Phenibut = Upregulation of PEA Sensitivity?

[Booda]

I recently posted in the B&D 6-apb thread about my recent unpleasant experience with a 6-apb pellet. I was heading into a hypertensive crisis and used a benzodiazapine to get it under control.

I was very confused as to why I had enjoyed the previous two 6-apb pellets with no problems and then suddenly the third nearly killed me. Could my use of phenibut have caused an upregulation of PEA sensitivity which led to this extreme reaction to a normal dose of 6-apb? It seems strange that one pellet could be so much more potent than the other two from the same source.

When I took the last pellet, I had just taken my usual ~2.5 grams of phenibut two days prior. I take phenibut two to three times a week at that same dose of ~2-3g. I wait two days before using phenibut again. I'm wondering if this has caused some sort of upregulation of PEA receptors or receptor sensitivity? I've been using phenibut on this schedule for around two months.

I always feel very relaxed the day after I take phenibut. I was actually concerned that any phenibut remaining in my system might ruin my roll on 6-apb, so I waited until the following day to take the 6-apb pellet. When I came up, it felt 10x more potent than my last two doses and my heart was beating so fast and so hard that I feared for my life. It would be easy to blame the pellet itself, but the fact that phenibut has been studied as a PEA antagonist makes me wonder if that's what really caused this reaction.

Any thoughts?

 

[sekio]

No, I think it's far more likely that the perople making your "pellets" have fucking zero quality control with regards to dose uniformity. That, or you're becoming sensitized to MDx (it happens with semi-infrequent use). Or it's possible you just panicked.
Phenibut is not a "PEA antagonist", it's a GABA-b agonist, it doesn't interact with any of the targets that phenethylamines hit.

ADD-->BDD

 

[Booda]

Gee, thanks for setting us all straight on that, sekio. 8)

The only problem is that the best literature on phenibut linked right here below clearly states that phenibut "..also stimulates dopamine receptors and antagonizes beta-phenethylamine (PEA)."

http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2001.tb00211.x/pdf

Direct quote from Izyaslav Lapin's "Phenibut (â-Phenyl-GABA):
A Tranquilizer and Nootropic Drug", probably the best literature currently available on phenibut:

"Antagonism of beta-phenethylamine (PEA). PB has been traditionally viewed as a
GABA derivative (Fig. 1). Therefore, most of the pharmacological studies with PB were
devoted to its GABA-like properties, its effects on GABA receptors and to comparison
with other GABAergic compounds (1–3,5,6,9,11,16–23,32,43,47–50). PB can be viewed,
however, also as a derivative of PEA (Fig. 2). The questions are whether the chemical similarity
of PEA and PB is of any relevance to the pharmacology of PB and since PEA was
thought to function as an endogenous anxiogenic substance, could not the anxiolytic
action of PB be due to the antagonism of PEA by PB?"

I realize you're a mod and everything, but maybe you ought to do a little research before posting such misinformation!

If someone could move this back to ADD I'd sure appreciate it! I doubt this will get any meaningful replies here in BDD and will likely just get nonsense responses like the one above. I was hoping someone who's really into neurochemistry would chime in on this.

 

[jambabomba]

I'm not sure about that PEA antagonism and upregulation. Personally I don't believe it is a issue at all because I've been using phenibut more than a year now everyday 5-20g/d but when I stopped it and changed to baclofen I didn't notice any effects that I could have linked to PEA.

Btw, I allways wonder when people say they "have hypertensive crisis" or as you said were heading to it but usually or allmost never offer any values! I'm sorry but I really doubt those unless you have have some numbers showing it or you had done some seriuous toxic substances and did some heavy lifting with it. So how did you know you "were heading to hypertensive crisis"? Blood pressure monitor?

Pressure of 180/100 is most time ok for short time. Nothing to worry about. Infact my friend has those kind of pressures at reast all the time. Other friend got pressures of about 200/xx at rest without any supplements. You really have to seriously fuck up your blood pressure if you are going to have some instant damage so thats why these kinds of "I was at hypertensive crisis omg" posts don't convice me at all! Think about it, when you are doing hard leg excercises of deadlift you could be having blood pressure up to 300/200!! Or at least something over 200 usually. So your blood pressure have to go really fucking high before your blood vessels start to breake or some other damage happens.

Of course high blood pressure is allways damaging to endothelial lining but not life threating instantly.

 

[Booda]

Another brilliant post lol^

Yeah, when most people say "hypertensive crisis" around here, they mean their heart feels like it's going to explode. That is the message it gets across. Nobody carries a blood pressure monitor around with them. Your rant is useless and completely off topic. Go start your own blood pressure terminology thread. This one is about phenibut and PEA.

