420 replies to this topic

[Galaxyshock]

Do you think it's specifially only mu-receptor dysfunction? Opioids seem to be feedback-chemicals as there are kappa- and nociceptin-receptors that produce dysphoria, anxiety and depression. Do you experience pain normally? I think pain and pleasure are mediated by the same pathways. For a period of time after my withdrawal from Phenibut last year I experienced consummatory anhedonia in that I really anticipated and wanted to experience pleasure but I never got the response. Pretty sure I would have been immune to opioid drugs. I've read people withdrawing from GHB abuse describing bad case of anhedonia so that even a speedball would barely have anything but some peripheral effects.

[Vieno]

Well one difference between the pleasure/reward response and the emotional response is that the former are always the same sensations, but the latter are many and varied, depending on context (for example, anger and/or fear if someone punches you on the face; jealousy if your girlfriend starts flirting with another guy; guilt if you have done something wrong). Emotions also often involve a strong body-wide physiological response (for example, anger or fear may cause increased heart rate an adrenaline to be pumped into the blood; embarrassment may make you blush red), but I am not aware of any body-wide physiological effects that pleasure or reward produce.

Also, most negative emotions will not involve a pleasure/reward response: anger, jealousy, envy, hatred, disgust, guilt, shame, embarrassment, etc tend not to evoke a pleasure/reward response.

However, it is hard to disentangle a lack of pleasure/reward response from a lack of an emotional response, because both response seem to be fundamental in providing the drive, meaning and purpose to human actions, and are therefore very similar in this respect.

My argument is that anhedonia is NOT a dysfunction of pleasure/reward response. I completely agree on everything you just wrote, could be written by me. My point is that since anhedonia is NOT a dysfunction of plesure response, it could be a dysfunction of emotion response. Why do I think it's not a dysfunction of pleasure response? Because anhedonics are able to feel consummatory pleasure, which' other name is - well, pleasure. Here we go with the semantics... remember that lack of pleasure is not the same as inability to experience it. Anhedonics may feel unable to experience pleasure and in fact in practicec often are this, however under right conditions and with the right attitude they can. Physiologically, their pleasure response seems intact. This has been documented.

Depression is included in the official disease definition list of symptoms that CFS can produce, but not anhedonia specifically. Plus I rarely hear of CFS patients talk about anhedonia. There are some motivational issues in CFS patients, though.

I checked CFS from wikipedia and some references and it indeed seems that anhedonia is not usually present in CFS. I really would have expected otherwise. Thanks for the information, I stand corrected.

Also the recent findings regarding anhedonia typically being of anticipatory nature suggests that motivational issues are, if not the same as anhedonia, at leasst very similar and probably linked.

I am not offering any theory here, just trying to replicate the benefits of kambo, by taking dermorphin, one of its main components. Though interestingly, many CFS patients find that mu-opioid pain relief drugs do actually bring noticeable relief from many of the cognitive symptoms of CFS, like brain fog, so I am also thinking about trying regular mu-opioid drugs.

Alrite, then it's worth trying. Go for a bigger dose, even with 40 times greater potency than of morphine 100mcg doesn't sound very much (4mg of morphine). Also do the cough codeine, it will be your chance to test a typical opioid. Quite interesting if opioids truly help CFS patients, can't see how but if it works then why not! Gotta google that.

Beta endorphins are low in CFS patients (ref: 1, 2), presumably resulting in under-activation of mu- and delta-opioid receptors. LDN stimulates beta endorphin production (by a rebound effect) and so is helpful in CFS.

Well that's not exactly mu-dysfunction, it is a dysfunction of the opioid system but more specifically not related to mu-receptors but to beta endorphin production, obviously. If it would be mu-dysfunction then taking mu agonists wouldn't really help since obviously the dysfunction should be fixed before the agonism would do anything. That's the case with my and medievil's condition!

Edited by Vieno, 17 May 2013 - 12:30 PM.

[Vieno]

Do you think it's specifially only mu-receptor dysfunction? Opioids seem to be feedback-chemicals as there are kappa- and nociceptin-receptors that produce dysphoria, anxiety and depression. Do you experience pain normally? I think pain and pleasure are mediated by the same pathways. For a period of time after my withdrawal from Phenibut last year I experienced consummatory anhedonia in that I really anticipated and wanted to experience pleasure but I never got the response. Pretty sure I would have been immune to opioid drugs. I've read people withdrawing from GHB abuse describing bad case of anhedonia so that even a speedball would barely have anything but some peripheral effects.

How fascinatign! What makes you think you would have been immune to opioid drugs?

I consider GHB probably the most potential treatment for my disorder as the GHB receptor is so glutamatergic. I don't know how phenibut could help but medievil says it helps some 50% so gotta try it - doing it right now. If phenibut withdrawal induces CA (specifically mu-dysfunction) it indicates it truly can work as a CA treatment as withdrawal often is the opposite of the drug's influence. I gotta read about GHB withdrawals! My enthusiasm for that chemical has lately grown a lot and now it's SKYROCKETING!!!!

[Vieno]

I know a lot of people feel I get stuck to semantics so let me give you some examples of why it's important to pay attention to them. On the previous page Dissolvedissolve called the process that reinforces actions "reward". However on the same page user Hip later called pleasure "reward" by referring to to the same concept with both pleasure and reward simply separated by a slash (pleasure/reward). Now, let me write something.

"I tested some low-dose LSD and found it to enhance reward."

What do I mean with that? You can't know if reward has no universally accepted definition. This kind of things happen all the time with psychiatry and therefore semantics must be considered. I'm not trying to be an ass :P

[Galaxyshock]

Do you think it's specifially only mu-receptor dysfunction? Opioids seem to be feedback-chemicals as there are kappa- and nociceptin-receptors that produce dysphoria, anxiety and depression. Do you experience pain normally? I think pain and pleasure are mediated by the same pathways. For a period of time after my withdrawal from Phenibut last year I experienced consummatory anhedonia in that I really anticipated and wanted to experience pleasure but I never got the response. Pretty sure I would have been immune to opioid drugs. I've read people withdrawing from GHB abuse describing bad case of anhedonia so that even a speedball would barely have anything but some peripheral effects.

How fascinatign! What makes you think you would have been immune to opioid drugs?

I consider GHB probably the most potential treatment for my disorder as the GHB receptor is so glutamatergic. I don't know how phenibut could help but medievil says it helps some 50% so gotta try it - doing it right now. If phenibut withdrawal induces CA (specifically mu-dysfunction) it indicates it truly can work as a CA treatment as withdrawal often is the opposite of the drug's influence. I gotta read about GHB withdrawals! My enthusiasm for that chemical has lately grown a lot and now it's SKYROCKETING!!!!

Just the fact that there wasn't any "release response" from anything. The tension and anticipation would build up from pleasure seeking things but no release. Also, alcohol (whiskey) at the time actually had unpleasant anxiety-dizziness effect - and the rewarding effect of alcohol seems to be mediated by the mu-opioid receptor. Later my condition switched to anticipatory anhedonia for several months that has finally gotten a lot better lately, but I definitely still lack part of the thrill. I think this tension - release thing is how the pleasure works in a lot of things: music, sex.. The greater the tension the bigger the release, and subjective experience of pleasure. An amphetamine would amp up the tension and an opioid would shoot up the release, but the no-response to opioid is quite a mystery. Perhaps it's GABA-B/GHB-receptor mediated glutamate that "signals back" the opioid responses and ultimately completes the experience.. just guessing..

I think it was Medievil who informed that Phenibut also has some glutamatergic action unlike Baclofen (another GABA-B agonist).

