64 replies to this topic

[Pereise1]

Hello all, similar to a few other members of Longecity, I've had a hell of a time with depersonalization/anhedonia. I've read through the several Kappa opioid threads and it seems to be a novel, potent target for these kinds of disorders, however, taking Kappa agonists in hopes of downregulating a notoriously stubborn receptor isn't an attractive idea. Nor is taking research chemicals that don't address the initial upregulation of the receptors in response to stress/social defeat/inflammation. So after hitting that pubmed, I'm curious if any of the following methods seem promising?

 

 

Gonadal hormones decrease temporomandibular joint κ-mediated antinociception through a down-regulation in the expression of kappa opioid receptors in the trigeminal ganglia Abstract

We have previously demonstrated that activation of κ-opioid receptor located in the temporomandibular joint (TMJ) of rats induces a significantly greater TMJ antinociception in diestrus females than in proestrus females (higher estradiol serum levels than diestrus) and males. These findings indicate that gonadal hormones decrease TMJ kappa-mediated antinociception. The aim of this study was to investigate some of the mechanisms by which gonadal hormones decrease TMJ kappa-mediated antinociception. Western blot analysis demonstrated a significantly lower κ-opioid receptor expression in the trigeminal ganglia of intact males than in intact and ovariechtomized (OVX) females and orchidectomized (ORX) males. In females, κ-opioid receptor expression in the trigeminal ganglia was significantly lower in proestrus than in diestrus and OVX females. Taken together these findings suggest that gonadal hormones, especially male gonadal hormones, down-regulate κ-opioid receptor expression. Co-application of the NOS inhibitor l-NMMA or the NO-sensitive guanylyl cyclase inhibitor ODQ with the κ-opioid receptor agonist U50,488 blocked TMJ kappa-mediated antinociception in males and females. These findings suggest that antinociception induced by activation of kappa opioid receptors in the TMJ region is mediated by the l-arginine/NO/cGMP pathway in both sexes. Despite the involvement of the l-arginine/NO/cGMP pathway in TMJ kappa-mediated antinociception in both sexes, gonadal hormones do not diminish the activity of this pathway to decrease TMJ kappa-mediated antinociception. Alternatively, they significantly reduce κ-opioid receptor expression in the trigeminal ganglia.

 

 

 

It would make sense that higher male sex hormones, which are downregulated by social defeat, would subsequently downregulate the Kappa Opioid receptors. Theoretically then, megadosing that Icariin should theoretically downregulate Kappa Opioid, although the cGMP effects of Icariin give me pause. The second point about KOR and the L-arginine/NO/cGMP being related is quite interesting, and goes nicely with the following abstract:

 

 

Regulation of kappa-opioid receptor mRNA level by cyclic AMP and growth factors in cultured rat glial cells.

Abstract

The mRNA of the kappa-opioid receptor (KOR) has been found recently in cultured astrocytes and in microglia. By using RT-PCR and Southern hybridization, we confirmed these observations and, in addition, we observed that KOR mRNA was expressed in oligodendrocytes and in the precursors of astrocytes and oligodendrocytes. KOR mRNA level was the highest in the immature astrocytes and decreased with their maturation. Very few data are available on the regulation of KOR level by extracellular signals. Therefore, we examined the effect of three growth factors known to be present in the adult brain, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF-BB) and leukemia inhibitory factor (LIF) and of two cyclic AMP (cAMP) generating systems, the cAMP analog, 8-(4-chlorophenylthio)-cAMP and forskolin, on this level. It was found that in astrocytes, KOR mRNA level decreased dramatically under the effect of cAMP and less under the effect of bFGF while it did not change significantly after LIF treatment. In oligodendrocytes, it also decreased with cAMP, but increased under the effect of bFGF and PDGF-BB. In microglia, a decrease was observed with cAMP and lipopolysaccharides (LPS), the most used activators of macrophages. These results shed new evidence on the expression of opioid receptor mRNA in the glial cells of the rat CNS. The regulation of KOR mRNA level under the effect of extracellular signals suggests that opioids take part in dynamic processes in glial cells, possibly related to glial-neuron communication.

