Has anyone tried a dopamine agonist?

[rocknroll714]

Originally Posted by euphoria

Isn't buspirone a weak D2 antagonist?

Indeed it is. See here:

http://www.socialanxietysupport.com/...ter-all-65191/

[honastud]

whats the verdict? ^ I'm ready to toss a couple of these back?

[miko]

Yeah, Buspar is weak D2 antagonist. For me, mianserin haven't antidepressant activity, but it's the only med that can help me with ssri-induced akathisia.

[Edwin]

Buspar imo, will just give you a dizzy ride through life. But I would agree it lowers anxiety. Sucks for sociability though.

[euphoria]

If anyone is taking pramipexole, they should be aware that NMDA antagonists are essential to any dopaminergic regimen, and also that pramipexole will make you feel awful unless you use high doses and/or wait through several weeks of the bad feelings.

[Edwin]

I've read up on Pramipexole, but is it due to autoreceptor agonism that you have an initial period of lowered dopamine activity?

[miko]

Something about acetylcholine and dopamine:

"We report that M1 deficiency leads to elevated dopaminergic transmission in the striatum and significantly increased locomotor activity. M1-deficient mice also have an increased response to the stimulatory effects of amphetamine. Our results provide direct evidence for regulation of dopaminergic transmission by the M1 receptor and are consistent with the idea that M1 dysfunction could be a contributing factor in psychiatric disorders in which altered dopaminergic transmission has been implicated."

"The Acetylcholinesterase Inhibitor Galantamine Inhibits d-Amphetamine-Induced Psychotic-Like Behavior in Cebus Monkeys"

"Multiple Muscarinic Acetylcholine Receptor Subtypes Modulate Striatal Dopamine Release, as Studied with M1-M5 Muscarinic Receptor Knock-Out Mice"

"Interestingly, in vivo microdialysis studies showed recently that M1 receptor-deficient mice have significantly elevated levels of extracellular dopamine in the striatum, probably because of increased dopamine release "

So maybe acetylcholine hyperactivity blocks dopamine release?
And that's why muscarinic receptors blocker Oxybutynin works on my depression...

[euphoria]

I know about the dopamine-acetylcholine link, but how can you think blocking acetylcholine is a good method of treating depression? It may make you a bit happier, but also very stupid and forgetful. Why not increase both dopamine and acetylcholine? Then you'll fight depression without potential for psychosis.

[miko]

Yes, increase dopamine is good, but acetylcholinesterase make depression ( more acetylcholine = depression ). There is study about that on net.

[itsamystery]

Please try a beta blocker (Inderal). Your doctor will easily prescribe it for social anxiety--you can take a small dose every day for your situational phobias--it works all day, doesn't cause addiction, is very inexpensive. It's been a lifesaver for me. Minimal side-effects as the low doses that it takes to prevent blushing, hand tremors, etc which plagued me for years.

[euphoria]

Originally Posted by miko

Yes, increase dopamine is good, but acetylcholinesterase make depression ( more acetylcholine = depression ). There is study about that on net.

I know, but if you simultaneously boost dopamine, you get better cognition AND less depression. Also, blocking muscarinic acetylcholine receptors causes tachycardia, which probably wouldn't help those with panic attacks.

Why not just take a beta-blocker like suggested? Or even a benzo, seeing as you're willing to sacrifice cognition and memory. Either are better than a crappy anticholinergic, seriously. It's the equivalent of drinking vodka all day to relieve anxiety -- it works, but is a very poor solution compared to the other things out there.

[crayzyMed]

Trivastal its on its way for me, its a non sedating dopamine agonist, so i wouldnt have to get trough all those side effects before it works.

Very interesting thread!

Also, shouldnt a low dose sulpiride block the sedation dopamine agonists cause? Because it blocks the autoreceptors that also seem to respond to a dapomine agonist.

[miko]

I want to try trivastal (piribedil) too, becouse on ropinrole I have a sleep attacks :f And it's have vasodilation effect. Dopamine agonists works good on my anhedonia.

