1565 replies to this topic

[Isochroma]

The sweetest cream of all:

Amelioration of cognitive deficits mediated by sunifiram was associated with stimulation of glycine-binding site of NMDAR [2012]

"Amelioration of cognitive deficits mediated by sunifiram was associated with stimulation of [the] glycine-binding site of NMDAR"

"In conclusion, the present study demonstrated that sunifiram ameliorates cognitive deficits in OBX mice and it enhances LTP induction via a glycine-binding site of NMDAR activity."

And the application to schizophrenia:

Novel Therapeutics for Schizophrenia: Targeting Glycine Modulation of NMDA Glutamate Receptors

Stephen M. Stahl, MD, PhD
CNS Spectr. 2007;12(6):423-427

Faculty Affiliation and Disclosures

Dr. Stahl is adjunct professor of psychiatry in the Department of Psychiatry at the University of California-San Diego in La Jolla.

Disclosures: Dr. Stahl receives grant/research support from AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Neurocrine Bioscience, Organon, Pfizer, Sepracor, Shire, Somaxon, and Wyeth; is a consultant to Acadia, Amylin, Asahi, AstraZeneca, Biolaunch, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, CSC Pharma, Cyberonics, Cypress Bioscience, Eli Lilly, Epix, Fabre Kramer, Forest, GlaxoSmithKline, Jazz, Neurocrine Bioscience, Neuromolecular, Neuronetics, Nova Del Pharma, Novartis, Organon, Otsuka, PamLab, Pfizer, Pierre Fabre, Sanfoi Synthelabo, Schering Plough, Sepracor, Shire, Solvay, Somaxon, Takeda, Tetragenix, and Wyeth; and is on the speaker’s bureau of Pfizer.

If you would like to comment on this column or submit a suggestion to Dr. Stahl for future columns, please e-mail vj@mblcommunications.com.

New Trend in Psychopharmacology

Currently, a major hypothesis for the pathophysiology of schizophrenia^1-10 proposes that numerous risk factors converge on the N-methyl-D-aspartate (NMDA) receptor for the neurotransmitter glutamate, resulting in neurodevelopmental abnormalities at glutamate synapses and hypofunction of NMDA receptors. This hypothesis was presented in a previous “Trends in Psychopharmacology” column.⁹ Novel treatments are now in development that can theoretically boost the function of NMDA receptors by enhancing actions at the glycine co-transmitter site of this receptor complex.^10-20 Early studies^15-20 already indicate that this may lead to improvement in negative and cognitive symptoms of schizophrenia, especially when added as augmenting agents to atypical antipsychotics.

New Treatment Strategies for Schizophrenia

The NMDA receptor hypofunction hypothesis for schizophrenia^1-5 arises from observations that the NMDA receptor antagonist phencyclidine can produce a psychotic condition similar to the positive, negative, and cognitive symptoms of schizophrenia. These observations, coupled with genetic studies in schizophrenia that also implicate dysfunctional NMDA receptors,⁶ have led to a new strategy for the treatment of schizophrenia, namely targeting mechanisms that enhance deficient NMDA receptor functioning.^3,10-20

Pharmacologic approaches that involve direct enhancement of glutamate risk excitotoxicity from excessive glutamate action.^3-5,10 Thus, a potentially safer way to enhance glutamate is to exploit the fact that NMDA glutamate receptors also require glycine actions at a co-transmitter site.^3,10-20 NMDA receptors are an interesting type of “coincidence detector” that can open to allow calcium into the neuron to trigger postsynaptic actions from glutamate neurotransmission only when three things occur at the same time: glutamate occupies its binding site on the NMDA receptor, glycine or D-serine binds to its site on the NMDA receptor, and depolarization occurs.^3,7,8,10

In order to understand the actions of new drugs directed at the glycine co-transmitter site on NMDA receptors, it is useful to review the synthesis of endogeneous agonists for this site, including glycine and D-serine.

Synthesis of Glutamate Co-transmitter Glycine

Glycine is not known to be synthesized by glutamate neurons, so glutamate neurons must acquire the glycine they need for their NMDA receptors from glycine neurons or from glial cells (Figure 1).^3,7,8,10 Glycine neurons release glycine. However, they contribute only a small amount of glycine to glutamate synapses, since glycine is unable to diffuse far from neighboring glycine neurons because the glycine they release is taken back up into those neurons by a type of glycine reuptake pump known as the type-2 glycine transporter (Figure 1).



