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PreprintCited by 7Psychedelics and Drug StudiesAlkaloids: synthesis and pharmacologyNeurotransmitter Receptor Influence on Behavior

Deciphering Ibogaine’s Matrix Pharmacology: Multiple Transporter Modulation at Serotonin Synapses

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Hwu, Christopher, Havel, Václav, Westergaard, Xavier, Mendieta, Adriana M., Serrano, Inis C., Hwu, Jennifer, Walther, Donna, Lankri, David +13 more·2025·Journal of the American Chemical Society
DOI 10.1101/2025.03.04.641351

Preprint — published as 10.1021/jacs.5c06325

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Abstract

Ibogaine is the main psychoactive alkaloid produced by the iboga tree ( Tabernanthe iboga ) that has a unique therapeutic potential across multiple indications, including opioid dependence, substance use disorders, depression, anxiety, posttraumatic stress disorder (PTSD), and traumatic brain injury (TBI). We systematically examined the effects of ibogaine, its main metabolite noribogaine, and a series of iboga analogs at monoamine neurotransmitter transporters, some which have been linked to the oneiric and therapeutic effects of these substances. We report that ibogaine and noribogaine inhibit the transport function of the vesicular monoamine transporter 2 (VMAT2) with sub-micromolar potency in cell-based fluorimetry assays and at individual synaptic vesicle clusters in mouse brain as demonstrated via two-photon microscopy. The iboga compounds also inhibit the plasma membrane monoamine transporters (MATs), prominently including the serotonin transporter (SERT), and a novel iboga target, the organic cation transporter 2 (OCT2). SERT transport inhibition was demonstrated in serotonin axons and soma in the brain and in rat brain synaptosomes, where ibogaine and its analogs did not act as substrate-type serotonin releasers. Noribogaine showed dual inhibition of VMAT2 and SERT with comparable potency, providing an explanatory model for the known neurochemical effects of ibogaine in rodents. Together, the updated profile of the monoamine transporter modulation offers insight into the complexity of the iboga pharmacology, which we termed “matrix pharmacology”. The matrix pharmacology concept is outlined and used to explain why ibogaine and noribogaine do not induce catalepsy, as demonstrated in our study, in contrast to other VMAT2 inhibitors. TOC Graphic:

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  • Noribogaine inhibits OCT2 and acts as a synaptic reuptake inhibitor, exerting dual inhibition on SERT and VMAT2, and inducing partial serotonin release from synaptic vesicles.

    “For instance, compounds such as noribogaine inhibit the organic cation transporter 2 (OCT2) and act as synaptic reuptake inhibitors (SynRIs). These compounds exert dual inhibition on the serotonin transporter (SERT) and the vesicular monoamine transporter 2 (VMAT2), with noribogaine also inducing partial serotonin release from synaptic vesicles, thereby regulating neurotransmitter availability in”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [6]

    The section “Ibogaine and noribogaine inhibit the function of multiple monoamine transporters” reports that noribogaine inhibits OCT2, SERT, and VMAT2; the Discussion identifies its comparable SERT and VMAT2 inhibition as the basis for the proposed SynRI class. The paper says VMAT2 inhibition is expected to limit vesicular neurotransmitter pools, but the passages found do not establish that noribogaine induces partial serotonin release from synaptic vesicles. (LLM, conf=0.86)

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  1. Bartlett, M. F.; Dickel, D. F.; Taylor, W. I. The Alkaloids of Tabernanthe Iboga. Part IV. 1 The Structures of Ibogamine, Ibogaine, Tabernanthine and Voacangine. J. Am. Chem. Soc. 1958, 80 (1), 126-136. https://doi.org/10.1021/ja01534a036. · DOI
  2. Pope, H. G. Tabernanthe Iboga: An African Narcotic Plant of Social Importance. Econ Bot 1969, 23 (2), 174-184. https://doi.org/10.1007/BF02860623. · DOI
  3. Mash, D. C.; Duque, L.; Page, B.; Allen-Ferdinand, K. Ibogaine Detoxification Transitions Opioid and Cocaine Abusers Between Dependence and Abstinence: Clinical Observations and Treatment Outcomes. Front. Pharmacol. 2018, 9, 529. https://doi.org/10.3389/fphar.2018.00529. · DOI
