420 replies to this topic

[Vieno]

Hello folks

Some people have found themselves stuck with depression that keeps on going even though they're in their right minds. In other words, the physiology of depression without the psychology of it. The typical sufferer of this complains about consummatory anhedonia that has lasted for months or years or even decades with only rare, very short windows to the normal feelingfullness. There are stories in the internet about parents who have watched their kids grow up from babies to adults without feeling the love. Younger folks browse the internet and study neurobiology in hopes of treatment.

Consummatory anhedonia is the core component of this condition. Other persisting components may be loss of libido, attention deficiency similar to ADD and psychomotoric drowsiness. All these exist regardless of psychological states or changes in them. The name of the thread comes from the fact that most people suffering from this refer to their condition simply as "anhedonia".

I was gonna make a thread about my own situation, but I realized that I'm not interested in sharing the details of my story or rambling about personal experiences: been there, done that. Instead, I have a goal common with the other anhedonics: finding viable treatment strategies. In this thread there is no need for convincing others about how it is not psychological and how it is consummatory instead of motivational and so on. Let's just discuss the physiology and the drugs.


Now, there are four strategies that have came to my mind. I'd like to get your opinions on them.

1. L-DOPA
Because of the developing tolerance L-DOPA shouldn't be used continuously, but it might remove the anhedonia (and possibly other depressive problems) temporarily and by doing so give insight about the problem's exact dopaminergic nature. Mucuna Pruriens would be a practical option. COMT-inhibitor and carefully MAO-B inhibitor supplements should be taken with it.

2. Selective Serotonin Reuptake Enhancer
SSRIs only worsen the anhedonia, which makes the SSRE a candidate worth trying. Unfortunately Tianeptine is only available in some countries, but I believe people who've suffered years can go to great lengths to try potential treatments.

3. Adaptogens
Adaptogens probably won't do very much for depression, but because they're easy and safe to use, they're worth trying. They can also be co-administrated with other choices of treatment and they may enhance their working. Rhodiola Rhosea seems to be perhaps the most common choice, but Echinacea Purpurea also seems to have many qualities that could possibly be anti-anhedonic. Nearly all true adaptogens seem to contain at least some mild anti-depressive features when tested with rodents.

4. Quetiapine
There is no solid evidence on Quetiapine actually working on anhedonia or depressive attention deficiency and it is also a dopamine antagonist. However its agonism for the serotonin receptors 1A and 2A is something noteworthy.

Thoughts? I decided to not to write in detail about the strategies, because my knowledge is so limited. However if you think these are something worth considering, for sure let's talk about them in greater details.

P.S. This is not just interesting research. I need a working treatment.

Edited by manic_racetam, 28 October 2012 - 06:43 AM.

[Luminosity]

It seems unlikely that this isn't psychological in many cases. If it was, a good talk therapist would likely help. They vary in quality.

"Some people have found themselves stuck with depression that keeps on going even though they're in their right minds. In other words, the physiology of depression without the psychology of it." --Vieno

People with depression can be lucid or non-delusional.

You seem to want to believe that this problem could be exclusively biological so I won't keep coming back to argue differently but I thought I should say something once.

Edited by Luminosity, 25 October 2012 - 04:47 AM.

[Vieno]

Thanks for the reply. If it was, a good talk therapist would likely help. If many good talk therapists haven't been able to help, then it likely isn't, right? I wanted this thread to be about those who have already done their research on the psychological side so that it doesn't need to be done here anymore. I am not a supporter of medical treatment for depression. For the majority of these 21 months that I've been having depressive problems I have insisted that it either must be psychological or at least have a psychological cause. It has been evaluated by numerous psychiatrists, neurologists, general practitioners, psychologists, neuropsychologists and therapists. I still continue to look for the psychological explanations and this physiological route is only a plan B. But in this thread, I want to focus on the Plan B, because it needs attention.

[malden]

The mind is an direct result of the brain, fixing a problem is far better than get therapy for learning to live with bad wiring.
psychiatry is pseudo science imo.

i have accutane induced ahedonia.. lately i find cdp choline very helpful. but i think ahedonia have many causes and categories

[Vieno]

Problematic thinking is its own topic and shall not be discussed here.

i have accutane induced ahedonia.. lately i find cdp choline very helpful. but i think ahedonia have many causes and categories

Thanks for the tip. Wikipedia notes an interesting thing: "Cocaine dependence is associated with depleted dopamine levels in the central nervous system. In cocaine-dependent individuals citicoline increases brain dopamine levels and reduces cravings".

