24 replies to this topic

[John250]

I’m having some trouble grasping the concept of restoring depleted dopamine from amphetamines. If my goal is to restore dopamine what is best to take? I see that ropinirole seems to be the king for this but won’t it just cause further depletion after cessation and could lead to DAWS? That would negate my entire goal. What will permanently restore it without deleting it after cessation?

[John250]

Shameless bump^^^

There’s gotta be something I can take that will replenish dopamine and not negatively impact it when stopping. ropinirole? Wellbutrin?,etc..?

[Galaxyshock]

Dopamine agonists and other stims will only make you worse long-term. 

 

Mucuna pruriens might restore endogenous levels of dopamine and its precursor L-DOPA (on top of that also serotonin and noradrenaline), and also has neurorestorative effects. It's a bit confusing herb though, sometimes I feel quite powerful effects from it, but after a while of taking it start to feel sick instead or get no effects at all.

https://onlinelibrar...0.1002/ptr.1514

 

Jiaogulan has some restorative effects at dopaminergic system.

 

NMDA-antagonists like DXM may upregulate the receptors or reverse tolerance to stimulants.

 

Another route could be simply increasing dopamine biosynthesis with stuff like 9-Me-BC, Cordyceps and Bromantane.

[John250]

Dopamine agonists and other stims will only make you worse long-term.

Mucuna pruriens might restore endogenous levels of dopamine and its precursor L-DOPA (on top of that also serotonin and noradrenaline), and also has neurorestorative effects. It's a bit confusing herb though, sometimes I feel quite powerful effects from it, but after a while of taking it start to feel sick instead or get no effects at all.
https://onlinelibrar...0.1002/ptr.1514

Jiaogulan has some restorative effects at dopaminergic system.

NMDA-antagonists like DXM may upregulate the receptors or reverse tolerance to stimulants.

Another route could be simply increasing dopamine biosynthesis with stuff like 9-Me-BC, Cordyceps and Bromantane.

Oh I see, so using a dopamine agonist would not be beneficial if my goals are to restore lost dopamine from amphetamine use. So basically I would have to use a NMDA antagonist while tapering down and then only use natural supplements that restore endogenous dopamine to fully recover it?

I ordered Memantine and ropinirole so I probably won’t end up using the ropinirole and just use the Memantine as an NMDA antagonist. I may order 9-ME-BC and Bromantane and give those a try.

I thought I read somewhere that Mucuna pruriens can further inhibit natural dopamine though But maybe I was wrong.

What dose/brand of Jiaogulan do you use? I picked up Solarays Jiaogulan(820mg)(Gynostemma pentaphyllium)(root and rhizome extract) [369mg {45%} Gypenosides]

Maybe I’ll add 350mg NALT a few hours after my last dose of adderall at well. I can take that stuff before bed and it doesn’t effect me at all with some L-Theanine as well.

Edited by John250, 04 June 2018 - 06:06 PM.

[Galaxyshock]

Oh I see, so using a dopamine agonist would not be beneficial if my goals are to restore lost dopamine from amphetamine use. So basically I would have to use a NMDA antagonist while tapering down and then only use natural supplements that restore endogenous dopamine to fully recover it?

I ordered Memantine and ropinirole so I probably won’t end up using the ropinirole and just use the Memantine as an NMDA antagonist. I may order 9-ME-BC and Bromantane and give those a try.

I thought I read somewhere that Mucuna pruriens can further inhibit natural dopamine though But maybe I was wrong.

What dose/brand of Jiaogulan do you use? I picked up Solarays Jiaogulan(820mg)(Gynostemma pentaphyllium)(root and rhizome extract) [369mg {45%} Gypenosides]

Maybe I’ll add 350mg NALT a few hours after my last dose of adderall at well. I can take that stuff before bed and it doesn’t effect me at all with some L-Theanine as well.

 

Yes dopamine agonists will further downregulate DA receptors and you become dependent on them, possibly facing horrible withdrawal syndrome (DAWS). Supposably very small doses of dopamine agonists may actually help you by only activating the autoreceptors, but I haven't looked much into this protocol. Try searching it to see if you could use ropinirole that way. Yeah a combination of NMDA-antagonist and restorative supps is the way I would do it.

 

 

I think with Mucuna those high L-DOPA extracts are what may mess with natural dopamine as they lack the synergistic goods, antioxidants etc. of the whole herb. I would use extract of max 20 % L-DOPA or so. Ojio has pretty decent Mucuna product.

