1565 replies to this topic

[nanomatrix]

Has someone tried sunifiram and noopept combo. Noopept stacks really well with aniracetam for me and many others - the "speedy" aspects of noopept are really well balanced by aniracetam.

Yes. Along with a 600mg Alpha GPC and Centrophenoxine 250mg. 20 mg Noopert, 10 mg sunifiram.

I like the increased alertness...

[nanomatrix]

I guess the real standout effect for me is being able to multi-task effectively and without stress. That is in part, I'm pretty sure, a memory thing. As well as the huge enormous reduction in anxiety when faced with new stuff to learn, deal with, and/or change strategies for. My mental and emotional flexibility is restored which pretty much helps everything else.

I actually rearraged my garage on this stuff... something I've been putting off for months.

[Isochroma]

Forget about 'wiping' old memories. You won't have any trouble forgetting about that worthless thought either since new memories are more poorly formed every year we age. It does not work and Climactic's suggestions - foolish as they are - will merely compromise your brain and body health. Even years of alcoholism fail to wipe those memories but they destroy the potential for new learning which can at least compensate for old trauma by enabling new thoughts, new memories and generally a new life to be created.

Cannabinoids work well for PTSD as proven in studies with less destructivity than creating a deficiency in Omega-3 fatty acids, vitamins or proteins but they do have their own side-effects.

Low doses of NDMArAs have long-term antidepressant capabilities as verified by both studies and user experiences on forums - Ketamine, MXE, DXM, the methoxy-PCP analogs among them. Low infrequent doses only. They also have their side effects though at the micro-doses used they are minimal.

Edited by Isochroma-Reborn, 15 October 2013 - 09:48 PM.

[free10]

I don't advise wiping memories, even if that was possible, but understanding them especially the emotional content, which is what really bothers people. A few points, guys haunted say by the Vietnam war often when they went back there decades later found no war and a very different world then what they remembered. This changes the emotional content of those memories and the false illusions it was still going on. Also with memories we have a tendency to have the habit of running them in our imaginations the same way (pattern) getting the same results we hate. Some have found it useful to mess with those memories running them forward and backwards fast as they can and putting cartoon characters and situations into them or other absurdities. What you are trying to do is break that pattern and mess it up, so the emotions are either not there, or they are quite a bit different and not the burden they once were. Controlling your emotions by knowing how to control what your mind thinks about will prevent a lot of new bad memories as well. Alcohol doesn't make anyone forget, just think about it over and over again, as it makes them lose control of what the mind thinks about. It also uses up the chemicals in our that makes us feel good. Worse maybe is it tells us we are having a good time when the world is running over us and there are other drugs that do the same things.

Edited by free10, 15 October 2013 - 11:20 PM.

[Climactic]

The memories don't need to be wiped. They just need to be unlinked - think of it as leaking memory in RAM, i.e. an object with no pointer to it. Once it's unlinked, it's buried and hard to recall. D-cycloserine is studied for fear extinction, although it is a NMDA agonist. Especially D-cycloserine but also propranolol may help with fear extinction by working on the amyglada, but I'm not suggesting they work the same way. This fear extinction approach is preferred over the memory unlinking approach.

Any nutritional suppression I suggested was only meant to be temporary, certainly no more than a month. As for getting many FDA approved drugs, websites like alldaychemist and thepharmacyexpress sell them. Dosages, etc. are mentioned at drugs.com.

Edited by Climactic, 15 October 2013 - 11:42 PM.

[Lucid_Reality]

Finally got my sunifiram order today. Well, I have to travel 10 miles to pick it up from a mail depot.
Well anyway I shall be taking my first dose later. It's been a long 17 day wait. I will be giving my opinions here of course.

[Lucid_Reality]

Well ok here's my opinion of suni after 4 days use. I have increased dosage from 3mg to 25mg. I have settled at 20mg 3 x day.

