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Ketamine works as anti-depressant by activating AMPA receptors?

anti-depressant ampa ketamine nmda glycine

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#1 lovaffect

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Posted 26 November 2016 - 01:33 PM


Hello. I have the person, she tried 5 mg of S-ketamine as anti-depressant. First hour she seemed a little talkative (maybe DAT inhibition or placebo), but later about 6 hours after she felt really worse, her depression became horribly worse and it continued.

Then I found this: https://www.nih.gov/...-its-metabolism

basically they say "The experiments confirmed that the rapid antidepressant-like effects require activation of AMPA receptors, not inhibition of NMDA receptors."

From previous experiences I got the idea that AMPA activation is bad for her, any racetams and ampakines like aniracetam made her feel bad.

Another thing says benzodiazepines reduce or block the anti-depressant effect of ketmaine: http://anp.sagepub.c...5590631.extract
At the same time GABA enhancing substances make her feel better. 300mg of pregabalin make her feel almost cured, baclofen also has very beneficial effect.

 

What ideas can be drawn from this? In what way the brain should be that different from "normal" to have such reactions?


Edited by lovaffect, 26 November 2016 - 01:35 PM.


#2 Mind_Paralysis

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Posted 26 November 2016 - 11:55 PM

Well, here's the thing though - there's some new data on this, and I'm not so sure S-Ketamine WOULD be an effective antidepressant... seems to me as if R-ketamine is actually better - mainly because that's the enantiomer that turns into Hydroxynorketamine, which so happens to be the compound which has AMPA-affinity.

 

Esketamine is mostly a DA-reuptake inhibitor and NMDA-antagonist - it seems to be responsible for most of the NON-antidepressant activities of Ketamine - the stimulant, euphoric and dissociative effects.

Not everyone gets any sort of antidepressant feelings from enhanced DA, which would be the result of concommitant DA-reuptake inhibition and NMDA-antagonism - in fact, some actually get a LOT more anxiety from increased DA.

 

And if anxiety is depressing for your friend... well, there you have it.

 

 

https://en.wikipedia...wiki/Arketamine

 

 

Tell your friend to use NSI-189 along with some potent form of anxiolytic - I recommend Duloxetine, since SNRI's have been proven to be the best for general anxiety and disorders, in the long-term treatment of those. I'm afraid Pregabalin is UTTERLY unsustainable and will eventually cause TOTAL depression when she reaches sufficient tolerance (which is inevitable).

 

 

The reactions to Racetams is difficult to decipher - perhaps she has some kind of abnormality in her Cholinergic systems...? And the depletion of aCh, which is the result of using those, or perhaps the increased ach-activity in general, makes her emotionally unstable.

 

Hmm... have you considered her having a diagnosis of CPTSD and...

 

BORDERLINE PERSONALITY DISORDER?!

 

Forgive the dramatics...but it's a dramatic disorder, quite possibly the deadliest and hardest to treat of all disorders - second only to Psychopathy-spectrum disorders when it comes to the chaos and death which they cause, for ALL LIFE as we know it. (think it through... whatever turns human society into sh*t could have lasting effects on all other forms of life on earth... hence these disorders, Narcicisstic ones at least, is a threat TO ALL LIFE! The eradication of sickening selfishness would be a boon to all that exists.)

 

 

Anyways, if she truly has that disorder, then cholinergics could hypothetically impact significantly on her - because we have an entire thread devoted to the new data implying cholinergic system malfunction along with abnormalities in the Amygdala and PFC in those with BPD - in essence, BPD is a SHIT term which means nothing - it's a neuropsychiatric disease - similar to both ADHD and Autism.

 

Luckily though, hypothetically, the Nicotinic Acetylcholine Receptor type 7 is central in the disease, aaand... Hydroxynorketamine potently inhibits activity of that receptor! = ) So, perhaps she just got the wrong type of Ketamine, yes?



