The role of sigma-1 receptor

[Progecitor]

I made a new topic as I feel that sigma-1 was not discussed properly even though it makes sound connections between several POISers’ experiences.

As it turns out sigma-1 agonists are very likely to be beneficial in my case. I have just done a one day trial on dextromethorphan (DXM) (Robitussin - Antitussicum) with a rather good experience. The amount I took was 3 times 5 ml (5 ml equals 5.86 mg DXM) (about 18 mg). The most remarkable effect was a very significant reduction in the burning pain of urination and I could pee relatively well while standing, which is rare nowadays. In the afternoon and evening I felt a rather good and prolonged anti-depressive effect as well, but I think that this may have been due to a synergy between DXM and bupropion/berberine that I take in the mornings and Yohimbine/SAM-e that I take in the afternoons.
DXM is structurally similar to codeine and morphine, so normally someone would suspect opioid involvement, however as a study shows DXM’s effect on urinary bladder contraction is due to either an antagonistic effect on NMDA receptors or an agonistic effect on sigma-1 receptors.

This made me recall Muon’s findings on sigma-1 receptors and all of this makes perfect sense and sigma-1 agonists could be indeed useful for the treatment of POIS. I also need to have my progesterone level measured ASAP!

Or would extra progesterone be produced by the body to counter over-activation of sigma receptors?

IDK. takedrugstoletgo said that her menstrual cycle induces POIS like symptoms when progesterone rises plus she becomes more attracted to same sex in POIS mode. So this could be pointing in the direction of progesterone. The latter could perturb some kind of balance. If the sigma's are overactive then, you would say, a rise in progesterone would decrease the POIS symptoms but the opposite is true in the example above, that is, if changes in progesterone affects POIS symptoms at all. So does progesterone rise upon orgasm?

I've tried medication that targets P4 receptors but without any noticable effect. Same dose as in the 2nd POIS paper. The sigma-1 receptor modulates calcium signaling through the IP3 receptor. I don't have knowledge about these mechanics. I already mentioned in my thread that decreases of intracellular calcium could play a role in lymphocytes regarding the lab data. There are other hormones that bind to sigma's as well. Sigma 2 is involved in mTOR which is linked to cancer (and mast cell activation). High levels in men: High progesterone levels are associated with family history of premature coronary artery disease in young healthy adult men

https://en.wikipedia.org/wiki/Sigma-1_receptor

The abundant neurosteroid steroid hormone DHEA is an agonist at sigma receptors and along with pregnenolone could be endogenous agonist ligands; opposed by sigma antagonistic activity from progesterone. Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with sigma-1.
Agonists: Choline, 4-PPBP, Afobazole, Anavex 2-73, Arketamine, Berberine, Citalopram, Cocaine, Dehydroepiandrosterone (DHEA), Dehydroepiandrosterone sulfate (DHEA-S), Dextromethorphan (DXM), Dextrorphan, N,N-Dimethyltryptamine (DMT), Dimemorfan, Ditolylguanidine, Escitalopram, Fluoxetine, Fluvoxamine, Igmesine, Ketamine, Lamotrigine, Memantine, Methamphetamine, Methylphenidate, Noscapine, Opipramol, Pentazocine, Pentoxyverine, Phencyclidine, Pregnenolone, Pregnenolone sulfate, Siramesine
Antagonists: Haloperidol, Panamesine, Phenothiazines, Progesterone, Rimcazole, Sertraline
https://en.wikipedia.org/wiki/Sigma_receptor

Activation of sigma-1 receptors should be neuroprotective and many of these agonists have been used successfully by POISers, ME/CFS and long-covid members.
As I have mentioned earlier I had some success with sertraline (Zoloft) in the past, however that may have been due to its SSRI mechanism. However when I was in sertraline withdrawal for a few days my POIS symptoms have almost completely disappeared, though they slowly crept back later unfortunately. Now I am rather convinced that this must have been due to the lost antagonist activity on sigma-1 receptors.

Recently, sigma-1R has been implicated in autophagosome formation and maturation. Autophagy is a broad homeostatic, metabolic, cytoplasmic quality control, and metabolic process affecting many functions in the cell. sigma-1R is targeted by the nsp6 protein of SARS-CoV-2 to inhibit autophagosome formation as a process competing with the coronavirus for cellular endomembranes that the virus needs for its own replication. This along with the observed beneficial effects of sigma-1 receptor agonist and SSRI fluvoxamine in patients with SARS-COV-2 infection has led to the hypothesis that the sigma-1 receptor could be a target for the treatment of SARS-COV-2.
There has been much interest in the sigma-1 receptor and its role in age-related neurodegenerative diseases such as Alzheimer's disease. During healthy ageing, the density of sigma-1 receptors has been shown to increase. However, in diseases such as Alzheimer's disease, there appears to be a reduction in sigma-1 receptor expression. It has been suggested that targeting the sigma-1 receptor along with other receptors could increase neuron survival and function in neurodegenerative disease. The activation of autophagy has also been suggested as a downstream mechanism linked to sigma-1 receptor activation.
https://en.wikipedia.org/wiki/Sigma-1_receptor

https://en.wikipedia.org/wiki/Fluoxetine#Pharmacodynamics

"Fluoxetine increases the concentration of circulating allopregnanolone, a potent GABAA receptor positive allosteric modulator, in the brain."

"In addition, fluoxetine has been found to act as an agonist of the sigma-1 receptor."

https://www.tandfonline.com/doi/abs/10.1080/14728222.2020.1805435

"For the treatment of multiple sclerosis, NMDA antagonist, and sigma-1 receptor agonist eliprodil, has been shown to increase myelination 2-fold."

This would make Eliprodil a very prospective treatment option for POIS, though the chance to get an actual prescription is very low.

The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors

Some POISers mention food seeking behaviour in POIS mode especially junk food. Cocaine shuts this Ghrelin(?) mediated behaviour down via Sigma-1 receptor agonism. POIS itself could be an antagonist of Sigma-1 receptor.

If this is true, then it could potentially explain my food cravings right after O. Of course I won’t use cocaine, but hopefully DXM and other sigma-1 agonists could help with this issue.

Even though POIS may be connected to a high progesterone level and S1R antagonism, I have to note that recently I had a great success with chasteberry capsules as well. I took a new product and used it for several days. It certainly provided a reliable benefit and had an evident anti-depressive effect. I stopped taking it for the time being as I am concerned over its possible effects on fertility. What is not clear how chasteberry is supposed to alter progesterone in man. It is also possible that it acts as an anti-progestin, which may explain to apparent contradiction, though I also believe that its ERbeta agonist compounds must have a role in the overall benefit.

I also have shy bladder syndrome that developed after years of POIS. Hopefully this will also help resolving that.