 

I use Paradise Herbs Jiaogulan about 3 capsules a day. It's 250mg of 12:1 extract.

 

Tyrosine supplements are pretty weak but can help a bit with the DA production. Don't take the same time as Mucuna though as it interferes. 

 

 

 

Edited by Galaxyshock, 04 June 2018 - 07:15 PM.

[John250]

Great thanks. The one I have is by Now:
2 capsule serving:
Velvet Bean Extract(Mucuna pruriens)(seed) (min 15% L-Dopa, naturally occurring) 800mg

L-Dopa 120mg*

[John250]

So what would the benefit of using a dopamine agonist like ropinirole be if it will just further deplete dopamine when discontinued? Would a short term run be beneficial in restoring dopamine and only long term would deplete it?

[John250]

So what would the benefit of using a dopamine agonist like ropinirole be if it will just further deplete dopamine when discontinued? Would a short term run be beneficial in restoring dopamine and only long term would deplete it?

Anyone?

[Galaxyshock]

Anyone?

 

I think it was so that when taken in very low doses a dopamine agonist binds mostly to the autoreceptor which controls dopamine release, and when it downregulates there will be increase in overall dopamine activity. This is based on some online forum speculation, so there's no real guarantee if it works.

[John250]

I think it was so that when taken in very low doses a dopamine agonist binds mostly to the autoreceptor which controls dopamine release, and when it downregulates there will be increase in overall dopamine activity. This is based on some online forum speculation, so there's no real guarantee if it works.

Do you happen to have the study where low dose L-Dopa will restore DA without any suppression? I’m wondering what the doses are and how “long term” is safe,etc...

Seems like right now for drugs that will not cause any suppression I’m limited to Memantine, Bromantane and 9-me-bc.

[John250]

What about St. John’s wort?


Dopaminergic Neurotransmission

A single high dose of hypericum perforatum (300mg/kg of 0.3% hypericin and 4.1% hyperforin) in otherwise normal rats appears capable of increasing extracellular dopamine in the prefrontal cortex by 40% after an hour;[11] this was associated with reduced levels of dopamine's metabolites DOPAC (15% of baseline) and HVA (53%) while noradrenaline (NA) remained unchanged, and due to no overall changes in tissue dopamine concentration this was attributed to increased turnover

[John250]

Looks like Metformin plays a role with dopamine

https://www.ncbi.nlm...les/PMC4965122/

[Galaxyshock]

Cistanche Deserticola appears to have upregulatory effect at dopamine:

https://www.ncbi.nlm...les/PMC5506466/

[John250]

Cistanche Deserticola appears to have upregulatory effect at dopamine:
https://www.ncbi.nlm...les/PMC5506466/

Well shiitttt mine as well add it to this dopamine arsenal:) and
hit dopamine from all angles each receptor, Nigrostriatal pathway, Mesocortical/Mesolithic pathway, Tuberoinfundibular pathway, TAAR, MOA, COMT, MANF, GDNF, CDNF, Tyrosine Hydroxylase,etc..

NALT
ALCAR
R-ALA(NA)
Taurine
Choline
Nicotine
Selenium
Vinpocetine
Ginkgo
Magnesium
Vitamin D
BenaGene
Gastrodin
Benfotiamine
NAC
Niagen
Glycine
Cordyceps
Lions Mane
Forskolin
DanShen
Uridine
Holy Basil
Rhodiola Rosea
Eleuthero
Panax
Schizandra
Jiaogulan
Ashitaba
Neuravera(green oat)
Mucuna Pruriens
skullcap baicalensis
Palmitoylethanolamide
Theanine
Tributyrin
Rehmannia Glutinosa
Thunbergia Laurifolia

Edited by John250, 16 July 2018 - 04:19 PM.

[Galaxyshock]

Well that might be a bit excess. Although herbs do generally combine surprisingly well. Maybe divide the supplementation to something like two phases, where in first phase you take stuff that hit dopamine more directly like nicotine, neuravera and mucuna, and some of the adaptogens like rhodiola and schizandra which actually potentiate mucuna. Then in second phase you switch to things that help a bit more indirectly with the DA synthesis etc. like cordyceps and NALT, and switch to different adaptogens than in the first phase. Vitamins and minerals I'd say take all the time. This is just an idea, it could work if you just take them all at once but then again it could have somewhat unpredictable effects at neurotransmitters etc. or maybe you get a diarrhea from the excess plant matter and shit them all out haha.

