High dose piracetam therapy to renew NMDA receptors

[MyExcuse]

I mainly wanted to get a discussion about this going as I've only found limited literature, and a few conflicting reports.

So as I'm sure some of you have noticed, after a period of using an NMDA antagonist, not only does tolerance build up but there is a marked drop in effects. The experience becomes foggier, has less to offer and overall loses some of it's magic.

Now it makes a whole lot of sense that this is due to down-regulation of the NMDA receptors (correct me if I'm wrong). Piracetam has been shown to increase NMDA receptor density by 20% (over a 14 day period in aged rats with 500mg/kg dose).

The only problem I can see would be that piracetam has been reported to diminish (when administered together) the effects of NMDA antagonists. This would mean that for the therapy period, effects from your desired dissociative agent would be negligible. Although the therapy might not be necessary all that often.

Thoughts? Any information to add?

Here is the info on the paper describing the NMDA density increase : http://content.karger.com/ProdukteD...36483&ProduktNr=224274&filename=000139100.pdf

 

[MeDieViL]

Id say you got tolerance to ndma ANTAGONISTS due to nmda upregulation as its not an agonist but an antagonist.

 

[Jamshyd]

Seeing the complexity of NMDA receptors, I imagine they do not downnregulate from continued use. Tolerance may be due to secondary cascade processes happening.

That said, while I had found a miracle medicine in Ketamine, I also found that Piracetam, like all other 'racetams I tried, causes me to feel suicidal after 3 days of continued use.

And yes, I can confirm that 'racetams are pretty much an "antidote" to Ketamine intoxication.

 

[lineartransform]

... I also found that Piracetam, like all other 'racetams I tried, causes me to feel suicidal after 3 days of continued use.

Thank you! I was wondering if I was alone in this strange effect. First day, bit of extra energy and focus. Second day, nothing too crazy. Third day, I'll wake up in the middle of the night with suicidal thoughts. There seems to be this strange mania that builds up.

 

[RGB]

Odd, I've been taking Piracetam regularly and haven't suffered from any mania. Then again, I don't often use NMDA antagonists, so perhaps it has something to do with that?

 

[iNOVA]

I'm wondering how people could claim to take Piracetam regularly and not feel suicidal.. Is this a fairly common occurrence?

I am extremely interested in starting a piracetam regimen to increase my focus and cognitive functions. Nootropics are supposed to help communication between the left and right hemispheres of the brain due to increase blood flow...

But I also have depressive tendencies and don't want to add suicidal thoughts to the mix..Do the benefits outweigh the side effects?

 

[The Monkey Mantra]

I'm in Jamshyd's camp. I can't do any 'racetams without incredible depression and anxiety ensuing. And I'll confirm: high-dose aniracetam basically blocked the effects of a 700 mg DXM dose. It did next to NOTHING.

One more thing: all that inter-hemisphere communication stuff is a load of horseshit.

 

[iNOVA]

all that inter-hemisphere communication stuff is a load of horseshit.

How so?

 

[grue]

Seeing the complexity of NMDA receptors, I imagine they do not downnregulate from continued use. Tolerance may be due to secondary cascade processes happening.

I mean ... if secondary cascade processes subsequent to glutamatergic agonism or antagonism change NMDA receptor density, this would be: it can happen, yea? Especially in terms of our functional purposes.

Check it out: http://www.sciencedirect.com/scienc...serid=10&md5=8cfb6a518b4d77f2a083012b782f40c9

Our data support the hypothesis that functional activity and number of NMDA receptors are regulated by strength of the glutamatergic input. Thus, reduced glutamate uptake resulting in increased concentration of ambient glutamate initiate a series of adaptive responses manifested as a gradual down-regulation of the functional activity and expression of NMDA receptors.

Also, we know that NMDA receptors seem to potentially reregulate region-specifically in response to morphine or, say, dopaminergic stimulants. I've talked about the changes in both pre-receptor measures and receptor density of both dopaminergic and glutamatergic system, that seem to occur downstream of introduction or withdrawal of these agents -- this in relation to opioid (and stimulant) tolerance and memantine.

I also think that glutamate rebound following the withdrawal (of the effect) of certain NMDA antagonists characterizes their overall effect, and IMO probably relates to the possibility of NMDA antagonist neurotoxicity too.

I remember well your posts about ketamine and its immense utility for you, for your bipolar depression. Is this still working out? The mechanics of rebound btw (or more precisely, the existence of these mechanics meaning that an overall effect has different characteristics) is the reason I don't think it's likely that memantine would have had an equivalent effect for you, or for a somewhat related matter why I suggest to people who have unsuccessfully tried ketamine or DXM for buffering of certain drug tolerances that it's not likely that the effects, within a certain time scheme, are all that comparable.

