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

[CSMLSM]

I got REALLY nauseated yesterday late afternoon, on two inhales of CBD. This was really odd. I felt super weird for about an hour.

Nauseated freaks me out. Because of the sudden gastroperesis crap that can happen around here. And I did panic a bit, then calmed back down.

Do you know the strain I will look it up and see any conflicting terpenes if any that may be giving you these issues. Is it a different strain of CBD than before and new experience or something you have tried before?

Is it highly lemon/orange or citrus smell/flavour by any chance? The limonene can affcet blood brain barrier. I get what you are talikng about if I drink too much lemon in tea and I feel it is this that causes it.

Inhaled limonene would be far worse an affect I believe. Strains do have limonene alot in CBD strains I believe.

 

[CSMLSM]

I"m having more trouble sleeping in 'the morning"...since I started this Mood Probiotic which may be altering cortisol..... so now I feel worn out from not sleeping enough...

I did some 24 hour cortisol thing a few years ago: did I get any results dunno...typical.

The thing is ME/CFS from my understanding suppresses Anandamide.

HPA axis and Cannabinoid system help regulated each other to keep homeostasis correct.

So if one is supressed it messes with the other basically.

You are maybe improving Cortisol levels but the corresponding Anandamide is lacking meaning less sleep.

Sleep is induced from what I understand by Oleamide raising to a certain level. Anandamide levels affect how Oleamide levels are.

So less Anandamide (via more FAAH production) means Oleamide does not build up as much and induce sleep. They are both degraded by FAAH enzyme.

One of Cortisols jobs is to wake you up and is why Cortisol is highest in the morning normally and lowers throughout the day so you can then sleep.

Less overall Anandamide and Oleamide means less sleep epsecially with a now raised Cortisol level.

What is happening to you from what I understand should be happening and raising Anandamide with CBD will address this.

Why THC helps you sleep but is not really natural mechanistically.

Taking CBD every 4 hours, 5 times a day. From waking to before bed, giving an 8 hour sleep window will naturally make Oleamide increase through the day inducing longer and better sleep.

When taking CBD in the morning take in bed before you do anything and wait 20-30minutes before trying to get up and be active in anyway. This will help hold back slightly the Cortisol spike in the morning and throughout the day giving the HPA a chance to rest and recover while still getting healthier from the affect of your probiotic.

Your HPA axis/Cannabinoid system balance will be better for it and you should slowly improve over time.

Acute and subchronic administration of anandamide or oleamide increases REM sleep in rats - PubMed (nih.gov)
Abstract
Anandamide and oleamide, induce sleep when administered acutely, via the CB1 receptor. Their subchronic administration must be tested to demonstrate the absence of tolerance to this effect, and that the sudden withdrawal of these endocannabinoids (eCBs) does not affect sleep negatively. The sleep-waking cycle of rats was evaluated for 24h, under the effect of an acute or subchronic administration of eCBs, and during sudden eCBs withdrawal. AM251, a CB1 receptor antagonist (CB1Ra) was utilized to block eCBs effects. Our results indicated that both acute and subchronic administration of eCBs increase REMS. During eCBs withdrawal, rats lack the expression of an abstinence-like syndrome. AM251 was efficacious to prevent REMS increase caused by both acute and subchronic administration of these eCBs, suggesting that this effect is mediated by the CB1 receptor. Our data further support a role of the eCBs in REMS regulation.

Cannabinoids and Sleep/Wake Control - PubMed (nih.gov)
Abstract
The sleep-wake cycle is a complex process that includes wake (W), non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. Each phase is regulated by specialized brain structures that, by means of different neurotransmitters, maintain the constant expression of the sleep-wake cycle. Molecules like orexin, serotonin, noradrenaline, histamine, for waking; GABA, adenosine, prostaglandins, for NREM sleep and acetylcholine and glutamate for REM sleep, among other molecules are responsible for the expression and maintenance of each phase. When the endocannabinoid system was being described for the first time, almost three decades ago, oleamide's sleep promoting properties were highlighted. Nowadays, enough evidence has been cumulated to support the endocannabinoid system role in the sleep-wake cycle regulation. The endocannabinoids oleamide anandamide, and 2-arachidonylglycerol promote NREM and/or REM sleep via the CB1R, thereby making this system a target to treat sleep disorders, such as insomnia.