[Vieno]

I think alcohol doesn't work quite like it should for me either. It's nothing unpleasant and the intoxication seems normal, but it's hardly pleasurable. It also doesn't really make me enjoy socializing etc. any more than sober. I haven't been drinking almost at all because it would be quite pointless with CA, but when I have been drunk, I have still been quite introverted. Just don't feel like talking. I believe naltrexone mostly blocks alcohol cravings but probably some of the intoxicated pleasure too, maybe this is something like that. Maybe you had the same thing.

Not sure what do you mean with that tension-release phenomenon. Pleasure is a simple thing, you get it when a stimuli induces a pleasure-inducing physiological reaction (probably has to do with mu). What exactly do you mean with tension?

Amphetamine surely adds to all the anticipation, excitement etc. - surely momentarily works well for anticipatory anhedonia - but it also appears to physiologically enhance mu-induced pleasure. People generally consider stims very pleasure-enhancing and they work well for medievil's CA and to some extent for mine too.

I don't really know shit about how the glutamate modulates the mu-pleasure, but there seems to be a strong connection. I'll give a try for any strong glutamatergic drug. I found that medievil's thread where you too talk, it's interesting but obviously not very detailed when it comes to phenibut's glutamatergism - that's all just wild speculation.

I read a bit about GHB withdrawals but found hardly anything resembling CA. People mostly just seem to talk about tachycardia, agitation, insomnia, delirium, all horrible shit but no CA-resembling stuff. Not even regular anhedonia very much.

[Galaxyshock]

http://www.bluelight...g-D2-antagonism

That was the thread that I stumbled upon when wondering what was the anhedonia about when I was early to post-acute withdrawal phase. I guess it's individual how one responds to the withdrawals and stress - is it depression, delirium or anhedonia. The dopamine-related discussion is probably misleaded by the belief of DA being responsible for reward altough it does play some part.

By tension I mean for example in sexual activity the build-up of excitement and pleasure before orgasm (release). At least for me in anticipatory anhedonia there is no pleasurable excitement (tension) altough the act itself can be pleasurable - and the endresult is a blunted experience. I think AA comes down to fight-or-flight response involving release of phenylethylamine (recognized as sort of an endogenous amphetamine), adrenaline etc. Interestingly Phenibut is phenylethylamine antagonist.

Edited by Galaxyshock, 17 May 2013 - 05:13 PM.

[Hip]

My argument is that anhedonia is NOT a dysfunction of pleasure/reward response. I completely agree on everything you just wrote, could be written by me. My point is that since anhedonia is NOT a dysfunction of plesure response, it could be a dysfunction of emotion response.

So if I get you right, what you are saying is that although anhedonic individuals are unable to feel pleasure and a sense of reward, you have a hunch that the fault lies not in the reward circuits of the brain, but in the emotional processing circuits of the brain.

Anhedonics may feel unable to experience pleasure and in fact in practicec often are this, however under right conditions and with the right attitude they can. Physiologically, their pleasure response seems intact. This has been documented.

I understand the point you are making. A similar thing happens in chronic fatigue syndrome: on some days, people with CFS can experience brain fog so bad, that they can literally forget their own name. I am not joking. Yet the next day, the severity of their brain fog can be much improved, and the CFS patient then starts thinking more clearly again. This daily variation in brain fog severity suggests that in CFS there is no permanent physical damage to the brain (as there is in Alzheimer's), but rather that there is some aberrant brain chemistry which prevents the brain working properly. On days when the brain chemistry falls into the correct balance, for whatever reason, the brain fog improves; but when the brain chemistry goes out of whack again, the brain fog worsens.

It is possible that the same thing is true in anhedonia: there may be no permanent physical damage to the brain in anhedonic individuals, but rather some aberrant brain chemistry that underpins anhedonia. So under the right circumstances, when you take all the right substances to try to get the brain chemistry back to balance, your anhedonia may disappear, even if just fleetingly, before the brain chemistry goes out of whack again.

One line of interest I have involves the neurotransmitter glutamate. Glutamate is unfortunately created in large quantities by microglial cells (which are part of the brain's internal immune system) when they are activated in an immune response. So if you have a chronic low level infection in the brain, the brain's own microglial cells will remain persistently activated, and can then pump out so much glutamate that you may completely imbalance glutamatergic brain chemistry.

This condition of chronically activated microglia is found in many mental health and neurological diseases, including: CFS, autism, multiple sclerosis, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, stroke, schizophrenia, bipolar, hepatitis C, lupus erythematosus, and Lyme neuroborreliosis.

I am particularly interested in the ways that the normal workings of the immune system can dramatically perturb brain function; this may underly many mental health and neurological diseases.

Alrite, then it's worth trying. Go for a bigger dose, even with 40 times greater potency than of morphine 100mcg doesn't sound very much (4mg of morphine). Also do the cough codeine, it will be your chance to test a typical opioid. Quite interesting if opioids truly help CFS patients, can't see how but if it works then why not! Gotta google that.

That was the plan, to carefully work up to larger doses of dermorphin.

Judging by dermorphin trip reports on the Internet, intranasal doses of 500 micrograms are used for recreational consumption, and I would not go higher that that. Intranasal doses of much more than 1000 mcg may prove fatal, so caution is required.

However, even at the relatively low 100 mcg dose, although this produced significant improvements in my CFS symptoms, it also led to some mild psychosis symptoms in me. Psychosis is a big no-no, and you don't want to be playing around with substances that can precipitate psychosis in you.

Thus, I have halted my dermorphin experiments for the moment, until I can figure out how to prevent the psychosis side effect. One idea I have is to take NMDA receptor blockers just prior to snorting dermorphin, as these may help prevent opioid receptor desensitization from opioids (ref: 1), and I have a hunch that this might help prevent the psychosis.

Beta endorphins are low in CFS patients (ref: 1, 2), presumably resulting in under-activation of mu- and delta-opioid receptors. LDN stimulates beta endorphin production (by a rebound effect) and so is helpful in CFS.

Well that's not exactly mu-dysfunction, it is a dysfunction of the opioid system but more specifically not related to mu-receptors but to beta endorphin production, obviously.

True, it's just that I have been more focused on the mu-opioid receptors than anything else. Agonism of mu-opioid receptors tends to be anti-inflammatory, which it likely to be helpful in CFS, whereas agonism of delta-opioid receptors tends to be pro-inflammatory, which is likely to worsen CFS symptoms. Though that's just my personal hunch.

Having said that, I have read good reports regarding the benefits of kratom (Mitragyna speciosa) for CFS, and at low doses, the active principles in kratom are delta-opioid receptor agonists. So I could be wrong, and it could be delta-opioid receptor agonism I should be trying in my experiments in treating CFS.



Regarding the distinction between pleasure and reward: I think the point made by Dissolvedissolve is interesting:

Consummatory pleasure is contemporaneous with the stimulus. It is enjoyment of the stimulus itself, not before or after. For instance, enjoying music, sex, the "runner's high" (ie endorphins), a back scratching or massage - these are all consummatory. Pleasure after a stimulus would likely be dopamine based - a reward response to a completed goal.

Edited by Hip, 17 May 2013 - 05:58 PM.

[Dissolvedissolve]

However, even at the relatively low 100 mcg dose, although this produced significant improvements in my CFS symptoms, it also led to some mild psychosis symptoms in me. Psychosis is a big no-no, and you don't want to be playing around with substances that can precipitate psychosis in you.

