MAOI tales - of (ir)reversible ones & Moclobemide + Selegiline

[dopamimetic]

Everywhere one gets warned of MAOIs, their potentially life-threatening side effects when combined with wrong drugs or tyrosine rich food and so on - the one or other not even knowing that there is a difference between MAO-A and MAO-B (remembering a dialogue with an old school chief of a big pharmacy) - on the other side, many people who desperately tried all these modern prescription psychoactives are promoting Phenelzine (Nardil®) or Tranylcypromine (Parnate®) despite the dietary restrictions these meds seem to require.

Then, oddly enough, Tranylcypromine is a monoamine / catecholamine releaser itself (with 10% the potency of d-amph) and is safe enough that some people got addicted to it and took massive dosages without harm (not counting withdrawal after doctors stopped supplying them with the drug- but that'd be the same with good old amphetamine).

Also, Selegiline being an irreversible MAOB-I, is said to reduce amphetamine neurotoxicity, but also to possibly potentiate its effects. As long as the dosage is kept below reaching MAO-A relevant levels, Selegiline is a relatively save drug.

Then we do have Moclobemide. They say it's a reversible MAOA-I, that you're able to eat anything including high-tyrosine food.. and it's got a half life of somewhat around 1,5 hours. But the effects last all day long - I really don't understand how that one works. Maybe it binds to the MAO enzyme but will dissociate after some time, or the binding gets destroyed by some other enzyme, whilst the drug itself gets excreted quickly.. I don't know.

But now the point - these old irreversible MAOIs seem to be more effective than Moclobemide (where some people even do not get any benefit from). So why not just combine Moclobemide with (low to moderately dosed) Selegiline? There's even a study about this combo, looks relatively safe and these two drugs potentiate each other. Something like a real "California Rocket Fuel" thingy.

I'm currently on 150mg of Moclobemide per day and recently added 2.5mg Selegiline to it. Instantly my mood, inner feelings changed to the better. I feel now like in the good old days when the SSRI drugs were new to my body and did their work. Probably even (much) better, as there are NO side effects, no nausea, no tachycardia, no appetite suppression (I even have more appetite than before- a good thing for me, being on the lowest end of BMI- comparable to the time I was on d-amphetamine, what made me hungry too). Just- ok, relatively heavy- insomnia. But when I finally fall asleep, the sleep is SO much more refreshing than the years ago. I wake up after seven or eight hours and am wide awake. No more "oh no, already morning... shit, do I really have to stand up".

Have to say that I am taking parallel Memantine (Ebixa®- damn expensive when oversea generics aren't available) 30-40mg/d (since quite long time, helps me stabilising my mood and stops these "cascades" when I get angry.. also probably does a good thing in keeping tolerances down, be it amphetamine or benzodiazepines. Only that nobody seems to use this med, despite many positive studies available) and Clonidine at 150 mcg/day- that one to counter act the imbalance between norepinephrine and serotonin caused by the lasting after effects /tolerance of taking Venlafaxine (Effexor®) for too long, and for sure that I stupidly combined it with DXM for some months added its part to the whole disaster. Earlier, taking a 150mcg pill of Clonidine, it put me asleep. Currently, it just takes the edge off the stimulation.

But enough personal stuff, sorry for that- just wanted to explain the background.

How safe / dangerous is this combination? Would I go better with taking straight Tranylcypromine, or is that maybe really the safer way...? Is that diet stuff really that important when taking lowish dosages?

Noticed that I am even able to take Amphetamine (2-F[M]A or d-Amp) in low dosages without problems or potentation whilst being on these meds. Strange enough. Coffee doesn't seem to be a problem either.

Now I'm really curious about your answers, maybe someone is able to shed some light on the biochemical / pharmaceutic side of all that. And if this does not fit into Advanced Drug Discussion, I do apologise and feel free to move it to a better category.

 

[sekio]

You're going to get burned taking 2 MAOIs and amphetamine at once.

 

[dopamimetic]

Do you mean hidden / unnoticed neurotoxicity, overexcitation etc.. or acute things like blood pressure crisis or serotonin syndrome?

I know it's playing with fire. It just does not feel like that.. I know that subjective feelings mean nothing, but on the other side I'm a somewhat sensible person, things (drugs, pharms) often felt "wrong" or toxic long before any clinical symptoms manifested. Blood pressure and pulse are normal, pulse was yesterday even (slightly) lower than usual...

 

[atara]

I imagine you're currently okay with taking stimulants because you still have some level of active monoamine oxidase in your brain. Selegiline is an irreversible inhibitor so its effects are cumulative and eventually you will almost certainly notice differences in amphetamine pharmacology.

It would be extremely stupid to continue taking amphetamine, based on what we know about dopamine metabolism. You could easily set yourself up for a hypertensive crisis.

Would I go better with taking straight Tranylcypromine, or is that maybe really the safer way...? Is that diet stuff really that important when taking lowish dosages?

Probably a question your doctor should answer, not us.