 

So Forskolin is an indirect KOR antagonist? Has anyone taking the CILTEP stack felt an improvement in depersonalization/anhedonia? It would be interesting if someone who's had a positive response to Forskolin/CILTEP and has tried one of the experimental KOR antagonists could compare the effect of the two.

 

As an aside, blocking Interleukin 1 beta might be something good to try:

 

 

Interleukin-1 beta contributes to the upregulation of kappa opioid receptor mrna in dorsal root ganglia in response to peripheral inflammation.

Abstract

During local painful inflammation, axonal transport of opioid receptors from dorsal root ganglia toward the periphery is increased, associated with a higher receptor density and enhanced efficacy of opioid analgesics at the injured site. To examine whether this increase is related to transcription, mRNA of the kappa opioid receptor in lumbar dorsal root ganglia was quantified by real time light cycler polymerase chain reaction. In dorsal root ganglia of naive rats, kappa opioid receptor mRNA expression was three-fold higher than previously shown for delta opioid receptor and two times lower than mu opioid receptor mRNA, respectively. After induction of unilateral paw inflammation by Freund's complete adjuvant, kappa opioid receptor mRNA was significantly upregulated with a peak at 12 h in ipsilateral dorsal root ganglia. This effect could be mimicked by intraplantar injection of the proinflammatory cytokine interleukin-1 beta. Kappa opioid receptor mRNA upregulation lasted longer in interleukin-1 beta-treated rats compared with Freund's complete adjuvant-treated rats. Furthermore, a significant increase in kappa opioid receptor positive neurons was detected by immunohistochemistry 24 h after local injection of Freund's complete adjuvant or interleukin-1 beta. In Freund's complete adjuvant-induced inflammation, kappa opioid receptor upregulation was blocked by treatment with interleukin-1 receptor antagonist without changing the leukocyte infiltration in the paw. In conclusion, kappa opioid receptor mRNA and protein in dorsal root ganglia are upregulated in response to peripheral inflammation. This effect can be mimicked by a single local injection of interleukin-1 beta, and Freund's complete adjuvant-induced upregulation in kappa opioid receptor mRNA and protein can be prevented by treatment with interleukin-1 receptor antagonist. These data suggest that the peripheral production of the proinflammatory cytokine interleukin-1 beta is a specific inducer of kappa opioid receptor expression in the dorsal root ganglia.

 

 

Any credence to these ideas? Looking for some feedback before smashing the Icariin/Cordyceps 

[peoplepleaser101]

Have you considered these two?

 

- Microdosing Salvia (strong, selective agonist of KOR) thereby downregulating the KOR

- Ketamine (Weak agonist of KOR) thereby downregulating the KOR

Edited by peoplepleaser101, 07 November 2017 - 11:49 PM.

[evan45245]

How would one go about microdosing Salvia? My honest opinion: there are too many factors in play regarding the downregulation of the kappa opioid receptors and Salvinorin A. Afaik there are no reports long-term benefits/changes after using Salvia. At best some report a short-lasting afterglow that can last into the next day.

Edited by evan45245, 10 November 2017 - 05:34 AM.

[Galaxyshock]

Has anyone taking the CILTEP stack felt an improvement in depersonalization/anhedonia?

 

 

The very first time I took CILTEP back in winter 2012-2013 it gave me short window of relief from Anhedonia. The radio was on and I suddenly found the music very beautiful and felt uplifted. But then I rather quickly reverted back to my anhedonic self and only got mild effects from CILTEP after that. I think that simply breaking the anhedonic homeostasis was the reason it helped. Couple other things worked kinda similarly initially.

[peoplepleaser101]

Well, Salvia is pretty darn dysphoric based on the anecdotal reports I've read. So I assume no-one in "their right mind" would dose Salvia long term.

 

I think chewing on a leaf or a VERY small of amount of the lowest extract you can find might be a viable method.

 

I am currently planning to start microdosing (10 micrograms) LSD 1-2 times a week because of the intense appreciation and enjoyment of music and life I get from psychedelics like LSD, LSA and shrooms.

