Skip to main content
Log in

hERG Blockade by Iboga Alkaloids

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine’s principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure–activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bartlett, M. F., Dickel, D. F., & Taylor, W. I. (1958). The alkaloids of Tabernanthe-Iboga. Part VI. The Structures of ibogamine, ibogaine, tabernanthine and voacangine. Journal of the American Chemical Society, 80, 126–136.

    Article  CAS  Google Scholar 

  2. Jana, G. K., Paul, S., & Sinha, S. (2011). Progress in the synthesis of iboga-alkaloids and their congeners. Organic Preparations and Procedures International, 43, 541–573.

    Article  CAS  Google Scholar 

  3. Alper, K. R. (2001). Ibogaine: A review. The Alkaloids: Chemistry and Biology, 56, 1–38.

    PubMed  CAS  Google Scholar 

  4. Glick, S. D., Maisonneuve, I. M., & Szumlinski, K. K. (2001). 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.

    PubMed  CAS  Google Scholar 

  5. Alper, K. R., Lotsof, H. S., & Kaplan, C. D. (2008). The ibogaine medical subculture. Journal of Ethnopharmacology, 115, 9–24.

    Article  PubMed  CAS  Google Scholar 

  6. Vastag, B. (2005). Addiction research. Ibogaine therapy: A ‘vast, uncontrolled experiment’. Science, 308, 345–346.

    Article  PubMed  CAS  Google Scholar 

  7. Antonio, T., Childers, S. R., Rothman, R. B., Dersch, C. M., King, C., Kuehne, M., et al. (2013). Effect of iboga alkaloids on μ-opioid receptor-coupled G protein activation. PLoS ONE, 8, e77262.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. National Institutes of Health. (2014). IND-Enabling Studies and GMP Scale-Up of 18-Methoxycoronaridine Hydrochloride (18 MC) Project Number: 1U01DA034986-01. http://projectreporter.nih.gov/project_info_description.cfm?aid=8448461&icde=16047111&ddparam=&ddvalue=&ddsub=&cr=41&csb=default&cs=ASC. Accessed January 05, 2015.

  9. Mash, D. C., Kovera, C. A., Pablo, J., Tyndale, R., Ervin, F. R., Kamlet, J. D., & Hearn, W. L. (2001). Ibogaine in the treatment of heroin withdrawal. The Alkaloids: Chemistry and Biology, 56, 155–171.

    PubMed  CAS  Google Scholar 

  10. Alper, K. R., Lotsof, H. S., Frenken, G. M., Luciano, D. J., & Bastiaans, J. (1999). Treatment of acute opioid withdrawal with ibogaine. The American Journal on Addictions, 8, 234–242.

    Article  PubMed  CAS  Google Scholar 

  11. Alper, K. R., Stajic, M., & Gill, J. R. (2012). Fatalities temporally associated with the ingestion of ibogaine. Journal of Forensic Sciences, 57, 398–412.

    Article  PubMed  CAS  Google Scholar 

  12. Hoelen, D. W., Spiering, W., & Valk, G. D. (2009). Long-QT syndrome induced by the antiaddiction drug ibogaine. New England Journal of Medicine, 360, 308–309.

    Article  PubMed  CAS  Google Scholar 

  13. Pleskovic, A., Gorjup, V., Brvar, M., & Kozelj, G. (2012). Ibogaine-associated ventricular tachyarrhythmias. Clinical Toxicology, 50, 157.

    Article  PubMed  Google Scholar 

  14. Dettmer, M. R., Cohn, B., & Schwarz, E. (2013). Prolonged QTc and ventricular tachycardia after ibogaine ingestion [(XXXIII International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT)). Clinical Toxicology, 51, 285.

    Google Scholar 

  15. Heling, D., Strassburg, C. P., & Wasmuth, J. C. (2014). Tod nach lbogain-Einnahme- Vergiftung durch Entgiftung (Death after ibogaine consumption—Intoxication by detoxification). Intensiv- und Notfallbehandlung, 39, 40–43.

    Article  Google Scholar 

  16. Shawn, L. K., Alper, K., Desai, S. P., Stephenson, K., Olgun, A. M., Nelson, L. S., & Hoffman, R. S. (2012). Pause-dependent ventricular tachycardia and torsades de pointes after ibogaine ingestion [2012 Annual Meeting of the North American Congress of Clinical Toxicology (NACCT)]. Clinical Toxicology, 50, 654.

    Google Scholar 

  17. Kannankeril, P., Roden, D. M., & Darbar, D. (2010). Drug-induced long QT syndrome. Pharmacological Reviews, 62, 760–781.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Sanguinetti, M. C., & Tristani-Firouzi, M. (2006). hERG potassium channels and cardiac arrhythmia. Nature, 440, 463–469.