Thus, neighboring glial cells are thought to be the source of most of the glycine available for glutamate synapses. Glycine itself can be taken up into glial cells either by a type-1 glycine transporter (GLY-T₁) or by a glial specific neutral amino acid transporter (Figure 1).^10,13-17 Glycine is released into glutamate synapses from glial cells by riding on a reversed GLY-T₁ transporter (Figure 1).¹⁰ Once outside, glycine can re-enter the glial cell by riding on an inwardly directed GLY-T₁, which functions as a reuptake pump and is the main mechanism responsible for terminating the action of synaptic glycine (Figure 1).¹⁰

Glycine can also be synthesized from the amino acid L-serine, which is transported into the glial cell by an L-serine transporter, and then converted from L-serine into glycine by the glial enzyme serine hydroxy methyl transferase (Figure 1).¹⁰ This enzyme functions in both directions, either converting L-serine into glycine or glycine into L-serine.¹⁰

Synthesis of Glutamate Co-transmitter D-serine

D-serine is unusual in that it is a D-amino acid, whereas the 20 known essential amino acids are all L-amino acids, including D-serine’s mirror image amino acid L-serine.^3,7,8,10 It just so happens that D-serine has a high affinity for the glycine site on NMDA receptors, and that glial cells are equipped with an enzyme that can convert regular L-serine into the neurotransmitting amino acid D-serine by means of an enzyme that can go back and forth between D- and L-serine (D-serine racemase) (Figure 2). Thus, D-serine can be derived from glycine or from L-serine, both of which can be transported into glial cells by their own transporters, and then glycine converted to L-serine by serine hydroxy methyl transferase, and finally L-serine converted into D-serine by the enzyme D-serine racemase (Figure 2). D-serine’s actions are not only terminated by synaptic reuptake via the inwardly acting glial serine transporter but also by an enzyme D-amino acid oxidase that converts D-serine into hydroxy-pyruvate (Figure 2).



Targeting Glycine Modulation of NMDA Receptors

Glycine Agonists

Agonists at the glycine site of NMDA receptors include the naturally occurring amino acids glycine and D-serine (Figure 3).^{3,5,7,8,10,15-19} An analogue of D-serine, called D-cycloserine is also active at the glycine co-agonist site of NMDA receptors. All of these agents have been tested in schizophrenia with evidence that they can reduce negative and/or cognitive symptoms.^5,7,8,10-19 Further testing of these naturally occurring agents is in progress and synthetic agonists with greater potency are in discovery.



GLY-T₁ Inhibitors

The GLY-T₁ reuptake pump is the major route of inactivation of synaptic glycine (Figure 1), so it is logical to explore the ability of GLY-T₁ inhibitors to enhance synaptic actions of glycine, and, thus, of NMDA receptors (Figure 4).^{3,5,7,8,10-17,19,20} Several GLY-T₁ inhibitors are now in testing, including the natural agent N-methyl-glycine, also known as sarcosine, as well as drugs in preclinical testing, such as SSR 504734, SSR 241586, JNJ17305600, and Org 25935. GLY-T₁ inhibitors are analogous to drugs that inhibit reuptake of other neurotransmitters, such as the serotonin selective reuptake inhibitors and their actions at the serotonin transporter. When GLY-T₁ pumps are blocked by a GLY-T₁ inhibitor, this increases the synaptic availability of glycine, and thus enhances NMDA neurotransmission (Figure 4). Sarcosine has been shown to improve negative, cognitive, and depressive symptoms, including symptoms such as alogia and blunted affect in schizophrenia.^19,20 The hope is that GLY-T₁ inhibitors with greater potency, such as those in preclinical testing mentioned above, will be even more effective.



Conclusion

An outgrowth of the NMDA receptor hypofunction hypothesis of schizophrenia is the novel therapeutic strategy of enhancing the glycine modulatory component of neurotransmission at these receptors. Already, early testing with direct-acting agonists at the glycine modulatory site, such as D-serine and D-cycloserine, as well as indirect enhancers of synaptic glycine that act by blocking the glycine reuptake transporter or GLY-T₁, such as sarcosine, is yielding encouraging results.

References

1. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;148:1301-1308.

2. Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology. 1999;20:201-225.

3. Stahl SM. Essential Psychopharmacology. 3rd ed. New York, NY: Cambridge University Press. In press.

4. Tamminga CA, Holcomb HH, Gao XM, Lahti AC. Glutamate pharmacology and the treatment of schizophrenia: current status and future directions. Int Clin Psychopharmacol. 1995;3:29-37.

5. Goff DC, Coyle RJ. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry. 2001;158:1367-1368.

6. Straub RE, Weinberger DR. Schizophrenia genes: from famine to feast. Biol Psychiatry. 2006;60:81-83.

7. Coyle JT, Tsai G, Goff D. Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann N Y Acad Sci. 2003;1003;318-327.

8. Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol. 2006;26:365-384.

9. Stahl SM. Beyond the dopamine hypothesis to the NMDA receptor hypofunction hypothesis of schizophrenia. CNS Spectr. 2007;12:265-268.

10. Millan MJ. N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology. 2005;179:30-53.

11. Betz H, Gomeza J, Armsen W, Scholze P, Eulenburg V. Glycine transporters: essential regulators of synaptic transmission. Biochem Soc Trans. 2006;34(pt 1):55-58.

