Insights into PSSD ~ A Collection of Data & Detailed Analysis of the Etiology and Pathology of Post-SSRI-Sexual Dysfunction as well as Possible Novel Treatment Approaches

PSSD is an immensely maddening, depressing and sometimes even psychologically and even physically debilitating; it is characterized by two main points. 

• You have used anti-depressants in the past, specifically of the selective serotonin reuptake inhibitor (SSRI) class - see this page or read below to see which drugs fall in this category. 
• You have one of or many of the serotonergic induced sexual deficits - which may be delayed ejaculation in men, lack of orgasm for both men and women,  severe erectile dysfunction or lack of arousal in women and dramatically reduced or even absent libido in either sex.

Drugs in this class (SSRI) include (trade names in parentheses): (Highlighted are common USA brands)

citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital)

dapoxetine (Priligy)

escitalopram (Lexapro, Cipralex, Seroplex, Esertia)

fluoxetine (Depex, Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND))

fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox, Floxyfral)

paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc)

sertraline (Zoloft, Lustral, Serlain, Asentra, Tresleen)

Now this is going to be a long article, so bear with me. I would like to point out some major and minor (but relevant) differences between each drug. One of the most distinguishable traits of all SSRI's, with the exception only of those with a short half life (and these are used for other purposes) ~ is that each SSRI not only generally has a very long half-life, but also that each drug tends to have prominent effects on liver enzymes; generally CYP3A4 and CYP2C19 or cytochrome P450. The implications of this binding are many, one of the main problems here is that by these drugs binding to liver enzymes, depending on which one ~ there is a possibility of changing the breakdown of other drugs, or delaying their elimination - this can lead to amplified side-effects of other drugs and thus further causes physiological disturbances especially if the other drugs have even so much of a parallel in regards to their mechanism of action. 


Let's take the anti-depressant drug LUVOX aka fluvoxamine for example...this drug inhibits cytochrome P450(!). This is an enzyme involved with breakdown of drugs, as well as estrogen metabolism(See Here), consequently, drugs that inhibit this enzyme may increase the concentration of other drugs, such as blood pressure pills like metaprolol(TOPROL). In doing so, this is seen as a mechanism apart from it's primary mechanism, which is serotonin reuptake inhibition. Depending on the person, the inhibition of this enzyme may lead to estrogen deficiency or excess(R1)(R2)(R3). For some , excess may be more apparent, but it is also possible to have symptoms of high estrogen levels when indeed one has low levels, especially when on a drug like fluvoxamine (luvox) the reason for this is because elevated prolactin can mimic the effects of elevated estrogen, and luvox and other SSRI's are also capable of inducing large increases in prolactin levels.

Now in regards to what these studies imply, the issues are compounded by a lack of knowledge, and there is no direct mandate that doctor's should get their patient's frequent bloodwork on hormones and other bio-factors. There are only indirect and out of context "suggestions" ~ mostly in medical literature that was preceded by and prompted by, numerous complaints of drug side-effects.

This is deeply disturbing.

 Now another big no-no, in fact one that is warned about ON-LABEL, is combining these anti-depressant drugs with NATURAL inhibitors of these enzymes, related cytochrome enzymes, or downstream , fairly related enzymes - one of the most discussed is GRAPEFRUIT JUICE.

By combining grapefruit juice you may increase the risk of overdosing on multiple drugs, and if you then take a second inhibitor, like LUVOX; the effects are then ADDITIVE....which essentially means that combining one simple 6oz glass of grapefruit juice with luvox, and then a blood pressure pill - could very easily KILL you or land you in the hospital with nearly uncontrollable bouts of panic, or immobilization stress and severe HYPOTENSION...if you do survive such a combination, the almost total loss of oxygen delivery during the periods of treatment and recovery may result in permanent nerve and blood vessel damage!

~RETURNING TO THE DISTINGUISHABLE DIFFERENCES~       ~BETWEEN DIFFERENT SSRI-DRUGS~

So now moving back to other differences, and yet again I will use luvox as a novel example, besides it's effects on liver enzymes, it also acts as a sigma-1 receptor agonist(!). That means the answer to what is luvox's true mechanism of action - besides serotonin reuptake inhibition ? COMPETING FOR NEUROSTEROID SITES IN THE BRAIN>>which can certainly lead to some anxiolytic effects but this may also alter the effects of DHEA & Pregnenolone supplementation. To be clear, this means that luvox does have an interaction with DHEA and pregnenolone supplements - and it may reduce or amplify the effects of these supplements based on it's competition for their binding sites..of course, neurosteroids also have other binding sites and individual pathways, but it is possible that luvox may amplify the stimulatory effects of DHEA while reducing the anxiolytic; anxiety relieving effects. I can understand the reason some may take these supplements, and that would be in attempt to counter the lethargy and low libido associated with SSRI-anti-depressants. 
However, the picture is much more complex than just testosterone and neurosteroids when it comes to these side-effects, because you see, hormones simply act as mediators and regulators of downstream signaling pathway - but there is no guarantee that a particular level of or supplementation of a certain specific hormone would reverse the side-effects related to SSRI use. THE REASON, is because these drugs bind so tightly to the same downstream signaling pathways and receptors that many hormones do, as well as the upstream ones..that it becomes almost impossible to tell what is really going on and how much competition is enough for that individual to see a particular change. Because everyone has a different set threshold for hormones, different biochemical and genetic backgrounds, different diets, different levels of exercise, and most importantly, different mindsets, it becomes incredibly complex and very foolish to assume the supplementation or optimization of a particular hormone will cure or treat PSSD.