  4. Alper, K. R. Chapter 1 Ibogaine: A Review. In The Alkaloids: Chemistry and Biology; Academic Press, 2001; Vol. 56, pp 1-38. https://doi.org/10.1016/S0099- 9598(01)56005-8. · DOI
  5. Alper, K. R.; Lotsof, H. S.; Kaplan, C. D. The Ibogaine Medical Subculture. Journal of Ethnopharmacology 2008, 115 (1), 9-24. https://doi.org/10.1016/j.jep.2007.08.034. · DOI
  6. Alper, K.; Bai, R.; Liu, N.; Fowler, S. J.; Huang, X.-P.; Priori, S. G.; Ruan, Y. hERG Blockade by Iboga Alkaloids. Cardiovasc Toxicol 2016, 16 (1), 14-22. https://doi.org/10.1007/s12012-015-9311-5. · DOI
  7. Rocha, J. M.; Reis, J. A. S.; Bouso, J. C.; Hallak, J. E. C.; dos Santos, R. G. Identifying Setting Factors Associated with Improved Ibogaine Safety: A Systematic Review of Clinical Studies. Eur Arch Psychiatry Clin Neurosci 2023, 273 (7), 1527- 1542. https://doi.org/10.1007/s00406-023-01590-1. · DOI
  8. Schenberg, E. E.; De Castro Comis, M. A.; Alexandre, J. F. M.; Tófoli, L. F.; Chaves, B. D. R.; Da Silveira, D. X. A Phenomenological Analysis of the Subjective Experience Elicited by Ibogaine in the Context of a Drug Dependence Treatment. Journal of Psychedelic Studies 2017, 1 (2), 74-83. https://doi.org/10.1556/2054.01.2017.007. · DOI
  9. Brown, T. K.; Noller, G. E.; Denenberg, J. O. Ibogaine and Subjective Experience: Transformative States and Psychopharmacotherapy in the Treatment of Opioid Use Disorder. Journal of Psychoactive Drugs 2019, 51 (2), 155-165. https://doi.org/10.1080/02791072.2019.1598603. · DOI
  10. Belgers, M.; Leenaars, M.; Homberg, J. R.; Ritskes-Hoitinga, M.; Schellekens, A. F. A.; Hooijmans, C. R. Ibogaine and Addiction in the Animal Model, a Systematic Review and Meta-Analysis. Transl Psychiatry 2016, 6 (5), e826-e826. https://doi.org/10.1038/tp.2016.71. · DOI
  11. Rodrı ǵuez, P.; Urbanavicius, J.; Prieto, J. P.; Fabius, S.; Reyes, A. L.; Havel, V.; Sames, D.; Scorza, C.; Carrera, I. A Single Administration of the Atypical Psychedelic Ibogaine or Its Metabolite Noribogaine Induces an Antidepressant-Like Effect in Rats. ACS Chem. Neurosci. 2020, 11 (11), 1661-1672. https://doi.org/10.1021/acschemneuro.0c00152. · DOI
  12. Koenig, X.; Hilber, K. The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation. Molecules 2015, 20 (2), 2208-2228. https://doi.org/10.3390/molecules20022208. · DOI
  13. Davis, A. K.; Averill, L. A.; Sepeda, N. D.; Barsuglia, J. P.; Amoroso, T. Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans. Chronic Stress 2020, 4, 247054702093956. https://doi.org/10.1177/2470547020939564. · DOI
  14. Cherian, K. N.; Keynan, J. N.; Anker, L.; Faerman, A.; Brown, R. E.; Shamma, A.; Keynan, O.; Coetzee, J. P.; Batail, J.-M.; Phillips, A.; Bassano, N. J.; Sahlem, G. L.; Inzunza, J.; Millar, T.; Dickinson, J.; Rolle, C. E.; Keller, J.; Adamson, M.; Kratter, I. H.; Williams, N. R. Magnesium-Ibogaine Therapy in Veterans with Traumatic Brain Injuries. Nat Med 2024, 30 (2), 373-381. https://doi.org/10.1038/s41591-023- 02705-w. · DOI
  15. Mash, D. C.; Staley, J. K.; Baumann, M. H.; Rothman, R. B.; Lee Hearn, W. Identification of a Primary Metabolite of Ibogaine That Targets Serotonin Transporters and Elevates Serotonin. Life Sciences 1995, 57 (3), PL45-PL50. https://doi.org/10.1016/0024-3205(95)00273-9. · DOI
  16. Baumann, M. H.; Rothman, R. B.; Pablo, J. P.; Mash, D. C. In Vivo Neurobiological Effects of Ibogaine and Its O-Desmethyl Metabolite, 12-Hydroxyibogamine (Noribogaine), in Rats. The Journal of Pharmacology and Experimental Therapeutics 2001, 297 (2), 531-539. https://doi.org/10.1016/S0022- 3565(24)29567-7. · DOI
  17. Knuijver, T.; ter Heine, R.; Schellekens, A. F. A.; Heydari, P.; Lucas, L.; Westra, S.; Belgers, M.; van Oosteren, T.; Verkes, R. J.; Kramers, C. The Pharmacokinetics and Pharmacodynamics of Ibogaine in Opioid Use Disorder Patients. J Psychopharmacol 2024, 38 (5), 481-488. https://doi.org/10.1177/02698811241237873. · DOI
  18. Popik, P.; Layer, R. T.; Fossom, L. H.; Benveniste, M.; Geter-Douglass, B.; Witkin, J. M.; Skolnick, P. NMDA Antagonist Properties of the Putative Antiaddictive Drug, Ibogaine. J Pharmacol Exp Ther 1995, 275 (2), 753-760.