12. Long KD, Mastropaolo J, Rosse RB, Manaye KF, Deutsch SI. Modulatory effects of d-serine and sarcosine on NMDA receptor-mediated neurotransmission are apparent after stress in the genetically inbred BALB/c mouse strain. Brain Res Bull. 2006;69:626-630.

13. Harsing LG Jr, Juranyi Z, Gacsalyi Tapolcsanyi P, Czompa A, Matyus P. Glycine transporter type-1 and its inhibitors. Curr Med Chem. 2006;13:1017-1044.

14. Sur C, Kinney GG. The therapeutic potential of glycine transporter-1 inhibitors. Expert Opin Investig Drugs. 2004;13:515-521.

15. Javitt DC. Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry. 2006;19:151-157.

16. Coyle JT, Tsai G. The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology. 2004;174:32-28.

17. Heresco-Levy U. Glutamatergic neurotransmission modulators as emerging new drugs for schizophrenia. Expert Opin Emerg Drugs. 2005;10:827-844.

18. Heresco-Levy U, Javitt DC, Ebstein R, et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry. 2005;57:577-585.

19. Lane HY, Chang YC, Liu YC, Chiu, CC, Tsai GE. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized double blind placebo-controlled study. Arch Gen Psychiatry. 2005;62:1196-1204.

20. Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter 1 inhibitor, N-methylglycine (sarcosine) added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 2004;55:452-456.

Edited by Isochroma-Reborn, 14 July 2013 - 01:01 AM.

[Isochroma]

Interview with Dr. Javitt on Glycine and Schizophrenia Research

Javitt: “The main tie of NMDA receptors to schizophrenia is that drugs, such as PCP, which block only NMDA receptors nevertheless produce the full range of symptoms and cognitive deficits that one would see in schizophrenia. Moreover, these agents produce few symptoms or cognitive abnormalities that would not be seen in schizophrenia. So, NMDA dysfunction is certainly sufficient in and of itself to account for all the symptoms that one would see in schizophrenia. The question is what is causing NMDA dysfunction.”

SZ.com: “What evidence (specifically concerning the neuropathology of schizophrenia symptoms) indicates that glycine might be an effective treatment or co-treatment?”

Javitt: “The main findings in support of the use of glycine come from its ability to reverse the effects of PCP in animals. Interestingly, these effects were first reported even before NMDA receptors had been discovered. Abel Lajtha, who is now head of Neurochemistry at Nathan Kline Institute, simply ran down a long list of amino acids to see if any were effective. Glycine was the only one that stood out. It was not until the discovery of the glycine site of the NMDA receptor that anyone was able to make sense of the finding. Since then, there have been numerous studies showing that glycine (and related drugs) can stimulate NMDA receptor functioning in a variety of brain regions, making it an ideal candidate for clinical trials.”

The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia [2004]

“Numerous clinical studies demonstrate that subanaesthetic doses of dissociative anaesthetics, which are non-competitive antagonists at the NMDA receptor, replicate in normal subjects the cognitive impairments, negative symptoms and brain functional abnormalities of schizophrenia. Post-mortem and genetic studies have identified several abnormalities associated with schizophrenia that would interfere with the activation of the glycine modulatory site on the NMDA receptor. Placebo controlled clinical trials with agents that directly or indirectly activate the glycine modulatory site consistently reduce negative symptoms and frequently improve cognition in patients with chronic schizophrenia, who are receiving concurrent typical antipsychotics. Thus, there is convincing evidence that the glycine modulatory site on the NMDA receptor is a valid therapeutic target for improving cognition and associated negative symptoms in schizophrenia.”

The NMDA Receptor in Schizophrenia

“Schizophrenia and Psychosis: Symptoms in schizophrenia, especially the negative symptoms of the disorder, may stem from reduced NMDA-R function that develops and accelerates in the late teenage years. This period is [normally] marked by a large increases in NMDA-R function (Hirsch et al., 1997; Olney & Farber 1995; Tsai et al., 1995) and this may help explain why schizophrenia rarely develops before adolescence.”

“The theory that low NMDA-R function contributes to schizophrenia symptoms is named the “Glutaminergic/NMDA-R Hypofunction” (NRH) theory of schizophrenia. It is not in conflict with the “Dopaminergic Theory of Schizophrenia,” because dopaminergic neurons are known to be inhibited by GABAergic neurons excited by glutamate at NMDA-Rs. Therefore a decrease in NMDA-R activity causes a downstream increase in dopamine activity that also may contribute to symptoms.”

Edited by Isochroma-Reborn, 14 July 2013 - 01:05 AM.

[Climactic]

Sunifiram and Unifiram are the first nootropics to market with sufficient power of positive allosteric NMDA modulation

There is zero evidence for allosteric modulation by sunifiram. Positive allosteric modulation is an extraordinary claim.

As far as activating the glycine-binding site of NMDAR is concerned, the safest (but not the most effective) way to do this would be using glycine itself. That this is useful for schizophrenia patients does not imply that it is a good thing to do for everyone.

