• N&PD Moderators: Skorpio | thegreenhand

Amphetamine Neurotoxicity and Tolerance Reduction/Prevention II

Status
Not open for further replies.
NAC is used as a prodrug for cystiene (and glutathione which is derived from cys.) because it is more bioavailiable than the unacetylated aminoa cid. Hence better oral absorbtion etc. Its main use is actually as an antidote for certain hepatotoxins like acetaminophen.

High doses of sulphur containing aminoa cids & prodrugs can cause side effects. Especially when large doses are administered orally, nausea is present with NAC sometimes at the very least.

Also, please be more specific when you refer to ALA. It can be one of three various chemicals (maybe more) - alpha-lipoic acid, a sulphur containing antioxidant; aminolevulinic acid, a chlorophyll precursor; or alpha-linolenic acid, an omega-3 fatty acid.

The "amazing" claims about glutathione supplementation I have yet to see. Best I can find is one pubmed study saying it slows the progression of untreated Alzheimers by ~40% versus placebo.Not really what I'd call a cure when you start looking at modern treatments like levo/carbidopa or segelegine.
 
Long post warning:

I have reviewed this thread fully and attempted to understand as much as possible as a "layman". I have attempted to research the below answers but the technical data is very difficult to interpret in a useful way without the required skills.

Can I confirm the accuracy of some conclusions? Any wording that i think may be perceived incorrectly, be inaccurate or i feel my not describe what i mean to satisfactory level will be in "". Dont go to any effort but if you know offhand...

1. Amphetamine Psychosis is in fact caused by physical "trauma", deficiencies and other easily explained physical conditions that would be considered unhealthy (for example hypoglycemia(hyper?)), and not the intended effect of the drug proceeding to a level where the experience is negatively perceived.
If so how does this explain experiences of similar psychosis presenting immediately through extreme doses as the first administration. Unless the physical conditions/requirements are created instantly by this, but it is my understanding that it will take some time to "deplete" the body to the point needed to cause psychosis.

2. Does the above conclusion also explain the perceived decreased mental faculties, paranoia, strange thoughts etc that can still be perceived as false, controlled etc. Basically the blatantly obvious negative mental states of mind that directly conflict with the expected effects of the drug. Can these be interpreted as an indication of the "beginnings" of an unhealthy physical state that would eventually progress to psychosis, or is this still subjective perception of your experience. Is there a perceived cut over point between subjective experienced based perceptions and mental states directly linked physical "trauma"? I have tried to repeat and reframe this to get my understanding across. Basically is there a functional way to interpret physical concerns during the experience.

3. Lastly where does the commonly accepted impact of sleep deprivation come into this? I understand it is a big part of the risk of psychosis. Does the sleep deprivation contribute to psychosis through exacerbating the physical "trauma" explanations for psychosis or does it impact in some other way. This was absent from this thread as far as i remember.

4. And at the risk of perhaps delving into the realm of pure theory: Any thoughts as to why the symptoms of psychosis in this regard, a seemingly chaotic unbalanced physical state of "unhealth" seem to present as rather surprisingly specific and consistent experiences which seem to follow some logical path. It would would seem the symptoms should present as they would with other forms of brain distress like random confusion, reduced mental function, memory loss, unconsciousness etc. Instead we see the same theme consistently.
After reading many experiences of amp induced psychosis it seems to almost always present as a feeling of absolute certainty of impending danger from others or the environment which is perceived as being watched, followed etc. This feels like a hardwired specific instinctual response to a certain issue, but it doesn't seem to correlate to the root cause being physical distress.
My conclusions in an attempt to make sense of this:
1. The physical distress causes an appropriate mental sense of overall danger without a clear source, which we then imprint on our environment in a conscious effort to make sense of and identify the source of danger.
2. What is most likely more accurate is that the fight or flight response is at work here in extremes, which is what i always reasoned, but now i question this due to my new understanding of psychosis being caused by physical distress and not the SNS.
3. Lastly is it simply a result of the combination of physical distress and increased SNS activity logically resulting in the symptoms.

I am going to take this opportunity to risk the below questions which are more irrelevant and experience based, which I find interesting anyway. Feel free to ignore.

5. Can the perceived enhancement of certain mental tools during the experience be confirmed as accurate and explained technically/medically or would it be technically accurate to write off any perceived enhancement to a subjective perception of the experience? (EG. Enhanced creative writing abilities are simply due to enhanced confidence and not a physical effect for example improved access to the creative centers of the brain). This question is very broad and does not need answering directly. Let this rather be a clarification of context for the next more specific question.

5. I would like to know if the perceived enhanced senses (specifically smell and audio) during the experience can be technically explained, confirmed as accurate or reasonably concluded, even if just in theory using scientifically backed assumptions/methods, as in fact an enhancement of the senses for all intents and purposes. Or must we conclude this perception is always a purely subjective experience that is equivalent to a hallucinatory response, when considering this from a technical or scientific point of view.

To reframe: If i where to ask a medical/scientific professional with all the required knowledge whether I can logically accept, trust or assume that my senses are in fact enhanced and could therefore be theoretically useful on some way, what would they say?
The sense enhancements are really the only perceived enhancement that i think might have some basis in fact but really i have no idea.

