48 replies to this topic

[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? 

 

 

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.

 

 

Call me skeptical, as there are so many moving parts to Atomoxetine. The peppermint oil experiment is going exceptionally well ATM. Focused energy with no anxiety. I'm assuming this is from rebound KOR antagonism effects from large nightly dosage of peppermint oil. Theoretically, I'm guessing the antagonism effect should only grow more pronounced - or at least stay steady - with continued KOR agonism. 

 

Results so far are definitely worth finding out.

Edited by Synaptik, 17 November 2016 - 08:36 PM.

[Synaptik]

The more I experiment with menthol (some experiences chronicled here), the more I'm thinking we have it all wrong. Perhaps low/medium does Kappa opioid agonism may be beneficial for depression & anxiety for long term, non-acute stressors (i.e. psychosocial stress causing social anxiety). Yes, KOR agonism is well documented as dysphoric and causing negative feedback activity in acute stress FST in rats, but what about kappa's inhibitory effects on serotonergic tone in the dorsal raphe nucleus?

 

Although this study to test their hypothesis that KOR agonism may induce anti-depressant effects at UC Davis is ongoing, I can confirm similar anti-depressant, avoidance attenuation and anti-anxiety effects through 4 weeks of using high dose menthol from pure peppermint oil. Half a tablespoon (with green tea) has me focused and moderately euphoric tonight, and has for the past 2 weeks. I believe my low-grade depression/avoidance anxiety stems from long term psychosocial awkwardness as a young teenager into my twenties. 

 

DESCRIPTION (provided by applicant): Psychosocial stress is an important risk factor for psychiatric disorders such as depression and anxiety. There has been increasing interest in targeting kappa opioid receptors (KOR) as a novel therapeutic target. Agonists for KOR have been reported to induce dysphoria and regulate the hypothalamic-pituitary-adrenal axis (HPA). New evidence suggests that there is a major gap in our understanding of the aversive properties of KOR. Studies showing that KOR mediates effects of stress on behavior primarily focus on short term effects of stress (15 min). However, after two days of psychosocial stress KOR loses its aversive properties. We hypothesize that this long term effect of psychosocial stress induces a neuroadaptation that fundamentally alters the effects of KOR. This is a critical idea because the field is working on the assumption that KOR antagonists have antidepressant properties. Our hypothesis suggests that KOR agonists will have stronger antidepressant properties for individuals exposed to long term psychosocial stress. Kappa opioid receptors inhibit serotonergic tone by inhibiting the activity of dorsal raphe nucleus (DRN) serotonin neurons. Increased serotonergic tone is linked to increased sensitivity to threat and increased inhibition o the HPA axis, and psychosocial stress can increase baseline activity of DRN serotonin neurons. By studying monogamous California mice, we are one of the only lab groups with the capability to study the effects of social defeat in both males and females. Females exposed to defeat exhibit social avoidance to non- threatening social stimuli. We hypothesize that defeat stress results in desensitization of the inhibitory effects of KOR on the DRN, which facilitates social avoidance. We predict that this effect is greater in females than males. If KOR inhibition of the DRN is stronger in stressed males, then social avoidance show be diminished and baseline corticosterone levels should be high. This is exactly what we have observed.

 

https://ucdavis.pure...les-and-females

 

 

This is the second such report I've read. I'm wondering whether anybody can add anything to the debate.

Edited by Synaptik, 11 December 2016 - 04:52 AM.

[Synaptik]

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.

 

I had the same effects, but unfortunately it's a controlled substance now. Based on my experiences with peppermint oil, I hypothesize that KOR receptors don't have to agonized all that much to get this antidepressant effect.

[Mind_Paralysis]

Hmm... curious. I must say that you are making a fairly good case here - there does seem to be pro's towards kappa-agonism after all.

 

I suppose the problem with why both agonism and antagonism show powerful anxiolytic and anti-depressive effects is solved by the fact that depression and anxiety are multi-modal diseases - not everyone will respond in the same way - it depends on how you're wired.

 

And then there's of course the old adage of Paracelsus: "The dosage makes the poison".

 

Still, Kappa-antagonist users have reported far, far more powerful results! Deadly powerful even. JDtic is a legend in the medical world for a reason, my friend! = )

 

 

I do wonder though, how does one identify which mechanism is correct for oneself? Trial and error can actually be a terribly dangerous process - are there any unifying traits and medical histories which signify the individuals who gain positive effects from Kappa-Agonism?

 

Antagonism is harder to pin down - since hardly anyone ALIVE has ever even had the chance to try that mechanism - it's a rare property!

[Synaptik]

Hmm... curious. I must say that you are making a fairly good case here - there does seem to be pro's towards kappa-agonism after all.

 

I suppose the problem with why both agonism and antagonism show powerful anxiolytic and anti-depressive effects is solved by the fact that depression and anxiety are multi-modal diseases - not everyone will respond in the same way - it depends on how you're wired.

 

And then there's of course the old adage of Paracelsus: "The dosage makes the poison".

 

Still, Kappa-antagonist users have reported far, far more powerful results! Deadly powerful even. JDtic is a legend in the medical world for a reason, my friend! = )

 

 

I do wonder though, how does one identify which mechanism is correct for oneself? Trial and error can actually be a terribly dangerous process - are there any unifying traits and medical histories which signify the individuals who gain positive effects from Kappa-Agonism?

 

Antagonism is harder to pin down - since hardly anyone ALIVE has ever even had the chance to try that mechanism - it's a rare property!

 

Yes, I have many questions about the mode of action causing this. Is it KOR receptor saturation and subsequent KOR antagonism causing these effects? Is it KOR agonism itself? If so, then why the long, consistent half-life of effects lasting over 24 hours? Sounds like rebound antagonist action to me. Or maybe the effects are serotonin inhibition in the HPA axis? I'm confused myself.

 

I have no doubt JDIC and Ibogaine have legendary effects for a reason. Perhaps both KOR antagonism and agonism are effective for different dosages and depression types. Perhaps antagonists are better for acute, non-responsive depression such as PTSD or the sudden violent death of a loved one. Agonism for non-acute GAD or Psychosocial stress building up over time affecting the amygdala.

 

Either way, it's probably pretty safe to experiment with peppermint oil or salvia in low doses. They are clean substances which don't touch much else. There's no risk of depersonalization off PM oil. 