    Article  PubMed  CAS  Google Scholar 

  19. Koenig, X., Kovar, M., Boehm, S., Sandtner, W., & Hilber, K. (2014). Anti-addiction drug ibogaine inhibits hERG channels: A cardiac arrhythmia risk. Addiction Biology, 19, 237–239.

  20. Thurner, P., Stary-Weinzinger, A., Gafar, H., Gawali, V. S., Kudlacek, O., Zezula, J., et al. (2014). Mechanism of hERG channel block by the psychoactive indole alkaloid ibogaine. Journal of Pharmacology and Experimental Therapeutics, 348, 346–358.

  21. Kontrimavičiūtė, V., Mathieu, O., Mathieu-Daudé, J. C., Vainauskas, P., Casper, T., Baccino, E., & Bressolle, F. M. (2006). Distribution of ibogaine and noribogaine in a man following a poisoning involving root bark of the Tabernanthe iboga shrub. Journal of Analytical Toxicology, 30, 434–440.

    Article  PubMed  Google Scholar 

  22. Mash, D. C., Kovera, C. A., Buck, B. E., Norenberg, M. D., Shapshak, P., Hearn, W. L., & Sanchez-Ramos, J. (1998). Medication development of ibogaine as a pharmacotherapy for drug dependence. Annals of the New York Academy of Sciences, 844, 274–292.

    Article  PubMed  CAS  Google Scholar 

  23. Mash, D. C., Kovera, C. A., Pablo, J., Tyndale, R. F., Ervin, F. D., Williams, I. C., et al. (2000). Ibogaine: Complex pharmacokinetics, concerns for safety, and preliminary efficacy measures. Annals of the New York Academy of Sciences, 914, 394–401.

    Article  PubMed  CAS  Google Scholar 

  24. Glue, P., Lockhart, M., Lam, F., Hung, N., Hung, C. T., & Friedhoff, L. (2014). Ascending-dose study of noribogaine in healthy volunteers: Pharmacokinetics, pharmacodynamics, safety, and tolerability. The Journal of Clinical Pharmacology,. doi:10.1002/jcph.1404.

    PubMed  Google Scholar 

  25. Koenig, X., Kovar, M., Rubi, L., Mike, A. K., Lukacs, P., Gawali, V. S., et al. (2013). Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug’s cardiac ion channel profile. Toxicology and Applied Pharmacology, 273, 259–268.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Huang, X. P., Mangano, T., Hufeisen, S., Setola, V., & Roth, B. L. (2010). Identification of human Ether-a-go-go related gene modulators by three screening platforms in an academic drug-discovery setting. Assay and Drug Development Technologies, 8, 727–742.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Roth, B. L. (2013). National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP) assay protocol book version II. Chapel Hill, NC: Department of Pharmacology, University of North Carolina at Chapel Hill.

    Google Scholar 

  28. Warrick, B., & Baltarowich, L. (2012). Ibogaine for opioid addiction: A deadly treatment [2012 Annual Meeting of the North American Congress of Clinical Toxicology (NACCT)]. Clinical Toxicology, 50, 656.

    Google Scholar 

  29. Jalal, S., Daher, E., & Hilu, R. (2013). A case of death due to ibogaine use for heroin addiction: Case report. The American Journal on Addictions, 22, 302.

    Article  PubMed  Google Scholar 

  30. Roden, D. M. (1998). Taking the “Idio” out of “Idiosyncratic”: Predicting Torsades de Pointes. Pacing and Clinical Electrophysiology, 21, 1029–1034.

    Article  PubMed  CAS  Google Scholar 

  31. Cubeddu, L. X. (2009). Iatrogenic QT abnormalities and fatal arrhythmias: Mechanisms and clinical significance. Current Cardiology Reviews, 5, 166–176.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Levin, K. H., Copersino, M. L., Epstein, D., Boyd, S. J., & Gorelick, D. A. (2008). Longitudinal ECG changes in cocaine users during extended abstinence. Drug and Alcohol Dependence, 95, 160–163.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Otero-Anton, E., Gonzalez-Quintela, A., Saborido, J., Torre, J. A., Virgos, A., & Barrio, E. (1997). Prolongation of the QTc interval during alcohol withdrawal syndrome. Acta Cardiologica, 52, 285–294.

    PubMed  CAS  Google Scholar 

  34. Vlaanderen, L., Martial, L. C., Franssen, E. J. F., van der Voort, P. H. J., Oosterwerff, E., & Somsen, G. A. (2014). Cardiac arrest after ibogaine ingestion. Clinical Toxicology, 52, 642–643.

    Article  PubMed  CAS  Google Scholar 

  35. Dhahir, H. I. (1971). A comparative study on the toxicity of ibogaine and serotonin (p. 163). Bloomington: Indiana University.

