420 replies to this topic

[Animal]

I would probably avoid agomelatine. The French drug company Servier just revealed that Valdoxan is very bad for the liver.

'Very bad' is an exaggeration; only 1.4% of patients who were treated with the standard dose of 25mg/day developed elevated liver enzymes. Which is less then the risk of seizure associated with 600mg/day of Wellbutrin.

The incidence of hepatic failure is 0.06%, which drops below statistical significance if elevated liver enzymes are not detected within the first 50 days (as a median) of treatment.

As for anhedonia, having suffered from it myself for many years, I can say with almost complete certainty that no one medication will provide sustained relief from it. Just to be clear, I don't consider Medievil's 'solution' of getting high on amphetamines or abusing research chemicals as sustained relief. It just disguises the anhedonia by flooding your brain with monoamines, causing cumulative damage in the process. If you want to retain your cognitive abilities beyond 30 I recommend you persevere with the less immediate remedies.

I would avoid phenibut, it's very transitory in it's positive effects due to the rapid onset of tolerance and dependence. If you abuse it for an extended period it'll only make the anhedonia worse when you stop taking it, I know this from first hand experience.

If you're willing to risk your neurons by trialling a research chemical, then surely you'd be open to the option of polypharmacy.

[Bruce6815]

I would probably avoid agomelatine. The French drug company Servier just revealed that Valdoxan is very bad for the liver.

'Very bad' is an exaggeration; only 1.4% of patients who were treated with the standard dose of 25mg/day developed elevated liver enzymes. Which is less then the risk of seizure associated with 600mg/day of Wellbutrin.

The incidence of hepatic failure is 0.06%, which drops below statistical significance if elevated liver enzymes are not detected within the first 50 days (as a median) of treatment.

Point well taken. I said "very bad" because of the exclamation marks on the Servier website. Also, not to make too fine a point of it, but the max dosage of Wellbutrin, as I understand it, is 400 mg/day.

As for anhedonia, having suffered from it myself for many years, I can say with almost complete certainty that no one medication will provide sustained relief from it. Just to be clear, I don't consider Medievil's 'solution' of getting high on amphetamines or abusing research chemicals as sustained relief. It just disguises the anhedonia by flooding your brain with monoamines, causing cumulative damage in the process. If you want to retain your cognitive abilities beyond 30 I recommend you persevere with the less immediate remedies.

I would avoid phenibut, it's very transitory in it's positive effects due to the rapid onset of tolerance and dependence. If you abuse it for an extended period it'll only make the anhedonia worse when you stop taking it, I know this from first hand experience.

If you're willing to risk your neurons by trialling a research chemical, then surely you'd be open to the option of polypharmacy.

I was doing fine for almost a year with Stablon and now cannot find it. I appreciate the insight into phenibut, as I had considered it and can now discard the idea without the trial. Would you say the same for the racetams, or are they worth trying for anhedonia?

Edited by Bruce6815, 30 November 2012 - 04:26 AM.

[anon2042]

I know phenibut has been mentioned here - I never tried it very much because I was afraid of withdrawl, but once I tried a decent size dosage it had quite a relaxing effect.

I was able to score some baclofen through my GP, and I have muscle pain as well, hoping it will help for general anxiety, but is the GABA profile too specific to target anhedonia like other GABA drugs?

[medievil]

I would probably avoid agomelatine. The French drug company Servier just revealed that Valdoxan is very bad for the liver.

'Very bad' is an exaggeration; only 1.4% of patients who were treated with the standard dose of 25mg/day developed elevated liver enzymes. Which is less then the risk of seizure associated with 600mg/day of Wellbutrin.

The incidence of hepatic failure is 0.06%, which drops below statistical significance if elevated liver enzymes are not detected within the first 50 days (as a median) of treatment.

As for anhedonia, having suffered from it myself for many years, I can say with almost complete certainty that no one medication will provide sustained relief from it. Just to be clear, I don't consider Medievil's 'solution' of getting high on amphetamines or abusing research chemicals as sustained relief. It just disguises the anhedonia by flooding your brain with monoamines, causing cumulative damage in the process. If you want to retain your cognitive abilities beyond 30 I recommend you persevere with the less immediate remedies.

I would avoid phenibut, it's very transitory in it's positive effects due to the rapid onset of tolerance and dependence. If you abuse it for an extended period it'll only make the anhedonia worse when you stop taking it, I know this from first hand experience.

If you're willing to risk your neurons by trialling a research chemical, then surely you'd be open to the option of polypharmacy.

I like to go beyond therapeutic doses at times but that doesnt mean you cant get anhedonia relief without being high. I stay with therapeutic doses at most periods which i just dont have anhedonia, and am not high in any way.

