14 replies to this topic

[VICREP]

I have been apprehensive to try an SSRI for my mood/anxiety problems that I have battled for the past 3 years, primarily due to the potential for SSRI induced sexual dysfunction.

I'm considering trying 2.5mg of lexapro combined with a 5ht2c antagonist. Why?

Apparently the activation of the 5ht2c receptor by SSRIs is responsible for the suppression of dopamine and norepinephrine in important brain regions, including the meso-limbic system.

By combining a SSRI with a 5ht2c antagonist, research has shown a stronger effect in on relieving depression as well as a far lower incidence of sexual side effects. (I will provide sources later when I have more time)

Agomelatine is often used for this purpose, however is prohibitively expensive, and also had potent melatonin agonist qualities, which I would rather avoid.

What other 5ht2c antagonist are there?

SB-243,213
- is actually an inverse agonist, which may even have a stronger clinical effect than antagonism

SB-242,084
- is an antagonist with research backing its effective augmentation with SSRIs

Sorry about the rushed post. Don't actually have time at the minute to provide relevant sources. Will update in time

Thoughts?

[datrat]

Actually, if they ship to Australia and if it can get through your Customs, TeamTLR sells a very affordable bulk agomelatine. I don't have any affiliation with them, but I have tried it and it seemed to work for me.

Edited by datrat, 21 November 2014 - 02:08 AM.

[Ok555]

First of all i take lexapro(2.5-5mg) and agomelatin 25mg. My sexual fuction is ok now but  less than it was and goes down as ssri dose increases(arousal mainly) Second, sexual dysfunction is due to 5HT2A stimulation(mainly) NOT 5HT2C(ok maybe partially due to this receptor type also but still 5HT2A is a problem).  Third why avoid melatonin receptor stimulation? It only gives better sleep without any sedation. Also i tried different ADs against anxiety(GAD) and i have to say ssri-snri are best, life without them is hell, with them-, heaven.

My advice to your to avoid sexual dysfunction with ssri,- find good 5ht2a antagonist(http://www.tocris.co...p?ItemId=191897)) and take 5ht2c antagonist agomelatine(it also has strong anti-anxiety effect believe me, weaker than ssri but damn still very helpful, and literally no adverse effects except of some constipation,-no cognitive slowing, no memory loss, no apathy(which have all ssrii's i tried)) 

As a simple 5ht2a antagonist you can use trazadone, in doses less than 15mg it saturates almost only these receptors.

Edited by Ok555, 21 November 2014 - 07:32 PM.

[VICREP]

Actually, if they ship to Australia and if it can get through your Customs, TeamTLR sells a very affordable bulk agomelatine. I don't have any affiliation with them, but I have tried it and it seemed to work for me.

 

Thanks for the source. I have been keen to try agomelatine for a while but couldn't afford it online for on prescription.

 

 

 

First of all i take lexapro(2.5-5mg) and agomelatin 25mg. My sexual fuction is ok now but  less than it was and goes down as ssri dose increases(arousal mainly) Second, sexual dysfunction is due to 5HT2A stimulation(mainly) NOT 5HT2C(ok maybe partially due to this receptor type also but still 5HT2A is a problem).  Third why avoid melatonin receptor stimulation? It only gives better sleep without any sedation. Also i tried different ADs against anxiety(GAD) and i have to say ssri-snri are best, life without them is hell, with them-, heaven.

My advice to your to avoid sexual dysfunction with ssri,- find good 5ht2a antagonist(http://www.tocris.co...p?ItemId=191897)) and take 5ht2c antagonist agomelatine(it also has strong anti-anxiety effect believe me, weaker than ssri but damn still very helpful, and literally no adverse effects except of some constipation,-no cognitive slowing, no memory loss, no apathy(which have all ssrii's i tried)) 

As a simple 5ht2a antagonist you can use trazadone, in doses less than 15mg it saturates almost only these receptors.

 

 

 

I think that 5ht2a receptors may be linked with the vasodilation required for sexual function, however my primary concern is with low sexual arousal/desire/libido. Therefore blocking the inhibition of DA and NE caused by activation of the 5ht2c is what I need to focus on if I wish to take an SSRI.