[Junipersun]

There is still the possibility to take pure menthol crystals at night, so you don't feel any of the dysphoric effects. Menthol is a weak KOR-agonist. There are a few anecdotal reports on longecity and reddit about its effects.

[peoplepleaser101]

I guess mentvol could work as well

[Pereise1]

 

Has anyone taking the CILTEP stack felt an improvement in depersonalization/anhedonia?

 

 

The very first time I took CILTEP back in winter 2012-2013 it gave me short window of relief from Anhedonia. The radio was on and I suddenly found the music very beautiful and felt uplifted. But then I rather quickly reverted back to my anhedonic self and only got mild effects from CILTEP after that. I think that simply breaking the anhedonic homeostasis was the reason it helped. Couple other things worked kinda similarly initially.

 

 

Hmm, you know, in addition to the KOR, there seems to be a number of related receptor sites that get talked about whenever Brain Fog/DPDR/Anhedonia gets brought up. I feel that this study groups them together pretty nicely:

 

The importance of the G protein-activation of KGchannel system in receptor-mediated regulation of cell responses is now more widely appreciated than before because a wide variety of membrane receptors, such as M2-muscarinic, A1 adenosine, α2-adrenergic, D2dopamine, μ-, δ-, and κ-opioid, 5-HT1Aserotonin, somatostatin, galanin, m-Glu, GABAB, and sphingosine-1phosphate receptors, have been shown to use this system in inhibiting cell excitation in various organs

 

 

It would make sense that many things would only help briefly, if whenever a certain receptor is silenced, another GIRK activating receptor picked up the slack and reduced cAMP. Seems to me that altering the GIRK would yield better results in shutting off the KOR's dysphoric effects:

 

 

Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons.

Abstract

 

The endogenous dynorphin-κ opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38α MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38α MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR(-/-) mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38α MAPK activation did not. Surprisingly, while p38α MAPK inactivation blocked U50,488-CPA, p38α MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38α MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that κ opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38α MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release.

SIGNIFICANCE STATEMENT:

Kappa opioid receptor (KOR) agonists have the potential to be effective, nonaddictive analgesics, but their therapeutic utility is greatly limited by adverse effects on mood. Understanding how KOR activation produces dysphoria is key to the development of better analgesics and to defining how the endogenous dynorphin opioids produce their depression-like effects. Results in this study show that the aversive effects of κ receptor activation required arrestin-dependent p38α MAPK activation in dopamine neurons but did not require inhibition of dopamine release in the nucleus accumbens. Thus, contrary to the prevailing view, inhibition of mesolimbic dopamine release does not mediate the aversive effects of KOR activation and functionally selective κ opioids that do not activate arrestin signaling may be effective analgesics lacking dysphoric effects.

 

[Pereise1]

It's endlessly frustrating, yet fascinating, the complexity of the brain. Here's another interesting role that dynorphin, the endogenous agonist for the KOR, plays in wakefulness. It's especially interesting for someone with Narcolepsy such as myself:

 

 

Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons.

Abstract

High activity of the histaminergic neurons in the tuberomammillary ™ nucleus increases wakefulness, and their firing rate is highest during waking and lowest during rapid eye movement sleep. The TM neurons receive a prominent innervation from sleep-active gamma-aminobutyric acidergic (GABAergic) neurons in the ventrolateral preoptic nucleus, which inhibits them during sleep. They also receive an excitatory input from the orexin- and dynorphin-containing neurons in the lateral hypothalamus, which are critically involved in sleep regulation and whose dysfunction causes narcolepsy. We have used intracellular recordings and immunohistochemistry to study if orexin neurons exert control over the GABAergic inputs to TM neurons in rat hypothalamic slices. Dynorphin suppressed GABAergic inputs and thus disinhibits the TM neurons, acting in concert with orexin to increase the excitability of these neurons. In contrast, both orexin-A and orexin-B markedly increased the frequency of GABAergic potentials, while co-application of orexin and dynorphin produced responses similar to dynorphin alone. Thus, orexins excite TM neurons directly and by disinhibition, gated by dynorphin. These data might explain some of the neuropathology of narcolepsy.