I dont see why stimulants in low therapeutic doses with something for tolerance cant be a good long term solution, IF combined with something like memantine and regular small breaks (like one or 2 days off every week) sustained relief can be achieved.

I havent seen any evidence of cumulative damage in ADHD, so i dont see why using them for anhedonia would.

As for phenibut it definatly cant be used chronically, and as for research chemicals the risks should be made clear, however for some there may not be a alternative, and living with anhedonia if its really bad is not really living, its unpleasant and you have to endure it the whole time, worse then being "bored".

Edited by medievil, 30 November 2012 - 02:27 PM.

[Vieno]

I will probably try MDAI for its anti-SSRI-like effect and methoxetamine for ketamine's potential as an antidepressant. I'm just afraid that the SSRI induced anhedonia is not consummatory but instead anticipatory/motivational. It's also often very sexual and whereas I do not get pleasure from sexual activity like I used to get, I don't suffer from anorgasmia or any sexual dysfunction. And ketamine may be a good antidepressant, but once again we don't know if this "depression" includes consummatory anhedonia, which is pretty much my only problem in addition to attention deficiency.

Here's something I was thinking about the pleasure process:

pleasurable stimulus > endorphin release > mu-receptor activation > phasic dopamine > pleasure

Now let's assume that one has too much of tonic dopamine: there's no dopamine left for phasic activity and therefore the pleasure can not occur even though the opioid system is functional. This would not only explain anhedonia but also explain lack of response to exogenous opioids:

exogenous opioid intake > mu-receptor activation > failed phasic dopamine due to excessive tonic dopamine > negligible pleasure

I have no idea if it works this way, just something that came to my mind. I don't know if it's only dopamine but possibly also other monoamines? Generally, I'd like to know substances that do just about anything for the phasicity/tonicity of the monoamines, would be interesting to see their effects.

Edited by Vieno, 30 November 2012 - 04:37 PM.

[medievil]

A few facts:

naltrexone blocks the reward of all drugs
naltrexone does not induce anhedonia
Personal anecdote: in my mdma abuse days when i took to much the high suddenly vanished and felt crappy but didnt return to feeling anhedonic, i had baseline reward like other ppl normally have (no idea why, prob high doses disrubted the reward caused by mu wich causes drug reward but not "human reward" as naltrexone does not cause anhedonia.

There seems to be a clear difference btw drug reward and human reward, opiates dont work for me without stimulants wich indicates human reward needs to be active before drug reward takes place (like when i got that thing with mdma, i noticed human reward was active).

We know that 5HT2A antagonists and ssri's that disrupt phasic sero can cause anhedonia wich indicates serotonin plays a role in human reward, 5HT2A agonists (psychedelics) induce reward, i wonder wheter naltrexone blocks the reward of them.

Also, 5HT2A induces glutamate release, now lets take a look at the non abusable substances that can work for anhedonia:
Amisulpiride acts on the GHB receptor wich induces glutamate release.
Zyprexa is the only ap that works for anhedonia, its closely related to clozapine wich is very glutaminergic, zyprexa shares some of those property's like the release of pregnenolone, i dont think its unlikely it shares another glutaminergic action that makes it effective for anhedonia.

So looks like mu is the main player in drug reward but isnt necesay for human reward where glutamate may be the main player.

"pleasurable stimulus > endorphin release > mu-receptor activation > phasic dopamine > pleasure"

no its mu that causes reward, not phasic dopamine, dopamine does not cause reward its associated with wanting.

D1 acts on glutaminergic pathways, so if glutamate causes human reward then phasic activation of it (like phasic activation of 5HT2A) may be players in human reward.

Im thinking that glutamate must be working properly before mu can cause reward, if glutamate causes human reward its the main player and mu comes secondary.

I know phenibut has been mentioned here - I never tried it very much because I was afraid of withdrawl, but once I tried a decent size dosage it had quite a relaxing effect.

I was able to score some baclofen through my GP, and I have muscle pain as well, hoping it will help for general anxiety, but is the GABA profile too specific to target anhedonia like other GABA drugs?

Baclofen does not help anhedonia, why phenibut does and baclofen doesnt is unclear.

[lourdaud]

I would probably avoid agomelatine. The French drug company Servier just revealed that Valdoxan is very bad for the liver.

'Very bad' is an exaggeration; only 1.4% of patients who were treated with the standard dose of 25mg/day developed elevated liver enzymes. Which is less then the risk of seizure associated with 600mg/day of Wellbutrin.

The incidence of hepatic failure is 0.06%, which drops below statistical significance if elevated liver enzymes are not detected within the first 50 days (as a median) of treatment.