I hope none of the above makes no sense or is plain stupid but feel free to let me know if it is.

Lastly a random thought. I think it would be really awesome and interesting for somebody with all the knowledge and experience to take all the info in this thread and all relevant and confirmed as accurate data and do a write up or paper of some sort that explains the perfect process, requirements, actions etc for the use of amphetamines recreationally and functionally based on theoretical, technical and scientific conclusions etc.
To clarify this would look like a detailed and step by step owners manual explaining exactly how to use amphetamines including everything that should be considered, physical defense strategies, supplementation, detailed dosage guides etc. A functional usable guide for anybody to understand.
I'm not asking or expect anybody to do this, simply thought that the whole concept of a functional summary of everything we know to date would be a worthy project and i dont think a well packaged and presented version of this idea exists anywhere, or does it?
Hell if i had the skills to do this responsibly, i would really enjoy this project i think. Also would be an awesome HR sticky for Other Drugs im sure. Anyways, just a random idea.

Love ADD and thanks to all the contributors, I could spam questions here all day, but I shall resist :).
 
I apologize for contributing nothing and only posing more questions:

I have pretty severe ADHD (by my account - I have been diagnosed but the severity modifier is MY addition) and am wondering if I should finally give low-dose adderall a proper trial. The only complication being that I am quite concerned about my brain and tend to stray away from anything that has the potential for long-term consequences. I drink once a month or so, and half of the time I go overboard, end up with a hangover, hate myself for having put my brain through dehydration, free radicals, potential excitotoxic rebound, etc, and swear off of it... until next time. That's another whole can of worms as far as my anxiety is concerned.

Anyway, I really only know one mechanism by which amphetamine may induce neurotoxicity in a primate, but I accept the likelihood of multiple tenets to this drug's toxic profile. For someone like me, that wants to use the drug therapeutically, and for a short trial (then, potentially, a longer one), is there any legitimate concern? I read frightening reports about reduced VMAT2, striatal dopamine, etc. *shivers* I know a fair amount, but not enough to understand brain pathways and metabolism.

I am getting my shit together in life either way, so if I skip out on this it may place more mechanical effort in the way of things, but ultimately I am going to the same place. It would be a major boon if I could garner some improved concentration from something relatively benign at the therapeutic level.
 
I apologize for contributing nothing and only posing more questions:

I have pretty severe ADHD (by my account - I have been diagnosed but the severity modifier is MY addition) and am wondering if I should finally give low-dose adderall a proper trial. The only complication being that I am quite concerned about my brain and tend to stray away from anything that has the potential for long-term consequences. I drink once a month or so, and half of the time I go overboard, end up with a hangover, hate myself for having put my brain through dehydration, free radicals, potential excitotoxic rebound, etc, and swear off of it... until next time. That's another whole can of worms as far as my anxiety is concerned.

Anyway, I really only know one mechanism by which amphetamine may induce neurotoxicity in a primate, but I accept the likelihood of multiple tenets to this drug's toxic profile. For someone like me, that wants to use the drug therapeutically, and for a short trial (then, potentially, a longer one), is there any legitimate concern? I read frightening reports about reduced VMAT2, striatal dopamine, etc. *shivers* I know a fair amount, but not enough to understand brain pathways and metabolism.

I am getting my shit together in life either way, so if I skip out on this it may place more mechanical effort in the way of things, but ultimately I am going to the same place. It would be a major boon if I could garner some improved concentration from something relatively benign at the therapeutic level.

Amphetamine is pretty benign, honestly. AFAIK well-controlled studies haven't found any negative effects (maybe slight positive ones) of even recreational amphetamine use... and there are a bunch of reasons I could give you for why neurotoxicity found in rodent studies is unlikely to apply to any reasonable human use. Amphetamine has been around a long time, so it's pretty safe to assume that its risks have been documented.
 
Two things I've discovered while recovering my prescription to vyvanse.

The first thing is that L-tryptophan supposedly has minor-major antagonistic effects on d-amphetamine(Here).

However, when I use L-tryptophan post D-amphetamine administration, it seems to intensify and enlongate the effects. There have been nights when I used L-tryptophan to go to bed and it lead to me standing right back up to clean my room or otherwise not sleep. Not necessarily in a bad way. The intensified effects seem to be centered more so around the pleasure center rather than excessive stimulation. I have been looking for a study that can give reason as to why this is in contrast to the previous study.




2nd thing was a source I read via wikipedia about buspirone, a D2 antagonist and 5-ht1a partial selective agonist, when combined with melatonin has the ability to repair brain tissue.

Wikipedia

Source 1

Source 2

A study of 142 patients showed positive results for the treatment of Depression when Buspirone was combined with Melatonin. It is suspected that the method of action differs from other SSRI medications. Preliminary research suggests that the combination of Buspirone and Melatonin stimulates the growth of new neurons in the brain, also known as neurogenesis

If this has been mentioned before, I apologize. After amphetamine use, this study was a god-send. I immediately tried it on myself. I woke 3 mornings later feeling normal. It was as if the "zombified" post-withdrawal use of amphetamine was non-existent. My anxiety and apathy were gone. I was back to the way I was before using any drug. I felt myself, able to socialize and connect easier with family and friends. Whereas in the past it would take close to 2-3 weeks without using my prescription to start coming back to normal.

