New review: on to dopamine phasic & tonic release [116 studies]
Re: New review: on to dopamine phasic & tonic release [116 studies]
Thanks mesolimbo. How the hell can you research this with cognitive dysfunction?
Re: New review: on to dopamine phasic & tonic release [116 studies]
Thanks for the feedback everyone! I hope this clears up the confusion on why dopaminergic drugs don't feel alike, and why only some of them work on mood disorders and the hedonistic response.
Please note that dopamine is not involved in pleasure, i.e. 'liking'. It's more a 'wanting' neurotransmitter. For pleasure, glutamate and opioid transmission play more intimate roles. Although dopamine interacts with those and can facilitate pleasure, it isn't the main driving factor. Dopamine is involved in anticipatory anhedonia, whereas these two are involved with consummatory anhedonia.
MAO-B inhibitors are generally better than dopamine agonists since by raising dopamine they also target D1/D5 receptors. D1 activation is pro-cAMP and facilitates glutamate release, so it's more involved in the hedonistic response.
I might discuss each dopamine receptor and their interaction with receptors of other neurotransmitters in a future article, if the community votes for it.
The people I've described who I hypothesize that they have high tonic release (so high to attenuate the response to phasic activation) are the ones who never experience negative symptom relief (anhedonia, blunted affect, loss of libido, etc) unless they take very high doses of phasic dopaminergic stimulants. They often crash hard for days or weeks after taking a stimulant because their dopaminergic system is so desensitized.
Rats get addicted to Bupropion because they don't metabolize it the same way we do. They get the main molecule which is far more powerful DRI than its metabolites, so they keep abusing it. I'd met a patient at the pharmacy I work at who had tried abusing Bupropion by snorting it (bypassing first-pass CYP2B6 metabolism). He messed up his nose (nosebleeds) and got a seizure doing so, but he said it has a dirty stimulant-like kick this way.
I've sent you a message on Patreon with my Discord account info. Hope to chat with you there soon!
If you have any questions, please feel free to ask.
Please note that dopamine is not involved in pleasure, i.e. 'liking'. It's more a 'wanting' neurotransmitter. For pleasure, glutamate and opioid transmission play more intimate roles. Although dopamine interacts with those and can facilitate pleasure, it isn't the main driving factor. Dopamine is involved in anticipatory anhedonia, whereas these two are involved with consummatory anhedonia.
MAO-B inhibitors are generally better than dopamine agonists since by raising dopamine they also target D1/D5 receptors. D1 activation is pro-cAMP and facilitates glutamate release, so it's more involved in the hedonistic response.
I might discuss each dopamine receptor and their interaction with receptors of other neurotransmitters in a future article, if the community votes for it.
I hope this gives hope to everyone. I really believe that PSSD is treatable symptomatically no matter how severe it is or how long it persists. As for a complete reversal cure, we will have to wait longer, but we will get there some day. No need to lose hope or contemplate suicide. There IS hope.succubus76 wrote:Everytime mesolimbo wrote a post my suicide rate drops to 0% . Thanks for the post. I ll give it a though
Thanks for everything!chemistry wrote:Amazing article especially since it was written in a week. Really informative. Please support and protect this man thank you.
My hypothesis only describes a subset of PSSD patients, not all of them. As in your case, you benefit from tonic dopamine releasers, which means you are in a general hypodopaminergic state affecting both phasic and tonic release. Tonic release is important in the first place, for phasic release to take place.sovietxrobot wrote:Its going to take me a while to work through this article, but your hypothesis is totally consistent with my experience. In addition to sexual dysfunction, I had all of the other symptoms you listed (avolition, anhedonia, fatigue, etc.). Interestingly, these are all negative schizophrenia symptoms (look up neuroleptic induced deficit disorder). I have seen significant recovery with bupropion, zinc, mucuna pruriens, and maca, which all have dopimanergic properties. I wonder if I should drop buspirone, which supposedly has some antidopaminergic effects.
The people I've described who I hypothesize that they have high tonic release (so high to attenuate the response to phasic activation) are the ones who never experience negative symptom relief (anhedonia, blunted affect, loss of libido, etc) unless they take very high doses of phasic dopaminergic stimulants. They often crash hard for days or weeks after taking a stimulant because their dopaminergic system is so desensitized.