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#3 lovaffect

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Posted 28 November 2016 - 01:21 PM

Stinkorninjor, thank you for your reply. Well, I had such thoughts, and if we devide ketmaine's effects on short-term, the "abuse" effects (dissosication, euphoria that come from DAT and NMDA inhibiton) and long-term - the anti-depressants effect. So when the K is abused, people have trip that lasts about an hour, in time of those effects she was feeling OK, fine, she started feeling worse much later, 6 hours after, that's excatly whe the "anti-depressant", the "AMPA" effect should have kicked in. And all sources say that R-ket is more effective anti-depressant, but they do not say that S-ket completly lacks the anti-depressant effect, or that it is negligible. So I think If it had been the R-ketamine, then the depression should've been worse. I may be wrong. But in case if I'm right, then trying R-ket will cause more than 3 days of suicidal depression, this is very life-threatening.

 

You got me intrested with cholinergics, she may have the borderline, at least some features, anyway, she tried every drug that is out there, but she didn't try cholinergics, so we shall try them. I'll research the topic, but can you name particular durgs that are used for borderline?

 

She most likely has PTSD, she's had lots of abusive events in life. with pregabalin, she's very afraid of tolerance, so she takes it not more than once a week. And she tried NSI-189, she was taking it for 4-5 days, and it didn't give any positive result, only the anxiety. I think that the whole "BNDF"-thing may not work for her, because with Ketamine, there's as I read the increase of BNDF by indirect AMPA-activation and  she didn't benefit from it. And I read that increasing BNDF in some areas may have the pro-depressant action. With aCh, she never used racetams, only tried, once tired supplementing with alpha-gpc, so increased ach-activity is possible.

She has undifferentiated connective tissue dysplasia.


Edited by lovaffect, 28 November 2016 - 02:20 PM.


#4 lovaffect

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Posted 30 November 2016 - 12:12 PM

I'll just post here my thoughts out loud.

 

I found this:

BioFreak, on 22 Apr 2013 - 11:13 PM, said:

    Just wondering, do you have a lot of empathy towards others, sacrifice yourself for others, etc? Thats a main sign for too much acetylcholine.

And it fits her perfectly.

 

Now I got the solid idea that she has too much acetylcholine. But where? Nicotinic or Muscarinic?

Bupropion makes her feel shit, but maybe that's from NE increase? But she's not that bad with Duloxetine or Milnacipran, so I can't be sure, so I need another Nicotinic antagoinst for test, but I can't find such a substance.

That idea with blocking nicitonic Alpha-7, she doesn't benefit from bupro, propranolol, nor from memantine. I don't know what to think here.

 

What about the muscarinic? She already takes Diphenhydramine for sleep occasionally, It does not give anything special, she says the tolerance builds up fast, but that says about Antihistamine effects, not the Anti-muscarinic.

 

There is Trihexyphenidyl, she reacts horrible to this. Does this say that she doen't have too much muscarinic?

Maybe Diphenhydramine and Trihexyphenidyl have anti-muscarinic proprieties in the wrong place or in the wrong way?

What about the Nutmeg or Scopolamine? They seem to have anti-depressant proprieties, ecspecialy scopolamine, Maybe try them?


Edited by lovaffect, 30 November 2016 - 12:28 PM.


#5 Mind_Paralysis

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Posted 30 November 2016 - 12:39 PM

What I think, is that she needs to go see a psychiatrist, who can give her an in-depth examination and interview - to finally give her a diagnosis.

 

Until we have more concrete data on her, we're shooting in the dark, and we can't really say too much, because none of us are Doctor's, and she needs a Dr. She needs to take tests as well, check her hormones and vitamins, minerals.

 

Oh, and some sources DO say that S-ketamine has only negligible antidepressant effects - guess you must have missed them. You can't use S-ketamine as a measurement of effect here.

 

If she has Borderline, then something like Lamotrigine or Aripiprazole might be beneficial to her.



#6 lovaffect

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Posted 01 December 2016 - 06:33 AM

She's been to a numerous number of doctors and she's had at least 3 or 4 diagnoses from different doctors. There was "Undifferentiated somatoform disorder" among them. But I'm 100% sure that no diagnosis would describe her condition.

Let's make it clear.

Usually she's very suppressed, quiet, never expresses her emotions, very convenient to others, very miserable inside, has psychosomatic pains, and acts like she has no self-respect at all.

