, Volume 127, Issue 1–2, pp 10–18 | Cite as

Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine

  • Julie K. Staley
  • Qinjie Ouyang
  • John Pablo
  • W. Lee Hearn
  • Donna D. Flynn
  • Richard B. Rothman
  • Kenner C. Rice
  • Deborah C. Mash
Original Investigation


The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. Ibogaine undergoes first pass metabolism and isO-demethylated to 12-hydroxyibogamine (12-OH ibogamine). Radioligand binding assays were conducted to identify the potency and selectivity profiles for ibogaine and 12-OH ibogamine. A comparison of 12-OH ibogamine to the primary molecular targets identified previously for ibogaine demonstrates that the metabolite has a binding profile that is similar, but not identical to the parent drug. Both ibogaine and 12-OH ibogamine demonstrated the highest potency values at the cocaine recognition site on the 5-HT transporter. The same rank order (12-OH ibogamine > ibogaine), but lower potencies were observed for the [3H]paroxetine binding sites on the 5-HT transporter. Ibogaine and 12-OH ibogamine were equipotent at vesicular monoamine and dopamine transporters. The metabolite demonstrated higher affinity at the kappa-1 receptor and lower affinity at the NMDA receptor complex compared to the parent drug. Quantitation of the regional brain levels of ibogaine and 12-OH ibogamine demonstrated micromolar concentrations of both the parent drug and metabolite in rat brain. Drug dependence results from distinct, but inter-related neurochemical adaptations, which underlie tolerance, sensitization and withdrawal. Ibogaine’s ability to alter drug-seeking behavior may be due to combined actions of the parent drug and metabolite at key pharmacological targets that modulate the activity of drug reward circuits.

Key words

Ibogaine 12-Hydroxyibogamine Ligand binding Neuroreceptors Neurotransporter Drug dependence 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Backstrom I, Bergstrom M, Marcusson (1989) High affinity [3H]paroxetine binding to serotonin uptake sites in human brain tissue. J Brain Res 486:261–268CrossRefGoogle Scholar
  2. Batki SL, Manfredi LB, Peyton J, Jones RT (1994) Flouxetine for cocaine dependence in methadone maintenance: quantiative plasma and urine cocaine/benzoylecgonine concentrations. J Clin Psychopharmacol 13:243–250Google Scholar
  3. Baumann MH, Brockington AM, Rothman RB (1993) Withdrawal from chronic cocaine enhances behavioral sensitivity to the 5-HT2/lc agonist DOI. Biol Psychiatry 34:576–577PubMedCrossRefGoogle Scholar
  4. Baumann MH, Becketts KM, Rothman RB (1995) Evidence for alterations in presynaptic serotonergic function during withdrawal from cocaine in rats. Eur J Pharmacol 282:87–93PubMedCrossRefGoogle Scholar
  5. Bowen WD, Vilner BJ, Williams W, Bertha CM, Kuehne ME, Jacobson AE (1995) Ibogaine and its congeners are sigma2 receptor-selective ligands with moderate affinity. Eur J Pharmacol 279:R1-R3PubMedCrossRefGoogle Scholar
  6. Broderick PA, Phelan FT, Eng F, Wechsler RT (1994) Ibogaine modulates cocaine responses which are altered due to environmental habituation: in vivo microvoltametric and behavioral studies. Pharmacol Biochem Behav 49:711–728PubMedCrossRefGoogle Scholar
  7. Bruns RF, Lu GH, Pugsley TA (1986) Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes. Mol Pharmacol 29:331–346PubMedGoogle Scholar
  8. Burris KD, Filtz TM, Chumpradit S, Kung MP, Foulon C, Hensler JG, Kung HF, Molinoff PB (1994) Characterization of [125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′propenyl) amino] tetralin binding to dopamine D3 receptors in rat olfactory tubercle. J Pharmacol Exp Ther 268:935–942PubMedGoogle Scholar
  9. Cappendijk SLT, Dzoljic MR (1994) Inhibitory effects of ibogaine on cocaine self-administration in rats. Eur J Pharmacol 241:261–265CrossRefGoogle Scholar
