Noribogaine Explained

Noribogaine (actually O-desmethylibogaine), or 12-hydroxyibogamine, is the principal psychoactive metabolite of the oneirogen ibogaine. It is thought to be involved in the antiaddictive effects of ibogaine-containing plant extracts, such as Tabernanthe iboga.[1] [2] [3] [4]

Pharmacology

Noribogaine is a potent serotonin reuptake inhibitor,[5] but does not affect the reuptake of dopamine.[6] Unlike ibogaine, noribogaine does not bind to the sigma-2 receptor.[7] [8] Similarly to ibogaine, noribogaine acts as a weak NMDA receptor antagonist and binds to opioid receptors.[9] It has greater affinity for each of the opioid receptors than does ibogaine.[10]

Noribogaine is a hERG inhibitor and appears at least as potent as ibogaine.[11] The inhibition of the hERG potassium channel delays the repolarization of cardiac action potentials, resulting in QT interval prolongation and, subsequently, in arrhythmias and sudden cardiac arrest.[12]

κ-Opioid receptor

Noribogaine has been determined to act as a biased agonist of the κ-opioid receptor (KOR).[13] It activates the G protein (GDP-GTP exchange) signaling pathway with 75% the efficacy of dynorphin A (EC50 = 9 μM), but it is only 12% as efficacious at activating the β-arrestin pathway. With an IC50 value of 1 μM, it can be regarded as an antagonist of the latter pathway.

The β-arrestin signaling pathway is hypothesized to be responsible for the anxiogenic, dysphoric, or anhedonic effects of KOR activation.[14] Attenuation of the β-arrestin pathway by noribogaine may be the reason for the absence of these aversive effects, while retaining analgesic and antiaddictive properties. This biased KOR activity makes it stand out from the other iboga alkaloids like ibogaine and the derivative 18-methoxycoronaridine (18-MC).

Benzofuran analog

In 2024, a synthetic benzofuran analog (oxa-noribogaine) was reported that is devoid of the pro-arrhythmic side effect. It has analgesic effects as a potent (atypical) kappa-opioid receptor partial agonist and, opposed to standard KOR agonists, is characterized by the absence of pro-depressant effects. It induces a robust KOR-dependent increase in GDNF protein levels in the ventral tegmental area and medial prefrontal cortex. After a single dose or short-term treatment, oxa-noribogaine induces long-lasting suppression of opioid drug seeking in rodent relapse models. It also counteracts persistent opioid-induced hyperalgesia.[15]

See also

Notes and References

  1. Mash DC, Ameer B, Prou D, Howes JF, Maillet EL . Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents . J. Psychopharmacol. (Oxford) . 30 . 7 . 688–97 . 2016 . 27044509 . 10.1177/0269881116641331 . 40776971 .
  2. Glick SD, Maisonneuve IS . Mechanisms of antiaddictive actions of ibogaine . Annals of the New York Academy of Sciences . 844 . 214–26 . May 1998 . 1 . 9668680 . 10.1111/j.1749-6632.1998.tb08237.x. 1998NYASA.844..214G . 11416176 .
  3. Baumann MH, Pablo J, Ali SF, Rothman RB, Mash DC . Comparative neuropharmacology of ibogaine and its O-desmethyl metabolite, noribogaine . The Alkaloids: Chemistry and Biology . 56 . 79–113 . 2001 . 11705118 . 10.1016/S0099-9598(01)56009-5.
  4. Kubiliene A, Marksiene R, Kazlauskas S, Sadauskiene I, Razukas A, Ivanov L . Acute toxicity of ibogaine and noribogaine . Medicina . 44 . 12 . 984–8 . 2008 . 10.3390/medicina44120123 . 19142057 . free .
  5. Book: Max M. Houck. Forensic Chemistry. 26 January 2015. Elsevier Science. 978-0-12-800624-5. 164–.
  6. Baumann MH, Rothman RB, Pablo JP, Mash DC . In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats . The Journal of Pharmacology and Experimental Therapeutics . 297 . 2 . 531–539 . May 2001 . 11303040 .
  7. Book: Paul Gahlinger. Illegal Drugs. 30 December 2003. Penguin Publishing Group. 978-1-4406-5024-6. 304–.
  8. Book: Alper KR, Glick SD . Ibogaine: Proceedings from the First International Conference. 2001. Gulf Professional Publishing. 978-0-12-053206-3. 107–.
  9. Book: Donald G. Barceloux. Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. 20 March 2012. John Wiley & Sons. 978-0-471-72760-6. 869–.
  10. Pearl SM, Herrick-Davis K, Teitler M, Glick SD . Radioligand-binding study of noribogaine, a likely metabolite of ibogaine . Brain Research . 675 . 1–2 . 342–344 . March 1995 . 7796150 . 10.1016/0006-8993(95)00123-8 . 28001919 .
  11. Alper K, Bai R, Liu N, Fowler SJ, Huang XP, Priori SG, Ruan Y . hERG Blockade by Iboga Alkaloids . Cardiovasc. Toxicol. . 16 . 1 . 14–22 . 2016 . 25636206 . 10.1007/s12012-015-9311-5 . 16071274 .
  12. Litjens RP, Brunt TM . How toxic is ibogaine? . Clin Toxicol . 54 . 4 . 297–302 . 2016 . 26807959 . 10.3109/15563650.2016.1138226 . 7026570 .
  13. Maillet EL, Milon N, Heghinian MD, Fishback J, Schürer SC, Garamszegi N, Mash DC . Noribogaine is a G-protein biased κ-opioid receptor agonist . Neuropharmacology . 99 . 675–88 . 2015 . 26302653 . 10.1016/j.neuropharm.2015.08.032 . free .
  14. Ehrich JM, Messinger DI, Knakal CR, Kuhar JR, Schattauer SS, Bruchas MR, Zweifel LS, Kieffer BL, Phillips PE, Chavkin C . Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons . J. Neurosci. . 35 . 37 . 12917–31 . 2015 . 26377476 . 10.1523/JNEUROSCI.2444-15.2015 . 4571610 .
  15. Havel V, Kruegel AC, Bechand B et al. . Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models . Nat Commun . 15 . 1 . 8118 . 2024 . 39304653 . 11415492 . 10.1038/s41467-024-51856-y .

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