40 replies to this topic

[Flex]

Promising new drug targets for cocaine addiction


January 20, 2014


Mount Sinai Medical Center


Finding suitable drug targets for treating cocaine addiction has proved daunting, but for the first time, researchers have shown that abundant enzyme PARP-1 and the sidekick-1 gene are found to enhance the brain's reward system.

Researchers from the Icahn School of Medicine at Mount Sinai have identified a new molecular mechanism by which cocaine alters the brain's reward circuits and causes addiction. Published online in the journal Proceedings of the National Academy of Sciences by Dr. Eric J. Nestler, MD, PhD, and colleagues, the preclinical research reveals how an abundant enzyme and synaptic gene affect a key reward circuit in the brain, changing the ways genes are expressed in the nucleus accumbens. The DNA itself does not change, but its "mark" activates or represses certain genes encoding synaptic proteins within the DNA. The marks indicate epigenetic changes -- changes made by enzymes -- that alter the activity of the nucleus accumbens.

In a mouse model, the research team found that chronic cocaine administration increased levels of an enzyme called PARP-1 or poly(ADP-ribosyl)ation polymerase-1. This increase in PARP-1 leads to an increase in its PAR marks at genes in the nucleus accumbens, contributing to long-term cocaine addiction. Although this is the first time PARP-1 has been linked to cocaine addiction, PARP-1 has been under investigation for cancer treatment.
"This discovery provides new leads for the development of anti-addiction medications," said the study's senior author, Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience and Director of the Friedman Brain Institute, at the Icahn School of Medicine at Mount Sinai. Dr. Nestler said that the research team is using PARP to identify other proteins regulated by cocaine. PARP inhibitors may also prove valuable in changing cocaine's addictive power.
Kimberly Scobie, PhD, the lead investigator and postdoctoral fellow in Dr. Nestler's laboratory, underscored the value of implicating PARP-1 in mediating the brain's reward center. "It is striking that changing the level of PARP-1 alone is sufficient to influence the rewarding effects of cocaine," she said.
Next, the investigators used chromatin immunoprecipitation sequencing to identify which genes are altered through the epigenetic changes induced by PARP-1. One target gene whose expression changed after chronic cocaine use was sidekick-1, a cell adhesion molecule concentrated at synapses that directs synaptic connections. Sidekick-1 has not been studied to date in the brain, nor has it been studied in relation to cocaine exposure. Using viral mediated gene transfer to overexpress sidekick-1 in the nucleus accumbens, investigators saw that this overexpression alone not only increased the rewarding effects of cocaine, but it also induced changes in the morphology and synaptic connections of neurons in this brain reward region.
The research opens the door to a brand new direction for therapeutics to treat cocaine addiction. Effective drug therapies are urgently needed. National data from the US National Institute of Drug Abuse reveal that nearly 1.4 million Americans meet criteria for dependence or abuse of cocaine.


Journal Reference:

• K. N. Scobie, D. Damez-Werno, H. Sun, N. Shao, A. Gancarz, C. H. Panganiban, C. Dias, J. Koo, P. Caiafa, L. Kaufman, R. L. Neve, D. M. Dietz, L. Shen, E. J. Nestler. Essential role of poly(ADP-ribosyl)ation in cocaine action. Proceedings of the National Academy of Sciences, 2014; DOI: 10.1073/pnas.1319703111

http://www.scienceda...40120173256.htm

Edited by Flex, 03 April 2014 - 03:36 AM.

[Flex]

Repeated acetyl-l-carnitine administration increases phospho-Thr34 DARPP-32 levels and antagonizes cocaine-induced increase in Cdk5 and phospho-Thr75 DARPP-32 levels in rat striatum.

http://www.ncbi.nlm....pubmed/15066157

Drug experience epigenetically primes Fosb gene inducibility in rat nucleus accumbens.

http://www.ncbi.nlm....pubmed/22836260

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

http://www.ncbi.nlm....pubmed/11268215


CRACKing the histone code: Cocaine's effects on chromatin structure and function
http://www.med.wayne...review_2011.pdf

Epigenetics of cocaine addiction

http://en.wikipedia....caine_addiction

Topiramate for the Treatment of Cocaine AddictionA Randomized Clinical Trial

http://archpsyc.jama...ticleID=1756816

Edited by Flex, 03 April 2014 - 03:56 AM.

[Flex]

Clinical & Translational Research Forum
February 12, 2014
PPARγ as a Therapeutic Target in Cocaine Relapse
Miller WR, Neuroscience. Fox R, Center for Addiction Research. Stutz S, Center for
Addiction Research. Cunningham K, Center for Addiction Research. Dineley KT,
Neurology.

Here we explore a novel therapeutic target peroxisome proliferator-activated receptor (PPAR),
using a preclinical model of addiction in vivo.
This ligand activated transcription factor belongs to the nuclear receptor family
and its gamma isoform (PPARγ) plays a vital role as a primary lipid sensor and regulator of lipid metabolism.
Thus, there are several FDA approved ligands that are clinically used for the treatment of diseases
such as type 2 diabetes. However PPARγ is also widely distributed in the CNS and is highly expressed in neurons.

Our lab has already demonstrated that PPARγ rescues hippocampal cognitive impairment in an animal model of Alzheimer's. This rescue partly involves the recruitment of hippocampal ERK MAPK activity to the nucleus
(Rodriguez et al., 2011) (Denner et al., 2012).
Given the important role for learning and memory in the process for which drug abuse transitions into addiction,
and our recent evidence that neuronal PPARγis involved in restoring cognitive deficits through ERK MAPK, we hypothesize that CNS PPARγrepresents a potential therapeutic target for maintaining drug abstinence during stimulant withdrawal.
Here we demonstrate that PPARγ agonism significantly attenuates cocaine seeking in a rodent model of cocaineself-administration, a preclinical model of cocaine addiction and relapse.

http://www.its.utmb....bstract2014.pdf

PPARγ Agonism Via Pioglitazone, see:
Evaluating Neuro-protective Targets to Revert Cocaine Toxicity

http://medicine.yale...ects/tannu.aspx

Edited by Flex, 03 April 2014 - 04:00 AM.

[Flex]

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

Edited by Flex, 03 April 2014 - 04:13 AM.

