Iboga alkaloids are a class of natural organic substances that have inspired chemists since the early 1900s. They owe their name to the Tabernanthe iboga, from which ibogaine, the main representative of the alkaloids contained in this plant, was first isolated. T. iboga is a 0.9 to 1.5 meters-height shrub belonging to the family of Apocynaceae. It grows in Central Africa, in the Congo basin. [1] The definition of “iboga alkaloids” has different levels, the first one refers to the above-mentioned botanical origin, and the second level refers to those psychoactive compounds that are used in Central African spiritual rituals. Finally, the third level refers to a common chemical structure, composed of an indole nucleus and an isoquinuclidine system. [2]
Even though there are around 100 compounds belonging to the iboga alkaloid class, ibogaine is by far the most studied and widely commercialized one. Its medical history in the Western world began in the early 1900s, when the substance was used to treat asthenia and as a neuromuscular stimulant, and nowadays ibogaine’s success is due to its high potential as an anti-addictive drug. [1]
Among the iboga alkaloids contained in T. iboga there are:
- Ibogaine
- Tabernanthine
- Voacangine
- Isovoacangine
- Coronaridine,
- Ibogaline
- Ibogamine
- Noribogaine
- Conophararyngine
Ibogaine’s power has been known and mastered since long before the Western discovery of this plant. Indeed, T. iboga is considered a sacred plant in the Bwiti religion, due to its entheogenic properties which play a central role in the associated rituals and philosophy. Furthermore, this plant acquired political relevance against the French occupation. [3]
Tribal and Spiritual Use
Iboga’s root bark has been used by the Central African native population against psychological and physical fatigue since ancient times. However, the discovery of this plant’s hallucinogenic power might not have been human. Indeed, several accounts by natives report the observation of boars, gorillas, and porcupines digging up T. iboga’s roots and eating them, only to go into a wild frenzy, jumping around and perhaps fleeing from frightening visions. [1]
According to the Bwiti tradition, Pygmies – an ethnic group native to the jungle of the Congo basin – have been the first ones to discover the psychoactive activity of T. iboga. Afterward, this substance was incorporated into the Bwiti’s cult, which spread out from Gabon to all the surrounding territories. Bwitists communities are small sects composed of 40-50 members, which makes the whole religion very heterogeneous and different from sect to sect. A common element within communities is precisely iboga, which is used both in normal celebrations and in initiations. [4]
Furthermore, the high importance of this plant to Bwitists is a cause of profound distance between them and other Christians in the area, particularly Catholic missionaries. Indeed, since the arrival of European settlers in the area, local people have been the object of a Christian conversion attempt that reached a peak of cruel persecution during French colonialism in the years from 1920 to 1940. [3], [4]
As a consequence, Bwiti’s cult has been deeply contaminated by Christianism and some Bwitists even consider themselves Christians. However, the consumption of iboga remained a factor of both resistance against Western occupation and preservation of identity. [3] The difference between Christians and Bwitists has been very clearly explained by Nengue Me Ndjoung Isidore, a Bwitist religious leader, who affirmed:
“The Catholic church is a beautiful theory for Sunday, the iboga on the contrary is the practice of everyday living. In church, they speak of God, with iboga, you live god”. [4]
As previously mentioned, iboga is used during initiations to the Bwiti’s cult. Here, the initiates assume a few hectograms of the powdered root over 12 hours. The ritual lasts 72 hours and the climax of the experience of contact with the sacred is reached on the third night.[4]
Another interesting fact is that natives prize iboga as an aphrodisiac even more highly valued than yohimbine, a constituent of Corinanthe yohimbe, probably the most famous African “aphrodisiac”. [1]
Importance in the Western World
The Western history of ibogaine and the other iboga alkaloids begins in 1864, when the French navy’s surgeon brought back from Gabon some specimens of T. iboga, having heard of its aphrodisiac power during his explorations. In 1901 Ibogaine was isolated and crystallized from T. iboga root bark. This substance quickly becomes popular in the treatment of “asthenia” and depression, both in Europe and the United States. However, at the beginning of the ’60s, the first study on 19 individuals was published regarding ibogaine’s effect on acute opioid withdrawal.
At the end of the same decade, in a global panorama of fight against hallucinogens, the World Health Assembly classifies ibogaine with hallucinogens and stimulants as “a substance likely to cause dependency or endanger human health” and the drug is banned from both American and European market. This decision caused a setback to research on ibogaine, but preclinical studies continued to be carried on, and, even though the substance is illegal in numerous states, some private clinics administer doses of iboga as an experimental drug to treat addiction. [5]
Regarding its production, ibogaine was first extracted from T. iboga but the first procedures to extract this compound – based on alcohol or haloalkanes extraction followed by chromatography – were very difficult and expensive and the main struggle was to identify ibogaine in the total alkaloids extract, which are at least 48 in T. iboga. Another way to obtain ibogaine with a much better purity degree, it’s to extract the total alkaloids with an acidic solution followed by alkaline treatment, hydrochlorination, and finally dissolution and recrystallization with ethanol. [6]
It should be noticed that extracting ibogaine from T. iboga presents some ethical and environmental issues. First, T. iboga is sacred to the Bwiti cult, and its cultivation and harvesting should serve only religious and spiritual functions. [7] Secondly, ibogaine only accounts for 0.3% of the root bark weight of T. iboga, which is too little considering that the plant has to be completely eradicated to extract ibogaine. In contrast, other plants have been found to contain iboga alkaloids that can be used as precursors for ibogaine’s semisynthesis. The most popular one is Voacanga Africana, whose roots contain ~1.7% of voacangine. This compound can be extracted easily and efficiently with methanol and ibogaine can be obtained with a two-step reaction.[7], [8]
Activity on the Central Nervous System
Ibogaine’s chemical effect on the nervous system is very complex since this molecule interacts with several neurotransmitter systems and receptors.
