# 5-ht2c antagonism



## mikoy (Aug 12, 2010)

Hey. What is the strongest 5-ht2c antagonist? I want to combine 5-ht2c antagonist with methylphenidate (5-ht2c antagonism can intensify stimulants). Now I'm on methylphenidate and mianserin but it's so strong antihistamine, and I don't like this sedative effect. Agomelatine is other option but it's so damn expensive...

Other options: cyproheptadine (don't know how strong it's 5-ht2c antagonist), amitryptyline.

thx


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## jim_morrison (Aug 17, 2008)

Probably Ritanserin, it's a selective 5HT2 (A/B/C) antagonist.


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## crayzyMed (Nov 2, 2006)

Agomelatine, problem is that 5HT2A antagonism has the opposite action of 5HT2C antagonsm with most other meds.


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## jim_morrison (Aug 17, 2008)

Good point Wes, I think they really need to come out with Agomelatine XR soon though before it will become very useful as the half life's so short.


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## mikoy (Aug 12, 2010)

So if med has 5-ht2a antagonism stronger than 5-ht2c it is useless? So combination of agomelatine and stimulant its good option?


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## jim_morrison (Aug 17, 2008)

mikoy said:


> So combination of agomelatine and stimulant its good option?


Possibly, but you'd likely have to take your dose of agomelatine at the same time as you take your stimulant, as agomelatine only lasts for about 2 hours.


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## JohnG (Sep 3, 2010)

Mirtazapine?


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## jim_morrison (Aug 17, 2008)

Pretty much the same drawbacks as mianserin ie; too much other stuff besides 5ht2c.


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## mikoy (Aug 12, 2010)

It's sad that mianserin block the effect of methylphenidate in my case :f maybe it's 5-ht2a antagonism. I feel like drunk on mianserin...****ty feeling. JohnG I see you're taking agomelatine with methylphenidate, so how it is? Is agomelatine good for depression?


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## mikoy (Aug 12, 2010)

I read that mirtazapine is stronger 5-ht2c antagonist than 5-ht2a and mianserin is stronger 5-ht2a antagonist than 5-ht2c - and I feel good on mirtazapine but not on mianserin. So it is important that 5-ht2c antagonism is stronger than 5-ht2a to good working? Crazymed write that 5-ht2a antagonism counteract 5-ht2c antagonism, so if 5-ht2c antagonism is stronger it's good for med? sorry for english

so how agomelatine is working if it's half life is only 2 hours? it's dwonregulating this receptors? JohnG how is your apetite on agomelatine? I want something to increase my apetite but I don't like this "drunk" feeling of h1 antagonists...


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## jim_morrison (Aug 17, 2008)

mikoy said:


> It's sad that mianserin block the effect of methylphenidate in my case :f maybe it's 5-ht2a antagonism. I feel like drunk on mianserin...****ty feeling.


Yeah it's partly because mianserin/mirtazapine are such strong (antihistamine) H1 antagonists, and H1 antagonism blocks the TMN (tuberomammillary nucleus), which is a major wake promoting region in the brain.

So knocking out the TMN with mianserin/mirtazapine is probably counterproductive for the OP's purpose, and Agomeltine would be a better option.


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## JohnG (Sep 3, 2010)

I'm using it mostly to replace the use of the benzo for sleep, works quite well for now (25 mg), anxiety (GAD) seems less during the day. About depression, I dont know, methylphenidate wins :yes ( I don`t see any interaction between them)


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## mikoy (Aug 12, 2010)

Thanks! I think 5-ht2c antagonism is important for me - I tired all SSRI without success and when I tried fluoxetine I felt improvement immediately!


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## mikoy (Aug 12, 2010)

Thanks! I think 5-ht2c antagonism is important for me - I tired all SSRI without success and when I tried fluoxetine I felt improvement immediately!


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## JohnG (Sep 3, 2010)

I think we share the same biochemistry, I have also big improvement (mostly for anxiety) from the 5-HT2C antagonism. I was interested in fluoxetine (that looks to antagonize that receptors) but I never tried it because of the bad story about SSRI's induced aphaty. How worked for you? Did you see any problem about motivation and focus ?