[Flex]

Here are some Herbal Parp1 antagonists

 

Dietary Flavones and Flavonoles Are Inhibitors of Poly(ADP-ribose)polymerase-1 in Pulmonary Epithelial Cells

http://jn.nutrition....37/10/2190.full

http://jn.nutrition.....expansion.html

 

Altough I dont know which one crosses the Blood brain barrier and about their Half lifes, I found at least Quercetin promizing.

The Flavonols Quercetin, Kaempferol, and Myricetin Inhibit Hepatocyte Growth Factor-Induced Medulloblastoma Cell Migration

http://jn.nutrition..../139/4/646.full

 

[Flex]

Blood thinning properties should be of course always be considered:

 

Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in humans

http://www.ncbi.nlm....pubmed/15613018

 

Side Effects of Bioflavonoid Quercetin & Bromelain

http://www.livestron...etin-bromelain/

 

Parp inhibition by Nicotinaminde

Box 1 | PARP inhibitors and their potential as therapeutic agents

http://www.nature.co...rm3376_BX1.html

 

B Vitamin May Be of Value in Ovarian Cancer and Breast Cancer

http://doctornalini....-breast-cancer/

[formergenius]

Flex, you seem to have been looking in to cocaine quite a bit. What I'm interested in, but can't find, are studies on single-dose or short-term exposure, which then record physiological changes responsible for thereof resulting behavioural changes and methods of reversing them. As you can imagine, that's a bit too specific for a search term, haha. Most studies seem to focus on addiction, whereas my interest lies more in reversing detriments from (short-term) exposure to cocaine. As you may remember, I took cocaine 3 days in a row about 6 months ago, and my perceptual and cognitive disturbances have become - and remained - much worse. I've yet to see any clear relation of this worsening to the physiological changes cocaine induces. The only thing I can come up with is some (frontal?) (hypo)dopaminergic dysfunction, and dynorphic upregulation, the latter currently not being exactly easy to target. Any input you may have would be well appreciated.

[Flex]

Its more an attempt of an amateur to compesate the rusty interaction of current Science to Clinical practice...

I´m a bit busy in the recent time, so this is what I´ve found in short

 

Cognitive Impairment in Cocaine Users is Drug-Induced but Partially Reversible: Evidence from a Longitudinal Study.

http://www.ncbi.nlm....pubmed/24651468

 

So, it seems, per se, mostly reversible in healthy People.

But there is some further data that mention Hypofrontality among other:

 

http://medicine.yale...ontalCortex.pdf

 

http://www.ncbi.nlm....pubmed/21692802

 

http://www.ncbi.nlm....les/PMC2939941/

 

http://adsabs.harvar...Natur.496..359C

 

http://pubmedcentral...les/PMC3405490/

 

http://www.ncbi.nlm....pubmed/19038779

 

Btw: Ashwagandha blocks revesible SP-1

http://www.pharmainf...haferin_a_0.pdf

 

But I´m still curious whethever this ammount is sufficient to cause a Hypofrontality, maybe there are some other causes like synaptic plasticity

 

 

 

 

Edited by Flex, 16 April 2014 - 08:29 AM.

[formergenius]

Thanks Flex. Yes, I'd thought it to be reversible with time as well; this has been my experience in the past (prior to having said conditions). However, considering the pre-existence of these conditions this time, perhaps my brain is more fragile, thus more susceptible. Such seems to be the case at least. Hmm.. hypofrontality. I'll do a 2 week prefrontal tDCS run soon, and report back To what extent have you found cocaine can affect synaptic plasticity? I am participating in the DIhexa group buy, but as far as I know, it only causes synaptogenesis.. not sure of its effects - if any - on synaptic plasticity.

[Flex]

Well Cocaine is afaik the "King" of Synaptic plasticity altering substances,

It rebuild or reconnects Your brain towards addiction.

 

A little anectode; My Dealer put once accidentically the stuff beside his girlfriends smelly lotion.

So, if I smell this relative common lotion in the Bus or Train, I get a litte euphoric. Even after 2 Years of abstinence !

 

So, some effects last 1 week, some parts of synaptic plasticity arround 10 weeks, and so on.

But some remains, see:

 

Cocaine-Evoked Synaptic Plasticity of Excitatory Transmission in the Ventral Tegmental Area

 

Cocaine leads to a strong euphoria, which is at the origin of its recreational use.

Past the acute effects, the drug leaves traces in the brain that persist long after it has been cleared from the body.

These traces eventually shape behavior such that drug use may become compulsive and addiction develops.

Here we discuss cocaine-evoked synaptic plasticity of glutamatergic transmission onto dopamine (DA) neurons

of the ventral tegmental area (VTA) as one of the earliest traces after a first injection of cocaine.

http://perspectivesi...ent/3/5/a012013

 

I cant tell You what for consequenses that means for the Cognition.

I for my self was a bit worried when I took the first time Cerebrolysin, because I was afraid that it would strenghten the alterations caused by cocaine.

But I refuse this Idea. Ultimately it was more important for me to get fixed.

Now I´m doing to some extend better. Therefore I´m beginning to try to erase the traces, a bit compulsive though.

 

If Dihexa affects Bdnf, then it should supposedly also affect synaptic plasticity.

Please keep me informed with the tDCS as well.

I´m allready thinking about to try it.

 

[Flex]

Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors.

 

Drug-evoked synaptic plasticity in the mesolimbic dopamine (DA) system reorganizes neural circuits that may lead to addictive behavior. The first cocaine exposure potentiates AMPAR excitatory postsynaptic currents (EPSCs) onto DA neurons of the VTA but reduces the amplitude of NMDAR-EPSCs. While plasticity of AMPAR transmission is expressed by insertion of calcium (Ca(2+))-permeable GluA2-lacking receptors, little is known about the expression mechanism for altered NMDAR transmission. Combining ex vivo patch-clamp recordings, mouse genetics, and subcellular Ca(2+) imaging, we observe that cocaine drives the insertion of NMDARs that are quasi-Ca(2+)-impermeable and contain GluN3A and GluN2B subunits. These GluN3A-containing NMDARs appear necessary for the expression of cocaine-evoked plasticity of AMPARs. We identify an mGluR1-dependent mechanism to remove these noncanonical NMDARs that requires Homer/Shank interaction and protein synthesis. Our data provide insight into the early cocaine-driven reorganization of glutamatergic transmission onto DA neurons and offer GluN3A-containing NMDARs as new targets in drug addiction.

http://www.ncbi.nlm....pubmed/24183704

 

Has annybody full acess to this ?

