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=The Extraction of Ibogaine= Tyler Butler CHEM 367 Fall 2009

Introduction
Ibogaine is an indole alkoloid found in the African shrub //Tabernanthe iboga//, as well as many other related plants. It and is known for its hallucinogenic and anti-addictive properties. Ibogaine shows much promise to be able to treat and cure addiction to heroin, alcohol, cocaine, methamphetamines, opioids, and nicotine, but a commercially significant method of synthesis has not yet been developed. To continue to analyze new plant species and their indole alkoloid content may prove to create an effective and economical way of curing people suffering from addiction all over the world.

Dybowsky and Landrin - 1901
Ibogaine was first extracted from the African shrub //Tabernanthe iboga// by the Frenchmen J. Dybowsky and E. Landrin and reported in their 1901 paper entitled “Plant Chemistry. //Concerning// Iboga, //its excitement-producing properties, its composition, and the new alkaloid it contains,// ibogaine.” They learned of iboga from the natives and extracted the new alkaloid ibogaine from the roots of the //Tabernanthe iboga//. Their turn-of-the-century procedure for extracting ibogaine was as follows: The root was finely powdered and milk of lime was added. The root powder was then allowed to dry and then stirred with ether. The ether was then stirred with aqueous sulfuric acid several times. The acidic aqueous layers were combined and caustic soda added in order to precipitate the crude alkaloids. The alkaloids were then purified in alcohol. Dybonsky and Landrin were able to obtain 6-10 g/kg of ibogaine from the //Tabernanthe iboga// root. The ibogaine that they isolated was very pure, with clear-cut several millimeter long amber crystals formed. This ibogaine melted at 152 °C and tasted a little like cocaine.

Dybowski, J. and Ed. Landrin. “Plant Chemistry. //Concerning// Iboga, //its excitement-producing properties, its composition, and the new alkaloid it contains,// ibogaine.” __C.R. Acad. Sci.__, 133:748 (1901). Translation from the French by William J. Gladstone (2005). [].

CW Jenks – 2002
A simple and affordable means of extracting ibogaine from the root of //Tabernanthe// //iboga// was developed by CW Jenks as a means to make available ibogaine in developing countries. This method uses only vinegar and ammonia, as opposed to the alkyl halides so often used in the organic extraction of the indole alkaloids. Jenks’ experiment was as follows: 1 kg of powdered //T. iboga// root was placed in a bucket with 5 L of 0.5% acetic acid for one hour with occasional stirring. The extract was then filtered through a cloth sack and wrung out. 60 mL of 30% ammonia was added to the filtrate to basify it. The solution was then gravity filtered through filter paper and rinsed with distilled water a few times. The residue on the filter paper was allowed to dry for several days. 30.037 g of hard, brown solid was then ground into a fine powder. 28 g of this powder was then placed upon filter paper and gently stirred with 450 mL of acetone. 2 mL of concentrated HCl was added dropwise until mixture was acidic. 0.4 mL of HCl was then added dropwise and the solution was refrigerated overnight. Yellow powder formed overnight, which was rinsed with 84 mL of acetone and dried. 9.712 of the alkaloid HCl was dissolved into 150 mL of boiling 95% ethanol, left overnight at room temperature and refrigerated for two hours. The yellow crystals were recrystallized from 95% ethanol and yielded 3.666 g of nearly pure ibogaine HCl.

Jenks CW. “Extraction studies of //Tabernanthe iboga// and //Voacanga africana//.” __Nat. Prod. Lett.__, 16.1 (2002): 71-76. [].

Other Plants
Plants from all over the world contain Ibogaine and iboga alkaloids. Some have been discovered and may be found in the literature, but the number of plants known to contain iboga alkaloids is likely a small fraction of the actual total number of ibogaine-containing plant species on Earth. Here are presented several successful extractions of ibogaine from a range of different genus of plants. These plants and the people who have used them for their biologically active properties of the alkaloids they contain span most of the planet's geography.