  19. Baumann, M. H.; Pablo, J.; Ali, S. F.; Rothman, R. B.; Mash, D. C. Chapter 5 Comparative Neuropharmacology of Ibogaine and Its O-Desmethyl Metabolite, Noribogaine. In The Alkaloids: Chemistry and Biology; Elsevier, 2001; Vol. 56, pp 79-113. https://doi.org/10.1016/S0099-9598(01)56009-5. · DOI
  20. El-Kasaby, A.; Just, H.; Malle, E.; Stolt-Bergner, P. C.; Sitte, H. H.; Freissmuth, M.; Kudlacek, O. Mutations in the Carboxyl-Terminal SEC24 Binding Motif of the Serotonin Transporter Impair Folding of the Transporter. J Biol Chem 2010, 285 (50), 39201-39210. https://doi.org/10.1074/jbc.M110.118000. · DOI
  21. Bhat, S.; Guthrie, D. A.; Kasture, A.; El-Kasaby, A.; Cao, J.; Bonifazi, A.; Ku, T.; Giancola, J. B.; Hummel, T.; Freissmuth, M.; Newman, A. H. Tropane-Based Ibogaine Analog Rescues Folding-Deficient Serotonin and Dopamine Transporters. ACS Pharmacol. Transl. Sci. 2021, 4 (2), 503-516. https://doi.org/10.1021/acsptsci.0c00102. · DOI
  22. Gassaway, M. M.; Jacques, T. L.; Kruegel, A. C.; Karpowicz, R. J.; Li, X.; Li, S.; Myer, Y.; Sames, D. Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-Induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound. ACS Chem. Biol. 2016, 11 (1), 77-87. https://doi.org/10.1021/acschembio.5b00678. · DOI
  23. Popik, P.; Layer, R. T.; Skolnick, P. 100 Years of Ibogaine: Neurochemical and Pharmacological Actions of a Putative Anti-Addictive Drug. Pharmacol Rev 1995, 47 (2), 235-253.
  24. Mash, D. C. IUPHAR -Invited Review -Ibogaine -A Legacy within the Current Renaissance of Psychedelic Therapy. Pharmacological Research 2023, 190, 106620. https://doi.org/10.1016/j.phrs.2022.106620. · DOI
  25. Glick, S. D.; Maisonneuve, I. M.; Szumlinski, K. K. Chapter 2 Mechanisms of Action of Ibogaine: Relevance to Putative Therapeutic Effects and Development of a Safer Iboga Alkaloid Congener. In The Alkaloids: Chemistry and Biology; Elsevier, 2001; Vol. 56, pp 39-53. https://doi.org/10.1016/S0099-9598(01)56006-X. · DOI · Paper page
  26. Ona, G.; Reverte, I.; Rossi, G. N.; dos Santos, R. G.; Hallak, J. E.; Colomina, M. T.; Bouso, J. C. Main Targets of Ibogaine and Noribogaine Associated with Its Putative Anti-Addictive Effects: A Mechanistic Overview. J Psychopharmacol 2023, 37 (12), 1190-1200. https://doi.org/10.1177/02698811231200882. · DOI
  27. Rickli, A.; Moning, O. D.; Hoener, M. C.; Liechti, M. E. Receptor Interaction Profiles of Novel Psychoactive Tryptamines Compared with Classic Hallucinogens. Eur Neuropsychopharmacol 2016, 26 (8), 1327-1337. https://doi.org/10.1016/j.euroneuro.2016.05.001. · DOI · Paper page
  28. Glatfelter, G. C.; Pottie, E.; Partilla, J. S.; Stove, C. P.; Baumann, M. H. Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited. ACS Pharmacol. Transl. Sci. 2024, 7 (3), 641-653. https://doi.org/10.1021/acsptsci.3c00192. · DOI
  29. Marton, S.; González, B.; Rodríguez-Bottero, S.; Miquel, E.; Martínez-Palma, L.; Pazos, M.; Prieto, J. P.; Rodríguez, P.; Sames, D.; Seoane, G.; Scorza, C.; Cassina, P.; Carrera, I. Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits. Front. Pharmacol. 2019, 10, 193. https://doi.org/10.3389/fphar.2019.00193. · DOI
  30. Havel, V.; Kruegel, A. C.; Bechand, B.; McIntosh, S.; Stallings, L.; Hodges, A.; Wulf, M. G.; Nelson, M.; Hunkele, A.; Ansonoff, M.; Pintar, J. E.; Hwu, C.; Ople, R. S.; Abi-Gerges, N.; Zaidi, S. A.; Katritch, V.; Yang, M.; Javitch, J. A.; Majumdar, S.; Hemby, S. E.; Sames, D. Oxa-Iboga Alkaloids Lack Cardiac Risk and Disrupt Opioid Use in Animal Models. Nat Commun 2024, 15 (1), 8118. https://doi.org/10.1038/s41467-024-51856-y. · DOI
  31. Govender, D.; Moloko, L.; Papathanasopoulos, M.; Tumba, N.; Owen, G.; Calvey, T. Ibogaine Administration Following Repeated Morphine Administration Upregulates Myelination Markers 2′, 3′-Cyclic Nucleotide 3′-Phosphodiesterase (CNP) and Myelin Basic Protein (MBP) mRNA and Protein Expression in the Internal Capsule of Sprague Dawley Rats. Front. Neurosci. 2024, 18, 1378841. https://doi.org/10.3389/fnins.2024.1378841. · DOI
  32. Biosca-Brull, J.; Ona, G.; Alarcón-Franco, L.; Colomina, M. T. A Transcriptomic Analysis in Mice Following a Single Dose of Ibogaine Identifies New Potential Therapeutic Targets. Transl Psychiatry 2024, 14 (1), 41. https://doi.org/10.1038/s41398-024-02773-7. · DOI
