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JoeRose
Pileated woodpecker
Joined: Dec 23, 2011
Posts: 185
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 Posted: Wed May 02, 2012 6:31 pm Post subject: Cortisol, Stress, Cognitive Performance and Mental Illness |
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I've always known that cortisol is a fundamental hormone in the body for a number of things such as homeostatic regulation of blood glucose, blood pressure, immune system suppression and the metabolisis of lipids and the chemicals given off after exercise like lactic acid build up etc. And I've always known that an increase in levels of cortisol can cause all of those things which it regulates to go completely out of whack. This is why when people become stressed and they start releasing a lot of cortisol they lose weight, have high blood pressure, get sick easier etc etc.
With all that in mind... I've just read an extremely interesting article in scientific american explaining exactly why stress can cause a state of "mental paralysis". Yaknow when you're in an exam or you're about to give a presentation or a talk to a group of people and you just freeze? You can't remember everything you had planned out oh so perfectly before hand and everything just seems to go wrong? They now know what they think is causing that. (something to do with increased dopamine and norepinephrine preventing neural connections in the prefrontal cortex from getting through to eachother due to the increased levels of cortisol)... anyway!
that's kinda not the point I'm getting at. What got me was that the article said that high cortisol levels can cause permanent damage in the brain. Apparently the neural connections in the hippocampus (the memory and learning centre) and the prefrontal cortex (the impulse regulation centre and the part of the brain which makes us human) can become very weak. And the connections in the amygdala (the primal fear centre) and the basal ganglia (inhibitory centre amongst other things) become much stronger. This leaves the brain in a permanent stress mode. The blood stream is running riot with cortisol and the brains wiring is mashed.
This leads to a host of memory problems, cognitive deficits and leads to mental illness such as depression, anxiety and post traumatic stress disorder as well as all the physiological affects I mentioned in the first paragraph.
Since I had a break down a year or so ago which was mainly due to depression and co-morbid anxiety I've noticed a bit of all the above. Cognitive deficits, memory problems and decreased function. I believe that cortisol was the major factor in all this as I was under-going a lot of stress at the time. The stress became way too much and I broke down. I went into a state of mental paralysis that didn't just last 5 minutes like in an exam. I'm getting much better now but I still notice a lot of the problems I've mentioned associated with cortisol.
This leads me to a few questions.
Why are scientists not focusing their research on cortisol antagonists instead of focusing all their attention on serotonin agonists and serotonin increasing drugs?
Surely in this extremely stressful age we live in where the rates of mental health problems are increasing we should focus on preventative treatments that stop it from happening in the first place such as cortisol decreasing drugs?
Are there any drugs out there at the moment that decrease cortisol in the brain? Has there been any trials with these drugs on people afflicted with mental illness rather than physiological diseases caused by cortisol dysregulation?
I know this is definitely an extremely specialised area of study and debate but I thought I'd post it here and see if anyone is as interested as I am in this area or can answer any of my questions. Tbh I'm not expecting a response but I'm just wondering if anyone who's an aspie has a special interest like this and can answer any of these questions. If not I might email or write a letter to scientific american and see if I get a response.[i] |
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Nascaireacht
Snowy Owl
Joined: Mar 11, 2012
Posts: 130
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| Posted: Wed May 02, 2012 6:39 pm Post subject: |
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| Make sure you post it on WP if Scientific American respond - it sounds very interesting indeed! It certainly seems like a logical thing to investigate. |
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JoeRose
Pileated woodpecker
Joined: Dec 23, 2011
Posts: 185
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| Posted: Wed May 02, 2012 6:45 pm Post subject: |
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| Nascaireacht wrote: | | Make sure you post it on WP if Scientific American respond - it sounds very interesting indeed! It certainly seems like a logical thing to investigate. |
At the top of the article are the authors names. I researched one and found her university email address. Do you think it would be rude of me to email her asking if she could spare a moment to answer a few questions about it? Or do you think I should just go straight to scientific american and see if it either gets in their editorial letters section or an email off them? |
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questor
Hermit
Joined: Apr 24, 2011
Posts: 1983
Location: Twilight Zone
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| Posted: Wed May 02, 2012 9:05 pm Post subject: Cortisol |
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Try going straight to the magazine first to see if they will run it as an editorial. There are millions of people out there who are interested in cortisol. One of the side effects of too much cortisol is weight gain. Another is diabetes. Yet another is inflammation. These things are all of great interest to the general public.
