CSMLSM
Senior Member
- Messages
- 973
I am sure you know that LDN affects IL6, NF-κB, TLR and microglia activation state. Also that it is used to treat opiate addiction.
Also I am sure you are aware that elevated Leptin has been seen by many in ME/CFS and Fibromyalgia separately in the research community.
Protective Effects of (E)-β-Caryophyllene (BCP) in Chronic Inflammation - PMC (nih.gov)
Taken from the above-
Experimental results show the ability of BCP to reduce pro-inflammatory mediators such as tumor necrosis factor-alfa (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus ameliorating chronic pathologies characterized by inflammation and oxidative stress, in particular metabolic and neurological diseases. Through the binding to CB2 cannabinoid receptors and the interaction with members of the family of peroxisome proliferator-activated receptors (PPARs), BCP shows beneficial effects on obesity, non-alcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) liver diseases, diabetes, cardiovascular diseases, pain and other nervous system disorders.
Cannabinoid receptor 2 is necessary to induce toll‐like receptor‐mediated microglial activation - Reusch - 2022 - Glia - Wiley Online Library
Taken from above-
We show that the CB2-mediated attenuation of TLR-induced microglial activation is mainly p38 MAPK-dependent. Taken together, we demonstrate that CB2 expression and signaling are necessary to fine-tune TLR-induced activation programs in microglia.
β-Caryophyllene protects against ischemic stroke by promoting polarization of microglia toward M2 phenotype via the TLR4 pathway - PubMed (nih.gov)
Taken from above-
The objective of the study was to determine whether β-caryophyllene (BCP) exerts a neuroprotective effect in cerebral ischemia-reperfusion (I/R) injury by inhibiting microglial activation and modulating their polarization via the TLR4 pathway.
The decrease in TLR4 activity mediated, at least in part, the anti-inflammatory effects of BCP and its ability to shift microglia polarization from the M1 to M2 phenotype.
The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation | Request PDF (researchgate.net)
Taken from above-
In conclusion, the low concentration of BCP has higher selective anti-inflammatory effects rather than high levels. On this occasion, BCP by modulating the microglia is able to have potential therapeutic effects in neuro-inflammation conditions and microglia cells such as MS and AD.
Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization - PMC (nih.gov)
Taken from above-
fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA) (an endogenous cannabinoid)
these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype.
Anandamide enhances IL-10 production in activated microglia by targeting CB(2) receptors: roles of ERK1/2, JNK, and NF-kappaB - PubMed (nih.gov)
Taken from above-
This suggests that by altering the cytokine network, AEA could indirectly modify the type of immune responses within the central nervous system (CNS). Accordingly, pharmacological modulation of AEA uptake and degradation might be a useful tool for treating neuroinflammatory diseases.
Leptin Activates the Anandamide Hydrolase Promoter in Human T Lymphocytes through STAT3 - ScienceDirect
Taken from above-
these results suggest that leptin, by up-regulating the FAAH promoter through STAT3, enhances FAAH expression, thus tuning the immunomodulatory effects of anandamide.
Leptin modulates cell morphology and cytokine release in microglia - PubMed (nih.gov)
Taken from above-
These results suggest that leptin has an important role in microglial function in inflammation and given that its circulating levels fluctuate across a number of conditions, these findings can have important implications for an individual's ability to mount an efficient and complete response to invading pathogens.
Effects of CB2 Receptor Modulation on Macrophage Polarization in Pediatric Celiac Disease - PMC (nih.gov)
Taken from above-
CB2 stimulation switches macrophage polarization towards the anti-inflammatory M2 phenotype thus reducing inflammation but also limiting the epithelial dysfunction. Therefore, we suggest CB2 receptor as a possible novel therapeutic target for CD by regulating macrophages polarization and by preventing mucosal barrier damage.
Beta-caryophyllene inhibits cocaine addiction-related behavior by activation of PPARα and PPARγ: repurposing a FDA-approved food additive for cocaine use disorder - PubMed (nih.gov)
Taken from above-
It also failed to maintain self-administration in a drug substitution test, suggesting that BCP has no abuse potential.
We found that BCP is more effective in attenuation of cocaine-enhanced oICSS than eICSS, the former driven by optical activation of midbrain dopamine neurons in DAT-cre mice. These findings indicate that BCP may be useful for the treatment of CUD, likely by stimulation of PPARα and PPARγ in the mesolimbic system.
