Pharmacology Questions about transmitter depletion and the pharmacology of combining reuptake inhibitors and releasers

[rentedbythehour]

I do not have a background in science and this might not be the correct place for this but could you tell me if I have this right or am I way off?

People use substances, sex, exercise, good food, etc and it releases dopamine in our brains. Now certain things, like drugs kinda kick dopamine into overdrive, not really regulating the amount that gets released. This is what causes all the pleasurable side effects we feel when we drink alcohol, smoke cigarettes, do dope, meth, benzos, etc. Because there really is no turn off switch while you're using, can't the dopamine get depleted? I would guess for long time users, the chemical levels in the brain would be on the low end. I myself don't feel great or euphoric when I've been using for a while. I feel tired and blah and have no interest in doing much of anything. I know someone said exercise can combat the fatigue, but it is sometimes impossible to get out of bed.
This is the part I'm curious about. I take Cymbalta, a SNRI, which I believe blocks serotonin and norepinephrine reuptake. From what I've read, dopamine levels are also increased with SNRI use. So because there are more neurotransmitters floating around when I use meth, does it potentiate the high? I'm also curious if it provides some sort of protective factor. I actually asked my neurologist at one point if the effects of long term drug use that affect the chemical depletion in your brain is permanent. How do you get those chemicals back in balance? Are there even meds out there that help with that?
I believe someone said it would be nice to develop something for long term benzo users. I am one of those. Am I wrong in thinking that something to help would basically be substituting one dopamine releasing drug for another? I know there are other ways, exercise, diet, socialization, but how long would that take to balance out? Years?
Sorry if this doesn't fit here but with some of the other postings, I thought someone might be able to explain.

 

[deficiT]

I do not have a background in science and this might not be the correct place for this but could you tell me if I have this right or am I way off?

People use substances, sex, exercise, good food, etc and it releases dopamine in our brains. Now certain things, like drugs kinda kick dopamine into overdrive, not really regulating the amount that gets released. This is what causes all the pleasurable side effects we feel when we drink alcohol, smoke cigarettes, do dope, meth, benzos, etc. Because there really is no turn off switch while you're using, can't the dopamine get depleted? I would guess for long time users, the chemical levels in the brain would be on the low end. I myself don't feel great or euphoric when I've been using for a while. I feel tired and blah and have no interest in doing much of anything. I know someone said exercise can combat the fatigue, but it is sometimes impossible to get out of bed.
This is the part I'm curious about. I take Cymbalta, a SNRI, which I believe blocks serotonin and norepinephrine reuptake. From what I've read, dopamine levels are also increased with SNRI use. So because there are more neurotransmitters floating around when I use meth, does it potentiate the high? I'm also curious if it provides some sort of protective factor. I actually asked my neurologist at one point if the effects of long term drug use that affect the chemical depletion in your brain is permanent. How do you get those chemicals back in balance? Are there even meds out there that help with that?
I believe someone said it would be nice to develop something for long term benzo users. I am one of those. Am I wrong in thinking that something to help would basically be substituting one dopamine releasing drug for another? I know there are other ways, exercise, diet, socialization, but how long would that take to balance out? Years?
Sorry if this doesn't fit here but with some of the other postings, I thought someone might be able to explain.

Can't really give a good answer to this at the moment, but if you get no good answers here, I'd be happy to move it to a better suited forum or thread if anyone can think of any that would be better.

You might be able to just make your own post in neuroscience. @Skorpio @someguyontheinternet would this post fit there? And if so can you move it there and start its own thread if needed

 

[rentedbythehour]

@someguyontheinternet
Thank you!

 

[JohnBoy2000]

Interesting questions to which I'm also curious about answers.

Conventional dopamine enhancement:

- Socialization, I think this may be the main one as it provides the best sense of excitement, "excitation".
- Exercise is great but again, this kind of requires good motivation and well being to engage in, difficult to do if one has low energy and poor recovery ability.
- A healthy lifestyle, again great, but it requires energy, motivation, well being, being healthy already.
- Basically all other feel-good endeavours that provide a sense of reward/accomplishment.

i.e. the things you've listed.

