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Is DMT a 5ht3 agonist?

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Rising Star
Is there any source at all that concludes DMT to be a 5-HT3 agonist? I haven't ever come across one, and many members have stated it is not a 5-HT3 receptor agonist, DMT doesn't affect that receptor.

As far as the Harmalas go, i'm not sure if it interacts with 5-HT3 either, but something tells me it might, and could perhaps be blocked with the right dosage of a 5-HT3 antagonist, like Zofran for example, but remember, Zofran is metabolized by CYP2D6 and CYP1A2 which are inhibited by the Harmalas, so a lower dosage would be needed. As an example, i take a medication called Tizanidine for sleep, which is metabolized by CYP1A2, and when i take a good dose of Rue/Harmalas, i have about up to 10 hours after consuming the Rue/Harmalas, that CYP1A2 remains inhibited, and thus my regular dose of 2 to 2 and a half tablets of Tizanidine, needs to be cut down into a half of a tablet for the same effects as 2 to 2 and a half tablets. CYP2D6 inhibition by the Harmalas, i think, is of similar potency, so anything being metabolized by that enzyme would also require a much lower dosage. So that's just something to keep in mind, it also applies to Caffeine which i've experienced being potentiated a lot when consumed with Rue/Harmalas, because it's metabolized by CYP1A2. Other than 5-HT3 for the Harmalas, i do think a good part of the Harmalas is cholinergic, which would cause some the motion sickness, and possibly some nausea or vomiting, i've always wondered about that. I wonder if people report any less nausea or vomiting when mixing Aya with an anti-cholinergic like Brugmansia, but either way, the Harmala reverse tolerance imo is still the best way to go to get rid of the nausea/vomiting and some other side-effects.

I know people can respond differently to the same compounds, but i'm telling you, it's definitely the Harmalas that are the main source of nausea and the source of the vomiting. The food poisoning, vertigo and motion sickness effect can be attributed to the Harmalas. Harmalas by themselves you may not notice much sickness unless you take a good dosage, but when DMT is added to the mix, more of the Harmalas effects are amplified and further more come to the surface.

The only thing about DMT that i've noticed that would contribute to nausea or vomiting, is it's intensity, and possibly some sort of cholinergic effect like motion sickness, which i've experienced with DMT-containing plants mixed with Moclobemide, DMT seems somewhat cholinergic, ime, though that could perhaps be some sort of interaction between DMT and the MAO-A inhibition and possibly not attributed to either one by itself, or it could've been attributed to my use of Cannabis during Aya/Pharma which also seems somewhat cholinergic or that it potentiates cholinergic effects, but that's the only thing about DMT i notice in terms of sickness. And it's intensity is mental, which being overwhelmed can definitely make you want to vomit, though voluntarily and not forcefully (as there's no stomach issues, it's just the intensity makes you want to vomit so it's psychological).

Once you do some good experimentation, i think your perspective on this will shift based on the understanding you gain by trying to figure out the source of the majority of nausea/vomiting, as i have. After awhile, it becomes quite clear that it's the Harmalas that are the purgatives, DMT may rush the purge along, but if you allow the stomach to become desensitized from the Harmalas by building up the reverse tolerance, you will see those side-effects go away.
SnozzleBerry said:
syberdelic said:
DMT is a 5-HT3 agonist.

May I ask where you got this information? You've posted it in numerous threads, but I don't believe it is correct (see here, the reference dreamer042 offered in a different thread that touched on this same issue). If you could point me in the direction of the source you are relying on for this claim, I would appreciate it :)
DMT has multiple receptor binding sites, but as far as i know the highest binding affinity is with the 5ht7 receptor,followed by 5ht1d..