Opioid analgesics structurally related to Dextromethorphan (DXM) also inhibit bladder contractions and produce urinary retention through a non-opioid mechanism.
Opioids have the unpleasant side effect of causing urinary retention. Perhaps the most direct way in which opioids might cause urinary retention is by inhibiting detrusor muscle contractions within the bladder.
Although relatively little is known about the role of sigma receptors in micturition, Shimizu et al. [2000, 2001] reported that sigma receptor agonists reduce the frequency of volume-induced bladder contractions, increase bladder capacity and raise the threshold pressure for micturition in anesthetized rats. The effects of DXM on micturition could thus be caused by either blockade of NMDA receptors or activation of sigma-1 receptors.
The major finding of this study is that DXM produced a dose-dependent inhibition of rat and mouse bladder contractions evoked by electrical FS, the muscarinic receptor agonist carbachol and elevated KCl concentrations. The ability of DXM to inhibit bladder contractions from all three modes of stimulation suggests that it acts through a direct effect on the cholinergic innervation of the bladder rather than on the bladder muscle itself.
Dextromethorphan is metabolized extensively to dextrorphan (DOR) which is also biologically active. Interestingly, DOR displays even higher affinity for NMDA and sigma-1 receptors than the parent compound. The DXM concentrations of plasma and urine are about 10-fold higher among patients who lack CYP2D6, the enzyme that initially metabolizes DXM, who comprise approximately 5-10% of the population.
Sigma-1 receptor mRNA is also found in both sympathetic and parasympathetic ganglia and activation of sigma-1 receptors has been shown to inhibit calcium channel currents in post-ganglionic autonomic neurons in vitro. Hence, it is plausible to hypothesize that DXM inhibits bladder contractions by interacting with either NMDA or sigma-1 receptors localized in autonomic ganglia or nerve terminals within the bladder.
These findings provide substantive evidence that sigma-1 receptor agonists are capable of inhibiting bladder contractions by acting in either the central nervous system or directly in the bladder. The present data along with published results suggest that DXM may also affect micturition by acting both within central nervous system and directly on the bladder although it remains to be determined whether the same receptor mediates the two responses.
Bladder contractions are also inhibited by opioids that are structurally different than morphine including loperamide, a phenylpiperidine and methadone, a phenylheptylamine and these effects are also unaffected by naloxone pretreatment.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Effects+of+dextromethorphan+on+in+vitro+contractile+responses+of+mouse+and+rat+urinary+bladders&btnG=

At the physiological level, it's involved in calcium signaling at the mitochondria and nucleus, and is important for cell survival and the cellular stress response, especially to oxidative stress. Activation of the receptor increases the survivability of cells under stress and exerts neurotrophic effects, such as NGF-induced neuritogenesis and BDNF-induced hippocampal growth. S1R agonists have been found to exert antidepressant effects in mice and humans, although they only act on a pathological substrate - that is, S1R is only activated when the system is in need of the cellular stress response.
The damage caused by stroke happens via a process called excitotoxosis, in which oxygen-deprived cells build up reactive oxygen species (ROS), become highly overactive (excess glutamatergic signalling), and die off. This occurs during a primary stroke episode, but also continues for some time following a stroke. Sigma-1R functions naturally to reduce ROS and prevent hypoxic cell death, and S1R ligands have been shown to do so in vitro.
Of the 6 major SSRIs (in the US anyway), fluvoxamine has the highest S1R affinity. Fluoxetine and escitalopram are ranked as the next most potent agonists, followed by citalopram and paroxetine, which display minimal S1R agonism. So, the antidepressant effects of SSRIs are probably not due solely to S1R agonism. There are definitely other ways to arrive there.
Also, digging a bit deeper, it seems that the interaction between S1R and 5-HT1A is crucial for the effects of dual agonists (including novel agonists, such as OPC-14523). If we block either the S1R actions or the 5-HT1A actions, the antidepressant effects are negated. Further, combining two drugs, one a 5-HT1A agonist and one a S1R agonist, we get similar antidepressant effects to SSRIs.
https://www.reddit.com/r/neuroscience/comments/8kifgs/the_sigma1_receptor/

S1R bind with high affinity to several classes of chemically unrelated ligands such as neurosteroids, neuroleptics, DXM, and several psychostimulants such as cocaine, methamphetamine, MDMA and methacathinone. Consequently, it is thought that S1R may mediate the immunosuppressant, antipsychotic and neuroprotective effects of many drugs.
S1Rs regulate a number of neurotransmitter systems, including the glutamatergic, dopaminergic [DA], serotonergic, noradrenergic and cholinergic systems.
Sigma-1 Agonists
Many S1R agonists are anti-amnestic, synaptogenetic, and neuroprotective in conditions of neuronal stress. They also mitigate disease and symptoms in experimental models of ALS, Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), stroke, and TBI.
S1R agonists promote neurogenesis in the hippocampus and they may mitigate memory impairment because they can stabilize mature, mushroom spines, which serve as sites of robust synaptic connections encoding lasting information.
They also appear to activate TrkB both through BDNF-dependent and independent mechanisms. This may involve regulation of BDNF expression and processing as well as direct interactions of S1R with the TrkB receptor.
Sigma-1 agonists have been found to improve cognitive function in a wide variety of animal models related to cholinergic dysfunction, NMDA receptor hypofunction, amyloid beta toxicity, aging, hypoxia, prenatal stress, and other conditions. The cognitive enhancement by sigma-1 agonists in these models is mediated via sigma-1 receptors. Proposed mechanisms underlying these pro-cognitive effects include facilitating the release of acetylcholine and glutamate, regulating NMDA receptor signaling, modifying calcium homeostasis, and promoting neuronal differentiation and plasticity.
Some antidepressant/anti-anhedonic medications and Alzheimer's medications like donepezil also happen to act as Sigma-1 receptor agonists, and this action likely contributes to their therapeutic effects on cognition. In summary, Sigma-1 receptors play an important neuromodulatory role in various processes fundamental to learning and memory. Sigma-1 agonists continue to show promise as cognitive enhancers, especially under pathological conditions involving cholinergic or glutamatergic deficits.
The problem with Sigma-1 agonism is that it has some issues. First, it can be potentially reinforcing, with Sigma-1 agonists being potentially addictive if co-administered with compounds which enhance dopamine release. Sigma-1 agonists also effect locomotor activity, which is not an optimal profile for a compound if high selectivity is the target. Agonism can also potentially cause immunosuppression.
Allosteric Sig1R Modulators
The first drug discovered as an allosteric modulator of Sig1R was phenytoin, an anti-convulsant drug that primarily acts by blocking the voltage-gated sodium channels.
Methylphenylpiracetam (E1R) was discovered to target only the Sig1R site in in vitro pharmacological profiling assays.
One study found that indole-N-methyl transferase (INMT), an enzyme that converts tryptamine into the sigma-1 ligand dimethyltryptamine (DMT), is also localized to postsynaptic sites of C-terminals in close proximity to the S1R. This close association of INMT and S1Rs suggest that DMT is synthesized locally to effectively activate S1R in MN (motoneurons).
Modulating Sigma-1, especially with PAMs, seems like a very promising mechanism of action for cognitive enhancement and also for treating numerous existing neurological disorders. Using allosterics rather than agonists seems to be the way to go, as they have a superior effect profile and efficacy.
A lot of existing pharmacological compounds are ligands at Sigma-1, however they lack selectivity and also lack allosteric affinity. Compounds with high selectivity and also with affinity for the allosteric site only are most likely superior candidate compounds.
Also:
- ShockLatter2787:
I believe on the supplement front both berberine and saffron are either Pam's or agonists.
- CombinatonProud:
I would expect them to be weak agonists. unlikely to be pams.
https://www.reddit.com/r/prefrontal/comments/18wwbas/the_neuroscience_of_sigma1_%CF%831_and_its_relevance/

[Progecitor]

I also found this accidentally, which I thought to be very interesting. I wonder if JM is actually a POISer. By the way I also have a really bad response to night shifts even if I had slept some before.

