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MAO-A induction

Unread postPosted: Wed Mar 13, 2019 8:03 am
by Mesolimbo
I'm reading up research on ways to reduce central serotonin level, one of them is MAO-A induction, and I came across this interesting study:

"Induction of type A monoamine oxidase by rasagiline by R1-Sp1 pathway"
Rasagiline binds to MAO-A and reduces R1 and increases MAO-A; mithramycin-A, an inhibitor of Sp1 binding, reduces mao-a induction by rasagiline [119]. Selegiline increases R1 and MAO-A, suggesting that selegiline increases MAO-A expression independently from R1 reduction. The first and second columns represent the protein amount of R1 and MAO-A in SH-SY5Y cells after treated with rasagiline or selegiline. I, II and III represent control, 10-6 and 10-9 M rasagiline or selegiline, respectively. MAO-A: Type A monoamine oxidase.

https://www.researchgate.net/figure/Induction-of-type-A-monoamine-oxidase-by-rasagiline-by-R1-Sp1-pathway-Rasagiline-binds_fig1_237058942

Re: MAO-A induction

Unread postPosted: Wed Mar 13, 2019 10:17 am
by Jaxx
Mesolimbo wrote:I'm reading up research on ways to reduce central serotonin level, one of them is MAO-A induction, and I came across this interesting study:

"Induction of type A monoamine oxidase by rasagiline by R1-Sp1 pathway"
Rasagiline binds to MAO-A and reduces R1 and increases MAO-A; mithramycin-A, an inhibitor of Sp1 binding, reduces mao-a induction by rasagiline [119]. Selegiline increases R1 and MAO-A, suggesting that selegiline increases MAO-A expression independently from R1 reduction. The first and second columns represent the protein amount of R1 and MAO-A in SH-SY5Y cells after treated with rasagiline or selegiline. I, II and III represent control, 10-6 and 10-9 M rasagiline or selegiline, respectively. MAO-A: Type A monoamine oxidase.

https://www.researchgate.net/figure/Induction-of-type-A-monoamine-oxidase-by-rasagiline-by-R1-Sp1-pathway-Rasagiline-binds_fig1_237058942

I would expect that if it would do significantly it can also trigger anxiety? Quick search didnt find this as a side effect.

Re: MAO-A induction

Unread postPosted: Wed Mar 13, 2019 11:10 am
by taarn
Jaxx wrote:
Mesolimbo wrote:I'm reading up research on ways to reduce central serotonin level, one of them is MAO-A induction, and I came across this interesting study:

"Induction of type A monoamine oxidase by rasagiline by R1-Sp1 pathway"
Rasagiline binds to MAO-A and reduces R1 and increases MAO-A; mithramycin-A, an inhibitor of Sp1 binding, reduces mao-a induction by rasagiline [119]. Selegiline increases R1 and MAO-A, suggesting that selegiline increases MAO-A expression independently from R1 reduction. The first and second columns represent the protein amount of R1 and MAO-A in SH-SY5Y cells after treated with rasagiline or selegiline. I, II and III represent control, 10-6 and 10-9 M rasagiline or selegiline, respectively. MAO-A: Type A monoamine oxidase.

https://www.researchgate.net/figure/Induction-of-type-A-monoamine-oxidase-by-rasagiline-by-R1-Sp1-pathway-Rasagiline-binds_fig1_237058942

I would expect that if it would do significantly it can also trigger anxiety? Quick search didnt find this as a side effect.


@Jaxx Why do you think that it will cause significantly elevated anxiety?

Serotonin, melatonin, adrenaline and noradrenaline are mainly broken down by MAO-A. Sure it has many other roles but I think by decreasing noradrenaline and adrenaline it has a signficant anti-anxiety effect as well. Serotonin's role in anxiety is not that clear but reducing melatonin won't be that good anxiety and/or sleep-wise.

