Ideas on Herpes Induced POIS

[nanna1]

  A while back, a fellow researcher sent me mice brains that they had infected with rabies virus which is a neurotropic virus. They were researching a specific brain disease and want me to use my equipment to study it. Then sometime later Muon told me about his medical test results (post). My (nanna1) medical test results are also published (post). These test remind me how similar POIS is to neurotropic virus infections. While I do not know for sure what causes POIS, I think that human herpes virus infections should be seriously considered.

  There have been a lot of post about herpes induced POIS and just I wanted to summarize here some of the ideas. My hope is that by putting some of this information in one place, it will be easier to find and further benefit the discussion. Supplements and treatments are mentioned, but I am not endorsing any of them in this post. I do not consider these my ideas. These are summaries of published research articles and discussions on POIScenter (both public and private messages) that relate to herpes virus infections. Many POIS members have contributed the following post.
Also, thanks aswinpra06 for sharing the link Chicken Pox and Shingles Virus: Prevent Reactivation

Table of Contents:

Brain diseases associated with herpes virus infection

POIS as a location-specific herpes infection

Stress Triggers for Herpes reactivation

Inflammation and disease

Alpha-Herpes Induced Autoimmunity (glutamate, kynurenine and NAD)

Testosterone, arousal shift physiology and autoimmunity

Methylation and herpes

Anti-herpes therapuedics

Anti-virals medications

Preventing Nocturnal Emissions POIS

Long-term herpes relief and permanent virus removal strategies

POIS literature review

[nanna1]

Diseases associated with herpes virus infection

"Evidence suggests that many cranial nerve syndromes, such as migraine headache, acute vestibular neuronitis, globus hystericus, carotidynia, acute facial paralysis (Bell's palsy), and Meniere's disease, are caused by the neurotropic herpes simplex virus (HSV)." -Herpes simplex polyganglionitis.

"Torrey (1986) has consistently proposed a theory suggesting a viral etiology for psychosis, especially schizophrenia. Due to the relatively chronic nature of the psychiatric disorders studied, and the absence of recent clinical infection data, the major focus of work has been on the latent viruses. As Torrey (1986) observed, the viruses most likely to cause behavioral disturbances belong to the herpes family. In addition to herpes simplex virus (HSV) and cytomegalovirus, there has been recent evidence to suggest that varicella zoster can also be isolated from trigeminal nuclei, while it is latent (Mahalingam et al 1990)." -Cerebrospinal Fluid Viral Antibodies in Obsessive Compulsive
Disorder in an Indian Population (1997)

Below is a list of diseases that are associated with recurrent reactivation of HSV-1, HSV-2, HHV-3, EBV or CMV:

• Alzheimers - hippocampus (Ref1, Ref2, Ref3)
• Parkinson's - substantia nigra (Ref)
• heart disease and atherosclerosis - smooth muscle (Ref1, Ref2, Ref3)
• migraine - trigeminal nerve (Ref)
• Tourettes - basal ganglia (Ref1, Ref2)
• Bell's Palsy - cranial nerve VII (Ref1, Ref2)
• epilepsy - temporal lobe and frontal lobe (Ref1, Ref2)
• chronic fatigue syndrome (CFS) - vagus nerve (Ref1, Ref2, Ref3)
• vagus nerve palsy - vagus nerve (Ref1, Ref2, Ref3)
• systemic lupus erythematosus (Ref1, Ref2, Ref3)
• schizophrenia - prefrontal cortex and substantia nigra (Ref1, Ref2, Ref3)
• Parsonage-Turner syndrome - (Ref)
• Guillain-Barre Syndrome - (Ref1, Ref2, Ref3)
• multiple sclerosis - myelin sheath (Ref1, Ref2, Ref3)
• postherpetic neuralgia - peripheral nerves (Ref)
• myasthenia gravis - anti-acetylcholine receptor (Ref1, Ref2)
• viral encephalitis - anti-NMDA receptor (Ref1, Ref2, Ref3, Ref4)
• Lymphocytic pleocytosi - (Ref)
• urethritis - penis (Ref1, Ref2)
• arthritis - joints (Ref1, Ref2, Ref3)
• mononucleosis (MONO) - (Ref1, Ref2)
• prostate cancer - prostate (Ref1, Ref2, Ref3)
• Urticaria/hives - skin (Ref1, Ref2, Ref3)

Below is a list of common human herpes virus types and their latency (infection) locations:

• HHV-1: herpes simplex virus-1 (HSV-1): neurons: prevalence > 60%
• HHV-2: herpes simplex virus-2 (HSV-2): neurons: prevalence > 20%
• HHV-3: Varicella-zoster virus (VZV): neurons
• HHV-4: Epstein-Barr virus (EBV): B-cells
• HHV-5: Cytomegalovirus (CMV): Epithelial mucosa: prevalence > 50%
• HHV-6: herpesvirus type 6 (HBLV): leukocytes and epithelia: prevalence >90%
• HHV-7: Human betaherpesvirus 7 (HHV-7): CD4+ T cells

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[nanna1]

POIS as a location-specific herpes infection

"On the basis of these findings, we conclude that the spread of HSV in the CNS after (eye injection) is not diffuse but is restricted to a small number of noncontiguous foci in the brain stem and cortex which become infected in a sequential fashion. Since these regions are synaptically related, the principal route of the spread of HSV in the CNS after ocular infection appears to be along axons, presumably via axonal transport rather than by local spread." (RefA)

  Herpes infections are highly localized to small groups of connected cells. Michael VanElzakker, who proposed the Vagus Nerve Infection Hypothesis (VNIH), bases his HHV-6 hypothesis for chronic fatigue syndrome on the fact that the causes of neurologic diseases are location specific. Meaning that the location of the infection will be the most important factor in creating symptoms of the disease. And as the location of the infection changes, the type of disease and symptoms change.

Below is a list of common human herpes virus types and their latency (infection) locations:

• HHV-1: herpes simplex virus-1 (HSV-1): neurons
• HHV-2: herpes simplex virus-2 (HSV-2): neurons
• HHV-3: Varicella-zoster virus (VZV): neurons
• HHV-4: Epstein-Barr virus (EBV): B-cells
• HHV-5: Cytomegalovirus (CMV): Epithelial mucosa
• HHV-6: herpesvirus type 6 (HBLV): leukocytes and epithelia
• HHV-7: Human betaherpesvirus 7 (HHV-7): CD4+ T cells

  I think there could be a POIS area of the CNS that when infected causes POIS. If a person's herpes infection does not cover the "POIS area", they would not experience POIS even if they experience other illnesses. Moreover, if a person has a herpes infection that covers the POIS area and many other parts of the nervous system, they may have POIS and many other transient and chronic diseases associated with the total infection coverage of the virus. If this is true, then this "POIS area" should be located in a part of the neuroendocrine system that is primarily active during sexual activity and has a high density of glutamate receptors. So this is a conjecture based on the fact that other neurological diseases are location specific. Below are philosophical diagrams of this POIS area - herpes infection idea.

CFS-chronic fatigue syndrome, IBS-irritable bowel syndrome, POIS-post orgasmic illness syndrome

Person 1 has herpes virus induced POIS, mild CFS and IBS, but he does not experience herpes induced arthritis.

Person 2 has herpes virus induced POIS, CFS and arthritis, but he does not experience herpes induced IBS.

Person 3 has herpes virus induced IBS, CFS and arthritis, but he does not experience herpes induced POIS.

 
  In the three above scenarios, the confounding symptoms are linked by a common cause, HHV. For Person 1, CFS and IBS may become worse following an orgasm, but this does not mean that CFS or IBS are related to POIS in general. The link between POIS, CFS and IBS in Person 1 is the result of his unique HHV infection volume, which is not shared by Person 2 or Person 3.

So far, it seems like the trigeminal nerve could be the area of the brain most associated with my POIS symptoms. This nerve extends from the spinal cord to the extremities of the face (back of eye, nose, inner ear, forehead and chin). Trigeminal nerves stimulation is also associated with orgasm (and coitus fantasy) induced sneezing (RefB, RefC).

  Infections of herpes viruses along the spinal cord can result in pain and other symptoms throughout the body. For example, infection of the S series of nerves (bottom: S1, S2, etc..) could cause an immune response and inflammation in the bladder and genitals. While a viral infection of the CNIII nerves (Ciliary ganglion) can cause eye pain and blurred vision. The diagram below shows how basal root ganglia nerves (CN) in the central nervous system and dorsal root ganglia nerves (C, T, L and S) in the spinal cord are connect to various organs of the body.