[Ruth]

What about high repetitive loading doses of curcumin-omega-3-vitamin-D3 capsules

https://www.research..._in_macrophages

Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1?, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100-500nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.

https://pubs.acs.org...rnalCode=acncdm

N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2

Several studies indicate that the n-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) contributes to an attenuated inflammatory status in the development of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. To explain these effects, different mechanisms are being proposed, including those involving endocannabinoids and related signaling molecules. Many of these compounds belong to the fatty acid amides, conjugates of fatty acids with biogenic amines. Conjugates of DHA with ethanolamine or serotonin have previously been shown to possess anti-inflammatory and potentially neuroprotective properties. Here, we synthesized another amine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and tested its immune-modulatory properties in both RAW 264.7 macrophages and BV-2 microglial cells. N-Docosahexaenoyl dopamine significantly suppressed the production of nitric oxide (NO), the cytokine interleukin-6 (IL-6), and the chemokines macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1), whereas its parent compounds, dopamine and DHA, were ineffective. Further exploration of potential effects of DHDA on key inflammatory mediators revealed that cyclooxygenase-2 (COX-2) mRNA level and production of prostaglandin E2 (PGE2) were concentration-dependently inhibited in macrophages. In activated BV-2 cells, PGE2 production was also reduced, without changes in COX-2 mRNA levels. In addition, DHDA did not affect NF-kB activity in a reporter cell line. Finally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in both cell types. Taken together, our data suggest that DHDA, a potentially endogenous endocannabinoid, may be an additional member of the group of immune-modulating n-3 fatty acid-derived lipid mediators.

https://www.scienced...388198117300902
Fatty acid amides (FAAs), conjugates of fatty acids with ethanolamine, mono-amine neurotransmitters or amino acids are a class of molecules that display diverse functional roles in different cells and tissues. Recently we reported that one of the serotonin-fatty acid conjugates, docosahexaenoyl serotonin (DHA-5-HT), previously found in gut tissue of mouse and pig, attenuates the IL-23-IL-17 signaling axis in LPS-stimulated mice macrophages. However, its presence and effects in humans remained to be elucidated. Here, we report for the first time its identification in human intestinal (colon) tissue, along with a series of related N-acyl serotonins. Furthermore, we tested these fatty acid conjugates for their ability to inhibit the release of IL-17 and CCL-20 by stimulated human peripheral blood mononuclear cells (PBMCs). Serotonin conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT) and oleic acid (OA-5-HT) were detected in higher levels than arachidonoyl serotonin (AA-5-HT) and DHA-5-HT, while eicosapentaenoyl serotonin (EPA-5-HT) could not be quantified. Among these, DHA-5-HT was the most potent in inhibiting IL-17 and CCL-20, typical Th17 pro-inflammatory mediators, by Concanavalin A (ConA)-stimulated human PBMCs. These results underline the idea that DHA-5-HT is a gut-specific endogenously produced mediator with the capacity to modulate the IL-17/Th17 signaling response. Our findings may be of relevance in relation to intestinal inflammatory diseases like Crohn's disease and Ulcerative colitis.


https://www.scienced...773224718305379
Aim of the present investigation is to develop a curcumin loaded nanocochleates (CU-NC) from the preformed nanoliposomes (CU-NL) using design of experiments. Plackett–Burman screening design (PBD) was implemented to investigate effects of formulation and process variables on particle size (Y1) and Entrapment Efficiency (Y2). Stirring speed (X5), amount of phospholipid (X4) and cholesterol (X8) were identified as significant (P < 0.05) factors, which were further optimized using Box-Behnken design (BBD). Optimized CU-NC showed particle size, Entrapment efficiency and zeta potential of 204.14 nm, 84.21 ± 1.91 and - 8.20 mV respectively. Curcumin was partially crystalline and amorphous form in Cu-NL and CU-NC respectively, X-ray diffraction and thermal study revealed. CU-NC retarded drug release up to 24 h and followed Higuchi release kinetic model. Noteworthy CU-NC showed 45.77 and 85.81% reduction in breast cancer MCF-7 cells viability than CU-NL and curcumin dispersion respectively. CU-NC treated cells showed nuclear condensation, and nuclear fragmentation of cells and the apoptotic bodies when observed using cell permeable nucleic acid stain. Statistical design of experiments can be used to formulate the CU-NC at the optimized conditions showing the desired constraints for particle size and entrapment efficiency with better anticancer potential.