Or putting the question the other way round:

Is it sufficient to activate Mglu1 receptors via N-acetyl cysteine to reverse noncanonial NMDARs ?

 

Btw: Regarding the Herbal Parp1 antagonist post,

I learned from the posted papers, that Myricetin is not capable to enter the Cell.

But Quercetin, Fisetin and another one does.

 

Be aware of the Bloodthinning effects (at least) of Quercetin

Edited by Flex, 20 April 2014 - 01:53 AM.

[Flex]

Thanks Flex. Yes, I'd thought it to be reversible with time as well; this has been my experience in the past (prior to having said conditions). However, considering the pre-existence of these conditions this time, perhaps my brain is more fragile, thus more susceptible. Such seems to be the case at least. Hmm.. hypofrontality. I'll do a 2 week prefrontal tDCS run soon, and report back To what extent have you found cocaine can affect synaptic plasticity? I am participating in the DIhexa group buy, but as far as I know, it only causes synaptogenesis.. not sure of its effects - if any - on synaptic plasticity.

 

Could You tell me, from where have You obtained the tDCS device and what is the price ?
 

Edited by Flex, 22 April 2014 - 04:12 PM.

[Flex]

PPARγ as a Therapeutic Target in Cocaine Relapse
http://www.its.utmb....bstract2014.pdf
Miller WR, Neuroscience. Fox R, Center for Addiction Research. Stutz S, Center for
Addiction Research. Cunningham K, Center for Addiction Research. Dineley KT,
Neurology.
Here we explore a novel therapeutic target,peroxisome proliferator-activated receptor(PPAR),
using a preclinical model of addiction in vivo. This ligand activated transcription factor belongs to the nuclear receptor family and its gamma isoform (PPARγ) plays a vitalrole as a primary lipid sensor and regulator of lipid metabolism.
Thus, there are several FDAapproved ligands that are clinically used for the treatment of diseases such as type 2 diabetes.
However PPARγ is also widely distributed in the CNS and is highly expressed inneurons.
Our lab has already demonstrated that PPARγrescues hippocampal cognitivenimpairment in an animal model of Alzheimer's. This rescue partly involves the recruitment of hippocampal ERK MAPK activity to the nucleus (Rodriguez et al., 2011)
(Denner et al.,2012). Given the important role for learning and memory in the process
for which drug abuse transitions into addiction, and our recent evidence that neuronal PPARγis involved in restoring cognitive deficits through ERK MAPK, we hypothesize that CNS PPARγ represents a potential therapeutic target for maintaining drug abstinence during stimulant withdrawal.
Here we demonstrate that PPARγagonism significantly attenuates cocaine seeking in arodent model of cocaine self-administration,a preclinical model of cocaine addiction andrelapse.

 

Modulation of PPAR-γ by Nutraceutics as Complementary Treatment for Obesity-Related Disorders and Inflammatory Diseases

http://www.hindawi.c...ar/2012/318613/

http://www.hindawi.c...12/318613/tab2/

-  alpha and gamma-tocopherol

- metabolites of DHA and EPA

 

Potential Health-modulating Effects of Isoflavones and Metabolites via Activation of PPAR and AhR

http://www.ncbi.nlm....les/PMC3257647/

- genistein

- daidzein

Edited by Flex, 23 April 2014 - 05:16 PM.

[Ritchie]

Flex, to follow up on the post that you posted on my thread about coca leaves. I found this study: http://www.encod.org...coca_en_pdf.pdf
which suggests that coca significantly improved the mental health of one third of cocaine addicted patients and socioeconomic functioning of almost half.

It also seems to state that giving cocaine addicts 100-200grams of coca leaf a week to chew significantly lowered relapse rates and reduced withdrawl symptoms.

[Flex]

Thank You very much

 

I couldn´t find it on my own.

Edited by Flex, 26 April 2014 - 10:38 PM.

[Eryximachus]

I want to like this forum, but there is really too much content here that pertains to the usage of illegal drugs.  As well, the forum increasingly appears to be a haven for those whose brains are fried from all matter of substance abuse. 

 

I would suggest that, if there are any forum moderators here, to prohibit the discussion of illegal drugs.  

 

[Ritchie]

I want to like this forum, but there is really too much content here that pertains to the usage of illegal drugs.  As well, the forum increasingly appears to be a haven for those whose brains are fried from all matter of substance abuse. 

 

I would suggest that, if there are any forum moderators here, to prohibit the discussion of illegal drugs.  

 

I do not understand your logic. Do you believe that nootropics and supplements should be reserved for only the people who are already healthy, and that the sick and damaged should stay sick and damaged?

 

Discussion of Illegal drugs is part of Longevity. Former drug abusers want to live long and healthily aswell. Who are you to deny them that right?

 

Edited by Ritchie, 28 April 2014 - 03:29 AM.

[Flex]

I want to like this forum, but there is really too much content here that pertains to the usage of illegal drugs.  As well, the forum increasingly appears to be a haven for those whose brains are fried from all matter of substance abuse. 

 

I would suggest that, if there are any forum moderators here, to prohibit the discussion of illegal drugs.  

 

 

This topic is made (to try) to reverse the effects of Cocaine as much as possible.

 

I guess, You are either too Young or had a too happy life, to dont know some of the bitter fates which lead unfortunaetly sometimes to illitic drug consumption.

 

And its actually a good thing that the people whose health is bad, come to this Froum to help each other and share some helpful suggestions and experiences. Cuz it was shown that the Doctors arent allways doing a good job.

This in turn can even warn some other people to be more careful on their own Drug consuption.

 

So therefore there is nothing bad, but helpful. And repression does help nobody at the end of the Day

 

 
 

Edited by Flex, 28 April 2014 - 04:19 AM.

