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Researchers say they have found a link in the pathology between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

SWAlexander

Senior Member
Messages
1,985
Article:
Researchers say they have found a link in the pathology between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Key points:
  • Griffith University researchers say their findings could help to treat those suffering from long COVID
  • A woman with chronic fatigue syndrome says she suffered a relapse in symptoms after contracting COVID earlier this year
  • AMA Queensland says the findings should be independently verified and that more funding for such research should be made available
The work is being carried out by professor Sonya Marshall-Gradisnik and the team at Griffith University's National Centre for Neuroimmunology and Emerging Diseases (NCNED).

"It is the first of its kind in the world to actually biologically identify the overlap in the dysfunction with long COVID and ME/CFS patients," she said.

Dr Marshall-Gradisnik said damaged receptors, like a dysfunctional lock and key, do not allow enough calcium in.

"The receptors are located on every cell in the body," she said.

"These ion channels, or the lock and the key that tries to open the door — when we look at ME/CFS patients, that's been significantly impaired.
continue reading: https://www.abc.net.au/news/2022-08...-fatigue-syndrome-pathology-overlap/101318522

Other related calcium publications:
Dysregulation of mitochondrial calcium signaling and superoxide flashes cause mitochondrial genomic DNA damage in Huntington disease: https://pubmed.ncbi.nlm.nih.gov/23250749/

Effects of Supplemental Vitamin D and Calcium on Oxidative DNA Damage Marker in Normal Colorectal Mucosa: A Randomized Clinical Trial: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805163/

Calcium-Sensing Receptor Gene: Regulation of Expression: https://www.frontiersin.org/articles/10.3389/fphys.2016.00394/full
 
Last edited:

heapsreal

iherb 10% discount code OPA989,
Messages
10,138
Location
australia (brisbane)
Article:
Researchers say they have found a link in the pathology between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Key points:
  • Griffith University researchers say their findings could help to treat those suffering from long COVID
  • A woman with chronic fatigue syndrome says she suffered a relapse in symptoms after contracting COVID earlier this year
  • AMA Queensland says the findings should be independently verified and that more funding for such research should be made available
The work is being carried out by professor Sonya Marshall-Gradisnik and the team at Griffith University's National Centre for Neuroimmunology and Emerging Diseases (NCNED).

"It is the first of its kind in the world to actually biologically identify the overlap in the dysfunction with long COVID and ME/CFS patients," she said.

Dr Marshall-Gradisnik said damaged receptors, like a dysfunctional lock and key, do not allow enough calcium in.

"The receptors are located on every cell in the body," she said.

"These ion channels, or the lock and the key that tries to open the door — when we look at ME/CFS patients, that's been significantly impaired.
continue reading: https://www.abc.net.au/news/2022-08...-fatigue-syndrome-pathology-overlap/101318522

Other related calcium publications:
Dysregulation of mitochondrial calcium signaling and superoxide flashes cause mitochondrial genomic DNA damage in Huntington disease: https://pubmed.ncbi.nlm.nih.gov/23250749/

Effects of Supplemental Vitamin D and Calcium on Oxidative DNA Damage Marker in Normal Colorectal Mucosa: A Randomized Clinical Trial: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805163/

I saw this on the news tonight. Disappointed when they mention a drug they have available to treat cfs/me/LC, it was LDN which you can find people on the forums using it 15yrs ago and it was very hit and miss and I can't recall hearing a cure from it. My personal experience from it was not positive.

While watching the news I honestly thought they were going to talk about low nk function as that's what most of Griffith University has studied in cfs. I'm still suprised there's no study on low nk function in LC. This would give evidence to a possible ongoing covid infection or reactivation of formerly suppressed viruses like ebv etc.
 

SWAlexander

Senior Member
Messages
1,985
BBC Inside Science segment on #MECFS, LongCovid and Microclots
1660242747699.png

 

CSMLSM

Senior Member
Messages
973
Dr Marshall-Gradisnik said damaged receptors, like a dysfunctional lock and key, do not allow enough calcium in.
"The receptors are located on every cell in the body," she said.
"These ion channels, or the lock and the key that tries to open the door — when we look at ME/CFS patients, that's been significantly impaired.
saw this on the news tonight. Disappointed when they mention a drug they have available to treat cfs/me/LC, it was LDN which you can find people on the forums using it 15yrs ago and it was very hit and miss and I can't recall hearing a cure from it. My personal experience from it was not positive.
I just wanted to show briefly the comparison of Caryophyllene and LDN. | Phoenix Rising ME/CFS Forums

