Helpful substances in the fight against anhedonia

[Neuroprotection]

I should’ve probably posted this in the neuroscience and pharmacology forum, however, I don’t seem to get many responses to anything I post there and also, I feel this subject is more relevant to people on this particular forum. I ask everyone to forgive me for my long posts and any grammatical errors as I am blind and using my iPhone dictation function to type. I have a lot to say but I hope it helps.

Basically, anhedonia is most commonly thought of as a loss of ability to feel pleasure, when in fact, in most cases it is a reward motivation/salience deficiency. this makes affected individuals perceive natural rewards as unworthy of their effort and of little to no value. in such cases, negative emotions usually fill the gap and anxiety sets in. since dopamine is the most studied chemical in this regard, it’s interesting to note that rats depleted of dopamine Will not pursue food and May die of starvation. However, if food is placed in their mouths, they will eat, and they exhibit a strong liking reaction when sugar solution is placed in their mouth. furthermore, even without dopamine, sugar solutions can be reinforcing in rats, although I guess it Took longer to establish and was smaller in magnitude. therefore, it is appropriate to say that dopamine is more involved in wanting rather than liking and drives a pursuit of pleasure rather than the experience of it. based on my own self diagnosed experience of anhedonia, i’ve come up with a theory that dopamine and associated reward seeking/impulsivity gives us a sense of direction and prevents us from overthinking things. in my next post, I will discuss my own personal experience of anhedonia as this one is already quite large, however, I will continue on this post below with some suggestions of methods/substances and ideas related to anhedonia.

As mentioned above, anhedonia is a reward deficiency syndrome and the most common Brain region associated with this is the nucleus accumbens. I know hardly anything about brain Science, but I believe the role of the nucleus accumbens includes reward calculation and attribution of value to the reward as well as the direct experience of reward itself. now, dopamine is the main neurotransmitter in discussions of the nucleus accumbens in reward/drugs of abuse, yet, it is well-known that serotonin, glutamate, and many others are also involved. unfortunately, as we already know, simply boosting dopamine is not sustainable especially if strong Psychostimulants like amphetamine are used.
Interestingly, examining changes in the nucleus accumbens following the long-term administration of addictive drugs or in response to prolonged unpredictable stress and social defeat stress in animals gives us some major clues about the development of anhedonia and how it could be easily reversed.
Apparently, dopamine associated reward is generated by decreased reactivity of certain neurons in the nucleus accumbens. i’m not sure which cells exactly or what this means for other neurons, but I guess it probably disinhibits other systems and acts as a signal that something valuable is being experienced.

So what are the main negative changes associated with long-term stress or drug abuse, and how do they cause anhedonia? to start, both these factors cause an increase in levels of the feel bad peptide Dynnorphin, Which, through activation of kappa opioid receptors decreases, dopamine signalling and release in the nucleus accumbens. interestingly, Kappa Opioid receptor activation also decreases release of glutamate, norepinephrine, GABA and serotonin in the nucleus accumbens and in other brain regions. Dynnorphin must serve some kind of beneficial purpose but it surely a nightmare molecule and disastrous in excess. thankfully, more and more small molecules are becoming available which selectively block the kappa opioid receptor. buprenorphine is apparently a kappa opioid antagonist and it’s combination with a Mu antagonist like naltrexone has been investigated for depression. although clinical trials were not particularly impressive, I feel that perhaps not enough time was given for optimum results. Also, disturbed by the extremely long pharmacological duration of action of the old Kappa antagonists like norbimiltorphamine or JDTIK, researchers instead focus on short-acting molecules that only last a few hours. Frankly, I don’t think that’s enough time, keep in mind that high levels of Dynnorphin and up-regulation of kappa receptors can be operating in the brain for weeks or months at a time. actually, a recent study I came across showed that prolonged Kappa receptor activation lead to long-term changes in expression of glutamate receptors that resulted in despair like behaviour and this behaviour far outlasted The kappa Opioid agonist. with that in mind, perhaps prolonged blockade of the kappa receptor alongside behavioural therapy and healthy lifestyle changes might go a very long way.

