30 replies to this topic

[Modest]

Hello

I am suffering from serious psychiatric disorder, related to DA and NE hyperactivity in the prefrontal cortex. I cant tell all the details because it is a very long story and my English is poor.

Which medications can decrease/inhibit dopamine and norepinephrine in the frontal cortex ?

I will be grateful for any help.

[Sciencyst]

Tetrahydropalmatine and sarcosine are the two best easily avilable supplements for treating psychoses.

For anxiety try ashwaghanda, bacopa, theanine, magnolol/honokiol, taurine, or baicailin.

Otherwise meditation is very effective once you reach the point of breaking away from current thought patterns (15 minutes in for me)

[Tom_]

There is no mental health condition that can be categorised as hyper or hypo activity of a certain area of the brain. Mental health problems are diffuse and very complex involving more than just neurotransmitters.

ADHD and Psychotic disorders may have hyperactive dopamine and noradrenaline in the PFC.

That being said the best medication for reducing dopamine and noradrenaline neuron firing in the PFC is pericyazine which is a moderate-strong D1 antagonist and also an alpha 2 a-c antagonist. Its rarely used as an antipsychotic now due to low potency but is an effective crisis drug helping to control severe mania, aggression, agitated delirium, anxiety and impulsive (typically suicidal) behaviour.

The next best options for your very specific request are the atypical antipsychotics: Olanzapine, Respiridone and Quetiapine are good options. A similar option is Aripiprazole which acts as a dopamine partial agonist reducing dopamine activity a bit but doing more to control large 'random' outbursts. All of them are at least reasonably potent alpha antagonists (which by themselves will reduce dopamine output).

It would be good to hear some more about your symptoms because quite frankly I expect you have made a mistake and antipsychotics aren't the best option for you.

[Modest]

There is no mental health condition that can be categorised as hyper or hypo activity of a certain area of the brain. Mental health problems are diffuse and very complex involving more than just neurotransmitters.

ADHD and Psychotic disorders may have hyperactive dopamine and noradrenaline in the PFC.

That being said the best medication for reducing dopamine and noradrenaline neuron firing in the PFC is pericyazine which is a moderate-strong D1 antagonist and also an alpha 2 a-c antagonist. Its rarely used as an antipsychotic now due to low potency but is an effective crisis drug helping to control severe mania, aggression, agitated delirium, anxiety and impulsive (typically suicidal) behaviour.

The next best options for your very specific request are the atypical antipsychotics: Olanzapine, Respiridone and Quetiapine are good options. A similar option is Aripiprazole which acts as a dopamine partial agonist reducing dopamine activity a bit but doing more to control large 'random' outbursts. All of them are at least reasonably potent alpha antagonists (which by themselves will reduce dopamine output).

It would be good to hear some more about your symptoms because quite frankly I expect you have made a mistake and antipsychotics aren't the best option for you.

Ok, I will try to describe the whole condition. I suffer from hellish anhedonia, related to the dysfunction of DA in the nucleus accumbens (the reward center). The mu receptors in nacc cant induce reward without dopamine (and maybe glutamate and acetylcholine are somehow related to this).I tried mu agonist codeine and it made me a little worse (sedative, vertigo and absolutely no reward - so I dont have opioid deficiency. My motivation and decision is normal, my brain just doesn’t want reward from anything. I can’t fell pleasure from anything : music, films, walking and all other interests I enjoyed in the past, even sleeping and eating aren’t rewarding any more. I am absolute zombie. I don’t have any depression, schizophrenia or other mental issues. It is just hellish anhedonia. The doctors in my city are absolutely stupid, they don’t even know what nucleus accumbens is, so I have to cure me myself. I tried a lot of things that increase DA, many of them worsened my illness. This were medications that increase DA and NE in prefrontal cortex. The only combo that worked was wellbutrin SR (after two months) 300 mg + high doses of baclofen or phenibut (these only 2 days a week) - that almost completely cured anhedonia (gaba b activation inhibits da in nacc then it compensates in da increasing( and maybe ACh). Baclofen and Phenibut very barely helped anhedonia on their own, without bupr (for 5- 7%)

At the beginning of treatment wellbutrin made me much worse - my frontal core was breaking off, it was hellish, indescribable feeling. I had terrible agitation, anxiety, insomnia, appetite loss, and the main shit - frontal core sever breaking. After some days all this started to decrease. Then I understood what was the thing. Bupropion SR at once increases DA and NE in the prefrontal cortex, but in nucleus accumbens - only after chronic treatment . Then I made a huge mistake. Instead of increasing Bupr to 450 (and maybe 600), which I think would start to cure my anhedonia even without gaba b agonists. I came off bupropion and tested some other meds which didn’t help absolutely. I started experimenting with amisulpride, memantine etc. And the worsest thing for me was Agomelatine (it increases Da and Ne in frontal cortex). That was absolute hell, and the effect was quit permanent. Now I am on benzos, they inhibit Da and Ne in this area, and only they are stopping me from suicide just now (benzos for short term, of course). Thing that also made my frontal core cracking and breaking was baclofen (on ist own, without bupr) withdrawal only after 3 days of use !! -of course it has nothing to do with glutamate - it was Ne and /or Da in prefrontal area. Healthy people won’t even notice that, and for me it was hellish suffering. I think this Is somehow related to imbalance between prefrontal core and dysfunction of nucleus accumbens and maybe some other deep brain structure. Because when I tried illegal (stims like amp and methyl are permitted in my shitty country) bought amphetamine (40 mg) and tried 20 mg all of my symptoms disappeared (including frontal core breaking). I again felt music, the whole world started to fill with colors... Holy god, that was a paradise day in hell. Amp normalized all the brain for 6 hours. And the second dosage - for the rest of the day. And if I stopped my experiments at that point, I would not suffer from frontal core hyperactivity... What a pity I cannot bye illegal amp any more, and don’t know, whether I will be able. You are lucky people, those in Usa and Europe. Doctor can prescribe you it off label for such life threatening conditions, including anhedonia. When my doctors heard that I used AmP, the only association for them was narcology. Amphetamine can really save my life ((

