Skip to main content

The adverse events of ibogaine in humans: an updated systematic review of the literature (2015–2020)

Abstract

Context

Ibogaine is the main alkaloid of the African shrub Tabernanthe iboga. It produces hallucinogenic and psychostimulant effects, but it is currently known for the anti-addictive properties. Despite the potential therapeutic effects, several cases of fatalities and serious adverse events related to ibogaine/noribogaine use can be found in the literature. Most studies consist in case reports or were conducted under non-controlled settings, so causation cannot be clearly established.

Objectives

To update (2015–2020) the literature on the adverse events and fatalities associated with ibogaine/noribogaine administration.

Methods

Systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Results

Eighteen studies were included in the final selection. Highly heterogeneous results were found in terms of kind of product used or the known dosages. The adverse events were classified in acute effects (< 24 h), mainly cardiac (the most common was QTc prolongation), gastrointestinal, neurological, and clinical alterations, and long-lasting effects (> 24 h), mainly persistent cardiac alterations, psychiatric, and neurological signs.

Conclusions

There is a high need of phase I clinical trials that can describe the safety of different dosages of ibogaine with standardized products. Further research should perform clinical profiling of vulnerable populations, and design effective screening methods and clinical procedures.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Aceto M, Bowman E, Harris L (1990) Dependence studies of new compounds in the rhesus monkey, rat, and mouse. Natl Instit Drug Addict Res Monogr 95:578–631

    CAS  Google Scholar 

  2. Alper KR (2001) Ibogaine: a review. Alkaloids Chem Biol 56:1–38. https://doi.org/10.1016/s0099-9598(01)56005-8

    CAS  Article  PubMed  Google Scholar 

  3. Alper KR, Lotsof HS. (2007) Psychedelic medicine: new evidence for hallucinogenic substances as treatments. Westport (CT): Praeger Perspectives. The use of ibogaine in the treatment of addictions; p. 43–66.

  4. Alper KR, Lotsof HS, Kaplan CD (2008) The ibogaine medical subculture. J Ethnopharmacol 115:9–24. https://doi.org/10.1016/j.jep.2007.08.034

    CAS  Article  PubMed  Google Scholar 

  5. Alper KR, Stajić M, Gill JR (2012) Fatalities temporally associated with the ingestion of ibogaine. J Forensic Sci 57(2):398–412. https://doi.org/10.1111/j.1556-4029.2011.02008.x

    CAS  Article  PubMed  Google Scholar 

  6. Alper K, Bai R, Liu N et al (2016) hERG blockade by iboga alkaloids. Cardiovasc Toxicol 16(1):14–22. https://doi.org/10.1007/s12012-015-9311-5

    CAS  Article  PubMed  Google Scholar 

  7. Barsuglia JP, Polanco M, Palmer R et al (2018) A case report SPECT study and theoretical rationale for the sequential administration of ibogaine and 5-MeO-DMT in the treatment of alcohol use disorder. Prog Brain Res 242:121–158. https://doi.org/10.1016/bs.pbr.2018.08.002

    Article  PubMed  Google Scholar 

  8. Baumann MH, Rothman RB, Pablo J et al (2001) In vivo neurobiological effects of ibogaine and its odesmethyl metabolite, 12-hydroxyibogaine (noribogaine) in rats. J Pharmacol Exp Ther 297:531–539. https://doi.org/10.1177/0960327107087802

    CAS  Article  PubMed  Google Scholar 

  9. Belgers M, Leenaars M, Homberg JR et al (2016) Ibogaine and addiction in the animal model, a systematic review and meta-analysis. Transl Psychiatry 6(5):e826. https://doi.org/10.1038/tp.2016.71

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Bouso JC, Fornís I, Vilamala MV et al (2020) An analytical study of iboga alkaloids contained in Tabernanthe iboga-derived products offered by ibogaine treatment providers. Arch Clin Psychiatry 47(2):51–54. https://doi.org/10.1590/0101-60830000000231

    Article  Google Scholar 

  11. Breuer L, Kasper BS, Schwarze B et al (2015) “Herbal seizures”-atypical symptoms after ibogaine intoxication: a case report. J Med Case Rep 9:243. https://doi.org/10.1186/s13256-015-0731-4