Edited by Synaptik, 11 December 2016 - 04:20 PM.

[Dumond]

So it is well known that kappa opioid agonists decrease dopamine levels in the nucleus accumbens and decrease the euphoric effects of drugs. They also increase prolactin levels. Would a low dose of nalmefene upregulate dopamine D2 receptors, upregulate mu opioid receptors and downregulate kappa opioid receptors? This wikipedia article on kappa opioid receptors states the following:

https://en.m.wikiped...opioid_receptor

"One area of the brain most strongly associated with addiction is the nucleus accumbens (NAcc) and striatum while other structures that project to and from the NAcc also play a critical role. Though many other changes occur, addiction is often characterized by the reduction of dopamine D2 receptors in the NAcc.[60] In addition to low NAcc D2 binding,[61][62] cocaine is also known to produce a variety of changes to the primate brain such as increases prodynorphin mRNA in caudate putamen (striatum) and decreases of the same in the hypothalamus while the administration of a KOR agonist produced an opposite effect causing an increase in D2 receptors in the NAcc.[63]"

"The anti-rewarding properties of KOR agonists are mediated through both long-term and short-term effects. The immediate effect of KOR agonism leads to reduction of dopamine release in the NAcc during self-administration of cocaine[77] and over the long term up-regulates receptors that have been down-regulated during substance abuse such as the MOR and the D2receptor. These receptors modulate the release of other neurochemicals such as serotonin in the case of MOR agonists and acetylcholine in the case of D2. These changes can account for the physical and psychological remission of the pathology of addiction. The longer effects of KOR agonism (30 minutes or greater) have been linked to KOR-dependent stress-induced potentiation and reinstatement of drug seeking. It is hypothesized that these behaviors are mediated by KOR-dependent modulation of dopamine, serotonin, or norepinephrine and/or via activation of downstream signal transduction pathways."

However, these studies show that KOR agonists cause downregulation dopamine D2 receptors:
https://www.ncbi.nlm...ubmed/11169785/
https://www.ncbi.nlm...6237381/related

And this study shows a 40% decrease in D2 receptors in the caudate putamen and a 65% increase in D2 receptors in the nucleus accumbens after being treated with a KOR agonist.
https://www.ncbi.nlm...pubmed/9776131/

Can someone shed some light on this? Do KOR agonists increase or decrease D2 receptors? I would think that a depletion of dopamine levels in the nucleus accumbens, causes the brain to compensate by increasing D2 receptor density. Correct me if I'm wrong. These studies confuse me.

Edited by Dumond, 18 January 2017 - 11:00 PM.

[satsumass]

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

Synaptik are you still using peppermint oil at night? How have the effects played out over time if so, and especially would like to hear about any side effects? I'm particularly interested in hearing about how you dosed and how much....because....well after reading this thread and another, I experimented with peppermint oil as salvia is troublesome for me, and I have always, ever since I was a kid, really had a thing for very strong peppermint candies. Think going through an entire box of altoiids in an hour or two. I tried a variety of smallish doses ranging from half a teaspoon to 1-4 ml of dropper.

HOWEVER. After reading in another thread about someone who took (if I recollect correctly) half a TABLESPOON of peppermint oil at night to good effect I very stupidly took two whole teaspoons one night last week. I had also come back for a trip via airplane the previous night, but when I woke up the next morning I was feeling extremely fatigued, aches and flu-like....and then the diarrhea came, and it hasn't let up for 5 days. So it could very well be the stomach flu from traveling, but I am also,worried it might be a result of overdosing the peppermint oil. Though I didn't have untoward effects at the 0.5-1 tsp dose range. I also notice some mad acidy stomach pain feeling when my stomach is empty....so hoping there isn't serious damage.

Going to see doctor today but just curious as to your response, dosing, side effects,

[Galaxyshock]

Vietnamese Ginseng seems to be a herbal kappa-opioid receptor antagonist. I made a thread about it few years ago:

http://www.longecity...ppa-antagonist/

Unfortunately it seems to be extremely difficult to obtain.

 

Panax Ginseng showed some sort of partial blockade of kappa-opioid in the same study - it can be helpful.

[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

Synaptik are you still using peppermint oil at night? How have the effects played out over time if so, and especially would like to hear about any side effects? I'm particularly interested in hearing about how you dosed and how much....because....well after reading this thread and another, I experimented with peppermint oil as salvia is troublesome for me, and I have always, ever since I was a kid, really had a thing for very strong peppermint candies. Think going through an entire box of altoiids in an hour or two. I tried a variety of smallish doses ranging from half a teaspoon to 1-4 ml of dropper.

HOWEVER. After reading in another thread about someone who took (if I recollect correctly) half a TABLESPOON of peppermint oil at night to good effect I very stupidly took two whole teaspoons one night last week. I had also come back for a trip via airplane the previous night, but when I woke up the next morning I was feeling extremely fatigued, aches and flu-like....and then the diarrhea came, and it hasn't let up for 5 days. So it could very well be the stomach flu from traveling, but I am also,worried it might be a result of overdosing the peppermint oil. Though I didn't have untoward effects at the 0.5-1 tsp dose range. I also notice some mad acidy stomach pain feeling when my stomach is empty....so hoping there isn't serious damage.

Going to see doctor today but just curious as to your response, dosing, side effects,

 

Hi sausumass, glad to provide an update.

 

I do still take peppermint oil, as I find it very helpful in eliminating unwanted or "looping" subtext of thoughts constantly echoing in my head. The running dialogue everyone hears and wants to ignore sometimes. It eliminates 80-90% of this condition I would anecdotally estimate. Amazing stuff.

 

As time has passed, I've noticed the extreme crankiness or "edginess" I would feel from the dopamine inhibition to be LESS of a factor. It's still present, but not as pronounced. Whereas before I would take a little tyrosine to balance it out, I no longer need to. However, the coffee cravings are still there.

 

Peppermint oil also fits into my anti-aging regimen and contains a decent ORAC score (similar to ginkgo), so that's a bonus. Menthol may very well be an mTOR inhibitor as well. Double bonus.

 

As for dosage, I take approximately 3/4 of a tablespoon, once in the morning. Anecdotally find the effects more pronounced without a few hours of sleep behind it. No stomach effects at all.