//Ervatamia hirta//
33 alkaloids have been isolated from this tree from Malaysia, including ibogaine. Historically, the //Ervatamia hirta// has been used for making poisoned arrows and to treat nose ulcers. Present day, French scientists research the alkaloid content of this 5-7 meter tall tree. It has been determined that ibogaine composes 2.17% of the tree’s root bark crude alkaloid mixture. To isolate the alkaloids of the //Ervatamia hirta//, its leaves were harvested, dried and powdered. 0.6 kg of powdered leaves were moistened with 50% NH4OH and extracted overnight in ethyl acetate. 2% sulfuric acid was used to extract the organic layer, and the aqueous layer was then made basic with NH4OH. The basic layer was the extracted with chloroform, and the chloroform was evaporated off, leaving 8.1 g of crude alkaloid mixture behind. The same procedure was performed with root bark, which yielded 37.5 g of crude alkaloid mixture. The crude alkaloid mixtures were then purified on silica gel with chloroform. Elution with chloroform, varying ratios of decreasing chloroform/methanol solution, and methanol in turn isolated the different alkaloids. Ibogaine was isolated and identified be its characteristic spectra.

Clivio, Pascale, Bernard Richard, Jean-Robert Deverre, Thierry Sevenet, Monique Zeches and Louisette Le Men-Oliver. “Alkaloids from the leaves and root bark of //Ervatamia hirta//.” __Phytochemistry__, 30.11 (1991): 3785-3792. [|http://dx.doi.org/10.1016/0031-9422(91)80111-D].

//Ervatamia orientalis//
This shrub may be found anywhere from northern Australia, to New Guinea, Malaysia, South East Asia to Polynesia. It may grow 10-15 high and has white flowers. Australian chemists have isolated the indole alkaloids from this shrub and determined there is ibogaine in the leaves. Crude alkaloids were extracted from the dried leaves of the shrub with a buffer solution at pH 5.4. An ibogaine-containing fraction was chromatographed with a column of alumina and eluted with a 4:1 solution of benzene/light petroleum. 1.8 g of an oily fraction formed, which was crystallized from methanol. Thick needles of ibogaine were formed and confirmed by an IR spectrum.

Knox, John R. and Jacob Slobbe. “Indole alkaloids from //Ervatamia orientalis//. I. Isolation of alkaloids and structural identification of two dimmers.” __Australian Journal of Chemistry__, 28.8 (1975): 1813-1823. [].

//Ervatamia yunnanensis//
Ibogaine has been isolated from the stems of the //Ervatamia yunnanensis// Tsiang plant, which is native to the Yunnan and Guangxi provinces of China. The stems have traditionally been used to treat stomachaches, dysentery, snakebites, rheumatic arthritis, hypertension and virus hepatitis. Chemists at the Second Military Medical University in Shanghai, China determined the indole alkaloid composition of these stems and first discovered that the plant contains ibogaine in 1987. In 2009, the extraction was repeated, this time using 5 kg of //Ervatamia yunnanensis// stems that were collected, air-dried and powdered. The powdered stems were then extracted with 95% ethanol by reflux. 400 g of an ethanol extract was obtained from the percolate via vacuum. The ethanol extract was placed into 2 L of water and acidified with a 2% HCl aqueous solution to pH 3-4. The acidic mixture was then centrifuged into two separate layers. The upper layer underwent column chromatography with an ethanol/water gradient solvent system, yielding three fractions: 30%, 60%, and 90% ethanol eluates. The 90% ethanol eluate was divided into six fractions by a silica gel CC elution with a CHCl­3-MeOH gradient. The third fraction was rechromatographed upon silica gel with a 30:1 CHCl­3/CH3OH elution. This fraction was then purified with a Sephadex LH-20. From this fraction were obtained 55 mg of ibogaine as a white amorphous powder and 56 mg of voacangine hydroxyindolenine as a white powder. Also detected in the 2009 extraction was a new indole alkaloid, ervataine, C20H24N2O, as a white amorphous powder.

Jin, Yong-Sheng, Jing-Ling Du, Hai-Sheng Chen, Li Jin and Shuang Liang. “A new indole alkaloid from //Ervatamia yunnanensis//.” __Fitoterapia__ 81.1 (2010): 63-65. [].

Luo, Xin Gen, Hai Sheng Chen, Shuang Liang, Mao Huang, Wei Dong Xuan and Li Jin. “Alkaloids from stems of //Ervatamia yunnanensis//.” __Chinese Chemical Letters__, 18.6 (2007): 697-699. [].

Gui, Liu; Xin, Liu and Xiao-zhang, Feng. "Ervayunine: A new indole alkaloid from Ervatamia yunnanensis.", Planta Medica, (1988), 54(6), 519-521. http://www.puzzlepiece.org/ibogaine/literature/gui1988.pdf.