JM is a 57-year-old adult male who works as a doctor at a public hospital in Spain. He developed some signs of musculoskeletal pain, especially in his limbs, and fatigue 10 years ago. These symptoms slowly increased and became more extensive until they reached disabling levels. The muscular pain limited him to moderate exercise, as it took him almost 1 week to completely recover from performing physical activity. JM also developed sleep disorders, waking up in the night due to pain. After working a night shift in the hospital’s emergency services, he again needed 1 week to recover physically and in terms of his sleep rhythm. Regarding his sexual life, it took a lot of effort for him to even caress his spouse because of the muscular pain in his arms. After intercourse, he also needed 1 week to recover, and ejaculation was painful, so he experienced decreased sexual desire. Other symptoms included an inability to lift heavy weights, decreased attentiveness, and vision with muted colors. He decided to visit a rheumatologist 3 years ago and was diagnosed with fibromyalgia and chronic fatigue.
Fluoxetine, however, was effective for both pain and fatigue, assisting JM to attain a rating of 3–4 on the pain scale again. Nevertheless, after 6 weeks of treatment, he decided to stop taking fluoxetine, because he developed autolytic ideation and annoying rumination, the symptoms that he had not previously experienced.
JM has attended five changa sessions so far. In the first session, he was only able to relax, because he did not know how to smoke. In the second session, 1 week later, he could smoke correctly and felt intense psychoactive effects. After this session, his pain disappeared almost completely for a period of 2 weeks. After the third session, which further took place after 2 weeks, his mood had also improved. The autolytic ideation disappeared and he felt much better. According to him, he was able to see colors brightly again. He had the same results after his fourth session, which took place 15 days after the previous one. After that session, he reported greater emotional stability, pain relief, and a slight decrease in fatigue as well. He participated in another changa session 1 month later, after which he confirmed the decrease in pain that lasted up to 15 days.
We can suggest various mechanisms through which changa may exert an analgesic effect. In this case, freebase DMT extracted from M. hostilis was used. DMT is an indole alkaloid widely found in plants and in mammals, including humans. It is a partial agonist of serotonin (5-HT) receptors (1A,2A and 2C) and also an agonist of sigma-1 receptors (sigma1R).
DMT also reduces inflammation via S1R. It has been observed that inflammation response can induce pain, and that inflammatory signals can induce changes in neurotransmitter metabolism, neuroendocrine function, and neuroplasticity. In this respect, DMT can also induce neuronal plasticity, which can play a vital role in the treatment of pain
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Long-lasting+analgesic+effect+of+the+psychedelic+drug+changa+%3A+A+case+report&btnG=

[Progecitor]

The effective mechanism of psilocybin or magic mushroom is clearly the activation of the sigma-1 receptor (S1R). Psilocybin is converted to dimethyltryptamine (DMT), which is the only known endogenous ligand for S1R. Psilocybin’s activity on 5-HT1A may also provide a synergism. Many of those who tried it felt better, though others did not find it useful or claim that it actually made them worse. I don’t really know the answer for the latter, but those who had success with it may want to try other S1R agonists that are possibly safer.

LSD and psilocybin proved anti-depressive for some POISers, but of course they are not a recommended treatment.

The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Psi binds with high affinity to 5-HT1A, 5-HT2A/C, 5-HT6, and 5-HT7 receptors. In humans, Psi is rapidly dephosphorylated to psilocin (4-N,N-dimethyltryptamine), which acts as a partial agonist at 5-HT2A and 5-HT1A receptors. Furthermore, given that 5-HT1A receptor stimulation has been associated with decreased, and 5-HT2A receptor stimulation has been associated with both decreased and increased, neuronal excitation of medial prefrontal neurons at rest. Interestingly, the structurally related psychotropic 5-HT2A/1A agonist lysergic acid diethylamide (LSD) increases extracellular medial prefrontal Glu release and prefrontal pyramidal cell activity in rodents.
https://www.pnas.org/content/pnas/113/18/5119.full.pdf

Hi everyone,

Let me introduce myself, I'm 21 and I have strong psycho and physical symptoms.

I tried magic mushrooms (psilocyb) 3 times while I was on pois and I experienced something very strange every time. At first I had the effect of the mushrooms but after 3 hours I started to feel very good, my mind was cristal clear, I could speak to anyone and I had real self-confidence. The exact opposit of my pois. Of course the next morning I was on pois again but it was increadible. My friends / girlfriend didn't experienced this second stage at all.

Your can't take magic mushrooms without having pscho effects. I know that it can prevent POIS kicking in.
Magic mushrooms will effect your outlook on life for a very long time. It is simply not a ling term treatment option in my view, although may have some medical research insight.

FB

@FloppyBanana you are probably right you can't have the second effect without having the psycho effect first. This being said, the article mention people free of depression 3 months after the treatment. Therefore I can only suppose that the psycho effect have disapeared a long time ago.

Yeah I tried micro dosing psilocybin this week and it has a good effect switching on my brain the way it should be working - it cures Neuroinflammotory conditions. I haven't tried for POIS yet though.

Had 2 Os yesterday and my symptoms today have been much better than they have been in the last two months.

Heres what I've been taking/doing nicotinamide riboside, matcha tea, nicotinamide extended release, NAC, epsom salt baths, byron white a fng, lymphatic drainage massage from groin lymph nodes (perrin technique), psilocybin micro dose, eating less/smaller meals, drinking alkaline water, epa oil, mediation with grounding pillow and band.

• Psilocybin (I'm not recommending this to anyone, but it does seem quite effective at boosting serotonin, increasing bodily awareness, activating the vagus nerve and releasing trauma and muscular tension)
• 5-HTP (not as effective for me as psilocybin, but I definitely feel an effect at low doses when my mood is low)

My first real mushroom trip happened earlier this year at a music festival. In a period of a few hours, I experienced what seemed equivalent to a few years of psychotherapy. I had the sensation that the weight of the world had lifted off my shoulders. The sense of calm was... almost unbelievable.

Psilocybin really has a knack for shooting you back into your body, and telling you exactly what's wrong in your mind, body and spirit. Even a large microdose (say 0.5g) will have that effect.

With that said, there are legal modalities that can accomplish similar things. They just require more work and/or money. Holotropic breathing is powerful stuff. My first impression of craniosacral therapy is that it could be a good alternative to psychedelic therapy.

Some racetams may work as allosteric modulators of the sigma-1 recptor. It may be possible that constant overactivation of sigma-1 could lead to receptor downregulation over time, which would result in antagonist-like effects.

Non psychoactive tryptamines barely help and they have similar side effects to psychoactive ones. Usually anti epileptic drugs help pois even milder medications like gabapentin, fasoracetam and extreme high dosages of taurine. Anti depressants like duloxetine and other neuroprotective SNRI helped long term with heat intolerance and vasospasms, eyesight and tingly feelings, brainfog, however the insomnia it causes is horrible and it does change your personality when you take it long term. Also withdrawals of duloxetine are the worst of all SNRI/SSRI. Some Heroin addicts say its harder to withdraw from high dosages of duloxetine than heroin.