How would the co-administration of L-DOPA and Citicoline work? Would the Citicoline possibly prevent the development of tolerance for L-DOPA?

Edited by Vieno, 25 October 2012 - 10:24 AM.

[malden]

Problematic thinking is its own topic and shall not be discussed here.

i have accutane induced ahedonia.. lately i find cdp choline very helpful. but i think ahedonia have many causes and categories

Thanks for the tip. Wikipedia notes an interesting thing: "Cocaine dependence is associated with depleted dopamine levels in the central nervous system. In cocaine-dependent individuals citicoline increases brain dopamine levels and reduces cravings".

How would the co-administration of L-DOPA and Citicoline work? Would the Citicoline possibly prevent the development of tolerance for L-DOPA?

Citicoline give me calmness in the mind, and let me more enjoy things. i think that will help with drug dependence indeed.


I have tried L dopa, it did me no good at all. (feel terrible) have tried almost all dopamin agonist non of them help for me.

eat paleo wheat and gluten reduction and adding healthy cofactors have help me the most.

[Vieno]

Citicoline give me calmness in the mind, and let me more enjoy things. i think that will help with drug dependence indeed.

According to wikipedia, Accutane does not have an (known) effect on dopamine, but instead does other thing such as reduces serotonin levels. These suggest that it does not induce the normal consummatory anhedonia relevant in depression. In the context of mental disorders, accutane seems to cause suicidality, psychosis and anxiety, which are different and possibly even reverse to anhedonia. Thus I wonder if your anhedonia is something different from the normal depressive consummatory anhedonia?

I have tried L dopa, it did me no good at all. (feel terrible) have tried almost all dopamin agonist non of them help for me.

If my thoughts on the nature of your Accutane induced anhedonia are correct, then it's no surprise dopamine agonism doesn't help you. Nothing seems to connect Accutane to dopamine. I just gotta try L-DOPA myself. I could even try amphetamine and cocaine to see the effect. It would help with diagnostics.

eat paleo wheat and gluten reduction and adding healthy cofactors have help me the most.

I'm familiar with paleo diet but never tried it. Many have suggested it for anhedonia. I'm sceptical, because changes in lifestyle have done nothing for me so far. What is the argument for paleo reducing anhedonia? And what cofactors do you mean?

[medievil]

http://www.longecity...ia/page__st__30

supplements[/url] should be taken with it.

2. Selective Serotonin Reuptake Enhancer
SSRIs only worsen the anhedonia, which makes the SSRE a candidate worth trying. Unfortunately Tianeptine is only available in some countries, but I believe people who've suffered years can go to great lengths to try potential treatments.

3. Adaptogens
Adaptogens probably won't do very much for depression, but because they're easy and safe to use, they're worth trying. They can also be co-administrated with other choices of treatment and they may enhance their working. Rhodiola Rhosea seems to be perhaps the most common choice, but Echinacea Purpurea also seems to have many qualities that could possibly be anti-anhedonic. Nearly all true adaptogens seem to contain at least some mild anti-depressive features when tested with rodents.

4. Quetiapine

There is no solid evidence on Quetiapine actually working on anhedonia or depressive attention deficiency and it is also a dopamine antagonist. However its antagonism for the serotonin receptors 1A and 2A is something noteworthy.]

Ldopa wont help as anhedonia has little to do with DA.

Tianeptine wont help either, nor do i see any mechanism behind adaptigens wich can help.

Seroquel DEF wont help at all, 5HT1A antagonism i cant see be of any help, besides its metabolitite is a partional 5HT1A agonist, 5HT2A agonists most likely help (low treshold doses of psychedelics abolish anhedonia,

[Vieno]

I woudn't go as far as saying anhedonia has little to do with DA. I've read the paper you're referring to and I am currently exploring opioids to be co-administrated with L-DOPA or other dopamine agonists, but consummatory anhedonia has also a lot to do with dopamine itself. Like I said, I'm not expecting L-DOPA to be a cure by itself. Just experimenting. No people with persistent consummatory anhedonia have found pure dopamine agonists to be a cure, but they most certainly have had a strong temporary effect. The reported over-emotionality occurring in Parkinson's treatment is an indication of this, too.

