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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 12 of 12. This is the beginning of the thread.
Posted by Quintal on March 30, 2007, at 10:34:01
I've just taken my first 0.125mg dose of Mirapex (pramipexole) and so far so good. I feel warm and comfortable, calm, a little bit light-headed and a leetle beet horny.......... It's reminiscent of my last trial of amisulpride, which worked well for me for two months and I'm hoping for more success with Mirapex.
I few questions that keep bugging me I'd like to throw to the general audience;
* Can dopamine agonists produce euphoria?
* If so, why aren't they scheduled and controlled like similar drugs that simulate dopamine release? I'm thinking that it might be that drug addicts haven't caught on to this yet and that dopamine agonists are rarely prescribed, and then only for serious conditions in which the sufferer is unlikely to sell their medication for profit. It seems unlikely that Big Brother FDA hasn't cottoned on to this 'risk' though.
* Alternatively dopamine agonists may not induce euphoria, and if so why not, when they simulate dopamine release - or am I mistaken in thinking this? What is so different about the action of dopamine agonists compared to say, a transport blocker like Ritalin that would make them less likely to induce euphoria?
* Why are they associated with drowsiness and sudden onset of sleep when dopaminergic drugs are usually stimulating?
* Many people seem to complain of short attention span and apathy with pramipexole. I'm wondering if the addition of reboxetine would help with this and also bolster the antidepressant effect?
* Dependence, addiction, tolerance and withdrawal syndrome. The four evils normally associated with powerful dopaminergic drugs - how do dopamine agonists compare to others in this respect?
All responses, ideas, opinions, suggestions etc. welcome.
Q
Posted by kaleidoscope on March 30, 2007, at 14:44:24
In reply to Dopamine Agonists, posted by Quintal on March 30, 2007, at 10:34:01
Hi Q
>Can dopamine agonists produce euphoria?
Generally not, although there may be exceptions.
>If so, why aren't they scheduled and controlled like similar drugs that simulate dopamine release?
Direct-acting dopamine agonists do not stimulate dopamine release, nor do they inhibit its reuptake. Pramipexole inhibits dopamine synthesis. Dopamine agonists activate certain dopamine receptors.....but not others.
>What is so different about the action of dopamine agonists compared to say, a transport blocker like Ritalin that would make them less likely to induce euphoria?
The relationship between direct-acting dopamine agonists and CNS stimulants (eg. Adderall, Ritalin) is no closer than the relationship between SSRIs and MDMA ie. very distant! Although they act on some of the same neurotransmitter systems, they affect the function of these systems in very different ways.
>Dependence, addiction, tolerance and withdrawal syndrome
The 'recreational value' of dopamine agonists is very low. As is the case with all CNS drugs, there might be a risk of withdrawal symptoms, but this issue has not received any real study.
Ed
Posted by Quintal on March 30, 2007, at 16:04:05
In reply to Re: Dopamine Agonists » Quintal, posted by kaleidoscope on March 30, 2007, at 14:44:24
>Direct-acting dopamine agonists do not stimulate dopamine release, nor do they inhibit its reuptake
I said "If so, why aren't they scheduled and controlled like similar drugs that *simulate* dopamine release?"; simulate (not stimulate) - i.e. they mimick the effect of dopamine.
__________________________________________________
A dopamine agonist is a compound that activates dopamine receptors, mimicking the effect of the neurotransmitter dopamine.
http://en.wikipedia.org/wiki/Dopamine_agonist
__________________________________________________So why aren't they energizing and euphoric in the same way as other drugs that either produce or mimic high levels of dopamine?
>Pramipexole inhibits dopamine synthesis.
Where did you find out about this and what are the consequences? For how long after the last dose is dopamine synthesis inhibited?
>Dopamine agonists activate certain dopamine receptors.....but not others.
It seems pramipexole is more selective to the D3 receptors, although I don't understand the consequences of this. Cabergoline is more selective to the D2 receptors and it appears this wiki article is hinting at possible recreational value for its pro-sexual side effects, although even pramipexole seems to be helping in that department.
__________________________________________________
Off-Label/Recreational UsesIt has at times been used as an adjunct to SSRI antidepressants as there is some evidence that it counteracts certain side effects of those drugs, such as reduced libido and anorgasmia. It also has been suggested online that it has a possible recreational use in reducing or eliminating the male refractory period. It is also used by bodybuilders to control gynocomastia caused by elevated prolactin levels caused by use of Trenbolone esters.
http://en.wikipedia.org/wiki/Cabergoline
__________________________________________________>The relationship between direct-acting dopamine agonists and CNS stimulants (eg. Adderall, Ritalin) is no closer than the relationship between SSRIs and MDMA ie. very distant! Although they act on some of the same neurotransmitter systems, they affect the function of these systems in very different ways.