As for anhedonia, having suffered from it myself for many years, I can say with almost complete certainty that no one medication will provide sustained relief from it. Just to be clear, I don't consider Medievil's 'solution' of getting high on amphetamines or abusing research chemicals as sustained relief. It just disguises the anhedonia by flooding your brain with monoamines, causing cumulative damage in the process. If you want to retain your cognitive abilities beyond 30 I recommend you persevere with the less immediate remedies.

I would avoid phenibut, it's very transitory in it's positive effects due to the rapid onset of tolerance and dependence. If you abuse it for an extended period it'll only make the anhedonia worse when you stop taking it, I know this from first hand experience.

If you're willing to risk your neurons by trialling a research chemical, then surely you'd be open to the option of polypharmacy.

Hm, what's your opionion on MAOI's (like phenelzine and tranylcypromine) if I may ask? Not a possible long-term solution?

[anon2042]

Tranylcypromine was AWFUL for me. I believe at the end I had titrated up to about 80mg (terrible as the pills ONLY come in 10mg), because the studies show that high doses can knock out treatment resistant depression when all else has failed. On paper, and the anecdotal reports I've read about it, it sounded amazing.

This drug didn't help me with my depression or anhedonia at all. In fact, it only served to ramp up my anxiety and I ended up in the worst breakdown I've had this year. It gave me terrible insomnia, so I wasn't able to keep a regular sleep schedule, which further contributed to my issues. In addition, the only safe thing you can take for sleep is benzos or low dose seroquel, both of which are bad options. The worst thing about tranylcypromine in my opinion is how it seemed to affect every function of my body severely. Every time I'd eat, and you can believe me I was sticking to a low/no-tyramine diet, I'd end up feeling oddly sick and have weird blood pressure spikes. In the end I had to change my diet to a few very bland foods that made me feel less weird after eating. I had a lot of orthostatic hypotension to the point where I'd go partially deaf after standing up (didn't black out though).

I would have been fine with this if it actually worked, but it did not. Please be careful with this drug - it just really got into my system and body like no other and made general living activities such as eating, standing up, etc. unbearable.

[Vieno]

A few facts:

naltrexone blocks the reward of all drugs
naltrexone does not induce anhedonia
Personal anecdote: in my mdma abuse days when i took to much the high suddenly vanished and felt crappy but didnt return to feeling anhedonic, i had baseline reward like other ppl normally have (no idea why, prob high doses disrubted the reward caused by mu wich causes drug reward but not "human reward" as naltrexone does not cause anhedonia.

There seems to be a clear difference btw drug reward and human reward, opiates dont work for me without stimulants wich indicates human reward needs to be active before drug reward takes place (like when i got that thing with mdma, i noticed human reward was active).

Good points.

We know that 5HT2A antagonists and ssri's that disrupt phasic sero can cause anhedonia wich indicates serotonin plays a role in human reward, 5HT2A agonists (psychedelics) induce reward, i wonder wheter naltrexone blocks the reward of them.

Do we know that ssri's cause consummatory anhedonia? I'd be happy to see some proof of that, I'm not denying it but I'm not sure.

Also, 5HT2A induces glutamate release, now lets take a look at the non abusable substances that can work for anhedonia:
Amisulpiride acts on the GHB receptor wich induces glutamate release.
Zyprexa is the only ap that works for anhedonia, its closely related to clozapine wich is very glutaminergic, zyprexa shares some of those property's like the release of pregnenolone, i dont think its unlikely it shares another glutaminergic action that makes it effective for anhedonia.

So looks like mu is the main player in drug reward but isnt necesay for human reward where glutamate may be the main player.

I just can't find info connecting glutamate to pleasure. Would you happen to know any links?

"pleasurable stimulus > endorphin release > mu-receptor activation > phasic dopamine > pleasure"

no its mu that causes reward, not phasic dopamine, dopamine does not cause reward its associated with wanting.

Dopamine is generally linked to all pleasure, but that may be an old-fashioned view. What's the role of phasic serotonin in this?

D1 acts on glutaminergic pathways, so if glutamate causes human reward then phasic activation of it (like phasic activation of 5HT2A) may be players in human reward.

Im thinking that glutamate must be working properly before mu can cause reward, if glutamate causes human reward its the main player and mu comes secondary.

What does it mean when glutamate is "working properly"? Do we need to inhibit glutamate decarboxylase? I'm completely unfamiliar with glutamate.

Tranylcypromine was AWFUL for me. I believe at the end I had titrated up to about 80mg (terrible as the pills ONLY come in 10mg), because the studies show that high doses can knock out treatment resistant depression when all else has failed. On paper, and the anecdotal reports I've read about it, it sounded amazing.