Thus, I have halted my dermorphin experiments for the moment, until I can figure out how to prevent the psychosis side effect. One idea I have is to take NMDA receptor blockers just prior to snorting dermorphin, as these may help prevent opioid receptor desensitization from opioids (ref: 1), and I have a hunch that this might help prevent the psychosis.

I would be cautious about NMDA antagonism. While NMDA antagonism does help prevent tolerance, which is obviously desired, there's also evidence of NMDA receptor hypofunction in schizophrenia, meaning that NMDA antagonism is something that you may want to avoid if you are concerned about psychosis.

Amphetamine surely adds to all the anticipation, excitement etc. - surely momentarily works well for anticipatory anhedonia - but it also appears to physiologically enhance mu-induced pleasure. People generally consider stims very pleasure-enhancing and they work well for medievil's CA and to some extent for mine too.

I don't really know shit about how the glutamate modulates the mu-pleasure, but there seems to be a strong connection. I'll give a try for any strong glutamatergic drug. I found that medievil's thread where you too talk, it's interesting but obviously not very detailed when it comes to phenibut's glutamatergism - that's all just wild speculation.

We know that DA releasing agents cause pleasure directly via cascading opioid peptide release. We also know that DA release triggers glutamate release, and we know that glutamate release is required to experience opiodergic pleasure. So it seems that - and I'm being very approximate here - the glutamate release sensitizes one to pleasure. This is also consistent with the pro-glutamate nature of serotonergic psychedelics - people report vastly enhanced sensitivity to pleasure.

Just the fact that there wasn't any "release response" from anything. The tension and anticipation would build up from pleasure seeking things but no release. Also, alcohol (whiskey) at the time actually had unpleasant anxiety-dizziness effect - and the rewarding effect of alcohol seems to be mediated by the mu-opioid receptor. Later my condition switched to anticipatory anhedonia for several months that has finally gotten a lot better lately, but I definitely still lack part of the thrill. I think this tension - release thing is how the pleasure works in a lot of things: music, sex.. The greater the tension the bigger the release, and subjective experience of pleasure. An amphetamine would amp up the tension and an opioid would shoot up the release, but the no-response to opioid is quite a mystery. Perhaps it's GABA-B/GHB-receptor mediated glutamate that "signals back" the opioid responses and ultimately completes the experience.. just guessing..

In some sense, everything leads back to the mu-opioid receptor, because that is the only receptor currently associated with consummatory pleasure. So each other receptor ultimately sensitizes or activates mu pathways to achieve pleasure. Alcohol works primarily as a GABA agonist and NMDA antagonist. GABA-A agonism is thought to inhibit inhibitory pathways on DA, or something like that. So alcohol is rewarding through that pathway. (Notice I said rewarding - I always say rewarding when referring to reinforcement and pleasurable when referring to mu opioid activation.) Alcohol's GABA-B agonism causes release of DA. And alcohol's NMDA antagonism I believe also causes DA release, although I can't remember the exact pathway. I know the NMDA and opioid pathways are connected, but I am not sure exactly what the relationship between NMDA antagonism and the mu opioid receptors is.

Anyway, my point is that alcohol is a very messy compound.

[Vieno]

http://www.bluelight...g-D2-antagonism

That was the thread that I stumbled upon when wondering what was the anhedonia about when I was early to post-acute withdrawal phase. I guess it's individual how one responds to the withdrawals and stress - is it depression, delirium or anhedonia. The dopamine-related discussion is probably misleaded by the belief of DA being responsible for reward altough it does play some part.

Wow, that user yaesutom's comment is mind blowing to me. I don't find that thread so convinging otherwise but no effect from hydrocodone after quitting GBL? WOW MAN! I am SO looking forward to testing GHB.

By tension I mean for example in sexual activity the build-up of excitement and pleasure before orgasm (release). At least for me in anticipatory anhedonia there is no pleasurable excitement (tension) altough the act itself can be pleasurable - and the endresult is a blunted experience. I think AA comes down to fight-or-flight response involving release of phenylethylamine (recognized as sort of an endogenous amphetamine), adrenaline etc. Interestingly Phenibut is phenylethylamine antagonist.

So it's the same as anticipation in the contex of anhedonia. Obviously the tension-release model of yours is the same as that of anticipation-consumption model of some. Sounds like you had consummatory anhedonia indeed. If one lacks pleasure (consummatory) that doesn't mean that there's mu-dysfunction involved as anticipatory anhedonia can easily appear as consummatory anhedonia, however if CA exists WITHOUT AA then it indeed seems like mu-dysfunction exists. Too bad you didn't try opioids when you had that acute GHB withdrawal! How long ago was that btw? Just curious.

So if I get you right, what you are saying is that although anhedonic individuals are unable to feel pleasure and a sense of reward, you have a hunch that the fault lies not in the reward circuits of the brain, but in the emotional processing circuits of the brain.

Almost like that. Depends on the definition of "being able". Physically, I argue that anhedonic individuals are able to feel pleasure. This means that if we inject heroin to their veins they'll go to heaven. However, in their everyday lives they may be unable to reach pleasure because the anhedonia gets in the way. Lack of emotions, motivation and energy definitely gets in the way. It will prevent them from getting their asses to parties and even if they're dragged there, the anhedonia, if severe enough, will get in the way of every single move and decision. Dissolvedissolve for example has anhedonia (AA) but it's probably not that sever since even though he has trouble having the motivation to go pary, once he goes he feels good.

One line of interest I have involves the neurotransmitter glutamate. Glutamate is unfortunately created in large quantities by microglial cells (which are part of the brain's internal immune system) when they are activated in an immune response. So if you have a chronic low level infection in the brain, the brain's own microglial cells will remain persistently activated, and can then pump out so much glutamate that you may completely imbalance glutamatergic brain chemistry.

This condition of chronically activated microglia is found in many mental health and neurological diseases, including: CFS, autism, multiple sclerosis, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, stroke, schizophrenia, bipolar, hepatitis C, lupus erythematosus, and Lyme neuroborreliosis.

I am particularly interested in the ways that the normal workings of the immune system can dramatically perturb brain function; this may underly many mental health and neurological diseases.

Yes, glutamate seems to be very much involved with mu-induced pleasure. It's intriguing how your excess glutamate and mine too low seem to induce similar symptoms, however in all honesty I doubt we have the same problem. We'll see once you'll do a larger opioid dose.

Regarding microglia, that's pretty interesting. A long time ago when I thought that I could benefit from LDN I asked a CFS expert about it and she said that if it works for depression, it's not the increased mu-activation that does it but some microglia-related function. Can't remember what exactly it was but nevertheless she knew the relation between anhedonia (the typical depressive type) and microglia.

That was the plan, to carefully work up to larger doses of dermorphin.

Judging by dermorphin trip reports on the Internet, intranasal doses of 500 micrograms are used for recreational consumption, and I would not go higher that that. Intranasal doses of much more than 1000 mcg may prove fatal, so caution is required.

However, even at the relatively low 100 mcg dose, although this produced significant improvements in my CFS symptoms, it also led to some mild psychosis symptoms in me. Psychosis is a big no-no, and you don't want to be playing around with substances that can precipitate psychosis in you.

Thus, I have halted my dermorphin experiments for the moment, until I can figure out how to prevent the psychosis side effect. One idea I have is to take NMDA receptor blockers just prior to snorting dermorphin, as these may help prevent opioid receptor desensitization from opioids (ref: 1), and I have a hunch that this might help prevent the psychosis.