Undercover Power of Endocannabinoids: Postsynaptic Ion-Channel Modulator -
ScienceDirect

Main Text
The endocannabinoid 2-AG, which is the focus of the study, and anandamide are the two main endogenous ligands of the cannabinoid receptors CB1 and CB2 (Pacher et al., 2006). Endocannabinoids have pleiotropic functions within and outside the brain. They are involved in regulation of pain, sleep, eating, stress, immune response, inflammation, and liver function. Until now, CB1 receptors were thought to mediate most of the effects of endocannabinoids in the brains of vertebrates, though CB2 receptor expression in astrocytes, microglia, and other neurons has also been reported. Over a decade of research indicates that, within the brain, endocannabinoids produced by the postsynaptic neurons regulate the strength of synaptic connections and serve as retrograde signals that activate presynaptic Gi-coupled CB1 receptors, suppressing synaptic transmission through the induction of short- and long-term synaptic plasticity (Lovinger, 2008).

In a series of elegant, clever experiments, Gantz and Bean (2017) provide the strongest evidence to date that the bioactive lipid 2-AG, at low concentration, has cellular actions beyond activation of cannabinoid CB1 and CB2 receptors in mammals. These findings could explain why endocannabinoids are found in invertebrate species that do not express CB1 or CB2 orthologs (Lucanic et al., 2011). Gantz and Bean show that activation of Gq-coupled receptors expressed on dopamine neurons—such as metabotropic glutamate, orexin, and neurotensin receptors—triggered 2-AG synthesis through phospholipase C (PLC) activation and increased neuronal excitability in these neurons (Figure 1).
1-s2.0-S0896627317301976-gr1.jpg


Figure 1. Novel and Canonical Endocannabinoid Actions in Dopamine Neurons
Endocannabinoid 2-AG is synthesized upon the activation of Gq protein-coupled receptors (GqPCR), such as metabotropic glutamate, orexin, and neurotensin receptors. Through its canonical actions, 2-AG serves as a retrograde signal to activate presynaptic CB1 receptors on excitatory and inhibitory synaptic terminals. Gantz and Bean (2017) show that novel postsynaptic actions of 2-AG on Kv4.3 channels inhibit A-type potassium currents and enhance the excitability of dopamine neurons.
The novel property of 2-AG as a modulator of native A-type potassium currents in midbrain dopamine neurons is congruent with previous findings made on a heterologous expression system (Barana et al., 2010, Oliver et al., 2004). The postsynaptic actions of 2-AG also resemble the more well-known actions of arachidonic acid (AA) on these and other ion channels. AA is a metabolite of 2-AG and anandamide degradation, and it has no effect or potency on CB1 and CB2 receptors. AA is known to inhibit voltage-gated sodium and calcium channels as well as some types of G-protein-coupled, inwardly rectifying potassium channels (Meves, 2008). AA potentiates M-type potassium channels, calcium-activated potassium channels, acid-sensing ion channels, the vanilloid type 1 receptor (TRPV-1) channels, and ligand-gated NMDA receptor currents. Anandamide, the other major endocannabinoid, is also known to have targets other than CB receptors. Anandamide was shown to act both on potassium channels and on TRPV-1 (Zygmunt et al., 1999) and also to inhibit gap junctions (Venance et al., 1995).

Since endocannabinoids and their metabolites can be readily produced on demand upon activation of PLC and other enzymes that are part of this pathway, these lipids might regularly influence neuronal activity though their direct actions on ion channels. Calcium influx is also sufficient to trigger endocannabinoid production in some neurons (Brenowitz et al., 2006); consequently, oscillation in intracellular calcium concentrations can act to further regulate endocannabinoid production and metabolism. Depending on the native composition of ion channels of each particular neuron, 2-AG and its metabolites could then either accelerate or decrease neuronal excitability.

To conclude, 2-AG is more than an endocannabinoid retrograde signal, and it has postsynaptic actions on the same cells that produce this bioactive lipid. More work is needed in order to determine how widespread and common these postsynaptic actions of 2-AG on A-type potassium channels and neuronal excitability are; this could also determine whether the postsynaptic effects of 2-AG could act in concert with its retrograde actions on presynaptic CB1 receptors that lead to the long-lasting depression of synaptic strength.