This drug didn't help me with my depression or anhedonia at all. In fact, it only served to ramp up my anxiety and I ended up in the worst breakdown I've had this year. It gave me terrible insomnia, so I wasn't able to keep a regular sleep schedule, which further contributed to my issues. In addition, the only safe thing you can take for sleep is benzos or low dose seroquel, both of which are bad options. The worst thing about tranylcypromine in my opinion is how it seemed to affect every function of my body severely. Every time I'd eat, and you can believe me I was sticking to a low/no-tyramine diet, I'd end up feeling oddly sick and have weird blood pressure spikes. In the end I had to change my diet to a few very bland foods that made me feel less weird after eating. I had a lot of orthostatic hypotension to the point where I'd go partially deaf after standing up (didn't black out though).

I would have been fine with this if it actually worked, but it did not. Please be careful with this drug - it just really got into my system and body like no other and made general living activities such as eating, standing up, etc. unbearable.

We know anhedonia is much more complex than just monoamine deficiency, so I see no use for MAOIs - at least not when used by themselves. Maybe in combination with something.

[medievil]

Dopamine just causes wanting and the levels of dopamine corrolate perfectly with pleasure wich is because the better the reward, the more we should want it, this corrolation made researchers first think that da causes reward, but now we know that da just causes wanting and mu is more implicated in liking.

The role of phasic sero? Well most monoamines play a role in reward, its very complex and all connected.

And about what it means glutamate working properly thats a good question, wouldnt be able to answer that it just seems like several things indicate glutamate is the main player in human reward but i cant say for sure.
Either way its the major neurotransmitter thats pretty much implicated in everything so involvement of glutamate could have been expected either way.

J Psychiatry Neurosci. 2004 Jul;29(4):296-310.
Glutamate co-transmission as an emerging concept in monoamine neuron function.

Trudeau LE.

Source

Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montréal, Que. louis-eric.trudeau@umontreal.ca

Abstract

Converging research efforts over the last 4 decades have established beyond a doubt that many, if not most, neurons release more than 1 neurotransmitter. Although much attention has been paid to the co-release of small-molecule neurotransmitters with neuropeptides, a number of examples of co-release of 2 small-molecule neurotransmitters have now been described. It has been suggested recently that monoamine neurons use glutamate as a co-transmitter. First, both serotonin (5-HT) and dopamine (DA) neurons in culture establish functional glutamatergic synapses in addition to classic terminals that release 5-HT or DA. Second, immunocytochemical work has provided evidence for the presence of neurotransmitter pools of glutamate in DA, 5-HT and noradrenergic neurons. Third, the recent cloning of 3 vesicular glutamate transporters (VGLUT1-3) has led to the discovery that noradrenergic neurons contain VGLUT2 mRNA, whereas 5-HT neurons contain VGLUT3 mRNA. Finally, although VGLUT2 mRNA does not appear to be abundant in DA neurons in the adult brain, DA neurons cultured from neonatal animals express VGLUT2, suggesting that these neurons may have the capacity to express this protein under specific conditions. Taken together with recent work describing the capacity of neurons to change neurotransmitter phenotype during development or in an activity-dependent manner, the finding of glutamate co-transmission in monoamine neurons may lead to significant revisions of current physiologic models of monoamine neuron function. In addition, the possible role of glutamate co-release in physiopathologic models of diseases that implicate central monoamine pathways, such as schizophrenia, must now be seriously considered.

An example how glutamate is like an adjunct to most things and that its functioning is essential for most things.

[medievil]

Tranylcypromine was AWFUL for me. I believe at the end I had titrated up to about 80mg (terrible as the pills ONLY come in 10mg), because the studies show that high doses can knock out treatment resistant depression when all else has failed. On paper, and the anecdotal reports I've read about it, it sounded amazing.

This drug didn't help me with my depression or anhedonia at all. In fact, it only served to ramp up my anxiety and I ended up in the worst breakdown I've had this year. It gave me terrible insomnia, so I wasn't able to keep a regular sleep schedule, which further contributed to my issues. In addition, the only safe thing you can take for sleep is benzos or low dose seroquel, both of which are bad options. The worst thing about tranylcypromine in my opinion is how it seemed to affect every function of my body severely. Every time I'd eat, and you can believe me I was sticking to a low/no-tyramine diet, I'd end up feeling oddly sick and have weird blood pressure spikes. In the end I had to change my diet to a few very bland foods that made me feel less weird after eating. I had a lot of orthostatic hypotension to the point where I'd go partially deaf after standing up (didn't black out though).