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## mikoy (Aug 12, 2010)

Hey, what 5-ht2c antagonist make improvement in your case? Agomelatine? I'm thinking about this med, but it's so expensive in my country - 50 euro for one month - 25 mg :f But it's the only one pure 5-ht2c antagonist. Like crazymed said - 5-ht2a antagonism inhibit dopamine release and it's not good for ADHD (I think?). Yes, it looks like we have similar chemistry of brain and anxiety/depression. I hate this depression...I was on prednisolone for few months, and it's so damn bad for my depression - first I was thinking it's good, becouse it made my energy levels up, but corticosteroids are not good for depression - especially melancholic depression. I think my depression is melancholic - my apetite is weak, my sleep is weak, I'm agitated, my mood is better in the evening and worse in the morning, and I have so damn anhedonia. 5-ht2c receptor is responsible for apetite, sleep, anxiety, depression, and agonism of it enhance HPA axis. I think 5-ht2c receptor is very important in my case - it's inhibiting dopamine from social communication, feeding, even coffee...I have upregulated or increased 5-ht2c receptors for sure...don't know why? Maybe cortisol or corticosteroids upregulate it? I know that cytokines upregulate this receptor. I'm wondering why mirtazapine is better than mianserin for me - I know that mirtazapine is stronger 5-ht2c antagonist than 5-ht2a antagonist, and mianserin is stronger 5-ht2a antagonist than 5-ht2c antagonist.

I'm taking methylphenidate (3x5mg a day) and I see improvement in concentration and I social interactions, and I know dopamine is very important for this. I feel moments of peace and calmness on ritalin. It's so good feeling. Another meds that brings me this peace are anticholinergics - I think it's dopamine too - acetylcholine counteracting dopamine.

About fluoxetine and concentration/motivation/focus - it's working in some way like SSRI's, but not so strong. I think it's becouse 5-ht2c antagonism and dopamine release. Fluoxetine is 5-ht2c antagonist but not so strong - agomelatine is better option for this. But fluoxetine, when we taking it for long, can downregulate this receptors? (maybe?) And it's indirect agonising 5-ht2a and downregulate 5-ht1a autoreceptors.

Really? Don't know what to do...I want good mood! :f Things I'm gonna try:
-tianeptine for long time (for my melancholic depression, and HPA hyperactivity)
-methylphenidate (for my motivation, concentration)
-agomelatine (for pure 5-ht2c antagonism, to see if it's 5-ht2c antagonism)

maybe:
-fluoxetine (for long time, if nothing helps with my bad mood, fluoxetine is the only SSRI I can tolerate)
-bupropion (for long time, for nicotinic antagonism)
-mirtazapine (for 5-ht2c antagonism)
-ropinirole


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## JohnG (Sep 3, 2010)

Don`t worry too much about the 5-HT2A agonism. It release more dopamine (in certain area) but can cause anxiety and paranoia ( a lot of psychedelics are 5-HT2A agonist ).

5-HT1A and -2C, at least in my case, are the good one. :yes (+ dopamine)

About the 5-HT2C downregulation, Also antagonism and agonist seems to downregulate that receptor. (that's the way SSRI are supposed to work) so an increase of serotonin, can be good thing too.


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## mikoy (Aug 12, 2010)

http://www.bluelight.ru/vb/showthread.php?p=8595706

"This fits well with findings from other groups that there are two types of serotonin receptor in the amygdala, a brain region linked to emotion and anxiety:* 5-HT2A receptors that inhibit anxiety*, and *5-HT2C receptors that promote it*. The roles of the receptors were identified by injecting drugs that either stimulated or inhibited each receptor and observing the animals' behavioural response."

So 5-ht2a agonism inhibit anxiety. I think psychodelics cause anxiety from 5-ht2c agonism.


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## Sil (Jul 17, 2011)

I'm surprised no one has mentioned Pizotifen (Sandomigran), I came across this substance by complete error & it ignited a whole new look at drugs which I had previously rather black & whitely dismissed outright, apart from of course the stimulants which I've partly tried with nasty side affects unfortunately & MAOIs which I don't seem to have a chance in hell getting . 

(I did try Fluoxetine in the past & it made me feel ****ter than you can ever imagine, I now have a hate for drugs that don't really know what they're actually doing.)

Anyway basically I woke up early one morning with awful hayfever symptoms, I don't usually take meds for it anymore hence why when I checked out the family box of random meds, I couldn't find anything recognizable, but the Sandomigran looked like they were some type of hayfever med. 

I took a 0.5mg pill & was really surprised how well it worked, usually hayfever meds only lessen the symptoms but these worked outright no symptoms whatsoever for the whole of the day either. Now the amazing part for me at least, I also felt noticebly a lot more motivated & positive about life in general, talking felt pleasent - not forced in anyway which it can do, everything basically felt more enjoyable. My whole mindset was just a lot more upbeat, I was actually mildly productive & thinking about cool things I could do in the future. 