The locations of the infections can be different for different people, which would cause different symptoms. However, for the virus theory to hold, there should be at least one common location or common organ of viral infection that all POIS sufferers share that is associated with orgasmic sensation.

  Nightingale, Hopeoneday and others have post about the vagus nerve infection hypothesis by Michael VanElzakker.

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[nanna1]

Stress Triggers for Herpes reactivation

"Typical (HSV-1) reactivating stimulators used include adrenergic agents such as epinephrine and timolol, applied either topically or by iontophoresis [140,141]. Epinephrine is most commonly used due to its high frequency of reactivation (approaching 100%) and long duration (typically 3-5 days) [66]." -Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated? (2011)

  Human herpes viruses (HSV-1, HSV-2, HHV-3) infect and are stored in cells (neurons and glia) of the nervous system, while CMV/HHV-5 and HHV-6 are latent in endothelial, smooth muscle, and macrophage cells. Latent herpes infections chronically elevate COX-2 expression in the infected cells through NF-kB and control host-cell metabolism by modifying gene transcription. Arousal/stimulation/intercourse causes the release of neurotransmitters glutamate and norepinephrine which stimulate the release of arachidonic acid and trigger the stress response gene JNK through increase PGE₂ production. According to this paper (and press release), the herpes viruses are kept latent by methyl groups attached to the virus DNA. Methyl groups act as the off-switch for the virus. When JNK is activated, methyl groups attached to the herpes DNA are removed. This DNA demethylation results in the virus replicating and spreading. Once herpes is reactivated, it starts to replicate and migrate to other parts of the nervous system through the dendrites (connections). The recurrent reactivation of the herpes virus triggers an immune response which stops the spread of the virus while causing POIS symptoms.

  This model incorporates the immune response mechanism described here. In this case, chemotaxis means T cell movement to the site of infection, and chemokines (i.e. IL-8) are types of cytokines that tell the T cells where to go.

  In this herpes model of POIS, as the virus spreads, the immune system attacks the herpes virus and herpes infected cells. The attack by the immune system on the virus causes inflammation and allergy, and you become sick. Therefore, in this virus model, POIS is an attack by an immune system on a spreading pathogen (virus). The immune system is trying to stop the spread of the virus (Ref). An HHV-3 infected person with a weak immune system would not get POIS. They would get shingles. Shingles occur when the immune system is weak and cannot fight the virus. And shingles can be triggered by stress.

Figure from "Virus Infections in the Nervous System". A more detailed explaination can be found here in the first 3 paragraphs of the section titled "State of the Art".

  The virus itself is not the main thing that makes you feel sick, even though it is doing some damage to your body. What makes you feel sick (POIS) is the immune system releasing different molecules (histamine, cytokines, reactive oxygen species, antigens, etc...) to kill or contain the virus. For POIS, it is important to remember that even though the immune system is making you feel sick, if the immune system fails to contain the virus, HHV could spread and cause permanent damage to the body and nervous system.

"If prostaglandins enhance virus spread in vivo as well as in vitro they would be good candidates for a 'skin-trigger', since they are released in the skin following many types of damage. Injection of PGE2 into the skin of mice induces recurrent disease" -Prostaglandins Enhance Spread of Herpes Simplex Virus in Cell Cultures (1978)

  HSV reactivation requires both JNK up-regulation and de-methylation of the herpes DNA [J2,J3]. The authors of this paper were able to stop herpes outbreaks by inhibiting the JNK gene alone [J1,J3]. The following article positively identifies prostaglandin E2 (PGE₂) as the required molecule for herpes reactivation (article). Previous papers had only showed that COX-2 inhibition could block herpes reactivation. But this paper shows that adding PGE₂ to neurons after inhibiting COX-2 can still cause the virus to replicate. So the arachidonic acid (AA) cascade (AA/COX-2/PGE₂) is the stress-sensing trigger for JNK and herpes virus replication.

Norepinephrine:
  In scientific studies, epinephrine is the most commonly used inducer of herpes simplex reactivation due to its high potency and long-lasting effects (Ref). Epinephrine is the technical name for adrenaline and norepinephrine is the technical name for noradrenaline. One of the most important roles of epinephrine and norepinephrine the regulation of muscle contractions in the body: heart muscle (heart rate), blood vessels (blood flow), muscles of the reproductive organs (orgasmic contraction, ejaculation). Epinephrine and norepinephrine blood levels rise sharply at the point of orgasm (Ref).

Glutamate:
"Glutamate treatment leads to a robust, progressive activation of the ERK and JNK/SAPK MAPK cascades." -Glutamate Induces Phosphorylation of.... Glutamate is a potent endogenous JNK activator (Ref1, Ref2, Ref3). Activation of the NMDA receptor increases the replication of CMV (HHV-5) (Ref).

Beta herpesvirus dependent POIS

"Furthermore, angioplasty-induced injury to the vessel wall and reperfusion after balloon angioplasty produce ROS8 and cytokines. The resulting activation of NF-kB can in turn stimulate the MIEP present in latently infected cells and thereby contribute to reactivation of latent CMV...Recent studies have shown that CMV infection of human cells leads to stimulation of arachidonic acid (AA) release." -Aspirin Attenuates Cytomegalovirus Infectivity and Gene Expression Mediated by Cyclooxygenase-2 in Coronary Artery Smooth Muscle Cells (1998)

  Cytomegalovirus (CMV, HHV-5) and HHV-6 are Betaherpesvirinae that primarily latently infect endothelial cells such as blood vessels and epithelial mucosa such as intestinal epithelia (Ref). This is unlike alpha-herpes viruses (HSV-1, HSV-2, VZV) which primarily latently infect neurons. Within minutes of infecting endothelial cells CMV upregulates reactive oxygen species (H₂O₂), NF-kB, COX-2 and cytokines (RefSE). These Betaherpesvirinae maintain this inflammatory environment while latent.

"These results suggest that infection by CMV or HHV-6 causes vascular endothelial injury, with HHV-6 having a stronger effect than CMV, and combined infection having a stronger effect than either virus alone."
-Endothelial damage caused by cytomegalovirus and human herpesvirus-6 (2003)

  CMV (and HHV-6) latency within endothelial cells leads to injury of vascular and smooth muscle tissue (Ref, Ref). Stretching this injured tissue causes a stress response of free radical production (RefGR) leading to reactivation and replication of the virus (RefSE). The reponse of the immune system to this virus replication is POIS.

"Enhancement of promoter activity by endogenous catecholamines is essential for high-level transgene expression from MIECMV within the vasculature." -Beta-Adrenoceptor Blockade Markedly Attenuates Transgene Expression From Cytomegalovirus Promoters Within the Cardiovascular System

  During orgasm there is a sudden rise in norepinephrine (noradrenaline) and epinephrine (adrenaline). This norepinephrine (and epinephrine) can cause vasodilation via the beta2-adrenergic receptor of the arteries in the brain and through out the body. Vasodilation creates a ballooning stress on the arteries that is normal under certain temporary conditions such as orgasm or exercise where increased blood flow is needed in certain areas of the body. However, any arteries that have been injured by latent infection of CMV (or HHV-6) will be triggered by this stretching stress to reactivate the virus (Ref) causing an immune response. Norepinephrine levels may fall shortly after orgasm. However, because of the immune response to reactivated CMV, histamine and nitric oxide levels rise causing a secondary vasodilation (stretching) of the arteries.

Eating induced POIS-related/POIS-like symptoms:
  This is of course just a hypothesis. Betaherpesvirae like CMV can infect and establish latency in intestinal epithelia (Ref). If the intestinal epithelia are infected by CMV (and/or HHV-6) at a certain location, food passing through the stomach can stretch the intestines at the location of the infection and causing stress-reactivation of the virus. This passing food would, by stretching that part of the intestine induce an immune response leading to either local irritable bowel syndrome (IBS) or systemic inflammation. This effect may lead people to think that specific foods are causing their IBS when it is just over eating. If there is a food that you really like or has MSG in it, you may be more inclined to over-eat. The MSG has nothing to do with the IBS. It is the inability to know when to stop eating that is causing the IBS/inflammation.
  To avoid IBS, eat smaller portions of food and drink water with your food to reduce friction and pressure in the area of the intestine that is infected with the virus.