I would have been fine with this if it actually worked, but it did not. Please be careful with this drug - it just really got into my system and body like no other and made general living activities such as eating, standing up, etc. unbearable.

Increasing da or other neurotransmitters wont help anhedonia, only rewarding substances like amphetamine wich induce reward trough mu (naltrexone blocks this) can help anhedonia.

[Vieno]

Dopamine just causes wanting and the levels of dopamine corrolate perfectly with pleasure wich is because the better the reward, the more we should want it, this corrolation made researchers first think that da causes reward, but now we know that da just causes wanting and mu is more implicated in liking.

Oh yea that makes sense.

The role of phasic sero? Well most monoamines play a role in reward, its very complex and all connected.

But you just said that dopamine has only to do with wanting, so how is it "all connected". You also earlier suggested to use MDAI for anhedonia because it induces phasic serotonin, so if this is true, then phasic serotonin is related to pleasure but phasic dopamine not? Serotonin has to do with pleasure but dopamine not?

And about what it means glutamate working properly thats a good question, wouldnt be able to answer that it just seems like several things indicate glutamate is the main player in human reward but i cant say for sure.
Either way its the major neurotransmitter thats pretty much implicated in everything so involvement of glutamate could have been expected either way.

I know that glutamate is the most important excitatory neurotransmitter, but doesn't that mean that if glutamate production isn't working, then one doesn't only suffer from anhedonia but from a much more comprehensive brain slowdown?

Increasing da or other neurotransmitters wont help anhedonia, only rewarding substances like amphetamine wich induce reward trough mu (naltrexone blocks this) can help anhedonia.

Amphetamine works on MU? :O That's new to me. How do you know? How about other stimulants?

[medievil]

All stimulants (actually all rewarding substances, everything people abuse, altough im not sure of psychedelics) induce reward trough the MU receptor. Ill reply more later and also post more info.

[gizmobrain]

More information concerning the pharmacology behind CILTEP + amphetamine as a treatment for anhedonia:


Forskolin enhancement of opioid currents in rat locus coeruleus neurons.

1.' class='bbc_url' title='External link' rel='nofollow external'>http://www.ncbi.nlm.nih.gov/pubmed/8890275']1. Opioids are known to hyperpolarize all neurons in the nucleus locus coeruleus (LC) and to inhibit adenylyl cyclase. Recent work has shown that activation of adenylyl cyclase with forskolin increased the amplitude of the opioid hyperpolarization in LC cells. The aim of the present study was to determine the mechanism of this augmented hyperpolarization. 2. Agonist-induced currents were studied in LC cells in brain slices using both intracellular and whole cell recordings. Forskolin increased the amplitude of mu-opioid- and alpha 2-adrenoceptor-mediated currents by approximately 30% of control measured at -60 mV. This effect of forskolin was dependent on the concentration having a threshold of approximately 1 microM and a peak effect at approximately 30 microM. Dideoxyforskolin (30 microM) caused a small reduction (-52 +/- 28 pA, mean +/- SE) in the amplitude of the opioid current. 3. Forskolin increased the agonist current in the outward direction over the entire potential range between -140 and -50 mV when recordings were made from neurons in cells recorded from slices cut in the horizontal plane. This augmented current produced a shift of the apparent reversal potential to more negative values. 4. Both the forskolin augmentation of the opioid current and the opoid current itself were reduced when the space clamp was improved by cutting the slice in the coronal plane, increasing the extracellular potassium concentration, and treating the slice with carbenoxolone. In addition, forskolin did not change the reversal potential of the opoid current. When expressed as a percentage change from control, forskolin had no significant effect on the opioid current in carbenoxolone (-13 +/- 13%) but produced a small augmentation in high extracellular potassium (15 +/- 4%) and coronoal slices (31 +/- 12%). 5. Two models were tested to explain the action of forskolin, one where cells are coupled electronically by a forskolin-sensitive conductance (coupled-cell model) and a second where opioids mediate an inhibition of a forskolin-induced cation conductance (2-conductance model). The experimental results were fit well only by the coupled-cell model, which predicted that the opioid/forskolin interaction is indirect and occurs primarily in response to forskolin increasing the degree of electrotonic coupling between LC neurons. The consequence of increased coupling would be to augment synchronous activity within the nucleus.

→ source (external link)

Edited by zrbarnes, 30 November 2012 - 08:55 PM.

[anon2042]

Tranylcypromine was AWFUL for me. I believe at the end I had titrated up to about 80mg (terrible as the pills ONLY come in 10mg), because the studies show that high doses can knock out treatment resistant depression when all else has failed. On paper, and the anecdotal reports I've read about it, it sounded amazing.