Now it may seem depressing as you are reading this, but do not lose hope...I didn't say that optimizing your hormones won't help - I am merely saying that you can't expect a specific volume of change if you don't know yourself . 

However, with combined and comprehensive treatment tactics, there is a possibility for hormone modulation to bridge the gap that leads to the successful resolution and reversal of this incredibly damaging disorder.


FLUOXETINE ; ALSO KNOWN AS PROZAC. 
Is also known to interact with and stimulate the sigma-1-receptor, but it is less potent than luvox in this regard.

Another manifestation of , specific sigma receptor agonism - is the inhibition of potassium related neurotransmitter efflux, and also a corresponding alteration in blood levels of potassium {SSRI Interactions with Potassium} while on these SSRI's. The results of such inhibition of potassium channels, are that there will be reductions of glutamate, norepinephrine(!), serotonin in the periphery(!), and dopamine in some areas of the brain(!), especially the amygdala ( a center of emotional processing) and prefrontal cortex(R1) {R2} [R3] (R4). In addition, the serotonin elevating effects of these anti-depressants may also further drain amydala region activity and neurotransmission - resulting in further emotional numbing. This region also plays a role in how we as humans form bonds, and the significant reduction in amygdala activity can lead to a lack of trust, bonding, and empathy for others....this may represent one mechanism by SSRI's can contribute to violent, erratic or even sociopathic behavior; the disinhibition brought about by the inhibition of amygdala activity.


Fluoxetine also has an effect on receptor expression in the hippocampus; an area heavily involved with spatial (directional memory and remembering where you place things) and active memory (able to respond to on-demand situations that require quick processing). Specifically, fluoxetine has been shown to increase dopamine D(1) expression in the hippocampus(!). This part in particular is a positive, and speaks of it's partially stimulating effects in terms of general cognition, however it reduces emotional and communicable cognition, generally.  Dopamine D(1) receptors are positively coupled to g-proteins/adenylyl cyclase ~ what this means is they increase central metabolism and even thyroid hormone output when activated - however, we are talking localized effects here as other brain regions affected by fluoxetine did not show this increase in receptor expression. This means the metabolic capacity of local cells is increased, and total brain region activity and neuron firing is increased....if then indeed the dopamine D1 EXPRESSION in the hippocampus is increased, then we have a central increase in glutamate, GABA and acetylcholine release in this brain region, but specifically in sub-regions of the hippocampus where dopamine D1 nerve terminals are present. 


Now you may ask , how does this relate to sexual dysfunction?

SIMPLY PUT, If cognitive and analytical processing is INCREASED, but emotional processing is DECREASED - then certainly, especially given the immense track record of them doing so - we are looking at a lack of desire to participate in social activities or an Overt indifference to all things pertaining to the pursuit of social activities - including forming relationships of all kinds, sexual included.

Thus indirectly, but directly, SSRI's such as PROZAC AND LUVOX, induce sexual dysfunction by not just physiological, vascular deficits (which we will get to in a bit), but overall emotional and motivational deficits....

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Now, let's look at LEXAPRO.

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LEXAPRO IS AN SSRI BUT ALSO A P-GLYCOPROTEIN SUBSTRATE & CYP2D6 INHIBITOR(!)
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This above mechanism of action can specifically increase the blood concentrations of antipsychotic drugs and it may also affect the breakdown of many dietary supplements. 

The popular fever reducing beverage known as "tonic water", containing quinine's, may interact with LEXAPRO (and other drugs) because of the p-glycoprotein occupation by lexapro as well as quinine and it's derivatives. THEREFORE, drinking tonic water with luvox, and then taking an antipsychotic drug, can result in life-threatening concentrations of those antipsychotic drugs. So does tonic water interact with SSRI's? YES. Well at least with LEXAPRO it does.

Thus the implications here are that lexapro can carry a high-risk of sexual dysfunction just as with other SSRI's - except that when lexapro is given in COMBINATION with antipsychotic drugs  - the result is a much broader and severe sexual dysfunction because lexapro elevates the level of antipsychotic drugs thus leading to a multi culprit, multipathway, and simultaneous dual antipsychotic-SSRI-induced sexual dysfunction and corresponding HYPERPROLACTINAEMIA (high prolactin level)....

Thus when antipsychotic drugs are given with lexapro specifically, the chances for other prolactin related complications are increased, and lexapro combined with antipsychotics may totally or mostly shut down sex hormone, thyroid hormone  and neurosteroid production in both men and women.  This is due to the feedback inhibition of prolactin induced by the combination of these two drugs, and their amplification of each other's blood levels. 

IN ADDITION, DIABETES, METABOLIC SYNDROME, AND THE RISK THEREOF ALSO ARE INCREASED DRAMATICALLY, WHEN LEXAPRO IS GIVEN WITH ANTIPSYCHOTIC DRUGS.
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NOW Here's a big one - ZOLOFT AKA SERTRALINE.

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Zoloft, unlike luvox and prozac, has contradictory studies regarding it's role at the sigma-1-receptor, with some studies showing it as an antagonist, namely the most recent ones  ~ (R1) ~ (R2)  ~ {New1}  ~ {New2} !!

Zoloft, unlike the other SSRI's also is associated with more weight gain, and is possibly active, very slightly at dopamine reuptake sites as well. Zoloft induced sexual dysfunction seems to be one of the worst - and this could very well be at least partially , due to long-term changes associated with inverse actions at the sigma receptors.