I’m less enthusiastic about other substances like Serotonergic psychedelics or NMDA antagonists, due to the range of side-effects, including memory impairment, psychotomimetic reactions or worsening of depression. whilst the NMDA antagonists have produced rapid antidepressant affects, these are short lived and come with the above-mentioned side-effects. additionally, they may paradoxically impair reward learning, interfering with motivation and the acquisition of new rewarding experiences. unlike these substances, the Kappa Opioid antagonists actually possess antipsychotic effects, despite enhancing dopamine release in the brain and producing a state analogous to cocaine sensitisation. extra dopamine with a decreased risk of psychosis sounds wonderful to me.

Sorry for the long rant, just hope to stimulate discussion that will help people for a long time to come.

 

[Neuroprotection]

here’s my own personal experience of what I believe to be temporary anhedonia. thankfully, I’ve made a full recovery but the experience still scares me.

Basically, I’ve always been an extremely impulsive and reward seeking individual, and if I like something, I get extremely obsessed with it and I’m happy to spend all day doing it. I also have an incredibly high libido, Poor self control with sugary foods amongst many others. however, like many of my other personality traits including extreme laziness, I developed strong self-control where necessary, for example, in front of people and masked it so well, people think I am the complete opposite.

A few months ago, a long bout of stress caused by unpleasant argumentative individuals followed by multiple cold and flu infections seem to have changed my mental state temporarily. throughout December and January of this year, I noticed a sudden drop in my libido to almost 0, but since I am an unmarried Muslim and masturbation is prohibited, I took it as a positive and just ignored it. however, this was quickly followed by a feeling of emotional darkness and the decreased ability to feel joy and excitement. I could still feel pleasure, for example, enjoying good food and if I was to masturbate, I would still enjoy that, but the intense desire and drive to pursue these things was non-existent. talk of the future brought feelings of dread as I could only imagine the stressful parts of it, I couldn’t imagine joy. I also became 10 times more sensitive to stress and anxiety, and whilst someone being aggressive to me once can normally ruin my day, during that period, it could ruin my entire week. i’d also just got a job for the first time and was working from home. My procrastination, laziness and anxiety were massively magnified. everything became like a chore, and the only thing I could seriously look forward to was the day ending so that the agony of pushing through boring/Tiring tasks would end. again, I hid this from those around me and no one suspected anything. thankfully, I still remained very empathetic and also had no suicidal thoughts or feelings. interestingly, this is where I came up with my above-mentioned theory about reward deficiency leading to enhanced anxiety. basically, in the absence of that intense dopamine drive to pursue pleasure or goals, I feel that my mind began wondering causing me to feel lost. I then became fixated on the possibility of bad things happening while simultaneously having no motivation or energy to deal with them. I think it was behavioural despair. interestingly, in animals, behavioural despair is supposed to be a protective mechanism that decreases the exertion of effort or energy on useless activities, if it is concluded that such activities won’t help them escape their stressful situation. unfortunately, for humans, this often is not the case, and despair only leads to more counter-productive behaviours and misery. also, the brain will probably seek stimulation through anxiety if there is no drive-through reward. as mentioned earlier, in my case, I feel that my impulsivity and reward seeking often do much of the thinking for me and the anticipation of future pleasure takes my mind off my negative thoughts/stress/ anxiety.
Also, I don’t know how to better describe the above mentioned emotional darkness I felt, but it included the absence of hope, joy and desire combined with a very mild but noticeable sense of eeriness and impending doom.

Thankfully, by the beginning of February God saved me. firstly, my sense of joy quickly returned and I began to hope for the future. This was followed by a rapid disappearance of that emotional darkness over a few days. at the same time, my impulsivity/Reward seeking came back as did my libido and after about a week, I had my old self back.
Interestingly, my favourite drug nicotine which I don’t get hold of often, helped speed up my recovery dramatically.