  10. Cappendijk SL, De Vries R, Dzoljic MR (1993) Excitatory amino acid receptor antagonists and naloxone-precipitated withdrawal syndrome in morphine-dependent mice. Eur Neuropsychopharmacol 3:111–116PubMedCrossRefGoogle Scholar
  11. Covi L, Hess JM, Kreiter NA, Haertzen CA (1995) Effects of combined fluoxetine and counseling in the outpatient treatment of cocaine abusers. Am J Drug Alcohol Abuse 21:327–344PubMedCrossRefGoogle Scholar
  12. Darchen F, Scherman D, Laduron PM, Henry J-P (1988) Ketanserin binds to the monoamine transporter of chromaffin granules and of synaptic vesicles. Mol Pharmacol 33: 672–677PubMedGoogle Scholar
  13. Deecher DX, Teitler M, Soderlund DM, Bornmann WG, Kuehne ME, Glick SD (1992) Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. Brain Res 571:242–247PubMedCrossRefGoogle Scholar
  14. DeKeyser J, Walraevens H, Ebinger G, Vauquelin G (1989) In human brain two subtypes of D1 receptors can be distinguished on the basis of differences in guanine nucleotide effect on agonist binding. J Neurochem 53:1096–1102CrossRefGoogle Scholar
  15. Di Chiara G (1995) Psychobiology of the role of dopamine in drug-abuse and addiction. Neurosci Res Commun 17:133–143Google Scholar
  16. Dzoljic ED, Kaplan CD, Dzoljic MR (1988) Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine dependent rats. Arch Int Pharmacodyn Ther 294:64–70PubMedGoogle Scholar
  17. Ferrari-Dileo G, Waelbroeck M, Mash DC, Flynn DD (1994) A novel strategy for the selective labeling and localization of the M4 (m4) muscarinic receptor subtype. Mol Pharmacol 46: 1028–1035PubMedGoogle Scholar
  18. Glennon RA (1990) Do classical hallucinogens act as 5HT2 agonists or antagonists? Neuropsychopharmacology 3:509–517PubMedGoogle Scholar
  19. Glick SD, Rossman K, Steindorf S, Maisonneuve IM, Carlson JN (1991) Effects and aftereffects of ibogaine on morphine self-administration in rats. Eur J Pharmacol 195:341–345PubMedCrossRefGoogle Scholar
  20. Glick SD, Rossman K, Rao NC, Maisonneuve IM, Carlson JN (1992) Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor. Neuropharmacology 31:497–500PubMedCrossRefGoogle Scholar
  21. Glick SD, Kuehne ME, Raucci J, Wilson TE, Larson D, Keller RW, Carlson NJ (1994) Effects ofiboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Brain Res 657:14–22PubMedCrossRefGoogle Scholar
  22. Gozlan H, El Mestikaway S, Pichat L, Glowinski J, Hamon M (1983) Identification of presynaptic serotonin autoreceptors using a new ligand:3H-PAT. Nature 305:140–142PubMedCrossRefGoogle Scholar
  23. Harsing LG, Sershen H, Lajtha A (1994) Evidence that ibogaine releases dopaine from the cytoplasmic pool in isolated mouse striatum. J Neural Transm 96:215–225CrossRefGoogle Scholar
  24. Hearn WL, Mash DC, Pablo J, Hime G, Sambol NC, Doepel FM (1995a) Pharmacokinetics of Ibogaine: analytical methods, animal-human comparisons, and the identification of a primary metabolite. In: Spiehler, V. (ed) proceedings of the TIAFT-SOFT Joint Congress. Omnipress, Ann Arbor, Mich., pp 325–334Google Scholar
  25. Hearn WL, Pablo J, Hime GW, Mash DC (1995b) Identification and quantification of ibogaine and anO-demethylated metabolite in brain and biological fluids using gas chromatographymass spectrometry. J Anal Toxicol 19:427–434PubMedGoogle Scholar
  26. Heidbreder CA, Goldberg SR, Shippenberg TS (1993) The kappa opioid receptor agonist U-69593 attenuates cocaine-induced behavioral sensitization in the rat. Brain Res 616:335–338PubMedCrossRefGoogle Scholar
  27. Jarvie KR, Niznik HB, Seeman P (1987) Dopamine D-2 receptors in canine brain: ionic effects on [3H]neuroleptic binding. Eur J Pharmacol 144:163–171PubMedCrossRefGoogle Scholar
  28. Jarvis MF, Schulz R, Hutchison AJ, Do UH, Sills MA, Williams M (1989) [3H]CGS 21680, a selective A2 adenosine receptor agonist directly labels A2 receptors in rat brain. J Pharmacol Exp Ther 251:888–893PubMedGoogle Scholar
  29. Karler R, Calder LD, Chaudhry IA, Turkanis SA (1989) Blockade of ‘reverse tolerance’ to cocaine and amphetamine by MK-801. Life Sci 45:500–606CrossRefGoogle Scholar
