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anxiety/depression/anhedonia/addiction/withdrawal

anxiety/depression/anhed opioid kappa dynorphin naltrexone endorphins ldn anhedonia

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#31 penisbreath

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Posted 02 September 2013 - 07:49 AM

I've given up on finding a sympathetic doctor. I'll probably just order from alldaychemist and then dissolve in water.

Is burprenorphine classified as an opiate? I was told it's actually illegal to prescribe opiates off-label in oz ..

I can live with just seeing what LDN does for me. Even if it alleviates some of my symptoms, that would be awesome.

Buspirone increased my anxiety (I believe it acts on one of the alpha adrenergic receptors), but I am curious about Prazosin

#32 celebes

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Posted 02 September 2013 - 09:39 AM

It's controlled less tightly than some opiates and more than others. Off-label is ok in the US/UK, Australia could well be stricter. LDN's half the equation so I hope it works out for you.

How long did you take Buspirone for? It increases anxiety for 2-4 weeks while it's hitting the pre-synaptic 5-HT1a receptors before downregulating them. Basically the same mechanism SSRIs have, just vastly more direct and specific so you avoid the bulk of the side effects that come with those. You also need to be taking a high enough dose to desensitize the receptors in the first place. If you're willing to suffer for a month it could be worthwhile trying again.

It's actually Prazosin that antagonizes the alpha-1 adrenergic receptor. Beyond blocking the fear response acutely (which it does brilliantly), I feel like it gradually trained my nervous system away from that response altogether. This is starting from a point where I would be paralyzed with terror if, say, I brushed my hand against a houseplant unexpectedly.This is over the course of a year or so.

Edited by celebes, 02 September 2013 - 10:01 AM.


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#33 penisbreath

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Posted 02 September 2013 - 10:19 AM

oh interesting; I had a girlfriend who used to take buspar prn, so always figured it took effect immediately .. I actually only remained on it for 4 days because the anxiety/agitation was difficult to tolerate, and can't recall what dose I was on

FWIW, buspar's metabolite is an alpha-2 antagonist (cf. http://www.ncbi.nlm..../pubmed/7619663)

can I ask what dose of prazosin you're on and how often you take it during the day?

#34 celebes

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Posted 02 September 2013 - 11:10 AM

I built up to 3mg 3 times a day. If you responded, and needed to, you could go up to twice that dose. I still take 3mg at night and occasionally 1mg during the day. It takes the edge off enough that I'm not quite 100% at work so I avoid it if I can. Just a little too relaxed where I need to be sharp, nothing like the zombification I got with propranolol. I literally spent hours just staring into space the first time I tried that. Never again.

1-PP and 6-OH-buspirone are supposed to be responsible for most of buspirone's effect in vivo. Maybe you were thinking of mCPP causing anxiety? Anyway, I would try prazosin first if you're in a bad way.

Edited by celebes, 02 September 2013 - 11:20 AM.


#35 penisbreath

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Posted 02 September 2013 - 01:07 PM

cool, thanks .. I'll put in an order for Prazosin and Naltroxene soon; if you know a better source than alldaychemist, could you please PM me?

to be honest, I'm not sure what was responsible for my reaction to Buspirone, but it did feel very 'adrenergic' to me and different to the start-up I get on SSRIs

#36 celebes

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Posted 02 September 2013 - 03:06 PM

At its simplest, your reaction to buspirone was from presynaptic (inhibitory) 5-HT1a receptors being stimulated and hence reducing the amount of serotonin in your hippocampus and forebrain. The difference with an SSRI is down to that stimulating ALL your 5-HT receptors at once. Icepick vs sledgehammer.

If you've been on SSRIs then buspirone is nothing to worry about. No real need to delay trying it.

Good luck, anyway.

#37 addx

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Posted 02 September 2013 - 03:32 PM

Serotonin mediates KOR effects.

Stress causes KOR upregulation meaning KOR will push serotonin more to mediate its effects. The increased pushing of serotonin will downregulate serotonin signalling. This will diminish the increased effects from KOR upregulation. Homeostatis is once again restored and instead of a normal KOR and normal serotonin we have upgraded KOR and downgraded serotonin - a more tonicly(average) negative state with blunted affect(blunted amplitude) that is infact quite appropriate for a high stress environment.

IMO this is the reason why SSRIs cause anxiety and suicidal ideation during the initiation period. While begining SSRIa we should have a situation of upgraded KOR and downgraded serotonin. If we upgrade serotonin then the upgraded KOR once is able to mediate its full effects because the downstream serotonin is now fully operational again. As we know KOR mediates dysphoria and anxiety, thus restoring serotonin function we restore KOR function as well, causing the week or two of negative feelings I guess until KOR downregulates(or something else gives in and the KORs remain upregulated).

Now thinking about it, SSRIs might actually make sense, but you would have to have a chemical picks exactly the right receptors that are downstream of KOR. And it is quite possible that there are no exactly right receptors downstream of KOR. It might also explain why Ibogaine is so robust at fixing withdrawal, it pushes serotonin receptors
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#38 hzwe

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Posted 30 October 2013 - 01:14 PM

Since the thread where I posted all this information is probably not getting much views and I seem to be obsessively pointing people to it I decided to make a separate thread explaining how all this works.


