Moclobemide Causing Paradoxical Somnolence

[CFC]

I've recently been prescribed Moclobemide (a RIMA) 600mg daily for depression/ADHD. While I'm pleased with the slight enhancement to focus and mood, I'm also experiencing an undesirable prolonged somnolent effect.

Now I'm not too surprised, as lower therapeutic doses of methylphenidate (especially) and meth/amphetamines (somewhat) also have this effect. However neurochemistry isn't my field and I'd like to understand the underlying causative processes a little better.

Unfortunately I've not been able to find any papers directly discussing these issues. My presumption thus far has been along the lines of RIMA > increased NE binding to alpha-2 receptors > reduced sympathetic outflow of NE. I am clutching a bit with this though.

I do realise that this may be a case of acute vs chronic effect, but despite titrating up and 3 weeks in, I'm still struggling to stay alert. The addition of low dose ephedrine produces some mild peripheral stimulation (particularly hidrosis and vasoconstriction) but enhances the lethargy.

Anyone with any better ideas, papers, or thoughts on how to counteract the effect?

 

[Cotcha Yankinov]

Hey CFC, I just thought I'd point out that in your post there is a lot of references to NE as opposed to 5-HT. I'm under the impression that moclobemide et cetera increases 5-HT moreso than NE.

 

[CFC]

Hey Cotcha, so are you thinking that some of the lethargy may be due to 5-HT? I was under the impression that, generally, 5-HT was associated with wakefulness?

I'm pretty sure I read that MOC increases NE and 5-HT at roughly equal ratios (about 50% at 1.5mg/kg), although there's a temporal effect - ie 5-HT increases first.

 

[JohnBoy2000]

Hey Cotcha, so are you thinking that some of the lethargy may be due to 5-HT? I was under the impression that, generally, 5-HT was associated with wakefulness?

I'm pretty sure I read that MOC increases NE and 5-HT at roughly equal ratios (about 50% at 1.5mg/kg), although there's a temporal effect - ie 5-HT increases first.

I'm
not an expert but - this has been an issue that has persisted with myself also - specifically the attempt to alleviate lethargy and cognitive impairment.

Would you mind outlining other medications you have tried with doses?

Obviously it's very paradoxical for a stimulant to incite lethargy but - there was reference in one neuropharm text that, with NE receptors become completely saturated, this can happen.
Again, I'm not an expert but - I would assume on some level that, there was no underlying issue with NE receptors so, flooding them with increased unnecessary NE incited fatigue.

This actually happened to a friend of mine, except that was with bupropion/wellbutrin.
Where's with myself, the opposite was true and, as you mention with 5HT - my friend found it DID incite wakefulness and energy, but for me, 5HT induced lethargy and fatigue.
I would guess in my case, no underlying issue with 5HT receptors or neurotransmission so, it's unnecessary enhancement brought about a counter productive outcome.

So - as you can tell, it does appear to be quite subjective.

You must have tried SSRI's or something though - right?
Moclobimide certainly wouldn't be first line, not with any doctor or organization in Europe anyways, unless you requested it specifically?

https://en.wikipedia.org/wiki/Pharmacology_of_antidepressants#Receptor_affinity

Have a look at this chart for receptor binding affinities RE: NE/5HT etc.

Moclobimide isn't listed as it's enzymatic based, from what I understand.

You could always try an a-typical approach like alpha 2 adrenergic blockade - you seemed to have an understanding of this receptor agonist vs blockade properties etc - Mianserin or Mirtazapine would be drugs of such a class.

 

[CFC]

Would you mind outlining other medications you have tried with doses?

Hey JohnBoy. I've had depression since I was about 10 and I'm now 37. So there've been quite a few that may be relevant:

Citalopram
Escitalopram
Sertraline
Mirtazapine
Venlafaxine
Fluoxetine
Bupropion
Atomoxetine
Imipramine
Memantine
Co-Dergocrine
Tramadol
Methylphenidate
Methamphetamine
Amphetamine
Modafinil
Various nootropics

There would be others I've tried but I can't really remember off the top of my head, nor the doses. Most doses would just have been standard adult male doses (eg escitalopram 20mg).

Ritalin was the best, cleanest, purest sleep aid I've ever used, but I couldn't afford to keep using it that way (I have to buy from online pharmacies. In the UK, until 2008, ADHD did 'not exist' in adults, and I haven't made the effort to get an adult diagnosis since).

Meth and amphetamines were mostly used recreationally, but I've also purified and synthesised into tablets for normal adult ADHD treatment protocols. I didn't find either particularly effective for ADHD, and the situational temptation to use recreationally is sometimes too strong.

