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Accumulation of MAO-A inhibition with selegiline?

R

rnd.id.

Bluelighter
Joined
Jan 1, 2006
Messages
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If selegiline's mode of MAO-A inhibition is irreversible as with MAO-B (is it?), is there a danger of accumulation of MAO-A inhibition over a course of weeks?

I've been taking 2.5mg/d selegiline sublingually for 4 days now in combination with my sertraline and so far I'm still alive 8) I'm just wondering whether I'm still running the danger of suddenly getting serotonin toxicity one day.

By the way, for the female bluelighters: Selegiline's oral bioavailability increases by a factor of 10 to 20 (!) if you're taking oral contraceptives. Added the citation on WP ;)
 
At 2.5mg the selectivity will remain intact. the selegiline patch emsam doses not come in a dose lower than 6mg/24hr because any less would run the risk of NOT inhibiting MAO-A (its an antidepressant).
 
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Hmm, even with 2.5mg sublingually?

From a quick look, the literature seems a bit ambiguous about exactly how risky this is. One study find that it's ok with citalopram, others mention cases of serotonin toxicity (though I don't know whether there were cases of deadly serotonin toxicity).
 
rnd.id. said:
I've been taking 2.5mg/d selegiline sublingually for 4 days now in combination with my sertraline and so far I'm still alive 8)
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Well then stop 8)

MAOIs are no joke, and there are a 1001 other ways to cure/improve whatever it is you're trying to change with Selegiline, especially combining it with an SSRI...
 
Jamshyd:

Well, the plan is to add some dopaminergic activity to the SSRI (and maybe to get some of the serotonergic effects back). You're probably thinking that I should take DRIs instead, but atm I don't have access to those.

I know that MAOIs are no joke, but the idea is that at 2.5mg I will at least see any serotonin toxicity coming rather than instantly dropping dead.
 
Cool. Not that I wouldn't believe you, but do you have a ref for further reading? Thanks in advance :)
 
Hmm, from a quick search I can only find Hedweb's site (selegiline.com) mentioning MAO-A reversibility, and it doesn't have a citation :(
 
rnd.id. said:
If selegiline's mode of MAO-A inhibition is irreversible as with MAO-B (is it?), is there a danger of accumulation of MAO-A inhibition over a course of weeks?

I've been taking 2.5mg/d selegiline sublingually for 4 days now in combination with my sertraline and so far I'm still alive 8) I'm just wondering whether I'm still running the danger of suddenly getting serotonin toxicity one day.

By the way, for the female bluelighters: Selegiline's oral bioavailability increases by a factor of 10 to 20 (!) if you're taking oral contraceptives. Added the citation on WP ;)
Click to expand...

You would have to take over 15 mg of deprenyl or 15 mg more than 3 weeks to effect MAO-A. At your dose I would not be concerned. However I would suggest switching to a non SSRI.
 
Ah, do you mean 15mg sublingual or by patch? Big difference I think (I think I think)
 
2.5mg sublingual selegiline might be equivalent to around 14mg orally.

I assume patch would be equivalent to a higher oral dose as well, since the critical factor here is skipping first-pass metabolism with both sublingual and patch administration.
 
grue said:
2.5mg sublingual selegiline might be equivalent to around 14mg orally.

I assume patch would be equivalent to a higher oral dose as well, since the critical factor here is skipping first-pass metabolism with both sublingual and patch administration.
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Selegiline is more rapidly absorbed from the 1.25 or 2.5 mg dose of ZELAPARTM (Tmax range: 10-15 minutes) than from the swallowed 5 mg selegiline tablet (Tmax range: 40-90minutes). Mean (SD) maximum plasma concentrations of 3.34 (1.68) and 4.47 (2.56) ng/mL are reached after single dose of 1.25 and 2.5 mg ZELAPARTM compared to 1.12 ng/mL (1.48) for the swallowed 5 mg selegiline tablets (given as 5 mg bid). On a dose-normalized
basis, the relative bioavailability of selegiline from ZELAPARTM is greater than from the swallowed formulation.