Just now I am seeking for drugs that can block NE and DA in the frontal cortex. Atypical mostly increase it there. I read in the study that Olanzapine can greatly increase DA in NAcc. But I am afraid to use it, due to its significant dopamine and norepinephrine increase in frontal cortex.
pericyazine sounds worth trying, can you give more details about its pharmacology (especially related to pfc) I didn’t find its detailed pharmacology in internet.

sorr for English mistakes and thanks for replying !

[Tom_]

Well I can assure you your english is fine.

Secondly I can tell you, your neuroscience is a little messed up. I

Thirdly you are depressed. Lack of pleasure, suicidal thoughts, psycho-social dysfunction, somatization are all massive indicators. I'm guessing you aren't sleeping great either (insomnia or hypersomnia), you may find your appetite is upset, you are clearly sad and hopeless (as indicated by suicidality). That is more than enough for a clinical diagnosis of major depression. Your short term response to amfetamine (it wouldn't have lasted I can assure you) is typical of a depressive disorder. Incidentally the only two drugs you have described a response to seriously increase both NA and DA concentrations in the PFC.

There is a good research base for trying an antidepressant that worked once (Bupropion) and I would strongly suggest you use that again. The gabanergic drugs (Benzo's, Baclophen, Phenibut) will typically worsen your condition long term, although they are great in a pinch. They are certainly addictive and to be avoided where possible. So I suggest you use the minimum dose of a single GABA agonist/mimetic while the Bupropion kicks in (they will also help stop the side effects of Burpopion if you get them again). Start with 150 xl or equivalent for 4 to 6 days and then increase the dose to 300mg. Stick that out for 6 weeks and see where you are. If you don't feel totally better increase the dose to 450, leave that four another 6 weeks. Ideally if that hasn't worked its likely best to add an SSRI - Sertraline or Escitlopram would be my suggestions, depending on where you live you could give Tianpetine a go combined with Bupropion. Its been shown to increase dopaminergic activity in the mesolimbic pathway (nucleus accumbus is part of this pathway) and also moderate glutemate.

If you go against my advice of re-trailing Bupropion then I would strongly suggest an SSRI or Tianpetine. Tianeptine like Bupropion may be particularity good at combating anhedonia.

Edited by Tom_, 26 February 2014 - 09:53 PM.

[downregulated]

Try venlafaxinum ... It's SSNRI and it's great, for short term... Il long term it makes you dull.

[Modest]

Well I can assure you your english is fine.

Secondly I can tell you, your neuroscience is a little messed up. I

Thirdly you are depressed. Lack of pleasure, suicidal thoughts, psycho-social dysfunction, somatization are all massive indicators. I'm guessing you aren't sleeping great either (insomnia or hypersomnia), you may find your appetite is upset, you are clearly sad and hopeless (as indicated by suicidality). That is more than enough for a clinical diagnosis of major depression. Your short term response to amfetamine (it wouldn't have lasted I can assure you) is typical of a depressive disorder. Incidentally the only two drugs you have described a response to seriously increase both NA and DA concentrations in the PFC.

There is a good research base for trying an antidepressant that worked once (Bupropion) and I would strongly suggest you use that again. The gabanergic drugs (Benzo's, Baclophen, Phenibut) will typically worsen your condition long term, although they are great in a pinch. They are certainly addictive and to be avoided where possible. So I suggest you use the minimum dose of a single GABA agonist/mimetic while the Bupropion kicks in (they will also help stop the side effects of Burpopion if you get them again). Start with 150 xl or equivalent for 4 to 6 days and then increase the dose to 300mg. Stick that out for 6 weeks and see where you are. If you don't feel totally better increase the dose to 450, leave that four another 6 weeks. Ideally if that hasn't worked its likely best to add an SSRI - Sertraline or Escitlopram would be my suggestions, depending on where you live you could give Tianpetine a go combined with Bupropion. Its been shown to increase dopaminergic activity in the mesolimbic pathway (nucleus accumbus is part of this pathway) and also moderate glutemate.

If you go against my advice of re-trailing Bupropion then I would strongly suggest an SSRI or Tianpetine. Tianeptine like Bupropion may be particularity good at combating anhedonia.