 

[Jerry Atrick]

I should’ve probably posted this in the neuroscience and pharmacology forum, however, I don’t seem to get many responses to anything I post there and also, I feel this subject is more relevant to people on this particular forum. I ask everyone to forgive me for my long posts and any grammatical errors as I am blind and using my iPhone dictation function to type. I have a lot to say but I hope it helps.

Basically, anhedonia is most commonly thought of as a loss of ability to feel pleasure, when in fact, in most cases it is a reward motivation/salience deficiency. this makes affected individuals perceive natural rewards as unworthy of their effort and of little to no value. in such cases, negative emotions usually fill the gap and anxiety sets in. since dopamine is the most studied chemical in this regard, it’s interesting to note that rats depleted of dopamine Will not pursue food and May die of starvation. However, if food is placed in their mouths, they will eat, and they exhibit a strong liking reaction when sugar solution is placed in their mouth. furthermore, even without dopamine, sugar solutions can be reinforcing in rats, although I guess it Took longer to establish and was smaller in magnitude. therefore, it is appropriate to say that dopamine is more involved in wanting rather than liking and drives a pursuit of pleasure rather than the experience of it. based on my own self diagnosed experience of anhedonia, i’ve come up with a theory that dopamine and associated reward seeking/impulsivity gives us a sense of direction and prevents us from overthinking things. in my next post, I will discuss my own personal experience of anhedonia as this one is already quite large, however, I will continue on this post below with some suggestions of methods/substances and ideas related to anhedonia.

As mentioned above, anhedonia is a reward deficiency syndrome and the most common Brain region associated with this is the nucleus accumbens. I know hardly anything about brain Science, but I believe the role of the nucleus accumbens includes reward calculation and attribution of value to the reward as well as the direct experience of reward itself. now, dopamine is the main neurotransmitter in discussions of the nucleus accumbens in reward/drugs of abuse, yet, it is well-known that serotonin, glutamate, and many others are also involved. unfortunately, as we already know, simply boosting dopamine is not sustainable especially if strong Psychostimulants like amphetamine are used.
Interestingly, examining changes in the nucleus accumbens following the long-term administration of addictive drugs or in response to prolonged unpredictable stress and social defeat stress in animals gives us some major clues about the development of anhedonia and how it could be easily reversed.
Apparently, dopamine associated reward is generated by decreased reactivity of certain neurons in the nucleus accumbens. i’m not sure which cells exactly or what this means for other neurons, but I guess it probably disinhibits other systems and acts as a signal that something valuable is being experienced.

So what are the main negative changes associated with long-term stress or drug abuse, and how do they cause anhedonia? to start, both these factors cause an increase in levels of the feel bad peptide Dynnorphin, Which, through activation of kappa opioid receptors decreases, dopamine signalling and release in the nucleus accumbens. interestingly, Kappa Opioid receptor activation also decreases release of glutamate, norepinephrine, GABA and serotonin in the nucleus accumbens and in other brain regions. Dynnorphin must serve some kind of beneficial purpose but it surely a nightmare molecule and disastrous in excess. thankfully, more and more small molecules are becoming available which selectively block the kappa opioid receptor. buprenorphine is apparently a kappa opioid antagonist and it’s combination with a Mu antagonist like naltrexone has been investigated for depression. although clinical trials were not particularly impressive, I feel that perhaps not enough time was given for optimum results. Also, disturbed by the extremely long pharmacological duration of action of the old Kappa antagonists like norbimiltorphamine or JDTIK, researchers instead focus on short-acting molecules that only last a few hours. Frankly, I don’t think that’s enough time, keep in mind that high levels of Dynnorphin and up-regulation of kappa receptors can be operating in the brain for weeks or months at a time. actually, a recent study I came across showed that prolonged Kappa receptor activation lead to long-term changes in expression of glutamate receptors that resulted in despair like behaviour and this behaviour far outlasted The kappa Opioid agonist. with that in mind, perhaps prolonged blockade of the kappa receptor alongside behavioural therapy and healthy lifestyle changes might go a very long way.