Re: MAO-A induction

Unread postPosted: Wed Mar 13, 2019 1:40 pm
by Jaxx
taarn wrote:
Jaxx wrote:
Mesolimbo wrote:I'm reading up research on ways to reduce central serotonin level, one of them is MAO-A induction, and I came across this interesting study:

"Induction of type A monoamine oxidase by rasagiline by R1-Sp1 pathway"
Rasagiline binds to MAO-A and reduces R1 and increases MAO-A; mithramycin-A, an inhibitor of Sp1 binding, reduces mao-a induction by rasagiline [119]. Selegiline increases R1 and MAO-A, suggesting that selegiline increases MAO-A expression independently from R1 reduction. The first and second columns represent the protein amount of R1 and MAO-A in SH-SY5Y cells after treated with rasagiline or selegiline. I, II and III represent control, 10-6 and 10-9 M rasagiline or selegiline, respectively. MAO-A: Type A monoamine oxidase.

https://www.researchgate.net/figure/Induction-of-type-A-monoamine-oxidase-by-rasagiline-by-R1-Sp1-pathway-Rasagiline-binds_fig1_237058942

I would expect that if it would do significantly it can also trigger anxiety? Quick search didnt find this as a side effect.



@Jaxx Why do you think that it will cause significantly elevated anxiety?

Serotonin, melatonin, adrenaline and noradrenaline are mainly broken down by MAO-A. Sure it has many other roles but I think by decreasing noradrenaline and adrenaline it has a signficant anti-anxiety effect as well. Serotonin's role in anxiety is not that clear but reducing melatonin won't be that good anxiety and/or sleep-wise.


well decreasing serotonin normally can induce anxiety, like yohimbe. thats why mao-a inhibitors help in managing anxiety.

my point isnt that this is bad, but more that IF it would decrease serotonin indeed, i would expect that anxiety is then a commen side effect.

Re: MAO-A induction

Unread postPosted: Wed Mar 13, 2019 2:53 pm
by Mesolimbo
Jaxx wrote:well decreasing serotonin normally can induce anxiety, like yohimbe. thats why mao-a inhibitors help in managing anxiety.

my point isnt that this is bad, but more that IF it would decrease serotonin indeed, i would expect that anxiety is then a commen side effect.

Yohimbine is a presynaptic 5HT1A agonist. Full agonists are anxiolytic after the adaptation period due to receptor downregulation, causing serotonin to flood the postsynaptic 5HT1A, modulating GABA release. But yeah, initially they would be anxiogenic, or at least neutral. That said, I believe that Yohimibine is anxiogenic due to its alpha-2 adrenergic blockade moreso than 5HT1A agonism.

Rasagiline, by blocking MAO-B, would increase dopamine receptor activation in a tonic manner. That alone can cause anxiety in some people, especially since dopamine is a precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine (DBH). So, it would increase anxiety whether serotonin is involved or not.

However, many people with PSSD aren't capable of experiencing any form of anxiety, despite of potent dopaminergics/adrenergics and stimulants. So, if Rasagiline restores some anxiety then it's a good indication that it effectively decreased central serotonin to a normal-ish level.

In my case, Rasagiline was useful but not enough to warrant daily intake. I'm still heavily debating this in my mind though.

Another pathway I'm reading up on is VMAT inhibiton, but that would also decrease dopamine/NE. Since Reserpine is mostly withdrawn from countries, Vincamine or even Vinpocetine would be the substitute with the added nootropic benefit. Maybe in combination with Rasagiline to keep dopamine from being too inhibited while decreasing serotonin even further.

VMAT are present on the membrane of presynaptic neurons, so VMAT inhibition would inhibit catecholamine release from the pre-synapses altogether. A fine balance is needed to be achieved with the potency of the VMAT inhibitor, as to not inhibit dopamine/NE release too much, with the help of MAO-B inhibitor to keep any released dopamine around for a longer period. This is just theoritical thinking of course, which could be very impractical.

Re: MAO-A induction

Unread postPosted: Wed Mar 13, 2019 3:33 pm
by taarn
What about microdosing Fenclonine or another tryptamine hydroxylase inhibitor? I have some Fenclonine but haven't tried it yet. I couldn't decide on if it's a good idea altogether.