You didn't understand me. I am not depressed and never was. And of course i have nothing related to major depressive disorder(except anhedonia). It is very hard to explain to another person who never struggled with anhedonia without depression. There are some people with that symptom on the forum. This anxiety is related to my pferontal cortex breaking and cracking. It is a result of drugs that increased DA and NE in it. And my suicidality was because i couldn't handle that incredible pain in my prefrontal cortex, no more. Benzos just now are blocking that. SSRI i tried before bupropion an they worsened my anhedonia a bit (they can probably cause anhedonia in depressed people)

When my anhedonia began, i had nor depression, neither anxiety or something else. I was just bored. Bored of everything (my real interests, study etc.) Then it worsened, and i lost reward for sleep, eat, stupid movies and series and other primitive things i enjoyed before). That was the beginning of hell. And i didn't have any anxiety or other depressive things. Know, mine is a complicated illness, but it is so.

Wellbutrin on its own didn't help me (only made my head clear). But it allowed baclofen or Phenibut to kick. Two days of relief in one week was a present to me. And there were nor tolerance or condition worsening issues.

As for Amp, i know about the tolerance issues. But if is taken 3 days, then 3 days off there wont be tolerant issues. If it is combined with Memantine or thing such as Ciltep that will greatly inhibit tolerance. Some people use such combinations for many months and even years for anhedonia without tolerance (just 2 days break every week or two). It was discussed a lot on longecity forum. But the problem is that i don't have it right now.

Tianeptine is amazing drug, indeed. Thank for the advice. I would want to try it on its own and especially with wellbutrin but those idiots in my country banned it several month ago. They say, it is "a fight against drug addiction". I cant believe it.

So my main problem just now is Da and Ne in frontal cortex. What about pericyazine ? Can you tell the whole pharmacology of that drug because i would like to try it.

Edited by Modest, 26 February 2014 - 11:04 PM.

[datrat]

When my anhedonia began, i had nor depression, neither anxiety or something else. I was just bored. Bored of everything (my real interests, study etc.) Then it worsened, and i lost reward for sleep, eat, stupid movies and series and other primitive things i enjoyed before). That was the beginning of hell.



I don't think you understand the meaning of depression. Being bored of everything is one of the classical signs of depression. You don't have anhedonia by itself nor is your problem due to a 'cracked' PFC, you have depression, which luckily is treatable, if you don't keep over analyzing what you have and get some help for it..

[Tom_]

This is well said. I'm afraid you are trying to explain your symptoms in a way that is impossible at our current level of technology.

I understood you perfectly. Your symptoms point towards a moderately severe depressive disorder (you meet enough criteria, you are suffering enough etc) not a non-existent disease process - the top scientists in the world can't explain what is happening in the brain at the level you just tried to.

But to be absolutely clear you aren't talking about a physical pain in the front off your head are you?

[Galaxyshock]

In my opinion that sounds surprisingly similar to what this person suffers from:
http://www.longecity...-brain-disease/

instead of depression or typical anhedonia.
Especially the lack of response to opioids (codeine) and GABA-B agonism, except that with a stimulant (wellbutrin) Phenibut works for you? interesting.

edit: well the increasing boredom as the beginning of symptoms does indicate depressive/anhedonia spectrum. But yet you say "motivation is normal", usually motivation is impaired in depression and typical anhedonia.

Edited by Galaxyshock, 27 February 2014 - 09:53 AM.

[Modest]

When my anhedonia began, i had nor depression, neither anxiety or something else. I was just bored. Bored of everything (my real interests, study etc.) Then it worsened, and i lost reward for sleep, eat, stupid movies and series and other primitive things i enjoyed before). That was the beginning of hell.



I don't think you understand the meaning of depression. Being bored of everything is one of the classical signs of depression. You don't have anhedonia by itself nor is your problem due to a 'cracked' PFC, you have depression, which luckily is treatable, if you don't keep over analyzing what you have and get some help for it..

What are you talking about ? I had some little depressive episodes in the past, i know WHAT depression is. My case is absolutely different. SSRI worsened my anhedonia long term. It is pure anhedonia. For example, i can repost here Zrbarnes post:

"I have dealt with anhedonia all while growing up, but it wasn't a sad, depressive anhedonia. It was more of a "perpetually bored" type of thing. I was always content with this until my college years. I tried to go to school for computer engineering at one of the top schools in the country. Even though I was naturally gifted, I had no drive or motivation to do my school work. Once the novel nature of a subject wore off, so also did my ability to focus on the subject.

After failing numerous times and switching schools, the rejection started to cause anxiety (which I had never experienced in my life). Then, my girlfriend of 5 years cheated on me. I guess some psych docs would say that I had PTSD type symptoms from this. Combine this with the underlying anhedonia, and you have a recipe for disaster. At this point, I pretty much just slept and tried to find things to amuse myself, accomplishing nothing but wracking up credit card debt as I foolishly tried to still attend school. I gradually worked my way out of the depression, insomnia, and the majority of the other symptoms related to a really bad heartbreak. But I still couldn't pass classes or pay attention. It was like my anhedonia had increased 10 fold.

I finally went to see my doctor. He prescribed me adderall. My anhedonia disappeared, but I had every side effect of amphetamines. My BP went ridiculously high too. After about 6 months of this, I quit school, quit adderall, and starting studying the brain.