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CITALOPRAM AKA CELEXA

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Many call this the most dysphoric out of the SSRI's, it tends to have a slower pace of action in terms of receptor downregulation, weaker sigma-1 agonism than luvox, prozac and zoloft, and yet seems to inhibit dopamine quicker. Because celexa is inferior in terms of increasing nerve growth factor (compared to other SSRI's) - one could theorize that not only is the sigma-1-agonism weaker (which promotes NGF) , but 5-ht1A de-sensitization is LESS prominent with celexa......

This means that celexa is damn near purely serotonergic, which explains the fact that most on celexa either get more anxious, no change or feel generally shittier in comparison to the other SSRI's.

Therefore, Celexa is a drug with tunnel-vision in comparison to the others. 

                                                  REFERENCE 1  ~ REFERENCE 2
                                                  -------------------------------------------------
                                      REFERENCE 3 ~  REFERENCE 4


RED HIGHLIGHT = SIGMA STUDIES ABOVE

....::~::.::SIMILARITIES BETWEEN ALL SSRI's::.::~::....
          

and ONE MECHANISM THEY ALL SHARE           REGARDING SEXUAL DYSFUNCTION

Well let me start with the most obvious - and that is the long-term inhibition of dopaminergic, glutamatergic, GABAergic, histaminergic and cholinergic output and activity caused by chronic SSRI administration - or long-term anti-depressant therapy where an SSRI is the primary, or only component.

What happens here is that long-term use of serotonergic drugs or compounds, lowers dopamine through both direct and indirect mechanisms, and through frequently those same mechanisms, glutamate and other neurotransmitters that normally act to provoke sexual responses by means of nitrergic(nitric oxide) and oxytocinergic (oxytocin) nerve activity are also reduced. 

Specifically, long-term direct inhibition of dopamine and other neurotransmitters,by synthetically altered serotonin levels - is associated with the downregulation of dopamine receptors as well as serotonin receptors associated with long-term SSRI use.  

Now you may ask, why would serotonin receptor downregulation be a bad thing in regards to this?

Well first let's get a clear look at what happens when a serotonin receptor is downregulated or blocked...because it is very similar.

YES, each receptor has their own specific effects, usually different then the next one - however the primary changes in neurotransmitter systems associated with downregulation or blockade or over-agonism of a certain receptor, come from the fact that the given neurotransmitter is simply now acting through other receptors that are more available, making the individual effects of those receptors more prominent.

So long-term use of SSRI's leads to two primary chemical changes in regards to serotonin cell activity.

1.) The downregulation of 5-HT2A and 5-HT2C receptors(!).
2.) The de-sensitization or downregulation of presynaptic*5-hT1A serotonin receptors(!).


     :: THE DOWNREGULATION OF 5-HT2A RECEPTORS ITSELF IS NOT BAD ::

HOWEVER ~ In both of these above cases, the problem is essentially the same. With less 5-ht2A AND 2C serotonin receptors - more is now binding to 5-HT1X family receptors, which are highly inhibitory upon dopamine and glutamatergic neurotransmission. In addition, if 5-ht1A receptors are de-sensitized or downregulated, you now have MORE serotonin altogether; due to 5-ht1A RECEPTORS being AUTORECEPTORS that act to INHIBIT serotonin release. Now you have compounded the problem by allowing for serotonin over-activation at 5-ht1B,1D,3A,5-HT4,5A, and 5-HT6 receptors, the only reason I didn't mention 5-ht7 is because that serotonin receptor can be pro-sexual and increases sex hormone production....

5-HT2C receptor downregulation is not like 5-ht2A downregulation, and occurs through a separate mechanism by SSRI's; likely the reduction in estrogen and testosterone levels that act to increase 5-ht2C expression - 5-ht2C has it's positives and negatives, but of all serotonin receptors is the strongest in regards to increasing oxytocin release, whereas most others inhibit oxytocin release. Thus 5-ht2C is an exception - however, over 5-ht2c activation may be bad at the same time, because it can induce cortisol and prolactin release as well as inhibit dopamine - so it is a bit of a paradox, and what remains is that although it's oxytocinergic function is a positive, it's usefulness is limited by circumstances...in other words, it is very unlikely you are going to have 5-ht2c activation over riding the other receptors, because clearly, if serotonin is around for one it is around for others...therefore  how can it be beneficial, it's like trying to counter a monsoon by nailing the tent down with a few more nails - it's still going to get hit.

This is the reason behind the notion of using yohimbine to treat SSRI-induced sexual dysfunction, because yohimbine blocks 5-ht1B,1D and 2B receptors, and acts to block alpha-2-adrenoreceptors which are thought to modulate serotonin release through the 5-ht1A receptor.

However my problem with yohimbine is a few things.

1.) It does not address 5-HT at the anti-sexual 5-ht2A SITE.
2.) It may encourage negative post-synaptic 5-ht1A activation.
3.) It raises prolactin because of the above.
4.) Is practically useless in severe PSSD cases where long-term dopamine damage is evident. 
5.) Does not correct hormone imbalance, and may make cortisol excess worse.
6.) Will encourage serotonin induced vasoconstriction by 5-ht4 receptors. 
7.) Without berberine , chamomile or another 5-ht4 blocker it's use is limited. 