I used amphetamines at high doses a couple years ago and eventually became depressed as the dopamine high was demotivating me to get dopamine through conventional means.

Had to take stock of the situation, stop using amphetamines, and re-introduce natural means to enhance dopamine activity.

I think the overall goal to a healthy life is to figure out how to acquire a good reliable hit of dopamine, naturally.

 

[Skorpio]

Hey, missed this one for a while. I’m about to start my day, and can expand on this more thoroughly later.


Neurotransmitter depletion is a term that I think gets used more than necessary. Your brain is constantly synthesizing new neurotransmitters.

The reason people feel bad after doing a lot of dopaminergic drug, is that your brain circuitry changes with extended use. Our bodies are homeostasis machines. They are so fucking good at adapting to whatever we throw at them. Unfortunately, with drugs these adaptations are not helpful, as they are adapting us to the “on drugs” state.

This can partially be described by receptor internalization and general subcellular changes in signaling, but one cannot neglect the effect of the brain forming new connections between neurons when high (learning, basically). These effects last for a long time, because it is really hard to completely erase neural connections, and even mild reactivation of them strengthens the connection in the long term.

 

[rentedbythehour]

So basically what you're saying is that because our brain adapts so well, the extra chemicals released eventually become the 'norm'. That's why it really doesn't feel like getting high anymore. It just feels normal. But what happens when you stop using, and those extra chemicals are no longer there? Does your brain just adapt to the new levels?

You are talking about synapses, the neural connections. I did learn about this in my A&P classes. Is this also the reason opiate use changes the way your brain reacts to pain? At one point I was going to the ER every week, every 2 weeks for terrible migraines. They would give me demerol for the pain. I also got lectures about how eventually I wouldn't respond to other meds because my brain would just want that Demerol. FYI, the Demerol never touched my pain. It just made me sleep for 16 hours or so. I'd still wake up with a headache.

 

[rentedbythehour]

I think I'm curious about this because I take a lot of meds that put me at high risk for serotonin syndrome. I've eliminated all opiates from my medications. I am still on duloxetine, Clonazepam, eszopiclone, methocarbamol, and I take triptans on an almost daily basis. I also smoke meth pretty much all the time. I do wonder the effects of it on my brain. I know it sounds crazy but the benefits of using have outweighed the negative in a lot of ways. I'm not getting as many headaches, mood, energy levels, interest in life, socialization, motivation have all gotten better.

 

[Skorpio]

So basically what you're saying is that because our brain adapts so well, the extra chemicals released eventually become the 'norm'. That's why it really doesn't feel like getting high anymore. It just feels normal. But what happens when you stop using, and those extra chemicals are no longer there? Does your brain just adapt to the new levels?

When you stop using drugs when your brain has adapted, you experience the physical and especially psychological withdrawals. Over time your brain gets back to normal and you begin to feel better.

You are talking about synapses, the neural connections. I did learn about this in my A&P classes. Is this also the reason opiate use changes the way your brain reacts to pain? At one point I was going to the ER every week, every 2 weeks for terrible migraines. They would give me demerol for the pain. I also got lectures about how eventually I wouldn't respond to other meds because my brain would just want that Demerol. FYI, the Demerol never touched my pain. It just made me sleep for 16 hours or so. I'd still wake up with a headache.

Partially.

From an evolutionary standpoint pain is incredibly important. You need to feel enough pain to alter your actions, and avoid harmful situations, but too much pain paralyzes a person and if you were an animal, it could impede say an escape from predation. Due to this importance, pain signaling is extremely tightly regulated, so the increase in pain from opioid use is brought about by many factors. Probably more important than changing the strength of opioid synapses, or the amount of endorphins, or amount of opioid receptors at a synapse is their role in neuroinflammation.