I’m less enthusiastic about other substances like Serotonergic psychedelics or NMDA antagonists, due to the range of side-effects, including memory impairment, psychotomimetic reactions or worsening of depression. whilst the NMDA antagonists have produced rapid antidepressant affects, these are short lived and come with the above-mentioned side-effects. additionally, they may paradoxically impair reward learning, interfering with motivation and the acquisition of new rewarding experiences. unlike these substances, the Kappa Opioid antagonists actually possess antipsychotic effects, despite enhancing dopamine release in the brain and producing a state analogous to cocaine sensitisation. extra dopamine with a decreased risk of psychosis sounds wonderful to me.

Sorry for the long rant, just hope to stimulate discussion that will help people for a long time to come.

Hi there. I read this post and am commenting on it before reading your second post. I don't have much to add other than to say thank you for doing this research and summarizing the data in one place.

I'm not sure if you have read the Coming off Invega/Paliperidone thread but anhedonia is one of the primary side effects of this antipsychotic. I apologize if I missed something you wrote or misinterpreted. While you mentioned the dopamine and serotonin aspects of anhedonia, have you found much info on what causes this dynamic in the brain? Like what I said above, the medication Invega is notorious for causing anhedonia. I've also previously been injected with Risperdal, which metabolizes into Parliperidone in the liver, and I got severe anhedonia from that.

Most of the patients who have recovered from Invega/Paliperidone report that it normally takes 8 months to a year or more for the side effects to begin going away. Do you think your hypotheses would apply to drug-induced anhedonia or just to anhedonia that has been organically developed from depression or some other mental ailment?

 

[Jerry Atrick]

here’s my own personal experience of what I believe to be temporary anhedonia. thankfully, I’ve made a full recovery but the experience still scares me.

Basically, I’ve always been an extremely impulsive and reward seeking individual, and if I like something, I get extremely obsessed with it and I’m happy to spend all day doing it. I also have an incredibly high libido, Poor self control with sugary foods amongst many others. however, like many of my other personality traits including extreme laziness, I developed strong self-control where necessary, for example, in front of people and masked it so well, people think I am the complete opposite.

A few months ago, a long bout of stress caused by unpleasant argumentative individuals followed by multiple cold and flu infections seem to have changed my mental state temporarily. throughout December and January of this year, I noticed a sudden drop in my libido to almost 0, but since I am an unmarried Muslim and masturbation is prohibited, I took it as a positive and just ignored it. however, this was quickly followed by a feeling of emotional darkness and the decreased ability to feel joy and excitement. I could still feel pleasure, for example, enjoying good food and if I was to masturbate, I would still enjoy that, but the intense desire and drive to pursue these things was non-existent. talk of the future brought feelings of dread as I could only imagine the stressful parts of it, I couldn’t imagine joy. I also became 10 times more sensitive to stress and anxiety, and whilst someone being aggressive to me once can normally ruin my day, during that period, it could ruin my entire week. i’d also just got a job for the first time and was working from home. My procrastination, laziness and anxiety were massively magnified. everything became like a chore, and the only thing I could seriously look forward to was the day ending so that the agony of pushing through boring/Tiring tasks would end. again, I hid this from those around me and no one suspected anything. thankfully, I still remained very empathetic and also had no suicidal thoughts or feelings. interestingly, this is where I came up with my above-mentioned theory about reward deficiency leading to enhanced anxiety. basically, in the absence of that intense dopamine drive to pursue pleasure or goals, I feel that my mind began wondering causing me to feel lost. I then became fixated on the possibility of bad things happening while simultaneously having no motivation or energy to deal with them. I think it was behavioural despair. interestingly, in animals, behavioural despair is supposed to be a protective mechanism that decreases the exertion of effort or energy on useless activities, if it is concluded that such activities won’t help them escape their stressful situation. unfortunately, for humans, this often is not the case, and despair only leads to more counter-productive behaviours and misery. also, the brain will probably seek stimulation through anxiety if there is no drive-through reward. as mentioned earlier, in my case, I feel that my impulsivity and reward seeking often do much of the thinking for me and the anticipation of future pleasure takes my mind off my negative thoughts/stress/ anxiety.
Also, I don’t know how to better describe the above mentioned emotional darkness I felt, but it included the absence of hope, joy and desire combined with a very mild but noticeable sense of eeriness and impending doom.