Mu and kappa opiod networks facilitate the basic reward/fear system.
Kappa opioid receptors(KOR) when activated shutdown dopamine in mesolimbic structures = this is the main cause of anhedonia
Kappa opioid receptors upregulate when there is too much dopamine in mesolimbic structures. They do this to tame the neurotoxic dopamine levels. You become more fearful/anxious and this counteracts the extra dopamine from whatever you're pushing into your system(cocaine, morphine)
Thus, kappa opioid network is the main network responsible for facilitating drug tolerance and withdrawal.
Once the drug use is stopped the kappa opioid network remains upregulated causing fear/anxiety(and not even having a source origin as in an event since the the cause was chemical). This state leads to drug relapse.
Tha kappa opioid network downregulates slowly, painfully slowly.
Thus, the only know substances to actually reverse tolerance are kappa opioid agonists.
Only known methods are salvia divinorum or ibogaine. Perhaps low dose ketamine could do it, ketamine does agonize kappa and I fear that the known ketamine afterglow glow effect is due to KOR downregulation, just as is Salvias and Ibogaines. Ibogaine has the extra merit of its metabolite noribogaine I think is an antagonist. So after Ibogaine downregulates it, the metabolite disables it for months.
Kappa antagonists on the other hand should not downregulate KORs it but should simply instantly stop the effect of it being upregulated. Kappa antagonists should immediately kill withdrawal.
Having said that, JDTic as a kappa antagonist infact in a way does downregulate KORs. It corrupts them. Thus the long effect. JDTic AFAIK corrupts receptors so its effects last until your brain grows new ones.
As far as mental health is concerned, most mental disorders are fear/anxiety fueled, these are people who have their kappa opioid system upregulated due to trauma, abuse or genetics. Thus, these chemicals are invaluable to treat the entire pallete of mental disorders.
The list starts with anxiety, anhedonia, depression, compulsions and goes on...
Fear causes anxiety. Anxiety is dopamine in the fear system. Fear also kills dopamine in the reward system. After a while the anxious dopamine causes downregulation of the fear-dopamine channels at which point you become less anxious and more lifeless, learned helplessness. So, you become a zombie, your reward dopamine is locked out by fear. And the same fear can't even produce dopamine to provide anxiety, just lethargy and anhedonia.
As you see, dopamine is just the perception-drive neurotransmitter, be it drive to approach or avoid. Thus stimulants cause anxiety more often than reward and prolonged use causes upregulation of KOR system killing dopamine in mesolimbinc structures leaving the stimulants to increase dopamine only for anxiety purposes eventually leading to paranoia.
The only question is, does the mu opioid system upregulate to counter anxiety-dopamine is does the numbing of anxiety only facilitated by dopamine receptor downregulation. If it does then antagonizing KORs in a state of upregulated MOR would lead the person into mania. This interplay might be the mechanism of bipolar as it obviously provides the mechanism for depression/anhedonia.


So, the KOR system facilitates the basis for depression, anxiety, anhedonia and drug tolerance/withdrawal/dependance. It seems like a miracle. But if you look at studies from way past you'll see that the KOR system was ignored by science for anything other than treating regional pain. They found out early that the pushing the KOR for pain management system doesn't cause tolerance unlike pushing mu opioid with moprhin and such. This is logical the KOR system actually facilitates drug tolerance. But they only started experimenting with KOR for other than pain management in the last few years. Almost all of the studies are still in animal testing phase. Only JDTic had a human trial start and it was halted allegedly due to some people having side-effects of heart arrythmia.



Here's some studies about all this, proving various points I made above. Some of the studies are summary studies that also confim this concept. Also, some of the studies link the KOR system to serotonin and GABA to show why meds that push those have some effects for anxiety. SSRIs antianxiety is iffy and benzos is not but they are sedating and cause dependancy and tolerance.



http://www.ncbi.nlm....pubmed/18395712

Depleting serotonin causes kappa opioid agonists failure to inhibit cocaine effects. I would that in that situation suspect kappa opioid receptors upregulate even further in an effort to try and control reward pathways neurotoxic dopamine levels. Providing serotonin enables kappa opioid network to produce its effects and reduces the need for it to upregulate. That's what I read from this, but it is jumping to conclusions.

My point is trying to link up the iffy efficacy of serotonin for depression/anxiety.

Ok, lets do some more

http://www.ncbi.nlm....pubmed/20939060

Acute activation of κ-opioid receptors (KOR) decreases dopamine (DA) extracellular levels in both the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Also, the acute activation of KOR prevents alterations in behavior and neurochemistry occurring after repeated use of psychostimulants. Opposing to the acute effects, repeated administration of the KOR agonist, U-6593, potentiates both high-potassium and amphetamine induced DA release in the NAc, suggesting that repeated activation of KOR sensitizes mesolimbic dopaminergic neurotransmission. This study investigated the effect of repeated treatment with U-69593 on basal and stimulated DA and serotonin (5HT) extracellular levels in the rat mPFC. Rats were injected once daily with U-69593 (0.16-0.32 mg/kg) or vehicle for 4 days. One day after the last injection, microdialysis experiments assessing DA and 5HT extracellular levels in mPFC were conduced. The repeated treatment with U-69593 significantly augmented potassium-stimulated DA extracellular levels, without affecting potassium-stimulated 5HT extracellular levels, suggesting an increase in DA releasability.

IMO this basicly says: kappa opioid agonists fix anhedonia(dopamine levels in mesolimbic structures) through periodical dosing. (remember what I wrote: salvia divinorum weekly/biweekly)


Not very interesting but still another study that proves the mechanism: http://www.ncbi.nlm....pubmed/19859697


But here we go in longecity style:

Knockdown of prodynorphin gene prevents cognitive decline, reduces anxiety, and rescues loss of group 1 metabotropic glutamate receptor function in aging. http://www.ncbi.nlm....pubmed/23904614

Prodynorphin is the precursor to dynorphin - the endogenous kappa opioid ligand


More,

Collectively, available data suggest that KOR disruption produces anti-stress effects and under some conditions can prevent the development of stress-induced adaptations. As such, KOR antagonists may have unique potential as therapeutic agents for the treatment and even prevention of stress-related psychiatric illness, a therapeutic niche that is currently unfilled

http://www.ncbi.nlm....pubmed/23836029


More

Together these data demonstrate that CeA dynorphin/KOR systems are dysregulated following excessive cocaine exposure and suggest KOR antagonism as a viable therapeutic strategy for cocaine addiction.
http://www.ncbi.nlm....pubmed/23751206


And more rats

Rats with a history of ethanol dependence showed a significant decrease in open-arm exploration after exposure to restraint, indicating an anxiety-like state, compared to similarly treated controls, an effect that was blocked by nor-BNI
http://www.ncbi.nlm....pubmed/23731692

nor-BNI is kappa opioid antagonist




Kappa opioid receptor signaling in the basolateral amygdala regulates conditioned fear and anxiety in rats.
http://www.ncbi.nlm....pubmed/21531393


Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats
http://www.ncbi.nlm....pubmed/21736885


This one just to connect to the standard benzo anxiety treatment:

Presynaptic inhibition of gamma-aminobutyric acid release in the bed nucleus of the stria terminalis by kappa opioid receptor signaling
http://www.ncbi.nlm....pubmed/22225848

GABA is just an infrastructure network. KOR inhibits GABA. So taking GABAergics is fixing the issue downstream of the source. As are dopaminergics and serotonergics.