Why wouldn't tianeptine help at all? If SSRIs cause anhedonia then isn't it logical to expect a reverse effect from a reverse drug? As for adaptogens, like I said I'm not counting on them, but aren't they suitable to some degree for pretty much anything? Trying won't hurt. I can't see how you can say you see no helping mechanism behind them: so many of them have found to have antidepressant effects. Again: not expecting much from them, but I find it to be an overexaggeration to claim that there is no helping mecchanism behind them.

I wrote 5HT-1A antangonist by accident, I meant agonist. In this paper http://www.ncbi.nlm....les/PMC2734449/ the role of 1A is discussed, starting from "The Role of Serotonin in Attentional Control". It's more about depressive attention deficiency than anhedonia, but they are strongly related in depression - and both, at least to some degree, are dopaminergic problems too. To understand that explanation better, in this paper the analytical reasonin refers to focus on one's own thoughts instead of deducing from external stimuli. But you're right about one thing: I should explore 5HT-2A more! :)

All in all, I believe the most important thing is to find out more about opioid (mu) receptors. Finding the right kind of combined mu-receptor and dopamine agonist medication could be a solution. What do you think about that?

Edited by Vieno, 27 October 2012 - 09:27 AM.

[CIMN]

http://www.longecity...ia/page__st__30

supplements[/url] should be taken with it.

2. Selective Serotonin Reuptake Enhancer
SSRIs only worsen the anhedonia, which makes the SSRE a candidate worth trying. Unfortunately Tianeptine is only available in some countries, but I believe people who've suffered years can go to great lengths to try potential treatments.

3. Adaptogens
Adaptogens probably won't do very much for depression, but because they're easy and safe to use, they're worth trying. They can also be co-administrated with other choices of treatment and they may enhance their working. Rhodiola Rhosea seems to be perhaps the most common choice, but Echinacea Purpurea also seems to have many qualities that could possibly be anti-anhedonic. Nearly all true adaptogens seem to contain at least some mild anti-depressive features when tested with rodents.

4. Quetiapine

There is no solid evidence on Quetiapine actually working on anhedonia or depressive attention deficiency and it is also a dopamine antagonist. However its antagonism for the serotonin receptors 1A and 2A is something noteworthy.]

Ldopa wont help as anhedonia has little to do with DA.

Tianeptine wont help either, nor do i see any mechanism behind adaptigens wich can help.

Seroquel DEF wont help at all, 5HT1A antagonism i cant see be of any help, besides its metabolitite is a partional 5HT1A agonist, 5HT2A agonists most likely help (low treshold doses of psychedelics abolish anhedonia,

Are there any OTC overthecounter 5ht2a agonist options?

[Dissolvedissolve]

Are there any OTC overthecounter 5ht2a agonist options?

Seeing as classical psychedelics are 5ht2a agonists, you will not find any. There are a number of research chemicals (primarily the 2C series) that are quasi-legal, but you need to have them synthesized, and they may still be illegal under the analogs act. They also aren't well-researched, so it's probably not wise to take RCs on a regular basis. The 2Cs, for instance, are phenethylamine derivatives, and some PEA derivatives are neurotoxic. The 5ht2a agonists that are well-researched and known to be safe are thoroughly illegal.

Edited by Dissolvedissolve, 28 October 2012 - 07:06 AM.

[Vieno]

Has anyone tried opioid agonostis for anhedonia? They most certainly appear to be of critical importance, but so little experimentation has been carried on with them in terms of pathologically depressive states. People use opioids to quickly induce euphoria for recreational purposes, but that's not a treatment for anhedonia. I am interested in lasting anti-anhedonic effect so that euphoria itself wouldn't be induced but instead the brain would enter a state in which it would be open to stimulus-induced euphoria. Like a healthy brain. Anyone has any knowledge of this?

[Dissolvedissolve]

There's an excellent review article that medievil posted recently that discusses some preliminary treatment options. In my experience, and based on the literature, most anhedonia is primarily anticipatory in character. In that case, dopamine reuptake inhibition or agonism (without dopamine downregulation) is desirable. The only commonly used DRI (actually an NDRI) is wellbutrin.