Garlic (Allium sativum) increases SIRT1 and SIRT2 gene expressions in the kidney and liver tissues of STZ- and STZ+niacinamide-induced diabetic rats
https://doi.org/10.1...jbcpp-2017-0079 Received May 22, 2017; accepted February 1, 2018 Abstract Background: Diabetic nephropathy and liver damage are important complications of diabetes mellitus (DM). Various factors, such as sirtuins (silent information regulators or SIRTs) are associated with these complications. Sirtuins are a family of NAD+-dependent proteins, and seven types of these can be found in mammalians. In this study, we evaluated the effects of aqueous garlic extract (G) on the expressions of SIRT1 and SIRT2 genes in the kidney and liver tissues of rats with types 1 and 2 diabetes. Methods: A total of 36 male Wistar rats (230–280 g) were randomly divided into six groups: C: normal control rats, D1M: type 1 diabetic rats (induced with streptozotocin, STZ), D1M + G: type 1 diabetic rats that treated with garlic extract, D2M: type 2 diabetic rats (induced with STZ and niacinamide), D2M + G: type 2 diabetic rats treated with garlic extract, and G: normal rats that received garlic extract. At the end of the treatment time, kidney and liver tissue samples were collected from all rats. The SIRT1 and SIRT2 gene expressions were determined by qRT-PCR. Results: The SIRT1 and SIRT2 gene expressions in the liver and kidney tissues of diabetic rats decreased significantly compared with those in the control rats (p < 0.05). After treatment with garlic extract, the gene expressions also
increased significantly compared with those in the diabetic rats and are close to normal level (p < 0.05). Conclusions: Garlic extract increased the SIRT1 and SIRT2 gene expressions in the livers and kidneys of diabetic rats. The antioxidant and anti-inflammatory effects of garlic have been proven in many studies. Thus, it is possible that garlic – with its effects on this pathway of gene expression – can have antioxidant and anti-inflammatory effects, thus decreasing diabetic complications.

https://www.scienced...567576918302844

Chronic airway inflammation is a characteristic feature of chronic obstructive pulmonary disease (COPD). Previous studies demonstrated that melatonin had a protective effect against COPD. In addition, silent information regulator 1 (SIRT1) was reported to be beneficial in COPD. However, whether SIRT1 is involved in the protective effect of melatonin against COPD remains unclear. In this study, we investigated the effect of melatonin on a rat model of COPD and explored the potential mechanisms. Twenty eight male Wistar rats were randomly assigned to four groups: control group, COPD group, COPD+Mel group and COPD+Mel+EX527 group. Rats were challenged with cigarette smoke and lipopolysaccharide (LPS) for 28 days with or without melatonin or EX527. The pulmonary function, lung histopathology, inflammatory cells count and the concentration of IL-1β in the BALF as well as the protein expressions of SIRT1, NLRP3, cleaved caspase-1 and ASC in the lung tissues were measured. The results demonstrated that melatonin prevented the development of COPD, which was attributed to the inhibition of airway inflammation by attenuating NLRP3 inflammasome and IL-1β. Furthermore, melatonin increased the expression of SIRT1 in lung tissues of rats with COPD, while inhibition of SIRT1 by EX527 abolished the protective effect of melatonin against COPD. In conclusion, these findings suggested that melatonin attenuated airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1β in rats with COPD.


http://n.neurology.o...plement/S29.008

Objective: To determine if AGIL-AADC administration can increase AADC activity in the putamen and subsequently dopamine to potentially improve neurological function and motor milestone acquisition.


Background: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, genetic disorder of neurotransmitter synthesis in children. AADC is responsible for the final decarboxylation step to produce dopamine and serotonin. Dopamine is a key neurotransmitter in the striatum for motor function. Children with severe AADC deficiency fail to achieve motor milestones. AGIL-AADC is a recombinant, adeno-associated virus containing the human cDNA encoding the AADC enzyme.


Design/Methods: Single-arm, open label clinical studies of AGIL-AADC compared to natural history cohort


Setting: Single-center, National Taiwan University Children Hospital


Subjects: Children with severe AADC deficiency


Interventions: Subjects received a total dose of 1.8×1011 vg of AGIL-AADC as bilateral, intraputaminal stereotactic infusions during a single, operative session.