I have encountered very similar effects as others here. I get hot flushes throughout the day which isn't unpleasant but weird. I have experianced 2 headaches which went away easily with paracetamol. I am unsure if they were caused caused by suni or not. I believe not as I believe they are withdrawal headaches from ceasing caffeine intake. I stopped caffiene due to the reports of it being potentiated by suni. I have been a long time user of coffee and am aware of what stopping does to me.

The suni has had drastic effects on my sleeping pattern. I cannot seem to sleep for more than 4-5 hours at a time. I don't really gain any hours in a day as I have on all 4 suni taking days had to take a nap in the afternoon due to tiredness. Today I awoke at 4.00 a.m after 4 hours sleep.
When I wake up I feel really tired for about 5 mins and then with a click of the fingers the tiredness vanishes and I no there's no chance of getting back to sleep as I feel I have to get up and do something. I believe it has affected my dreams aswell. I have been dreaming madly with excellent vivid quality.

1 thing I am 100% certain about with suni. If there are any of you out there that can draw, give it a go on suni. I have noticed a big improvement. Usually I would have to draw 2 practice portraits before doing my "serious" 3rd. On suni, I'm faster, don't obsess over mistakes and just flow amazingly.
I think suni for me, has a big enhancement on hand to eye co-ordination, and that explains why I'm drawing better.
I just seem to enjoy drawing more like when I was a kid. It's hard to explain, but, Suni just seems to give you something you have lost. I can't explain.
Listening to music while drawing is very good.

I have attempted to get some coding in Python done yesterday on a little project I have on but just couldn't do it knowing I could be doing something else.
I thinks its too earlier for me to comment on what beneficial effects it has had on my ability to learn etc, I am always aware of the potential for placebo so will report back after I have had chance to push myself with a few things. I have just spent 2 days trialling over a weekend after all.

[Geoffrey]

Thanks for the report, Lucid_Reality. Regarding tiredness, I got this when I wasn't taking enough choline with sunifiram. I needed a lot more than I thought I did to banish side-effects such as lethargy, a feeling of being "drained", and mild headache. On the other hand, I get these effects from 3-5mg at most twice a day if I don't have enough choline. I can't imagine how I would cope with 20mg 3 x day! I suggest you reconsider whether you really need that much to have an effect, for safety reasons. After all, this chemical has not had any safety trials in humans, and I'm not sure how focused on safety animal trials were.

[Lucid_Reality]

After all, this chemical has not had any safety trials in humans, and I'm not sure how focused on safety animal trials were.

We will see what it does to me. Others here are taking more than what I am taking. I increased my dose untill I got noticable results. 5 - 10mg doesn't do squat for me. 20mg is noticeable and I can feel when it wears off.
If I develop any signs of discomfort I shall reduce dose or cease all together.

Thanks for the concern though. All nootropic's I have taken will not work for me unless I take larger doses.

[Lucid_Reality]

Actually I forgot to mention something earlier.
Does anyone have any explination as to why this substance seams to make tennitus more noticeable? From my very first doses I have noticed that I hear the tennitus in my ears all day long. I hope it doesn't get any louder. I only really noticed it before when it was quiet and I was in bed trying to get to sleep.
I know others have mentioned this side effect. It is a bit annoying.

[Climactic]

Actually I forgot to mention something earlier.
Does anyone have any explination as to why this substance seams to make tennitus more noticeable? From my very first doses I have noticed that I hear the tennitus in my ears all day long. I hope it doesn't get any louder. I only really noticed it before when it was quiet and I was in bed trying to get to sleep.
I know others have mentioned this side effect. It is a bit annoying.

Yes, it's spelled tinnitus, and overactivation of NMDA receptors in the auditory system (by sunifiram) will do this to you. You are risking damage to auditory neurons and thereby to your hearing. I suggest you lower your dose or discontinue.

[Isochroma]

Lucid_Reality: good report!

5.5 Hours sleep for over two months on it. At first felt like I needed more and often did for a while.

However, in the last few weeks my sleep has finally increased to 7h and now to 8h - still on 20mg x 6/day.

Perhaps it's the 7mg/day oral & 14mg/day intranasal Dianabol which makes me very sleepy after 10:00p but now I sleep like a baby.