[Flex]

http://www.parenther...e-behaviors.htm
 ... A novel compound that targets an important brain receptor has a dramatic effect against a host of cocaine addiction behaviors, including relapse behavior, a University at Buffalo animal study has found.
The research provides strong evidence that this may be a novel lead compound for treating cocaine addiction, for which no effective medications exist.
The UB research was published as an online preview article in Neuropsychopharmacology last week.
In the study, the compound, RO5263397, severely blunted a broad range of cocaine addiction behaviors.
"This is the first systematic study to convincingly show that RO5263397 has the potential to treat cocaine addiction," said Jun-Xu Li, MD, PhD, senior author and assistant professor of pharmacology and toxicology in the UB School of Medicine and Biomedical Sciences.
"Our research shows that trace amine associated receptor 1 - TAAR 1-holds great promise as a novel drug target for the development of novel medications for cocaine addiction," he said....
 Phenethylamine, which is a releaser aswell, seems to be helpful in those regards
http://en.wikipedia.org/wiki/TAAR1
Trace amines and common biogenic monoamines
Trace amines are those found in 0.1-10 nM concentrations, constituting less than 1% of total biogenic amines in the mammalian nervous system.^%5B11%5D The endogenous trace amines are para/meta-tyramine, tryptamine, phenylethylamine, and para/meta-octopamine. These share structural similarities with the three common monoamines: serotonin, dopamine, and norepinephrine. Each ligand has a different potency, measured as increases cyclic AMP (cAMP) concentration after the binding event. The currently accepted rank order of ligand affinity for brain hTAAR1 is as follows: p-tyramine > PEA > octopamine > m-tyramine > dopamine > tryptamine > histamine > serotonin > norepinephrine.^{%5B3%5D%5B4%5D%5B11%5D} The EC₅₀ values for cAMP production caused by p-tyramine and PEA binding events are 214 and 324 nM, respectively.^%5B4%5D Dopamine and serotonin have a 5 to 25-fold lower potency than either p-tyramine or PEA.^%5B6%5D The discrepancies in ligand potency may act to balance the differences in monoamine concentrations, common amines being less potent than trace amines.
 But unfortunaetly, it is prooxidant to the Brain:
http://www.ncbi.nlm....pubmed/23638910
beta-phenethylamine--a phenylalanine derivative in brain--contributes to oxidative stress by inhibiting mitochondrial complexes and DT-diaphorase: an in silico study.
Mazumder MK¹, Paul R, Borah A. AIM:
Till date, the mode of action of β-PEA on neurons is not well illustrated. We tested the hypothesis that β-PEA has the ability to cause oxidative stress by inhibiting the antioxidant enzyme DT-diaphorase and mitochondrial complexes (Complex-I and complex-III).
METHODS:
Using molecular docking as a tool, we here studied and compared the inhibitory capacity of beta-PEA on DT-diaphorase and mitochondrial complexes. Three-dimensional structures of mitochondrial complexes and DT-diaphorase and their ligands were downloaded from the respective data banks, and free energy of binding (docking scores) were determined.
RESULTS:
The present finding demonstrated for the first time that β-PEA potentiates reactive oxygen species generation by inhibiting the antioxidant enzyme DT-diaphorase, in addition to the mitochondrial complex-I and complex-III.
CONCLUSION:
As lowering of cellular antioxidant molecules is evident in many neurodegenerative disorders, beta-PEA-induced lowering of DT-diaphorase activity may have the capability to cause neurodegeneration, which may be potentiated by its ability to inhibit mitochondrial complexes. Thus, beta-PEA due to its cumulative actions may be more potent in causing neurodegeneration as compared to other endogenous neurotoxins.

Edited by Flex, 28 April 2014 - 04:37 AM.

[addx]

I've been doing low dose cocaine for a while now a few years. And simultaneously smoking skunk. There is some interaction between the two.

The effects I've had are the following.

Cocaine is somewhat "empowering" for the first few minutes after consuming a line. Afterwards a slight nausea, nervousness and profuse armpit sweating begins. Appetite is supressed, sleep is reduced. At that time I get craving for skunk and usually take a few hits. A At that point my heart beat often goes up. Cold in extremities is paired with profuse armpit sweating. Keeping the extremities warm reduces armpit sweating. At the same time I feel the dysphoric warmth in my stomach or central area causing me to be almost naked centrally by with extremities clothed. I take a line or two, I do have a kind of craving to take them but nothing that strong, I usually stop after a few as the sweating and nervousness increases too much. I can break through it with large doses but it comes back with a vengeance.

I often "interrupt" the "addiction" via memantine. Memantine chagnes cocaine effects drastically but not so much anymore, probably need to take 2 pills now(it's still a low dose). Memantine almost removes all the effects above and replaces them with opposite. A line of cocaine on memantine causes a kind of sleepyness and often increases appetite and removes cocaine induced impotence as well. More lines of cocaine do not change this but increase it, but if I really binge then it starts getting weird(I beleive I start getting paranoid or something like that, it's not physiologically bad, but psychologically I went to a few bad places in that state). Memantine also provides something to break off cocaine more easily.


Anyway, the long term psychological effects I've noticed are: ability to cry and be touched by events, movies or real life events. Ability to feel deep compassion. More calmness and acceptance of reality. Reduced drive towards world domination so to speak, a tendency to "think smaller". Most interestingly, the reasons I loved taking cocaine when I was younger is that I get perfect singing ability, in fact I am able to "feel" notes emotionally and this enables me to sing them properly, it's like some different part of the mind is activated for music and it works emotionally. Well, this only happened on deep cocaine binges, usually after some mid-binge tolerance has already started. Now, I have this all the time. I actually, after 30 years of being unable to sing noted am able to sign and hear them, but hear them "emotionally", dunno how to explain, people who "truly hear" notes probably dont know how it is for people who dont and vice versa.

I'm not sure what I'm doing to myself, but I can see some positive effects. Negative effects seem to mostly revolve around, well, spending money on it and other than that muscle stiffness, back pain, probably also hemorrhoids.

I'm also asking myself, what's the difference between low dose cocaine(meaning avoiding binge-level intoxication) and some trycyclic antidepressant or something to that effect?

I beleive the increased calmness and acceptance comes from long term frustration caused by cocaine withdrawal during work time(and a short deadlined complex project and stupid people) causing increased frustration exposure which eventually I got used to by developing increased calmness and ability to cope. Something like that..

[Ritchie]

I've been doing low dose cocaine for a while now a few years. And simultaneously smoking skunk. There is some interaction between the two.

The effects I've had are the following.