 

I would recommend this to anyone with non-acute depression or OCD where long term KOR stress may be the activator.

 

If anyone has solid links to bulk peppermint oil supplies, please PM me. Currently purchasing small 30ml viles at my grocery store, but there has to be a more economical way.

 

I hope this helps.

[Mind_Paralysis]

@Synaptik - we're moving ahead with synthesizing CERC-501 - a selective kappa antagonist - would you be interested in joining the GROUP BUY?

 

We could use another member of the buy - so If you want to try antagonism instead of down-regulation, then this is your shot.

 

 

 

 

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

Synaptik are you still using peppermint oil at night? How have the effects played out over time if so, and especially would like to hear about any side effects? I'm particularly interested in hearing about how you dosed and how much....because....well after reading this thread and another, I experimented with peppermint oil as salvia is troublesome for me, and I have always, ever since I was a kid, really had a thing for very strong peppermint candies. Think going through an entire box of altoiids in an hour or two. I tried a variety of smallish doses ranging from half a teaspoon to 1-4 ml of dropper.

HOWEVER. After reading in another thread about someone who took (if I recollect correctly) half a TABLESPOON of peppermint oil at night to good effect I very stupidly took two whole teaspoons one night last week. I had also come back for a trip via airplane the previous night, but when I woke up the next morning I was feeling extremely fatigued, aches and flu-like....and then the diarrhea came, and it hasn't let up for 5 days. So it could very well be the stomach flu from traveling, but I am also,worried it might be a result of overdosing the peppermint oil. Though I didn't have untoward effects at the 0.5-1 tsp dose range. I also notice some mad acidy stomach pain feeling when my stomach is empty....so hoping there isn't serious damage.

Going to see doctor today but just curious as to your response, dosing, side effects,

 

Hi sausumass, glad to provide an update.

 

I do still take peppermint oil, as I find it very helpful in eliminating unwanted or "looping" subtext of thoughts constantly echoing in my head. The running dialogue everyone hears and wants to ignore sometimes. It eliminates 80-90% of this condition I would anecdotally estimate. Amazing stuff.

 

As time has passed, I've noticed the extreme crankiness or "edginess" I would feel from the dopamine inhibition to be LESS of a factor. It's still present, but not as pronounced. Whereas before I would take a little tyrosine to balance it out, I no longer need to. However, the coffee cravings are still there.

 

Peppermint oil also fits into my anti-aging regimen and contains a decent ORAC score (similar to ginkgo), so that's a bonus. Menthol may very well be an mTOR inhibitor as well. Double bonus.

 

As for dosage, I take approximately 3/4 of a tablespoon, once in the morning. Anecdotally find the effects more pronounced without a few hours of sleep behind it. No stomach effects at all.

 

I would recommend this to anyone with non-acute depression or OCD where long term KOR stress may be the activator.

 

If anyone has solid links to bulk peppermint oil supplies, please PM me. Currently purchasing small 30ml viles at my grocery store, but there has to be a more economical way.

 

I hope this helps.

 

 

So you're not taking it during the night anymore...? Doesn't the kappa-agonism cause INTENSE acute dysphoria (like what happens with Salvia, only less pronounced), hence why it's recommended to take the substance when going to sleep, preferrably with something Gaba to make sure you're OUT COLD - and then... when you wake up, you will suddenly feel IMMENSELY better.

 

Err... how do you stand the salvia-like existential pain that kappa-agonism causes?

 

Last couple of weeks I've finally started feeling the effects of 4-Hydroxyatomoxetine -induced depressive thoughts from Strattera btw - didn't feel anything until about a month into treatment, but now it's finally here... depressive thoughts, negative thinking regarding my situation, a kind of hopelessness which I haven't felt in a very, very long time.

 

It's been a hellish couple of days... That SKULL on the packaging is no f***ing joke! Of course, the depressive thoughts are probably not just a result of slight kappa-activation, but the modulation of norepinephrinergic activity it causes as well - NE is not just a neurotransmitter but a STRESS-hormone as well...! That, and coupled with my metabolism, which causes Atomoxetine to metabolise 5 times slower than in others... meaning there's a CHRONIC presence of kappa-activation in my system now, is probably why I started becoming rather down about two weeks ago.

 

But I was prepared, and I finally got the funds, so I scored some Tianeptine and have been using it for 4 days now - yesterday, and today especially, I'm noticing the effects of a more balanced opioid signalling! : D My depression is already decreased, by about 33% I should say - I can only surmise that it'll continue to improve in the next week or so.

 

Thank GOD for Tianeptine!

 

And GOD-DAMN for Kappa-agonism! >: ((
 

 

A bothersome side-effect of adding Tianeptine to my regimen is that it seems to enhance the somnolence I get from both NSI-189 and Atomoxetine though... I litterally overslept like 3.5 hours today - going in and out of consciousness as my various clock-alarms went off every hour or so - still couldn't get up - like if I was GLUED to the bed...!

 

My attention seems somewhat less impaired today as well... how odd! Or maybe not - Tianeptine has shown some effects on ADHD (and I do have that diagnosis). Actually finished watching a movie today, after weeks of not being able to finish it! : D

[satsumass]

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

Synaptik are you still using peppermint oil at night? How have the effects played out over time if so, and especially would like to hear about any side effects? I'm particularly interested in hearing about how you dosed and how much....because....well after reading this thread and another, I experimented with peppermint oil as salvia is troublesome for me, and I have always, ever since I was a kid, really had a thing for very strong peppermint candies. Think going through an entire box of altoiids in an hour or two. I tried a variety of smallish doses ranging from half a teaspoon to 1-4 ml of dropper.

HOWEVER. After reading in another thread about someone who took (if I recollect correctly) half a TABLESPOON of peppermint oil at night to good effect I very stupidly took two whole teaspoons one night last week. I had also come back for a trip via airplane the previous night, but when I woke up the next morning I was feeling extremely fatigued, aches and flu-like....and then the diarrhea came, and it hasn't let up for 5 days. So it could very well be the stomach flu from traveling, but I am also,worried it might be a result of overdosing the peppermint oil. Though I didn't have untoward effects at the 0.5-1 tsp dose range. I also notice some mad acidy stomach pain feeling when my stomach is empty....so hoping there isn't serious damage.