But that's bullshit, that's not why she is, she's was not like that in her early childhood.

And so when drugs "work", she says that her mind-control of her emotions weakens, and she gets the expression! and then there's less of a nightmare inside.

And the drugs like mood-stabilizers, like anti-psychotics, they make the condition worse, they further suppress!

 

After the esketamine try she's been in tears and suicidal for four days now.  But just before that, very unexpectedly the combo of Milnacipran and Imipramine made her feel better, like she never felt in many months! but after the K that combo stopped working.

 

I need to come out with some quick temporary solution to win time, to hold her. I would have given Scopolamine to her or Dexedrine, but they need 2-3 weeks to get them. I don't want to believe that there's no way no hope in here.



#7 Mind_Paralysis

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Posted 01 December 2016 - 09:23 AM

She's been to a numerous number of doctors and she's had at least 3 or 4 diagnoses from different doctors. There was "Undifferentiated somatoform disorder" among them. But I'm 100% sure that no diagnosis would describe her condition.

Let's make it clear.

Usually she's very suppressed, quiet, never expresses her emotions, very convenient to others, very miserable inside, has psychosomatic pains, and acts like she has no self-respect at all.

But that's bullshit, that's not why she is, she's was not like that in her early childhood.

And so when drugs "work", she says that her mind-control of her emotions weakens, and she gets the expression! and then there's less of a nightmare inside.

And the drugs like mood-stabilizers, like anti-psychotics, they make the condition worse, they further suppress!

 

After the esketamine try she's been in tears and suicidal for four days now.  But just before that, very unexpectedly the combo of Milnacipran and Imipramine made her feel better, like she never felt in many months! but after the K that combo stopped working.

 

I need to come out with some quick temporary solution to win time, to hold her. I would have given Scopolamine to her or Dexedrine, but they need 2-3 weeks to get them. I don't want to believe that there's no way no hope in here.

 

So, you have known her since early childhood? The way you describe her however, VERY MUCH so sounds like Borderline - of the "quiet" type.

 

Could you try and list the 3 or 4 diagnoses she has had? We can then analyse those diagnoses, and see which ones fit the best, and see which combo, perhaps two of them, which would describe her most accurately.

 

We can then select medications based on those diagnoses, which she has not yet trialled, or trialled insufficiently (too low dose, too short of a treatment-period, et c).

 

Also, please hold on for using Scopolamine and Dexedrine - as you probably know, Scopolamine is a DELIRIANT and if she doesn't have high aCh, then that can be very, very dangerous (you're probably aware that those sorts of drugs can cause traumatizing hallucinations of EVIL forces causing even PSYCHOSIS in some), and Dexedrine is known to cause anxiety, and she seems to have a lot of anxiety.

 

NO ONE, but ADHD-ers should use stimulants - and I'm DEAD SERIOUS about that!

 

 

If you want to try something stimulating, then I suggest the combo of Tianeptine and Modafinil, which could be a highly synergistic combo, according to our friend Jack_Black here on the forums - he's got a very interesting thread about it.

 

Also, I can give you contact-information for a source of NSI-189, which I'm actually a bit surprised that you haven't tried yet. It's a good idea to try and combine it with something anxiolytic though, because it almost always causes anxiety.



#8 lovaffect

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Posted 01 December 2016 - 12:18 PM

Diagnoses were: "depressive epdisode", "Undifferentiated somatoform disorder", "masked depression with somatic symptoms" then the "schizotypal disorder" and finely "hypochondriac schizophrenia". But the "schizo" stuff is complete bullshit. Most doctors here are very superficial, the put schizo-label on everyone, and anti-pshychotics are the first line treatemnt for everything, like ADHD, OCD, insomnia, depression.

She gets nasty akathisia even from small doses of antipsychotics, not talking about the mental side.

 

She says that she's sure she has the Borderline.



#9 lovaffect

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Posted 01 December 2016 - 09:31 PM

Stinkorninjor, I feel uncomfortable refusing every suggestion, but that's how it is. She tried NSI:

And she tried NSI-189, she was taking it for 4-5 days, and it didn't give any positive result, only the anxiety. I think that the whole "BNDF"-thing may not work for her, because with Ketamine, there's as I read the increase of BNDF...