One for the topic at hand:

The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety.
http://www.ncbi.nlm....pubmed/22515275


One summary study saying exactly what I'm saying:

Addictions to cocaine or heroin/prescription opioids [short-acting μ-opioid receptor (MOPr) agonists] involve relapsing cycles, with experimentation/escalating use, withdrawal/abstinence, and relapse/re-escalation. κ-Opioid receptors (KOPr; encoded by OPRK1), and their endogenous agonists, the dynorphins (encoded by PDYN), have counter-modulatory effects on reward caused by cocaine or MOPr agonist exposure, and exhibit plasticity in addictive-like states. KOPr/dynorphin activation is implicated in depression/anxiety, often comorbid with addictions. In this opinion article we propose that particular stages of the addiction cycle are differentially affected by KOPr/dynorphin systems. Vulnerability and resilience can be due to pre-existing (e.g., genetic) factors, or epigenetic modifications of the OPRK1 or PDYN genes during the addiction cycle. Pharmacotherapeutic approaches limiting changes in KOPr/dynorphin tone, especially with KOPr partial agonists, may hold potential for the treatment of specific drug addictions and psychiatric comorbidity.
http://www.ncbi.nlm....pubmed/22709632



Another withdrawal, this time nicotine

Chronic nicotine enhanced the affective, anxiogenic, and neurochemical effects produced by KOR activation in adult rats. Our data suggest that chronic nicotine elicits an increase in KOR function, and this may contribute to nicotine withdrawal since KOR activation facilitated and KOR blockade prevented withdrawal signs upon removal of nicotine.
http://www.ncbi.nlm....pubmed/22659976


One general, proving that dynorphin regulates fear acquiring and extinction:

Dynorphins regulate fear memory: from mice to men.
http://www.ncbi.nlm....pubmed/22764240


Antidepressant-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats.
http://www.ncbi.nlm....pubmed/19924112


Another summary study:

Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many aversive effects of stress are mimicked or exacerbated by stimulation of KORs in limbic brain regions. Although KOR signaling during acute stress may increase physical ability (by producing analgesia) and motivation to escape a threat (by producing aversion), prolonged KOR signaling in response to chronic or uncontrollable stress can lead to persistent exp<b></b>ression of behavioral signs that are characteristic of human depressive disorders (i.e., "prodepressive-like" signs). Accumulating evidence suggests that KORs contribute to the progressive amplification (sensitization) of stress-induced behaviors that occurs with repeated exposure to stress. Many of the aversive effects of stress are blocked by KOR antagonists, suggesting that these agents may have potential as therapeutics for stress-related conditions such as depression and anxiety disorders. This review summarizes current data on how KOR systems contribute to the acute (rapid), delayed, and cumulative molecular and behavioral effects of stress. We focus on behavioral paradigms that provide insight on interactions between stress and KOR function within each of these temporal categories. Using a simplified model, we consider the time course and mechanism of KOR-mediated effects in stress and suggest future directions that may be useful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the exp<b></b>ression of stress-induced behaviors, or both.
http://www.ncbi.nlm....pubmed/19782055



AAAAnd I didnt read this study before writing all this but here it is, like someone read my threads from various forums:

The dynorphin-like peptides have profound effects on the state of the brain reward system and human and animal behavior. The dynorphin-like peptides affect locomotor activity, food intake, sexual behavior, anxiety-like behavior, and drug intake. Stimulation of kappa-opioid receptors, the endogenous receptor for the dynorphin-like peptides, inhibits dopamine release in the striatum (nucleus accumbens and caudate putamen) and induces a negative mood state in humans and animals. The administration of drugs of abuse increases the release of dopamine in the striatum and mediates the concomitant release of dynorphin-like peptides in this brain region. The reviewed studies suggest that chronic drug intake leads to an upregulation of the brain dynorphin system in the striatum and in particular in the dorsal part of the striatum/caudate putamen. This might inhibit drug-induced dopamine release and provide protection against the neurotoxic effects of high dopamine levels. After the discontinuation of chronic drug intake these neuroadaptations remain unopposed which has been suggested to contribute to the negative emotional state associated with drug withdrawal and increased drug intake.
http://www.ncbi.nlm....pubmed/19804796



And for all ADHD treated kids:

Kappa-opioid system regulates the long-lasting behavioral adaptations induced by early-life exposure to methylphenidate.
http://www.ncbi.nlm....pubmed/18923399


So there, we have it all covered, all addictions, depression, anhedonia and anxiety. And the underlying mechanism. And even some relations to why current medication semi-works.


So, I can't really find anything that doesn't support this concept. I would value someone actually trying to follow me on this and see how correct this really is because I'm either insane or brilliant and I have been both in the past so...


Comments welcome



#39 hzwe

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Posted 30 October 2013 - 01:22 PM

I recently discovered your topic and i am very impressed. Due to the language barrière (i'm Dutch) i have difficulty to comprehend your theory. For now i think your brilliant and if your theory proves right, you should earn a Nobel-price.

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#40 wanderviolet

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Posted 31 October 2013 - 01:50 AM

I am 100% on board with your theory, so I'm hoping for it to be brilliance! I have come across basically the same conclusion myself recently, although with far less collection of sources, I can be a bit slack that way! But I have built the same picture that it is the opioid system and indeed the mu/kappa area that is key to a lot more than anyone seems to have considered.

#41 lourdaud

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Posted 31 October 2013 - 02:24 AM

How can one get hold of ibogaine?

#42 Eruditus

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Posted 01 November 2013 - 08:35 AM

This explains a fuckload and I cannot thank you enough for sharing your highly interesting conclusions regarding this common pathological root of most mental illness with us all.

I have recently quit just about every drug I have ever abused in my life ranging from nicotine and cannabis to alcohol and an unhealthy diet. Over the past two months I've noticed vast improvements due to my quitting, but what was worrying me the most was that beneath all these improvements I still felt nagging senses of self doubt that were wearing down my initial reasoning to quit and live a healthier life in the first place. I've kept myself going purely on discipline and self-knowledge that I had my reasons to stop in the first place and should therefore stick by them even though they feel less important now then when I first started.