All other drugs only made pois worse or created a temporary bandaid. I liked citalopram because it helped the most with anxiety and didn't had adverse effect on other drugs neither did it change my personality. Iboprufen, diclofenac (nsaids) , anti histamine all help with itch, inflammation and histamine related effects. Kratom helped with pain. And benzodiazapines helped with spinal nerve pain and reduced motor function in muscles.

Psychedelic mushrooms made pois worse long term. Same for MDMA , 6-apb, cathinones, 2C-X drug classes, phenylphentamines and other synthetic shit. Almost all of these synthetic drugs have extremely potent anti histamine/anti inflammatory effects (similar to 120 mg cetirizin or higher ) but long term i think they probably make pois worse. 4-FMP  was also good  but it simply **** language  up your kidneys with local vasoconstriction.

Most promising is mescaline (especially derived from trichocereus bridgessi) and 5-meo-mipt with the latter being shitty because of side effects ( even for me), but i do have to admit it kinda works. Ketamine and phenidines were the best for neuropathy and overall depression (even used once every 2 weeks) but didn't do much for pois itself. If you have depression of pois do ketamine therapy if its legal in your country.

Tried all syntethic drugs out there..only ones i avoided are obvious ones like meth, heroin , mdpv, pcp etc.  I recommend not taking drugs at all, the cost is not worth  the risk and there are purity issues. I always had suppliers who provided me pharmceutical quality. What lead me to do it was desperation and exploration because i know how neurobiochemistry works and pois clearly (to me)  is related to neurochemistry. I also know about receptor affinity of substances and that kinda stuff. Most of the times i knew what i was doing and sometimes i made mistakes. Drugs target way more receptors than research papers show alot of them alter substance P and many other exotic systems, they all cause nerve growth (not always the right kind, be aware) and almost all target BDNF.

Drugs you absolutely have to stay away from all together is magic mushrooms , MDMA, cathinones (3-mmc, 4-mmc etc cathinones simply too addictive even with one dose). They all make pois worse i even believe they probably could cause pois if you abuse them. I can see people using magic mushrooms when their pois headache  is bad, i would defo not take this daily or weekly.

All drugs create a false sense of wellbeing (some are authentic tho) and usually create a bandaid on pois but do zero for the underlaying mechanism of pois. Someone who never had MDMA and try it for the first time think they cured pois but in fact making it worse long term.

Also im really experienced ..i had many bad trips and can brush them off and survive while staying sane. Someone who uses tryptamines and take 1mg too much can easily lose his mind. Its not for the faint hearted or minded, also they can worsen emotions caused by pois like depression, isolation etc. Alot of drugs also boost libido, if you stay celibate for 2 months and use drugs one could be compelled to seek release , this could also be an issue. Drugs change your behaviour short term this is guaranteed, this also relates to self control and discipline..

DMT im not sure about ...sometimes it seems to help pois and other times it makes it worse. Even tho it is natural it doesn't always means its good for you. Cannabis is hit and  miss, helps long term with inflammation but is more of a bandaid when it comes to pois. At a certain point cannabis made my chronic fatigue worse and made me emotionally blunt..i tried well over 30 strains inc. Cbd strains vaped, eaten and smoked. CBD is an anti psychotic and lowers % neurotransmitters transmitted, it is marketed as anti depressant but in fact is an depressant like all other anti psychotics. I stopped using it because it made depression worse long term, it sedates you so you think it feels better...again another bandaid.

Smart drugs / nootropics like noopept and racetams all have beneficial effects on bdnf and nerve protection/ growth. Noopept worked wonders  for cognitive recovery but can drop blood sugar or deplete acetylcholine. Sublingual fasoracetam worked really well. I 100% recommend people trying these 2 nootropics, they work wonders on pois brainfog, depression and anxiety. Best 2 things i have tried next to mescaline and tryptamines.

I've been microdosing 100mg of dried psilocybin mushrooms and that works great. Any more than that actually causes acne, headaches, inflammation, and insomnia for me.
https://www.reddit.com/r/POIS/comments/173jh9e/strategies_for_coping_with_pois_symptoms/

What cured my slight POIS
Just came across this subforum and thought i throw my experience in. I never had extreme POIS, but when i overdid it (like once a day) i could feel ill, like with a beginning flu and miserable. When i spread it to once every 3-4 days, i was fine. Never had these extreme symptoms some of you describe, though.

Until i started to microdose magic mushrooms (since more then a year now). Since i microdose, im horny as hell and any POIS symptoms are gone, no matter the frequency. Not sure why and how, but shrooms seem to balance brain chemicals, so that may be that.

" The psilocybin dose was moderately high (20 mg/70 kg) in session 1 and was high (30 mg/70 kg) "

A typical microdose is considered between 0.03g and 0.3g according to the reddit community. As everyones different, youd have to find your personal dose. My dose is 0.2g every other day, my wife takes 0.12g every other day. Unfortunately, shrooms are illegal in most countrys but you can easily grow your own with a growbox (google) or try some magic truffles, which seem to be legal in many countrys.

My experience is nothing short but life changing. Whereas before i had to drag myself to work, i suddenly had fun working and it made me realize, that i suffered from derealization without knowing it - because the shrooms stabilize my awareness of the world around me.

How long did it take for microdosing to stop your POIS?
I guess it was quite fast, a week or two at max but probably shorter. I didnt pay too much attention as i didnt expect this.

Thanks. Do you think if you were to stop the microdosing the POIS would return or do you think it would have long lasting effects even after stopping treatment?
Thats an interesting question i cant answer, as i never stopped for longer then a week. Having said that, people report lasting (positive) effects from microdosing.
https://www.reddit.com/r/POIS/comments/ma6k6e/what_cured_my_slight_pois/

[Progecitor]

Although not proven, it is thought that DMT is secreted during sleep by the pineal gland to regulate the REM cycles. If this is true then the antioxidant effect of the REM sleep phase could be at least partly due to DMT’s action on the sigma-1 receptors.

Sleep disturbances – This refers to difficulty falling asleep, staying asleep, or achieving restful sleep. Factors like stress, anxiety, depression, and pain can affect sleep quality. DMT is believed to help maintain healthy sleep cycles linked to dreaming, especially during rapid eye movement (REM) sleep. While the DMT produced in the brain may regulate REM sleep, consuming external DMT can disrupt this balance and impact overall sleep quality.
https://www.my5palms.com/addiction-blog/side-effects-of-dmt/

There is a theory on the antioxidant effects of sleeping that fits my personal experiences really well. As we have an elevated base level of lipid peroxidation we show signs of sleep deprivation even when rested. This is one of the most evident links to ME/CFS and other similar conditions. The constant presence of depression and fatigue is a clear indication of the ongoing oxidative stress. When I am tired previously effective supplements have a way reduced benefit on POIS. In my case conventional sleep deprivation leads to a kind of super POIS state, which is a superposition of the condition and indicates a very robust oxidative stress. I also wake up feeling better when I dreamt, but I hardly ever dream or remember the fact if I did, which indicates a lack of paradoxical sleep, especially in the acute POIS phase.

