Influence of ibogaine on expression of genes

Ibogaine is an indole alkaloid, naturally present in the root of plant Tabernanthe iboga. Attention that is paid in recent decades from scientists and laics as well is due to it's antiaddiction, antidepressive and stimulant properties.
Besides, story goes well behind in a manner of ritual use of plant for spiritual reasons, which has been practiced in tribal communities in Africa for centuries. There it is considered as a perception expanding drug that enables user to reach depths of subconsciousness or as a stimulant in smaller doses. These "fantasy-enhancing" properties are in favour by some psychotherapists. This effect is acute, lasting from 12 to 24 hours and can be explained by receptor or enzyme binding properties of ibogaine.
What is interesting in the pharmacodynamics of ibogaine is that some of the effects last much longer than pharmacokinetic model could support. The main, mood elevating effect usually appears in day or two after application, when tissue concentrations of ibogaine are already in minute quantities. Effect also lasts from days to weeks, when substance itself, nor metabolites, are no longer present in a measurable quantities. The proposed explanation of prolonged action of alkaloid by very long half-life of ibogaine or it's active metabolite noribogaine due to their high lipid-solubility and two compartment kinetics cannot sustain duration of effects in terms of weeks after a single dose.
So, besides acute effects on different receptor and enzyme sites, more complex biochemical and possible structural changes in terms of brain plasticity are suspected. Signal transduction and modulation of gene and protein expression could be the basis for such hardware adaptations.
In this study we analyzed proteome changes in the brains of ibogaine-treated rats by two-dimensional electrophoresis which is a good tool for differentiation of protein profiles between treated and non-treated subjects.
The most significant alterations in protein expression were observed in rat brains 72 h after ibogaine administration. Among the up-regulated spots, four spots were identified as metabolic enzymes involved in glycolysis and citric acid cycle. These are glyceraldehyde-3-phosphate dehydrogenase, aldolase, pyruvate kinase and malate dehydrogenase. They are increased about 2.5-, 3.2-, 2.9-, and 3.6- fold ratio, respectively, compared to control samples.
This indicates that mechanism of action of ibogaine is at least partially mediated through an influence on the brain energy metabolism. It is interesting in this context that chronic exposure to morphine has the opposite effect as assumed due to lowered glycolysis and citric acid cycle intermediates levels in rat brains.
Whether the elevated energy pool and availability 72 hours after application is secondary as a compensation of possibly elevated demand on energy during acute phase in first hours, or is it event per se, remains unclear. Higher quantity of enzyme doesn't affect much steady state equilibrium since we don't deal with saturation, zero order kinetics. The effect is best seen in the states of high energy demand, where induced enzymes are capable to support greater runaway of product with bigger influx in the pool and to maintain high ATP/ADP ratio.
Enhanced neuronal activity under the influence of ibogaine is ATP consuming due to transmitter turnover and reestablishment of transmembrane potential. Since energy dissipating detoxification and reversion of tolerance to opioids needs underlying functional and structural changes in cell, higher metabolic turnover is favourable. If we are dealing with morphological changes as suspected because of glial neurotrophine release, the extra need for energy is expected.
It is reasonable to assume that induction of energy metabolism enzymes improve all mental skills, starting with learning and memory, proceeding with retrieval of repressed memories and ending with insight into one's own psychical status. These can lead to complex psycho-organic changes that result in a drug free life. Maybe the word "illumination" would be a proper one to illustrate what is at this point difficult to explain.