As for tinnitus, I hardly notice it if it all. Other conditions make my ears and brain ring so much more that it's lost in the noise

[Lucid_Reality]

Thanks Isochroma I will update in a while after I have experienced more under better trialing situations.

Climactic I doubt I will stop taking Sunifiram or lower the dose, even given the risks. This nootropic has had the strongest effect of all things I have tried. I would be willing to risk far more than my hearing to find what I am looking for. Thanks for the answer to my wrongly spelled question though.

[Isochroma]

Sunifiram is safe alone even at 300mg/dose which I have taken on multiple occasions.

However, I take no alcohol, stimulants, etc. with it including caffeine.

I did megadose on black pepper day before yesterday and today. Six tablespoons day before last and 1.25 yesterday. The 1.25 weighed 3.8g.

Noticed some bad systemic toxicity from the pepper's Piperine.

Sunifiram is 1-Benzoyl,4-PropanyolPiperazine.

The effects of the Piperine have lasted 24+ hours after each dose and it may be possible that Sunifiram has potentiated it. I have noticed severe skin sensitization in all the areas of skin inhabited by TRPV1 receptors which Piperine activates and itself potentiates along with hyperthermia (thermogenesis) lasting days from a single dose. Unable to get quality sleep for the last two nights due to hyperthermia. Sleep requires a 1C drop in body temperature. Fever is the sleep destroyer. Piperine is also a systemic CNS stimulant and is lipophilic and long-lasting. Normal sprinkles of pepper on foods is OK. Cayenne's Capsaicin may also be a hazard in large doses by itself or combined with Sunifiram but less likely due to a lack of Piperazine or Piperidine ring.

I recommend not taking Piperine with Sunifiram nor any other PIperazine or Piperidine-framed stimulants.

Edited by Isochroma-Reborn, 22 October 2013 - 12:26 AM.

[Lucid_Reality]

Isochroma, I will ask you this as apposed to climactic who brought it up seeings as though you are taking similar doses to me. It is regarding the hearing loss potential brought up by climactic.
I have done an hours research and what I found on the matter, if right, is that over activating the nmda receptors causes a build up of glutamate toxicity. Are you taking anything that would counter-act this toxicity? Or do you believe the risk to be so low that it's not worth worrying about?

[Isochroma]

Sunifiram is a PAM. Positive Allosteric Modulator of NMDA receptors. See here for a nice diagram: http://en.wikipedia....ptor_antagonist.

Sunifiram works on the secondary site - the Glycine site, where Glycine normally acts. Sunifiram does not create activation by itself and indeed cannot since Glutamate is also required at the orthostatic site. Instead, it increases the NMDA receptor's open time and its unit conductance when naturally activated.

This is why - just like racetam nootropics like Piracetam - one can take a very high dose and achieve no more effect than a minimally-active dose. I have taken 300+ mg Sunifiram doses on multiple occasions with zero additional effects.

To sum it up: Sunifiram merely makes the NMDA receptor work more efficiently. It does not by itself activate the receptor. If it did so then higher doses would show more and more activation, causing stimulant type side effects that would be obvious. These do not occur. You can test it for yourself by taking a high 300mg dose - at least 10x the peak effective dose. You will achieve no more effects than the peak effective dose.

There is no hazard in taking any dose of Sunifiram alone, however - combining it with other molecules that force the channel open can either create a damaging situation or increase the damage they cause because Sunifiram enhances NMDA receptor activity - both natural and unnaturally caused by agents that act at the orthostatic (main) site. Drugs which would normally be incapable of over-activating NMDA receptors alone due to the limiting factor of the NMDA receptor's requirement for a ligand at the allosteric site - normally the amino acid Glycine - become neurotoxic when the receptor's efficiency is increased by Sunifiram's positive allosteric modulation at the allosteric site. This is one kind of potentiation.

