking state that was accompanied by a decrease in the total amount of SWS and REM sleep, in a similar pattern as traditional psychedelics.

Abstract

“Introduction: Ibogaine is a potent psychedelic alkaloid that has been the focus of intense research because of its intriguing anti-addictive properties. According to anecdotic reports, ibogaine has been originally classified as an oneirogenic psychedelic; i.e., induces a dream-like cognitive activity while awake. However, the effects of ibogaine administration on wakefulness (W) and sleep have not been thoroughly assessed. The main aim of our study was to characterize the acute effects of ibogaine administration on W and sleep.

Methods: For this purpose, polysomnographic recordings on chronically prepared rats were performed in the light phase during 6 h. Animals were treated with ibogaine (20 and 40 mg/kg) or vehicle, immediately before the beginning of the recordings. Furthermore, in order to evaluate associated motor behaviors during the W period, a different group of animals was tested for 2 h after ibogaine treatment on an open field with video-tracking software.

Results: Compared to control, animals treated with ibogaine showed an increase in time spent in W. This effect was accompanied by a decrease in slow wave sleep (SWS) and rapid-eye movements (REM) sleep time. REM sleep latency was significantly increased in animals treated with the higher ibogaine dose. While the effects on W and SWS were observed during the first 2 h of recordings, the decrement in REM sleep time was observed throughout the recording time. Accordingly, ibogaine treatment with the lower dose promoted an increase on locomotion, while tremor and flat body posture were observed only with the higher dose in a time-dependent manner. In contrast, head shake response, a behavior which has been associated in rats with the 5HT_2A receptor activation by hallucinogens, was not modified.

Discussion: We conclude that ibogaine promotes a waking state that is accompanied by a robust and long-lasting REM sleep suppression. In addition, it produces a dose-dependent unusual motor profile along with other serotonin-related behaviors. Since ibogaine is metabolized to produce noribogaine, further experiments are needed to elucidate if the metabolite and/or the parent drug produced these effects.“

Authors: Joaquín González, José P. Prieto, Paola Rodríguez, Matías Cavelli, Luciana Benedetto, Alejandra Mondino, Mariana Pazos, Gustavo Seoane, Ignacio Carrera, Cecilia Scorza2 & Pablo Torterolo

Summary

INTRODUCTION

Ibogaine is a naturally occurring indole alkaloid found in the root bark of the shrub Tabernanthe iboga, originally from Congo and Gabon. It has been shown to reduce addiction to drugs of abuse and craving.

Ibogaine is classified as an oneirogenic psychedelic drug because it induces vivid dream-like episodes while awake with eyes closed, without loss of contact with the environment. Ibogaine induces an activation of the electroencephalogram (EEG) that resembles the effect of the electrical stimulation of the activating reticular system. The effect of ibogaine on wakefulness (W) and sleep remains unclear, existing only a few early studies regarding this issue.

Ibogaine has been shown to induce different behavioral responses in animal models, depending on the dose, time points assayed, and length of the recordings.

Ibogaine promotes a dose-dependent increase in locomotor activity in rats, but higher doses produce deleterious effects in the vestibular function and a dose-dependent reduction in the detection of sensory stimuli. Ibogaine also produces serotonin syndrome-like behaviors in rats, similar to subjective reports in humans.

We performed polysomnographic recordings in chronically prepared rats and studied the acute effects of ibogaine on sleep and waking state using an open-field assay.

Ibogaine

Ibogaine was obtained from T. iboga root bark and purified as follows: the material was suspended in aqueous 10% NaOH solution, extracted with ethyl acetate, dried with Na2 SO4, and evaporated in vacuo. The residue was purified by column chromatography.

Experimental Animals

Wistar adult rats were maintained on a 12-h light/dark cycle and housed four – six per cage before behavioral testing. Twenty-six animals were used for all performed studies, and all procedures were conducted in agreement with the National Animal Care Law.

Surgical Procedures

Eight animals were chronically implanted with electrodes to monitor the states of sleep and wakefulness. The electrodes were placed on the skull above frontal, parietal, occipital cortices (bilateral), the right olfactory bulb, and cerebellum (reference electrode).

Sleep Recordings

Rats were housed individually in transparent cages containing wood shaving material in a temperature-controlled room, with water and food ad libitum. Polysomnographic data were acquired and stored in a computer for further analysis using Spike 2 software (CED, Cambridge, United Kingdom).

Rats received ibogaine 20 mg/kg, 40 mg/kg, or vehicle i.p. in different days in a counterbalanced order, and the wash-out period between doses was 3 days.

Motor Behavior

Eighteen naive (not operated) rats were used in this experiment. They were placed in a square area with transparent plastic walls indirectly illuminated (35 luxes) and a quiet experimental room with controlled temperature (22 2 C). Animals were randomly assigned to different experimental groups, and their behaviors were assessed every 30 min during 2 h after ibogaine administration. Serotonin syndrome-like continuous behaviors such as tremor, flat body posture, piloerection, hind limb abduction, and Straub tail were scored using a graded scale.