Edited by Climactic, 14 July 2013 - 01:15 AM.

[Isochroma]

Unfortunately, correct on first point but no evidence does not equal no function.

If you'd taken the time to read the posted materials you would know that using an agonist like glycine is the most dangerous and unsmart way to activate NMDArs [a pure activator tends to produce excitotoxicity] has many other problems and thus work has shifted to positive modulators. It's the equivalent of using a pure stimulant vs. a nootropic. One generates false signals while the other facilitates function to enhance existing signals.

Enhacement at the glycine site is the most viable option at this time.

The goal is not stimulation but potentiation.

Now, anyone with diagnosed schizophrenia please reply to the thread or message me. It's time to test the hypothesis.

Wasting time with more theory is pointless because Sunifiram is on the market to be tested directly by those affected. Time is critical because schizophrenia is a condition of progressive deterioration. Risks exist and your headache is case-in-point but increasing insanity and progressive brain deterioration are far worse - those are what await all schizophrenics as they age.

This is the first proposal to use Sunifiram for the treatment of schizophrenia. The creators had Alzheimer's in mind but it's a slowly-progressing disease whose treatments will only yield conclusive results in years or decades.

I have a feeling that schizophrenia will be the quickest to test with possible immediate relief of symptoms without the nasty side-effects of existing antipsychotics. The reason for my hunch that rapid relief will occur is due to the downstream regulation of the dopaminergic system by NMDArs. Simply increasing suboptimal NMDAr activity should result in immediate or rapid decreases in excessive dopaminergic activity.

Edited by Isochroma-Reborn, 14 July 2013 - 01:45 AM.

[KoolK3n]

As far as activating the glycine-binding site of NMDAR is concerned, the safest (but not the most effective) way to do this would be using glycine itself. That this is useful for schizophrenia patients does not imply that it is a good thing to do for everyone.

Have you looked into Taurine? It's a glycine receptor agonist.

[Isochroma]

Multiple reports from schizophrenics indicate that supplemental Taurine produces only short-term reductions in anxiety that disappear in days.

The brain has negative-feedback regulatory mechanisms for these amino acids - so besides the fact that they are agonists [they don't enhace the efficiency of the NMDAr] - the brain will tend to normalize their concentrations due to autoregulation.

That explains why the forum posters above received only short-term decreases in anxiety which were quickly abolished by internal compensation.

[Isochroma]

The surge of posted material is a result of my observation that Sunifiram has a remarkable capacity to prevent NMDA-antagonist-induced insanity even at high doses of antagonist. And yes, more than a decade ago I also experienced first-hand the deliciously perfect and pure insanity produced by regular overdoses of a particular NMDA+PCP1 antagonist. So I know well how schizophrenia feels.

Edited by Isochroma-Reborn, 14 July 2013 - 01:54 AM.

[Isochroma]

The current use of dopaminergic-blocking agents in the treatment of schizophrenia is the worst possible option because it causes autoregulatory mechanisms to 'see' less dopaminergic activity and thus increase dopaminergic activity to even higher levels to maintain a genetically-predetermined 'correct' value.

A better solution is to alter regulation at upstream site(s) in the most indirect manner possible.

Edited by Isochroma-Reborn, 14 July 2013 - 02:24 AM.

[jeftrit]

There is a relative of Ondansetron that teats schizo. &is also very good nootropic. Wish I had access to some. It seems like it has multiple benefits. This relative of Zofran is called TROPIsetron. Like zofran it is used for nausea as well. I'm trying to locate a source. Is the alldaychemist site trustworthy? Does anyone know? Appreciate any input as it looks like a good source for Donepezil/memantine combo in 1pill & nice price other than the $25 S&H Charge.

[Climactic]

Is the alldaychemist site trustworthy? Does anyone know? Appreciate any input as it looks like a good source for Donepezil/memantine combo in 1pill & nice price other than the $25 S&H Charge.

ADC is trustworthy, but oftentimes their online credit card processing doesn't work due to rejections by transaction processors, so they may call you to run your card offline. I'd go with separate donepezil and memantine pills to allow one to experience them separately, and also for finer adjustment of their doses.

One thing to note with them is that at least the previous version of their website emptied out your Shopping Cart after a short period of inactivity. I therefore make it a point to save my Cart locally frequently.

Edited by Climactic, 15 July 2013 - 02:05 AM.

[jeftrit]

Thanks climactic for the adc advice. Oh and my suni headache most recent experiment: took 100 mg then 100 more 90 min. Later. (My tolerance is now elevated after 1 month daily suni intake. so don't try this unless you know you can tolerate that much) ok that being said in 15 min. my headache was quite prevalent. I then took 10mg donepezil and promptly fell asleep. Upon awakening 2 1/2 hours later I felt totally refreshed no headache at all. 36 hours later exp.#2: took 15mg donepezil waited 3hours then ingested 200mg Sunifiram added a few hard boiled eggs & 150mg pantethine. No ill effects whatsoever! In fact~best I've felt in a long time. Hope this helps anyone that might have had a suni suspected headache.