    Article  PubMed  PubMed Central  Google Scholar 

  12. Brown TK (2013) Ibogaine in the treatment of substance dependence. Curr Drug Abuse Rev 6(1):3–16. https://doi.org/10.2174/15672050113109990001

    CAS  Article  PubMed  Google Scholar 

  13. Brown TK, Alper K (2018) Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes. Am J Drug Alcohol Abuse 44(1):24–36. https://doi.org/10.1080/00952990.2017.1320802

    Article  PubMed  Google Scholar 

  14. Celeste RK (2008) Erros metodológicos mais comuns encontrados em artigos dos tipos relatos e série de casos. Federação Brasileira das Sociedades de Ginecologia e Obstetrícia

  15. Cloutier-Gill L, Wood E, Millar T et al (2016) Remission of severe opioid use disorder with ibogaine: a case report. J Psychoactive Drugs 48(3):214–217. https://doi.org/10.1080/02791072.2016.1180467

    Article  PubMed  PubMed Central  Google Scholar 

  16. Dos Santos RG, Bouso JC, Hallak JEC (2016) The antiaddictive effects of ibogaine: a systematic literature review of human studies. J Psychedelic Studies 1(1):20–28. https://doi.org/10.1556/2054.01.2016.001

    Article  Google Scholar 

  17. Dos Santos RG, Hallak JEC (2020) Therapeutic use of serotoninergic hallucinogens: a review of the evidence and of the biological and psychological mechanisms. Neurosci Biobehav Rev 108:423–434. https://doi.org/10.1016/j.neubiorev.2019.12.001

    Article  PubMed  Google Scholar 

  18. Dworkin SI, Gleeson S, Meloni D et al (1995) Effects of ibogaine on responding maintained by food, cocaine and heroin reinforcement in rats. Psychopharmacol (berl) 117(3):257–261. https://doi.org/10.1007/BF02246099

    CAS  Article  Google Scholar 

  19. Dzoljic ED, Kaplan CD, Dzoljic MR (1988) Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine dependent rats. Arch Int Pharmacodyn Ther 294:64–70

    CAS  PubMed  Google Scholar 

  20. Ernst E, Bartu A, Popescu A (2002) Methadone-related deaths in Western Australia 1993–99. Aust N Z J Public Health 26:364–370. https://doi.org/10.1111/j.1467-842X.2002.tb00188.x

    Article  PubMed  Google Scholar 

  21. Fernandez JW (1982) Bwiti: an Ethnography of the religious imagination in Africa. Princeton University Press, Princeton

    Book  Google Scholar 

  22. Frances B, Gout R, Cros J et al (1992) Effects of ibogaine on naloxone-precipitated withdrawal in morphine-dependent mice. Fundam Clin Pharmacol 6(8–9):327–332. https://doi.org/10.1111/j.1472-8206.1992.tb00127.x

    CAS  Article  PubMed  Google Scholar 

  23. Glick SD, Kuehne ME, Raucci J et al (1994) Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tumorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Brain Res 657(1–2):14–22. https://doi.org/10.1016/0006-8993(94)90948-2

    CAS  Article  PubMed  Google Scholar 

  24. Glick SD, Rossman K, Rao NC et al (1992) Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor. Neuropharmacol 31:497–500. https://doi.org/10.1016/0028-3908(92)90089-8

    CAS  Article  Google Scholar 

  25. Glue P, Cape G, Tunnicliff D et al (2016) Ascending single-dose, double-blind, placebo controlled safety study of noribogaine in opioid-dependent patients. Clin Pharmacol Drug Dev 5(6):460–468. https://doi.org/10.1002/cpdd.254

    CAS  Article  PubMed  Google Scholar 

  26. Glue P, Winter H, Garbe K et al (2015) Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers. J Clin Pharmacol 55(6):680–687. https://doi.org/10.1002/jcph.471

    CAS  Article  PubMed  Google Scholar 

  27. Goutarel R, Gollnhofer O, Sillans R (1993) Pharmacodynamics and therapeutic applications of iboga and ibogaine. Psych Monogr Essays 6:70–111