Cocaine is somewhat "empowering" for the first few minutes after consuming a line. Afterwards a slight nausea, nervousness and profuse armpit sweating begins. Appetite is supressed, sleep is reduced. At that time I get craving for skunk and usually take a few hits. A At that point my heart beat often goes up. Cold in extremities is paired with profuse armpit sweating. Keeping the extremities warm reduces armpit sweating. At the same time I feel the dysphoric warmth in my stomach or central area causing me to be almost naked centrally by with extremities clothed. I take a line or two, I do have a kind of craving to take them but nothing that strong, I usually stop after a few as the sweating and nervousness increases too much. I can break through it with large doses but it comes back with a vengeance.

I often "interrupt" the "addiction" via memantine. Memantine chagnes cocaine effects drastically but not so much anymore, probably need to take 2 pills now(it's still a low dose). Memantine almost removes all the effects above and replaces them with opposite. A line of cocaine on memantine causes a kind of sleepyness and often increases appetite and removes cocaine induced impotence as well. More lines of cocaine do not change this but increase it, but if I really binge then it starts getting weird(I beleive I start getting paranoid or something like that, it's not physiologically bad, but psychologically I went to a few bad places in that state). Memantine also provides something to break off cocaine more easily.


Anyway, the long term psychological effects I've noticed are: ability to cry and be touched by events, movies or real life events. Ability to feel deep compassion. More calmness and acceptance of reality. Reduced drive towards world domination so to speak, a tendency to "think smaller". Most interestingly, the reasons I loved taking cocaine when I was younger is that I get perfect singing ability, in fact I am able to "feel" notes emotionally and this enables me to sing them properly, it's like some different part of the mind is activated for music and it works emotionally. Well, this only happened on deep cocaine binges, usually after some mid-binge tolerance has already started. Now, I have this all the time. I actually, after 30 years of being unable to sing noted am able to sign and hear them, but hear them "emotionally", dunno how to explain, people who "truly hear" notes probably dont know how it is for people who dont and vice versa.

I'm not sure what I'm doing to myself, but I can see some positive effects. Negative effects seem to mostly revolve around, well, spending money on it and other than that muscle stiffness, back pain, probably also hemorrhoids.

I'm also asking myself, what's the difference between low dose cocaine(meaning avoiding binge-level intoxication) and some trycyclic antidepressant or something to that effect?

I beleive the increased calmness and acceptance comes from long term frustration caused by cocaine withdrawal during work time(and a short deadlined complex project and stupid people) causing increased frustration exposure which eventually I got used to by developing increased calmness and ability to cope. Something like that..

When you say low doses, how low are we talking about? Also do you purify you're cocaine or do you snort it when it is still cut to hell with adulterants.

Also what are you using cocaine to medicate? Lack of motivation? Depression? Anxiety?

To answer your question, the only difference between prescription anti-depressants and cocaine is that cocaine is extremely damaging to the heart. Other than that, it's fine. It's much less neurotoxic than adderall and can even be slightly neuroprotective.

 

 

[Flex]

Cocaine is not a simple* Tricyclic. It has various actions at various/critical sites e.g. altered Nmda/Ampa ratio in the VTA, decrease of Mglu2 and Vmat2, Epigenetics and so on..

And (at least in its pure form) it increases proapoptic mechanisms

Cocaine-induced changes in the expression of apoptosis-related genes in the fetal mouse cerebral wall

http://www.ncbi.nlm....pubmed/15681117

 

Regarding TCA´s Its not all about the potency of reputake inhibition i.e. 10nm. there is another attribute ( Unfortunaetly I forgott the name)  which describes how fast this inhibition happens. This is one of the things what makes drugs to drugs.

But I never get a TCA so I dont know.

* Nothing is just simple, everthing acts on various sites. but the effects of Coke are more profound than most Medicaments

 

Btw:

- You should consider that Cocaine and Amphetamine as well, increase the incident of Brain-hemorrage or Stroke within 24h after consumption

( Interresting; some of the ingredients of the Coca plant do counteract the vasoconstrictive effects)

- Taking Memantine with another substance which could interfere with Glutamate is problematic !

I´m no Doc, but in the case of feeling progression of decreased response to Memantine, the reason behind could be also a Excitotoxicity instead of a simple downregulation.

But this is just my assumption.

 

http://www.ncbi.nlm....pubmed/11923456

+

http://www.ncbi.nlm....pubmed/11602227

 

 

 

Edited by Flex, 29 April 2014 - 06:09 AM.

[addx]

When you say low doses, how low are we talking about? Also do you purify you're cocaine or do you snort it when it is still cut to hell with adulterants.
Also what are you using cocaine to medicate? Lack of motivation? Depression? Anxiety?
To answer your question, the only difference between prescription anti-depressants and cocaine is that cocaine is extremely damaging to the heart. Other than that, it's fine. It's much less neurotoxic than adderall and can even be slightly neuroprotective.

I'm not sure what a "low dose" would actually be. I can only be descriptive as I don't really make a regime of this, it's more of a light addiction in some sense.

Anyway, I take a line and then wait for it to wear out - completely including withdrawal. I then might take another line. Sometimes I take 2-3 lines and the wait for them to wear out.

I very rarely binge, basicaly I don't anymore, I don't like it, it's not appealing, not even during cocaine intoxication.

My "addiction hiding idea" basically stemmed from the fact that after a while of small dose(taken just for kicks) I noticed that I sometimes have a "nice feeling"(viscerally) during withdrawal (in fact probably just after it is done).

So taking a line and suffering the withdrawal for each line kinda felt like a different process than simply getting addicted to cocaine. I seem to get kinda unaddicted as well at the same time.

----

I have created huge concepts how the mind works and within those concepts there are explanations of this.

Cocaine increases perception of control ability during intoxication. Withdrawal is in fact "loss of artifically enhanced control ability" meaning everything that happens feels less controlled - causing relative frustration. The frustration causes fear learning.
Fear learning causes increase in KOR/dynorphin tone in key areas that is associated to cocaine addiction.

The process can be easily demonstrated by successive negative contrast experiments (reward downshitf paradigm)

http://www.ncbi.nlm....pubmed/11812535

http://www.ncbi.nlm....pubmed/15839790

The process is in fact governed by opioids as I have proposed many times on this forum.

http://www.ncbi.nlm....pubmed/16135386

There are detailed PDFs of these studies available, M. Papini did most of such experimentation and he tested opioids.