Gamma herpesviruses
  Reactivation and replication of gamma herpesviruses like Epstein-Barr virus (EBV, HHV-4) and Kaposi's Sarcoma Associated Herpesvirus (KSHV, HHV-8) are uniquely inhibited by agonist of the cannabinoid receptors (Ref). Cannabinoid agonist such as THC inhibit HHV-4 reactivation but do not inhibit HSV-1, HSV-2 or CMV.

Other stress-triggers:

• E series prostaglandins (i.e. PGE₂)
• F series prostaglandins (i.e. PGF_2alpha)
• reactive oxygen species (ROS)
• PDE4 (breaks down cyclic AMP)
• cyclic GMP
• UV light, UV induces herpes activation
• inflammatory cytokines
• nicotine (smoking)
• heat and hot weather, hyperthermia induce HSV activation
• stretching vascular tissue (i.e. blood vessels)
• cortisol, epinephrine, norepinephrine (human study 1, human study 2, human study 3)
• stretching vascular tissue (i.e. blood vessels)

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[nanna1]

Herpes latency and reactivation dynamics

---under construction---

  Once herpes viruses HSV-1 and CMV infect a cell they rapidly change the redox state of that host cell. First there is an upregulation of xanthine oxidase which leads to increased production of superoxide (O₂^-), peroxide (H₂O₂) and other reactive oxygen species (ROS). This increase in ROS and more specifically peroxide chronically activates NF-kB.

  Once latent infection has been established, herpes viruses modify the cell metabolism to benefit their own replication. More specifically, herpes viruses increase the glucose and glutamine consumption of infected cells(Ref1, Ref2).

  Here is an example of a healthy immune response which could be viewed as a hypothesis for POIS.

   On the Disease Path (right side), there are many steps between Tryptophan and Natural Killer cells (NK cells). If one of these steps fails, then stress hormones like norepinephrine (Trigger Path, left side) will likely make the person sick (viral reactivation). For example, sleep deprivation reduces a persons immunity and makes them vulnerable to stress-induced sickness. And stress-induced sickness is often caused by viral shedding (human study 1, human study 2). On the other hand, if all of the steps between Tryptophan and NK cells succeed, then NK cells will suppress the reactivation of an infection and prevent stress-induced sickness. While NK cells mostly respond to virus infections, neutrophils mostly respond to bacteria infections. So an analogous diagram could be drawn for neutrophils suppressing bacterial growth.
  Immune cells can detect viruses through receptors on their surface. This initiates the activation of genes such as NF-kB which bind DNA and initiate transcription. The immune response is explained in the bottom left of the diagram in white letters. Click below image to see full size.

Figure from QIAGEN: NF-kappaB Activation by Viruses

While latent, herpes infection chronically elevates COX-2 expression in infected nerve cells through NF-kB.

NF-kB inhibitors:

Vitamin D3:
  Vitamin D3 is a strong inhibitor of NF-kB and COX-2 expression [Ref, Post]. D3 also inhibits the production of inflammatory cytokines such as TNF-a, IL-1B, IL-6, etc... [schematic diagram]

Plasma levels of ascorbic acid and vitamin D were correlated with levels of antibodies to Epstein-Barr virus (EBV). We found an inverse correlation between EBV VCA IgM and vitamin C in plasma in patients with mononucleosis and CFS meaning that patients with high levels of vitamin C tended to have lower levels of antigens in the acute state of disease. In addition, a relation was found between vitamin D levels and EBV EA IgG with lower levels of EBV early antigen IgG for higher levels of vitamin D. -Effect of high dose vitamin C on Epstein-Barr viral infection

Thiol anti-oxidants:
   In RefSE1 they found that anti-oxidants that decreased superoxide (O₂^-) and hydrogen peroxide (H₂O₂) also decreased the amount of CMV virus reactivation in a linear concentration fashion.

Figure 5: "N-acetylcysteine (NAC) treatment decreases viral titer of infected coronary smooth muscle cells (SMC). The effect of NAC on viral titer is concentration dependent. Shown are virus yields per milliliter of a 10% SMC homogenate and cell counts from parallel cultures at 96 hours after infection (mean of three experiments)." from RefSE1
HCMV = human cytomegalovirus

Acetylcholinesterase (AChE) inhibitors:
  Stimulation of the alpha7-acetylcholine receptor (a7-AChR) inhibits NF-kB and systemic immune response due to local tissue damage or infection (Ref). This effect is commonly known in the scientific literature as the "Cholinergic Anti-inflammatory Pathway" (Ref, Ref). Acetylcholinesterase (AChE) inhibitors can increase the available acetylcholine in the vagus nerve leading to increased a7-AChR stimulation and reduced immune (cytokine) response (Ref, Ref).

Figure 2: from "Physiology and immunology of the cholinergic antiinflammatory pathway"

  Through this indirect activation of a7-AChR, AChE inhibitors also lead to reduced JNK activation (Ref). Common AChE inhibitors include donepezil, galantamine, huperzine and pyridostigmine. Of these AChE inhibitors, Huperzine A does not produce tolerance with chronic use. Emirnazim has posted his experiences with acetylcholinesterase inhibitors here. FloppyBanana has posted his experiences with acetylcholinesterase inhibitors here.

Zyrtec (cetirizine) and Xyzal (Levocetirizine):
  Cetirizine and levocentirizine are strong inhibitors of NF-kB (Ref) and down-regulate NF-kB-dependent inflammatory proteins (Ref).

"Levocetirizine treatment inhibited the (human rhinovirus) HRV-induced increase in ICAM-1 mRNA and protein levels, as well as the HRV-induced expression of IL-6 and IL-8 mRNA and protein levels. Viral titer, as measured by culture in MRC-5 cells, was reduced by levocetirizine. Levocetirizine treatment also reduced the increased nuclear factor-kappa B (NF-kappaB) expression seen with HRV infection." -Levocetirizine inhibits rhinovirus-induced ICAM-1 and cytokine expression and viral replication in airway epithelial cells.

"Recent studies have demonstrated that Levocetirizine (LCT) has anti-inflammatory properties that are mediated by inhibitory effects on NF-κB in addition to classic antihistaminic effects." -Levocetirizine inhibits rhinovirus-induced bacterial adhesion to nasal epithelial cells through down-regulation of cell adhesion molecules

Useful resources:
CMV: A common virus that may accelerate immune senescence.

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[nanna1]

Inflammation and disease

  Inflammation is oxidation that is destructive to the cells of the body. The word inflammation comes from the root word flame, meaning combustion. Combustion is an oxidation process where an oxide (with a catalyst) is used to burn something. Without oxidation there is no inflammation. The endogenous mediators of inflammation are the reactive oxygen species (ROS) O₂^- (superoxide), H₂O₂ (peroxide), HO (hydroxide), NO (nitric oxide), etc... Outside of the mitochondria, ROS are produced primarily by oxidative enzymes.
List of oxidative enzymes associated with inflammation (ROS production):

• XO (xanthine oxidase) - (xanthine)
• COX-2 - (arachidonic acid)
• 5-LOX and 12-LOX - (arachidonic acid, glutamate, homocysteine)
• TDO - (tryptophan)
• IDO - (tryptophan)
• KMO - (kynurenine)
• iNOS - (arginine)
• MAO-A - (dopamine, norepinephrine, serotonin)

Most of these enzymes use superoxide O₂^- as a cofactor. For example, TDO and IDO:

Xanthine oxidase (XO) is a creator of superoxide (O₂^-) and feeds the other oxidative enzymes with ROS. There is a cascade of inflammatory events:
1. Some herpes viruses (and influenza virus, and HIV) upregulate XO to increase superoxide O₂^- (RefSE2000).
2. Superoxide is then used by the other oxidative enzymes (COX-2, IDO, etc...) to oxidize substrates (arachidonic acid, tryptophan, etc...)
3. This produces (PGE₂, kynurenine) and peroxide (H₂O₂)
4. H₂O₂ activates NF-kB
5. chronically elevated NF-kB primes the cell for viral activation and replication

  Inflammatory cytokines (i.e. IL-1, IL-6, INF-gamma, etc...) induce inflammation by up-regulating the activity of the above listed oxidative enzymes. Metal ions such as iron, copper, lead, cadmium and aluminum increase the activity of oxidative enzymes and ROS production. Anti-inflammatory cytokines reduce inflammation by down-regulating the above listed oxidative enzymes. Substances that inhibit or down-regulate oxidative enzymes have a net antioxidant (anti-inflammatory) effect in the body.