Going to see doctor today but just curious as to your response, dosing, side effects,

Hi sausumass, glad to provide an update.

I do still take peppermint oil, as I find it very helpful in eliminating unwanted or "looping" subtext of thoughts constantly echoing in my head. The running dialogue everyone hears and wants to ignore sometimes. It eliminates 80-90% of this condition I would anecdotally estimate. Amazing stuff.

As time has passed, I've noticed the extreme crankiness or "edginess" I would feel from the dopamine inhibition to be LESS of a factor. It's still present, but not as pronounced. Whereas before I would take a little tyrosine to balance it out, I no longer need to. However, the coffee cravings are still there.

Peppermint oil also fits into my anti-aging regimen and contains a decent ORAC score (similar to ginkgo), so that's a bonus. Menthol may very well be an mTOR inhibitor as well. Double bonus.

As for dosage, I take approximately 3/4 of a tablespoon, once in the morning. Anecdotally find the effects more pronounced without a few hours of sleep behind it. No stomach effects at all.

I would recommend this to anyone with non-acute depression or OCD where long term KOR stress may be the activator.

If anyone has solid links to bulk peppermint oil supplies, please PM me. Currently purchasing small 30ml viles at my grocery store, but there has to be a more economical way.

I hope this helps.

Thanks! This is super helpful. I just want to confirm though that you are taking 3/4th of a TABLEspoon not teaspoon...that's quite a bit over 2 teaspoons. I like the rush myself of the menthol but you haven't had any tummy problems? Do you take it empty stomach or food and have you noticed any difference?

I'm pretty certain my bout of gastroenteritis was due to actual stomach flu not the peppermint oil.

[Synaptik]

@Synaptik - we're moving ahead with synthesizing CERC-501 - a selective kappa antagonist - would you be interested in joining the GROUP BUY?

 

We could use another member of the buy - so If you want to try antagonism instead of down-regulation, then this is your shot.

 

 

 

 

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

Synaptik are you still using peppermint oil at night? How have the effects played out over time if so, and especially would like to hear about any side effects? I'm particularly interested in hearing about how you dosed and how much....because....well after reading this thread and another, I experimented with peppermint oil as salvia is troublesome for me, and I have always, ever since I was a kid, really had a thing for very strong peppermint candies. Think going through an entire box of altoiids in an hour or two. I tried a variety of smallish doses ranging from half a teaspoon to 1-4 ml of dropper.

HOWEVER. After reading in another thread about someone who took (if I recollect correctly) half a TABLESPOON of peppermint oil at night to good effect I very stupidly took two whole teaspoons one night last week. I had also come back for a trip via airplane the previous night, but when I woke up the next morning I was feeling extremely fatigued, aches and flu-like....and then the diarrhea came, and it hasn't let up for 5 days. So it could very well be the stomach flu from traveling, but I am also,worried it might be a result of overdosing the peppermint oil. Though I didn't have untoward effects at the 0.5-1 tsp dose range. I also notice some mad acidy stomach pain feeling when my stomach is empty....so hoping there isn't serious damage.

Going to see doctor today but just curious as to your response, dosing, side effects,

 

Hi sausumass, glad to provide an update.

 

I do still take peppermint oil, as I find it very helpful in eliminating unwanted or "looping" subtext of thoughts constantly echoing in my head. The running dialogue everyone hears and wants to ignore sometimes. It eliminates 80-90% of this condition I would anecdotally estimate. Amazing stuff.

 

As time has passed, I've noticed the extreme crankiness or "edginess" I would feel from the dopamine inhibition to be LESS of a factor. It's still present, but not as pronounced. Whereas before I would take a little tyrosine to balance it out, I no longer need to. However, the coffee cravings are still there.

 

Peppermint oil also fits into my anti-aging regimen and contains a decent ORAC score (similar to ginkgo), so that's a bonus. Menthol may very well be an mTOR inhibitor as well. Double bonus.

 

As for dosage, I take approximately 3/4 of a tablespoon, once in the morning. Anecdotally find the effects more pronounced without a few hours of sleep behind it. No stomach effects at all.

 

I would recommend this to anyone with non-acute depression or OCD where long term KOR stress may be the activator.

 

If anyone has solid links to bulk peppermint oil supplies, please PM me. Currently purchasing small 30ml viles at my grocery store, but there has to be a more economical way.

 

I hope this helps.

 

 

So you're not taking it during the night anymore...? Doesn't the kappa-agonism cause INTENSE acute dysphoria (like what happens with Salvia, only less pronounced), hence why it's recommended to take the substance when going to sleep, preferrably with something Gaba to make sure you're OUT COLD - and then... when you wake up, you will suddenly feel IMMENSELY better.

 

Err... how do you stand the salvia-like existential pain that kappa-agonism causes?

 

Last couple of weeks I've finally started feeling the effects of 4-Hydroxyatomoxetine -induced depressive thoughts from Strattera btw - didn't feel anything until about a month into treatment, but now it's finally here... depressive thoughts, negative thinking regarding my situation, a kind of hopelessness which I haven't felt in a very, very long time.

 

It's been a hellish couple of days... That SKULL on the packaging is no f***ing joke! Of course, the depressive thoughts are probably not just a result of slight kappa-activation, but the modulation of norepinephrinergic activity it causes as well - NE is not just a neurotransmitter but a STRESS-hormone as well...! That, and coupled with my metabolism, which causes Atomoxetine to metabolise 5 times slower than in others... meaning there's a CHRONIC presence of kappa-activation in my system now, is probably why I started becoming rather down about two weeks ago.

 

But I was prepared, and I finally got the funds, so I scored some Tianeptine and have been using it for 4 days now - yesterday, and today especially, I'm noticing the effects of a more balanced opioid signalling! : D My depression is already decreased, by about 33% I should say - I can only surmise that it'll continue to improve in the next week or so.

 

Thank GOD for Tianeptine!

 

And GOD-DAMN for Kappa-agonism! >: ((
 

 

A bothersome side-effect of adding Tianeptine to my regimen is that it seems to enhance the somnolence I get from both NSI-189 and Atomoxetine though... I litterally overslept like 3.5 hours today - going in and out of consciousness as my various clock-alarms went off every hour or so - still couldn't get up - like if I was GLUED to the bed...!

