Ibogamine A better alternative to ibogaine for those who cannot tolerate or dislike

[Solipsis]

I suppose that the NMDA-antagonism and the fact that noribogaine is an SSRI, also contributes to the anti-addictive effect. Addiction is often rooted in depression, and these two mechanisms are both antidepressant. Noribogaine can stay within the bloodstream for long enough to have this effect. And i believe that both ibogaïne as well as noribogaine have some dopaminergic effect as well.

I believe typical NMDA antagonist AD effects are indirect and now thought to be a result of IIRC change in LTP and learning, but I doubt that the week or fortnight long mood lift are critical to the anti-addictive effects (as in: it would suffice on its own), maybe it contributes like other NMDA antagonists can have acute AD effect, but so powerfully anti-addictive is not seen with other NMDA antagonists right?
SSRI's take a long while to change brain chemistry, like weeks (wasn't it because changes in serotonin levels take time to downregulate receptors or somesuch which provides the actual benefit?) so even the pretty long iboga therapy sessions wouldn't be long enough, even if noribogaine would stay in the blood for weeks which I highly doubt, you would just only start to see improvement when levels drop off completely. SSRI's are also notorious for causing problematic effects in that transition time, so if in this period you transition to and fro isn't that just extra destabilizing?

Not the most elegant explanation being a two-parter, but it may be that the combination of NMDA antagonism and LTP related AD effects in conjunction with the physical effects of kappa opioid activity which perhaps upregulates other receptors makes for a physical reset and a mental reset that allow a synergistic recalibration that accounts for anti-addictive effects? How it would still help with different types of addiction is still curious, can the reward pathways be rewired that quickly?

 

[Dracarys]

I think that noribogaine actually does stay in the blood for more than a month. So the AD effects of noribogaine could actually slowly start to kick in when the NMDA mediated AD effects begin wearing off.

I think that ibogaïne as well as noribogaine have powerfull dopaminergic effects though, that are realy crucial for it's effect on addiction. The thing is that these effects are the combined effect of several mechanisms simultaneously at play, like the kappa agonism, MAOI effects, and activity on some dopamine receptors.

I'm saying this because in my experience, an iboga flood dose will hugely alter, or rather amplify, the effects of cannabis, and this effect holds on for definately more than a month. I've spoken to more people who've experienced this. My explanation for this effect is simply that this is due to iboga's dopaminergic effects, because i experienced something simmilar, just less powerfull, when i was taking st johns worth for a while.

 

[DotChem]

"Mechanisms of antiaddictive actions of ibogaine." https://www.ncbi.nlm.nih.gov/pubmed/9668680

Ibogaine, an alkaloid extracted from Tabemanthe iboga, is being studied as a potential long-acting treatment for oploid and stimulant abuse as well as for alcoholism and smoking. Studies in this laboratory have used animal models to characterize ibogaine's interactions with drugs of abuse, and to investigate the mechanisms responsible. Ibogaine, as well as its metabolite, noribogaine, can decrease both morphine and cocaine self-administration for several days in some rats; shorter-lasting effects appear to occur on ethanol and nicotine intake.

Acutely, both ibogaine and noribogaine decrease extracellular levels of dopamine in the nucleus accumbens of rat brain. Ibogaine pretreatment (19 hours beforehand) blocks morphine-induced dopamine release and morphine-induced locomotor hyperactivity while, in contrast, it enhances similar effects of stimulants (cocaine and amphetamine). Ibogaine pretreatment also blocks nicotine-induced dopamine release.

Both ibogaine and noribogaine bind to kappa opioid and N-methyl-D-aspartate (NMDA) receptors and to serotonin uptake sites; ibogaine also binds to sigma-2 and nicotinic receptors. The relative contributions of these actions are being assessed. Our ongoing studies in rats suggest that kappa agonist and NMDA antagonist actions contribute to ibogaine's effects on opioid and stimulant self-administration, while the serotonergic actions may be more important for ibogaine-induced decreases in alcohol intake. A nicotinic antagonist action may mediate ibogaine-induced reduction of nicotine preferences in rats. A sigma-2 action of ibogaine appears to mediate its neurotoxicity.