Analogy: Sunifiram - unlike a stimulant like Amphetamine - does not by itself create a false signal. However, it turns up the amplification of the stereo system. That's OK with only natural NMDA receptor activation but it is not OK with some stimulants which create a false signal that adds to the level of natural activation to the point that the final output is 'clipped': a lethal squeal or scream of over-activation that fries neurons. Any agent that turns up the amplification of any receptor system has that potential though Sunifiram was carefully evaluated at various doses on its own and found to be safe.

It's a good argument to not take stimulants at all - Sunifiram or not. All stimulants have neurotoxic potential if overdosed or potentiated: Caffeine, Amphetamines, Adrafinil, Modafinil and lots more. Furthermore, stimulants themselves are negatory to the body's health - especially the brain. With a correct nootropic regime combined with optimal vitamin and mineral supplementation and good sleep habits they are never needed.

Edited by Isochroma-Reborn, 22 October 2013 - 02:39 PM.

[Lucid_Reality]

I knew from reading all this thread to get caffeine out my system. I remember the guy whole was hospitalized from the workout stuff he took which had copious amounts of caffeine in.
I can't understand now after reading your response why climactic would suggest I stop taking suni. I said earlier in the thread I had ceased any stimulants in preparation for suni intake.

Is there any other specific nootropics that you suggest work well along side suni? I am hoping to try the 2 new ones coming up from NSN when they get it in but, as long as the suni keeps doing its thing, I might get something else in the meantime.

Edited by Lucid_Reality, 22 October 2013 - 03:01 PM.

[Climactic]

I knew from reading all this thread to get caffeine out my system. I remember the guy whole was hospitalized from the workout stuff he took which had copious amounts of caffeine in.
I can't understand now after reading your response why climactic would suggest I stop taking suni. I said earlier in the thread I had ceased any stimulants in preparation for suni intake.

Is there any other specific nootropics that you suggest work well along side suni? I am hoping to try the 2 new ones coming up from NSN when they get it in but, as long as the suni keeps doing its thing, I might get something else in the meantime.

I told you why. Given your induced tinnitus, feel free to keep taking it if you don't value your hearing or your sense of balance (equilibrioception). There is nothing wrong with moderate amounts of stimulants. Sunifiram remains a clinically untested substance. It is also known to disrupt healthy sleep. It is very easy to take the wrong thing along with sunifiram, e.g. any one of various agonist-like LTP agents, and screw it all up. Finally, there is also the metastatic brain cancer risk from PKCa overactivation.

Edited by Climactic, 22 October 2013 - 03:35 PM.

[Isochroma]

I have personally verified that Sunifiram does not increase the energy generation efficiency of cellular Mitochondria - the coverters of 80% of our body and brain's glucose into ATP - the energy molecule - by taking it alone when first starting. I stopped racetam use and the resulting loss of mental and physical energy was obvious after only two days.

Racetams do that. Racetams are ideal complements to Racerams. Oxiracetam in particular shows the highest efficiency at restoring mitochondrial energy generation damaged by aging and/or toxics and/or bad genes. Subjectively it also has the best effects on my awareness and also body energy and has a low cost per dose, nice sweet taste and easy measureability due to its granularity and water-solubility. Thus it is my choice of racetam for raceram complementation.

Aniracetam causes a decrease in thoughts - empty-head syndrome, accompanied by a slowing of mental function. Pramiracetam causes no slowdown but silences thought as well. The two are the most side-effect ridden racetams in existence and so I avoid them. How much you notice these effects if you take these two racetams alone or combined will depend on your dose, dosing regime and genetics but they will always be present to some extent. I don't like that dirtiness.

Piracetam is the weakest of all the racetams and tastes bitter. After months of use it causes a kind of fatigue - likely adrenal exhaustion or similar. It has the least beneficial effect on cellular mitochondria of all the racetams and has the weakest effects on memory and cognition. I avoid Piracetam. It is not worth the financial cost alone at least inside my budget. If I had plenty of extra money I would buy it as an addition to Oxiracetam - which it complements quite nicely. The Oxiracetam rescues mitochondrial energy generation and prevents the negative exhaustion effects of Piracetam from occurring. I call the combination PirOxiClear and it is the best but has a high cost. Saturation dosing of Piracetam costs the same per month (1kg) as saturation dosing of Oxiracetam (100g) but with much poorer effects.