[crayzyMed]

Originally Posted by miko

I want to try trivastal (piribedil) too, becouse on ropinrole I have a sleep attacks :f And it's have vasodilation effect. Dopamine agonists works good on my anhedonia.

Heres a list of trivastal experiences, it looks pretty good, studies look promosing too:

Psychomotor and cognitive effects of piribedil,
a dopamine agonist, in young healthy volunteers
by
Schuck S, Bentue-Ferrer D, Kleinermans D,
Reymann JM, Polard E, Gandon JM, Allain H.
Laboratoire de Pharmacologie Experimentale et Clinique,
Universite de Rennes I - Faculte de Medecine,
CS 34317, 35 043 Rennes cedex, France.
Fundam Clin Pharmacol. 2002 Feb;16(1):57-65

ABSTRACT

Piribedil is a dopamine agonist acting on D2 and D3 central nervous system dopamine receptors. This drug has been administered to 12 young healthy male volunteers (age 22 +/- 2 years) according to a single center randomized, double-blind, two ways cross-over, placebo controlled trial, including a washout period of one week. Placebo and piribedil were administered by a single intravenous infusion over 2 h (3 mg). Psychomotor performance and cognitive functions were assessed through a standardized and computerized psychometric tests battery and a continuous electroencephalogram (EEG) mapping. Piribedil improved simple reaction time (P=0.02), immediate (P=0.045 and 0.004), and delayed free recall (P=0.05), dual coding test (P=0.02) and increased theta and fast beta waves on the EEG (P < 0.05 and 0.001, respectively). No deleterious effect was observed on the tests exploring attention and concentration via the other procedures. It is concluded that a single intravenous perfusion of piribedil 3 mg improves alertness and the information processing speed within the central nervous system, in healthy volunteers.

Great Stuff. 50 mg first thing in the morning.

Hey everyone,

It's been a long time since I've posted here. Anyways, has anyone else ever tried Trivastal(piribedil)? I tried it for the first time today. I've noticed better concentration, improvement with information processing, verbal fluency, etc. It's completely different than any other dopamine agonist I've tried. Hopefully, the effects continue. Has anyone had experience with it?

Yes, I've been using Trivastal (piribedil) for quite some time, and have to say its the best dopaminergic drug out there, without side-effects. Pretty much same effects as yours + libido over the roof ;-)

Yeah, I've found most dopamine agonists to be somewhat sedating(Mirapex, Bromo, Cabergoline). I don't notice any sedating effect with Trivastal though. I think it's because of the additional noradrenergic properties. I'm interested to hear if other people have a similar experience.

I tried trivestal briefly, and I HATED it. Both times I tried it I descended into a hopeless depression-like feeling which lasted for the rest of the day. I lied huddled under blankets shivering on my couch, eating take out food with a kind of desperation. To each his own, I have 27 tablets left if anyone (US preferred) wants to take them off my hands for $45 shipping included.

ok...took it 50mg dose with breakfast before going to work.

30-40 minutes later i star getting ranndom erections on the office.

about 1 hour after dosing i star getting anxius and feeling not good...with heart palpitations and ****.

2 hours later anxiousness stopps and heart returns to normal...now all i am feeling is a incredible focus energy and actually wanting some work to do ( had no players to be consulted today) I generally don´t want extra work because this soccer players are some times really retarded and givving dietarie advices for them is energy demending as really stressful. I allso felt a burst of happyness. this drug made me some how more happy...i don´t know the reason for that though...I just felt good..

I just felt a really incredible burst of energy and focus power on this drug. more cordanation. more concentration, more libido......i really liked......really really clean....no side effects felt( only at the begining of the onset).

tomorrow i will dose again...i bought 15 pils...gonna use them all and report overall satisfacton..but as for now i really enjoy it.

50mg feedback:

I took it just with my regular vitamins, and a little green tea.