  Substances like progesterone, curcumin, quercetin, celecoxib and allopurinol do not directly scavenge ROS. However, they all have strong anti-oxidant effects due to their down-regulation or inhibition of activity from oxidative enzymes (COX-2, 5-LOX, IDO, XO, etc...) and up-regulation of anti-oxidant enzymes (catalase, superoxide dimutase (SOD), glutathione peroxidase).

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[nanna1]

Alpha-Herpes Induced Autoimmunity (glutamate, kynurenine and NAD)

"The most obvious way to base a therapeutic strategy for neuroprotection on the kynurenine pathway is to mimic the glutamate blocking activity of kynurenic acid, since overactivation of the various glutamate receptors may be a key characteristic of brain damage in stroke or neurodegeneration." -Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection (2012)

"quinolinic acid (QA)...is a putative N-methyl-D-aspartate (NMDA) receptor agonist....schizophrenia and psychosis are hypothesized to arise from increased metabolism of the NMDA receptor antagonist, kynurenic acid (KynA)...Here we present results that challenge the model of excess KynA production in affective psychosis. After rigorous control of potential confounders and multiple testing we find significant reductions in serum KynA and/or KynA/QA in acutely ill in patients with major depressive disorder (N=35), bipolar disorder (N=53) and schizoaffective disorder (N=40) versus healthy controls (N=92)." -Serum kynurenic acid is reduced in affective psychosis (2017)

  The diagrams below have been simplified for this discussion. More detailed diagrams of the Tryptophan pathways can be found here. The research articles cited below on herpes induced autoimmunity are only relevant to alpha-herpes viruses (HSV-1, HSV-2, HHV-3). Gamma-herpes (EBV) and beta-herpes (CMV, HHV-6) viruses may not induce autoimmunity in the below stated manner.

  In the absence of disease, tryptophan is metabolized to produce serotonin, melatonin, and niacin. In the CNS, "Regarding tryptophan (TRP) utilization by each pathway, 95% of ingested TRP is broken down via the kynurenine (KYN) pathway, 1-2% is used for protein synthesis and, 1-2% for serotonin synthesis" (Ref: section: TRP Breakdown by KYN Enzymes). Throughout the body, the serotonin pathway uses less than 3 percent of the total metabolized tryptophan (Ref: first paragraph). Therefore, kynurenine is the dominant usage for metabolized tryptophan in all tissues. The primary purpose of kynurenine pathway is to produce niacin and increase NAD levels.

  A stress-trigger activates the arachidonic acid cascade. Then PGE₂ reactivates herpes (HHV) through the AA->COX-2->PGE₂->JNK cascade (post1). PGE₂ also up-regulates IDO and TDO through the AA->COX-2->PGE₂->INF-gamma->(IDO and TDO) cascade (post2). The upregulation of IDO causes an initial increase in quinolinic acid which increases NMDA receptor signalling, neurotoxicity and virus replication. When the immune glia (astroglia/microglia) cells detect the spreading virus, they down-regulate KMO to increase the production of KynA (the NMDA receptor inhibitor). The inhibition of NMDAR by KynA, slows the replication of the virus.

  Since KMO inhibition also blocks the production of niacin (and NAD), the body cannot use kynurenic acid (KynA) very long for NMDA receptor inhibition. Therefore, the peripheral immune cells invade the site of infection and produce anti-NMDA receptor antibodies to block NMDA receptors in the infected region (Ref). The anti-NMDA receptor antibodies replace KynA as the NMDAR blocker (Ref). This allows KMO levels to rise to normal and niacin production to resume. Anti-NMDA receptor antibodies are therefore a longer-term solution to the problem of needing to use kynurenine for NAD production instead of KynA production. It is important to note that blocking the NMDA receptor (by both KynA production and anti-NMDA antibodies) is the correct funtioning of a healthy immune system in response to herpes virus activation. In this case, autoimmunity is not a disease of the immune cells, but rather it is an effective immune strategy to stop virus replication. However, it could take up to a week for the peripheral immune cells to produce sufficient anti-NMDA antibody levels. During this time, NAD levels decline due to glia KMO inhibition causing a reduction in ATP (energy) levels. Creatine buffers the ATP pool to prevent a decrease in ATP due to decreased NAD levels.

  The diagrams above have been simplified for this discussion. More detailed diagrams of the Tryptophan pathways can be found here.

  NAD is a negative feedback inhibitor of IDO and TDO (Figure, Ref2).

And NAD reduces the negative effects KynA production:

"Pharmacological doses of NAD precursors repeatedly provide dramatic therapeutic benefit for rheumatoid arthritis, type 1 diabetes, multiple sclerosis, colitis, other autoimmune diseases, and schizophrenia in either the clinic or animal models. Collectively these observations support the idea that autoimmune disease may in part be considered as localized pellagra manifesting symptoms particular to the inflamed target tissues. Thus pharmacological doses of NAD precursors (nicotinic acid/niacin, nicotinamide/niacinamide, or nicotinamide riboside) should be considered as potentially essential to the therapeutic success of any IDO-inducing regimen for treating autoimmune diseases." -Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease

  Vitamin B6 (PyridoxaL 5-Phosphate) is required to convert 5-HT into serotonin. Vitamin B6 (PLP) is also the primary dietary regulator of kynurenine metabolic pathway.

  B6 (PLP) also regulates the kynurenine pathway enzymes after 3-hydroxykynurenine:

"...tryptophan is metabolized to kynurenine via either indoleamine 2,3 dioxygenase (IDO1 or IDO2) or tryptophan 2,3 dioxygenase (TDO). Other than 3-hydroxykynurenine (HK), all subsequent metabolites require a vitamin B-6 (PLP)-dependent enzyme for generation. They show that ratios of HK to metabolites downstream of PLP-dependent enzymes [xanthuranic acid (XA), 3-hydroxylanthranilic acid (HAA), and kynurenic acid] correlate with PLP concentrations better than HK alone. The relation was strongest at the lowest PLP concentrations, and importantly, the ratios normalized after vitamin B-6 supplementation was instituted." -Kynurenine pathway metabolites: relevant to vitamin B-6 deficiency and beyond

The expression of these enzymes in the body can be found here (right most column).

  GABA-A receptor signalling is a potent inhibitor of autoimmunity (Ref1, Ref2). It is not clear whether GABA-B can display this property. Therefore, substances which selectively enhance GABA-A receptor signalling may reduce herpes mediated immune reactions with fewer side-effects. Taurine and beta-alanine stimulate the two inhibitory receptors GABA-A and Glycine receptors. Serotonin increases the sensitivity of taurine and beta-alanine in stimulating GABA-A.

Ciccio has also posted about herpes and kynurenine in the thread "Kynurenine/Tryptophan and the link with infection and fatigue". Quantum, Starsky, G-man and many others have also post about the kynurenine pathway and POIS. Kurtosis has many post about NADH. A list of niacin experiences can be found here (SUMMARY: Niacin and Xanthinol Nicotinate experiences).

Acetylcholine receptor autoimmunity:
  Stimulation of the alpha7-acetylcholine receptor (a7-AChR) can suppress systemic inflammation and immune response due to local tissue injury (Ref, Ref). Lymphocytes (T cells and B cells) are also responsible for creating the autoimmune antibodies for the acetylcholine receptor (a7-AChR) (Ref, Ref). Some herpes viruses can tricks the T and B cells of the immune system into producing autoimmune antibodies for the AChR. For example, HSV-1 does this by expressing a fake AChR on its surface. The immune system then creates an antibody to bind the fake herpes-AChR in an attempt to disable the virus (Ref, Ref). However, this antibody also binds the real human AChR and inhibits its function. This inhibition of AChR by antibodies blocks the anti-inflammatory properties of acetylcholine. In this way, diseases such as myasthenia gravis can be triggered (Ref, Ref).