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CHANGES IN AROMATASE AND OTHER HORMONE PARAMETER'S DUE TO SSRI-USE
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All serotonin reuptake inhibitors will induce cortisol and prolactin release, and the long-term increases in cortisol because of serotonin activation of 5-ht1A, 5-ht2A (although to a lesser extent after downregulation occurs), and 5-ht3 & 4 receptors - can lead to increases in aromatase expression - HOWEVER, the net effect because of other factors like prolactin release is a decrease in all sex hormones; testosterone, estradiol, DHT, progesterone, DHEA, pregnenolone etc......

ALSO - because 5-HT1A activation inhibits NMDA-glutamate pathways - over time, this leads to reduction of nitric oxide synthase enzymes and a reduction in NMDA-induced synapse formation as well as a reduction in neurosteroids that NMDA would normally activate. Because of this inevitable pathway ,  the increases in brain-derived neurotrophic factors and nerve growth factor induced by SSRI's may eventually be short-circuited by depletion of endogenous neurosteroids and nitric oxide dysfunction.

POSSIBLE PSSD TREATMENTS

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Genetic Expression Modifiers

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PDE-5 mRNA : Target and Downregulate

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-We want to aim to promote a favorable balance between contractility & relaxation, and we also want to re-boot and / or restore dopaminergic nerve activity, and nitrergic and oxytocinergic nerve activity. These are the long-term goals. 

For both men and women, PDE-5 expression modification would be a prudent course of action.
Specifically we aim to do what Viagra does, but rather than a short-term band-aid, we reduce the total level of the enzymes Viagra normally inhibits - this would also act as an effective vehicle for long-term restoration of sexual function.

There are two ways I have come across to do this....

1.) The supplementation of two specific products ; Horny Goat Weed 60% ICARIIN and the supplement called "Berberine".      ICARIIN REFERENCE  ~ BERBERINE REFERENCE
                                           BERBERINE              HORNY GOAT WEED 60%
                                         


2.) Maximizing thyroid output and / or antagonizing opiate receptors.

Besides opiates ability to increase serotonin in the hypothalamus (postulated as one of the mechanisms by which SSRI's induce sexual dysfunction), they also increase phosphodiestearase enzymes; mainly by the kappa receptor - thus providing an anti-Viagra, pro-constrictive state. Also , the thyroid hormone T3 is a potent naturally produced PDE inhibitor - so maximizing thyroid hormones should increase (and has been documented to) sexual function in general.

Because SSRI's frequently lower thyroid output, and they also cause endorphin changes - a good course of action would be to restore proper thyroid function and especially T3 levels...opiate antagonism is also a good idea, however the side-effects can be immense when blocking all opioid's - as with naltrexone. 

Instead, using a natural kappa selective opioid antagonist should reverse the SSRI induced increases in PDE enzymes - one natural kappa opioid antagonist would be known as "amentoflavone".

Analyzed supplements produces the best of Amentoflavone and has a patent on it ; "AmentoMax" ..shown below.
                                                                        



To increase T3 Naturally we would need to both optimize metabolism and thyroid output in general, such as with exercise and IODINE SUPPLEMENTATION. Then to promote specific conversion of TSH (Thyroid-Stimulating-Hormone) to T4 THEN --> T3 we should utilize the following stack; which consists of forskolin and olive leaf extract - forskolin raises T4 levels and olive leaf promotes T3 production - olive leaf and forskolin also have pro-testosterone effects and can lower high blood presssure.

               OLIVE LEAF                     FORSKOLIN

                                                                                                                                                                                             
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METHOD #2 for PSSD Treatment - Tactical Serotonin Receptor Modulation (TSRM)

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This concept has been much discussed, what with the rise of cyproheptadine and similar compounds as novel serotonin antagonists.

This method can work very well - and cyproheptadine itself has been shown to prove useful in sexual dysfunction related to serotonergic drugs and compounds. (!) (!)

The notion behind this is to reverse some of the dopamine depleting effects of serotonergic drugs by blocking serotonin's inhibitory effects on dopamine and / or enhancing dopamine by the pathway itself - regardless of current serotonin state. 

My issue with cyproheptadine itself is a few things.
 .::.::.Keep in mind I am not saying not to try it, it could very well help many, but you should know the downsides in either case, so as to explore every viable option and possibility.::.::.

• Cyproheptadine blocks muscarinic receptors, and acts as a potent antihistamine - both of which can cause or worsen sexual dysfunction (!)(!), and may in some individuals over ride the benefits of it's serotonin antagonism - especially since part of the goal with serotonin blockade is to restore normal levels of acetylcholine (which cyproheptadine blocks).

                                              ROLE OF HISTAMINE IN HUMAN PENILE ERECTION

• Cyproheptadine doesn't have any affinity to antagonize 5-HT4, 1B. 1D - and excess serotonin at these receptors also inhibits sexual function (!) {!} [ ! ] .

• Cyproheptadine also possesses some anti-dopaminergic activity(!) (!).

• A lesser-known and well held back fact, that is hidden from common booklets, is that cyproheptadine also shows a very high affinity to the histamine H(2) receptor as an antagonist(!). Histamine H2's are important in stimulating GABA release, cyclic AMP, thyroid hormones, nitric oxide and testosterone levels...! (!) (!) (!)

Now I've created a nice little chart that should clarify what I believe is a much stronger, but also a more expensive serotonin-modulation cocktail.

The reason I didn't include 5-HT5A,5-HT1F or 5-HT7, is because each of these receptors are pretty irrelevant to sexual function, or they are the exceptions and can play a positive role. Besides the serotonin receptor 5-hT2C, 5-HT7 is also pro-sexual, and 5-HT5A is irrelevant because it is merely an autoreceptor, and so the activation of, if anything, is positive in PSSD sufferers.

