25i nbome 5ht2a receptor sensitization

[jacktheripper42]

Hey yall,

I'm back with another question regarding 25i NBOMe. I've been talking to Dr. Nichols recently and he has speculated that there is a chance that my 5ht2a receptors could be sensitized causing the symptoms that I've been experiencing. Here's the email.

"
Pimavanserin is an inverse agonist. It will shut off any 5-HT2A activity that is occurring naturally. I am just speculating here, but if your receptors were somehow sensitized so that they are more active than they should be, an inverse agonist will shut them off. It is a long shot, but I had the idea the other day."

Should I get on these meds or is there no reason to believe that my 5ht2a receptors have become sensitized? If they have become sensitized what symptoms would I be experiencing? Would I be experiencing OCD and Insomnia related symptoms?What even causes sensitization of these receptors? I've been talking to Cotcha a bit in PMS but it sucks that you have to wait 3 hours before you can send another message.

You guys are really helpful here so I'd love any input you guys could provide.

 

[perpetualdawn]

I would say that you could proceed cautiously by getting some pimavanserin and testing it out to see if it shuts off your symptoms, that will be a way to probe your system to learn about whats going on. I wouldn't say you should just jump on it immediately and assume it will fix your issues and get yourself a prescription and stay on it chronically or anything.

Whatever you end up doing, make sure to share your experience and results here so everyone can learn from what you're going through.

 

[Hodor]

5HT2A antagonism (or inverse agonism) = what an atypical antipsychotic does.

So yes, you will probably experience some measure of relief from taking something that blocks your 5HT2A receptors. It doesn't have to be pimavanserin - that stuff one was developed specifically for people with Parkinson's disease (who cannot tolerate even the very mild dopamine antagonism of a 2nd generation antipsychotic). Most patients will get much better results with an antipsychotic that hits a broader range of pharmacological targets (5HT1A, 5HT2C, 5HT3, alpha-adrenergic, H1...). Also, chances are as a specialty drug pimavanserin will be expensive as hell, and good luck getting your insurance to pay for it when you don't have Parkinson's.

On the other hand, doctors love to prescribe quetiapine ("seroquel") because it is both very well-tolerated and cheap as fuck if you're getting one of the many generics. Olanzapine ("zyprexa") is even more effective against 5HT2A, and blocks a number of other clinically relevant receptors, although it tends to cause side-effects like weight gain.

 

[Solipsis]

Theoretically, an inverse antagonist could change back a conformational change in the receptor... isn't that also how something like flumazenil is supposed to help with people who have protracted benzo PAWS supposedly from that same problem?

So while Hodor is right that neutral 5-HT2A antagonists could offer temporary relief from symptoms, they wouldn't likely cause that same (potential) conformational fix.

Still, a reason to first try a regular antipsychotic which is a neutral antagonist for 5-HT2A and sure a bit more broad spectrum, would be as a control. If it only works temporarily but if you try something like pimavanserin later with more lasting results you'd have better evidence of / clues to what's happening. If you skip to pimavanserin straight away it should be the lasting relief it could bring even after discontinuation and not any acute relief to focus on. Although if you at least get the acute relief you can take it as a sign that you may benefit from being on a cheaper typical anti-psychotic for a while.

IMO insomnia is definitely associated with serotonergic dysfunction, but I think I would also expect psychosis-like symptoms a bit. OCD is tricky and hard to pin to something like this, seems to involve not particular neurotransmitters or receptors AFAIK but a broken feedback mechanisms in the brain involved in checking if things are okay and safe. I guess it's possible if the sensitization causes failure of a certain kind of inhibition meant to act on the feedback mechanism.

 

[SONN]

I'm super interested to know why Nichols thinks 25i sensitized your 5ht2a receptors, considering in 2012 I vaporized a large dose of it and it was a relatively lifechanging experience

 

[jacktheripper42]

Thanks for replying everyone.

I'll try to get one of these medications prescribed to me at my next appointment.

I think Nichols stated that because I told him about the HPPD related symptoms I was experiencing such as mild visual trails when waving a phone in front of my face in a dark room. Mild after-images and warping in certain dark environments.

I wonder if the sensitization is causing my anxiety related symptoms or if it's self perpetuated.

What dose did you vaporize and how was it a lifechanging experience? Was it a good lifechanging experience?

 

[jacktheripper42]

Is 5ht2a superrsensitization a result of the neurons that regulate these receptors dying off just as it would happen in Parkinson's patients? Or is it a result of the NBOMe going in and making these receptors more sensitive and coming out. Maybe they aren't even sensitized and this is all self-created but what do you guys think?

 

[Cotcha Yankinov]

Theoretically, an inverse antagonist could change back a conformational change in the receptor...