Epstein-Barr virus (HHV-4) induced systemic lupus erythematosus
Lupus is known to be caused by the human herpes virus 4 (EBV, HHV-4). See the following references:
--Epstein-Barr virus infection induces lupus autoimmunity.
--Lupus and Epstein-Barr
--Epstein-Barr Virus and Systemic Lupus Erythematosus

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[nanna1]

Testosterone, arousal shift physiology and autoimmunity

"The activities of neurosteroids are dependent on brain regions and types of neurons. In addition to the slow genomic action of the parent steroids, the non-genomic, and rapid actions of neurosteroids play a significant role in the GABA_A-receptor function and shift in mood and memory function." -Neurosteroids and GABA-A receptor function

  Testosterone is a steroid hormone that is elevated during sleep, exercise and sexual activity. Testosterone is often associated with muscle growth and masculine physical features. However, testosterone also controls mood and bodily functions by regulating the expression of neurotransmitter receptors. More specifically, elevated testosterone upregulates the D2-dopamine receptor (RefA, RefB) and GABA-A receptors. Testosterone also downregulates alpha2-adrenergic receptors (RefF). Additionally, testosterone changes the ratios of the various acetylcholine receptors throughout the reproductive system (RefE, RefF) which can redirect blood flow to different parts of the body. Let us call this testostrone-induced shift in the ratios of neurotransmitter receptors the TEST-shift. This TEST-shift changes which brain regions are most active. "Regions of brain activation were correlated with testosterone plasma levels and penile tumescence (erection)." -Physiology of Penile Erection and Pathophysiology of Erectile Dysfunction

The overall effect of this TEST-shift includes (but is not limited to):

• redirection of blood flow to different areas of the nervous system and different locations in the brain
• increase the excitability/sensitivity of certain neurons
• decrease the excitability/sensitivity of other neurons
• modify mood (aggression, arousal)
• suppression of autoimmunity in the brain

  For example, D2-dopamine receptors are envolved in the sensation of sexual pleasure. However, elevating dopamine by itself is not enough to induce this effect. However, dopamine released during a TEST-shift of the D2-dopamine receptor produces this type of pleasure.
Also, acetylcholine causes erections to occur. However, elevating acetylcholine levels is not enough to induce this effect. But an acetylcholine release in the reproductive system occuring during a TEST-shift of the acetylcholine receptors does produce erections.

  Testosterone is a strong suppressor of autoimmune encephalomyelitis (brain damage) (Ref, Ref, Ref). This suppression of autoimmune encephalomyelitis by testosterone could be related to its upregulation of GABA-A receptors (Ref).

Androgens (T=testosterone, DHT=dihydrotestosterone) are decreased in the cerebral spinal fluid (CSF) and brain during chronic autoimmune encephalomyelitis.

from Sex-dimorphic changes in neuroactive steroid levels after chronic experimental autoimmune encephalomyelitis.

  For those with low testosterone levels, probiotics may restore testosterone levels to normal (Probiotic Microbes Sustain Youthful Serum Testosterone Levels and Testicular Size in Aging Mice).

demografx and many others have posted their experiences with TRT.

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[nanna1]

Methylation and herpes

 In the (herpes) virus model, a stress-trigger activates a gene called JNK through the (AA/COX-2/PGE₂) pathway. JNK then activates the dormant herpes virus causing it to replicate and spread. According to this paper (and press release), the herpes viruses are kept dormant by methyl groups attached to the virus DNA. Methyl groups act as the off-switch for the virus (and DNA replication in general)(RefAWWH). When a gene called JNK is activated, the methyl groups that were attached to the herpes DNA are eventually removed (demethylation). This DNA demethylation results in the virus replicating and spreading.
The diagram below shows the homocysteine cycle (methylation cycle). The purpose of the homocysteine cylce is to produce SAMe the universal methyl-donor. Purple arrows inserted by me:

(1)SAMe, (2)TMG (betaine) or choline, (3)B12, (4)B6, (5)B9 (metafolin)

The homocycteine cycle requires ATP to function. Creatine acts as a ATP buffer to maintain the function of the homocysteine cycle. NADH may also aid in supplying energy to the homocysteine cycle.

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[nanna1]

Anti-herpes therapuedics

COX-2/PGE₂ inhibitors:
Indomethacin:
  Indomethacin is a potent inhibitor of COX-2 (blocking PGE₂ production). While Indomethacin is classified as a COX inhibitor and NSAID. It also protects the blood-brain-barrier (BBB) during neuroinflammation (Ref). I have taken indomethacin in prepack form and can validate that it inhibits 85 percent of POIS symptoms without using any other supplements. Indomethacin can only be taken as a prepack and not on a regular basis because it is not selective for COX-2. Indomethacin also inhibits COX-1 and CYP3A2. Egordon has shared his experience with indomethacin (Post1, Post2). POISse has shared his experience (Post). Here is my (nanna1) experience:

  My neurologist once prescribed the COX-2 inhibitor, indomethacin, to me to treat orgasm induced headaches. I didn't take it at the time because indomethacin has longterm side effects on the stomach and liver. Recently, I tested indomethacin (~30 min prior to sex) without taking the POIS Cascade Stack for one-week. Indomethacin alone stopped 85% of my POIS symptoms. Their was some mild discomfort in my left ear and left side of forehead. This discomfort did not effect my productivity at work. I took a second dose of indomethacin the next day along with a Gen-1 H1-histamine receptor blocker, and all of my POIS symptoms were gone.

More recently, I did another trial of indomethacin here.
  In one study, indomethacin was the most potent inhibitor of cytomegalovirus (CMV, HHV-5) induced inflammation (lower RF numbers are better). Click below image to see full size.

A relative comparison of other COX inhibitors can be found here.

N-acetylcysteine:
  N-acetylcysteine (NAC) is the rate limiting prodrug for glutathione synthesis (RefDB). Hydrogen peroxide (H₂O₂) is a major activator of NF-kB. NAC scavenges H₂O₂ and reduces NF-kB induce HHV-5 (HCMV) reactivation (RefSE1, RefXX).

Figure 5: N-acetylcysteine (NAC) treatment decreases viral titer of infected coronary smooth muscle cells (SMC). The effect of NAC on viral titer is concentration dependent. From RefSE1

selenomethionine:
  Selenomethionine is needed to produce all the glutathione recycling enzymes, glutathione peroxidase. Selenium can repair peroxidative damage and increase activity of the three main anti-oxidant enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase above normal levels (Ref).

Aloe emodin:
  Aloe emodin is one of the active ingredients in aloe vera leaves and is highly concentrated in aloe vera gel. Aloe vera gel is know for its therapeutic properties of the skin. But aloe emodin has been shown to inhibit herpes virus (HSV-1, HSV-2, VZV, CMV) replication and to be virucidal (RefFRMA, RefRSRB, RefKZZR, RefKSWW). Aloe emodin is also inhibits the activity of NF-kB and down-regulates the expression of the MMP-2, JNK and MAPK genes used in collagen breakdown, stress sensing and viral replication (RefMPSK, RefLLCS). Aloe emodin reduces blood vessel inflammation by downregulating MMP-2, MMP-9 and VEGF through inhibition of NF-kB (RefPSSG).

ID₅₀ values of aloe emodin Inactivation of enveloped viruses by anthraquinones extracted. Serum profiles after oral administration of emodin at a dosage of 2 g/kg in mice (163 mg/kg in humans) showed that the peak serum concentration of emodin is 700 μM (RefHCHT).

Allopurinol:
  Cytomegalovirus (CMV, HHV-5) increases ROS and NF-kB activity through increasing xanthine oxidase (XO). Allopurinol is a XO inhibitor which inhibits CMV replication (RefIN, RefSE1). Allopurinol also inhibits indomethacin induced oxidation and was more effective than superoxide dimutase (SOD) and catalase.

sodium ascorbate (intravenous vitamin C):
see Long-term herpes relief and permanent virus removal strategies

nicotinic acid (flush-niacin):
  Nicotinic acid increases the production and release of Prostaglandin D2 (PGD₂) through COX-1. PGD₂ blocks the actions of PGE₂, and PGD₂ inhibits herpes virus replication (Ref1, Ref2, Ref3). Other effects of flush-niacin are discussed here. NAD, a derivative of niacin, is a negative feedback inhibitor of IDO and TDO (Figure). Observer (post) and Daveman have shared their experience with niacin. A list of niacin experiences by many POIScenter users can be found here (SUMMARY: Niacin and Xanthinol Nicotinate experiences).

d-limonene:
RefAAPS

PDE5 inhibitors:
  While PGE₂ can cause activation (replication and spreading) of the different herpes viruses.