I expect opioid agonists would work very well, but I would be wary of them due to the extremely high potential for dependence.

[Galaxyshock]

5-HT2C antagonism could work.

http://en.wikipedia....ceptor#Function

[Vieno]

There's an excellent review article that medievil posted recently that discusses some preliminary treatment options. In my experience, and based on the literature, most anhedonia is primarily anticipatory in character. In that case, dopamine reuptake inhibition or agonism (without dopamine downregulation) is desirable. The only commonly used DRI (actually an NDRI) is wellbutrin.

I expect opioid agonists would work very well, but I would be wary of them due to the extremely high potential for dependence.

I am very familiar with that paper, indeed has contributed to my understanding of the physiology of anhedonia a lot. My anhedonia is consummatory in nature: there's a very clearly observable difference between me and most depressed people. Therefore, I am interested in opioids. I hadn't read the paper when making this thread so that's why I'm not talking about opioids in the OP... :P yes, dependence is the key issue - so I need to find a way to activate the mu-receptor without dependency.

Galaxyshock, thanks for the tip - seems interesting. Gotta study it. Are you saying it could work for consummatory anhedonia or depression in general or what?

Edited by Vieno, 28 October 2012 - 08:49 PM.

[medievil]

Are there any OTC overthecounter 5ht2a agonist options?

Seeing as classical psychedelics are 5ht2a agonists, you will not find any. There are a number of research chemicals (primarily the 2C series) that are quasi-legal, but you need to have them synthesized, and they may still be illegal under the analogs act. They also aren't well-researched, so it's probably not wise to take RCs on a regular basis. The 2Cs, for instance, are phenethylamine derivatives, and some PEA derivatives are neurotoxic. The 5ht2a agonists that are well-researched and known to be safe are thoroughly illegal.

Lisuride is one, however its also a potent D2 antagonist, perhaps adding a typical ap with strong affinity for D2 could work (not too much so you risk TD).

Has anyone tried opioid agonostis for anhedonia? They most certainly appear to be of critical importance, but so little experimentation has been carried on with them in terms of pathologically depressive states. People use opioids to quickly induce euphoria for recreational purposes, but that's not a treatment for anhedonia. I am interested in lasting anti-anhedonic effect so that euphoria itself wouldn't be induced but instead the brain would enter a state in which it would be open to stimulus-induced euphoria. Like a healthy brain. Anyone has any knowledge of this?

Buprenorphine seems to work long term for depression so that should be a possibility.

Seroquel:
It causes retardation, complete loss of personality, dominance (because of 5HT2A and 5HT2C antagonism) and apathy and worsens anhedonia for me, many anecdotes confirm this, shizo's would like it as it blocks the worst of their symptions, you also dont notice the lack of personality like me on risperdal.

5-HT2C antagonism could work.

http://en.wikipedia....ceptor#Function

By what mechanism then?

Why wouldn't tianeptine help at all? If SSRIs cause anhedonia then isn't it logical to expect a reverse effect from a reverse drug?

They inhibit phasic sero, sero releasers like mdai dont cause anhedonia.

Why wouldn't tianeptine help at all? If SSRIs cause anhedonia then isn't it logical to expect a reverse effect from a reverse drug?

They inhibit phasic sero, sero releasers like mdai dont cause anhedonia.

Edited by medievil, 28 October 2012 - 09:05 PM.

[Vieno]

Buprenorphine seems to work long term for depression so that should be a possibility.

How does it exactly work? What is a drug used for treatment of opioid dependency exactly: how does it differ from other opioids like morphine for example? Have you tried it btw?

Seroquel:
It causes retardation, complete loss of personality, dominance (because of 5HT2A and 5HT2C antagonism) and apathy and worsens anhedonia for me, many anecdotes confirm this, shizo's would like it as it blocks the worst of their symptions, you also dont notice the lack of personality like me on risperdal.

I take it this is a comment to the Quetiapine strategy, which I pretty much have given up on :P

They inhibit phasic sero, sero releasers like mdai dont cause anhedonia.

This I don't understand. So what that MDAIs don't cause anhedonia? SSRIs do. They aren't the same. Why does SSRI cause anhedonia if serotonin release doesn't cause anhedonia?