Oleamide: an endogenous sleep-inducing lipid and prototypical member of a new class of biological signaling molecules - PubMed (nih.gov)
Abstract
Oleamide is an endogenous fatty acid primary amide that accumulates in the cerebrospinal fluid under conditions of sleep deprivation and induces physiological sleep in animals. A review covering its discovery, its implications, and the emerging biology surrounding its discovery is presented. Consistent with its role as a prototypical member of a new class of biological signaling molecules, enzymatic regulation of endogenous concentrations of oleamide have been characterized or proposed. Fatty acid amide hydrolase (FAAH) is an integral membrane protein that degrades oleamide and potent inhibitors with physiological sleep-inducing properties have been disclosed. The characterization, cloning, and neuronal distribution of FAAH have been detailed and the enzyme was found to possess the ability to hydrolyze a range of fatty acid amides including anandamide which serves as the endogenous ligand for the cannabinoid receptor. An additional endogenous substance with REM sleep-inducing properties, 2-octyl gamma-bromoacetoacetate, was characterized as a potent FAAH inhibitor. Oleamide has been shown to modulate serotonergic neurotransmission and inhibit intercellular gap junction communication and detailed studies of its well defined and selective structural features required for activity have been disclosed.

I am sorry for the length, I hope this is helpful to you or anyone else.

 

[Rufous McKinney]

Do you know the strain I will look it up

I don't know (called COAST)
..its was the 13% THC 9% CBD stuff...they don't id terpenes...there probably were a few present.

I have only tried that twice. I'll try it again, maybe not today. kinda TIRED (sigh)

Why THC helps you sleep but is not really natural mechanistically.

yes, well the sleep lack was brutal, and menopause messes the hormones and I was literally not sleeping at all. I"d do the thing I had to do, anyway (give a speech, say) and then entirely fall apart. I was facing...unable to work, meaning unable to survive. As I had to support my family.

Taking CBD every 4 hours, 5 times a day.

so this should be sublingual too? I worry because I may be unable to tolerate sublingual at all. I have blood blisters (odd that the Peruvians mentioned that symptom nobody else mentions)

***
in other news, my husband found droppers, but no bottle to screw it onto, so he did not buy me the dropper.

I was: perplexed. I said: NEED EYE DROPPER

 

[SWAlexander]

SW, did you have polio?

I never had a polio vaccine.
Last month I finally found a doctor who diagnosed me with PPS.
Symptoms started at age 5 after I was for nearly 4 weeks sick with a high fever.

 

[Niklas]

Just to circle back to the main thread.

What i find really interesting, is that CBD to my understanding does not only block FAAH but also does what naltrexone do, that is increasing calcium into the cells. So double the fun for the money

From same authors as the COVID paper:

The discovery of the widely expressed Transient Receptor Potential Melastatin 3 (TRPM3) as a nociceptor channel substantially targeted by certain opioid receptors, and its implication in calcium (Ca2+)-dependent Natural Killer (NK) cell immune functions has raised the possibility that TRPM3 may be pharmacologically targeted to treat characteristic symptoms of ME/CFS. Naltrexone hydrochloride (NTX) acts as an antagonist to the mu (μ)-opioid receptor thus negating its inhibitory function on TRPM3.

https://pubmed.ncbi.nlm.nih.gov/34326841/

And how CBD affect CA2+ levels:

Abstract

The phytocannabinoid cannabidiol (CBD) is at the forefront of therapeutic cannabinoid research due to its non-psychotropic properties. Research supports its use in a variety of disorders, yet the cellular mechanisms of its action remain unclear. In this study, the effect of CBD upon Ca2+ homeostasis in hippocampal cells was characterised. CBD (1 microM) elevated intracellular Ca2+ ([Ca2+]i) by approximately +45% of basal Ca2+ levels in both glia (77% responders) and neurones (51% responders). Responses to CBD were reduced in high excitability HEPES buffered solution (HBS), but not affected in low excitability/low Ca2+ HBS. CBD responses were also significantly reduced (by 50%) by the universal Ca2+ channel blocker cadmium (50 microM) and the L-type specific Ca2+ channel blocker nifedipine (20 microM). Interestingly, intracellular store depletion with thapsigargin (2 microM) had the most dramatic effect on CBD responses, leading on average to a full block of the response. Elevated CBD-induced [Ca2+]i responses (>+100%) were observed in the presence of the CB1 receptor antagonist, AM281 (1 microM), and the vanilloid receptor antagonist, capsazepine (CPZ, 1 microM). Overall, our data suggest that CBD modulates hippocampal [Ca2+]i homeostasis via intracellular Ca2+ stores and L-type VGCC-mediated Ca2+ entry, with tonic cannabinoid and vanilloid receptor signalling being negatively coupled to this pathway.

https://pubmed.ncbi.nlm.nih.gov/16386766/

Am I understanding this correctly, that increasing calcium onto cells again make the body function properly?

Also, this article says that THC increase calcium currents, but I am not sure it is the same channel.

THC, but not CBD, may also increase the amount of calcium entry following T-type channel activation by stabilizing open states of the channel. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259625/

Ca2+ is a L-type channel so I wounder if it would be beneficial to open this T-type channel too?

What are you guys thoughts?

 

[Violeta]

The thing is ME/CFS from my understanding suppresses Anandamide.

HPA axis and Cannabinoid system help regulated each other to keep homeostasis correct.

So if one is supressed it messes with the other basically.

You are maybe improving Cortisol levels but the corresponding Anandamide is lacking meaning less sleep.

Sleep is induced from what I understand by Oleamide raising to a certain level. Anandamide levels affect how Oleamide levels are.

So less Anandamide (via more FAAH production) means Oleamide does not build up as much and induce sleep. They are both degraded by FAAH enzyme.

One of Cortisols jobs is to wake you up and is why Cortisol is highest in the morning normally and lowers throughout the day so you can then sleep.

Less overall Anandamide and Oleamide means less sleep epsecially with a now raised Cortisol level.

What is happening to you from what I understand should be happening and raising Anandamide with CBD will address this.

Why THC helps you sleep but is not really natural mechanistically.

Taking CBD every 4 hours, 5 times a day. From waking to before bed, giving an 8 hour sleep window will naturally make Oleamide increase through the day inducing longer and better sleep.

When taking CBD in the morning take in bed before you do anything and wait 20-30minutes before trying to get up and be active in anyway. This will help hold back slightly the Cortisol spike in the morning and throughout the day giving the HPA a chance to rest and recover while still getting healthier from the affect of your probiotic.

Your HPA axis/Cannabinoid system balance will be better for it and you should slowly improve over time.







I am sorry for the length, I hope this is helpful to you or anyone else.

I can't thank you enough, Daniel, for bringing this info to Phoenix Rising.


I feel as though I have been ripped off by not being told about anandamide for all these years. It just makes so much more sense now.

And when I looked up FAAH, (inhibition of FAAH helps raise anandamide), the number of drugs for inhibition of FAAH that drug companies have been trying to formulate is ridiculous. Research into several has had to be ended due to adverse outcome.

Meanwhile, cannabidiol is on the same list as all those drugs, but NONE of the drug companies and no one in the medical community that I know of has spent a lick of time informing us.

Look at the list here.

https://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase

 

[Violeta]

I am looking for causes of increased FAAH activity.

So far I have found it can be related to dopamine.

This is from a study related to ADHD. I found it by looking up FAAH + ADHD because I wondered if ADHD displayed a similar set of circumstance.