IF what you post is correct and it makes a hell of a lot of sense to me I could greatly speed up the anxiety reduction process by involving downregulation of the kappa receptors as a course of treatment. To me this reads almost like cold shower therapy in the way that by giving the body what it wants you cause it to grow weak and out of balance while by sending it into a state of shock you cause it become more dynamic and adaptable, reforging the original balance it was always intended to sustain.

In any way I intent to place an order for some salvia divinorum x20 extract as soon as possible. I have tried this extract before and it really knocked my down, like literally I was just gaping at a ceiling for 15 minutes contemplating how the entire universe was made out of little cubical segments and that I should not be moving in any way to prevent myself from being distorted by changing my allocation in these segments, sort of like feeling stuck in a yellow glowy matrix system; weird as fuck, to be honest no words can describe it. I did not experience any positive effects from the KOR modulation that time however this can be attributed to the fact that I was still continually abusing drugs before and after my salvia use, being blissfully unaware of this plants extraordinary medical potential. I will experiment with salvia again and report back my findings on whether this plant can truly effectuate my ability to sustain an addiction free life while hopefully regaining some balance in my emotional health too.

Edit: I'm getting very excited about the possible eventuality that this might be the way forward in treating my mental health issues; here are just two anecdotal reports but they seem to affirm that while antidepressants are like quick patches to treat depression, they will only work temporarily and have a need to be used continuously, while salvia is more a cure that can be used occasionally to temporarily by making more logical use of homeostatic mechanisms rather then straining them in the wrong direction.
http://www.erowid.or...xp.php?ID=57536
http://www.erowid.or...xp.php?ID=57536

Edited by Eruditus, 01 November 2013 - 09:22 AM.

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#43 addx

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Posted 01 November 2013 - 10:56 AM

Thank you all, I hope that at least half is right.

I normally post on a different forum and all this is fueled by my need to understand and possibly cure NPD - in a neruologic way. NPD features life long defense patterns of narcissism. Anhedonia, depression, anxiety all also appear in parallel with narcissism in all humans. Therein lies the connection, narcissism is an aroused state, paranoid-schizoid state of M. Klein. Simple as that. I have been refining my stuff so some stuff below may not match exactly, not sure.

I will copy paste selected parts of my posts that are not that relative to NPD but more generally explain what is neurologically described above in a more comprehensive, psychological way, so you can all understand this in practice.

------

Reward is felt when an event that transpires causes one to learn/increase certainty and ability to operate/control/predict reality(detected by senses) in a way that provides pleasure or reduces pain(detected by senses). In short, reward/success is felt when a pleasuring scenario is learned through corporal senses.

Stress/failure is felt when an event that transpires causes one to doubt learned certainty in ability to operate/control/predict reality in a way that provides pleasure or reduces pain. In short, stress/failure is felt when a stressing scenario is learned through corporal senses.

Desire is the urge to repeat a rewarding scenario to increase the certainty of its availability. Desire is there to say "this part of reality is important because it makes you feel good, acquire it, protect it, learn how to use it best and with least effort"

Fear is the urge to avoid a scenario to increase the certainty of its avoidance/nonavailability/to confirm its nonexistance.

Fear is also created as a doubt in an existing desire scenario when it doesn't deliver expected result.

The urge to avoid a scenario may create a desire to destroy a part of reality that is the initiator of the scenario. Or to avoid it. The person will choose depending on certainty of availability of each.


The emotion of fear

Pure fear with absence of any other emotions is felt as terror or impending doom - a fear without a consciously known origin.

It is quite rare to feel pure fear as there is usually a consciusly known origin. The emotion of pure fear can be induced chemically via kappa opioid receptor agonists. Salvia Divinorum is a plant that achieves exactly that.

"Unpure" fear is felt when there is an origin in the sense of detected threatening cues. It is unpure because the existence of a known origin causes an interplay of emotions tainting the purity which we will discuss further down.

Regulation of fear

The brain will regulate the "amount of fear" or better yet "inevitability of stress" in accordance with detected salience of threatening cues facilitated by noradrenergic signalling in the amygdala. Noradrenalin signals both distance from stress and the return signal of aggression/anger.

The emotion of desire

Pure desire with absence of any other emotions is felt as bliss, impending heaven - a desire without a consciously known origin. It can be induced chemically via mu opioid receptor agonists. An example, although not a pure mu opioid agonist would be heroin/opium/etc.

"Unpure" desire is felt when there is an origin in the sense of detected rewarding cues. It is unpure because the existence of a consciously known origin causes an interplay of emotions tainting the purity which we will discuss further down.

Regulation of desire

The brain will regulate the "amount of desire" or better yet "inevitability of reward" in accordance with detected salience of rewarding cues facilitated by dopaminergic signalling in the mesolimbic region. Dopamine signals both distance from desire and the return signal of drive/vigor/elation.

Interplay of desire and fear

Each reward cue automatically spawns a desire to acquire and each stress cue automatically spawns a fear of not avoiding it.

So, when a person is "aroused" by cues, there is an anticipation of a projected future that is either desired or feared, but given the complexity explained below it is usually both.

All desires except possibly innate desires(they might feed in directly at a lower level from other nervous subsystems) stem from basic root fears possibly all connected to a single root fear of annihilation/disintegration/death. So each desire is spawned out of a fear - as a solution to remove the fear.

Once a cue is detected it is time for the brain to calculate possibility of this desired or feared "projection of future" coming true.

In order to do that the brain "systemizes"/works out neccessary steps or "subprojections of the future" that are needed to succeed and the "subprojections of the future" that must be avoided to achieve or avoid the final anticipated "projection of the future". These we can call subdesires and subfears.

Each "subprojection of the future" is then assessed for possibility of success/failure to approach or avoid from learned experience. The values are then "merged" or "superimposed" or "summed up" to create the endresult possibility of success/failure to approach or avoid the final anticipated "projection of the future".


Desire and fear together are infact urges to find ways of controlling a known pleasuring or a painful object. Nothing more or less than that.


Demonstration of interplay

A basketball player wants to score. In order to score he needs to avoid the defending player and score a point.