I spent more money then I could ever afford on nootropics and supplements, and spent months researching. Then, I started taking the CILTEP stack before Abelard Lindsay even posted it publicly. I noticed a change in my brain, which was one of the first times I actually felt anything from any "noots" or supplements (with the except of methylcobalamin which caused euphoria for several days when I first started taking it). But I still was getting nothing done. In frustration, I went back to the doctor, and got a script for Adderall (this was about a year after I had stopped). I also decided to try Selegiline, in order to hopefully reduce the dosage of Adderall. Because of the contraindication between the 2, I decided to start out very small. 5mg of each.

From the very first day, my brain fired up and started working again. Similar to when I had previously adderall (at a much higher dosage), without the tunnel vision and side effects. I was amazed... shocked... I had my life in my control all of a sudden. I told the doctor how excited I was. He was shocked and amazed. He even stopped worrying about the possible interaction, since I was taking such low doses.

Did I mention I never stopped taking CILTEP during this trial? Because I kind of forgot this small detail at the time. I starting noticing massive amounts of productivity on some days, yet none on others. These productive days always "happened" to fall on days which I took artichoke and forskolin along side of my selegiline and adderall. I started playing with the doses and found that I didn't even need the Selegiline. I also needed 1/4 of the forskolin dose I was taking.

That is the story of how I stumbled upon the stack that saved my life. Fast forward to 8 months later: I'm getting married in three months; I have my own business; and I have an interview for a part time job tomorrow. I'm anhedonia free, and with a few tweaks to the original regimen, I feel healthier than ever. Of course, if I ever miss a day, I'm right back to my usual self (which is nice for relaxing on vacation!).

The important part of this whole thing is to note that I was never chemically depressed or anxious for no reason, which is why I never entertained the ideas of SSRI's. My depression and anxiety came from the real life consequences of a lifelong struggle with anhedonia. Once I was able to conquer anhedonia, the hopelessness dissolved, and with it so did any lingering depression and anxiety.

It's very important to be able to get to the root of the problem if you are ever going to defeat it. I've never been able to quite pin down the exact cause of my issue (though I've entertained several theories), but it's clear that I am either too stongly influenced by one of the inhibitory neurotransmitters, or not enough by one of the excitatory ones. I still continue my search, but at least I am enjoying life and accomplishing my goals while I continue to expand my knowledge about the human brain."

Amp also helped me. I have not the same, but very similar case, much severe. And the root of my problem is dysfunction of nucleus accumbens. Why ? I don't know.

Edited by Modest, 27 February 2014 - 03:26 PM.

[Modest]

This is well said. I'm afraid you are trying to explain your symptoms in a way that is impossible at our current level of technology.

I understood you perfectly. Your symptoms point towards a moderately severe depressive disorder (you meet enough criteria, you are suffering enough etc) not a non-existent disease process - the top scientists in the world can't explain what is happening in the brain at the level you just tried to.

But to be absolutely clear you aren't talking about a physical pain in the front off your head are you?

I don't suffer from depression. How much time i should repeat that ? The pain in frontal cortex is not physical, and it occurs only when Ne and Da are elevated in the prefrontal cortex. I just cant describe it in English. It is like my frontal cortex is air pumped and going to explode. My hypothesis is that this hellish feeling is somehow related to dysfunction of nucleus accumbens. Because when i increase DA in NACC it dissapears. (and that helps anhedonia) I think it is imbalance of the brain structures.

In my opinion that sounds surprisingly similar to what this person suffers from:
http://www.longecity...-brain-disease/

instead of depression or typical anhedonia.
Especially the lack of response to opioids (codeine) and GABA-B agonism, except that with a stimulant (wellbutrin) Phenibut works for you? interesting.

edit: well the increasing boredom as the beginning of symptoms does indicate depressive/anhedonia spectrum. But yet you say "motivation is normal", usually motivation is impaired in depression and typical anhedonia.

Yeah mine is so rare case. But codein works on bupropion too. Bupropion long-term increases activity in nacc and allows other drugs to reward. And in 450 mg or 600 i think it bupropion can start alleviating anhedonia on its own.

The difference between mine anhedonia and Vienos is that i am responding to amphetamine and wellbutrin + gaba b agonist combo. So mine is curable. But the most hellish thing is when Da and Ne are increasing in my prefrontal cortex.

[Sciencyst]

Curable

Or

Treatable?

[Vieno]

Brother, clearly your shit is treatable, so do not worry. But let's examine the details.

Anhedonia is a tricky concept. Take a look at this for starters: http://www.ncbi.nlm....les/PMC3005986/

Basically, anhedonia has traditionally been defined as inability to experience pleasure, however, that isn't really the case. What is referred to as anhedonia is usually lack of motivation and mental energy, and IMO most importantly, lack of emotions. SSRIs typically blunt emotions, and they are considered to be very bad for something called "anhedonic depression" - often, worsening it. This basic anheodonia usually respons very well to any type of stimulants, especially DA/NE reuptake inhibitors/releasers such as amphetamines or methylphenidate. Serotonin releasers and the oddball reuptake inhibitor St. John's Wort often work too and, frankly, pretty much any recreational drug, although side effects may be problematic.

What I have is a whole another story, I don't have anhedonia. I feel completely normal, I just don't get pleasure from anything, not even any drug. You probably can't understand what this really means. I have all emotions including the positive ones. Feeling upbeat at the moment. Just zero pleasure. I can take shitloads of drugs and get zero euphoria.