Thankfully, by the beginning of February God saved me. firstly, my sense of joy quickly returned and I began to hope for the future. This was followed by a rapid disappearance of that emotional darkness over a few days. at the same time, my impulsivity/Reward seeking came back as did my libido and after about a week, I had my old self back.
Interestingly, my favourite drug nicotine which I don’t get hold of often, helped speed up my recovery dramatically.

Thank you for sharing your personal story. Other than the cold and flu injections, were you prescribed any other medications? The reason I ask is that sometimes anhedonia can be a side effect of medication.

Also, have you had a blood test in a while? I would get my testosterone and thyroids checked in addition to the other common checks. As far as I know, low testosterone can cause depression and lethargy. Same with low thyroid counts. When I was prescribed Lithium a year and a half ago, it caused my thyroid counts to drop and I quickly became very depressed and was tired all the time; seemed like the precursor to anhedonia. My primary doctor told me my two choices were to quit Lithium or begin taking thyroid medication, which I would have to take for the rest of my life. Of course, I quit Lithium and replaced it with a different mood stabilizer and have been fine ever since.

Anyways, these are just a couple of thoughts. I'm glad your anhedonia has seemed to subside.

 

[Neuroprotection]

Hi there. I read this post and am commenting on it before reading your second post. I don't have much to add other than to say thank you for doing this research and summarizing the data in one place.

I'm not sure if you have read the Coming off Invega/Paliperidone thread but anhedonia is one of the primary side effects of this antipsychotic. I apologize if I missed something you wrote or misinterpreted. While you mentioned the dopamine and serotonin aspects of anhedonia, have you found much info on what causes this dynamic in the brain? Like what I said above, the medication Invega is notorious for causing anhedonia. I've also previously been injected with Risperdal, which metabolizes into Parliperidone in the liver, and I got severe anhedonia from that.

Most of the patients who have recovered from Invega/Paliperidone report that it normally takes 8 months to a year or more for the side effects to begin going away. Do you think your hypotheses would apply to drug-induced anhedonia or just to anhedonia that has been organically developed from depression or some other mental ailment?

I’m not a neuroscientist or expert in this field by any means, so please take what I say with a pinch of salt. i’ve come across the thread you were talking about, however, I’ve never actually looked at it since I’ve never used antipsychotics so it never caught my attention. However, I will check it out soon to get a better idea of peoples experiences of anhedonia.

Regarding your question on what exactly causes the changed dynamics in the brain, no one is exactly sure. However, there are some very convincing ideas. For example, activation of D1 receptors, which are important for encoding new reward memories and helping strengthen existing or growing new synapses, also results in increased Dynnorphin production. As I mentioned in my previous post, Dynnorphyn is most well-known to decrease brain dopamine release, though it also drastically decreases serotonin, glutamate, GABA, serotonin and norepinephrine across the brain. it does so in a manner that favours The onset of severe depression, anhedonia and psychosis.

In terms of antipsychotic induced anhedonia, I assume that’s down to their blockade of dopamine receptors combined with extremely long half life and probably a whole host of other mechanisms that could lead to imbalances in the brain. this might be a bit controversial but it’s just my opinion on schizophrenia medication. Personally, I believe that D2 antagonists have had their days and with all the technology and advancement we have today, The fact we are still using them is a poor sign of our progress. I don’t know who to blame, but I assume pharmaceutical companies could be partly responsible for maintaining D2 antagonism as the main course of treatment. this is because it only temporarily addresses one aspect of schizophrenia, predominantly psychosis and such medications are expected to be used lifelong. therapies focused on glutamate or chemical inhibitors of the HDACs May turn out to be cheaper, much more effective including in reversing all aspects of schizophrenia and might produce a disease modifying effect that means they might not have to be taken as often. personally, I’m not a fan of conspiracy theories and many do exist around medications. however, schizophrenia treatment is quite profitable and as research increasingly shows that the disease is only due to minor synaptic changes and not brain atrophy as previously thought, A cure might come much quicker than expected.

