6 replies to this topic

[Speculosity]

I've been taking NSI-189 for 2 days now, and plan to start Dihexa tomorrow.

 

I learned about what each of them does separately, but I have a slight worry that taking them both at the same time may cancel or diminish the effects of one or both of them, regarding the neurogenesis and growth of axons/dendrites. 

 

Is there any precedent for this? Is it possible that this could happen at all?

 

I just don't want to waste the money I spent on the Dihexa, it was expensive!

Edited by Speculosity, 26 September 2015 - 04:16 AM.

[Logic]

dihexa + nsi 189 synergy

http://www.longecity...si-189-synergy/

 

http://cse.google.co...=dihexa nsi 189

Edited by Logic, 26 September 2015 - 03:24 PM.

[gamesguru]

Both increase hippocampal growth, but high does of both would be kind of experimental/suspicious to me, personally

Also, it could be no synergy at all.  It could be that a larger-than-average hippocampus has no behavioral benefits over a average-sized one, and that shrunked/diseases hippocampi should be restored just to average-size.  After all, the hippocampus is shrunken and has reduced neurogenesis in depressive models.  But it's doubtful a larger-than-average one will give you superhuman abilities.

The pro-cognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-Met system
A subset of angiotensin IV (AngIV)-related molecules are known to possess pro-cognitive/ anti-dementia properties and have been considered as templates for potential therapeutics. However, this potential has not been realized because of two factors: 1) a lack of blood-brain barrier (BBB) penetrant analogs; and 2) the absence of a validated mechanism of action. The pharmacokinetic barrier has recently been overcome with the synthesis of the orally active, BBB permeable analog Dihexa (N-hexanoic-tyrosine-isoleucine-(6) aminohexanoic amide) (McCoy et al., 2013). Therefore, the goal of this study was to elucidate the mechanism that underlies Dihexa's pro-cognitive activity. Here we demonstrate that Dihexa binds with high affinity to hepatocyte growth factor (HGF) and both Dihexa and its parent compound Norleucine 1-AngIV (Nle1-AngIV) induce c-Met phosphorylation in the presence of subthreshold concentrations of HGF and augment HGF-dependent cell scattering. Further, Dihexa and Nle1-AngIV induce hippocampal spinogenesis and synaptogenesis similar to HGF itself. These actions were inhibited by an HGF antagonist and a sh-RNA directed at c-Met. Most importantly the pro-cognitive/anti-dementia capacity of orally delivered Dihexa was blocked by an HGF antagonist delivered intraventricularly as measured using the Morris water maze task of spatial learning.

 

One concern with raising all these growth factors (NGF/HGF, BDNF/GDNF, VEGF) is risk of cancer, because cancer depends on angiogensis and proliferation.

So I would consider low, conservative doses, improved diet/lifestyle, closely monitoring effects, or forgoing the combination altogether.  Just exercising/erring on the side of caution, perhaps too much here.

Because one of the ways green tea inhibits cancer is via a reduction in VEGF, eg)

Green tea inhibits vascular endothelial growth factor (VEGF) induction in human breast cancer cells.
Investigators have shown that green tea and its main catechin epigallocatechin-3 gallate (EGCG) may decrease the risk of cancer. Our previous study showed that green tea extract (GTE) as well as its individual catechin components inhibited MDA-MB231 breast cancer cell and human umbilical vein endothelial cell (HUVEC) proliferation. Further, GTE suppressed breast cancer xenograft size and decreased the tumor vessel density in vivo. In the current study, we investigated the effect of GTE on the major angiogenic factor vascular endothelial growth factor (VEGF) in an in vitro experiment. GTE or EGCG (40 mg/L) significantly decreased the levels of the VEGF peptide secreted into conditioned media. This occurred in both HUVEC and human breast cancer cells and the effect was dose dependent. Furthermore, GTE and EGCG decreased the RNA levels of VEGF in MDA-MB231 cells. This inhibition occurred at the transcriptional regulation level and was accompanied by a significant decrease in VEGF promoter activity. We also showed that GTE decreased c-fos and c-jun RNA transcripts, suggesting that activator protein (AP)-1-responsive regions present in the human VEGF promoter may be involved in the inhibitory effect of GTE. Furthermore, GTE suppressed the expression of protein kinase C, another VEGF transcription modulator, in breast cancer cells. Inhibition of VEGF transcription appeared to be one of the molecular mechanism(s) involved in the antiangiogenic effects of green tea, which may contribute to its potential use for breast cancer↓ treatment and/or prevention.

