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Can fluoxetine be cycled intermittently as a 5-HT2c antagonist?

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silvermane

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Jan 11, 2013
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I've been considering my options for a 5-HT2c receptor antagonist for the treatment of social anxiety (and comorbid depression). I realize many antipsychotics and SSRIs exist with this mechanism, however most of these produce unwanted effects (e.g., downregulated 5-HT receptors with prolonged SSRI treatment). I've searched for a natural alternative over the past two days, but unfortunately the only substance I could find was Kudzu (puerarin), which presumably has an extremely short half-life. This led my back to synthetic drugs: fluoxetine, in particular. The question I have now is whether fluoxetine's affinity for 5-HT2c antagonism is implicated with its more typical reuptake activity. Basically, I'd like to be able to use fluoxetine in a controlled manner strictly for the former effect. I wouldn't be using more than the minimal dose, which I can only assume is somewhere around 10mg (no more than 3 times per week)? Is this a realistic off-label application for the drug?

Alternatively, would it be possible to combine fluoxetine at a low dosage on a daily basis (say 10mg; I'm 6 feet, 200lbs) with mild serotonin agonists/enhancers (i.e., very moderate cannabis and psilocybin use, 5-HTP supplementation, and curcumin)? or is this a recipe for serotonin syndrome?
 
Fluoxetine isn't considered to be a 5ht2c antagonist - it's a SSRI... (I know it does have activity, but the SSRI activity is the strongest)
Realistically i think you will find that on-and-off treatment with SSRIs will probably make you feel rather worn out. If you want a 5ht2c antagonist a more selective one is probably better.

As neither cannabis, curcumin nor psilocybin are serotonin releasers to any extent, fluoxetine cotherapy is probably OK, although it may decrease the efficacy of psilocybin. Generally serotonergic psychedelics 'work best' when you have a minimum of interferign ligands.
 
sekio said:
Fluoxetine isn't considered to be a 5ht2c antagonist - it's a SSRI... (I know it does have activity, but the SSRI activity is the strongest)
Realistically i think you will find that on-and-off treatment with SSRIs will probably make you feel rather worn out. If you want a 5ht2c antagonist a more selective one is probably better.
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Yeah, I've pretty much given up on fluoxetine. I've come to accept that there are no viable selective 5ht2c antagonists for the applications I have in mind. It just seemed plausible that fluoxetine's 5-HT2c antagonism would take effect before it established a sufficient metabolism for SSRI activity.

sekio said:
As neither cannabis, curcumin nor psilocybin are serotonin releasers to any extent, fluoxetine cotherapy is probably OK, although it may decrease the efficacy of psilocybin. Generally serotonergic psychedelics 'work best' when you have a minimum of interferign ligands.
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I'm not an expert in pharmacology (this is why I originally posted this question in the basic drug discussion forum), but I was under the impression that cannabidiol was a potent 5-HT1a agonist, that psilocybin strongly mimicked serotonin at the 5-5HT2a receptor (e.g., Passie et al., "The Pharmacology of Psilocybin," 2002), that curcumin was a mild MAO-A inhibitor, and that 5-HTP was involved in serotonin synthesis. Wouldn't these be contributing, at least synergistically, to higher serotonin levels in the brain, and therefore to an increased risk of developing serotonin syndrome? I could be way off the mark here. I've only been researching these questions for the past week. Feel free to correct me.

Epsilon Alpha said:
I can see your logic, however fluoxetine is has a 1.4nM Ki for the SERT, but only a 64nM Ki for 5HT2C (granted that's the bovine value). It would be an SSRI at a far lower does than an effective 5HT2C antagonist.
http://www.bindingdb.org/data/mols/tenK8/MolStructure_81875.html
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Thanks, I don't disagree with this. I understand fluoxetine is a far more powerful SSRI than 5-HT2c antagonist. It just seemed that, properly cycled and in low doses, you could still get effective 5-HT2c antagonism without giving fluoxetine enough time to develop into a full-blooded SSRI.
 
A bit off topic but when I was taking low doses of DXM HBr daily for 2 weeks (30mg twice per day i think) I noticed my social anxiety more or less completely abolished. Also It never really returned to what it was upon stopping.

Not suggesting you try this nor is it really 5-ht2c related but still perhaps of interest. Though technically DXM does release 5-HT which then binds to 5-ht2c.
 
Scroll down to the 5-HT2C row in this link, it has a list of well known psychiatric drugs that antagonize the receptor.

I can recommend mirtazapine, when dosed correctly, and trazodone. Both will make you tired and incredibly hungry if you are prescribed a dosage that is too high or to be taken too often. If anxiety is a big part of your depression, then mirtazapine will help alleviate it as well as the dopamine/norepinephrine inhibitory action that the receptor subtype modulates. It also has some trippy inverse agonist action at 5-HT2A receptors which contrasts trazodone's complete antagonism which leads to a 'less connected' sensory experience with others and the world. You will become one with absurd amounts of sugar though.
 