Opioids govern the immediate effect of frustration which can be completely "saved" by delta opioids(this would mean that delta opioids would supress tolerance growth). Once the frustration is learned as a fear the fear can be controlled via kappa opioids which is already noticed by science and stemmed all the kappa opioid antagonist (JDTic) research. The delta opioid involvement into addiction is also detected by other studies that go in that direction.

The studies with reward downshift are for me probably the most imporant studies of all. The rat refuses to drink the diluted sucrose because he remembers it should be 32% and he invests frustration (rather than indulge in the diluted sucrose as do control rats) into finding out the contextual difference to why it wasn't 32% and this is an investement into the future so he'd always get 32% sucrose.

The frustration of cocaine withdrawal can only conclude that cocaine is required for the "artificial levels of control" that were induced during cocaine intoxication.

----

So, in light of this, I see reason why my usage of cocaine (basicaly using it for withdrawal) results in slightly different effects than what is normally accomplished by addicts.

It seems, or so I presume, I've gotten my brain used to the sense of control loss and that pretty much sums up my first post explaining it - acceptance of things as they happen. My point is that I've had little of such acceptance to begin with, I coulnd't be at peace with anything, so in that sense, I actually think I improved a part of me.

The positive effects of a line of cocaine have become completely minimized for me and last for a minute or two at most.

My brain obviously immediately prepares for the loss of control that is imminent by increasing KOR signalling(fear expectation) which is then countering cocaine intoxication (this is how it works, heaps of studies, KOR agonists acutely rescue/antagonize cocaine intoxication effects).

The "preparation/expectation" by KOR is experienced as loss of cocaine positive effects and results in nervousness and paranoia (expecting for the imminent loss of control during withdrawal). This effectively makes a line of cocaine mostly a bad experience for me(minus the first minute or two). I still have slight urges to take it, but it is in fact no fun and can be easily stopped or resisted.

I normally choose to use drugs to "snap out of it" or change mood. Not so much to improve it or anything, just switch it. It started when I started working and living with a G/f. I just zone out after work.. Can't do anything. Or I'm to busy thinking of something or I can't think at all. I was also very "delicate" at those times, I couldn'te be asked to do anything or I'd get really angry and pissed because I can't go home and stare into space. It wasn't much of a problem when living alone but like this... so I started doing various drugs to snap out of it. Mostly weed.

---


No, I'm using it adulterated. Currently I'm off in fact.

The heart issue you mentioned is somewhat unnerving, I know all stimulants waste the heart, simply from being stimulants, I did not think of this much as I don't binge. Anyway, question would be, is cocaine special in regards to heart damage, compared to adderal and other stimulants? Does some specific of cocaine attack the heart?

The cocaine I'm using is of somewhat good quality. I might consider trying different stimulants but Adderral is illegal, I don't like methylphenidate and the street amphetamines that I can get are of much worse quality than cocaine I can get.

Edited by addx, 29 April 2014 - 10:59 AM.

[Flex]

I have to add that Quercetin has reinforced my specific depression that I suffer from Ethylphenidate and chronic stress.

But I´ve made very good improvements through Cerebrolysin, fitness and occasional sunbaths

( which decreases even Parkinson symptoms, through more than 10.000 IU Vitamin D3 body production)

 

Here are some links:

Quercetin targets cysteine string protein (CSPalpha) and impairs synaptic transmission

http://www.ncbi.nlm....pubmed/20548785

 

This explains to some extend my depressive symptoms

http://www.mindandmu...pression-2.html

 

I´m currently looking for an alternative.

Up till now I could only find Adenosine thiamine triphosphate and Fisetin as an alternative.

But Fistein which is far more Costy than Quercetin and has about the same potency like Quercetin has to be dosed,

according my calculations, up to about 16 grams(!) to inhibit Parp-1 to 100%

 

I considered the Rat/Mouse to Human conversion as well as the Bioaviability, but for quercetin.

Maybe a mistake has happened, You never know. Therefore I´m of course open for any corrections.

 

Adenosine thiamine triphosphate (AThTP) inhibits poly(ADP-ribose) polymerase-1 (PARP-1) activity.

http://www.ncbi.nlm....pubmed/21697640

http://cgp.iiarjourn.../4/169.full.pdf

 

Btw:

 

BDNF could be helpful via 7,8 dihydroxyflavone

 

Infralimbic BDNF/TrkB enhancement of GluN2B currents facilitates extinction of a cocaine-conditioned place preference.

In contrast, extinction was strengthened by potentiation of TrkB receptor activity with infralimbic infusions of BDNF or systemic injections of 7,8 dihydroxyflavone (7,8DHF), the newly synthesized TrkB receptor agonist. The 7,8DHF-induced enhancement of extinction was prevented by infralimbic infusions of a GluN2B-specific receptor antagonist, demonstrating that TrkB receptor activation enhances extinction of cocaine-CPP via GluN2B-containing NMDARs.

http://www.ncbi.nlm....pubmed/24760865

 

Reversal of Cocaine-Induced Behavioral Sensitization and Associated Phosphorylation of the NR2B and GluR1 Subunits of the NMDA and AMPA Receptors

http://connection.eb...-ampa-receptors

 

http://www.cell.com/...6273(06)00810-5

 

In addition to affecting GABA receptors, BDNF has been shown to enhance glutamatergic synaptic transmission in several systems (5, 9-11, 24, 25). In vitro, BDNF has been shown to enhance NMDA receptor-mediated postsynaptic responses in several different neural cells types (9, 10) and produce phosphorylation of NR1 and NR2 subunits (9, 10).

http://www.ncbi.nlm....les/PMC3183156/

Edited by Flex, 15 June 2014 - 04:28 PM.

[scitris]

Its off-topic, but people like Eryximachus are dangerous. Demanding something arbitrary for everyone and everything without any rational reason and arguments, only because it fits to his limited mind. And whats the best for him its the best for all.

Seeking direct contact to the highest instance and trying to convince to apply his ideology to all and that above all heads, knowing that most of them are different opinion and on the top directly in front of all of that faces.