Some effects of ibogaine (e.g., on morphine and cocaine self-administration, morphine-induced hyperactivity, cocaine-induced increases in nucleus accumbens dopamine) are mimicked by kappa agonist (U50,488 and/or a NMDA antagonist (MK-801). Moreover, a combination of a kappa antagonist and a NMDA agonist will partially reverse several of ibogaine's effects. Ibogaine's long-term effects may be mediated by slow release from fat tissue (where ibogaine is sequestered) and conversion to noribogaine. Different receptors, or combinations of receptors, may mediate interactions of ibogaine with different drugs of abuse.

Paying article...http://onlinelibrary.wiley.com/doi/...ionid=67BAB60D2BC46F3FE1ABF308C9DCC42A.f03t04

 

[serotonin2A]

"Mechanisms of antiaddictive actions of ibogaine." https://www.ncbi.nlm.nih.gov/pubmed/9668680

Paying article...http://onlinelibrary.wiley.com/doi/...ionid=67BAB60D2BC46F3FE1ABF308C9DCC42A.f03t04

That article is way out of date (18 years old).

Glick now thinks that ibogaine produces anti-addictive effects primarily by blocking alpha3beta4 nicotinic receptors.

http://www.ncbi.nlm.nih.gov/pubmed/12895678
http://www.ncbi.nlm.nih.gov/pubmed/16626688
http://www.ncbi.nlm.nih.gov/pubmed/26022277

 

[Cotcha Yankinov]

Glick now thinks that ibogaine produces anti-addictive effects primarily by blocking alpha3beta4 nicotinic receptors.

I would love some elaboration on the function of alpha3beta4 receptors... It seems MDMA/METH can upregulate nicotinic receptors (http://www.ncbi.nlm.nih.gov/pubmed/20132834 http://www.ncbi.nlm.nih.gov/pubmed/17614110) and I wonder if this can partially account for increased dopamine seen in abstinent MDMA users via an interaction involving the habenula and interpeduncular nucleus (https://www.ncbi.nlm.nih.gov/pubmed/2424555).

I would assume that the nicotinic receptor upregulation is somewhat persistent if this study is true https://www.ncbi.nlm.nih.gov/pubmed/24239118 - "During chronic nicotine exposure, nicotinic acetylcholine receptors containing the β4 subunit were upregulated in somatostatin interneurons clustered in the dorsal region of the IPN." Unless that upregulation is not a direct consequence of nicotine binding to b4 containing receptors, and it is rather dopamine etc. somewhere else that leads to the upregulation of the b4 containing receptors. Which, if it is dopamine that leads to upregulation of those receptors, and abstinent MDMA users have increased dopamine, I suppose that alone could cause persistent a3b4 upregulation?

It would be really cool to see a normalization of dopamine in abstinent MDMA users utilizing a3b4 antagonists...

Also guys just thought I would point out some of these a-conotoxins appear really promising as far as a selective a3b4 antagonist goes http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358631/

 

[DotChem]

That article is way out of date (18 years old).

Glick now thinks that ibogaine produces anti-addictive effects primarily by blocking alpha3beta4 nicotinic receptors.

http://www.ncbi.nlm.nih.gov/pubmed/12895678
http://www.ncbi.nlm.nih.gov/pubmed/16626688
http://www.ncbi.nlm.nih.gov/pubmed/26022277

True but it is not like there are tons of studies since: Ibogaine beeing a schedule I substance (ie banned) the Gov won't fund any research on it. And the second biggest funder aka BigPharma won't fund anti-addiction research in general. why? because there is no money to be made. On the contrary, addictive opioids painkillers make more $$, isnt it? So you won't really see much formal studies on Ibogaine.

imho there is lot to be learn on how the drug works. It actually may be working by both nicotinic anatgonism (for its effect on nicotine and alcohol addiction) AND by kappa opioid agonism (for its effect on Psychostimulans and opiates addiction): The data on earlier Glick work look pretty confincing to me. Plus there is huge current literature (i'll pill out some review later) supporting the anti-addictive effect of Kappa agonists.

https://www.ncbi.nlm.nih.gov/pubmed/9668680
So till then we can only hope for more data..(BTW the data from the ref you cited are all for Conoradine or its 18-methoxylated analog 18-MC (their binding profile is rather different from Ibogaine and/or its major metabolite norIBG ie ratios of NMDA OP Nicotinic Serotonergic..etc.. cf)

by the way South Africa just pull Ibogaine and all its different preparations out of the list of schedule substances 2-3 weeks ago. So it is now legal there. More clinical data will be forthcoming from there.