    Google Scholar 

  28. Grogan J, Gerona R, Snow JW et al (2019) Ibogaine consumption with seizure-like episodes, QTc-prolongation, and captured cardiac dysrhythmias. J Emerg Med 57(4):e99–e104. https://doi.org/10.1016/j.jemermed.2019.06.052

    Article  PubMed  Google Scholar 

  29. Helsley S, Fiorella D, Rabin RA et al (1997) Effects of ibogaine on performance in the 8-arm radial maze. Pharmacol Biochem Behav 58(1):37–41. https://doi.org/10.1016/s0091-3057(96)00476-5

    CAS  Article  PubMed  Google Scholar 

  30. Henstra M, Wong L, Chahbouni A et al (2017) Toxicokinetics of ibogaine and noribogaine in a patient with prolonged multiple cardiac arrhythmias after ingestion of internet purchased ibogaine. Clin Toxicol (phila) 55(6):600–602. https://doi.org/10.1080/15563650.2017.1287372

    CAS  Article  Google Scholar 

  31. Hildyard C, Macklin P, Prendergast B et al (2016) A case of QT prolongation and torsades de pointes caused by ibogaine toxicity. J Emerg Med 50(2):e83-87. https://doi.org/10.1016/j.jemermed.2015.06.051

    Article  PubMed  Google Scholar 

  32. Jebberi Z, Marazzato J, De Ponti R et al (2019) Polymorphic wide QRS complex tachycardia: differential diagnosis. Card Electrophysiol Clin 11(2):333–344. https://doi.org/10.1016/j.ccep.2019.02.004

    Article  PubMed  Google Scholar 

  33. Kapur J (2018) Role of NMDA receptors in the pathophysiology and treatment of status epilepticus. Epilepsia Open 3(2):165–168. https://doi.org/10.1002/epi4.12270

    Article  PubMed  PubMed Central  Google Scholar 

  34. Knuijver T, Belgers M, Markus W et al (2018) Hallucinogen persisting perception disorder after ibogaine treatment for opioid dependence. J Clin Psychopharmacol 38(6):646–648. https://doi.org/10.1097/JCP.0000000000000966

    Article  PubMed  Google Scholar 

  35. Koenig X, Hilber K (2015) The anti-addiction drug ibogaine and the heart: a delicate relation. Molecules 20(2):2208–2228. https://doi.org/10.3390/molecules20022208

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Kuryshev YA, Bruening-Wright A, Brown AM et al (2010) Increased cardiac risk in concomitant methadone and diazepam treatment: pharmacodynamic interactions in cardiac ion channels. J Cardiovasc Pharmacol 56:420–430. https://doi.org/10.1097/FJC.0b013e3181f1d21b

    CAS  Article  PubMed  Google Scholar 

  37. Larsen P (2019) The opioid epidemic: a public health emergency. Rehabil Nurs 44(2):67–68

    Article  Google Scholar 

  38. Luz M, Mash DC (2021) Evaluating the toxicity and therapeutic potential of ibogaine in the treatment of chronic opioid abuse. Expert Opin Drug Metab Toxicol. https://doi.org/10.1080/17425255.2021.1944099

    Article  PubMed  Google Scholar 

  39. Marta CJ, Ryan WC, Kopelowicz A et al (2015) Mania following use of ibogaine: a case series. Am J Addict 24(3):203–205. https://doi.org/10.1111/ajad.12209

    Article  PubMed  Google Scholar 

  40. Mash DC, Duque L, Page B et al (2018) Ibogaine detoxification transitions opioid and cocaine abusers between dependence and abstinence: clinical observations and treatment outcomes. Front Pharmacol 9:529. https://doi.org/10.3389/fphar.2018.00529

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Matamoros-Castillo JM, Jávega-Manjó C, Sierra-San PM et al (2019) The paradox of iboga: intoxication by a natural detoxification remedy. Actas Esp Psiquiatr 47(2):70–78

    PubMed  Google Scholar 

  42. Mazoyer C, Carlier J, Boucher A (2013) Fatal case of a 27-year-old male after taking iboga in withdrawal treatment: GC-MS/MS determination of ibogaine and ibogamine in iboga roots and postmortem biological material. J Forensic Sci 58:1666–1672. https://doi.org/10.1111/1556-4029.12250