I can't see how an mu-agonist could induce psychosis. However obviously that has happened like with this case: http://www.ncbi.nlm..../pubmed/4000376

If I were you I would take codeine as it's so well known (and definitely not known to be psychosis-inducing despite that one case) and gradually increase the dosage. If psychotic symptoms reappear then stop. Indeed just like Dissolvedissolve said, I'd be VERY wary of using an NMDA antagonist as an anti-opioid-psychosis agent.

We know that DA releasing agents cause pleasure directly via cascading opioid peptide release. We also know that DA release triggers glutamate release, and we know that glutamate release is required to experience opiodergic pleasure. So it seems that - and I'm being very approximate here - the glutamate release sensitizes one to pleasure. This is also consistent with the pro-glutamate nature of serotonergic psychedelics - people report vastly enhanced sensitivity to pleasure.

Yeah, I was referring to these mechanisms, just didn't want to go into detail as I surely would have gotten something wrong.

In some sense, everything leads back to the mu-opioid receptor, because that is the only receptor currently associated with consummatory pleasure.

This is very true and it must be taken into consideration all the time, however it opens up a bunch of puzzling questions. This mu-ergic hypothesis assumes that all pleasure is born through the activation of the mu-receptor. However the pleasure-inducing receptor has been idetified to be mu2, which also induces a lot of other things such as analgesia, constipation, respiratory depression and miosis. Why are these not present when pleasure is derived from drugless stimuli like music, sex or food?

If indeed mu is responsible for all pleasure, then there must some mechanism that allows the mu to induce only pleasure. Maybe some endogenous ligand is able to do that. Endorphin can not be that, it's like like morphine, it induces all the same effects as any typical exogenous opioid.

However, whatever the truth is, considering mu as the pleasure-inducing receptor is a highly usable model. It clearly separates pleasure processes from anticipation processes which is crucial.

[Hip]

I would be cautious about NMDA antagonism. While NMDA antagonism does help prevent tolerance, which is obviously desired, there's also evidence of NMDA receptor hypofunction in schizophrenia, meaning that NMDA antagonism is something that you may want to avoid if you are concerned about psychosis.

Thanks for the warning.

Though in CFS, there is some speculation that NMDA receptor overactivation may be a problem, and many people with CFS find that NMDA receptor blockers like dextromethorphan, L-taurine and high dose transdermal magnesium help reduce symptoms. I often use these, sometimes all together, and I have always found these beneficial, and have not noticed any psychosis arising from their use.



In terms of the interconnection of NMDA and opioid receptors, and the fact that blocking the NMDA receptors can help prevent tolerance build-up and opioid receptors desensitization, the mechanism for this may be explained in this study on morphine-induced tolerance. In this study the authors actually propose a model in which signals from an activated mu-opioid receptor are picked up by the associated NMDA receptor, which in turn exerts a negative feedback effect on mu-opioid receptor signaling. So in other words, the NMDA receptor mediates the desensitization and tolerance build-up of the mu-opioid receptor to mu-opioid drugs. Block the NMDA receptor, and you block this tolerance build-up and desensitization of the opioid receptors.

Having said that, this study found that what is observed with morphine cannot always be extended to opioids in general; in particular, the study found that for selective mu and delta opioids, the mechanisms of tolerance may be different to that of morphine.



This article on the inflammation model of schizophrenia is interesting:

Is a Schizophrenic Brain an Inflamed Brain?

I should point out that, in relation to the talk about astrocyte cell dysfunction at the end of the article, that nasty virus called coxsackievirus B, which some researchers believe is a major cause of CFS, is known to infect astrocyte cells in the brain.

Edited by Hip, 18 May 2013 - 12:32 AM.

[Vieno]

Okay so everything so far has failed. Despite the strikingly similar symptoms, none of the drugs that have helped medievil have worked for me. I have done many stimulants with all doses and they only helped at extremely big doses which are unsustainable of course, and additionally they make me otherwise feel bad. I have done LSD at all doses ranging from 10mcg to 140mcg and whereas it induces all the typical psychedelic effects, it doesn't enable any pleasure. The highest phenibut dose I have done is 4,5g and it caused absolutely zero effects. With GHB my threshold is about 2,5g: the highest I've done is 3,5g and it induces slight intoxication with a small mood boost but with zero pleasure.

I have zero response to opioids and very little response to GABA-Bergics (phenibut and GHB). I have reasoned that I have an extremely high threshold for various brain phenomena, at least pleasure and certain depressant-sedative functions (mu, GABA-B). Indeed I generally do suffer from excess stimulation, sometimes I feel like I'm on stims when I'm on nothing. Stimulants make me feel ok per se but they induce horrible comedowns and only little pleasure.

In general I can say that in addition to having totally lost pleasure in drugless life, not a single drug has made be experience pleasure/euphoria. Psychedelics (LSD) and dissociatives (DXM) have induced all the typical interesting effects, however nothing pleasurable/euphoric.

Cannabis induces bad effects. Tachycardia, hypotension, anxiety, dizziness, loss of coordination and difficulty to recollect.

I have not done benzos yet but alcohol has a normal effect on me so GABA-A seems to work. Alcohol is not pleasurable/euphoric for me.

I have yet to try serotonergics, antimuscarianics and racetams. What else could be helpful? I want to try stuff like antipsychotics as I feel I could use some general sedation/anti-stimulant action, however I can not see antipsychotics, any sedatives or any psychiatric medications bearing much anti-CA (consummatory anhedonia) potential.

MPEP, also MTEP appear potential, however this is entirely speculative: http://en.wikipedia....thynyl)pyridine

"recently it was shown to reduce self-administration of nicotine,^[15][16] cocaine,^[17][18] ketamine and heroin in animals,^[19] possibly through an MPEP-induced potentiation of the rewarding effect of the self-administered drug,^[20] and MPEP was also shown to possess weak reinforcing effects by itself.^[21

Thoughts?

P.S. I'm getting fucking desperate. Hard to stay alive. Please help me guys :/

Edited by Vieno, 10 June 2013 - 04:54 PM.

[Vieno]

It seems that I have extremely high endogenous tolerance for the following things:

pleasurable/rewarding stimuli (as they don't reward me)
opioids
GABA-B agonists

The tolerance differs from drug-induced tolerance in that I have no withdrawal-like symptoms.

I think there must be either excess tonic activity of some neurotransmitter so that there is no molecules left for phasic action which would enable pleasure and drug effects. Either this or then the release of some neurotransmitter is just dysfunctional for some reason. Reuptake enhancement would help with excess tonic activity, however such exists only for serotonin. Releasing agents exist for all monoamines but not for other neurotransmitters like glutamate or opioids. However it is possible to indirectly induce release and probably reuptake enhancement too, for example I've read that NMDA-antagonism may cause the brain to compensate for the antagonized glutamate receptors by releasing more glutamate (therefore, NMDA-antagonists may indirectly be glutamate releasers). They don't work for me however.

[Galaxyshock]

Antimuscarinics/-cholinergics are worth a try. I find that excess acetylcholine (through AChE inhibition) can in fact make me feel pretty horrible and induce anhedonia and zombieness. How did your anhedonia start or has it always been there? If it was not a gradual change induced by chronic/extreme stress or something, my wild guess could be in fact presence of some poisonic compound that causes excess acetylcholine activity completely shutting down the pleasure pathways. I mean quasi-irreversible acetylcholine esterase inhibitors are used as chemical weapons and insecticides. It could also explain excess stimulation you experience. Perhaps in sub-lethal amounts those can cause horrible anhedonia etc.