 

Do you have a source supporting low dose Trazadone being mainly a 5ht2a antagonist? Trazadone has affinity for a vast amount of neurtransmitters I'm not interested in hitting.

[VICREP]

Tocris.com, are they a reliable vendor?

[Ok555]

Do you have a source supporting low dose Trazadone being mainly a 5ht2a antagonist? Trazadone has affinity for a vast amount of neurtransmitters I'm not interested in hitting.

 

http://www.cnsspectr...hlfig2(big).jpg

http://www.cnsspectr...?articleid=2373

 

Point is that due to trazadone's selectivity to 5HT2A receptors low doses (less than 25mg hypnotic dose) saturates only them. 

[lammas2]

Fluoxetine? Two-in-one: SSRI + 5HT2c antagonist. However it still has high rates of sexual dysfunction.

PS. Don't forget the fact that agomelatine is hepatoxic. Not to be used for extended periods without blood tests.

[Gorthaur]

If it's available in your country, I would suggest trying Viibryd (vilazodone) before lexapro and agomelatine. Viibryd is a new, unconventional SSRI which has a negligible effect on sexuality for most people. 

[deeptrance]

Have you considered taking the approach of directly stimulating dopamine receptors via increased dopamine and/or taking a dopamine agonist? You could look into pramepexole and ropinirole, for example, which are agonists of D2, 3, and 4 receptors.

 

Cabergoline may be helpful in maintaining dopamine signalling. I've been on a micro-dose of cabergoline for nearly a year. I tried it because I had developed anorgasmia so I was missing out on one of life's greatest pleasures. It worked brilliantly for me but some people don't get any benefit.

 

Cyproheptadine is a 5HT antagonist but probably works against SSRIs because of its activity at the 5ht2b receptor. Although there is no proof or consensus as to how SSRIs work, at least one study has demonstrated that activity at the 5ht2b receptor is necessary. I started using cyproheptadine occasionally at bedtime for 3 reasons. One, I use it to put the brakes on the 5ht agonists I sometimes take for recreation. Two, it helps me sleep because it is an antihistamine. And three, I speculate that antagonizing 5ht receptors overnight may have a benefit of up-regulating them. A word of caution on this drug is that it can plunge you into depression if taken during the day. I once took it when I wanted to go back to sleep for a few hours. It was around 4 AM and I when I woke up around 8, I felt a sense of doom and hopelessness. It was bizarre! But this doesn't happen if you take it within an hour of bedtime and you sleep for at least 6 hours, because its effects wear off by the time you awaken. How any of this would pertain to sexual function during the day, I have no clue. Useless paragraph here?

 

Dopamine-increasing supplements are another avenue you could try. Mucuna pruriens is promising; don't take the highly concentrated stuff (mostly l-dopa) because then you miss out on the benefits of other substances in the plant material. I take a 5% extract and I wouldn't go higher than 10 or 15. And if you try it, buy bulk powder from one of the few suppliers who have been used by many of us, because there's no reason to pay a big mark-up to a company that puts it in capsules and possibly uses fillers.

 

Catuaba is helpful for many people and it has dopaminergic properties. I make my own catuaba extract from Trichilia catigua bark, obtained from a highly reputable company. I go to this trouble because it's hard to obtain high quality catuaba, and many products don't even use the correct species. It also has antidepressant capabilities: http://www.citeulike...article/2416027 --- inhibits reuptake of both dopamine and serotonin, but the effect is much stronger for dopamine. In this situation, if you were to combine with an SSRI you'd want to keep catuaba dosage low so that the serotinin reuptake factor is negligible but you would still obtain some dopaminergic benefit.

 

Check the thread about dopaminergic herbs and supplements for many more possibilities. And good luck. SSRIs can turn a person's life around like a miracle drug, so it may be worth the negative side effects if that's the right drug for you. I've tried several of them and had terrible experiences with all of them. What ended up working for me was to take micro-doses (sub-threshold) of a very specific psychedelic that acts as an SNRI, but without the type of side effects I experienced on prescription SNRIs. The substance in question is highly pro-sexual, increasing libido and the sensory pleasure of sex, but in order to obtain it you have to incur some legal risk.