PDE5 inhibitors:

• caffeine and it's metobolites
• viagra
• cialis

  Of these PDE5 inhibitors, caffeine is the most attractive in that it has high bioavailability, high brain penetration (crosses blood-brain-barrier), and high potency. The side-effects of caffeine are well characterized. The anti-inflammatory effects of caffeine are well know (see Caffeine: Pharmacodynamics: Enzyme Targets section).

Caffeine (and other PDE4 inhibitors) potently downregulates JNK and NF-kB activation:
Caffeine induces beneficial changes in PKA signaling and JNK and ERK activities in the striatum and cortex of Alzheimer's transgenic mice.
Role of secondary mediators in caffeine-mediated neuroprotection in maneb and paraquat-induced Parkinson's disease phenotype in the mouse.

cytosolic phospholipase A₂ (cPLA2) inhibitors:
  When cytosolic phospholipase A₂ is activated, it releases arachidonic acid and initiates the cells stress response (i.e. JNK) (post) Phospholipase A₂ is inhibited by cellular cyclic-AMP (cAMP). So any supplement that inhibits PDE4 will also indirectly inhibit Phospholipase A₂.

• progesterone
• curcumin
• indomethacin
• propranolol (beta-blocker)

"The results suggest that curcumin affects arachidonic acid metabolism by blocking the phosphorylation of cPLA2, decreasing the expression of COX-2 and inhibiting the catalytic activities of 5-LOX. These activities may contribute to the antiinflammatory and anticarcinogenic actions of curcumin and its analogs." -Modulation of arachidonic acid metabolism by curcumin and related b-diketone derivatives: effects on cytosolic phospholipase A2, cyclooxygenases and 5-lipoxygenase

Many anti-psychotic medications such as lithium function as phospholipase A₂ inhibitors (post)

"We have also found that lithium and carbamazepine, when administered chronically at therapeutically relevant concentrations, reduced mRNA, protein, and activity levels of cPLA2-IV, and each of the three drugs, as well as lamotrigine (LTG), another FDA-approved mood stabilizer (Bowden, 2005; FDA, 2009), decreased protein and mRNA of COX-2 in rat brain." -Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain (2012)

Steroid anti-inflammatory drugs also function as phospholipase A2 inhibitors

Useful resources:
1. Divergent Effects of Human Cytomegalovirus and Herpes Simplex Virus-1 on Cellular Metabolism
2. Dynamics of the Cellular Metabolome during Human Cytomegalovirus Infection
3. drug pharmacokinetics

Animal to human dose conversion chart (Ref)

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[nanna1]

Anti-virals medications

"It is interesting to us that acyclovir caused a replicable improvement of tics and behavioral symptoms in the absence of an overt herpes exacerbation (or outbreak). Since herpes simplex is a neurotropic virus, it is possible that it played a role in the induction of this patient's neuropsychiatric symptoms. While a placebo effect cannot be ruled our in this single case, the potential role of a viral infection in initiating and/or exacerbating symptoms of Tourette's Syndrome must be strongly considered and warrants further investigation."
-VIRAL INFECTION AND TIC EXACERBATION

  Anti-herpetic antiviral medications (such as acyclovir (Zovirax), famciclovir (Famvir), penciclovir (Denavir) and valacyclovir (Valtrex)) have been used to treat a number of neurological diseases (epilepsy, migraine headaches, irritable bowel syndrome and fibromyalgia)
Antiviral medications like acyclovir and penciclovir are only active against herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2) and Varicella-zoster virus (VZV, HHV-3). These medications are not effective against Epstein-Barr virus (EBV, HHV-4), Cytomegalovirus (CMV, HHV-5) or herpesvirus type 6 (HBLV, HHV-6). And they are only active once a virus has reactivated or there is an outbreak. Antivirals have no effect on the inflammation caused by a latent herpes virus and cannot prevent the latent virus from reactivating. However, these medications are effective at inhibiting viral DNA replication, thereby preventing the spread of the virus.

See http://poiscenter.com/forums/index.php?topic=2659.msg23395#msg23395 and Antiviral therapy of varicella-zoster virus infections:

POISrival and Nas have offered their experiences with antivirals at "(UPDATED) Antivirals".

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[nanna1]

Preventing Nocturnal Emissions POIS

--underconstruction--

  Since sleep typically last for 8 hours, one strategy could be to take supplements that have a long half-life. Here is a list of beneficial supplements with long half-lives:
-vitamin D3 (2000 IU, sublingual), half-life=360hours
-melatonin (20 mg, sublingual), > 4 hrs
-vitamin B12 (>50mcg, sublingual), 144hrs
-conjugated linoleic acid (CLA, 2 g), >18hrs
-omega-3 (1 g), 48hrs

  During sleep testosterone levels rise and shift the body into an aroused state (through enhanced D2-dopamine receptor signalling). Strategies that suppress glutamate-NMDA signaling and/or enhance GABA signaling can negate the arousal effect of testosterone.
NMDA inhibitors:
-magnesium threonate, magnesium gluconate

GABA agonist:
-beta-alanine

This post is intended to facilitate discussion, not to endorse treatment.

[nanna1]

Long-term herpes relief and permanent virus removal strategies

"High dose IV vitamin C is in unexpectedly wide use by Complementary and Alternative Medicine practitioners. Other than the known complications of IV vitamin C in those with renal impairment or glucose 6 phosphate dehydrogenase deficiency, high dose intravenous vitamin C appears to be remarkably safe."
-Vitamin C: Intravenous Use by Complementary and Alternative Medicine Practitioners and Adverse Effects (2010)

In vivo human trials treating herpes complications:
The effects of intravenous vitamin C (ascrobate) against herpes have been shown in promising human trials.

  Case 1: "Five days after taking the pregabalin and vitamin C IV, she reported a complete resolution of the pain and stopped taking the medication. At 3 months follow-up, she continued to have no pain without any complications." -Administration of Vitamin C in a Patient with Herpes Zoster - A case report (2011)

  Case 2: 7.5g vitamin C, 2-4 times/week "...the study presented here demonstrates that concomitant intravenous administration of ascorbic acid has positive effects on herpes zoster-associated pain and zoster-associated dermatologic findings. Furthermore, common clinical symptoms in patients with shingles, such as general fatigue and impaired concentration, were significantly improved and the risk of developing postherpetic neuralgia was reduced."
-Intravenous Vitamin C in the treatment of shingles: Results of a multicenter prospective cohort study (2012) (NIH ClinicalTrials.gov Identifier: NCT00921934)

  Case 3: Vitamin C IV infusions cure post-herpetic neuralgia in two patients, shown by reduced VAS pain score.

  "Sudden and total remission of the neuropathic pain (measured on the basis of the visual analogous-scale, VAS) could be observed. Remission of the cutaneous lesions was noted within 10 days." -Intravenous administration of vitamin C in the treatment of herpetic neuralgia: two case reports (2010) (click figure to show full resolution)

  Case 4: Ascorbate IV reduces Epstein-Barr virus early antigen IgG antibody levels as well as improving symptoms of virus related disease (measured by percent of decrease in EBV EA IgG from the 0 baseline). After 10 IV injections all patients showed at least a 17% reduction in viral IgG. With increasing number of vitamin C IV infusions, some patients showed IgG reductions approaching 100%.

  "We found an inverse correlation between EBV VCA IgM and vitamin C in plasma in patients with mononucleosis and chronic fatigue syndrome (CFS) meaning that patients with high levels of vitamin C tended to have lower levels of antigens in the acute state of disease...In addition, a relation was found between vitamin D levels and EBV EA IgG with lower levels of EBV early antigen IgG for higher levels of vitamin D....The clinical study of ascorbic acid and EBV infection showed the reduction in EBV EA IgG and EBV VCA IgM antibody levels over time during IVC therapy" -Effect of high dose vitamin C on Epstein-Barr viral infection (2014) (click figure to show full resolution)

Case: 5 "We treated this patient with IV 2.5 g ascorbate... on days 1, 3, and 5. His intermittent, spontaneous, shooting pain completely resolved within 1 wk, and his baseline pain decreased to a level of 3 (his plasma vitamin C level reached 14.9 mg/L). We advised him to increase his intake of fruits and vegetables. On follow-up examination 3 mo later he has had no recurrence of the extreme intermittent pain, and his plasma vitamin C level was 11.6 mg/L."
-Treatment of Postherpetic Neuralgia with Intravenous Administration of Vitamin C (2006)