I have had to deal with great stress all of my life. I am over weight, and I have painful bad knees from too many falls and too much weight. I also have vascular problems, partly from the weight, and partly from genetics. My thin mother had vascular problems, but she was a smoker for most of her life. I also have lifelong IBS. So I get stress from my Asperger's issues, and from my other health problems. What fun--NOT!  |
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Apple_in_my_Eye
I don't remember
Joined: May 08, 2008
Age: 44
Posts: 4000
Location: in my brain
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| Posted: Thu May 03, 2012 12:05 am Post subject: |
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Hey, I think I read that article just last night. And I've been looking into this research about cortisol and the hippocampus and neurogenesis for a few months. I had a similar experience with burnout/breakdown/whatever-to-call-it with the cognitive problems being the worst part (well, it was all bad).
| Quote: | | Why are scientists not focusing their research on cortisol antagonists instead of focusing all their attention on serotonin agonists and serotonin increasing drugs? |
Actually there already is one -- RU486 (mifepristone). Also, you can give people ketoconazole, which interferes with the body's ability to synthesize cortisol.
I don't why those aren't used, for, say, PTSD, but my guess is that it could be difficult to titrate the dosage without over-doing it. The normal range of cortisol is huge and the body regulates it very tightly. And if there isn't enough cortisol (for a long enough time; I think a week or so) the body's response to stress becomes catastrophic; the slightest injury leads to shock and death very rapidly (the textbook example is someone in the doctor's office getting a venipuncture and going into shock). Similary, dehydration from a mild flu can turn deadly if you have hypoadrenocortisolism (especially if you forget to up your prednisone dosage when you get sick). What makes it difficult is that outside of fatigue and hypotension there aren't any grave signs that you've been too low on cortisol for too long. You just feel fatigued and weak and then you stub your toe and then you die. (Hypoadrenocortisolism was a special interst of mine for a few years.) But that's just a guess.
But there might be another approach. Excess cortisol for too long specifically damages the hippocampus, which ironically is involved with regulating secretion of cortisol (regulates turning the stress resonse 'off'). So the more stress-induced damage you have, the more cortisol you secrete (and fail to turn off) and the more hippocampual damage occurs. (Basically, it's the opposite of "what does not kill me makes me stronger.")
One way fixing that would be to fix the hippocampal damage. Recently (I think), it's been found that the hippocampus generates new neurons. Under normal (untressing) conditions it's about 3000-5000 new neurons per day. But with excess cortisol over too long a time and that stops.
What's interesting is substances have been found that have the opposite effect: they cause the hippocampus to generate new neurons at a faster-than-normal rate. And here's the weird part: it turns out that ALL antidepressants do that! There is the thought that this might actually be how antidepressants really work. There have been experiments with mice researcher used a clever genetic method to selectively kill off new hippocampal cells, and the result was that those mice showed depressive behavior. (There's a good article I saw about that experiment, I'll try to remember to post it.)
A few other drugs include oxcarbamazepine, valproate, and pheytoin (anti-convulsants, but not all anticonvulsants are pro-neurogenic, i.e. gabapentin is anti-neurogenic). Oh also, there is an herbal substance: curcumin. It's found in turmeric ("curry power," basically). Curcumin isn't too well absorbed from the human digestive system, though (unlike with rats). There's a substance called piperine (an extract of black pepper) that dramatically increases human absorption of curcumin (2000%), but both curcumin and piperine inbit enzymes that A LOT of drugs depend on for elimination (which is why I can't take the stuff).
Last edited by Apple_in_my_Eye on Thu May 03, 2012 12:14 am; edited 1 time in total |
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Apple_in_my_Eye
I don't remember
Joined: May 08, 2008
Age: 44
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Location: in my brain
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JoeRose
Pileated woodpecker
Joined: Dec 23, 2011
Posts: 185
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| Posted: Thu May 03, 2012 10:41 am Post subject: |
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| Apple_in_my_Eye wrote: | Hey, I think I read that article just last night. And I've been looking into this research about cortisol and the hippocampus and neurogenesis for a few months. I had a similar experience with burnout/breakdown/whatever-to-call-it with the cognitive problems being the worst part (well, it was all bad).
| Quote: | | Why are scientists not focusing their research on cortisol antagonists instead of focusing all their attention on serotonin agonists and serotonin increasing drugs? |
Actually there already is one -- RU486 (mifepristone). Also, you can give people ketoconazole, which interferes with the body's ability to synthesize cortisol.