//Peschiera lundii//
The Brazilian species //Peschiera lundii// (D.C.) Miers belongs to the //Peschiera// genus, which bears a close relation to the genus //Tabernaemontana//, which is known for its store of indole alkaloids, including ibogaine. In the 1960s, American chemists determined that //Peschiera lundii// contains ibogaine as well. 16 kg of the plants leaves, stems and bark were extracted with alcohol and this extract was in turn extracted by 2% tartaric acid solution. This extract was washed three times with 2/1 portions of diethyl ether. Dilute hydrochloric acid was used to extract the ether layer and was combined with the tartaric acid extract. The aqueous layer was made pH 8-9 by the addition of ammonia and was then extracted with chloroform. The chloroform was evaporated off and the remaining alkaloids were dissolved into 0.2 M H3PO4 and extracted with ether. 55 g of the aqueous solution was extracted with a 1-week ether extract. This fraction was washed with a buffer of pH 4.5-5.5 and was concentrated and chromatographed with alumina. Ammonia was added to make the buffer basic. This solution was the extracted with chloroform and was concentrated. 400 mg of ibogaine was revealed via chromatography over Florisil with chloroform elution.

Hwang, Bruce, Jerry A. Weisbach, Bryce Douglas, Robert F. Raffauf, Michael P. Cava and Kiyoshi Bessho. “Problems in chemotaxonomy. V. Alkaloids of //Peschiera lundii//. Isolation and structure elucidation of voacristine pseudoindoxyl and iboxygaine hydroxyindolenine.” __The Journal of Organic Chemistry__, 34.2 (1969): 412-415. [].

//Tabernaemontana australis//
The plant //Tabernaemontana australis// (Müell. Arg) Miers (sin. Peschiera australis) is plentiful throughout Brazil, Argentina, Uruguay and Paraguay, and is also a source of indole alkaloids such as ibogaine and voacangine. Brazilian chemists harvested //T. australis// and dried 631 g of the plant’s stalk at 80 °C for seven days. The dried stalks were then ground up and extracted with ethanol, yielding 53 g of a brown residue. The extract was added to 300 mL of 5% HCl solution and extracted four times with 80 mL of methanol. NH4OH was added until the solution reached a pH of 9, and the solution was again extracted four times, this time with 100 mL of CHCl3. The solution was dried with anhydrous sodium sulfate and 2.6 g of a chloroform extract was obtained via vacuum. Silica gel open column chromatography was performed upon 1.5 g of the chloroform extract in a cyclohexanol/ethyl acetate/methanol gradient elution, yielding nine fractions. 29 mg of pure voacangine was identified via silica gel column chromatography with a cyclohexane/ethyl acetate gradient upon fraction two. Ibogaine was obtained in mixture form via silica gel column chromatography upon the other fractions.

Andrade, Marcelo T., Josélia A. Lima, Angelo C. Pinto, Claudia M. Rezende, Meriane P. Carvalho and Rosângela A. Epifanio. “Indole alkaloids from //Tabernaemontana australis// (Müell. Arg) Miers that inhibit acetylcholinesterase enzyme.” __Bioorg. Med. Chem.__, 13.12 (2005): 4092-4095. [].

//Tabernaemontana bovina//
Vietnamese and German chemists have determined the indole alkaloid makeup of the //Tabernaemontana bovina// (Apocynaceae) bush which grows in Cochinchina. The leaves and stems of the approximately one meter high bush contain an ibogaine yield of 0.0017%. The scientists dried 3 kg of //T. Bovina// leaves and stems at room temperature. The plant matter was ground and extracted with 95% methanol. The methanol was evaporated off in a vacuum. The aqueous solution was extracted with //n//-hexane and the //n//-hexane was evaporated off in a vacuum. The solution was then extracted by ethyl acetate and //n//-butanol in turn, and each of these solvents was evaporated off in the same manner. The ethyl acetate and butanol residues were combined and partitioned between 0.2 M HCl and a 1:1 solution of toluene/ethyl ether. KHCO3 was added and the aqueous layer was extracted with a 2:1 solution of chloroform/ethanol. The solvents were evaporated in a vacuum and a mixture of alkaloids was left behind. The alkaloids were chromatographed with silica gel and a 4:1 solution of ethyl acetate///n//-hexane. They were then chromatographed once more with ethyl acetate and increasing amounts of methanol in order to isolate the ibogaine.

Lien, Trinh Phuong, Helmut Ripperger, Andrea Porzel, Kurt Merzweiler, Tran Van Sung and Günter Adam. “Indole alkaloids from //tabernaemontana bovina//.” __Phytochemistry__, 49.5 (1998): 1457-1461. [|http://dx.doi.org/10.1016/S0031-9422(98)00127-7].