[Racetams]

Has anybody found a reliable Euro supplier of Sunifiram, i am extremely interested in this compound and would love a domestic (UK) supplier if possible, hope we can get a vendor list for certain compounds. Thanks in advance

[Isochroma]

As usual, check the Racetam Prices list - vantagecc's eBay Sunifiram sales are listed there.

He ships from the UK.

Edited by Isochroma-Reborn, 15 July 2013 - 08:46 AM.

[Isochroma]

How wrong I was about the powers of Methoxetamine.

The minor NMDA antagonism allowed by concomittantly taking Sunifiram (25mg x 6/day) and Oxiracetam (500mg x 6/day) was enough by itself for the emotive effects but they were masked not by Sunifiram but by cannabinoid withdrawal - having run out of 5F-AKB48 a few days before the shipment arrived after building about a three-month tolerance to this potent synthetic CB1/CB2 agonist.

My mistake was to forget that salient fact.

It's been two days since the second and final test dose of Methoxetamine and I have some kind of miracle to report.

Regarding the dose, no doubt it was ridiculously high and unncessary to take 83mg - likely 10-15mg would have done just fine.

A revolutionary discovery was made tonight. Scraped the last traces - literally nearly invisible - of 5F-AKB48 from the inside of three ziplocs (third scraping btw.) on some old ashes. Not expecting anything - first and second scrapings barely produced anything a week ago - and knowing the maximal effect with no tolerance at all - I was shocked.

A dual effect flooded over me - one so powerful that It swept away the first times of both 5F-AKB48 and the first times of every other drug ever consumed along with lots of other experiences of the emotive kind. Complete reversal of cannabinoid tolerance - no - far, far further than that - some kind of superpotentiation - such that a microdose of about 1-2mg produced an effect which for about two minutes was 'too high' came on and in addition something new which never happened before on anything ever for an entire lifetime. MXE's creator was right:

"3-MeO-PCP and 3-MeO-PCE are simply incredible drugs. They have a true capacity for healing, as the 3-methoxy group infers µ-opioid receptor affinity3 and removes the manic pressure of thought that can make PCP quite a disturbing and unpleasant drug. With the 3-methoxys there is such incredible laughter and boundless sexual energy."

The other effect stunned me - two days after all the MXE's half-lives were over - an absolutely unmistakable and unbelievable wave of the most powerful emotions that I have never felt in all of life flooded through the heretofore parched dryness of that internal desert that had not seen a rain in living memory. Absolutely nothing prepared me for what happened only a half-hour ago. Nothing in past history even came close.

Not a simplistic feel-good effect but an entire chord - no, an entire symphony of feeling - the insidiously encroached emotive flatness of time erased in a matter of minutes by a tidal wave of all emotions - as the endocannabinoid system - which is apparently needed for the functional long-term 'antidepressant' effect to work - was enabled to normalcy. I assume that someone without such a suppressed natural production due to exogenous CB1/CB2 agonists would not require that extra component. It was my abnormally low endocannabinoid levels that prevented the restoration of emotive depth and my lack of investigational intelligence to dismiss the numerous reports of MXE's therapeutic efficiency without further thought.

Luckily I did not dispose of the remaining MXE - it is still safely hidden away. It was 98% pure as advertised and now my soul can attest to that fact.

The effect is not some like some 'antidepressant' ie. Prozac et al. but what it is is the colours again. The colours of the heart in vivid hues of every imaginable composition - all of them, all of them in perfect balance. In the darkness under a skyful of stars with only the trees and wind chimes and forest for company. A complete opening and full clarity of mind simultaneously with no effects other than total and complete relaxation and, suprisingly - about 80% disappearance of physical pains at sites of affliction such as joints and lower back.

This beats everything Big Pharma could ever come up with. None of these effects were observed on either of the two MXE doses taken two and three days ago respectively - absolutely none. Since two days ago the MXE has been locked up in the closet - none taken. The entire effect is pure brain rewiring as the molecule was not even present since two days ago. In other words it seems I'm the owner of a newly-reconditioned emotive system.

I just cannot believe it. This changes the entire equation. Sunifiram combined with Oxiracetam should provide sufficient protection. The miracle of Sunifiram and likely Unifiram is that they will enable this molecule to be used safely at a low dose [10-15mg] every 3-7 days to effect what appears to be at least a semi-permanent neural rewiring such that the losses of time in the empathic system can be reversed. The necessary amount should not produce any noticeable effect at the time of consumption since the desired effect is retrocompensative rewiring. The disease of emotive loss has silently grown over the decades in a creeping, insidious way whose worst aspect is its ability to hide itself under innumerable other causes and problems. It is curable. It is fully curable. Everyone should be aware of this. It will be my dedication to test and learn how to safely use this new and amazing system of therapeutics both to get the best results from CB1/CB2 agonists due to resensitization - more like supersensitization - and to also affect a broad change to what had become a monchrome emotive landscape.