 

[dopamimetic]

I imagine you're currently okay with taking stimulants because you still have some level of active monoamine oxidase in your brain. Selegiline is an irreversible inhibitor so its effects are cumulative and eventually you will almost certainly notice differences in amphetamine pharmacology.

Thanks for your answer - this is about what I had in my mind too. That dosage is -very- important here, and also the thing that I'm currently just having less active MAO enzymes, but if it will build up to a complete blockade, the problems will rise.

It would be extremely stupid to continue taking amphetamine, based on what we know about dopamine metabolism. You could easily set yourself up for a hypertensive crisis.

I remember an old thread here about potentiating stimulants (mostly MPH, but also d-amph) with selegiline, of course with dosage titration from very, very few mg or even mcg's. Other thing is, literature says that blocking MAO-B could reduce amphetamine neurotoxicity, this does not really fit in here...? But of course, my target is to get to a point where I don't need these psychostimulants anymore.. I am already using microdosages (3-5 mg's of 2-FMA) and will go without tomorrow.

Sad thing, to chase the state of mind I had -before- they put me stupidly on psychopharms ... tried tapering down & stay sober for months, nearly a year-then the panic attacks got so worse that I was willing to take anything that helps...and so I was very quick back in the pharm's mill.

But back to the pharm talk. I really don't understand Moclobemide's way of action. What makes it reversible, and why are biogenic amines in food so much less dangerous than with an irreversible one? Is "reversible" maybe even the wrong term and it should be called "partial"?

Probably a question your doctor should answer, not us.

If I just had such a doctor, with whom I could talk about these things... then I would not ask here. It is very difficult to get audience for the more involved doc's.. and too many told me (or others I knew / heard from) too much bullshit. Some literally threw you out of their building if you ask too much "wrong" or critical / detailed questions about these meds that in the end I have to put into my body.. If I wouldn't have taken over by myself, I'd be still on heavy neuroleptics, probably dyskinetic and cognitively mud. Saw too much people ruined that way.

(Of course, playing guinea pig whilst being a half-educated layman is not better at all, soberly considered...)

 

[Abject]

I was on Moclobemide at 600mg for 2 months and it didn't really help me.
I stopped taking it for a bit, and then I decided to dose 1.5-1.8g and after about 20 minutes started feeling quite racey
it's hard to explain, I had to sit there and listen to someone talk and it was excruciating
this passed and then I felt somewhat boosted, reminded me of a low dose of DXM (3mg/kg ish)

anyway, I might experiment with high doses more spread out, as I have 2 repeats left.
maybe 900mg in the morning and 900mg at night

 

[ebola?]

It just does not feel like that.. I know that subjective feelings mean nothing, but on the other side I'm a somewhat sensible person, things (drugs, pharms) often felt "wrong" or toxic long before any clinical symptoms manifested. Blood pressure and pulse are normal, pulse was yesterday even (slightly) lower than usual...

Not too veer into scare tactics, but these are the things that hypertensive crises are made out of. Multiple ADD regulars have incurred hypertensive crises on fairly carefully measured doses of stimulants and selegiline, let alone adding another MAOI to the mix. If you still decide that this is something that you must do, I wrote a guide on the matter, found here:

http://www.bluelight.ru/vb/threads/...ola-and-nuke?p=7659100&viewfull=1#post7659100

Basically, you need Shulginesque titration with your stimulants of choice, not "pretty low" doses.

ebola

 

[checktest]

Funny mentioning the pulse possibly lowering. I'm on 70 of tranylcypromine, and just had my first moderate blood pressure event. (Likely from some spoiled or misprepared food, unfortunately. I have had no diet problems on the med otherwise...besides not having any of my friend's homebrew beer.)

My pulse went from an average of 100, (med again- before it used to be about 60. Orthostatic stuff) to around 60 again. BP went from 100/65 to 200?/ 115 about 10 mins after food. Not a big deal for some, but by far the only hypertensive event for me.

Pulse. Also- the reversibles don't form the same types of bonds, at doses, as the irreversibles. Tyramine will displace them, avoiding the food effect.

 

[dopamimetic]

Got off the selegiline for now, was in depressive mood again and so either the dosage was too low, or I just don´t respond well to selegiline (tried that one alone some years ago, also without success. Then I was told I probably dosed too low, but now with Moclobemide it´s not the right time to try that.)

[--edited--]

@checktest: How does tranylcypromine compare to other meds you have tried? Is it that mood brightening like described sometimes? And how long are you taking it - without strong diet, if I understand you correctly? Tranylcypromine was my favorite when decided to try a MAOI, but unfortunately was not available in the country I was that time. So I got on Moclobemide instead. Don´t know if I should up its dosage (currently 225mg/d) or if it is just "not enough" for me, especially on dopamine - Tranylcypromine seems to be somewhat like Moclobemide + low-dosed amph (70mg having monoamine releasing potency of ~7mg of Amphetamine).

--

Also- the reversibles don't form the same types of bonds, at doses, as the irreversibles. Tyramine will displace them, avoiding the food effect.