//Tabernaemontana citrifolia//
The Caribbean island of Guadeloupe is rich in tropical flora, including the ibogaine-containing species //Tabernaemontana citrifolia//. Scientists from Guadeloupe have obtained ibogaine and voacangine from //T. citrifolia// plant material and have found these indole alkaloids to show antimycobacterial activity when tested against //Mycobacterium tuberculosis//, //M. avium//, and //M. kansasii//.

Rastogi, Nalin, Jacqueline Abaul, Khye Seng Goh; Anne Devallois, Emile Philogene and Paul Bourgeois. “Antimycobacterial activity of chemically defined natural substances from the Caribbean flora in Guadeloupe.” __FEMS Immunology and Medical Microbiology__, 20.4 (1998): 267-273. [].

//Tabernaemontana crassa//
Ibogaine had not been known to be contained in the tropical African species //Tabernaemontana crassa// Benth. (Apocynaceae) until 1985 when scientists from the Netherlands determined that the alkaloid ibogaine was the major component of the plant’s stembark, though the plant had long been used as a medicine. 800 g of the stem bark was ground and then extracted with 96% ethanol for 15 hours under a pressure of 0.2 atm. The extract was cooled to –16 °C and a precipitate of steroids and triterpenes formed and was removed from the solution. The solution was then evaporated to dryness, yielding 10 g of residue. 5 g of this residue was partitioned between chloroform and 2% acetic acid. The aqueous layer was removed and NH4OH was added to it in order to increase the pH of the solution to 10. The solution was twice extracted with chloroform, and this organic layer was dried with sodium sulfate and evaporated with a vacuum to give 0.97 g of tertiary alkaloids. 100 mg of the tertiary alkaloid mixture was separated with TLC, yielding 12 mg of ibogaine as the major amorphous product which was identified with UV, MS and H-NMR spectra.

Van Beek, T.A., C. De Smidt and R. Verpoorte. “Phytochemical investigation of //Tabernaemontana crassa//.” __J. Ethnopharmacol.__, 14.2-3 (1985): 315-318. [|http://dx.doi.org/10.1016/0378-8741(85)90096-0].

//Tabernaemontana divaricata//
Scientists in Malaysia have extracted 23 alkaloids from the leaves of the //Tabernaemontana divaricata// (double flower variety), including ibogaine. The leaves of the tree were ground and extracted with ethanol. The ethanol extract was then extracted with dilute acid. Initial column chromatography on silica gel with chloroform and varying amounts of methanol was used in order to isolate the alkaloids. Centrifugal TLC was also used to further isolate certain fractions. The total yield of ibogaine in this extraction was 0.002 g/kg.

Kam, Toh-Seok, Huey-Shen Pang and Tuck-Meng Lim. “Biologically active indole and bisindole alkaloids from //Tabernaemontana divaricata//.” __Org. Biomol. Chem.__, 1 (2003): 1292-1297. [].

//Tabernaemontana markgrafiana//
This tree grows in South America and has traditionally been used for as many purposes as a disinfectant, a contraceptive, to treat toothaches, a fungicide and to treat insect bites by different groups of people throughout time. Scientists have isolated the indole alkaloids and terpenoids from the //Tabernaemontana markgrafiana//, and among the alkaloids of this tree may be found ibogaine. Over 90% of the alkaloids extracted from the bark were iboga alkaloids. About 4-5% of the alkaloid content of the bark has been determined to be ibogaine. Extraction of the dried and ground bark with dichloromethane and methanol extracted the ibogaine. The alkaloids were separated by extracting with 1% hydrochloric acid. The solution was made basic with the addition of sodium bicarbonate. The alkaloids in the dichloromethane extract were separated on via chromatography upon a silica gel column with petrol/dichloromethane and dichloromethane/methanol mixtures. 219 mg of ibogaine was obtained in this way.

Nielsen, Helene B., Alan Hazell, Rita Hazell, Felipe Ghia and Kurt B. G. Torssell. “Indole alkaloids and terpenoids from //Tabernaemontana markgrafiana//.” __Phytochemistry__, 37.6 (1994): 1729-1735. [|http://dx.doi.org/10.1016/S0031-9422(00)89601-6].