Results: Eighteen subjects ranged from 21 months to 8.5 years at the time of AGIL-AADC administration. At baseline no child had developed full head control, sitting unassisted or standing capability, consistent with the published, natural history cohort of 82 severe AADC patients who never achieve these motor milestones over their lifetime. Of the 18 subjects given AGIL-AADC, 15 are now two-years, and 7 five-years post-gene therapy. Subjects had evidence of sustained de novo dopamine production by F-DOPA PET imaging. Compared to the natural history cohort, after AGIL-AADC administration 5/15 gain full head control (p<0.0001); 4/15 gain sitting unassisted (p=0.0004) and one subject standing with support at 2 years. After five years 4/7 gain full head control and sit unassisted (p<0.0001) and 2/7 stand with support (p=0.0054). Adverse events, in general, were associated with overall disease state.


Conclusions: Gene therapy with AGIL-AADC is a potential therapeutic for patients with AADC deficiency to achieve and maintain motor milestones inconsistent with the natural disease course.


https://link.springe...2640-018-9880-8
"AMPH inhibited AKT and GSK-3β phosphorylation levels and increased total GSK-3β levels. Furthermore, AMPH caused an increase in the activity of protein phosphatase 2 (PP2A), a signaling protein upstream of AKT, which in turn inhibited phosphorylated AKT levels. Okadaic acid, a PP2A inhibitor, protected PC12 cells against AMPH-induced apoptosis. Together, our results suggest that the PP2A/AKT/GSK3β pathway plays an important role in AMPH-induced neurotoxicity."

Edited by Ruth, 19 July 2018 - 07:33 PM.

[John250]

Well that might be a bit excess. Although herbs do generally combine surprisingly well. Maybe divide the supplementation to something like two phases, where in first phase you take stuff that hit dopamine more directly like nicotine, neuravera and mucuna, and some of the adaptogens like rhodiola and schizandra which actually potentiate mucuna. Then in second phase you switch to things that help a bit more indirectly with the DA synthesis etc. like cordyceps and NALT, and switch to different adaptogens than in the first phase. Vitamins and minerals I'd say take all the time. This is just an idea, it could work if you just take them all at once but then again it could have somewhat unpredictable effects at neurotransmitters etc. or maybe you get a diarrhea from the excess plant matter and shit them all out haha.

I have to split them up because many work best on an empty stomach so I don’t take them all at once at the same time but during the same day yes. I’m not sure how this with drawl is going to go but I have confidence because I did it before about two years ago and didn’t even use half the supplements. But a year later I still felt like my dopamine was still naturally depleted so maybe this time around I can restore the shit out of it and I’ll probably always stay on supplements that increase dopamine and MAO-B as I genetically produce less.


Something I recently ordered was SynaptaLean(KB220)

https://mybiohack.co...220-kb220z-naat

https://www.ncbi.nlm...les/PMC5421552/

https://www.ncbi.nlm...les/PMC5551501/

I like how it’s regarded as a natural way to restore dopamine versus dopamine agonist and antagonist.

Edited by John250, 19 July 2018 - 07:21 PM.

[John250]

What about high repetitive loading doses of curcumin-omega-3-vitamin-D3 capsules

https://www.research..._in_macrophages

Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1?, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100-500nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.

https://pubs.acs.org...rnalCode=acncdm

N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2

Several studies indicate that the n-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) contributes to an attenuated inflammatory status in the development of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. To explain these effects, different mechanisms are being proposed, including those involving endocannabinoids and related signaling molecules. Many of these compounds belong to the fatty acid amides, conjugates of fatty acids with biogenic amines. Conjugates of DHA with ethanolamine or serotonin have previously been shown to possess anti-inflammatory and potentially neuroprotective properties. Here, we synthesized another amine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and tested its immune-modulatory properties in both RAW 264.7 macrophages and BV-2 microglial cells. N-Docosahexaenoyl dopamine significantly suppressed the production of nitric oxide (NO), the cytokine interleukin-6 (IL-6), and the chemokines macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1), whereas its parent compounds, dopamine and DHA, were ineffective. Further exploration of potential effects of DHDA on key inflammatory mediators revealed that cyclooxygenase-2 (COX-2) mRNA level and production of prostaglandin E2 (PGE2) were concentration-dependently inhibited in macrophages. In activated BV-2 cells, PGE2 production was also reduced, without changes in COX-2 mRNA levels. In addition, DHDA did not affect NF-kB activity in a reporter cell line. Finally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in both cell types. Taken together, our data suggest that DHDA, a potentially endogenous endocannabinoid, may be an additional member of the group of immune-modulating n-3 fatty acid-derived lipid mediators.