I know Ed, that's what this thread is about - how dopamine agonists affect the dopamine system in different ways to drugs of abuse, and the reasons mimicking dopamine in this way seemingly lacks euphoria and abuse potential. Most likely the nucleus accumbens is involved somewhere in this equation?
>As is the case with all CNS drugs, there might be a risk of withdrawal symptoms, but this issue has not received any real study.
I suppose most patients never do withdraw from them in Parkinson's disease, but I read somewhere, maybe on crazymeds (not the most reliable source admittedly) about people suffering projectile vomiting and other lovelies on abrupt withdrawal. They were saying Mirapex was harder to quit than Heroin and Crack, which seemed odd and a little far fetched.
Q
Posted by Quintal on March 30, 2007, at 19:34:32
In reply to Dopamine Agonists, posted by Quintal on March 30, 2007, at 10:34:01
__________________________________________________
Mirapex, a deceitful drugI've been on Mirapex for 7-8 years. At first I thought it was a miracle drug. Aside from the cost ($3 pill) I had no side effects. I soon found though, that I was continually upping the dosage because my RLS was becoming more severe. I thought it was just the nature of RLS... it gets worse with age. I found that the Mirapex was triggering the RLS (sometimes within 5-10 minutes of taking it) and learned that Mirapex causes augmentation (just like Sinemet only slower). It also causes a dependency that makes it nearly impossible to go off of it! I was trying last February with the help of hydrocodone to quit Mirapex only to go through sheer hell. RLS all over my body for 7 hours straight. Nothing would make it stop. Since then I've lowered my dose with the help of methadone, but that's another very bad drug that I don't tolerate well. Mirapex may only cause augmentation in 35% of RLS sufferers but if you've ever had problems with other dopamine agonists, DO NOT try Mirapex, your RLS will only get worse. I'm still struggling to find a way off of it.
http://www.remedyfind.com/ratinglong.aspx?RatingID=60458
__________________________________________________Why would they prescribe opiates to ease dopamine agonist withdrawal? Is there some crossover in effects? Mirapex does feel a lot like an opiate to me, but more of the 'nodding' phase rather than the initial 'rush' of euphoria. Interesting.
Q
Posted by rvanson on March 30, 2007, at 19:39:26
In reply to Dopamine Agonists, posted by Quintal on March 30, 2007, at 10:34:01
> I've just taken my first 0.125mg dose of Mirapex (pramipexole) and so far so good. I feel warm and comfortable, calm, a little bit light-headed and a leetle beet horny.......... It's reminiscent of my last trial of amisulpride, which worked well for me for two months and I'm hoping for more success with Mirapex.
>
> I few questions that keep bugging me I'd like to throw to the general audience;
>
> * Can dopamine agonists produce euphoria?Yes, but not often.
> * If so, why aren't they scheduled and controlled like similar drugs that simulate dopamine release? I'm thinking that it might be that drug addicts haven't caught on to this yet and that dopamine agonists are rarely prescribed, and then only for serious conditions in which the sufferer is unlikely to sell their medication for profit. It seems unlikely that Big Brother FDA hasn't cottoned on to this 'risk' though.<<Give them time. They can only pass so many unneeded laws each year !
> * Alternatively dopamine agonists may not induce euphoria, and if so why not, when they simulate dopamine release - or am I mistaken in thinking this? What is so different about the action of dopamine agonists compared to say, a transport blocker like Ritalin that would make them less likely to induce euphoria?Cant say, as I am not a chemical/biological scientist, except that Ritalin affects the NE system as well, if I recall correctly.
> * Why are they associated with drowsiness and sudden onset of sleep when dopaminergic drugs are usually stimulating?I never had that effect with them but nuasuea is common enough.
> * Many people seem to complain of short attention span and apathy with pramipexole. I'm wondering if the addition of reboxetine would help with this and also bolster the antidepressant effect?
It could for some. My expericence with Reboxetine is not a good one. If you have anxiety, it will increase it, in most cases, much like we see with EMSAM.
> * Dependence, addiction, tolerance and withdrawal syndrome. The four evils normally associated with powerful dopaminergic drugs - how do dopamine agonists compare to others in this respect?I never experienced much withdrawal off of these medications.
Nothing like Paxil or Effexor withdrawal at all.
Posted by Quintal on March 30, 2007, at 19:42:46
In reply to Re: Dopamine Agonists » Quintal, posted by kaleidoscope on March 30, 2007, at 14:44:24
>I was trying last February with the help of hydrocodone to quit Mirapex only to go through sheer hell. RLS all over my body for 7 hours straight. Nothing would make it stop.
Sounds to me as if she could be describing akathisia, which has some logic to it given that akathisia occurs where there is a defecit of some kind in the dopamine system?
You know what Eddy? The closest thing I've felt to pramipexole is those 'Mind Music' herbal high tablets that are sold as a legal opiate substitute.
