Author Topic: Possible to convert ibogaine into noribogaine?  (Read 6517 times)

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Offline Bancopuma

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Possible to convert ibogaine into noribogaine?
« on: April 03, 2012, 01:59:55 PM »
I am under the impression that there is a small amount of noribogaine among the alkaloids in iboga root bark and full spectrum alkaloid extract, and that this is what ibogaine is converted to in the liver. It is the noribogaine which hangs around in one's system for a long while, acting as an antidepressant and raising GDNF expression in the brain. So this seems to be a really beneficial substance with a long half life.

Do you think if one was to ingest pure noribogaine, it would be less taxing or incapacitating on one's system to some degree than pure ibogaine or full spectrum alkaloids? And does anyone with any chemistry knowledge know how hard this would be to achieve? I know the liver can pull it off, but could one do that part prior to ingestion and save it the job?? Curious is all.  :)
« Last Edit: April 03, 2012, 02:05:51 PM by Bancopuma »

Offline rOm

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Re: Possible to convert ibogaine into noribogaine?
« Reply #1 on: April 03, 2012, 03:42:38 PM »
Banco, I have no idea but this would be very interesting indeed.
Hope we can shed some light onto this.

Reclaim your Brain, Feed your Head.
Awaken the Heart, To the Core.

Iboga Panacea

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Re: Possible to convert ibogaine into noribogaine?
« Reply #2 on: April 03, 2012, 06:05:12 PM »
I just had this epiphany...
To convert it maybe just maybe...
Do like you would making TA extract.  My version is 1/2 organic grain alcohol and 1/2 an 8% red wine vinegar (alcohol so it keeps for much longer in it's powder form)...

BUT adding a whole heap of digestive enzymes and pancreatic enzymes???

I guess it's worth a try with some micro doses. 

Thanks for your report Banco that was highly entertaining.  Honestly so much resonates I almost can't comment on it. 

Iboga Panacea

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Re: Possible to convert ibogaine into noribogaine?
« Reply #3 on: April 03, 2012, 08:57:02 PM »
Woops forgot the crucial element.  So since it is processed in the liver I am assuming that using a liver glandular supplement might be able to replace ones own liver in the processing into noribogaine.  So in addition to the digestive enzymes to use a liver glandular supplement might be able to mimic the bodies system.  This is the product I picked up on the expiration shelves a while back, being a non animal eater I wondered why I got it, I guess I know why now...

But probably the powder would be better in this TA extraction tech...

I will try with the caps to cut them open or what not.  Give me a month or two.  I think I will also get some Bioperine powder for future experiments with this to see if that absorbtion factor can also parallel the bodies digestion in the liver.  Honestly to the crux of you question I doubt that it is possible for those with chemistry knowledge, I think it will come from avant garde cats like us.  Pumas, Jaguars, Lions, Ocelots, Margays, Asian Leopards and all us cats of the interstellar forest.
« Last Edit: April 03, 2012, 09:28:41 PM by Kambogahuasca Panacea »

Offline Bancopuma

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Re: Possible to convert ibogaine into noribogaine?
« Reply #4 on: April 04, 2012, 02:37:04 PM »
Hi peeps thanks for the feedback. Interesting stuff KP, would be good to experiment, and good to know that liver powder is immediately frozen, being proteins enzymes tend to be pretty fragile outside of their optimum conditions. It appears that the enzyme Cytochrome P4502D6 (CYP2D6), or two or more variants of it, are responsible for the O-demethylation of ibogaine to 12-hydroxyibogamine (noribogaine) in human liver microsomes:

The question is though, is only this enzyme capable of catalyzing this reaction, or would there be a way of achieving the same means through chemicals?

From the paper abstract in the link below:

"Most importantly, NORIBO [noribogaine] appears less likely to produce the adverse effects associated with IBO [ibogaine] (i.e., tremors and stress-axis activation), suggesting that the metabolite may be a safer alternative for medication development."

So I think this would definitely an interesting area to look into, but it would take someone with more knowledge of chemistry than I to look at this and come up with some useful conclusions.
« Last Edit: April 04, 2012, 02:47:21 PM by Bancopuma »

Offline insomnia

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Re: Possible to convert ibogaine into noribogaine?
« Reply #5 on: April 06, 2012, 05:10:20 AM »
12-hydroxyibogamine (Noribogaine)
Effects of noribogaine on the development of tolerance to antinociceptive action of morphine in mice.

The effects of noribogaine, a metabolite of ibogaine, on the development of tolerance to the antinociception action of morphine was determined in male Swiss-Webster mice. Ibogaine is an alkaloid isolated from the bark of the African shrub, Tabernanthe iboga. Morphine tolerance in mice was developed by two different methods. Mice were rendered tolerant to morphine either by subcutaneous implantation of a pellet containing 25 mg morphine free base for 4 days or by injecting morphine (20 mg/kg, s.c.) twice a day for 4 days. Placebo pellet implanted mice or vehicle injected mice served as controls. To determine the effect of intraperitoneally administered noribogaine on tolerance development, the drug was injected in the appropriate dose twice a day. In pellet implanted mice, a dose of 20 mg/kg of noribogaine attenuated the tolerance to morphine whereas lower doses had no effect. Similarly, in mice given multiple injections of morphine, noribogaine attenuated tolerance development at 20 and 40 mg/kg doses. Previous studies from this laboratory had shown that ibogaine at 40 and 80 mg/kg doses inhibited tolerance to morphine. Because noribogaine could attenuate morphine tolerance at lower doses than ibogaine, it is concluded that the attenuating effect of ibogaine on morphine tolerance may be mediated by its conversion to noribogaine, a more active metabolite.