[Area-1255]

Agomelatine, mirtazapine, mianserin, are all 5-ht2C antagonists, but .....5-ht2c is involved in the male sexual response as indicated here...might not always be good to block.

 

http://pharmrev.aspe.../4/811.full.pdf

http://66.199.228.23...d_addiction.pdf

http://www.ncbi.nlm..../pubmed/9085055

 

Eur J Pharmacol. 1997 Mar 5;321(3):R11-3.

Potentiation of fluoxetine-induced penile erections by combined blockade of 5-HT1A and 5-HT1B receptors.

Millan MJ1, Perrin-Monneyron S.

Author information

 

Abstract

The serotonin reuptake inhibitor, fluoxetine (10.0 mg/kg, s.c.), elicited penile erections in rats. Selective blockade of 5-HT1A autoreceptors with WAY 100,635 ((N-(2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl)-N-(2-pyridinyl) cyclo-hexanecarboxamide) (0.16 mg/kg, s.c.), or of 5-HT1B autoreceptors with GR 127,935 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-me thyl- 1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide) (2.5 mg/kg, s.c.), slightly (1.5- to 2-fold) increased fluoxetine-induced penile erections. However, conjoint administration of WAY 100,635 and GR 127,935 markedly (5-fold) potentiated induction of penile erections by fluoxetine. Penile erections were abolished by the novel 5-HT2C receptor antagonist, SB 206,553 (5 methyl-1-(3-pyridil-carbamoyl)-1,2,3,5- tetrahydropyrrolo[2,3-f]indole). These data provide functional evidence for redundancy in autoreceptor control of 5-HT release. Combined blockade of 5-HT1A and 5-HT1B autoreceptors markedly enhances the actions of serotonin reuptake inhibitors.

PMID:   9085055   [PubMed - indexed for MEDLINE]

 

 

 

Edited by Area-1255, 30 November 2014 - 09:21 PM.

[deeptrance]

 

Agomelatine, mirtazapine, mianserin, are all 5-ht2C antagonists, but .....5-ht2c is involved in the male sexual response as indicated here...might not always be good to block.

 

 

Based only on my experience and not on any research, I find that if my serotonin receptors are less active then I don't enjoy sex as much, and orgasms are less pleasurable. What I notice is a trade-off between dopamine and serotonin, where the dopamine side leads to easier performance and ability to orgasm, but serotonin leads to more sensuality and pleasure in the experience.

 

HOWEVER, i am over-simplifying this to the point of absurdity. I know that the many physiological features of sex involve many different receptors and chemicals in the body and brain, and so it's nearly impossible to make a definitive statement as to what is ideal or how it all works together. So I rely on information found online in studies, articles, and forums, plus personal experience and experimentation.

 

My experimentation has been adventurous. With regard to your comments about dopamine agonists, I understand and generally agree with your concern about down-regulating those receptors, but the way I use the agonists is on an acute basis. Like, before engaging in sexual activity I take a dopamine agonist to enhance the experience, and it works fairly well. I don't use the agonists at any other time so I'm probably not molesting those receptors too badly. And cabergoline did wonders for my ability to achieve orgasm, but I have to micro-dose it or else it makes it TOO easy to orgasm and there is less pleasure from it. I take 0.25mg/week. It's potent shit, and the half-life is insanely long.

 

I visited your website and read a few of the articles/blogs. Interesting stuff. Thanks for contributing to this forum and bringing a more academic approach to the discussion. I don't recall, and am too lazy to check, if you mentioned melanotan II or its relatives here in this thread, but what is your opinion about those? I know, very controversial but the rumors are pretty enticing and I'm tempted to dip my toes into those waters, unless it requires using a needle.

[Area-1255]

 

 

Agomelatine, mirtazapine, mianserin, are all 5-ht2C antagonists, but .....5-ht2c is involved in the male sexual response as indicated here...might not always be good to block.

 

 

Based only on my experience and not on any research, I find that if my serotonin receptors are less active then I don't enjoy sex as much, and orgasms are less pleasurable. What I notice is a trade-off between dopamine and serotonin, where the dopamine side leads to easier performance and ability to orgasm, but serotonin leads to more sensuality and pleasure in the experience.