 

[serotonin2A]

True but it is not like there are tons of studies since: Ibogaine beeing a schedule I substance (ie banned) the Gov won't fund any research on it.

Savant received a 6 million dollar grant from NIDA in 2013 to support phase I testing with 18-MC. NIDA provided several million dollars of funding for ibogaine research and clinical trials in the 1990s, but further development was derailed by the discovery of ibogaine-induced cerebellar degeneration. The reasons why ibogaine isn't being pursued by NIH-funded research (deaths due to arrhythmia, concerns about neurotoxicity, etc) have nothing to do with the fact that it is schedule I or because there is some conspiracy by pharmaceutical companies. It just isn't viewed as being safe enough for widespread use. That being said, privately-funded ibogaine research is continuing. For example, there is currently a group running ibogaine studies with patients in Tijuana, Mexico.

There have been numerous studies with ibogaine and 18-MC since the 1998 review was published. That is how they identified the nicotinic mechanism. There aren't as many ibogaine studies being published now compared with 20 years ago because Glick identified a more selective ibogaine derivative that seems to be as efficacious as ibogaine. So of course they dropped ibogaine and moved on to 18-MC for development. Their findings with 18-MC suggest that effects on alpha3beta4 nicotinic receptors and potentially kappa and mu opioid receptors are sufficient to produce ibogaine-like anti-addictive effects.

BTW the data from the ref you cited are all for Conoradine or its 18-methoxylated analog 18-MC (their binding profile is rather different from Ibogaine and/or its major metabolite norIBG ie ratios of NMDA OP Nicotinic Serotonergic..etc.. cf)

The last study also included info about ibogaine. I know that most of the work I cited was done with 18-MC...that is exactly my point. If 18-MC has the same efficacy as ibogaine then that strongly suggests that the sites 18-MC targets are the sites responsible for the efficacy of ibogaine. That is a classic strategy in pharmacology for determining mechanism-of-action -- if you can take a nonselective drug and subtract pharmacological effects without compromising efficacy, then that is evidence that those pharmacological effects are not therapeutically relevant. The pharmacology of ibogaine is so dirty that it is difficult to determine exactly how it works, hence to need to pick apart the SAR of its derivatives.

 

[MeDieViL]

I think the argument for finding a less psychoactive version of ibogaine (hence the development of 18-MC) is that far too many people die during ibogaine treatment due to arrhythmia or because they use opioids while on ibogaine. It has also still never been worked out whether the tremorgenic effects of ibogaine (due to sigma-2 activation) reflect neurotoxicity. My understanding is that ibogamine is actually more potent than ibogaine at sigma-2 receptors.

Any idea what causes the arrythmia? that way we can prevent te risk, ive taken it in microdoses with etylphenidate, mpa and 5 meo dalt before, but id rather experiment more safely in the future.

No point in making it non psychoactive just throw a 5ht2a antagonist like seroquel on top of it.

 

[MeDieViL]

That article is way out of date (18 years old).

Glick now thinks that ibogaine produces anti-addictive effects primarily by blocking alpha3beta4 nicotinic receptors.

http://www.ncbi.nlm.nih.gov/pubmed/12895678
http://www.ncbi.nlm.nih.gov/pubmed/16626688
http://www.ncbi.nlm.nih.gov/pubmed/26022277

If that was true wellbutrin would be as good, maybe it isnt because its underdosed but then ppld would die of a seizure, well they can take the pick btw that or arrythemia.

