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Is DMT a 5ht3 agonist?

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And btw, this is not me being rude or anything, i'm just telling you, i know what's going on with this stuff, based on personal experience. I've taken this stuff way too much to not know what's going on. You can come up with other explanations but it's all just speculation unless you personally experiment around quite a lot and see for yourself what does what. I know you're convinced it's the DMT, but i'm telling you, it's not, and there are ways to figure this out, but you would need to work with this stuff more regularly, but i understand where you're coming from, no doubt, and i know people can't just take this stuff regularly like i have, i had/have a lot of free time so i was able to dive in and learn, but others unfortunately aren't as lucky.

But i'm telling you with every bone in my body, it's the Harmalas. I'd bet 100$ that it's the Harmalas, because i'm that certain, based on experience and observation. I'm a very scientific person and have done a lot of experimentation, so i for one know what's going on, i don't know the exact mechanism, but i do know it's the Harmalas that cause the nausea/vomiting, and when the DMT is added, it triggers the Harmala purge, but if the reverse tolerance is built up, the Harmala purge goes away and DMT no longer triggers it. It could have something to do with 5-HT3, but so far all the evidence seems to show that 5-HT3 is not activated by Harmalas or by DMT, so i'm willing to bet that it has something to do with Acetylcholinesterase, if not, then idk, but i do know for certain it's the Harmalas that cause the nausea/vomiting, if you want a purge-free experience, either go for Moclobemide with oral DMT, go for vaped DMT, or build up the Harmala reverse tolerance.

As for Lemon EO, ime it did seem to help with the Harmala's purgative effects, so that's definitely something to check out (6 drops in a capsule, maybe an hour before taking Aya/Pharma, may need to take the Lemon EO for a few days before mixing it with Aya/Pharma because Limonene builds up in the body because it's fat soluble and is more effective after a few days or so), however i'm not sure how much Lemon EO may alter the experience. I know it cleans up how the Harmalas feel, with or without DMT, but it may alter the DMT part of the experience as well. I haven't done much experimentation with Lemon EO combined with Aya/Pharma, so i definitely need to experiment around more with it, but i do think it helped and would be something useful to look into rather than taking Ginger or Zofran.
 
If you want an oral DMT experience without nausea/vomiting, there are at least 3 things you could do, build up the Harmala reverse tolerance by consuming a moderate to high dosage of the Harmalas at least 3 to 4 times a week for a couple weeks or so, or by using Moclobemide instead of the Harmalas, or perhaps by taking Lemon EO. So far, that's what has worked for me, and has been the most beneficial out of everything that i've tried.

If i seriously thought or even had a gut feeling or the experience that would suggest it's the DMT that causes the nausea/vomiting, i would certainly say so, but it's definitely the Harmalas. If you want to figure this stuff out, all i can say is, do the experimentation and you will see. Other than that, idk.
 
We need a "science of the Ayahuasca purge" thread, and i think some scientific research should definitely be done on this. I don't think demystifying the purgative effects would be an issue, and would help to settle this discussion.
 
*Bump*

I definitely think it could very well be because of the Harmala's Acetylcholinesterase inhibition, it makes perfect sense and pretty much every Acetylcholinesterase inhibitor i've looked up on have nausea/vomiting/diarrhea/abdominal pain/headache and other side-effects, so apparently it's quite common to reverse Acetylcholinesterase inhibition. It pretty much lists all the side-effects i've experienced from Rue/Harmalas, and Acetylcholinesterase inhibition could activate both Nicotinic and Muscarinic receptors, though i'm not sure how potently. I have noticed that Rue/Harmalas give me a similar sickness that Tobacco gave me after i had quit and started back, it made me really nauseous and vomit several times, though the Rue/Harmalas is definitely stronger, but i wonder if it'd be similar to orally ingested Tobacco. I'm not sure if the purging is Nicotinic or Muscarinic related though.

Has anyone who has mixed anti-cholinergics (like Brugmansia, Mandrake, Belladonna, etc) or some synthetic anti-cholinergic with their Aya/Pharma noticed any reduction in nausea/vomiting? We also have to keep in mind that it could be a certain receptor that may not be antagonized by these Muscarinic antagonists. Are there any known natural Nicotinic receptor antagonists?

Also, there's a plant called Lobelia Inflata, which has side-effects such as - "sweating, nausea, vomiting, diarrhea, tremors", so it's similar in cholinergic action to Acetylcholinesterase inhibitors and other cholinergic agents.

So far, this would be the most logical conclusion imo, so i'd really like for others to chime in and help to figure this out.
 