Modafinil gives strong anxiety, no positive effects, tianeptine is also negative, causes headaches. they seem glutamate enhancing. I was thinking about something euphoric.

 

Also, please hold on for using Scopolamine and Dexedrine - as you probably know, Scopolamine is a DELIRIANT and if she doesn't have high aCh, then that can be very, very dangerous (you're probably aware that those sorts of drugs can cause traumatizing hallucinations of EVIL forces causing even PSYCHOSIS in some)

I would prefer taking that risk, instead of doing nothing, the problem with them is time to get them.


Edited by lovaffect, 01 December 2016 - 09:40 PM.


#10 Finn

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Posted 02 December 2016 - 05:12 AM

At the same time GABA enhancing substances make her feel better. 300mg of pregabalin make her feel almost cured, baclofen also has very beneficial effect.

 

What ideas can be drawn from this?

 

 

After the esketamine try she's been in tears and suicidal for four days now.  But just before that, very unexpectedly the combo of Milnacipran and Imipramine made her feel better, like she never felt in many months! but after the K that combo stopped working.

 

I need to come out with some quick temporary solution to win time, to hold her. I would have given Scopolamine to her or Dexedrine, but they need 2-3 weeks to get them. I don't want to believe that there's no way no hope in here.

 

I would prefer taking that risk, instead of doing nothing, the problem with them is time to get them.

 

Why was a high risk self-administered ketamine treatment tried if there was already positive response to less risky stuff? 



#11 lovaffect

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Posted 02 December 2016 - 12:54 PM

deleted


Edited by lovaffect, 02 December 2016 - 12:57 PM.


#12 Mind_Paralysis

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Posted 02 December 2016 - 01:34 PM

 

At the same time GABA enhancing substances make her feel better. 300mg of pregabalin make her feel almost cured, baclofen also has very beneficial effect.

 

What ideas can be drawn from this?

 

 

After the esketamine try she's been in tears and suicidal for four days now.  But just before that, very unexpectedly the combo of Milnacipran and Imipramine made her feel better, like she never felt in many months! but after the K that combo stopped working.

 

I need to come out with some quick temporary solution to win time, to hold her. I would have given Scopolamine to her or Dexedrine, but they need 2-3 weeks to get them. I don't want to believe that there's no way no hope in here.

 

I would prefer taking that risk, instead of doing nothing, the problem with them is time to get them.

 

Why was a high risk self-administered ketamine treatment tried if there was already positive response to less risky stuff? 

 

 

Good point, Finn.

 

Lovaffect: have you considered trying the Milnacipran/Imipramine combo AGAIN? It's been a while now, so perhaps it will work once more, yes?



#13 Finn

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Posted 03 December 2016 - 06:38 AM

 

Bupropion makes her feel shit

 

 

 

Modafinil gives strong anxiety, no positive effects, tianeptine is also negative, causes headaches. they seem glutamate enhancing. I was thinking about something euphoric.

 

http://www.longecity...lerance-to-ads/

 

 

They don't give her anything, mostly side effects, now she's getting emotional dulling from them, sort of suppression, they also give her severe headaches, stimulant kinds of ADs give more headaches.

 

---

Tianeptine (branded stablon), all nootrpics, phenylpiracetam, fasoracetam seem to worsen her symptoms, headaches. Modafinil - intense anxiety, also worsening.

 

 

Esketamine inhibits dopamine transporters eight times more than arketamine. Ketamine is a disassociative anaesthetic, that has a combination of stimulant, depressant, hallucinogenic, and analgesic properties. S Ketamine is euphoric and has stimulant properties. Modafinil, tianeptine and buproprion are all mild euphorics, while not usually heavily regulated in most countries like stronger euphorics, they are generally much more euphoric  than SSRIs, SNRIs, tricyclics etc, and have more stimulant-like properties than those substances.

 

Based on her bad responses to euphorics and drugs with stimulant like components, Dexedrine (dextroamphetamine) doesn't sound like a good idea.


Edited by Finn, 03 December 2016 - 06:57 AM.