Following dermal application of EMSAM to humans, 25%-30% of the selegiline content on average is delivered systemically over 24 hours (range ~ 10%-40%). Consequently, the degree of drug absorption may be 1/3 higher
than the average amounts of 6 mg to 12 mg per 24 hours. Transdermal dosing results in substantially higher exposure to selegiline and lower exposure to metabolites compared to oral dosing, where extensive first-pass metabolism occurs (Figure 2). In a 10-day study with EMSAM administered to normal volunteers, steady-state selegiline plasma concentrations were achieved within 5 days of daily dosing. Absorption of selegiline is similar when EMSAM is applied to the upper torso or upper thigh. Mean (95% CI) steady-state plasma concentrations in healthy men and women following application of EMSAM to the upper torso or upper thigh are shown in Figure 3.
 
NeuronalPerception said:
You would have to take over 15 mg of deprenyl or 15 mg more than 3 weeks to effect MAO-A. At your dose I would not be concerned. However I would suggest switching to a non SSRI.
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Er selegeline is a competetive inhibitor of MAO-A and as such, some degree of inhibition will occur at clinical doses of 2.5-5mg. In fact 5-10mg daily can cause a clinically significant inhibition of MAO-A; that said, because it's a competetive inhibitor, increasing the concentration of a substrate would lead to more being metabolized (that's why reversible aka competetive inhibitors of MAO-A such as meclobemide are much safer for clinical use than the old MAOI like the hydrazine derivative, which irreverible bound to MAO-A meaning that even slight levels of compounds with pressor activity could rapidly progress to a hypertensive crisis)

Even so, you can still end up in deep shit with competetive MAO-A inhibitors if you either take a large dose of the inhibitor (making it seem less reversible due to enzyme kinetics) or a large dose of some pressor agent (such that you reach a toxic level before there is adequate reversal of the MAO-inhibition). Basically, what's important is the plasma concentration of the two compounds, which in turn is significantly altered by different routes of administration - that's why 2C-T-7, which has moderate competeive inhibitory action on MAO-A at plasma levels achived by an active dose taken by mouth can become fatal if taken by the nasal route as this produces a much higher peak plasma level (hence much greater inhibition). All the fatalities due to 2C-T-7 seem to invole routes other than oral and displayed classic symptoms of having the enzyme inhibited in the presence of drugs that are substrates for MAO-A ie hypertension, hyperthermia & convulsions.


I've been taking 2.5mg/d selegiline sublingually for 4 days now in combination with my sertraline and so far I'm still alive I'm just wondering whether I'm still running the danger of suddenly getting serotonin toxicity one day.
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Simple answer - yes it's a distinct possibility


PS as an additional aside, any compound metabolized by MAO-A is technically a competetive inhibitor as a molecule of enzyme cannot metabolize anything else while it's got another compound in it's active site. As such, amphetamine is technically a competetive inhibitor, but normal clinical plasma levels get nowhere near the IC50 (concn that inhibits 50 perent of the enzyme) for MAO-A. This isn't the case for selegeline(deprenyl)
 
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rnd.id. said:
If selegiline's mode of MAO-A inhibition is irreversible as with MAO-B (is it?), is there a danger of accumulation of MAO-A inhibition over a course of weeks?

I've been taking 2.5mg/d selegiline sublingually for 4 days now in combination with my sertraline and so far I'm still alive 8) I'm just wondering whether I'm still running the danger of suddenly getting serotonin toxicity one day.
Click to expand...


Sublingual selegiline 2.5 mg is more like 10 mg oral. 10 mg is the boundary for a lot of people in crossing over to non-selective inhibition, but not for all. Sometimes, it takes up to 20 mg.

You should definitely stop taking the selegiline as long as you are on an SSRI. That is a huge contraindication.

Without the SSRI, you could still wind up with serotonin toxicity if you stayed on the selegiline for extended periods of time, which is why sabbaticals are crucial.

This is not meant to be mean, but because selegiline + SSRI is such a hugely apparent contraindication, please do more research into compounds before you put them into your body.

Epocrates, an online psychiatric database is a very useful tool because it will give you every documented negative possibility with a drug and with combinations.

Fastandbulbous, at a sublingual dose of 2.5-5mg of selegiline then yes, it is likely that non-selective inhibition will occur, but with an oral ROA, I don't think 2.5-5mg is documented as crossing to MAO-A. At low doses (2.5-10mg oral) it's a non-competitive MAO-B inhibitor.
 