(that's a far as 'agonist' goes, maybe there is antagonist data on 5ht3 somewhere)

ps on ayahusca and purging, rather than part of a 'spiritual experience', the other interpretation for why it is considered positive (by curanderos etc) is in cleaning out of the gut
I for one don't necessarily have an issue with the vomiting, i just don't like the nausea. But at the same time, after awhile of vomiting so much, you kinda just wanna have purge-free experiences. I don't have an issue with people purging a few good times, but to purge each and everytime when it's not really necessary, just isn't something i think has to be a part of the experience, especially if you're a regular consumer like i am. I've had full on and clean-feeling experiences by building up the Harmala reverse tolerance which does away with the nausea/vomiting, and that to me is a lot better than the more "raw" version of the experience with the nausea/vomiting and all.
syberdelic and ShamensStamen i am completely sympathetic to not wanting nausea to detract, and minimising that, and that harmalas affect people differently and some are very sensitive..often the curandero approach is to encourage and bring about purging so that the person can be relieved of that, and what is being purged, as soon as possible..however remaining nauseous after purging and throughout is not a good thing..which leads to a certain debated topic in a moment

harmalas can be anthelmintic and possibly effective on certain gut bugs, though i theorise elsewhere that the purging is partly or largely due to amines, as that system to deal with them has been inhibited, some amines being more toxic than others, and of course dmt is an amine..and in high doses harmalas can cause nausea..from experience in minimising physical distress and of some curandero points of view, i am brought back to the debated topic of diet see this thread:
and others, where it is debated..and certainly not agreed on

so i'd be curious if dietary food or supplement precautions of any kind were also utilised by those indicating extreme discomfort in terms of ongoing nausea or repeated vomiting..?but as i said it's a theory and there is much variation between people..in the thread linked my general position is again that the tradition is not about 'spiritual' as much as practical reality..where the emphasis is 'cleansing' on a physical level as much or more than having 'visions'..in some jungle traditions of ayahusca, but again i realise there is variance..like people..it's this i personally see as a core difference with dmt smoked, other than duration, rate and modulation by harmala psychoactive effects..diet i discuss in general only to try and be helpful, not to uphold some 'traditional' way as being better..
syberdelic said:
SnozzleBerry said:
syberdelic said:
DMT is a 5-HT3 agonist.

May I ask where you got this information? You've posted it in numerous threads, but I don't believe it is correct (see here, the reference dreamer042 offered in a different thread that touched on this same issue). If you could point me in the direction of the source you are relying on for this claim, I would appreciate it :)

I know I have seen this in other places as well, but my previous research was very layered and not documented. The information is there, but would require time that I don't have right now. But I remember seeing this here:
If you go to 17:00 and listen to his explanation of the graph and notice that DMT has 5HT3 activity. It certainly isn't antagonist activity as this would make the nausea less. The one thing I don't know is how strong of a 5HT3 agonist it is.

So, in that video, when asked if DMT/DPT are agonists at those sites, Cozzi's reply is:

Cozzi said:
Don't know. This is purely a binding profile. We know that they're partial agonists at some sites and so on.

Given that Cozzi's research appears to offer no commentary on whether or not DMT is a 5ht3 agonist (just that it has some binding affinity), and the paper linked by dreamer explicitly documents that the 5ht3 receptor was one of seven receptor sites for which there were no hits (no indication of agonist activity), I'm not sure it makes sense to cite Cozzi's talk as supporting evidence for that claim.

And regarding the questions raised about agonist "strength"...

Nen pointed out that the highest binding affinity is with the 5ht7 receptor (Ki value of 87.5), followed by the 5ht1d receptor (Ki value of 93). The paper dreamer linked shows that the 5ht3 receptor had a Ki value of over 10,000.
syberdelic said:
I would be very surprised if Harmine is a 5HT3 agonist.