Altered Anandamide Degradation in Attention Deficit Hyperactivity Disorder

https://www.pediatricneurologybriefs.com/articles/10.15844/pedneurbriefs-23-6-7/

Stimulation of dopamine (DA) D2 class receptors inhibits FAAH activity and increases the level of AEA in the brain. A complex interaction between DA and the AEA endocannabinoid system (ECS) is found experimentally, and ECS is implicated in other DA-related disorders such as Parkinsonism. Dysfunction of the dopamine system is proposed to explain the clinical manifestations of ADHD. [1]

 

[CSMLSM]

What are you guys thoughts?

Hi, the cannabinoid system as a whole is really a homeostatic regulator. So if it is supressed it causes homeostasis to be off.
It is not that increasing calcium makes you more healthy but the proper homeostasis/balance of it is healthy.

HPA axis and Cannabinoid system help to regulate homeostasis together. Its not one is better than the other but that both are needed for proper functioning and correct flow of biological processes back and forth to keep balance.

We are stuck in active HPA axis with little cannabinoid system involvement.

Basically the engines always running and never shut down to cool down and have a service.

HPA axis wakes you, gets you up, motivated, aware, ready to respond.

Cannabinoid system is eat, sleep, rest, digest, repair and protect.

Balance= Homeostasis.

When one is engaged too much at the expense of the other problems arise. Both are equally needed but not equally affected.

Cannabinoid system is inhibited in ME/CFS.

Leptin has been shown already to be high in ME/CFS and Leptin raises FAAH enzyme which degrades Anandamide and Oleamide.

Lack of Oleamide causes sleep issues. Cortisol wakes you up. See what I mean!

 

[CSMLSM]

Look at the list here.

Yes they are trying their best to make a patentable version that tries to be as safe as CBD.

 

[CSMLSM]

And when I looked up FAAH, which helps raise anandamide

FAAH inhibition helps raise Anandamide.

 

[CSMLSM]

yes, well the sleep lack was brutal, and menopause messes the hormones and I was literally not sleeping at all. I"d do the thing I had to do, anyway (give a speech, say) and then entirely fall apart. I was facing...unable to work, meaning unable to survive. As I had to support my family.

If THC helps you sleep then use it in the interim until you can get the Anandamide and Oleamide levels up from inhibiting FAAH with CBD.

Sleep is very important.

 

[CSMLSM]

Am I understanding this correctly, that increasing calcium onto cells again make the body function properly?

Not exactly. It may be that calcium homeostasis is dysfunctional one way and may be improved by changing another component of the process.

Ultimately the overall homeostatic regualtors are not regulating the calcium balance.

Think of it like the tide of the ocean. The back and forth, up and down that helps create the proper conditions for the biological life to thrive, like the bilogical processes in your body.

Everything is in balance and in ME/CFS that balance is way off.

 

[Niklas]

I 100% agree there has been too little talk about this. But things are happening.

Here is a very informative little article about Endocannobinoid system:

https://aor.ca/wp-content/uploads/AOR-Marketing-Truth-Series-PEA-2.pdf

And this table shows FAAH inhibitors.

Also, L-carnitine is super important to transport fatty acids into mitochondria.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967041/

https://www.healthrising.org/blog/2...chronic-fatigue-syndrome-iacfs_me_conference/

 

[Niklas]

I just want to add something that just blew my mind.

Red clover does not only contain Biochanin A, which is a FAAH inhibitor.

It is one of the plants with a lot of formononotin wich is a Enterovirus 71 antivral. (mind blown). Along with Yangonin (kaava) and aruptine.

https://www.sigmaaldrich.com/NO/en/tech-docs/paper/927831

Characterization of three small molecule inhibitors of enterovirus 71 identified from screening of a library of natural products.

 

[Violeta]

FAAH inhibition helps raise Anandamide.

Yes, let me go and fix that.


Do you know what causes a rise in leptin?

Also, I have been able to eat more variety (which is still very limited, though) since starting CBD, and am going to look into why it helps that.

 

[Niklas]

Hi, the cannabinoid system as a whole is really a homeostatic regulator. So if it is supressed it causes homeostasis to be off.
It is not that increasing calcium makes you more healthy but the proper homeostasis/balance of it is healthy.