[Vieno]

An extension to the previous post: I have read a lot about opioid related anhedonia and especially buprenorphine today. I am amazed by the findings. I'm skeptical because some of the people promoting buprenorphine seem to be somehow monetarily involved with it or are opioid addicts who are not necessarily very objective, but neurobiological data nevertheless supports these findings at least to some degree. So since those some people do claim it's a cure:

Has anyone tried buprhenorphine (or another opioid without dangerous (morphine/heroinelike) tolerance issues) for consummatory anhedonia and/or depression? What arguments are there against trying such opioids? Tolerance seems to be an issue for every opioid, but for a short-time experiment - what opposing arguments there are? If you medievil have tried it please share your experience, if you haven't, why?

Edited by Vieno, 29 October 2012 - 07:15 PM.

[medievil]

An extension to the previous post: I have read a lot about opioid related anhedonia and especially buprenorphine today. I am amazed by the findings. I'm skeptical because some of the people promoting buprenorphine seem to be somehow monetarily involved with it or are opioid addicts who are not necessarily very objective, but neurobiological data nevertheless supports these findings at least to some degree. So since those some people do claim it's a cure:

Has anyone tried buprhenorphine (or another opioid without dangerous (morphine/heroinelike) tolerance issues) for consummatory anhedonia and/or depression? What arguments are there against trying such opioids? Tolerance seems to be an issue for every opioid, but for a short-time experiment - what opposing arguments there are? If you medievil have tried it please share your experience, if you haven't, why?

Opiates only work for me in combination with stimulants because of my mental issues that retilate to shizophrenia, Da seems to play a permissive role in euphoria such as glutamate, it also corrolates with consumptionary anhedonia because the more rewarding something is the more wanting da has to cause, otherwise we would want to go to dentist everyday instead of doing something thats fun, it has to exactly corrolate.

Tolerance to opiates should be possible to counteract with nmda antagonists, addiction perhaps with low daily treshold doses of ibogaine (would also work for tolerance) proglumide is another option for tolerance issues.

The argument against them are the tolerance and addiction issues wich i beleive can be counteracted but most ppl are skeptic this would work, without even trying it, like how everyone was skeptical nmda antagonists would help tolerance untill i convinced people to try it everywhere and it worked.

I find the skeptical people quite amusing as they for example live their life depressed due to not willing to try other things, well its their own fault id say, no compassion (perhaps i should be more carefull with my advices tough as they can lead to addiction but strangely i just dont care as more people would more likely be helped.

Bad person i am:)

There is a difference btw phasic and tonic monoamine release, phasic are surges induced by the activity your doing while tonic is whats there in the background like when you sit on the bed and stare to the ceiling, ssri's shift balance to tonic serotonin.

There's an excellent review article that medievil posted recently that discusses some preliminary treatment options. In my experience, and based on the literature, most anhedonia is primarily anticipatory in character. In that case, dopamine reuptake inhibition or agonism (without dopamine downregulation) is desirable. The only commonly used DRI (actually an NDRI) is wellbutrin.

I expect opioid agonists would work very well, but I would be wary of them due to the extremely high potential for dependence.

Stimulants work because they load to mu activation, bupropion barely increases da unless your a mouse and is pretty much useless for anhedonia.

[protoject]

Tolerance to opiates should be possible to counteract with nmda antagonists

I can double for this one, memantine is a pretty good candidate as it is long-acting. As per mu-opioid agonists, kratom may be a good option, some people may be able to get by on a low dose of this without much risk or complication. [obligatory warning label: yes , it can still cause addiction and may or may not be good to mix with other drugs], in terms of addiction the withdrawal usually only lasts like 3 days and only if you are doing large doses day to day or constantly redosing.

I have to disagree about MDAI, I think MDAI is horrible suicidal-ideation promoting crap. Then again, I'm an MDMA burnout 'victim' so my neurons are probably fried and react differently to SA releasers.

5ht1a agonists- cannabidiol may be a good candidate.

[medievil]

If MDAI is horrible suicidal inducing then thats simply because youv been abusing it, i used 30 mg 3 times a day for a while without issues.

Thats like saying treating adhd with amphetamine is a bad idea because its horrible suicidal inducing when your abusing it the whole time.

[anon2042]

Just going through this thread - I have had anhedonia for almost a year now following my ECT. It has shown no signs of letting up.