Another thing I found was that each time I did it, it seemed to maintain D-amphetamine's strength the next day. The tolerance increase was far less than it would have been otherwise naturally.
 
Last edited:
blight12, re glutathione.

I've been researching glutathione a lot for a while now. It's amazing how little mainstream attention it has given the massive amounts of published science on it (100,000+ search results on PubMed compared to under 50,000 for vitamin c/ascorbic acid), then again not so surprising given there hasn't been very effective glutathione supplement until recently.

Send me a pm, you've missed the new glutathione supp with a cysteine pro-drug that is far superior to whey or NAC. For starters here is a number of studies relating methamphetamine neurotoxicity, low glutathione levels and glutathione supplementation. My post I had written just got eaten so I'll write more again elaborating very soon.


http://www.ncbi.nlm.nih.gov/pubmed/15199373

These results suggest that NAC could attenuate the reduction of DAT (dopamine transporter ) in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235/?tool=pubmed

The idea that oxygen-based free radicals are involved in METH neurotoxicity is further strengthened by reports that the drug can reduce the levels of glutathione

http://www.ncbi.nlm.nih.gov/pubmed/9839724

Our observations provide further evidence in support of the oxidative stress hypothesis of MA neurotoxicity and indirectly suggest that drugs designed to increase glutathione might protect against such damage.

http://www.ncbi.nlm.nih.gov/pubmed/10642830

We have shown that dietary Selenium attenuated methamphetamine neurotoxicity and that this protection involves Glutathione Peroxidase-mediated antioxidant mechanisms

http://www.ncbi.nlm.nih.gov/pubmed/10913590

These findings indicate selectivity of methamphetamine for the glutathione system and a role for methamphetamine in inducing oxidative stress.

http://www.ncbi.nlm.nih.gov/pubmed/12018843

METH toxicity seems to be produced by oxidative stress, as it was attenuated by the antioxidant glutathione

http://www.ncbi.nlm.nih.gov/pubmed/21882243

We found that Nrf2 deficiency exacerbated METH-induced damage to dopamine neurons

http://www.ncbi.nlm.nih.gov/pubmed/11746378

A dose-dependent depletion of total glutathione levels was detected in human brain microvascular endothelial cells exposed to METH

http://www.ncbi.nlm.nih.gov/pubmed/12230306

These results suggest that METH-induced disturbances in cellular redox status and that activation of AP-1 can play a critical role in signaling pathways leading to upregulation of inflammatory genes in vivo

http://www.ncbi.nlm.nih.gov/pubmed/15234256

These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.

http://www.ncbi.nlm.nih.gov/pubmed/15111252

It was found that acute administration of methamphetamine (5 and 15 mg kg(-1)) resulted in production of oxidative stress as demonstrated by decreased glutathione and increased oxidized glutathione levels

http://www.ncbi.nlm.nih.gov/pubmed/16038959

Enantiomers of trans-phenylpropylene oxide (Pyrolytic products of smoked methamphetamine) were stereoselectively and regioselectively conjugated in a Phase II drug metabolism reaction catalyzed by human liver cytosolic enzymes consisting of conjugation with glutathione

http://www.ncbi.nlm.nih.gov/pubmed/16760923

The levels of the reduced form of glutathione (GSH) in striatum, amygdala, hippocampus and frontal cortex were significantly lower in METH-treated mice compared to control during the period of conditioned place preference training. Acute and repeated administration of NAC to METH-treated mice restored the decreased brain GSH but had no effect on controls.

http://www.ncbi.nlm.nih.gov/pubmed/22354084

This suggests that METH induces oxidative stress in various organs and that a combination of N-acetylcysteine amide as a neuro- or tissue-protective agent, in conjunction with current treatment, might effectively treat METH abusers.
 
So in conclusion methylene blue is what we are looking for, for tolerance issues:
It depletes glutamate and nitric oxide the main players in tolerance, besides that its neuroprotective but dunno wheter that apply's to amp, the 40% increase in mitochondrial function may make it easier for the body to handle amp's overdrive (dunno wheter thats true, just saying something).

MB will be a far better option then mem for tolerance as it doesnt impair some glut related issues like LTP, it actually enhances it, besides that its an antipsychotic something ppl may need on amp binges.
 
Guanylate cyclase is another MB acts on and indeed seems implicated in tolerance:
Guanylate cyclase inhibition by methylene blue as an option in the treatment of vasoplegia after a severe burn. A medical hypothesis.
Farina Junior JA, Celotto AC, da Silva MF, Evora PR.
Source
Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, SP, Brazil.
Abstract
Today it is known that severe burns can be accompanied by the phenomenon of vasoplegic syndrome (VS), which is manifested by persistent and diffuse vasodilation, hypotension and low vascular resistance, resulting in circulatory and respiratory failure. The decrease in systemic vascular resistance observed in VS is associated with excessive production of nitric oxide (NO). In the last 2 decades, studies have reported promising results from the administration of an NO competitor, methylene blue (MB), which is an inhibitor of the soluble guanylate cyclase (sGC), in the treatment of refractory cases of vasoplegia. This medical hypothesis rationale is focused on the tripod of burns/vasoplegia catecholamine resistant/methylene blue. This article has 3 main objectives: 1) to study the guanylate cyclase inhibition by MB in burns; 2) to suggest MB as a viable, safe and useful co-adjuvant therapeutic tool of fluid resuscitation, and; 3) to suggest MB as burns hypotensive vasoplegia amine-resistant treatment.<br />
Ill keep editing my posts for more updates out of compassion for the ppl that aint got some speed and cant read as fast:)
 
