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    Senior Member KimberCT's Avatar
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    I'm having a hard time figuring this one out. Amitriptyline and nortriptyline when added to my SSRI (haven't tried them alone) immediately eliminate every trace of anxiety I have. I sleep better, wake up with energy, and don't have that constant feeling of panic that I do without it.

    Unfortunately, they also come with nasty side effects. At 25mg I get chest pain, urinary retention, and epididymitis (?!).

    I'm trying to track down what is responsible for amitriptyline's anxiolytic effect and/or what's causing the side effects. I'm pretty sure it's not a1 or 5-ht2c antagonism, nor norepinephrine reuptake since I've tried things like mirtazapine/mianserin, carvediol. Sigma receptor agonism? Channel blocking? Muscarinic receptor antagonism?

    Anyone here have any ideas?

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    Senior Member Ex Dubio's Avatar
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    <div class='quotetop'>QUOTE (KimberCT @ Jan 22 2010, 10:24 AM) <{POST_SNAPBACK}></div><div class='quotemain'>I'm having a hard time figuring this one out. Amitriptyline and nortriptyline when added to my SSRI (haven't tried them alone) immediately eliminate every trace of anxiety I have. I sleep better, wake up with energy, and don't have that constant feeling of panic that I do without it.

    Unfortunately, they also come with nasty side effects. At 25mg I get chest pain, urinary retention, and epididymitis (?!).

    I'm trying to track down what is responsible for amitriptyline's anxiolytic effect and/or what's causing the side effects. I'm pretty sure it's not a1 or 5-ht2c antagonism, nor norepinephrine reuptake since I've tried things like mirtazapine/mianserin, carvediol. Sigma receptor agonism? Channel blocking? Muscarinic receptor antagonism?

    Anyone here have any ideas?</div>

    Amitriptyline has so many actions, you're going to have a hell of a time pinpointing it. Here's a few thoughts.

    Sigma-1 agonism: have you tried sertraline? Did it have effects that resembled amitriptyline?

    Sodium channel antagonism: ever tried any anticonvulsants like oxcarbazepine or lamotrigine? This are known for "brain-quieting" properties and function as anxiolytics in some.

    Calcium channel anagonism: kind of a far-fetched idea, but amitriptyline also hits Ca2+ channels; calcium channel blockers have shown some antidepressatn efficacy IIRC...ever tried one?

    NMDA antagonists: amitriptyline modulates NMDA at the same site as PCP, if I recall; ever tried other NMDA antagonists to compare effects on your neurophysiology?

    5-HT2C/2A, alpha1, H1 antagonism: compare with trazodone. If trazodone elicits similar anxiolytic effects, you can probably narrow down the probable pathways. If not, you still can eliminate these from the list.

    Then there's the fact that amitriptypline agonizes the BDNF receptor binding sites, muscarinic receptors, and 5-HT6/7 receptors, the latter of which is simply not that well investigated.

    I figure you probably know most of this, but your best bet is to compare and contrast with drugs that more specifically target pathways activated by amitiptyline.

    Alternatively, if you want to go the polypharmacy route, try grabbing agonists of the receptors antagonized by amitriptyline and see if they reduce anxiolytic efficacy.


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    Senior Member KimberCT's Avatar
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    Yeah, I've been going the trial and error route for awhile now without any luck and right now I'm looking for possible clues. I wasn't aware of the NMDA antagonism. Maybe it's time I finally add some DXM to my memantine.

    I have the following coming to me soon...

    Diltiazem for calcium channel antagonism. Oxcarbazepine for sodium channel antagonism. Trazodone for more 5-HT2 testing. Cyclobenzaprine because of its effects on the locus coeruleus.

    I have to locate some scopolamine to test the muscarinic receptors.

    I can probably rule out 5-HT7 as mianserin hits it with higher affinity than amitriptyline. Sigma-1 is a possibility. I haven't tried sertraline, but I do take citalopram which I think is also a sigma-1 agonist.

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    Senior Member Ex Dubio's Avatar
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    <div class='quotetop'>QUOTE (KimberCT @ Jan 22 2010, 01:22 PM) <{POST_SNAPBACK}></div><div class='quotemain'>Yeah, I've been going the trial and error route for awhile now without any luck and right now I'm looking for possible clues. I wasn't aware of the NMDA antagonism. Maybe it's time I finally add some DXM to my memantine.