I do volunteering, I was a lot more sociable the next day after I took it again - the night before this time, I was also mildly confident socially which is something I didn't even really feel on Methylphenidate (Ritalin) in the same way. I find it hard to describe but the bottom line is it didn't make me feel high whatsoever like Ritalin, it was just subtle, almost as if you wouldn't really feel it much if you were say just sat in a box with no interaction or anything sort of thing.

I checked out Pizotifen on the net to find out what action it had & why it might be helping me out, it was then I noticed it was marketed as a treatment to prevent migraines, my sister apparently had it prescribed WAY back lol. Turns out it's a 5ht2a & 5ht2c antagonist, with H1 antihistamine action, it's also mildly anticholinergic. Now the side affects weren't to bad at all, I'd wake up with quite a dry mouth, also later in the day if I was doing anything strenuous it would make me feel a little physically weak but at the same time I was mentally more energetic. After I ran out of the Pizotifen, I found (just 5 tablets) I went to the doc to ask for a prescription, he said it was an antimigraine medication & that it was probably the antihistamine affect that was improving my mood, he couldn't prescribe it as per guidelines. After I ran out I did have tight leg muscles & was feeling quite stiff & wooden the next day but that went after a couple of days. Since then I've tried basic anti histamines - they certainly didn't improve my mood. Cetirizine hydrochloride made me feel like **** & all spacey & Loratadine worked well but I just felt neutral with maybe a little weakness like I had partly on Pizotifen but without all the other positive affects of Pizotifen.

I have a diagnosis of Sensory Processing Disorder & ADHD-PI along with this I have Social Phobia for sure but never seeked a diagnosis because it comes with the others really. Very happy I found this thread when searching for answers, some helpfull information on here that isn't available anywhere else. I couldn't find any information on the net about which receptor it antagonizes more & for how long etc it'd be nice if someone who knows more about this could add something. 

*Oh sorry it now seems that Cyproheptadine which is mentioned in the first post by mikoy is possibly very similar, oh well typed it all now.


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## michael10364 (Feb 4, 2011)

yeah cyproheptadine worked very well for my mirapex induced anhedonia


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## mikoy (Aug 12, 2010)

Sil it can be anticholinergic effect - anticholinergic drugs works for me quite similar.


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## Sil (Jul 17, 2011)

mikoy said:


> Sil it can be anticholinergic effect - anticholinergic drugs works for me quite similar.


Interesting, guess I'll never know for sure unless I take something that's specifically anticholinergic to a similar degree or something that primarily antagonises my 5-Ht2c receptor without any anticholinergic affects.

I had to visit my doctor again today, while I was there I asked if he could prescribe me Cyproheptadine as an antihistamine since it's very similar to Pitzotifen, he agreed unfortunately when I went to fill my prescription no pharmacist in the area had any in stock, the wholesalers didn't even have stock, turns out the manufacturer won't be producing anymore until the middle of September because of problems.


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## mikoy (Aug 12, 2010)

Try mirtazapine - it's strong 5-ht2c antagonist without anticholinergic, or oxybutynin (ditropan) - it's clear anticholinergic.


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## Sil (Jul 17, 2011)

mikoy said:


> Try mirtazapine - it's strong 5-ht2c antagonist without anticholinergic, or oxybutynin (ditropan) - it's clear anticholinergic.


I won't try Mitrazapine, don't want anything that's going to increase serotonin as a side effect, fluxetine did this & it was the worst feeling I can ever imagine - pure absolute nothingness, don't think I have a chance getting hold of oxybutyin. Have you tried either of these?

I did get my prescription for Cyproheptadine today though, so chuffed one pharmacist was really amazing & managed to get it imported for me. Not sure on what dosage I should take compared to Pizotifen though? I was taking 0.5 Pizotifen every night.


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## DaneV (Aug 3, 2011)

jim_morrison said:


> Good point Wes, I think they really need to come out with Agomelatine XR soon though before it will become very useful as the half life's so short.


I think they shouldn`t and haven`t done it for a reason.
First of all you *do not *want too much agomelatine in your blood during daytime, as the stimulation of the melatonin receptors will mess up your circadian rhythm.

Also, the 5HT2c receptors downregulate (not upregulate) due to the antagonism. The 5-6 hours agomelatonine will work, are probebly enough to cause this downregulation over a period of time...

Taking stimulants at daytime, and ago at nighttime could be beneficial i guess. Maybe fluoxetine is another option, as it also antagonises 5ht2c, allthough i don`t know how relevant this effect is. I did notice my wellbutrin was working WAY stronger when I was taking fluoxetine with it, but that could also be because of the NE effect fluoxetine has...