  33. Nardou, R.; Sawyer, E.; Song, Y. J.; Wilkinson, M.; Padovan-Hernandez, Y.; De Deus, J. L.; Wright, N.; Lama, C.; Faltin, S.; Goff, L. A.; Stein-O'Brien, G. L.; Dölen, G. Psychedelics Reopen the Social Reward Learning Critical Period. Nature 2023, 618 (7966), 790-798. https://doi.org/10.1038/s41586-023-06204-3. · DOI · Paper page
  34. Kristensen, A. S.; Andersen, J.; Jørgensen, T. N.; Sørensen, L.; Eriksen, J.; Loland, C. J.; Strømgaard, K.; Gether, U.; Simonsen, U. SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation. Pharmacological Reviews 2011, 63 (3), 585-640. https://doi.org/10.1124/pr.108.000869. · DOI
  35. Yang, D.; Gouaux, E. Illumination of Serotonin Transporter Mechanism and Role of the Allosteric Site. Sci Adv 2021, 7 (49), eabl3857. https://doi.org/10.1126/sciadv.abl3857. · DOI
  36. Belmer, A.; Klenowski, P. M.; Patkar, O. L.; Bartlett, S. E. Mapping the Connectivity of Serotonin Transporter Immunoreactive Axons to Excitatory and Inhibitory Neurochemical Synapses in the Mouse Limbic Brain. Brain Struct Funct 2017, 222 (3), 1297-1314. https://doi.org/10.1007/s00429-016-1278-x. · DOI
  37. Young, L. W.; Darios, E. S.; Watts, S. W. An Immunohistochemical Analysis of SERT in the Blood-Brain Barrier of the Male Rat Brain. Histochem Cell Biol 2015, 144 (4), 321-329. https://doi.org/10.1007/s00418-015-1343-1. · DOI
  38. Rothman, R. B.; Baumann, M. H. Monoamine Transporters and Psychostimulant Drugs. European Journal of Pharmacology 2003, 479 (1), 23-40. https://doi.org/10.1016/j.ejphar.2003.08.054. · DOI
  39. Aggarwal, S.; Mortensen, O. V. Overview of Monoamine Transporters. Current Protocols in Pharmacology 2017, 79 (1), 12.16.1-12.16.17. https://doi.org/10.1002/cpph.32. · DOI
  40. Torres, G. E.; Gainetdinov, R. R.; Caron, M. G. Plasma Membrane Monoamine Transporters: Structure, Regulation and Function. Nat Rev Neurosci 2003, 4 (1), 13-25. https://doi.org/10.1038/nrn1008. · DOI
  41. Rothman, R.; Baumann, M. Therapeutic Potential of Monoamine Transporter Substrates. CTMC 2006, 6 (17), 1845-1859. https://doi.org/10.2174/156802606778249766. · DOI
  42. Organic Cation Transporters in the Central Nervous System; Daws, L. C., Ed.; Handbook of Experimental Pharmacology; Springer International Publishing: Cham, 2021; Vol. 266. https://doi.org/10.1007/978-3-030-82984-1. · DOI
  43. Yaffe, D.; Forrest, L. R.; Schuldiner, S. The Ins and Outs of Vesicular Monoamine Transporters. J Gen Physiol 2018, 150 (5), 671-682. https://doi.org/10.1085/jgp.201711980. · DOI
  44. Wu, D.; Chen, Q.; Yu, Z.; Huang, B.; Zhao, J.; Wang, Y.; Su, J.; Zhou, F.; Yan, R.; Li, N.; Zhao, Y.; Jiang, D. Transport and Inhibition Mechanisms of Human VMAT2. Nature 2024, 626 (7998), 427-434. https://doi.org/10.1038/s41586-023-06926-4. · DOI
  45. Chen, J. J.; Ondo, W. G.; Dashtipour, K.; Swope, D. M. Tetrabenazine for the Treatment of Hyperkinetic Movement Disorders: A Review of the Literature. Clin Ther 2012, 34 (7), 1487-1504. https://doi.org/10.1016/j.clinthera.2012.06.010. · DOI
  46. Lesch, K.-P.; Waider, J. Serotonin in the Modulation of Neural Plasticity and Networks: Implications for Neurodevelopmental Disorders. Neuron 2012, 76 (1), 175-191. https://doi.org/10.1016/j.neuron.2012.09.013. · DOI · Paper page
  47. Staley, J. K.; Ouyang, Q.; Pablo, J.; Hearn, W. L.; Flynn, D. D.; Rothman, R. B.; Rice, K. C.; Mash, D. C. Pharmacological Screen for Activities of 12- Hydroxyibogamine: A Primary Metabolite of the Indole Alkaloid Ibogaine. Psychopharmacology 1996, 127 (1), 10-18. https://doi.org/10.1007/BF02805969. · DOI
  48. Hu, G.; Henke, A.; Karpowicz, R. J.; Sonders, M. S.; Farrimond, F.; Edwards, R.; Sulzer, D.; Sames, D. New Fluorescent Substrate Enables Quantitative and High- Throughput Examination of Vesicular Monoamine Transporter 2 (VMAT2). ACS Chem Biol 2013, 8 (9), 1947-1954. https://doi.org/10.1021/cb400259n. · DOI