This study shows in mice that Noribogaine was better than Ibogaine at attenuating morphine tolerance, in which Noribogaine was only needed only half of the dosage as compared to ibogaine.

Ibogaine-like effects of noribogaine in rats
Ibogaine is a naturally occurring alkaloid that has been claimed to be effective in treating addiction to opioids and stimulants; a \i1191c
dose is claimed to be effective for 6 months. Analogously, studies in rats have demonstrated prolonged (one or more days) effcclh 01
ibogaine on morphine and cocaine self-administration even though ibogaine is mostly eliminated ffql” the body in several hours. These
observations have suggested that a metabolite may mediate some of the effects of ibogaine. Recently, noribogaine was identified as a
metabolite of ibogaine. Accordingly, the present study sought to determine, in rats, whether noribogaine had pharmacological effects
mimicking those of ibogaine. Noribogaine (40 mg/kg) was found to decrease morphine and cocaine self-administration, reduce the
locomotor stimulant effect of morphine, and decrease extracellular levels of dopamine in the nucleus accumbens and stiiatum. All of these effects were similar to effects previously observed with ibogaine (40 mg/kg); however, noribogaine did not induce any ibogaine-like tremors. The results suggest that noribogaine may be a mediator of ibogaine’s putative anti-addictive effects.

"The similarity of ibogaine’s and noribogaine’s effects
raises the issue of the extent to which ibogaine’s effects
are mediated by conversion to noribogaine. If noribogaine
were totally responsible for ibogaine’s effects, it might be
expected that noribogaine would be much more potent
than ibogaine"

Whole PDF here


Molecular structures of ibogaine and noribogaine. Ibogaine undergoes O-demethylation to
form 12-hydroxyibogamine (noribogaine).
Similar spectral characteristics of this peak to ibogaine’s spectrum
defined it as an ibogaine metabolite, which is formed by the loss of a methyl
group (Figure 1). The site for metabolic demethylation of ibogaine was the
methoxy group, resulting in the compound 12-hydroxyibogamine (noribogaine).

So in this Figure, it shows that when Ibogaine goes through Demthylation to remove the methyl group, it formed Noribogaine.
So it seems that would be one way to achieve this semi synth. But its a mystery to me what would be used for Demethylation, and most chemicals used are quite dangerous to the semi novice clandenstine chemists. So I think this should be a last choice if possible, unless we can achieve this safely.
But Ill continue to look into this method as well.

This information was retrieved from ibogaine in the treatment of heroin withdrawal

Ibogaine and Noribogaine:
Comparing Parent Compound to Metabolite

Ibogaine has an acute and a prolonged effect on neurochemistry and behavior. Its metabolite, noribogaine (12-hydroxyibogamine),
is produced through metabolic demethylation soon after oral ibogaine administration. Although, they share similar chemical structures, ibogaine and noribogaine display different binding profiles. In rodents both, ibogaine and noribogaine, decreased morphine and cocaine intake and modulated dopaminergic transmission. In rats trained to discriminate ibogaine from saline, complete generalization to noribogaine was obtained. Attempts to correlate brain levels of both, the parent compound and the metabolite indicate that noribogaine is primarily responsible for ibogaine discriminative stimulus. Ibogaine-induced neurotoxicity tends to occur at doses much higher than the proposed dose for humans, but caution is important when extrapolating data from ibogaine’s effects observed in rodents. Although a definitive clinical validation of purported ibogaine effects is still unavailable, ibogaine has opened new perspectives in the investigation of pharmacotherapies for drug addiction.
"The significant correlation between the distribution coefficient and maximal brain concentration
of certain iboga alkaloids, including ibogaine and noribogaine, indicates that
lipid solubility is an important factor for the initial concentration of the alkaloids in the
brain (110). The 100-fold concentration of the drug in fatty tissue is consistent with the
highly lipophilic nature of ibogaine (44). Ibogaine is lipophilic and concentrated in fat,
and might be converted to noribogaine after slow release from fatty tissue.
tissue may serve as a reservoir of ibogaine, generating the release and metabolism over
longer periods (44)."

"It was hypothesized that sequestration of ibogaine into lipophilic compartments in the brain may result in lower drug concentrations in the extracellular fluid and that noribogaine may achieve higher extracellular fluid concentration than the parent compound due to the more polar nature of the metabolite (104). Slow elimination of noribogaine could result from O-demethylation of central nervous system (CNS)-stored ibogaine, which could contribute to some of the reported aftereffects of single dose of ibogaine (104)."

"Noribogaine is produced by metabolic demethylation of ibogaine soon after oral ibogaine
is given, indicating first-pass metabolism. Cytochrome P4502D6 catalyzes the Odemethylation
of ibogaine to noribogaine (68). The most probable site for metabolic
demethylation of ibogaine is the methoxy group (68). Both ibogaine and noribogaine are
stable in a human plasma matrix at room temperature for a period of at least 1 week (2)."