It feels like C+Y almost, no measurable increase in focus, feel a lot more agitated and "excitotoxic" and worse, I feel no serotonine whatsoever. dissapointed thus far. what is the HL of this compound? this could be becasue I'm exausted mentally today but heck this is why I need this :-)

I'm 61. I've been retired since '99. At this age, things are wearing out. I was having mild depression with melancholy. I had no dreams. I was sleepy, had no motivation, and lethargic. I was drinking coffee all morning. As we age, we loose mental sharpness and memory skills. I felt like I was mentally dead.

I began to use 100mg of 5-HTP about one hour before bed. The depression symptoms left within several days. I began dreaming again. I began to sing a little to myself during the day.

During the past year, I have used 2.5 mg / day of Eldepryl from time to time as a neuro-protective. I observed no effect from that small dose.

For the past 45 days, I've been using the above plus 50mg of Trivastal. I observed little or no effect from the Trivastal until after about 30 days. I haven't had that exceptional experience as Dan described, but now, my brain is beginning to be quick, sharp, alert, and with improved memory. It feels like it did 20 years ago. The manufacturer, Servier, recommends using Trivastal for at least 3 months.

In addition to the above, I've been using undenatured whey protein for breakfast, the usual multi-vitamins/minerals, and ~100mg Idebenone / day. That Idebenone really boosts energy levels and puts lead in your pencil.

I use medicine for mild high blood pressure and cholesterol. None of the above has any effect on pressure or blood profile. When the weather permits, I walk about an hour / day. Recently, I've felt so good, that I've begin to work out with weights.

I feel like the age clock has been turned back. I feel mentally and physically energetic, optimistic, and happy. I've grown tired of the retirement life and enrolled to get a teaching certificate.

None of this stuff has potential for euphoria, but it certainly seems to have brought me back from the dead, and that's enough euphoria for me.

Well this morning I downed one 50mg pill and so far i have been slightly dissapointed...it's hard to describe what i'm feeling slight energy but also with the occassional yawn but i am noticing when typing this the words come out a little bit better but that could be placebo...who knows

Would it be bad to throw in 500mgs of DLPA in hope that it'll synergize with it?

I might post at the end of the day and give a full evaluation of it!

[rocknroll714]

Regarding anticholinergics and depression:

Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine: A Randomized, Placebo-Controlled Clinical Trial

CONTEXT: The need for improved therapeutic agents that more quickly and effectively treat depression is critical. In a pilot study we evaluated the role of the cholinergic system in cognitive symptoms of depression and unexpectedly observed rapid reductions in depression severity following the administration of the antimuscarinic drug scopolamine hydrobromide (4 microg/kg intravenously) compared with placebo (P = .002). Subsequently a clinical trial was designed to assess more specifically the antidepressant efficacy of scopolamine. OBJECTIVE: To evaluate scopolamine as a potential antidepressant agent. DESIGN: Two studies were conducted: a double-blind, placebo-controlled, dose-finding study followed by a double-blind, placebo-controlled, crossover clinical trial. SETTING: The National Institute of Mental Health.Patients Currently depressed outpatients aged 18 to 50 years meeting DSM-IV criteria for recurrent major depressive disorder or bipolar disorder. Of 39 eligible patients, 19 were randomized and 18 completed the trial. INTERVENTIONS: Multiple sessions including intravenous infusions of placebo or scopolamine hydrobromide (4 microg/kg). Individuals were randomized to a placebo/scopolamine or scopolamine/placebo sequence (series of 3 placebo sessions and series of 3 scopolamine sessions). Sessions occurred 3 to 5 days apart. MAIN OUTCOME MEASURES: Psychiatric evaluations using the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale were performed to assess antidepressant and antianxiety responses to scopolamine. RESULTS: The placebo/scopolamine group showed no significant change during placebo infusion vs baseline; reductions in depression and anxiety rating scale scores (P<.001 for both) were observed after the administration of scopolamine compared with placebo. The scopolamine/placebo group also showed reductions in depression and anxiety rating scale scores (P<.001 for both) after the administration of scopolamine, relative to baseline, and these effects persisted as they received placebo. In both groups, improvement was significant at the first evaluation after scopolamine administration (P< or =.002). CONCLUSION: Rapid, robust antidepressant responses to the antimuscarinic scopolamine occurred in currently depressed patients who predominantly had poor prognoses.