    CAS  Article  PubMed  Google Scholar 

  43. Meisner JA, Wilcox SR, Richards JB (2016) Ibogaine-associated cardiac arrest and death: case report and review of the literature. Ther Adv Psychopharmacol 6(2):95–98. https://doi.org/10.1177/2045125315626073

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Moher D, Liberati A, Tetzlaff J et al (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med 6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097

    Article  PubMed  PubMed Central  Google Scholar 

  45. O’Connell CW, Gerona RR, Friesen MW et al (2015) Internet-purchased ibogaine toxicity confirmed with serum, urine, and product content levels. Am J Emerg Med 33(7):985–986. https://doi.org/10.1016/j.ajem.2014.12.023

    Article  PubMed  Google Scholar 

  46. Pleskovic A, Gorjup V, Brvar M (2012) Ibogaine-Associated Ventricular Tachyarrhythmias Clin Toxicol (phila) 50(2):157. https://doi.org/10.3109/15563650.2011.647031

    Article  Google Scholar 

  47. Popik P, Layer RT, Fossom LH et al (1995) NMDA antagonist properties of the putative antiaddictive drug, ibogaine. J Pharmacol Exp Ther 275(2):753–760

    CAS  PubMed  Google Scholar 

  48. Ruan Y, Bai R, Liu N, et al (2014) Herg blockade by iboga alkaloids. In Proceedings of the European Society of Cardiology Congress, Barcelona, Spain.

  49. Sharpe LG, Jaffe JH (1990) Ibogaine fails to reduce naloxone-precipitated withdrawal in the morphine-dependent rat. NeuroReport 1(1):17–19

    CAS  Article  Google Scholar 

  50. Sowunmi A, Salako LA, Laoye OJ et al (1990) Combination of quinine, quinidine and cinchonine for the treatment of acute falciparum malaria: correlation with the susceptibility of Plasmodium falciparum to the cinchona alkaloids in vitro. Trans R Soc Trop Med Hyg 84:626–629. https://doi.org/10.1016/0035-9203(90)90127-z

    CAS  Article  PubMed  Google Scholar 

  51. Steinberg C, Deyell MW (2018) Cardiac arrest after ibogaine intoxication. J Arrhythm 34(4):455–457. https://doi.org/10.1002/joa3.12061

    Article  PubMed  PubMed Central  Google Scholar 

  52. Tournier N, Chevillard L, Megarbane B et al (2010) Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). Int J Neuropsychopharmacol 13(7):905–915. https://doi.org/10.1017/S1461145709990848

    CAS  Article  PubMed  Google Scholar 

  53. Vlaanderen L, Martial LC, Franssen EJ (2014) Cardiac arrest after ibogaine ingestion. Clin Toxicol (phila) 52:642–643. https://doi.org/10.3109/15563650.2014.927477

    CAS  Article  Google Scholar 

  54. Wilkins C, dos Santos RG, Solá J et al (2017) Detoxification from methadone using low, repeated, and increasing doses of ibogaine: A case report. J Psychedelic Studies 1(1):29–34. https://doi.org/10.1556/2054.01.2017.005

    Article  Google Scholar 

  55. Wilson C, Millar T, Matieschyn Z (2021) Novel treatment of opioid use disorder using ibogaine and iboga in two adults. J Psychedelic Studies 4(3):149–155. https://doi.org/10.1556/2054.2020.00133

    Article  Google Scholar 

Download references

Funding

JMR received funding from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil). JECH is recipient of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) 1A productivity fellowship. Research was supported in part by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). RGS is Fellow of the Programa Nacional de Pós-Doutorado, Brazil (PNPD/CAPES).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Rafael G. dos Santos.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article belongs to a Special Issue on Psychopharmacology on Psychedelic Drugs

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 124 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ona, G., Rocha, J.M., Bouso, J.C. et al. The adverse events of ibogaine in humans: an updated systematic review of the literature (2015–2020). Psychopharmacology (2021). https://doi.org/10.1007/s00213-021-05964-y

Download citation

Keywords

  • Ibogaine
  • Noribogaine
  • Adverse events
  • Safety
  • Drug interactions