Nootropics DET/DMT synergy suggest a distinct "Psychedelic Modulator" subclass—structural & observational notes

[pantsoph]

It would be interesting to see if they stand out in the progression from methyl to propyl.

Also, just gonna be forthright with my bias here: I think in silico work is great for hypothesis generation, but it needs validation in actual biological systems.

I agree.

Classic Psychedelic Reference Compounds at 5-HT₂A

Compound	Amine–ASP155 (Å)	TRP Score	4-Sub Contacts	Key Contacts
DOM	2.86	0.246	ASN343 (3.40 Å), LEU229 (3.40 Å)	TYR370
DET	4.90	0.135	N/A	SER159, PHE340
DMT	4.59	0.178	N/A	SER159, PHE339/PHE340
DOET	4.27	0.293	SER242 (3.67 Å), PHE340 (3.77 Å)	ILE152 (2.70 Å)
2C-D	6.48	0.316	LEU229, SER239, ASN343	SER242-amine, PHE339/PHE340
2C-E	6.45	0.304	ASN343 (3.52 Å), PHE339 (3.99 Å)	SER242-amine, PHE339/PHE340
α-Ethyl-DOM	3.43	0.284	SER239 (3.41 Å), ASN343 (3.62 Å), LEU229 (3.68 Å)	TRP151 (3.80 Å)

Key Observations:
1. DOM is the structural reference standard
DOM maintains the tightest amine–ASP155 salt bridge (2.86 Å). The 4-methyl group packs cleanly against LEU229 and ASN343 without displacing the amine. The anchor is prioritized, and the TRP score remains moderate (0.246).
2. 2C-D and 2C-E lose the salt bridge entirely
Both compounds have the amine displaced > 6 Å from ASP155. This is a major structural shift:

• The amine instead H-bonds to SER242.
• ASP155 contacts the 2-methoxy group instead of the amine.
• 2C-E has a tighter ASP155–methoxy contact (3.32 Å) than 2C-D (3.46 Å) , suggesting the ethyl group pushes the ring further into the pocket and pulls the methoxy closer to ASP155.
• Both gain higher TRP scores (0.316 and 0.304) as the ring drops deeper into the orthosteric pocket.
• The 4-ethyl in 2C-E reaches further into the lipophilic pocket than the 4-methyl in 2C-D, touching PHE339 CZ at 3.99 Å.

3. DOET balances both anchor and lid
DOET maintains a moderate amine anchor (4.27 Å) while achieving a strong TRP score (0.293) and the best lid contact of the set (ILE152, 2.70 Å). The 4-ethyl contacts SER242 and PHE340.
4. α-Ethyl-DOM is the most balanced modulator candidate
α-Ethyl-DOM maintains a good amine anchor (3.43 Å) while achieving a strong TRP score (0.284). The α-ethyl reaches toward TRP151 (3.80 Å), distributing contacts across the deep pocket, the anchor, and the lid simultaneously.
5. DMT and DET maintain moderate anchors but low lid engagement
DMT and DET keep moderate amine anchors (4.59/4.90 Å) but have the lowest TRP scores (0.178/0.135). The tryptamine scaffold does not stack effectively with the pocket tryptophans.

Metrics:
Amine–ASP155 (Å): Distance between the ligand amine nitrogen and the closest ASP155 carboxylate oxygen. Lower = tighter salt bridge. < 3 Å = strong ionic H-bond; 3–5 Å = moderate; > 5 Å = amine displaced.
TRP Score: π-stacking between the ligand aromatic ring and all pocket tryptophans (TRP141, TRP151, TRP336, TRP367). Higher = more π-stacking.
4-Substituent Contacts: Receptor residues within 4 Å of the 4-position substituent carbons. Shows where the 4-sub packs—deep pocket, backbone, or lid.

 

[Skorpio]

I agree.