The Antidepressant Effects of Anticholinergic Drugs

Acetylcholine is a neurotransmitter that is important for communication between neurons and muscle, is involved in direct neurotransmission in the autonomic parasympathetic nervous system, and has been implicated in cognitive processing, arousal, and attention in the brain. The cholinergic-adrenergic hypothesis of mood disorders states that a given affective state might represent a balance between central cholinergic and adrenergic neurotransmitter activity in those areas of the brain regulating moods. According to this hypothesis, depression would be the clinical manifestation of a state of cholinergic dominance, whereas mania would reflect adrenergic dominance. On the basis of this hypothesis, anticholinergic drugs have been investigated as potential treatments for depression, but study results have not shown consistent antidepressant effects. However, the dosage dependency of scopolamine's effect across different studies and the lack of antidepressant effects with other anticholinergic drugs suggest that a specific muscarinic receptor subtype might be most relevant to the potential antidepressant mechanism of action of anticholinergic drugs.

Scopolamine As An Antidepressant Agent: Theoretical and Treatment Considerations

[no abstract available - click here for full-text; enjoy :) (yay for piracy)]

In summary, the dopamine and acetylcholine systems are negatively cross-linked. It's more complicated than simply one goes up, the other goes down, however, but regarding the net effect, it's generally a sufficient way of looking at the picture. Some distinctions.. predominantly, D1-like (D1 and D5) receptors enhance acetylcholine release, D2-like (D2, D3, and D4) receptors inhibit acetylcholine release, M1, M2, and M5 receptors inhibit dopamine release, and M3 and M4 receptors enhance dopamine release. It's still even more complicated than that by far, but I suppose that's a relatively good overview.

Note that not all anticholinergics are significantly antidepressant. If you read the study abstracts I included above you'd have noticed that. It depends on their varying selectivities for the different muscarinic receptors.. for example, the ones that prefer M1, M2, and/or M5 likely have something to do with antidepressant response, whereas M3 and/or M4 probably have an opposing role.

Unfortunately, although many, many anticholinergics are known, their affinities and selectivities for the different muscarinic receptors has been studied very, very little, and it's difficult to say currently what they're doing exactly. All we can really go on for now is that general acetylcholine depletion results in antidepressant and anxiolytic effects, general acetylcholine enhancement results in depressive and anxiogenic effects, and certain muscarinic anticholinergics like scopolamine produce antidepressant and anxiolytic effects, while most others do not.

In any case, I don't suggest anyone here run off and obtain anticholinergics for therapeutic purposes. Dan made a really good analogy with his comparison to alcohol example; anticholinergics aren't anywhere near as nice as alcohol though, but their side effect profiles certainly rival it. Take my word for it.. I've tried several anticholinergics, including dimenhydrinate, doxylamine, and promethazine, some of which at very high doses that sent me moderately delirious, and none of them were really appealing to me at all. Scopolamine might prove to be different but I still wouldn't recommend it for obvious reasons (side effects).

[rocknroll714]

Originally Posted by honastud

whats the verdict? ^ I'm ready to toss a couple of these back?

Go for it and tell us what happens!

Originally Posted by Freesix88

Pramipexole

I've seen that thread already. I'm asking about your experience (or whoever it was I was asking about).

Originally Posted by euphoria

If anyone is taking pramipexole, they should be aware that NMDA antagonists are essential to any dopaminergic regimen, and also that pramipexole will make you feel awful unless you use high doses and/or wait through several weeks of the bad feelings.

