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Cycling between racetams and NMDA antagonists

ampa racetam nmda glutamatergic glutimate

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#1 Fenix_

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Posted 29 September 2014 - 01:13 AM


Racetams can inhibit the action of NMDA antagonists and vice versa. NMDA antagonists can provide a valuable antidepressant and anxiolytic function, which might persist for days after administration.

 

I have begun cycling various racetams + creatine for when I am out during the day and magnesium + agmatine for when I am relaxing at home. It feels more natural than constantly being on racetams, and I am getting less brain fog and overstimulation now when I do take them.

 

I feel I have achieved a new level of balance as well as a wider spectrum of beneficial brain activity by alternating between glutamatergic stimulation and inhibition. So what do you think, does NMDA antagonization reset the glutamate system? Or am I just getting a nice dose of placebo?


Edited by Fenix_, 29 September 2014 - 01:14 AM.


#2 Plasticperson

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Posted 29 September 2014 - 04:33 AM

chemically induced off and on switch might have to give it out a try 

 


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#3 Peder Holdgaard Pedersen

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Posted 01 October 2014 - 04:49 PM

I believe NMDA antagonism activates reuse of unused or strongly inhibited neurons and/or pruning of weak synapses. When the excitatory levels change the brain could respond with BDNF to restructure the brain. This could explain the anti-depressive effects of BDNF - repressed memories are pruned, and the synapses/neurons reused for something constructive. Inhibitory signalling energy is saved, usable for better things, and more synapses are available for new awesome stuff. The anxiolytic effect might be caused by the repressed memories no longer being passively/ weakly triggered by random things and causing corticosteroid release. I believe this is why some people become alcoholics - not only do they become physically addicted - they also increase repression of bad things via the NMDA antagonism of alcohol. However if there is nothing new to learn, the BDNF might just reestablish the old connections, or just rewire them to require less inhibitory signalling.

See: http://www.scienceda...10815162235.htm and http://www.ncbi.nlm.nih.gov/pubmed/16441270

This also explains why low blood sugar upregulates BDNF. The brain tries to improve energy effiency and facilitate creative thinking/learning new ways of getting food.

So the racetams upregulate BDNF via increase in (possibly frequency) excitation, and NMDA-antagonists upregulate BDNF via the opposite mechanism. The brain wants to remove inefficient and useless energy and neuron usage, so it prompts restructuring. 


Edited by Peder Holdgaard Pedersen, 01 October 2014 - 04:56 PM.

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#4 Fenix_

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Posted 11 October 2014 - 07:50 AM

Update - I have decided to get rid of agmatine as it seems to have a very wide range of action and not enough research for me to feel comfortable with. It also has a very long half-life which I feel is counter-productive as I do not want to be stuck in reset-mode constantly.

 

I am now experimenting with nitrous oxide as my NMDAR blocker. It is appealing for several reasons. The pharmacology of N2O is very similar to ketamine, which has proven antidepressant effects. And just as is clinically done with ketamine, I am only using it acutely (once or twice a week). Also supplementing 2000ug B12 daily (very important when using N2O!). Placebo is a definite possibility here but I do feel good for days after cracking a few whippets on the weekend. It definitely feels like hitting some kind of reset button on my brain. After effects wear off (half life is extremely short, measured in minutes), I find there is no haze really at all. It actually seems easier to make conversation with people immediately after the high. This is probably due to a lack of anxiety and heightened mood, though.

 

I realize how controversial this topic is as I do not believe there has been any research into using nitrous oxide for anything other than anaesthesia. But I do believe that nitrous oxide is a safer, more well-understood alternative to agmatine.



#5 kemiclinguist

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Posted 11 October 2014 - 08:09 AM

How about memantine?  I'm about to order some.

 

What is your racetam stack if you don't mind my asking?  I've been out of the loop for years.


Edited by kemiclinguist, 11 October 2014 - 08:09 AM.


#6 Fenix_

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Posted 11 October 2014 - 09:28 AM

I take noopept and aniracetam daily. Phenylpiracetam on work days only. I just obtained coluracetam and only take it when I have not taken any other choline supplements. Coluracetam is definitely the strongest racetam I have tried but I find it difficult to dose as it is really easy to get overwhelmed by it (presumably from too much choline uptake). As coluracetam is also a novel substance with less research than the rest, I reserve it only for experimental use. I take these racetams mainly for their anxiolytic and pro-focus effects. Phenylpiracetam provides a very nice energy boost as well. This stack towers above any medication a doctor in America would prescribe for anxiety or ADHD.