//Tabernaemontana wallichiana//
//Tabernaemontana wallichiana// Steud (Apocynaceae) may not naturally contain any ibogaine, but it contains the iboga alkaloid voacangine, which may be used to synthesize ibogaine, as chemists from the University College of Science in Calcutta have shown. 0.8 kg of stem bark from the plant was dried and powdered. Light petrol was used to extract it, followed by chloroform then ethanol. The light petrol residue contained the voacangine, and was chromatographed over alumina. Voacangine was crystallized from methanol. In order to convert the voacangine to ibogaine, 0.13 g of voacangine was placed in 20 mL 60% ethanol with 1.2 g potassium hydride and refluxed on a steam bath for 6 hours. The ethanol was then evaporated off. The residue was dissolved in 35 mL HCl and steam bathed for 1 hour. Ammonium hydroxide was added to the solution until basic. The solution was then extracted with ether. Ibogaine, in the form of colorless needles, was then isolated via chromatography over alumina.

Talapatra, S. K., S. Sen Gupta, M. Bhattacharya and B. Talapatra. "Alkaloids of //Tabernaemontana wallichiana//." __Indian Journal of Chemistry, Section B: Organic Chemistry, Including Medicinal Chemistry__, 14B.5 (1976): 385-387. [].

//Trachelospermum jasminoides//
//Trachelospermum jasminoides//, or more commonly known as “star jasmine”, is originally native to China, but is popular in the American south. The leaves and stems of this common plant contain ibogaine. 50 kg of dried leaves and stems were extracted with ethanol. The ethanol extract was concentrated and then partitioned between 10% HCl and chloroform. Anhydrous sodium sulfate was used in order to dry the chloroform extract, and this layer was concentrated into a paste-like phase. Aqueous ammonia was added to the aqueous layer to basify it. Then chloroform at different pH values was used to extract the aqueous layer. At pH 5, the chloroform extracted the ibogaine. The 20 g of alkaloid fraction was chromatographed upon a silica column and eluded with mixtures of petroleum ether, chloroform, ethyl acetate and methanol. From elution with a 3:1 solution of chloroform/ethyl acetate, a fraction containing four alkaloids was obtained. Flash chromatography using varying amounts of petroleum ether in acetone separated the four alkaloids, though ibogaine was still mixed with tabernaemontanine. Ibogaine was isolated by TLC on silica gel with a 6:3.95:0.05 petroleum ether/acetone/ammonia solution. The Ibogaine was positively identified by its spectra.

Fatima, T., S. Ijaz, G. Crank, S. Wasti. “Indole Alkaloids from //Trachelospermum jasminoides//.” __Planta Medica__, 53.1 (1987): 57-59. [].

Paghat the Ratgirl. “Star Jasmine.” []. 12-5-2009.

//Voacanga schweinfurthii//
Samples of ground seeds, stem bark and ground root bark of the //Voacanga schweinfurthii// Stapf var. //puberula// Pichon were obtained from Zaire, and the alkaloids extracted by French chemists. Ibogaine was found in the ground root bark with a yield of 0.2 g/kg. 300 g of the ground root bark was basified with NH4OH then extracted with ethyl acetate to yield a 13.2 g mixture of crude alkaloids. An LH-20 Sephadex column was used with a 7:3 mixture of methanol/chloroform to separate the alkaloids. Ibogaine was found in the 10:1 chloroform/methanol elution.

Richard, B., C. Delaude, G. Massiot, L. Le Men-Olivier. “Alkaloids from //Voacanga schweinfurtii// var. //puberula//.” __J. Nat. Prod.__, 46.2 (1983): 283-284. [].

//Voacanga thouarsii//
The alkaloids of //Voacanga thouarsii// var, //obtusa// were extracted from bark obtained from the species in the Republic of Congo by Belgian chemists, and it was determined that ibogaine comprised 2.0% of the crude extract. To extract the indole alkaloids, 6.6 kg of the bark was first moistened with 10% aqueous NH4OH. The moist bark was then extracted with methanol. The methanol extract was mixed with 10% aqueous acetic acid. The solution was then filtered and extracted with chloroform. The chloroform was evaporated and the alkaloid mixture was separated by counter-current distribution. The fraction containing ibogaine was crystallized from methanol, yielding 2.4 g of ibogaine.

Goldblatt, A, C. Hootele and J. Percher. “The alkaloids of //voacanga thouarsii// var. //obtusa//.” __Phytochemistry__, 9.6 (1970): 1293-1298. [|http://dx.doi.org/10.1016/S0031-9422(00)85321-2].