Have you tried megadose of St. John's Wort? It does 5-HT2A upregulation, GABA-B effects, acetylcholine modulation and NMDA antagonism, and is in fact serotonin-dopamine-noradrenaline-glutamate-GABA re-uptake inhibitor and a MAOI. All effects are generally quite smooth though but in megadoses it can work pretty strongly and quickly. Something that alone was able to cure most of my anhedonia back in the winter when it was really bad. There is also ECT that seems to have worked for some suffering of extreme case like you, a similar thread on another forum:
http://www.depressio...riences/page-38

Do not give up.

[Hip]

@Vieno

Below is my list of emotion boosting and anti-anhedonia supplements. I found these supplements work for me. It took me years of trial and error testing to find the supplements and drugs that treat my emotional flatness and anhedonia symptoms.

I find that if I take 6 or 7 (or even more) of the supplements listed below all together in a stack, within an hour or so, they will usually (but not always) put me in an emotionally receptive state — an emotionally receptive state that lasts for a good 4 hours before it wears off.

By an emotionally receptive state, I mean a mental state in which you can watch an emotional movie on the TV, and experience a normal human emotional response. I find I can even cry sometimes at a sad movie, but only when I take these supplements. For me, crying is an amazing cathartic experience, because normally, my emotional circuits are as dry as a desert. I can rarely feel any emotions without these supplements, and it would normally be more or less impossible for me to cry. So clearly these supplements do work.

Although the emotionally receptive state only lasts for around 4 hours, if you take these emotion boosting supplements and then watch a movie that has a strong emotional theme, you will get emotionally involved in the movie, and you find the movie gives your emotions a nice workout. This emotional workout is a great vacation from the desert of emotional flatness.



HIP'S SUPPLEMENTS AND DRUGS FOR TREATING EMOTIONAL FLATNESS & ANHEDONIA


Choline bitartrate 1000 mg + Vitamin B5 100 mg + Inositol 2 heaped teaspoons.

Glutamine 1 heaped tsp.

Vinpocetine 10 to 20 mg (best taken with food - increases absorption).

Royal jelly 2000 mg +
Vitamin B5 500 mg gets the emotions flowing within an hour or so.

Ravensara essential oil 10 drops diluted in 30 ml of baby oil, and rubbed on skin (where it is absorbed). Creates a happy feeling in my mind.

Bacopa monnieri (Brahmi) 1000 mg.

Myrrh essential oil 10 drops diluted in 30 ml of baby oil, and rubbed on skin (where it is absorbed). Myrrh contains sesquiterpenes which increase oxygen in the pineal, pituitary and hypothalamus. Myrrh is well known in herbalist circles for boosting emotions.

Pregnenolone 50 mg.

Phosphatidylserine 300 mg
works best with cod liver oil / fish oil.

L-carnitine 1000 mg and acetyl-L-carnitine 500 mg are good for combating anhedonia - I notice an emotion-boosting effect after a few hours on carnitine or ALC.

Korean ginseng 500 mg

He Shou Wu herb 3 grams (this herb can sometimes cause hallucinations as a side effect in some people).

Bael Fruit herb powder (also called bilva powder) 3 grams. Bael Fruit is known by Ayurvedic herbalists to increase the emotion of compassion. I can vouch for the fact that it does work.

Colostrum powder 2 heaped teaspoons (14 grams) on an empty stomach - colostrum I find takes one or two days before its anti-anhedonia and emotion boosting effects kick in. For most supplements listed here, their effects kick in after an hour or so, but colostrum takes longer.

Imipramine (a TCA antidepressant).

Very low dose amisulpride 12.5 to 50 mg (an atypical antipsychotic that works for anhedonia).

Edited by Hip, 10 June 2013 - 08:05 PM.

[Anewlife]

I have anhedonia right now due to 200mg sertraline for ocd, hopefully adding bupropion for it soon but right now extended release iron with vitamin c is helping. Don't take this without first checking your ferritin level, mine is lowish.

[Vieno]

Thanks guys but I need to clarify something. Anhedonia is not the term to describe my condition despite the thread's name suggesting otherwise. All my emotions are intact. I am touched and moved by films and stuff just like before, but I don't get pleasure. No matter if I eat candy, have an orgasm, listen to music or ingest opium I get zero pleasure (with the latest, oddly I don't get any effects so mu is entirely non-responsive).

I don't know if I should call my condition a subtype of anhedonia (consummatory anhedonia) or some completely distinct state but most certainly it is not the same as your typical anhedonia. I have all emotions, no baseline apathy or feeling of emptiness or flattness, it's just that there is no pleasure and no euphoria. NOT AT ALL. Stimulants, opioids, GHB, psychedelics, cannabis, none of these rewarding substances make me feel pleasure except stims at extremely large doses. I know that the normal anhedonia is difficult to treat but I bet if an anhedonic shoots up some heroin or smokes a pile of meth, life ain't that bad for a moment even though it surely returns to misery after the drug effects wean off.

I know that anhedonia is a horrible thing and I'm not trying to claim it's something else. But I do think that despite the seemingly pleasure-lacking life that it induces, it is not a problem in the pleasure pathways per se. It just leads to a lack of pleasure in general as lack of emotions drives one to a non-rewarding lifestyle. I'm not sure if anticipatory anhedonia is a good term for the regular anhedonia, but nevertheless anticipatory and other cognitive aspects are pronounced in the regular anhedonia, unlike in my condition.

Antimuscarinics/-cholinergics are worth a try. I find that excess acetylcholine (through AChE inhibition) can in fact make me feel pretty horrible and induce anhedonia and zombieness. How did your anhedonia start or has it always been there? If it was not a gradual change induced by chronic/extreme stress or something, my wild guess could be in fact presence of some poisonic compound that causes excess acetylcholine activity completely shutting down the pleasure pathways. I mean quasi-irreversible acetylcholine esterase inhibitors are used as chemical weapons and insecticides. It could also explain excess stimulation you experience. Perhaps in sub-lethal amounts those can cause horrible anhedonia etc.

Have you tried megadose of St. John's Wort? It does 5-HT2A upregulation, GABA-B effects, acetylcholine modulation and NMDA antagonism, and is in fact serotonin-dopamine-noradrenaline-glutamate-GABA re-uptake inhibitor and a MAOI. All effects are generally quite smooth though but in megadoses it can work pretty strongly and quickly. Something that alone was able to cure most of my anhedonia back in the winter when it was really bad. There is also ECT that seems to have worked for some suffering of extreme case like you, a similar thread on another forum:
http://www.depressio...riences/page-38

Do not give up.

I know that antimuscarianics are known to enhance opioid effects so they theoretically seem good for me - I need to enable those mu-induced effects (not sure if drugless pleasure happens via mu-activation but they're related nevertheless). However all this talk about cholinergia's relation to anhedonia/depression is relatively useless for me as it always discusses the typical anhedonia, not specific lack of pleasure. Remember that my lack of pleasure is as hard core as it gets, I get zero of it, yet I have zero "zombieness" so this doesn't sound like excess acetylcholine.

I had the first moments of CA about four years ago, then about 2,5 years ago it had kicked in so severely that it forced me to quit music and re-design my life and last September is the last time I've experienced a brief window to normalness, non-CAness.

I have no idea what is this and surely your theory of poisoning is interesting, yet I have to say that my brother seems to have this too (albeit to a lesser extent) and we have led very different lives for years. Also he seems to have been "infected" a bit later. His response to opioids is very diminished but it's not nonexistent like mine.

I want to emphasize the lack of response to opioids as a key symptom of my condition, as it separates this from everything else (including typical anhedonia) and clearly shows how the pleasure system is fucked up. Mechanisms responsible for pleasure are not clear but mu is probably somehow implicated and since my mu is completely dysfunctional, I'm sure it has everything to do with my inability to feel pleasure.

