Chemistry:Noribogaine

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Noribogaine, also known as 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]

The drug appears to have a complex mechanism of action, with many different observed activities.[5][6][7][8][9] Some of its most potent actions is atypical κ-opioid receptor agonism[10] and serotonin reuptake inhibition.[11] Noribogaine has potent psychoplastogenic effects similarly to ibogaine.[12][13][14]

Noribogaine was first described in the scientific literature by at least 1958[15] and was first identified as a metabolite of ibogaine by 1995.[16] It was first studied in humans in 2015.[17][18]

Use and effects

Noribogaine is the major active metabolite of the oneirogen ibogaine and is thought to be primarily though not exclusively responsible for its effects.[19][6] In contrast to ibogaine, noribogaine has been limitedly evaluated in humans.[19] It was noted in 2007 that administration of noribogaine to humans had not yet been reported.[19] In 2015 and 2016 however, two clinical studies of noribogaine were published.[17][18] It was tested at relatively low doses of 3 to 180 mg in these studies.[17][18] At these doses, no hallucinations, dream-like states, or other hallucinogenic effects were reported.[17][18] Similarly, it produced no μ-opioid receptor agonistic pharmacodynamic effects, such as pupil constriction or analgesia.[17] At higher doses, in the area of 400 to 1,000 mg or more, ibogaine has been reported to produce hallucinogenic effects.[19][20][21]

Adverse effects

Side effects of noribogaine include visual impairment (specifically increased light perception sensitivity), headache, nausea, vomiting, and QT prolongation.[17][18]

Pharmacology

Pharmacodynamics

Noribogaine activities
Target Affinity (Ki, nM) Species
5-HT1A >100,000 (Ki)
IA (EC50)		 Rat
Human
5-HT1B >100,000 (Ki)
IA (EC50)		 Calf
Human
5-HT1D >100,000 (Ki)
IA (EC50)		 Calf
Human
5-HT1E ND (Ki)
IA (EC50)		 ND
Human
5-HT1F ND (Ki)
IA (EC50)		 ND
Human
5-HT2A >100,000 (Ki)
IA (EC50)		 Rat
Human
5-HT2B ND (Ki)
IA (EC50)		 ND
Human
5-HT2C >100,000 (Ki)
IA (EC50)		 Calf
Human
5-HT3 >100,000 (Ki)
ND (EC50)		 Mouse/rat
ND
5-HT4 ND (Ki)
IA (EC50)		 ND
Human
5-HT5A ND (Ki)
IA (EC50)		 ND
Human
5-HT6 ND (Ki)
IA (EC50)		 ND
Human
5-HT7 ND ND
α1A–α1D ND ND
α2A–α2C ND ND
β1–β3 ND ND
D1, D2 >10,000 Calf
D3 >100,000 Calf
D4, D5 ND ND
H1–H4 ND ND
M1 15,000 Calf
M2 36,000 Calf
M3–M5 ND ND
nACh ND (Ki)
6,820 (IC50)		 ND
Human
I1, I2 ND ND
σ1 11,000–15,006 Calf/guinea pig
σ2 5,226–19,000 Calf/rat
MOR 1,520 (Ki)
7,420–16,050 (EC50)
3–36% (Emax)		 Human
Human
Human
DOR 5,200–24,720 (Ki)
IA (EC50)		 Calf
Human
KOR 720 (Ki)
110–8,749 (EC50)
13–85% (Emax)		 Human
Human
Human
NOP >100,000 Bovine
TAAR1 ND ND
PCP 5,480–38,200 Various
SERT 41 (Ki)
280–326 (IC50)
840 or IA (EC50)
~30% or IA (Emax)		 Human
Human
Human
Human
NET ND (Ki)
39,000 (IC50)
ND (EC50)		 ND
Bovine
ND
DAT 2,050 (Ki)
6,760 (IC50)
ND (EC50)		 Human
Human
ND
VMAT2 570–29,500 (IC50) Human
OCT2 6,180 (IC50) Human
VGSC 17,000 (Ki) Bovine
VGCC ND (IC50) ND
hERG 1,960 (Ki)
2,860 (IC50)		 Human
Human
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [22][23][5][6][7][8][9][13][12][24]
[25][26][27][28][29][30][31]

Noribogaine has been determined to act as a biased agonist of the κ-opioid receptor (KOR).[10] 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.[10] With an IC50 value of 1 μM, it can be regarded as an antagonist of the latter pathway.[10]

The β-arrestin signaling pathway is hypothesized to be responsible for the anxiogenic, dysphoric, or anhedonic effects of KOR activation.[32] Attenuation of the β-arrestin pathway by noribogaine may be the reason for the absence of these aversive effects,[10] 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).[10]