There's a lot of speculation, but does anyone have any personal stories for things that have worked for them? What concerns me is that people tend to say things like, "Oh, that's just a symptom of the depression, it will go away..." when it seems that at times that's the only thing I'm suffering from.

Also I +1'd the second reply on therapy. My depression is so, so chemical in nature, and I think anhedonia is one of the worst contenders that I can think of for therapy. It makes sense that CBT etc. can (and does for some people) work to reduce negative thinking, etc, but how in the world is a therapist supposed to talk you into actually enjoying or liking something? I'm sure we've all had moments in our lives where we've tried to force or feign interest in something when it just isn't happening (to please others, belong in a group, etc.). And it's awful...For me, anhedonia makes almost everything like that.

Edited by amnesiagirl, 31 October 2012 - 10:02 PM.

[Dissolvedissolve]

Stimulants work because they load to mu activation, bupropion barely increases da unless your a mouse and is pretty much useless for anhedonia.

Could you provide a citation for the claim that bupropion doesn't increase brain DA levels? A quick wikipedia citation search provides this article: http://guilfordjourn...apn.2008.13.5.6 ("occupancy of [DAT]... was 6-22%") and the authors of the review seemed to be very optimistic as well. Obviously, if someone has a problem with consummatory anhedonia, then bupropion may not be effective.

[Vieno]

Medievil: I came across some extremely interesting writings, but well I think you know them all. The talk is about "Endogenous Opioid Deficiency" or "Endorphine Deficiency". The thing that makes me optimistic now is that consummatory anhedonia is the only thing I'm suffering from, and nothing describes is better than absolute inability to feel euphoria. At this point I think this kind of anhedonia is about endogenous opioid deficiency. I will definitely look into those anti-addictive substances you mentioned, I'm definitely open for all things. Yet, so far I have never self-medicated (or even accepted the drugs prescribed by a doc lol). So no worries about me risking my health

I am already planning my next moves. I'll try to see if my psychiatrist could prescribe me some Low-Dose Naltrexone; however, she is insane, so I doubt it. I may buy morphine or buprenorphine from the streets for a test use. Whenever I actually try something, I'll report to you guys.

Amnesiagirl, I sent you a PM!

Fuck these font sizes btw... can't handle 'em

[protoject]

If MDAI is horrible suicidal inducing then thats simply because youv been abusing it, i used 30 mg 3 times a day for a while without issues.

Thats like saying treating adhd with amphetamine is a bad idea because its horrible suicidal inducing when your abusing it the whole time.

I did not abuse mdai, i just used about 50 MG, ive heard of other non-abusing people having the same horrible experience as I did.

Its like with AMT, I don't get nearly the pleasent anti-depressant effect that some people [like yourself] mention..

But again the mdma abuse spanning years back could definitely be a complication... even though the one time MDAI was tried was years ahead of time.

[anon2042]

Thanks, just replied to the PM.

When I was struggling looking for a new doctor and all I could say to them, "The only thing I haven't tried are stims and opiates" (as in the star-d study for treatment resistant depression, they'd be suggested at this level) they stay far, far away.

I had a tonsillectomy a few months ago and was given Oxycodone for my pain which I took in steady doses for about a week. Maybe it was the whole crippling pain thing, but I didn't notice any mood related effects. I was also on the scop-patch for nausea, and left it on more or less for over a week, nothing there either :/ I am so non reactive to meds, so even if I did get prescribed an opiate if I could handle the nausea, I just don't think I'd respond...

As for "stimulants", the closest I've gotten is Wellbutrin and Parnate. The Wellbutrin (so I've told) helped a little bit, but the parnate screwed me over in so many ways. I do tend to have (although I guess a lot of others struggling with anhedonia would have this problem) a less energetic depression, so SSRIs and other deactivating meds are bad for me. But on the other hand, I can get very overstimulated by my environment and suffer more anxiety when on those sorts of drugs.

Edited by amnesiagirl, 01 November 2012 - 12:27 AM.

[medievil]

Stimulants work because they load to mu activation, bupropion barely increases da unless your a mouse and is pretty much useless for anhedonia.