Oxiracetam has a unique ability not shared among other racetams except for a metabolite of Phenylpiracetam: they have a hydroxy group at the 4-position on the pyrrolidine ring. They are also the only two racetams that show enhanced energy generation in whole-body mitochondria - not just brain mitochondria. Subjective reports indicate that both have a strong ability to reduce physical fatigue in addition to their cognitive benefits.

The difference between the two is first, that Phenylpiracetam is very expensive compared to Oxiracetam and second, by many forum reports Phenylpiracetam use results in rapid tolerance often to the point that further doses have no effect at all. The combination of high cost and likely tolerance has decided me against Phenylpiracetam and for Oxiracetam which exhibits no tolerance-inducement by my own experience and forum reports.

Edited by Isochroma-Reborn, 22 October 2013 - 03:53 PM.

[Climactic]

Oxiracetam in particular shows the highest efficiency at restoring mitochondrial energy generation

Thanks. I will have to give it a try instead of the 75-150mg armodafinil which I have been using lately.

[Isochroma]

Racetam Mitochondrial Energy Paper:

The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by ß-amyloid peptide

Check the graphs on PDF page 5 very carefully. Unfortunately Aniracetam was never tested except in 0.001 and 0.01 mM concentration - a different scale than the Piracetam and Oxiracetam tests. Personal testing puts it in-between Piracetam and Oxiracetam in energy generation restoration.

Edited by Isochroma-Reborn, 22 October 2013 - 04:27 PM.

[jeftrit]

Of intersest; links AMPA, NMDA & cannibinoids for neuroprotect

http://informahealth...archHistoryKey= NMDA receptor antagonism strategies

http://informahealth...archHistoryKey= AMPA
Introduction: AMPA receptors represent an interesting target to develop innovative therapeutic drugs such as positive allosteric modulators, a subclass of modulators known to potentiate the effect of glutamate through this kind of glutamatergic ionotropic receptors. The enhancement of AMPA signals is expected to be beneficial in the management of several neurological disorders, such as depression, schizophrenia, Parkinson's disease and learning–memory deficits linked to Alzheimer's disease. AMPA receptor positive allosteric modulators continue to be the object of intensive research as evidenced by the diversification in the range of chemotypes explored.
Areas covered: This article examines recent discoveries of new AMPA receptor modulators mainly described in the patent literature from 2008 to 2012.
Expert opinion: An important challenge is to discover an ideal drug candidate exhibiting appropriate in vivo activity after oral administration with an acceptable safety profile. The future remains promising because such compounds have proved to be able to stimulate the exp<b></b>ression of the neurotrophic factor BDNF, a unique property opening interesting perspectives in new therapeutic applications



Read More: http://informahealth...archHistoryKey= http://informahealth...archHistoryKey=