Thats a really good way to show no respect, i would be ashamed, besides you only have 4 posts and trying to apply your ideas on people that have hundred and thousands of posts. Appointing that they have spent much more time on this board/community and made their contribution. Man could assume if someone has something to say then it would be the board-staff and longtime active members with positive resonance from community or all in form of a democracy.

 

I dont like to get dictated.

You should know that your way of thinking could anytime turning against you.

 

And its not because im taking illegal drugs, because Im not taking them, but its an fundamental thing.

Freedom.

 

only my 2cents

 

 

 

 

 

 

 

 

 

 

 

 

Edited by scitris, 18 June 2014 - 01:22 PM.

[addx]

As per my "therapy"

http://www.ncbi.nlm....pubmed/10972463
 

Pharmacological reversal of behavioral and cellular indices of cocaine sensitization in the rat.

Li Y1, White FJ, Wolf ME.


Author information




Abstract


RATIONALE AND OBJECTIVES:

Behavioral sensitization has been proposed as an animal model for the intensification of drug craving in cocaine addiction. Interactions between dopamine and glutamate systems are important for the induction and maintenance of sensitization. The goal of this study was to determine if established cocaine sensitization could be reversed by pharmacological manipulation of these transmitter systems.

METHODS:

Rats received 15 mg/kg cocaine (IP) on days 1-10 and were challenged with cocaine (10 mg/kg) on day 13 to verify that sensitization had occurred. On days 14-20, separate groups of sensitized rats received daily injections of dopamine D1- or D2-class agonists, an NMDA receptor antagonist, or a dopamine agonist with an NMDA antagonist. Three days or 2 weeks later, all rats were again tested for their response to cocaine to determine if sensitization had been reversed.

RESULTS:

Reversal of sensitization was produced by repeated administration of either a D1-class agonist (SKF 81297) or the combination of an NMDA receptor antagonist and a D2-class agonist. Effective combinations were cocaine+MK-801, quinpirole+MK-801, quinpirole+CGS 19755, and pergolide+memantine. The latter drugs are approved for human use. Reversal of sensitization persisted for at least 2 weeks after cessation of drug treatment. Electrophysiological studies revealed that these drug treatments also reversed dopamine D1 receptor supersensitivity in the nucleus accumbens, a cellular correlate of sensitization.

CONCLUSIONS:

These results demonstrate that pharmacotherapy can reverse behavioral and cellular adaptations associated with repeated cocaine administration, and may do so without the need for continued medication.

It seems they reversed cocaine sensitization by using cocaine and MK801 together!! (MK801 IIRC is a full NMDA antagonist similar ketamine but more selective)

If you read my previous post you'll see that I have noticed exactly that antagonizing effect Memantine has on cocaine "stimulation" and described it. This should be researched more. Aside from that as emphasized in my previous post cannabinoids have serious implications for conditioned place preference as well, IIRC blockade of cannanbinoid receptors completely disrupts conditioned place preference memory formation and retrieval I think as well.

I am confused to the abstract a little as they claim what is required is an NMDA receptor antagonist and a D2-class agonist - memantine is actually both and it's D2 agonism is noticeable, not negligeable, it doesnt need a second chemical to achieve this or maybe the process requires more D2 agonism than Memantine provides?

Edited by addx, 30 June 2014 - 12:42 PM.

[Flex]

@addx

OK maybe this could be helpful for the addiction,

but the effects of cocaine on rewiring the Brain, is more complicated.

 

There have been some studies on the changed DAT aviability in the brain of Cocaine users.

Of course Vmat2 ( but sometimes inconclusive) changes in Gene expression ( hundreds of genes!) and many other.

 

Btw: Regarding the gene expression: Methylphenidate is as worse as Cocaine.. if not worser

In contrast, 306 genes were differentially expressed in the striatum and among them, 252 were downregulated.

http://www.behaviora...content/10/1/17

But for how long, is another question like in the case of cocaine.

Nevertheless a certain ammount of genes stay changed in the case of cocaine

 

Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins.

http://www.ncbi.nlm....pubmed/19447090

 

microRNA-Seq reveals cocaine-regulated expression of striatal microRNAs.

http://www.ncbi.nlm....pubmed/21708909

 

Drug addiction is a major public health issue. It is typically a multigenetic brain disorder, implying combined changes of expression of several hundred genes.

http://genomemedicin...content/2/12/92

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

 

Next one:

Cocaine modulates the expression of transcription factors related to the dopaminergic system in zebrafish

http://www.sciencedi...306452212011633

 

Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers

http://www.ncbi.nlm....cles/PMC122957/

 

..Nodal-related protein, Ndr2, and transcription factors such as Lmx1b, Otp, Nurr1 and Pitx3 are very important in the differentiation, function and maintenance of mesodiencephalic dopaminergic neurons, and are necessary for the activation of tyrosine hydroxylase (TH) and dopamine (DA) transporter expression..

 

So, Nurr1 is important for the expression of DAT and Vmat2 but according to another Study.However in contrast to here, seemingly not !?

http://www.ncbi.nlm....pubmed/12915123

(And yes I know that even brains of Mice and Rats behave different to the Human and Zebrafish would be more different, but I´m a amateur so ..)

 

Here are some compounds that increases Nurr1 ( but I dont know what ammount is needed !):

- n -butylidenephthalide (BP), which is isolated from the chloroform extract of Angelica sinensis

Orphan nuclear receptor, Nurr-77 was a possible target gene of butylidenephthalide chemotherapy on glioblastoma multiform brain tumor.

http://onlinelibrary...008.05432.x/pdf

http://www.ncbi.nlm....pubmed/18419761

 

- 9-Methyl-beta-carboline from e.g. tht.co

9-Methyl-beta-carboline up-regulates the appearance of differentiated dopaminergic neurones in primary mesencephalic culture.

http://www.ncbi.nlm....pubmed/17913302

 

- beta-boswellic acid (?)