 

[MeDieViL]

IMHO, Iboga indoles alkaloids "hallucinations may be required for anti-addiction activity. At least with psychostimulants and opiates but not alcohol or nicotine!. Here is why imho:

For one, Ibogaine is a kappa opioiod receptor agonist and kappa activation is pretty well known to induce hallucinations. Example: the selective kappa agonist Salvia (Salvinorum A) is hallucinogenic . So Ibogaine might be inducing similar type of "hallucinations" as Salvia divinorum via kappa agonism but not via 2A like DMT/LSD... One should note that it is not really "psychedelic hallucination" via 2A activation. So technically Ibogaine, Salvia or other kappa shouldn't be classified psychedelic. Anybody who've tried acid and Salvia should know the difference. Iboga hallucination is very much close to lucid dreaming ie waking up in a dream with all the dream characters, plots, interactions..etc That's for one.

Second, Kappa agonists (this one compound in particular) was shown to give some of the effect of Ibogaine. Plus, Kappa antagonists block (some of)the "hallucinogenic" action of ibogaine. (https://www.ncbi.nlm.nih.gov/pubmed/9668680) The anti-addictive effect (both short-term and long term) of Kappa agonists is pretty much very well established now (see kappa wp entry and refs there). Especially beneficial is the long-term kappa agonists treatment since kappa activation induces up-regulation of D2 receptors in the nucleus accumbens and striatum that opiates or psychostimulants long-term use down-regulate. Back to baseline with the added bonus of resenzitation to opiates and stims. Like for example sexual drive back to pre-stims use!

So I think Ibogaine may be inducing the anti-addiction effect via kappa activation. And since Kappa activation induces BOTH hallucinations AND detox (it virtually reverses effect of opiates/stims on NAcc/striatum), it is going be hard to separate the two effects with Ibogaine by using non-hallucinogenic analogs...but that's assuming detox mechanism via kappa ?

imho if one is seriously considering Ibogaine detox (stim/opiates but not alcohol or benzos) and worry about cardiac toxicity, then he should try a Kappa agonist+NMDA antagonist to get same result as Ibogaine without worrying about cardiac problems. The so-called "hallucinations" will still be there though only this time via a kappa agonist other than Iboga indoles alkaloid. The reason for adding NMDA antagonist is that it counters the dysphoric effect of kappa agonism so it makes it make it easier to redose without beeing pissed off by the dysphoria of kappa agonists. Remember, kappa seems to do the exact opposite of stim/opiates in NAcc and striatum including the opposite of euphoric effect of stims ie dysphoria and aversion... Which may help explains why Ibogaine as well as other kappa agonists developed by pharma don't work on alcohol or nicotine addiction. I guess they won't work on GABAergic benzos either!!?

So bottom line: the anti-addiction effect of ibogaine and the hallucinations are one and the same thing. Just my opinion.

(someone on this forum or reddit has mention a3b5 nicotinic channels blockade by Ibogaine as basis of its anti-addiction properties. does anubdy have a ref on that? thanks)

The combination of a 5ht3 antagonist and a d2 agonist reverses sensitisation, any data on d2?

Witch regards to the toxiticy a nmda antagonist would solve that problem, or very strong antioxidants that cant turn pro oxidant, as glutamate damage is ultimately done due to oxidative stress.

IMHO, Iboga indoles alkaloids "hallucinations may be required for anti-addiction activity. At least with psychostimulants and opiates but not alcohol or nicotine!. Here is why imho:

For one, Ibogaine is a kappa opioiod receptor agonist and kappa activation is pretty well known to induce hallucinations. Example: the selective kappa agonist Salvia (Salvinorum A) is hallucinogenic .

I disagree with this, remember every drug upregulates KAPPA, and kappa is basicly the evil reward receptor, the opposite of mu which is the end pleasure receptor, thats why naltrexone doesnt cause anhedonia, it also blocks the evil receptor.

also plenty anecdotes involving daily treshold doses contradict you, and for example the rodent study showing it reverses epigenetic changes of meth addiction.

Also comeone they must know what causes the arrythemia, im sure it can easily by counteracted.

 

[Cotcha Yankinov]

If that was true wellbutrin would be as good, maybe it isnt because its underdosed but then ppld would die of a seizure, well they can take the pick btw that or arrythemia.