Noribogaine is a potent serotonin reuptake inhibitor,[11] but does not affect the reuptake of dopamine.[33] Unlike ibogaine, noribogaine does not bind to the sigma σ2 receptor.[34][35] Similarly to ibogaine, noribogaine acts as a weak NMDA receptor antagonist and binds to opioid receptors.[36] It has greater affinity for each of the opioid receptors than does ibogaine.[37] Noribogaine has been reported to be a low-efficacy serotonin releasing agent, although findings are conflicting and other studies have found that it is inactive as a serotonin releasing agent.[30][29]

Noribogaine is a hERG inhibitor and appears at least as potent as ibogaine.[38] 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.[39]

Noribogaine has been reported to be a potent psychoplastogen similarly to ibogaine.[12][13][14][30]

Ibogaine and the structurally related hallucinogen harmaline are tremorigenic, whereas noribogaine is not or is much less so.[13][9][40][41]

Pharmacokinetics

Noribogaine is highly lipophilic and shows high brain penetration in rodents.[8][5]

The elimination half-life of noribogaine is 24 to 50 hours.[5][17][18]

History

Noribogaine was first described in the scientific literature by at least 1958.[15][41] It was first identified and described as a metabolite of ibogaine by 1995.[16][42][37][43] The first evaluation of noribogaine in humans was published in 2015.[17][18]