  30. Kish SJ, Distefano LM, Dozic S, Robitaille Y, Rajput A, Deck JH, Hornykiewicz O (1990) [3H]Vesamicol binding in human brain cholinergic deficiency disorders. Neurosci Lett 117:347–352PubMedCrossRefGoogle Scholar
  31. Kleber HD (1995) Pharmacotherapy, current and potential, for treatment of cocaine dependence. Clin Neuropharmacol 18 [Suppl. 1]:S96-S109Google Scholar
  32. Kung MP, Canney DJ, Frederick D, Zhuang Z, Billings JJ, Kung HF (1994) Binding of125I-iodovinyltetrabenazine to CNS vesicular monoamine transport sites. Synapse 18:225–232PubMedCrossRefGoogle Scholar
  33. Levy AD, Baumann MH, Van de Kar LD (1994) Monoaminergic regulation of neuroendocrine function and its modification by cocaine. Frontiers Neuroendocrinol 15:85–156CrossRefGoogle Scholar
  34. Lotsof HS (1995) Ibogaine in the treatment of chemical dependency disorders: clinical perspectives. Multidisciplinary Association for Psychedelic Studies 5:16–27Google Scholar
  35. Mach RH, Smith CR, Childers SR (1995) Ibogaine possesses a selective affinity for sigma2 receptors. Life Sci 57:PL57–62PubMedCrossRefGoogle Scholar
  36. Malgouris C, Flamand F, Doble A (1993) Autoradiographic studies of RP 62203, a potent 5-HT2 receptor antagonist. Pharmacological characterization of [3H]RP62203 binding in the rat brain. Eur J Pharmacol 233:36–45Google Scholar
  37. Mash DC, Staley JK, Pablo JP, Holohean AM, Hackman JC, Davidoff RA (1995a) Properties of ibogaine and its principal metabolite (12-hydroxyibogamine) at the MK-801 binding site of the NMDA complex. Neurosci Lett 192:53–56PubMedCrossRefGoogle Scholar
  38. Mash DC, Staley JK, Baumann MH, Rothman RB, Hearn WL (1995b) Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. Life Sci 57:PL45–50PubMedCrossRefGoogle Scholar
  39. Nestler EJ (1994) Molecular neurobiology of drug addiction. Neuropsychopharmacology 11:77–87PubMedGoogle Scholar
  40. Nestler EJ, Hyman S (1993) Molecular foundations of psychiatry. American Psychiatric Press, Washington, DC.Google Scholar
  41. Ni Q, Xu H, Partilla JS, de Costa BR, Rice KC, Rothman RB (1993) Selective labeling of kappa 2 opioid receptors in rat brain by [125I]IOXY: interaction of opioid peptides and other drugs with multiple kappa 2a binding sites. Peptides 14:1279–1293PubMedCrossRefGoogle Scholar
  42. Nock B, Rajpara A, O’Connor LH, Cicero TJ (1988) Autoradiography of [3H]U69593 binding sites in rat brain: evidence for kappa opioid receptor subtypes. Eur J Pharmacol 154:27–34PubMedCrossRefGoogle Scholar
  43. O’Hearn E, Molliver ME (1993) Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. Neuroscience 55:303–310PubMedCrossRefGoogle Scholar
  44. Parsons LH, Koob GF, Weiss F (1995) Serotonin dysfunction in nucleus accumbens of rats during withdrawal after unlimited access to intravenous cocaine. J Pharmacol Exp Ther 274: 1182–1191PubMedGoogle Scholar
  45. Pearl SM, Herrick-Davis K, Teitler M, Glick SD (1995) Radioligand-binding study of noribogaine, a likely metabolite of ibogaine. Brain Res 675:342–344PubMedCrossRefGoogle Scholar
  46. Popik P, Layer RT, Skolnick P (1994) The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex. Psychopharmacology 114:672–674PubMedCrossRefGoogle Scholar
  47. Popik P, Layer RT, Sholnick P (1995) 100 Years of ibogaine: neurochemical and pharmacological actions of a putative anti-addictive drug. Pharmacol Rev 47:235–253PubMedGoogle Scholar
  48. Pudiak CM, Bozarth MA (1993) L-NAME and MK-801 attenutate sensitization to the locomotor-stimulating effect of cocaine. Life Sci 53:1517–1524PubMedCrossRefGoogle Scholar
  49. Reid MS, Souza KH, Broderick P, Berger P (1994) Evidence that ibogaine modulates dopamine via a kappa receptor mechanism. NIDA Res Monogr 153:392Google Scholar