Sixteen years ago, the first two reports of retrograde endocannabinoid signaling were published in this same journal (Kreitzer and Regehr, 2001, Wilson et al., 2001). A brand-new field emerged in neuroscience, fueling our understanding of synaptic transmission and plasticity. In a similar fashion, we anticipate an explosion in the number of future studies reporting postsynaptic effects of 2-AG in other neurons throughout the brain and beyond.
 

SWAlexander

Senior Member
Messages
1,985
There is one other hormone nearly nowhere mentioned in any research. It is prostaglandin and its multi properties.
Am I on the wrong pass?

From some of my earlier (sloppy) notes:
Prostaglandin I to R, commonly known as process light cycling, prevents splinted aggregation, whereas thromboxane promotes platelet aggregation.
Several prostaglandin types could have different and opposing functions and which are both important in terms of physiology pgf.
On other hand stimulates uterine muscle contraction and due to its property like this, it is sometimes used to terminate pregnancy.
PG e and PG f has opposing role in terms of broncho constriction and broncho dilation.
PG NF leads to bronchial smooth muscle contraction whereas PG e leads to the dilation of the bronchioles. Pge2 and PG d to increase the capillary permeability enabling neutrophil and other immune cells to be extracted from the particular blood capillary.
The most important use for prostaglandin is to dissolve fibrin, also fibrinogen, that keeps platelets locked and creates thrombosis.
So, why not use "arachidonic acid" to open microclots to see what is hidden inside virus or bacteria.
1660312661716.png
 

CSMLSM

Senior Member
Messages
973
There is one other hormone nearly nowhere mentioned in any research. It is prostaglandin and its multi properties.
Am I on the wrong pass?

From some of my earlier (sloppy) notes:
Prostaglandin I to R, commonly known as process light cycling, prevents splinted aggregation, whereas thromboxane promotes platelet aggregation.
Several prostaglandin types could have different and opposing functions and which are both important in terms of physiology pgf.
On other hand stimulates uterine muscle contraction and due to its property like this, it is sometimes used to terminate pregnancy.
PG e and PG f has opposing role in terms of broncho constriction and broncho dilation.
PG NF leads to bronchial smooth muscle contraction whereas PG e leads to the dilation of the bronchioles. Pge2 and PG d to increase the capillary permeability enabling neutrophil and other immune cells to be extracted from the particular blood capillary.
The most important use for prostaglandin is to dissolve fibrin, also fibrinogen, that keeps platelets locked and creates thrombosis.
So, why not use "arachidonic acid" to open microclots to see what is hidden inside virus or bacteria.
View attachment 48848
Taking arachiadonic acid will not help and will be counter productive as it has the opposite affect to anandamide. Arachiadonic acid causes inflammation. The main problem with seed oils is the Arachiadonic acid which is polyunsaturated omega-6 fatty acid. Everyone consumes way too much omega 6 in their diet.
Taking too much omega 6 will only increase inflammation and it will not be made into more anandamide if you consume more.
Your immune system and endocrine system regulate the production of endogenous cannabinoids and in turn the cannabinoid system regulates the immune and endocrine systems.
Omega 3 however is also required and is anti inflammatory and increased intake is beneficial to the cannabinoid system and health.
Emerging Class of Omega-3 Fatty Acid Endocannabinoids & Their Derivatives - PMC (nih.gov)
Abstract
Cannabinoid receptor activation is involved in homeostatic regulation of the body. These receptors are activated by cannabinoids, that include the active constituents of Cannabis sativa as well as endocannabinoids (eCBs). The eCBs are endogenously synthesized from the omega-6 and omega-3 polyunsaturated fatty acids (PUFAs). The consumption of omega-3 fatty acids shifts the balance towards a higher proportion of omega-3 eCBs, whose physiological functions warrants further investigation. Herein, we review the discovery of omega-3 fatty acid derived eCBs that are generated from long chain omega-3 PUFAs - docosahexaenoyl ethanolamide (DHA-EA or synaptamide), docosahexanoyl-glycerol (DHG), eicosapentaenoyl ethanolamide (EPA-EA), eicosapentanoylglycerol (EPG). Furthermore, we outline the lesser known omega-3 eCB-like molecules that arise from the conjugation of the omega-3 fatty acids with neurotransmitters serotonin and dopamine - DHA-serotonin (DHA-5HT), EPA-serotonin (EPA-5HT), DHA-dopamine (DHA-DA) and EPA-dopamine (EPA-DA). Additionally, we describe the role of these omega-3 eCBs and their derivatives in different disease states such as pain, inflammation and cancer. Moreover, we detail the formation and potential physiological roles of the oxidative metabolites that arise from the metabolism of omega-3 eCBs by eicosanoid synthesizing enzymes - cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 epoxygenase (CYP450). In summary, we outline the novel findings regarding a growing class of signaling molecules, omega-3 eCBs, that can control the physiological and pathophysiological processes in the body.
 