#14 psychejunkie

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Posted 03 December 2016 - 08:15 AM

I've been thought Hydroxynorketamine was responsible for long-lasting anti-depressant effects of Ketamine usage



#15 Mind_Paralysis

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Posted 03 December 2016 - 10:50 AM

I've been thought Hydroxynorketamine was responsible for long-lasting anti-depressant effects of Ketamine usage

 

It IS.

 

And that metabolite is EXCLUSIVELY formed by the ARketamine enantiomer.

Hence, why Esketamine is useless as an antidepressant.



#16 lovaffect

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Posted 03 December 2016 - 03:09 PM

I've been thought Hydroxynorketamine was responsible for long-lasting anti-depressant effects of Ketamine usage

 

There are (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine, each coming from corresponding S - R ketamine isomer.

 

It IS.

 

And that metabolite is EXCLUSIVELY formed by the ARketamine enantiomer.

Hence, why Esketamine is useless as an antidepressant.

 

Can you provide a proof? In the paper you're referring to, they say

"We note that (2S,6S)-HNK does also exert antidepressant actions at higher doses".

https://www.ncbi.nlm...les/PMC4922311/

 

S-ketamine produces (2S,6S)-hydroxynorketamine which IS active at α7-nicotinic receptor:

https://www.ncbi.nlm...pubmed/23183107

 

There's a controversy which of enantiomers is a better anti-depressant. Esketamine is in phase III clinical trials for treatment-resistant depression by Johnson & Johnson, link in the wikipedia. So saying that it is useless as an antidepressant I believe is wrong.


Edited by lovaffect, 03 December 2016 - 03:11 PM.


#17 lovaffect

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Posted 03 December 2016 - 03:18 PM

Modafinil, tianeptine and buproprion are all mild euphorics, while not usually heavily regulated in most countries like stronger euphorics .... Based on her bad responses to euphorics and drugs with stimulant like components, Dexedrine (dextroamphetamine) doesn't sound like a good idea.

They all are "dirty", they enhance glutamatergic transmisson, bupropion is not euphoric at all.

 

Esketamine inhibits dopamine transporters eight times more than arketamine. <...> S Ketamine is euphoric and has stimulant properties

 

In time of THOSE effects (1-1.5 hours) she was FINE, she felt bad from long-langsting effects that come from metabolites like HNK, that are living in body for 7-10 days.


Edited by lovaffect, 03 December 2016 - 03:23 PM.


#18 Finn

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Posted 03 December 2016 - 05:42 PM

 

Modafinil, tianeptine and buproprion are all mild euphorics, while not usually heavily regulated in most countries like stronger euphorics .... Based on her bad responses to euphorics and drugs with stimulant like components, Dexedrine (dextroamphetamine) doesn't sound like a good idea.

They all are "dirty", they enhance glutamatergic transmisson, bupropion is not euphoric at all.

 

 

 

 

https://www.ncbi.nlm...les/PMC4345909/

 

"Modulation of the glutamatergic transmission by Dopamine: a focus on Parkinson, Huntington and Addiction diseases"

 

http://www.jneurosci...tent/24/22/5131

 

" A critical component in DA actions is its modulation of glutamate transmission, which can be different when specific receptors are activated. "

 

Modafinil has no affinity for glutamate transporter or any glutamate receptor, yet it has effect on glutamate transmission, because it has effect on dopamine transmission.
 

 

http://onlinelibrary...CO;2-6/abstract
 

 

"Cocaine and amphetamine preferentially stimulate glutamate release in the limbic system: Studies on the involvement of dopamine"

 


Edited by Finn, 03 December 2016 - 05:44 PM.


#19 lovaffect

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Posted 04 December 2016 - 02:09 PM

So.... here's the data:

This burst of glutamate is thought to occur via blockade of muscarinic or NMDA receptors by scopolamine or ketamine, respectively, on GABA interneurons, resulting in the disinhibition of glutamate transmission (see supplementary Fig. 1). Glutamate – AMPA receptor activation leads to stimulation of voltage-dependent calcium channels and release of BDNF, which then stimulates mTORC1 signaling and synaptogenesis (Duman and Aghajanian, 2012; Voleti et al., 2013). These studies also demonstrate that a single dose of scopolamine or ketamine rapidly increases the number and function of spine synapses on layer V pyramidal neurons in the mPFC

https://www.research...ation-of-mTORC1

 

So, the lady I'm talking about DOES NOT benefit from ketamine, instead it's making her depressed, the mechanism of scopolamine action seems very similar, so probably she won't benefit from scop either.