So, his anticipated projected future is to score. He desires to approach it. But this, as explained above is not the beginning of it. He desires to approach it because he fears losing the game. Or he desires winning the game because he fears being a loser...It's a recursive relationship.

So he works out his "game-plan".

First he needs to avoid the defending player, this is the first "subprojection of future". He desires to avoid him and fears not avoiding him. He estimates possibility of this desire coming true and this fear coming true.

Second, he needs to score a point, this is the second "subprojection of the future". He estimates the possibility of this coming true or failing to come true as well.

He sums up the possibilities of approach to all subdesires of subprojections and sums up the possibilities of avoidance of all subfears of subprojections and yields an endresult of possibility of approaching "scoring a point" and an endresult possibility of failing to score a point.

The resulting predicted possibility of approaching desire causes a matching intensity of motivation via dopamine.
The resulting predicted possibility of avoiding fear causes a matching intensity of confidence via noradrenalin.

So you see this forms a matrix of mood responses.

High motivation + high confidence = high drive + high aggression = active-aggression
High motivation + low confidence = high drive + low aggression = passive-aggression + anxiety
Low motivation + high confidence = low drive + high aggression = reactive-aggression
Low motivation + low confidence = low drive + low aggression = passive

This all stems, as said, from success possibility calculations/predictions which are outputed via dopamine(motivation) and noradrenaline(confidence).


The interplay of desire and fear goes to much more granular levels than just 2 situations per play in basketball.

Here's a much more granular view of the said dynamics:

When a person wants to move their hand, they desire it to relocate to a different position. If the hand is holding a weight it will be difficult to move and the person will also fear that the hand might not move. Confidence in avoiding the fear of not being able to lift the weight will generate the aggression(noradrenalin) required to lift the weight. Desire to lift it will guide the hand to the target position(dopamine).

Imagine the other scenario. A persons hand suddenly goes completely numb. He is unable to move it no matter how aggressively he tries and instantly, as this is realized, his calculated possibility/confidence to move his hand is recalculated to be zero - which eliminates the possibility to place the hand in the desired position by moving it(flexing muscles). This means the desire possibility is eliminated completely and only the fear of not being able to move hand remains. At this point the person feels panic while he searches for a different method of moving his hand and as he eliminates any other possibility almost instantly a feeling of terror is revealed.
There is no detected obstacle and yet the person is unable to move the hand causing fear of disintegration without conscious origin - terror. Finally the terror is reduced by being pushed into the subconscious disabling the person from considering their hand as a controllable object.
This is in fact quite similar to, for example, overt NPD who are disabled from thinking the other people are not controllable objects. This will be explained further below.

Feeling the interplay

We have commented the emotions of desire and fear as pure and we have now seen how they get tainted through the interplay.

Desire, fear, motivation and aggression are separate feelings that are hard to discern.

Motivation alone is felt as agitation
Desire and motivation with confidence is felt as elation->euphoria.
Fear and motivation with no confidence is felt as anxiety->paranoia.

Since we're always running both a fear and desire we always have a ratio elation vs anxiety. This can be noticed when people in extreme situations keep switching attention to one or the other, flipping between extremes of mood. This can happen if the desire resulting moods are of the same intensity as fear avoiding moods. It's a small difference and each new cue tips the balance on the other side. If the moods are very intense the flipping will be very obvious.

And there are many possible combinations each yielding a mix of elation/anxiety/depression/confidence

At all times, when "aroused" our emotional state is determined by the intensity of the active desire and the active fear and by possibility of active desire approach success vs possibility of active fear avoid success.
Each newly detected cue in relation to running fears and desires causes the balance to shift in one direction.

Fear/reward learning

The brain learns reward through mu opioid network when reward is delivered. The brain compares the delivered reward(mu opioid in one part of the brain) to what was predicted(mu opioid in a second part of the brain). If there is an increase in delivered reward in comparison with what was predicted, reward value is increased/reinforced(mu opioid in the second part of the brain). If there is a decrease from predicted reward to received reward - fear is learned through kappa opioid network.

There also exists a third opioid newtork - delta opioid.

Delta opioid network is in charge to reduce fear learning from perceived reward reduction and most probably to facilitate reward learning from perceived reward increase.

If there is enough delta opioid agonism, fear from failure to acquire predicted reward will not be learned, delta agonism will inhibit kappa opioid fear learning from reward prediction error.

Here's a very detailed study on reward prediction error(negative contrast) causing fear learning(not that explicitely stated but everything I said can be found proven but not so much explained in this study)

http://www.comparati...09/4.Papini.pdf
http://personal.tcu....iniHandbook.pdf

Delta opioids reduce acute frustration from reward failure - in short. They stop the induction of the current frustrated state to be analyzed and recorded by the brain as a fear cue - they stop fear cue learning that would result from reward failure.

Addiction

As we can see from the above process, addiction stems from fear learning which is why symptoms of drug abuse and mental disorders converge as they get more intense.

We can explain the process of addiction in the following way: Artificially increasing predicted reward values and delivered reward values(by flooding receptors with drugs) causes increased control learning during acute drug intoxication. That means everything you do is seems more under control and this control is learnt and this learning is the pleasure you get out of the drug.

Once the drug, for example, cocaine, wears of, everything becomes less controlled(on some weird level because the flooding caused it, it is undetectable in a direct way). As we can see from the above paragraph, the perceived reduction of control during withdrawal causes "stealth" fear learning(if delta opioids do not inhibit it). This result in an increase in kappa opioid tone(fearfulness).
Increasing fear infact causes tolerance - fear/kappa opioids oppose the positive effects of the drug(mu opioid effects) and in the end only paranoia remains.
Kappa opioids infact are the receptors that cause acute tolerance and long term tolerance. Cocaine is only good while you're increasing perception of level of control, at some point you reach a maximum level of control at which point you can only learn fear from losing control - this is kappa opioid action. This causes the acute tolerance of cocaine and the mechanism causes KOR upregulation overtime causing chronic/tonic tolerance.

Notice that we said - if delta opioids do not inhibit it - delta opioids have been found to inhibit development of drug tolerance and are themselves much more resistant to tolerance. If I am correct, delta opioids infact inhibit fear and reward conditioning/learning which inhibits tolerance.


