48 replies to this topic

[chasefooo]

I've seemed to find myself on a wild goose chase on the most effective methods of down regulating k-opioid.

There are drugs being developed like ALKS-5461, which is a combination drug of Buprenorphine and a μ-opioid receptor antagonist (to block addictive potential and additional side effects of buprenorphine.)

Buprenorphine is a k-opioid receptor antagonist which alone is proven to be effective in treating various ailments including depression, anxiety, and depersonalization.

There is quite a bit of increasing interest in kappa-opiod's role in mental health.

Obviously the pharmaceutical industry is in the business to make money, as a majority of all leading drugs pushed by healthcare make everyone recurring revenue.

It's no secrete that most any level of prolonged antagonist or agonist action will inversely up or down regulate the system people are trying to heal.

Along all of the k-opiod hype, i have found that there is a similar rate of anecdotal evidence where people are self medicating with things like Salvia (which greatly agonizes KOR) In claimed success of downregulating their KOR in times they need it, like during the day. I hope to get some people experimenting with this to chime in.

My biggest question is this. What is the currently recognized best way of actually achieving acceptable results in this?

Daily antagonism and tapering off when needed? 

Agonists at safe times to down regulate in more long term manner?

Or, hopefully, there is a better more efficient method or theories that exist or are being pursued.

Obviously the correct answer wont be either of the two methods because they are not permanent and probably don't solve the root problems of how these imbalances were brought about.

But I'm interested in discussion, and hope to get pointed in some good research on the mater.

If there are multiple methods of achieving something, people should know the one with the best success rate to try first.

thanks

 

[sativa]

Menthol found in peppermint oil is a kappa agonist.

Amentoflavone is also a kappa agonist

[fntms]

What would be a safe dose of menthol eo to get some kor benefits?... Nobody knows I assume...

[chasefooo]

Thanks for the tip on Amentoflavone, I will read in to that more.
I've read lots of conflicting things on menthol and wether it crosses the bbb or if it is even psychoactive. I'm also looking to test this out though. I'm just planning on having a peppermint tea every night and adding an increasing number of drops of peppermint extract to see what happens. I believe that you will reach the point of not being able to tolerate it, or gastrointestinal problems before any serious effects would occur.
I am obtaining some salvia and will report back with more details when the time comes.

[fntms]

TeamTlr has a kor antagonist :
KORX-OX - Kappa Opioid Receptor Antagonist Optimized Xtract First-In-Class orally bioavailable, long-acting kappa-opioid receptor (KOR) antagonist herbal extract.  Activates the c-Jun pathway to 'corrupt' the KOR akin to that of the class of synthetic KOR antagonists such as JDTic
For the brave researcher...

[umop 3pisdn]

I microdose salvia pretty regularly (0.05g of plain leaf, vaporized) and it is helpful for my (admittedly mild) depression. Some people suggest getting enough salvinorin A that you actually feel some dysphoria, but I find a smaller dose to be better for a more consistent dosing protocol, since I do that about two times a day from four to seven days a week. If I am consistently consuming enough that I get some acute dysphoria, then after a few days I cease using it, because it's unpleasant enough that I lose the motivation to dose. The effect is pretty mild but it does hit a few targets for me (quiets obsessive thoughts, increases motivation), but I haven't been doing it long enough to notice longer term effects. I do think microdosing is a viable approach to taking a lot of substances like these, though.

Edited by umop 3pisdn, 01 November 2015 - 08:01 PM.

[fntms]

Interesting, at what temperature do you vaporize? (I think I read that salvinorin a didn't vaporize at realistic temperatures or some other issue with vaping Salvia).

[umop 3pisdn]

Interesting, at what temperature do you vaporize? (I think I read that salvinorin a didn't vaporize at realistic temperatures or some other issue with vaping Salvia).

 

I don't know the exact temperature because my vaporizer (Da Buddha) only has an analog knob, but it's supposed to range from 200-900 degrees Fahrenheit and almost anywhere in the latter third area seems to work fine. It was the one that came up the most often in my research of cases where people had success with vaporizing salvia, so I bought it for those reasons. I'm not sure how it would work if a person was aiming for breakthrough dose or something like that, but I don't have any interest in that anyways.