    I have the following coming to me soon...

    Diltiazem for calcium channel antagonism. Oxcarbazepine for sodium channel antagonism. Trazodone for more 5-HT2 testing. Cyclobenzaprine because of its effects on the locus coeruleus.

    I have to locate some scopolamine to test the muscarinic receptors.

    I can probably rule out 5-HT7 as mianserin hits it with higher affinity than amitriptyline. Sigma-1 is a possibility. I haven't tried sertraline, but I do take citalopram which I think is also a sigma-1 agonist.</div>

    Sounds like you're on top of it. IIRC though, sertraline is something like a 10x stronger sigma-1 agonist than escitalopram/citalopram, at least at normal dosage.

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    Senior Member KimberCT's Avatar
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    <div class='quotetop'>QUOTE (Ex Dubio @ Jan 22 2010, 03:51 PM) <{POST_SNAPBACK}></div><div class='quotemain'>Sounds like you're on top of it. IIRC though, sertraline is something like a 10x stronger sigma-1 agonist than escitalopram/citalopram, at least at normal dosage.</div>

    Hmmm, I think I'll give it a try... it shouldn't be difficult to switch from citalopram.

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    Senior Member MeDieViL's Avatar
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    Afobazol is a sigma agonist, altough its also a MAOA inhibitor so you cant add it to a SSRI.
    One
    Exceeding, going further, crossing boundery's, taking risks greater then most, next level.

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    Senior Member KimberCT's Avatar
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    Well, looks like I can eliminate trazodone and atomoxetine from my list.

    I tried 20mg atomoxetine Friday night and it just made me sleepy and anxious... plus a decent headache the following day.

    I took 50mg trazodone last night. I thought this stuff was supposed to be sedating... I laid awake for a few hours before falling asleep. I felt like hell all day today which I imagine is due to the mCPP metabolite. I guess that means that 5-HT2C plays at least a partial role in my anxiety/brain fog.

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    <div class='quotetop'>QUOTE (Ex Dubio @ Jan 22 2010, 10:23 AM) <{POST_SNAPBACK}></div><div class='quotemain'>Amitriptyline has so many actions, you're going to have a hell of a time pinpointing it. Here's a few thoughts.</div>

    Perhaps because 'pinpointing it' is looking for a tree in a situation where the aesthetic appeal is derived from the forest as a whole.

    Phenomenological affect doesn't correspond to any particular receptor site. In all likelihood, it's some function of perception, memory consolidation and retrieval, turning the gears of allostasis. You see all kinds of "exciting new site-specific agents" come down the pipe-line; how many of them ever amount to shit? For depression, the cluster-fuck drugs, e.g., amp, MAOi, nicotine, etc., still reign supreme (though lamictal shows quite a bit of promise). Sedating TCA's work awesomely well for anxiety, without the quasi-manic behavior that comes along with benzodiazepines.

    Personally, I think people need to focus more on fixing their lives than fixing their heads. What you see in these fora is just like Intervention, played over and over again... person gets isolated, treated, seems happy and fine; put them out into the day-to-day and suddenly "it stopped working." A plant won't thrive in toxic soil, no matter how much fertilizer you give it. Neither will people. People have preferences. When those preferences are frustrated, people experience distress. That's just reality. Every time I see someone looking exceptionally hard inside, my eye wanders to their outside, and my evaluation is usually, "god.. who wouldn't be miserable living in those conditions?"

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    An old post, but thought I should point out research is suggesting Sertraline is actually a Sigma 1 Antagonist, while Fluvoxamine (Luvox) is a Sigma 1 Agonist.

    http://www.bentham.org/cmccnsa/openaccessa...sa9-3/0006T.pdf

    http://www.annals-general-psychiatry.com/content/9/1/23




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    It's anticholinergic effect !!! Always makes me calm and in good mood. Don't know why, but to find it out I tried oxybutynin (M1,M2,M3 cholinergic antagonist) and it's work even better. For me anticholinergic drugs have great effect, but higher doses makes poor concentration and coordination.