Don't get too excited about zrbarnes. User DissolveDissolve brought up the matter of motivational anhedonia in my big thread, and zrbarnes came to explain that's exactly what he has, further explaining he has always been able to enjoy in the moment or something like that. Music, sun in the sky etc. He simply never had motivation until he took speed. In the end - how weird is that? Happens all the time. Yoy stated yourself that you have all the motivation. Be carefuly identifying with anhedonics - you might have something different. It all comes down to emotions though... IMO...

I can bet my balls zrbarnes would've immensely enjoyed opioids. Not only do I lack pleasure from opioids, I lack ALL the effects. How exactly do opioids work for you? How's sedation, analgesia, miosis, constipation, itch? You stated yourself that you have all the motivation.

How are your emotions? This is a key issue. If you have normally intense emotions yet still can't get pleasure from music, sex, food or most recreational drugs, then indeed you don't have anything I'd call anhedonia. Resembles medievil's case, as stims work for him too. He also describes his off-meds anhedonic state as "hellish", as do you. I wouldn't say the same for me. I'm ok. Life is pointless like this but as long as I have hope in finding a treatment, I'm ok - this state of being is not painful per se.

However. Honestly, if speed works wonders for you, why on earth are you trying to find alternative for it when you could focus on finding means to procure it? Man, there IS NO alternative to DRI (DA reuptake inhibitor), which amphetamine is (the release of DA is not so significant). No supplement or antidepressant can compare to a real DRI. As you seem to know, with NMDA antagonists stimulant tolerance is manageable. So go for it. Take something for side effects if they trouble you. Don't get addicted to benzos though, warning you.

I recommend you to check my thread "The Anhedonia Thread", see with whom do you identify with. My understanding of the matters develops as the talk goes on and at one point I no longer consider myself anhedonic.

P.S. I no longer much write on this forum as my stuff is so unique, it's mostly pointless talking about it here. But I'll keep an eye on this thread.

Edited by Vieno, 28 February 2014 - 08:32 AM.

[Modest]

Brother, clearly your shit is treatable, so do not worry. But let's examine the details.

Anhedonia is a tricky concept. Take a look at this for starters: http://www.ncbi.nlm....les/PMC3005986/

Basically, anhedonia has traditionally been defined as inability to experience pleasure, however, that isn't really the case. What is referred to as anhedonia is usually lack of motivation and mental energy, and IMO most importantly, lack of emotions. SSRIs typically blunt emotions, and they are considered to be very bad for something called "anhedonic depression" - often, worsening it. This basic anheodonia usually respons very well to any type of stimulants, especially DA/NE reuptake inhibitors/releasers such as amphetamines or methylphenidate. Serotonin releasers and the oddball reuptake inhibitor St. John's Wort often work too and, frankly, pretty much any recreational drug, although side effects may be problematic.

What I have is a whole another story, I don't have anhedonia. I feel completely normal, I just don't get pleasure from anything, not even any drug. You probably can't understand what this really means. I have all emotions including the positive ones. Feeling upbeat at the moment. Just zero pleasure. I can take shitloads of drugs and get zero euphoria.

Don't get too excited about zrbarnes. User DissolveDissolve brought up the matter of motivational anhedonia in my big thread, and zrbarnes came to explain that's exactly what he has, further explaining he has always been able to enjoy in the moment or something like that. Music, sun in the sky etc. He simply never had motivation until he took speed. In the end - how weird is that? Happens all the time. Yoy stated yourself that you have all the motivation. Be carefuly identifying with anhedonics - you might have something different. It all comes down to emotions though... IMO...

I can bet my balls zrbarnes would've immensely enjoyed opioids. Not only do I lack pleasure from opioids, I lack ALL the effects. How exactly do opioids work for you? How's sedation, analgesia, miosis, constipation, itch? You stated yourself that you have all the motivation.

How are your emotions? This is a key issue. If you have normally intense emotions yet still can't get pleasure from music, sex, food or most recreational drugs, then indeed you don't have anything I'd call anhedonia. Resembles medievil's case, as stims work for him too. He also describes his off-meds anhedonic state as "hellish", as do you. I wouldn't say the same for me. I'm ok. Life is pointless like this but as long as I have hope in finding a treatment, I'm ok - this state of being is not painful per se.

However. Honestly, if speed works wonders for you, why on earth are you trying to find alternative for it when you could focus on finding means to procure it? Man, there IS NO alternative to DRI (DA reuptake inhibitor), which amphetamine is (the release of DA is not so significant). No supplement or antidepressant can compare to a real DRI. As you seem to know, with NMDA antagonists stimulant tolerance is manageable. So go for it. Take something for side effects if they trouble you. Don't get addicted to benzos though, warning you.

I recommend you to check my thread "The Anhedonia Thread", see with whom do you identify with. My understanding of the matters develops as the talk goes on and at one point I no longer consider myself anhedonic.

P.S. I no longer much write on this forum as my stuff is so unique, it's mostly pointless talking about it here. But I'll keep an eye on this thread.