If you don’t mind, could you share your personal experience of anhedonia? if so, could you still experience actual pleasure? would you agree with my statement that anhedonia indirectly leads to anxiety because our minds have more time to focus on it, when we are not chasing rewards?

 

[Neuroprotection]

here’s an interesting link about dynnorphinn in schizophrenia. Sorry I seem obsessed with this, but I feel it has a lot of potential, given that it is a molecule biologically designed to cause anhedonia and it does it extremely well.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442669/

 

[Neuroprotection]

Thank you for sharing your personal story. Other than the cold and flu injections, were you prescribed any other medications? The reason I ask is that sometimes anhedonia can be a side effect of medication.

Also, have you had a blood test in a while? I would get my testosterone and thyroids checked in addition to the other common checks. As far as I know, low testosterone can cause depression and lethargy. Same with low thyroid counts. When I was prescribed Lithium a year and a half ago, it caused my thyroid counts to drop and I quickly became very depressed and was tired all the time; seemed like the precursor to anhedonia. My primary doctor told me my two choices were to quit Lithium or begin taking thyroid medication, which I would have to take for the rest of my life. Of course, I quit Lithium and replaced it with a different mood stabilizer and have been fine ever since.

Anyways, these are just a couple of thoughts. I'm glad your anhedonia has seemed to subside.

You’re welcome. Thanks for showing an interest and for your advice. I’m not on any medication and I’ve never had a psychiatric disorder. however, I think my anhedonia could partly be a response to repeated stressful experiences i’ve had throughout my life, many of them related to argumentative siblings, One of these with severe anger problems. I think it’s this long-term unpredictable stress, that constant tension in the air that someone with anger problems creates, which made it very difficult for me to relax. on top of this, I’m now in my late 20s, and perhaps you are right, maybe a drop in testosterone had occurred. i’m not a big fan of going to the doctors, but now I’m seriously considering getting some blood tests and if my testosterone is declining, I will be happy to receive replacement therapy.

 

[Jerry Atrick]

I’m not a neuroscientist or expert in this field by any means, so please take what I say with a pinch of salt. i’ve come across the thread you were talking about, however, I’ve never actually looked at it since I’ve never used antipsychotics so it never caught my attention. However, I will check it out soon to get a better idea of peoples experiences of anhedonia.

Regarding your question on what exactly causes the changed dynamics in the brain, no one is exactly sure. However, there are some very convincing ideas. For example, activation of D1 receptors, which are important for encoding new reward memories and helping strengthen existing or growing new synapses, also results in increased Dynnorphin production. As I mentioned in my previous post, Dynnorphyn is most well-known to decrease brain dopamine release, though it also drastically decreases serotonin, glutamate, GABA, serotonin and norepinephrine across the brain. it does so in a manner that favours The onset of severe depression, anhedonia and psychosis.

In terms of antipsychotic induced anhedonia, I assume that’s down to their blockade of dopamine receptors combined with extremely long half life and probably a whole host of other mechanisms that could lead to imbalances in the brain. this might be a bit controversial but it’s just my opinion on schizophrenia medication. Personally, I believe that D2 antagonists have had their days and with all the technology and advancement we have today, The fact we are still using them is a poor sign of our progress. I don’t know who to blame, but I assume pharmaceutical companies could be partly responsible for maintaining D2 antagonism as the main course of treatment. this is because it only temporarily addresses one aspect of schizophrenia, predominantly psychosis and such medications are expected to be used lifelong. therapies focused on glutamate or chemical inhibitors of the HDACs May turn out to be cheaper, much more effective including in reversing all aspects of schizophrenia and might produce a disease modifying effect that means they might not have to be taken as often. personally, I’m not a fan of conspiracy theories and many do exist around medications. however, schizophrenia treatment is quite profitable and as research increasingly shows that the disease is only due to minor synaptic changes and not brain atrophy as previously thought, A cure might come much quicker than expected.

