40 replies to this topic

[Metagene]

Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene.

http://www.ncbi.nlm....?i=18&from=Tet1

[Flex]

Thank You Mate

[gavino]

Chronic N-acetylcysteine after cocaine self-administration produces enduring reductions in drug-seeking

Although it is difficult to extrapolate preclinical findings to cocaine-dependent patients, the use of NAC has recently crossed the translational bridge from preclinical animal models of addiction to clinical trials. To date, NAC has shown promising results in subjects with cocaine, heroin, and tobacco addiction. An initial pilot open-label study demonstrated that NAC was well tolerated at doses of 1200, 2400, and 3600 mg/day. Of the subjects that finished the study, most terminated or reduced cocaine use during the treatment (Mardikian et al, 2007). NAC also decreased desire for cocaine in a cue-reactivity procedure as measured by psychophysical and subjective data in response to slides depicting cocaine and cocaine use (LaRowe et al, 2007). Additionally, recent data indicate that repeated administration (4 days) of NAC (1200–2400 mg/day) to cocaine-dependent participants reduced craving following an experimenter-delivered IV injection of cocaine (Amen et al, 2011).

http://www.nature.co...pp2011164a.html

Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement


Both pre-clinical and clinical studies indicate that N-acetylcysteine (NAC) may be useful in treating relapse to addictive drug use. Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT-1 in the nucleus accumbens, and NAC treatment normalizes these two glial processes critical for maintaining glutamate homeostasis. However, it is not known if one or both of these actions by NAC is needed to inhibit relapse to cocaine seeking. To determine whether the restoration of GLT-1 and/or cystine-glutamate exchange is required for NAC to inhibit cue-induced reinstatement of cocaine seeking, we utilized the rat self-administration/extinction/reinstatement model of cocaine relapse. Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT-1 or xCT (catalytic subunit of the cystine-glutamate exchanger) overlapping with daily NAC administration during extinction (100 mg/kg, i.p. for the last 5 days). Rats then underwent cue-induced reinstatement of active lever pressing in the absence of NAC, to determine if preventing NAC-induced restoration of one or the other protein was sufficient to block the capacity of chronic NAC to inhibit reinstatement. The vivo-morpholino suppression of xCT reduced cystine-glutamate exchange but did not affect NAC-induced reduction of reinstated cocaine seeking. In contrast, suppressing NAC-induced restoration of GLT-1 not only prevented NAC from inhibiting reinstatement, but augmented the capacity of cues to reinstate cocaine seeking. We hypothesized that the increased reinstatement after inhibiting NAC induction of GLT-1 resulted from increased extracellular glutamate, and show that augmented reinstatement is prevented by blocking mGluR5. Restoring GLT-1, not cystine-glutamate exchange, is a key mechanism whereby daily NAC reduces cue-induced cocaine reinstatement.

http://onlinelibrary....12127/abstract

HDAC/Epigenetic Changes

There are several HDAC targets, who interfere with the changes who are induced by Cocaine:

HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner
http://www.ncbi.nlm....pubmed/23297220

Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation.
http://www.ncbi.nlm....pubmed/23475113
Histone deacetylase 5 limits cocaine reward through cAMP-induced nuclear import.
http://www.ncbi.nlm....pubmed/22243750


The HDAC 3 Inhibitors who I could find so far is Amitriptyline (in a Concetration about 15-30 muM)
and Curcumin ( I dont know about its potency)

Curcumin, a potent anti-tumor reagent, is a novel histone deacetylase inhibitor regulating B-NHL cell line Raji proliferation
...can inhibit the expression of class I HDACs (HDAC1, HDAC3, and HDAC8)...
http://www.ncbi.nlm....pubmed/15842781

The tricyclic antidepressant amitriptyline inhibits D-cyclin transactivation and induces myeloma cell apoptosis by inhibiting histone deacetylases
Full Text @:
http://www.google.de....57967247,d.Yms

This is important regarding Amtriplyines safety, because it can be Neurotoxic like some other Tricyclic Antidepressants( e.g. Clomipramine):
http://www.ncbi.nlm....pubmed/21120605
Coenzyme Q10 and alpha-tocopherol protect against amitriptyline toxicity.
http://www.ncbi.nlm....pubmed/19263520