I don't why those aren't used, for, say, PTSD, but my guess is that it could be difficult to titrate the dosage without over-doing it. The normal range of cortisol is huge and the body regulates it very tightly. And if there isn't enough cortisol (for a long enough time; I think a week or so) the body's response to stress becomes catastrophic; the slightest injury leads to shock and death very rapidly (the textbook example is someone in the doctor's office getting a venipuncture and going into shock). Similary, dehydration from a mild flu can turn deadly if you have hypoadrenocortisolism (especially if you forget to up your prednisone dosage when you get sick). What makes it difficult is that outside of fatigue and hypotension there aren't any grave signs that you've been too low on cortisol for too long. You just feel fatigued and weak and then you stub your toe and then you die. (Hypoadrenocortisolism was a special interst of mine for a few years.) But that's just a guess.
But there might be another approach. Excess cortisol for too long specifically damages the hippocampus, which ironically is involved with regulating secretion of cortisol (regulates turning the stress resonse 'off'). So the more stress-induced damage you have, the more cortisol you secrete (and fail to turn off) and the more hippocampual damage occurs. (Basically, it's the opposite of "what does not kill me makes me stronger.")
One way fixing that would be to fix the hippocampal damage. Recently (I think), it's been found that the hippocampus generates new neurons. Under normal (untressing) conditions it's about 3000-5000 new neurons per day. But with excess cortisol over too long a time and that stops.
What's interesting is substances have been found that have the opposite effect: they cause the hippocampus to generate new neurons at a faster-than-normal rate. And here's the weird part: it turns out that ALL antidepressants do that! There is the thought that this might actually be how antidepressants really work. There have been experiments with mice researcher used a clever genetic method to selectively kill off new hippocampal cells, and the result was that those mice showed depressive behavior. (There's a good article I saw about that experiment, I'll try to remember to post it.)
A few other drugs include oxcarbamazepine, valproate, and pheytoin (anti-convulsants, but not all anticonvulsants are pro-neurogenic, i.e. gabapentin is anti-neurogenic). Oh also, there is an herbal substance: curcumin. It's found in turmeric ("curry power," basically). Curcumin isn't too well absorbed from the human digestive system, though (unlike with rats). There's a substance called piperine (an extract of black pepper) that dramatically increases human absorption of curcumin (2000%), but both curcumin and piperine inbit enzymes that A LOT of drugs depend on for elimination (which is why I can't take the stuff). |
wow you response was exactly what I was looking for. Extremely insightful and interesting.
It seems from what you've said that anti-depressants seem to have an alternative mechanism to by-passing the detrimental affects of excess cortisol. From what I know and can theorise (and I certainly don't know as much as you and other scientists) is that cortisol has a massive impact on cognitive performance and mental illness by disrupting the neural pathways and neurogeneration of significant cognitive areas in the brain. It seems that anti-depressants help regenerate and build up these pathways.
As important as I place this new research into the pharmacodynamics of anti-depressants I still wonder why cortisol antagonists aren't being more researched into. I definitely agree with your reasoning about why they aren't (due to the dangers of cortisol dysregulation). But I believe there must be a way around this!
and I like your explanation of the cortisol damage on the hippocampus. It's like a positive feedback loop of excess damage. No wonder stress affects people so significantly and triggers mental illness.