CSMLSM

Senior Member
Messages
973
I'll wait for replication of their findings before getting excited. My guess is that it won't turn out to be important.
The finding just shows that calcium ion channels are affected in both ME/CFS and Long Covid patients. Calcium ion channels are regulated by cannabinoids.

Here is how cannabinoids are related to the symptomology of ME/CFS.

Leptin is raised in ME/CFS and upregulates a cannabinoid degrading enzyme called Fatty Acid Amide Hydrolase (FAAH) which degrades anandamide. Anandamide modulates various ion channels including T-type Ca2+ channels. Anandamide also helps modulate the HPA axis dampening its response and also modulates the immune system in the cental nervous system. Anadamide also modulates neuronal activity dampening it and modulating pain. It is also involved in stress resilience and affords a more resilient state of mind in adverse conditions and is thought to be suppressed in PTSD. It also regulates the gut.
Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide - PubMed (nih.gov)

Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges - PMC (nih.gov)
In the central nervous system (CNS), these processes include regulation of appetite, pain sensation, mood, and memory, whereas in the peripheral tissues, e.g., bone formation, spermatogenesis, sebum production, etc., and, maybe most importantly, immune functions (7, 2937). Indeed, eCB signaling was shown to be an important orchestrator of both the innate and adaptive immune responses. Although there are some contradictions in the literature, ECS is generally considered to be a homeostatic “gate-keeper” of the immune system, preventing the onset of pathological, overwhelming proinflammatory responses.

Abstract
It is well known that certain active ingredients of the plants of Cannabis genus, i.e., the “phytocannabinoids” [pCBs; e.g., (−)-trans-Δ9-tetrahydrocannabinol (THC), (−)-cannabidiol, etc.] can influence a wide array of biological processes, and the human body is able to produce endogenous analogs of these substances [“endocannabinoids” (eCB), e.g., arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol (2-AG), etc.]. These ligands, together with multiple receptors (e.g., CB1 and CB2 cannabinoid receptors, etc.), and a complex enzyme and transporter apparatus involved in the synthesis and degradation of the ligands constitute the endocannabinoid system (ECS), a recently emerging regulator of several physiological processes. The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, antitumor, as well as antipathogen immune responses, etc. Based on this knowledge, many in vitro and in vivo studies aimed at exploiting the putative therapeutic potential of cannabinoid signaling in inflammation-accompanied diseases (e.g., multiple sclerosis) or in organ transplantation, and to dissect the complex immunological effects of medical and “recreational” marijuana consumption. Thus, the objective of the current article is (i) to summarize the most recent findings of the field; (ii) to highlight the putative therapeutic potential of targeting cannabinoid signaling; (iii) to identify open questions and key challenges; and (iv) to suggest promising future directions for cannabinoid-based drug development.

Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology | Journal of Translational Medicine | Full Text (biomedcentral.com)

Role for fatty acid amide hydrolase (FAAH) in the leptin-mediated effects on feeding and energy balance - PubMed (nih.gov)
Abstract
Endocannabinoid signaling regulates feeding and metabolic processes and has been linked to obesity development. Several hormonal signals, such as glucocorticoids and ghrelin, regulate feeding and metabolism by engaging the endocannabinoid system. Similarly, studies have suggested that leptin interacts with the endocannabinoid system, yet the mechanism and functional relevance of this interaction remain elusive. Therefore, we explored the interaction between leptin and endocannabinoid signaling with a focus on fatty acid amide hydrolase (FAAH), the primary degradative enzyme for the endocannabinoid N-arachidonoylethanolamine (anandamide; AEA). Mice deficient in leptin exhibited elevated hypothalamic AEA levels and reductions in FAAH activity while leptin administration to WT mice reduced AEA content and increased FAAH activity. Following high fat diet exposure, mice developed resistance to the effects of leptin administration on hypothalamic AEA content and FAAH activity. At a functional level, pharmacological inhibition of FAAH was sufficient to prevent leptin-mediated effects on body weight and food intake. Using a novel knock-in mouse model recapitulating a common human polymorphism (FAAH C385A; rs324420), which reduces FAAH activity, we investigated whether human genetic variance in FAAH affects leptin sensitivity. While WT (CC) mice were sensitive to leptin-induced reductions in food intake and body weight gain, low-expressing FAAH (AA) mice were unresponsive. These data demonstrate that FAAH activity is required for leptin's hypophagic effects and, at a translational level, suggest that a genetic variant in the FAAH gene contributes to differences in leptin sensitivity in human populations.

Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice - PubMed (nih.gov)
Abstract
Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C->A substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.

The role of the endocannabinoid system in the brain-gut axis - PMC (nih.gov)
Abstract
The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system. The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid receptors CB1 and CB2. The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility. Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation. We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain. The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic–pituitary–adrenal pathways via actions in specific brain regions—notably the prefrontal cortex, amygdala, and hypothalamus. Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders.

Amygdala FAAH and anandamide: mediating protection and recovery from stress - PMC (nih.gov)
Abstract
A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis and degradation upon neuronal activation, the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region – the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA–CB1 (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress.

Endocannabinoid Signaling, Glucocorticoid-Mediated Negative Feedback and Regulation of the HPA Axis - PMC (nih.gov)
Therefore, the role of the endocannabinoid system in HPA axis regulation extends beyond the acute stress phase to chronic stress plasticity, and the endocannabinoid system plays an integral part in the changing expression of the HPA response to a continually fluctuating and often challenging environment.

Abstract
The hypothalamic-pituitary-adrenal (HPA) axis regulates the outflow of glucocorticoid hormones under basal conditions and in response to stress. Within the last decade, a large body of evidence has mounted indicating that the endocannabinoid system is involved in the central regulation of the stress response; however, the specific role endocannabinoid signalling plays in phases of HPA axis regulation, or the neural sites of action mediating this regulation, was not mapped out until recently. This review aims to collapse the current state of knowledge regarding the role of the endocannabinoid system in the regulation of the HPA axis to put together a working model of how and where endocannabinoids act within the brain to regulate outflow of the HPA axis. Specifically, we discuss the role of the endocannabinoid system in the regulation of the HPA axis under basal conditions, activation in response to acute stress and glucocorticoid-mediated negative feedback. Interestingly, there appears to be some anatomical specificity to the role of the endocannabinoid system in each phase of HPA axis regulation, as well as distinct roles of both anandamide and 2-arachidonoylglycerol in these phases. Ultimately, the current level of information indicates that endocannabinoid signalling acts to suppress HPA axis activity through concerted actions within the prefrontal cortex, amygdala and hypothalamus.

Endocannabinoid system, stress and HPA axis - ScienceDirect
Abstract
The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana's psychoactive ingredient ∆9-tetrahydrocannabinol (∆9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors. In addition to its recreational actions, some of the earliest reports regarding the effects of Cannabis use on humans were related to endocrine system changes. Accordingly, the ∆9-THC and later on, the ECS signalling have long been known to regulate the hypothalamic-pituitary-adrenocortical (HPA) axis, which is the major neuroendocrine stress response system of mammals. However, how the ECS could modify the stress hormone secretion is not fully understood. Thus, the present article reviews current available knowledge on the role of the ECS signalling as important mediator of interaction between HPA axis activity and stressful conditions, which, in turn could be involved in the development of psychiatric disorders.

Am I making my point yet :)
 

BrightCandle

Senior Member
Messages
1,172
I did a complete cortisol test at the beginning of my condition, something like 7 or 8 data points through the day and it all came out completely normal despite the clear sleep disruption. At the time I was clearly suffering from something adrenaline based and was wired and tired but my cortisol was fine. If now it was dysregulated I would argue its simply a downstream effect of everything else getting broken.
 

CSMLSM

Senior Member
Messages
973
Here it is again - hormones!

View attachment 48850
Yes dysregulated HPA axis from over activation, fatigue of adrenals and glucocorticoid receptor blunting/desensitisation or sensitivity that varies between people because of level of pushing themselves or not, causing different phenotypes of the dysregulation in this complex system that relies on feedback loops to control homeostasis that brake down as the system is overactivated chronically.
 