 

My attention seems somewhat less impaired today as well... how odd! Or maybe not - Tianeptine has shown some effects on ADHD (and I do have that diagnosis). Actually finished watching a movie today, after weeks of not being able to finish it! : D

 

There's nothing "hellish" about taking peppermint oil, as it doesn't provide the intense salvia-like dysphoria. So I'm able to take it in the morning no problem. It keeps any sort of depression or ruminating thoughts at bay, at least for me.

 

About the only "hellish" thing about it is the decreased dopamine which to me is obvious. I'm more quick tempered with things that bother me and things like that. It kinda feels like the day after using amphetamines, where dopamine stores have been exhausted. That's the one drawback with peppermint oil in my experience.

 

However, it's not a deal breaker because of the other benefits it provides. Some people may definitely need a D2 balancer.

 

How much would the group buy dose cost? I consider my "depression" or co-morbid "anxiety" relatively mild, and I don't have the most funds ATM. 

[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

Synaptik are you still using peppermint oil at night? How have the effects played out over time if so, and especially would like to hear about any side effects? I'm particularly interested in hearing about how you dosed and how much....because....well after reading this thread and another, I experimented with peppermint oil as salvia is troublesome for me, and I have always, ever since I was a kid, really had a thing for very strong peppermint candies. Think going through an entire box of altoiids in an hour or two. I tried a variety of smallish doses ranging from half a teaspoon to 1-4 ml of dropper.

HOWEVER. After reading in another thread about someone who took (if I recollect correctly) half a TABLESPOON of peppermint oil at night to good effect I very stupidly took two whole teaspoons one night last week. I had also come back for a trip via airplane the previous night, but when I woke up the next morning I was feeling extremely fatigued, aches and flu-like....and then the diarrhea came, and it hasn't let up for 5 days. So it could very well be the stomach flu from traveling, but I am also,worried it might be a result of overdosing the peppermint oil. Though I didn't have untoward effects at the 0.5-1 tsp dose range. I also notice some mad acidy stomach pain feeling when my stomach is empty....so hoping there isn't serious damage.

Going to see doctor today but just curious as to your response, dosing, side effects,

Hi sausumass, glad to provide an update.

I do still take peppermint oil, as I find it very helpful in eliminating unwanted or "looping" subtext of thoughts constantly echoing in my head. The running dialogue everyone hears and wants to ignore sometimes. It eliminates 80-90% of this condition I would anecdotally estimate. Amazing stuff.

As time has passed, I've noticed the extreme crankiness or "edginess" I would feel from the dopamine inhibition to be LESS of a factor. It's still present, but not as pronounced. Whereas before I would take a little tyrosine to balance it out, I no longer need to. However, the coffee cravings are still there.

Peppermint oil also fits into my anti-aging regimen and contains a decent ORAC score (similar to ginkgo), so that's a bonus. Menthol may very well be an mTOR inhibitor as well. Double bonus.

As for dosage, I take approximately 3/4 of a tablespoon, once in the morning. Anecdotally find the effects more pronounced without a few hours of sleep behind it. No stomach effects at all.

I would recommend this to anyone with non-acute depression or OCD where long term KOR stress may be the activator.

If anyone has solid links to bulk peppermint oil supplies, please PM me. Currently purchasing small 30ml viles at my grocery store, but there has to be a more economical way.

I hope this helps.

Thanks! This is super helpful. I just want to confirm though that you are taking 3/4th of a TABLEspoon not teaspoon...that's quite a bit over 2 teaspoons. I like the rush myself of the menthol but you haven't had any tummy problems? Do you take it empty stomach or food and have you noticed any difference?

I'm pretty certain my bout of gastroenteritis was due to actual stomach flu not the peppermint oil.

 

Yeah, no issues at all at that dose. I used to feel a hint of low level KOR agonism effects(just a hint of that salvia feeling), but don't anymore. Stop issues have never been an issue. In fact, peppermint oil is recommended for IBS but in lower doses.

[Mind_Paralysis]

However, it's not a deal breaker because of the other benefits it provides. Some people may definitely need a D2 balancer.

 

How much would the group buy dose cost? I consider my "depression" or co-morbid "anxiety" relatively mild, and I don't have the most funds ATM. 

 

 

The group buy dose should cost you between 200 and 250$ - it's not a bad price! = ) If we get only 5 more people, then the price will go down dramatically!
 

[cetacean]

However, it's not a deal breaker because of the other benefits it provides. Some people may definitely need a D2 balancer.

How much would the group buy dose cost? I consider my "depression" or co-morbid "anxiety" relatively mild, and I don't have the most funds ATM.

The group buy dose should cost you between 200 and 250$ - it's not a bad price! = ) If we get only 5 more people, then the price will go down dramatically!

I am definitely interested. I sent you a personal message about it.

I have gotten fantastic inprovements in mood and motivation from LD naltrexone so I presume there's something off in my opiate system. Yet it has also seemed to increase my cravings for opiates and alcohol and I have read that blocking kappa receptors reduces addictive tendencies.

Edited by cetacean, 03 April 2017 - 04:24 PM.

[SoundsAboutRight]

So it is well known that kappa opioid agonists decrease dopamine levels in the nucleus accumbens and decrease the euphoric effects of drugs. They also increase prolactin levels. Would a low dose of nalmefene upregulate dopamine D2 receptors, upregulate mu opioid receptors and downregulate kappa opioid receptors? This wikipedia article on kappa opioid receptors states the following:

https://en.m.wikiped...opioid_receptor

"One area of the brain most strongly associated with addiction is the nucleus accumbens (NAcc) and striatum while other structures that project to and from the NAcc also play a critical role. Though many other changes occur, addiction is often characterized by the reduction of dopamine D2 receptors in the NAcc.[60] In addition to low NAcc D2 binding,[61][62] cocaine is also known to produce a variety of changes to the primate brain such as increases prodynorphin mRNA in caudate putamen (striatum) and decreases of the same in the hypothalamus while the administration of a KOR agonist produced an opposite effect causing an increase in D2 receptors in the NAcc.[63]"

"The anti-rewarding properties of KOR agonists are mediated through both long-term and short-term effects. The immediate effect of KOR agonism leads to reduction of dopamine release in the NAcc during self-administration of cocaine[77] and over the long term up-regulates receptors that have been down-regulated during substance abuse such as the MOR and the D2receptor. These receptors modulate the release of other neurochemicals such as serotonin in the case of MOR agonists and acetylcholine in the case of D2. These changes can account for the physical and psychological remission of the pathology of addiction. The longer effects of KOR agonism (30 minutes or greater) have been linked to KOR-dependent stress-induced potentiation and reinstatement of drug seeking. It is hypothesized that these behaviors are mediated by KOR-dependent modulation of dopamine, serotonin, or norepinephrine and/or via activation of downstream signal transduction pathways."