"Ibogaine and noribogaine have different affinities for several molecular targets
(104,105). Although sharing similar chemical structures, noribogaine and ibogaine display
different binding profiles. Noribogaine binds to the serotonin (5-HT) transporter in the
mid-nanomolar range with a 10-fold higher potency than ibogaine and elevates 5-HT
levels in the same range compared to ibogaine (63). Noribogaine was 50-fold more potent
at displacing radioligand binding at the 5-HT transporter than at the dopamine (DA) transporter
"Conflicting results have been found regarding ibogaine and noribogaine affinities for
the 5-HT1A and 5-HT2 receptors. Studies have shown the absence of significant potency in
both the parent compound and the metabolite for binding to the 5-HT1A and 5-HT2 receptors
(104) or a lack of affinity of ibogaine for serotonin receptors (types 1A, 1B, 1C, 1D,
2, and 3) (20). Another study demonstrated, however, potencies in the low micromolar
range for ibogaine binding to the 5-HT2 ([3H]ketanserin, Ki = 4.8 ± 1.4 ?M) and 5-HT3
([3H]GR-65630, IC50 = 3.9 ± 1.1 ?M) receptor subtype (105). Ibogaine did not inhibit
binding at the 5HT1 receptor in concentrations of up to 1 mM (105)."

"Noribogaine is more active than ibogaine at both ?- and ?-opioid receptors and, unlike
ibogaine, is active at the ? receptor (75,78,104). Ibogaine selectively inhibits the development
of tolerance to morphine, a ?-opioid receptor agonist, but not to U-50,488 or
DPDPE, ?- and ?-opioid receptor agonists, respectively (16). Ibogaine interacts significantly
with ?- (87) and ?-opioid (19) receptors, expressing at the latter a two-site binding
model. Noribogaine acts as a full agonist at the ?-opioid receptor with a level of intrinsic
activity comparable to the full agonists DAMGO and morphine (75). Evidence for roles of
?-opioid and NMDA receptors in the mechanism of the action of ibogaine have been presented
elsewhere (36).
Ibogaine has been regarded as a noncompetitive blocker of nicotinic receptors, since it
has blocked 22NaCl influx through the ganglionic-type nicotinic receptor channels of rat
pheochromocytoma PC12 cells (5). Low concentration of ibogaine had a potent inhibitory
action on nicotinic acetylcholine receptor-mediated catecholamine release as observed in
cultured chromaffin cells (96). Ibogaine inhibits human muscle-type and ganglionic nicotinic
acetylcholine receptors with IC50 values of 22.3 and 1.06 ?M, respectively (27)."

[MY ADDITION: For those unaware of what the opioid symbols mean, here is a quick summary
?- =kapa receptor, aka KOP, aka OP2
?- =mu receptor, aka MOP, aka OP3
?- =delta receptor, aka DOP, aka OP1

Retreived from this PDF

So as shown in this study, Ibogaine, and Noribogaine, both effect different opioid receptors, and the ones that both effect the same receptors, effect them at different levels.  So it might not be the best to convert Ibogaine to Noribogaine, in hopes of getting a cleaner experience. 
Because one might be thinking of this in a sense of the Opiate, Morphine conversion. That Morphine would be the best choice as all opiates just end up converting to morphine in the body anyway. But since Ibogaine also plays its own role, it may not be best to skip the ibogaine part and just go with the noribogaine.

Maybe the best thing to do would be methods of speeding up the ibogaine conversion in the body. As stated earlier that Ibogaine is lipophilic and is slowly released and converted into noribogaine overtime, maybe it would be best to speed up lipid breakdown in the body. Maybe say, taking Hoodia and Green tea extract pills or something of the sort?

But now that all that is covered, we need to fully understand what parts of the Ibogaine are necessary, and if it really would be beneficial to skip the ibogaine aspect, or speeding it up.

But also as shown in the "Ibogaine-like effects of noribogaine in rats" article that I first quoted, they used pure noribogaine so that shows there is a process to get the pure noribogaine, so I need to find out how they got it, and hope it was a semi-synthesis from ibogaine and not just a complete synthesis with no ibogaine conversion.

Also to add, from the same article Ibogaine and Noribogaine: Comparing Parent Compound to Metabolite
A single injection of 18-methoxycoronaridine (i.p.) significantly attenuated alcohol preferring
rats’ preference for alcohol and alcohol consumption in a two-bottle choice procedure
(89). Ibogaine reduced preference of C57BL/6By mice for cocaine consumption,
which was developed after a period of forced exposure to either cocaine HCl or water

Shows that 18-methoxycoronaridine has a better effect on Alcohol addiction than ibgoaine, and ibogaine has a better effect on cocaine and nicotine addiction. And as shown in the Ibogaine-like effects of noribogaine in rats article, Noribogaine seemed to show a better effect on the addiction of Morphine.
So they seem to work differently, and have their own uses for different addictions.
So this also may be the reason why some seem to not to have a difference in their addiction after an ibogaine treatment. Cant say for sure, this is just a theory I came to just now. But if the person were to recieve ibogaine HCL in their treatment, it may not help them as much as say a TA extract would. Something to ponder eh?