 

 

This is quite interesting as loss of orexin producing neurons causes Narcolepsy, and apparently the simultaneous loss of dynorphin exacerbates the problem. Here's another snippet showing how highly co-expressed the two are:

 

Several lines of evidence now support this hypothesis. Disrupted orexin signaling is sufficient to produce the major symptoms of narcolepsy in several animal models 10, 12–14. In mice lacking the orexin neurons 13, the orexin field completely lacks prodynorphin mRNA 5 and NARP (R.E.; data not shown), further supporting the co-localization of these markers. We now show that within the orexin field of people with narcolepsy, the number of neurons containing prodynorphin mRNA, orexin, or NARP is reduced to 5–10% of normal. This cell loss is probably limited to the orexin neurons because we detected no loss of NARP or prodynorphin outside the orexin field. Although the orexin neurons might fail to produce multiple peptides, these observations make selective neurodegeneration or an autoimmune attack on the orexin neurons much more likely.

 

 

So given this knowledge, perhaps a good method of lowering anhedonia would be through agonism of orexin or NARP, thereby increasing hypothalamic dynorphin and signaling to the Ventrolateral Preoptic Nucleus, as opposed to the VTA or striatum. It'd also be interesting to see which parts of the brain current KOR antagonists work on. If they antagonize KOR in the VLPO, it might actually be counterproductive by lowering wakefulness. Just an interesting discovery.

[DaveX]

I must say, trying to downregulate Kappa Opioid receptors by agonism is a really bad idea. It is mentioned here or there that opioid receptors actually don't regulate inversely, but they upregulate by agonism and downregulate by antagonism, at least in most cases (there seem to be paradoxes in some opioid reactions). One can try this oneself by taking menthol, which is absolutely sufficient in concentrated form as an agonist, and look whether high doses of it ever yield a better result - or any other result from its acute action - than one evening's high dose of chamomille (with apigenin) which in turn is completely sufficient for antagonism.

[peoplepleaser101]

I must say, trying to downregulate Kappa Opioid receptors by agonism is a really bad idea. It is mentioned here or there that opioid receptors actually don't regulate inversely, but they upregulate by agonism and downregulate by antagonism, at least in most cases (there seem to be paradoxes in some opioid reactions). One can try this oneself by taking menthol, which is absolutely sufficient in concentrated form as an agonist, and look whether high doses of it ever yield a better result - or any other result from its acute action - than one evening's high dose of chamomille (with apigenin) which in turn is completely sufficient for antagonism.

 

Supply sources.

[gintrux]

Did you attempt to microdose salvia or found anything else to downregulate kappa?

[Rorororo]

I believe KOR antagonists are mediated through activation of JNK.  I believe there is a few studies that will state this and this is how JDTic (well-established KOR antagonist) works.

 

 

Don't ask me why.....but I found some natural JNK activators...that should, theoretically, antagonize KOR 

 

Actein - Found in Cimicifuga foetida 

 

Polyphyllin I - Found in Paris polyphylla

 

Juglanin - Found in common buckwheat extract 

 

Guggulsterone

 

 

Also, this requires more work...but...you can always get Purple Prairie Clover (well-established KOR antagonist) seeds and make an oil\tincture from them.  You will then have your KOR antagonist

 

 

The dosaging part shouldn't be hard either. In-fact, it should be easier than making the oil...

 

Random video on making oil:

https://www.youtube....h?v=agpk-OsCdEY

 

Seed source:

https://www.naturess...prairie-clover/

Edited by Rorororo, 13 May 2020 - 09:41 AM.

[jacobjerondin]

I believe KOR antagonists are mediated through activation of JNK.  I believe there is a few studies that will state this and this is how JDTic (well-established KOR antagonist) works.