The question is: What stage of this chain does the split between her and the regular people begin at?

Dose she benefit from synaptogenesis? Probably, yes. Does she benefit from mTORC1 activation?

Does increasing BDNF help her or the opposite?

 

God damn it! How complicated this all IS! I need help with all this!!!

 



#20 Mind_Paralysis

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Posted 04 December 2016 - 02:47 PM

What happened with trying Milnacipran/Imipramine combo again? Aren't you even going to consider it?
 

I mean, it really DOES seem as if she had the best results when on that combo.

Don't give up on it yet - you say it stopped working after Esketamine-exposure - ok - but when WAS that? Perhaps that effect has now passed? I think you need to try again.

 

 

It IS.

 

And that metabolite is EXCLUSIVELY formed by the ARketamine enantiomer.

Hence, why Esketamine is useless as an antidepressant.

 

Can you provide a proof? In the paper you're referring to, they say

"We note that (2S,6S)-HNK does also exert antidepressant actions at higher doses".

https://www.ncbi.nlm...les/PMC4922311/

 

S-ketamine produces (2S,6S)-hydroxynorketamine which IS active at α7-nicotinic receptor:

https://www.ncbi.nlm...pubmed/23183107

 

There's a controversy which of enantiomers is a better anti-depressant. Esketamine is in phase III clinical trials for treatment-resistant depression by Johnson & Johnson, link in the wikipedia. So saying that it is useless as an antidepressant I believe is wrong.

 

 

Hmm, you do make a good case here - I had mostly read the reports which say that Arketamine are superior.

 

There is a fact that Esketamine IS different, pharmacologically from Arketamine though - and as I understand it, the two hydroxynorketamine's are believed to have different pharmacological activity at the alpha-7-receptor.

 

It's not entirely out of the question that the two metabolites work inversely at a7: one is an agonist, the other, an antagonist.

 

So, you can't say with such certainty that Arketamine and (2R,6R)-HNK will really effect her the same as Esketamine.

 

 

 

 

Modafinil, tianeptine and buproprion are all mild euphorics, while not usually heavily regulated in most countries like stronger euphorics .... Based on her bad responses to euphorics and drugs with stimulant like components, Dexedrine (dextroamphetamine) doesn't sound like a good idea.

They all are "dirty", they enhance glutamatergic transmisson, bupropion is not euphoric at all.

 

 

I wouldn't call them "dirty" - just because a compound has more than one mode of effect doesn't make them dirty - Modafinil and Tianeptine has more than one mode of effect, but their side-effects profile is incredibly good - you will find raving fans of both compounds because of this, and they really ARE less dangerous than other drugs when taken in overdose as well.

 

Truly dirty drugs is stuff like TCA's or old typical Antipsychotics - Haldol for instance. One could also make a case for Mirtazapine, since it hits a BOAT-load of receptors, while also causing both 5htp and NE-reuptake.
 

 

And you're wrong about Bupropion - when taken intranasally or intravenously the euphoric effects are immediately noticeable. I detest this use, but it's actually common in prisons in the U.S.A.

Now, the euphoric effects are not at all as common when taken orally, but there are reports of it - for instance, my ex-girlfriend who suffers from BPD/HPD also reported initial euphoric effects from Bupropion, I myself however, did not - but I'm SCT, I don't get euphoric that easily, because of low vigilance and highly upregulated kappa-receptor networks.

 

(punishment-sensitivity have been noted in SCT-individuals, as well as an overall LOWER propensity for abuse than among the mainline population - learned helplessness is something I have as well, a feature of dystymia, and that would blunten euphoria too)

 

On another note - seems like poor Bupropion is joining Tianeptine as another excellent drug which is about to get a bad rep because of KROKODIL-like abuse! : ( People have started shooting the pills, resulting in those deplorable bite-like wounds that inevitably lead to severe tissue-damage.