Like is shown here
Other reports, however, indicated that ibogaine failed to reduce these signs in the morphine-
dependent mice (26) and rats (102)......
In morphine-
dependent mice, ibogaine did not reduce withdrawal signs but significantly increased
the number of vertical jumps induced by naloxone within different epochs of
chronic morphine treatment (26). In morphine-dependent monkeys, ibogaine reduced the
total number of withdrawal signs but did not substitute completely for morphine, although
signs of toxicity were evident particularly at the highest dose (8 mg/kg, s.c.) (1).

Also something to ponder
It is noteworthy that s.c. injections of ibogaine failed to block opiate
withdrawal in animal as well as to reduce alcohol intake in alcohol-preferring rats (see
below), whereas the i.p. route administration produced positive results in both circumstances.
As mentioned previously, considerably higher ibogaine levels were detected in
most tissues, particularly in fat, after s.c. administration (44). Factors, such as formation of
local depots, poor absorption of ibogaine into the circulation, and lack of metabolic activation
by the liver after s.c. administration, were cited as possible causes for ineffectiveness
s.c. injection = subcutaneous injection [administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis]
i.p. injection = Intraperitoneal injection [injection into the peritoneum (body cavity)]

I highly recommend the Ibogaine and Noribogaine: Comparing Parent Compound and Metabolite article. Its 23 pages. and goes into much more than I could go into here. VERY INFORMATIVE!
Heres the link again, to the PDF file.

Heres another great reading on Noribogaine.
In accordance with the present invention, surprising and unexpected properties of noribogaine have been discovered. This compound is known to be a metabolite of ibogaine and is chemically identified as 12-hydroxyibogamine. In particular, noribogaine has been found to be useful as a non-addictive analgesic agent and as a treatment for drug dependency or abuse. Pharmaceutical compositions of noribogaine can be combined with one or more known opioid antagonists to treat addiction such that withdrawal symptoms are substantially eliminated or, at a minimum, surprisingly reduced. Such compositions are conveniently prepared in unit dose form with one or more unit doses providing a therapeutically effective amount of active ingredient.

Noribogaine, a metabolite of ibogaine, has properties that are well suited to the treatment of pain and to the withdrawal symptoms associated with drug dependency or abuse. In particular, it has been discovered that noribogaine binds to two classes of opioid receptors that have been associated with pain relief, the ? and ? receptors. In the case of the ?-type receptors, it appears that noribogaine acts as a full opiate agonist. In addition, noribogaine elevates brain serotonin levels by blocking synaptic reuptake. It is believed that such levels (as well as ligand interactions at the ? and ? opiate receptors) play a role in the anxiety and drug cravings experienced by addicts during withdrawal.

Noribogaine is synthesized by the O-demethylation of ibogaine. This may be accomplished, for example, by reacting ibogaine with boron tribromide/methylene chloride at room temperature and then purifying the product using known procedures. At present, noribogaine may also be obtained from the National Institute on Drug Abuse (Rockville, Md.). The compound has the following structure:

Chemical Form of Noribogaine

The present invention is not limited to any particular chemical form of noribogaine and the drug may be given to patients either as a free base or as a pharmaceutically acceptable acid addition salt. In the latter case, the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used. Examples of such acids include, without limitation, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, and the like. As discussed above, noribogaine itself may be formed by the O-demethylation of ibogaine which, in turn, may be synthesized by methods known in the art (see e.g., Huffman, et al., J. Org. Chem. 50:1460 (1985)).
Seriously go to that link of this article/patent. It is VERY VERY VERY informative on the subject, with great information on treatment, and very good info on using other substances with noribogaine for treatment, like Naloxone, Buprenorphine, etc.
Seriously check it out.

Its US PATENT US20100311724
and heres the PDF
I will also attach the pdfs in this post as well.

This patent can be found here
Noribogaine Composition
Demethylation may be accomplished by conventional techniques such as by reaction with boron
tribromide/methylene chloride at room temperature followed by conventional purification.

Ibogaine possesses hallucinogenic properties and is a Schedule 1 -controlled substance in the USA. Accordingly, methods for preparing noribogaine from ibogaine require high levels of assurance that contamination with unacceptable amounts of ibogaine is avoided. However, noribogaine so prepared has not been reported as being substantially free of ibogaine (e.g., not more than 0.5 wt% relative to noribogaine). At best, U.S. Patent No. 6,348,456 claims an essentially pure noribogaine compound but fails to disclose any methods for purification let alone what the phrase "essentially pure" encompassed or, for that matter, the level of ibogaine remaining in the composition. The synthesis of noribogaine from ibogaine was reported in U.S. Patent No. 2,813,873. However, the '873 patent is also silent as to the purity of the noribogaine obtained in that synthetic process.

And here is a couple long detailed synthesis' of Noribogaine from Ibogaine from the Noribogaine Composition patent.

[0030] It is contemplated that noribogaine can be prepared and/or purified from ibogaine by utilizing solid support as shown in the following Schemes, where PG represents an amine protecting group, LG represents a leaving group (e.g. a halo or a mesylate, tosylate, or such other group), L represents a cleavable linking group (e.g. a carbonyl compound such as a carbonate or carbamate) and the shaded circle represents a solid support.