How high of a Harmine dosage have you tried? I've tried up to 300mgs on it's own (haven't tried it with DMT yet though) and no nausea or vomiting was noticed, but then again it was at a time when i had the Harmala reverse tolerance built up. Have you tried Harmaline, or Harmaline/Harmine mix, or the actual Syrian Rue or B. Caapi plant? Have you tried taking higher/stronger dosages of the Harmalas or the plants on their own without DMT? I assure you, if you have a high enough dosage of Harmalas, even pure extract, you will get nauseous and vomit. I took a super heavy dosage of purified Harmaline/Harmine mix in tincture form one night and vomited several times (like 6 times) that night, and had wave after wave of nausea and stomach contractions followed by another purge, all without DMT in the mix.

Take some stronger dosages of Harmalas or the plants, and you'll see.

Idk for sure if Harmalas are 5-HT3 agonists, but it sure seems that way to me. Ibogaine also causes nausea/vomiting, and is similar in some ways to Harmaline apparently from what i've read. Harmine seems like a pretty gentle/weak compound compared to Harmaline. But i'm quite sure Harmine still causes the nausea/vomiting, as that's the main active in Caapi and a heavy Caapi dose will definitely make you vomit, not because of the taste of the tea, not because of tannins, but because of it's purgative actions.
Here's the relevant info:

For this study, the NIMH-PDSP (PDSP) has assayed sixteen phenylalkylamines, eight tryptamines and one ergoline (twenty-two psychedelics and three controls, Fig. 1) against a panel of fifty-one receptors, transporters, and ion channels. The methodology has been described previously by Glennon et al. [12]. Each compound is initially assayed at 10 µM against each receptor, transporter or ion channel (primary assay). Those that induce >50% inhibition (“hit”) are then assayed at 1, 10, 100, 1,000, and 10,000 nM to determine Ki values (secondary assay). Each Ki value (equilibrium dissociation constant, concentration at which 50% of the hot ligand is displaced by the test ligand) is calculated from at least three replicated assays. Details of how individual assays were conducted can be found at the NIMH-PDSP web site: http://pdsp.med.unc.edu/pdspw/binding.php.

Table S2 shows raw Ki data for the current study combined with data collected from the literature for the ten additional compounds; a total of thirty-five drugs and sixty-seven receptors, transporters and ion channels which were assayed. The table has been divided into three sections.

The second section displays seven sites at which most compounds were assayed, but at which there were no hits: 5ht3 (serotonin-3 receptor), H3 (histamine-3 receptor), H4 (histamine-4 receptor), V1 (vasopressin-1 receptor), V2 (vasopressin-2 receptor), V3 (vasopressin-3 receptor), GabaA (GABA-A receptor).

And you can review the table yourself...but unless I'm misunderstanding something (and my apologies if I am), none of the compounds tested were identified as 5ht3 agonists.
DMT, Harmine, and Harmaline all have little to no activity at the 5ht3 receptors. This is why attempting to combat nausea with a 5ht3 antagonist makes no sense. I don't know of any studies on the 5ht binding profile of THH off the top of my head.

Keep in mind the MAO-A inhibition effect of harmine and harmaline by definition means there will be greater concentration of serotonin in the synapse, and serotonin does agonize the 5ht3 receptors, so excess serotonin is likely part of reason for the nausea in rue/caapi. This applies to Moclobemide as well. This is also why combining a 5ht3 antagonist with harmalas or other MAO inhibitors will put one at increased risk for serotonin syndrome. Which is basically the point I was making in that other thread.

Which leads me back to my initial point in that thread. If you want a (mostly) nausea free tryptamine experience, go for 4-AcO-DMT or a sublingual psilocybin tincture or just stick with LSD. B. caapi and P. harmala are purgatives, if you are afraid of nausea or purging, these are not the droids you are looking for.

Be smart, be safe, respect the natural action of the plants.
As for the Harmalas being 5-HT3 agonists, i'm not sure if they are, but there's definitely some mechanism there responsible for the Harmala nausea/vomiting. More Serotonin due to MAO-A inhibition definitely won't cause vomiting at least, maybe it could cause a little bit of nausea but all times i've taken Moclobemide i've never gotten nausea from it, much less vomited from it, and i've taken up to about 450mgs, maybe a little more, but never felt nauseous or vomited from it. And with Harmalas, once you build up the reverse tolerance, you still get full MAO-A inhibition yet the nausea/vomiting goes away with the reverse tolerance so excess Serotonin due to MAO-A inhibition just can't be the cause of the nausea/vomiting, imo.