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## jonny neurotic (Jan 20, 2011)

O-desmethyltramadol is a 2C antagonist. This combined with the mu-opioid agonism will disinhibit dopamine greatly. It is also a noradrenaline reuptake inhibitor so caution should be observed if attempting to combin it with methylphenidate. I intend to combine it with ethylphenidate(which is far less noradrenergic) which I have been using with some success for my ADHD. The additional noradrenaline may be good. I intend to use clonidine with the ethylphenidate when I am indoors doing paperwork, etc. and the O-desmethyltramadol when I have to go out. Maybe some fluoxetine with the O-desmethyltramadol combo. IDK.


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## srschirm (Jun 25, 2006)

Mirtazapine is easily the weirdest thing I've tried, I felt "spaced out" after the first dose. Only took it for two days for this reason, maybe I should've given it more of a shot.


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## jonny neurotic (Jan 20, 2011)

srschirm said:


> Mirtazapine is easily the weirdest thing I've tried, I felt "spaced out" after the first dose. Only took it for two days for this reason, maybe I should've given it more of a shot.


I really don't like the look of these tetracyclics. Their pharmacology is all over the place and they are all potent antihistamines(ie. put you to sleep). Don't like the look of them at all...


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## srschirm (Jun 25, 2006)

jonny neurotic said:


> I really don't like the look of these tetracyclics. Their pharmacology is all over the place and they are all potent antihistamines(ie. put you to sleep). Don't like the look of them at all...


Yeah that's the only one I've tried. The antihistinergic effects may be a large reason I felt like I did. That was 6-7 years ago now. Overall Paxil has been the most beneficial thing I've tried, in particular a Paxil/Klonopin combo.


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## jonny neurotic (Jan 20, 2011)

crayzyMed said:


> Agomelatine, problem is that 5HT2A antagonism has the opposite action of 5HT2C antagonsm with most other meds.





mikoy said:


> So if med has 5-ht2a antagonism stronger than 5-ht2c it is useless? So combination of agomelatine and stimulant its good option?


I am not so sure about this hypothesis. I will look into myself but my thoughts currently are that the dopamine disinhibition is not where the most beneficial effects of 2C antagonism comes from. The 2C receptor in the basolateral amygdalae precipitates a fear response and blocking it(in rats at least) reduces fear. I do not know if the 2A antagonism would render this effect null or not but wont the 2A receptor upregulate in response to antagonism? If so then after a course of a drug that blocks both would one not feel less fearful generally? IDK...



JohnG said:


> Don`t worry too much about the 5-HT2A agonism. It release more dopamine (in certain area) but can cause anxiety and paranoia ( a lot of psychedelics are 5-HT2A agonist ).
> 
> 5-HT1A and -2C, at least in my case, are the good one. :yes (+ dopamine)
> 
> About the 5-HT2C downregulation, Also antagonism and agonist seems to downregulate that receptor. (that's the way SSRI are supposed to work) so an increase of serotonin, can be good thing too.


I'd like to see more data on this. Does the 2A antagonism cancel out the effect of the 2C antagonism in the basolateral amygdalae? I am not sure it this would be too much of an issue but IDK...


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## jonny neurotic (Jan 20, 2011)

I had been wondering about why this receptor downregulates in response to antagonism as well as agonism. My thoughts were that, in an evolutionary context, if there are lots of things in our environment to be scared of then it pays to be allert. Therefor, if the 2C receptor is consistently activated it will upregulate to make us more fearful and more wary of things in our environment. By blocking the receptor we can fool the brain into thinking everything is alright and thereby cause the 2C receptor to downregulate. 

The downregulation that occurs in response to over activation is just an automatic safety mechanism such as that which causes the D2 receptor to downregulate...


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## jonny neurotic (Jan 20, 2011)

Evidence that 5-HT2C receptor antagonists are anxiolytic in the rat Geller-Seifter model of anxiety




> The action of the 5-HT2C/5-HT2A receptor antagonists tested is therefore consistent with anxiolysis.


It would appear that antagonism of the 2A receptor does not inhibit the effects of the 2C antagonism to any significant extent if at all...


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## jonny neurotic (Jan 20, 2011)

Role of 5-HT2A receptors in the stress-induced down-regulation of brain-derived neurotrophic factor expression in rat hippocampus.



> Pretreatment with a selective 5-HT2A receptor antagonist, MDL100,907, significantly blocked the influence of stress on expression of BDNF mRNA. In contrast, pretreatment with either a selective 5-HT2C or 5-HT1A receptor antagonist did not influence the stress-induced decrease in levels of BDNF mRNA.


Perhaps there is good reason for blocking the 2A receptor too...


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