Last edited:
It seems like CCK regulates also nitric oxide and glutamate, wich also explains that very succesfull anecdote on proglumide someone posted here a while ago, i wonder what the "ultimate" regular is we need to hit thus we can avoid the downsides of supressing first nmda, then it became clear no plays a bigger role that regulates nmda, and from first glance it seems cck plays a very big role here, lets see what i can dig out.

Some shit MB
Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue.
Rojas JC, Bruchey AK, Gonzalez-Lima F.
Source
Departments of Psychology, Pharmacology and Toxicology, University of Texas at Austin, 1 University Station A8000, Austin, TX 78712, USA.
Abstract
This paper provides the first review of the memory-enhancing and neuroprotective metabolic mechanisms of action of methylene blue in vivo. These mechanisms have important implications as a new neurobiological approach to improve normal memory and to treat memory impairment and neurodegeneration associated with mitochondrial dysfunction. Methylene blue's action is unique because its neurobiological effects are not determined by regular drug-receptor interactions or drug-response paradigms. Methylene blue shows a hormetic dose-response, with opposite effects at low and high doses. At low doses, methylene blue is an electron cycler in the mitochondrial electron transport chain, with unparalleled antioxidant and cell respiration-enhancing properties that affect the function of the nervous system in a versatile manner. A major role of the respiratory enzyme cytochrome oxidase on the memory-enhancing effects of methylene blue is supported by available data. The memory-enhancing effects have been associated with improvement of memory consolidation in a network-specific and use-dependent fashion. In addition, low doses of methylene blue have also been used for neuroprotection against mitochondrial dysfunction in humans and experimental models of disease. The unique auto-oxidizing property of methylene blue and its pleiotropic effects on a number of tissue oxidases explain its potent neuroprotective effects at low doses. The evidence reviewed supports a mechanistic role of low-dose methylene blue as a promising and safe intervention for improving memory and for the treatment of acute and chronic conditions characterized by increased oxidative stress, neurodegeneration and memory impairment.
Alternative mitochondrial electron transfer as a novel strategy for neuroprotection.
Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan LJ, Ju X, Liu R, Qian H, Marvin MA, Goldberg MS, She H, Mao Z, Simpkins JW, Yang SH.
Source
Department of Pharmacology and Neuroscience, Institute for Alzheimer's Disease and Aging Research, University of North Texas Health Science Center, Fort Worth, Texas 76107-2699, USA.
Abstract
Neuroprotective strategies, including free radical scavengers, ion channel modulators, and anti-inflammatory agents, have been extensively explored in the last 2 decades for the treatment of neurological diseases. Unfortunately, none of the neuroprotectants has been proved effective in clinical trails. In the current study, we demonstrated that methylene blue (MB) functions as an alternative electron carrier, which accepts electrons from NADH and transfers them to cytochrome c and bypasses complex I/III blockage. A de novo synthesized MB derivative, with the redox center disabled by N-acetylation, had no effect on mitochondrial complex activities. MB increases cellular oxygen consumption rates and reduces anaerobic glycolysis in cultured neuronal cells. MB is protective against various insults in vitro at low nanomolar concentrations. Our data indicate that MB has a unique mechanism and is fundamentally different from traditional antioxidants. We examined the effects of MB in two animal models of neurological diseases. MB dramatically attenuates behavioral, neurochemical, and neuropathological impairment in a Parkinson disease model. Rotenone caused severe dopamine depletion in the striatum, which was almost completely rescued by MB. MB rescued the effects of rotenone on mitochondrial complex I-III inhibition and free radical overproduction. Rotenone induced a severe loss of nigral dopaminergic neurons, which was dramatically attenuated by MB. In addition, MB significantly reduced cerebral ischemia reperfusion damage in a transient focal cerebral ischemia model. The present study indicates that rerouting mitochondrial electron transfer by MB or similar molecules provides a novel strategy for neuroprotection against both chronic and acute neurological diseases involving mitochondrial dysfunction.