As for 5-HT3 receptor antagonists, i'm not aware of it causing Serotonin Syndrome in combination with MAO-A inhibition. As far as i know, Zofran is merely a 5-HT3 receptor antagonist, and according to this article - Can 5-HT3 Antagonists Really Contribute to Serotonin Toxicity? A Call for Clarity and Pharmacological Law and Order - "Ondansetron and related compounds have been demonstrated not to possess these properties to a significant degree and are not reliably documented as causing ST. It is therefore highly doubtful that these drugs are capable of contributing to ST, a conclusion that can be confidently predicted from their pharmacological actions. Therefore, to justify the postulate that they are involved in ST will require clear and convincing evidence, which we can contend does not presently exist." If i'm wrong though, feel free to correct me.

I have combined Zofran with my Pharma a few times in experimentation, and while it turned out to be a nightmare (in the sense that it altered the experience significantly and made it feel kinda chaotic and weird), i'm pretty sure that wasn't because of the Zofran itself, but rather me taking an 8mg tablet which due to the Harmalas' CYP1A2 and CYP2D6 inhibition potentiated the Zofran and so i most likely only needed maybe 0.5mgs to 2mgs at most. I take a medication for sleep called Tizanidine which is metabolized by CYP1A2 and when i take it up to 10 hours after consuming a good strong dosage of Harmalas/Rue, i only need a half of a tablet (2mgs) compared to the 2 to 2 and a half tablets (8 to 10mgs) i would need without the CYP1A2 inhibition. Caffeine is also pretty potentiated by the CYP1A2 inhibition, so i'd imagine with both CYP1A2 and CYP2D6 inhibited by the Harmalas, a pretty small dose of Zofran would be and do fine. I still have a few Zofran tablets i'm going to experiment with sometime or another and see how that goes (as always, i'm a cautious risk taker, so i know what i'm doing). I should also note that i could tell when i took the Zofran with the Pharma those few times, i could definitely tell it blocked out some portion of the Harmalas, whether that was through 5-HT3 antagonism or just some of the effects of the Zofran overriding those of the Harmalas.
So again,

What exactly is the point of taking an understudied cocktail of pharmaceuticals to overcome the purgative action of purgative compounds instead of taking psilocybin? :?
Because this medicine can be really awesome as it is, but it can be even more awesome without the undesirable side-effects. One thing i like about Aya/Pharma, is that there can be different recipes/flavors and different kinds of experiences and be used in many different ways, there is no "one way" to use this stuff.

If i take Shrooms or even 4-ACO-DMT, i'm taking them with Harmalas. I love Harmalas/Rue, i'm a "huasca" kind of guy. Just because people wanna remove the stomach discomfort does not in any way mean this stuff can't still be as powerful or beneficial or magical. I've had plenty of nausea/vomit-free experiences because of the reverse tolerance, and it was just as full on, if not more so, than the more raw experiences. I like all different kinds of experiences though, but i see a lot of potential in this kind of medicine/concoction and making it a bit more user-friendly and being able to access these states/experiences with less discomfort is worth looking into and pursuing imo. It's one of my goals. I feel like finding the right plant combinations can really help us access different aspects of this medicine and bring out more of it's potential/usability. I'm particularly excited about trying out different plants or compounds with it to help increase memory retainment/recall so we can remember and retain more about what we encounter during these experiences and have the understandings and such really stick with us.
First off, plain and simple these compound don't bind at 5ht3, thus the whole line of thinking that nausea can be prevented by antagonizing 5ht3 is flawed.