http://informahealth...archHistoryKey= 5 categories of Glycine antagonists here

Neurosci Bull. 2011 Aug;27(4):275-85. doi: 10.1007/s12264-011-1008-6.
Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury.
Alonso-Alconada D, Alvarez A, Hilario E.
Source
Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain.
Abstract
Perinatal hypoxia-ischemia remains the single most important cause of brain injury in the newborn, leading to death or lifelong sequelae. Because of the fact that there is still no specific treatment for perinatal brain lesions due to the complexity of neonatal hypoxic-ischemic pathophysiology, the search of new neuroprotective therapies is of great interest. In this regard, therapeutic possibilities of the endocannabinoid system have grown lately. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. Concerning perinatal asphyxia, the neuroprotective role of this endogenous system is emerging these years. The present review mainly focused on the current knowledge of the cannabinoids as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury.
Rev Neurol. 2011 Dec 16;53(12):758-64.
[Therapeutic potential of the endocannabinoid system in perinatal asphyxia].
[Article in Spanish]
Alonso-Alconada D, Álvarez A, Álvarez-Granda L, Hilario E.
Source
Departamento de Biología Celular e Histología, Facultad de Medicina y Odontología, Universidad del País Vasco, Leioa, Vizcaya, España.
Abstract
INTRODUCTION:
Perinatal asphyxia is the most frequent cause of neonatal brain injury and, despite advances in neonatology, it has not been possible to reduce its incidence. This is due to the difficulty to diagnose with precision the presence and onset of hypoxia and also to the existence of a limited period of time in which rescue strategies are effective. Thus, it is necessary to find out new and more effective therapeutic strategies, appearing the use of cannabinoids as a promising one.
DEVELOPMENT:
The endocannabinoid system modulates a wide range of physiological processes in mammals, being its participation in the retrograde system of signaling one of the most important, so it has been considered as an endogenous neuroprotective system. In experimental models of perinatal asphyxia, modulation of the endocannabinoid system through the administration of synthetic cannabinoids and endocannabinoids has demonstrated neuroprotective effects both in vitro and in vivo, by inhibition the intracellular calcium influx, decreasing the release of glutamate and cytokines, diminishing the inflammatory response and leading hypothermia. Moreover, it seems to play an important role in the development of the central nervous system, as it appears in the fetal period since the beginning.
CONCLUSION:
Modulation of the endocannabinoid system appears as a novel therapeutic strategy against neonatal hypoxic-ischemic brain injury.
CNS Neurosci Ther. 2011 Dec;17(6):637-44. doi: 10.1111/j.1755-5949.2010.00195.x. Epub 2010 Sep 28.
The multiplicity of action of cannabinoids: implications for treating neurodegeneration.
Gowran A, Noonan J, Campbell VA.
Source
Department of Physiology, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
Abstract
The cannabinoid (CB) system is widespread in the central nervous system and is crucial for controlling a range of neurophysiological processes such as pain, appetite, and cognition. The endogenous CB molecules, anandamide, and 2-arachidonoyl glycerol, interact with the G-protein coupled CB receptors, CB(1) and CB(2). These receptors are also targets for the phytocannabinoids isolated from the cannabis plant and synthetic CB receptor ligands. The CB system is emerging as a key regulator of neuronal cell fate and is capable of conferring neuroprotection by the direct engagement of prosurvival pathways and the control of neurogenesis. Many neurological conditions feature a neurodegenerative component that is associated with excitotoxicity, oxidative stress, and neuroinflammation, and certain CB molecules have been demonstrated to inhibit these events to halt the progression of neurodegeneration. Such properties are attractive in the development of new strategies to treat neurodegenerative conditions of diverse etiology, such as Alzheimer's disease, multiple sclerosis, and cerebral ischemia. This article will discuss the experimental and clinical evidence supporting a potential role for CB-based therapies in the treatment of certain neurological diseases that feature a neurodegenerative component.
© 2010 Blackwell Publishing Ltd.
PMID:
20875047
[PubMed - indexed for MEDLINE]
http://www.ncbi.nlm....pubmed/20875047

http://www.ncbi.nlm....pubmed/23855825 IDRA-21
Theor Biol Med Model. 2013 Jul 15;10:46. doi: 10.1186/1742-4682-10-46.
Identification of novel modulators for ionotropic glutamate receptor, iGluA2 by in-silico screening.
Padmanabhan B.
Source
Department of Biophysics, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, India. paddy@nimhans.kar.nic.in
Abstract
BACKGROUND:
Ionotropic glutamate receptors (iGluAs, IUPHAR nomenclature) are the major excitatory amino acid neurotransmitter receptors in the mammalian central nervous system (CNS). iGluAs are potential therapeutic drug targets for various neurological disorders including ischemia, epilepsy, Parkinson's and Alzheimer's diseases. The known iGluA modulators, cyclothiazide (CTZ), IDRA-21, and other benzothiadiazide derivatives (ALTZ, HCTZ, and CLTZ) bind to the ligand-binding domain of flip-form of iGluA2 at the dimer interface, thereby increasing steady-state activation by reducing desensitization.
METHODS:
To discover new modulator compounds, we performed virtual screening for the ligand binding domain (LBD) of iGluA2 against NCI Diversity Set III library containing 1597 compounds, and subsequently performed binding-energy analysis for selected compounds. The crystal structure of rat iGluA2 S1S2J (PDB ID: 3IJO) was used for docking studies.
RESULTS AND CONCLUSION:
From this study, we obtained four compounds: (1) 10-2(methoxyethyl)-3-phenylbenzo[g]pteridine-2,4-dione, (2) 2-benzo[e]benzotriazol-2-yl-aniline, (3) 9-nitro-6H-indolo-(2,3,-b)quinoxaline, and (4) 1-hydroxy-n-(3-nitrophenyl)-2-napthamide. The binding mode of these four compounds is very similar to that of abovementioned established modulators: two molecules of each compound independently bind to the protein symmetrically at the dimer interface; occupy the subsites B, C, B' and C'; potentially interact with Ser518 and Ser775. Binding energy analysis shows that all the four hits are comparable to the drug molecule, CTZ, and hence, we propose that the discovered hits may be potential molecules to develop new chemical libraries for modulating the flip form of iGluA2 function.
http://www.ncbi.nlm....les/PMC3718743/