Memantine and co-dergocrine (ergoloid) were just me thinking outside the box a bit while playing around with nootropics for exam periods.

Modafinil has been effective for both depression and ADHD (well, somewhat), though occasionally it provokes a mild hypomania and I can never sleep on it, even low-dosed very early A.M. (so by day 2, I feel absolutely wrecked).

Obviously it's very paradoxical for a stimulant to incite lethargy but - there was reference in one neuropharm text that, with NE receptors become completely saturated, this can happen.
Again, I'm not an expert but - I would assume on some level that, there was no underlying issue with NE receptors so, flooding them with increased unnecessary NE incited fatigue.

I based my assumption partly on the way I understand α2 adrenergic agonists to work. I would tend to think that, in people with different neutrotransmitter signalling patterns (like ADHD), it's quite plausible that idiosyncratic densities or concentrations of α2 adrenoceptors in certain parts of the brain could potentially lead to acute paradoxical reactions from localised elevations of NE. I'm hoping that - over time - this may resolve itself.

MOC does to appear to interact with µ/δ-opioid receptors with roughly half the affinity of naloxone, though I don't know how relevant that might be to somnolence (probably not at all).

I would guess in my case, no underlying issue with 5HT receptors or neurotransmission so, it's unnecessary enhancement brought about a counter productive outcome.

So - as you can tell, it does appear to be quite subjective.

Assuming the normal distribution curve also applies to reactions to various drugs, I think we could inherently assume that, although the majority will react in the specified manner, we would nevertheless expect certain proportions of a standard population to react in contrary or exaggerated ways to various drugs or combinations thereof.

Moclobimide certainly wouldn't be first line, not with any doctor or organization in Europe anyways, unless you requested it specifically?

I did have to request moclobemide. I was looking for something with a gentle side-effect profile. My experience with typical SSRIs, mirtazapine etc hasn't been good. A drug which starts to work almost immediately, can be controlled easily due to a short half-life, has no extrapyramidal symptoms and is minimally affected by tyramine seemed worthy of a shot.

Have a look at this chart for receptor binding affinities RE: NE/5HT etc.

Moclobimide isn't listed as it's enzymatic based, from what I understand.

MOC interacts with 5-HT2 receptors slightly in the rat cortex, but not at all with ɑ1 and ɑ2. So it seems quite pure from that point of view, like you say. Though in humans...?

You could always try an a-typical approach like alpha 2 adrenergic blockade - you seemed to have an understanding of this receptor agonist vs blockade properties etc - Mianserin or Mirtazapine would be drugs of such a class.

Have you tried this? Any success? One of my degrees is in regular pharmacology, but that was a long time ago

 

[JohnBoy2000]

lol - well you know a lot more than me then pal.
I'm studying pharmacology myself now, just the entry level book by Rang, and Stahls and Nestlers books.

Mirtazapine was effectivel in proportion to the degree it implicates noradrenaline - i.e. relatively mild - though a great sleep aid and appetite stimulant.

I've started Mianserin 2 weeks ago, and yes already it's a step ahead mirtazapine in my case, though I'm not on the full dose yet.

I'm also on Lofepramine (the european version of desipramine -a pro drug) - but can only tolerate the starter dose due to sedation at higher doses.
I've been attempting to figure out if this is due to NE receptor saturation, or secondary drug effects at higher doses - thus whether a more selective NRI might work better/i.e. I could tolerate a higher dose - but I don't have a thorough enough understanding of pharmacology (yet) to really come to a conclusion on that.

I'm proceeding slowly and cautiously with varying my regiment.

I'm optimistic regarding the fact that mianserin has, according to it's mechanism - raised NE neurotransmission, but not induced the lethargy side effect of a higher dose of desipramine - so perhaps that does allude to that side effect being relative to desipramine being an old school tricyclic, and not it inciting receptor saturation - in turn making me optimistic that a more selective NRI like reboxetine might work better....

 

[Cotcha Yankinov]

Hey Cotcha, so are you thinking that some of the lethargy may be due to 5-HT? I was under the impression that, generally, 5-HT was associated with wakefulness?

I'm pretty sure I read that MOC increases NE and 5-HT at roughly equal ratios (about 50% at 1.5mg/kg), although there's a temporal effect - ie 5-HT increases first.

From what I've understand SSRIs tend to cause a decrease in REM sleep but an increase in SWS (but it's possible there is overall less time asleep in some people and that the increased NREM and stage 1/2 is just "filling the gap" where there would have normally been REM). When it comes to 5-HT modulating the function of the cortex I'm sure no human is identical though, as no cortex is identical.

