https://www.nature.com/articles/s41586-020-3008-z

Abstract:

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine—like those of other psychedelic compounds—are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog—a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

I have a hunch this will come with its own safety concerns. Like most other synthetic molecules.

"Non-hallucinogenic?! Thank God! We wouldn't want our patients to have an experience that teaches them lessons and shows them the origin of their behavior..." /s

It's a pretty simply molecule: essentially a 6-methoxy-DMT with the side chain closed onto the 2-position of the indole to form a seven-membered azepine ring. This is like pruning off the complicated terpenoid shrubbery of the ibogaine molecule.

Structure attached.

The psychedelic experience obviously has important benefits, conferring psychological insight. However, it seems the trip and the anti-addiction effects of ibogaine are occurring independently, through distinct psychological and physiological mechanisms. Ibogaine has a different safety profile to the classical psychedelics, it can affect the heart, and induces ataxia and nausea. So if the molecule can be rendered safer, more user-friendly & still useful, that seems like a step forward to me.

That’s great! This will let people who are physiologically dependent on opioids but have medical problems with their heart or who have tendencies to enter psychosis or mania access the main thing ibogaine is used for! I personally know addicts with both.

I mean yeah, it’s a cool psychedelic guys, but c’mon, do you REALLY give a crap about the people with the addictions here if this is somehow upsetting to you? People who take ibogaine by and large just want a monkey off their back, if they want a psychedelic experience to supplement their recovery they can go with ayahuasca, cactus, mushrooms, or LSD afterward if it’s psychologically safe for them to do so with zero risk of physical toxicity.

This is a good thing, it made a detox drug more accessible 🥳

A pharmaceutical grade analog of noribogaine was indeed the goal here, and I'd like to see what we will have. Cause it's true that it could help tremendously the neurotransmission.

I see your point, I just worry that this will reinforce the idea that addiction is a disease completely devoid of spiritual/emotional context, and predict that the chemical will have its own unforeseen side effects.

Iboga is very unique in its psychedelic effects; I don't think other entheogens can replace it.

But considering its safety profile, I think this is a positive development.

The psychedelic experience can play an important role in addiction treatment, as evidenced by the psychedelics that don't exhibit the same physical addiction treatment properties as iboga (LSD, ayahuasca), but it seems cruel to force a psychedelic experience onto someone who needs withdrawal taken off their back to restore a semblance of sanity.

That said, I find the iboga experience to have a relatively low freak-out factor, compared to ayahuasca for example. The visions brought on by a flood dose are intense at the beginning, but it's relatively easy to keep the mind calm.

My biased opinion:

The issue with ibogaine is that it can affect the heart. Why does the research say " possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential." It seems like they are assuming that removing the psychedelic effect is a good thing (?). That seems like an unfounded assumption, as mentioned by others in this thread. A key misstep in professional science is not being aware of (or accepting) unfounded assumptions.

They should separate out all the effects. A reductionist breakdown could me:

1) Natural Ibogaine
2) Modified to remove cardiac effects, keep others (psychedelic effects and withdrawl suppression)
3) Modified to remove cardiac and psychedelic effects (keep withdrawl suppression)
4) Modified to remove psychedelic effects (keep cardiac and withdrawl suppression)

If they are ignoring group 2) and jumping straight to group 3), they are making a mistake (again, in my biased opinion). Going for option 4) seems like scientific malpractice. I'm not sure what they went for on this paper, I'd need to spend some time with it to understand.

But how do we know it doesn't have any hallucinogenic effects?

From my personal experience with mice i can say they aren't very talkative, and i suppose the same is true for zebrafish.

I thought that with mice there was a rough head twitching rate correlation, but I'm not sure. More recently there has been a suggestion to use a magnetometer coil.

Review

I'd say with the structure used, given the methoxy being at the indole 6-positon hallucinogenic activity is fairly unlikely, eat least at 5-HT2a receptors. Will need to look at a general receptor affinity/activity profile to be able to comment on other routes of action.

But a great part of the therapeutic effects from ibogaine comes from activity on the k-opioid receptor and probably the NMDA antagonism as well.

I don't know if this new molecule is designed to also affect those receptors, but if it would be, the main difference between therapeutic and hallucinogenic use would be dose.

But anyway, if this is supposed to be a noribogaine analogue, i don't know for sure if it would be totally void of psychedelic effects. The last stage of an iboga journey is pretty distinct. Maybe the noribogaine merely modulates the effects of ibogaine, but i'm not sure it doesn't have any effects of it's own.

A few days after taking iboga rootbark, i still had some mild visual effects when i woke up in the morning. Sometimes i also had the sensation for just a few seconds, of time speeding up or slowing down.

Is it possible to get access to the full paper without paying? I don't have the means but would like to read it.

Particularly on the metabolism of this new compound. Normally iboga alkaloids are metabolized by CYP2D6 (if I'm correct) and the resulting compound(s) are responsible for long term lasting effects.

So I would be curious how this works for this new molecule.

Copy paste the paper link to sci-hub.st (or any new mirror if this one goes down) to download the full paper

This is great imo, anything that can help people with addiction should be welcomed. It might allow some people to shake their old selves in different ways, the psychological process might simply happen afterward when experiencing life without as much need and going back to noticing things in a new way.

Psychedelic both do something to you and allow you to see what is hapenning in a melting way. But life is also psychedelic and such a therapy could be coupled with meditation practices or art related things, so it might not be needed for everybody.

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