5HT5A also has anxiolytic properties, aside from the effects on negative feedback from serotonergic nerve terminals - and the activation of would allow for less anxiety, which can disrupt sexual function.

                                 MIRTAZAPINE (Remeron) 5-HT2A Antagonist

               { BUY ONLINE BY CLICKING IMAGE }

                                                    

YOHIMBINE - 1B Blocker,1D,2B                    BERBERINE - 5-HT4/PDE5 BLOCKER
                                                                     

                                               MAGNOLIA -  5-HT6 ANTAGONIST
                                                                 

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METHOD #3 - DOPAMINERGICS; AND THEIR MANY FLAWS AND BENEFITS IN ATTEMPTING TO TREAT PSSD         

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{You can buy each of these online, simply click the image corresponding to which one you want and it will take you to a store where you can buy them without a prescription and not research grade but brand name}      

                                                                            

Dopaminergics are somewhat promising, however, there a few downsides.
Though they can have efficacy, particularly in reducing prolactin, and restoring testosterone production if it applies (!) (!)

The problem one would have with dopaminergics, is a few things - now again, I am not saying do not attempt, they have and will help many people - just be aware of the possible downsides.

• Many of them can induce hypotension (low blood pressure) at moderate doses. 
• They won't help restore glutamate or acetylcholine that is lowered by SSRI treatment.
• Thus they do not help an understimulated nervous system , and if you are one individual who's suffering more from the hypoactive glutamate and cholinergic systems - then dopaminergics may very well make it worse since they tend to lower glutamate and acetylcholine themselves.
• Tyrosine Hydroxylase (TH) is the enzyme that allows you to PRODUCE dopamine in the first place, by transforming tyrosine into L-Dopa, which then converts to dopamine. Anything that lowers cyclic AMP will reduce tyrosine hydroxylase , and thus lower dopamine net production. 
• Dopaminergics directly and potently lower cyclic AMP, with only cabergoline and apomorphine as exceptions...and thus even though you are getting agonism at one beneficial receptor, you will be losing natural dopamine at the others.
• Thus dopaminergics are best used in combination with forskolin and muira puama to help counter the side-effects, a dopaminergic at night, and muira puama and forskolin in the morning / throughout the day.
• Reason is because muira puama acts as a D1 and beta-adrenergic-agonist, thus raising cyclic AMP and fitting into the receptors that classical dopaminergics do not activate or tend to de-activate.
• Therefore, if you have PSSD, you should be careful of using dopaminergics alone - and consider all of the above information.

The parameter's that dopaminergics would in theory benefit themselves , would be.

• Low libido in men and women, but again, only if nervous system isn't trending to understimulated/low sympathetic activity. If you are prone to overstimulation, then dopaminergics may benefit you.
• May help reduce an otherwise high refractory period in men, and restore orgasm capacity.
• May restore vaginal lubrication in women, and raise general arousal as well, but again, take into consideration that lethargy that may be caused by dopaminergics may also worsen this in theory, in women/girls as well.

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METHOD #4 - Pharmacological Manipulation of Adrenergic Activity (mainly male)
Poster Child Thread : Ultimate Adrenergic Control of Erections
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A journal notes that the combined use of doxasozin and Viagra was able to potentiate each other and result in a greater effect in erectile dysfunctions. 

Another study notes the improvement in sexual function when doxasozin is given in combination with ketanserin and other serotonin antagonists.


This is consistent with both adrenaline via both alpha-1 and alpha-2 receptors, inhibiting sexual function  - these are the ONLY adrenaline receptors that inhibit sexual function. Block these two and there is a guaranteed shift between contraction and relaxation, vasoconstriction and vasodilation....

Some at this point may ask,
Q : Well why do some people get erectile dysfunction on clenbuterol or beta-agonists, if these receptors do not cause vasoconstriction??

REASON : INDIRECT AGONISM OF ALPHA RECEPTORS.
When beta receptors are activated, the release of cyclic AMP goes up, which triggers dopamine synthesis, thyroid hormone enhancement and an overall increase in noradrenaline and glutamate...which can then lead to more alpha-agonism indirectly. 

If you were to SUFFICIENTLY BLOCK BOTH ALPHA-RECEPTORS, then this would no longer be an issue - unfortunately, it's not always that easy because EVERYONE WILL REQUIRE A DIFFERENT DOSE OF EACH ALPHA BLOCKER.....

If you have low body fat and still have impaired sexual function, then it is likely you do NOT need an alpha-2-blocker , as the number of alpha-2-receptors in our blood and body, are dependent on body fat...which means, with lower body fat - it is MORE LIKELY you will need alpha-1-blockade - if indeed your problem comes from adrenaline in the first place..however, ALMOST EVERY CASE OF IMPAIRED SEXUAL FUNCTION COMES AT LEAST IN PART, BY ADRENALINE OVERLOAD....

PART of the problem with SSRI use is that your noradrenergic systems are out of control because of long-term nitric oxide and dopaminergic deficiencies caused by these drugs, both dopamine and nitric oxide are ESSENTIAL to reducing excess adrenergic (adrenaline) activity.... in the periphery especially.

Generally, in terms of sexual function, the goal to , as seen in threads above would be to obtain both blockers of alpha-1 and alpha-2-receptors.....

A potent adrenergic modulation stack for returning / enhancing sexual function would be.

• Either prazosin, doxasozin or trazodone at night.
• Plus either mianserin or mirtazapine (Remeron) at night.
• Yohimbine during the day.