 

HOWEVER, i am over-simplifying this to the point of absurdity. I know that the many physiological features of sex involve many different receptors and chemicals in the body and brain, and so it's nearly impossible to make a definitive statement as to what is ideal or how it all works together. So I rely on information found online in studies, articles, and forums, plus personal experience and experimentation.

 

My experimentation has been adventurous. With regard to your comments about dopamine agonists, I understand and generally agree with your concern about down-regulating those receptors, but the way I use the agonists is on an acute basis. Like, before engaging in sexual activity I take a dopamine agonist to enhance the experience, and it works fairly well. I don't use the agonists at any other time so I'm probably not molesting those receptors too badly. And cabergoline did wonders for my ability to achieve orgasm, but I have to micro-dose it or else it makes it TOO easy to orgasm and there is less pleasure from it. I take 0.25mg/week. It's potent shit, and the half-life is insanely long.

 

I visited your website and read a few of the articles/blogs. Interesting stuff. Thanks for contributing to this forum and bringing a more academic approach to the discussion. I don't recall, and am too lazy to check, if you mentioned melanotan II or its relatives here in this thread, but what is your opinion about those? I know, very controversial but the rumors are pretty enticing and I'm tempted to dip my toes into those waters, unless it requires using a needle.

 

I tried PT-141; subq injection, it didn't do much until 2mg (dosed at 12 midnight) for me - in which case, the whole next day (almost,on and off,morning and evening mainly) was empowered with a stiff hard on and supercharged libido (more so than usual) - very strong stuff. 

It wasn't priapism though, as it wasn't painful, and I have experienced similar reactions with high dose naltrexone as well.

 

Though naltrexone made me feel incredibly irritable and depressed at night time, whereas usually night time is my super motivated time, it seems like opiate antagonists tend to rewrite circadian rhythyms, they might be useful for people who want to switch around day and night time habits...but , only if there is a way to counteract the despair and irritability with them.

 

Cabergoline and dopaminergics just make me want to sleep all day on average, though, if I use yohimbine the next day, I find there is a powerful synergism with them. Something neither one did alone, I think given dopaminergic agonists have CNS depressant properties, due to their D2 only activity, that yohimbine simply balances it out ----- now on the other hand, if one dopamine agonist affected both D1-like and D2-lke receptors, then it would be less depressant and more balanced...like APOMORPHINE for example, apomorphine was good as well for enhancement!

 

Serotonin is libido-dampening, I'm not sure given the amount of evidence available with this topic, especially considering the prevalence of PSSD from serotonergic drugs and supplements, that you would experience any sort of prosexual effect from serotonin, with exception only to 5-ht2C agonists or antagonists, depending on the person and situation....most serotonin receptors AT THE VERY LEAST, delay ejaculation or orgasm, BUT, it is possible you have low serotonin to begin with, so raising yours delays ejac enough to strengthen orgasm, by preventing either pre-E or providing a balance of EFS/Electric Reaction Output.

 

Your serotonin receptors might also be different than the average individual.

Edited by Area-1255, 01 December 2014 - 05:24 PM.

[deeptrance]

Cabergoline and dopaminergics just make me want to sleep all day on average, though, if I use yohimbine the next day, I find there is a powerful synergism with them. Something neither one did alone, I think given dopaminergic agonists have CNS depressant properties, due to their D2 only activity, that yohimbine simply balances it out ----- now on the other hand, if one dopamine agonist affected both D1-like and D2-lke receptors, then it would be less depressant and more balanced...like APOMORPHINE for example, apomorphine was good as well for enhancement!

I'm not familiar with apomorphine but I'm experienced with dopamine agonists and yohimbine. Pramipexole and ropinirole are both agonists of D2, 3, and 4 receptors, which does provide some balance although apparently some people can feel sleepy on them. I don't experience that effect. But I use small doses. As for yohimbine, I've had a hypertensive crisis from just a half of a suggested dose of yohimbe extract, and even the tiniest amount of the stuff makes me break out in cold sweats and feel agitated, but it's a horny agitation. So for me, it's a potent libido enhancer and it works brilliantly for every aspect of sex, with the minor problem of having almost life-threatening side effects. Needless to say, I don't use it anymore.