Could you provide a citation for the claim that bupropion doesn't increase brain DA levels? A quick wikipedia citation search provides this article: http://guilfordjourn...apn.2008.13.5.6 ("occupancy of [DAT]... was 6-22%") and the authors of the review seemed to be very optimistic as well. Obviously, if someone has a problem with consummatory anhedonia, then bupropion may not be effective.

I find that doubtfull, i have to dig up references but i beleive more inhibition needs to take place for therapeutic effects.
"The occupancy of dopamine transporter (DAT) by bupropion and its metabolites in the human brain as measured by positron emission tomography was 6–22% in an independent study[129] and 12–35% according to GlaxoSmithKline researchers.[130] Based on analogy with serotonin reuptake inhibitors, higher than 50% inhibition of DAT would be needed for the dopamine reuptake mechanism to be a major mechanism of the drug's action. By contrast, approximately 65% occupancy or greater of DAT is required to achieve euphoria and reach abuse potential.[131] "
Refs are on wiki but will dig them up when requested, also the ref that





J Clin Psychopharmacol. 2003 Jun;23(3):233-9.
Neurochemical and psychotropic effects of bupropion in healthy male subjects.

Gobbi G, Slater S, Boucher N, Debonnel G, Blier P.

Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montréal, Quebec, Canada.
Abstract

Bupropion is a weak inhibitor of noradrenaline (NE) and dopamine (DA) reuptake and has no direct action on serotonin (5-HT) neuronal elements. In the rat brain, bupropion suppresses NE neuron firing activity via the activation of alpha(2)-adrenoceptors and increases that of 5-HT neurons through an indirect action on NE neurons. Twenty-five healthy young male volunteers, with no previous history of psychiatric disorders, were randomized to one of four 7-day regimens: placebo, bupropion (150 mg) once daily, bupropion (150 mg) twice a day, and methylphenidate SR (20 mg daily). To assess the activity of the NE reuptake process, the blood pressure response to intravenous tyramine was determined. A decrease in the systolic pressure response to tyramine was considered evidence of NE reuptake inhibition. Effects on 5-HT reuptake were assessed by measuring whole blood 5-HT concentration, with a decrease serving as an index of 5-HT reuptake blockade. The Profile of Mood States (POMS) scale was used to assess behavioral and psychological changes. Neither bupropion nor methylphenidate altered the tyramine pressor response, in contrast to previous data that demonstrated decreases were obtained with NE reuptake inhibitors. Neither drug modified 5-HT concentrations. However, POMS scores revealed that bupropion at a dosage of 150 mg/day increased composedness, agreeability, and energy, whereas 300 mg/day improved only attention. In contrast, methylphenidate improved only energy. These data provide no evidence that bupropion acts as an inhibitor of NE or 5-HT reuptake in healthy humans. Presumably it enhances synaptic availability of NE by increasing release. Yet, because its behavioral profile is different from that of methylphenidate, it may not share all the biochemical properties of psychostimulants.



Psychopharmacology (Berl). 2001 Apr;155(1):52-7.
Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment.

Dong J, Blier P.

Department of Psychiatry and Neuroscience, McKnight Brain Institute, University of Florida, P.O. Box 100256, Gainesville, FL 32610, USA.
Abstract

RATIONALE: Bupropion is widely used in the treatment of depression and as an anti-craving medication for the cessation of tobacco smoking. Because it is a very weak inhibitor of norepinephrine (NE) and dopamine (DA) reuptake, its mechanisms of action remain to be elucidated.

METHODS: Bupropion was administered subcutaneously via osmotic minipumps over 2 days to determine its effects on the spontaneous firing activity of NE, serotonin (5-HT), and DA neurons in the brain of anaesthetised male Sprague-Dawley rats. This treatment was used in order to obtain levels of the parent compound and its putatively active metabolites that would more adequately reflect the clinical condition than utilizing acute injections.

RESULTS: When given by minipump for 2 days, bupropion produced a dose-dependent attenuation of the mean spontaneous firing NE neurons (7.5 mg/kg per day: 15%; 15 mg/kg per day: 61%; 30 mg/kg per day: 80 which was reversed by the alpha 2-adrenoceptor antagonist idazoxan. At the highest regimen, the mean firing rate of 5-HT neurons was 100% higher than in control rats, but unaffected in NE-lesioned rats. In contrast, DA neurons in the ventral tegmental area displayed a normal firing rate during the latter bupropion treatment.