  49. Lee, W.-L.; Westergaard, X.; Hwu, C.; Hwu, J.; Fiala, T.; Lacefield, C.; Boltaev, U.; Mendieta, A. M.; Lin, L.; Sonders, M. S.; Brown, K. R.; He, K.; Asher, W. B.; Javitch, J. A.; Sulzer, D.; Sames, D. Molecular Design of SERTlight: A Fluorescent Serotonin Probe for Neuronal Labeling in the Brain. J Am Chem Soc 2024, 146 (14), 9564-9574. https://doi.org/10.1021/jacs.3c11617. · DOI
  50. Warren, A. L.; Lankri, D.; Cunningham, M. J.; Serrano, I. C.; Parise, L. F.; Kruegel, A. C.; Duggan, P.; Zilberg, G.; Capper, M. J.; Havel, V.; Russo, S. J.; Sames, D.; Wacker, D. Structural Pharmacology and Therapeutic Potential of 5- Methoxytryptamines. Nature 2024, 630 (8015), 237-246. https://doi.org/10.1038/s41586-024-07403-2. · DOI
  51. Tod, P.; Varga, A.; Román, V.; Lendvai, B.; Pálkovács, R.; Sperlágh, B.; Vizi, E. S. Tetrabenazine, a Vesicular Monoamine Transporter 2 Inhibitor, Inhibits Vesicular Storage Capacity and Release of Monoamine Transmitters in Mouse Brain Tissue. Br J Pharmacol 2024, 181 (24), 5094-5109. https://doi.org/10.1111/bph.17348. · DOI
  52. Tatsumi, M.; Groshan, K.; Blakely, R. D.; Richelson, E. Pharmacological Profile of Antidepressants and Related Compounds at Human Monoamine Transporters. Eur J Pharmacol 1997, 340 (2-3), 249-258. https://doi.org/10.1016/s0014- 2999(97)01393-9. · DOI · Paper page
  53. Owens, M. J.; Morgan, W. N.; Plott, S. J.; Nemeroff, C. B. Neurotransmitter Receptor and Transporter Binding Profile of Antidepressants and Their Metabolites. J Pharmacol Exp Ther 1997, 283 (3), 1305-1322.
  54. Yasumoto, S.; Tamura, K.; Karasawa, J.; Hasegawa, R.; Ikeda, K.; Yamamoto, T.; Yamamoto, H. Inhibitory Effect of Selective Serotonin Reuptake Inhibitors on the Vesicular Monoamine Transporter 2. Neurosci Lett 2009, 454 (3), 229-232. https://doi.org/10.1016/j.neulet.2009.03.049. · DOI
  55. Wang, X.; Marmouzi, I.; Finnie, P. S. B.; Bucher, M. L.; Yan, Y.; Williams, E. Q.; Støve, S. I.; Lipina, T. V.; Ramsey, A. J.; Miller, G. W.; Salahpour, A. Tricyclic and Tetracyclic Antidepressants Upregulate VMAT2 Activity and Rescue Disease- Causing VMAT2 Variants. Neuropsychopharmacology 2024, 49 (11), 1783-1791. https://doi.org/10.1038/s41386-024-01914-2. · DOI
  56. Meyer, A. C.; Horton, D. B.; Neugebauer, N. M.; Wooters, T. E.; Nickell, J. R.; Dwoskin, L. P.; Bardo, M. T. Tetrabenazine Inhibition of Monoamine Uptake and Methamphetamine Behavioral Effects: Locomotor Activity, Drug Discrimination and Self-Administration. Neuropharmacology 2011, 61 (4), 849-856. https://doi.org/10.1016/j.neuropharm.2011.05.033. · DOI
  57. German, D. C.; McMillen, B. A.; Sanghera, M. K.; Saffer, S. I.; Shore, P. A. Effects of Severe Dopamine Depletion on Dopamine Neuronal Impulse Flow and on Tyrosine Hydroxylase Regulation. Brain Res Bull 1981, 6 (2), 131-134. https://doi.org/10.1016/s0361-9230(81)80037-8. · DOI
  58. Nickell, J. R.; Krishnamurthy, S.; Norrholm, S.; Deaciuc, G.; Siripurapu, K. B.; Zheng, G.; Crooks, P. A.; Dwoskin, L. P. Lobelane Inhibits Methamphetamine- Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter- 2. J Pharmacol Exp Ther 2010, 332 (2), 612-621. https://doi.org/10.1124/jpet.109.160275. · DOI
  59. Partilla, J. S.; Dempsey, A. G.; Nagpal, A. S.; Blough, B. E.; Baumann, M. H.; Rothman, R. B. Interaction of Amphetamines and Related Compounds at the Vesicular Monoamine Transporter. J Pharmacol Exp Ther 2006, 319 (1), 237-246. https://doi.org/10.1124/jpet.106.103622. · DOI
  60. Kruegel, A. C.; Rakshit, S.; Li, X.; Sames, D. Constructing Iboga Alkaloids via C-H Bond Functionalization: Examination of the Direct and Catalytic Union of Heteroarenes and Isoquinuclidine Alkenes. J. Org. Chem. 2015, 80 (4), 2062- 2071. https://doi.org/10.1021/jo5018102. · DOI
  61. Hughes, A. J.; Hamelink, C. R.; Townsend, S. D. Disrupting Substance Use Disorder: The Chemistry of Iboga Alkaloids. European Journal of Organic Chemistry 2024, 27 (36), e202400432. https://doi.org/10.1002/ejoc.202400432. · DOI
  62. Iyer, R. N.; Favela, D.; Domokos, A.; Zhang, G.; Avanes, A. A.; Carter, S. J.; Basargin, A. G.; Davis, A. R.; Tantillo, D. J.; Olson, D. E. Efficient and Modular Synthesis of Ibogaine and Related Alkaloids. Nat. Chem. 2025, 1-9. https://doi.org/10.1038/s41557-024-01714-7. · DOI