Further Antidepressants and Mood stabilisers who affect mitochondrial function:
http://www.ncbi.nlm....pubmed/20588251
http://www.ncbi.nlm....pubmed/11230808
http://www.ncbi.nlm..../pubmed/2931948

And further Informations about what Up/Down regulates which HDAC:
Neuroprotective Effects of Psychotropic Drugs in Huntington’s Disease
PDF downloadable @:
http://www.google.de....57967247,d.Yms

 

[gavino]

[Sorry about quoting that whole post...I'm pretty new to 'posting']   Anyways, I just figured I'd put this out there and just casually ask you (Flex) your opinion on long-term TCA administration w/r/t 'neurotoxicity'.  Long story short, I've been through the STAR*D more times than I'd like to admit and the past 2 years of Clomipramine at 150mg/day seems to be the only thing that's offered me any kind of longterm 'stability'.  Side-note: I also take 45mg mirtazapine/day.  So, stopping the clomipramine really ain't in the cards and I figured I'd ask permission to pick your brain w/r/t what the hell I should do to make sure the clomipramine doesn't totally screw over my mitochondria (and, now that I'm reading the linked studies, it seems like it does some pretty nasty stuff...).

 

By the way, despite the fact that I've never had anything to do with cocaine, I find the studies you've posted to be right up my alley.  I've been tinkering with the idea of ppar-gamma agonism for a number of reasons.  Unfortunately, one of the more likely side-effects is 'gradual' weight gain, and I've put on over 50 lbs in the past 2 years. Blah.  While some of the weight gain has likely been from the clomipramine + mirtazapine (which was started a year after clomipramine), most of the weight gain has been to very high stress levels. Working 20-30 hours/week at a grocery store and returning to (community) college got the ball rolling; but having to move back home last fall to take care of my very sick Mother really just caused incredibly rapid weight gain.  She died over the winter.  On top of all the emotional grieving, she was single and I'm the only kid, so I've been wading through a bucket of proverbial shi* ever since.  I'm finally starting to at least attempt to give a damn about eating and exercise, but it's definitely gonna be a long road back to anything that vaguely approximates health.  Exercise seems to trump everything else out there...

 

FWIW, I've wasted my fair share of money on supplements over the past decade.  I've settled on keeping the Boring Stuff above all else: magnesium, iodine(low dose, none of this Lugol's insanity), K2, decent probiotics (AOR 3 something or other), winter+fall D3, occasional low-dose lithium and NAC (long-term 3600mg/day seems to help the OCD).  The only Other Stuff I've been fooling around with has been MitoQ, 'good' Curcumin (despite hating proprietary formulations, terrynaturally's "CurcuMed" seems to work the best for me) - bcm-95 + turmeric essential oils in a phospholipid base @ 750mg b.i.d.  Oh, I take a swig of some buckminsterfullerene gobbledygook once a month.  Presumably, the MitoQ would supercede the CoQ10 referenced in the study.  Unfortunately, I can't access the full-text, and I really don't know how well zebrafish embryos translate to humans.

 

Thank you

[Flex]

Sorry to hear that...

 

In regards of mitochondria concerns, You could try pyrroloquinoline quinone or just PQQ

 

Pyrroloquinoline Quinone Stimulates Mitochondrial Biogenesis through cAMP Response Element-binding Protein Phosphorylation and Increased PGC-1α Expression*

http://www.ncbi.nlm....les/PMC2804159/

 

Here on longecity are also several threads about it.

 

In regards of TCA, sigh.. some SNRI and almost all SSRI could cause impotence and asexuallity.. for a few months to 10 Years or longer.

Look for PSSD (post ssri sexual disorder)

 

I would ask the guys on Reddit whether a certain dosage of xx would prevent the toxic effects of Clomipramine and Mirtazapine.

Activities of respiratory chain complexes and citrate synthase influenced by pharmacologically different antidepressants and mood stabilizers.

http://www.ncbi.nlm....pubmed/20588251

 

 

http://www.reddit.com/r/AskDocs/

http://www.reddit.com/r/Psychiatry/

and maybe

http://www.reddit.co...hopharmacology/

 

Just out of curiousity, have You tried other TCA´s than that ?

 

For the Access:

I´ve heard that theres a way to get to some papers via google drive but I´m not sure.