CSMLSM

Senior Member
Messages
973
I did a complete cortisol test at the beginning of my condition, something like 7 or 8 data points through the day and it all came out completely normal despite the clear sleep disruption. At the time I was clearly suffering from something adrenaline based and was wired and tired but my cortisol was fine. If now it was dysregulated I would argue its simply a downstream effect of everything else getting broken.
Dependant on the individual persons symptom phenotype the Adrenal hormones can be high, low, normal and related receptors can be desensitised or sensitised depending on several factors. It depends on if you push yourself, rest and pace really well and everything inbetween. There is so much that can brake down in this complex system that it goes wrong differently in different people. It ultimately starts with an immune issue like an infection (EBV, Covid ect) that suppresses the cannabinoid system and this leads to a sensitive HPA axis and everything else associated with suppressed cannabinoids. This over time becomes more and more dysfunctional.
 

CSMLSM

Senior Member
Messages
973
I did a complete cortisol test at the beginning of my condition, something like 7 or 8 data points through the day and it all came out completely normal despite the clear sleep disruption. At the time I was clearly suffering from something adrenaline based and was wired and tired but my cortisol was fine. If now it was dysregulated I would argue its simply a downstream effect of everything else getting broken.
Here is something I wrote about overactive stress response leading to suppressed cortisol production via vasopressin V1a receptor desensitisation but still being in an activated HPA axis state. This could be why you have a more normal cortisol level and still feel wired.

Post 1
(PDF) Vasopressin as a Stress Hormone (researchgate.net)
Vasopressin is a small neuropeptide initially identified as the physiologically essential antidiuretic hormone more than 50 years ago. Since then, it has increasingly become apparent that vasopressin is an important hormonal component of the response to stress. In fact, it appears that the antidiuretic effect is only one of several biologically significant actions of vasopressin exerted during the response to stress. This review highlights the main features of vasopressin as a stress hormone produced by relatively simple hypothalamic neurons that release their neurotransmitters into the blood stream and also send axonal projections to key parts of the brain that control the response to stressful environmental challenges. Special focus is on the role of vasopressin in (1) setting the efficacy of adrenal corticosteroid feedback inhibition; (2) the stress of pain; and (3) supporting the response to inflammation.
1660002823275-png.48804



Say when you first develope an overactive stress response you have a normal vasopressin response level and it regulates the adrenal corticosteroids in the body correctly.
But maybe a chronically active stress response ultimately ends up taxing this response (production of vasopressin). This disrupts the feedback loop of adrenal corticosteroids having less vasopressin to set the efficacy of the feedback loop. Braking the feedback loops balance. Causing deficient vasopressin. Thus causing thirst as the antidiuretic affect is lost and we do not hold onto as much fluid.

1660003376877-png.48805


So we then have issues with salt balance. ME/CFS patients tend to have low magnesium and potassium which are electrolyte salts. We also tend to urinate more frequently, likely caused by low vasopressin which would expell salts as we are excreting more fluid, I think.

1660003815179-png.48806


So in this scenario the vasopressin is lacking and so stress induce analgesia is lacking. This would explain some pain sensitivity in ME/CFS.

1660004030007-png.48807


This low vasopressin could be a direct influence on the dysfunctional HPA axis and immune system emanating from the PVN of the hypothalamus.
A combination of overactive HPA axis and stagnated vasopressin production causes the cortisol that HPA axis needs and is looking for to switch off is not as strong as it should be so does not fully initiate the loop and so the adrenals are still being asked to produce cortisol, causing a damaging stuck process that only degrades from there.

So cannabinoid systems affect on stress maybe would give this time to rest and restore function of the vasopressin production. Correcting some of the feedback loops malfuction but not all until the immune influence is addressed which also would have been altered by low vasopressin.

Either low vasopressin or V1 vasopressin receptor blunting/desensitisation would have similar affects I think.