This drug didn't help me with my depression or anhedonia at all. In fact, it only served to ramp up my anxiety and I ended up in the worst breakdown I've had this year. It gave me terrible insomnia, so I wasn't able to keep a regular sleep schedule, which further contributed to my issues. In addition, the only safe thing you can take for sleep is benzos or low dose seroquel, both of which are bad options. The worst thing about tranylcypromine in my opinion is how it seemed to affect every function of my body severely. Every time I'd eat, and you can believe me I was sticking to a low/no-tyramine diet, I'd end up feeling oddly sick and have weird blood pressure spikes. In the end I had to change my diet to a few very bland foods that made me feel less weird after eating. I had a lot of orthostatic hypotension to the point where I'd go partially deaf after standing up (didn't black out though).

I would have been fine with this if it actually worked, but it did not. Please be careful with this drug - it just really got into my system and body like no other and made general living activities such as eating, standing up, etc. unbearable.

Increasing da or other neurotransmitters wont help anhedonia, only rewarding substances like amphetamine wich induce reward trough mu (naltrexone blocks this) can help anhedonia.

But tranylcypromine is an amphetamine analog - shortly after taking it you get a bit of a buzz as well, and it can show up erroneously in drug tests as amphetamines. How does that work into things? What are you including when you say "amphetamines"?

[medievil]

It may be an analogue but its just a maoi basicly, has some neglible amp like action wich wont do much.

I include all rewarding stimulants, pretty much all stims, there's a small list in my stims thread as an example.

More information concerning the pharmacology behind CILTEP + amphetamine as a treatment for anhedonia:


Forskolin enhancement of opioid currents in rat locus coeruleus neurons.

1.' class='bbc_url' title='External link' rel='nofollow external'>http://www.ncbi.nlm.nih.gov/pubmed/8890275']1. Opioids are known to hyperpolarize all neurons in the nucleus locus coeruleus (LC) and to inhibit adenylyl cyclase. Recent work has shown that activation of adenylyl cyclase with forskolin increased the amplitude of the opioid hyperpolarization in LC cells. The aim of the present study was to determine the mechanism of this augmented hyperpolarization. 2. Agonist-induced currents were studied in LC cells in brain slices using both intracellular and whole cell recordings. Forskolin increased the amplitude of mu-opioid- and alpha 2-adrenoceptor-mediated currents by approximately 30% of control measured at -60 mV. This effect of forskolin was dependent on the concentration having a threshold of approximately 1 microM and a peak effect at approximately 30 microM. Dideoxyforskolin (30 microM) caused a small reduction (-52 +/- 28 pA, mean +/- SE) in the amplitude of the opioid current. 3. Forskolin increased the agonist current in the outward direction over the entire potential range between -140 and -50 mV when recordings were made from neurons in cells recorded from slices cut in the horizontal plane. This augmented current produced a shift of the apparent reversal potential to more negative values. 4. Both the forskolin augmentation of the opioid current and the opoid current itself were reduced when the space clamp was improved by cutting the slice in the coronal plane, increasing the extracellular potassium concentration, and treating the slice with carbenoxolone. In addition, forskolin did not change the reversal potential of the opoid current. When expressed as a percentage change from control, forskolin had no significant effect on the opioid current in carbenoxolone (-13 +/- 13%) but produced a small augmentation in high extracellular potassium (15 +/- 4%) and coronoal slices (31 +/- 12%). 5. Two models were tested to explain the action of forskolin, one where cells are coupled electronically by a forskolin-sensitive conductance (coupled-cell model) and a second where opioids mediate an inhibition of a forskolin-induced cation conductance (2-conductance model). The experimental results were fit well only by the coupled-cell model, which predicted that the opioid/forskolin interaction is indirect and occurs primarily in response to forskolin increasing the degree of electrotonic coupling between LC neurons. The consequence of increased coupling would be to augment synchronous activity within the nucleus.

→ source (external link)

So cilltep works better against anhedonia then just amp for you?

[gizmobrain]

So ciltep works better against anhedonia then just amp for you?

I started out taking adderall IR 20mg/day, and over the course of a year, the doctor had increased the dose to 60mg/day. This is what happens when you try to treat anhedonia as ADHD-PI. The side effects were unbearable.

I've taken 10mg of Forskolin + 1g of Artichoke + 5mg of Adderall for several months now with very few side effects (I think extended release d-amphetamine in place of Adderall would knock out these minor side effects as well).

On contrast, 5mg of Adderall alone feels like drinking a cup of coffee, and does virtually nothing for me since it is so weak. The addition of Forskolin and Artichoke not only increase the duration from ~4-6 hours to 8-10 hours, but also potentiates the positive effects, without introducing the side effects that larger doses of amphetamines cause.