Regarding VMAT so far I have achieved the biggest improvements in sexual function with Bupropion which is a weak DAT inhibitor and somewhat stronger NET inhibitor, especially it's metabolite Hydroxybupropion. It is thought to increase vesicular monoamine transport through VMAT2, probably that's why it caused me that kind of libido increase? I've tried 3 dopamine agonists and amphetamine, but haven't noticed such an improvement like with bupropion. To be honest I mostly did small doses of amphetamine and never took it consecutively.
I've yet to try other dopaminergic agents but I'm still thinking giving a longer trial to bupropion however looking at its pharmacology I don't understand why was it superior to everything I tried so far.

Re: MAO-A induction

Unread postPosted: Thu Mar 14, 2019 1:15 pm
by Mesolimbo
taarn wrote:What about microdosing Fenclonine or another tryptamine hydroxylase inhibitor? I have some Fenclonine but haven't tried it yet. I couldn't decide on if it's a good idea altogether.

Fenclonine is very interesting. I'm in the process of getting Siberian Ginseng to inhibit tryptophan hydroxylase. Let's see how that goes.

taarn wrote:Regarding VMAT so far I have achieved the biggest improvements in sexual function with Bupropion which is a weak DAT inhibitor and somewhat stronger NET inhibitor, especially it's metabolite Hydroxybupropion. It is thought to increase vesicular monoamine transport through VMAT2, probably that's why it caused me that kind of libido increase? I've tried 3 dopamine agonists and amphetamine, but haven't noticed such an improvement like with bupropion. To be honest I mostly did small doses of amphetamine and never took it consecutively.

Buproprion reverses reserpine-induced behavioral despair, so VMAT may be involved. It also seems to inhibit nNOS a bit, and pretreatment with L-arginine prevents its antidepressant effect.

nNOS is important for the sexual response, but too much nNOS would cause neuroinflammation and depression. Perhaps with reduced neuroinflammation, you have gotten a better response than on other dopaminergics that don't target neuroinflammation.

Have you tried microglial de-activators, such as low dose Naltrexone (LDN) or any TLR4 antagonist? Does Panax Ginseng make you feel worse?

Re: MAO-A induction

Unread postPosted: Thu Mar 14, 2019 4:34 pm
by taarn
Mesolimbo wrote:
taarn wrote:What about microdosing Fenclonine or another tryptamine hydroxylase inhibitor? I have some Fenclonine but haven't tried it yet. I couldn't decide on if it's a good idea altogether.

Fenclonine is very interesting. I'm in the process of getting Siberian Ginseng to inhibit tryptophan hydroxylase. Let's see how that goes.

taarn wrote:Regarding VMAT so far I have achieved the biggest improvements in sexual function with Bupropion which is a weak DAT inhibitor and somewhat stronger NET inhibitor, especially it's metabolite Hydroxybupropion. It is thought to increase vesicular monoamine transport through VMAT2, probably that's why it caused me that kind of libido increase? I've tried 3 dopamine agonists and amphetamine, but haven't noticed such an improvement like with bupropion. To be honest I mostly did small doses of amphetamine and never took it consecutively.

Buproprion reverses reserpine-induced behavioral despair, so VMAT may be involved. It also seems to inhibit nNOS a bit, and pretreatment with L-arginine prevents its antidepressant effect.

nNOS is important for the sexual response, but too much nNOS would cause neuroinflammation and depression. Perhaps with reduced neuroinflammation, you have gotten a better response than on other dopaminergics that don't target neuroinflammation.

Have you tried microglial de-activators, such as low dose Naltrexone (LDN) or any TLR4 antagonist? Does Panax Ginseng make you feel worse?


Siberian Ginseng also seems interesting. To be honest I haven't really resarched ginsengs yet. There was a period I took Panax Ginseng but now it's hard to gauge how I felt on it. I think it made me a bit better cognition-wise (less brain fog) and I had better sleep if I recall well but I usually took it in the morning.