^ I was under the impression that MAO-B is non-copmpetetively inhibited at all doses (just might not be enough to take out all of the MAO-B in the body).

If you think about it non-competetive inhibitors will not be competetive inhibitors (at any dose) to eather ras it involves binding then refusing to let go (hence non-competetive)
 
fastandbulbous said:
^ I was under the impression that MAO-B is non-copmpetetively inhibited at all doses (just might not be enough to take out all of the MAO-B in the body).

If you think about it non-competetive inhibitors will not be competetive inhibitors (at any dose) to eather ras it involves binding then refusing to let go (hence non-competetive)
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no, yea of course. i'm just saying that after looking at quite a few studies (i can find some links i suppose), i haven't seen anything about MAO-A inhibition lower than 10mg oral, and usually no less than 20mg.

the top link is an abstract from the compilation of studies asserting that no MAO-A inhibition occured in rats after chronic treatment. there are many more examples in the bottom link, referring to deprenyl as the archetypal MAO-B inhibitor.

everything inducing MAO-A inhibition is transdermal.

http://www.ihop-net.org/UniPub/iHOP/pm/1174458.html?nr=6&pmid=9263197

http://www.ihop-net.org/UniPub/iHOP/gs/321987.html

i just think it's a bit extreme to refer to noticeable MAO A inhibition at low oral doses.
 
Ell said:
Sublingual selegiline 2.5 mg is more like 10 mg oral. 10 mg is the boundary for a lot of people in crossing over to non-selective inhibition, but not for all. Sometimes, it takes up to 20 mg.

You should definitely stop taking the selegiline as long as you are on an SSRI. That is a huge contraindication.

Without the SSRI, you could still wind up with serotonin toxicity if you stayed on the selegiline for extended periods of time, which is why sabbaticals are crucial.

This is not meant to be mean, but because selegiline + SSRI is such a hugely apparent contraindication, please do more research into compounds before you put them into your body.

Epocrates, an online psychiatric database is a very useful tool because it will give you every documented negative possibility with a drug and with combinations.

Fastandbulbous, at a sublingual dose of 2.5-5mg of selegiline then yes, it is likely that non-selective inhibition will occur, but with an oral ROA, I don't think 2.5-5mg is documented as crossing to MAO-A. At low doses (2.5-10mg oral) it's a non-competitive MAO-B inhibitor.
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Sorry, I've been listening to 20 tracks of ambien music already so this posting may not be the peak demonstration of my eloquence.

Calm down a bit ;) I've been taking the 2.5mg sublingualy for several weeks now (->steady state) and I'm still among the living. I know the symptoms of ST rather well, so I could seek help when I notice them. I did notice some leg tension, but I sometimes get that anyway and it was not too bad.

Your assumption that I'm not doing sufficient research before putting substances into my mind is false. I'm doing more research than is good for me; I'm a bit obsessed with psychopharmacology.

The literature was ambiguos. One study found no probs in combo with citalopram, other studies mentioned several incidents (deadly? don't remember). Sorry, by the time I look it up in the papers, my flow will be gone ;)

Contraindications are a general rule. This doesn't mean insta-dead for everyone in a room together with the contraindicees. I figured, for myself, personally, that the risk was acceptable, because:

- I guessed 2.5mg subling could be a problem, but won't kill my so quickly that I can't even get help quickly enough (I also have a benzo on hand)
- MAOIs rightly raise red flags because a serious MAO-A + SRI-type med *will* kill you. They're playing safe and don't want to make an exception for selegiline
- It was urgent; I'd been in the depressed fog for weeks and something somehow needed to change

It was subtly effective the first week (a hint of "lovingness" and a somewhat increased inclination to talking) and some brief reinstatement of the SSRI Sub-Hypomania (yay!). By now I don't know whether it's doing anything. Well, at least it will slow the dying of my neurodudular friends in my nucleus accumbens & co.

peace love unity respect

p.s. sorry for the bad ambien joke ;)

Sober edit: As you can see, zolpidem has some curious effects on this poster. My apologies ;)
 
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