Also, there is no desire to be abusive with this stack. Redosing forskolin or adderall leads to feeling terrible for the rest of the day. So for anyone looking to "get high", this is probably not the stack for you. But as long as I get the dosage and timing right, I feel great most days. I won't lie; polypharmacy is much trickier to initially figure out than just taking one pill everyday, but I feel like it's the only way to get sustainable results. You have to fine tune it to your individual biochemistry.

Edited by zrbarnes, 30 November 2012 - 09:45 PM.

[anon2042]

It may be an analogue but its just a maoi basicly, has some neglible amp like action wich wont do much.

I include all rewarding stimulants, pretty much all stims, there's a small list in my stims thread as an example.

Seems to be strictly amphetamines - what about things like caffiene, NRIs (NDRIs etc.), modanfil, nicotine?

[gizmobrain]

Seems to be strictly amphetamines - what about things like caffiene, NRIs (NDRIs etc.), modanfil, nicotine?

I know that I saw (virtually) no improvement of my symptoms with Caffeine, Atomoxetine, Methylphenidate, Armodafinil, or Nicotine Polacrilex.

[medievil]

Amphetamine is very glutaminergic while ritalin isnt, if there are problems in that department it may render ritalin useless while you can find succes with amp.

It may be an analogue but its just a maoi basicly, has some neglible amp like action wich wont do much.

I include all rewarding stimulants, pretty much all stims, there's a small list in my stims thread as an example.

Seems to be strictly amphetamines - what about things like caffiene, NRIs (NDRIs etc.), modanfil, nicotine?

ndri's will all work too yes, nri's wont neither will modafinil or nicotine.

I would probably avoid agomelatine. The French drug company Servier just revealed that Valdoxan is very bad for the liver.

'Very bad' is an exaggeration; only 1.4% of patients who were treated with the standard dose of 25mg/day developed elevated liver enzymes. Which is less then the risk of seizure associated with 600mg/day of Wellbutrin.

The incidence of hepatic failure is 0.06%, which drops below statistical significance if elevated liver enzymes are not detected within the first 50 days (as a median) of treatment.

As for anhedonia, having suffered from it myself for many years, I can say with almost complete certainty that no one medication will provide sustained relief from it. Just to be clear, I don't consider Medievil's 'solution' of getting high on amphetamines or abusing research chemicals as sustained relief. It just disguises the anhedonia by flooding your brain with monoamines, causing cumulative damage in the process. If you want to retain your cognitive abilities beyond 30 I recommend you persevere with the less immediate remedies.

I would avoid phenibut, it's very transitory in it's positive effects due to the rapid onset of tolerance and dependence. If you abuse it for an extended period it'll only make the anhedonia worse when you stop taking it, I know this from first hand experience.

If you're willing to risk your neurons by trialling a research chemical, then surely you'd be open to the option of polypharmacy.

I like to go beyond therapeutic doses at times but that doesnt mean you cant get anhedonia relief without being high. I stay with therapeutic doses at most periods which i just dont have anhedonia, and am not high in any way.

I dont see why stimulants in low therapeutic doses with something for tolerance cant be a good long term solution, IF combined with something like memantine and regular small breaks (like one or 2 days off every week) sustained relief can be achieved.

I havent seen any evidence of cumulative damage in ADHD, so i dont see why using them for anhedonia would.

As for phenibut it definatly cant be used chronically, and as for research chemicals the risks should be made clear, however for some there may not be a alternative, and living with anhedonia if its really bad is not really living, its unpleasant and you have to endure it the whole time, worse then being "bored".

Any elaboration behind that negative point on my post, zrbarnes also just confirmed you can get anhedonia relief without being high, in fact everyone that tried it can confirm this.

[medievil]

Kent Berridge, University of Michigan, MI, USA. F1000 Prime Neuroscience
20 Apr 2012 | Confirmation, New Finding
DOI: 10.3410/f.14267051.15779178
If dopamine is not a pleasure neurotransmitter, then why is amphetamine so pleasantly euphoric? This important study reports that amphetamine elicited elevations of human endogenous opioid neurotransmitters in brain structures such as nucleus accumbens striatum and limbic regions of prefrontal cortex. Release of natural brain opioids might therefore explain why amphetamine and related dopaminergic drugs can be so pleasurable.