The synergistic effect of beta-boswellic acid and Nurr1 overexpression on dopaminergic programming of antioxidant glutathione peroxidase-1-expressing murine embryonic stem cells.

http://www.bioportfo...paminergic.html

 

- Effect of Bushen Huoxue Decoction on the orphan receptor and tyrosine hydroxylase in the brain of rats with Parkinson's disease.

http://www.ncbi.nlm....pubmed/21258896

 

Ingredients are:

Placenta Hominis, Radix Rehmanniae Preparata, Radix Salviae Miltiorrhizae, Radix Angelicae Sinensis, Radix Dipsacus asperoides, Eucommia ulmoides, Dioscorea opposita, Flos Rosae Rugosae, Rhizoma Ligustici Chuanxiong, and Semen Coicis

Effects of “Bu Shen Huo Xue Decoction” on the Endometrial Morphology and Expression of Leukaemia Inhibitory Factor in the Rat Uterus during the Oestrous Cycle

http://www.hindawi.c...am/2013/496036/

 

This recipe seems to differ

Alternative and Complementary Therapies for Cancer: Integrative Approaches and discovery of conventional drugs

Moulay Alaoui-Jamali

http://books.google....hmannia&f=false

 

- Ginkgo egb761 extract

Ginkgo biloba extract (EGb 761) modulates the expression of dopamine-related genes in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice

http://sciencealerts...sm_in_mice.html

 

Other things:

 

Oral administration of levo-tetrahydropalmatine attenuates reinstatement of extinguished cocaine seeking by cocaine, stress or drug-associated cues in rats.

http://www.ncbi.nlm....pubmed/21196089

 

Problem:

Cocaine Regulates MEF2 to Control Synaptic and Behavioral Plasticity

http://www.cell.com/...6273(08)00538-2

 

Possible solution:

Caffeine induces hyperacetylation of histones at the MEF2 site on the Glut4 promoter and increases MEF2A binding to the site via a CaMK-dependent mechanism.

http://www.ncbi.nlm....pubmed/18198354

 

About Mef2:

'Switch' in Alzheimer's and stroke patient brains prevents generation and survival of neurons

http://www.scienceda...40703125214.htm

 

 

I´ve found out that several Chinese herbs do change the Gene-expression.

So I thought, if Cocaine and Ethylphenidate have changed those, then I have maybe only to find the fitting Herb(als)

and that I should try at least the most promising ones and see whether it changes anything.

I know that this is like shooting in the Dark. But if the Herbals are not polluted by Heavy-metals and Pesticides or I dont get inner bleedings from the Herbs due overdosage , it would be better than nothing..

 

I´ve tried uptill now scutellaria baicalensis (baicalin) and gardenia jasminoides (jasminoidin) and can tell that scutellaria baicalensis had a rgeat antidepressive effect for me and lastet 3-5 days untill I used NSI-189 which increased my Depression.

(Btw: I was abusing Cannabis and Ethylphenidate aswell,from which I suffer depressions. So therefore it is hard to differentiate the one from another)

Gardenia jasminoides had a subtle pro cognitive and "cold" stimulant effect, hard to explain.. no effects like glutamergic, monoamines & etc

but I do function better.

 

This is the abstract which gave me the idea to try those Herbals

Ameliorative effects of a combination of baicalin, jasminoidin and cholic acid on ibotenic acid-induced dementia model in rats.

http://www.ncbi.nlm....pubmed/23437202

 

Here is another "gene altering" Herb

Gene expression profiling reveals the mechanism of action of anticonvulsant drug QYS.

http://www.ncbi.nlm....pubmed/15982525

Gene expression analysis using Agilent oligo microarray showed that total of 134 genes were either up- or down-regulated during AGS (high-intensity noise induced audiogenic seizure). QYS prevented many of the AGS induced gene expression changes. Nevertheless, some of the AGS induced genes were further enhanced or reversed by QYS treatment.

Edited by Flex, 15 August 2014 - 07:08 PM.

[Flex]

When a TRP goes bad: Transient receptor potential channels in addiction

http://www.ncbi.nlm....les/PMC3593944/

 

Capsaicin and Cannabis do activate, at least, the TRPV channel and e.g. ursolic acid blocks it.

 

Ursolic acid from Agastache mexicana aerial parts produces antinociceptive activity involving TRPV1 receptors, cGMP and a serotonergic synergism.

Similarly, UA at 2 mg/kg produced significant antinociception in the intracolonic administration of 0.3% capsaicin (a TRPV1 agonist) in mice. It has been reported the inhibition produced by UA on the calcium-flux induced by capsaicin on TRPV1 receptor suggesting the antagonistic activity of this receptor.

http://www.ncbi.nlm....pubmed/23932918

[Flex]

Heres the reference in regards of the micro-stroke that happens everytime when consuming Coke:

 

Cocaine and ministrokes

Nov 07 2012 Published by scicurious under Behavioral Neuro

http://scicurious.sc...nd-ministrokes/

 

Cocaine-induced cortical microischemia in the rodent brain: clinical implications.

http://www.ncbi.nlm....pubmed/22124273

 

And this is the reason why a nitric oxide spray, Arginine or any other vasodilator which is based on NO is contraproductive.

It accelerates apostosis (cell death)

 

Selective Nitric Oxide Synthase Inhibitor 7-Nitroindazole Protects against Cocaine-Induced Oxidative Stress in Rat Brain

http://www.hindawi.c.../aa/157876/ref/

 

Behavioral Effects of Cocaine Mediated by Nitric Oxide-GAPDH Transcriptional Signaling

http://www.sciencedi...896627313002687

 

Cocaine-mediated apoptosis in bovine coronary artery endothelial cells: role of nitric oxide.

http://www.ncbi.nlm....pubmed/11408540

 

 

On the other hand, inhibiting NO could be helpful

 

Molecular roots of cocaine addiction in brain uncovered: Promising new anti-addiction drug revealed

http://www.scienceda...30522123015.htm

 

Ask Your Doc and check Your bloodpressure before inhibiting NO !!

 

From my amateurish knowledge:

You could harm Your self.. dont know,  worst case would be a stroke (?)

Edited by Flex, 26 April 2015 - 09:20 PM.

[Flex]

Just some News.

The latter seems very interresting i.e. decrease of Tet1 and its consequences on gene expression in the reward center (nucleus accumbens)

It seems that its too early to find something about the causes and/or to increase the expression:

 

Differential regulation of MeCP2 and PP1 in passive or voluntary administration of cocaine or food

http://ijnp.oxfordjo...tent/17/12/2031

 

Role of Tet1 and 5-hydroxymethylcytosine in cocaine action

http://www.nature.co...bs/nn.3976.html

Edited by Flex, 30 April 2015 - 06:33 PM.