 

I would prefer not to take memantine because I do not believe that a constant inhibition of NMDA receptors is right for me. Memantine shares the downside of agmatine with regards to NMDA antagonism in that it has a long half-life. Conversely, nitrous oxide has a shorter half-life of almost any medication. I do not like the idea of chronically quieting a portion of my brain. Chronic NMDA antagonism would also be counter-intuitive to the nootropic effects of creatine which seem to arise from positive NMDAR modulation [ http://examine.com/s...ine/#summary5-0 ]. I would rather treat NMDA antagonists as a hard reset (though sleep should serve this purpose, clearly there is more to the story as evidenced by the antidepressant action of acute ketamine dosing [ https://en.wikipedia...mine#Depression ].

 

Now, I am not saying N2O is a perfect solution by any means. It has a very strong potential for abuse and can lead to debilitating health problems if taken overboard. Though many are sure to disagree, I am trying to tread these waters carefully. Once something better comes out, sign me up. I hope NRX-1074 can live up to the hype.


Edited by Fenix_, 11 October 2014 - 09:31 AM.


#7 Guest_Funiture2_*

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Posted 17 September 2015 - 09:27 PM

Update - I have decided to get rid of agmatine as it seems to have a very wide range of action and not enough research for me to feel comfortable with. It also has a very long half-life which I feel is counter-productive as I do not want to be stuck in reset-mode constantly.

 

I am now experimenting with nitrous oxide as my NMDAR blocker. It is appealing for several reasons. The pharmacology of N2O is very similar to ketamine, which has proven antidepressant effects. And just as is clinically done with ketamine, I am only using it acutely (once or twice a week). Also supplementing 2000ug B12 daily (very important when using N2O!). Placebo is a definite possibility here but I do feel good for days after cracking a few whippets on the weekend. It definitely feels like hitting some kind of reset button on my brain. After effects wear off (half life is extremely short, measured in minutes), I find there is no haze really at all. It actually seems easier to make conversation with people immediately after the high. This is probably due to a lack of anxiety and heightened mood, though.

 

I realize how controversial this topic is as I do not believe there has been any research into using nitrous oxide for anything other than anaesthesia. But I do believe that nitrous oxide is a safer, more well-understood alternative to agmatine.

 

Do you think its possible that the improved social aspect, loss of anxiety and better mood could be from the rebound effects of blocking the NMDA receptor? I wouldn't think that the NMDA antagonism from Nitrous Oxide would last for days like you say. Maybe Nitrous potentiates or upregulates NMDA long-term and you are enjoying a surge of glutamate.

 

Recently I tried out Nitrous Oxide, and while I didn't notice an immediate effect, after an hour or two I became more extroverted and driven. That state of mind, where conversation comes spontaneously rather than forced is what I have been striving for. I do not intend to use Nitrous Oxide on a regular basis, only as a indicator what is wrong. I have had the strongest responses to supplements that affect the glutamate/NMDA system (Zinc, Magnesium, NAC, Pregnenolone, Ginkgo, Memantine, Manganese). Oddly enough, Memantine, an NMDA Antagonist, made me loopy and brain fogged and inhibited my social drive. It has a very long half life, something like 4 days, so I think any rebound effect would be less noticeable.
 



#8 Area-1255

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Posted 17 September 2015 - 09:48 PM

Oddly enough, Memantine, an NMDA Antagonist, made me loopy and brain fogged and inhibited my social drive. It has a very long half life, something like 4 days, so I think any rebound effect would be less noticeable.

I don't like NMDAR blockers either - they make me feel scatter-brained and angry. So it's very obvious that glutamate is necessary to actually regulate other processis and anxiety in general...my feeling is low glutamate is actually worse than high glutamate in the short-term. 

Although NMDA is somewhat atypical because it doesn't HAVE to be activated by glutamate - instead can be activated by aspartic acid, serine derivatives, and other D-AMINO's in which are catalyzed by support enzymes and ultimately affected by the antioxidant concentrations in the blood. 

 

Also PH has a strong correlation with the magnitude/firing of NMDAR's and their respective ion-channels and as well the pre-synaptic currents operating outside of the NMDAR complex's which may manifest the same effect; paralleling NMDAR activity without actually affecting that specific complex.

 

Regulation of Presynaptic NMDA Responses by External and Intracellular pH Changes at Developing Neuromuscular Synapses

 

Here's some other interesting stuff.