HPA axis and Cannabinoid system help to regulate homeostasis together. Its not one is better than the other but that both are needed for proper functioning and correct flow of biological processes back and forth to keep balance.

We are stuck in active HPA axis with little cannabinoid system involvement.

Basically the engines always running and never shut down to cool down and have a service.

HPA axis wakes you, gets you up, motivated, aware, ready to respond.

Cannabinoid system is eat, sleep, rest, digest, repair and protect.

Balance= Homeostasis.

When one is engaged too much at the expense of the other problems arise. Both are equally needed but not equally affected.

Cannabinoid system is inhibited in ME/CFS.

Leptin has been shown already to be high in ME/CFS and Leptin raises FAAH enzyme which degrades Anandamide and Oleamide.

Lack of Oleamide causes sleep issues. Cortisol wakes you up. See what I mean!

Amazing explanation! Thank you!

 

[Niklas]

Fantastic video on the endocannabinoid system:

 

[Niklas]

Not exactly. It may be that calcium homeostasis is dysfunctional one way and may be improved by changing another component of the process.

Ultimately the overall homeostatic regualtors are not regulating the calcium balance.

Think of it like the tide of the ocean. The back and forth, up and down that helps create the proper conditions for the biological life to thrive, like the bilogical processes in your body.

Everything is in balance and in ME/CFS that balance is way off.

So... another clue to depletion of endocannabinoids from stress (stress or inflammation) and why CQ10 work.

Stress/innflammation = cortisol long term = degraded endocannabinoids = FAAH going nuts = degrade Electron Transport Chain + a lot of innflammation.

And also as I understand it, closure of Ca2+ channels?

"The receptor CB1 is considered to be the most abundant G-protein-coupled receptor in mammalian brain. Its activation can typically initiate responses such as the closure of Ca2+ channels, opening of K+ channels, inhibition of adenylyl cyclase activity, and stimulation of kinase. Furthermore, CB1 agonists inhibit N- and P/Q-type voltage-activated Ca2+ channels.18–20". https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1038/psp.2013.72



Results
CB1 increased osteogenic differentiation potential and mitochondrial energy metabolism, including the OCR, MMP, and enhanced the expressions of Nrf1 and Nrf2 in hBMSCs without or with TNF-α or INF-γ stimulation. Then, the inhibitor of mitochondrial electron transport chain (ETC), rotenone (ROT), inhibited the osteogenic differentiation in hBMSCs, and CB1 could rescue ROT impaired osteogenic differentiation potentials of hBMSCs without or with TNF-α or INF-γ stimulation. Activation of ETC by Coenzyme Q10 (CoQ10) could restore the impaired osteogenic differentiation of hBMSCs by depletion of CB1 without or with TNF-α or INF-γ stimulation. Mechanismly, CB1 could activate the JNK signaling pathway, p38 MAPK signaling pathway, and inhibit the Erk1/2 signaling pathway.

So, taking CBD, CQ10 and Naltrexone would stop FAAH dominance, restore ETC and increase intracellular calsium.

What do you think?

 

[CSMLSM]

And this table shows FAAH inhibitors.

Yes it actually shows Caryophyllene as a FAAH inhibitor with the strongest evidence but has CBD missing, interesting.
I was holding back on talking about caryophyllene as a FAAh inhibitor as I had not yet seen research showing this only second hand information like the Caryophyllene video I have in a thread.
It adds to CBD`s affect and works with it if FAAH is indeed an enzyme that degrades caryophyllene also, which this appears to show it is.