    Both this drugs have hard anticholinergic effect. Try oxybutynin to figure out.

    http://cme.medscape.com/viewarticle/545534

    If you want to try sigma agonism, try opipramole.

  11. #11
    Senior Member KimberCT's Avatar
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    <div class='quotetop'>QUOTE (Endogenous Variable @ Jun 29 2010, 11:50 PM) <{POST_SNAPBACK}></div><div class='quotemain'>An old post, but thought I should point out research is suggesting Sertraline is actually a Sigma 1 Antagonist, while Fluvoxamine (Luvox) is a Sigma 1 Agonist.

    http://www.bentham.org/cmccnsa/openaccessa...sa9-3/0006T.pdf

    http://www.annals-general-psychiatry.com/content/9/1/23</div>

    Did not know that. *Thanks for those links.



    <div class='quotetop'>QUOTE (miko84 @ Jun 30 2010, 12:49 AM) <{POST_SNAPBACK}></div><div class='quotemain'>It's anticholinergic effect !!! Always makes me calm and in good mood. Don't know why, but to find it out I tried oxybutynin (M1,M2,M3 cholinergic antagonist) and it's work even better. For me anticholinergic drugs have great effect, but higher doses makes poor concentration and coordination.

    Both this drugs have hard anticholinergic effect. Try oxybutynin to figure out.

    http://cme.medscape.com/viewarticle/545534

    If you want to try sigma agonism, try opipramole.</div>

    Yeah, I test the anticholinergic theory awhile back. *I used scopolamine, but all it did was sedate me and then make me nauseous when it wore off.


    Before I gave up trying to figure it out, I was leaning toward it being the channel blocking properties of amitriptyline.


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    Senior Member eclypz's Avatar
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    <div class='quotetop'>QUOTE (KimberCT @ Jun 30 2010, 04:32 AM) <{POST_SNAPBACK}></div><div class='quotemain'>Yeah, I test the anticholinergic theory awhile back. *I used scopolamine, but all it did was sedate me and then make me nauseous when it wore off.</div>

    Section8 had a really good point. In addition to his larger message about tending to your own garden before worrying about what medicine to take (which i think is well deserved and yet this forum is also about chemicals and understanding them so there's going to be some tradeoffs) he also made a point about the symphony of effects that one medicine has.

    If ever there was a dirty drug it's amitryptilline. To say the reason it gave you a profound sense of anxiolysis is because of one or the other specific channel is very shortsighted. Now I sure as hell don't know as much about all the specifics of neurochemistry like ex dubio and while he is a scientist that likes to poke and prod these very specific receptors and agonists, it's the whole thing that makes it so powerful for you. It's also the novelty. Your brain experiences something it hasn't before and for quite some time that's all it takes to be wrapped in a cocoon of satisfaction.

    Scopolamine is another dirty drug. Hell, I think it's closely related to a very powerful poison isn't it? So using that as a test to see if reduced cholinergic activity is the cause of your calmness is a bad move too.

    Hell even something pretty straightforward like amphetamine can be ruined by blocking endorphins. It all comes down to the specific way the drug rubs your brain and your brain's response to that rub. Nicotine made me throw up when I first tried it. Couldn't stand it. But I kept insisting and eventually nicotine was an anxiolytic for me. It was pleasurable because my brain decided to make me think it was, once it needed that stimulation to keep dopamine levels going properly.

    So I guess I'm saying

    1 ) Some drugs work well because they play a chord of effects, simultaneous agonism and antagonism of certain receptors that lead to their desired effect.

    2 ) Sometimes the positive effect we receive from a chemical isn't the direct effect of the chemical itself but our brain rewarding us for finding such a chemical and giving it to ourselves.

  13. #13
    Senior Member KimberCT's Avatar
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    All true, however, even if it is several of amitriptyline's properties that create its anxiolysis, I'm sure there are several others that are completely unnecessary. Since I posted this 6 months ago, my investigation into amitriptyline eventually led me to the regime I'm on now. One that is better than amitriptyline and also lacking the nasty side effects.

    I also wouldn't call scoplamine a dirty drug at all. It's quite selective for muscarinic receptors.

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