St. John's Wort appears influence a rather wide selection of functions and receptors, never looked into it. As my condition is so different from typical anhedonia/depression, I don't think it'll help but I guess at this point I should try just about anything.

I'm very familiar with that thread that you linked - in fact, I was an active contributor to it a long time ago. I left it when I realized my condition is different from theirs. I hope Trevor and other figure their shit out.

@Vieno

Below is my list of emotion boosting and anti-anhedonia supplements. I found these supplements work for me. It took me years of trial and error testing to find the supplements and drugs that treat my emotional flatness and anhedonia symptoms.

I find that if I take 6 or 7 (or even more) of the supplements listed below all together in a stack, within an hour or so, they will usually (but not always) put me in an emotionally receptive state — an emotionally receptive state that lasts for a good 4 hours before it wears off.

By an emotionally receptive state, I mean a mental state in which you can watch an emotional movie on the TV, and experience a normal human emotional response. I find I can even cry sometimes at a sad movie, but only when I take these supplements. For me, crying is an amazing cathartic experience, because normally, my emotional circuits are as dry as a desert. I can rarely feel any emotions without these supplements, and it would normally be more or less impossible for me to cry. So clearly these supplements do work.

Although the emotionally receptive state only lasts for around 4 hours, if you take these emotion boosting supplements and then watch a movie that has a strong emotional theme, you will get emotionally involved in the movie, and you find the movie gives your emotions a nice workout. This emotional workout is a great vacation from the desert of emotional flatness.



HIP'S SUPPLEMENTS AND DRUGS FOR TREATING EMOTIONAL FLATNESS & ANHEDONIA


Choline bitartrate 1000 mg + Vitamin B5 100 mg + Inositol 2 heaped teaspoons.

Glutamine 1 heaped tsp.

Vinpocetine 10 to 20 mg (best taken with food - increases absorption).

Royal jelly 2000 mg +
Vitamin B5 500 mg gets the emotions flowing within an hour or so.

Ravensara essential oil 10 drops diluted in 30 ml of baby oil, and rubbed on skin (where it is absorbed). Creates a happy feeling in my mind.

Bacopa monnieri (Brahmi) 1000 mg.

Myrrh essential oil 10 drops diluted in 30 ml of baby oil, and rubbed on skin (where it is absorbed). Myrrh contains sesquiterpenes which increase oxygen in the pineal, pituitary and hypothalamus. Myrrh is well known in herbalist circles for boosting emotions.

Pregnenolone 50 mg.

Phosphatidylserine 300 mg
works best with cod liver oil / fish oil.

L-carnitine 1000 mg and acetyl-L-carnitine 500 mg are good for combating anhedonia - I notice an emotion-boosting effect after a few hours on carnitine or ALC.

Korean ginseng 500 mg

He Shou Wu herb 3 grams (this herb can sometimes cause hallucinations as a side effect in some people).

Bael Fruit herb powder (also called bilva powder) 3 grams. Bael Fruit is known by Ayurvedic herbalists to increase the emotion of compassion. I can vouch for the fact that it does work.

Colostrum powder 2 heaped teaspoons (14 grams) on an empty stomach - colostrum I find takes one or two days before its anti-anhedonia and emotion boosting effects kick in. For most supplements listed here, their effects kick in after an hour or so, but colostrum takes longer.

Imipramine (a TCA antidepressant).

Very low dose [b]amisulpride 12.5 to 50 mg (an atypical antipsychotic that works for anhedonia).

Like I said previously, I have no emotional flattness or anything like that. You have to understand that none of drugs that normally take people to heaven on instant make me experience pleasure/euphoria. I just can't see how some herb would help. It's completely useless information for me that Ayurvedic herbalists use something to increase the emotion of compassion. I can not feel opioids or GHB, would a herb restore my response? I doubt. Not trying to be rude, I just want to make sure everyone understands the nature of my problem.

I thought about amisulpride before as it's a GHB agonist, however since GHB doesn't work I bet it doesn't either.

I have anhedonia right now due to 200mg sertraline for ocd, hopefully adding bupropion for it soon but right now extended release iron with vitamin c is helping. Don't take this without first checking your ferritin level, mine is lowish.

Same applies to this as to the posts above, drugs that work for typical anhedonia are useless for me.

Edited by Vieno, 11 June 2013 - 09:05 AM.

[airplanepeanuts]

You have to understand that none of drugs that normally take people to heaven on instant make me experience pleasure/euphoria. I just can't see how some herb would help.

Herbs can be very powerful especially in combination. Just that you don't respond to some hard drugs doesn't mean that you are immune to all herbs. You might learn something...

[Galaxyshock]

Yeah I forgot about the specifics of your case, Vieno. Sounds very hard situation. The fact that your brother seems to have it too, altough not as complete vanishment, gets me thinking about genetic disposition to some rare neurodegenerative disease that selectively affects the reward pathways and opioid mu-function. Extreme stimulant dose being able to still activate something there tells the pathways aren't completely destructed. The process of neurodegeneration is quite poorly understood though and I don't know could it in fact be implicated to this.. You told feeling generally excessively stimulated? It could be hyperactivity of some transmission that is hindering the pleasure response, and that something unexpected like an antipsychotic could surprisingly work. Cholecystokinin function also came to mind as it has been noted to play a major role in inducing tolerance to opioids. Or perhaps histamine could also have something to do with it as it seems to be closely connected to opioid function.. It might very well be disorder of something "secondary" like this, since bombing the typical NT-systems don't seem to work.

[Vieno]

Will post tomorrow, too tired atm. Just wanted to let you know I'm still around if you know what I mean.

[Vieno]

Before responding to the posts above I want to share with you a noteworthy finding I just made.

Two days ago I took perphenazine (a medium potency typical antipsychotic), first 2mg and later 6mg. It induced pleasant and functional sedation suppressing negative arousal (anxiety, negative emotions, hyperactivity) and I spent the day extremely energetic, sociable and optimistic. Eventually I fell asleep before 2 AM which has been impossible for me for years due to the overarousal that is prevalent especially at nighttime.

It is my understanding that antipsychotics usually make people feel bad. They may help with psychotic and anxiogenic symptoms, but they induce apathy, maybe (anticipatory) anhedonia, make people "zombielike". For me perphenazine has been good in many ways. It appears to possess anti-depressant, pro-focus and pleasantly sedating (both mentally and physically) effects. It didn't restore my pleasure response at all, but the pleasant and useful effects nevertheless give me optimism because it seems that despite recreational drugs have not been good for me, others may be. I think this is largely congenial with what Galaxyshock just wrote. What do you think?

Gonna do more of this during next days.

[Vieno]

Now, let me tell you more about my excessive endogenous stimulation.

A couple of years ago I observed tackiness accumulating in my hair and light colored paste appearing in the comb. I went on asking hairdressers and even a doctor, no explanation, skin and hair were just fine. Washing always helped momentarily. For a similar length of time I've also experienced difficulty falling asleep, which about 1,5 years ago I discovered to be caused by excessive feeling of warmth during nights. I need low temperature (about 15 celcius) or a very thin blanket to be able to sleep. Often then I wake up cold some hours later and get some extra blankets. I cannot change my sleeping habits, I fall asleep in early morning and wake up late. The later I go to bed, the less I experience problems with temperature. Then about a year ago I noticed an oily layer coming off my skin. I peeled it off in shower but it reappeared from time to time. Later I noted that this layer is similar to the tacky substance in my hair. Then finally when I overdosed on methamphetamine my skin problem momentarily became greatly excarbated so that I scratched my skin to a bloody condition. I did some googling and found out that this typically happens with prolonged meth use as the body temperature stays high and thus the skin becomes oily and loose. I realized that my skin always got oily and came off as a consequence of a hot night. If I regularly go to bed not until 6-7 AM, I am freed from both sleep and skin problems. I have since measured my body temperature and it doesn't seem to increase during particular times however the measurements have not been the most accurate and I'm not sure about my skin temperature.

