Tabernanthalog (TBG), a pro-neuroplasticity non-hallucinogenic psychoplastogen

#1

A Phenomenological Report on the Novel Non-Hallucinogenic Psychedelic Tabernanthalog

There is growing interest in the possibility of non-hallucinogenic psychedelics. The promise of such substances is to retain the psychoplastogenic effects of classic psychedelics while removing the trip. This is being done in the hopes that it would result in a drug which can be more widely and cheaply administered than classic psychedelics. It is a somewhat controversial idea, and I have written about it in more depth in an article I wrote earlier this year.

The critics of this approach point out the correlation between certain phenomenological aspects of the psychedelic trip, such as mystical experiences, and positive therapeutic outcomes. Given that these kinds of experiences also correlate with general strength of the effects, and thus dose, it is possible for those on the pro non-hallucinogenic side to then argue that perhaps the phenomenology is just a correlate of the actual underlying therapeutic effects, such as dendritic growth or changes in epigenetics. While this debate has largely been theoretical, that may not be the case for much longer. A number of potential non-hallucinogenic psychedelics are being developed, and some of them have even begun evaluation in human clinical trials as treatments for depression.

What is Tabernanthalog?

One of these potential therapeutic drugs is Tabernanthalog. It gets its name from the Tabernanthe iboga plant (the name meaning tabernanthe-analogue), which is the source of the psychedelic compound Ibogaine.

Read the full blog post here:

https://awjuliani.medium.com/a-phenomenological-report-on-the-novel-non-hallucinogenic-psychedelic-tabernanthalog-ed2fc601c1dc

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#2

Interesting stuff!

Company developing drugs around this compound and target:

#3

It’s way different from the classical psychedelics at 5-HT2A receptor. I feel like there’s a billion drugs and supplements that increase ‘neuroplasticity’ and other buzzwords. If they don’t have a clinically significant effect in a clinical trial, then it’s probably not going to do anything. Of course once you have a drug with significance then you can block the psychedelic effect, seems the better approach?

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#4

How does taking a NON-hallucinogenic “#psychedelic” compound feels like? An interesting blog report on the compound Tabernanthalog used in #DavidOlson Lab came out today, suggesting it induced a feeling of an almost “supernatural patience”, without any visual effect.

More… see this thread: https://x.com/tommaso_barba/status/1740434271284924780?s=20

#5

There’s a new paper with stronger ibogaine analogues…

Structure-based Discovery of Conformationally Selective Inhibitors of the Serotonin Transporter

Even some of the nootropics enthusiasts and biohackers appear to have moved on from TBG, too. One user suggested that the member responsible for coordinating the synthesis of TBG focus instead on “Molecule 8219”, adding that it appears to be “very potent” and “could replace TBG completely”. They’re referring to one of the molecules discussed in Singh et al. (2023), ZINC000443438219.

Figure 2.

Figure 2. Hit to lead optimization of the compound ‘2313 leading to nM SERT inhibitors.

(A) Chemical structures of the parent compound, ‘2313 and its corresponding analogs including compound ‘8090 (Ki = 14 nM) and compound ‘8219 (Ki = 3 nM). The variable group in the analogs with respect to the parent compound are colored in magenta. (B) Docked pose of the parent compound, ‘2313, (C) the optimized lead ‘8090 (D) and the most potent lead ‘8219 are represented as cartoon. Dashed circles represent the improved stacking of F335 with ring substitutions in going from parent compound to the most potent lead.

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#6

I believe most of the TBG circulating is coming from a US-based vendor. I would vouch for the few items (bromantane, TAK-653, and tropisetron) I’ve tried from them, although I haven’t tried their TBG.

There’s quite a few of these non-psychedelic 5-HT2A agonists, although it’s not known whether they also increase cortical spinogenesis. Probably the most famous is the prescription drug lisuride, and quite the effort has been made to understand why it lacks psychedelic effects.

Another example is 4C-D, which I’ve tried a handful of times myself. It doesn’t induce psychedelic effects but it certainly affects mood, in a subtle but positive way.

I feel like there’s a billion drugs and supplements that increase ‘neuroplasticity’ and other buzzwords. If they don’t have a clinically significant effect in a clinical trial, then it’s probably not going to do anything.

Ketamine’s efficacy in depressive disorders has been demonstrated in numerous clinical trials, and I think there’s quite a bit of evidence that this is occurring through neuroplasticity. Although I think the most convincing body of preclinical research suggests this occurs through functional plasticity in the hippocampus, rather than structural plasticity (e.g neurogenesis, spinogenesis, synaptogenesis, etc).

There’s also evidence that the deliriant and muscarinic antagonist scopolamine has efficacy in depression, while the related molecule benzoyltropine has low affinity for muscarinic receptors (unlikely to be deliriant), and like scopolamine increases cortical spinogenesis.

It will be interesting to know what role (if any) cortical spinogenesis and synaptogenesis plays in scopolamine’s putative antidepressant effects. The sustained antidepressant effects of scopolamine and ketamine are believed to require similar hippocampal modulation of a protein which binds methylated DNA sequences, although scopolamine’s acute effects on hippocampal functional plasticity are different than ketamine’s.

Ketamine and scopolamine also both activate mTORC1, so in that regard I wonder if they might have a negative impact on brain longevity. I certainly hope not, as I’ve used quite a bit of ketamine in my life.

I’m aware of a paper showing mTORC1 activation with chronic psychedelic administration, but I can’t remember if this has been shown with acute administration. Psychedelics will also activate the MEK-ERK and PKC axes, both of which are probably anti-longevity.

On the bright side, 5-HT2A receptors are positively coupled to transcription of VEGF, which is one of the most promising pro-longevity proteins. It’s actually been shown that 5-HT2A activation can rejuvenate aged liver in a VEGF-dependent manner.

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#7

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This IS the best solution, other than possibly MXE and tFUS (and maybe some of the other analogs discussed above). This may even be the best replacement for the loss of methoxetamine…

One of my friends went through DXM+bupropion.

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#8

Why do you think TBG will work? Why do you think MXE, etc, are the best solution?

#9

Is there evidence psychedelics improve IQ or fluid intelligence long-term in healthy animals with normal baseline in vivo? In vitro results showing increased neurogenesis are not enough, as these show the opposite effects are possible.

Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.

https://sci-hub.st/10.1016/j.bbr.2014.04.025