Now, part of my problem with yohimbe is that I usually have other things in my system which have a bad interaction with yohimbine. Generally speaking, my issues seem to arise from beta adrenergic stimulation and/or hyperserotonemia (sp?).
 

Serotonin is libido-dampening, I'm not sure given the amount of evidence available with this topic, especially considering the prevalence of PSSD from serotonergic drugs and supplements, that you would experience any sort of prosexual effect from serotonin, with exception only to 5-ht2C agonists or antagonists, depending on the person and situation....most serotonin receptors AT THE VERY LEAST, delay ejaculation or orgasm, BUT, it is possible you have low serotonin to begin with, so raising yours delays ejac enough to strengthen orgasm, by preventing either pre-E or providing a balance of EFS/Electric Reaction Output.
 
Your serotonin receptors might also be different than the average individual.

They might be different indeed. I suffered serotonin syndrome on a starter dose of an SSRI, and I've come close to the syndrome a couple other times on relatively minor doses of combinations that anyone else would have been able to handle.

What really enhances sexual pleasure for me are the sensual drugs like entactogens and very small doses of certain psychedelics. So maybe 5ht2c agonism is a factor. I was under the impressing that 2b is also involved because it is such a prominent feature of a few of the sex-enhancing drugs. However, the entactogens are also S-N-R releasers and reuptake inhibitors, and have multiple binding affinities to many different receptors, which may include one or more of the D's and god knows what else.

As for psyechedlics,5-meo-mipt and 5-meo-dipt are both known for pro-sexual effects, and they both inhibit reuptake of serotonin and norepinephrine in addition to being dopaminergic. And since all of these effects interact in complex ways, it's difficult to say precisely what is generating the sex-positive aspect of any of them.

[VICREP]

Agomelatine, mirtazapine, mianserin, are all 5-ht2C antagonists, but .....5-ht2c is involved in the male sexual response as indicated here...might not always be good to block.

http://pharmrev.aspe.../4/811.full.pdf
http://66.199.228.23...d_addiction.pdf
http://www.ncbi.nlm..../pubmed/9085055

Eur J Pharmacol. 1997 Mar 5;321(3):R11-3.
Potentiation of fluoxetine-induced penile erections by combined blockade of 5-HT1A and 5-HT1B receptors.
Millan MJ1, Perrin-Monneyron S.
Author information

Abstract

The serotonin reuptake inhibitor, fluoxetine (10.0 mg/kg, s.c.), elicited penile erections in rats. Selective blockade of 5-HT1A autoreceptors with WAY 100,635 ((N-(2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl)-N-(2-pyridinyl) cyclo-hexanecarboxamide) (0.16 mg/kg, s.c.), or of 5-HT1B autoreceptors with GR 127,935 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-me thyl- 1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide) (2.5 mg/kg, s.c.), slightly (1.5- to 2-fold) increased fluoxetine-induced penile erections. However, conjoint administration of WAY 100,635 and GR 127,935 markedly (5-fold) potentiated induction of penile erections by fluoxetine. Penile erections were abolished by the novel 5-HT2C receptor antagonist, SB 206,553 (5 methyl-1-(3-pyridil-carbamoyl)-1,2,3,5- tetrahydropyrrolo[2,3-f]indole). These data provide functional evidence for redundancy in autoreceptor control of 5-HT release. Combined blockade of 5-HT1A and 5-HT1B autoreceptors markedly enhances the actions of serotonin reuptake inhibitors.

PMID: 9085055 [PubMed - indexed for MEDLINE]

My main problem is with libido/desire and not erectile dysfunction. Maybe the ED caused by a 5ht2c receptor antagonist in this study is a consequent of vasoconstriction caused by more norepinephrine being released.

I'm not sure. It's a tricky conceit trying to categorise receptors as either good or bad. But I feel safe in make the general assumption that more DA and NE in the lambic system through 5ht2c receptor blockade would be advantageous for libido.