Well idk if 5-HT3 plays a role or not, perhaps it could be activated through a downstream effect by cholinergic receptor stimulation which might release Serotonin in some way, but idk, i think it really is as simple as Acetylcholinesterase inhibition causing the nausea/vomiting and such. In the case of Zofran, i think Zofran has effects of it's own because when i've taken it before by itself i definitely notice a change in how my body and mind feels, things feel a bit cleaner like an anti-depressant effect, and i get a similar feeling from Ginger as well, so i think that could help cut back on nausea/vomiting in general but also alters how the Rue/Harmalas feel and alters something about the DMT, so 5-HT3 antagonism isn't what we're looking for in terms of a solution. Idk the specifics about what all 5-HT3 antagonism can do, but to me it seemed like it was counteracting the medicine in some way, so i think we should definitely be looking at the Acetylcholine receptors especially since the side-effects are pretty much identical. I've had my instincts and observations tell me quite a lot that this stuff is cholinergic in nature, and it makes sense.

As for Histamine 1 being involved, i don't think it is. I think neurochemistry is a bit complex and different receptor agonists/inverse agonists/antagonists can have certain effects that may override things due to other receptors. And as for the rectal ROA, i've tried it a few times before, but i didn't like it as much, certainly got some effects though but one way or the other i always purge and wasn't able to hold it in the bum bum for long, lol. Besides, i very much like the oral route better, so my quest is in finding out exactly what's going on that causes these side-effects and to counteract them if possible so one wouldn't need to build up the reverse tolerance for the side-effects to go away.

As a side-note though, i've also noticed that if CYP2D6 is inhibited it can potentiate the dosage of Harmine/Harmaline and thus a lower dosage of Rue or Caapi could be used while the Harmalas would be potentiated, not only would it help one to use less plant material for full dosages, but at least in Rue's case it feels quite a bit cleaner since with lower dosages there's not as much of the other alkaloids around but you can still get the side-effects of the Harmine/Harmaline. I feel like part of it's reverse tolerance is due to Harmalas inhibiting their own metabolization with regular consumption via CYP2D6 inhibition, so the Harmalas get stronger, and less plant material can be consumed.
 
I should also note that vaped Nicotine's cholinergic effects can be potentiated/amplified by the Rue/Harmala's Acetylcholinesterase inhibition.

And, from wikipedia - "They (Nicotinic Acetylcholine receptors) possess similarities with GABAA receptors, glycine receptors, and the type 3 serotonin receptors", idk if there's a connection there or if it's just saying they posses similarities like in structure, though i think it's talking merely about structure. And, in terms of the Rue/Harmala's reverse tolerance (aside from CYP2D6 inhibition making the Harmalas stronger), the side-effects are reduced or go away possibly because of Nicotinic or maybe Muscarinic receptor desensitization.
 
Same here, they really need to study this scientifically.

But based on everything i've read and observed and experienced personally, it's definitely Acetylcholinesterase inhibition triggering Acetylcholine receptors of some kind, i highly highly doubt 5-HT3 or H1 is involved, especially since there's no existing evidence for DMT or Harmalas activating such receptors, but there's evidence for Harmine/Harmaline's Acetylcholinesterase inhibition and based on the side-effects of other Acetylcholinesterase inhibitors that to me indicates that's what's going on.

DMT definitely isn't causing the purgative effects though, it's definitely the Harmalas, i know this is difficult to wrap your head around but trust me on this, i know what i'm talking about, lol. I've done a lot of experimentation and research and i can relatively easily feel/understand this stuff through direct experience. Even if you don't get Harmala-related nausea/vomiting with moderate dosages, it can still cause nausea/vomiting when DMT is added to the mix.

One thing to take into consideration though is that a lot of different receptor systems can cause nausea/vomiting, so it doesn't have to be 5-HT3 or H1 receptors. And there's many different Acetylcholine-related sub-receptors which i know the motion sickness and vertigo and such is Acetylcholine-related, so that can be blocked out with some Acetylcholine receptor antagonist, but i'm thinking there could be other receptors that are also being activated that common anti-histamines may not antagonize, but once again common antagonists are usually Muscarinic antagonists so idk if there's any Nicotinic antagonists.

It's a given that Acetylcholinesterase inhibition causes nausea/vomiting/diarrhea/abdominal pain/headache and some other side-effects, and especially with Harmalas because they are pretty potent/strong inhibitors, especially in higher/heavier dosages, but also at moderate dosages (just not as strong, but still significant). And remember, with Moclobemide oral DMT doesn't cause any nausea or vomiting, so it's definitely something the Harmalas are doing, and i'm pretty certain based on all the evidence and personal experience/observations, that it's the Acetylcholinesterase inhibition.