Opioids bind to opioid receptors to produce the majority of immediate effects. Euphoria comes from the mu opioid receptor, but the delta and kappa opioid receptors contribute to analgesia. They also bind to an immune receptor called toll like receptor 4. In the brain, these receptors are on a class of immune cell called glial cells. These kill bacteria, engulf and dispose of debris, and maintain a healthy environment for neurons by secreting growth factors and other hormones that modify their function. Toll like receptor 4 is also activated by the membrane of bacteria and engages an immune response to get rid of the bacteria that have been detected.

Unfortunately this inflammatory state also modifies nearby neurons. It causes them to become easier to fire, and in pain neurons the function of pain signaling becomes enhanced.

Blocking toll like receptors in animal studies is shown to reduce the development of hyperalgesia and alydonia from long term opioid use (hyperalgesia is where mild pain becomes excruciating, and alydonia is where non-painful stimuli becomes painful).

I think I'm curious about this because I take a lot of meds that put me at high risk for serotonin syndrome. I've eliminated all opiates from my medications. I am still on duloxetine, Clonazepam, eszopiclone, methocarbamol, and I take triptans on an almost daily basis. I also smoke meth pretty much all the time. I do wonder the effects of it on my brain. I know it sounds crazy but the benefits of using have outweighed the negative in a lot of ways. I'm not getting as many headaches, mood, energy levels, interest in life, socialization, motivation have all gotten better.

How long have opioids been away? You could be recovering from the changes induced while on them. Also, being on meth could simply be making you feel better, it’s quite a powerful drug, and could also explain everything but the lack of headaches.

As to the specific effects on serotonin and dopamine, it is quite hard to predict with all of the different drugs in play. The SSRIs should raise serotonin levels, but meth already increases serotonin release to a fairly large degree.

Recent research about ssris indicates that they work by increasing the production of a growth factor in the brain called bdnf. The science isn’t really settled on whether this is a serotonin receptor dependent or independent phenomenon with ssris, with some pretty plausible evidence for both explanations.

 

[Mjäll]

When you stop using drugs when your brain has adapted, you experience the physical and especially psychological withdrawals. Over time your brain gets back to normal and you begin to feel better.


Partially.

From an evolutionary standpoint pain is incredibly important. You need to feel enough pain to alter your actions, and avoid harmful situations, but too much pain paralyzes a person and if you were an animal, it could impede say an escape from predation. Due to this importance, pain signaling is extremely tightly regulated, so the increase in pain from opioid use is brought about by many factors. Probably more important than changing the strength of opioid synapses, or the amount of endorphins, or amount of opioid receptors at a synapse is their role in neuroinflammation.

Opioids bind to opioid receptors to produce the majority of immediate effects. Euphoria comes from the mu opioid receptor, but the delta and kappa opioid receptors contribute to analgesia. They also bind to an immune receptor called toll like receptor 4. In the brain, these receptors are on a class of immune cell called glial cells. These kill bacteria, engulf and dispose of debris, and maintain a healthy environment for neurons by secreting growth factors and other hormones that modify their function. Toll like receptor 4 is also activated by the membrane of bacteria and engages an immune response to get rid of the bacteria that have been detected.

Unfortunately this inflammatory state also modifies nearby neurons. It causes them to become easier to fire, and in pain neurons the function of pain signaling becomes enhanced.

Blocking toll like receptors in animal studies is shown to reduce the development of hyperalgesia and alydonia from long term opioid use (hyperalgesia is where mild pain becomes excruciating, and alydonia is where non-painful stimuli becomes painful).




How long have opioids been away? You could be recovering from the changes induced while on them. Also, being on meth could simply be making you feel better, it’s quite a powerful drug, and could also explain everything but the lack of headaches.

As to the specific effects on serotonin and dopamine, it is quite hard to predict with all of the different drugs in play. The SSRIs should raise serotonin levels, but meth already increases serotonin release to a fairly large degree.

Recent research about ssris indicates that they work by increasing the production of a growth factor in the brain called bdnf. The science isn’t really settled on whether this is a serotonin receptor dependent or independent phenomenon with ssris, with some pretty plausible evidence for both explanations.