Thanks for replying, Vieno

I see you have your own interpretation of what anhedonia is. I have also read that paper. I refer myself to consumattory anhedonics. But i dont have opioid deficiency. Opioids on their own gave me sedation, little vertigo and brain fog. On chronic bupropion 300mg they worked. The same thing with gaba b agonists (except that they helped a bit on its own). St johns worth brands in my country are so shitty that even 30 tablets gave nothing - they are hypericin standardized. Do you know where i can by something really good like sc27 through international delivery ? Because amazone sale it only in Us.

As for my emotions, they are not normal. I cant enjoy rain, sky or other related things.I very, very barely fell love, sadness or anger. And of course i cant fell pleasure from everything. My brain just DONT WANT REWARD. This is nucleus accumbens dysfunction. And this is hell, because i am absolute zombie. Or you mean the external emotions - Flat Affect ? I don't have it. Only internal.

Amp of course can save my life. But stims are illegal in my shitty country. I don't know, whether I will be able to get it again.

However, there are some more treatments - RTMS, ECT, EBS, ICSS etc. What should absolutely heal my anhedonia is DBS of nucleus accumbens. But it is so expensive, i don't have money for that.

Here is another paper describing anhedonia issue (i attached that)  PIIS0166223611001925.pdf   748.89KB   17 downloads

[Galaxyshock]

It seems that your anhedonia is essentially inability to feel reward and anticipatory. Not complete and absolute loss of reward like Vieno's case. Interesting paper, but the fundamentals of pleasure and reward track down to mu-opioid hedonic hotspot in Ventral Pallidum (VP), which is connected to Nucleus Accumbens (NAcc) though. NAcc to my understanding is essential for reward prediction and also has the "hedonic hotspot", and is dysfunctional in anhedonia. But it is VP that determines if there is reward/pleasure or not. Dopamine isn't necessary for reward, altough plays a major role in wanting and anticipating. Flooding the brain with mesolimbic dopamine (Amphetamine) will surely treat anhedonia, and may even activate VP even if it is dysfunctional. So GABA-B agonist do work partially? My theory is that GABA-B is the crucial link between anticipation and consummatory pleasure itself, and necessary for mu-opioid to be functional and pleasure to be experienced.

[Galaxyshock]

I do find it interesting though that bupropion enhances GABA-B agonists for you. Vieno has zero response to GABA-B agonism, and it is still a mystery if there is a neurological explanation.

Have you tried GHB (or GBL)?

Edited by Galaxyshock, 28 February 2014 - 06:05 PM.

[Galaxyshock]

The keys in hedonia to my insight are:

5-HT2A: Emotion and hedonic perception (antipsychotics working as 5-HT2A antagonists are known to kill emotion / zombify :: 5-HT2A agonist psychedelics have anecdotes of treating anhedonia and are known to enhance emotion and perception)
Mesolimbic dopamine/noradrenaline: Wanting and anticipation (antipsychotics are also dopamine antagonists killing motivation/desire :: amphetamine and cocaine flood the brain with mesolimbic dopamine and are extremely reinforcing stimulants)
GABA-B: Shift from anticipation to consumption (Phenibut and GHB are found very rewarding in an unique way, even amphetamine with dopamine-antagonist becomes rewarding again when Phenibut is introduced)(Baclofen is found very effective anti-addiction drug, and what I think happens is that you get to the pleasure easier and thus the drug cravings [the catalyst for DA/NA] become "unnecessary")
Mu-opioid: Reward (If anything above is dysfunctional the experience of pleasure is blunted, but only the loss of the GABA-B response is capable to completely diminish it, because you're stuck in the anticipation and won't recieve any of the reward)

[Galaxyshock]

http://www.nel.edu/p...-Stefano_p_.pdf

[Vieno]

Thanks for providing more details. The picture is clearer to me now, but perhaps only to me. Honestly, I got curious about this as I was wondering if you have something similar to my condition, but it now seems that is not the case. So for me your response revealed many things about the nature of your disorder, but I don't think any of my realizations are of much help for you. Why would you care about my conceptual rantings This is rather interesting though so I'll follow your progression...

In a nutshell, yeah, I think you indeed have anhedonia. I originally questioned this, wondering if you might have something similar to my case, but it now seems that's not true. Anhedonia is probably a very accurate description of your state. You just have it to an extreme degree. It seems to me that the anhedonia as a symptom may stem from various different types of brain dysfunction, but like Galaxyshock is saying, I'd guess serotonin, particularly the 5-HT2A, and dopamine, and perhaps noradrenaline are relevant. However I'm not an expert.

Itstrevor maybe has a similar situation to yours: http://www.depressio...ve-experiences/

I'm not sure if the science in that thread is very accurate, however you might be interested in something. Also there's a guy at mindandmuscle.net who took SSRIs for a long time and got extreme anhedonia, unusual in the sense that not even recreational drugs made him feel good - can't find the thread now.

For medievil, DRI stimulants enable benzos which otherwise do not work for him at all. Perhaps something similar to your experience of bupropion potentiating opioids and GABA-B agonists. Inspired by your case I might try to get more kick into depressants, especially GABA-Bergics, with some stims, however I don't have high hopes for the basic DA/NE stims - at least they do very, very little to my pleasure on their own.

As for St. John's Wort, Perika and perhaps Kira brands are considered top-notch. If they don't work at high doses (10-20x the normal dose, start from lower), then I don't think SJW will work at all. iHerb is the golden standard for international orders of herbal products, but there are other vendors as well. Google helps.