Issue with amp:
Frontal glucose hypometabolism in abstinent methamphetamine users.
Kim SJ, Lyoo IK, Hwang J, Sung YH, Lee HY, Lee DS, Jeong DU, Renshaw PF.
Source
Department of Psychiatry, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Abstract
Changes in relative regional cerebral glucose metabolism (rCMRglc) and their potential gender differences in abstinent methamphetamine (MA) users were explored. Relative rCMRglc, as measured by (18)F-fluorodeoxyglucose positron emission tomography, and frontal executive functions, as assessed by Wisconsin card sorting test (WCST), were compared between 35 abstinent MA users and 21 healthy comparison subjects. In addition, male and female MA users and their gender-matched comparison subjects were compared to investigate potential gender differences. MA users had lower rCMRglc levels in the right superior frontal white matter and more perseveration and nonperseveration errors in the WCST, relative to healthy comparison subjects. Relative rCMRglc in the frontal white matter correlated with number of errors in the WCST in MA users. In the subanalysis for gender differences, lower rCMRglc in the frontal white matter and more errors in the WCST were found only in male MA users, not in female MA users, relative to their gender-matched comparison subjects. The current findings suggest that MA use causes persistent hypometabolism in the frontal white matter and impairment in frontal executive function. Our findings also suggest that the neurotoxic effect of MA on frontal lobes of the brain might be more prominent in men than in women.
Beneficial network effects of methylene blue in an amnestic model.
Riha PD, Rojas JC, Gonzalez-Lima F.
Source
Departments of Psychology, Pharmacology and Toxicology, University of Texas at Austin, Austin, TX 78712, USA.
Abstract
Posterior cingulate/retrosplenial cortex (PCC) hypometabolism is a common feature in amnestic mild cognitive impairment and Alzheimer's disease. In rats, PCC hypometabolism induced by mitochondrial dysfunction induces oxidative damage, neurodegeneration and memory deficits. USP methylene blue (MB) is a diaminophenothiazine drug with antioxidant and metabolic-enhancing properties. In rats, MB facilitates memory and prevents neurodegeneration induced by mitochondrial dysfunction. This study tested the memory-enhancing properties of systemic MB in rats that received an infusion of sodium azide, a cytochrome oxidase inhibitor, directly into the PCC. Lesion volumes were estimated with unbiased stereology. MB's network-level mechanism of action was analyzed using graph theory and structural equation modeling based on cytochrome oxidase histochemistry-derived metabolic mapping data. Sodium azide infusions induced PCC hypometabolism and impaired visuospatial memory in a holeboard food-search task. Isolated PCC cytochrome oxidase inhibition disrupted the cingulo-thalamo-hippocampal effective connectivity, decreased the PCC functional networks and created functional redundancy within the thalamus. An intraperitoneal dose of 4 mg/kg MB prevented the memory impairment, reduced the PCC metabolic lesion volume and partially restored the cingulo-thalamo-hippocampal network effects. The effects of MB were dependent upon the local sub-network necessary for memory retrieval. The data support that MB's metabolic-enhancing effects are contingent upon the neural context, and that MB is able to boost coherent and orchestrated adaptations in response to physical alterations to the network involved in visuospatial memory. These results implicate MB as a candidate intervention to improve memory. Because of its neuroprotective properties, MB may have disease-modifying effects in amnestic conditions associated with hypometabolism.
Neuro- and cardioprotective effects of blockade of nitric oxide action by administration of methylene blue.
Wiklund L, Basu S, Miclescu A, Wiklund P, Ronquist G, Sharma HS.
Source
Department of Surgical Sciences, Uppsala University Hospital, SE-75185 Uppsala, Sweden. [email protected]
Abstract
Methylene blue (MB), generic name methylthioninium (C(16)H(18)ClN(3) S . 3H(2)O), is a blue dye synthesized in 1876 by Heinrich Caro for use as a textile dye and used in the laboratory and clinically since the 1890s, with well-known toxicity and pharmacokinetics. It has experimentally proven neuroprotective and cardioprotective effects in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. This effect has been attributed to MB's blocking effect on nitric oxide synthase and guanylyl cyclase, the latter blocking the synthesis of the second messenger of nitric oxide. The physiological effects during reperfusion include stabilization of the systemic circulation without significantly increased total peripheral resistance, moderately increased cerebral cortical blood flow, a decrease of lipid peroxidation and inflammation, and less anoxic tissue injury in the brain and the heart. The last two effects are recorded as less increase in plasma concentrations of astroglial protein S-100beta, as well as troponin I and creatine kinase isoenzyme MB, respectively.
 
Last edited:
@campers: Just the type of feedback I was looking for, thank you. I would love to hear anything else you might have on the topic of GSH and/or your interpretations on the functional use of GSH supplementation in context of this thread.

Cheers.
 
I wonder what the negatives of depleting no and glutamate will be with MB? I do have the impression individual receptor functions are potentiated leading to even greater LTP for example from glut is depleted, but this makes me wonder would tolerance still be able to occur to then?
 
After various proglumide trials I can conclude various things:

Proglumide seems to be an inhibitory neurotransmitter for not just dopamine but for various excitatory transmitters, glutamate, NO, etc.

Your comment medievil just sparked a thought finding./...

http://www.jneurosci.org/content/30/15/5136.full.pdf

Cholecystokinin Facilitates Glutamate Release by Increasing the Number of Readily Releasable Vesicles and Releasing Probability

"CCK reduced the coefficient of variation and paired-pulse ratio of AMPA EPSCs suggesting that CCK facilitates presynaptic glutamate release. CCK
increased the release probability and the number of readily releasable vesicles with no effects on the rate of recovery from vesicle
depletion. CCK-mediatedincreasesin glutamate release requiredthefunctions of phospholipase C,intracellular Ca2+
release and protein kinase C. CCK released endogenously from hippocampal interneurons facilitated glutamatergic transmission. Our results provide a
cellular and molecular mechanism to explain the roles of CCK in the brain."