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METHOD #5 - Viagra,Cialis,Levitra and Other PDE-5 Inhibitors.
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Direct PDE-5 inhibition could have some benefits, unfortunately it is short-lived when there is no actual production of nitric oxide - thereby, these drugs will do nothing in the face of nerve damage..so if you ask "why isn't viagra or cialis etc working?"

Two things.

1.) Production of nitric oxide is diminished, therefore these drugs won't do much of anything because they only work by sustaining what nitric oxide is ALREADY AROUND.
2.) You have either nerve issues or adrenaline excess - both of which the common E.D drugs will not touch.

That being said, Viagra and Cialis can have their benefits as a quick-aid , but nothing more..they can also be used in combination with the other methods above, but I would caution ANYONE who has hypotension against using any of these chemicals.

If you were to choose between Viagra and Levitra, you should go with levitra, as it has a lessened side-effect profile and faster onset of action - and is more potent all for all. However, Cialis may very well be the best out of these - because of it's long half life and even lesser side-effects than both Levitra and Viagra altogether.

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DHT Derivatives; Their Benefits and Why They May or May Not work For PSSD {MALE}
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DHT is the most masculinizing hormone; the most androgenic form of testosterone, and thus the primary, and only "true" male sex hormone; it also has been shown to play an important in maintaining normal erectile function.

Let's start with some basic evidence.

http://www.ncbi.nlm.nih.gov/pubmed/7534702

Endocrinology. 1995 Apr;136(4):1495-501.

Dihydrotestosterone is the active androgen in the maintenance of nitric oxide-mediated penile erection in the rat.

Androgens are essential for the expression of normal libido in the male, but their role in the maintenance of the erectile response in humans is controversial. It has been shown previously in the rat that castration induces 1) loss of penile reflexes; and 2) considerable reduction in the erectile response to electric field stimulation (EFS) of the cavernosal nerve. Both of these effects can be reversed by testosterone replacement. The current study was performed to determine whether these testosterone effects are mediated via its conversion to dihydrotestosterone (DHT), and to what extent the synthesis of the mediator of penile erection, nitric oxide, is affected by castration and androgen replacement. Five-month-old rats were either castrated or left intact. The orchiectomized rats were implanted with SILASTIC brand silicon tubing (Dow Corning) containing testosterone or DHT with or without daily injections of the 5 alpha-reductase inhibitor finasteride. After 7 days, rats were submitted to EFS and the intracavernosal pressure was recorded. Castration reduced the EFS-induced erectile response by 50% in comparison with intact rats and testosterone restored this decrease to normal. When finasteride was given to these testosterone-treated castrate rats, erectile response was not restored. DHT was as effective as testosterone in restoring response to EFS in castrates and this effect was not decreased by finasteride. Nitric oxide synthase activity in the penile cytosol was measured by the arginine-citrulline conversion and was found to correlate with the EFS determinations. These results show that DHT is the active androgen in the prevention of erectile failure seen in castrated rats, and suggest that this effect may be mediated, at least partially, by changes in nitric oxide synthase levels in the penis.

PMID: 7534702 [PubMed - indexed for MEDLINE]

First I want to make it perfectly clear, that there is very little evidence that androgens (even despite the above, read context and references) have any direct effect on libido - mainly because the studies showing they increase libido did NOT take into the account the ratio of Androgen:Estrogen or they weren't properly performed under parameter's that would distinguish androgen from estrogen effects. Indeed, some aromatization can sustain a healthy libido, but only in the proper ratio with androgens. Too little or too much aromatization, leads to loss of libido - but by each totally different mechanisms. However, DHT is the active androgen in maintaining normal erectile function and responsivity , it may indirectly increase libido to an extent - but only through it's secondary mediations on free testosterone and estrogen levels. Because DHT binds to SHBG; sex hormone binding globulin ; it allows for less testosterone and estradiol to be bound by the same and thus both of these hormones are "freed up" in essence. DHT also modulates estrogen by antagonizing or regulating estrogen receptor expression. Thus optimizing the circuitry by which estrogen operates, while minimizing the side-effects of estrogen. There are a couple studies showing that DHT promotes sexual responsivity, specifically in response to a female - aka PHEROMONAL RESPONSE - but not to erotic imagery. 

This means that ANDROGENS play a role in the pursuit of more realistic sexual activities (aka wanting the real thing instead of porn) - but by a social mechanism , and also by social disinhibition. Because androgens supply a sense of confidence, they indirectly may increase libido - but not necessarily fantasies , only do they increase the "mood for" as a remnant of a more stable personality. 

WHEN ESTROGEN IS DEFICIENT - LIBIDO IS STILL LOWERED - HOWEVER, DHT REPLACEMENT CAN CORRECT SOME PARAMETER'S OF SEXUAL FUNCTION, BUT MAY NOT RESTORE FANTASIES AND OTHER COMPLEX SEXUAL THOUGHTS.

