Ibogaine

Endabuse40, 12-methoxyibogamine40

Ibogaine is a psychedelic tryptamine alkaloid first isolated in 1901 from the root bark of the Tabernanthe iboga shrub (also called iboga) of Central Africa,1 and the root bark of a shrub in the genus Tabernaemontana found in the Congo.2 Since that time, ibogaine has been isolated from several plant species particularly those in the family Apocynaceae to which T. iboga belongs.

Iboga plants have been used for centuries in the religious rituals of people living in the western part of Central Africa in countries such as the Republic of the Congo, Gabon, and Cameroon.3 The ceremonial cocktails contained a mixture of the naturally-occurring molecules found in the plant. Harrison G. Pope of the Harvard Botanical Museum theorized in 1969 that humans learned about the effects of iboga by watching the behavior of animals.4 First-hand accounts describe native animals like porcupines, boars, and gorillas digging up and eating iboga roots. After ingesting the roots, they would enter “a wild frenzy.” These indigenous people also use less potent versions of ibogaine cocktails to treat fatigue, hunger, and thirst.

In the 1930s, French pharmacists developed ibogaine as a pure drug, not a full plant extract, which was sold as a stimulant under the trade name Lambaréné.5 The drug was taken off the market in the 1960s when France declared ibogaine illegal.

The Chemistry of Ibogaine

Ibogaine was first isolated by Dybowski and Landrin in 1901.1 The crystalline structure of ibogaine was determined in 1960.6 It was first synthesized in 19667 and a simplified total synthesis was published in 2012.8 A detailed summary of ibogaine synthesis is found in Wasko et al., 2018.9 Ibogaine has two separate chiral centers and four stereoisomers but they are difficult to resolve.10

Ibogaine crystallizes into prismatic needles from ethanol.11 In addition to ethanol, it is soluble in ether, chloroform, acetone, and benzene. It is practically insoluble in water. The hydrochloride salt of ibogaine is soluble in water, as well as methanol and ethanol. It is slightly soluble in acetone and chloroform, but practically insoluble in ether.

The Pharmacology of Ibogaine

Ibogaine is cardiotoxic at micromolar levels.12–15 Specifically, studies have noted a prolongation of the heart’s QTc interval. Ibogaine has also been shown to be neurotoxic in rodents.16 At higher doses, the effects include tremors, convulsions, nervous behavior, and paralysis of the limbs.17 However, the doses used in these studies are below what would be used in a clinical setting.12

In terms of pharmacodynamics, ibogaine shows no clear preferences, having a moderate to weak affinity for a variety of receptors and transport proteins (see summary in Wasko et al. 2018). As a result, the hallucinogenic effects of ibogaine cannot be attributed to the activation of the serotonin 5-HT2A receptor (Ki = 16 µM).16 However, ibogaine’s principal metabolite noribogaine has sub-micromolar affinity (0.61 µM) as a partial agonist of the kappa opioid receptor.18 The mechanism of the dissociative effects caused by ibogaine may be similar to that of ketamine and other NMDA (N-methyl-D-aspartate) channel blockers.19,20

Ibogaine also binds in the low micromolar range to the mu opioid receptor, as does noribogaine in sub-micromolar range.21,22 This may explain the ability of ibogaine to decrease self-administration of morphine in rats.23,24

Studies indicate that ibogaine’s anti-opiate effects may be due to its noncompetitive antagonist action at nicotinic acetylcholine receptor subtypes including α1ß1 and α3ß4.25,26

The Applications and Potential of Ibogaine

Howard Lotsof was the first person to realize the potential of ibogaine to treat substance addictions.27 He was a heroin addict when he tried ibogaine in 1962 with several of his friends who were also addicts. They were surprised to find it caused marked reductions in their cravings and withdrawal symptoms. All of them quit using heroin as a result. Lotsof went on to become a scientist and dedicated his life to studying ibogaine for treating addiction.

In 1988, Dzoljic et al. were the first to publish on the ability of ibogaine to relieve withdrawal from narcotics addiction.28 Maisonneuve et al. elucidated the pharmacological interactions between ibogaine and morphine in 1991.24 After this, several other researchers showed ibogaine’s ability to reduce or interrupt the self-administration of opiates in rats and mice and alter their behaviors.23,29–32 Additional study results showed ibogaine was more effective in multiple administrations over time than from a single dose.23,29

Recent review papers and meta-analyses have concluded that ibogaine is effective for treating substance addiction and warrants further investigation.33–35 Several current studies have found ibogaine effective for treating opioid addiction.36–39