Dan, I'm inclined to disagree. NMDA antagonists are known to modulate dopamine release both positively and negatively (pro-D1-like, anti-D2-like), and as evidenced by the dysphoria and apathy caused by high dose dissociatives like ketamine (which is even a dopamine reuptake inhibitor yet the effects persist..), I believe that the net effect is an inhibition and that it's probably best to stay away from them. Not to mention their tolerance-inhibiting properties have only officially been demonstrated to apply to opioids and not stimulants, thus far at least.

Originally Posted by Edwin

I've read up on Pramipexole, but is it due to autoreceptor agonism that you have an initial period of lowered dopamine activity?

Yes, exactly right, until the autoreceptors downregulate over the course of 2-4 weeks or high enough doses in which would also agonize postsynaptic receptors and overcome the inhibition are used.

Originally Posted by miko

Something about acetylcholine and dopamine:

"We report that M1 deficiency leads to elevated dopaminergic transmission in the striatum and significantly increased locomotor activity. M1-deficient mice also have an increased response to the stimulatory effects of amphetamine. Our results provide direct evidence for regulation of dopaminergic transmission by the M1 receptor and are consistent with the idea that M1 dysfunction could be a contributing factor in psychiatric disorders in which altered dopaminergic transmission has been implicated."

"The Acetylcholinesterase Inhibitor Galantamine Inhibits d-Amphetamine-Induced Psychotic-Like Behavior in Cebus Monkeys"

"Multiple Muscarinic Acetylcholine Receptor Subtypes Modulate Striatal Dopamine Release, as Studied with M1-M5 Muscarinic Receptor Knock-Out Mice"

"Interestingly, in vivo microdialysis studies showed recently that M1 receptor-deficient mice have significantly elevated levels of extracellular dopamine in the striatum, probably because of increased dopamine release "

So maybe acetylcholine hyperactivity blocks dopamine release?
And that's why muscarinic receptors blocker Oxybutynin works on my depression...

Correct, see my above post. Curious about oxybutynin, it may have selectivity similar to scopolamine based on it working for your depression. Can you describe the effects (trip report please :p)?

Originally Posted by euphoria

I know about the dopamine-acetylcholine link, but how can you think blocking acetylcholine is a good method of treating depression? It may make you a bit happier, but also very stupid and forgetful. Why not increase both dopamine and acetylcholine? Then you'll fight depression without potential for psychosis.

There's still some potential for psychosis I believe. Don't forget about NMDA. Not to mention if cholinergics produced significant antipsychotic effects in the treatment of schizophrenia you'd think someone would have investigated them as pharmaceuticals by now (though maybe they do and simply nobody has done anything about it yet, who knows). Also, I'd say anticholinergics have some promise for treating depression, as evidenced by scopolamine working well even for treatment-resistant patients. Of course the field is still in its infancy, however..

Originally Posted by itsamystery

Please try a beta blocker (Inderal). Your doctor will easily prescribe it for social anxiety--you can take a small dose every day for your situational phobias--it works all day, doesn't cause addiction, is very inexpensive. It's been a lifesaver for me. Minimal side-effects as the low doses that it takes to prevent blushing, hand tremors, etc which plagued me for years.

Beta blockers generally suck but I suppose they have their place. They're really only good for physical/performance anxiety if you ask me. I certainly don't like their cognitive effects.. as I've mentioned around here before, all three of the beta-adrenergic receptors are antidepressant and to my knowledge play a positive role in dopamine efflux. Blocking them is likely to result in apathy/anhedonia and antisocial effects, despite paradoxical anxiolysis. A peripherally-selective beta blocker sounds somewhat nice though..

[rocknroll714]

Originally Posted by crayzyMed

Trivastal its on its way for me, its a non sedating dopamine agonist, so i wouldnt have to get trough all those side effects before it works.

Very interesting thread!

Also, shouldnt a low dose sulpiride block the sedation dopamine agonists cause? Because it blocks the autoreceptors that also seem to respond to a dapomine agonist.