[Speculosity]

Yea one of my fears is cancer, hopefully, me being young, and no one in my family having a history of cancer, will keep me safe.

 

I have MDMA damage, so I'm just trying to get myself back to normal, not above average.

 

My worry is that NSI-189's MoA is unknown, so I don't want it to be contradictory to Dihexa's.

[gamesguru]

NSI is an unknown, but its effect is to increase neurogenesis with little apparent detriment.  If combining the two I recommend low, monitored doses.

How severe is the damage/what was your pattern of use?

It's my understanding MDMA's behavioral effects are due as much to prefrontal dysregulation as striatal toxicity, tho both are bad.  (So if there's only a 10.5% reduction in size, NSI+Dihexa is potentially overkill, and not addressing the whole picture of the problem, eg. prefrontal dysregulation/function).
 

Preliminary evidence of hippocampal damage in chronic users of ecstasy
Various studies have shown that ecstasy (3,4-methylenedioxymethamphetamine) users display significant memory impairments, whereas their performance on other cognitive tests is generally normal. The hippocampus plays an essential role in short-term memory. There are, however, no structural human data on the effects of ecstasy on the hippocampus. The objective of this study was to investigate whether the hippocampal volume of chronic ecstasy users is reduced when compared with healthy polydrug-using controls, as an indicator of hippocampal damage. The hippocampus was manually outlined in volumetric MRI scans in 10 male ecstasy users (mean age 25.4 years) and seven healthy age- and gender-matched control subjects (21.3 years). Other than the use of ecstasy, there were no statistically significant differences between both groups in exposure to other drugs of abuse and alcohol. The ecstasy users were on average drug-free for more than 2 months and had used on average 281 tablets over the past six and a half years. The hippocampal volume in the ecstasy using group was on average 10.5% smaller than the hippocampal volume in the control group (p=0.032). These data provide preliminary evidence that ecstasy users may be prone to incurring hippocampal damage, in line with previous reports of acute hippocampal sclerosis and subsequent atrophy in chronic users of this drug.

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The Nature of 3, 4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonergic Dysfunction: Evidence for and Against the Neurodegeneration Hypothesis

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Effect of repeated exposure to MDMA on the function of the 5-HT transporter as assessed by synaptosomal 5-HT uptake.
Recent studies have demonstrated that a preconditioning regimen (i.e., repeated low doses) of MDMA provides protection against the reductions in tissue concentrations of 5-HT and 5-HT transporter (SERT) density and/or expression produced by a subsequent binge regimen of MDMA. In the present study, the effects of preconditioning and binge treatment regimens of MDMA on SERT function were assessed by synaptosomal 5-HT uptake. Synaptosomal 5-HT uptake was reduced by 72% 7 days following the binge regimen (10 mg/kg, i.p. every 2 h for a total of 4 injections). In rats exposed to the preconditioning regimen of MDMA (daily treatment with 10 mg/kg for 4 days), the reduction in synaptosomal 5-HT uptake induced by a subsequent binge regimen was significantly less. Treatment with the preconditioning regimen alone resulted in a transient 46% reduction in 5-HT uptake that was evident 1 day, but not 7 days, following the last injection of MDMA. Furthermore, the preconditioning regimen of MDMA did not alter tissue concentrations of 5-HT, whereas the binge regimen of MDMA resulted in a long-term reduction of 40% of tissue 5-HT concentrations. The distribution of SERT immunoreactivity (ir) in membrane and endosomal fractions of the hippocampus also was evaluated following the preconditioning regimen of MDMA. There was no significant difference in the relative distribution of SERTir between these two compartments in control and preconditioned rats. The results demonstrate that SERT function is transiently reduced in response to a preconditioning regimen of MDMA, while long-term reductions in SERT function occur in response to a binge regimen of MDMA. Moreover, a preconditioning regimen of MDMA provides protection against the long-term reductions in SERT function evoked by a subsequent binge regimen of the drug. It is tempting to speculate that the neuroprotective effect of MDMA preconditioning results from a transient down-regulation in SERT function.

