Ibogaine Has Sex-Specific Plasma Bioavailability, Histopathological and Redox/Antioxidant Effects in Rat Liver and Kidneys: A Study on Females

Abstract

Ibogaine induces rapid changes in cellular energetics followed by the elevation of antioxidant activities. As shown earlier in male rats, ibogaine treatment with both 1 and 20 mg/kg b.w. per os led to significant glycogenolytic activity in the liver. In this work, female rats treated with the same doses of ibogaine per os displayed lower liver glycogenolytic activity relative to males, dilatation of the central vein and branches of the portal vein, and increased concentration of thiols 6 h after treatment. These changes were followed by increased catalase activity and lipid peroxidation, and decreased xanthine oxidase activity after 24 h. In kidneys, mild histopathological changes were found in all treated animals, accompanied by a decrease of glutathione reductase (after 6 and 24 h at both doses) and an increase of catalase (6 h) and xanthine oxidase activity (6 and 24 h). Ibogaine did not affect antioxidant enzymes activity in erythrocytes. Bioavailability of ibogaine was two to three times higher in females than males, with similar kinetic profiles. Compared to previous results in males, ibogaine showed sex specific effect at the level of antioxidant cellular system. Effects of ibogaine in rats are sex- and tissue-specific, and also dose- and time-dependent.

5-HT2A Receptor Knockout Mice Show Sex-Dependent Differences following Acute Noribogaine Administration

“…In the case of ibogaine, preclinical studies have shown sex-specific effects in rodents. For example, after ibogaine's administration, females showed higher plasma bioavailability and concentration in the brain than male rodents [33,34]. Yet, to our knowledge, there are no previous preclinical reports studying sex differences following noribogaine administration.…”

Ibogaine Induces Cardiotoxic Necrosis in Rats—The Role of Redox Processes

“…Furthermore, female sex is among the additional risk factors for drug-induced TdP arrhythmias that should be considered before the use of ibogaine [ 6 ]. Previous results have shown that the bioavailability of ibogaine and its principal in vivo metabolite, noribogaine, is two to three times higher in female rats than in male rats [ 9 , 10 ] and that ibogaine has sex-specific effects on the central nervous system [ 11 , 12 , 13 ], liver, and kidneys, with ibogaine-induced pathological changes being more pronounced in female rats [ 10 , 14 , 15 ].…”

“…It has been shown in several in vitro, ex vivo and in vivo experimental models that the biological activity of ibogaine, in addition to involving interaction with various types of receptors [ 2 , 16 , 17 ], is caused by rapid depletion of ATP, which is followed by an induction of enzymes related to energy metabolism, as well as increases in cellular reactive oxygen species (ROS) and the activity of antioxidant enzymes [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. In our previous experiments in rats treated per os it was shown that ibogaine affected energy metabolism, antioxidant defense, and redox balance without life-threatening pathological effects on the liver and kidneys [ 10 , 14 , 15 ].…”

“…Considering the pharmacokinetics of ibogaine, adverse cardiac effects and sex-based differences, as well as its influence on energy metabolism, ROS and antioxidant enzyme activity, as studied in various experimental models in vitro [ 21 ], ex vivo [ 19 , 20 , 21 , 22 , 23 ], and in vivo [ 10 , 14 , 15 ], we here present the effects of ibogaine on the hearts of male and female Wistar rats in vivo 6 and 24 h after treatment with a single oral dose of 1 or 20 mg/kg body weight (b.w.) (human-equivalent doses based on body surface area of 0.16 or 3.2 mg/kg b.w., respectively).…”

“…(human-equivalent doses based on body surface area of 0.16 or 3.2 mg/kg b.w., respectively). Ibogaine doses were selected according to the most common doses used to facilitate abstinence from a variety of addictive drugs, suggestions from the Global Ibogaine Therapy Alliance (GITA), and doses in clinical trials approved by the U.S. Food and Drug Administration (FDA) Advisory Panel, as well as previous results from laboratory-animal studies [ 10 , 14 , 15 ]. Because of the cardiotoxicity of ibogaine, histologic analyzes were performed to investigate possible pathologic changes in cardiac tissue morphology.…”