Current experimental evidence suggests that sleep deprivation promotes oxidative stress. Wakefulness involves high neuronal metabolism to maintain neuronal electrical potentials, which requires a great amount of oxygen, resulting in a significant production of oxidants. Thus, sleep represents a state with an increased antioxidant activity which promotes a brain protection against free radicals via a diminution in oxidant production. The ROS and other oxidative stress markers could be accumulated in the brain tissue during wakefulness, and after reaching out a threshold, they could behave as sleep promoters.
In the present report we addressed evidence that supports the hypothesis that sleep is a dynamic-resting state with antioxidative properties. In order to accomplish the aim of the present paper we also contemplated in our revision evidence that suggests that oxidative stress may be the inductor of sleep and thus confirmed its antioxidant properties.
Paradoxical sleep (PS, also called rapid eye movement (REM) sleep) is associated with high neuronal metabolic activity and loss of muscular tone, whereas slow-wave sleep (SWS) is characterized by low neuronal metabolic activity. The original hypothesis about the antioxidant properties of sleep referred that SWS would accomplishes for the most antioxidative part of sleep. This assumption would be confirmed once SWS is associated with low neuronal metabolic activity and therefore with less oxygen consumption. The experimental data extracted from PSD points out to a different perspective: paradoxical sleep plays a significant role as antioxidative element and whenever prevented, oxidative stress increases.
https://onlinelibrary.wiley.com/doi/full/10.1155/2015/234952

[Progecitor]

Some antihistamines like promethazine (e.g. Lergigan), hydroxyzine (e.g. Atarax), diphenhydramine (e.g. Benadryl) and azelastine are sigma-1 receptor agonists and that is clearly the reason why they are particularly effective in the treatment of POIS.
Sigma-1 agonists show a wide spectrum antiviral effect. However this doesn't necessarily mean that POIS is caused by viral infection or reactivation. Nevertheless it is very likely that many natural antiviral remedies are actually sigma-1 agonists that should benefit us majorly. A few examples could be saffron, lungwort, lactoferrin and cleavers, but many more can be found with a little research. I believe "carefully" combining such supplements and also possibly some safer sigma-1 drugs could lead to very significant POIS improvement probably with less side-effects than singular high dose drugs.
None seems to have tried azelastine so far, which should theoretically have a great effectiveness. I am going to try azelastine eye drops soon and hopefully it will provide some relief for eye symptoms at least and maybe more.
Our experiences also seem to confirm scientific research, which is a superb evidence in itself in my opinion.

Hydroxyzine was previously shown to inhibit ACE2 catalytic activity and exhibited a molecular docking deltaG score of ?8.6 kcal/mol. Azelastine was predicted to bind the active site of ACE2 (dG -9.9 kcal/mol), whereas diphenhydramine was not predicted to bind ACE2 with high affinity (dG 6.9 kcal/mol). The affinities of hydroxyzine and diphenhydramine for sigma-1 receptor were previously measured, showing an estimated Kd of 192 nM for hydroxyzine, 1.7 uM for diphenhydramine. Molecular docking showed that azelastine was predicted to bind sigma-1 receptor with a higher affinity (dG -11.3 kcal/mol) than diphenhydramine (dG -8.2 kcal/mol). These data suggest that ACE2 and sigma-1 receptor binding mechanisms may regulate antiviral effects mediated by hydroxyzine and azelastine.
The sigma-1 receptor is a membrane bound chaperone highjacked by SARS-CoV-2 to link the replicase/transcriptase complex to the endoplasmic reticulum by binding directly to nonstructural protein NSP6, which forms a complex with NSP3 and NSP4. Hydroxyzine binds the sigma-1 receptor with high affinity, potentially interfering with the virus life cycle by blocking protein-protein interactions with NSP6.
https://www.sciencedirect.com/science/article/pii/S0006291X20321409

This study found antiviral activity associated with agonism of the sigma-1 receptor (e.g., SA4503), ligation of the sigma-2 receptor (e.g., CM398), and a combination of the two pathways (e.g., AZ66).
Although the on- and off-target binding mechanisms that mediate anti-SARS-CoV-2 activity are not clear, two classes of molecules were previously found to effectively inhibit virus infectivity: protein biogenesis inhibitors (e.g., zotatifin, ternatin-4, PS3061) and ligands of the sigma-1 and sigma-2 receptors (e.g., haloperidol, clemastine, cloperastine).
Common antihistamines that exhibit off-target antiviral activity include hydroxyzine, azelastine and diphenhydramine.
The sigma receptor-1 is an ER resident chaperone that normally functions to modulate the ER stress response. Coronavirus infection activates pathways to facilitate adaptation of ER stress to virus proliferation. These pathways are thought to hijack the host cell ER stress response to modulate protein translation, ER protein folding capacity and ER-associated degradation.
Collectively, these data indicate that antiviral activity against SARS-CoV-2 was driven by agonism of the sigma-1 receptor (e.g., SA4503), and by ligation of the sigma-2 receptor (e.g., CM398).
Since antiviral activity against SARS-CoV-2 was driven by agonism of the sigma-1 receptor (e.g., SA4503, sigma-1 receptor agonist), but not by antagonism of the sigma-1 receptor (CM304, sigma-1 receptor antagonist).
Sigma-1 receptor ligands have been shown to exert antiviral activity against CoVs and non-CoVs, including Ebola, HCV, SARS-CoV, SARS-CoV-2, DENV, MERS-CoV, FLUAV (H5N1), HCV, HIV and HSV-1.
Since antihistamines act as nasal decongestants and cough suppressants, the on- and off-target binding properties of drugs such as diphenhydramine may have broad utility in prevention and treatment of COVID-19.
In addition to the anti-viral effects of AZ66, binding of the sigma receptors reduces nociception.
Specific antihistamines exhibit off-target sigma receptor binding activity, and also exhibit antiviral activity against SARS-CoV-2, including clemastine, cloperastine, astemizole, hydroxyzine, azelastine and diphenhydramine. Since diphenhydramine is the most commonly used antihistamine exhibiting antiviral activity, we asked if antiviral activity could be improved by combining a sigma receptor ligand with lactoferrin, an antiviral agent that binds distinct targets. We found that co-administration of 400 ug/mL of lactoferrin with diphenhydramine reduced SARS-CoV-2 induced cytotoxicity and decreased the EC50. The antiviral enhancement effects of lactoferrin were more apparent at lower, therapeutically relevant concentrations of diphenhydramine. Combining lactoferrin with diphenhydramine resulted in synergistic effects on antiviral activity against SARS-CoV-2.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Highly+Specific+Sigma+Receptor+Ligands+Exhibit+Anti-Viral+Properties+in+SARS-CoV-2+Infected+Cells&btnG=

Hydroxyzine has a moderate affinity for sigma-1 receptors with IC50 concentrations of about 200 nmol/mL which is probably too low for relevant effects mediated by sigma-1 sites under therapeutic conditions. However, its in vivo interaction with the sigma-1 receptor requires substantially lower doses than one would expect from the in vitro binding affinity. This is probably caused by a metabolite with much higher in vivo activity which would suggest sigma-1 sites as possible targets of hydroxyzine.
https://www.thieme-connect.com/products/ejournals/html/10.1055/a-1717-2381

The antihistamine promethazine was previously found to bind S1R in our lab (unpublished results) and was also included as a potential candidate drug. Promethazine was 5-fold selective for S1R over S2R with an affinity of 157 nM.
The amount of BDNF secreted ranged from 24 to 103% of the maximum response, where promethazine had the highest response. All other compounds had significantly lower efficacy than 4-PPBP.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9358981/

Oxeladin as another sigma-1 agonist may be bought in some countries under the trade name of Paxeladine.