This intricate interaction probably contributes to iboga’s remarkable psychoactive properties and can explain some of its paradoxical effects on the nervous system. [2], [9]
All iboga alkaloids have similar activity on the nervous system but, as already mentioned, ibogaine stood up for its anti-addictive properties. Once again, this activity might result from a synergistic effect on several receptors:
- First of all, ibogaine shows light agonist activity on µ- and κ-opioid receptors, which results, as some works state, in the reduction of cocaine and morphine self-administration in mice and rats.[5], [9]
- There is evidence of ibogaine acting as an antagonist on the N-methyl-D-aspartate receptor (NMDA) receptor.
- This class of molecules induces a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia.
- Another activity that might affect both the hallucinatory process and anti-addictive activity is the interaction with the serotonergic system. Indeed, ibogaine binds to serotonin transporters causing altered serotonin neurotransmission. In particular, it inhibits the uptake of serotonin, resulting in an anti-depressant effect. [5], [9]
- Ibogaine lowers the concentration of dopamine but increases its metabolites concentration and, finally, it binds with high affinity to sigma 2 receptors, which might be linked to the occurrence of tremors after ibogaine assumption, which is one of the drug’s adverse effects.
18-methoxycoronaridine (18-MC) is an ibogaine synthetic equivalent that was found to be a good equivalent to the latter for its anti-addictive activity but without tremorigenic side effects.[5], [10] However, 18-MC presents the same adverse effects of ibogaine on heart rate, since both substances modulate cardiac ion channels. They prolong the QT interval, inducing bradycardia. Between 1990 and 2008, 19 fatalities were associated with ibogaine assumption: six were attributed to acute heart failure or cardiopulmonary arrest. However, the majority of the subjects presented pre-existing pathologies or were found to have other opioids in circulation. [10]
Ibogaine presents a half-life of 2-4 hours and its primary metabolite called noribogaine not only presents anti-addictive properties as well but has a much longer half-life, accounting for 24-49 hours.[9] Therefore many biological effects might have been mistakenly attributed to ibogaine instead of noribogaine. [10] Furthermore, the latter compound, as long as another iboga alkaloid called ibogamine, possesses acetylcholinesterase inhibitory activity, which might be promising for the treatment of Alzheimer’s. [9]
Ibogaine shows great potential for the treatment of addiction, but its side effects might represent a strong hurdle to such an application. However, since ibogaine toxicity is strongly dose-dependent, microdosing could be a good solution to avoid side effects while maintaining beneficial ones. Furthermore, the many and diverse iboga alkaloids present similar structures and biological activity and certainly deserve further studies to unlock intriguing alternatives to ibogaine with potentially reduced toxic effects. [9]
Bibliography
[1] H. G. Pope, “Tabernanthe iboga: an African Narcotic Plant of Social Importance.”, Econ. Bot., vol. 23, no. 2, pp 174-184, 1969.
[2] C. Lavaud and G. Massiot, “The Iboga Alkaloids,” Prog Chem Org Nat Prod, 2017. doi: 10.1007/978-3-319-49712-9_2.
[3] M. Kohek, M. Ohren, P. Hornby, M. Á. Alcázar-Córcoles, and J. C. Bouso, “The Ibogaine Experience: A Qualitative Study on the Acute Subjective Effects of Ibogaine,” Anthropol Conscious, vol. 31, no. 1, pp. 91–119, 2020, doi: 10.1111/anoc.12119.
[4] “Samorini/buiti.” Accessed: Sep. 13, 2024. [Online]. Available: https://www.samorini.it/doc1/sam/bui_int.htm
[5] K. R. Alper, “Ibogaine: A Review, Alkaloid”, Chem Biol, vol 56, pp 51-69, 2001.
[6] C. W. Jenks, “Extraction studies of Tabernanthe iboga and Voacanga africana,” Nat Prod Lett, vol. 16, no. 1, pp. 71–76, 2002, doi: 10.1080/1057563029001/4881.
[7] R. N. Iyer, D. Favela, G. Zhang, and D. E. Olson, “The iboga enigma: The chemistry and neuropharmacology of iboga alkaloids and related analogs,” Nat Prod Rep, vol. 38, pp. 307-329, 2021, doi: 10.1039/d0np00033g.
[8] F. Krengel, M. V. Mijangos, M. Reyes-Lezama, and R. Reyes-Chilpa, “Extraction and Conversion Studies of the Antiaddictive Alkaloids Coronaridine, Ibogamine, Voacangine, and Ibogaine from Two Mexican Tabernaemontana Species (Apocynaceae),” Chem Biodivers, vol. 16, no. 7, 2019, doi: 10.1002/cbdv.201900175.
[9] B. M. M. Michele and A. A. Sophie, “A review of the mechanisms involved in the neuroprotection and neurotoxicity of Iboga alkaloids,” Pharmacological Research – Natural Products, vol. 1, 2023, doi: 10.1016/j.prenap.2023.100006.
[10] X. Koenig and K. Hilber, “The anti-addiction drug ibogaine and the heart: A delicate relation,” Molecules, vol. 20, 2015, doi: 10.3390/molecules20022208.