  63. González, B.; Fagúndez, C.; Peixoto de Abreu Lima, A.; Suescun, L.; Sellanes, D.; Seoane, G. A.; Carrera, I. Efficient Access to the Iboga Skeleton: Optimized Procedure to Obtain Voacangine from Voacanga Africana Root Bark. ACS Omega 2021, 6 (26), 16755-16762. https://doi.org/10.1021/acsomega.1c00745. · DOI
  64. Mori, A.; Mizusaki, T.; Ikawa, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Palladium on Carbon-Diethylamine-Mediated Hydrodeoxygenation of Phenol Derivatives under Mild Conditions. Tetrahedron 2007, 63 (5), 1270-1280. https://doi.org/10.1016/j.tet.2006.11.060. · DOI
  65. Whittaker, V. P. Thirty Years of Synaptosome Research. J Neurocytol 1993, 22 (9), 735-742. https://doi.org/10.1007/BF01181319. · DOI
  66. Johnson, C. B.; Walther, D.; Baggott, M. J.; Baker, L. E.; Baumann, M. H. Novel Benzofuran Derivatives Induce Monoamine Release and Substitute for the Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine. J Pharmacol Exp Ther 2024, 391 (1), 22-29. https://doi.org/10.1124/jpet.123.001837. · DOI
  67. Stein, W. The Movement Of Molecules Across Cell Membranes; Academic Press: New York, 1967.
  68. Wells, G. B.; Lopez, M. C.; Tanaka, J. C. The Effects of Ibogaine on Dopamine and Serotonin Transport in Rat Brain Synaptosomes. Brain Res Bull 1999, 48 (6), 641- 647. https://doi.org/10.1016/s0361-9230(99)00053-2. · DOI
  69. Pereira, D. B.; Schmitz, Y.; Mészáros, J.; Merchant, P.; Hu, G.; Li, S.; Henke, A.; Lizardi-Ortiz, J. E.; Karpowicz, R. J.; Morgenstern, T. J.; Sonders, M. S.; Kanter, E.; Rodriguez, P. C.; Mosharov, E. V.; Sames, D.; Sulzer, D. Fluorescent False Neurotransmitter Reveals Functionally Silent Dopamine Vesicle Clusters in the Striatum. Nat Neurosci 2016, 19 (4), 578-586. https://doi.org/10.1038/nn.4252. · DOI
  70. Tatara, A.; Shimizu, S.; Shin, N.; Sato, M.; Sugiuchi, T.; Imaki, J.; Ohno, Y. Modulation of Antipsychotic-Induced Extrapyramidal Side Effects by Medications for Mood Disorders. Prog Neuropsychopharmacol Biol Psychiatry 2012, 38 (2), 252-259. https://doi.org/10.1016/j.pnpbp.2012.04.008. · DOI
  71. Mann, A.; Chesselet, M.-F. Chapter 8 -Techniques for Motor Assessment in Rodents. In Movement Disorders (Second Edition);
  72. LeDoux, M. S., Ed.; Academic Press: Boston, 2015; pp 139-157. https://doi.org/10.1016/B978-0-12-405195- 9.00008-1. · DOI
  73. Cunningham, M. J.; Bock, H. A.; Serrano, I. C.; Bechand, B.; Vidyadhara, D. J.; Bonniwell, E. M.; Lankri, D.; Duggan, P.; Nazarova, A. L.; Cao, A. B.; Calkins, M. M.; Khirsariya, P.; Hwu, C.; Katritch, V.; Chandra, S. S.; McCorvy, J. D.; Sames, D. Pharmacological Mechanism of the Non-Hallucinogenic 5-HT2A Agonist Ariadne and Analogs. ACS Chem Neurosci 2023, 14 (1), 119-135. https://doi.org/10.1021/acschemneuro.2c00597. · DOI
  74. González, J.; Prieto, J. P.; Rodríguez, P.; Cavelli, M.; Benedetto, L.; Mondino, A.; Pazos, M.; Seoane, G.; Carrera, I.; Scorza, C.; Torterolo, P. Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile. Front Pharmacol 2018, 9, 374. https://doi.org/10.3389/fphar.2018.00374. · DOI
  75. Ma, X.; Peng, J.; Chen, Y.; Wang, Z.; Zhou, Q.; Yan, J.; Jiang, H. Esketamine Anesthetizes Mice With a Similar Potency to Racemic Ketamine. Dose Response 2023, 21 (1), 15593258231157563. https://doi.org/10.1177/15593258231157563. · DOI
  76. Franks, N. P. General Anaesthesia: From Molecular Targets to Neuronal Pathways of Sleep and Arousal. Nat Rev Neurosci 2008, 9 (5), 370-386. https://doi.org/10.1038/nrn2372. · DOI
  77. Teng, M. Z.; Merenick, D.; Jessel, A.; Ganshorn, H.; Pang, D. S. J. Consistency in Reporting of Loss of Righting Reflex for Assessment of General Anesthesia in Rats and Mice: A Systematic Review. Comp Med 2024, 74 (1), 12-18. https://doi.org/10.30802/AALAS-CM-23-000063. · DOI
  78. Podurgiel, S. J.; Milligan, M. N.; Yohn, S. E.; Purcell, L. J.; Contreras-Mora, H. M.; Correa, M.; Salamone, J. D. Fluoxetine Administration Exacerbates Oral Tremor and Striatal Dopamine Depletion in a Rodent Pharmacological Model of Parkinsonism. Neuropsychopharmacology 2015, 40 (9), 2240-2247. https://doi.org/10.1038/npp.2015.69. · DOI
  79. Leo, R. J. Movement Disorders Associated with the Serotonin Selective Reuptake Inhibitors. Journal of Clinical Psychiatry 1996, 57 (10), 449-454.