Lack of emotional awareness, depersonalization, derealization, dissociation

Kappa opioid network(fear) causes oxytocin and vasopressin supression. It seems mu opioid probably does this as well but at higher levels.

http://www.ncbi.nlm..../pubmed/1665795

This causes lack of emotional awareness of others - lack of "empathy" in fearful situations. It probaly also causes lack of emotional awareness of self experienced as depersonalization.
Even higher levels start to cause dissociation - which is infact desensitization - loss of senses. First you lose mammalian emotions(depersonalization - loss of familiarity with self, derealization - complete loss of familiarity) then, via a different mechanism, senses(dissociation).

Senses are lost through a different mechanism than oxytocin. I believe kappa opioid overactivity causes nNOS(neuronal nitric oxide synthase) to induce NDMA receptor shutdown via nitric oxide. NDMA receptors mediate all senses so this effectively causes dissociation.

Dissociation is therefore also caused by NDMA antagonists/blockers as well, such as ketamine.
Dissociation is also caused by nitric oxide - laughing gas.
Dissociation can also be caused by various other infection, trauma all causing elevated nitric oxide.

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

I have a lot more to copy paste but it's mostly plagued with references to NPD behavior, hard to weed it out, if anyone is interested, I'm sure you can find the original location where I'm writing this.

Edited by addx, 01 November 2013 - 11:10 AM.

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#44 addx

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Posted 01 November 2013 - 12:56 PM

Salvia only seems to work in some people, I'll paste an email I sent to someone to provide a better understanding of what needs to be done to get better.

This email was a follow up to a study, I tried to get some info with it. The study performed successfull fear extinction on humans. They concluded that fear response causes the fear memory schema to become unstable, volatile for an average of 6 hours. If the fear is extincted(by succesfull exposure) during those 6 hours the memory settles back into the long term memory without the fear component - completely extincted. This was done with no pharmacology.

---------


It seems that fear memory is recalled and enabled for reconsolidation via kappa opioid receptors and dynorphin.

Kappa opioid receptors initiate the fear response which freezes the innate intent and engages the paranoid-schizoid challenge-learning mode. It is induced when reality doesn't happen the way it is learned to happen according to the intent. The animals intention is obstructed by an unknown or uncontrolled threat, the animal is paused to reasses the context and make a better plan to avoid or defeat the threat to realize its intent. The innate response of aggression is subdued by kappa opioid receptor mediated sedation. Pain is releived by kappa opioid receptor mediated antinociception in order to allow animal time for thinking etc. The animal is frozen by temporary dopaminergic depression via kappa opioid receptor mediated inhibition of dompaniergic neurons in mesolimbic areas. The animal is disabled until it resolves a plan(desire) that it has confidence to execute. This process is also key to depression. Long exposure to fear context with no confidence to resolve it pushes the fear into subconscious probably via serotonergic action and REM sleep.

It is also interesting to note that endorphins antagonize kappa opioid receptors.

It seems the window for fear extinction of 6 hours is the time dynorphin keeps the fear response active enough. What is consolidated in that time is what is learned for long term. During the challenge the animal/person gets endorphins for success to realize his intentions – success causes learning of certainty of method/scenario and one feels rewarded for attaining certainty of method to pleasure self or escape pain. Endorphins are normaly thought to agonize mu opioid receptors but interestingly also antagonize kappa opioid receptors/dynorphin. I would deduct that fear extinction requires endorphins to antagonize dynorphin which causes the memory to reconsolidate without the fear component(which dynorphin would associate through kappa opioid action but can't since antagonized). And endorphins are created by cues of success and dynorphins by cues of failure. So, during those 6 hours a person is really trying to create as much as endorphins through success to remove all the dynorphins(past failures) from the memory schema in order to uncondition himself.

The opioid system is the paranoid-schizoid challenge learning system. It is activated when something causes doubt in learned certainty of how to use reality(as perceived and operated by corporal senses). The opioid system causes one to learn how to use its surroundings for maximal pleasure, minimum pain and minimum efforts. Certainty of use(„muscle memory“ or dopaminergic-memory is the best explaining term) is learned and tracked by dopaminergic networks. The opioids latch onto to key nerual circuit points to recognize success in dopaminergic intent. They also latch onto noradrenaline neurons to determine failure in dopaminergic intent – which results in innate frustration before the fear response takes over. The opioids latch onto pain senses to recognize pain and numb it in response. Certainty of use is first learned for own body, moving hands and legs. Then for external objects like sword or steering wheel and in the end people as objects or even social concepts. Fear is invoked each time certainty of action and reaction is doubted, engages the learning/challenge mode to learn the new context and remove threats, learn most effortless/painless/plesureful use of reality. Learning certainty provides reward until 100% certainty is achieved after which there is no reward – this is infact the mechanism that causes drug tolerance. After certainty is learned one can only feel fear when certainty of use comes in question. The drugs cause the user to learn more certainty than possible in reality which causes fear-doubt depression in withdrawal. It also explains the paranoia created by dopaminergic drugs.

(Interestingly, laughter seems to have some effect of denying the result was unexpected, stopping the induction of the fear response, this seems to be caused by delta opioid network. There's successive negative reward contrast studies with rats which indicate this, and alcohol effects are interesting in relation to this as well)

------

From this, one can see that Ibogaine seems like a best bet for healing most of these conditions. Ibogaine causes fear memory recall via its kappa opioid agonism. Ibogaine trips normally involve a fear extincting session. All fears are recalled and become volatile memory. The conscious can only process one at a time, so the biggest fear passes the ramp. Ibogaine thanks to its metabolite is infact a two stage drug. The activated fears are probably immediately resolved due to ibogaines mu opioid action. This causes the next fear in line to reach consciousness and get extincted immediately.
Ibogaine sessions often involve rapid fear extinction where the person reviews hunderds of past emotional situations in a rapid manner often not being able to even grasp all of them. Ibogaine also hits the psychedelic 5ht2a receptor and this probably enables the memories attached to the subconscious fears to reach the conscious and get extincted as well from the fear schema.

So, salvia is lacking the mu opioid action, it just induces the fear response and after that it's up to the person how will their brain process this. Which is why I think some people do better some don't.