[0031] In the following Schemes, the O-demethylation of the aryl methoxy group to yield the corresponding phenol can be accomplishing using any suitable method known in the art. Suitable reagents include a Lewis acid (e.g. BBr 3 , A1C1 3 ), a nucleophile (e.g. RS-, N 3 -, SCN-), NaCN at high pH (e.g. pH 12), and the like. In some embodiments, the O- demethylation should be performed without affecting the linkage to the solid support or altering the stereochemistry of the stereochemical centers on the molecule. Suitable reagents can be readily ascertained by one of skill in the art and can be found, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Fourth Edition, Wiley, N.Y., 2007 (see, e.g., the reactivity charts at pages 1006-1008 and 1022-1032), and references cited therein.

Scheme 1

[0032] Noribogaine 5 can be prepared and purified from ibogaine 10 by any one of the routes shown in Scheme 1. Noribogaine, compound 5, is differentiated from ibogaine by virtue of the fact that the methoxy group of ibogaine is converted to a hydroxyl group in noribogaine. In one embodiment, the indole amine of ibogaine can be protected using an amine protecting group to yield compound 1, followed by either tandem O-demethylation and removal of the protecting group using L-SELECTRIDE®, for example, or sequential O-demethylation and removal of the protecting group to yield noribogaine 5. In addition, in one embodiment, noribogaine can be directly prepared and purified from the O- demethylation of ibogaine using methods known in the art and then purified by appending noribogaine to a solid support (compound 12 or 13), washing contaminants, cleaving the linking group L, and recovering the noribogaine 5. In the above syntheses, one or more of the noribogaine or intermediates shown above can be purified using standard purification techniques known in the art (e.g. column chromatography, HPLC, and the like).

Compounds of formula 11 are commercially available or can be synthesized in one or two steps from commercially available starting materials (see, e.g. commercially available resins from Sigma-Aldrich®). [0033] In another embodiment, noribogaine can be prepared and purified from ibog in the manner described in Scheme 2 below:

Scheme 2

wherein Pg is hydrogen or an amino protecting group and the shaded circle represents a solid support.

[0034] Specifically, in Scheme 2, amino protected ibogaine, compound 1, is contacted with boron tribromide or other conventional demethylating agent in e.g., methylene chloride using conditions well known in the art to yield the amino protected noribogaine, compound 2.

[0035] In Scheme 2, attachment of amino protected noribogaine, compound 2, to a solid support is accomplished by use of a chloroformate/solid support, compound 3, under conventional conditions to yield compound 4 wherein the carbonate group is shown for illustrative purposes only as the cleavable linking group. Other cleavable linking groups can likewise be used in Scheme 2. As amino protected ibogaine does not contain a functional group reactive with compound 3, only amino protected noribogaine, compound 2, will react with the solid support and yield compound 4. Repeated washing of compound 4 will remove a portion of amino protected ibogaine contaminating the sample of amino protected noribogaine used in this reaction. Furthermore, at any time, a small portion of the solid support can be removed to provide a sample of noribogaine (after cleavage and deprotection). The sample can then be analyzed for purity relative to any ibogaine present by conventional methods such as GC/MS, NMR, C 13 -NMR, etc. [0036] Upon achieving the desired level of purity of noribogaine relative to any contaminating ibogaine, noribogaine, can be recovered from the solid support by cleavage of the cleavable linker and subsequent deprotection of the amino group. Both cleavage and deprotection are well known in the art.

[0037] As desired, exceptionally pure noribogaine, compound 5, can be obtained by repeating the process of forming the amino protected noribogaine, compound 2, binding compound 2 to a solid support via the hydroxyl group of amino protected noribogaine and washing a portion of contaminating ibogaine from the solid support. By repeating this process as often as necessary and preferably no more than 5 times, it is contemplated that noribogaine compositions having not more than 0.5 wt%, not more than 0.3 wt%, or not more than 0.1 wt% ibogaine relative to the amount of noribogaine present in the composition can be prepared.

[0038] In another embodiment, the solid support is an anion exchange resin, where noribogaine is ionically bound thereto. Such a resin allows uncharged ibogaine to pass through by simple elution. Nonlimiting examples of anion exchange resins include solid supports, preferably those derivatized with quaternary ammonium containing moieties, such as trialkylbenzyl ammonium containing moieties. Suitable trialkylbenzyl ammonium groups include trimethylbenzyl ammonium, dimethyl-2-hydroxyethylbenzyl ammonium, and the like. Nonlimiting examples of commercially available anion exchange resins include AMBERLITE® Type I, AMBERLITE® Type II, DOWEX® Type I, and

DOWEX® Type II, anion exchange resins. Recovery of noribogaine by pH adjustment is known to one well- versed in the art.