Sleep Recordings

The experimental design for the sleep analysis was a within-subject design, and statistical significance was evaluated utilizing one-way repeated measures analysis of variance and Bonferroni as a post hoc test.

Motor Behavior

Depending on the comparison performed, data from motor activity were analyzed by ANOVA or by Newman-Keuls multiple comparison post hoc test.

Ibogaine’s Effect on Wakefulness and Sleep

The time spent in W and SWS were increased by I 20 and I 40, respectively, and the total amount of REM sleep was diminished by I 20 and I 40.

The duration of W episodes increased after I 20 administration, and the duration of SWS episodes decreased after I 40 administration. The number of REM sleep episodes decreased without affecting the duration of the episodes.

Ibogaine effects were analyzed in 2-h blocks. The time of wakefulness was significantly increased for both doses, accompanied by a decrease in slow wave sleep and REM sleep, without any appreciable change in light sleep.

Ibogaine’s Effect on Motor Behavior

A detailed study of motor behaviors was carried out to obtain further insights about the animal behavior during the ibogaine-induced waking state. The results showed that the animals injected with Ibogaine 40 exhibited a significant decrease in locomotor activity compared to control and I 20 .

Naive rats were more active in the first period of the recording session, but the control group became virtually inactive at the end of the 60-min recording time. I 40 significantly reduced the ability to induce rearing behavior, but not I 20 .

Figures 4A,B show that ibogaine induces serotonin syndrome-like behaviors and hyposomal serotonin reflex in rats. However, the total 120 min session did not reveal any significant differences between experimental groups for forepaw treading, piloerection, or Straub tail and hind limb abduction.

DISCUSSION

In the present study, 20 and 40 mg/kg of ibogaine produced a robust effect on sleep and W, promoting a waking state that is accompanied by a robust and long-lasting REM sleep suppressive effect. The higher dose (I 40 ) also showed disabling behaviors like tremor and flat body posture.

Ibogaine administration promoted W in rats, accompanied by a decrease in the total amount of SWS and REM sleep. The effects on REM sleep lasted through the entire recording.

A similar impact upon sleep architecture has been reported for traditional psychedelics (5HT2A agonists), such as LSD and DOI. Subcutaneous administration of selective antagonists of 5HT2A and 5HT2C receptors promotes SWS; while surprisingly decreases REM sleep time.

The long-lasting REM sleep suppression induced by ibogaine administration may be explained by an altered W pattern, which could have subtle electrophysiological traits of REM sleep, which could explain the oneirogenic cognitive effect of the drug.

Ibogaine and noribogaine increase serotonin levels in the brain, which promotes wakefulness and suppresses REM sleep. This could explain the long-lasting REM sleep suppressive effect of ibogaine, as well as its W-promoting and REM sleep suppressive effects.

Schneider and Sigg (1957) proposed that ibogaine can promote wakefulness by activating cholinergic pathways. However, the effects of ibogaine on other neurotransmitters and on REM sleep promoting neurons should also be considered.

Another possibility is that the increase in W could be caused by an unspecific effect, such as irritation or pain. However, we did not observe any behavior suggesting this kind of effect.

We hypothesized that the effects seen in each 2-h block could be attributed to ibogaine itself and its principal metabolite, noribogaine, as well as to the long-lasting noribogaine.

Regarding motor behavior, I 20 administration produced a higher total locomotor activity suggesting a more vigilant animal response, while I 40 administration produced serotonin syndrome-like behaviors such as tremor and flat body posture mainly during the first part of the recording session.

Ibogaine induces tremor and flat body posture, which suggest a putative interaction with serotonin transmission. However, Baumann et al. (2001b) speculate that sigma or NMDA receptors might also explain these behaviors. Regarding the induction of HSR, no changes were found for both ibogaine treatments (Figure 4B). This is probably because ibogaine interacts with several neurochemical systems, and does not produce the typical interferences in thinking, identity distortions, and space – time alteration produced by traditional psychedelics drugs.

CONCLUSION AND FUTURE PERSPECTIVES

In this study, ibogaine induced a stimulant profile in rats, but an abnormal environment habituation with significant tremor and flat body posture was detected in rats treated with ibogaine 40 mg/kg.

ETHICS STATEMENT

This study was carried out in accordance with the National Animal Care Law and the Guide to the care and use of laboratory animals.

AUTHOR CONTRIBUTIONS

IC, GS, PT, and CS provided financial support, JG, JP, PR, MC, LB, AM, and MP performed the experimental procedures, and JG, JP, IC, PT, CS, and GS wrote the manuscript.

ACKNOWLEDGMENTS

We thank ANII, CSIC-UdelaR and Eleuterio Umpiérrez for financial support, Bruno González for help with GC-MS analysis and Dr. Charles Nichols for discussions.