One thing I'll point out is that increasing 5-HT with MAOIs/SSRIs/SRAs is all going to be a bit different, whether it's SSRIs disrupting some of the SERT's regulation of non-synaptic volume transmission a bit or that MAOIs increase the 5-HT stored in vesicles available to be released "naturally" as well as reducing extracellular metabolism of 5-HT. And I suppose the spatial distribution of MAO-A vs. SERT could play a role in the differences too.

SSRIs are also agonists at 5-HT2B and while it's not very clear, it seems to be important https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525030/

An interesting thing to note is that some people report a lot of sleepiness and lethargy with MDMA. Seems rare though.

I'm not too sure about the 5-HT vs. NE with MAO-A inhibition though, and to boot MAO-B inhibition is complicating MOC's picture I'm sure, but this study says https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525030/

"In the case of moclobemide, increase in the level of serotonin is the most pronounced."

It does also mention increased GH. Supposedly MOC has effects on cytokines and prolactin too.


I'll also copy pasta part of the wiki here "In healthy people moclobemide has a relatively small suppressing effect on REM sleep; in contrast, depressed people who have been treated with moclobemide, progressively show improved sleep over a 4-week period, with an increase in stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.[8]

There have been conflicting findings with regard to moclobemide altering cortisol levels and whether moclobemide increases growth hormone levels.[8] Testosterone levels increase significantly with long-term use of moclobemide in depressed males.[109]"

Hope this was helpful. Seems like there is a lot going on with MOC, and we may have some of the age old chronic vs. acute effects thing going on.

 

[JohnBoy2000]

I'm not necessarily trying to alter the trajectory of this thread but - I've been thinking about something and - I need place to outline it.
We're on the general topic here relative to the OP's hypothesis regarding the drugs mechanism of action relative to induction of lethargy so, here goes:


I was taking 45 mg remeron - the alpha 2 blocker, but not alpha 1 - thus, simultaneous enhancement of noradrenaline, and serotonin - mmkay?
I commenced lofepramine, for all intents and purposes, desipramine - first 70 mg, 140, then the full 210 mg.
It alleviated my IBS, and NE transport blockers always do.
It gave me energy, strength, better sleep etc - the full she-bang.
Happydays.

But alas, the happiness came to an end, with the encroaching prevalence of the dreaded primary symptom - fatigue.

So - I titrated down to the starter dose - 70 mg - where of course the full therapeutic does not transpire, but, even at that dose, did incite nice symptom alleviation.

Then - to potentiate the NE effect further, and mitigate the unnecessary and hindering 5HT enhancing effects in my regiment (5HT enhancement induced fatigue and exacerbated IBS in my case) - I replaced remeron, with - Mianserin - it's earlier sister compound of Organon, the same Dutch drug manufacturers.

Now - 2 weeks been on Mianserin.
Two thirds the full dose.
Tonight, I said fuck it, and pushed it up to the full dose - 90 mg - just to see how it would affect sleep and appetite - as remeron did and is known to do.
Some people claim remeron becomes more activating at the higher doses.
Some say more sedating.
It's obviously subjective, depending on their reliance of the anti-H property, and requisite for the NE enhancement.
But in my case - higher dose remeron = more sedation/sleep - which was very welcome to alleviate insomnia.
Tonight, I guess I'll find out whether or not this is replicated with mianserin.


But - to the point - Mianserin has a strong blockade on alpha 1 adrenergic receptors concurrently with alpha 2.
Alpha 1 post-synaptic receptors on the 5HT neuron, when blocked, inhibit the release of serotonin.
It is known that, these alpha 1 post synaptic receptors on the 5HT neuron, when stimulated with NE, release 5HT - i.e. increase 5HT neurotransmission.

Therefore, with Remeron - there is no block of alpha 1 - so the addition of a NE transporter blocker, increasing synaptic NE, would concurrently have the dual effect of increase 5HT - due to the concurrent use of Remeron in addition to desipramine, the NE enhancer.

But effectively if the 5HT enhancing property of remeron is replaced with the 5HT inhibiting property of mianserin - then the increase in synaptic NE via desipramine would theoretically then incite less concurrent 5HT increase, as the receptor that mediated that increase is now blocked via mianserin.

Therefore, possibly - theoretically - the lethargy inducing effect of high dose desipramine with remeron - could be mitigated via the replacement of remeron with Mianserin.

So, theoretically, I could go on high dose desipramine now, and not experience the lethargy I experienced previously whilst concurrently taking remeron....?