High-throughput screening was used to identify Sigma-1 receptor selective binding and stimulation of brain-derived neurotrophic factor (BDNF) release for several potential ligands that are already approved for other indications. Two lead compounds, promethazine (an antihistamine) and oxeladin (a cough suppressant), were advance to in vivo studies.
https://www.ahajournals.org/doi/abs/10.1161/str.53.suppl_1.TP234

Antihistamines are probably somewhat effective in themselves, but the bulk of the effect clearly comes from sigma-1 receptor agonism. OpiesDad's and a reditter's experience further confirms this when comparing the binding strength of hydroxyzine and diphenhydramine to sigma-1 receptors.

I prefer hydroxyzine to benadryl.  I think both are more effective than allegra zyrtec etc, because the former (but not the latter) cross the blood brain barrier and seem to relieve cognitive symptoms as well as body symptoms.

- treeeeeeeeeeeeeee:
I take hydroxyzine before O (10mg) - and it reduces my symptoms the next day by a lot, sometimes entirely. hydroxyzine is the strongest antihistamine you can get, but requires a prescription. Benadryl also helped me a bit but not as much.
https://www.reddit.com/r/POIS/comments/rs8l92/want_to_try_a_antihistamine_which_one_do_you/

I believe someone else post about hydorxyzine on reddit. They claimed it is the strongest antihistamine.

Yeah my psychiatrist said it's like "Super Benadryl" But unlike Benadryl or the other OTC antihistamines, hydroxyzine actually works for me. I honestly haven't heard of it until the psychiatrist brought it up.

Can now confirm that Lergigan works well year around, having had some days with -6 degrees.

Having sex several times per week with my girlfriend. No issues at all. Medicine needs to be combined with strict FODMAP for me.

Wow, I have to say I didn't expect it to work, but it did, and it was a massive success. If I wasn't required to take it before each orgasm, I'd even call it the ultimate cure for POIS.

For my trial, I used Rhinathiol Promethazine (liquid), with a dosage of 7.5mL to 10mL. Luckily, it's available at any pharmacy in my area without a prescription for as little as $2 USD.

My main POIS symptoms are both cognitive and physical: brain fog, short-term memory loss, intense fatigue, and inflammation lasting for about 3 days.

I took my first dose on August 9th, and an hour later I had an orgasm. And like you said, 0 POIS symptoms. The following day, I felt the physical symptoms, but they were minimal, only about 25% of the usual pain. And they only last for 2 days but I wasn't really feeling it that much compared to the usual pois. I suspect this might be partly due to my poor physical health, as POIS has kept me from working out and eating healthy for years. I imagine that with a regular workout routine, along with fenugreek and beetroot, the physical symptoms would cease to exist.

The best part is my brain functions remains fully intact, and it stays like that permanently, no time limits. No more waking up the next day post orgasm wondering what I did yesterday. It really feels like a protective shield for my brain. I've even returned to work at full performance after years of being on hiatus.

In my case, when I take it even 5 mins post orgasm, it won't work. It has to be explicitly 45-60 mins before orgasm. I still orgasmed like two or three times it still wouldn't make a difference in my symptoms, which is most impressive. even if I delayed my orgasm like 80-100 mins after my dose it would still work.
I've tried Niacin in the past, but it only managed to alleviate the physical symptoms. I still struggled with brain fog, and it was challenging to stay in a flushed state for it to work.
But with Promethazine, you just take the dose, wait an hour, and that's it. I do still experience an intense headache about three hours after the dose, lasting for two hours. I found that taking more than 8mL causes intense anxiety and headache, even when taken at night, it can still make sleeping super hard for a few hours. So I found my sweetspot to be 7.5mL, your mileage may vary.
This has genuinely transformed my life and perspective. After years of suffering, I can finally live POIS-free. I no longer have to worry about the symptoms, which used to hinder every aspect of my life.

I'm now even more curious about how it actually works to prevent my symptoms. How did you come to the conclusion that this might work?was it advice from a doctor or something you discovered through research?

I've been taking it for 3 weeks now, (I orgasm 3-4 times each week, so that's 3-4 doses) I've waited this long before posting to verify that it is not some placebo effect. No issues so far.
I'll never forget this post, and your name, Mike. From the bottom of my heart, thank you

Thinking conservatively ... things that worked for me .. medicines: promethazine or hydroxyzine (antihistamines).
Phytotherapy: kava kava and passiflora.
B Vitamins and Magnesium
Dipirone: analgesic and makes me a little drowsy ....
Muscle relaxant at low doses such as cyclobenzaprine .. Use at most 5 mg.
I have never used benzodiazepine and when I am very tense, alcohol also works but I only take it in the last case.
Weaker antihistamines such as fexofenadine and ebastine help but do not act as intensely as CNS sedatives.

- Wolvesinthestreet:
I have tried Promethazine, and if I have it 1.5 hours before O it does wonders
It makes me drowsy, so in a way it’s a bit harder to O, but not so much, also I gain tolerance to if it taken daily

Regarding diphenydramine I could quote the whole Benadryl thread, but that would be too much.

Topic: Benadryl seems to be the only thing that works for me
https://poiscenter.com/forums/index.php?topic=2288.msg18677#msg18677

So maybe a bit of an odd post, but I got a prescription for hydroxyzine hcl and for whatever reason I'm feeling very anxious about trying it. Anybody have any experience with it that could help me push past this anxiety?

Hi Jay,
Effect is very similar to Benadryl (diphenydramine).  Main side effect is drowsiness.

It helped some with pois, if do i one ejaculation but if i do multiple it doesn't. 
If i use antihistamines everyday they help with pois alot but i cant use them everyday because within a week they start to affect my short term memory. And this are the gen2 that are less likely to cross the BBB. Because of that i didn't try hydroxyzine daily just pre O.

Posted this on r/POIS as well: https://www.reddit.com/r/POIS/comments/gw5rxt/story_treatment_my_background_and_latest_finding/

...So I took the hydroxyzine, had an orgasm, went to sleep. The following day would normally be filled with irritability and agony under typical circumstances but instead I got a pretty feel-normal kind of day, to a point in which I had to double check my log to see if I did in fact have an orgasm the day before. Turns out I did. Absolutely incredible. Wow. I realized then, after 20+ years, I found something that finally truly helped provide relief from this suffering and have a better quality of life all around. Super thankful to have made this discovery, just wish I could've discovered this sooner. Better late than never, I suppose...