Thanks again for moving this thread to BDD, sekio. 8)

 

[Swimmingdancer]

I agree with you that this is not a basic question. ADD is for in-depth advanced discussion of journal articles, drug science and other theoretical topics, but it's up to the ADD mods whether or not this thread fits. Since they already moved it out of ADD, for now I'm going to move it to Other Drugs (OD), which is for intermediate level and in-depth discussion of drugs (that aren't covered in other focus forums). If you want it moved back to ADD please PM the ADD mods.

Also, maybe try not to use so much sarcasm etc if you want people to help you. I know it's annoying if you don't feel someone's answer was well-researched, but you can explain the additional info you are aware of in a kinder way without alienating people. I didn't see anything wrong with or rude about jambabomba's post, I thought asking you to elaborate on why you thought you were "heading into a hypertensive crisis" was relevant.

Unfortunately I don't think enough is understood about phenibut or 6-APB to give you an answer that isn't purely speculation or at best an educated guess. Some studies have found that phenibut antagonizes the effects of phenylethylamine (PEA) while others found no effect on PEA, while some found it affected PEA in some ways but not others. It is not fully understood. Not sure what that means for 6-APB's effects.

I am also wondering were you not taking phenibut at all when you used 6-APB in the past?

All I know about phenibut's effect on receptors is that phenibut binds the GABAB metabotropic receptor, (the same site responsible for the sedative effects of baclofen) and might bind to the GABAA ionotropic receptor, (there is dispute in the literature about this with some suggesting that it perhaps it does but only when taken in large amounts).

BDD -> OD

 

[sekio]

Phenethylamine does not share effects with MD(M)A or the APBs. Showing that phenibut was able to antagonise a mediocre, non-serotonergic stimulant (seriously, phenethylamine is only marginally active at multi-gram doses in man) says absolutely nothing about its ability to paradoxically enhance the effects of a potent serotonin releaser!
c.f. its almost nonexistient EC50 for serotonin release.

I also agree that without actual hard data from a b.p./heart rate monitor it is hard to diagnosre hypertensive crisis. It is far more liekly you had a panic attack typical of MD(M)A abuse. (it happens).

Please, provide a hypothesis that somehow links
1. antagonism of the effects of a weak, easily metabolised stimulant (totally unrelated to 5/6-APB in terms of its effects)
2. a paradoxical effect to a drug that had previously been administered with no problem

My money still remains on either drug sensitization or on poor quality control of the gray market drug industry.

 

[Swimmingdancer]

Leaving out PEA for the moment, if they had built up a tolerance/dependence to phenibut, could that cause changes to their receptors/sensitivity (like changes to GABA), and then if they didn't take the phenibut but did take the 6-APB, could that make the effects of the 6-APB stronger? Or if they were taking the phenibut at the same time as the 6-APB in the past (I don't know if they were or not yet), could that have decreased the effects of the 6-APB at that time, making the effects of the 6-APB seem stronger when they took it on an occasion where they hadn't taken phenibut for 2 days?

I have to agree that there are other far more likely potential reasons for the 6-APB feeling stronger or causing greater side effects than it has in the past though.

 

[sekio]

SD, both of those copuld have happened as well. However it is unlikely that phenibut would produce no withdrawal symptoms at all upon discontinuation, until combined with other drugs. Assuming he's been taking phenibut the same as when he was dosing APB before, there is no reason to expect drug withdrawal to have caused these bad effects. It is also likely the w/d symptoms would recur after the benzodiazepine wore off, were that the case.

As phenibut is primarily a GABA-b agonist it is nowhere near as "damaging" for your GABA-system in the long term as e.g. benzodiazepines. and does not produce anywhere near as severe w/d symptoms.

I think the usage of phenibut & MDA-type hallucinogens is pretty unrelated. Also, hypertensive crises are not typically well-controlled by benzodiazepines, I thought?

 

[Booda]

You do realize that 6-apb is a substituted phenethylamine, right? Anything which acts on PEA could very well act on 6-apb as well. We're not talking about trying to take recreational doses of crystalline PEA, we're talking about phenibut blocking the effects of endogenous PEA and substituted phenethylamines like 6-apb, which in turn could lead to up-regulation and thus increased sensitivity. I do agree that the 6-apb pellets could have been to blame. But this is one other possibility which is worth consideration. 6-apb isn't just a serotonin releaser, it also releases lots of dopamine, which is what causes the stimulation (and overstimulation in this case).