Finally, let me emphasize that the effect was very balanced and in no case was any negative effect noted. Nothing but the most perfect and soft gentleness and ease with zero 'push' since no MXE was present to affect such a thing and the tiny amount of CB1/CB2 agonist was only just enough to equal an exogenous-cannabinoid naive state. Radical like a tidal wave yet as gentle as the ocean breeze; it could not upset a feather. Of course side effects were not present since the MXE itself was not present. Utterly strange. Should be impossible. Clean is not even the word. 'Immaculate' is the word. Utterly Immaculate. Pristine. There are only a few safe words in English to describe it. I would not tolerate anything else.

I wonder if they will ever figure out how MXE works. Full of colour yet totally neutral in the sense that not one iota of the experience was forced. In a totally gentle way complete and utter tranquil peace and understanding flooded through body and mind - an effect which as of now continues unabated. It will be a challenge to tune the protocol to carefully maintain optimal function and guard against memory deficits. I expect Sunifiram and Oxiracetam will do the shielding work and low, infrequent dosing will take care of the rest.

Edited by Isochroma-Reborn, 15 July 2013 - 10:15 AM.

[Isochroma]

A final note regarding the power of that emotive awakening: it was and is full of intelligence of a deep kind. Not stupid, trivial or careless in the slightest but a kind of balanced in-proportion co-function of executive thought and emotive colour without either unbalanced or in dominance. Not for a second did this 'tidal wave' carry away a smidgen of executive function or reason of any kind.

The word I forgot to use in the previous post - the only word needed in this circumstance to describe such a restoration - natural. Completely natural.

Grown from earthy soil yet reaching up to the Sun and stars.

[deeptrance]

That this is useful for schizophrenia patients does not imply that it is a good thing to do for everyone.

Bingo. All that discussion of schizophrenia and NMDAr hypofunction had me wondering, "How many of us on this forum suffer from schizophrenia?" and "Of those who do NOT suffer from it [presumably most if not all], how many would benefit from taking drugs that are potentially helpful for schizophrenics?" Being out of balance is undesirable, whether the balance is tipped in favor of hyperfunction or hypofunction of receptors.

Multiple reports from schizophrenics indicate that supplemental Taurine produces only short-term reductions in anxiety that disappear in days.

There are 2 reports on that page. Three posts total, 2 very brief comments about taurine.

I'm not pointing this out as if it were an important issue, but merely as an example of how you seem to be very determined to make sunifiram look good. I'm relatively new to this forum and don't know much about you, but it's my first impression that you get quite emotionally attached to, and/or ego-invested in, any new supplement or drug that you hope and believe will be a breakthrough for enhancing some aspect of mind and body. I recognize this because I do it myself. I've had to check my own wishful thinking at the door many times because I purchase an herb or chemical in the hope that it will solve a problem or give me some kind of positive effect. Ultimately I've probably been wasting my money on these things but that's the cost of doing what we're here for, to be guinea pigs on behalf of ourselves and others who might benefit from new substances.

I think it's probably helpful to be very modest in our claims and humble in admitting that we know very little, regardless of how many research papers we've looked at.

[Geoffrey]

Can we try to get to the bottom of whether (s)unifiram is a positive allosteric modulator of the NMDA receptor via its glycine binding site and/or of the AMPA receptor or not? There seem to be claims and counter-claims about this. The original research on sunifiram used the phrase "AMPA-mediated" regarding many of its effects but didn't work out its precise biochemistry AFAIK. Is there any research that is hinting in this direction? It seems to be the missing link for joining up some of the dots in relation to the research papers cited by Isochroma.

Edited by Geoffrey, 15 July 2013 - 05:00 PM.

[Isochroma]

Indeed you are right - I'm always hunting for the next big thing in enhancement.

It comes with its hazards too. Life is risky.

As for Sunifiram's ability or lack thereof to affect positive allosteric NMDA modulation - it's already settled that it positively enhances function by doing something at the glycine site. The glycine site is one of the NMDA receptor's two orthostatic sites so Sunifiram may indeed be an agonist in addition to having a potentiation function. My subjective experience votes in favor of minor agonism and some kind of positive potentiation in addition.

Such a mix with no downregulation is actually ideal for subfunctional NMDA receptors - a minor orthostatic boost coupled with a stronger allosteric positive modulation.

The most powerful piece of evidence in favor of Sunifiram's major effect being allosteric positive modulation while orthostatic boost being a minor component is lack of tolerance - ie. downregulation. Agents that are primarily agonists usually cause downregulation while agents that are potentiators rarely do. I note no tolerance to Sunifiram's effects after three months @ 150mg/day and have not noted many or any forum reports of tolerance either. If anyone has such a report please chime in.