Such an awesome writeup as always, thank you Skorpio!

My amateur mind got to thinking: Does mitragynine and its relatives also activate toll-like receptor 4? It has been revealed that these alkaloids don't activate the beta arrestin pathway of opioid signalling, which means negative and dangerous opioid side effects are less pronounced. If kratom doesn't activate this toll-like receptor 4 either, that could be an added advantage. I'm just speculating here and sorry everyone if veering off topic.

https://www.researchgate.net/publication/382308803_Mitigation_of_Lps-induced_Anxiety_and_Oxidative_Stress_Through_Mitragynine_Targeting_Tlr-4_and_Mda_Modulation

I found this study and it seems to imply that mitragynine affects TLR4 although i honestly don't fully comprehend whether it has the same effect as you describe in typical opioids or the opposite. If i'm guessing correctly, the paper seems to show that mitragynine does have a similar effect as other opioids. But i guess the intensity of this effect in proportion to other effects could still differ in a significant way. I think you just got me hyped on more studies about kratom and TLR4 so thanks for that.

 

[rentedbythehour]

I stopped opiates just over a year ago. I was on 15 mg oxy for several years. I was always careful with opiates because I knew if I ever went down that rabbit hole I would be lost. I never let myself take it too far. I did experience withdrawals after years of taking them. I started on regular 5/325 percs and very very slowly made my way to 15 mg oxy. I'm talking like 15 years. I feel less pain and do feel better physically since stopping them.

I asked about the lack of headaches while using meth when I first joined. The best answer I got was that it is a vasoconstrictor, just like triptans are.

Is the recent studies you looked at just for SSRIs? I take an SNRI. I know it increases the serotonin and norepinephrine levels in the brain and I wondered if that actually potentiates the meth, making it work better?

 

[Skorpio]

I’m not sure if mitragynine activates toll like receptors as do other opioids. The is due to direct binding, so it should not be affected by ligand bias (also I feel like the whole biased signaling thing is a bit of an oversimplification, but that is really a can of worms for another time).

I think that paper is saying it counteracts LPS based activation of the receptor. I feel like the elevated plus maze and open field results could very well be due to being on an opioid and the mice feeling good. However it does seem to alter the change in receptor abundance (based on the western blots).

I would have liked to see mitragynine compared with other opioids, but this seems to be one of those papers touting “uses” for kratom that does all it can to avoid calling kratom an opioid…

Toll like receptor signaling is pretty complex, and a bit out of my area, so I definitely need to read up. It does seem to have two possible pathways, which result in transcription of different inflammatory genes. One thing I saw was that non-opioid isomers of opioids are able to activate/block its activation (it’s unclear to me if opioids actually bind with it at all or if they simply cause its activation based on their signaling. Tapentadol was listed on the brief Wikipedia page as a mixed agonist or antagonist, whether this means that it is a partial agonist, or it activates one pathway but not the other, or if it is plain incorrect is beyond me.

I want to read a bunch of papers about it, but I am going to choose sleep, and I’ll try and bone up in the future days.

 

[Skorpio]

I stopped opiates just over a year ago. I was on 15 mg oxy for several years. I was always careful with opiates because I knew if I ever went down that rabbit hole I would be lost. I never let myself take it too far. I did experience withdrawals after years of taking them. I started on regular 5/325 percs and very very slowly made my way to 15 mg oxy. I'm talking like 15 years. I feel less pain and do feel better physically since stopping them.

I asked about the lack of headaches while using meth when I first joined. The best answer I got was that it is a vasoconstrictor, just like triptans are.

Is the recent studies you looked at just for SSRIs? I take an SNRI. I know it increases the serotonin and norepinephrine levels in the brain and I wondered if that actually potentiates the meth, making it work better?

that is an interesting explanation for the headaches. It’s weird other stimulants aren’t known to cure headaches, but it could be an explanation.