One thing that just came to mind is the "SSRI start up period", personally in my current job I've seen how rough that can be on certain people. With that said, cycling use could be a bad idea should you respond poorly to the SSRI component.
 
Wouldn't these be contributing, at least synergistically, to higher serotonin levels in the brain, and therefore to an increased risk of developing serotonin syndrome?
Click to expand...

Not really, no. Generally postsynaptic serotonin agonists do not elevate serotonin concentrations indescriminately like SSRIs or MAOIs. And your body does have regulatory systems that prevent 5HT levels from raising too high from e.g. incgestion of 5HTP.

Curcumin is about as strong a MAO as rhodiola, that is, it's not at human-scale consumption levels. If you were on phenelzine it would be a much different story.
 
Epsilon Alpha said:
One thing that just came to mind is the "SSRI start up period", personally in my current job I've seen how rough that can be on certain people. With that said, cycling use could be a bad idea should you respond poorly to the SSRI component.
Click to expand...

I have no strong plans for using fluoxetine. I reviewed around a dozen drug reports online and I'm fairly convinced the SSRI component isn't as benign as I first thought, even in micro doses. I've abandoned that strategy. What I'm wondering now if whether there might not be a way to get selective blocking on 5-HT2c by stimulating some other receptor site. Not sure where to start looking for an answer to that question. Worse case, I'll focus on increasing dopamine and noradrenaline and ignore the 5-HT2c receptors altogether.

sekio said:
Not really, no. Generally postsynaptic serotonin agonists do not elevate serotonin concentrations indescriminately like SSRIs or MAOIs. And your body does have regulatory systems that prevent 5HT levels from raising too high from e.g. incgestion of 5HTP.

Curcumin is about as strong a MAO as rhodiola, that is, it's not at human-scale consumption levels. If you were on phenelzine it would be a much different story.
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You make a good point about the agonists. I wasn't entirely clear about that. Still, I'm left somewhat concerned about the curcumin and co. Right now I'm injesting about 120-200mg of curcumin per day in what feels like a highly bioavailable form. I prepare a large tablespoon of turmeric (6-7,000mg) in hot milk combined with 1/2 tsp black pepper, 1/2 tsp cinnamon, and 1 tsp honey. Subjectively, it's very strong, and I'm starting to think the effects are cumulative. I haven't started the 5-HTP or psilocybin just yet and there's a definite possibility that I'll be using some rhodiola in the future to amplify the MAOI activity. Supposing I actually did want to add fluoxetine to that cocktail, it's not at all clear to me how safe it would actually be. I doubt it would matter in my own case since my serotonin levels are likely depleted with all the smoking I've done over the past 14 years. But for someone else... I don't know. From the research I've done, it sounds like this mix has the potential to be lethal. At any rate, I plan on stacking these things slow to measure effects and will report back if I encounter any problems.
 
Subjective feeling is not an indicator of pharmacological activity.
 
fettered said:
Scroll down to the 5-HT2C row in this link, it has a list of well known psychiatric drugs that antagonize the receptor.

I can recommend mirtazapine, when dosed correctly, and trazodone. Both will make you tired and incredibly hungry if you are prescribed a dosage that is too high or to be taken too often. If anxiety is a big part of your depression, then mirtazapine will help alleviate it as well as the dopamine/norepinephrine inhibitory action that the receptor subtype modulates. It also has some trippy inverse agonist action at 5-HT2A receptors which contrasts trazodone's complete antagonism which leads to a 'less connected' sensory experience with others and the world. You will become one with absurd amounts of sugar though.
Click to expand...

This is not true, mirtazapine has a ridiculously high affinity for H1-receptors, which means that these receptors will get saturated at really low dosis, probably somewhere in between 3-10 mg's. Anything higher then that is going to make the drug less sedating.
 
Wizzle said:
This is not true, mirtazapine has a ridiculously high affinity for H1-receptors, which means that these receptors will get saturated at really low dosis, probably somewhere in between 3-10 mg's. Anything higher then that is going to make the drug less sedating.
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I should have worded that better, I meant that trazodone in large doses will be too sedating and frequent dosing of Remeron will make you hungrier because of its long half-life and serotonin antagonism.
 
Agomelatine is a 5ht2c antagonist. However I feel as if I've seen tolerance crop up with its use as well, fwiw, so cycling might still be a good idea.
 
What about buspirone? Only a weak 5-h2tc antagonist, method of action is 5-ht1a partial agonism, but it might help your anxiety.
 
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