  80. Sulzer, D.; Sonders, M. S.; Poulsen, N. W.; Galli, A. Mechanisms of Neurotransmitter Release by Amphetamines: A Review. Progress in Neurobiology 2005, 75 (6), 406-433. https://doi.org/10.1016/j.pneurobio.2005.04.003. · DOI
  81. Couroussé, T.; Bacq, A.; Belzung, C.; Guiard, B.; Balasse, L.; Louis, F.; Le Guisquet, A.-M.; Gardier, A. M.; Schinkel, A. H.; Giros, B.; Gautron, S. Brain Organic Cation Transporter 2 Controls Response and Vulnerability to Stress and GSK3β Signaling. Mol Psychiatry 2015, 20 (7), 889-900. https://doi.org/10.1038/mp.2014.86. · DOI
  82. Wei, D.; Maisonneuve, I. M.; Kuehne, M. E.; Glick, S. D. Acute Iboga Alkaloid Effects on Extracellular Serotonin (5-HT) Levels in Nucleus Accumbens and Striatum in Rats. Brain Res 1998, 800 (2), 260-268. https://doi.org/10.1016/s0006- 8993(98)00527-7. · DOI
  83. Bulling, S.; Schicker, K.; Zhang, Y.-W.; Steinkellner, T.; Stockner, T.; Gruber, C. W.; Boehm, S.; Freissmuth, M.; Rudnick, G.; Sitte, H. H.; Sandtner, W. The Mechanistic Basis for Noncompetitive Ibogaine Inhibition of Serotonin and Dopamine Transporters. J Biol Chem 2012, 287 (22), 18524-18534. https://doi.org/10.1074/jbc.M112.343681. · DOI
  84. Coleman, J. A.; Yang, D.; Zhao, Z.; Wen, P.-C.; Yoshioka, C.; Tajkhorshid, E.; Gouaux, E. Serotonin Transporter-Ibogaine Complexes Illuminate Mechanisms of Inhibition and Transport. Nature 2019, 569 (7754), 141-145. https://doi.org/10.1038/s41586-019-1135-1. · DOI
  85. El-Kasaby, A.; Koban, F.; Sitte, H. H.; Freissmuth, M.; Sucic, S. A Cytosolic Relay of Heat Shock Proteins HSP70-1A and HSP90β Monitors the Folding Trajectory of the Serotonin Transporter. J Biol Chem 2014, 289 (42), 28987-29000. https://doi.org/10.1074/jbc.M114.595090. · DOI
  86. Singh, I.; Seth, A.; Billesbølle, C. B.; Braz, J.; Rodriguiz, R. M.; Roy, K.; Bekele, B.; Craik, V.; Huang, X.-P.; Boytsov, D.; Pogorelov, V. M.; Lak, P.; O'Donnell, H.; Sandtner, W.; Irwin, J. J.; Roth, B. L.; Basbaum, A. I.; Wetsel, W. C.; Manglik, A.; Shoichet, B. K.; Rudnick, G. Structure-Based Discovery of Conformationally Selective Inhibitors of the Serotonin Transporter. Cell 2023, 186 (10), 2160- 2175.e17. https://doi.org/10.1016/j.cell.2023.04.010. · DOI
  87. Rudnick, G.; Krämer, R.; Blakely, R. D.; Murphy, D. L.; Verrey, F. The SLC6 Transporters: Perspectives on Structure, Functions, Regulation, and Models for Transporter Dysfunction. Pflugers Arch 2014, 466 (1), 25-42. https://doi.org/10.1007/s00424-013-1410-1. · DOI
  88. Zhang, Y.-W.; Turk, B. E.; Rudnick, G. Control of Serotonin Transporter Phosphorylation by Conformational State. Proc Natl Acad Sci U S A 2016, 113 (20), E2776-2783. https://doi.org/10.1073/pnas.1603282113. · DOI
  89. Courtiol, E.; Menezes, E. C.; Teixeira, C. M. Serotonergic Regulation of the Dopaminergic System: Implications for Reward-Related Functions. Neurosci Biobehav Rev 2021, 128, 282-293. https://doi.org/10.1016/j.neubiorev.2021.06.022. · DOI
  90. Peters, K. Z.; Cheer, J. F.; Tonini, R. Modulating the Neuromodulators: Dopamine, Serotonin, and the Endocannabinoid System. Trends Neurosci 2021, 44 (6), 464- 477. https://doi.org/10.1016/j.tins.2021.02.001. · DOI
  91. Dagher, M.; Perrotta, K. A.; Erwin, S. A.; Hachisuka, A.; Iyer, R.; Masmanidis, S. C.; Yang, H.; Andrews, A. M. Optogenetic Stimulation of Midbrain Dopamine Neurons Produces Striatal Serotonin Release. ACS Chem Neurosci 2022, 13 (7), 946-958. https://doi.org/10.1021/acschemneuro.1c00715. · DOI
  92. Maisonneuve, I. M.; Keller, R. W.; Glick, S. D. Interactions between Ibogaine, a Potential Anti-Addictive Agent, and Morphine: An in Vivo Microdialysis Study. Eur J Pharmacol 1991, 199 (1), 35-42. https://doi.org/10.1016/0014-2999(91)90634-3. · DOI · Paper page