Case 6: "In the patient who received the intravenous administration of vitamin C and cantharidin patches beside standard analgesis and virostatic treatment, a swift regression and clinical improvement of the herpes zoster-induced efflorescences was obtained, rapid pain reduction was illustrated by the NAS-scores and possibly of prevention of a later ongoing PHN were presented. The rapid therapy benefits were impressive." -Cantharidin patches and intravenous administration of vitamin C in the concomitant treatment of herpes zoster: A case report (2011)

Case 7: "Clinical and subjective response to three consecutive daily 50 g IV vitamin C was excellent. Symptoms remitted in five days following beginning of therapy... The therapy was well tolerated and no adverse side effects were noted. The quickness of the patient response to high-dose IV vitamin C was dramatic... Our case provides evidence that high dose (50g) intravenous vitamin C therapy has a positive effect by reducing illness symptoms, disease duration and viral antibody levels."
-Intravenous Vitamin C and Infectious Mononucleosis: A Case Report (2018)

Other pathogens treated with IV ascorbate (vitamin C):

• HIV
• influenza virus (RefGO2018)
• Chikungunya virus (RefGC2014)
• Zika virus (RefGA2016)

  The Riordan Clinic are the leading specialist in IV Vitamin C administration. They describe their protocol in detail here: RiordanIVCprotocol

Vitamin C pharmacokinetics:

Fig. from: "Vitamin C pharmacokinetics: implications for oral and intravenous use", Ann Intern Med. 2004 (Ref) (click figure to show full resolution)

  Liposomal vitamin C is more than 60 times less bioavailable than intravenous ascorbate. See liposomal VC bioavailability graph (Fig 3) from: "Pharmacokinetics of Vitamin C: insights into the oral and intravenous administration of ascorbate", PRHSJ (2008) (Ref). Therefore, oral vitamin C supplementation cannot replace intravenous vitamin C.

  Many high-dose intravenous ascorbate studies are done in cancer patients. So cancer-ascorbate studies may provide useful information for experience with bioavaibility, tolerability and side-effects.

Fig. from: "Clinical experience with intravenous administration of ascorbic acid: achievable levels in blood for different states of inflammation and disease in cancer patients", Journal of Translational Medicine 2013 (click figure to show full resolution)

In vitro virucidal mechanism for copper + intravenous vitamin C:
  The inactivation of viruses by vitamin C (ascorbate) requires copper ions (Inactivation of Vaccinia Virus by Ascorbic Acid). Copper II ions (CuII) binds to the guanine (G base) of latent herpes RNA. Then vitamin C (ascorbate, AscH^-) reduces the copper ion in a Fenton reaction producing reactive oxygen species (free radicals: O_2*, H₂O₂, HO*) (Ref, Ref1987).

From Scheme 1

  The free radical HO* cuts and separates the virus RNA at the G base location of the bound copper ion (Ref1983, Ref1997, Ref1983). This removes the latent virus by destroying herpes genetic material and virus in the cytoplasm. CuII-ascorbate also disables viruses in the capsid (Ref1986).

  Intravenous vitamin C (ascorbate) is safe in humans (Ref2010) and has been used in clinical practice as both adjunct and primary therapy to treat various symptoms related to viral infections (Ref, Ref, Ref). The maximum tolerable daily dose is 18g (Ref2015).

Vitamin C (ascorbate) + copper (CuII) toxicity:
  Sodium Ascorbate can be taken intravenously up to 30g per day in healthy humans without complications. Cu(II) is natural found in the blood at a concentration of  1mg/L or 16uM (RefSL1997). However, if copper is also supplemented to superphysiological levels, then the dose of vitamin C will have to be monitored more closely.

Fig. from: "Inactivation of HSV-2 by ascorbate-Cu(II) and its protecting evaluation in CF-1 mice against encephalitis", Journal of Virological Methods 120 (2004) 161-165 (click figure to show full resolution)

Vitamin C: optimal dosages, supplementation and use in disease prevention (2105)
Vitamin C IV infusion is safe: Vitamin C: Intravenous Use by Complementary and Alternative Medicine Practitioners and Adverse Effects
DNA- and Protein-Scission Activities of Ascorbate in the Presence of Copper Ion and a Copper-Peptide Complex (1983)
Mechanism of copper-mediated inactivation of herpes simplex virus. (1997)
Virucidal agents in the eve of manorapid synergy (2007)
A Clinical Pilot Study of Lignin-Ascorbic Acid Combination Treatment of Herpes Simplex Virus (2009)
Inactivation of Vaccinia Virus by Ascorbic Acid (1964)
Inactivation of Vaccinia Virus by Ascorbic Acid and Glutathione (1937)
The antiviral properties of vitamin C (2019)

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[nanna1]

POIS literature review

References:

• Progesterone deficiency, "Benign coital headache relieved by partner's pregnancies with implications for future treatment" (Selwyn Dexter, 2009)
• Neuroendocrine malfunction, "CASE REPORT: Postorgasm Illness Syndrome: A Spectrum of Illnesses" (Ashby and Goldmeier, 2010)
• Semen IgE allergy (type I) and antigen (type IV), "Postorgasmic Illness Syndrome (POIS) in 45 Dutch caucasian males: clinical characteristics and evidence for an immunogenic pathogenesis (Part 1)" and "(Part 2)" (Waldinger, et al, 2011)
• Non-semen related allergy/hypersensitivity, "Post-orgasmic illness syndrome: a case report" (Attia, et al, 2013)
• Mu-opioid receptor dysfunction, "Postorgasmic Illness Syndrome (POIS) in a Chinese Man: No Proof for IgE‐Mediated Allergy to Semen" (Jia Yin, et al, 2015)
• (for sex headaches) Renin/Angiostentin induced alpha1-adrenergic receptor over-expression, "Successful Reversal of Intractable Sexual Headache by Renin Antagonist" (Wei-Hsi Chen, et al, 2015)
• Semen antigen (type IV) only, "Post orgasmic illness syndrome (POIS)" (Waldinger, 2016)
• Semen IgE allergy (type I), "Intralymphatic Immunotherapy With Autologous Semen in a Korean Man With Post-Orgasmic Illness Syndrome" (Lee, et al 2018)
• Neurobiological mechanism, "Negative allergy study in a case of postorgasmic illness syndrome (POIS)" (N. Depreux, et al, 2018)
• "Immunophenotypical Characterization of a Brazilian POIS (Post-Orgasmic Illness Syndrome) Patient: Adding More Pieces to Puzzle" (K. De Amicis, et al, 2019)
• sympathetic dysregulation, autonomic hyperreflexia, alpha1 adrenergic receptor"Postorgasmic illness syndrome: potential new treatment options for a rare disorder" (H. Pierce, et. al., 2019)

Review:
  The name "Post-Orgasmic Illness Syndrome" was first proposed by Waldinger and Schweitzer (2002). Waldinger, et al (2011) were also the first to give a diagnostic criteria and classifying symptoms related to POIS into clusters. In this article, the investigators propose that POIS is a combination of type I (IgE allergy) and type II (hapten-antigen) hypersensitivities to the male's own semen. However, 22 percent of the patients did not have positive skin prick test of the autologous semen.

  Dexter (2009) treated a POIS patient who was relieved from symptoms by vaginal intercourse only during his wife's pregnancies. When his wife was not pregnant, any form of sexual activity and/or nocturnal emissions produced POIS symptoms. The patient was successfully treated with a synthetic progesterone (norethisterone, 5mg daily) a experienced 95 percent relief of post-orgasm symptoms.
  Ashby and Goldmeier (2010) treated two patients prophylactically with the non-selective COX inhibitor diclofenac. One of the patients responded to this drug with 80 percent relief of POIS symptoms. In communications with Abdalla Attia, David Goldmeier has suggested that the therapeutic benefit of diclofenac (50mg) is superior to other NSAIDs like ibuprofen (400mg) (Attia, et al, 2013). As of February 2019, prophylactic diclofenac (50mg) and daily norethisterone (5mg) are the only two drug therapies that have demonstrated success in treating Post-orgasmic Illness Syndrome in a peer reviewed publication.

  Jia Yin, et al (2015), disputed the Waldinger (2011) hypothesis by demonstrating a negative case of type I (IgE-dependent) hypersensitivity in the presence of a positive skin reaction to autologous seminal fluid. Instead Jia Yin, et al (2015), proposed that POIS might be caused by a disregulation of the mu-opiod receptor using an plausibility argument related to other diseases with similar symptoms.