See also

References

  1. ↑ "Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents". Journal of Psychopharmacology (Oxford, England) 30 (7): 688–697. Jul 2016. doi:10.1177/0269881116641331. PMID 27044509. 
  2. ↑ "Mechanisms of antiaddictive actions of ibogaine". Annals of the New York Academy of Sciences 844 (1): 214–226. May 1998. doi:10.1111/j.1749-6632.1998.tb08237.x. PMID 9668680. Bibcode: 1998NYASA.844..214G. 
  3. ↑ "Comparative neuropharmacology of ibogaine and its O-desmethyl metabolite, noribogaine". The Alkaloids. Chemistry and Biology 56: 79–113. 2001. doi:10.1016/S0099-9598(01)56009-5. PMID 11705118. 
  4. ↑ "Acute toxicity of ibogaine and noribogaine". Medicina (Kaunas, Lithuania) 44 (12): 984–988. 2008. doi:10.3390/medicina44120123. PMID 19142057. 
  5. ↑ 5.0 5.1 5.2 5.3 "DARK Classics in Chemical Neuroscience: Ibogaine". ACS Chemical Neuroscience 9 (10): 2475–2483. October 2018. doi:10.1021/acschemneuro.8b00294. PMID 30216039. "Unlike LSD, mescaline, and psilocybin, the hallucinogenic properties of ibogaine cannot be ascribed to 5-HT2A receptor activation.". 
  6. ↑ 6.0 6.1 6.2 "Mechanisms of action of ibogaine: Relevance to putative therapeutic effects and development of a safer iboga alkaloid congener". The Alkaloids. Chemistry and Biology 56: 39–53. 2001. doi:10.1016/S0099-9598(01)56006-X. ISBN 978-0-12-469556-6. ISSN 1099-4831. OCLC 119074996. PMID 11705115. http://www.ibogaine.desk.nl/ch02.pdf. "Indeed, an active metabolite of ibogaine, noribogaine, has already been well characterized both in vivo (e.g., 2,3) and in vitro (e.g., 35,36). Although some investigators (37) consider noribogaine to be the major determinant of ibogaine's pharmacology in vivo, studies in this laboratory (20) indicated that the elimination of noribogaine was also too fast for it to be responsible for all of ibogaine's prolonged effects. [...] The short-half lives of ibogaine and 18-MC strongly suggest that the pharmacological actions of both alkaloids are attributable to one or more active metabolites; although noribogaine has been proposed (2,37) as the mediator of ibogaine's prolonged action, it would appear that noribogaine alone cannot account for ibogaine's effects since brain levels of noribogaine also decline rapidly after ibogaine administration to rats (20).". 
  7. ↑ 7.0 7.1 "18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action". Annals of the New York Academy of Sciences 914: 369–386. September 2000. doi:10.1111/j.1749-6632.2000.tb05211.x. PMID 11085336. 
  8. ↑ 8.0 8.1 8.2 "How toxic is ibogaine?". Clinical Toxicology (Philadelphia, Pa.) 54 (4): 297–302. 2016. doi:10.3109/15563650.2016.1138226. PMID 26807959. 
  9. ↑ 9.0 9.1 9.2 "100 years of ibogaine: neurochemical and pharmacological actions of a putative anti-addictive drug". Pharmacological Reviews 47 (2): 235–253. June 1995. doi:10.1016/S0031-6997(25)06842-5. PMID 7568327. https://www.researchgate.net/publication/15631445. "Like the structurally relate harmaline, ibogaine produces tremors. In mice, ibogaine is tremorigenic, both when given intracerebrally (ED50 127 nmol/g brain, pg/g with a latency to tremor of about 1 min) (Singbarth et al., 1973) and systemically (ED50 12 mg/kg subcutaneous) (Zetler et al., 1972). Zetler et al. (1972) also established the tremorigenic structure-activity relationship of several ibogaine-like compounds, with the descending order of potency: tabernanthine > ibogaline > ibogaine > iboxygaine > noribogaine. Recently, Glick et al. (1994) found that, whereas ibogaine and tabernanthine produced tremors, ibogamine and coronaridine were devoid of such an effect.". 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 "Noribogaine is a G-protein biased κ-opioid receptor agonist". Neuropharmacology 99: 675–688. Dec 2015. doi:10.1016/j.neuropharm.2015.08.032. PMID 26302653. 
  11. ↑ 11.0 11.1 Forensic Chemistry. Elsevier Science. 26 January 2015. pp. 164–. ISBN 978-0-12-800624-5. https://books.google.com/books?id=POpDBAAAQBAJ&pg=PA164. 
  12. ↑ 12.0 12.1 12.2 "A non-hallucinogenic psychedelic analogue with therapeutic potential". Nature 589 (7842): 474–479. January 2021. doi:10.1038/s41586-020-3008-z. PMID 33299186. Bibcode: 2021Natur.589..474C. 
  13. ↑ 13.0 13.1 13.2 13.3 "The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs". Natural Product Reports 38 (2): 307–329. March 2021. doi:10.1039/d0np00033g. PMID 32794540. 
  14. ↑ 14.0 14.1 "Psychedelics Promote Structural and Functional Neural Plasticity". Cell Reports 23 (11): 3170–3182. June 2018. doi:10.1016/j.celrep.2018.05.022. PMID 29898390. 
  15. ↑ 15.0 15.1 "The Alkaloids of Tabernanthe iboga. Part IV. 1 The Structures of Ibogamine, Ibogaine, Tabernanthine and Voacangine". Journal of the American Chemical Society 80 (1): 126–136. 1958. doi:10.1021/ja01534a036. ISSN 0002-7863. Bibcode: 1958JAChS..80..126B. https://pubs.acs.org/doi/abs/10.1021/ja01534a036. Retrieved 1 August 2025. 
  16. ↑ 16.0 16.1 "Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin". Life Sciences 57 (3): PL45–PL50. 1995. doi:10.1016/0024-3205(95)00273-9. PMID 7596224. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 Cite error: Invalid <ref> tag; no text was provided for refs named Glue_2015
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 Cite error: Invalid <ref> tag; no text was provided for refs named Glue_2016
  19. ↑ 19.0 19.1 19.2 19.3 Alper, K. R., & Lotsof, H. S. (2007). The use of ibogaine in the treatment of addictions. Psychedelic Medicine: New Evidence for Hallucinogenic Substances as Treatments, 2, 43–66. https://web.archive.org/web/20220828090846/https://s3.ca-central-1.amazonaws.com/ibosafe-pdf-resources/Ibogaine/The+use+of+ibogaine+in+the+treatment+of+addictions.pdf