    References
  1. Dybowski J, Landrin E. PLANT CHEMISTRY. Concerning Iboga, its excitement-producing properties, its composition, and the new alkaloid it contains, ibogaine. CR Acad Sci. 1901;133:748. https://ibogainedossier.com/dybowski.html.
  2. Haller A, Heckel E. Sur l’ibogaine, principe actif d’une plante du genere Tabernaemontana, originarie du Congo. Comptes Rendus de l’Academie des Seances. 1901;133:850-853.
  3. Popik P, Layer RT, Skolnick P. 100 Years of Ibogaine: Neurochemical and Pharmacological Actions of a Putative Anti-Addictive Drug. Pharmacological Reviews. 1996;47(2):235-253. http://rabbit.if-pan.krakow.pl/~popikp/download/5397_popik_ibogaine_pharm_rev.pdf.
  4. Pope HG. Tabernanthe iboga: an African narcotic plant of social importance. Econ Bot. 1969;23(2):174-184. doi:10.1007/BF02860623
  5. Hay M. This Psychedelic Drug Targets Addiction and Depression. Vice Tonic. September 2017. https://tonic.vice.com/en_us/article/bjj9x4/this-psychedelic-drug-targets-addiction-and-depression. Accessed January 31, 2019.
  6. Arai G, Coppola J, Jeffrey GA. The structure of ibogaine. Acta Crystallographica. 1960;13(7):553-564. doi:10.1107/S0365110X60001369
  7. Bûchi G, Coffen DL, Kocsis K, Sonnet PE, Ziegler FE. The Total Synthesis of Iboga Alkaloids. Journal of the American Chemical Society. 1966;88(13):3099-3019. doi:10.1021/ja00965a039
  8. Jana GK, Sinha S. Total synthesis of ibogaine, epiibogaine and their analogues. Tetrahedron. 2012;68(35):7155-7165. doi:10.1016/j.tet.2012.06.027
  9. Wasko MJ, Witt-Enderby PA, Surratt CK. DARK Classics in Chemical Neuroscience: Ibogaine. ACS Chem Neurosci. 2018;9(10):2475-2483. doi:10.1021/acschemneuro.8b00294
  10. Shulgin A, Shulgin A. Psilocybin Mushrooms of the World. First Edition. Berkeley, California: Transform Press; 2002.
  11. Alper KR. Chapter 1 Ibogaine: A review. In: The Alkaloids: Chemistry and Biology. Vol 56. Academic Press; 2001:1-38. doi:10.1016/S0099-9598(01)56005-8
  12. Alper KR, Stajić M, Gill JR. Fatalities Temporally Associated with the Ingestion of Ibogaine. Journal of Forensic Sciences. 2012;57(2):398-412. doi:10.1111/j.1556-4029.2011.02008.x
  13. Koenig X, Hilber K. The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation. Molecules. 2015;20(2):2208-2228. doi:10.3390/molecules20022208
  14. Henstra M, Wong L, Chahbouni A, Swart N, Allaart C, Sombogaard F. Toxicokinetics of ibogaine and noribogaine in a patient with prolonged multiple cardiac arrhythmias after ingestion of internet purchased ibogaine. Clinical Toxicology. 2017;55(6):600-602. doi:10.1080/15563650.2017.1287372
  15. Vlaanderen L, Martial LC, Franssen EJF, Voort PHJ van der, Oosterwerff E, Somsen GA. Cardiac arrest after ibogaine ingestion. Clinical Toxicology. 2014;52(6):642-643. doi:10.3109/15563650.2014.927477
  16. Glick SD, Kuehne ME, Maisonneuve IM, Bandarage UK, Molinari HH. 18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine self-administration and on mesolimbic dopamine release in rats. Brain Research. 1996;719(1):29-35. doi:10.1016/0006-8993(96)00056-X
  17. Kubilienė A, Marksienė R, Kazlauskas S, Sadauskienė I, Ražukas A, Ivanov L. Acute toxicity of ibogaine and noribogaine. Medicina. 2008;44(12):984. doi:10.3390/medicina44120123
  18. Maillet EL, Milon N, Heghinian MD, et al. Noribogaine is a G-protein biased κ-opioid receptor agonist. Neuropharmacology. 2015;99:675-688. doi:10.1016/j.neuropharm.2015.08.032
  19. Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. British Journal of Pharmacology. 1983;79(2):565-575. doi:10.1111/j.1476-5381.1983.tb11031.x
  20. Mash DC, Staley JK, Pablo JP, Holohean AM, Hackman JC, Davidoff RA. Properties of ibogaine and its principal metabolite (12-hydroxyibogamine) at the MK-801 binding site of the NMDA receptor complex. Neuroscience Letters. 1995;192(1):53-56. doi:10.1016/0304-3940(95)11608-Y
  21. Glick SD, Maisonneuve IM. Development of Novel Medications for Drug Addiction: The Legacy of an African Shrub. Annals of the New York Academy of Sciences. 2000;909(1):88-103. doi:10.1111/j.1749-6632.2000.tb06677.x
