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

Villalba, Sofía; González, Bruno; Junge, Stephanie; Bernardi, Alejandra; González, Joaquín; Fagúndez, Catherine; Torterolo, Pablo; Carrera, Ignacio; Urbano, Francisco J.; Bisagno, Verónica

doi:10.3390/ijms25020687

Cited by 3 publications

(1 citation statement)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

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

Vidonja Uzelac,

Tatalović,

Mijović

et al. 2024

IJMS

View full text Add to dashboard Cite

Ibogaine is an organic indole alkaloid that is used in alternative medicine to combat addiction. Numerous cases of life-threatening complications and sudden deaths associated with ibogaine use have been reported, and it has been hypothesized that the adverse effects are related to ibogaine’s tendency to induce cardiac arrhythmias. Considering that the bioavailability of ibogaine and its primary metabolite noribogaine is two to three times higher in female rats than in male rats, we here investigated the effect of a single oral dose (1 or 20 mg/kg) of ibogaine on cardiac histopathology and oxidative/antioxidant balance. Our results show that ibogaine induced dose-dependent cardiotoxic necrosis 6 and 24 h after treatment and that this necrosis was not a consequence of inflammation. In addition, no consistent dose- and time-dependent changes in antioxidant defense or indicators of oxidative damage were observed. The results of this study may contribute to a better understanding of ibogaine-induced cardiotoxicity, which is one of the main side effects of ibogaine use in humans and is often fatal. Nevertheless, based on this experiment, it is not possible to draw a definitive conclusion regarding the role of redox processes or oxidative stress in the occurrence of cardiotoxic necrosis after ibogaine administration.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Vidonja Uzelac,

Tatalović,

Mijović

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models

Havel,

Kruegel,

Bechand

et al. 2024

Nat Commun

View full text Add to dashboard Cite

Ibogaine and its main metabolite noribogaine provide important molecular prototypes for markedly different treatment of substance use disorders and co-morbid mental health illnesses. However, these compounds present a cardiac safety risk and a highly complex molecular mechanism. We introduce a class of iboga alkaloids – termed oxa-iboga – defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds lack the proarrhythmic adverse effects of ibogaine and noribogaine in primary human cardiomyocytes and show superior efficacy in animal models of opioid use disorder in male rats. They act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa opioid agonists. Oxa-noribogaine induces long-lasting suppression of morphine, heroin, and fentanyl intake after a single dose or a short treatment regimen, reversal of persistent opioid-induced hyperalgesia, and suppression of opioid drug seeking in rodent relapse models. As such, oxa-iboga compounds represent mechanistically distinct iboga analogs with therapeutic potential.

show abstract

Ibogaine administration following repeated morphine administration upregulates myelination markers 2′, 3′-cyclic nucleotide 3′-phosphodiesterase (CNP) and myelin basic protein (MBP) mRNA and protein expression in the internal capsule of Sprague Dawley rats

Govender,

Moloko,

Papathanasopoulos

et al. 2024

Front. Neurosci.

View full text Add to dashboard Cite

Ibogaine is a psychedelic alkaloid being investigated as a possible treatment for opioid use disorder. Ibogaine has a multi-receptor profile with affinities for mu and kappa opioid as well as NMDA receptors amongst others. Due to the sparsity of research into ibogaine's effects on white matter integrity and given the growing evidence that opioid use disorder is characterized by white matter pathology, we set out to investigate ibogaine's effects on two markers of myelination, 2′, 3′-cyclic nucleotide 3′-phosphodiesterase (CNP) and myelin basic protein (MBP). Fifty Sprague Dawley rats were randomly assigned to five experimental groups of n = 10; (1) a saline control group received daily saline injections for 10 days, (2) a morphine control group received escalating morphine doses from 5 to 15 mg/kg over 10 days, (3) an ibogaine control group that received 10 days of saline followed by 50 mg/kg ibogaine hydrochloride, (4) a combination morphine and ibogaine group 1 that received the escalating morphine regime followed by 50 mg/kg ibogaine hydrochloride and (5) a second combination morphine and ibogaine group 2 which followed the same morphine and ibogaine regimen yet was terminated 72 h after administration compared to 24 h in the other groups. White matter from the internal capsule was dissected and qPCR and western blotting determined protein and gene expression of CNP and MBP. Morphine upregulated CNPase whereas ibogaine alone had no effect on CNP mRNA or protein expression. However, ibogaine administration following repeated morphine administration had an immediate effect by increasing CNP mRNA expression. This effect diminished after 72 h and resulted in a highly significant upregulation of CNPase protein at 72 h post administration. Ibogaine administration alone significantly upregulated protein expression yet downregulated MBP mRNA expression. Ibogaine administration following repeated morphine administration significantly upregulated MBP mRNA expression which increased at 72 h post administration resulting in a highly significant upregulation of MBP protein expression at 72 h post administration. These findings indicate that ibogaine is able to upregulate genes and proteins involved in the process of remyelination following opioid use and highlights an important mechanism of action of ibogaine's ability to treat substance use disorders.

show abstract

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

Cited by 3 publications

References 64 publications

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

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

Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models

Ibogaine administration following repeated morphine administration upregulates myelination markers 2′, 3′-cyclic nucleotide 3′-phosphodiesterase (CNP) and myelin basic protein (MBP) mRNA and protein expression in the internal capsule of Sprague Dawley rats

Contact Info

Product

Resources

About