I'm not sure if hydroxyzine will help you but it certainly has helped me even when other antihistamines haven't really helped. Hoping this story helps someone out there who's in a similar experience w/ POIS as I am. I was on the verge of unironically entertaining the idea of castrating myself until I made this discovery. Stay strong, brothers! Keep searching until you find something that truly helps you. I'm hoping you find it soon.

I'm going to visit an allergy clinic next week to get their take on it as well. For now I'm taking it as needed, within 1 hour before having an orgasm ideally.

TL;DR Had POIS since puberty, tried many things, Hydroxyzine and Loratadine by far has helped eliminate POIS for me.

Thanks! There may be some changes and additions as I'm still very new to taking hydroxyzine (have only done this for about 2 months or so but have multiple successes). As I'm learning now, 25mg used to be enough for the first few times but unfortunately it feels like it's not quite enough to take care of the symptoms entirely anymore . I've tried taking 50mg hydroxyzine pamoate and while it does remove the symptoms completely again, my new problem is fighting off the sedation and drowsiness that lingers all day on that dosage, on top of the 12+ hours of sleep needed! (I don't get that nearly as much with 25mg).

Hey all, it's been a while but I thought I'd give an update since the discovery that hydroxyzine has provided consistent POIS relief for me. Some time after sharing this I actually found that loratadine alone was completely sufficient in preventing POIS and I no longer take the hydroxyzine which besides requiring a prescription in order to obtain also gave me hours of drowsiness as a side effect whereas with loratadine it's available OTC and the side effects are relatively negligible.
...

Awww THANK YOU!  Definitely trying to gather as much info as possible as this just hit me like a ton of bricks.  Very helpful resource you've got there, probably the best on the internet.  Still hanging onto hope that it goes away when I get off the griseofulvin or the COVID after-effects go away.  Unlikely but maybe possible?  Meh. 

Just coming back to record that taking 2 Vistaril (hydroxyzine) about 30 minutes before a session seemed to help keep the worst symptoms away today.  Also took 2 codeine right before falling asleep with my sleep aids.  Was already feeling crummy from a previous "session" the night before (I know, I know lol) so this is kinda significant.  Normally I'd be sleeping like a rock right now.  I take soooo many drugs & supplements daily that it'll be hard to ever discern what helps/hurts but I'm counting this as a success for now.

Muon:
Objective: We describe two patients affected by POIS, their symptomatology, and the treatment methods that were successful in alleviating their symptoms.
Methods: Patient A is a 24 year old male who started having symptoms at age 14. His main symptoms included feeling drained post-orgasm, conjunctivitis, as well as sinus pain, headache, and stomach pains. Patient B is a 32 year old male whose symptoms included post-orgasm fatigue, somnolence, and cold-like symptoms, but the most bothersome was the deep internal fatigue. Both men reported that symptoms persisted weeks after orgasm. Both patients had no significant past medical history, normal genitourinary physical exams, and normal laboratory workups. Patient A was trialed on a combination of pseudoephedrine and hydroxyzine, which led to a marked improvement in his symptoms. He was advised to take 50 mg hydroxyzine nightly and pseudoephedrine 1 hour before orgasm. Patient B was trialed on 25mg tramadol, which he took immediately post orgasm. The tramadol led to a significant improvement of his symptoms, most significantly, the fatigue. Both men were also enrolled in sex therapy as part of their treatment.

Treatments I've Tried:

Fasting - Works like magic. This is the only thing keeping me sane. Multi-day fasts have allowed me to continue to stay on top of important things in my life, and my eating schedule has allowed me to not lose weight or vitamin/mineral density, although I've had to cut back on exercise routines.
Wellbutrin - Helps with many cognitive symptoms and stabilizes my mood when POIS is extremely bad.
Benadryl - Alleviates many physical symptoms, but makes me feel like a complete zombie. I get incredibly fatigued and can't focus on anything.
Hydroxyzine - Similar experience as benadryl, but better and longer-lasting physical symptomatic relief.
Advil - Alleviates physical symptoms with less fatigue than the prior substances, but it doesn't last very long.
Zoloft - Numbed many of my mental symptoms but came with serious side effects which caused me to stop taking it after a few months. One of the primary reasons I considered trying Zoloft was that people tend to complain online that it lowers their sex drive and makes it difficult to achieve orgasm. I never experienced this. It may have slightly lowered my drive, but I continued to have nocturnal emissions atleast once a week while taking it (I believe I was on 50mg).
CBD - Helps alleviate anxiety and a few other mental symptoms, but it tends to make me nauseous.
Nicotine - Worsens every symptom, physical and mental.
Alcohol - Worsens all physical symptoms, but alleviates anxiety. I never drink alcohol these days because it physically makes me feel horrible.

Vitamin B, Vitamin C, and Vitamin D complexes: Seemed to do nothing. I think my levels of each vitamin were high prior to my supplementation, so I may not have needed these due to my diet.
Magnesium - Helps with calming/relaxation. Useful for improving sleep quality while recovering from POIS.
Zinc - Seems to speed up recovery times but simultaneously increases nocturnal emission frequency. For this reason, I no longer take it.
Maca Root - Did nothing.
Tribulus - Did nothing.
Ashwaganda - May have improved sleep quality, bad anxiety and testosterone levels, but I ceased taking it due to increased NE frequency.
Curcumin - Unsure of whether it had an effect on NE frequency. Didn't seem to do anything for inflammation levels, but it's possible my dose was too small. I took it daily over a period of three months and observed no noticeable changes.
Reishi Mushroom - Decrease in NE frequency. I'm assuming this is due to 5-AR inhibition properties.
Lion's Mane Mushroom - This stuff felt like taking a mild stimulant. I felt more focused and less absorbed in my negative psychological POIS-symptoms. Only took it for two months.
Shilajit - Did nothing noteworthy.

Hi everyone, I just wanted to share a treatment that has been working pretty well for me. My doctor prescribed me hydroxyzine a while back for my awful POIS symptoms which were overall fatigue, joint pain, headaches. This was the first thing to really have an impact on eliminating my symptoms. I also took Sudafed to help with the photophobia and eye issues I have with POIS.

Recently I tried Dramamine, which is usually taken to help with motion sickness, and it has been working a lot like hydroxyzine. They are both antihistamines with a lot of the same properties so the fact that they both work well doesn?t surprise me. Has anyone else tried this as a treatment?

Trying Atarax now. It seems to reduce my POIS symptoms but i still have muscle tiredness and mental symptoms. Also taking fenkarol for food allergies (i just feel much worse after eating). Taking different types of sedatives. For anxiety. Anxiety and some aggression/panic attacks triggered by sounds. Also anxiety of not being successful in life ?. I feel like i missed the train. Idk what to do. The whole situation in my life doesn't seem to become better. I am so envy for others. And this mental condition of mix of many feelings: anger, sadness, unhappiness. Because of aggression i have to take tranquilizers. I take many sedatives. Common sedatives don't work, except for valerian root but i have to take so much. I am also taking non benzo tranquillizer bafazol, and also sometimes when i feel very bad and angry i just take gidazepam. But i feel like all these medications do more damage to me instead of healing me. They just reduce symptoms.

I was not aware re caffeine and wellbutrin.  Luckily coffee is not my thing any longer.  Feel considerably better this morning.  Added Hydroxyzine last night and feel considerably better today.  I can live with one day POIS bouts.