Colasanti and colleagues here gave ordinary men an oral dose of amphetamine before measuring subjective ratings of euphoria, and using positron emission tomography (PET) neuroimaging to measure synaptic levels of endogenous opioid neurotransmitters (via displacement by the natural ligands of bound radioactive [11C]carfentanil from mu opioid receptors). The authors report that amphetamine produced increases in endogenous opioid release (reflected in reduced drug binding) in subcortical ventral striatum (nucleus accumbens), dorsal striatum (caudate and putamen) and thalamus, as well as increased cortical release in orbitofrontal cortex, anterior cingulate cortex and insula cortex. Of special interest, subjective ratings of euphoria produced by amphetamine were positively correlated, significantly and specifically, with ventral striatum displacement, implying that nucleus accumbens opioids might mediate subjective pleasure of the drug.

Given that dopamine is no longer regarded by many neuroscientists to be a pleasure neurotransmitter after all, the intense pleasure of drugs that specifically elevate synaptic dopamine (e.g. amphetamine and cocaine) has presented something of a puzzle. Colasanti et al.'s results suggest a possible resolution: amphetamine's dopamine stimulation of opioid levels might cause the pleasure via endogenous opioid stimulation of mu receptors in hedonic circuits involving nucleus accumbens.
Acknowledgments
This evaluation was prepared with Professor Marco Leyton (McGill University, Montreal, Canada), who found this paper.
Disclosures
None declared
Cite this Recommendation

[noos]

Could LDN help with anhedonia?

[Vieno]

Seems that amphetamine definitely deserves a try. I'm busy for a couple of days but I'll get back to this thread later, I will try to get my hands on amphetamine as soon as possible. Thanks medievil for that abstract, very fascinating.

Could LDN help with anhedonia?

No, not consummatory anhedonia. Check out my longish post on previous page. Appears that even though pleasure is created by the mu-receptor, it needs something else too and that anhedonics' problems are not directly opioidergic. There are people who lack endogenous opioids and LDN helps them tremendously; however, it appears that they suffer from dysphoria, not anhedonia. Their mood sucks but they have at least some, though possibly diminished, response to pleasurable stimulus.

[Vieno]

Amnesiagirl: you are not sure if your anhedonia is a part of depression or not. The thing is that if one's anhedonic symptoms - no matter if they're psychological or physiological - are caused by psychological problems, they will probably go away when the psychology is corrected and therefore looking for help in this thread is probably harmful. But if you do think that you have consummatory anhedonia independent of psychology, then this is the right place for you. Although I recommend clearing your mind of all psychological issues first if possible: treating anhedonia is easier if it is the only problem. There's no room for confusion and misdiagnosing then.

[Vieno]

Oh and medievil, maybe you already said this but why don't you continue using the drugs that you have found helpful in anhedonia, like amphetamine?

[airplanepeanuts]

But if you do think that you have consummatory anhedonia independent of psychology, then this is the right place for you.

How could anybody know that for sure. I also seems not very likely that a lot of people would develop anhedonia totally unrelated to psychology.

Edited by whitetealeaves, 02 December 2012 - 03:48 PM.

[Vieno]

But if you do think that you have consummatory anhedonia independent of psychology, then this is the right place for you.

How could anybody know that for sure. I also seems not very likely that a lot of people would develop anhedonia totally unrelated to psychology.

This thread is not for discussions about whether it's psychological or not. This thread is for those who believe that their anhedonia is not related to psychology.

[medievil]

Oh and medievil, maybe you already said this but why don't you continue using the drugs that you have found helpful in anhedonia, like amphetamine?

I take mdai, mdpv and desoxypipradol instead of amp, phenibut and other stuff, i prefer to amp and are damn cheap i cant afford amphetamine.

But if you do think that you have consummatory anhedonia independent of psychology, then this is the right place for you.

How could anybody know that for sure. I also seems not very likely that a lot of people would develop anhedonia totally unrelated to psychology.

Well you know that if you dont have depression or other psychological symptions, would be hard to tell if you got bad tough.
Its not unlikely at all, dont seem why it would be.

[Vieno]

Oh and medievil, maybe you already said this but why don't you continue using the drugs that you have found helpful in anhedonia, like amphetamine?

I take mdai, mdpv and desoxypipradol instead of amp, phenibut and other stuff, i prefer to amp and are damn cheap i cant afford amphetamine.

Earlier I got the impression that you consider amphetamine a solution to anhedonia and others (like what you're taking now) less effective so is the price only reason why you prefer them over amp? Did amphetamine make you completely anhedonia-free, how about other drugs? You have listed many different drugs to possibly remove anhedonia but what have personally done that for you?

[medievil]

I find the desoxy mdpv combo far better then amphetamine tbh, amp does make me completely anhedonia free so do all stimulants and GHB and psdychedelics but the last 2 dont work for my sa nor make me feel normal like stims.