Is 25i NBOMe Neurotoxic?

[jacktheripper42]

We can sit here and lay to rest specific concerns but I think you need to take a step back and realize that you got your symptoms after researching, therefore it was *thinking* that got you into this mess, and it won't really be thinking that gets you out of it.

It wouldn't have made a difference if you took a synthetic 5-HT2A agonist or magic mushrooms, or another class of drugs entirely.

You said earlier that you've previously had problems with obsessing as well.

Yeah I know I can't change anything now. I'm going to look into Lions Mane Mushroom for it's NGF properties. Does affinity necessarily mean how hard it hits the receptor? Would 16 times the potency of 2Ce just mean that it stays on there 16 times the duration of 2Ce or does it hit the receptor with 16 times the force of 2Ce? Either way wouldn't this make it more susceptible to a halogen entering and disrupting neuronal function? Any input about this is greatly appreciated.

 

[drseltsam]

What would this input change? You are not listening to what we, David Nichols or anyone else is saying.

 

[Cotcha Yankinov]

You don't need a magic herb or otherwise homeopathic quick fix, you need professional help, mindfulness and possibly medication.

Affinity doesn't really have anything to do with the ligand "hitting" the receptor, it's just off-time on-time ratio.

But just to reiterate, ligands do not get taken up by receptor internalization. Receptors tend to be sequestered in protective vesicles when they are internalized anyways. Once again, I asked a PhD about this and he shot the notion of pseudo irreversible ligands being taken up by internaliation.

 

[jacktheripper42]

Awesome, so you think it's safe to say I'm 100% in the clear when it comes to any sort of brain damage and this is all just due to an overactive imagination?

 

[Cotcha Yankinov]

I think youre 100% in the clear, people develop OCD/anxiety all the time without drugs and you've apparently had problems before so I think it's safe to say the psychedelic had zilch to do with your present situation, other than it is an object of your ruminations.

 

[jacktheripper42]

I think your 100% in the clear, people develop OCD/anxiety all the time without drugs and you've apparently had problems before so I think it's safe to say the psychedelic had zilch to do with your present situation, other than it is an object of your ruminations.

Awesome ok, I'll close this chapter in my life. I wonder when more scientific research about NBOMes is going to happen

 

[jacktheripper42]

You don't need a magic herb or otherwise homeopathic quick fix, you need professional help, mindfulness and possibly medication.

Affinity doesn't really have anything to do with the ligand "hitting" the receptor, it's just off-time on-time ratio.

But just to reiterate, ligands do not get taken up by receptor internalization. Receptors tend to be sequestered in protective vesicles when they are internalized anyways. Once again, I asked a PhD about this and he shot the notion of pseudo irreversible ligands being taken up by internaliation.

Does this following post not sound convincing at all? There's so many people on different various forums making this claim and it's been really frustrating me. Why are there so many constrasting opinions regarding this matter in addition to lots of people coming on here and reporting long term effects?


"The 5HT2A receptor has 2 phenylalanine amino acids that are thought to be the basis of its function, phe339 and phe340. Most phenethylamine psychedelics (2c-e, mescaline, etc) are thought to interact primarily with phe340. 25i-NBOMe and other NBOMe compounds, however, interact with both phe339 and phe340 and form an incredibly strong bond with the 5HT2A receptor.

What's spectulated to happen with a normal psychedelic is that after a while the bond is broken between the psychedelic and phe340. The receptor goes about business as usual and the psychedelic is broken down by enzymes and removed from the body. However, because the 25x-NBOMe compounds form such a strong bond with the receptor, this doesn't happen. Instead, the cell undergoes what is called receptor-mediated endocytosis, in which the 5HT2A receptor, along with the NBOMe compound, is actually taken inside the cell to be degraded. You end up with nasty halogens from the NBOMe compound floating around and are one less 5HT2A receptor strong than you were before the trip.

And that's just for ONE molecule/receptor complex."

 

[Cotcha Yankinov]

It's rampant speculation. There is no evidence for what that person says. Once again, I've asked a brilliant scientist about this occurring with irreversibly binding (covalent bond forming) ligands and he shot it down.

That person also shows complete disregard for OCD/anxiety (it's like telling someone who has an irrational fear of cosmic rays that billions of neutrinos pass through us every second - it's plain old not helpful). That he doesn't realize this says a lot.

 

[jacktheripper42]

So you think that notion is entirely false? It just seems that a substance such as 25i is more likely to cross the cell membrane due to its incredible potency

 

[Cotcha Yankinov]

Consider this; supposedly an average dose of 25i may be around 500micrograms. Compare this to 100micrograms of LSD, which is actually thought to bind psuedoirreversibly unlike 25i.