Classic Psychedelic Reference Compounds at 5-HT₂A

Compound	Amine-ASP155 (Å)	TRP Score	4-Sub Contacts	Key Contacts
DOM	2.86	0.246	ASN343 (3.40 Å), LEU229 (3.40 Å)	TYR370
DET	4.90	0.135	N/A	SER159, PHE340
DMT	4.59	0.178	N/A	SER159, PHE339/PHE340
DOET	4.27	0.293	SER242 (3.67 Å), PHE340 (3.77 Å)	ILE152 (2.70 Å)
2C-D	6.48	0.316	LEU229, SER239, ASN343	SER242-amine, PHE339/PHE340
2C-E	6.45	0.304	ASN343 (3.52 Å), PHE339 (3.99 Å)	SER242-amine, PHE339/PHE340
α-Ethyl-DOM	3.43	0.284	SER239 (3.41 Å), ASN343 (3.62 Å), LEU229 (3.68 Å)	TRP151 (3.80 Å)

DOM is the reference standard — tightest amine-ASP155 salt bridge (2.86 Å). The 4-methyl packs cleanly against LEU229 and ASN343 (both 3.40 Å) without displacing the amine. Anchor is the priority.
2C-D and 2C-E lose the salt bridge entirely — amine at 6.48/6.45 Å from ASP155. In exchange, they gain the highest TRP scores (0.316/0.304). The ring drops deeper into the orthosteric pocket. ASP155 contacts the 2-methoxy instead (3.46/3.32 Å). The 4-ethyl reaches further into the lipophilic pocket than 4-methyl, touching PHE339 CZ at 3.99 Å.
DOET balances both — moderate amine anchor (4.27 Å) with strong TRP score (0.293) and the best lid contact of the set (ILE152, 2.70 Å). The 4-ethyl contacts SER242 and PHE340.
α-Ethyl-DOM is the most balanced — maintains a good amine anchor (3.43 Å) while achieving a strong TRP score (0.284). The 4-methyl packs against SER239, ASN343, and LEU229. The α-ethyl reaches toward TRP151 (3.80 Å). This compound distributes contacts across the deep pocket, the anchor, and the lid simultaneously.
DMT and DET keep moderate anchors (4.59/4.90 Å) but the lowest TRP scores (0.178/0.135). The tryptamine scaffold can't stack effectively with the pocket tryptophans.

Metrics:
Amine-ASP155 (Å): Distance between the ligand amine nitrogen and the closest ASP155 carboxylate oxygen. Lower = tighter salt bridge. < 3 Å strong ionic H-bond, 3-5 Å moderate, > 5 Å amine displaced.
TRP Score: π-stacking between the ligand aromatic ring and all pocket tryptophans (TRP141, TRP151, TRP336, TRP367). Calculated as exp(−(d − d₀)/λ) × (90 − θ)/90 where d = ring centroid distance, θ = plane angle, d₀ = 7 Å, λ = 2 Å. Higher = more π-stacking.
4-Substituent Contacts: Receptor residues within 4 Å of the 4-position substituent carbons. Shows where the 4-sub packs — deep pocket, backbone, or lid.

Yeah like all of this ai construction really feels like you are running with a basic hypothesis and building so many other elements on top of it.

I worry that LLMs allow people to string together a web of plausible hypotheses, any one of which is interesting and worth testing, but as a whole they are as nimble and as long lived as a rat-king.

 

[pantsoph]

Yeah like all of this ai construction really feels like you are running with a basic hypothesis and building so many other elements on top of it.

I worry that LLMs allow people to string together a web of plausible hypotheses, any one of which is interesting and worth testing, but as a whole they are as nimble and as long lived as a rat-king.

I appreciate the concern about AI-generated webs. That's a real risk. But this framework is anchored in measurable docking data. For reference: (R)-EaM has an amine-to-ASP155 distance of 4.59 Å. This checks out when compared with my own personal experience with the compound when compared to my experience with other phenethylamines and reports I've read. 25E-NBOH has a salt bridge of 3.81.