[chasefooo]

TeamTlr has a kor antagonist :
KORX-OX - Kappa Opioid Receptor Antagonist Optimized Xtract First-In-Class orally bioavailable, long-acting kappa-opioid receptor (KOR) antagonist herbal extract.  Activates the c-Jun pathway to 'corrupt' the KOR akin to that of the class of synthetic KOR antagonists such as JDTic
For the brave researcher...

 

I have read some good reviews of KOR-OX, and hope to find more information on it.

What are your thoughts on activation through c-Jun pathway, and it's lasting effects? Is it understood to consequently upregulate KOR after antagonism? Or is it considered a permanent antagonist to where the brain has to regrow kappa receptors after they are "corrupt?"

[chasefooo]

I microdose salvia pretty regularly (0.05g of plain leaf, vaporized) and it is helpful for my (admittedly mild) depression. Some people suggest getting enough salvinorin A that you actually feel some dysphoria, but I find a smaller dose to be better for a more consistent dosing protocol, since I do that about two times a day from four to seven days a week. If I am consistently consuming enough that I get some acute dysphoria, then after a few days I cease using it, because it's unpleasant enough that I lose the motivation to dose. The effect is pretty mild but it does hit a few targets for me (quiets obsessive thoughts, increases motivation), but I haven't been doing it long enough to notice longer term effects. I do think microdosing is a viable approach to taking a lot of substances like these, though.

Thanks for adding your experience!

I'm definitely a fan of microdosing. I will for sure be microdosing salvia, as i am very sensitive to episodes of psychosis.

Although depending on how it feels, i may try grazing the edges of a breakthrough with some help of a benzo.

Since you have been dosing regularly, do you find the unpleasant effects to have a consistent duration? Around the same amount of time for breakthrough trips (15-20 minutes)?

[umop 3pisdn]

Thanks for adding your experience!

I'm definitely a fan of microdosing. I will for sure be microdosing salvia, as i am very sensitive to episodes of psychosis.

Although depending on how it feels, i may try grazing the edges of a breakthrough with some help of a benzo.

Since you have been dosing regularly, do you find the unpleasant effects to have a consistent duration? Around the same amount of time for breakthrough trips (15-20 minutes)?

 

 

I'm not sure why it is, but I find that the dysphoria lasts for about ten minutes or so, while the acute effects in general last a little while longer. So it is pretty transient, but before when I was trying to hit a low to medium dose I'd end up getting so down on myself that emotionally I couldn't really motivate myself to continue with the dosing protocol. Taking a hard look at your life and taking inventory of everything is fine sometimes, but the idea that I had in my head was to gradually and habitually downregulate KOR with pretty frequent dosing, so the two didn't really mesh for me.

[fntms]

TeamTlr has a kor antagonist :
KORX-OX - Kappa Opioid Receptor Antagonist Optimized Xtract First-In-Class orally bioavailable, long-acting kappa-opioid receptor (KOR) antagonist herbal extract. Activates the c-Jun pathway to 'corrupt' the KOR akin to that of the class of synthetic KOR antagonists such as JDTic
For the brave researcher...

I have read some good reviews of KOR-OX, and hope to find more information on it.
What are your thoughts on activation through c-Jun pathway, and it's lasting effects? Is it understood to consequently upregulate KOR after antagonism? Or is it considered a permanent antagonist to where the brain has to regrow kappa receptors after they are "corrupt?"

I was quoting the teamtlr website, they have some more "thoughts" in the product description but I think it's fair to say there is not much proof or even a clear rationale at this point...

[sativa]

What would be a safe dose of menthol eo to get some kor benefits?... Nobody knows I assume...

Some of us have experience and insight into essential oils and "alternative methods"

Lately I've had a suspicion that peppermint essential Oil is psychoactive, and I read in this fantastic e-book that IS in fact sedating, stimulating, pain relieving. Here is some other interesting information included:

Short Term Effects: Increase mental agility, increase focus, stimulate mind, reduce stress.

Long Term Effects: Abortifacient, anodyne, antibacterial, anti-infl ammatory, antiemetic, antifungal,
antiseptic, antispasmodic, antiviral, aromatic, carminative, cholagogue, choleretic, diaphoretic,
nervine, rubefacient, stomachic, tonic, vasodilator, vermifuge.