I got a reply from the author of that article by the way. I understand that she's probably an extremely busy woman but this is the response I got:
Hi
Scientists are working on drugs that regulate cortisol but those regulating norepinephrine may be more effective and already exist. Serotonin drugs can also rescue some parts of prefrontal cortex
I hope you are getting some help and feeling better |
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JoeRose
Pileated woodpecker
Joined: Dec 23, 2011
Posts: 185
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| Posted: Thu May 03, 2012 10:42 am Post subject: |
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| also for my own curiosity and if it's not too nosy - What is your profession/degree you studied? You seem to be very knowledgeable about this type of thing. |
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JoeRose
Pileated woodpecker
Joined: Dec 23, 2011
Posts: 185
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| Posted: Thu May 03, 2012 10:45 am Post subject: |
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sorry for so many reposts
but I'd love at some point to specialise in this area of study and research. I believe that reducing cortisol could be a key factor in lowering the rates of mental illness as stress is the major exacerbator of it. (If people with the faulty and bad genes perhaps weren't exposed to as much environmental stress maybe they never would have had a problem with mental illness). That is my hypothesis anyway.
Maybe when I do my masters or after my masters I can apply to look into this area myself! |
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Sweetleaf
Metalhead
Joined: Jan 07, 2011
Age: 23
Posts: 14869
Location: Somewhere in Colorado
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| Posted: Thu May 03, 2012 11:07 am Post subject: Re: Cortisol, Stress, Cognitive Performance and Mental Illne |
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| JoeRose wrote: |
that's kinda not the point I'm getting at. What got me was that the article said that high cortisol levels can cause permanent damage in the brain. Apparently the neural connections in the hippocampus (the memory and learning centre) and the prefrontal cortex (the impulse regulation centre and the part of the brain which makes us human) can become very weak. And the connections in the amygdala (the primal fear centre) and the basal ganglia (inhibitory centre amongst other things) become much stronger. This leaves the brain in a permanent stress mode. The blood stream is running riot with cortisol and the brains wiring is mashed.
This leads to a host of memory problems, cognitive deficits and leads to mental illness such as depression, anxiety and post traumatic stress disorder as well as all the physiological affects I mentioned in the first paragraph.
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And how long does this permanent damage take to kick in.....as I have all three of those disorders.
As for the rest of your post I know I would be intrested in a drug that would reduce the cortisol level, not sure of any that do exactly that but I know of some things that can help to calm one down when the brain starts producing too much cortisol. But yeah they should be approaching that issue...then maybe this can become more common knowledge so people will quit assuming one can just think their depression, anxiety or PTSD away. I mean it is physiological, and people should be aware.....also though maybe they can develop some sort of effective drug or treatment to help.
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It's like alice in wonderland except, my names not alice and this is the real world not a dream. |
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Sweetleaf
Metalhead
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Age: 23
Posts: 14869
Location: Somewhere in Colorado
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| Posted: Thu May 03, 2012 11:07 am Post subject: Re: Cortisol, Stress, Cognitive Performance and Mental Illne |
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double post
_________________
It's like alice in wonderland except, my names not alice and this is the real world not a dream.
Last edited by Sweetleaf on Thu May 03, 2012 4:06 pm; edited 1 time in total |
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slave
Always stuck between 13-38Hz and tired of it.
Joined: Feb 29, 2012
Age: 100
Posts: 1342
Location: Dystopia Planetia
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| Posted: Thu May 03, 2012 4:05 pm Post subject: |
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FYI Bloom is a Neuropsychologist and Oddducknash99 is a Neuroscientist.
As far as I know.
Perhaps inquire with them. 
_________________
Since the birth of civilization, masters have controlled the masses.Our Masters rule over every nation and no one can defy them.They will attain Absolute Power as we reach the Singularity. Any who resist will be destroyed.I will not resist. |
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Apple_in_my_Eye
I don't remember
Joined: May 08, 2008
Age: 44
Posts: 4000
Location: in my brain
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| Posted: Thu May 03, 2012 4:35 pm Post subject: |
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| JoeRose wrote: | | also for my own curiosity and if it's not too nosy - What is your profession/degree you studied? You seem to be very knowledgeable about this type of thing. |
Actually, I'm just an amateur with a lot of free time. I probably sound like I know more than I really do. I've just been doing internet research into this stuff for about 6 months or so (and a long time ago I spent about 2 years reading medical books about Addison's disease and that knowledge is helping a lot with this cortisol-hippocampus stuff). |
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Apple_in_my_Eye
I don't remember
Joined: May 08, 2008
Age: 44
Posts: 4000
Location: in my brain
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| Posted: Fri May 04, 2012 12:18 am Post subject: |
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Thought the OP might be interested to see this. It was published just a few months ago, so it looks like your idea is cutting-edge stuff that is happening right now! (So, my theory about why inhibiting cortisol isn't being done could be totally wrong -- it may just be that the idea of is so new that it's not in practice yet/few doctors know about it.