 

[Skorpio]

I appreciate the concern about AI-generated webs. That's a real risk. But this framework is anchored in measurable docking data. For reference: (R)-EaM has an amine-to-ASP155 distance of 4.59 Å. This checks out when compared with my own personal experience with the compound.

I think we might have to simply agree to disagree on this one. I am not really party to the whole “drug experiences counting as evidence for chemical/biophysical phenomena” due to the messy subjectivity of the experience.

It feels like you are using that docking dataset to both create and validate your hypothesis which is a bit tautological.

 

[pantsoph]

I think we might have to simply agree to disagree on this one. I am not really party to the whole “drug experiences counting as evidence for chemical/biophysical phenomena” due to the messy subjectivity of the experience.

It feels like you are using that docking dataset to both create and validate your hypothesis which is a bit tautological.

i dont know what tautological means but sounds good

 

[Allylbenzene]

i dont know what tautological means but sounds good

Is English your first language?
I'm asking since if you're using some kind of translation software it could be helpful to know.

 

[pantsoph]

Is English your first language?
I'm asking since if you're using some kind of translation software it could be helpful to know.

yes english is my first language haha

 

[Skorpio]

i dont know what tautological means but sounds good

Circular reasoning. You are using data to make your hypothesis and then using that same data to test the hypothesis. It will be correct by definition.

It would be like me asking “if I stuck a screwdriver into an apple and then removed it, would the screwdriver fit into the hole left in the apple?”

 

[pantsoph]

Circular reasoning. You are using data to make your hypothesis and then using that same data to test the hypothesis. It will be correct by definition.

It would be like me asking “if I stuck a screwdriver into an apple and then removed it, would the screwdriver fit into the hole left in the apple?”

i made the hypothesis and then generated the data. The original Modulator post went up on August 10th. The docking table went up today (August 12th). The timeline is in the thread.

 

[Skorpio]

i made the hypothesis and then generated the data. The original Modulator post went up on August 10th. The docking table went up today (August 12th). The timeline is in the thread.

Forgive me, I thought all of this data was included in that paper you are working on.

Are docking programs still shit at handling mutagenesis? Because you could bolster your data by doing an alanine screen of key residues and analyzing the effect on your binding data. That would be a decent control.

 

[pantsoph]

Forgive me, I thought all of this data was included in that paper you are working on.

Are docking programs still shit at handling mutagenesis? Because you could bolster your data by doing an alanine screen of key residues and analyzing the effect on your binding data. That would be a decent control.

yeah i could mutate the 6wgt pdb in chimerax and compare thedocking results. which residues do you think would be best to inspect?

 

[Skorpio]

yeah i could mutate the 6wgt pdb in chimerax and compare thedocking results. which residues do you think would be best to inspect?

Honestly for rigor I would go with all of the Trps in the TRP score metric, Asp155, as well as any mentioned contact point you mention.


Does your docking system allow relaxation and equilibration of the mutated protein? This could be an issue if a switching a hydrophilic amino acid for an alanine (though I wouldn’t go for a glycine as that will mess up folding even more).

Another decent test to see how the system handles mutagenesis is throwing a bunch of bulk into the binding pocket (PHE usually) or removing the side chains (by mutating to Gly) and seeing how the binding is affected. If things still bind after these interventions than your binding software isn’t suited for mutagenesis.

 

[pantsoph]

Honestly for rigor I would go with all of the Trps in the TRP score metric, Asp155, as well as any mentioned contact point you mention.


Does your docking system allow relaxation and equilibration of the mutated protein? This could be an issue if a switching a hydrophilic amino acid for an alanine (though I wouldn’t go for a glycine as that will mess up folding even more).

Another decent test to see how the system handles mutagenesis is throwing a bunch of bulk into the binding pocket (PHE usually) or removing the side chains (by mutating to Gly) and seeing how the binding is affected. If things still bind after these interventions than your binding software isn’t suited for mutagenesis.

