This metabolite profiling study examined antiaddictive alkaloids from alternative plant sources and identified four structurally related iboga type alkaloids – coronaridine, ibogamine, voacangine, and ibogaine – as the predominant chemical feature of four Mexican Tabernaemontana species – T. alba, T. amygdalifolia, T. arborea, and T. donnell-smithii – and the African shrub Tabernanthe iboga.
Abstract
“Introduction: Ibogaine and other ibogan type alkaloids present anti-addictive effects against several drugs of abuse and occur in different species of the Apocynaceae family.
Methods: In this work, we used gas chromatography-mass spectrometry (GC/MS) and principal component analysis (PCA) in order to compare the alkaloid profiles of the root and stem barks of four Mexican Tabernaemontana species with the root bark of the entheogenic African shrub Tabernanthe iboga.
Results: PCA demonstrated that separation between species could be attributed to quantitative differences of the major alkaloids, coronaridine, ibogamine, voacangine, and ibogaine. While T. iboga mainly presented high concentrations of ibogaine, Tabernaemontana samples either showed a predominance of voacangine and ibogaine, or coronaridine and ibogamine, respectively.
Discussion: The results illustrate the phytochemical proximity between both genera and confirm previous suggestions that Mexican Tabernaemontana species are viable sources of anti-addictive compounds.”
Authors: Felix Krengel, Quentin Chevalier, Jonathan Dickinson, Josefina Herrera Santoyo & Ricardo R. Chilpa
Summary
Ibogaine and Addiction Treatment
Ibogaine is a monoterpenoid indole alkaloid (MIA) belonging to the ibogan type subclass that has been used as an aid to drug detoxification and alternative psychotherapy for decades. Ibogaine is restricted by legislation in several countries, but New Zealand, South Africa, and Sao Paolo, Brazil have policies that allow for its use. The majority of ibogaine treatment occurs outside of prescription programs, through private providers.
Tabernanthe iboga is a shrub endemic to Central African rainforests that is commonly known as iboga. It has a long history of cultural use as a ritual entheogen and medicine, but has been exposed to unregulated exploitation in order to meet the expanding demand for this substance from mostly western therapeutic communities.
Ibogaine has been found in a variety of species of the Apocynaceae family, particularly within the Tabernaemontana and Voacanga genera. The pantropical Tabernaemontana genus produces 11 classes of MIAs, including ibogaine. Tabernaemontana alba, Tabernaemontana amygdalifolia JACQ., Tabernaemontana arborea ROSE ex J.D.SM., and Tabernaemontana donnell-smithii ROSE ex J.D.SM. are known to produce ibogan type alkaloids as major compounds and thrive in disturbed areas associated with tropical
We have previously reported that Tabernaemontana alba and T. arborea are potentially viable sources of ibogaine and voacangine. The results of this study confirm the potential of the former as sources of anti-addictive ibogan type alkaloids and the phytochemical proximity between the five species.
Interspecific Comparison of the MIA Contents by PCA
The alkaloid profiles of T. alba root bark and T. alba stem bark were similar to those of T. arborea root bark and T. donnell-smithii bark, with T. arborea root bark being more similar to T. donnell-smithii bark.
The alkaloid profiles of root and stem bark from the same Tabernaemontana alba plant could be either similar or considerably different. Two outliers were identified in the scores plot: one T. amygdalifolia stem bark sample and one T. iboga root bark sample.
PCA separated samples into ibogamine, coronaridine, ibogaine, and voacangine, which are all structurally related to the ibogan type of MIAs. Ibogaine could either originate from the hydroxylation-methoxylation of ibogamine or the deesterification-decarboxylation of voacangine.
The transcriptomic study of Tabernaemontana iboga led to the discovery of two enzymes: ibogamine 10-hydroxylase (I10H) and noribogaine-10-O-methyltransferase (N10OMT). The outer root bark of T. amygdalifolia and T. arborea accumulated higher concentrations of non-esterified compounds than the inner root bark.
The CIVI-complex was found in all five species, reflecting the close relationship between the Tabernaemontana and Tabernanthe genera. The minor alkaloids could possibly serve as species-specific chemical markers, either on a whole-plant or organ-specific level.
Tabernaemontana alba and T. arborea can be used to produce ibogaine, with yields of between 0.95 % of voacangine and 0.22 % of ibogaine of root bark dry weight of T. alba and T. arborea, respectively, suggesting that yields could be substantially improved by selecting appropriate chemo- and genotypes. Tabernaemontana root bark contains more non-esterified MIAs than T. iboga root bark, and this could be used to make more precise comparisons with iboga products. T. amygdalifolia and T. donnell-smithii barks produced small amounts of ibogaine, but reasonable concentrations of voacangine. The first species presented considerable concentrations of ibogamine and coronaridine.
Quantification of Ibogaine in Tabernanthe iboga Root Bark
Two samples of T. iboga showed alkaloid profiles characteristic of the species, with ibogaine being by far the most abundant compound. One sample showed a 4-times higher value than the other, suggesting that the high alkaloid content in sample 15r is the result of sophisticated plant selection or specific local growing conditions. In any case, the results underline the difficulty of correct dosing when using iboga root bark, as it can have cardiotoxic effects, particularly in combination with risk factors involving preexisting cardiovascular diseases or adverse drug interactions.
There is a controversy concerning the degree to which fatalities are caused by the consumption of ‘false iboga’. The sample purchased on a local market in Cameroon (16r) probably contained other plant materials, including reserpiline, yohimbine, and ajmalicine (all corynanthean type).
Conclusions
Our research offers rare quantitative data on the MIA profiles of five Mexican Tabernaemontana species and the African shrub Tabernanthe iboga. This suggests that the five species are promising candidates for the production of antiaddictive alkaloids from alternative plant sources.
Plant Material
Root and stem bark samples of Tabernanthe iboga BAILL. were taken from young and mature plants in Veracruz, Mexico, and San Antonio Mulix, Yucatán, Mexico.
Analysis of Alkaloid Extracts by GC/MS
The extracts were dissolved in methanol and analyzed using an Agilent 7890B/5977A GC/MSD with a HP-5ms (30 m) capillary column following the method described by Krengel et al.[26]. The ibogaine and voacangine contents of the samples were calculated by the respective formula.
Acknowledgements
The authors would like to thank Rosamond Ione Coates Lutes, Delfino lvaro Campos Villanueva, Leonardo Osvaldo Alvarado Cárdenas, Marisol Reyes Lezama, Everardo Tapia Mendoza, and Mayra León Santiago for their support, as well as Bob Sisko and Phytostan Enterprises, Inc. for their donation. This work was supported by the UNAM Posgrado en Ciencias Biológicas, the CONACYT Beca Nacional para Estudios de Posgrado, and the Région Grand-Est under Grant number 1601023035.
Author Contribution Statement
F. K., Q. C., and R. R. C. collected the Tabernaemontana plant material, and F. K. and Q. C. conducted the GC/MS and statistical analyses.