 

Damn fools...

 

 

References:

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

Intravenous administration and abuse of bupropion: a case report and a review of the literature.

https://www.ncbi.nlm...pubmed/24950138

 

Focus on bupropion toxicity and abuse

http://www.dpic.org/...icity-and-abuse

 

 

Antidepressant Wellbutrin becomes ‘poor man’s cocaine’ on Toronto streets

http://globalnews.ca...oronto-streets/

 


Edited by Stinkorninjor, 04 December 2016 - 03:05 PM.


#21 lovaffect

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Posted 10 December 2016 - 08:53 PM

What happened with trying Milnacipran/Imipramine combo again? Aren't you even going to consider it?
 

I mean, it really DOES seem as if she had the best results when on that combo.

 

She continued taking it immediately after the K try.

 

Over the time, she has traced several patterns.

 

There was thing, that for about half a year the stimulant types of ADs worked best for her, then there's a switch, when she was doing better on sedative ones like amitriptyline. The time when the new drug or the new antidepressant scheme was working, it was shrinking. From months it shrank to several days. And also just finding the scheme that would work, was getting harder. Until it got to the point when nothing works like now.

 

This all concerns conventional serotoninergic ADs. This all sounds so bad....f***.


Edited by lovaffect, 10 December 2016 - 08:55 PM.


#22 jack black

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Posted 11 December 2016 - 01:05 AM

if that person benefits from GABA stimulation,why not going in that direction with something hopefully nonaddictive (like taurine)? some people swear by GABA supplement even though it's not supposed to cross B/B barrier.



#23 lovaffect

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Posted 13 December 2016 - 08:15 AM

Found out that Tramadol has antagonism in nicotinic alpha-7 and already got some.

Don't know how she's gonna react to opiate effect. She only tried Kratom once, it didn't seem positive, made her vomit.

Kratom stays in body for 4-5 days, it made pregabalin not to work in those days, and venlafaxine became very nausea-inducing, probably because of it's own opiate effect, but other SNRIs also seem to have that effect(nausea).


Edited by lovaffect, 13 December 2016 - 08:22 AM.


#24 Finn

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Posted 16 December 2016 - 08:48 PM

.The time when the new drug or the new antidepressant scheme was working, it was shrinking. From months it shrank to several days. And also just finding the scheme that would work, was getting harder. Until it got to the point when nothing works like now.

 

 

 

 

 

http://www.longecity...lerance-to-ads/

 

She's twenty seven and has been taking antidepressants for six years now. They helped her for around 2 years.

She was good on amitriptyline at first, then were paxil and pirlindole (weak reversible maoi), quit that scheme because of weight gain, fluvoxamine-pirlindole, some other schemes with SSRI and SNRI.

 

The important point to note, she had an immediate response to antidepressants, literary with the first pill. Almost no any side effects, no emotional dullness, no libido reduction, no any typical SSRI side-effects, weight gain from paxil was the only exception.

She's been on diffident antidepressant treatments over the years.

Now she's switching ADs every day, or every 2-3 days. 

 

 

While most antidepressants and other psychiatric medications are not considered euphoric in general, all of them have potential to cause euphoria in some individuals. Neurotransmitters are interconnected through various negative and positive feedback loops. 

 

Typically you don't get immediate response, from the first pill, with antidepressants. That kind of immediate, fully positive, no side effects response sounds somewhat like euphoria. Also the time of how long each scheme works getting shorter and shorter, and finding a new working scheme being harder and harder that also corresponds with euphoria. Euphoria can temporarily "cure" you of almost any condition, but unfortunately euphoria is unsustainable state, so the more you have experienced pharmaceutic induced euphoria, the harder it gets to induce it further. 

 

I think re-adjusting expectations could be helpful. If I had thought the euphoria that I experienced at the beginning of some medication schemes, was the genuine cure, how I'm supposed to feel, I would be really disappointed with my current medication and I would probably also think that my medication stopped working. But since I recognized it for what it was, and didn't set my expectations to that level I'm relatively happy with my medication. 