And most studies studying BDNF and antidepressants find the same effect for SSRIs and SNRIs. Frankly a lot of the literature just kind of treats them as “stimulating ssris”. I think that’s just leftover focus from when the serotonin hypothesis ruled psychiatry; there is definately a good amount to untangle with norepinephrine signaling, though it looks like they don’t have different effects on depression/neuron growth.

 

[Mjäll]

I’m not sure if mitragynine activates toll like receptors as do other opioids. The is due to direct binding, so it should not be affected by ligand bias (also I feel like the whole biased signaling thing is a bit of an oversimplification, but that is really a can of worms for another time).

I think that paper is saying it counteracts LPS based activation of the receptor. I feel like the elevated plus maze and open field results could very well be due to being on an opioid and the mice feeling good. However it does seem to alter the change in receptor abundance (based on the western blots).

I would have liked to see mitragynine compared with other opioids, but this seems to be one of those papers touting “uses” for kratom that does all it can to avoid calling kratom an opioid…

Toll like receptor signaling is pretty complex, and a bit out of my area, so I definitely need to read up. It does seem to have two possible pathways, which result in transcription of different inflammatory genes. One thing I saw was that non-opioid isomers of opioids are able to activate/block its activation (it’s unclear to me if opioids actually bind with it at all or if they simply cause its activation based on their signaling. Tapentadol was listed on the brief Wikipedia page as a mixed agonist or antagonist, whether this means that it is a partial agonist, or it activates one pathway but not the other, or if it is plain incorrect is beyond me.

I want to read a bunch of papers about it, but I am going to choose sleep, and I’ll try and bone up in the future days.

Yes, we need more comparative studies with other opioids. Seeing as this paper is so recent, i'm kind of hopeful.

Thanks a big bunch again for taking the time to disseminate your knowledge!

 

[rentedbythehour]

And most studies studying BDNF and antidepressants find the same effect for SSRIs and SNRIs. Frankly a lot of the literature just kind of treats them as “stimulating ssris”. I think that’s just leftover focus from when the serotonin hypothesis ruled psychiatry; there is definately a good amount to untangle with norepinephrine signaling, though it looks like they don’t have different effects on depression/neuron growth.

I actually take it for fibromyalgia. I'm going to look into BDNF so I can understand this better. Thank you for taking the time to respond and explain things. When I originally posted this thread, I wasn't sure if anyone would know what I was talking about. I can't help but wonder what your background is that you know all this stuff. It's fascinating to me.

 

[Skorpio]

I’ve been pretty interested in the formal study of drugs since high school. I am in a admn adjacent field and have a lot of exposure to that world. I don’t consider myself to have specialized enough knowledge to work in that field; I’d probably need to read 10-50x more papers to be on top of the literature.

 

[chippermonk]

This has been an interesting discussion, thank you all. I have been wondering about opioids ( in particular kratom) causing increased sensitivity/sensation of pain with regular use. I know it is known that at least the classic opioids can cause OIH (opioid induced hyperalgesia) when people have a regular addicted habit, but I was wondering about if that can happen with irregular non-addicted use.
In my case, I take kratom irregularly, averaging maybe a couple times a week, about 2.5 g generally. Sometimes skipping weeks, sometimes taking a little more often. I also occasionally take very small doses of oxycodone or hydrocodone ( like 2.5 mg). I take these things to get a mild high or get out of a mental funk, but it is also the case that I have been suffering from chronic knee pain all year, and it just so happens that it began not long after I started taking kratom. It has made me wonder if my use of opioids has been enough to screw up my natural ability to handle pain. I also use it enough that I will crave getting high, but I'm pretty good at avoiding use for awhile regardless.
I actually did injure my knees, so there was a legitimate cause of pain, but it seems like I have reached a point where maybe they have healed but I am overly sensitive to residual pain. It sucks!
Sorry for the TLDR and if I have hijacked the thread somewhat. Kratom really seems to have a different and unique effect from oxy and hydro and such and I don't feel like it has been as well studied as it should.