This paper has various interesting approaches; one being that through na+ or ca+ proglumide does not facilitate glutamate transmission- however through k+ channels it does in a manner similar to 4-amino pyridine, suggesting that 4-AP and CCK interact and block K+ channels in a similar manner. thus facilitating glutamate transmission via this indirect means.


the final conclusion being that

Our results indicate that CCK augments glutamate release at PP-GC, CA3-CA3 and CA3-CA1 synapses with no effects at MF-CA3 synapses. CCK increases the number of readily releasable vesicles and release probability without effects on the rate of recovery from vesicle depletion. The effects of CCK on glutamate release are mediated by inhibition of a 4-AP-sensitive Kchannel and requirethe functions of CCK-2 receptors, PLC,intracellular Ca2release and PKC. We
further demonstrate that CCK endogenously released from interneurons increases glutamatergic transmission inthe hippocampus.
Whereas CCK has been shown to activate a cationic conductance in rat neostriatal neurons (Wu and Wang, 1996) andsupraoptic nucleus neurons (Chakfe andBourque, 2001), our results demonstrate that CCK does not facilitate glutamate release in the hippocampus by activating cationic channels because CCK failed to modulate mEPSCs recorded from dentate granule cells and CCK had no effects on the resting membrane potentials recorded
from stellate neurons in the entorhinal cortex. Our results also demonstrate that CCK does not increase glutamate release by direct interaction with and facilitation of presynaptic Ca 2 channels because application of the selective P/Q- and N-type Ca 2 channel blockers did not block CCK-induced increases in AMPA EPSCs and application of CCK failed to alter Ca 2 channel currents recorded from stellate neurons, the cell body of the perforant pathway. Actually, CCK slightly inhibits Ca 2
channels in CA1 pyramidal neurons (Shinohara and Kawasaki, 1997). Our results support the scenario that CCK inhibits IK resulting in increases in presynaptic Ca 2
influx via voltage-gated Ca 2
channels to facilitate glutamate release in the hippocampus because application of 4-AP at micromolar concentration blocked CCKinduced increases in AMPA EPSCs and application of CCK inhibited IK recorded from stellate neurons in the entorhinal cortex. In agreement with our results, CCK has been shown to
inhibit other K channels in a variety of neurons (Branchereau et al., 1993; Cox et al., 1995; Miller et al., 1997; Deng and
Lei, 2006; Yang et al., 2007; Chung et al., 2009). Furthermore,
CCK-induced increases in glutamate release gauged by measuring glutamate concentration in the perfusate of hippocampal slices (Migaud et al., 1994) and in purified rat hippocampal
synaptosomes (Breukel et al., 1997) are Ca 2 -dependent. CCKinduced augmentation of presynaptic Ca2 concentration likely
contributes to its increased effects on the number of readily releasable vesicles and release probability because both the mobility
zation of vesicles from the reserve pool to the readily releasable
pool and the release probability are Ca 2
-dependent (Zucker
and Regehr, 2002).
We have shown that CCK-mediated facilitation of glutamate
release requires the functions of CCK-2 receptors. This conclusion is consistent with the results obtained by measuring glutamate concentration in the perfusate of hippocampal slices
(Migaud et al., 1994) and in purified rat hippocampal synaptosomes (Breukel et al., 1997) after application of CCK. The following three lines of evidence indicate that presynaptic CCK-2
receptors should be responsible for CCK-induced glutamate release in the hippocampus. First, enriched CCK-binding sites have
been detected in layer II of the entorhinal cortex where the cell
bodies of the perforant path are located in (Ko¨hler and ChanPalay, 1988). Second, inclusion of GDP--S, a G-protein inhibitor, in the recording pipettes failed to change CCK-induced
increases in AMPA EPSCs whereas it blocked CCK-induced depression of IK
recorded from the stellate neurons in layer II of the
entorhinal cortex. Third, Breukel et al. (1997) have shown that
CCK increases glutamate release in purified hippocampal synaptosomes because in this preparation the continuity of presynaptic
and postsynaptic structures should be disconnected. We further
demonstrate that the down-stream targets of CCK-2 receptors,
PLC, intracellular Ca
2
and PKC are involved in CCK-induced
increases in glutamate release. Because our results demonstrate
that CCK augments glutamate release by inhibiting presynaptic IK, it is reasonable to speculate that the activated PKC phosphorylates IK or IK
-associated proteins resulting in an inhibition of IK . Consistent with our results, activation of PKC has been shown to inhibit IK in neurons cultured from rat hypothalamus
and brainstem (Pan et al., 2001) and in cerebrocortical synaptosomes (Barrie et al., 1991) and IK expressed in Xenopus oocytes (Peretz et al., 1996).
CCK has been shown to transiently increase GABA release in hippocampal CA1 region (Miller et al., 1997; Deng and Lei, 2006;
Fo¨ldy et al., 2007; Karson et al., 2008). However, these studies did not examine the late effect of CCK on GABAergic transmission.
We have previously shown that CCK exerts bidirectional modification, with initial transient enhancement followed by a persistent depression, of GABAergic transmission onto the granule
cells of the dentate gyrus (Deng and Lei, 2006). Here, we further
assessed the contribution of glutamatergic and GABAergic transmission to CCK-mediated modification of the excitability of
granule cells. Our results demonstrate that CCK-mediated initial
transient enhancement of GABA release does not lead to a perceptible inhibition of the excitability of granule cells when both
GABAergic and glutamatergic transmissions are functional. The
possible reason is that the inhibition derived from CCK-induced
transient augmentation of GABA release is inundated by its action on glutamate release because the initial inhibitory effect of
CCK on neuronal excitability was unfolded when glutamatergic
transmission was inhibited. However, these results do not deny a
potential function for CCK-induced initial increase in GABAergic transmission because it is possible that this kind of modification may exert a fine-tuning on neuronal network activity.
Nonetheless, CCK-induced late phase inhibition on GABAergic
transmission is in line with its effect on glutamatergic transmission. The concerted actions of CCK on GABAergic and glutamatergic transmissions likely lead to an increase in neuronal
excitability. CCK has long been known to exert anxiogenic
effects in both animal models and humans (Rehfeld, 2000) and
the generation of anxiety can be due to a reduction in GABAergic
(Rupprecht et al., 2006; Whiting, 2006) and/or an increase of
glutamatergic (Bergink et al., 2004) function. Our results are
agreeable with this scenario and may serve as the cellular and
molecular mechanisms to explain the anxiogenic effects of CCK.
In addition, CCK has also been implicated in modulating other important brain functions including satiety, analgesia, learning and
memory processes (Sebret et al., 1999; Rehfeld, 2000; Beinfeld,
2001), which are closely related to both glutamate and GABA. Our
results therefore provide a basis to explain the roles of CCK in these
physiological functions as well.