Very interesting take. You have done some homework. I agree that the pharmaceutical companies carry most of the blame for the prevalence of the prescription of antipsychotics. Of course, the doctors are no doubt complicit in this scheme because most of them promote the same narrative of lifetime use and many fail to acknowledge the multiple pitfalls of taking antipsychotics. However there is a small minority of psychiatric practitioners who believe that psychosis is more a result of external stimuli in the social environment and how our brain compensates. They feel that talk therapy and plugging into a helpful community and family environment can provide more long term success rather than throwing pills at the symptoms while ignoring the causes. Then the issue arises: what should someone do if they have no community or understanding family with which to lean on? A question with complex answers. Many of the same psychiatrists do not completely discount the use of antipsychotics for extreme cases but they also say the medications should be prescribed short term and once the storm has passed, that one should taper off. Joanna Moncrieff is one such psychiatrist and has published a lot of books and articles on the subject.

If you don’t mind, could you share your personal experience of anhedonia? if so, could you still experience actual pleasure? would you agree with my statement that anhedonia indirectly leads to anxiety because our minds have more time to focus on it, when we are not chasing rewards?

For one, I didn't even know what I experienced had a clinical name until a decade after I had it and it passed. Actually it was here on Bluelight where I first read the term and I realized that it is exactly what happened to me after being injected with Risperdal several times while on order in a state hospital. I could not experience pleasure in doing anything. I was bored with television and other hobbies and stopped playing musical instruments for a while. The thing is, it stifled all of my emotions not just pleasure. I don't recall even feeling anxiety, anger, or sadness. I literally did not feel anything. Had I used Bluelight at that time and the Invega thread existed then, it might have caused me to understand what was happening and I might have at least felt mad at the people who injected me and maybe even had the urge to break free from the system. But instead, I had no insight and just accepted it as a new normal. I knew I was different from before but also didn't care.

No, I continued following the advice of my treatment team and am still on antipsychotics to this day. I don't have much of a sympathetic community outside of Bluelight and while my family is helpful, they are also a bunch of far right conservatives that I am constantly at odds with and do not really trust them to cooperate with my own medical decisions. As for my mental health, I don't feel as bad as I once did and have much more insight into my condition such that I know if I'm veering from reality and also know that if side effects from medication cause any discomfort, I can talk to my doctor and we can adjust some things. Maybe one day I will make the leap to taper off antipsychotics completely but that day has not come yet.

 

[Neuroprotection]

here is just one of many very interesting articles that review the role of the kappa opioid receptor in anhedonia and stress/depression like behaviours. it appears to be that the kappa opioid receptor is especially important for turning acute behavioural responses to stress into chronic pathophysiological maladaptive responses that manifest themselves as trauma and depression related disorders in humans.

Dynorphin, stress, and depression

Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many ...

www.ncbi.nlm.nih.gov

 

[Neuroprotection]

Ampakines reportedly have major potential to rapidly reverse depression and anhedonia though I think clinical trials are still far off and safety concerns still exist. Some Nootropics work through enhancing AMPA receptor transmission, has anyone had any success with those?

 

[Mimi Bordeaux]

I should’ve probably posted this in the neuroscience and pharmacology forum, however, I don’t seem to get many responses to anything I post there and also, I feel this subject is more relevant to people on this particular forum. I ask everyone to forgive me for my long posts and any grammatical errors as I am blind and using my iPhone dictation function to type. I have a lot to say but I hope it helps.