Curr Drug Targets CNS Neurol Disord. 2004 Jun;3(3):181-94.
AMPA receptor potentiators for the treatment of CNS disorders.
O'Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES.
Source
Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. Oneill_Michael_J@Lilly.com
Abstract
Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF exp<b></b>ression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the exp<b></b>ression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the exp<b></b>ression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin exp<b></b>ression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin exp<b></b>ression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery
Sorry bout the bad terminal used here, will update later

[Geoffrey]

Does anyone have any explination as to why this substance seams to make tennitus more noticeable? From my very first doses I have noticed that I hear the tennitus in my ears all day long. I hope it doesn't get any louder. I only really noticed it before when it was quiet and I was in bed trying to get to sleep.
I know others have mentioned this side effect. It is a bit annoying.

How strange -- as I've mentioned before, sunifiram dampens tinnitus caused by noopept, oxiracetam and (especially) aniracetam in my case. As I often co-administer noopept and sunifiram, I've had a chance to observe this effect regularly and predictably. If I take noopept on its own, about 30 minutes after administration I get a slight, but certainly noticeable, very high-pitched ringing in my ears. If I then take sunifiram, the ringing diminishes within 15 minutes or so, and eventually disappears. As sunifiram is shorter lived than noopept (for me), the return of the ringing after a few hours is a good sign to me that I need to take another dose of sunifiram. I don't understand how a chemical can have such different effects on such a specific symptom in different people.

[8bitmore]

Does anyone have any explination as to why this substance seams to make tennitus more noticeable? From my very first doses I have noticed that I hear the tennitus in my ears all day long. I hope it doesn't get any louder. I only really noticed it before when it was quiet and I was in bed trying to get to sleep.
I know others have mentioned this side effect. It is a bit annoying.

How strange -- as I've mentioned before, sunifiram dampens tinnitus caused by noopept, oxiracetam and (especially) aniracetam in my case. As I often co-administer noopept and sunifiram, I've had a chance to observe this effect regularly and predictably. If I take noopept on its own, about 30 minutes after administration I get a slight, but certainly noticeable, very high-pitched ringing in my ears. If I then take sunifiram, the ringing diminishes within 15 minutes or so, and eventually disappears. As sunifiram is shorter lived than noopept (for me), the return of the ringing after a few hours is a good sign to me that I need to take another dose of sunifiram. I don't understand how a chemical can have such different effects on such a specific symptom in different people.

This is a good point - it underscores neatly that our individual biochemistry is vastly different to the point where it is invariably more important to sense ones own body's reaction to a given substance than it is to find "proof" of various mechanisms in various research material. To this day people are still coming up with new findings in relation to how the most basic of substances work (often proving older explanations faulty in the process) so I honestly think it is borderline time-waste to to pin-point stuff to one receptor or another unless it is your full-time professional occupation or simply just entertaining of course

For me Sunifiram gives absolutely no tinnitus, whereas Piracetam does give a little ringing (full disclosure: I'm not using either at the moment since their effects are minimal at best) but only in small doses at certain times of the day! I don't expect the last bit of information is applicable to anyone else than myself but that is exactly the point. I do agree with Climactic that the lack of human clinical trials with Sunifiram is less-than-optimal but on the other hand there's plenty of human trials on Aspirin which is considered a over-the-counter safe drug and people still die up and down the road from all its side-effects.