However, these studies show that KOR agonists cause downregulation dopamine D2 receptors:
https://www.ncbi.nlm...ubmed/11169785/
https://www.ncbi.nlm...6237381/related

And this study shows a 40% decrease in D2 receptors in the caudate putamen and a 65% increase in D2 receptors in the nucleus accumbens after being treated with a KOR agonist.
https://www.ncbi.nlm...pubmed/9776131/

Can someone shed some light on this? Do KOR agonists increase or decrease D2 receptors? I would think that a depletion of dopamine levels in the nucleus accumbens, causes the brain to compensate by increasing D2 receptor density. Correct me if I'm wrong. These studies confuse me.

Regarding the last study you posted: https://www.ncbi.nlm...pubmed/9776131/

 

U-69593, the selective K-opioid agonist, was repeatedly administered in single daily injections (0.32 mg/kg) to male, Sprague-Dawley rats. Two or ten days later, the rats were euthanized and dopamine D1 and D2 receptors were measured using (3H]SCH 23390 or [3H]sulpiride, respectively, in caudate putamen and nucleus accumbens.

 

caudate putamen: Two days after the last of three injections, dopamine D2 receptors in the caudate putamen were decreased by approximately 40%, with no change in D1 receptors. Dopamine D2 receptor number had returned to normal by 10 days posttreatment.

 

The changes in the caudate putamen were only temporary downregulated. 

 

nucleus accumbens: In contrast, in the nucleus accumbens there was a small, nonsignificant decrease in dopamine D2 receptors 2 days after treatment, but a large increase (65%) after 10 days. In agreement with the changes in D2 receptors, there was a significant downward shift in the locomotor activity curve for the D2 agonist quinpirole after a 2-day withdrawal.

 

The receptors were increased in the nucleus accumbens

 

 

Regarding the first study: https://www.ncbi.nlm...ubmed/11169785/

 

Acute administration of quinpirole significantly decreased striatal DA levels in control animals, but in animals treated with U69593, the inhibitory effects of quinpirole were significantly reduced. Quinpirole produced a dose-related increase in locomotor activity in control animals, and this effect was significantly attenuated in U69593-treated animals. These data reveal that prior repeated administration of a selective kappa-opioid receptor agonist attenuates quinpirole-induced alterations in DA neurotransmission and locomotor activity. These results suggest that both pre- and postsynaptic striatal DA D2 receptors may be downregulated following repeated kappa-opioid receptor agonist administration.

 

Someone might have to correct me, but quinpirole is a agonist of the D2/D3 receptors and would inherently downregulate the dopamine receptors. Not sure how you can isolate the downregulation caused by the quinpirole from the U69593. Locomotor activity refers to spontaneous movement - wouldn't that indicate increased motivation? The study above also indicates a sharp decline in the locomotor activity after 2 days withdrawal from quinpirole. Second, the inhibitory effects of quinpirole were reduced by U69593 - isn't that positive?

 

haha this is an attempt to understand these studies - take it with a grain of salt. Any feedback would be appreciated...

 

Edited by mfad, 04 July 2017 - 09:50 AM.

[RedStaR]

@Synaptik - we're moving ahead with synthesizing CERC-501 - a selective kappa antagonist - would you be interested in joining the GROUP BUY?

 

We could use another member of the buy - so If you want to try antagonism instead of down-regulation, then this is your shot.

 

 

 

 

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

Synaptik are you still using peppermint oil at night? How have the effects played out over time if so, and especially would like to hear about any side effects? I'm particularly interested in hearing about how you dosed and how much....because....well after reading this thread and another, I experimented with peppermint oil as salvia is troublesome for me, and I have always, ever since I was a kid, really had a thing for very strong peppermint candies. Think going through an entire box of altoiids in an hour or two. I tried a variety of smallish doses ranging from half a teaspoon to 1-4 ml of dropper.

HOWEVER. After reading in another thread about someone who took (if I recollect correctly) half a TABLESPOON of peppermint oil at night to good effect I very stupidly took two whole teaspoons one night last week. I had also come back for a trip via airplane the previous night, but when I woke up the next morning I was feeling extremely fatigued, aches and flu-like....and then the diarrhea came, and it hasn't let up for 5 days. So it could very well be the stomach flu from traveling, but I am also,worried it might be a result of overdosing the peppermint oil. Though I didn't have untoward effects at the 0.5-1 tsp dose range. I also notice some mad acidy stomach pain feeling when my stomach is empty....so hoping there isn't serious damage.

Going to see doctor today but just curious as to your response, dosing, side effects,

 

Hi sausumass, glad to provide an update.

 

I do still take peppermint oil, as I find it very helpful in eliminating unwanted or "looping" subtext of thoughts constantly echoing in my head. The running dialogue everyone hears and wants to ignore sometimes. It eliminates 80-90% of this condition I would anecdotally estimate. Amazing stuff.

 

As time has passed, I've noticed the extreme crankiness or "edginess" I would feel from the dopamine inhibition to be LESS of a factor. It's still present, but not as pronounced. Whereas before I would take a little tyrosine to balance it out, I no longer need to. However, the coffee cravings are still there.

 

Peppermint oil also fits into my anti-aging regimen and contains a decent ORAC score (similar to ginkgo), so that's a bonus. Menthol may very well be an mTOR inhibitor as well. Double bonus.

 

As for dosage, I take approximately 3/4 of a tablespoon, once in the morning. Anecdotally find the effects more pronounced without a few hours of sleep behind it. No stomach effects at all.

 

I would recommend this to anyone with non-acute depression or OCD where long term KOR stress may be the activator.

 

If anyone has solid links to bulk peppermint oil supplies, please PM me. Currently purchasing small 30ml viles at my grocery store, but there has to be a more economical way.

 

I hope this helps.