Do you think wellbutrin's a3b4 antagonism is significant? I'd sure like to try it...

 

[serotonin2A]

If that was true wellbutrin would be as good, maybe it isnt because its underdosed but then ppld would die of a seizure, well they can take the pick btw that or arrythemia.

Wellbutrin is a potent NET inhibitor. You might not be able to achieve more than a small amount of nicotinic blockade before you hit a dose that causes a seizure.

Any idea what causes the arrythmia? that way we can prevent te risk, ive taken it in microdoses with etylphenidate, mpa and 5 meo dalt before, but id rather experiment more safely in the future.

Arrhythmia is often cause br hERG channel blockade or inhibition of another cardiac ion channel. No way to block those types of effects.

No point in making it non psychoactive just throw a 5ht2a antagonist like seroquel on top of it.

Ibogaine is not simply a 5-HT2A agonist. In fact, that action is probably a minor component. The two main effects appear to be kappa agonism and NMDA-R blockade. You could give a kappa antagonist, but good luck blocking the action on NMDA.

 

[MeDieViL]

Wellbutrin is a potent NET inhibitor. You might not be able to achieve more than a small amount of nicotinic blockade before you hit a dose that causes a seizure.
Arrhythmia is often cause br hERG channel blockade or inhibition of another cardiac ion channel. No way to block those types of effects.




Ibogaine is not simply a 5-HT2A agonist. In fact, that action is probably a minor component. The two main effects appear to be kappa agonism and NMDA-R blockade. You could give a kappa antagonist, but good luck blocking the action on NMDA.

I was just replying to the discussion of making a non psychoactive version, eg just block the psychoactive receptor, well dunno how strong it acts on kappa, i dont think strong enoug for psychoactive effects as kappy agaonists tend the need to induce sensitization or whatever before they become psychoactive, eg salvia, also i never tough its nmda antagonist was psychoactive, it doesnt sound to be dissociactive.

Well i admit im not familiar with the cardiac ion channels that much, but we can for example counteract calcium channel induced arrythemia with a antagonist or even phenytoin or other anti arrythemic agents, any info on how much they can "overwrite:" eachother, for example the anti arrythemic effect of propranolol can easily be reversed by calcium agonism, while verapamil and phenytoin cover more broad sprectrum caused problems.

 

[adder]

Ibogaine doesn't sound to be dissociative? All the reports of flood doses I read sound like deep dissociative state and wandering around your mind, actually sounds a lot like Salvia Divinorum experience but much much longer lasting. It could be a result of both dissociative effect caused via NMDA receptors and/or sigma receptors and serotonin reuptake inhibition. I experienced similar states after DXM though they were mostly abstract at moderate doses rather than making up long stories that you take part in. Certain arylcyclohexanamines produce similar effects too. Still, that's what dissociation is in my experience, losing contact with your environment and experiencing deep continuous introspection however it is effected.

 

[MeDieViL]

I stand corrected in that case, still the fact remains that it works in low daily treshold doses for plenty of people so i doubt a dissociative experience is implicated, the actual trip.

As i hypothised earlier that i suspected it also acts on d2, as its a 5ht3 antagonist and that combination reverses sensitization, which can mean a drug becoming active, a drug inducing brain changes or a drug inducing addiction it seems that a quick google search shows up some results, but as my girlfriend completely crashed my computer trying to download porn im running android from usb so its very slow, so if anyone is willing to look at the literature..

Ibogaine really seems to target everything, its a common thing in nature, alot of supplements target alot of benefical health pathways which also induce negative effects, but at the same time do something to counteract that negative effect. This is the evidence of god, or rather the evidence of completel and utter chaos and ramndomness with things that do it just right, like that girlfriend tells me

 

[serotonin2A]

I was just replying to the discussion of making a non psychoactive version, eg just block the psychoactive receptor, well dunno how strong it acts on kappa, i dont think strong enoug for psychoactive effects as kappy agaonists tend the need to induce sensitization or whatever before they become psychoactive, eg salvia, also i never tough its nmda antagonist was psychoactive, it doesnt sound to be dissociactive.