    Google Scholar 

  36. Glick, S. D., Maisonneuve, I. M., Hough, L. B., Kuehne, M. E., & Bandarage, U. K. (1999). (±)-18-Methoxycoronaridine: A novel iboga alkaloid congener having potential anti-addictive efficacy. CNS Drug Reviews, 5, 27–42.

    Article  CAS  Google Scholar 

  37. Binienda, Z. K., Pereira, F., Alper, K., Slikker, W, Jr, & Ali, S. F. (2002). Adaptation to repeated cocaine administration in rats. Annals of the New York Academy of Sciences, 965, 172–179.

    Article  PubMed  CAS  Google Scholar 

  38. Schneider, J. A., & Rinehart, R. K. (1957). Analysis of the cardiovascular action of ibogaine hydrochloride. Archives Internationales de Pharmacodynamie et de Therapie, 110, 92–102.

    PubMed  CAS  Google Scholar 

  39. Mash, D. C., Allen-Ferdinand, K., Mayor, M., Kovera, C. A., Ayafor, J. F., Williams, I. C., et al. (1998). Ibogaine: Clinical observations of safety after single oral dose administrations. In Problems of drug dependence, 1998: Proceedings of the 60th annual scientific meeting, June 12–17 (p. 294). Scottsdale, Arizona: The College on Problems of Drug Dependence, Inc.

  40. Samorini, G. (1998). The initiation rite in the Bwiti Religion (Ndea Narizanga Sect, Gabon). Jahrbuch für Ethnomedizin und Bewusstseinsforschung, 6–7, 39–56.

    Google Scholar 

  41. Alper, K., Reith, M. E. A., & Sershen, H. (2012). Ibogaine and the inhibition of acetylcholinesterase. Journal of Ethnopharmacology, 139, 879–882.

    Article  PubMed  CAS  Google Scholar 

  42. Kolecki, P. F., & Curry, S. C. (1997). Poisoning by sodium channel blocking agents. Critical Care Clinics, 13, 829–848.

    Article  PubMed  CAS  Google Scholar 

  43. Sanchez-Chapula, J. A., Navarro-Polanco, R. A., Culberson, C., Chen, J., & Sanguinetti, M. C. (2002). Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block. Journal of Biological Chemistry, 277, 23587–23595.

    Article  PubMed  CAS  Google Scholar 

  44. Le Men, L., & Taylor, W. I. (1965). A uniform numbering system for indole alkaloids. Experientia, 21, 508–510.

    Article  PubMed  Google Scholar 

  45. Alper, K. R., & Cordell, G. A. (2001). A note concerning the numbering of the iboga alkaloids. In Ibogaine: Proceedings of the first international conference (also published as The Alkaloids Chemistry and Biology Vol. 56) (Alper, K. R., Glick, S. D., & Cordell, G. A., eds), pp. xxiii–xxiv. San Diego: Academic Press.

  46. Coi, A., Massarelli, I., Testai, L., Calderone, V., & Bianucci, A. M. (2008). Identification of “toxicophoric” features for predicting drug-induced QT interval prolongation. European Journal of Medicinal Chemistry, 43, 2479–2488.

    Article  PubMed  CAS  Google Scholar 

  47. Yan, G. X., Wu, Y., Liu, T., Wang, J., Marinchak, R. A., & Kowey, P. R. (2001). Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome : Direct evidence from intracellular recordings in the intact left ventricular wall. Circulation, 103, 2851–2856.

    Article  PubMed  CAS  Google Scholar 

  48. Bai, R., Lu, J. G., Pu, L., Liu, N., Zhou, Q., Ruan, Y. F., et al. (2005). Left ventricular epicardial activation increases transmural dispersion of repolarization in healthy, long QT, and dilated cardiomyopathy dogs. PACE-Pacing Clinical Electrophysiology, 28, 1098–1106.

    Article  Google Scholar 

  49. Wang, L., Lu, J., Zhang, F., Bai, R., & Wang, L. (2006). Effects of amiodarone on transmural dispersion of ventricular effective refractory periods across myocardial layers in the normal and hypertrophic canine heart. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban, 26, 182–184.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Drs. Rong Bai and Nian Liu were supported by the National Natural Science Foundation of China (NSFC-81370290 and NSFC-81370292). We thank Stevenson Flemer and Bruce O’Rourke from the University of Vermont for HPLC/MS analyses. We thank Dr. Maarten E. A. Reith and Dr. Dave Nichols for helpful discussion and Reith Lab for logistical support regarding the research compounds.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yanfei Ruan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alper, K., Bai, R., Liu, N. et al. hERG Blockade by Iboga Alkaloids. Cardiovasc Toxicol 16, 14–22 (2016). https://doi.org/10.1007/s12012-015-9311-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-015-9311-5

Keywords

Navigation