Clin Endocrinol (Oxf). 1999 Oct;51(4):517-24.Role of oestrogen in male sexual behaviour: insights from the natural model of aromatase deficiency.
AbstractOBJECTIVE:In order to evaluate the role of oestrogens on human male sexual behaviour, the gender-identity, psychosexual orientation and sexual activity of a man with a congenital lack of oestradiol resulting from an inactivating mutation of the aromatase P450 gene was investigated. The psychosexual and sexual behavioural evaluations were performed before and during testosterone treatment and before oestradiol treatment, during three phases of different dosages of oestradiol treatment.DESIGN:The study was performed before (phase A) and during (phase B) testosterone enanthate treatment (250 mg i.m. every 10 days, for 6 months), during testosterone withdrawal (phase C), and during each of the following transdermal oestradiol treatments: 50 microg twice a week for 6 months (phase D); 25 microg twice a week for 9 months (phase E), and 12.5 microg twice a week for 9 months (phase F).MEASUREMENTS:Sexual behaviour was investigated by a sexological interview and by a 2-month self-reported daily diary performed during each phase of the protocol study. Furthermore, during each oestradiol treatment (phase C, D, E and F), a study of depression, anxiety trait and sexual behaviour was performed by the Beck Depression Inventory (BDI), the Spielberger Trait Anxiety Inventory (STAI) and the Golombok-Rust Inventory of Sexual Satisfaction (GRISS), respectively. Sexual orientation and gender-identity were evaluated by the BEM Sex Role Inventory (BSRI). Serum testosterone and oestradiol were measured during each phase of the study.RESULTS:Before oestradiol treatment (phase C), serum oestradiol was undetectable, while it rose to 356.1, 88.1 and 55.1 pmol/l during phases D, E and F, respectively. Before any oestradiol treatment, during phase D, phase E and phase F serum testosterone was 18.13, 0.72, 14.3 and 18.51 nmol/l, respectively. The patient's gender-identity as assessed by BSRI and by the sexological interview was clearly male. The psychosexual orientation evaluated by BSRI, by the sexological interview and by the analysis of the self-filled diary was heterosexual. Relevant modification of the patient's sexual behaviour occurred only during oestrogen treatment. This was more evident during both phase E and phase F, and concerned the behavioural parameters with an increase of libido, frequency of sexual intercourse, masturbation and erotic fantasies. A reduction of BDI and STAI scores was detected during the oestrogen phases.CONCLUSIONS:The study of the sexual behaviour in this man with aromatase deficiency suggests that oestrogens in humans do not affect gender-identity and sexual orientation but could have a role in male sexual activity.PMID: 10583321 [PubMed - indexed for MEDLINE]

Always read the fine print, here's another study and specifically remember we are talking about SEXUAL FUNCTION, not necessarily libido.

J Sex Med. 2014 Oct;11(10):2562-70. doi: 10.1111/jsm.12550. Epub 2014 Apr 20.Male Sexual Function Can Be Maintained Without Aromatization: Randomized Placebo-Controlled Trial of Dihydrotestosterone (DHT) in Healthy, Older Men for 24 Months.
Abstract

INTRODUCTION:Male sexual function is highly androgen dependent but whether aromatization of testosterone (T) to estradiol is required remains contentious.AIM:This study aims to investigate the effects of selective estrogen deficiency induced by a nonaromatizable androgen, dihydrotestosterone (DHT), on sexual function of healthy middle-aged and older men.METHODS:Randomized clinical trial of daily transdermal DHT (70 mg) or placebo gel treatment in 114 healthy middle-aged and older (>50 years, mean 60.5 years) men without known prostate disease maintaining selective estrogen deficiency for 24 months.

OUTCOME MEASURES AND ANALYSIS:The end points were responses to a psychosexual and mood questionnaire completed before, at 3 months, then at 6 monthly intervals during and 3 months after study. Data were analyzed by mixed model analysis of variance for repeated measures using age and body mass index (BMI) as covariates and including interactions of treatment with age and time-on-study.

RESULTS:DHT treatment increased serum DHT with complete suppression of serum T, luteinizing hormone, follicle stimulating hormone, and estradiol throughout the 24-month study resulting in reduced spinal bone density. There were no spontaneous complaints, or discontinuations for, adverse effects on sexual function during the study. DHT administration had no effects on any of 33 measures of sexual function and mood, apart from a mild, but significant decrease in overall sexual desire, which was reversible after cessation of treatment. Increasing age and less often increasing BMI were associated with significant decreases in most aspects of sexual function.

CONCLUSIONS:We conclude that aromatization plays only a minimal role in maintenance of sexual function in healthy eugonadal middle-aged or older men, but age and obesity are significantly associated with decreases in most aspects of self-reported sexual function and satisfaction. The dependence of male sexual function on aromatization may be conditional on age and obesity and can be overcome by a nonaromatizable androgen. Sartorius GA, Ly LP, and Handelsman DJ. Male sexual function can be maintained without aromatization: Randomized placebo-controlled trial of dihydrotestosterone (DHT) in healthy, older men for 24 months. J Sex Med 2014;11:2562-2570.© 2014 International Society for Sexual Medicine.KEYWORDS:Age; Androgen; Aromatase; Aromatization; DHT; Men; Obesity; Sexual Function; Testosterone

So now let's dive into the complexities of specific androgen-estrogen-serotonin interactions. 

Being that androgens play a role in both normal erectile function and female stimulated sexual response (but not other markers) - can we then conclude that DHT is a promising treatment in PSSD sufferers?

Let's go over a few things.

SSRI's may lower testosterone by raising prolactin and cortisol levels, as well as by modifying endorphin activity to produce more anti-gonadotropic feedback. They also may lower important intracellular cyclic AMP levels ; leading to a decrease in thyroid output , testosterone and steroidogenic acute regulatory protein *sTAR) - all of this will lower libido. 

But why not just optimize hormone levels...that seems like a more feasible and long-term solution?

In fact, there is no why not, that should be the first course of actions... restoring and optimization testosterone production. 