Basically, anhedonia is most commonly thought of as a loss of ability to feel pleasure, when in fact, in most cases it is a reward motivation/salience deficiency. this makes affected individuals perceive natural rewards as unworthy of their effort and of little to no value. in such cases, negative emotions usually fill the gap and anxiety sets in. since dopamine is the most studied chemical in this regard, it’s interesting to note that rats depleted of dopamine Will not pursue food and May die of starvation. However, if food is placed in their mouths, they will eat, and they exhibit a strong liking reaction when sugar solution is placed in their mouth. furthermore, even without dopamine, sugar solutions can be reinforcing in rats, although I guess it Took longer to establish and was smaller in magnitude. therefore, it is appropriate to say that dopamine is more involved in wanting rather than liking and drives a pursuit of pleasure rather than the experience of it. based on my own self diagnosed experience of anhedonia, i’ve come up with a theory that dopamine and associated reward seeking/impulsivity gives us a sense of direction and prevents us from overthinking things. in my next post, I will discuss my own personal experience of anhedonia as this one is already quite large, however, I will continue on this post below with some suggestions of methods/substances and ideas related to anhedonia.

As mentioned above, anhedonia is a reward deficiency syndrome and the most common Brain region associated with this is the nucleus accumbens. I know hardly anything about brain Science, but I believe the role of the nucleus accumbens includes reward calculation and attribution of value to the reward as well as the direct experience of reward itself. now, dopamine is the main neurotransmitter in discussions of the nucleus accumbens in reward/drugs of abuse, yet, it is well-known that serotonin, glutamate, and many others are also involved. unfortunately, as we already know, simply boosting dopamine is not sustainable especially if strong Psychostimulants like amphetamine are used.
Interestingly, examining changes in the nucleus accumbens following the long-term administration of addictive drugs or in response to prolonged unpredictable stress and social defeat stress in animals gives us some major clues about the development of anhedonia and how it could be easily reversed.
Apparently, dopamine associated reward is generated by decreased reactivity of certain neurons in the nucleus accumbens. i’m not sure which cells exactly or what this means for other neurons, but I guess it probably disinhibits other systems and acts as a signal that something valuable is being experienced.

So what are the main negative changes associated with long-term stress or drug abuse, and how do they cause anhedonia? to start, both these factors cause an increase in levels of the feel bad peptide Dynnorphin, Which, through activation of kappa opioid receptors decreases, dopamine signalling and release in the nucleus accumbens. interestingly, Kappa Opioid receptor activation also decreases release of glutamate, norepinephrine, GABA and serotonin in the nucleus accumbens and in other brain regions. Dynnorphin must serve some kind of beneficial purpose but it surely a nightmare molecule and disastrous in excess. thankfully, more and more small molecules are becoming available which selectively block the kappa opioid receptor. buprenorphine is apparently a kappa opioid antagonist and it’s combination with a Mu antagonist like naltrexone has been investigated for depression. although clinical trials were not particularly impressive, I feel that perhaps not enough time was given for optimum results. Also, disturbed by the extremely long pharmacological duration of action of the old Kappa antagonists like norbimiltorphamine or JDTIK, researchers instead focus on short-acting molecules that only last a few hours. Frankly, I don’t think that’s enough time, keep in mind that high levels of Dynnorphin and up-regulation of kappa receptors can be operating in the brain for weeks or months at a time. actually, a recent study I came across showed that prolonged Kappa receptor activation lead to long-term changes in expression of glutamate receptors that resulted in despair like behaviour and this behaviour far outlasted The kappa Opioid agonist. with that in mind, perhaps prolonged blockade of the kappa receptor alongside behavioural therapy and healthy lifestyle changes might go a very long way.

I’m less enthusiastic about other substances like Serotonergic psychedelics or NMDA antagonists, due to the range of side-effects, including memory impairment, psychotomimetic reactions or worsening of depression. whilst the NMDA antagonists have produced rapid antidepressant affects, these are short lived and come with the above-mentioned side-effects. additionally, they may paradoxically impair reward learning, interfering with motivation and the acquisition of new rewarding experiences. unlike these substances, the Kappa Opioid antagonists actually possess antipsychotic effects, despite enhancing dopamine release in the brain and producing a state analogous to cocaine sensitisation. extra dopamine with a decreased risk of psychosis sounds wonderful to me.

Sorry for the long rant, just hope to stimulate discussion that will help people for a long time to come.

Good stuff thank you