 

 

Don't ask me why.....but I found some natural JNK activators...that should, theoretically, antagonize KOR 

 

Actein - Found in Cimicifuga foetida 

 

Polyphyllin I - Found in Paris polyphylla

 

Juglanin - Found in common buckwheat extract 

 

Guggulsterone

 

 

Also, this requires more work...but...you can always get Purple Prairie Clover (well-established KOR antagonist) seeds and make an oil\tincture from them.  You will then have your KOR antagonist

 

 

The dosaging part shouldn't be hard either. In-fact, it should be easier than making the oil...

 

Random video on making oil:

https://www.youtube....h?v=agpk-OsCdEY

 

Seed source:

https://www.naturess...prairie-clover/

 

Wow that's some very novel and fascinating info, thanks so much for the share man!! I assume you haven't tried it this yourself yet - if you do please let us know how it is.

 

In addition to its powerful pro-euphoric/hedonic effect, kappa opioid antagonism is basically willpower/executive function/goal directed behavior in a pill so everyone should want to try this. If anyone does try this please report back!! 

 

By the way, another easy way to potentially downregulate KOR might be Hesperidin, you can buy it from bulk supplements off Amazon and it acts as a kappa opioid agonist, so it should downregulate KOR over time. In response to what DaveX said, I believe that KOR does actually downregulate in response to agonism over time if you use the right sort of ligand.

Edited by jacobjerondin, 15 May 2020 - 07:45 PM.

[Rorororo]

Wow that's some very novel and fascinating info, thanks so much for the share man!! I assume you haven't tried it this yourself yet - if you do please let us know how it is.

 

In addition to its powerful pro-euphoric/hedonic effect, kappa opioid antagonism is basically willpower/executive function/goal directed behavior in a pill so everyone should want to try this. If anyone does try this please report back!! 

 

By the way, another easy way to potentially downregulate KOR might be Hesperidin, you can buy it from bulk supplements off Amazon and it acts as a kappa opioid agonist, so it should downregulate KOR over time. In response to what DaveX said, I believe that KOR does actually downregulate in response to agonism over time if you use the right sort of ligand.

 

 

I would NOT do down-regulation over time by agonist. It sounds like a horrible idea.  I would also increase NO, icariin should be able to do this. 

 

This should be your winning ticket:

https://www.ncbi.nlm...pubmed/20580678

Edited by Rorororo, 15 May 2020 - 10:56 PM.

[Rorororo]

Piceatannol

 

Looks like this will down-regulate KOR (theoretically).  It's also structured similarly to pawhuskin a

 

In regards to the dose:

 

https://www.ncbi.nlm...les/PMC5444415/

 

A quick read from that will tell you more (my guess is it would be dosed similar to pycnogenol)

 

As far as the actual product:

 

No one seems to sell it. A quick search lead me to the discovery that passionfruit seeds contain around 5mg/(g of seeds); under the assumption that you are getting the cold pressed oil.  You can buy it in bulk, it's called maracuja

 

 

This site seems cheap:

https://www.naturein...it_maracuja_oil

 

 

You get 5 grams of Piceatannol/kg of oil.  I would first start out with a dose around 100mg of Piceatannol and go from there (to avoid costs and allergic reactions...)

Edited by Rorororo, 16 May 2020 - 12:59 AM.

[Rorororo]

Wait, maybe not

 

https://sci-hub.tw/1...32.2009.04727.x

[Rorororo]

I am not really interested in this but make sure it activates c-jun\jnk.  You can look for this by looking for articles that compare it (potential substance) with sp600125 (c-jun\jnk inhibitor). A quick google search will do.  P.S. it actually looks like quercetin might do the trick. I also read that prolactin can stimulate c-jun but I would NOT mess with hormones (even tho I am going to suggest increasing test ).  You can look for more pathways though, I am sure you can find something out.  I say play it smart and safe (low risk pathways) - Look for different angles of attack then combine them by microdosing the substances.  Just make sure there isn't any contradictions. A lot of people forget liver metabolism.  

 

Icariin + forskholli attacks it by 3 different angels (test, cAmp & N.O. ) but you need to look into cGmp

 

I would look for something that stimulates phosphorylated c-Jun N-terminal kinase without any contradictions or amplifications of the other drugs.  