Active Constituents: 1,8-Cineol, Acetaldehyde, Alpha-Pinene, Alpha-Terpineol, Alpha-Thujone,
Alpha-Tocopherol, Amyl-Valerate, Anethole, Arginine, Ascorbic Acid, Benzyl-Alcohol, Benzyl-Cyanide,
Betaine, Bisabolene, Caffeic-Acid, Carvacrol, Carveol, Carveol-Acetate, Carvone, Caryophyllene,
Caryophyllene-Oxide, Chlorogenic-Acid, Cineole, Cinerol, Citronellic-Acid, Citronellol, Coumarin,
Cryptone, Cyclopentanol, Delta-Jasminlactone, Dihydro-Limonen-10-Ol, Dihydro-Terpineol-Acetate,
Dihydrocarvone, Diosphenol, Dipentene, Eugenol, Eupatorin, Gamma-Decalactone, Geraniol-Acetate,
Guaiacol, Hesperetin, Isoamyl-Phenylacetate, Isomenthyl-Acetate, Isovaleric-Acid, Lavandulol,
Limonene, Linalool, Lithospermic-Acid, Luteolin, Magnesium, Menthacubanone, Menthocubanone,
Menthofuran, Menthokubanone, Menthol, Menthone, Menthoside, Menthyl-Acetate, Menthyl-
Isovalerate, Menthyl-Valerate, Methionine, Menthofurane, Myrcene, Neoisomenthol-Acetate,
Neomenthol, Neomenthone, Neomenthyl-Acetate, Nerol, Niacin, P-Cymene, Phenolic Acids,
Phenylalanine, Pinene, Pulegone, Pyridine, Rosmarinic-Acid, Selenium, Stearic-Acid, Thiamine, Thymol,
Tryptophan, Tyrosine, Vanillin, Vit-B-6, Xanthomicrol, Zinc

In terms of dosage, 6 drops in a vanilla milkshake tastes amazing and has nice effects, whereas I imagine with 10-12 drops there are slightly psychedelic effects as well. One would want to encapsulate the higher doses of oil, and I would not ingest more than 15 drops, due to negative side effects (those of which may be found in that e-book).

Source: http://herbs.mxf.yuk...is-Psychoactive

Edited by sativa, 04 November 2015 - 06:29 AM.

[sativa]

From another thread on this forum:

Another thing I'm experimenting with is peppermint oil, which is a weak kappa opioid agonist. I put a dozen or so drops in my mouth guard at night, and the oil stays with my all day. I swear I can feel slight dysphoria some mornings because of its action. My goal is to downregulate my kappa opioid receptors during the day. I'm also hoping using peppermint oil the night before a lose dose salvia session could add a slight "kick" to it's anti-depressive action. Hard to say whether added benefit has materialized at this point.

[drg]

fake an opiate addiction to get a supply of suboxone, though that would be desperation territory,
but meh it is a potent antidepressant noone can deny that about opioids,

 

going to one of those clinics would probably put a permanent mark in your medical records but...

Buprenorphine is long acting so it would be better than anything you can get on the street, maybe use in a take as needed basis not sure if they watch you take it, or you need to go in everyday for more, on the other hand it could give you a real opioid addiction easily if you are not careful

[sativa]

Black cumin/onion seed (Nigella Sativa) potentiates opiates as it acts upon all 3 opiate receptors... This would allow lower doses of the primary opiate to be used.

[chasefooo]

Thanks for the input everyone.
I aquired a bit of salvia to experiment with a few weeks ago, but have been too hesitant to consider trying it yet.
I'm thinking of maybe first experimenting with suboxone (I know my way around this area) to add validity to k-opioid down regulation being able to alleviate the mental issues I wish to target. Since suboxone is a shorter acting k-opioid antagonist, I assume it would give me a good idea of what would come from down regulation.

I'm now looking for more information on JDtic and its safety. I understand the reason for it being shelved is due to ventricular tachycardia issues, but are there any more studies confirming this? Also I read from a user post on another site that the VT was due to direct heart interaction from the chemical and that by insufflation, the chemical would be directly absorbed by the brain. This sounds logical, obviously though I'm just a hobby researcher and wondered if anyone else had information on this?

[sativa]

Hesperidin from citrus peels is also a kappa agonist. I got some 98% Hesperidin and the KOR activity is noticeable!

[normalizing]

mind me asking, whats a noticeable kappa activity for you?

[sativa]

I feel the unpleasant nature of kappa activation. For me this is fear and dysphoria.

This isn't present as much when prolactn is inhibited and NMDA antagonized, combined with D2 activation (similar to salvia's mode of action but slightly tweaked)

Edited by sativa, 01 August 2016 - 06:56 PM.