So via CCK antagonism we can block CCK's ability to bind to CCKA OR CCKB receptor thus increasing synaptic density but where will this take us? Sometimes proglumide made me feel spacy and even somewhat stupid, i'm not sure what the right dose is...




Also:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154098/

"Cholecystokinin Exerts an Effect via the Endocannabinoid System to Inhibit GABAergic Transmission in Midbrain Periaqueductal Gray"

CCK also appears to inhibit GABA in a manner similar to modafinil/opiates(indirect GABA inhibition is one of the possible explanations to opiate wakefullness besides typical DA activity increase. ) but different- through an endocannabinoid system?


If someone can go through this I think a correct proglumide dose+ pramiracetam or nefiracetam or PDE inhibition may be key with stimulants/many drugs of abuse/reward...
 
Last edited:
Whats the benefit of targetting CCK as we can target glutamate more selectively? eg only the nmda receptors, less activation of ampa and other receptors could have detrimental effects?

I want to try something simular with mb wich depletes glut and no but my concern is negative effects caused by hypoactivation of receptors we would want to see agonized?

What are your results with prog? its good to see someone else doing some experiments instead of saying " its too good to be true, you cant only help tolerance a bit" we know better hehe:)

Shame all those tolerance techniques are ignored mostly.
 
Wait a sec, you want to deplete no and glut with cck to later add in a pro no and pro glutamate substance? altough nefi blocks morphine tolerance but thats due the cAMP increase wich clearly does seem to overpower the possible tolerance acceleration of increased nmda activity.
I may be missing a few points tough as my exact knowledge of this isnt up to date.
 
Hey all. I would like to suggest creatine malate to possibly help fight amphetamine-induced mental fatigue (i.e. long-term usage wearing you down). I assume that is what is generally meant by "amphetamine neurotoxicity" ?

My current hypothesis is that supplementing creatine replenishes ATP levels in the brain. Since you are using amphetamine, you are overstimulating your (primarily) dopaminergic neurons. More specifically, the dopamine is trapped in the synaptic cleft and activates dopamine receptors. These are class A GPCRs, which are coupled to adenylyl cyclase.

Adenylyl cyclase is an enzyme that catalyzes lots of ATP to be cAMP.

Hence, if you use lots of amphetamine... you're going to be using up lots of ATP too.

...

;P

FYI - creatine malate NOT regular creatine because regular is hard to digest and swallow... malate form is much better. =)
 
Last edited:
Hey all. I would like to suggest creatine malate to possibly help fight amphetamine-induced mental fatigue (i.e. long-term usage wearing you down). I assume that is what is generally meant by "amphetamine neurotoxicity" ?

My current hypothesis is that supplementing creatine replenishes ATP levels in the brain. Since you are using amphetamine, you are overstimulating your (primarily) dopaminergic neurons. More specifically, the dopamine is trapped in the synaptic cleft and activates dopamine receptors. These are class A GPCRs, which are coupled to adenylyl cyclase.

Adenylyl cyclase is an enzyme that catalyzes lots of ATP to be cAMP.

Hence, if you use lots of amphetamine... you're going to be using up lots of ATP too.

...

;P

FYI - creatine malate NOT regular creatine because regular is hard to digest and swallow... malate form is much better. =)


"Many individuals on this forum likely already take creatine for its ergogenic (or nootropic) effects, so much of this will be old news. However, there have been a number of posts recently asking for advice on nootropic compounds, and creatine, one of the best-proven cognitive enhancing compounds, has often been left out.



I'll keep this short. Creatine is safe, ergogenic, and neuroprotective. It also appears to enhance cognition -- in healthy humans no less -- and may in fact have anti-depressant properties. That creatine is safe and ergogenic is well-proven, so I won't go into that here.