 

 

OR quercetin +  forskholli + Ginger

 

OR quercetin +  forskholli + butea superba

Edited by Rorororo, 16 May 2020 - 04:30 AM.

[Rorororo]

Icariin inhibits hydrogen peroxide-induced toxicity through inhibition of phosphorylation of JNK/p38 MAPK and p53 activity

 

Don't use Icariin.

 

 

Also according to this: 

 

https://www.ncbi.nlm...les/PMC6671172/

 

you will want to inhibit p38 but also activate JNK

 

Looks like seaweed(fucoidan) will do the trick:

https://www.ncbi.nlm...pubmed/25787883

 

My recommendation so far:

 

OR quercetin +  forskholli + (Ginger AND\OR Butea Superba) + seaweed + l-Citrulline (taken quite after quercetin)

 

Perhaps:

 

AM stack:

quercetin 

forskholli 

Butea Superba

seaweed

 

PM stack:

forskholli 

Ginger 

seaweed

l-Citrulline 

 

Wow....talk about a safe and cheap stack to tackle this problem.  I must admit that Butea Superba isn't well studied but its a PDEi; it will raise cAmp.   

 

P.S. cordyceps is worth investigating 

Edited by Rorororo, 17 May 2020 - 12:27 AM.

[Rorororo]

I am pretty sure quercetin will do this trick, but be the judge yourself:

 

 

https://www.ncbi.nlm.../pubmed/9643451

https://www.ncbi.nlm...pubmed/26065412

https://www.ncbi.nlm...pubmed/13129835

https://www.ncbi.nlm...pubmed/32410385

https://www.ncbi.nlm...pubmed/31644887

https://www.ncbi.nlm...pubmed/16236279

 

 

There is some contradicting stuff (like with everything....) but I would like to say yes(?)

 

 

This looks interesting:

Lithospermum erythrorhizon

 

Which might be responsible for the anti-analgesic

 

in:

 

https://www.ncbi.nlm...pubmed/31752825

 

Also fenugreek seems promising for a couple of reasons (test and prolactin...if you want to mess with hormones but I wouldn't)

Edited by Rorororo, 17 May 2020 - 07:34 AM.

[Rorororo]

 

Icariin inhibits hydrogen peroxide-induced toxicity through inhibition of phosphorylation of JNK/p38 MAPK and p53 activity

 

Don't use Icariin.

 

 

Also according to this: 

 

https://www.ncbi.nlm...les/PMC6671172/

 

you will want to inhibit p38 but also activate JNK

 

Looks like seaweed(fucoidan) will do the trick:

https://www.ncbi.nlm...pubmed/25787883

 

My recommendation so far:

 

OR quercetin +  forskholli + (Ginger AND\OR Butea Superba) + seaweed + l-Citrulline (taken quite after quercetin)

 

Perhaps:

 

AM stack:

quercetin 

forskholli 

Butea Superba

seaweed

 

PM stack:

forskholli 

Ginger 

seaweed

l-Citrulline 

 

Wow....talk about a safe and cheap stack to tackle this problem.  I must admit that Butea Superba isn't well studied but its a PDEi; it will raise cAmp.   

 

P.S. cordyceps is worth investigating 

 

 

WAIT, I was wrong...looks like seaweed might activate p38.  I swear, this and this alone is such a hard task to accomplish.  I believe I jumped to a conclusion with seaweed and didn't do proper research but everything else has contradicting stuff... 

 

I also think TeamTLR korx-ox extract or whatever it's called uses: Licochalcone.  I found out Licochalcone is a p38 inhibitor but Licochalcone A also inhibits c-jun?  I read that korx-ox smells like licorice  too

Edited by Rorororo, 18 May 2020 - 03:59 PM.

[gamesguru]

Before jumping to conclusions it helps to know the etiology of the disease a bit more.  Oftentimes these things have a simple explanation, like low magnesium causing anxiety, which leads to depersonalization-derealization.  So I would start there, something simple, like magnesium.  Oftentimes people take too general or specific an approach, like trying to lower glutamate globally when it is just high in one area instead of addressing the specific dopamine issue leading to it.  So I would think about that before concluding it is a kappa-opioid specific issue which is best addressed at that site.