However as seen in other parts of this article - permanent aromatase changes may occur with long-term SSRI use, and even a decrease in androgen receptors based on long-term sTAR-downregulation induced by SSRI's as well as corticosteroid induced alterations in neuronal activity.....especially in the paraventrical nucleus which determines sexual function. 


The result in here would beg that one should choose a multi-faceted approach, simultaneously reducing a high estrogen level, or taking an anti-prolactin and anti-cortisol agent to get these levels down - upon doing so ...we can begin to see the light on the horizon. 

Now you may ask, "can we just temporarily use a DHT analogue to restore sexual function while re-balancing hormones, or can this be a permanent solution"?

The answer is a little complex, yes you can use DHT analogues to restore sexual function, they can be used in a pinch to activate sexual function but they are expensive and not viable long-term therapies - add insult to injury because DHT also inhibits the hypothalamus - through estrogen receptor beta cross activation and through endorphin release. Thus to keep your natural testosterone production going while on a DHT analogue, would require both estrogen antagonism and opiate antagonism - or at least a ridiculous number of other mechanisms e.g "natural test boosters" - perhaps being stacked with hCG - human chorionic gonadotropin.

Taken together, the extent of applicability of DHT analogues is limited by it's price tag and it's effects on natural production, and if you so choose to go this route you will be adding up more expenses trying to keep your natural production going. 

But...it's not even that simple!

Let's assume that we do have the close to 90 or 100 bucks a month to afford masteron or another DHT analogue, as well as the 40 bucks plus, to afford aromatase inhibitors and another 40-50 bucks, depending on where you get it, for the opiate antagonist....the issue now is that we are now playing with fire because we could also possibly lower estrogen too much, and there is a very fine line between low and deficient as far as estrogen levels go..by crossing this line we may eradicate libido even if we restore sexual "function". Refer to earlier studies at the top. 

WHAT GOOD IS HAVING THE TOOL BUT NOT HAVING A DESIRE TO USE IT?


That being said , there are some benefits short-term and certainly some people who will be very respondent to DHT drugs, and again, sexual function being a primary target but indirectly via estrogen modulation.

Let's go over a few of these compounds now. I will go over the positives and negatives.

PROVIRON {ORAL} ~ Proviron is also known by it's chemical name ; as mesterolone - it is a methylated DHT derivative that is orally active, however, some studies show very little protein binding and this limits it's bioavailability. Proviron also is more mild in terms of HPTA suppression, with doses up to 25 mg showing minimal gonadotropin suppression. Proviron may be ideal for those who can't / won't inject a stronger DHT derivative. Proviron may be able to boost strength and stimulate the CNS. It has been used to increase libido and improve fertility and erectile function.

Click on the image below to buy {proviron}.

Proviron for Cheap Online

< DOWNSIDES : Poor Bioavailability, needs consistent dosing during the day.

{REFERENCE ONE}  (REFERENCE TWO) 

                                                                                               
http://www.old.health.gov.il/units/pharmacy/trufot/alonim/3368.pdf

MASTERON (Injectable) Mast, or masteron, is also known by it's chemical name DROSTANOLONE PROPIONATE.  Also known as drostanolone propionate, is an injection, and has full bioavailability when injected intramuscularly, it also has a half-life of 2-3 days, meaning it can be injected only once every 2 or 3 days, the benefits of this are based on it's bioavailibility and uptake, high blood brain barrier penetration and thus exerting a powerful effect on androgen mediated signals.  Masteron will bind SHBG more rapidly than proviron, and for those who can tolerate it - it will likely exert a much more potent, quick and long--lasting pro-sexual effect.

The downsides of masteron ; are that it can inhibit natural hormone production to a much great extent than proviron, and this is harder to counteract due to the half life - though in theory , one can still use an opiate antagonist and an anti-E. However. this may amplify the effects on blood pressure as well - and the continuum becomes much more complex - as combined opiate antagonism and estrogen reduction will also raise blood pressure. Blood pressure balance may be achieved by redcuing estrogen, but this is mediated by electrolyte changes as opposed to nervous system activity. In feedback, CNS activity reaches a higher peak, and blood pressure goes up even with masteron alone - not just because of it's anti-estrogen effects itself, but because DHT itself stimulates the CNS.

Again, yes DHT cross activates estrogen receptor beta to inhibit the hypothalamus, but assuming that grounding estrogen into the floor will help is utter ignorance, my implication is that you can increase hypothalamic output this way - but then you will still need opiate antagonism . 

In addition, by no means is it simple enough, to stop this negative feedback from such a potent steroidal compound - you may also need to counter act the adrenaline rise produced by it and it's interactions with other brain chemicals...which means the ONLY way you can both stop the negative feedback induced by masteron or DHT derivates, as well as counter act blood pressure increasing effects...is by forming a very precise and coordinated cocktail that provides three things.

1.) Alpha-1-receptor blockade...because DHT increases alpha-1-adrenoreceptors and adrenaline.
2.) Opiate antagonism (because DHT raises beta-endorphin, which can then raise PDE's and exert negative feedback by other mechanisms)
3.) Estrogen Modulation ; likely a SERM and an AI.


Thus , a formidable cocktail would be 

1.) Either tamulosin, doxasozin or phentolamine. Preferably one of the first two - due to better half lives.
2.) Naltrexone , anywhere from 10-25 mg or more. (can produce very ugly side effects though )
3.) Clomid plus arimidex or another aromatase inhibitor.

Masteron carries a quicker onset of effect than proviron and may rapidly boost libido, and erectile function, as well as provide a strong anti-estrogen effect and consequently, diuresis and decreases in body fat.