If there was even a shred of evidence that 5-HT3 or H1 receptors play a role in this, i would seriously investigate it, and indeed i have tried to see if there's any connection but i'm just not seeing it. I think you may either need to shift your perspective on this matter a bit, or gain some more experience so you can see/understand what i'm talking about here. You're pretty much making assumptions based on little evidence/experimentation, so i'd say focus more on the anti-cholinergic perspective. I too used to be focused on the 5-HT3 receptor, but Acetylcholinesterase inhibition makes so much more sense. I personally notice quite a bit of cholinergic effects from Rue on it's own, and especially with Rue and DMT.
 
As far as i know, that's the only source that states DMT acts at 5-HT3, and there have been other studies that contradicts his findings apparently.

If DMT was a 5-HT3 agonist, if enough was consumed, it would cause nausea/vomiting with Moclobemide and other MAO-A inhibitors, and would also cause nausea/vomiting with Harmalas when the Harmala reverse tolerance is built up, but it doesn't, so with both Moclobemide and Harmalas it doesn't cause nausea/vomiting, the Harmalas are already known purgatives, it's a highly recognized/accepted fact that Harmalas cause purgative effects, and as i said, even if those purgative effects aren't noticeable with moderate dosages when Harmalas are taken by themselves, that doesn't mean they can't still cause nausea/vomiting with DMT in the mix because they very well can.

I know you're dead set for DMT being a 5-HT3 agonist, but i assure you it's not, if that source is all you have to go on, then that really doesn't say much at all. Also, as i've stated before, if DMT activated the 5-HT3 receptor it would cause nausea/vomiting when vaporized/smoked, or when injected through IV/IM, because there's 5-HT3 receptors in the brain and the gut. It would also cause nausea/vomiting through the rectal route if it was a 5-HT3 agonist, since rectal goes into the bloodstream which goes right into the brain which could trigger the 5-HT3 receptor, obviously. So if you're thinking about going the rectal route, might wanna keep that in mind. Personally i'd just suggest you try Moclobemide if you want to experience DMT outside of vaping, it's much better than going the rectal route i assure you.
 
Also it might help you better understand this stuff if you used something like Rue or Harmine/Harmaline mix, instead of pure Harmine. Harmaline is stronger than Harmine, and as such could help you understand that the Harmalas cause nausea/vomiting, because with pure Harmine it's a bit more difficult to tell since you don't really feel much in the way of side-effects from it by itself in a moderate dosage, but just like Harmaline, when DMT is added to the mix, the Harmala nausea/vomiting gets brought out. From my experience it's quite easy to understand this stuff and you would understand too if you were able to do some experimentation, which i understand you can't or don't want to but without the necessary experience you just can't really know much about how this stuff works, the best way to figure this stuff out is direct experience and trial/error/experimentation.

In fact, the other day i had taken 2.5 grams of Rue seed in capsules by itself and the Harmalas were potentiated by some CYP2D6 inhibition and it was enough to cause me to get nauseous and vomit. So it's definitely the Harmalas responsible for the nausea/vomiting, there's just no way one can deny those aspects of Harmalas. And once again, i've had pure Harmala extracts make me nauseous/vomit by themselves so it's definitely the Harmalas.
 
syberdelic said:
Unless you can discredit the NIMH or Nicholas Cozzi, you cannot say that DMT does not have some action on the 5-HT3 receptors.
Click to expand...
Cozzi never mentions DMT being a 5ht3 agonist at all, you are very much putting words in his mouth to support your own confirmation bias. I'm still waiting to see the actual data that graph was drawn from. A thorough search of all Cozzi's publications via google scholar did not turn up the assay that graph comes from, so we are still know nothing about the methodology used and exactly what the binding values were.

Meanwhile, we do have data that does provide methodology and values that very clearly demonstrates extremely weak affinity for 5ht3 to the point where any action at the receptor would be negligible in terms playing any role in causing or preventing nausea.

If you still want to claim DMT is a 5ht3 agonist based on a single chart in someone else's presentation, I'm afraid the burden of proof is your own.
 
syberdelic said:
I have not seen anything that contradicts the idea that DMT has ACTIVITY at the 5-HT3 site. I have seen things that indicate that it is not an effective antagonist or agonist.

Until someone brings new data to the table, I'm done with this circle jerk.
Click to expand...