Ibogaine microdosing is also interesting, I've have a friend on a forum who cured multiplie identities within a week by microdosing it. Ibogaine disables you from escaping yourself, it grounds you, connects you to yourself and the world, it disables you from burying your emotions. Microdosing ibogaine in troubled individuals causes them to start pouring out emotions, unable to stop them, repress them, deny them. It forces people to be true to themselves by not allowing disconnection.

So, Ibogaine is still my best bet... but kappa opioid antagonists like JDTic might prove very usefull as well.
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#45 Eruditus

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Posted 01 November 2013 - 01:14 PM

Well for those of you interested in purchasing some ibogaine I just found this link https://maya-ethnobo...bernanthe-iboga

Seeing as it is illegal to order in my country I will not be trying it just yet, If you decide to take this substance I would strongly advise people to get trip sitters with phones on hand ready to dial 911 if possible seizures were to occur. If positive persistent changes were to occur to those daring enough please let us all know. Might be I try some at a later date if it turns out to live up to its reputation :)

So, salvia is lacking the mu opioid action, it just induces the fear response and after that it's up to the person how will their brain process this. Which is why I think some people do better some don't.



So what if it were combined with a cheap otc mu opiate agonist like ethylmorphine or codeine or do you think something a little stronger would be required for this purpose of complete fear extinction?

Edited by Eruditus, 01 November 2013 - 01:43 PM.


#46 addx

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Posted 01 November 2013 - 02:31 PM

Dunno, I'm guessing, conjecturing a lot... I can't recommend any of this stuff, I just compiled it for others to review and make their own conclusions. It might work, it doesn't sound that dangerous, but still, salvia can be pretty dangerous on its own, causing prolonged hallucination and dissociation for months in some people. Also, it is a question of how well different mu-opioid drugs penetrate different brain areas and work with different subtypes of mu receptors.

I am afraid of salvia more than ibogaine. I will order ibogaine (ibogaworld seems to be a reputable source and I have contacted them, they seem nice)... I will probably microdose it, I'm afraid of the trip as it seems iboga sometimes shreds personality disordered people, they don't let go of their fear, iboga is unable to extinct it, it actually makes it worse, all of such trips I've found had the 'I wouldn't let go' moment, and all the other succesfull trips had the same moment but they did let go. It was probably a case of too low dosage to break through. Anyway, I won't be playing with it like that for now. I've found an account of microdosing iboga for controlling NPD over the span of a year and more, it seems quite promising, but it's just one person. Nevertheless I'll try it and report, but probably around christmas when my work schedule settles.

Edited by addx, 01 November 2013 - 02:35 PM.


#47 Steve Zissou

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Posted 04 November 2013 - 01:08 AM

Dont know why everyone is dismissing salvia. It's not that hard to get and is legal in most countries. The trip only lasts for a few mins as opposed to ibogaine.

#48 Virtual Reality

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Posted 28 December 2013 - 06:24 PM

perhaps amentoflavone is worth trying?

#49 chziime

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Posted 07 January 2014 - 12:45 AM

Menthol (found in Peppermint Essential Oil) is a weak full KOR agonist. Would nightly use of this (which for several reasons induces vivid dreaming) downregulate the KOR?

#50 VERITAS INCORRUPTUS

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Posted 28 February 2014 - 03:35 PM

perhaps amentoflavone is worth trying?


Amentoflavone has been shown in published research to diplay: (1) k-opioid selective anatagonism (within the assayed opioid receptors) (2) antidepressant effects, speculated to potentially be predominantly mediated by said KOR antagonism (3) GABAergic antagonism which produces a stimulant oriented effect; that potentially can produce convulsions at dose thresholds that may be within a potential therapeutic threshold (4) lack of BBB permeability, which is most important if any of this matters in practical applications.

If it does not cross the BBB significantly, which was indicated within a study in the literature demonstrating that it appears to not have a significant BBB penetrability in vivo, it will of course not exert any psychoneurological effects. Amentoflavone may have peripheral beneficial health effects due to other pathways it modulates that have shown such, however, I see it unlikely it is effective for neurological conditions due to the noted lack of significant BBB permeability. Though I have not pursued tp ascertain the selectivity of GABAergic vs Opoidergic modulation, nor the correlative doses as relates to general peripherally derived health benefits, I do not see any general use ever denoting any degree of psychoneurologically derived real-world effects.
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#51 socialpiranha

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Posted 28 February 2014 - 04:22 PM

perhaps amentoflavone is worth trying?


The place where i got 7,8 dhf also has amentoflavone i ordered a small amount to try. it's a kappa antagonist though, i believe hesperidin is an agonist it may be useful for the homeostatic hypothesis

Hesperidin antidepressant action via kappa agonism (could support homeostatic hypothesis)

http://www.ncbi.nlm....pubmed/23178563

menthol is also a weak agonist

#52 Galaxyshock

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Posted 28 February 2014 - 05:03 PM

I bet amentoflavone works in combination with the other compounds in St. John's wort for therapeutic effects. When you isolate things they may lose some of their value. I found St. John's partially effective for fear extinction, but I think it's also somewhat empathogenic and anti-addiction agent. Very good herb for the issues discussed.

#53 Ultravioletbllc

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Posted 01 March 2014 - 03:05 AM

Agmatine works wonders for everything you listed as one big co-morbidcy

along with
d3
DLPA
ACETYL L Carnitine Arginate
CDP-Choline
VinPocetine
Green tea extract
Sulbutiamine
Inositol
5-mhtf/Deplin
Methylcobalamin
Trim-Methyl-GlyCine
HuperaZine-A
Magnesium L threonate
Lions Mane Mushroom
Curcumin

Tianepetine adrafinil and Deprenyl(no adrafinil plus selegiline...however selegiline with tianepitine is far more effective with my current stack at treating my diagnosed Adhd-Pi /C-Ptsd then any other therapies ive ever engaged
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#54 Galaxyshock

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Posted 15 March 2014 - 08:29 AM

Effects of vietnamese ginseng on opioid agonist — and conditioned fear stress-induced antinociception