Thank you for moving this, Swimmingdancer. I didn't mean to come off sarcastic, but sekio's original post was rather rude and incorrect. He simply wrote me off as a n00b and didn't take the time to see that my chemical question was legit.

Regarding the term "hypertensive crisis", you're all correct that this is not the best term for what was occurring. Tachycardia, (extreme tachycardia) is what I was experiencing. I'm new to the MDA/MDMA substances and I actually borrowed that term "hypertensive crisis" from someone's post on this very board regarding a 6-apb overdose. What I experienced wasn't a panic attack, I have been around a while and know what a panic attack is. This was a case of being extremely chemically overstimulated. I had to take a benzo to slow my heart down or I would have probably had some sort of cardiac event.

But I think it is a bit off topic to get too caught up in terminology about chemical overstimulation of the heart. We can call it whatever. I'm more interested in the PEA antagonist aspect of phenibut and how it very possibly could have caused my feeling of overdosing on only one pellet. If this is possible then I think it's actually good to get this info out here on the board so other people can learn from it. That's what this forum is for, right?

 

[sekio]

6-apb being a substituted phenethylamine has nothing to do with its effects as a drug. Phenethylamine is the odd child out when it comes to drug effects.

There is a russian article that suggests phenibut will reduce the effects of threshold doses of amphetamine in cats.

Again, how does phenibut, which counteracts the effect of amphetamines/phenethylamines, mysteriously and suddenly increase the effects of a serotonergic stimulant? Bear in mind that phenibut reduces the efefcts of PEA by indirect, not direct mechanisms. That is, phenibut does not act against PEA by blocking it at DA/NE transporters. It is also wise to not discount the effect of norepinephrine, whigh is likely the real culprit here (dopamine is associated more with psychosis- and dependence- related thinking, not physical overstimulation. ref- mice with NET blocked do not get stimulatory effecs from MDMA).
I am seriously interested to hear your proposed explanation for phenibut & suddenly mysertiously increasing norepinephrine release.

You have to provide evidence to back up your speculation if you wantto be respected. Openly shitting on people disproving your theories for no reason other than you don't like their arguments isn't good science.

 

[Booda]

You don't seem to understand. 6-apb and all sorts of amphetamines are derivatives of PEA. Their molecular structure is extremely similar to the natural phenethylamine in our brains. If you take some PEA powder and eat it, you will experience stimulation. PEA is not so different from amphetamines. It's just not as recreational or enjoyable. But receptor sites don't care about that!

The fact that this Russian study showed that phenibut blocked the effects of amphetamines in cats could actually be evidence that it was acting as a PEA antagonist. It may have been binding to receptor sites, preventing amphetamine from doing its thing. Either that or the GABA-b activity was counteracting the stimulation.

The reason why this could cause an extreme sensitivity to phenethylamines is basic drug chemistry and you should probably know these things before throwing out someone's thread. If you block receptor sites with an antagonist, your brain tries to compensate by creating more receptor sites, AKA up-regulation. So when you are using a drug like phenibut that may antagonize phenethylamines, you can get more receptor sites just waiting to grab those molecules. When the phenibut wears off, like it had last Sunday when I took my 6-apb pellet, all those additional receptor sites get clusterfucked by phenethylamines. You dig?

I'm not a professional neuroscientist--hopefully one will chime in and set us all straight. But most of this is basic chemistry. The body is always seeking homeostasis. When we flood our bodies with antagonists, you can get up-regulation. When you flood your body with agonists you can get down-regulation, or tolerance. This is basic stuff. What I experienced could easily be explained by such a mechanism.

I'm not trying to shit on you, I just think you handled this thread very poorly.

 

[Swimmingdancer]

So we know it is possible that phenibut could reduce the effects of 6-APB, correct?

A possible analogy: The plant Pau D'Arco inhibits a liver enzyme, and then the body responds by making more of this enzyme, so when the inhibition wears off the enzyme is induced. So its effects on drugs metabolized by that enzyme will vary depending on when you took the Pau D'Arco. There are other examples of this as well. An analogy involving receptors could be how when you take an opioid antagonist, after it wears off you are more sensitive to opioids. This is kind of what I figured Booda was asking, in a broader sense (whether or not the mechanism involves receptors is a more specific issue). Could phenibut, after it wears off, make the body/brain more sensitive to 6-APB? Even if the PEA theory is discounted, could using phenibut decrease 6-APB's action temporarily or if you took them right at the same time, but increase it after the phenibut has worn off? Booda said the 6-APB was taken 2 days after taking the phenibut, not at the same time.