Wellbutrin 300 mg + Propranolol 60 mg + Hydroxyzine 25 mg  regimen still working guys.  I have been jerking off fairly regularly again (once a week). I do still get a painful fatigue that lasts a few hours, but it resolves fairly quickly and from there I am close to 100% save for some acid reflux (take pepcid 20 mg as well).  The norepinephrine theory may still be in play, especially because the post O crash could reflect the low level of norep, but it more quickly refills returning me to a more balanced state + the other medications handle the other physiological symptoms.

I mean, for the most part I feel normal again and I'm really excited about it!!!

Hi everyone, I've had POIS for about 10 years now and recently found out the 100 mg hydroxyzine and 60 mg sudafed are the #1 things that help my POIS, the hydroxyzine for overall body fatigue and the sudafed for the sinus issues that come from POIS. Another thing I've always experience is a flushing like rash on my body when I'm in nervous situations, drink alcohol, and during sex/masturbation, does anyone else get that? I'm on the never ending journey to find out the core issue here and I feel like the flushing rash I get might have something to do with POIS?

I found a post on NakedScientists where he said he also had a crash on day 4 and 5 when using weak antihistamines. At least I think that's what he means. It's hard to understand the sentence.

Hello everyone,
I am happy2.  I found the cure for POIS at Christmas time.  I am now 100% POIS free.  B Jim, Daveman, or whoever, e-mail me, and I will let you know how I did it.  I posted years ago with a severe case of POIS.  I suffered for almost 20 years.  3 1/2 years ago I went to a urologist.  He said he had never heard of this before.  However, he told me to get on an anti-histamine, which I did.  30 days later, after being on Claritin daily I orgasmed.  I immediately got out of bed and popped 2 benadryls and as I reported 3 1/2 years back, this reduced POIS symptoms by 95%.  I went back to same urologist 3 years later, this last July.  He told me to get on Zyrtec because this was more powerful of an anti-histamine than Claritin.  I experimented with Zyrtec next POIS session on days 1, 2, and 3.  Usually with physical or mental exertion on any POIS day for me has caused fatigue, or crash days, the following days after POIS, days 4 and 5.  This time was different, however.  I had no crash days on 4 and 5.  So, I started taking both Claritin and Zyrtec together, daily.  Two months later, I orgasmed, popped the usual 2 benadryls, and waited, 30 seconds, 1 minute, and nothing.  Mind did not fog over for the first time in 20 years following an orgasm.  This occurred at Christmas time, 2015.  I experimented for the next 4 weeks, orgasming 12 times.  Every time was the same result, NO POIS.  Thank God I found this cure.  I tried one benadryl instead of two, and it did not give the same result.  So, to recap, one Claritin and one Zyrtec daily, and exactly 2 benadryls immediately, within 20 seconds or so following orgasm.  NO POIS.  Thanks to the people on this site that gave me so much information about POIS.  I would have never known what it was except for this site.  Like I said, moderators, feel free to contact me.  Thanks to all.

So I went to my doctor and got a prescription for Hydroxyzine (Atarax) on advice of someone on reddit who says a single dose of 50mg before O relieves him of POIS. The doctor says this is the strongest antihistamine available. I will experiment with a single dose because I don't want to take daily antihistamines like Happy2 if I can avoid it. But if I continue to crash on day 4 and 5 I may have to take a weak antihistamine daily plus the Hydroxyzine before O.

Thanks for the links and that you do not leave people alone with the problem, I will read all this in the near future, I would like to say that (50mg) hydroxyzine has stopped these worst symptoms

I have nothing to lose, I will also try supplements and change diets

- aquantiV:
I do not notice that personally, my symptoms remain steady, brain fog at the beginning then an increasing cascade of every kind of pain my body is capable of, but mostly muscle and nerve pains. I haven't gone through full symptoms in over two years due to having hydroxizine, cleavers extract, and firsthand knowledge of my diet's relationship with my POIS.
https://www.reddit.com/r/POIS/comments/jrmw1q/changing_symptoms/

- premdon69:
Yeah everything you said matches what I've tried. I’ve tried a lot of psychiatric meds and you just build a tolerance and stack up side effects. Hydroxyzine can sometimes help but it gives some intense dreams.
I have noticed that as I try to heal my gut and abstain, I am requiring less medication to sleep. So I guess something is happening. Thanks
https://www.reddit.com/r/POIS/comments/hy8bbm/insomnia_24_hrs_after_orgasm/

- connorg__:
Diphenhydramine 50mg 15 seconds after orgasm. After taking the Diphenhydramine I didn't feel any POIS symptoms just felt a little tired.
https://www.reddit.com/r/POIS/comments/hbf5m5/update_from_my_last_post/

- SnooBreakthroughs120
I've been taking 50 mg hydroxyzine Hcl for 2 weeks now along with 60 mg of Sudafed before O. The hydroxyzine has by far been the single most helpful thing to my POIS so far. I've had the issue of major eye pain headaches weakness after O, now all of that is definitely improved. I still can feel minor effects but I am feeling sooo much better than I did before. I've had 5 Os since last Monday, without taking this I would feel miserable. I'm starting to wonder if it works because it’s an antihistamine or because of its effect on serotonin? My mood is also calmer after I take it. I'm still working with my doctor to see if I can keep improving this but at the moment I am very encouraged by what hydroxyzine has done for me.
- connorg__ :
That's really good news!! I'm currently taking Loratadine every morning and Diphenhydramine after O. They're both antihistamines and I feel like they're helping me but I the next day I don't feel 100% with the diphenhydramine probably 85%. I kinda get memory issues, a bit of brain fog the next day but clears on the 2 day. How would you say you feel the next day after taking hydroxyzine ? I'm thinking about asking my gp if I can try it but I also suffer from anxiety.
https://www.reddit.com/r/POIS/comments/hat5d8/is_anyone_trying_hydroxyzine/

- JacaDura:
Yes, most of these without the back pain for me. My symptoms improved but didn't totally go away when I started taking antihistamines, singulair, and hydroxyzine (at night). I am always fighting brain fog and these medicines allowed me to keep my job. I was useless at work (except late at night) and had massive anxiety and anger problems, constant arguments at work, etc. My personal theory is that POIS is a variant of a mast cell activation disorder because sexual functions are heavily intertwined with histamines and for me, all my weird food allergies, brain fog, POIS, and migraines started when I quit taking propecia (post finasteride syndrome). I try to have sex only in the weekends and ideally on Friday night so the weekend days are not totally ruined.
https://www.reddit.com/r/POIS/comments/mnea4u/is_it_just_me_or_you_guys_have_these_extreme/

- HerbieDerrb:
Several days ago I took 25 mg Benadryl 30 minutes before and it's helping a lot.
https://www.reddit.com/r/POIS/comments/1hltfiw/has_any_one_found_solution_to_this/

- Acceptable_Click:
u/AquantiV with his hydroxizine+cleavers extract+cayennes pepper+advil+L-Theanine+Zinc Picolinate stack has 99% of POIS under control if he takes it before/after ejaculation and does it only once a day
https://www.reddit.com/r/POIS/comments/ut6ea5/what_poisers_need_are_medicines_not_abstinence/