Paper Proposing Hypotheses for DiPT's mechanism of Sound Distortion

[tuppingtoncity]

https://doi.org/10.1093/braincomms/fcag093

This paper is pretty interesting. Although purely hypothetical, I'm glad to see someone at least proposing a mechanism for what is in my opinion one of the most fascinating neuropharmacological mysteries to me in the realm of psychedelics.

The first hypothesis suggested by the paper tries to explain DiPT's tonal distortion mechanism as a result of tonotopic disruption. The second hypothesis suggests that there may be some sort of potassium channel disruption causing DiPT to alter the stiffness of cochlear membranes.

I don't know enough about the auditory system to know if these hypotheses are tenable, but the latter seems straightforward to test experimentally. Not entirely sure about the first, maybe some fMRI magic?

 

[Allylbenzene]

Interesting. Considering the variety of receptors involved, here's a comparison between DiPT and LSD from this paper:

A new method is introduced for normalizing affinity (Ki) data that factors out potency so that the multi-receptor affinity profiles of different drugs can be directly compared and contrasted.

DIPT: 4.00 5ht1a, 3.53 Imidazoline1, 3.48 5ht2b, 2.98 SERT, 2.83 Sigma1, 2.68 Alpha2C, 2.65 Sigma2, 2.62 Alpha2B, 2.56 D3, 2.55 5ht7, 2.53 H1, 2.51 5ht1d
• 0.00: 5ht2a, D4, 5ht5a, D1, D2, Alpha2A, 5ht6, D5, Beta1, Beta2, 5ht2c, DAT, NET, 5ht1b, Alpha1B, 5ht1e, DOR, KOR, MOR, M1, M2, M3, M4, M5, Alpha1A, H2, CB2, CB1, Ca+Channel, NMDA

LSD: 4.00 5ht1b, 3.77 5ht7, 3.75 5ht6, 3.73 5ht1a, 3.70 5ht1d, 3.64 5ht5a, 3.54 5ht2a, 3.16 D3, 3.11 5ht2b, 3.11 5ht2c, 2.93 Alpha2A, 2.62 5ht1e, 2.55 D2, 2.39 D4, 2.34 D1, 2.05 D5, 1.54 Alpha1A, 1.40 H1, 1.39 Beta1, 1.05 Beta2, 0.65 Alpha1B
• 0.00: KOR, DOR, DAT, SERT, MOR, NET

 

[arrall]

This is fascinating!
I've long used DiPT as an example of the wonders that psychedelics can have for research (including at a talk I gave at a conference last year and a similar talk I am giving next month) so this is very useful
Thank you for sharing!

 

[arrall]

PDF link for those interested in reading - https://academic.oup.com/braincomms/article/8/2/fcag093/8644266?login=false

 

[tuppingtoncity]

PDF link for those interested in reading - https://academic.oup.com/braincomms/article/8/2/fcag093/8644266?login=false

thanks for that! my bad I thought the doi would be functional

 

[tuppingtoncity]

DIPT: 4.00 5ht1a, 3.53 Imidazoline1, 3.48 5ht2b, 2.98 SERT, 2.83 Sigma1, 2.68 Alpha2C, 2.65 Sigma2, 2.62 Alpha2B, 2.56 D3, 2.55 5ht7, 2.53 H1, 2.51 5ht1d
• 0.00: 5ht2a, D4, 5ht5a, D1, D2, Alpha2A, 5ht6, D5, Beta1, Beta2, 5ht2c, DAT, NET, 5ht1b, Alpha1B, 5ht1e, DOR, KOR, MOR, M1, M2, M3, M4, M5, Alpha1A, H2, CB2, CB1, Ca+Channel, NMDA

interesting that DiPT has absolutely no affinity for 2a. I guess that makes sense given the lack of psychedelics effects; but I think I was naturally assuming some affinity, just very low efficacy. Guess not!

 

[Allylbenzene]

interesting that DiPT has absolutely no affinity for 2a. I guess that makes sense given the lack of psychedelics effects; but I think I was naturally assuming some affinity, just very low efficacy. Guess not!

The overall picture is quite unexpected in some ways. 5HT7 looks to be as important as 2a. There's a good video presentation about this on Shulgin's publisher site:

Breadth and Depth - TransformPress

Tom Ray builds on the work of the Shulgins, taking the next steps they envisioned:

transformpress.com

 

[TheLightBringer]

Interesting, I wonder what the long term ramifications of dosing something that disrupts potassium channels and alters cochleal stiffness would be. Say if someone took this daily for months…

 

[tuppingtoncity]

Interesting, I wonder what the long term ramifications of dosing something that disrupts potassium channels and alters cochleal stiffness would be. Say if someone took this daily for months…

definitely an interesting question, I would assume probably nothing too severe, DiPT's 5-HT2b agonism might be a bigger worry if dosing for months at a time. Luckily I doubt any human will ever do that, unless they're being a guinea pig for the sake of being a guinea pig

 

[TheLightBringer]

definitely an interesting question, I would assume probably nothing too severe, DiPT's 5-HT2b agonism might be a bigger worry if dosing for months at a time. Luckily I doubt any human will ever do that, unless they're being a guinea pig for the sake of being a guinea pig

Hahaha true, I was mainly concerned about it altering the function of the cochlea long term possibly leading to changes in hearing. But youre right that 5ht2b agonism will likely getcha first…