Btw, opioid deficiency refers to a disorder where depressive symptoms are removed without any side effects by low doses of opioids or low-dose naltrexone (LDN).

I will check that article you linked, always interested to learn more about the topic - thanks.

When talking about anhedonia, by the way, diet, excercise, psychology and lifestyle should always be checked first.

There clearly are many treatments to what you have. Keep digging. Don't expect to know anything until you verify your ideas with experimentation: brain function is probably much more complex than you think. Don't let obstacles prevent you from procuring a treatment.

Keep up the good work!

Edited by Vieno, 28 February 2014 - 08:22 PM.

[Reformed-Redan]

https://en.wikipedia...pride#Dysthymia

[Modest]

It seems that your anhedonia is essentially inability to feel reward and anticipatory. Not complete and absolute loss of reward like Vieno's case. Interesting paper, but the fundamentals of pleasure and reward track down to mu-opioid hedonic hotspot in Ventral Pallidum (VP), which is connected to Nucleus Accumbens (NAcc) though. NAcc to my understanding is essential for reward prediction and also has the "hedonic hotspot", and is dysfunctional in anhedonia. But it is VP that determines if there is reward/pleasure or not. Dopamine isn't necessary for reward, altough plays a major role in wanting and anticipating. Flooding the brain with mesolimbic dopamine (Amphetamine) will surely treat anhedonia, and may even activate VP even if it is dysfunctional. So GABA-B agonist do work partially? My theory is that GABA-B is the crucial link between anticipation and consummatory pleasure itself, and necessary for mu-opioid to be functional and pleasure to be experienced.

For my own experience there wont be reward without dopamine. It is the key to reward. But yes, anhedonia i so complicated thing...

I do find it interesting though that bupropion enhances GABA-B agonists for you. Vieno has zero response to GABA-B agonism, and it is still a mystery if there is a neurological explanation.

Have you tried GHB (or GBL)?

Bupropion long-term inhibits the reuptake of Da in Nacc (and general activity, may be) and allows gaba b and other things to reward. If i would be able to decrease Da an Ne in my frontal cortex just now... Then i would go to 450 and 600 mg bupropion a day (and maybe there will be surprise ?) I just cant understand why drugs increasing da and ne in my frontal cortex give my hellish suffering- at that moment i am thinking my frontal core gonna explode. It occurs only when i am anhedonic. There must be some important connection between nacc and pfc. Just cant solve that riddle.

As for GHB, haven't tried it. And for gbl i don't have access to it. A tried amisulpride which is a weak ghb agonist and it did nothing (on its own).

[Modest]

Thanks for providing more details. The picture is clearer to me now, but perhaps only to me. Honestly, I got curious about this as I was wondering if you have something similar to my condition, but it now seems that is not the case. So for me your response revealed many things about the nature of your disorder, but I don't think any of my realizations are of much help for you. Why would you care about my conceptual rantings This is rather interesting though so I'll follow your progression...

In a nutshell, yeah, I think you indeed have anhedonia. I originally questioned this, wondering if you might have something similar to my case, but it now seems that's not true. Anhedonia is probably a very accurate description of your state. You just have it to an extreme degree. It seems to me that the anhedonia as a symptom may stem from various different types of brain dysfunction, but like Galaxyshock is saying, I'd guess serotonin, particularly the 5-HT2A, and dopamine, and perhaps noradrenaline are relevant. However I'm not an expert.

Itstrevor maybe has a similar situation to yours: http://www.depressio...ve-experiences/

I'm not sure if the science in that thread is very accurate, however you might be interested in something. Also there's a guy at mindandmuscle.net who took SSRIs for a long time and got extreme anhedonia, unusual in the sense that not even recreational drugs made him feel good - can't find the thread now.

For medievil, DRI stimulants enable benzos which otherwise do not work for him at all. Perhaps something similar to your experience of bupropion potentiating opioids and GABA-B agonists. Inspired by your case I might try to get more kick into depressants, especially GABA-Bergics, with some stims, however I don't have high hopes for the basic DA/NE stims - at least they do very, very little to my pleasure on their own.

As for St. John's Wort, Perika and perhaps Kira brands are considered top-notch. If they don't work at high doses (10-20x the normal dose, start from lower), then I don't think SJW will work at all. iHerb is the golden standard for international orders of herbal products, but there are other vendors as well. Google helps.

Btw, opioid deficiency refers to a disorder where depressive symptoms are removed without any side effects by low doses of opioids or low-dose naltrexone (LDN).

I will check that article you linked, always interested to learn more about the topic - thanks.

When talking about anhedonia, by the way, diet, excercise, psychology and lifestyle should always be checked first.

There clearly are many treatments to what you have. Keep digging. Don't expect to know anything until you verify your ideas with experimentation: brain function is probably much more complex than you think. Don't let obstacles prevent you from procuring a treatment.

Keep up the good work!

You mentioned itstrevor but his situation is different. When i started to read his topic, i thought - thats it !! But then i went deeper i realized that his condition is also unique - as i remember, he has genetically overactive nmda receptors and doesn't respond to stims and other drugs. I have read the topic several months ago and don't know what became to him after his several ECT treatments.