  20. ↑ Shulgin, Alexander; Shulgin, Ann (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252. http://www.erowid.org/library/books_online/tihkal/tihkal.shtml. 
  21. ↑ "Basic Pharmacology and Effects". Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. 2003. pp. 67–137. ISBN 978-0-12-433951-4. https://bibliography.maps.org/resources/download/12634. "Ibogaine is an active hallucinogen in the 400 milligram area and has been clinically studied for the treatment of heroin addiction. In this latter role, the dosages employed may range as high as 1500mg. A primary human metabolism is via O-demethylation to give the free phenol 12-hydroxyibogamine. This metabolite, misnamed nor-ibogaine in the literature, appears to be pharmacologically active in its own right." 
  22. ↑ "Kᵢ Database". 31 July 2025. https://pdspdb.unc.edu/kidb2/kidb/web/kis-results/index?KisResultsSearch%5Binput_receptors%5D=&KisResultsSearch%5Binput_sources%5D=&KisResultsSearch%5Binput_species%5D=&KisResultsSearch%5Binput_hot_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=11476&KisResultsSearch%5Binput_citations%5D=&KisResultsSearch%5BsearchType%5D=&KisResultsSearch%5Bki_val_from%5D=&KisResultsSearch%5Bki_val_to%5D=&KisResultsSearch%5Bcustom_ki_val%5D=. 
  23. ↑ "BindingDB BDBM50067814 17-ethyl-(1R,17S)-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18nonadeca-2(10),4(9),5,7-tetraen-7-ol (noribogaine)::CHEMBL343956"]. Journal of Medicinal Chemistry 41 (23): 4486–4491. 1998. doi:10.1021/jm980156y. PMID 9804688. https://bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50067814. Retrieved 31 July 2025. 
  24. ↑ "Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine". Psychopharmacology 127 (1): 10–18. September 1996. doi:10.1007/BF02805969. PMID 8880938. 
  25. ↑ "Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation". PLOS ONE 8 (10). 2013. doi:10.1371/journal.pone.0077262. PMID 24204784. Bibcode: 2013PLoSO...877262A. 
  26. ↑ "Noribogaine is a G-protein biased κ-opioid receptor agonist". Neuropharmacology 99: 675–688. December 2015. doi:10.1016/j.neuropharm.2015.08.032. PMID 26302653. 
  27. ↑ "Properties of ibogaine and its principal metabolite (12-hydroxyibogamine) at the MK-801 binding site of the NMDA receptor complex". Neuroscience Letters 192 (1): 53–56. June 1995. doi:10.1016/0304-3940(95)11608-y. PMID 7675310. 
  28. ↑ "The effects of ibogaine on dopamine and serotonin transport in rat brain synaptosomes". Brain Research Bulletin 48 (6): 641–647. April 1999. doi:10.1016/s0361-9230(99)00053-2. PMID 10386845. 
  29. ↑ 29.0 29.1 "Deciphering Ibogaine's Matrix Pharmacology: Multiple Transporter Modulation at Serotonin Synapses", bioRxiv, 10 March 2025, doi:10.1101/2025.03.04.641351 
  30. ↑ 30.0 30.1 30.2 "Efficient and modular synthesis of ibogaine and related alkaloids". Nature Chemistry 17 (3): 412–420. March 2025. doi:10.1038/s41557-024-01714-7. PMID 39915657. Bibcode: 2025NatCh..17..412I. 
  31. ↑ "hERG Blockade by Iboga Alkaloids". Cardiovascular Toxicology 16 (1): 14–22. January 2016. doi:10.1007/s12012-015-9311-5. PMID 25636206. 
  32. ↑ "Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons". The Journal of Neuroscience 35 (37): 12917–12931. Sep 2015. doi:10.1523/JNEUROSCI.2444-15.2015. PMID 26377476. 
  33. ↑ "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. doi:10.1016/S0022-3565(24)29567-7. PMID 11303040. http://jpet.aspetjournals.org/content/297/2/531. 
  34. ↑ Illegal Drugs. Penguin Publishing Group. 30 December 2003. pp. 304–. ISBN 978-1-4406-5024-6. https://books.google.com/books?id=kPszgXPVQAsC&pg=PA304. 
  35. ↑ Ibogaine: Proceedings from the First International Conference. Gulf Professional Publishing. 2001. pp. 107–. ISBN 978-0-12-053206-3. https://books.google.com/books?id=jPa5cuAFW14C&pg=PA107. 
  36. ↑ Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. John Wiley & Sons. 20 March 2012. pp. 869–. ISBN 978-0-471-72760-6. https://books.google.com/books?id=OWFiVaDZnkQC&pg=PA869. 
  37. ↑ 37.0 37.1 "Radioligand-binding study of noribogaine, a likely metabolite of ibogaine". Brain Research 675 (1–2): 342–344. March 1995. doi:10.1016/0006-8993(95)00123-8. PMID 7796150. 
  38. ↑ "hERG Blockade by Iboga Alkaloids". Cardiovascular Toxicology 16 (1): 14–22. Jan 2016. doi:10.1007/s12012-015-9311-5. PMID 25636206. https://cdr.lib.unc.edu/downloads/qr46r634b. 
  39. ↑ "How toxic is ibogaine?". Clinical Toxicology (Philadelphia, Pa.) 54 (4): 297–302. 2016. doi:10.3109/15563650.2016.1138226. PMID 26807959. 
  40. ↑ "Noribogaine (12-hydroxyibogamine): a biologically active metabolite of the antiaddictive drug ibogaine". Annals of the New York Academy of Sciences 914 (1): 354–368. September 2000. doi:10.1111/j.1749-6632.2000.tb05210.x. PMID 11085335. Bibcode: 2000NYASA.914..354B. 
  41. ↑ 41.0 41.1 "Cerebral pharmacokinetics of tremor-producing harmala and iboga alkaloids". Pharmacology 7 (4): 237–248. 1972. doi:10.1159/000136294. PMID 5077309. 
  42. ↑ "Identification and quantitation of ibogaine and an o-demethylated metabolite in brain and biological fluids using gas chromatography-mass spectrometry". Journal of Analytical Toxicology 19 (6): 427–434. October 1995. doi:10.1093/jat/19.6.427. PMID 8926737. 
  43. ↑ "Noribogaine, a primary Ibogaine metabolite, reduces alcohol intake in P and fawn-hooded rats.". Alcohol: Clin. Exp. Res. 19: 15A. 1995. https://scholar.google.com/scholar?cluster=14893290148637792675. 



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