Post 2
I would say Vasopressin V1a receptor desensitisation is the mechanism behind excessive thirst and I believe this is the case in a chronically activated HPA axis. This constant over activation of HPA axis causes vasopressin to be chronically activating vasopressin V1a receptors which quickly and effectively desensitise them. Because vasopressin sets the efficacy of adrenal corticosteroid feedback inhibition it normally causes greater and more prolonged elevations of adrenal corticosteroid in the blood. So vasopressin V1a receptor desensitisation ultimately causes a lack of adrenal corticosteroid when trying to finish the feedback loop in the stress response with adrenal corticosteroid. The feedback loop does not engage fully and remains stuck in flight or fight response not shutting down (Cortisol levels do not raise enough due to the vasopressin V1a receptor desensitisation caused by chronically active HPA axis).

Like when in a prolonged stressful situation you end up with dry mouth. Likely because of this mechanism but is much more pronounced in chronically activated HPA axis, stuck in flight or fight response like ME/CFS, POTS, Dysautonomia. It causes excessive thirst, salt imbalances and maybe blood pressure issues as a result.

Mechanism of desensitization of the cloned vasopressin V1a receptor expressed in Xenopus oocytes - PubMed (nih.gov)
Abstract
The vasopressin V1a receptor exerts its effects by G protein-mediated increases in cytosolic Ca2+ (Cai2+) and activation of protein kinase C. The V1a receptor also undergoes autologous desensitization. To clarify the mechanism of this desensitization, we expressed the cloned receptor in Xenopus oocytes, and vasopressin-induced Cai2+ waves were examined as an index of V1a activation using confocal microscopy. Pretreatment of oocytes with a minimal concentration of vasopressin inhibited further generation of Cai2+ waves upon maximal stimulation. Such pretreatment did not abolish Cai2+ waves induced by subsequent microinjection of inositol trisphosphate, suggesting that this phenomenon represents receptor desensitization rather than depletion of inositol trisphosphate-sensitive Cai2+ stores. Pretreatment with phorbol dibutyrate, ionomycin, or 8-bromoadenosine 3',5'-cyclic monophosphate had no effect on vasopressin-induced Cai2+ waves. Oocytes recovered from desensitization within 1 h, but the microtubule inhibitor methyl-5-[2-thienylcarbonyl]-1H-benzimiidazol-2-yl)-carbamate (nocodazole) inhibited this recovery. Receptor binding sites were reduced by over 50% within 10 min of exposure to vasopressin, with no associated change in the Kd for the V1a receptor. These findings indicate that 1) expression of the cloned V1a receptor in Xenopus oocytes, coupled with subcellular Cai2+ imaging, provides a useful system to examine mechanisms of V1a desensitization, 2) the V1a receptor undergoes autologous desensitization in this experimental system, and 3) protein kinase C, Cai2+, and adenosine 3',5'-cyclic monophosphate do not appear responsible for this desensitization, but 4) microtubule-dependent recycling of the receptor is preserved in this system and may be important for receptor desensitization.


This is a theory for now!
 

SWAlexander

Senior Member
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1,985
For over 50 years I followed every lead about weakness related to hormones. It was during pregnancy with twins, that I lost one of the twins due to low cortisol. Naturally back in the days, there was not much science available but I had then and still have a suspicion that ME is related to hormones because it resamples a (prolonged) Addison's crisis.
There is no question that VZV, EBV and Herpes could be one of the causes but there is one more virus that has nobody tested yet or included in ME/CFS research. It is POLIO.
One other clue I have since 2011. I have a epigenetic gene (methylation) "phospholipase a2 (Gene PLA2R1)" iMN https://n.neurology.org/content/33/4/447
Last year I have written to many Labs and Universities and also to Prof. Akiko Iwasaki asking to include the polio virus in their research, but no answer.
One other problem seems to be, that most ME patients never had a cortisol/ACTH or/and catecholamines test.
There is an eery silence about Post Polio (symptoms) in connection with the hypothalamic-pituitary-adrenal (HPA) axis among scientists and ME.
 