  50. Rothman RB, Cadet JL, Akunne HC, Silverthorn ML, Baumann MH, Carroll FI, Rice KC, de Costa BR, Partilla JS, Wang JB, Uhl G, Glowa JR, Dersch CM (1994) Studies of the biogenic amine transporters. IV. Demonstration of a multiplicity of binding sites in rat caudate membraines for the cocaine analog [123I]RTI-55. J Pharmacol Exp Ther 270:296–309PubMedGoogle Scholar
  51. Sershen H, Hashim A, Harsing L, Lajtha A (1992) Ibogaine antagonizes cocaine-induced locomotor stimulation in mice. Life Sci 50:1079–1086PubMedCrossRefGoogle Scholar
  52. Sershen H, Hashim A, Lajtha A (1994) Ibogaine reduces preference for cocaine consumption in C57BL/6By mice. Pharmacol Biochem Behav 47:13–19PubMedCrossRefGoogle Scholar
  53. Sisko B (1993) Interrupting drug dependency with ibogaine: a summary of four case histories. Multidisciplinary Association for Psychedelic Studies IV:15–24Google Scholar
  54. Spanagel R, Shippenberg TS (1993) Modulation of morphine-induced sensitization by endogenous k-opioid systems. Neurosci Lett 153:232–236PubMedCrossRefGoogle Scholar
  55. Spanagel R, Herz A, Shippenberg TS (1992) Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci USA 89: 2046–2050PubMedCrossRefGoogle Scholar
  56. Staley JK, Basile M, Flynn DD, Mash DC (1994) Visualizing dopamine and serotonin transporters in the human brain with the potent cocaine analogue [125I]RTI-55: in vitro binding and autoradiographic characterization. J Neurochem 62:540–556Google Scholar
  57. Staley JK, Boja JW, Carroll FI, Seltzman H, Wyrick CD, Lewin AH, Abraham P, Mash DC (1995) Mapping the dopamine transporter in human brain with the novel selective cocaine analog [125I]RTI-121. Synapse 21:364–372PubMedCrossRefGoogle Scholar
  58. Sweetnam PM, Lancaster J, Snowman A, Collins JL, Perschke S, Bauer C, Ferkany J (1995) Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine’s putative anti-addictive activity. Psychopharmacology 118: 369–376PubMedCrossRefGoogle Scholar
  59. Tejani-Butt S, Brunswick DJ, Frazer A (1990) [3H]Nisoxetine: a new radioligand for norepinephrine uptake sites in brain. Eur J Pharmacol 191:239–243PubMedCrossRefGoogle Scholar
  60. Touchette N (1993) Ibogaine neurotoxicity raises new questions in addiction research. NIH Res 5:50–55Google Scholar
  61. Trujillo KA, Akil H (1991) Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251:85–87PubMedCrossRefGoogle Scholar
  62. Trujillo KA, Akil H (1995) Excitatory amino acids and drugs of abuse: a role forN-methyl-d-aspartate receptors in drug tolerance, sensitization and physical dependence. Drug Alcohol Depend 38:139–154PubMedCrossRefGoogle Scholar
  63. Walsh SL, Preston KL, Sullivan JT, Fromme R, Bigelow GE (1994) Fluoxetine alters the effects of intravenous cocaine in humans. J Clin Psychopharmacol 14:396–407PubMedGoogle Scholar
  64. Whitaker PM, Seeman P (1977) Hallucinogen binding to dopamine/neuroleptic receptors. J Pharm Pharmacol 29:506–507PubMedGoogle Scholar
  65. Zabetian CP, Staley JK, Flynn DD, Mash DC (1994) [3H]-(+)-Pentazocine binding to sigma recognition sites in human cerebellum. Life Sci 55:389–395CrossRefGoogle Scholar
  66. Zetler G, Singbartl G, Schlosser L (1972) Cerebral pharmacokinetics of tremor-producing harmala and iboga alkaloids. Pharmacology 7:237–248PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Julie K. Staley
    • 1
  • Qinjie Ouyang
    • 1
  • John Pablo
    • 1
  • W. Lee Hearn
    • 2
  • Donna D. Flynn
    • 3
  • Richard B. Rothman
    • 4
  • Kenner C. Rice
    • 5
  • Deborah C. Mash
    • 1
    • 3
  1. 1.Department of Neurology (D4-5)University of Miami School of MedicineMiamiUSA
  2. 2.Metro-Dade County Medical Examiners DepartmentMiamiUSA
  3. 3.Department of Molecular and Cellular PharmacologyUniversity of Miami School of MedicineMiamiUSA
  4. 4.Clinical Psychopharmacology Section, Intramural Research Program, National Institute of Drug Abuse/National Institutes of HealthAddiction Research CenterBaltimoreUSA
  5. 5.Section on Drug Design and Synthesis, Laboratory of Medicinal Chemistry, NIDDKNational Institutes of HealthBethesdaUSA

Personalised recommendations