Regarding nNOS as far as I know it is mostly involved in the erection part of the sexual response. The thing is that I have very bad sexual dysfunction, low libido, zero pleasure in genital area and pleasureless orgasms but my erections are quite good. Since taking L-arginine and citrulline malate before my workouts I'm having erections which accompany most of my sleep time. I can also have erections to visual stimuli, of course weird and pleasureless and without feeling too much turned on. I can't get my head around this thing and I'm trying to understand the whole sexual response cycle especially pleasure and orgasms.

I've tried LDN. Because 50mg tablets are hard to split usually I took average 7.5 mg doses just before sleep. It made me feel blunted the next day and somewhat decreasing anxiety at the same time. I've always did it just for a few days and after that I noticed improvements in anhedonia/better emotions, I guess because of the rebound effect. An interesting addition is that recently I started taking occasional agomelatine to help with sleep. It helped but I felt blunted and had some brain fog the next day, I also had somewhat worse mood. But the combination of agomelatine and LDN is interestingly produces a synergistic effect for me. Only just a slight brain fog but much improved mood and anhedonia remission. Idk why.

And to stay at topic, with tomorrow I'll start taking β-Alanine.
It seems to reduce serotonin (or at least it's metabolite 5-HTT): https://www.ncbi.nlm.nih.gov/pubmed/20099004
Increasing BDNF and also helps with PTSD: https://www.ncbi.nlm.nih.gov/pubmed/25758106

I don't expect too much of it but I have mild OCD, anxiety and sometimes a PTSD-like response to the fear of sleep deprivation so it may be beneficial for me. If it has any positive effect on PSSD because of it's effect on 5-HT then even better.

Re: MAO-A induction

Unread postPosted: Fri Mar 15, 2019 8:41 am
by Mesolimbo
taarn wrote:Regarding nNOS as far as I know it is mostly involved in the erection part of the sexual response. The thing is that I have very bad sexual dysfunction, low libido, zero pleasure in genital area and pleasureless orgasms but my erections are quite good. Since taking L-arginine and citrulline malate before my workouts I'm having erections which accompany most of my sleep time. I can also have erections to visual stimuli, of course weird and pleasureless and without feeling too much turned on. I can't get my head around this thing and I'm trying to understand the whole sexual response cycle especially pleasure and orgasms.

This sounds like a blunted dopamine release problem. How do you react to Melatonin? it inhibits dopamine release https://www.ncbi.nlm.nih.gov/pubmed/30043140.

Agomelatine is a 5HT2C antagonist, so melatonin-receptor agonism mediated inhibition of dopamine could have been counteracted, I assume.

Vincamine depletes cerebral serotonin, but I don't have access to the full paper:
https://www.ncbi.nlm.nih.gov/pubmed/13900578
Can someone post it? it seems that my VMAT theory could work via vincamine + rasagiline.

Re: MAO-A induction

Unread postPosted: Fri Mar 15, 2019 9:05 am
by taarn
Mesolimbo wrote:
taarn wrote:Regarding nNOS as far as I know it is mostly involved in the erection part of the sexual response. The thing is that I have very bad sexual dysfunction, low libido, zero pleasure in genital area and pleasureless orgasms but my erections are quite good. Since taking L-arginine and citrulline malate before my workouts I'm having erections which accompany most of my sleep time. I can also have erections to visual stimuli, of course weird and pleasureless and without feeling too much turned on. I can't get my head around this thing and I'm trying to understand the whole sexual response cycle especially pleasure and orgasms.

This sounds like a blunted dopamine release problem. How do you react to Melatonin? it inhibits dopamine release https://www.ncbi.nlm.nih.gov/pubmed/30043140.

Agomelatine is a 5HT2C antagonist, so melatonin-receptor agonism mediated inhibition of dopamine could have been counteracted, I assume.

Vincamine depletes cerebral serotonin, but I don't have access to the full paper:
https://www.ncbi.nlm.nih.gov/pubmed/13900578
Can someone post it? it seems that my VMAT theory could work via vincamine + rasagiline.


Sure I have dopamine issues. I guess it's the combination of dopaminergic issues like downregulation/desensitization + the effect of serotonergic disturbances which can further blunt dopaminergic signaling. I have the feeling that the additional low serum DHT doesn't help the situation.

Check the link for the paper:
https://bit.ly/2T9t5J1