Low striatal serotonin transporter protein in a human polydrug MDMA (ecstasy) user: a case study.
SERT protein levels were markedly (-48% to -58%) reduced in striatum (caudate, putamen) and occipital cortex and less affected (-25%) in frontal and temporal cortices, whereas TPH protein was severely decreased in caudate and putamen (-68% and -95%, respectively) ... Although acknowledging limitations of a case study, these findings extend imaging data based on SERT binding and suggest that high-dose MDMA exposure could cause loss of two key protein markers of brain serotonin neurones, a finding compatible with either physical damage to serotonin neurones or downregulation of components therein.

Persistent Nigrostriatal Dopaminergic Abnormalities in Ex-Users of MDMA (‘Ecstasy'): An 18F-Dopa PET Study
Ecstasy (±3,4-methylenedioxymethamphetamine, MDMA) is a popular recreational drug with known serotonergic neurotoxicity. Its long-term effects on dopaminergic function are less certain. We used 18F-dopa positron emission tomography (PET) to investigate the long-term effects of ecstasy on nigrostriatal dopaminergic function in a group of male ex-recreational users of ecstasy who had been abstinent for a mean of 3.22 years. We studied 14 ex-ecstasy users (EEs), 14 polydrug-using controls (PCs) (matched to the ex-users for other recreational drug use), and 12 drug-naive controls (DCs).

The putamen 18F-dopa uptake of EEs was 9% higher than that of DCs (p=0.021). The putamen uptake rate of PCs fell between the other two groups, suggesting that the hyperdopaminergic state in EEs may be due to the combined effects of ecstasy and polydrug use. There was no relationship between the amount of ecstasy used and striatal 18F-dopa uptake. Increased putaminal 18F-dopa uptake in EEs after an abstinence of >3 years (mean) suggests that the effects are long lasting. Our findings suggest potential long-term effects of ecstasy use, in conjunction with other recreational drugs, on nigrostriatal dopaminergic functions. Further longitudinal studies are required to elucidate the significance of these findings as they may have important public health implications.

 

though the 5-HT depletion and toxicity feed on each other, probably the same is true of the dopamine dysregulation

Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT.
Although the exact mechanism involved in the long-term depletion of brain serotonin (5-HT) produced by substituted amphetamines is not completely known, evidence suggests that oxidative and/or bioenergetic stress may contribute to 3,4-methylenedioxymethamphetamine (MDMA)-induced 5-HT toxicity. In the present study, the effect of supplementing energy substrates was examined on the long-term depletion of striatal 5-HT and dopamine produced by the local perfusion of MDMA (100 microM) and malonate (100 mM) and the depletion of striatal and hippocampal 5-HT concentrations produced by the systemic administration of MDMA (10 mg/kg i.p. x4). The effect of systemic administration of MDMA on ATP levels in the striatum and hippocampus also was examined. Reverse dialysis of MDMA and malonate directly into the striatum resulted in a 55-70% reduction in striatal concentrations of 5-HT and dopamine, and these reductions were significantly attenuated when MDMA and malonate were co-perfused with nicotinamide (1 mM). Perfusion of nicotinamide or ubiquinone (100 microM) also attenuated the depletion of 5-HT in the striatum and hippocampus produced by the systemic administration of MDMA. Finally, the systemic administration of MDMA produced a 30% decrease in the concentration of ATP in the striatum and hippocampus. These results support the conclusion that MDMA produces a dysregulation of energy metabolism which contributes to the mechanism of MDMA-induced 5-HT neurotoxicity.

[Speculosity]

My working memory is shot. I lost a lot of passion for things, and my visual perception is always as if I'm buzzed. Been like this for half a year now.