Booda - I am also still wondering whether or not you were taking phenibut when you used 6-APB in the past?

 

[Booda]

^You've got it exactly right, Swimmingdancer. You put it better than I did.

I started dabbling with phenibut just shortly before I took my first dose of 6-apb. I haven't really abused phenibut, but I only skip 2 days between doses, which is probably a minimal "washout" period. I've been dosing like this for around 2 months. Exactly as you put it, Swimmingdancer, I'm wondering if this considerable phenibut usage has led to increased sensitivity to phenethylamines.

Maybe it would only be due to reduced GABA activity. But I find it interesting that phenibut has that phenyl ring and it has been suggested that it is not only a GABA analog but also a PEA antagonist due to the structural similarity to phenethylamines.

 

[Swimmingdancer]

There are SO many other factors that could affect your experience from the 6-APB that I don't think you can conclude it was something to do with the phenibut. It is very common for someone to get side effects they have not previously experienced or stronger effects from a drug than they did on past occasions.

But I am thinking that IF this was something to do with a phenibut interaction and not just a coincidence, then either:
a) when you took the 6-APB in the past the phenibut was blocking some of the effects, and it wasn't this time (because perhaps you didn't take the phenibut as close to the 6-APB this time, or you now have a tolerance to the phenibut) - did you take the phenibut closer to the 6-APB last time? or that:
b) taking phenibut for 2 months has affected your GABA receptors.

The group of phenethylamine derivatives (substituted phenethylamines, substituted amphetamines, and substituted methylenedioxyphenethylamines), referred to as "the phenethylamines", is a series of broad and diverse classes of compounds that include drugs from many different classes, with very different effects. Both phenibut and 6-APB share structural similarities with phenylethylamine, as do many other drugs. I wouldn't get hung up on the PEA thing. As sekio said, "phenibut reduces the effects of PEA by indirect, not direct mechanisms. That is, phenibut does not act against PEA by blocking it at DA/NE transporters". So phenibut is not a "PEA antagonist" in the way that, say, naloxone is an opioid antagonist, there are no "PEA receptors" it is blocking. I would think more about the mechanisms of action of each drug rather than concern yourself with PEA and PEA derivatives.

Phenibut binds to the GABA-B receptors and possibly or to a lesser extent the GABA-A receptors. GABA basically decreases the ability of other neurotransmitters to work. Rather than encouraging communication between cells like dopamine, serotonin or norepinephrine, GABA reduces communication (and I read that an increase in GABA or GABA-ergic drugs can also cause a reduction in these neurotransmitters, not just in their effects). This is why GABA-ergics, like phenibut, can decrease the effects of other drugs, such as those that affect serotonin, dopamine and norepinephrine, like 6-APB and PEA.

With chronic use, the body can respond to GABA-ergic drugs by modifying the GABA receptors. This down-regulation is responsible for tolerance and dependence (although other mechanisms likely contribute to both as well - tolerance is not well understood).

I have no idea though if phenibut could cause an increased sensitivity to 6-APB when it wears off if someone had only taken it once, (like the Pao D'Arco example I gave above which was involving totally different mechanisms), but it makes sense to me that it could be possible that taking phenibut regularly and then not taking it for a few days could potentially have an impact on one's sensitivity to 6-APB. You can build a tolerance to GABA-ergics without having withdrawal symptoms when you don't take them. But I don't know how likely it is.

I have a friend who drinks and takes benzos a lot and even when he goes a while without drinking/taking benzos he doesn't get noticeable effects from psychedelics. You would think if your theory was widely applicable he would get extra heightened effects from psychedelics. I have to agree with sekio that it is more likely that the 6-APB pellets are not consistant, that you're becoming sensitized to 6-APB, or that something else affected your reaction.

 

[CrimpJiggler]

Interesting thread. I get a severe adverse reaction when I take amphetamine the day after phenibut in which I get overloaded with physical aggitation, and start blacking out temporarily (less than a second each time, feels like I'm falling asleep). The same thing happens when I take amphetamine the day after GHB. I notice that it didn't happen after the first couple of nights I slept on GHB, then the 3rd day it happened and kept happening. With that in mind, this theory about phenethylamine sensitization is more plausible. I don't know if GHB acts as a phenethylamine antagonist also or not though. Is phenibut supposed to be a competitive antagonist? Phenethylamine itself is a competitive GABA-B antagonist (not sure how strongly it binds though) so phenibut and GHB act as non competitive antagonists of phenethylamines anxiolytic effects in that sense.