 

 

So you're not taking it during the night anymore...? Doesn't the kappa-agonism cause INTENSE acute dysphoria (like what happens with Salvia, only less pronounced), hence why it's recommended to take the substance when going to sleep, preferrably with something Gaba to make sure you're OUT COLD - and then... when you wake up, you will suddenly feel IMMENSELY better.

 

Err... how do you stand the salvia-like existential pain that kappa-agonism causes?

 

Last couple of weeks I've finally started feeling the effects of 4-Hydroxyatomoxetine -induced depressive thoughts from Strattera btw - didn't feel anything until about a month into treatment, but now it's finally here... depressive thoughts, negative thinking regarding my situation, a kind of hopelessness which I haven't felt in a very, very long time.

 

It's been a hellish couple of days... That SKULL on the packaging is no f***ing joke! Of course, the depressive thoughts are probably not just a result of slight kappa-activation, but the modulation of norepinephrinergic activity it causes as well - NE is not just a neurotransmitter but a STRESS-hormone as well...! That, and coupled with my metabolism, which causes Atomoxetine to metabolise 5 times slower than in others... meaning there's a CHRONIC presence of kappa-activation in my system now, is probably why I started becoming rather down about two weeks ago.

 

But I was prepared, and I finally got the funds, so I scored some Tianeptine and have been using it for 4 days now - yesterday, and today especially, I'm noticing the effects of a more balanced opioid signalling! : D My depression is already decreased, by about 33% I should say - I can only surmise that it'll continue to improve in the next week or so.

 

Thank GOD for Tianeptine!

 

And GOD-DAMN for Kappa-agonism! >: ((
 

 

A bothersome side-effect of adding Tianeptine to my regimen is that it seems to enhance the somnolence I get from both NSI-189 and Atomoxetine though... I litterally overslept like 3.5 hours today - going in and out of consciousness as my various clock-alarms went off every hour or so - still couldn't get up - like if I was GLUED to the bed...!

 

My attention seems somewhat less impaired today as well... how odd! Or maybe not - Tianeptine has shown some effects on ADHD (and I do have that diagnosis). Actually finished watching a movie today, after weeks of not being able to finish it! : D

 

I know this is an old post, but if you are a PM for CYP2D6, then you should not worry about Kappa agonism, as the primary metabolite is severely reduced, by almost half or more.

[Mind_Paralysis]

 

@Synaptik - we're moving ahead with synthesizing CERC-501 - a selective kappa antagonist - would you be interested in joining the GROUP BUY?

 

We could use another member of the buy - so If you want to try antagonism instead of down-regulation, then this is your shot.

 

 

Hi sausumass, glad to provide an update.

 

 

I do still take peppermint oil, as I find it very helpful in eliminating unwanted or "looping" subtext of thoughts constantly echoing in my head. The running dialogue everyone hears and wants to ignore sometimes. It eliminates 80-90% of this condition I would anecdotally estimate. Amazing stuff.

 

As time has passed, I've noticed the extreme crankiness or "edginess" I would feel from the dopamine inhibition to be LESS of a factor. It's still present, but not as pronounced. Whereas before I would take a little tyrosine to balance it out, I no longer need to. However, the coffee cravings are still there.

 

Peppermint oil also fits into my anti-aging regimen and contains a decent ORAC score (similar to ginkgo), so that's a bonus. Menthol may very well be an mTOR inhibitor as well. Double bonus.

 

As for dosage, I take approximately 3/4 of a tablespoon, once in the morning. Anecdotally find the effects more pronounced without a few hours of sleep behind it. No stomach effects at all.

 

I would recommend this to anyone with non-acute depression or OCD where long term KOR stress may be the activator.

 

If anyone has solid links to bulk peppermint oil supplies, please PM me. Currently purchasing small 30ml viles at my grocery store, but there has to be a more economical way.

 

I hope this helps.

 

 

So you're not taking it during the night anymore...? Doesn't the kappa-agonism cause INTENSE acute dysphoria (like what happens with Salvia, only less pronounced), hence why it's recommended to take the substance when going to sleep, preferrably with something Gaba to make sure you're OUT COLD - and then... when you wake up, you will suddenly feel IMMENSELY better.

 

Err... how do you stand the salvia-like existential pain that kappa-agonism causes?

 

Last couple of weeks I've finally started feeling the effects of 4-Hydroxyatomoxetine -induced depressive thoughts from Strattera btw - didn't feel anything until about a month into treatment, but now it's finally here... depressive thoughts, negative thinking regarding my situation, a kind of hopelessness which I haven't felt in a very, very long time.

 

It's been a hellish couple of days... That SKULL on the packaging is no f***ing joke! Of course, the depressive thoughts are probably not just a result of slight kappa-activation, but the modulation of norepinephrinergic activity it causes as well - NE is not just a neurotransmitter but a STRESS-hormone as well...! That, and coupled with my metabolism, which causes Atomoxetine to metabolise 5 times slower than in others... meaning there's a CHRONIC presence of kappa-activation in my system now, is probably why I started becoming rather down about two weeks ago.

 

But I was prepared, and I finally got the funds, so I scored some Tianeptine and have been using it for 4 days now - yesterday, and today especially, I'm noticing the effects of a more balanced opioid signalling! : D My depression is already decreased, by about 33% I should say - I can only surmise that it'll continue to improve in the next week or so.

 

Thank GOD for Tianeptine!

 

And GOD-DAMN for Kappa-agonism! >: ((
 

 

A bothersome side-effect of adding Tianeptine to my regimen is that it seems to enhance the somnolence I get from both NSI-189 and Atomoxetine though... I litterally overslept like 3.5 hours today - going in and out of consciousness as my various clock-alarms went off every hour or so - still couldn't get up - like if I was GLUED to the bed...!

 

My attention seems somewhat less impaired today as well... how odd! Or maybe not - Tianeptine has shown some effects on ADHD (and I do have that diagnosis). Actually finished watching a movie today, after weeks of not being able to finish it! : D

 

I know this is an old post, but if you are a PM for CYP2D6, then you should not worry about Kappa agonism, as the primary metabolite is severely reduced, by almost half or more.

 

 

Actually, yes I'm aware of that - the reason I finally dared to try ATX originally was because I finally figured out the pm for CYP2D6 would actually mean LESS of the metabolite.