I'm with you, anyway, on the ridiculous complexity of these glutamate systems, subsystems. As they say, "primary exicitatory neurotransmitter in the nervous system", and linked to plenty of inhibitory processes too. Beyond that specificities and confusing contradictions abound!

http://www.ncbi.nlm.nih.gov/pubmed/16009352

Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons.
Maler JM, Esselmann H, Wiltfang J, Kunz N, Lewczuk P, Reulbach U, Bleich S, Rüther E, Kornhuber J.

Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Germany. [email protected]

The present study examined the effect of memantine, an uncompetitive NMDA receptor antagonist, on ethanol-induced NMDA receptor up-regulation. Primary glutamatergic rat hippocampal neurons were exposed to ethanol and memantine for 5 days. The ethanol-sensitive NMDA receptor subunits NR1, NR2A and NR2B were quantified by Western immunoblot analysis. Exposure to ethanol (50 mM) caused an increase in the levels of NR1 (137 +/- 11% of untreated control, P = 0.009), NR2A (128 +/- 14%, P = 0.022) and NR2B (136 +/- 19%, P = 0.012). Coincubation with memantine (10 microM) completely blocked the ethanol-induced up-regulation of NR1 (102 +/- 4%), NR2A (95 +/- 7%) and NR2B (105 +/- 13%). No effect of memantine on NR subunit expression was observable, except for NR2A, where a decrease (79 +/- 6%, P = 0.034) was noted. Neither ethanol nor memantine alone or in combination were toxic in the concentrations tested. These results may provide a molecular explanation for beneficial effects of memantine on ethanol-induced glutamatergic hyperexcitability reflected in the ethanol withdrawal syndrome and on the development of ethanol dependence.

 

[rebinator]

all I know is that sometimes piracetam restores shit I drank to forget in the first place. Therefore, the solution is not obliteration (such objects of oblivion will come out in the DMT wash at the end of the human lifespan anyway), but understanding and peace.

To wit... after a three-month piracetam fast, during which more phenylethylamines were consumed, more cheeba smoked, more wine quaffed, etc, SWIM popped piracetam/choline at 2g/1.2g ratio, and immediately experienced lucid dreams, and reexperienced a 20-year old (almost to the _day_) well-deserved punch to the head that had SWIM F-booking the bastard to see where he lived. After 20 years.

Plus, SWIM got extreme serotonergic/dopaminergic effects out of _one_ glass of wine after only one-day's break from all that aforementioned binge drinking. Mind you, it was a 15 percent first growth

Racetams will put you back in the game mentally; they won't force you to study, and they won't move your sorry ass through the 5th dimension (2nd temporal).

Consider this mileage variance disclaimer an understanding comment from a fellow erstwhile past-worshipper.

 

[hamhurricane]

There thread definitely does not reflect a typical response to the racetams. I find them enormously helpful with ADHD and they, if anything, exert an antidepressant effect for me. I respond especially well to pramiracetam and experience no depression even after months of sustained use. Also re interhemispheric connectivity:

Piracetam-induced facilitation of interhemispheric transfer of visual information in rats
O. Burešová and J. Bureš
The effect of Piracetam (UCB 6215, 2-pyrrolidone-acetamide) on learning mediated by transcommissural information flow was studied in hooded rats. Acquisition of monocular pattern discrimination was faster in drug-treated rats (100 mg/kg, 30 min before training) than in untreated controls. Subsequent relearning with one hemisphere functionally eliminated by cortical spreading depression showed that the strength of the primary engram formed under Piracetam in the hemisphere contralateral to the trained eye remained unaffected but that the secondary trace (in the ipsilateral hemisphere) was considerably improved and almost equalled the primary one (savings increased from 20–30% to 50–60%). Learning with uncrossed optic fibers was unaffected by the drug. Interhemispheric transfer of lateralized visual engrams acquired during functional hemidecortication was facilitated by Piracetam administration preceding the five transfer trials performed with the untrained eye open (imperative transfer). Piracetam was ineffective when the trained eye was open during transfer trials (facultative transfer). After a visual engram had been lateralized by 5 days of monocular overtraining, Piracetam facilitated formation of the secondary engram induced by 3 interocular transfer trials. It is concluded that Piracetam enhances transcommissural encoding mechanisms activated in the initial stage of monocular learning and in some forms of interhemispheric transfer, but does not affect the transcommissural readout. This effect is interpreted as a special case of the Piracetam-induced facilitation of the phylogenetically old mechanisms of redundant information storage which improve liminal or subnormal learning.

 

[CesarMillan]

I haven't researched piracetam much at all after I first discovered it about 10 years ago. But back then I did read a lot of interesting and genuine research with consistent results... that I've also experienced directly on and off for the last decade... a mild but certain increase in focus and memory that slowly fades (or you just get use to it) over a couple mouths.