Good point. Do you know if there's published mutagenesis data for 5-HT₂A at ASP155 or the ECL2 tryptophans? If there's experimental work to compare against, it could help verify the docking results.

 

[Skorpio]

I agree that in silico needs biological validation. I'd be more interested in comparing against published mutagenesis data for 5-HT₂A if it exists—docking into mutated structures and seeing if the predictions line up with experimental binding shifts. I'm not sure how much data is out there for the residues I'm looking at, but that would be the more meaningful test than running more docking in isolation.

Look into work coming out of the Coyote-Maestras lab at UCSF. Willow and his grad students have done some pretty interesting mutational screens on GCPRs and you might be able to find a decent resource.

I’d worry that you might not find a wealth of point mutants in the PDB just because crystallizing and shooting a protein tends to be quite labor intensive, which constrains things.

I would certainly reccomend against using Alphafold or rosettafold to perform the mutagenesis as per this paper’s concerns

https://www.biorxiv.org/content/10.64898/2026.06.29.735309v1

 

[pantsoph]

Look into work coming out of the Coyote-Maestras lab at UCSF. Willow and his grad students have done some pretty interesting mutational screens on GCPRs and you might be able to find a decent resource.

I’d worry that you might not find a wealth of point mutants in the PDB just because crystallizing and shooting a protein tends to be quite labor intensive, which constrains things.

I would certainly reccomend against using Alphafold or rosettafold to perform the mutagenesis as per this paper’s concerns

https://www.biorxiv.org/content/10.64898/2026.06.29.735309v1

Appreciate the pointer—I'll look into the Coyote-Maestras lab's work and see what mutational data they've published. And good to know about the AlphaFold/RosettaFold caveat; I've been using the experimental structures (6WGT, 6WHA) for docking, so I'd want to stay with those for any mutation comparisons rather than switching to predicted structures.

 

[Skorpio]

I've been using the experimental structures (6WGT, 6WHA) for docking, so I'd want to stay with those for any mutation comparisons rather than switching to predicted structures.

I think this is quite prudent.

 

[xdrc]

I haven't read much of the other stuff here, but...

Could the gentleness simply be a consequence of the pharmacokinetic properties which result in a longer duration?

Also how much longer is the duration of DOEt than DOM, and how much more gentle is it considered? I feel like that comparison should be a lot more linear, as the DMT->DET comparison also has major differences in monoamine oxidase susceptibility which confound the comparison at the 5HT2a receptor.

A friend recently tried DOET. It's psychedelia really seems to be muted even at higher dosages. I always thought Shulgin's hint that it is not psychedelic was just because they did not want DOET to have the same fate as DOM so they did not report of higher dosages, but that is not true.

IIRC he also tried some sort of "nootropic"-ish combination of DOET/Ariadne/2C-D he was fond of.

 

[pantsoph]

I haven't read much of the other stuff here, but...

A friend recently tried DOET. It's psychedelia really seems to be muted even at higher dosages. I always thought Shulgin's hint that it is not psychedelic was just because they did not want DOET to have the same fate as DOM so they did not report of higher dosages, but that is not true.

IIRC he also tried some sort of "nootropic"-ish combination of DOET/Ariadne/2C-D he was fond of.

thank you for sharing! I'll need to look into what Ariandne is, but that sounds very interesting.

I tagged this thread under nootropics because I have gotten than same idea from my four experiences with (R)EaM.

It feels more like a nootropic or a functional smart drug than a classic drug to me. One of my friends tried it and said they didn't really feel anything from it. It's utility is as a modulator or functional stimulant at low dosages imo. Its all very preliminary so I am proceeding with caution. I think I'm gonna be experimenting with doses below 100ug for a while.