Does that sound plausible??

 

[Cotcha Yankinov]

See these

https://www.ncbi.nlm.nih.gov/m/pubmed/12872296/

https://www.ncbi.nlm.nih.gov/m/pubmed/20043931/

 

[WSH]

A possible explanation could be that the tonic increase in NEP by moclobemide actually reduces the phasic release of NEP.

 

[JohnBoy2000]

See these

https://www.ncbi.nlm.nih.gov/m/pubmed/12872296/

https://www.ncbi.nlm.nih.gov/m/pubmed/20043931/

Thank you very much.
Again - I scour pubmed - but so often have difficulties in locating the relevant studies....

"Moreover, prazosin pre-infusion into terminal areas prevented the increase in citalopram-induced increase in serotonin levels with systemic cirazoline or reboxetine administration."

Seems to suggest that yes - alpha 1 blocked does indeed inhibit enhancement of 5HT activity.

I guess the only thing to do is try and see what happens:

If lethargy is re-incited - would perhaps suggest it is a secondary drug mechanism of desipramine at work (though given previous clinical observations, that would be unlikely - but possible).
If the lethargy does not transpire on this occasion, given the remerson/mianserin switch out, well - in terms of the pharmacodynamic hypothesis, that would suggest that the above mechanism is at work and that, the initial lethargy was induced due to the NE enhanced mediated - mediation, as it were - of 5HT, via remerons mechanics; and that the exclusion of that, negates the 5HT enhancement - and thus hopefully lethargy induction is also excluded.

 

[CFC]

From what I've understand SSRIs tend to cause a decrease in REM sleep but an increase in SWS (but it's possible there is overall less time asleep in some people and that the increased NREM and stage 1/2 is just "filling the gap" where there would have normally been REM). When it comes to 5-HT modulating the function of the cortex I'm sure no human is identical though, as no cortex is identical

Thanks for the reply mate. I do experience changes to my global sleep patterns on SSRIs. I also experience quite a bit of brain fog. Subjectively I'd say MOC has had a (slight) negative impact on sleep quality as well, but without any affect on mental clarity.

However the fatigue I feel on MOC is quite specific: it follows within 30-45 mins of a dose and lasts 3-4 hours, so I suspect it's unrelated to any sleep debt. It also doesn't feel like classic sedation or fatigue but rather a purer somnolence, akin to my experiences with MPH and ATM - like someone's flipped a switch.

Since ATM - which feels similar - appears to exert its effects predominantly via NE rather than 5-HT, this further aroused my suspicion as to the role of NE and α2 adrenoceptors. The addition of ephedrine enhancing the central effects (somnolence) while still activating α1 (peripheral effects) seems consistent with this.

One thing I'll point out is that increasing 5-HT with MAOIs/SSRIs/SRAs is all going to be a bit different, whether it's SSRIs disrupting some of the SERT's regulation of non-synaptic volume transmission a bit or that MAOIs increase the 5-HT stored in vesicles available to be released "naturally" as well as reducing extracellular metabolism of 5-HT. And I suppose the spatial distribution of MAO-A vs. SERT could play a role in the differences too.

SSRIs are also agonists at 5-HT2B and while it's not very clear, it seems to be important https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525030/

I'm not too sure about the 5-HT vs. NE with MAO-A inhibition though, and to boot MAO-B inhibition is complicating MOC's picture I'm sure, but this study says https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525030/

"In the case of moclobemide, increase in the level of serotonin is the most pronounced."

It does also mention increased GH. Supposedly MOC has effects on cytokines and prolactin too.

The complexity is both fascinating and frustrating, since for a detail person like myself ("can't see the wood for the trees") grasping the necessary overview is challenging

There is a subjective similarity between this somnolence and that which I experience from acute GH and ghrelin-mimetic pulsing. They also tend to hit clean, hard and fast. Following on from that, I was thus considering the effect of an acute blood sugar change; mild hypo sometimes feels similar. Orexin could also come into this, though ghrelin-mimetics and hypoglycaemia provoke OX release

 

[CFC]

A possible explanation could be that the tonic increase in NEP by moclobemide actually reduces the phasic release of NEP.

Thanks WSH, that's a good point and something I'll have to read more about.

 

[Cotcha Yankinov]

A possible explanation could be that the tonic increase in NEP by moclobemide actually reduces the phasic release of NEP.