 

Euphoria at the beginning of treatment can be nice boost, but if you don't recognize it as just temporary euphoria, and start to think that that's how working medication scheme is supposed to feel all the time, then you might be really disappointed and start to feel that the medication does nothing after the euphoria is over, even if it still does something beneficial.


Edited by Finn, 16 December 2016 - 08:53 PM.


#25 lovaffect

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Posted 18 December 2016 - 06:00 PM

 

I think re-adjusting expectations could be helpful. If I had thought the euphoria that I experienced at the beginning of some medication schemes, was the genuine cure, how I'm supposed to feel, I would be really disappointed with my current medication and I would probably also think that my medication stopped working. But since I recognized it for what it was, and didn't set my expectations to that level I'm relatively happy with my medication. 

 

Euphoria at the beginning of treatment can be nice boost, but if you don't recognize it as just temporary euphoria, and start to think that that's how working medication scheme is supposed to feel all the time, then you might be really disappointed and start to feel that the medication does nothing after the euphoria is over, even if it still does something beneficial.

 

 

That's bullshit about "re-adjusting expectations", you haven't seen her, she's in agony.

And actually she said all the same herself. First uses of lyrica were very euphoric, then the euphoria faded but benefical effects did not (once a week usage). She doesn't have any misconeptions about normal state and euphoria.

 

That first pill responce to anti-depressants is not necessarily euphoria. It is a sign of Bipolar Disorder:

Patients whose depression is due to Bipolar Disorder tend to have difficulties when taking antidepressants. They may experience rapid relief followed by loss of efficacy (the “poop-out” effect).

....

Many people have repeated episodes of depression. Sometimes the first several episodes respond fairly well to antidepressant medication, but after a while the medications seem to "stop working". ....

Many people have the odd experience of feeling the depression actually improve with antidepressants, yet overall —perhaps even months later —they somehow feel worse overall. In most cases this "worse" is due to agitation, irritability, and insomnia. In some cases, an antidepressant works extremely well at first, then "poops out". The benefits usually last several weeks, often months, and occasionally even years before this occurs.

https://claytonbehav...-means-bipolar/

http://www.dr-bob.or...sgs/468932.html

 

So sounds perfect, she should be bipolar. Practically and chemically this means adding mood-stabilizer. I tried giving her 5 mg Lamotrigine. Shit effects. Pretty much like anti-psychotic for her.

She's had bad experiences with normothymic agents before, but I insisted to try again. 

Tried very lose dose, but "stabilizers" are downers for her. She fades, i.e. no will, no enthusiasm, no interests, no emotions, but still painful inside and cannot sleep from pain. Damn it.


Edited by lovaffect, 18 December 2016 - 06:01 PM.


#26 lovaffect

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Posted 18 December 2016 - 08:23 PM

I never wanted to make excuses or decribe in detail how bad everything is, because this IS NOT helpful. I wanted a consructive talk about things that really matter. But you make me to do so.

 

When I said:

But just before that, very unexpectedly the combo of Milnacipran and Imipramine made her feel better, like she never felt in many months!

 

She was not functional, maniac or happy. She was fatigued, sad and crying, but she was not suicidal in pain.

And she appreciated it.



#27 jack black

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Posted 19 December 2016 - 01:39 PM

 I tried giving her 5 mg Lamotrigine


 

 

 

5mg, seriously?
 



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#28 Mind_Paralysis

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Posted 19 December 2016 - 02:04 PM

 

 I tried giving her 5 mg Lamotrigine


 

 

 

5mg, seriously?
 

 

 

You should probably add that 5 mg is a very, very low dose, and often not effective for nearly anyone - irregardless of if you have unipolar or bipolar depression.

 

@Lovaffect:

 

Your trial of Lamotrigine was insufficient - you can't write it off completely, not yet.

 

There's also the case that many psychiatric drugs can actually temporarily worsen conditions, before improving them - hence one can't give up on a drug this fast.
 

25 mg is often the starting dose, and some patients need up to a HUNDRED milligrams before achieving remission of symptoms.

 

 

References:

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

Lamotrigine Dosage guide

https://www.drugs.co...amotrigine.html


Edited by Stinkorninjor, 19 December 2016 - 02:08 PM.






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