https://www.scienced...388198117300902
Fatty acid amides (FAAs), conjugates of fatty acids with ethanolamine, mono-amine neurotransmitters or amino acids are a class of molecules that display diverse functional roles in different cells and tissues. Recently we reported that one of the serotonin-fatty acid conjugates, docosahexaenoyl serotonin (DHA-5-HT), previously found in gut tissue of mouse and pig, attenuates the IL-23-IL-17 signaling axis in LPS-stimulated mice macrophages. However, its presence and effects in humans remained to be elucidated. Here, we report for the first time its identification in human intestinal (colon) tissue, along with a series of related N-acyl serotonins. Furthermore, we tested these fatty acid conjugates for their ability to inhibit the release of IL-17 and CCL-20 by stimulated human peripheral blood mononuclear cells (PBMCs). Serotonin conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT) and oleic acid (OA-5-HT) were detected in higher levels than arachidonoyl serotonin (AA-5-HT) and DHA-5-HT, while eicosapentaenoyl serotonin (EPA-5-HT) could not be quantified. Among these, DHA-5-HT was the most potent in inhibiting IL-17 and CCL-20, typical Th17 pro-inflammatory mediators, by Concanavalin A (ConA)-stimulated human PBMCs. These results underline the idea that DHA-5-HT is a gut-specific endogenously produced mediator with the capacity to modulate the IL-17/Th17 signaling response. Our findings may be of relevance in relation to intestinal inflammatory diseases like Crohn's disease and Ulcerative colitis.


https://www.scienced...773224718305379
Aim of the present investigation is to develop a curcumin loaded nanocochleates (CU-NC) from the preformed nanoliposomes (CU-NL) using design of experiments. Plackett–Burman screening design (PBD) was implemented to investigate effects of formulation and process variables on particle size (Y1) and Entrapment Efficiency (Y2). Stirring speed (X5), amount of phospholipid (X4) and cholesterol (X8) were identified as significant (P < 0.05) factors, which were further optimized using Box-Behnken design (BBD). Optimized CU-NC showed particle size, Entrapment efficiency and zeta potential of 204.14 nm, 84.21 ± 1.91 and - 8.20 mV respectively. Curcumin was partially crystalline and amorphous form in Cu-NL and CU-NC respectively, X-ray diffraction and thermal study revealed. CU-NC retarded drug release up to 24 h and followed Higuchi release kinetic model. Noteworthy CU-NC showed 45.77 and 85.81% reduction in breast cancer MCF-7 cells viability than CU-NL and curcumin dispersion respectively. CU-NC treated cells showed nuclear condensation, and nuclear fragmentation of cells and the apoptotic bodies when observed using cell permeable nucleic acid stain. Statistical design of experiments can be used to formulate the CU-NC at the optimized conditions showing the desired constraints for particle size and entrapment efficiency with better anticancer potential.

I can’t use too much Curcumin since it is an iron chelator and I need to restore my ferritin from too many phlebotomies. I’ll probably use 1000mg at night though and take my iron in the morning. I take 10,000-15,000 VitD daily as well as 6g Omegas, 4g krill oil, 5-10g black cumin seed oil and 300mg Sytrinol as well.

Edited by John250, 19 July 2018 - 07:26 PM.

[Ruth]

I can’t use too much Curcumin since it is an iron chelator and I need to restore my ferritin from too many phlebotomies. I’ll probably use 1000mg at night though and take my iron in the morning. I take 10,000-15,000 VitD daily as well as 6g Omegas, 4g krill oil, 5-10g black cumin seed oil and 300mg Sytrinol as well.