From that point of view, we may be less apt to worry about the "ultra potent synthetic full agonist!!" when you may need to take 1/5th as much LSD to achieve equivalent effects, and we know that LSD is binding psuedoirreversibly. But people wouldn't worry as much about LSD because its been around for a while. So even if 25i is just another ligand, I think people tend to freak out about it more.

There are FDA approved drugs that are full on irreversible binders - see for example Risperidone's irreversible 5-HT7 binding. I've seen people freak out about this before as well, but I was on it for 6 months and it was extremely helpful. Supposedly the 5-HT7 blockade is actually playing a role in its efficacy for depression. Its also a potent 5-HT2A inverse agonist (selective for the signaling pathway that causes 5-HT2A internalization). But yet many people do great on it, like myself.

What really matters are not the receptors, but rather the neurons and circuits. When you're ruminating, you're activating particular circuits and this is causing you to feel bad - but this has nothing to do with the 25i. For whatever reason, your ruminating/worrying circuits are strong and your anti-rumination circuits are weak, but just like muscles, things strengthen and weaken all the time. With the right encouragement, your brain will correct itself just like new.

 

[jacktheripper42]

Although the dosage of LSD at 100 ug and 25i at 500 ug would be similar, wouldn't the receptor potency/affinity still be different? Isn't 25i still 100 times the potency of LSD at 5HT2A receptors due to its extreme affinity at said receptors. That quote from above talking about receptor-mediated endocytosis and interactions with phe 339 and phe 340 seems fairly knowledgeable. I definitely do need to work on altering the ruminating circuits right now but I'm worried that it may be out of my control in a sense due to brain damage from the halogens entering the neuron.

 

[Cotcha Yankinov]

My point was really that you see the same level of physiological effects at a lower dose of LSD - this is because LSD interacts so strongly with the receptor (yet people worry about the newer ligands).

Re: the shroomery guy - people can have great technical knowledge but have horrible application of that knowledge. He is probably completely oblivious to the fact that you are obsessive/anxious irrespective of 25i and that what he said has caused you to obsess more; the 25i was not the cause of your obsessions/anxiety because you've had issues before and now you have 25i related obsessions because you started researching, which is common with every drug that people have problems after.

Sorry if I seem impatient, it's just that I've been through this before with others and they've gone on to recover 100% if not better than before they actually dealt with their issues.

One was the same story as you except with MDMA which is actually shown to be neurotoxic in animals (completely different from direct agonists), anyways he only got his anxiety after researching (he was fine for months at first after his usage, then he researched, heard about the serotonin neurotoxic stuff and off he went). Then he went on SSRIs, then he freaked out about "SSRI damage".

Eventually he immersed himself in mindfulness after some convincing, and even went on to do a mindfulness retreat. He made a full recovery, even though he certainly couldn't see the light at the end of the tunnel at some points.

The halogen entering the neuron through receptor internalization stuff is BS - ignore that shit. You've got anxiety man.

 

[jacktheripper42]

My point was really that you see the same level of physiological effects at a lower dose of LSD - this is because LSD interacts so strongly with the receptor (yet people worry about the newer ligands).

Re: the shroomery guy - people can have great technical knowledge but have horrible application of that knowledge. He is probably completely oblivious to the fact that you are obsessive/anxious irrespective of 25i and that what he said has caused you to obsess more; the 25i was not the cause of your obsessions/anxiety because you've had issues before and now you have 25i related obsessions because you started researching, which is common with every drug that people have problems after.

Sorry if I seem impatient, it's just that I've been through this before with others and they've gone on to recover 100% if not better than before they actually dealt with their issues.

One was the same story as you except with MDMA which is actually shown to be neurotoxic in animals (completely different from direct agonists), anyways he only got his anxiety after researching (he was fine for months at first after his usage, then he researched, heard about the serotonin neurotoxic stuff and off he went). Then he went on SSRIs, then he freaked out about "SSRI damage".

Eventually he immersed himself in mindfulness after some convincing, and even went on to do a mindfulness retreat. He made a full recovery, even though he certainly couldn't see the light at the end of the tunnel at some points.

The halogen entering the neuron through receptor internalization stuff is BS - ignore that shit. You've got anxiety man.

It's nice hearing other people recover from potential brain damage related issues. The thing that bothers me about this entire situation is the fact that a bunch of other people have been experiencing anxiety afterwards too. The substance itself carries that halogen and people over the internet are talking about it potentially entering the neuron and act as a catalyst for ROS species. The notion that this could even be a possibility causes anxiety in me. There has been no neurotoxicity testing in animals right?