It's interaction with other drugs is unpredictable and fascinating too.

 

[ferinox]

all I know is that sometimes piracetam restores shit I drank to forget in the first place. Therefore, the solution is not obliteration (such objects of oblivion will come out in the DMT wash at the end of the human lifespan anyway), but understanding and peace.

To wit... after a three-month piracetam fast, during which more phenylethylamines were consumed, more cheeba smoked, more wine quaffed, etc, SWIM popped piracetam/choline at 2g/1.2g ratio, and immediately experienced lucid dreams, and reexperienced a 20-year old (almost to the _day_) well-deserved punch to the head that had SWIM F-booking the bastard to see where he lived. After 20 years.

Plus, SWIM got extreme serotonergic/dopaminergic effects out of _one_ glass of wine after only one-day's break from all that aforementioned binge drinking. Mind you, it was a 15 percent first growth

Racetams will put you back in the game mentally; they won't force you to study, and they won't move your sorry ass through the 5th dimension (2nd temporal).

Consider this mileage variance disclaimer an understanding comment from a fellow erstwhile past-worshipper.

I can agree with racetams bringing stuff back. Stuff that I haven't thought about since it actually happened. After ingesting aniracetam the other day, I wound up finishing a debate I had in sixth grade in my mind. I like it though, I don't feel quite as empty inside with all these memories coming back from a more innocent time.

 

[roganmaster]

I've run piracetam for 28 days at doses between 3200-4800mg/day and I've never felt suicidal. I used it to decrease my stimulant tolerance as well as MDMA tolerance. No depression, no suicide. I love piracetam, it's amazing.

 

[mad_scientist]

There thread definitely does not reflect a typical response to the racetams. I find them enormously helpful with ADHD and they, if anything, exert an antidepressant effect for me. I respond especially well to pramiracetam and experience no depression even after months of sustained use.

Personally I fall somewhere in between...the weak racetam drug piracetam I found to be a useful nootropic with a mild mood-elevating effect, the stronger aniracetam and oxiracetam I found made me anxious but still had a nootropic effect, while the even stronger again pramiracetam made me instantly shitty and irritable with a tendency towards depressive thoughts...maybe individual preference for these drugs depends on your natural level of NMDA activity.

 

[AlkaloidsEye]

Does anyone have quantitative data concerning how much their tolerances for various substances were lowered by? I have yet to try any of the -acetams, but i am interested in it's possible nootropic effects in general and tolerance lowering/re-establishment in regards to MDXX's.

excellent thread. The depression side effects have been noted, although i don't really lean towards being depressed much.

 

[cola]

hmmm...also intrested in piracetam's possible lowing the tolerance to dissociatives , mainly ket...

and i need to find out : is piracetam safe to take with 5-htp? I'm thinking neurotransmitter renewal-wise?

 

[Limpet_Chicken]

With 5HTP? I see no potential interaction here.

Tolerance to dissociatives....hmm....I posted a thread on that, or something close to it recently although it got few replies, regarding AMPAkines, 'racetams and tolernce to NMDA antagonists.

I was under the impression that NMDAr function was regulated by AMPAr mediated glutamatergic input (probably not as simple as that, it never is, but it is at least one main mode of regulation of the expression and activity of the NMDA receptor)

Increased AMPAr activation=more depolarization of neurone->more efficient removal of bound Mg2+ in the NMDAr ion channel and a net increase in expression of NMDARs/NMDAr activity. And thus more receptors to antagonise, surely meaning increased tolerance to dissociatives.

 

[clubberdude]

There thread definitely does not reflect a typical response to the racetams. I find them enormously helpful with ADHD and they, if anything, exert an antidepressant effect for me. I respond especially well to pramiracetam and experience no depression even after months of sustained use. Also re interhemispheric connectivity:

This. I found Piracetam to be a very potent antidepressant in me. Not quite sure how it works, but is almost too much when taken with a low dose SSRI.

In addition, I think it helps me concentrate on things better (when taken w/ Caffeine).

Unfortunately it appears to have a depleteorous effect on the psychedelic and general well, weirdness qualities of Ketamine. That said, short half life of Piracetam means only a couple of doses maximum would need be missed before getting the likely full effect of the Ketamine. Quite the contrast to SSRI depotentiation, which requires several days abstinence.

 

[mirrorlake]

My experience is similar to Hamhurricane's.

Antidepressant effect, motivation, no weird thoughts, just focus.

It does make Ketamine and MXE mostly ineffective.

I have used more Ketamine than almost anybody and a good bit of MXE as well, and take Piracetam in between. My Ket/MXE tolerance is currently almost none at all. This may or may not apply to you. And I can't be sure it's the Piracetam, but I suspect it is.