Q
Posted by Quintal on March 30, 2007, at 21:20:13
In reply to Re: Dopamine Agonists, posted by rvanson on March 30, 2007, at 19:39:26
>Cant say, as I am not a chemical/biological scientist, except that Ritalin affects the NE system as well, if I recall correctly.
Yes it does, but it's usually the dopamine reuptake that's attributed to the euphoria since NE reuptake inhibitors are not usually euphoric at all and other pure DA reuptake inhibitors are. But maybe it's the combination that's responsible?
>It could for some. My experience with Reboxetine is not a good one. If you have anxiety, it will increase it, in most cases, much like we see with EMSAM.
I had a bad experience with reboxetine too, but I'm thinking the pramipexole could modify the effects due to its sedating/mellowing nature and make reboxetine more tolerable? There's only one way to find out I suppose.
Q
Posted by linkadge on March 31, 2007, at 13:35:14
In reply to Re: Dopamine Agonists » rvanson, posted by Quintal on March 30, 2007, at 21:20:13
>Alternatively dopamine agonists may not induce >euphoria, and if so why not, when they simulate >dopamine release - or am I mistaken in thinking >this? What is so different about the action of >dopamine agonists compared to say, a transport >blocker like Ritalin that would make them less >likely to induce euphoria?
Not all dopamine reuptake inhibitors produce euphoria. For instance clinical doses of SJW produce a >50% inhibition of dopamine trasporters but produces no euphoria, probably owing to lack of effect on dopamine uptake in neucleus accumbens. Some other investigaitonal DRI's also show little affinity for NAA dopamine transporters.
It depends on the brain region involved. Dopamine agonists do not necessarily bind with high affinity to reward regions wherase a non region specific DRI will activate such regions.
Linkadge
Posted by Quintal on March 31, 2007, at 14:12:03
In reply to Re: Dopamine Agonists, posted by linkadge on March 31, 2007, at 13:35:14
I was just thinking of amineptine actually, it wasn't associated with the kind of euphoria Ritalin and amphetamines usually produce (although it did have abuse potential). I'm starting to associate high dopamine with mellow contentment than speedy euphoria, but perhaps a sudden increase in dopamine can cause a 'rush'? It seems that most of the euphoric dopaminergic drugs bar opiates are also powerful NA reuptake inhibitors.
I'm thinking of experimenting with adding a NRI agent to see if that helps focus and motivation. I have reboextine and sibutramine and I'm thinking sibutramine might have additional benefits on the serotonin system, but it's also a little 'messier' than reboextine. I think I'll try reboxetine first, is there any interaction info/problems between these drugs?
>It depends on the brain region involved. Dopamine agonists do not necessarily bind with high affinity to reward regions whereas a non region specific DRI will activate such regions.
Is it possible to create a dopamine agonist that binds directly to receptors in the nucleus accumbens? I want one!
Q
Posted by linkadge on March 31, 2007, at 14:27:38
In reply to Re: Dopamine Agonists » linkadge, posted by Quintal on March 31, 2007, at 14:12:03
>I was just thinking of amineptine actually, it >wasn't associated with the kind of euphoria >Ritalin and amphetamines usually produce
>(although it did have abuse potential). I'm >starting to associate high dopamine with mellow >contentment than speedy euphoria, but perhaps a >sudden increase in dopamine can cause a 'rush'? >It seems that most of the euphoric dopaminergic >drugs bar opiates are also powerful NA reuptake >inhibitors.This is it. Most drugs are not clean enought to make inferences about a particular mechanism.
>I'm thinking of experimenting with adding a NRI >agent to see if that helps focus and motivation. >I have reboextine and sibutramine and I'm >thinking sibutramine might have additional >benefits on the serotonin system, but it's also >a little 'messier' than reboextine. I think I'll >try reboxetine first, is there any interaction >info/problems between these drugs?Not that I know of.
>Is it possible to create a dopamine agonist that >binds directly to receptors in the nucleus >accumbens? I want one!I'm sure its possable. Thought I don't know how the brain would respond long term.
Linkadge
Posted by Quintal on March 31, 2007, at 14:39:57
In reply to Re: Dopamine Agonists, posted by linkadge on March 31, 2007, at 14:27:38
>I'm sure its possable. Thought I don't know how the brain would respond long term.
Probably by downregulating the receptors? I certainly wouldn't want to go through a nucleus accumbens dopamine agonist withdrawal either. Probably the most severe anhedonia imaginable.
I wonder if this would be the mechanism of a real life 'Havidol'? http://www.dr-bob.org/babble/20070213/msgs/733345.html. We already seem to have a 'Fukitol XR' in cabergoline.
Q
Posted by Jeroen on March 31, 2007, at 17:21:46
In reply to Re: Dopamine Agonists » Quintal, posted by kaleidoscope on March 30, 2007, at 14:44:24
what do you mean with 2 months and then nothing???
This is the end of the thread.
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