Dr. Nichols has stated that the substance is not neurotoxic and can not damage receptors or neurons because the halogen doesn't enter the cell it just acts interacts with a hydrophobic amino acid throguh weak van der Waals forces. I just have to have faith in his expertise. In the back of my mind I get paranoid thoughts that Dr. Nichols has incentive to not be completely honest about the situation so that he is not liable for brain related damage as a result of 25i. This is why I have been putting a bit less value on his input vs. more neutral stuff that I find on the internet.

Do you whole-heartedly believe that quote from that guy is complete BS? I want to be assured that this is completely in my control

 

[Solipsis]

25I has high affinity and thus binds well to 5-HT2A, but I don't think it is necessarily more efficacious because LSD binds pseudo-irreversibly to make up for it. This is not because it is is "just potent", it is potent because it happens to get snagged on the receptor so that LSD gets stuck for a long time.

Even if hypothetically 25I would get internalized (which I don't think there is reason to think that it does in very special ways), halogens don't get cleaved off of the rest of the molecule to start behaving like a 'halogen on the loose'. It stays attached to the rest of the molecule, which is metabolized to form the 5-O-demethylated metabolite which is then glucuronidated. These breakdown products have been detected, the halogen is always attached of course. And a bound organic halide like that does not behave remarkably or toxic just from being a halogen compound.

If 25I would cause that internalization of the neuron it would be due to functional selectivity, not it's potency.
- Not all 5-HT2A agonists are created equal, they can trigger different biological chain reactions called signal cascades / pathways.
- That functional selectivity means a preference for certain chain reactions over others.
- Our own serotonin for example is not psychedelic, it does not trigger the arachidonic acid pathway which psychedelics do trigger so this is thought to be the reason.
- Our serotonin does trigger the PKC pathway which is essential in triggering internalization, so serotonin appears to cause internalization itself!
- LSD is psychedelic of course, but it should not particularly cause internalization because it does not trigger the IP3 pathway that activates PKC.
- So, it's possible that 25I or other psychedelics do cause this internalization but it should not be particularly problematic because our own serotonin does it too.
- There would also be no problem with 25I getting inside the neuron for the reasons Cotcha explained.
- DOI is a psychedelic amphetamine with an iodine, similar in structure to 25I, which does activate this PLC pathway. It has been a widely studied psychedelic for years, yet - unsurprisingly - nobody remotely found something like the internalization + iodine going on the loose like you are worried about.
- Loss of active 5-HT2A receptors like due to internalization or other effects like from tolerance should really not cause your symptoms. Actually conversely it might be therapeutic for you and calm you down. Furthermore, it's doubtful that it would cause chronic effects considering how (relatively) quickly psychedelic tolerance is restored. 5-HT2A appears to have a high turnover rate.

I believe you when you say others have developed anxiety problems afterwards as I see it here in PD too now and then, but it is likely this is getting exacerbated by NBOMe's via effects on a larger scale than organic damage to individual neurons. Not damage but a change in function in the brain. As this has a major psychological basis you should be able to influence it as you are hoping, and it should also not be particularly persistent... therefore like I said before it should be treated like the anxiety disorder / OCD type thing it might turn out to be (I am not the one to make that call, unsure if there is currently a disorder to speak of but sounds like it).

^I see now what Cotcha wrote - about the circuits which relates to my point.

Everything Nichols said to you is consistent and entirely credible. Be thankful for his informative response and lie this to rest.

And I agree with Cotcha that while sometimes people do get various kinds of problems like these, normally this heals over time... just sometimes it takes quite a while and IMO it requires trying to adapt and working on progressive recovery. It may require therapy.
With anxiety it is easy to 'cramp' up and this can get pretty painful. And it can seem like it is hard to influence cramps to stop them. First thing about panic is realizing that it is panic and how relative your panicked subjective view is. Try to learn to step out of it. Preferably without having to first control the shit out a situation.

 

[jacktheripper42]

Amazing thorough reply Solipsis. So there's virtually 0% chance that the halogen gets in the neuron and acts toxic. So I'm absolutely in the clear here? This is relieving news.

I'm going to trust you guys and Dr. Nichols and try to completely end my obsessions revolving this topic.

Thank you all for your help and input

 

[Cotcha Yankinov]

The thing that bothers me about this entire situation is the fact that a bunch of other people have been experiencing anxiety afterwards too.

Lots of people use psychedelics and lots of people develop anxiety, when those two intersect in remotely the same timeframe one may place the blame at the feet of the psychedelic, but this is probably distracting from the real issue at hand (especially considering you've had previous issues). 5-HT2A agonists are not neurotoxic. Try to relax

Dr. Nichols has stated that the substance is not neurotoxic and can not damage receptors or neurons because the halogen doesn't enter the cell it just acts interacts with a hydrophobic amino acid throguh weak van der Waals forces. I just have to have faith in his expertise. In the back of my mind I get paranoid thoughts that Dr. Nichols has incentive to not be completely honest about the situation so that he is not liable for brain related damage as a result of 25i. This is why I have been putting a bit less value on his input vs. more neutral stuff that I find on the internet.