We investigated the effects of Vietnamese ginseng (VG) extract, VG saponin and the VG major saponin constituent majonoside-R2 on opioid receptor agonist-induced antinociception using the tail-pinch and hot-plate tests in mice and on conditioned fear stress-induced antinociception using the tail-flick test in rats. VG extract (50–100 mg/kg, p.o.), VG saponin (12.5–25 mg/kg, p.o.) and majonoside-R2 (6.2–12.5 mg/kg, p.o.), as well as Panax ginseng extract (PG extract, 50–100 mg/kg, p.o.), dose-dependently attenuated the μ-opioid agonist morphine-induced antinociception in the tail-pinch and hot-plate tests. Moreover, repeated administration of VG saponin and majonoside-R2 suppressed the development of morphine tolerance in the tail-pinch test. VG extract (100–200 mg/kg, p.o.) also dose-dependently blocked the antinociceptive effects of the selective κ-opioid agonist U-50, 488H in the tail-pinch and hot-plate tests, while PG extract (100–200 mg/kg, p.o.) dose-dependently attenuated the U-50,488H-induced antinociception in the hot-plate test but not in the tail-pinch test. VG saponin (6.2–25 mg/kg, p.o.) blocked the U-50,488H-induced antinociception in the tail-pinch test but not in the hot-plate test. Furthermore, VG saponin (25 mg/kg, i.p.) and majonoside-R2 (6.2 mg/kg, i.p.), as well as naloxone (2 mg/kg, i.p.), reversed the tail-flick latency increased by conditioned fear stress in rats. These results indicate that VG and its major saponin constituent, majonoside-R2, attenuate the antinociception caused by opioid agonists and conditioned fear stress.


http://www.sciencedi...944711396800079


Vietnamese Ginseng seems better than "true" Ginseng in this regard. Anyone know where to buy it from? VG may be quite rare, it doesn't seem to be sold at iHerb.

Edited by Galaxyshock, 15 March 2014 - 08:43 AM.


#55 FeelsNumbMan

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Posted 25 March 2014 - 02:34 AM

Interesting topic... Perhaps, some people will chime in with their experiences with kappa opioid agonists/antagonists. It doesn't seem like there's much out there that's easily obtainable though, so that's pretty unfortunate. If there are some legal ones out there, someone please list 'em!

#56 celebes

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Posted 25 March 2014 - 04:22 AM

Here's how I described the effect of kappa antagonism via Buprenorphine + Naltrexone elsewhere:

I perceived more, took more in; a richer, wider field of vision; smoother, more flexible attention; took more pleasure in everything; but more than that, there was a background of strength and confidence and self-worth instead of fear, uncertainty and inadequacy. The word I think best describes the effect overall is 'rejuvenation'. At the right dose, I'm brought back to how my being worked 10 years ago, before I ever got sick.


Edited by celebes, 25 March 2014 - 04:32 AM.


#57 FeelsNumbMan

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Posted 26 March 2014 - 01:24 AM

Buprenorphine and Naltrexone? Could I PM you to hear a little more about it? Or if you're willing to share your experiences or link through to that topic. Anyways, I was wondering is it easy to obtain and how often did you have to keep taking it? Was it like a once in a while thing where you took and felt good afterwards for some days/weeks? Or was it something you had to be high on to feel normal or whatever?

Hmm, my case seems to be that I'm anhedonic, but I don't even know why. I never really had an addiction to any drugs except for weed, but I don't know if you could even call that an addiction because I could go days without it. Nowadays, I don't even smoke weed as it makes me feel out of place.

Edited by FeelsNumbMan, 26 March 2014 - 01:30 AM.


#58 FeelsNumbMan

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Posted 29 May 2014 - 06:58 PM

Bump. Would like to know if there's any KOR agonists/antagonists out available and easily obtainable... It's a pain in the ass trying to experiment with stuff that hardly anyone is even giving any attention to.

 

Unfortunately, there's not much research and clinical trials on the KOR compared to others but I must thank you for this thread as it has a lot of info...



#59 Steve Zissou

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Posted 02 June 2014 - 06:56 AM

Salvia. Get an alcoholic extract in a dropper bottle. You can agonize your KOR without psychoactive effects besides some sedation. Must be taken subliminally because the active ingredient doesn't get absorbed by the stomach.

 

Unfortunately people are irrationally scared of salvia, because they watch people take massive doses on youtube and assume all doses are like that. You wouldn't compare a beer with half a bottle of vodka.

 

Your heartbeat increases after consumption, but is back to normal after 15 to 20 mins. In the short term (12 hours) it reduces dopamine. The positive effects are felt the next day.



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#60 Steve Zissou

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Posted 02 June 2014 - 09:08 AM

Also the latest research on KOR:

 

Quaternary ammonium salt of U50488H, a new κ-opioid receptor agonist, protects rat heart against ischemia/reperfusion injury.

It is suggested Q-U50488H, a new compound of κ-opioid receptor agonist, which is not able to pass the blood-brain barrier, elicits a protective effect against myocardial ischemia/reperfusion injury. The cardioprotective effect of Q-U50488H is associated with the opening of KATP.

https://www.ncbi.nlm...pubmed/24855042

 

Effect of Activated Peripheral κ-Opioid Receptors on the Action of Nicotine and its Withdrawal in Nicotine-Dependent Rats.

Activation of peripheral κ-opioid receptors apparently suppressed (via vagal afferent pathways) central κ-opioid activity and reduced nicotine withdrawal symptoms in nicotine-dependent subjects.

https://www.ncbi.nlm...pubmed/24770739

 

Methamphetamine induces autophagy as a pro-survival response against apoptotic endothelial cell death through the Kappa opioid receptor.

Our studies indicate that kappa opioid receptor can be therapeutically exploited for attenuating METH-induced Blood Brain Barrier dysfunction.

https://www.ncbi.nlm...pubmed/24603327

 

Role of the kappa-opioid receptor system in stress-induced reinstatement of nicotine seeking in rats.

These findings support the hypothesis that the kappa-opioid system is involved in relapse to nicotine seeking induced by stress, but not by conditioned cues. KOR antagonists such as nor-BNI may therefore be useful novel therapeutic agents for decreasing the risk of stress-induced drug relapse.

https://www.ncbi.nlm...pubmed/24583188

 

 







Also tagged with one or more of these keywords: anxiety/depression/anhed, opioid, kappa, dynorphin, naltrexone, endorphins, ldn, anhedonia

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