Noribogaine

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. In contrast to ibogaine, noribogaine has been limitedly evaluated in humans. It was noted in 2007 that administration of noribogaine to humans had not yet been reported. In 2015 and 2016 however, two clinical studies of noribogaine were published. It was tested at relatively low doses of 3 to 180mg in these studies. At these doses, no hallucinations, dream-like states, or other hallucinogenic effects were reported. Similarly, it produced no μ-opioid receptor agonistic pharmacodynamic effects, such as pupil constriction or analgesia. At higher doses, in the area of 400 to 1,000mg or more, ibogaine has been reported to produce hallucinogenic effects.

Adverse effects

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

Interactions

Noribogaine may interact with monoamine oxidase inhibitors (MAOIs), for instance due to its serotonin reuptake inhibition.

Pharmacology

Pharmacodynamics

Noribogaine has been determined to act as a biased agonist of the κ-opioid receptor (KOR). 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. 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). Some other examples of atypical or biased KOR agonists include RB-64, 6'-GNTI, herkinorin, and nalfurafine.

Noribogaine is a potent serotonin reuptake inhibitor, but does not affect the reuptake of dopamine. Unlike ibogaine, noribogaine does not bind to the sigma σ2 receptor. Similarly to ibogaine, noribogaine acts as a weak NMDA receptor antagonist and binds to opioid receptors. It has greater affinity for each of the opioid receptors than does ibogaine. 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.

Noribogaine is a hERG inhibitor and appears at least as potent as ibogaine. 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.

Ibogaine and the structurally related hallucinogen harmaline are tremorigenic, whereas noribogaine is not or is much less so.

Noribogaine, but not ibogaine, produces potent psychoplastogenic effects in vitro in preclinical research. This can be blocked by the serotonin 5-HT2A receptor antagonist ketanserin, by the mTOR inhibitor rapamycin, and by a TrkB antagonist.

Pharmacokinetics

Noribogaine is highly lipophilic and shows high brain penetration in rodents.

The elimination half-life of noribogaine is 24 to 50hours.

Chemistry

Analogues

Analogues of noribogaine include ibogaine, ibogamine, desethylibogamine, voacangine, tabernanthine, coronaridine, oxa-noribogaine, and GM-3009, among others.

History

Noribogaine was first described in the scientific literature by at least 1958. It was first identified and described as a metabolite of ibogaine by 1995. The first evaluation of noribogaine in humans was published in 2015.

References

References

1. (February 2015). "Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability". Journal of Clinical Pharmacology.
2. (November 2016). "Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients". Clinical Pharmacology in Drug Development.
3. (Jul 2016). "Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents". Journal of Psychopharmacology.
4. (May 1998). "Mechanisms of antiaddictive actions of ibogaine". Annals of the New York Academy of Sciences.
5. (2001). "Comparative neuropharmacology of ibogaine and its O-desmethyl metabolite, noribogaine". The Alkaloids. Chemistry and Biology.
6. (2008). "Acute toxicity of ibogaine and noribogaine". Medicina.
7. 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
8. {{CiteTiHKAL
9. (2003). "Hallucinogens: A Forensic Drug Handbook". Elsevier Science.
10. (January 2026). "Safety and Efficacy of Monoamine Oxidase Inhibitors in Patients Who Use Psychoactive Substances: Potential Drug Interactions and Substance Use Disorder Treatment Data". CNS Drugs.
11. (31 July 2025). "Kᵢ Database".
12. (1998). "BindingDB BDBM50067814 17-ethyl-(1R,17S)-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18]nonadeca-2(10),4(9),5,7-tetraen-7-ol (noribogaine)::CHEMBL343956". Journal of Medicinal Chemistry.
13. (October 2018). "DARK Classics in Chemical Neuroscience: Ibogaine". ACS Chemical Neuroscience.
14. (2001). "Mechanisms of action of ibogaine: Relevance to putative therapeutic effects and development of a safer iboga alkaloid congener". The Alkaloids. Chemistry and Biology.
15. (September 2000). "18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action". Annals of the New York Academy of Sciences.
16. (2016). "How toxic is ibogaine?". Clinical Toxicology.
17. (June 1995). "100 years of ibogaine: neurochemical and pharmacological actions of a putative anti-addictive drug". Pharmacological Reviews.
18. (January 2021). "A non-hallucinogenic psychedelic analogue with therapeutic potential". Nature.
19. (September 1996). "Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine". Psychopharmacology.
20. (2013). "Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation". PLOS ONE.
21. (December 2015). "Noribogaine is a G-protein biased κ-opioid receptor agonist". Neuropharmacology.
22. (June 1995). "Properties of ibogaine and its principal metabolite (12-hydroxyibogamine) at the MK-801 binding site of the NMDA receptor complex". Neuroscience Letters.
23. (April 1999). "The effects of ibogaine on dopamine and serotonin transport in rat brain synaptosomes". Brain Research Bulletin.
24. (10 March 2025). "Deciphering Ibogaine's Matrix Pharmacology: Multiple Transporter Modulation at Serotonin Synapses".
25. (March 2025). "Efficient and modular synthesis of ibogaine and related alkaloids". Nature Chemistry.
26. (January 2016). "hERG Blockade by Iboga Alkaloids". Cardiovascular Toxicology.
27. (Sep 2015). "Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons". The Journal of Neuroscience.
28. (26 January 2015). "Forensic Chemistry". Elsevier Science.
29. (May 2001). "In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats". The Journal of Pharmacology and Experimental Therapeutics.
30. (30 December 2003). "Illegal Drugs". Penguin Publishing Group.
31. (2001). "Ibogaine: Proceedings from the First International Conference". Gulf Professional Publishing.
32. (20 March 2012). "Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants". John Wiley & Sons.
33. (March 1995). "Radioligand-binding study of noribogaine, a likely metabolite of ibogaine". Brain Research.
34. (Jan 2016). "hERG Blockade by Iboga Alkaloids". Cardiovascular Toxicology.
35. (2016). "How toxic is ibogaine?". Clinical Toxicology.
36. (September 2000). "Noribogaine (12-hydroxyibogamine): a biologically active metabolite of the antiaddictive drug ibogaine". Annals of the New York Academy of Sciences.
37. (December 2023). "Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview". J Psychopharmacol.
38. (March 2021). "The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs". Natural Product Reports.
39. (October 2025). "Changing your mind: neuroplastic mechanisms underlying the therapeutic effect of psychedelics in depression, PTSD, and addiction". Prog Neuropsychopharmacol Biol Psychiatry.
40. (June 2018). "Psychedelics Promote Structural and Functional Neural Plasticity". Cell Rep.
41. (1958). "The Alkaloids of Tabernanthe iboga. Part IV. 1 The Structures of Ibogamine, Ibogaine, Tabernanthine and Voacangine". Journal of the American Chemical Society.
42. (1972). "Cerebral pharmacokinetics of tremor-producing harmala and iboga alkaloids". Pharmacology.
43. (1995). "Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin". Life Sciences.
44. (October 1995). "Identification and quantitation of ibogaine and an o-demethylated metabolite in brain and biological fluids using gas chromatography-mass spectrometry". Journal of Analytical Toxicology.
45. (1995). "Noribogaine, a primary Ibogaine metabolite, reduces alcohol intake in P and fawn-hooded rats.". Alcohol: Clin. Exp. Res..