[0039] Alternatively, noribogaine hydrochloride was prepared from ibogaine hydrochloride by first converting it to a free base, ibogaine, by treating with methanol followed by treatment with a base such as potassium carbonate in a solvent such as methylene chloride. Ibogaine was then converted to noribogaine hydrobromide by treating with boron tribromide or other conventional demethylating agent in a solvent such as methylene chloride followed by quenching with methanol to give noribogaine hydrobromide. Noribogaine hydrobromide was then converted to the free base by treating with a base such as potassium carbonate in a solvent such as methylene chloride, followed by purification over silica, and then by conversion to the hydrochloride salt using HC1 in a solvent such as isopropanol as shown in Scheme 3 below. Scheme 3

noribogaine hydrochloride noribogaine hydrobromide

[0040] Another method of demethylating is also contemplated as shown in Scheme 4 below.

Scheme 4

noribogaine hydrochloride

Use of BCI 3 instead of BBr 3 for removing the methyl ether is contemplated to have several advantages. For example, it provides the noribogaine hydrochloride in one step, without having to convert the noribogaine hydrobromide obtained, when BBr 3 is used, into the hydrochloride salt. Furthermore, it is contemplated that using BC1 3 substantially reduces the halogenation of the aromatic ring as obtained when BBr 3 is used. [0041] In one embodiment, the amount of ibogaine in a noribogaine composition can be determined by starting with a 14 C enriched methoxy group on ibogaine. The amount of 14 C over background in the final composition can be correlated to the amount of ibogaine in the noribogaine composition which can then be used to validate that the synthetic protocols employed are at or below the maximum amount of ibogaine permitted in the noribogaine composition. A 14 C enriched methoxy group on ibogaine can readily be prepared by methylating the 12-hydroxyl group of noribogaine with an enriched 14 C methylating agent. Techniques for determining the amount of a 14 C in a composition are well known in the art and detection limits are below 1 ppt.

[0042] It will be apparent to those skilled in the art that many modifications of the above exemplary methods, both to materials and methods, may be practiced without departing from the scope of the current invention.

[0043] The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. Unless otherwise stated, all temperatures are in degrees Celsius.

Compositions Of Noribogaine

[0044] This invention provides noribogaine compositions which are enantiomerically enriched and substantially free of ibogaine.

[0045] In one embodiment, this invention provides a composition comprising noribogaine wherein at least 95% of the noribogaine is present as the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer and further wherein said composition comprises not more than 0.5 wt% ibogaine relative to the total amount of noribogaine. In another embodiment, said composition comprises not more than 0.3 wt% ibogaine relative to the total amount of noribogaine. In another embodiment, said composition comprises not more than 0.1 wt% ibogaine relative to the total amount of noribogaine.

[0046] In another embodiment, this invention provides a composition comprising noribogaine wherein at least 98%> of the noribogaine is present as the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer and further wherein said composition comprises not more than 0.5 wt% ibogaine relative to the total amount of noribogaine. In another embodiment, this invention provides a composition comprising noribogaine wherein at least 98% of the noribogaine is present as the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer and further wherein said composition comprises not more than 0.3 wt% ibogaine relative to the total amount of noribogaine. In another embodiment, said composition comprises not more than 0.1 wt% ibogaine relative to the total amount of noribogaine.


[0047] In the examples below, the abbreviations have their generally accepted meaning.

Example 1 - Synthesis and Purification of Noribogaine from Ibogaine

[0048] Example 1 illustrates one method for the synthesis and purification of noribogaine from ibogaine which method follows Scheme 5 below:

Scheme 5

[0049] Specifically, in Scheme 5, ibogaine is contacted with a stoichiometric excess of benzyl chloroformate in an inert solvent such as methylene chloride. The reaction mixture further contains at least a stoichiometric equivalent of diisopropylethylamme relative to ibogaine so as to scavenge the acid generated during the reaction. The reaction is maintained at room temperature under an inert atmosphere until the reaction is

substantially complete as evidenced by, for example, thin layer chromatograpy. At which time, an O-demethylation reagent (e.g. boron tribromide or aluminum trichloride), or preferably a stoichiometric excess thereof, is added to the reaction mixture which is then maintained under conditions (e.g. room temperature) wherein the methoxy group of ibogaine has been converted to the hydroxyl group of noribogaine. [0050] The hydroxyl group generated above is then employed as a complementary functionality for attachment of a solid support. In particular, an excess of chloroformate bound to a solid support is combined with N-CBz-noribogaine under conventional conditions wherein a carbonate bond is formed. Chloroformate bound to a solid support can be prepared from a hydroxy-bearing polymer support (e.g. hydroxymethyl)polystyrene or polymer-bound benzyl alcohol, both commercially available from Sigma- Aldrich®) and carbonyl dichloride. As CBz-ibogaine does not readily react under these O-demethylation conditions, it will remain in the solution phase of the reaction mixture and can be washed from the reaction mixture by conventional techniques including placing the solid support into a column and passing excess solvent through the column.

[0051] In one particular example, 1 kg of solid support containing CBz-noribogaine is loaded onto a column. The stopper of the column is partially opened so that a flow rate through the column of 0.5 liters per hour is maintained. Methylene chloride is

continuously fed to the top of the column and recovered at the base of the column. The recovered methylene chloride is removed to provide residual CBz-ibogaine. A portion of the solid support is then loaded into a hydrogenation vessel together with methanol and a catalytic amount of palladium on carbon. Hydrogenation is continued under elevated pressure for approximately 5 hours. The reaction is then stopped and the methanol recovered and removed, thus yielding noribogaine. Additional purification of noribogaine can be achieved by HPLC as desired.