I ujdersrood your point. But the psychoactive effects of ibogaine are a combination of effects on NMDA-R, kappa, 5-HT2A. In addition, there is the weird sigma2-cerebellar excitation, which undoubtely influences the subjective effects. Ibogaine doesn't have ketamine-like effects but that doesn't mean that NMDA-R blockade doesn't make an important contribution to the psychoactive effects.

Importantly, ibogaine substitutes for the discriminative stimulus effects of the NMDA-R antagonist MK-801: http://www.ncbi.nlm.nih.gov/pubmed/7473163

l

Well i admit im not familiar with the cardiac ion channels that much, but we can for example counteract calcium channel induced arrythemia with a antagonist or even phenytoin or other anti arrythemic agents, any info on how much they can "overwrite:" eachother, for example the anti arrythemic effect of propranolol can easily be reversed by calcium agonism, while verapamil and phenytoin cover more broad sprectrum caused problems.

Those types of effects are a death sentence for drugs in development. There is no way to effectively and reliably block the effects in all patients. The only solution is to look for an analog that doesn't produce the effect

 

[MeDieViL]

Im quite positive that ppl with arrythemia suffer from some type of simular dysfunctioning, eg ppl have arrrythemia because of all sorts of causes and drugs can compltely controll that in most cases, rodent research where ibogaine is administired togheter with other arrythemia excarbuating agents and looking what substances that can inhibit it, i beleive can give us a good idea on safely.

For example, no matter what causes long QT syndrome a high dose of a beta blocker ipretty much allways counters the dangers, as it just blocks the flood right before hilary clintons mansion. In hilarys case its allright if it faile to make something better.

 

[MeDieViL]

Haha im so higly educated on tolerance and addiction, i know what meds work and what pathways are involved, i just tought of CCK as proglumide works for morphine tolerance in studies and one anecdotes reported dramatic tolerance reversal to all drugs after just one time administration, and what i found

changes in gene expression and signal transduction following
www.ibogaine.desk.nl/ch07.pdf
by ES ONAIVI - ‎Cited by 2 - ‎Related articles
A. Ibogaine: Changes in Programs of Gene Expression and ..... (GABA), dynorphin, serotonin (5-HT), and cholecystokinin (CCK), in the Acb and in other brain

Again i cant read much info as i cant load windows because of all the spyware my girlfriend installed trying to get porn on a blocked mobile hotspot lol.

Im just thinking off another target lets see wheter im spot on again

 

[serotonin2A]

Im quite positive that ppl with arrythemia suffer from some type of simular dysfunctioning, eg ppl have arrrythemia because of all sorts of causes and drugs can compltely controll that in most cases, rodent research where ibogaine is administired togheter with other arrythemia excarbuating agents and looking what substances that can inhibit it, i beleive can give us a good idea on safely.

For example, no matter what causes long QT syndrome a high dose of a beta blocker ipretty much allways counters the dangers, as it just blocks the flood right before hilary clintons mansion. In hilarys case its allright if it faile to make something better.

It is true that arrhythmia can occur for a number of reasons and can sometimes be reversed in an emergency. But even with treatment, some people die of arrhythmia. The FDA would never approve a medication that is only safe if has to be taken with another medication. There is always the possibility that some patients couldn't tolerate the second medication or that it wouldn't work in some patients.

Many many drugs in the pipeline have been killed by hERG activity or by similar cardiac side-effects. It is a huge red flag. Despite what you think, drug development normally doesn't move forward when a drug is found to have that type of activity.

If ibogaine is truly effective then it should be possible to develop a derivative with a better safety profile. What is so special about the ibogaine molecule that it can't be tweaked structurally to produce a safer version?

 

[Cotcha Yankinov]

I was under the impression CCK antagonists might be relieving the anti-opoid effects of CCK rather than mediating some more genuine tolerance reduction (https://www.ncbi.nlm.nih.gov/m/pubmed/9185235/?i=5&from=/8783319/related) but I suppose if upregulation of CCK is playing a role in opiate tolerance then CCK antagonists are indeed dealing with tolerance reduction (at least while the CCK antagonist is bound). I suppose in that case a CCK inverse agonist would be pretty cool?