Neuroprotection



Improves DA cell survival in models of PD. (PMID: 16355565, PMID: 15890457)
Improves survival of striatal GABAergic neurons. (PMID: 16045451)




Cognition Enhancement (Nootropic)



Reduces mental fatigue during simple task repetition and increases cerebral oxygen utilization. (PMID: 11985880)
Improvement in cognitive function on almost all tasks studied in elderly individuals. (PMID: 17828627)
Decreases variability in responses to a choice reaction-time task in healthy individuals. Also improves memory in healthy vegetarians, who presumably have lower baseline creatine intake. (PMID: 21118604)
Improves memory in healthy volunteers and reduced fMRI BOLD signal, indicating possible increase in efficiency. (PMID: 20570601)
During sleep deprivation, improves PFC-loaded tasks relative to placebo. (PMID: 16416332)
Improves executive functioning.




Mood Enhancement (Anti-depressant)



Beneficial effects on unipolar depression in a small trial. (PMID: 17988366)
During sleep deprivation, improves mood. (PMID: 16416332)
Shows antidepressant effects in females only in rodents. (PMID: 19829292)




Note this is just a small sampling of studies regarding creatine. But note that while piracetam, choline citrate, and dozens of other "nootropics" have no evidence for efficacy in healthy volunteers, creatine in fact does.



I should note, in closing, that there is one negative study on creatine enhancing cognitive performance in healthy volunteers (PMID: 18579168), but the dose used was fairly low (0.03/g/kg/day, or 2.2g/day in a 75kg man, about half of the more frequently used dose of 5g/day) and there are a number of other studies (see above) showing positive results."
 
Hey all. I would like to suggest creatine malate to possibly help fight amphetamine-induced mental fatigue (i.e. long-term usage wearing you down). I assume that is what is generally meant by "amphetamine neurotoxicity" ?

My current hypothesis is that supplementing creatine replenishes ATP levels in the brain. Since you are using amphetamine, you are overstimulating your (primarily) dopaminergic neurons. More specifically, the dopamine is trapped in the synaptic cleft and activates dopamine receptors. These are class A GPCRs, which are coupled to adenylyl cyclase.

Adenylyl cyclase is an enzyme that catalyzes lots of ATP to be cAMP.

Hence, if you use lots of amphetamine... you're going to be using up lots of ATP too.

...

;P

FYI - creatine malate NOT regular creatine because regular is hard to digest and swallow... malate form is much better. =)
Dopamine receptors don't all crank out cAMP, a lot of them in fact inhibit its production. Creatine is a good place to look though, as you can throw all the neurotransmitters at a cell you want and have nothing happen unless its metabolically supported.
 
Dopamine receptors don't all crank out cAMP, a lot of them in fact inhibit its production.

Do you have a paper/source on this I can check out? I've never heard of this happening personally. I just pulled out my (handy dandy) qiagen pathway map reference guide and see only GPCRs coupled to Galpha-short and Galpha-long directly activate adenylyl cyclase. It was my understanding that most class A/B GPCRs were coupled to either one though. I'd be interested to see otherwise.

Anyways yeah the whole "creatine is neuroprotective" idea seems a bit vague to me. Its not that I disagree with it, just I hate those types of blanket statements about "neuroprotection." Of course, there could be some general way that having high levels of ATP provide this property to neurons. But I am more of a rational thinker and try to think my way through the molecular basis as much as possible on something like this.

I've been having great success using creatine malate to prevent me from getting brain zaps from using my precious MXE/6APB combo weekend in-weekend out here recently. I had to quit for a while in the spring/summer and even before in last winter because they kept getting so bad at night days after letting sobriety hit me following a weekend.

But it was only an inadvertent realization. I just started using the creatine for my workouts, and started using the drugs again shortly thereafter. Lo and behold this time I am not getting the zaps... and I've been hitting it just like I was previously.

So I am guessing it might help for people using any type of stimulants that put a lot of stress on GPCRs, or just drugs that cause the user to use up a lot of ATP. Of course, again, it could be some general "neuroprotective" effect... but I really like the ATP depletion hypothesis. ATP is pretty important... this all has me wondering just how important it is though, like on a scale of 1 to 10 compared to all the other widely used, general metabolic small molecules. . . .

Also I had skimmed through the thread, regarding stuff like amphetamine neurotoxicity mechanisms. Things like free radical damage. Personally I'd be more weary of the effect of general wear and tear over the long run resulting from simply the face that amphetamine will cause overstimulation in the brain. I mean that's how it works right; it makes your dopamine receptors work harder than normal. Over the long-term, this can get grueling. Well, I'm a bit skeptical this wouldn't be the biggest issue. Anyways that's it for now.
 
Last edited:
Do you have a paper/source on this I can check out? I've never heard of this happening personally. I just pulled out my (handy dandy) qiagen pathway map reference guide and see only GPCRs coupled to Galpha-short and Galpha-long directly activate adenylyl cyclase. It was my understanding that most class A/B GPCRs were coupled to either one though. I'd be interested to see otherwise.
.

http://en.wikipedia.org/wiki/D2-like_receptor
D2, D3, and D4 all inhibit cAMP formation.
 
Status
Not open for further replies.
Top