 

However, I still got a bit depressed by ATX! I no longer believe it's connected to the Kappa-metabolite though, the evidence does not support it.

It should be noted that I tried Reboxetine for about a month as well, and that did not cause depression - it did cause some anxiety at times though, but the two are not the same. I actually think depressive thoughts got a bit better with Reboxetine! Well, until I was struck with the tremendous pseudo-anticholinergic side-effects, that is - it became an utter slog and a chore to get through my trial then. : \

 

The depressive side-effect some people, and I, have reported from ATX must be caused by some other mechanism than kappa-agonism - not sure what though?? NMDA-antagonism? But that's being researched as a method of treating depression... So, it's all a bit confusing, and certainly made me realize how complicated things are, when it comes to the effects of drugs.

 

It IS rather interesting that Tianeptine had such a robust effect on the negative thoughts though - and it does alter the signalling-ratio between NMDA and AMPA-receptors, so maybe there's something to NMDA-antagonism causing depression in certain circumstances.

[RedStaR]

 

 

@Synaptik - we're moving ahead with synthesizing CERC-501 - a selective kappa antagonist - would you be interested in joining the GROUP BUY?

 

We could use another member of the buy - so If you want to try antagonism instead of down-regulation, then this is your shot.

 

 

Hi sausumass, glad to provide an update.

 

 

I do still take peppermint oil, as I find it very helpful in eliminating unwanted or "looping" subtext of thoughts constantly echoing in my head. The running dialogue everyone hears and wants to ignore sometimes. It eliminates 80-90% of this condition I would anecdotally estimate. Amazing stuff.

 

As time has passed, I've noticed the extreme crankiness or "edginess" I would feel from the dopamine inhibition to be LESS of a factor. It's still present, but not as pronounced. Whereas before I would take a little tyrosine to balance it out, I no longer need to. However, the coffee cravings are still there.

 

Peppermint oil also fits into my anti-aging regimen and contains a decent ORAC score (similar to ginkgo), so that's a bonus. Menthol may very well be an mTOR inhibitor as well. Double bonus.

 

As for dosage, I take approximately 3/4 of a tablespoon, once in the morning. Anecdotally find the effects more pronounced without a few hours of sleep behind it. No stomach effects at all.

 

I would recommend this to anyone with non-acute depression or OCD where long term KOR stress may be the activator.

 

If anyone has solid links to bulk peppermint oil supplies, please PM me. Currently purchasing small 30ml viles at my grocery store, but there has to be a more economical way.

 

I hope this helps.

 

 

So you're not taking it during the night anymore...? Doesn't the kappa-agonism cause INTENSE acute dysphoria (like what happens with Salvia, only less pronounced), hence why it's recommended to take the substance when going to sleep, preferrably with something Gaba to make sure you're OUT COLD - and then... when you wake up, you will suddenly feel IMMENSELY better.

 

Err... how do you stand the salvia-like existential pain that kappa-agonism causes?

 

Last couple of weeks I've finally started feeling the effects of 4-Hydroxyatomoxetine -induced depressive thoughts from Strattera btw - didn't feel anything until about a month into treatment, but now it's finally here... depressive thoughts, negative thinking regarding my situation, a kind of hopelessness which I haven't felt in a very, very long time.

 

It's been a hellish couple of days... That SKULL on the packaging is no f***ing joke! Of course, the depressive thoughts are probably not just a result of slight kappa-activation, but the modulation of norepinephrinergic activity it causes as well - NE is not just a neurotransmitter but a STRESS-hormone as well...! That, and coupled with my metabolism, which causes Atomoxetine to metabolise 5 times slower than in others... meaning there's a CHRONIC presence of kappa-activation in my system now, is probably why I started becoming rather down about two weeks ago.

 

But I was prepared, and I finally got the funds, so I scored some Tianeptine and have been using it for 4 days now - yesterday, and today especially, I'm noticing the effects of a more balanced opioid signalling! : D My depression is already decreased, by about 33% I should say - I can only surmise that it'll continue to improve in the next week or so.

 

Thank GOD for Tianeptine!

 

And GOD-DAMN for Kappa-agonism! >: ((
 

 

A bothersome side-effect of adding Tianeptine to my regimen is that it seems to enhance the somnolence I get from both NSI-189 and Atomoxetine though... I litterally overslept like 3.5 hours today - going in and out of consciousness as my various clock-alarms went off every hour or so - still couldn't get up - like if I was GLUED to the bed...!

 

My attention seems somewhat less impaired today as well... how odd! Or maybe not - Tianeptine has shown some effects on ADHD (and I do have that diagnosis). Actually finished watching a movie today, after weeks of not being able to finish it! : D

 

I know this is an old post, but if you are a PM for CYP2D6, then you should not worry about Kappa agonism, as the primary metabolite is severely reduced, by almost half or more.

 

 

Actually, yes I'm aware of that - the reason I finally dared to try ATX originally was because I finally figured out the pm for CYP2D6 would actually mean LESS of the metabolite.

 

However, I still got a bit depressed by ATX! I no longer believe it's connected to the Kappa-metabolite though, the evidence does not support it.

It should be noted that I tried Reboxetine for about a month as well, and that did not cause depression - it did cause some anxiety at times though, but the two are not the same. I actually think depressive thoughts got a bit better with Reboxetine! Well, until I was struck with the tremendous pseudo-anticholinergic side-effects, that is - it became an utter slog and a chore to get through my trial then. : \

 

The depressive side-effect some people, and I, have reported from ATX must be caused by some other mechanism than kappa-agonism - not sure what though?? NMDA-antagonism? But that's being researched as a method of treating depression... So, it's all a bit confusing, and certainly made me realize how complicated things are, when it comes to the effects of drugs.

 

It IS rather interesting that Tianeptine had such a robust effect on the negative thoughts though - and it does alter the signalling-ratio between NMDA and AMPA-receptors, so maybe there's something to NMDA-antagonism causing depression in certain circumstances.

 

 

I would say k-opiod antagonism is the only mechanism that could cause depressive symptoms. Ketamine I believe works its anti-depressant effects through AMPA more than NMDA, so NMDA antagonism might also be a factor. We should also consider SERT inhibition. Although all 3 (except NMDA maybe?) of those are mainly caused by the 4-OH-ATX, but should still be available in sufficient quantities to exert their effect.