I think it deserves re-iterating that Nichols didn't create 25i, his team just investigated it because of its utility in doing medical research

 

[Solipsis]

Yeah correction about what I said earlier: he doesn't want to call it 'feeling responsible', but he was still very sad about people overdosing on it as a result of deciding to even take it in the first place, and was shocked to hear about an OD from the victim's mother who called. You can imagine he is not necessarily that responsible for the tragedies directly but merely made it possible for people to do it to themselves.

Even if he did feel responsible I feel safe in predicting that the guy would still be honest.

 

[jacktheripper42]

Yeah correction about what I said earlier: he doesn't want to call it 'feeling responsible', but he was still very sad about people overdosing on it as a result of deciding to even take it in the first place, and was shocked to hear about an OD from the victim's mother who called. You can imagine he is not necessarily that responsible for the tragedies directly but merely made it possible for people to do it to themselves.

Even if he did feel responsible I feel safe in predicting that the guy would still be honest.

Thanks once again for your input Solipsis and Cotcha. So you guys believe there's absolutely no chance that the halogen gets separated due to receptor degradation?

This is another one of the quotes from the same personMonkey: No, it isn't only the NBOMe series that contains halogens. 2C-I, 2C-B, 2C-C, 2C-F also contain them. However, the 2C-X series very likely never crosses the cell membrane and therefore remains in the extracellular fluid. What you have to worry about is the cell itself pulling the receptor/NBOMe complex inside the cell (receptor mediated endocytosis) and degrading it (thus leaving you with halogens in your neurons)

Here's the forum discussion from 2012 if anyone's interested:
https://www.shroomery.org/forums/showflat.php/Number/17056030/fpart/2/vc/1#17056030

 

[Cotcha Yankinov]

Once again, it's rampant speculation.

I'm not exactly sure what symptoms you're hoping to explain with this anyways - if it's anxiety/obsessions, then it's ironic that the main thing you're anxious about is 5-HT2A/25i related matters. If you went on SSRIs, then you'd probably be worried about damaging your serotonin transporters.

But I still don't know why you are so worried about the receptor internalization deal when you had problems previous to 25i and also didn't have problems until researching? That right there should be enough to put your mind at ease about that specific matter, but I'm not sure if the goal with anxiety should really be to ease your mind about every specific concern (because a busy mind can always come up with more concerns, so the problem is really the busy mind rather than the concerns)

 

[Volsam]

jacktheripper42, how often do you exercise?..

It is a well-known fact that exercising increases BDNF (brain derived neurotrophic factor) - Certain types of physical exercise have been shown to markedly (threefold) increase BDNF synthesis in the human brain, a phenomenon which is partly responsible for exercise-induced neurogenesis and improvements in cognitive function.^{[16][17][18][19]} Niacin appears to upregulate BDNF and tropomyosin receptor kinase B (TrkB) expression as well.^[20]

I also suggest you try Noopept, it is pretty magical for cases like yours in doses of 40mg daily, especially if you feel obsessed and can't let go of something. I vouch for Noopept being an effective anti-anxiety and anti-intrusive thoughts med. It also increases BDNF and NGF (nerve growth factor), I'd provide links but most research on it in Russian.

Noopept's major metabolite appears to induce an anxiolytic effect in rodents as assessed by an elevated maze plus test at the injected dose of 0.05mg/kg (0.1mg/kg appeared less effective and 0.2mg/kg was ineffective)^[2] where only the L-isomer is active and the D-isomer is wholly inactive.^[2]

In humans, one study^[3] investigated 53 persons with cognitive ailment (37 with vascular cerebral damage and 17 with post-traumatic damage; 41 finishing the trial) at two daily doses of 10mg compared to the active control of Piracetam (1200mg daily) over 56 days noted universal improvement on parameters of vascular cerebral damage and improvement on half of measured parameters of trauma. Fatigue, anxiety, irritability, apathy, and affective lability were improved in both groups while further benefits were noted on mood, sleep, and wakefullness in those with cognitive ailment stemming from vascular damage.^[3] Noopept was more effective over 56 days in improving the MMSE score relative to Piracetam, while it was effective in post-trauma patients (Piracetam was not) although when comparing all scores on MMSE, BPRS, and CCSE there was no significant difference.^[3]

Also you may want to check out Tianeptine as a mild anti-depressant.

Be safe!