D2-like receptor agonists may actually be somewhat sedating, which makes sense based on their intrinsic inhibitory nature (D1-like on the other hand are excitatory and therefore predominantly stimulating in contrast, hence via the net effect, DRIs/DRAs are classified as stimulants). I took a high dose D2-like agonist once and experienced marked sedative effects which were not autoreceptor-mediated (the dose was so high I vomited, hence indication that I got postsynaptic receptors pretty good too). Physical euphoria, semi-opioid-like analgesia, and anxiolysis were all present as well. My pharmacology-unfriendly buddy who tried it with me actually thought it was a painkiller of some kind, but it was definitely a D2-like agonist. It was very nice for social situations.. I'd say my SA was cut down by at least 50%. I didn't really like it for the most part though, and the nausea was horrid (I vomited with nothing in my stomach -- bile, ewww). My friend didn't really like it much either. This was a fairly ambiguous research chemical however; I'd still love to try pramipexole, piribedil, rotigotine, or ropinirole; pramipexole seemingly being the best of the lot.

As for taking a low dose D2-like antagonist to block autoreceptors in combination with a moderate-high dose D2-like agonist, absolutely not! If combined, they'll directly and dose-dependently antagonize one another. It's a matter of preference and occupation; ligands preferentially occupy autoreceptors; with an agonist occupying the autoreceptors to a high extent and postsynaptic receptors to a low extent, the antagonist will prefer the postsynaptic receptors due to the high competition at the autoreceptors, and it'll significantly reduce postsynaptic activation and therefore positive therapeutic benefits. It simply does not work the way you're thinking.

Originally Posted by miko

I want to try trivastal (piribedil) too, becouse on ropinrole I have a sleep attacks :f And it's have vasodilation effect. Dopamine agonists works good on my anhedonia.

An experience report would be delightful :D

I'd like to see more reports related specifically to SA with these agents.

[miko]

Yes,yes,yes. Don't compare beta blockers with antimuscarinic agents! Beta blockers doing just a little for my SA - lower heart rate and less sweating. Anticholinergic / antimuscarnic doing something other. It's hard to describe (especially to guy from east-my english is not good :f), but i feel dopamine on this meds - like from no other med - wellbutrin (just a little, and noradrenaline makes me anxious).

Dopamine agonists it's good too. Many things makes me happy, and I feel pleasure from music, sport and other things. Like in the past...

Oxybutynin is very similar to scopolamine. It's blocks M1,M2,M3, not only M1. And it's cheap

I'm reading now interesting text above - thanks for it.

"D2-like (D2, D3, and D4) receptors inhibit acetylcholine release, M1, M2, and M5 receptors inhibit dopamine release, and M3 and M4 receptors enhance dopamine release." - very interesting. So thats why block of M1,M2 can release dopamine? And maybe D2 dopamine agonist can block acetylcholine release.

"All we can really go on for now is that general acetylcholine depletion results in antidepressant and anxiolytic effects, general acetylcholine enhancement results in depressive and anxiogenic effects, and certain muscarinic anticholinergics like scopolamine produce antidepressant and anxiolytic effects, while most others do not." -true

That's why tricyclic have antidepressants effect if SSRI don't work. But taking it for a long time... a little scary...

[Medline]

Originally Posted by miko

"All we can really go on for now is that general acetylcholine depletion results in antidepressant and anxiolytic effects, general acetylcholine enhancement results in depressive and anxiogenic effects, and certain muscarinic anticholinergics like scopolamine produce antidepressant and anxiolytic effects, while most others do not." -true

That's why tricyclic have antidepressants effect if SSRI don't work. But taking it for a long time... a little scary...

Most TCAs work as NRIs which might be one reason they work when SSRIs don't. I also don't think that general acetylcholine enhancement results in depressive and anxiogenic effects.

[jim_morrison]

Not to mention that most TCA's also cause 5HT-2 blockade, which may be another reason why they may work when SSRI's don't.