Haha, yeah. I'm aware that my articles can be a bit hard to follow so I've been thinking about incorporating some humorous remarks without going over the top. What do you think?naiverat wrote:Great read. Information parallels experiences with dopaminergic a pretty closely.
I like how the tone of the paper was quite formal and technical, then meso threw in a "Weak-ass DRI" phrase.
Rats get addicted to Bupropion because they don't metabolize it the same way we do. They get the main molecule which is far more powerful DRI than its metabolites, so they keep abusing it. I'd met a patient at the pharmacy I work at who had tried abusing Bupropion by snorting it (bypassing first-pass CYP2B6 metabolism). He messed up his nose (nosebleeds) and got a seizure doing so, but he said it has a dirty stimulant-like kick this way.
Thanks for the donation! patrons make it possible for me to continue doing this. With your contributions, I will keep digging deep until we beat this condition.TalkingAntColony wrote:Thanks for your contributions to understanding PSSD. I donated on your Pateron
I've sent you a message on Patreon with my Discord account info. Hope to chat with you there soon!
I'm a pharmacist so I already studied a bit of neurology and pharmacology back in uni days. So, it's easy for me to understand and research these things despite of brain fog. Neuropsychopharmacology is also the passion of my life, and to be able to utilize my knowledge for the benefit of the community is really motivating enough to keep pushing.cdraham wrote:Thanks mesolimbo. How the hell can you research this with cognitive dysfunction?
If you have any questions, please feel free to ask.
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- dangerwood
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Re: New review: on to dopamine phasic & tonic release [116 studies]
Hi Meso. Prior to you doing the SSRI reinstatement were you on your symptomatic relief regime? If so what kind of relief did this regime give you from PSSD. What percentage of relief do you estimate it gave you? Thanks so much you’re giving so many people hope.Mesolimbo wrote: I hope this gives hope to everyone. I really believe that PSSD is treatable symptomatically no matter how severe it is or how long it persists. As for a complete reversal cure, we will have to wait longer, but we will get there some day. No need to lose hope or contemplate suicide. There IS hope.
We're all gonna make it brah
Re: New review: on to dopamine phasic & tonic release [116 studies]
Prior to SSRI reinstatement, I was on my symptomatic relief regimen, yes.dangerwood wrote: Hi Meso. Prior to you doing the SSRI reinstatement were you on your symptomatic relief regime? If so what kind of relief did this regime give you from PSSD. What percentage of relief do you estimate it gave you? Thanks so much you’re giving so many people hope.
Before my Vortioxetine trail, my symptomatic relief regimen gave me 90% relief across all symptoms, including sexual, cognitive, emotional and hedonistic symptoms.
Regimen: (Donepezil, Rasagiline, Memantine, Baclofen, diet coke + occasional NAC at bed time).
Right after the failed Vortioxetine trial, Baclofen has had completely stopped working due to Vortioxetine-induced downregulation of 5HT1A receptors. Over the next 2 months after Vortioxetine withdrawal, I have regained some of Baclofen's effects - but never fully. For this reason, I'd say if I start taking it again, it works for 60-70% of symptoms as I would no longer experience pro-emotional and pro-hedonistic effects as profoundly as before Vortioxetine.
Postsynaptic 5HT1A receptors are known to take a very long time to upregulate/sensitize again, as with the case of MDMA tolerance.
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Re: New review: on to dopamine phasic & tonic release [116 studies]
I thought about goint on Donepezil, Rasagiline, Memantine, Baclofen, diet coke + NAC too, but im not sure if its a good idea to start with this with my type of PSSD, or if I should try something else first. Maybe you could have a quick look here: http://www.pssdforum.com/viewtopic.php?f=41&t=3144Mesolimbo wrote:Prior to SSRI reinstatement, I was on my symptomatic relief regimen, yes.dangerwood wrote: Hi Meso. Prior to you doing the SSRI reinstatement were you on your symptomatic relief regime? If so what kind of relief did this regime give you from PSSD. What percentage of relief do you estimate it gave you? Thanks so much you’re giving so many people hope.
Before my Vortioxetine trail, my symptomatic relief regimen gave me 90% relief across all symptoms, including sexual, cognitive, emotional and hedonistic symptoms.
Regimen: (Donepezil, Rasagiline, Memantine, Baclofen, diet coke + occasional NAC at bed time).
