- introduced in the context of the effects of ibogaine and iboga alkaloids at monoamine neurotransmitter transporters.

How does ibogaine accomplish its wide variety of therapeutic and psycho-social effects? This article (@J_A_C_S) is the foundational piece of a new theory - the iboga matrix pharmacology –🧵 pubs.acs.org/doi/full/10.102…

Check out the Nature Research Briefing on this: nature.com/articles/d41586-0…

A Molecular Tale of Toad Psychedelic and the Role of 5-HT1A Receptor in Psychedelic and Therapeutic Effects: nature.com/articles/s41586-0… Congratulations to @LankriDavidIL and Audrey and all coauthors in this collab with @WackerLab and @ScottRusso, published in @Nature.

SERTlight, a fluorescent substrate of SERT, enables the visualization of serotonergic neurons without genetic manipulation. It doesn't modulate serotonin/other receptors, providing a new tool for the study of the 5-HT system & therapeutics. @J_A_C_S pubs.acs.org/do21/jacs.3c116…

In our view, if the latter was the case, we would have seen a signal with > 40K compounds and millions of peptides. However, to be clear, we have not published on psychedelics and TrkB activity yet. Stay tuned, we aim to report on this topic in the near future. (12/12)

To summarize, our results and experience indicate that TrkB is not readily modulated by small molecule drugs, which stands in sharp contrast to the claims that TrkB is modulated by a variety of antidepressants, now including psychedelics. (11/)

Our findings were supported by an independent publication by another group (journals.plos.org/plosone/ar…) and a number of personal email communications attesting to failures of small molecule modulators of TrkB. (10/)

Furthermore, we have screened ~ 100M small peptides using the phage display technology - with the same overall negative results. (9/)

Further, in collaboration w/ @BroadInstitute at MIT and Harvard, we have screened a 40K+ drug-like compound library; none of the hits survived confirmatory tests to show robust and dose- dependent TrkB activity in either agonistic or PAM modes. (8/)

...and his PhD dissertation (academiccommons.columbia.edu…). In brief, we have found that none of the published compounds act as direct modulators of TrkB. (7/)

Our lab has been working on these plasticity-inducing agents for more than 10 years. We have invested major effort to find small molecule agonists and PAMs of TrkB, as you can see in Umed Boltaev’s paper science.org/doi/10.1126/scis… (6/)

The topic was quite controversial at the time, reproducibility issues were discussed at conferences and via personal communications within the TrkB/RTK (receptor tyrosine kinases) field. (5/)

The flavonoid 7,8-DHF in particular has attracted much attention (>100 papers) as a plasticity-inducing compound and a TrkB agonist. (4/)

In many ways, this is a throwback to papers published yrs ago that reported a variety of small molecules acting as either direct agonists or allosteric modulators of TrkB. Plus various small peptides were reported to bind and or modulate TrkB directly. (3/)

These reports together suggest that TrkB is a shared molecular node for a diverse set of antidepressants; they also suggest that TrkB is readily “drug-able” with small molecule therapeutics. (2/)

The noted paper in Nature Neuroscience claims LSD & psilocin directly bind the BDNF receptor TrkB and facilitate its signaling as an allosteric modulator. This report is a follow-up to prev. work claiming ketamine, fluoxetine, and imipramine also bind to & potentiate TrkB. (1/)

Thank you for your comments and questions, in response we elaborate here. (Thread)