Example 2 - Synthesis and Purification of Noribogaine Hydrochloride from Ibogaine hydrochloride

Scheme 6

noribogaine hydrochloride noribogaine hydrobromide

Step 1. Purification of crude ibogaine hydrochloride and release of ibogaine free base from the purified material

[0052] A 10 L flange reactor was charged under nitrogen with ibogaine (428.5 g) and ethanol (4.30 L). The resulting suspension was heated to 65-75°C for 1 h 20 minutes and allowed to cool to room temperature under stirring overnight. A pale buff suspension was obtained. The solid was collected by filtration and washed with methylene chloride

(DCM, 2 x 0.5 L). The filter cake was dried under nitrogen until of constant weight (279 g). The solid was stored under nitrogen and in exclusion of light for 5 days. In-process control (IPC) by high performance liquid chromatography (HPLC) showed ibogaine

(97.38%), ibogamine (2.31%) and ibogaline (0.31%). The filtrates were concentrated in vacuum to dryness to afford a pale brown solid (72 g). IPC by HPLC showed ibogaine (59.49%), ibogamine (17.31%), ibogaline (20.12%) and unknowns (total 3.04%). The purified ibogaine hydrochloride (279 g, 97.38%) was suspended under nitrogen in DCM (2.85L). 25 Wt% aqueous potassium carbonate solution (470 ml) was added and the phases were mixed vigorously for 10 minutes. The phases were separated. The aqueous layer was extracted with further DCM (2 x 720 ml). The aqueous layer was discarded.

The combined organic phases were washed with water (0.73 L), split into two almost equal portions and concentrated in vacuum at 50°C to afford a pale brown foam. The foam was dried under vacuum to constant weight. IPC by HPLC showed ibogaine

(93.15%), ibogamine (2.28%), ibogaline (0.31%) and unknowns (total 4.26%).

Step 2. Conversion of Ibogaine Free Base to Noribogaine Hydrobromide

[0053] A 3 L flange flask fitted with a thermometer, gas bubbler, overhead stirrer, Schott addition bottle and scrubber was charged under nitrogen atmosphere with methylene chloride (400 ml) and BBr 3 in methylene chloride (1 M, 368 ml). The mixture was cooled to 0-5°C under stirring. A Schott bottle was charged with ibogaine free base (75 g, MLR/629/73-1) and methylene chloride (300 ml) to afford a pale brown solution. The bottle was purged with nitrogen, covered in foil and connected to the flange reactor via a pressure addition line. The solution was added slowly to the reactor over 110 minutes. Upon addition, a suspension was formed. When the addition was complete, the reactor content was allowed to warm up to room temperature overnight. The mixture was cooled to 0-5°C and quenched with methanol, allowed to warm up to room temperature and stirred overnight. The solid was collected by filtration, washed with DCM and dried (yield: 81%).

[0054] It is contemplated that the reaction of ibogaine free base with BBr 3 gives a brominated side product, the formation of which can be avoided by using BC1 3 instead of BBr 3 which directly gives the corresponding HC1 salt.

Step 3. Conversion of Noribogaine hydrobromide to Noribogaine hydrochloride

[0055] A 10 L flange separating funnel fitted with a nitrogen inlet, gas bubbler, overhead stirrer, thermometer and dropping funnel was charged noribogaine hydrobromide (214.35 g ), MeOH (1.95 L) and methylene chloride (4.18 L) to afford a suspension. Under stirring and nitrogen atmosphere K 2 CO 3 (234 g, 3.0 eq) dissolved in water (1.65 L) was added over one hour. During the addition the internal temperature rose from 18.9°C to 23.2°C. Stirring was continued until a two phase system was obtained. The lower organic phase was separated. The upper aqueous phase was extracted with methylene chloride (2 x 1.46 L). The combined organic phases were washed with water (1 x 1.95 L). The organic layer was split into two portions, each portion was and concentrated in vacuo to dryness to afford a pale brown solid (1 x 88.9 g, 1 x 79.3). The solids were and subjected to a chromatographic purification using flash silica gel (7.20 kg, 43 wt eq.) eluting with methylene chloride /acetonitrile/triethyl amine (1 : 1 :0.5); a total of 16 fractions (5 L each) were collected of which fractions 5-16 showed desired product by TLC and HPLC. Based on the results of use test work for the salt formation, fractions 7-11 were combined and concentrated to dryness to afford a beige-colored solid (136 g). The solid was charged to a 5 L flange flask fitted with a nitrogen inlet, gas bubbler, overhead stirrer, dropping funnel and thermometer. Isopropanol (3.27 L) was added and the mixture was heated under stirring and nitrogen atmosphere to 45-55°C over one hour to afford a clear solution.

Isopropanol/HCl (5 M, 128.6 ml, 1.4 eq) was added over one hour. Precipitation of an off- white solid was observed and the suspension was allowed to cool under stirring to room temperature overnight. The mixture was further chilled to 0-5°C. After 30 minutes the solid was collected by filtration and washed with dichloromethane (2 x 0.49 L) and sucked dry to constant weight under nitrogen purge. The solid was further dried under vacuum at 60°C for four days.