[Rorororo]

Before jumping to conclusions it helps to know the etiology of the disease a bit more.  Oftentimes these things have a simple explanation, like low magnesium causing anxiety, which leads to depersonalization-derealization.  So I would start there, something simple, like magnesium.  Oftentimes people take too general or specific an approach, like trying to lower glutamate globally when it is just high in one area instead of addressing the specific dopamine issue leading to it.  So I would think about that before concluding it is a kappa-opioid specific issue which is best addressed at that site.

 

I think everyone agrees with this.......If you blindly are trying to regulate something then you are going in a world of hurt. 

 

 

Another way to test it is by using:

 

agmatine

 

(I don't know if you can 100% use this correlation and don't want to do the research..... but you can start here: https://www.scienced...014299995006699)

 

Lions mane

 

(this, I know forsure...I don't have articles handy atm though)

 

If you are more depressed then you can have a KOR mis-regulation

 

or an extreme, Salvia  

 

BTW: Polygonum aviculare  + l-Citrulline seems to be promising 

Edited by Rorororo, 19 May 2020 - 08:39 PM.

[gamesguru]

agmatine

 

Lions mane

 

or an extreme, Salvia  

 

BTW: Polygonum aviculare  + l-Citrulline seems to be promising 

 

I did find a report about Lion's mane curing dp, so maybe it has to do with depression and NGF more than anything.  Apparently major depressive disorder (MDD) is the most common comorbid condition not just with anhedonic traits but also with affective depersonalization,

According to APA, depersonalization/derealization disorder is most commonly comorbid with major depressive disorder, any type of anxiety disorder, and several personality disorders (avoidant, borderline, and obsessive-compulsive personality disorders, which also have elements of dissociation in their diagnostic criteria).

 

I just think we don't know enough about OP's condition to make a call.  Need more details.  More history of what has worked and what hasn't, and the specific progression of disease.

 

Salvia I don't think is the answer, especially micro dose.  By definition that is a dose that fails to produce an effect, save for the placebo effect.  The whole microdose movement is a farce.  I would recommend it in low-medium doses, not because it would work on a daily basis (it leaves you too exhausted like any psychedelic, and a light dose every few days could work.. if you believe all ligands are equal like serotonin and DMT), but mainly because it would be interesting how the OP responds to a few days in a row consumption.  It could be a positive or negative reaction, no idea.  For example, if he has bad reaction to Cannabis likely NMDA and glutamate are also involved.

 

If glutamate is involved it would mean agmatine could help, but so could turmeric and ginseng.

[Rorororo]

I did find a report about Lion's mane curing dp, so maybe it has to do with depression and NGF more than anything.  Apparently major depressive disorder (MDD) is the most common comorbid condition not just with anhedonic traits but also with affective depersonalization,

 

I just think we don't know enough about OP's condition to make a call.  Need more details.  More history of what has worked and what hasn't, and the specific progression of disease.

 

Salvia I don't think is the answer, especially micro dose.  By definition that is a dose that fails to produce an effect, save for the placebo effect.  The whole microdose movement is a farce.  I would recommend it in low-medium doses, not because it would work on a daily basis (it leaves you too exhausted like any psychedelic, and a light dose every few days could work.. if you believe all ligands are equal like serotonin and DMT), but mainly because it would be interesting how the OP responds to a few days in a row consumption.  It could be a positive or negative reaction, no idea.  For example, if he has bad reaction to Cannabis likely NMDA and glutamate are also involved.

 

If glutamate is involved it would mean agmatine could help, but so could turmeric and ginseng.

 

 

In regards to lions mane, here is one of many articles that state it's a KOR agonist.