 

[rentedbythehour]

Don't worry about hijacking. You're good. I'm curious about this too. I'm just trying to remember if kratom attaches to the same opioid receptors in the brain. I definitely think it's a possibility that you're having some pain from using the kratom. It's also possible it's just your knees. The knees are the most complicated joint in the body.
I can also tell you that I never used oxy or any opiate on a daily basis. My script was only enough to cover the times I would run out of my migraine meds, which was about 2 weeks. For half the month I would take triptans, the other half I would take oxy. I went thru withdrawals every month when I ran out. I didn't even realize at that time that so much of what I was feeling, like my feet hurt when I got out of bed in the morning. I could barely walk sometimes. Hip pain, backaches, other random pains have pretty much disappeared. I think if your pain is limited to your knees, it could be your injury still.

 

[rentedbythehour]

I’ve been pretty interested in the formal study of drugs since high school. I am in a admn adjacent field and have a lot of exposure to that world. I don’t consider myself to have specialized enough knowledge to work in that field; I’d probably need to read 10-50x more papers to be on top of the literature.

After reading chippermonks post, it made me think about how they prescribe SNRIs (cymbalta) for chronic pain. I believe it's the go to choice for fibromyalgia as well. I am curious what is so different about this drug that it covers all that? Depression, anxiety, chronic pain, fibromyalgia, which is a CNS disorder. I read an interesting article about the science of fibromyalgia and there is a belief that it's caused from the chemicals in the brain and the messaging system malfunctioning. I'll link to the article if you're interested. It's pretty similar to what we were talking about yesterday, about how opiates change how your brain responds to pain. For me fibro came on when I was in my 30s. I have had migraines since I was 11. My headaches, and body reaction completely changed the older I got I would feel like I got hit by a truck after a bad migraine. I would have all over body aches so severe, even the lightest touch hurt. I had to stay in bed for days afterwards. I had no clue what was going on at the time. Once I was diagnosed with it, I started taking cymbalta. It's worked great not just for fibro, but for depression as well. I will say that getting off the opiates completely also helped. More than I ever believed it would.

 

[rentedbythehour]

Link to that article I mentioned

The Science of Fibromyalgia - PMC

Fibromyalgia (FM) is a common chronic widespread pain disorder. Our understanding of FM has increased substantially in recent years with extensive research suggesting a neurogenic origin for the most prominent symptom of FM, chronic widespread pain. ...

pmc.ncbi.nlm.nih.gov

 

[chippermonk]

Don't worry about hijacking. You're good. I'm curious about this too. I'm just trying to remember if kratom attaches to the same opioid receptors in the brain. I definitely think it's a possibility that you're having some pain from using the kratom. It's also possible it's just your knees. The knees are the most complicated joint in the body.
I can also tell you that I never used oxy or any opiate on a daily basis. My script was only enough to cover the times I would run out of my migraine meds, which was about 2 weeks. For half the month I would take triptans, the other half I would take oxy. I went thru withdrawals every month when I ran out. I didn't even realize at that time that so much of what I was feeling, like my feet hurt when I got out of bed in the morning. I could barely walk sometimes. Hip pain, backaches, other random pains have pretty much disappeared. I think if your pain is limited to your knees, it could be your injury still.

Wow, fibromyalgia sounds awful! I gather you have it under control?
Interesting point that if my pain is limited to my knees then perhaps it's less likely opioid/Kratom related. I don't know, I guess I figured one thing could happen was that the perception of pain would be amplified. So an injury, arthritis, whatever would be perceived as more painful because of the OIH effect. I mean, I'm sure I have physical problems, but maybe they just seem worse? But that could also tie into depression, which I have.
My only experience with antidepressants was taking Prozac and Wellbutrin many years ago. I did seem to get less depressed, and at the same time, my back pain seemed to get better. But I also made changes in my life that helped with my mood, and I have never been sure how effective the drugs really were.
You like Cymbalta, I gather, for both pain and depression. I have been wondering if I should give meds a try again, because I'm suffering here, mood and pain both. As it is I sporadically take small amounts of opioids and it isn't really doing the job.