[0056] The yield Noribogaine free base was 168.2 g (99%), that of noribogaine free base (purified) was 136 g, (81%), and that of noribogaine hydrochloride was 150 g, (98%>). The overall yield (based on the steps of free base formation, purification, and salt formation) was 79%. Analytical results were as follows. Pre final drying there was noribogaine hydrochloride (99.3%>), a by-product (0.5%>), and ibogaine (0.1%>). After 3 days drying, there was noribogaine hydrochloride (99.10%), the by-product (0.33%>), ibogaine (0.07%>), ibogamine (0.08%>), and unknowns (total 0.42%>). Another batch gave noribogaine hydrochloride (99.34%>), ibogaine (0.02%>), ibogamine (<0.01%>), and ibogaline (0.02%).

[0057] The above process demonstrates that noribogaine substantially free of ibogaine is prepared according to this invention. While this process provides noribogaine that is substantially free of ibogaine, a small amount of ibogaine, approximately 0.02 wt% or 200 ppm relative to noribogaine, was still observed in the noribogaine thus prepared via ibogaine.


So hope all this helps. Spent a couple hours on it. Gotta get some sleep now.
But it was worth it. Learned a bunch! :)

Seems like Ibogaine-like alkaloids deserve much more respect, and deserve much more research as well! 
I am a firm believer that when used in treatment one should only use Total Alkaloid extract instead of Ibogaine HCL.

I am glad these topics are being brought up! Would be very interesting to see some start to get pure Noribogaine, and Coronaridine, 18-methoxycoronaridine, etc. 
I myself am going to look into these as well! I am very glad you brought this up, and really sparked my interest on the subject. I am very interested now.

But as stated earlier. One thing we need to think about, is whether we really want pure noribogaine and skip the ibogaine aspect, or would it be preferred to speed up the ibogaine step in the body, or to even prolong the storage of ibogaine and slowly release the ibogaine to convert to noribogaine over time?
So thats some things we need to take into account here.
Think about it.

Peace, Love and Light.
« Last Edit: April 06, 2012, 05:15:00 AM by insomnia »

Offline Bancopuma

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Re: Possible to convert ibogaine into noribogaine?
« Reply #6 on: April 07, 2012, 11:45:59 AM »
Hi there, thanks a bunch for all the great info and papers and taking the time to share this. :) So there is a chemical way of converting ibogaine into noribogaine. But one may miss out on some of the healing through iboga if one skips this step. Still though in terms of long term healing effects it seems that the noribogaine is the more important molecule. So it is the ibogaine as oppose to the noribogaine which is lipophilic and hangs around in body tissues being gradually converted? I was under the impression it was the noribogaine that hangs around in the body tissues but I could certainly be wrong. Interesting also in one of the studies, blood noribogaine levels of rats were actually higher than blood ibogaine levels following administration of appears the vast majority of ibogaine goes to the liver when ingested, where its converted into noribogaine by enzymes there, and this conversion is a very important component of iboga's long term healing and afterglow. Definitely unique among shamanic plants in this respect I think.

Offline insomnia

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Re: Possible to convert ibogaine into noribogaine?
« Reply #7 on: April 07, 2012, 10:48:14 PM »
So it is the ibogaine as oppose to the noribogaine which is lipophilic and hangs around in body tissues being gradually converted? I was under the impression it was the noribogaine that hangs around in the body tissues but I could certainly be wrong.

Yeah what I came to the coclusion is, that the ibogaine is what hangs in the fatty tissue and is slowly released as lipids are broken down overtime and then is quite instantly converted to noribogaine.

So you could think of it like THC, because it stores in the lipid cells of the body, and overtime as fatty tissue is broken down, it is converted into its metabolite. (Just like ibogaine converting to noribogaine) Which is how you can test positive for cannabis 30 days + since your last ingestion. They test for the metabolite.

Offline Bancopuma

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Re: Possible to convert ibogaine into noribogaine?
« Reply #8 on: September 13, 2012, 05:00:54 AM »
A little info from Dr Chris Jenks on noribogaine that may be of interest.

What little I've heard about noribogaine is that it isn't psychoactive,
at least at doses where ibogaine would be. Yes, rat studies suggested that
it should reduce withdrawal, but if it were very useful I would have
expected Deborah Mash to jump on it long ago, since she owns the patent on
it. The simplest way I know to make it is from ibogaine using
refluxing hydrobromic acid, as described in the 1957 patent of Janot and
All it means if noribogaine reaches higher levels than ibogaine (at that
point in time) is that ibogaine is metabolized faster than noribogaine,
allowing noribogaine to build up temporarily. The theory that noribogaine
accounts for the long-term effects of ibogaine assumes that the intensity
of a drug's effects reflects the concentration of that drug in the blood.
Based on what I've read, this assumption is often wrong in two ways.
Tolerance causes the effects of many drugs to subside before they are
eliminated, and long-term receptor binding or changes to nerve cells can
cause a drug, like LSD for example, to continue having an effect even
after it has been eliminated. Still, I would like to know if noribogaine
is useful for anything, since it's legal after all. But I have more hope
in the alkaloids which are similar to ibogaine, like ibogaline, ibogamine
and tabernanthine.