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CSMLSM

Senior Member
Messages
973
One other clue I have since 2011. I have an epigenetic gene (methylation) "phospholipase a2 (Gene PLA2R1)"
I am unsure what you are saying here. It seems confused and makes no sense, could you retype please. Do you mean you have a bad variant. Epigenetics uses methylation as a marker on the DNA so that the DNA winds round the histones a certain way so as to allow or not allow transcription of certain genes. You do not have a epigenetic gene unless you are refering to the regulation of the epigenetic process, say SIRT1. SIRT1 has to do with epigenetic stability and repair.
Last year I have written to many Labs and Universities and also to Prof. Akiko Iwasaki asking to include the polio virus in their research, but no answer.
You are a patient and not their colleague I would not expect them to respond to you. Many viruses cause Post Viral Conditions and Polio is seen as an old under control virus so no money or need in their eyes to investigate, reality.
One other problem seems to be, that most ME patients never had a cortisol/ACTH or/and catecholamines test.
There is an eery silence about Post Polio in connection with the hypothalamic-pituitary-adrenal (HPA) axis among scientists
I am sure there is nothing to be suspicious about here. Medicine is used to dealing with drug A treats disease X because it does Z
It is just starting to come to the realisation of the microbiome and how we all (us and the microbes) work and live together. This condition is very complicated and it is difficult to get across to people with there fingers in their ears.
I am completely normal now and am only having to rebuild my atrophied muscles. I go all day, drink alcohol, eat curry and whatever I like, I cook, I clean, I garden, I dig, I build and much more and feel no fatigue anymore whatsoever. My memory and cognitive ability continues to improve with use and I am super sharp and reactions faster than ever. If you know any completely heathly people who play Street Fighter 5 that are any good, I dare you to ask them to play me and report back to you. I have the same name on that game as on here and use Dhalsim.
 

JES

Senior Member
Messages
1,335
I saw this on the news tonight. Disappointed when they mention a drug they have available to treat cfs/me/LC, it was LDN which you can find people on the forums using it 15yrs ago and it was very hit and miss and I can't recall hearing a cure from it. My personal experience from it was not positive.

While watching the news I honestly thought they were going to talk about low nk function as that's what most of Griffith University has studied in cfs. I'm still suprised there's no study on low nk function in LC. This would give evidence to a possible ongoing covid infection or reactivation of formerly suppressed viruses like ebv etc.

It's a bit annoying and depressing when research is still at the stage where they believe treatments like LDN, which is cheap and relatively easy to access, haven't been trialed a million times by the patient community already. Even more annoying is the re-hashing of news such as "Researchers find cause behind poorly understood illness (ME/CFS)" and then it almost invariably turns out to be nothing close to a breakthrough.

I actually remember this very same news title from several years ago from previous work by the same people at Griffith, this one from 2019 and might have been some from earlier as well. I wonder what the novelty here is other than to mention long COVID in the same context, which they probably got money to study. I'd actually make a case that LDN not working as any kind of cure for us is evidence against their faulty TRP receptor hypothesis being a significant causative factor in ME/CFS. As you mentioned, there is a lot more immune dysfunction in ME/CFS beyond TRP receptors and to me the null hypothesis, almost the default assumption, is chronic infections.
 

Rufous McKinney

Senior Member
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13,467
It's a bit annoying and depressing when research is still at the stage where they believe treatments like LDN, which is cheap and relatively easy to access, haven't been trialed a million times by the patient community already. Even more annoying is the re-hashing of news

so annoying...
 

heapsreal

iherb 10% discount code OPA989,
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10,138
Location
australia (brisbane)
It's a bit annoying and depressing when research is still at the stage where they believe treatments like LDN, which is cheap and relatively easy to access, haven't been trialed a million times by the patient community already. Even more annoying is the re-hashing of news such as "Researchers find cause behind poorly understood illness (ME/CFS)" and then it almost invariably turns out to be nothing close to a breakthrough.

I actually remember this very same news title from several years ago from previous work by the same people at Griffith, this one from 2019 and might have been some from earlier as well. I wonder what the novelty here is other than to mention long COVID in the same context, which they probably got money to study. I'd actually make a case that LDN not working as any kind of cure for us is evidence against their faulty TRP receptor hypothesis being a significant causative factor in ME/CFS. As you mentioned, there is a lot more immune dysfunction in ME/CFS beyond TRP receptors and to me the null hypothesis, almost the default assumption, is chronic infections.
I follow them on Facebook, honestly it looks like cfsme is used by the University so people can study it and get their Masters degree in biology. It would probably be an amazing number of people in Australia with a Master degree in biology or similar science that got that qualification by studying cfsme. But you will struggle to find a Dr who actually understands much at all about cfsme. Maybe one day all their research might add up to something other than the university pumping out students with post graduate studies in some cfs dysfunction.
It's been going since 2009 as that's when I was in one of their original nk function studies. 13 years later?? There would be a few jobs lost at the university if LDN or something else was discovered to cure cfsme. It doesn't seem like it would be in their interest to solve it now.
 
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