Edited by Isochroma-Reborn, 15 July 2013 - 08:32 PM.

[Climactic]

Such a mix with no downregulation is actually ideal for subfunctional NMDA receptors - a minor orthostatic boost coupled with a stronger allosteric positive modulation.

The most powerful piece of evidence in favor of Sunifiram's major effect being allosteric positive modulation while orthostatic boost being a minor component is lack of tolerance - ie. downregulation.

Here we go again... there is zero scientific evidence for any allosteric modulation by sunifiram. An absence of compensatory downregulation does not in itself imply allostericity. Lots of substances with low tolerance, e.g. nicotine, armodafinil, etc. are not allosteric at all. If sunifiram was allosteric, it wouldn't have ruined my sleep at night.

If you're taking cannabinoids with sunifiram, aren't you canceling some of the effects of both?

Edited by Climactic, 15 July 2013 - 08:48 PM.

[8bitmore]

Such a mix with no downregulation is actually ideal for subfunctional NMDA receptors - a minor orthostatic boost coupled with a stronger allosteric positive modulation.

The most powerful piece of evidence in favor of Sunifiram's major effect being allosteric positive modulation while orthostatic boost being a minor component is lack of tolerance - ie. downregulation.

Here we go again... there is zero scientific evidence for any allosteric modulation by sunifiram. An absence of compensatory downregulation does not in itself imply allostericity. Lots of substances with low tolerance, e.g. nicotine, armodafinil, etc. are not allosteric at all. If sunifiram was allosteric, it wouldn't have ruined my sleep at night.

If you're taking cannabinoids with sunifiram, aren't you canceling some of the effects of both?

No, there's no scientific evidence for any allosteric modulation by sunifiram but then all Isochroma-Reborn is saying is that a given thing is "...in favor of Sunifiram's major effect being allosteric positive modulation" - this does not equal him claiming that there's scientific evidence for it.

[Isochroma]

Zero scientific evidence - well, the tests are yet to be performed.

Evidence does not self-manifest without trials of one kind or another.

Correct on the compensatory downregulation not implying allostericity but again still no definitive answers.

For now we have peoples' experiences and some animal test reports.

In the end what matters is how well the agent works - after all, that's the desire - to effect wanted change in the target system(s).

I like to use theory not as an internal self-cycle like those stuffy academics but as a lauchpad into new physical investigations. I think it's the most productive approach. Just a hint or whiff is enough to send me into new avenues of research - it's inspiring!

Rather than going in circles arguing with insufficient evidence I will continue to enjoy the effects while awaiting replies from the two lead schizophrenia researchers who I sent proposals to by email yesterday. It will be fun to test the schizophrenia hypothesis.

Edited by Isochroma-Reborn, 15 July 2013 - 08:58 PM.

[Climactic]

After reading the recent report of toxic bulk "choline", I no longer feel inspired to use any Chinese bulk powders that have not been independently tested for purity and contaminants by at least two reliable third-party testing labs. There also are corresponding posts on Longecity about it. These companies can't even get their make-believe-CoAs together. There are plenty of drugs from legit pharmaceutical companies to keep me occupied for a while.

Edited by Climactic, 15 July 2013 - 09:11 PM.

[Isochroma]

Wow, thanks for posting!

Bad synth. And Cerebral Health too!

Seems they jumped the shark years ago - I stay away from them and Nootrabiolabs.

That case is evidence that even buying from well-established Western resellers just means you're paying more for unknown Chinese product.

I like my poisons cheap. Then at least I could afford compensative therapy :)

Finding a trusted vendor - whether they be reseller or producer - involves plenty of investigational work, especially if one intends to save money by buying cheap.

Edited by Isochroma-Reborn, 15 July 2013 - 09:17 PM.

[violetechos]

It will be fun to test the schizophrenia hypothesis.

*sighs*

please, report in full detail.

[deeptrance]

Sunifiram may have detrimental effect on REM sleep:

"NMDA (5 nmol) and AMPA (0.4 nmol) induced an increase in wakefulness and an inhibition of slow-wave sleep. AMPA, but not NMDA, also caused a decrease in desynchronized sleep." http://www.ncbi.nlm....pubmed/10564223

Apologies if that particular study has already been posted elsewhere in this thread. Someone who knows more about the interplay between AMPArs and NDMArs might be able to explain why an effect in AMPA doesn't (in this case) lead to the downstream effect in NMDA.
What this suggests to me is the possibility that NMDA antagonists won't necessarily reverse all the effects of AMPA potentiation/agonism, as there are certain processes which are evidently independent.

[Isochroma]

Funny, I've been having the most insanely intense multiple dreams for weeks with a culmination of last night's hyperreal dreams that just blew me away. Furthermore, since starting Sunifiram my dream quality has improved.

Finally, I noticed that my shortened sleep hours after starting Sunifiram resulted in the preferential sacrifice of NREM sleep rather than REM sleep. The brain is greedy and takes for itself the needed regen time first.