  22. Glick SD, Maisonneuve IM, Szumlinski KK. 18-Methoxycoronaridine (18-MC) and Ibogaine: Comparison of Antiaddictive Efficacy, Toxicity, and Mechanisms of Action. Annals of the New York Academy of Sciences. 2000;914(1):369-386. doi:10.1111/j.1749-6632.2000.tb05211.x
  23. Glick SD, Rossman K, Steindorf S, Maisonneuve IM, Carlson JN. Effects and after effects of ibogaine on morphine self-administration in rats. European Journal of Pharmacology. 1991;195(3):341-345. doi:10.1016/0014-2999(91)90474-5
  24. Maisonneuve IM, Keller RW, Glick SD. Interactions between ibogaine, a potential anti-addictive agent, and morphine: an in vivo microdialysis study. European Journal of Pharmacology. 1991;199(1):35-42. doi:10.1016/0014-2999(91)90634-3
  25. Arias HR, Rosenberg A, Targowska-Duda KM, et al. Interaction of ibogaine with human α3β4-nicotinic acetylcholine receptors in different conformational states. The International Journal of Biochemistry & Cell Biology. 2010;42(9):1525-1535. doi:10.1016/j.biocel.2010.05.011
  26. Fryer JD, Lukas RJ. Noncompetitive Functional Inhibition at Diverse, Human Nicotinic Acetylcholine Receptor Subtypes by Bupropion, Phencyclidine, and Ibogaine. J Pharmacol Exp Ther. 1999;288(1):88-92. http://jpet.aspetjournals.org/content/288/1/88.
  27. Hevesi D. Howard Lotsof Dies at 66; Saw Drug Cure in a Plant. The New York Times. https://www.nytimes.com/2010/02/17/us/17lotsof.html. Published February 17, 2010.
  28. Dzoljic ED, Kaplan CD, Dzoljic MR. Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats. Arch Int Pharmacodyn Ther. 1988;294:64-70. http://europepmc.org/abstract/med/3233054.
  29. Cappendijk SLT, Dzoljic MR. Inhibitory effects of ibogaine on cocaine self-administration in rats. European Journal of Pharmacology. 1993;241(2):261-265. doi:10.1016/0014-2999(93)90212-Z
  30. Broderick P, Phelan F, Berger S. Ibogaine alters cocaine-induced biogenic amine and psychostimulant dysfunction but not [3H] GBR-12935 binding to the dopamine transporter protein. NIDA Research Monograph Series. 1992;119:285. https://www.researchgate.net/profile/Kenner_Rice/publication/21719706_The_cannabinoid_receptor-pharmacologic_identification_anatomical_localization_and_cloning/links/55229a4d0cf2a2d9e145857b.pdf#page=315.
  31. Broderick PA, Phelan FT, Eng F, Wechsler RT. Ibogaine modulates cocaine responses which are altered due to environmental habituation: In vivo microvoltammetric and behavioral studies. Pharmacology Biochemistry and Behavior. 1994;49(3):711-728. doi:10.1016/0091-3057(94)90092-2
  32. Sershen H, Hashim A, Lajtha A. Ibogaine reduces preference for cocaine consumption in C57BL/6By mice. Pharmacology Biochemistry and Behavior. 1994;47(1):13-19. doi:10.1016/0091-3057(94)90105-8
  33. Schenberg EE, de Castro Comis MA, Chaves BR, da Silveira DX. Treating drug dependence with the aid of ibogaine: A retrospective study. J Psychopharmacol. 2014;28(11):993-1000. doi:10.1177/0269881114552713
  34. Winkelman M. Psychedelics as Medicines for Substance Abuse Rehabilitation: Evaluating Treatments with LSD, Peyote, Ibogaine and Ayahuasca. Current Drug Abuse Reviews. 2014;7(2):101-116. PMID:25563446.
  35. Belgers M, Leenaars M, Homberg JR, Ritskes-Hoitinga M, Schellekens AFA, Hooijmans CR. Ibogaine and addiction in the animal model, a systematic review and meta-analysis. Translational Psychiatry. 2016;6(5):e826. doi:10.1038/tp.2016.71
  36. Noller GE, Frampton CM, Yazar-Klosinski B. Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study. The American Journal of Drug and Alcohol Abuse. 2018;44(1):37-46. doi:10.1080/00952990.2017.1310218
  37. Mash DC, 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. doi:10.3389/fphar.2018.00529
  38. Brown TK, Alper K. Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes. The American Journal of Drug and Alcohol Abuse. 2018;44(1):24-36. doi:10.1080/00952990.2017.1320802
  39. Davis AK, Barsuglia JP, Windham-Herman A-M, Lynch M, Polanco M. Subjective effectiveness of ibogaine treatment for problematic opioid consumption: Short- and long-term outcomes and current psychological functioning. Journal of Psychedelic Studies. 2017;1(2):65-73. doi:10.1556/2054.01.2017.009
  40. PubChem. 12-Methoxyibogamine. https://pubchem.ncbi.nlm.nih.gov/compound/197060.