And Vieno, did you go through some genetic inspection or brain testing (PET,MRI). That may be your case.

Anyway, thanks for positive reply, Vieno !

[celebes]

The keys in hedonia to my insight are:

5-HT2A:
Mesolimbic dopamine/noradrenaline:
GABA-B:
Mu-opioid:

Yes!

[Sciencyst]

Dopamine is anticipatory and opioids equate to pleasure itself, according to the literature.. But dopamine can reinforce fear and opioids can punish (negative reward). Our neurochemicals are highly dualistic.

For me the only thing that lets me feel extreme, uninhibited, primal emotion is 5HT2A agonists. Everything else is shit. Bk-MDMA made my eyes roll hard and all that, but I felt zero actual pleasure from it. In fact towards the end of my experience with it, it began making me extremely fearful and uncomfortable. Zero pleasure, yet the reinforcement from the anticipatory nature of it was very much present.

Anhedonia and the like may also lie in the NMDA/glutamate system. Dissociatives make me emotionally detached and uninterested in any and everything. Whereas "associatives" (psychedelics) make everything intensely ibteresting and full of life. They actually work by binding to metabotropic glutamate/5ht2a heterodimer receptors, which are different than 5ht2a receptors by themselves.

Doing psychedelics is playing with the fire that is emotion, and it is easy to get burned if you do not know what you are doing or do not respect the drug.

Edited by katuskoti, 01 March 2014 - 10:00 PM.

[celebes]

For me the only thing that lets me feel extreme, uninhibited, primal emotion is 5HT2A agonists.

I've had the same response. I just wish I hadn't had to downregulate/desensitize them in the process of making the discovery.

The pharmacology is almost perverse. Low levels are found in atypical depression, autism, heavy metal poisoning and schizophrenia (and IME in trauma too). Antipsychotics have been variously found to both upregulate and down regulate. SSRIs and corticosteroids likewise. Nefazodone down regulates at a high-normal dose.

Beyond being seemingly ligand specific, the response might involve time-dependence. I'm currently looking for signs that intermittent low dose Trazodone might have a promotive effect. I had a substantial return of emotional responsiveness in the 6 months after I stopped a fairly short course of TRZ. Off the top of my head, the only things I've taken that compared have been salvia and ginseng, which taken chronically increases 2A response (and receptor density?).

There are only two substances that are clearly shown to upregulate that don't involve a custom synth:
SJW upregulates 2A and 1A at a HED of 21g (and probably 10g) but by a massive amount. It's unclear if it has the same effect at the quite low doses that seem to be most effective. Best case, that turns out to be substantially how its anti-anhedonic effect is mediated
CB2 agonists up regulate 2A near an attainable dose, while 2A activation itself increases endocannabinoid production. Without access to research chemicals, and avoiding THC, there's only source: Echinacea. Fortunately there is one brand with alkylamide levels high enough to be practical. I'm not relishing the endocrine effects involved though.

In the absence of a groundswell for an -Anserin group buy and given how rewarding going through life numb is, I'm going to press on with the above. Hopefully I'll have results to report before too long.

Edited by celebes, 03 March 2014 - 01:42 PM.

[Sciencyst]

Some SSRIs also upregulate 5HT2A, and IME this hasnt been a good experience, as high density of 5HT2A can cause bad OCD, bipolar, and the like.

[username]

Anhedonia is a symptom of depression. It's also a symptom of schizophrenia. Instead of saying that you're not depressed or schizophrenic, I would see it this way:

If this symptom is commong in depressed and schizophrenic people, why shouldn't substances help you that help them? Psychiatric disorders have a high comorbidity and the diagnostic system is far from perfect. Go to 10 different psychiatrists and you will get several different diagnoses or combination of diagnoses.
So my first suggestion: Instead of trying to diagnose yourself, try to look at the psychiatric diseases that list anhedonia as a symptom.
And just because you had a bad experience with an SSRI doesn't mean that anything that helps depression will not help you! There are quite a few people who have the typical suicide/guilt/withdrawal/worthlessness depression and have had a bad experience with an SSRI.

step 1: address (possible) deficiencies
I would try EPA 1-2g (from fish oil). It helped with depression, schizophrenia, bipolar disorder, ADHD in several studies. And if it doesn't help (if it does, it take up to a month), so what? It's still beneficial overall.
Optimize Vitamin D levels. (30-60 ng/ml)
Optimize magnesium, zinc, vitamin b9 and b12 levels (especially b12 deficiency can cause a crazy set of symptoms)

step 2: add stuff that helps with depression/schizophrenia
sarcosine 1-3g (addresses NMDA receptor hypofunction)
SAMe (depression)
saffron extract (depression)
NAC (schizophrenia - was used as an add-on to antipsychotics in studies)
ginkgo (also used as an add-on in several studies)

step 3: give it a couple of weeks

Sarcosine is good stuff. If you just wanna pick one of all these, take the sarcosine!

[Sciencyst]

Sarcosine is amazing. I began to feel a lot more like myself on it.

[celebes]

Some SSRIs also upregulate 5HT2A, and IME this hasnt been a good experience, as high density of 5HT2A can cause bad OCD, bipolar, and the like.

Do you know which ones? Definitely, over expression is as much a disorder as under.