Separately from all these observations, I generally have some trouble focusing. It caused me to get ADHD diagnosis, however the diagnosis must be untrue as these problems have been present only for a couple of years. Also, since stims are bad and DA antagonist good, it really seems like ADHD can not be the case. Similarly to having trouble concentrating, I sometimes get so excited about stuff that I literally can not sit still but I have to move around and talk about something - if no one is present then I talk to myself. I can't help this excitation. I get racing thoughts. During these particular episodes the difficulty to focus is at its worst, however I have some focus problems almost all the time. It seems to me that it's not hypoactive DA causing my inattentiveness but hyperactive DA instead, it's like I'm too stimulated to focus on reading, I just want to jump up and down and read five books at the same time.


To give you guys more insight into my story with this consummatory anhedonia, let me paste here something I wrote previously as sort of notes.

2,5 years ago I noticed that I didn't succeed in creating music anymore. "Inspiration has been lost". As months went on I noticed that I didn't get the "feeling" from listening to music anymore that had previously been so strong. I also noticed later that neither did other art and entertainment experiences (literature, films, tv) produce this "feeling" anymore. I suspected that this must be something temporary.

For a year I focused on work and waited for the situation to pass. Eventually I got fed up with it and pulled a life-changing stunt including moving abroad etc. with a career in music in mind hoping the freshness of a change to bring back the lost feelings. I succeeded in making the change and made new friends and music contacts, took part in having fun and settled down. For two months I continued this but did not manage to create any new music and also constantly felt unsatisfied, inexplicably "empty". After two months of this I came to the conclusion that my life wasn't feeling like it should feel at all, that I couldn't get that normal "feeling" from people, from the new amazing scenery or from anything. This finding was extremely depressing.

I returned to my home country to seek for a solution with help from professionals. I tried to explain the problem with depression on the plea of anhedonia, which I believed to suffer from. Turned out that my state doesn't resemble anhedonics' state at all and that I was not depressed. Neither did the psychiatrist nor the psychologist find any signs of other psychiatric disorders. The situation severely depressed me. I decided to seek for a physiological explanation and started to study the brain (which endeavour effectively lifted the depression). After finding various opioidergic explanations I started to mirror the lost "feeling" to the experience which I believed opium and heroin to induce, and I felt I was on to something: "I don't get that experience anymore even in the slightest amounts as a reaction to life's positive events", was my idea. By that experience I meant that subjective experience you normally get for example when listening to music, hanging out with a friend or being outdoors on a sunny day.

I noted that several times throughout the past 1-2 year period I had shortly experienced the pleasure of the good old times. Among other things, once when watching a musical performance on youtube I suddenly experienced pleasure, as well as once when chatting with a friend on facebook. These have cumulated to a total of 10-11, they have lasted from 2 to 24 hours and they have occurred seemingly randomly, although never when I have felt particularly low/depressed.

As my investigations proceeded, I realized many more things among them the fact that losing enjoyment in eating sweet foods is not a part of growing up and that the lost sweet tooth could be explained by the brain disorder. I have not found enjoyment in sweet foods for a couple of years.

Finally I remembered that I had experienced a short window to consummatory anhedonia as long as four years ago, when I went to see a movie and didn't "feel" it. I found that weird but didn't know what to make of it. I assume it did happen more than once but if I was only having a shit, I probably didn't notice it.

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

And now back to your comments. Galaxyshock, I think you're on to something. I've had those ideas recently myself regarding antipsychotics, genetics, neurodegeneration and stuff. There definitely is a genetic component here.

Could you recommend antihistamines or cholecystokinergic drugs?

I think that despite basic monoaminergic modulation has not been successful for me, norepinephrine and serotonin still need to be further explored. For me dopamine agonism is bad and antagonism good but I have not modulated serotonin yet. Also, despite DA and NE modulating stimulants have not been good, the precise role of NE is not known yet. I think an SNRI would be an interesting trial. Certainly NE may play some role in pleasure. It is usually seen as the most physical of the monoamines but it has mental functions too.

So as for drugs to be trialled, I will do at least:
diphenhydramine
scopolamine
SSRIs
Serotonin releasers
SNRIs
atypical antipsychotics (many of them as their mechanisms vary greatly)
racetams

Maybe I could even try some NMDA agonist, I hear they make anticipatory anhedonia worse just like NMDA antagonists work for it - could be good for me as AA seems opposite to CA in some ways (at least in my CA there's excess stimulation whereas in AA there's often lack of stimulation).

Oh and also I need to try higher doses of opioids to see if it's just about high endogenous tolerance.

Airplanepeanuts, I'm not against using herbs. However I'm not aware of any of them that could be particularly helpful for my condition. My CA seems extremely severe and absolute and therefore I doubt adaptogenic correction of NT balances would be enough. Feel free to suggest some if you have ideas though!

Edited by Vieno, 13 June 2013 - 04:41 PM.

[Hip]

Then finally when I overdosed on methamphetamine....

Do you regularly use methamphetamine? Methamphetamine screws with dopamine receptors, and it is dopamine that drives the pleasure response.

[Galaxyshock]

Histamine could be a culprit and be connected to your sleep issues. It's major player in sleep regulation - histaminergic cells completely stop firing during REM and non-REM sleep. H3 (found mostly in central nervous system) is an auto-receptor though and agonism leads to decreased neurotransmitter release. Antihistamine like Diphenhydramine is worth a try to see what happens, or perhaps a selective H3-receptor modulator if the issue would be specific of the receptor. Another thing that comes to mind regarding the excess stimulation is hypoactivity of adenosine (inhibitory NT and also linked to sleep), which would lead to excess activity of dopamine and glutamate. If caffeine makes the issue significantly worse this could be something to investigate. I think the problem of sleep regulation and consummatory anhedonia may be strongly connected, and even explain the periods when your anhedonia would disappear - did they ever last more than a day? Also, have you tried sleep deprivation?

I agree that most herbs probably aren't going to do absolutely anything. There are these two though that I think are be worth a try:
Ginseng - has antipsychotic, tranquilizing and histamine-modulating actions, altough stimulating qualities too (cAMP). Potentiates antipsychotics, prevents tolerance to morphine and methamphetamine. It seems to be a strong dopamine-modulator that might shift the negative activity you're suspecting. When I had the period of restlessness, high anxiety and quite significant consummatory anhedonia (not absolute ever though, I think) after Phenibut withdrawal , Panax Ginseng was something I actually found to mostly "correct" me.
St. John's wort - like said has a lot of neurotransmitter modulation (SNDRI, glutamate, GABA, MAOI, adenosine..), in a megadose.

Different antipsychotics are probably worth experimenting since you had somewhat positive response. I'm not knowledged about them, perhaps Medievil can help. And surely trying selective serotonin and noradrenaline modulators can't hurt if others fail. And if high-dose opiates have at least some effect, perhaps even Ibogaine..

Edited by Galaxyshock, 13 June 2013 - 07:07 PM.

[Vieno]

Do you regularly use methamphetamine? Methamphetamine screws with dopamine receptors, and it is dopamine that drives the pleasure response.