Yet another example of where theory falls flat on its paper face when compared to human reality.

An update on sleeptimes: after three months of Sunifiram 25mg x 6/day, my sleep cycle has normalized at 7-7.25 hours. Before Sunifiram it was 8-8.5 hours and immediately after starting it declined to 5.5-6 hours.

Edited by Isochroma-Reborn, 18 July 2013 - 09:19 PM.

[deeptrance]

Funny, I've been having the most insanely intense multiple dreams for weeks with a culmination of last night's hyperreal dreams that just blew me away. Furthermore, since starting Sunifiram my dream quality has improved.

Yes, that was the same for me, in fact it was one of my favorite things about sunifiram. My dreams were extraordinary. They weren't all "good" but that's OK, I was just getting off on how crazy real they were. It's a free journey to a parallel universe, so I don't complain about the different rules by which the alternate world plays.

I slept less than normal (IIRC) but wasn't any more or less tired than usual. Your NREM observation is interesting, I suppose that could help explain these things.

[xsiv1]

Funny, I've been having the most insanely intense multiple dreams for weeks with a culmination of last night's hyperreal dreams that just blew me away. Furthermore, since starting Sunifiram my dream quality has improved.

Yes, that was the same for me, in fact it was one of my favorite things about sunifiram. My dreams were extraordinary. They weren't all "good" but that's OK, I was just getting off on how crazy real they were. It's a free journey to a parallel universe, so I don't complain about the different rules by which the alternate world plays.

I slept less than normal (IIRC) but wasn't any more or less tired than usual. Your NREM observation is interesting, I suppose that could help explain these things.

I'm more curious (as I still haven't tried my 2 small batches) as to why you wouldn't prefer deeper sleep stages where memories and the like are consolidated. I mean, don't get me wrong here, I enjoy having vivid or even lucid dreams on occasion - but I much prefer a deep delta wave (iirc) sleep. Leads me to wonder if Suni can be used sporadically like I use phenypiracetam with positive effect. What doses did you start off with Deep? I know you've stated it somewhere in this long ass thread lol, so, my apologies in advance.

[deeptrance]

...I enjoy having vivid or even lucid dreams on occasion - but I much prefer a deep delta wave (iirc) sleep. Leads me to wonder if Suni can be used sporadically like I use phenypiracetam with positive effect. What doses did you start off with Deep?

I'm pretty sure that suni would work well as an occasional dream enhancing agent for some people. My best dreaming on it was during the first few nights after I began taking it, which coincides with the highest doses I took. These were in the neighborhood of 20 to 25 mg taken 2 or 3 times a day. As for sleep quality, I must admit that I tend to feel most rested after I have a vivid and positive dream, but that's probably a misperception based on the fact that I wake up in a good mood on such mornings, which doesn't necessarily translate to feeling well-rested for the remainder of the day. However, I think that sunifiram has a way of compensating for the sleep loss, as Isochroma has testified. I got that effect from it too.

Here's something I just found, a Sunifiram-induced dream that I wrote about in an e-mail to my brother:

The gist of it was that we lived in Russia, and Russia was an extremely creative and beautiful country teeming with brilliant people and culture. You had gotten into some sort of academy for people with creative genius, where you were nurturing numerous talents. Dad was young (50s?), healthy, vibrant, and intensely supportive of anything to do with the arts and humanities. He was quite involved with community and had some kind of important position with the government, which was a very benign thing because this government would make the Goddard College administration and faculty look like a 16^th century ecclesiastical tribunal.

I can see visuals of the scenery, gorgeous sweeping vistas of verdant mountains dotted with large innovative architectural wonders, one of which was the institution you had been admitted to.

That’s about all I can remember. It was pretty friggin awesome and I felt a warm glow from it, which I always feel when I wake from a good dream. I don’t put much spin on dreams like this; in some ways it’s just obvious and simple. On another level, I see it as a manifestation of one of the infinity of possible earths in parallel universes. Either way, the only impact such a dream has on me is to remind me that this present moment is the only reality that is pertinent, and it exists in an infinity of realities and is thus utterly insignificant and yet paradoxically precious.

To put it in context, I've never had dreams of this type, ever. It was a radically new level of dreaming in which I felt completely immersed in a beautiful alternate life. I still don't have the courage to try sunifiram again, even at a dramatically reduced dosage. It took so long to get over the negative sides.

Edited by deeptrance, 19 July 2013 - 04:16 AM.

[Racetams]

In answer to my own question i have just found a UK website that will be selling Sunifiram, and by the looks of things Phenylpiracetam, it says they're in the "coming soon" section and they got a page about them. Fingers crossed it arrives soon as i really want a EU/UK supplier. Added benefit to these guys is they have tablet form instead of powder, for most stuff actually, might give em a go. Anyone used them before, i'm a little dubious that i have not seen them mentioned?? nootropics.co.uk