Edited by 8bitmore, 22 October 2013 - 08:05 PM.

[Novabrain]

>> Please post your experience and dosages with it that would be great!

Noopept from New Star Nootropics is way more potent (for me)
than what I had got elsewhere before.

I use 1/2 tiny scoop that NSN sends with the item which is about
3 mg. I TAKE IT SUBLINGUALLY.
Plenty powerful for me. Do not expect better results with
higher dosages. In my experience that is the way with racetams
in general.

I also have Sunifiram from NSN, and use the same very low dosage
(about 3 mg, SUBLINGUAL). Very potent for me!

The Sunifiram lasts much longer than the Noopept, but seems more
of a speedy effect than the Noopept. Again, start very low and titrate up.

[Novabrain]

I tried 5 mg of sunifiram (half a 10mg pill in the morning) and actually seemed to have positive effects (was feeling less cold outside, slightly less fatigued and in slightly better mood).

Yes, I would NOT recommend anyone to start off with a 10mg pill of sunifiram. For a newbie, the effects of that amount are quite noticeable. Even 5mg I found to be a strong, albeit pleasant, dose when I first started. Sunifiram seems to be cumulative (but I find all the -racetams to be cumulative and that they take a long time to wash out of my system, or at least their aftereffects take a long time to subside). I cannot now take more than 4-5mg, often every other day, with a washout period all weekend. Taking too much has a paradoxical effect on me. But this is also how I react to noopept, oxiracetam and (most recently) phenylpiracetam (which I found made me lethargic and drained at the recommended dose).

My experience virtually the same. I take slightly less of Sunifiram (3 mg). Otherwise, I too skip a day,
and effect seems to be cumulative. Phenylpiracetam leaves me drained also.

My understanding is that Sunifiram and Noopept are peptides, meaning small molecules, and
are able to pass the blood-brain barrier easily, which accounts for their very high potencies.

[Climactic]

My understanding is that Sunifiram and Noopept are peptides, meaning small molecules, and
are able to pass the blood-brain barrier easily, which accounts for their very high potencies.

This understanding is totally wrong, with the exception that noopept is indeed a peptide.

[Novabrain]

My understanding is that Sunifiram and Noopept are peptides, meaning small molecules, and
are able to pass the blood-brain barrier easily, which accounts for their very high potencies.

This understanding is totally wrong, with the exception that noopept is indeed a peptide.

Okay, thanks for the clarification.

Is Sunifiram nevertheless a small molecule like Noopept?

I am wondering how it can be so potent in such a small dosage.

[Isochroma]

http://en.wikipedia..../Small_molecule

[Climactic]

Is Sunifiram nevertheless a small molecule like Noopept?

I am wondering how it can be so potent in such a small dosage.

Yes, going by the definition linked by Isochroma, sunifiram and noopept are both small molecules, but not all small molecules are peptides. While noopept is a peptide, sunifiram is not because it is not a chain of amino acids. Peptides are often vulnerable to stomach acid and warm temperatures. A source of the confusion is that the term "peptide" has been incorrectly/unclearly used to mean "illegal secretagogue" and "peptide hormones" in sports doping - we should try to use the term correctly.

Being a small molecule itself doesn't grant a drug access into the brain. There are small molecule drugs that specifically don't work in the brain, e.g. atenolol. The section https://en.wikipedia...eting_the_brain may be of some interest. I forgot where I read this, but drugs like sunifiram induce a conformational change (structural change) in the NMDA and AMPA receptors making them more easily activated. (citation needed)

Thank you for bringing up these concerns.

Edited by Climactic, 01 November 2013 - 05:52 PM.