[sativa]

KOR activation causes a release in prolactin, and since elevated prolactin can subdue the dopamine system aka low motivation & mood etc (due to their inverse relationship) a prolactin inhibitor neutralizes this.

Edited by sativa, 01 August 2016 - 08:14 PM.

[normalizing]

do you have connection to some list that states which inhibits and which boosts prolactin? as D2 low density problem, i think its wise to inhibit prolactin and to watch for things that encourage its production yes?

[sativa]

Google it! Pretty easy to find.

One's that come to mind are vit E, vit B6, sam-E, most dopamine agonists.

Also, prolactin levels rise after orgasm.

Yes, it would make sense to limit prolactin levels from getting to high if you have a reduced dopamine receptor density.

Re kappa, Oxytocin should also somewhat help to subdue the kappa agonism dysphoria. Not entirely though.

Edited by sativa, 02 August 2016 - 09:16 AM.

[Ames]

I haven't found anything that will acceptably agonize KOR, in a central and specific enough manner, that one can simply procure outside of the States where Salvia can be legally obtained. I've resolved to the reality that we simply have to wait for a widely available boutique research drug. You won't get there with Menthol, imo. I get coagulation issues with Hesperidin and can't recommend it.

[sativa]

Re hesperidin, perhaps an anticoagulant might be beneficial:

Anticoagulant activities of curcumin and its derivative.

...
Therefore, these results suggest that curcumin and BDMC possess antithrombotic activities and daily consumption of the curry spice turmeric might help maintain anticoagulant status.

www.ncbi.nlm.nih.gov/pubmed/22531131

[Synaptik]

Over the past 3 days, I've taken several ml of pure peppermint oil at night in attempts to down regulate KOR during the day. The results have been quite positive. Don't know if it's placebo or sustainable, but I've been very social, clear minded and focused/driven during this time. No social anxiety whatsoever. Over the previous week, I had been in a mild depression which I periodically get in cyclical waves throughout my life. I've also taken Ginkgo Biloba in the morning in order to upregulate D2, as I haven't been waking up in this state (along with my usual niacin, vitamin C, turmeric). Perhaps I should isolate the peppermint/ginkgo for a few days solo.

 

Another thing I've noticed about the peppermint oil, is that it's definitely activating Kappa opioid receptors to some degree. I've taken Salvia several times, and while it's obviously not intense in like effects, I can definitely feel low grade salvia-type undertones in perceptions and slightly dysphoric mindset - 100% not placebo. It's a similar feeling to quidding a small amount of salvia extract in your gums to get low grade effects.

 

Interestingly, I came across a recent paper which surmises that kappa opioid agonists (salvia) can have antidepressant effects in lower doses in NON-ACUTE depression. This is perhaps why numerous anecdotal reports document the antidepressive effects of Salvia, since most depression stems from chronic stress as opposed to acute stress. Several studies showing Salvia as pro-depressive were in higher doses with Forced Swim Test mice, which of course is acute stress. I'm going to search for this paper and re-post the link.

 

Anyway, I wonder if KOR agonists could offer the best of both worlds - anti depressive/increased focus in low levels, and nice effects from KOR down regulation on the back end in conjunction with a dopamine booster.

 

 

Edit: Found the link, which is well worth the read if you're interested in this topic. 

 

 

 

https://pdfs.semanti...b9b67f7b741.pdf

Edited by Synaptik, 16 November 2016 - 04:40 AM.

[gamesguru]

Maybe it's partly why low dose marijuana is nootropic.  Might also explain the flattened affect at higher doses (see second study).  So I would use kappa agonists sparingly.

J Neurosci. 2002 Feb 1;22(3):1146-54.

Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors.

Ghozland S¹, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado R.

 

Abstract

Repeated THC administration produces motivational and somatic adaptive changes leading to dependence in rodents. To investigate the molecular basis for cannabinoid dependence and its possible relationship with the endogenous opioid system, we explored delta9-tetrahydrocannabinol (THC) activity in mice lacking mu-, delta- or kappa-opioid receptor genes. Acute THC-induced hypothermia, antinociception, and hypolocomotion remained unaffected in these mice, whereas THC tolerance and withdrawal were minimally modified in mutant animals. In contrast, profound phenotypic changes are observed in several place conditioning protocols that reveal both THC rewarding and aversive properties. Absence of microreceptors abolishes THC place preference. Deletion of kappa receptors ablates THC place aversion and furthermore unmasks THC place preference. Thus, an opposing activity of mu- and kappa-opioid receptors in modulating reward pathways forms the basis for the dual euphoric-dysphoric activity of THC.