Whether or not the warnings from the large health organizations on taking these medications alone are valid, those warnings and that paper refuting them only apply to taking these compounds alone, even that refutation paper warns about potential MAOI interactions.

So let us assume you predose a 5ht3 antaganist. You have now plugged up your 5ht3 receptors.

Then you take an MAO inhibitor, you've disabled the ability of the body to break down excess serotonin in the synapse plus plugged up one subset of receptors. Now you are reliant on the reuptake mechanism (which has a limited capacity) as your only safety mechanism against SS.

You didn't just take an MAO inhibitor however, you also added DMT to the mix. Now you are plugging up 5ht1, 5ht2, 5ht7, etc... with DMT, in addition to plugging up 5ht3, and having disabled the MAO failsafe mechanism. At this point you are building up a significant excess of serotonin since it has nowhere to bind and is not being broken down by MAO. Now you are really taxing the SERT pathway's ability to take up the extra serotonin.

Now if happened to take caapi, you likely have THH present as well, which has SSRI activity and will be plugging up that already overtaxed SERT pathway. If you took a full spectrum rue extract you also have several other beta-carbolines present who's pharmacokinetics are not as well understood.

You see how the available information saying these pharmaceuticals are (probably) safe (on their own) are not taking into account the whole picture when you start mixing in plant based mao inhibitors and 5ht active compounds? You see how the effects of these things stack together causing a highly increased risk for dangerous situations?
I'm not sure that i follow what you're trying to say. The 5-HT3 receptor, as far as i know, plays no role in the breakdown/metabolization of Serotonin. Secondly, what you're talking about, and what the article mentioned, refers mostly to Serotonin Reuptake Inhibitors, and how there's no action by Zofran that would indicate it would release Serotonin or prevent it's metabolization, as you are suggesting.

"The communication to the public and health professionals about a proposed risk of ST from use of 5-HT3a blockers and serotonergic drugs may have multiple unintended consequences, including, but not limited to: needless avoidance of ondansetron for patients taking SRIs, unnecessary and potentially dangerous situations where SRIs are abruptly discontinued, and health care professionals having to spend extra time explaining this issue to patients. At worst, it may make it difficult for future warnings from HC, the WHO, or the FDA to be taken seriously. Clinicians need to have access to reliable information so that they know what drug combinations must always be avoided (e.g. MAOIs and SRIs), what combinations may be used safely (e.g. SRIs and trazodone or mirtazapine), and which drugs can elevate serotonin, and be aware of commonly used drugs which also possess SRI properties (e.g. meperidine, tramadol, fentanyl, pentazocine) or MAOI properties (e.g. linezolid)."

"As for ondansetron, this 5-HT3 antagonist possesses no agonist properties and thus would not be expected to produce serotonergic effects."

Why would you think a 5-HT3 receptor antagonist, would somehow interact with an MAO-A inhibitor, or an SSRI? I'm not quite understanding your point here. As a 5-HT3 receptor antagonist, if i'm not mistaken, it merely deactivates that receptor meaning an agonist can't trigger/activate it, that's it, it has nothing to do with releasing Serotonin.

Also, even if the Harmalas do not bind to the 5-HT3 receptor, i think 5-HT3 receptor antagonists have their own anti-emetic effect aside from simple 5-HT3 receptor antagonism. But i don't see the harm/risk in trying Zofran with Harmalas so long as a low dosage is used due to the potentiation. I've done it before personally, and i will do it again in future experimentations. When i've taken it with Pharma, i didn't notice any SS symptoms, and i took waaaaay more Zofran than i needed to due to the potentiation.
But, even if a 5-HT3 receptor antagonist is pointless, there's always the Harmala reverse tolerance which does away with the nausea/vomiting anyways. And ime Lemon EO seems to be able to block out the Harmala-related nausea/vomiting and even some of the body load, and one can use that to build up the reverse tolerance and then stop taking it when the reverse tolerance is built up enough and then add DMT into the mix.
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