Yeah that's what i meant, showing that DMT doesn't have any affinity for 5-HT3.

And look man, i'm simply trying to help, you having an attitude or not allowing yourself to shift your view/perspective is not helping. This isn't a "circle jerk", this is me telling you what's going on, and you denying it in favor of a view that doesn't stand ground. Is it really so difficult to believe/accept that Harmalas cause nausea/vomiting and DMT doesn't?

But i agree, i'm done because i've given way more information on this than any others around here it seems, but none of it seems appreciated so i'll just do my own thing and figure this stuff out on my own, as i have been.

Gain some experience, do some experimentation, and then you can join the big boy table, until then, stop whining and either do some experimentation or let go of this view that DMT causes the nausea/vomiting. As i've stated before i know exactly why you and others would think it does, but i assure you it doesn't and experience can show you that.

Which btw, i'm not saying 5-HT3 receptor antagonists can't work for the Aya/Pharma-related nausea/vomiting, because as i said i think something like Zofran or Ginger have their own effects (or at least it feels that way) and could possibly aid in nausea/vomiting, but just because 5-HT3 antagonists may help doesn't mean the 5-HT3 receptor is otherwise activated/involved, or maybe the actions on Acetylcholine receptors can trigger the 5-HT3 receptor, idk. But based on my 2 and a half years of daily/near daily consumption/experimentation and another year of occasional consumption/experimentation with Harmalas and DMT, everything leads to the Harmalas being the culprit, with or without DMT in the mix. Ime Lemon EO seems to help with nausea/vomiting from the Harmalas, but idk the exact mechanism behind it and i haven't done much experimentation with it so i can't say for sure, though i think it may have something to do with getting digestion going and moving forward rather than 5-HT3 antagonism, but as i said i'm not sure and need to do more experimentation with it.

It's actually quite easy to understand this stuff when you've had the necessary experience with it, there's no doubt in my mind it's something the Harmalas are doing, if i had any evidence to the contrary, i'd definitely look more into it.
 
I'm saying it's the Harmalas because it is, if there wasn't some action of the Harmalas causing the nausea/vomiting, then it wouldn't happen with or without the DMT.

As i said awhile back, i think there's something about the Harmalas that makes the stomach more sensitive to things, or it makes the stomach think DMT is something that shouldn't be there, or DMT does something cholinergic (maybe through Serotonergic, Adrenergic, or Dopaminergic receptor activation?) which together with the Acetylcholinesterase inhibition causes the Harmala purge. Don't get me wrong, i'm not set in stone in my views but i do have hunches and gut feelings, insights, observations, experimentation/experience that had led me to what i currently believe.

If DMT was a 5-HT3 receptor agonist, it would cause nausea/vomiting regardless of how it's consumed, i would think, but it only causes nausea/vomiting with the Harmalas, and only when the Harmala reverse tolerance isn't built up (or without receptor desensitization, possibly for some cholinergic receptors).

I'm wondering if consuming a strong Tobacco tea (like they do in the jungle for Tobacco cleanses) would produce a similar purgative effect (in terms of how it feels) compared to Harmalas, or maybe something like Lobelia Inflata. If it does produce similar feeling side-effects, then that would be a strong indicator that the Harmala purge is cholinergic in nature, not serotonergic.

Either way, i just really don't see the big deal, i mean yes we would all love to experience purge-free Ayahuasca and believe me i'm working on it, but in the mean time one can either consume Harmalas fairly regularly to build up the reverse tolerance and do away with the nausea/vomiting (maybe even mixing Lemon EO with the Harmalas to counteract the nausea/vomiting in the mean time, if it does indeed work which i think it does based on my limited experience with Lemon EO and Harmalas so far, and then stop taking it when the reverse tolerance is built up) so that when DMT is consumed it no longer triggers the Harmala purge, or take DMT orally with Moclobemide.

And about Cozzi's findings, i'm not saying to discredit his findings, i'm just saying before we start talking about a DMT and 5-HT3 connection, more studies need to be done, which more studies need to be done anyways regardless. At this point all we can do is hypothesize based on personal experience and existing research, and there's not much research out there about this stuff so the second best way is direct experience and experimentation, which if you were to work with this stuff regularly and try out different experiments, you'd be able to figure this stuff out more, as i have.

Don't get me wrong, as i said i too believed 5-HT3 had to be involved, but after a good bit more experience, i've been led to believe that it's the Harmalas that are the issue, and it's purgative effects for some reason or another manifest themselves even at a moderate dosage when DMT is added to the mix.
 

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