  Attia, et al (2013) also directly disputed the plausibility of a semen-induced hypersensitivity (type I and type IV), arguing that such a disease would likely require the disruption of the blood-testis barrier and produce symptoms inhibiting fertility which are not commonly observed in patients with POIS. Instead Attia, et al (2013) proposed that POIS is a hypersensitivity response that occurs outside of the reproductive organs and is not dependent on contents of the semen. In a reply to a reviewer of their publication they state the following: "If allergy to the patient's own semen is a suspected cause of POIS, it will be necessary to measure serum and seminal plasma anti-sperm antibodies; IgA, IgG and IgM, to conduct immunobead and MAR testing and to report on the patient's seminogram changes. This might also suggest that POIS patients would be mostly infertile due to formation of anti sperm antibodies."

  Later, Waldinger (2016) proposed that POIS was mediated by antigens released from prostatic tissue and are not bound to human sperm. This hypothesis was based on the newly documented observation that women experience POIS and the fact that male POIS patients that undergo a sterilization treatment continue to experience POIS even after they no longer can produce spermatozoa (Waldinger, 2016). This proposed sperm-independent antigen (type IV hypersensitivity) partially circumvented the objections that Attia et al (2013) presented to the reviewer concerning sperm mediated allergy. However, since sperm cells are not the sole determiner of fertility in men, questions raised by Abdalla Attia concerning the integrity of the blood barrier, the production of antibodies and the absence of observed infertility in patients still remain.

  In agreement with Attia's concerns about the semen mediated immune hypersensitivity model, some members of POIScenter.com online forum who self-diagnose as experiencing POIS, also report POIS-like symptoms from activities that do not involve sexual arousal, sexual stimulation, orgasm or non-sexual stimulation of the reproductive organs. These POIS-like symptoms mirror in-part or in-whole the syndrome that they experience after orgasm or ejaculation. The most common non-sexual triggers of these symptoms include physical exercise, warm temperatures and loss of sleep (message 24788). Moreover, several members of POIScenter.com self-report symptoms which are left-right asymmetric with respect to the locations in the body of where POIS symptoms occur. In these members some observed symptoms only occur on one side of the body (message 24788). This observation may contradict POIS hypotheses where an aggravating molecule (allergen/antigen) of long half-life diffuses through the blood unless there are antibodies in the blood to reduce the effective half-life of the antigen and limit its dissemination.

  More recently, questions have been raised about the methods used in the studies by Waldinger, et. al. (2011):

"Limitations of the studies by Waldinger et al. include a lack of healthy control men for the autologous semen SPT results and the observational study design."
Post-Orgasmic Illness Syndrome: A Review (Hellstrom, 2018)

  Moreover, given the fact that semen is a rich source of prostaglandins, cytokines and polyamines (Semen composition), there are still questions as to whether the subcutaneous autologous semen injections in the Waldinger, et al (2011) study actually functions as a hyposensitization therapy. The immune signaling molecules (i.e. prostaglandins, cytokines and polyamines) contained in semen are directly immune modulatory on their own (FC Denison, et al, 1999). To support the conclusion that autologous semen injection produces hyposensitization, the suspected antigenic proteins would need to be separated from these signalling molecules prior to injection.

  Jia Yin, et al (2015), did not find IgE reactivity with semen proteins in three patients even though skin test with autologous semen were positive. Lee, et al (2018) established correlation but not causation for IgE responsiveness to one patients semen. However, in another patient Depreux, et al, (2018) found no IgE mediated response to semen proteins. They also found no immune response to autologous semen skin-prick test or intracutaneous injection indicating that there was no hypersensitivity to semen components in this patient.

Other valuable resources:

• Post-Orgasmic Illness Syndrome: A Review (Hellstrom, et al, 2018)
• Postorgasmic Illness Syndrome: What do we know so far? (Hellstrom, et al, 2018)
• NIH: NCATS: GERD: Postorgasmic illness syndrome
• Gather and Post Here Your Medical Tests Results - Discussion Thread: message 24788
• "Immunophenotypical Characterization of a Brazilian POIS (Post-Orgasmic Illness Syndrome) Patient: Adding More Pieces to Puzzle" (2019)
• Neuroendocrine responses to arousal and orgasm

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[Hopeoneday]

Hi Nana1 thanks a lot.
Because of this link (post on botom) here and ragarding to symptomes i conect this posible viral couse to some of us. VAGUS nerve palsy coused by viral infections is rare. I hawe sypmtomes of dysphonia, dysphagia and i found this conection.

See - https://www.ncbi.nlm.nih.gov/pubmed/11551239

[Ciccio]

Thank you for your very very good work nanna1!!!

[aswinpras06]

Very very informative and useful info.  Thanks  a lot Nanna1 for your painstaking work.

Gene editing as a way to eradicate latent viruses is currently researched as per this article.  So in the near future it may be one more tool to fight pois, if it is caused by latent viruses.

https://www.smithsonianmag.com/science-nature/can-we-gene-edit-herpes-away-180968551/

[Nas]

Thanks alot Nanna in your effort.
Although I have my doubts about Herpes; since I tried aciclovir myself and nothing changed. But most importantly the herpes infection needs to be tested in laboratory to confirm that what we have is a dormant hepres virus.
I'm 100% for an anti-inflammational treatment to the brain, but the problem is that celebrex is not that common of a medication. And not so many medication can cross the BBB. So this needs to be our focus point, which is finding an anti-inflammatory that can cross the BBB and is accessable to some degree for the public.
In a seance, I would like to know what would a doctor perscribe for us if we explained to him what we have ib detail.

[nanna1]

Thanks All for sharing your articles, suggestion, questions. I'm learning so much from everybody and I love to learn new things. We beat POIS together! Also it helps to know that others go through what you go through. Over this past week I have been going out eating with friends and eating the wrong foods (cheese, chicken beef). Now I have that familiar headache even without the O. It sucks. The diet requires discipline that I am hoping to avoid one day.

Nas, when I described my symptoms to a neurologist, he said that I have Sex Headaches. The standard treatment for sex headaches is phospholipase A2 inhibitors. This is how I found out about indomethacin. I about a year ago I was diagnosed with sex headaches and the doctor prescribed indomethacin. But I didn't take it then because I read about the side effects of daily use. But here is a recent test:

  My neurologist once prescribed the COX-2 inhibitor, indomethacin, to me to treat orgasm induced headaches. I didn't take it at the time because indomethacin has longterm side effects on the stomach and liver. Recently, I tested indomethacin (~30 min prior to sex) without taking the POIS Cascade Stack for one-week. Indomethacin alone stopped 85% of my POIS symptoms. Their was some mild discomfort in my left ear and left side of forehead. This discomfort did not effect my productivity at work. I took a second dose of indomethacin the next day along with a Gen-1 H1-histamine receptor blocker, and all of my POIS symptoms were gone.

Some doctors also prescribe tripsans (5-HT₁ agonist) to treat sex headaches. Phospholipase inhibitors and tripsans are basically migraine and cluster headache medications. Sex headaches mainly occur in men but are not a rare disease like POIS. My symptoms are definitely broader and longer lasting than typical sex headaches. Here is some more info:
https://en.wikipedia.org/wiki/Sexual_headache
https://www.migrainesurvival.com/orgasmic-headaches
https://americanmigrainefoundation.org/understanding-migraine/orgasmic-pre-orgasmic-headache/

[Nas]

Nas, when I described my symptoms to a neurologist, he said that I have Sex Headaches. The standard treatment for sex headaches is phospholipase A2 inhibitors. This is how I found out about indomethacin. I about a year ago I was diagnosed with sex headaches and the doctor prescribed indomethacin. But I didn't take it because I read about the side effects of daily use.
Some doctors also prescribe tripsans (5-HT₁ agonist) to treat sex headaches. Phospholipase inhibitors and tripsans are basically migraine and cluster headache medications. Sex headaches mainly occur in men but are not a rare disease like POIS. My symptoms are definitely broader and longer lasting than typical sex headaches. Here is some more info:
https://en.wikipedia.org/wiki/Sexual_headache
https://www.migrainesurvival.com/orgasmic-headaches
https://americanmigrainefoundation.org/understanding-migraine/orgasmic-pre-orgasmic-headache/

Hey Nanna
Yes they perscribed to you treatment for sexual headaches but what would they describe in the case of brain inflammation? I don't see why a doctor would perscribe treatment for sexual headache while what we clearly have is brain inflammation.