No, I use nothing regularly. I dislike stimulants and have done meth only twice. Also DA is not very directly implicated in actual pleasure, this has been discussed in this and other threads numerous times and thoroughly. There's both research and anecdotes backing this up. Glutamate and opioids appear most directly implicated in pleasure, though indirectly a whole plethora of NTs meddle in including DA. Nevertheless, stimulant withdrawal is not known to induce CA.

Histamine could be a culprit and be connected to your sleep issues. It's major player in sleep regulation - histaminergic cells completely stop firing during REM and non-REM sleep. H3 (found mostly in central nervous system) is an auto-receptor though and agonism leads to decreased neurotransmitter release. Antihistamine like Diphenhydramine is worth a try to see what happens, or perhaps a selective H3-receptor modulator if the issue would be specific of the receptor. Another thing that comes to mind regarding the excess stimulation is hypoactivity of adenosine (inhibitory NT and also linked to sleep), which would lead to excess activity of dopamine and glutamate. If caffeine makes the issue significantly worse this could be something to investigate. I think the problem of sleep regulation and consummatory anhedonia may be strongly connected, and even explain the periods when your anhedonia would disappear - did they ever last more than a day? Also, have you tried sleep deprivation?

I agree that most herbs probably aren't going to do absolutely anything. There are these two though that I think are be worth a try:
Ginseng - has antipsychotic, tranquilizing and histamine-modulating actions, altough stimulating qualities too (cAMP). Potentiates antipsychotics, prevents tolerance to morphine and methamphetamine. It seems to be a strong dopamine-modulator that might shift the negative activity you're suspecting. When I had the period of restlessness, high anxiety and quite significant consummatory anhedonia (not absolute ever though, I think) after Phenibut withdrawal , Panax Ginseng was something I actually found to mostly "correct" me.
St. John's wort - like said has a lot of neurotransmitter modulation (SNDRI, glutamate, GABA, MAOI, adenosine..), in a megadose.

Different antipsychotics are probably worth experimenting since you had somewhat positive response. I'm not knowledged about them, perhaps Medievil can help. And surely trying selective serotonin and noradrenaline modulators can't hurt if others fail. And if high-dose opiates have at least some effect, perhaps even Ibogaine..

Thanks, your input is highly appreciated. Good to get new ideas, I've only thought about pro-glutamatergic drugs as possible CA-antidotes for a long time.

You mentioned so many things, I will need to familiarize myself with all that. Takes a couple of days

Regarding periods of CA disappearing, I have recorded a total of 11 of them since the "onset" of my CA (ie since CA became so significant that I had to adjust my life to it). They all have lasted from two hours to a maximum of two days (more like 1,5d actually), however there is one period when, I believe, pleasure was sort of hovering around for a couple of weeks. I'm not sure about this though, didn't think about it so much at that time. I don't want to go into detail regarding my brother, but I can tell that it appears that his CA slowly occurred over the course of months, then was strong for a couple of months, then weakened for some months (opioids worked at this time) and then came back strong to stay - opioids stopped working (normally) too. I have not tried sleep deprivation on purpose but I have sometimes stayed up for 48 hours or something and I have never noticed it to change anything regarding CA.

As for atypical antipsychotics, they really have very diverse function profiles. For example, some are GHB agonists and some are 5-HT antagonists - there are very few drugs in general that possess these functions.

I will go check out all the mentioned substances: DPH, Gingseng and St. John's. Also obviously I should try an NRI, for some reason when posting my previous post I thought no selective NRIs exist but surely they do.

Ibogaine does almost everything and would indeed be interesting to test.

Excellent! New impetus.

Edited by Vieno, 13 June 2013 - 11:01 PM.

[Hip]

I agree that most herbs probably aren't going to do absolutely anything.

Well, I know for a fact that the supplements I listed above work fairly well for me, in treating emotional flatness (blunted effect, to give the technical name). I tried hundreds of different supplements; most did not help, but the ones I listed did. Some I discovered by accident (I bought a supplement for a different purpose, but then found it had an emotion boosting effect).

So for anyone here who does suffer from emotional flatness, consider these supplements.

However, note that the effect of each individual supplement is not strong, so in order to get a noticeable effect, you need to take many together at once. That may be beyond some people's budget; but it depends on how badly you want some relief from emotional flatness.

DA is not very directly implicated in actual pleasure, this has been discussed in this and other threads numerous times and thoroughly

Yes I know, and I have read it numerous times.

Edited by Hip, 14 June 2013 - 12:39 AM.

[Galaxyshock]

I agree that most herbs probably aren't going to do absolutely anything.

Well, I know for a fact that the supplements I listed above work fairly well for me, in treating emotional flatness (blunted effect, to give the technical name). I tried hundreds of different supplements; most did not help, but the ones I listed did. Some I discovered by accident (I bought a supplement for a different purpose, but then found it had an emotion boosting effect).

So for anyone here who does suffer from emotional flatness, consider these supplements.

However, note that the effect of each individual supplement is not strong, so in order to get a noticeable effect, you need to take many together at once. That may be beyond some people's budget; but it depends on how badly you want some relief from emotional flatness.

Yes herbs and other supplements have their uses and have definitely helped with my bluntedness and anticipatory anhedonia. I was referring to Vieno's case which seems to be extreme and highly specific, where they just won't have the capability to do the trick. Most herbs have wide range of therapeutic effects - but like you said, weak and often need to be stacked. The wide range could become useful though with something like Ginseng or SJW if they would at least reveal something, but a megadose may be needed.

[Galaxyshock]

Another hypothesis could be some metabolic disorder affecting neuropeptides. Hyperexpression of cholecystokinin or overactivation of cholecystokinin -A receptor, leading to both high endogenous opiate tolerance and hyperactivity of Orexin / Hypocretin (http://www.jneurosci...tent/25/32/7459). Hypocretin is another wakefulness modulator (low in narcolepsy for example) and central administration of orexin-A strongly promotes wakefulness, increases body temperature, locomotion and elicits a strong increase in energy expenditure (you mention body temperature issues and excitability strong enough to be unable to stand still). It's also linked to mood and social interaction (http://www.nature.co...ncomms2461.html), you mentioned sudden lift from anhedonia when talking to a friend and the connections to music. Cholecystokinin A also regulates the release of dopamine and beta-endorphin (http://www.ncbi.nlm....ermToSearch=886). This is again wild guessing I'm doing based on some connections I picked up but some very novel approach I'm pretty sure is needed. There are at least some cholecystokinin A antagonist drugs, and the herbs Gotu Kola and Neem have CCK modulative effects too. I'm thinking high CCK-blocking to see if any relief or effect, and perhaps then try an opiate if the tolerance would have reversed.

Has your appetite/satiety been affected or any gastrointestinal symptoms? Could give some indications about neuropeptide activity.

Edited by Galaxyshock, 14 June 2013 - 11:08 AM.

[Vieno]

Thanks, will read upon that stuff too but I'll comment only antihistamines now. There's a whole plethora of H1 antagonists known and I'm sure I can access some of them. DPH will be an excellent testing tool as it possesses two potentially therapeutic functions, antihistaminic and antimuscarinic. Also it's great how many antipsychotics are also antihistamines, they may have many therapeutic functions combined. If anyone knows of any particularly promising compounds, let me know.

But how about those H3 agonists, are there any easily accessible ones? It is my understanding that H3 agonism, not antagonism, is the desired function.

Edited by Vieno, 15 June 2013 - 04:18 PM.

[stablemind]

Ginseng works very well as a mood boost, thanks Galaxyshock! I feel I get pretty tired around 5 PM if I take it in the morning, does this ever happen to you? I'm going to keep testing this gem.