Correct, and inverse agonists will be signaling through arrestins which do more than just cause the cell to pull back in the receptor, arrestins can signal through e.g. MAPK to produce cellular changes

As an aside there is actually evidence that the failure of Eli Lily's mGlu2/3 agonist for schizophrenia is due to the patients in that trial having had previous exposure to AAPs with 5-HT2A inverse agonist properties

So while Hodor is right that neutral 5-HT2A antagonists could offer temporary relief from symptoms, they wouldn't likely cause that same (potential) conformational fix.

Still, a reason to first try a regular antipsychotic which is a neutral antagonist for 5-HT2A and sure a bit more broad spectrum, would be as a control.

One key thing about 5-HT2A receptors is that they are constitutionally active - meaning that they can signal randomly even when no serotonin is binding. A silent antagonist which just sits on top of the receptor won't shut down such constitutive activity and apparently doesn't help much with Parkinson's disease hallcuinations, however an inverse agonist will shut down constitutive activity.

In the case of Parkinson's disease, the supersensitivity wouldn't be expected to be as much of an issue since there is very little serotonin around to activate the receptors, but in comes constitutive activity.

Also, some atypical antipsychotics are inverse agonists at 5-HT2A, e.g. Risperidone was designed with Ketanserin in mind, one of the older selective 5-HT2A inverse agonists before Pimavanserin


For what its worth I think OP is having visual disturbances that aren't too far outside the norm to be really concerned, and the major cause of his suffering is anxiety.
CY

 

[jacktheripper42]

Hey Cotcha,

It's reassuring that you think my visual disturbances are within the normal realm Cotcha. I have a few questions if you don't mind. Okay so the dose for 25i NBOMe that I took was 1000 ug allegedly. If 25i has 16 times the affinity of 2CE for this receptor, does that mean a 62.5 mg dose of 2CE is roughly the same amount of stimulation on 5HT2A receptors and neurons.

I was looking at this website that discusssed a potential analogy for parrtial vs. full agonists and the effects they elicit. The site compared a partial agonist to being able to reach the fourth floor in a 10th floor elevator regardless of how high the doseage gets, the partial agonist can not get past this fourth floor. Now with a full agonist, you have the potential to go all the way up to the 10th floor. Could this be why 25i's effects lingering effects last longer than other psychedelics?

Is 25i NBOMe the only full agonist psychedelic right now? Why is is that a common dose of 25i is found in 1000 ug tabs while a common dose of LSD is 120 ug, yet LSD has way less affinity for the 5ht2a receptors. If a person took a 100 ug dose of LSD, does this mean that their 5ht2a receptors were hit 100 times less as hard as a 25i user who took a 1000 ug dose?

Also, does body weight play any role in potential neurotoxicity/toxicity? If a 50kg person took a 1000 ug dose vs. an 80 kg person, is the lighter person more likely to suffer from toxic/neurotoxic effects? Or is body size irrelevant for these drugs and instead brain size is what matters.

Thanks so much

 

[Solipsis]

LSD may be a bad comparison because it binds for extremely long times to 5-HT2A and 5-HT2B i believe, so this seems to be why it is so potent while the affinity isn't so extremely high (but still not bad).

I do believe there are plenty of other derivatives which are also full agonists, but not sure.

I also think that full agonists aren't magically evil by being on par with the endogenous ligand, partial agonists are still on a gradual scale towards that point so I don't see how quite suddenly a full agonist is inherently bad compared to a 90% efficacy partial agonist. However I will say that I think full agonists are often best avoided, not for being in their own league but because they tend to be very powerful and by comparison seem to produce more unhealthy effects if you just think of some full agonists of say opioid or benzo type.
I'm interested to know whether high affinity compounds have particular ways of deregulating a neurotransmitter system.

You cannot just calculate dosage with affinity like that in a linear fashion. ^ The more important factor is efficacy: not how likely a drug is to bind to a receptor but to also activate it. There is usually a correlation between efficacy and potency I think, but you still shouldn't try to do a simple calculation like that.

The insomnia fits but I agree with Cotcha that your main problem seems to be anxiety (IMO with possible OCD tendencies) which is not something I would quickly associate with serotonergic issues. HPPD maybe (no idea if there is any literature on that).

I would try to investigate how many markers for anxiety there were before you ever took 25I. Any psychedelic can generally sensitize people apparently, make them more sensitive but also more vulnerable. If you had a preexisting condition a psychedelic may have exacerbated it.

This is new territory but I think you only got just a partial match with 5-HT2A hyperactivity and should focus on regular therapy. You don't seem to be so much mad from dosing 25I as driving yourself mad over what it might have done.

It's hard to say if it is worth the cost of trying such medications based on this, something for you to decide. But IMO if you decide this you should also decide whether you will commit to therapy for some apparent anxiety disorder if the medication does not improve anything.