 

I can literally feel a feeling of blockage in my left dorsolateral prefrontal cortex, and left hippocampus. This is consistent with studies on MDMA damage regarding damage to those areas.

 

Yea one of my worries is that NSI-189 will only partially fix the problem. Even though the studies it increases electrical coherence in the prefrontal cortex, but I don't know if that translates to fixing the problem.

 

I did find a comment on reddit of someone who had MDMA damage similar to mine, who says his symptoms were reversed. https://www.reddit.c...reports/cs52ib3

 

I can only hope to assume he had the exact same structural deficiencies as me, and that NSI-189 will cure it in time.

[gamesguru]

Increased electrical coherence could even do excitotoxicity, though probably more along the lines of LTP or improved metabolism/connectivity.  As well, the areas in question do not all undergo neurogenesis (I have in mind much of the frontal cortex)... according to wki, it's just the nucleus accumbens, hippocampus (dentate gyrus) and subventricular zone.

 

It's not all due to cytotoxicity, there's some metabolic dysregulation too.

That's to suggest part of the problem is easier to solve, just by restoring metabolism or less functions, rather than lost cells/dendrites/axons.

Verbal memory deficits are correlated with prefrontal hypometabolism in (18)FDG PET of recreational MDMA users.
3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational club drug with supposed neurotoxic effects selectively on the serotonin system. MDMA users consistently exhibit memory dysfunction but there is an ongoing debate if these deficits are induced mainly by alterations in the prefrontal or mediotemporal cortex, especially the hippocampus. Thus, we investigated the relation of verbal memory deficits with alterations of regional cerebral brain glucose metabolism (rMRGlu) in recreational MDMA users.
Brain glucose metabolism in rest was assessed using 2-deoxy-2-((18)F)fluoro-D-glucose positron emission tomography ((18)FDG PET) in 19 male recreational users of MDMA and 19 male drug-naïve controls. (18)FDG PET data were correlated with memory performance assessed with a German version of the Rey Auditory Verbal Learning Test.
As previously shown, MDMA users showed significant impairment in verbal declarative memory performance. PET scans revealed significantly decreased rMRGlu in the bilateral dorsolateral prefrontal and inferior parietal cortex, bilateral thalamus, right hippocampus, right precuneus, right cerebellum, and pons (at the level of raphe nuclei) of MDMA users. Among MDMA users, learning and recall were positively correlated with rMRGlu predominantly in bilateral frontal and parietal brain regions, while recognition was additionally related to rMRGlu in the right mediotemporal and bihemispheric lateral temporal cortex. Moreover, cumulative lifetime dose of MDMA was negatively correlated with rMRGlu in the left dorsolateral and bilateral orbital and medial PFC, left inferior parietal and right lateral temporal cortex.
Verbal learning and recall deficits of recreational MDMA users are correlated with glucose hypometabolism in prefrontal and parietal cortex, while word recognition was additionally correlated with mediotemporal hypometabolism. We conclude that memory deficits of MDMA users arise from combined fronto-parieto-mediotemporal dysfunction.

 

(just one suggestion on how to restore disturbed metabolism, admittedly not that diligently researched and totally plant-based/probably not too effective)

Do polyphenols enter the brain and does it matter? Some theoretical and practical considerations

Furthermore, the regulation of brain integrity and function must not be seen in isolation but as strongly dependent on feedback information (in the form of hormones, nutrients, metabolites and, of course, sensory neuron signalling) of the body periphery. In addition, mainly physico-mechanical parameters, such as the amount of blood supplied to the brain, are important factors to consider when assessing CNS effects of patho-physiological events and preventive/therapeutic interventions (e.g. drugs and diet). Endothelial dysfunction, for example, is associated with reduced cerebral perfusion and the occurrence of dementia (Ghosh and Scheepens 2009). Reasonable evidence exists that PPs from cocoa (Francis et al. 2006; Heiss et al. 2007; Heiss et al. 2010) and other dietary sources, such as tea (Grassi et al. 2009) and grapes (Lekakis et al. 2005), increase blood flow in humans, thus possibly helping to provide the brain with greater amounts of oxygen and glucose. Negative studies, however, have also been published on this topic...