  93. Chang, Q.; Hanania, T.; Mash, D. C.; Maillet, E. L. Noribogaine Reduces Nicotine Self-Administration in Rats. J Psychopharmacol 2015, 29 (6), 704-711. https://doi.org/10.1177/0269881115584461. · DOI
  94. Arias, H. R.; Targowska-Duda, K. M.; Feuerbach, D.; Jozwiak, K. Coronaridine Congeners Inhibit Human Α3β4 Nicotinic Acetylcholine Receptors by Interacting with Luminal and Non-Luminal Sites. The International Journal of Biochemistry & Cell Biology 2015, 65, 81-90. https://doi.org/10.1016/j.biocel.2015.05.015. · DOI
  95. Maisonneuve, I. M.; Glick, S. D. Anti-Addictive Actions of an Iboga Alkaloid Congener: A Novel Mechanism for a Novel Treatment. Pharmacol Biochem Behav 2003, 75 (3), 607-618. https://doi.org/10.1016/s0091-3057(03)00119-9. · DOI
  96. Williams, B. M.; Steed, N. D.; Woolley, J. T.; Moedl, A. A.; Nelson, C. A.; Jones, G. C.; Burris, M. D.; Arias, H. R.; Kim, O.-H.; Jang, E. Y.; Hone, A. J.; McIntosh, J. M.; Yorgason, J. T.; Steffensen, S. C. Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of Α6-Nicotinic Receptors and Dopamine Transporters. ACS Chem Neurosci 2024, 15 (9), 1738- 1754. https://doi.org/10.1021/acschemneuro.3c00478. · DOI
  97. Quinn, G. P.; Shore, P. A.; Brodie, B. B. Biochemical and Pharmacological Studies of RO 1-9569 (Tetrabenazine), a Nonindole Tranquilizing Agent with Reserpine-like Effects. J Pharmacol Exp Ther 1959, 127, 103-109.
  98. Pletscher, A. The Discovery of Antidepressants: A Winding Path. Experientia 1991, 47 (1), 4-8. https://doi.org/10.1007/BF02041242. · DOI
  99. Fernandez, J. W.; Fernandez, R. L. "Returning to the Path": The Use of Iboga[Ine] in an Equatorial African Ritual Context and the Binding of Time, Space, and Social Relationships. Alkaloids Chem Biol 2001, 56, 235-247. https://doi.org/10.1016/s0099-9598(01)56017-4. · DOI

Cited by

Sorted by citations

Authors
Hwu, C., Havel, V., Westergaard, X., Mendieta, A. M., Serrano, I. C., Hwu, J., Walther, D., Lankri, D., Selinger, T. L., He, K., Liu, R., Shern, T. P., Sun, S., Ma, B., González, B., Goodman, H. J., Sonders, M. S., Baumann, M. H., Carrera, I., Sulzer, D., & Sames, D.
Affiliations
  • Columbia University (US)
  • Columbia University Irving Medical Center (US)
  • National Institutes of Health (US)
  • Barnard College (US)
  • New York State Psychiatric Institute (US)
  • Universidad de la República de Uruguay (UY)
  • Department of Chemistry, Columbia University, New York, New York 10027, United States
ORCID
Venue
Journal of the American Chemical Society
Publisher
openRxiv
Published
2025-03-10
Volume
148
Issue
1
Pages
175-193
ISSN
0002-7863 (ISSN-L)
DOI
10.1101/2025.03.04.641351
OpenAlex
W7117317655
Cited by
7
References
0
Citations by year
2026: 7
FWCI
8.27
Type
journal article
Language
en
Open access
Licence
www.biorxiv.org/about/FAQ#license (vor)
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
Funders
  • G. Harold and Leila Y. Mathers Foundation (MF-2107-01880)
  • William H. Donner Foundation
  • National Institutes of Health (1s10od026749-01)
  • National Institute of Mental Health (R01MH108186)
  • National Institute on Drug Abuse (R01DA050613, R01 DA07418, R01DA007418)
  • NIH Office of the Director (S10OD026749)
  • Mailman School of Public Health, Columbia University
  • Freedom Together Foundation
  • Intramural Research Program (NIDA ZIADA00052-17)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
ibogaine, noribogaine, iboga alkaloids, vesicular monoamine transporter 2, serotonin transporter, organic cation transporter 2, serotonin release, synaptic vesicles, plasma membrane transporters, catalepsy, opioid use disorder, substance use disorders
MeSH terms
Animals, Humans, Ibogaine, Serotonin, Synapses, Serotonin Plasma Membrane Transport Proteins, Vesicular Monoamine Transport Proteins, Mice

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