Also did you know plain old paracetamol is a FAAH inhibitor-

First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid - PMC (nih.gov)
Abstract
Paracetamol is arguably the most commonly used analgesic and antipyretic drug worldwide, however its mechanism of action is still not fully established. It has been shown to exert effects through multiple pathways, some actions suggested to be mediated via N-arachidonoylphenolamine (AM404). AM404, formed through conjugation of paracetamol-derived p-aminophenol with arachidonic acid in the brain, is an activator of the capsaicin receptor, TRPV1, and inhibits the reuptake of the endocannabinoid, anandamide, into postsynaptic neurons, as well as inhibiting synthesis of PGE2 by COX-2. However, the presence of AM404 in the central nervous system following administration of paracetamol has not yet been demonstrated in humans. Cerebrospinal fluid (CSF) and blood were collected from 26 adult male patients between 10 and 211 minutes following intravenous administration of 1 g of paracetamol. Paracetamol was measured by high-performance liquid chromatography with UV detection. AM404 was measured by liquid chromatography-tandem mass spectrometry. AM404 was detected in 17 of the 26 evaluable CSF samples at 5–40 nmol⋅L−1. Paracetamol was measurable in CSF within 10 minutes, with a maximum measured concentration of 60 μmol⋅L−1 at 206 minutes. This study is the first to report on the presence of AM404 in human CSF following paracetamol administration. This may represent an important finding in our understanding of paracetamol’s mechanism of action, although measured concentrations were far below the previously documented IC50 for this metabolite.

Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172 | PNAS
From the Abstract
The endogenous cannabinoid anandamide is removed from the synaptic space by a high-affinity transport system present in neurons and astrocytes, which is inhibited by N-(4-hydroxyphenyl)-arachidonamide (AM404). After internalization, anandamide is hydrolyzed by fatty-acid amide hydrolase (FAAH), an intracellular membrane-bound enzyme that also cleaves AM404.

I just want to add something that just blew my mind.

Red clover does not only contain Biochanin A, which is a FAAH inhibitor.

It is one of the plants with a lot of formononotin wich is a Enterovirus 71 antivral. (mind blown). Along with Yangonin (kaava) and aruptine.

Dude thats so cool

Do you know what causes a rise in leptin?

Eating and being full and the immune system has control over it.

I cannot find the information on this as I am still super unorganised and I am currently dealing with my cat being very ill so I will get back to you on this when I can focus on things more.

I may need to build a coffin for her tomorrow.

Also, I have been able to eat more variety (which is still very limited, though) since starting CBD, and am going to look into why it helps that.

Really glad to read this. Hows the copaiba going or have you not started yet? Gelatin capsules with 1 or 2 drops to start will help too. I use 5-6 drops when I do take it this way but not as frequently as before.

Fantastic video on the endocannabinoid system:

Excellent video

So... another clue to depletion of endocannabinoids from stress (stress or inflammation) and why CQ10 work.

Stress/innflammation = cortisol long term = degraded endocannabinoids = FAAH going nuts = degrade Electron Transport Chain + a lot of innflammation.

And also as I understand it, closure of Ca2+ channels?

What do you think?

Yes, apart from the immune system is elevating the FAAH which degrades endocannabinoids. Stress in normal people increases cannabinoids to balnce biological processes again but in us that is messed with by the immune system being affected by an infection like EBV and then the HPA axis becomes unbalanced over time and starts to become dysfunctional as a result of the now inhibited cannabinoid system that otherwise would keep balance.

The calcium channels are just another thing to keep in balance/homeostasis. Cannabinoid system makes and degrades ligands at each site. This is how you can have problems in specific places but not everywhere to do with the cannabinoid system.
It can be a very local affect when caused say by an immune cell giving off cytokines. Or it can have global affects in the body when say the brain coordinates a more robust immune control in a more severe infection.

So, taking CBD, CQ10 and Naltrexone would stop FAAH dominance, restore ETC and increase intracellular calsium.

What do you think?

Not sure about Naltrexone but everything else I would say yes, except it is likely to improve intracellular calcium balance/homeostasis.

 

[Violeta]

I cannot find the information on this as I am still super unorganised and I am currently dealing with my cat being very ill so I will get back to you on this when I can focus on things more.

I may need to build a coffin for her tomorrow

Oh no! So sorry! That breaks my heart. I thought I was going to lose my dog a little over a week ago, so I have partially gone through the grief. She went several days without eating. She's had problems for over a year but that was the scariest.

I will hope beyond hope that she will somehow be okay, but if not, I at least hope you will be okay.