 

[jacktheripper42]

Thank you for your thorough response Solipsis, you the man bro.

I think I honestly did fuck up though... Using such a high dose of 25i was stupid. I have no idea the amount on the tab since I wasn't the one who placed it.

Regardless, this doesn't change the fact that I took it.

I've been doing research on 5ht2a and found out that it is responsible for breathing and ventilation. If this is the case, this matches this breathing problem some people get after 25i. I met a guy on an Empty Nose Syndrome who believes that his 7 uses of 25i messed up his breathing - like something is wrong with it phsycailly in his body/brain.


I talked to Dr. Nichols about 5ht2a and breathing and he said that if one receptor doesn't work, others take over to compensate. He even linked me this abstract which was very helpful. - "Previous work in intact awake and sleeping goats has found that unilateral blockade of excitatory inputs in the ventral respiratory column (VRC) elicits changes in the concentrations of multiple neurochemicals, including serotonin (5-HT), substance P, glycine, and GABA, while increasing or having no effect on breathing. These findings are consistent with the concept of interdependence between neuromodulators, whereby attenuation of one modulator elicits compensatory changes in other modulators to maintain breathing. Because there is a large degree of redundancy and multiplicity of excitatory inputs to the VRC, we herein tested the hypothesis that combined unilateral blockade of muscarinic acetylcholine (mACh), neurokinin-1 (NK1, the receptor for substance P), and 5-HT2A receptors would elicit changes in multiple neurochemicals, but would not change breathing. We unilaterally reverse-dialyzed a cocktail of antagonists targeting these receptors into the VRC of intact adult goats. Breathing was continuously monitored while effluent fluid from dialysis was collected for quantification of neurochemicals. We found that neither double blockade of mACh and NK1 receptors, nor triple blockade of mACh, NK1, and 5-HT2A receptors significantly affected breathing (P >/= 0.05) in goats that were awake or in non-rapid eye movement (NREM) sleep. However, both double and triple blockade increased the effluent concentration of substance P (P < 0.001) and decreased GABA concentrations. These findings support our hypothesis and, together with past data, suggest that both in wakefulness and NREM sleep, multiple neuromodulator systems collaborate to stabilize breathing when a deficit in one or multiple excitatory neuromodulators exists."

So if my 5ht2a receptors were non-functional or blocked off, other parts of my brain would compensate. Now, what if these receptors were sensitized so that they are more active than they should be? Could this potentially cause rapid shallow breathing patterns? If so, the solution would be to completely block off 5ht2a with an inverse agonist. I would love to see what you think about this.

Also, there seems to be a fair amount of literature that indicates the potential neurotoxicity of synthethic cannabinoids - mainly white matter alterations. Is it safe to assume that the mechanism behind this damage is the high affinity and full agonism displayed on the CBD receptors vs marijuana which is a lower affinity partial agonist? The studies I looked at measured daily users that used everyday of the week for at least a year - so obviously there was abuse involved.

I just HATE the fact that I took such a large dose of such a potent research chemical that affects such a vital receptor in our brain. It's not right honestly, the fact that this substance became so popular and readily available. People started selling it like it was candy and under the impression it was LSD... It just frustrates me that I could have ruined my life for a decision I made as a 17 year old.

Anyways, enough with the self pity. Thank you guys so much for providing your input and helping me get to the bottom of this. It doesn't feel good to constantly be worried about your health especially when it pertains to serotonin - which prettty much controls everything.. (e.g: breathing, body temperature, sleep, memory).

I could also have a case of extremely mild sensitization since my after images and trails aren't too bad compared to some others and could even fall within the realm of visual phenomenon - so that's giving me potential relief.

 

[jacktheripper42]

Also what do you guys think even caused this sensitzation of the receptors? Apparently in parkinsons patients its a result of serotonin cells dying off and in order to compensate, the brain makes the remaining receptors much more sensitive so that they can still elicit a strong response.

Is this what happened with the 25i? It killed some of the neurons regulating my 5ht2a receptors and in order to compensate, my brain made these receptors more sensitive? Or is the potential sensitization just a result of using an ultra affinity full agonist that stimulates the receptor to its full capability making it more sensitive? I really hope its the latter and the former... That would make me feel better to know that my neurons are still intact and functioning..

 

[jacktheripper42]

Hate to spam my own thread. But I have so many psychedelic based questions that I can't seem to find the answers to.

Do psychedelics also go to the receptors in your stomach? Or do they exclusively target the brain?

Also since 95% of the serotonin system is found in the gut. Does this mean that body weight plays a role into psychedelic neurotoxicity/toxcitity? I asked Dr. Nichols and he said brain matter only matters but why is body weight irreleavent if the GI tract plays a role? By brain size does he mean the size of your GI tract too?