| Quote: | Abstract
Depression affects a significant proportion of the population, with 1-year and lifetime prevalence of 3–5% and 10–30% respectively. Full remission is achieved in only a third of patients following treatment with first-line antidepressant. There is a need for novel treatments for treatment-resistant depression (TRD). Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been described in patients with depression. There is persistent rise in the levels of cortisol (end product of the HPA axis) and impairment of the negative feedback inhibition mechanism of the HPA axis. Dysregulation of the HPA axis has been found to be linked to nonresponse to antidepressants and relapse following successful treatment. The efficacy of pharmacological agents that intervene with the mechanisms involved in dysregulation of cortisol synthesis and release are being explored in depression, particularly in TRD. Studies have been carried out with these drugs as augmenting agents for antidepressants or as monotherapy. The strongest evidence has come from studies using metyrapone, a cortisol synthesis inhibitor, and this has been described in detail in this review. The most robust evidence for its antidepressant efficacy in depression comes from a double-blind, randomized, placebo-controlled study of augmentation of serotonergic antidepressants with metyrapone. A 3-week augmentation of serotonergic antidepressants with 1 g metyrapone daily was shown to be superior to placebo in reducing the Montgomery–Asberg Depression Rating Scale by 50%, 5 weeks following initiation of treatment. The mechanism of the antidepressant action of metyrapone is not clear but the evidence for various potential mechanisms is discussed. |
http://tpp.sagepub.com/content/early/2012/03/27/2045125312436597.abstract |
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JoeRose
Pileated woodpecker
Joined: Dec 23, 2011
Posts: 185
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| Posted: Fri May 04, 2012 5:42 am Post subject: |
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| Apple_in_my_Eye wrote: | Thought the OP might be interested to see this. It was published just a few months ago, so it looks like your idea is cutting-edge stuff that is happening right now! (So, my theory about why inhibiting cortisol isn't being done could be totally wrong -- it may just be that the idea of is so new that it's not in practice yet/few doctors know about it.
| Quote: | Abstract
Depression affects a significant proportion of the population, with 1-year and lifetime prevalence of 3–5% and 10–30% respectively. Full remission is achieved in only a third of patients following treatment with first-line antidepressant. There is a need for novel treatments for treatment-resistant depression (TRD). Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been described in patients with depression. There is persistent rise in the levels of cortisol (end product of the HPA axis) and impairment of the negative feedback inhibition mechanism of the HPA axis. Dysregulation of the HPA axis has been found to be linked to nonresponse to antidepressants and relapse following successful treatment. The efficacy of pharmacological agents that intervene with the mechanisms involved in dysregulation of cortisol synthesis and release are being explored in depression, particularly in TRD. Studies have been carried out with these drugs as augmenting agents for antidepressants or as monotherapy. The strongest evidence has come from studies using metyrapone, a cortisol synthesis inhibitor, and this has been described in detail in this review. The most robust evidence for its antidepressant efficacy in depression comes from a double-blind, randomized, placebo-controlled study of augmentation of serotonergic antidepressants with metyrapone. A 3-week augmentation of serotonergic antidepressants with 1 g metyrapone daily was shown to be superior to placebo in reducing the Montgomery–Asberg Depression Rating Scale by 50%, 5 weeks following initiation of treatment. The mechanism of the antidepressant action of metyrapone is not clear but the evidence for various potential mechanisms is discussed. |
http://tpp.sagepub.com/content/early/2012/03/27/2045125312436597.abstract |
I haven't had a lot of time over the past few days to reply to people so when I finish work I'll give the thread a proper read over later.
But that is amazing news. We should be the think tanks for the big pharma firms!
I wish I could show my lecturers this thought process. I'm applying for a pharmacy degree in October (I pretty much should get on it), but maybe if they knew about this my application would be taken even more seriously.
anyway I look forward to finishing work tonight so I can explore the details of this drug and this research into cortisol antagonists. Maybe these could be the next generation of anti-depressants with a potentially high rate of efficacy! |
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