 

Neuropathic Pain Alters Reward and Affect via Kappa Opioid Receptor (KOR) Upregulation

Shiwei Liu, Christopher Cook, Eric Thai

Abstract

The kappa opioid receptor (KOR) is crucial for the regulation of mood and reward pathways in the brain. Activation of this receptor with endogenous ligand dynorphin or KOR agonists can lead to dysphoria in humans. It is hypothesized that chronic neuropathic pain leads to a decreased dopaminergic tone within the mesocorticolimbic pathway, which could induce depression, insomnia, anxiety, demotivation, and anhedonia. In this study, we aimed to determine the role of KOR signaling on the negative affective component of neuropathic pain.

We produced neuropathic pain (NP) in adult C57/BL6 male mice by implanting a polyethylene cuff around their left sciatic nerve. Using qRT-PCR analysis, we found that NP mice exhibited significant increases in dynorphin and KOR gene expression in the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala when compared to sham counterparts. Furthermore, we observed increased KOR protein availability and activation in NP mice via phosphorylated KOR immunoblotting of brain tissue punches and agonist-stimulated [³⁵S]GTPγS autoradiography of coronal brain slices, suggesting a link between KOR and the resulting decrease in dopamine levels within these regions. To understand the functional consequences of the increase in KOR expression and activity, we tested the effects of KOR antagonist on pain induced affective like behaviors. NP mice also displayed negative affect symptoms such as increased anxiety in the light-dark test and increased depression in the forced swim test when compared to sham surgery mice. When NP mice were given the KOR-specific antagonist, JDTic, these symptoms were attenuated.

These results demonsrate that neuropathic pain increases the expression and activation of KOR, which subsequently leads to decreased dopamine release in brain regions important for reward and affect. This mechanism contributes to negative affect in chronic pain, and that inhibiting KOR activity can reduce the symptoms, thereby suggesting a novel therapeutic to treat chronic pain.

 

J Neurochem. 2015 Jan;132(2):206-17. doi: 10.1111/jnc.12976. Epub 2014 Nov 17.

Differential effects of exercise on brain opioid receptor binding and activation in rats.

Arida RM¹, Gomes da Silva S, de Almeida AA, Cavalheiro EA, Zavala-Tecuapetla C, Brand S, Rocha L.

Abstract

Physical exercise stimulates the release of endogenous opioid peptides supposed to be responsible for changes in mood, anxiety, and performance. Exercise alters sensitivity to these effects that modify the efficacy at the opioid receptor. Although there is evidence that relates exercise to neuropeptide expression in the brain, the effects of exercise on opioid receptor binding and signal transduction mechanisms downstream of these receptors have not been explored. Here, we characterized the binding and G protein activation of mu opioid receptor, kappa opioid receptor or delta opioid receptor in several brain regions following acute (7 days) and chronic (30 days) exercise. As regards short- (acute) or long-term effects (chronic) of exercise, overall, higher opioid receptor binding was observed in acute-exercise animals and the opposite was found in the chronic-exercise animals. The binding of [(35) S]GTPγS under basal conditions (absence of agonists) was elevated in sensorimotor cortex and hippocampus, an effect more evident after chronic exercise. Divergence of findings was observed for mu opioid receptor, kappa opioid receptor, and delta opioid receptor receptor activation in our study. Our results support existing evidence of opioid receptor binding and G protein activation occurring differentially in brain regions in response to diverse exercise stimuli. We characterized the binding and G protein activation of mu, kappa, and delta opioid receptors in several brain regions following acute (7 days) and chronic (30 days) exercise. Higher opioid receptor binding was observed in the acute exercise animal group and opposite findings in the chronic exercise group. Higher G protein activation under basal conditions was noted in rats submitted to chronic exercise, as visible in the depicted pseudo-color autoradiograms.

 

Adv Exp Med Biol. 2001;493:81-7.

Morphine upregulates kappa-opioid receptors of human lymphocytes.

Suzuki S¹, Chuang TK, Chuang LF, Doi RH, Chuang RY.