I think I need the iron chelation, but I can go up to 15g for DHA-oil...but mostly around 3g for anything else(krill or fish/algae)

[Ruth]

Botanicals as epigenetic modulators for mechanisms contributing to development of metabolic syndrome
Epigenetics refers to heritable changes in gene expression that are not attributable to changes in DNA sequence and impacts many areas of applied and basic biology including developmental biology, gene therapy, somatic cell nuclear transfer, somatic cell reprogramming, and stem cell biology. Epigenetic changes are known to contribute to aging in addition to multiple disease states. Epigenetic changes can be influenced by environmental factors that in turn can be inherited by daughter cells during cell division and can also be inherited through the germ line. Thus, it is intriguing to consider that epigenetics, in general, may play a role in human conditions that are strongly influenced by changes in the environment and lifestyle. In particular, metabolic syndrome, a condition increasing in prevalence around the world, is one such condition for which epigenetics is postulated to contribute. Epigenetic defects (epimutations) are thought to be more easily reversible (when compared with genetic defects) and, as such, have inspired efforts to identify novel compounds that correct epimutations or prevent progression to the disease state. These efforts have resulted in the development of a rapidly growing new field being referred to as epigenetic therapy. To date, 2 classes of drugs have received the most attention, that is, DNA methyltransferase inhibitors and histone deacetylase inhibitors; but recent data suggest that botanical sources may be a rich source of agents that can potentially modulate the epigenome and related pathways and potentially be useful in attenuating the progression of many factors related to development of metabolic syndrome. This review will provide an overview of the field of epigenetics, epigenetic therapy, and the molecules currently receiving the most interest with respect to treatment, and review data on botanical compounds that show promise in this regard.

https://scinapse.io/papers/1970508603
Methamphetamine (METH) is a major drug of abuse which causes neurotoxicity by depleting dopamine, its metabolites, high-affinity dopamine uptake sites and tyrosine hydroxylase activity in the striatum. Dopamine depletion and reduced dopamine transit are associated with depression. S-Adenosylmethionine (SAM) is the chief methyl donor used in dopamine and other neurotransmitter metabolism in mammals. Low SAM is associated with depression and other psychological and neurological disorders in humans. SAM is used to treat depression and some other neurological and psychiatric disorders. The present study was designed to determine if single or multiple doses of METH induce alterations in blood or liver SAM in mice and if these correlate with dopamine levels in the striatum. Adult male C57 mice were injected intraperitoneally with either single (1 × 40 mg/kg) or multiple (4 × 10 mg/kg) doses of METH. Animals were sacrificed at various intervals. A single injection of METH resulted in slightly higher blood SAM levels at 4 hr. Multiple doses of METH resulted in decreased hepatic and blood SAM levels at 72 hr. Blood SAM returned to control levels by 1 wk. Published work shows that dopamine levels increase hours after a single injection of METH, whereas dopamine decreases days after multiple injections of METH. These present data clearly demonstrate that METH dosing leads to significant alterations in liver and blood SAM and that these changes in SAM levels correlate with changes in striatal dopamine levels.


https://pubs.acs.org....1021/jf000050n
the cacao liquor polyphenols showed potent antimutagenic activity in bacteria treated with activated forms of HCA, compared with quercetin. We also evaluated the effect of these compounds on enzymatic activation of HCA. They weakly suppressed the production of activated HCA. In the host-mediated assay in mice, a method used to estimate the potential carcinogenicity of chemicals ex vivo, oral administration of the cacao liquor polyphenols, reduced the number of colonies of revertant bacteria recovered from the liver. These data suggest that the cacao liquor polyphenols have an antimutagenic effect not only in vitro, but also ex vivo.

Edited by Ruth, 19 July 2018 - 07:44 PM.

[John250]

Wow I didn’t realize berberine had so many positives

https://examine.com/...ents/berberine/

https://www.ncbi.nlm...ubmed/26616870/

https://www.ncbi.nlm...ubmed/24535622/

[kurdishfella]

L dopa is probably the closest to natural and best way. If dopamine fast is real. That your body creates less dopamine cause your too stimulated, then where does precursors amino acids to dopamine get sent to and used by? surely your body still uses them up and not just absorb less or pee (not poop?) it out? I think another part of your body/brain increases someway when that decreases.

Edited by kurdishfella, 02 April 2021 - 04:00 PM.

[treonsverdery]

barely related LEF has a combination of phellodrendron (not philodendron) and adenosylcobalamin called dopamine advantage.

[treonsverdery]

I think I read that delta Fosb which causes drug habituation has a half life of about 40 days, so, just perhaps, you get half your dopamine responsiveness back after 40 days and 3/4 of it back after 80 days

[kurdishfella]

In a normal human being it restores by itself you don't need to do anything but eat.
In my case I produce zero endorphins because i dont absorb the nutrients and it isnt a priority for the body. so i feel pain as much as is possible which really makes you strong after a while and you get somewhat used to it and you learn in a more cautious way.

Edited by kurdishfella, 04 January 2024 - 11:47 AM.