But You could ask Metagene

http://www.longecity...27977-metagene/

 

For PPAR gamma, You could look into herbs:

http://www.google.de...herb&gsc.page=1

 

They might not act solely on this and not so potent but maybe theres something interresting.

 

Best wishes

[Flex]

I´ve seemingly didnt mention that which makes me wonder, anyway:

Delta fosB is highly implicated into addiction forming memories. Its actually one of the things that lasts for years because its degradation is really slow, in addition to that, it exerts on it self effects on gene exprression and repression but it "can" also prevent further addictive states. It might be antidepressive

 

DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses.

http://www.ncbi.nlm....pubmed/20473292

 

but this paper states, at least to me, something different:

 

Overexpression of DeltaFosB in nucleus accumbens mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment

http://www.ncbi.nlm....les/PMC4148937/

 

Delta fos B activates fruthermore CDK-5 which has an (inhibitory?) impact on DARPP-32 function (which increases then dopamine signalling??) as well as an decreased expression of the dopamine D2 and attenuation of the pathway   and Canabinoid receptor desentitation in some parts of the Brain:

 

Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5

http://www.nature.co...s/410376a0.html

 

Cdk5 Phosphorylates Dopamine D2 Receptor and Attenuates Downstream Signaling

http://journals.plos...al.pone.0084482

 

Delta FosB and AP-1-mediated transcription modulate cannabinoid CB₁ receptor signaling and desensitization in striatal and limbic brain regions.

http://www.ncbi.nlm....pubmed/25093286

 

DARPP-32 Is a Robust Integrator of Dopamine and Glutamate Signals

http://journals.plos...al.pcbi.0020176

 

Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons.

http://www.ncbi.nlm....pubmed/10604473

 

CDK-5 can also be neurotoxic, afaik depending on the induced splice variant

 

A survey of Cdk5 activator p35 and p25 levels in Alzheimer's disease brains.

http://www.ncbi.nlm....pubmed/12123804

 

------------------------------------------------------------

Rhodiola rosea, Rhus parviflora and kaempferol and quercetin can inhibit CDK-5 but seemingly just transiently, so a reduction of delta fos b  would/could be more enduringly.

 

Effects of natural flavones and flavonols on the kinase activity of Cdk5.

http://repositorio.u....pdf?sequence=1

 

CDK5 Inhibitors and Therapeutic Uses Thereof

http://www.google.co...s/US20120270821

 

Potential neuroprotective flavonoid-based inhibitors of CDK5/p25 from Rhus parviflora

http://www.researchg...Rhus_parviflora

-------------------------------------------------------------

 

The Reason why Delta Fos B is so durable:

 

Serum response factor and cAMP response element binding protein are both required for cocaine induction of ΔFosB.

http://www.ncbi.nlm....pubmed/22649236

 

I found at first only this but it seems that this is just an in vitro (means: petri dish) study, anyway:

 

Regulation of ΔFosB Stability by Phosphorylation

Furthermore, we show that ΔFosB is a phosphoprotein in brain and that phosphorylation of a highly conserved serine residue (Ser27) in ΔFosB protects it from proteasomal degradation. We provide several lines of evidence suggesting that this phosphorylation is mediated by casein kinase 2

http://www.jneurosci...26/19/5131.full

 

--> Now the mechanism and in vivo ( living organism with several factors which make it stable over several years)

 

Results from Rat Study May Lead to Prevention of Cocaine Addiction in Humans

 

Investigators at Michigan State University (East Lansing, USA) reported in the March 6, 2013, issue of the Journal of Neuroscience that delta-FosB was phosphorylated by CaMKII-alpha at the protein-stabilizing serine-27 residue,

and that CaMKII-alpha was required for the cocaine-mediated accumulation of delta-FosB in rat NAc. Conversely, they showed that delta-FosB was both necessary and sufficient for cocaine induction of CaMKII-alpha gene expression in vivo.

http://www.biotechda..._in_humans.html

 

Behavioral and structural responses to chronic cocaine require a feedforward loop involving ΔFosB and calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell.

http://www.ncbi.nlm....les/PMC3658178/

 

---------------------------------------

 

An attempt to tackle it:

 

According to the last study above, CaMKIIα and ΔFosB reinforce each other in a positive loop. So, if I understand it right, inhibiting CaMKIIα could break the cycle.