 

Dehydration-Induced Synaptic Plasticity in Magnocellular Neurons of the Hypothalamic Supraoptic Nucleus

 

Vasopressin Differentially Modulates Non-NMDA Receptors in Vasopressin and Oxytocin Neurons in the Supraoptic Nucleus


Edited by Area-1255, 17 September 2015 - 09:49 PM.

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#9 gamesguru

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Posted 17 September 2015 - 10:03 PM

I wouldn't necessary rely on ketamine, N2O, or even mematine or for up-regulating NMDARs.
 

Effects of exercise on NMDA receptor subunit contributions to bidirectional synaptic plasticity in the mouse dentate gyrus.
We examined synaptic plasticity in the dentate gyrus (DG) of the hippocampus in vitro in juvenile C57Bl6 mice (28-40 days of age), housed in control conditions with minimal enrichment (Controls) or with access to an exercise wheel (Runners). LTP expression was significantly greater in slices from Runners than in those from Controls, but could be blocked by APV, a selective and competitive NMDA receptor antagonist, in both groups. LTP was significantly reduced by NR2B subunit antagonists in both groups. NVP-AAM077, an antagonist with a higher preference for NR2A subunits over NR2B subunits, blocked LTP in slices from Runners and produced a slight depression in Control animals. LTD in the DG was also blocked by APV, but not by either of the NR2B specific antagonists. Strikingly, NVP-AAM077 prevented LTD in Runners, but not in Control animals, suggesting an increased involvement of NR2A subunits in LTD in animals that exercise. NVP-AAM077 did not block LTD in NR2A Knock Out (KO) animals that exercised, as expected. In an attempt to discern whether NMDA receptors located at extrasynaptic sites could play a role in the induction of LTD, DL-TBOA was used to block excitatory amino acid transport and increase extracellular glutamate levels. Under these conditions, LTD was not blocked by the co-application of a specific NR2B subunit antagonist in either group, but NVP-AAM077 again blocked LTD selectively in Runners. These results indicate that NR2A and NR2B subunits play a significant role in LTP in the DG, and that exercise can significantly alter the contribution of NMDA NR2A subunits to LTD.

 

Individual and combined effects of rhynchophylline and ketamine on proliferation, NMDAR1 and GluA2/3 protein expression in PC12 cells.
Rhynchophylline is an active component of the Uncaria species, which is a member of the Rubiaceae family. Our studies show that the downregulation of N-methyl-d-aspartate (NMDA) receptor subunit GluN2B expression in the nucleus accumbens, amygdala, medial prefrontal cortex, and hippocampal CA1 area by rhynchophylline is beneficial for the treatment of psychological dependence on amphetamines. The individual and combined effects of rhynchophylline and ketamine on proliferation and GluN1 and GluA2/3 protein expression in PC12 cells were investigated. PC12 cells were differentiated into neuron-like cells by treatment with nerve growth factor (50 ng/mL). After treatment for 48 h, differentiated PC12 cell proliferation and GluN1 and GluA2/3 protein expression were analyzed. The viability of PC12 cells was reduced by ketamine at doses of 0.50, 1.00, 1.50, and 2.00 mmol/L, with the viability of cells treated with 1.50 and 2.00 mmol/L of ketamine significantly lower than that of the control cells. However, PC12 cells treated with rhynchophylline showed no toxicity at doses of 0.25, 0.50, 0.75, or 1.00 mmol/L. While GluA2/3 protein expression was upregulated by ketamine, it was not influenced by rhynchophylline. GluN1 protein expression was downregulated by rhynchophylline (1 mmol/L), while treatment with ketamine, either alone or with rhynchophylline, had no effect. These findings demonstrate that rhynchophylline suppresses GluA2/3 expression in ketamine-induced PC12 cells and downregulates GluN1 expression. Ketamine's lack of effect on GluN1 expression offers a partial explanation for ketamine addiction and the anti-addictive properties of rhynchophylline.

Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig.
Glutamate excitotoxicity is implicated in both the genesis of neural injury and noise-induced hearing loss (NIHL). Acoustic overstimulation may result in excessive synaptic glutamate, resulting in excessive binding to post-synaptic receptors and the initiation of a destructive cascade of cellular events, thus leading to neuronal degeneration and NIHL. The purpose of this study was to determine whether this apparent excitotoxicity can be attenuated by kynurenic acid (KYNA), a broad-spectrum glutamate receptor antagonist, and protect against noise-induced temporary threshold shifts (TTS). Guinea pigs were randomly assigned to three separate groups. Base-line compound action potentials (CAP) thresholds and cochlear microphonics (CM) were recorded. Group I was treated with physiologic saline as a vehicle control applied to the round window membrane that was followed by 110 dB SPL wide-band noise for 90 min. Group II received 5 mM KYNA followed by noise exposure, and group III received 5 mM KYNA alone without noise exposure. Post-drug and noise levels of CAP thresholds and CM were then obtained. Noise exposure in the control group caused a significant temporary threshold shift (TTS) of 30-40 dB across the frequencies tested (from 3 kHz to 18 kHz). Animals that received 5 mM KYNA prior to noise exposure (group II) showed statistically significant protection against noise-induced damage and demonstrated a minimal TTS ranging between 5 and 10 dB at the same frequencies. Animals in group III receiving KYNA without noise exposure showed no change in thresholds. Additionally, cochlear microphonics showed no considerable difference in threshold shifts when controls were compared to KYNA-treated animals. These results show that antagonizing glutamate receptors can attenuate noise-induced TTS, suggesting that glutamate excitotoxicity may play a role in acoustic trauma.

 

NMDA/glutamate mechanism of magnesium-induced anxiolytic-like behavior in mice.
The anxiolytic-like activity of magnesium in mice during the elevated plus maze (EPM) has been demonstrated previously. In the present study, we examined the involvement of NMDA/glutamate receptor ligands on the magnesium effect on the EPM. We demonstrated that low, ineffective doses of NMDA antagonists (the competitive NMDA antagonist CGP 37849, 0.3 mg/kg; an antagonist of the glycineB sites, L-701,324, 1 mg/kg; a partial agonist of the glycineB sites, D-cycloserine, 2.5 mg/kg; and the non-competitive NMDA antagonist MK-801, 0.05 mg/kg) administered together with an ineffective dose of magnesium (10 mg/kg) evoked a significant increase in the percentage of time spent in the open arm of the maze (an index of anxiety). Moreover, magnesium-induced anxiolytic-like activity (20 mg/kg) was antagonized by D-serine (100 nmol/mouse), an agonist of glycineB site of the NMDA receptor complex. The present study demonstrates the involvement of the NMDA/glutamate pathway in the magnesium anxiolytic-like activity in the EPM in mice, and that this activity particularly involves the glycineB sites.

 

Effect of exercise training on long-term potentiation and NMDA receptor channels in rats with cerebral infarction
http://www.ncbi.nlm....les/PMC3829711/

Treadmill exercise enhances NMDA receptor expression in mice
http://www.e-jer.org...mber=2013600095


Edited by gamesguru, 17 September 2015 - 10:08 PM.


#10 pipe_49

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Posted 19 February 2017 - 08:18 PM

Unfortunately, a lot of the science and mechanisms you are discussing are outside of my field, so I'm struggling a bit to follow what you are proposing. Is OP suggesting that racetams can be used to reset NDMA receptors after they have been previously inhibited by an NMDA antagonist?

 

Also, what does "NMDA receptor expression" mean?


Edited by pipe_49, 19 February 2017 - 08:23 PM.


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#11 cjt3po

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Posted 22 January 2019 - 01:27 PM

I've tried this with lower recreational doses (~2mg/kg) of Dextromethorphan after finding out about the neuroprotective research done on the drug. It seems it can even be used safely as an anesthetic in infants. It seems to really help bring up some nagging concerns with my emotional affect towards life and I choose to deal with them from the brutally honest perspective it gives that somehow is profoundly blunted from pain without sacrificing (but instead amplifying) my mind's ability to grapple more realistically with the pain from the point of view of archetypes (a technical term for a specific type of generalization) of my experience.

I believe, and please correct me if I'm mistaken, NMDA receptor antagonists are used in conjunction with acetylcholineerase inhibitors for Alzheimer's treatment, and I believe fundamentally it's increasing the signal to noise of some of the more well traveled connections of the brain?

Also my use of low dose DXM (~45-250mg @ 97kg) has also been been benefited strongly by extremely small doses of Aniracitam, which has some NMDA antagonism at low doses (personal estimate: 5<50mg intranasally or vaporized)

Edited by cjt3po, 22 January 2019 - 01:38 PM.






Also tagged with one or more of these keywords: ampa, racetam, nmda, glutamatergic, glutimate

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