[Area-1255]

 

Agomelatine, mirtazapine, mianserin, are all 5-ht2C antagonists, but .....5-ht2c is involved in the male sexual response as indicated here...might not always be good to block.

http://pharmrev.aspe.../4/811.full.pdf
http://66.199.228.23...d_addiction.pdf
http://www.ncbi.nlm..../pubmed/9085055

Eur J Pharmacol. 1997 Mar 5;321(3):R11-3.
Potentiation of fluoxetine-induced penile erections by combined blockade of 5-HT1A and 5-HT1B receptors.
Millan MJ1, Perrin-Monneyron S.
Author information

Abstract

The serotonin reuptake inhibitor, fluoxetine (10.0 mg/kg, s.c.), elicited penile erections in rats. Selective blockade of 5-HT1A autoreceptors with WAY 100,635 ((N-(2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl)-N-(2-pyridinyl) cyclo-hexanecarboxamide) (0.16 mg/kg, s.c.), or of 5-HT1B autoreceptors with GR 127,935 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-me thyl- 1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide) (2.5 mg/kg, s.c.), slightly (1.5- to 2-fold) increased fluoxetine-induced penile erections. However, conjoint administration of WAY 100,635 and GR 127,935 markedly (5-fold) potentiated induction of penile erections by fluoxetine. Penile erections were abolished by the novel 5-HT2C receptor antagonist, SB 206,553 (5 methyl-1-(3-pyridil-carbamoyl)-1,2,3,5- tetrahydropyrrolo[2,3-f]indole). These data provide functional evidence for redundancy in autoreceptor control of 5-HT release. Combined blockade of 5-HT1A and 5-HT1B autoreceptors markedly enhances the actions of serotonin reuptake inhibitors.

PMID: 9085055 [PubMed - indexed for MEDLINE]
 

My main problem is with libido/desire and not erectile dysfunction. Maybe the ED caused by a 5ht2c receptor antagonist in this study is a consequent of vasoconstriction caused by more norepinephrine being released.

I'm not sure. It's a tricky conceit trying to categorise receptors as either good or bad. But I feel safe in make the general assumption that more DA and NE in the lambic system through 5ht2c receptor blockade would be advantageous for libido.

 

No, it's due to the oxytocin release of serotonin 5-ht2C receptors, as most studies point out it has to do with pheromonal/female stimulated response. That receptor also correlates with vasopressin mRNA in the paraventrical nucleus; that's the area most associated with sexual response and vasopressin; as most should know - is a potent natural aphrodisiac and naturally present in men more than women.

 

Serotonin is involved in basal and stress-induced regulation of hypothalamus and pituitary gland hormones such as prolactin, adrenocorticotropic hormone (ACTH), vasopressinand oxytocin, mainly via actions of receptor subtypes 5-HT_2A and 5-HT_2C.^[14] As such, the 5-HT_2C receptor is a significant modulator of the hypothalamic–pituitary–adrenal axis (HPA axis).^[15] The HPA axis is the main controller of acute sympathetic stress responses related to fight-or-flight response. Prolonged activation and disturbances of the HPA axis contribute to depressive and anxiety symptoms seen in many psychopathological conditions.

Stimulation of 5-HT_2C receptors leads to increase of corticotropin releasing hormone (CRH) and vasopressin mRNA in the paraventricular nucleus and proopiomelanocortin in the anterior pituitary lobe. In rats, restraint stress (which can produce depressive symptoms if being chronic) induces secretion of prolactin, ACTH, vasopressin and oxytocin which is partially mediated via 5-HT_2C receptor. Responses during such conditions as dehydration or haemorrhage causes the release oxytocin via serotonergic response that is partly mediated via 5-HT_2C. In addition, peripheral release of vasopressin involves serotonergic response which is partially mediated via 5-HT_2C.

Expression of the 5-HT_2C receptor in the CNS is modulated by female sex hormones estradiol and progesterone. Combination of the hormones decrease the receptor concentration in the ventral hippocampus in rats and could thus affect mood.^[16]

 

But ^   - it really is about balance again, because there are certainly negatives, and imHo if you have an estrogen issue or cortisol issue, you're better off blocking it.    http://www.ncbi.nlm.nih.gov/pubmed/18208678

Edited by Area-1255, 02 December 2014 - 12:29 PM.