Interesting, I had never even thought about phasic release here. I've read that the autoreceptors that facilitate phasic serotonin release desensitize with chronic SSRIs and thus high tonic levels ensue, but I wonder if the same thing happens with NT release at a2 expressing terminals (if a2 participates in the phasic signal)

 

[Cotcha Yankinov]

Since ATM - which feels similar - appears to exert its effects predominantly via NE rather than 5-HT, this further aroused my suspicion as to the role of NE and α2 adrenoceptors. The addition of ephedrine enhancing the central effects (somnolence) while still activating α1 (peripheral effects) seems consistent with this.

Interesting. I forgot to mention regarding extracellular concentrations that its possible one NT plays a much bigger role in the changes even if its concentrations are lower than another one. So for example lets just say MOC leads to 80% increase in 5-HT and 20% increase in NE - its possible that NE plays the bigger role in impacting mood/cognition/energy et cetera.

https://www.ncbi.nlm.nih.gov/pubmed/16256247 "Compared to those in the dorsal raphe nucleus, the neurones in the median raphe nucleus which were inhibited by 5-HT had: (1) lower basal firing rates in the continuous presence of phenylephrine (1microM), (2) smaller excitatory responses to higher concentrations of phenylephrine (3-10microM), (3) smaller excitatory responses to brief application of norepinephrine (10-100microM) and (4) smaller inhibitory responses to 5-HT (10-50microM).

The lower sensitivity of median raphe neurones to alpha(1)-adrenoceptor excitation and 5-HT(1A) receptor inhibition will have consequences for 5-HT neurotransmission in forebrain regions innervated by the two nuclei."

There is a subjective similarity between this somnolence and that which I experience from acute GH and ghrelin-mimetic pulsing. They also tend to hit clean, hard and fast. Following on from that, I was thus considering the effect of an acute blood sugar change; mild hypo sometimes feels similar. Orexin could also come into this, though ghrelin-mimetics and hypoglycaemia provoke OX release

Hmmmmm, I wonder how your blood glucose is looking..

 

[WSH]

here's some additional reading on my idea:

A risk inherent in increased NE activity is that of provoking anxiety. This is avoided however by the attenuation of the phasic reactivity of the firing of NE neurons through prolonged administration of SSRI and SNRI. [...] Milnacipran increases tonic NE activity, while attenuating phasic NE reactivity

The noradrenergic symptom cluster: clinical expression and neuropharmacology

Milnacipran is an SNRI, but moclobemide also effects both serotonin and NEP, so I think this study is at least somewhat relevant.

 

[JohnBoy2000]

Thank you very much.
Again - I scour pubmed - but so often have difficulties in locating the relevant studies....

"Moreover, prazosin pre-infusion into terminal areas prevented the increase in citalopram-induced increase in serotonin levels with systemic cirazoline or reboxetine administration."

Seems to suggest that yes - alpha 1 blocked does indeed inhibit enhancement of 5HT activity.

I guess the only thing to do is try and see what happens:

If lethargy is re-incited - would perhaps suggest it is a secondary drug mechanism of desipramine at work (though given previous clinical observations, that would be unlikely - but possible).
If the lethargy does not transpire on this occasion, given the remerson/mianserin switch out, well - in terms of the pharmacodynamic hypothesis, that would suggest that the above mechanism is at work and that, the initial lethargy was induced due to the NE enhanced mediated - mediation, as it were - of 5HT, via remerons mechanics; and that the exclusion of that, negates the 5HT enhancement - and thus hopefully lethargy induction is also excluded.

I like that we're all on the topic of NE and lethargy, though from different angles.

I don't think my little theory is gonna work.

I upped my dose of desipramine and - anxious, lethargic, huge red rings under my eyes after an inadequate session at the gym.

Tarnation!

What could explain that?

Is there the potential for another different NRI to work, where desipramine hasn't?
A more selective one?
What auxiliary property of desipramine might incite the lethargy?
Blockade of calcium or sodium channels - that would not occur with more modern and selective NRI's?

 

[CFC]

So finally, after 4 weeks, the somnolence went away.

Unfortunately I'm obviously not sleeping properly/deeply either and feel dreadful on waking.

So I cut out the evening dose, and immediately the following day (on taking a dose) the somnolence (and also slight dizziness) came right back. Phasic/tonic reaction may well be at play here.

 

[jaiho]

Adding modafinil to Moclobemide is nice.
I wouldn't do that daily though, it feels abit strong.
Dosing before mid day is probably wise to ensure decent sleep. Maybe augment with melatonin or Agomelatine.

 

[CFC]

Even 25mg modafinil with moclobemide produces excessive peripheral stimulation for me, and ensures my sleep quality will be atrocious, even dosed at 6am. It does partially attenuate the somnolence though.