 

[iom]

A friend recently tried DOET. It's psychedelia really seems to be muted even at higher dosages. I always thought Shulgin's hint that it is not psychedelic was just because they did not want DOET to have the same fate as DOM so they did not report of higher dosages, but that is not true.

Interesting. I'm not aware of many reports of DOET at all. I don't know if it was ever circulated widely, perhaps because of its effects profile. Even more interesting is that DOPR does appear psychedelic and is spoken of favorably in the few reports I've seen.

Also this report in PIHKAL is not like the others:

(with 2.5 mg [DOET]) There is much, too much, movement with my eyes closed.And an awful lot there with my eyes open. The movement on the concrete floor in the basement when I went downstairs for wood for the fireplace, was too much. I felt almost sea-sick. And I am having reality problems--I cannot seem to find my centering point of reference. There has to be a place to pin myself down to, and it is not findable anywhere I look. And my legs are twitching, and feeling as if they are falling asleep, and I had a crawling sensation on my body, so the body is not at peace either. In the morning I was still++, but there is a clear indication that I am repairing. Anyway, I survived the experience. This is definitely not my thing.

Possible genetic differences? It would be nice to know.

 

[Freeotrope]

That’s a fascinating paper—the dimer model could actually provide a mechanistic explanation for what we're seeing. If the receptor operates as a dimer, a modulator binding to one subunit could allosterically influence the other, which would explain the extended duration and shifted profile without a simple additive effect. The Owsley reference is also very interesting; I hadn’t seen that clip before, but it lines up with the anecdotal reports I've heard. To answer your other question—yes, LSD has been reported to extend DMT trips in some contexts, but the effect seems to be less consistent than with DET. I think that's partly due to LSD’s own strong receptor activation and long duration, which may not allow for the same modulation profile.



The DET/DMT observations come from community lore—the grapevine rather than a single published source. Shulgin alludes to similar synergy in his notes on DET and DOET, and I've seen it corroborated in multiple informal reports. The (R)-EaM data, however, comes from my own personal experience, which I documented in a trip report here: https://www.bluelight.org/community/threads/trip-report-the-dennis-brown-session.955029/ That report includes the full stack, ROA, and observations on the modulator’s role in stretching duration and smoothing the experience. If anyone else has experience with modulator combinations, I'd be very interested to hear it.

I wouldn't have even remembered it except for the source. If so you that provides a whole other pharmaceutical approach - how does 50% saturationg of ht2a with det or perhaps a longer lasting version of det changing the signaling of endogenous serotonin?


that homomer study was in transfected cells, its interesting to mecause it shows corsstalk between the two units, but it is in transfected so in artificial system (chinese hamstery ovary cells)


another study shows the psychedelic induced head twitch response is absent in mGluR2 knock out mice, as well as activation of the transcription factor egr-2, suggesting the psychedelic effect may depend on 5ht2a/mglur2 heteromers . https://pmc.ncbi.nlm.nih.gov/articles/PMC3064746/

5ht2a is also thought to heteromize with i think D2 dopamine receptor, CB-1 receptor and even maybe grhelin, the receptor related to hunger? is that why I don't feel hungry till i come down? There's a lot of gpcrs out there, and then also tons of other stuff they bind to they go in lipid rafts bind to caveolin 1. so these things can form large complexes . its systems thing, transcription factors could change the balance of heteromers that could change intracellular signaling that could feed back on entirely other sets of genes, or something lol


there also appars to be a functional inracellular pool of 5ht2a.

There's also this paper tests 5ht2a 5ht2c and mglur2/3 agonists/antagonists in drug discrimination tasks for dmt and DiPT trained rats or mice: https://pmc.ncbi.nlm.nih.gov/articles/PMC4282596/

I wonder if its safe to take mglur2 or mglur2/3 agonists and antagonists with psychedelics

ketamine works through nmdr glutamate receptors, i wonder how pyschedelics modulate glumate signaling through mglur2. what happens if i take a mglur2 agonist or antagonist? while tripping? Anyone ever try it?