Interesting, read that just this morning on another place - so does Tyrosine have stronger affinity to the MAO-A enzyme than, for example 5-HT? Or is moclobemide by its nature weaker in its antidepressant power / inhibition of serotonine metabolism than the irreversible ones?

 

[atara]

An irreversible inhibitor does not follow the normal statistical binding laws. It is irreversible, which means that once it is attached to the enzyme, it (slowly, eventually) reacts with it, forming a covalent bond. Essentially it destroys the enzyme: once the covalent bond is formed, the Ki is zero, regardless of the affinity of the unbonded inhibitor. The body is always producing more, of course, so enzyme activity is never totally abolished, but reversible vs. irreversible is not a simple question of affinity.

http://en.wikipedia.org/wiki/Irreversible_inhibition#Irreversible_inhibitors

http://en.wikipedia.org/wiki/Diisopropylfluorophosphate#Uses_as_toxin

 

[ebola?]

But really, amphetamine (therapeutic dose) + moclobemide [+ memantine] don´t interact, at least not in a bad way.

Christ! They do interact, literally, objectively, in a way that tends to be dangerous and unpredictable. You have been lucky. Let's hope that no one follows in your footsteps.

ebola

 

[checktest]

Yeah, affinity isn't really the way to think about reversibility/irreversibility. Irreversibles deactivate the enzyme. The only usual thing is that "selective" irreversible drugs lose selectivity at higher doses, through the standard MOA.

[Also- tyramine is the one, not tyrosine. A trace monoamine versus an amino acid. Tyrosine isn't directly touched by MAO; it is broken down by tyrosine hydroxylase instead. (Although any neurotransmitter effects would be extended. I'm unsure about tyrosine supplementation- I'll admit to trying it a few times after seeing some reports and looking at a few studies, although mainly along the lines of questioning any significant effects, to be honest. Really a bad idea. I tried 500-1000mg and didn't have any positive or notable effects, or blood pressure/pulse effects. Of course, this doesn't mean anything.]

I've been on 70 of tranylcypromine for three months, barring a period of trying to increase it for about two weeks or so, and have been on the drug for 10 months. It is certainly the best single antidepressant I've been on, and the best overall for me in coming back from a level of depression when combined with 600 of lithium, but I have a lot of trouble with orthostatic side effects. I haven't had the switch on that some have had, but I've been able to work consistently and have started to get back into some things. The sleep effects take a bit of time to get used to, and you definitely have to figure out a proper time schedule for the medicine, but it really is a big hitter. Again, postural hypotension is one of the limiting factors for me. I have some weird parasympathetic/sympathetic thing going on that hopefully will get sorted out some this year. Certainly do not notice anything like an adderall effect, which was calming for me at 10-20mg. It does help social anxiety some. Just an overall range of improvements.

Meds in past: Escitalopram, Bupropion, Buspirone, Duloxetine, (Effexor), Sertraline, Lithium, Quetiapine, Clonazepam/maybe Alprazolam, Aripiprazole, Desipramine, (Unknown tricyclic), Lamotrigine. (Also Ambien, with nothing too notable.)

*Fluoxetine: Was used with wellbutrin, buspirone and lithium one time, as well as desipramine and lithium another time. Didn't notice anything until about 40mg. At 80mg it was probably the 2nd best, in combination, for the depression. Was on it for over a year. Wearing, some odd periods of mood lability at that dose, fatigue. Quite notable tinnitus, but that didn't bug me too much. I would go back on it if other things didn't pan out, to stay at a level of mid-moderate depression.

Extra:
Low-dose naltrexone: The first time I tried it, while on fluoxetine and perhaps lithium and wellbutrin, I noticed nothing whatsoever. I tried it again while on the tranylcypromine and found it to help with experiencing things. Food tasted better, colors, etc. Not sure what to really think.

 

[riloal]

dopamimetic, how are you doing? I suffer from ADHD. My regimen was Ritalin, tianeptine and memantine. It stopped working, so I decided to change all my meds. I started moclobemide two weeks ago, low dose of selegine but it stop working so I stopped the selegine. This week I restarted the memantine, I usually cycle the memantine I take three months then I stopped for one week cause i develop tolerance and then restarted with low doses until slowly I up the doses. Since started the memantine with the moclobemide i had a terrible week, hypersomnia. fatigue, depressed. I think that perhaps the combo doesn,t work. I think i,m going to stop the memantine, what,s your experiences with coblobemide and memantine?

 

[lowerthanlow]

Most people reporting about this combination seem to 1) confirm its safety and 2) nag about the hyperstimulation resulting from the increased noradrenaline (apparently both moclobemide and selegiline increase it for some reason). My guess is that what makes your combination so successful is the addition of clonidine, an anti-adrenergic, which as you said yourself would be able to take the edge off the stimulation.
I'm reading up on all of this because currently I'm in possession of p-f-deprenyl, PPAP and moclobemide and was thinking about possible combinations. If only I could get my hands on some clonidine...