 

 

What Lion’s Mane is probably most known for are its medicinal properties. It is rare that something can be both edible and safe to eat in quantity, while at the same time possessing well-studied medicinal action. In this case the compounds in question are Erinacines, which are complex kappa-opioid receptor agonists that have been shown to be potent neuro-protectors with the potential to treat everything from memory recall in 

alzheimer’s patients, to neuropathic pain, to addiction and depression. The safety profile of these compounds is incredible, even at high doses, and there are no known negative side-effects.

https://everythingmu...101-lions-mane/

 

Random reddit post too: https://www.reddit.c..._kappa_agonist/

 

I said, if you think you have a KOR problem and then take lions mane and then you get depressed....it will be a good verification method

 

I never said lions mane causes depression, those are two completely different things

 

Agmatine also helps depression (in some people....).  Too little of something or too much of something can produce the same results. I am sorry if I wasn't clear enough to leave room for inferences.

 

 

Also the OP specifically stated he was looking for help with KOR downregulation. He did not say he was looking for help with depression. Those are two different things.  It's cool to give a disclaimer (assuming you know enough to give a proper disclaimer) but I am trying to help for what he\she asked about.  I am not trying to make a call, I am simply helping for what he\she asked for.  I am also trying to help people that wonder into this thread looking for the same problem.  I don't want to hijack this thread, I hope someone can chime in someday with more info. 

 

 

Edited by Rorororo, 20 May 2020 - 05:02 PM.

[Rorororo]

I found this site that sells Dalea purpurea

 

https://naturalcommu...temum-purpureum

 

 

Which you can make your own tincture.

 

 

according to:  https://doi.org/10.17077/etd.9jb2s90u

 

You will have: 39 mg of pawhuskin A for every 234 grams of Dalea purpurea.

 

I also *believe* it is 3 fold times weaker than JDtic.  You have to compare the values to find a correct dosage. Don't  just take my word for it. 

Edited by Rorororo, 23 May 2020 - 02:29 AM.

[Rorororo]

It looks like pawhuskin A has mu and some delta antagonist properties.  Perhaps a mix of Black Cohosh (U - agonist) and red clover (U and delta agonist) will even things out. 

Edited by Rorororo, 23 May 2020 - 04:17 AM.

[Rorororo]

It looks like pawhuskin A has mu and some delta antagonist properties.  Perhaps a mix of Black Cohosh (U - agonist) and red clover (U and delta agonist) will even things out. 

 

Also start eating some white button mushrooms to avoid the increase in estrogen from red clover.  

 

By adding a little black cohosh to red clover, you're making the U agonist more potent btw as the mu antagonist properties are slightly stronger (in Dalea purpurea) than deltas. *Almost* by a fold I believe.  

Edited by Rorororo, 23 May 2020 - 06:23 AM.

[Rorororo]

Also start eating some white button mushrooms to avoid the increase in estrogen from red clover.  

 

By adding a little black cohosh to red clover, you're making the U agonist more potent btw as the mu antagonist properties are slightly stronger (in Dalea purpurea) than deltas. *Almost* by a fold I believe.  

 

 

I think this is your best bet along with purple prairie clover

 

https://www.ncbi.nlm...les/PMC2993511/

 

No need to worry about estrogen 

[Rorororo]

Also start eating some white button mushrooms to avoid the increase in estrogen from red clover.  

 

By adding a little black cohosh to red clover, you're making the U agonist more potent btw as the mu antagonist properties are slightly stronger (in Dalea purpurea) than deltas. *Almost* by a fold I believe.  

 

 

I think this is your best bet along with purple prairie clover

 

https://www.ncbi.nlm...les/PMC2993511/

 

No need to worry about estrogen 

 

OR, if you want to be smart about it....pair it with the lotus flower.

 

KOR antagonist

 

MOR and DOR agonist:

 

https://www.thieme-c.../s-0034-1382574

 

There is more affinity to DOR than MOR so you might want to throw in a selective MOR agonist or a combination with chaste tree but you need to look at the values and compare (i haven't done so yet).  I am guessing that the chaste tree has a higher affinity for MOR.

 

This is what the Chinese did before we had labs (combine different herbs for an objective treatment) 

 

Edited by Rorororo, 23 May 2020 - 08:48 PM.