Abstract

Opioids such as morphine are potent analgesic and addictive compounds. Chronic morphine use also induces immunomodulatory and immunosuppressive effects, as especially evident in HIV-infected patients. Morphine acts on the immune cells primarily through its binding to mu-opioid receptors on the plasma membrane. However, morphine modulation of immune functions still exists in mu-opioid receptor knockout mice, suggesting that in addition to the mu opioid receptors, morphine may also act by mechanisms mediated by either delta or kappa opioid receptors. To determine whether morphine activates kappa opioid receptors (KOR), a quantitative competitive RT-PCR procedure was utilized to quantify the KOR gene expression of morphine-treated cells. A segment of KOR transcript spanning the second extracellular loop, which has the reported dynorphin specificity, and the seventh transmembrane domain of the receptor was amplified from the total RNA of morphine-treated CEM x174 lymphocytes, along with a competitor molecule. The competitor was constructed by deleting a 33-nucleotide fragment from KOR. The results of the competitive RT/PCR indicated that CEM x174 cells expressed KOR mRNA constitutively, in the order of femto-grams. Treatment of 10 microM of morphine resulted in the up-regulation of KOR gene expression 24 hr post-treatment. The observed morphine effect could be reversed by treating the cells with either naloxone (a KOR-partially selective antagonist) or nor-Binaltorphimine (a KOR-selective antagonist).

[Mind_Paralysis]

Kappa agonists are f***ing POISON to those of us who have had a constant stress-induction since childhood (read: people with adhd, Sct or autism), so, from my point of view, I honestly don't get why you are f***ing around with AGONISTS??

 

Have all of you MISSED the fact that Atomoxetine - because of its active metabolite - has the highest amount of suicidal idea of ANY drug currently widely used for the treatment of disorders?? Are you that BLIND to the effects?!

 

Seriously, forget agonism... join the Kappa-ANTagonist group buy instead!

Edited by Stinkorninjor, 16 November 2016 - 07:53 PM.

[Synaptik]

Kappa agonists are f***ing POISON to those of us who have had a constant stress-induction since childhood (read: people with adhd, Sct or autism), so, from my point of view, I honestly don't get why you are f***ing around with AGONISTS??

 

Have all of you MISSED the fact that Atomoxetine - because of its active metabolite - has the highest amount of suicidal idea of ANY drug currently widely used for the treatment of disorders?? Are you that BLIND to the effects?!

 

Seriously, forget agonism... join the Kappa-ANTagonist group buy instead!

 

From what I can tell, Atomoxetine is only a partial KOR agonist and classified as a norepinephrine (noradrenaline) reuptake inhibitor (NRI) with significant effects on serotonin pathways. How is this comparable to selective KOR agonists? 

[Mind_Paralysis]

 

Kappa agonists are f***ing POISON to those of us who have had a constant stress-induction since childhood (read: people with adhd, Sct or autism), so, from my point of view, I honestly don't get why you are f***ing around with AGONISTS??

 

Have all of you MISSED the fact that Atomoxetine - because of its active metabolite - has the highest amount of suicidal idea of ANY drug currently widely used for the treatment of disorders?? Are you that BLIND to the effects?!

 

Seriously, forget agonism... join the Kappa-ANTagonist group buy instead!

 

From what I can tell, Atomoxetine is only a partial KOR agonist and classified as a norepinephrine (noradrenaline) reuptake inhibitor (NRI) with significant effects on serotonin pathways. How is this comparable to selective KOR agonists? 

 

 

Perhaps it's not comparable 1:1, but the fact that Atomoxetine produces more suicidal ideation is definitely something to worry about - if you look at Reboxetine and Viloxazine, you will find that they lack kappa-agonistic properties, and they don't produce suicidal ideation to the same extent at all!

 

Atomoxetine has a terribly bad rep, when compared to the other two, and the only reason I can figure why, is the Kappa-agonism.

 

Kappa-antagonists appear to have powerful anxiolytic and antidepressant properties - they even cause mild dopaminergic release. When this is taken into account, surely you can see why I find it very, very dangerous to play around with kappa agonists?
 

Now, with that said - the SI from Atomoxetine is probably a result of simultaneous increased NE-signalling, which when combined with Kappa-agonism pretty much PERFECTLY simulates the feeling of being terribly, terribly stressed and in a very dangerous situation, and it should also simulate the feeling of... well, FAILURE, really.