CONCLUSIONS: Sustained bupropion administration decreased the firing rate of NE neurons due to an increased activation of their inhibitory somatodendritic alpha 2-adrenoceptors. This effect of the bupropion treatment would be attributable mainly to an enhancement of NE release and not to reuptake inhibition. This contention is based essentially on the observation that NE reuptake blockers leave unaltered the firing rate of 5-HT neurons, whereas bupropion enhanced it via a NE-dependent mechanism. The present study did not put into evidence any DA activity of bupropion at the level of the cell body of mesolimbic/cortical DA neurons at a regimen exerting profound alterations of the firing activity of NE and 5-HT neurons.

PMID: 11374336
The metabolite does increase da enough but to get that you must be a rodent or have a rodent liver.

[medievil]

I suppose cannabinoids would help as well, but they have their own issues (such as causing lazyness or cognitive decline)

As for psychedelics.

Been taking low ~3-5mg morning doses of 2C-E recently mostly as an exercise / weight-training companion.

Highly recommended.

A little Theobromine and Creatine Ethyl Esther for energy, low doses of Phenibut and Diphenhydramine as recommended here to reduce general Phenethylamine discomfort, add some Whey Protein, and I've been making some pretty good progress.

I find low-dose 2C-E to be a smooth, almost trance-inducing way to ensure lasting motivation during physical exertion.


About a million times more useful/safe than real stimulants.

~1 mg 2C-P does the trick for me!

I'm an artist and I often have trouble forcing myself to work and be productive... But 5 minutes after a speck of 2cp I am drawing furiously for hours... good stuff too! Then I go to bed feeling satisfied, sleep well with great dreams, and wake up totally refreshed!


Modulate with hashish to your taste

I have done this extensively... in fact it's become my main usage of psychedelics. My favorite booster, so to speak, is DOC, though DOM also works nearly as well. I take .5 to 1mg and it brings on the plateau stage effects, which for me are energy, mood boost and extreme mood stabilization, cognitive enhancement, empathy, and a sort of a general feel that everything is easier and goes with the flow. Low doses like this allow me to sleep at the end of the day easily and they really don't drain me at all... there's a slight tolerance build-up so I generally wouldn't do it 2 days in a row but I have done it up to 4 or 5 days in a row with reduced effects but without burnout.

Ive taken both low doses of 2ce and 2ci on separate occasions. 2C-I gave me a boost of energy and a mood lift, it was perfect for just riding my bike. I was able to exercise a lot longer, as I didn't feel fatigued. I've also taken extremely low doses at work, and its usually enjoyable. Have to be careful cuz it hits me a lot harder in that environment.

2C-E on the other hand doesn't really offer stimulation, so I got tired of riding my bike pretty quick. I was just left wanting more.

This is great for getting things done around the house and in the yard. Not my fav for being around strangers, too much behavioral affectation. Usually I run errands before hand, eat a meal, then go for the dose.

2ce: works at .25 mg to 2mg (oral). This mixes well with +/- 1g of pramiracetam. Rhodiola combines with either/both, increasing physical stamina effect and the lightly trippy headspace without adding to confusion. I get a spacey confusion at 3mg-12mg - it's too much to be focused and functional and not enough to be comfortable.

Mescaline (hcl preferred, cactus powder too variable): 10mg-50mg gives the day a sparkle. 50mg-100mg is where things get a little strange and productivity takes a hit. Beyond that is linear into tripping territory. Coffee amps the body up a bit, hardly the mind. 25mg in the morn with coffee to titrate wakefulness is great. You can really keep a nice eye on the Effect/Time curve with this one. Piracetam makes it pretty speedy (synergy) so dose down accordingly.

4-ho-met: <1mg is all really. Stuff gets too spacey and wonky on this one. Better suited for sitting down and doing something, not really all that functional. A couple mg's is nice for a video game, but well outside the purpose of the thread.


Mushies: .1g-.5g and is similar to ho-met in effect but not as clear. Coffee or green tea is a ticket to aimlessly racing thoughts and the uncomfortable sides of too much caffeine.

Daily low treshold MXE doses wich i did for a few weeks may be helpfull too.

[Vieno]

Medievil, is that latter post about anhedonia or a response to Dissolvedissolve?

[medievil]

About anhedonia.