I found Scutellarin from Scutellaria Baicalensis (pinyin name is Huang Qin) as an inhibitor,

although I dont know whether there are other compounds in this herb that actually counter this effect.

 

Scutellarin exerts its anti-hypertrophic effects via suppressing the Ca2+-mediated calcineurin and CaMKII signaling pathways.

http://www.ncbi.nlm....pubmed/20052460

 

as well as Catalpol (from Rehmannia glutinosa/chinese foxglove, pinyin: sheng di huang) and Gastrodia Ellata ( Tian Ma)

 

Neuroprotective activities of catalpol against CaMKII-dependent apoptosis induced by LPS in PC12 cells.

http://www.ncbi.nlm....pubmed/23550774

 

Gastrodin inhibits glutamate-induced apoptosis of PC12 cells via inhibition of CaMKII/ASK-1/p38 MAPK/p53 signaling cascade.

http://www.ncbi.nlm....pubmed/24619207

----------------------------------

 

I´ve tried all 3 herbs in medium doses but still feel the Coke-memory flaming up for a few days when using a dopamine noradrenaline reputake inhibitor like psoralea corylifolia, though I dont know whether its related to DeltafosB & etc.

 

Inhibitive effects of Fructus Psoraleae extract on dopamine transporter and noradrenaline transporter.

http://www.ncbi.nlm....pubmed/17555897

 

Edited by Flex, 18 June 2015 - 11:06 PM.

[Flex]

Habe to note that CaMKII inhibition can be problematic, the Author didnt said why:

 

Because CaMKII is ubiquitous and required for many basal neuronal and behavioral functions, direct use of CaMKII inhibitors has been avoided as an addiction treatment.

 

 

Behavioral and Structural Responses to Chronic Cocaine Require a Feed-Forward Loop Involving ΔFosB and CaMKII in the Nucleus Accumbens Shell

http://www.ncbi.nlm....les/PMC3658178/

[Multivitz]

L-Tyrosine and adiquate exercise, will power, and a very good supportive diet.
Drugs will only feed micro parrasites and send the biome into dissaray! There's no short cut, drugs act as a plaster IMO.
The recipient should be aware or the minds cycles of addiction behaviour and how strong old patterns appear when a good diet is embarked apon. Enough said.

[Flex]

a supportive diet contains polyphenoles, flavonoids & etc (e.g. curcuma, green-tea- afaik herbs and spices in general) which exert also phyisiological effects like some medicaments do. be it blood thinning, anti-cancer, anti-depressant, signal-pathway related or afaik epigenetic. All which might aid to a recovery and are anyway present in food.

 

Not saying that will power & etc isn´t neccessary but from what I´ve read, not sufficent in the case of e.g. the horrible and years lasting: dopamine agonist withdrawal symptoms (DAWS)

 

imo neither a generalisation nor a compulsive pushing approach is appropriate to tackle some problems. Time will tell at least

Edited by Flex, 01 July 2016 - 06:42 PM.

[Flex]

Seems that there are some OTC CaMKII inhiibitors:

 

Curcumin is an inhibitor of calcium/calmodulin dependent protein kinase II.

http://www.ncbi.nlm....pubmed/22989913

Found in:

http://www.life-enha...d-complications

 

Gastrodin from Gastrodia elata aka Tian Ma:

Gastrodin inhibits glutamate-induced apoptosis of PC12 cells via inhibition of CaMKII/ASK-1/p38 MAPK/p53 signaling cascade.

http://www.ncbi.nlm....pubmed/24619207

 

and aparently a compound from scutellaria baicalensis IIRC but I cant find it

 

as usual, I´m just scrambling any informations. They might not work & etc.

[Flex]

Possible Inhibitor from Traditional Chinese Medicine for the β Form of Calcium-Dependent Protein Kinase Type II in the Treatment of Major Depressive Disorder

http://www.hindawi.c...ri/2014/761849/

 

Found in Cyathula capitata Moq (aka chuan niu xi) according to the study

or in Polygala Senega according to:

http://www.megabione...cmid/herb/6994/

http://tcm.cmu.edu.t...php?herbid=4921

 

I´m unsure about the 2nd one because the reffered site shows no results. Also I couldnt find the content in each plant, which might be very low.

 

 

Edited by Flex, 17 August 2016 - 03:56 AM.