Right after the failed Vortioxetine trial, Baclofen has had completely stopped working due to Vortioxetine-induced downregulation of 5HT1A receptors. Over the next 2 months after Vortioxetine withdrawal, I have regained some of Baclofen's effects - but never fully. For this reason, I'd say if I start taking it again, it works for 60-70% of symptoms as I would no longer experience pro-emotional and pro-hedonistic effects as profoundly as before Vortioxetine.
Postsynaptic 5HT1A receptors are known to take a very long time to upregulate/sensitize again, as with the case of MDMA tolerance.
Re: New review: on to dopamine phasic & tonic release [116 studies]
This symptomatic relief regimen is not for everyone, as I suffer from very complex, stubbornly treatment-resistant PSSD. I'm using many hard-hitting medications, with some having heavy side-effects. I will read your thread and reply there soon.cdraham wrote:I thought about goint on Donepezil, Rasagiline, Memantine, Baclofen, diet coke + NAC too, but im not sure if its a good idea to start with this with my type of PSSD, or if I should try something else first. Maybe you could have a quick look here: http://www.pssdforum.com/viewtopic.php?f=41&t=3144
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- AnhedonicApe
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Re: New review: on to dopamine phasic & tonic release [116 studies]
Hey @mesolimbo. I have a guy I talk to which has the most severe case of PSSD I have come across. Extremely anhedonic, can't eat, can't sleep, can't get out of bed. He tells me often how when he dreams and sleeps, he can feel emotions again and pleasure, as if he is normal again. He can feel hunger even again, feels good, its very weird. When he wakes up he feels a short afterglow, following with panic and within minutes he goes back to the severe anhedonia. Now, I found this article about dopamine increasing in sleep. ''Prominent Burst Firing of Dopaminergic Neurons in the Ventral Tegmental Area during Paradoxical Sleep'' https://www.nature.com/articles/1301251
I am interested in what ur take is on this. Does it have to do something with tonic/phasic dopamine? Thanks for the work man.
I am interested in what ur take is on this. Does it have to do something with tonic/phasic dopamine? Thanks for the work man.
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Re: New review: on to dopamine phasic & tonic release [116 studies]
I experience the exact same things (except the panic attacks in the morning) and have also been wondering about this! Good question! I Wonder if Its an overall increase in neurotransmitter levels/activity. I vaguley remember reading something about increased acetylcholine during dreams but i might be wrong here.
Looking forward to hearing your take on this Meso!
Looking forward to hearing your take on this Meso!
Re: New review: on to dopamine phasic & tonic release [116 studies]
AnhedonicApe wrote:Hey @mesolimbo. I have a guy I talk to which has the most severe case of PSSD I have come across. Extremely anhedonic, can't eat, can't sleep, can't get out of bed. He tells me often how when he dreams and sleeps, he can feel emotions again and pleasure, as if he is normal again. He can feel hunger even again, feels good, its very weird. When he wakes up he feels a short afterglow, following with panic and within minutes he goes back to the severe anhedonia. Now, I found this article about dopamine increasing in sleep. ''Prominent Burst Firing of Dopaminergic Neurons in the Ventral Tegmental Area during Paradoxical Sleep'' https://www.nature.com/articles/1301251
I am interested in what ur take is on this. Does it have to do something with tonic/phasic dopamine? Thanks for the work man.
During sleep, various neurotransmitters change their pattern of firing, i.e. some even stop firing altogether. There are significant changes that occur across brain region, like the posterior hypothalamus shutting down. Due to these changes, you can experience various emotional and sexual states while dreaming that you don't experience during waking time. It's definietly not related to dopamine only, it' far more complex than that. I haven't looked much into this, though.lordofpssd wrote:I experience the exact same things (except the panic attacks in the morning) and have also been wondering about this! Good question! I Wonder if Its an overall increase in neurotransmitter levels/activity. I vaguley remember reading something about increased acetylcholine during dreams but i might be wrong here.
Looking forward to hearing your take on this Meso!
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Re: New review: on to dopamine phasic & tonic release [116 studies]
I can confirm, I have experiences intense sexual emotions and feelings whilst asleep. Upon waking though, that's another story - back to emotional blunting nothingness.
Sleep deprivation also helps greatly with being able to 'feel' again. Sleeping 'resets' me back to crapness.
Sleep deprivation also helps greatly with being able to 'feel' again. Sleeping 'resets' me back to crapness.
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