Naltrexone a potential therapeutic candidate for COVID-19 - PMC (nih.gov)
Taken from above-
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of Coronavirus Disease (COVID-19) that has resulted in a global pandemic. At the time of writing, approximately 16.06 million cases have been reported worldwide. Like other coronaviruses, SARS-CoV-2 relies on the surface Spike glycoprotein to access the host cells, mainly through the interaction of its Receptor Binding Domain (RBD) with the host receptor Angiotensin-Converting Enzyme2 (ACE2). SARS-CoV-2 infection induces a profound downstream pro-inflammatory cytokine storm. This release of the pro-inflammatory cytokines is underpinning lung tissue damage, respiratory failure, and eventually multiple organ failure in COVID-19 patients. The phosphorylation status of ERK1/2 is positively correlated with virus load and ERK1/2 inhibition suppressed viral replication and viral infectivity. Therefore, molecular entities able to interfere with binding of the SARS-CoV-2 Spike protein to ACE2, or damping hyperinflammatory cytokines storm, blocking ERK1/2 phosphorylation have a great potential to inhibit viral entry along with viral infectivity. Herein, we report that the FDA-approved non-peptide opioid antagonist drug, naltrexone suppresses high fat/LPS induced pro-inflammatory cytokine release both from macrophage cells and Adipose Tissue Macrophage. Moreover, Low Dose Naltrexone (LDN) also showed its activity as an ERK1/2 inhibitor. Notably, virtual docking and simulation data also suggest LDN may disrupt the interaction of ACE2 with RBD. LDN may be considered as a target as the treatment and (or) adjuvant therapy for coronavirus infection. Clinical toxicity measurements may not be required for LDN since naltrexone was previously tested and is an approved drug by the FDA.
β-Caryophyllene, A Natural Dietary CB2 Receptor Selective Cannabinoid can be a Candidate to Target the Trinity of Infection, Immunity, and Inflammation in COVID-19 - PubMed (nih.gov)
Taken from above-
Based on its pharmacological properties, molecular mechanisms, and the therapeutic potential of BCP as an immunomodulator, anti-inflammatory, organ-protective, and antiviral, we hypothesize that BCP could be a promising therapeutic and/or preventive candidate to target the triad of infection, immunity, and inflammation in COVID-19. In line with numerous studies that proposed the potential of cannabinoids in COVID-19, BCP may be a novel candidate compound for pharmaceutical and nutraceutical development due to its unique functional receptor selectivity, wide availability and accessibility, dietary bioavailability, nonpsychoactivity, and negligible toxicity along with druggable properties, including favorable pharmacokinetic and physicochemical properties. Based on reasonable pharmacological mechanisms and therapeutic properties, we speculate that BCP has potential to be investigated against COVID-19 and will inspire further preclinical and clinical studies.
So with LDN you have an issue with having to stop pain medication before you start and this is an issue obviously because ME/CFS causes pain. Caryophyllene treats pain also.
Caryophyllene is safe and Copaiba which contains high amounts of Caryophyllene is deemed safe-
From Wiki
The Food and Chemicals Codex lists copaiba oil as safe as a flavoring agent for foods.[9] Copaiba oil has both an acute oral and dermal LD50 exceeding 5 g/kg,[10] which classifies it as non-toxic.[
Copaiba oil-resins extracted have been used in folk medicine dating back to the 16th century by the natives of north and northeastern Brazil. The folk remedies were administered orally or used as an ointment in the treatment of various diseases.[5] In Panama, the Yaviza people mix the resin with honey and give it to newborns to impart knowledge and ward off hexes.[6] Within the Peruvian Amazon near Iquitos, it is also used as an insect repellent.
As you can see it has a long human use with proven safety and has no legal barriers to use at all, not even a prescription required, no need to prove safety and is relatively low cost.
Also I am sure you are aware that elevated Leptin has been seen by many in ME/CFS and Fibromyalgia separately in the research community.
Protective Effects of (E)-β-Caryophyllene (BCP) in Chronic Inflammation - PMC (nih.gov)
Taken from the above-
Experimental results show the ability of BCP to reduce pro-inflammatory mediators such as tumor necrosis factor-alfa (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus ameliorating chronic pathologies characterized by inflammation and oxidative stress, in particular metabolic and neurological diseases. Through the binding to CB2 cannabinoid receptors and the interaction with members of the family of peroxisome proliferator-activated receptors (PPARs), BCP shows beneficial effects on obesity, non-alcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) liver diseases, diabetes, cardiovascular diseases, pain and other nervous system disorders.
Cannabinoid receptor 2 is necessary to induce toll‐like receptor‐mediated microglial activation - Reusch - 2022 - Glia - Wiley Online Library
Taken from above-
We show that the CB2-mediated attenuation of TLR-induced microglial activation is mainly p38 MAPK-dependent. Taken together, we demonstrate that CB2 expression and signaling are necessary to fine-tune TLR-induced activation programs in microglia.
β-Caryophyllene protects against ischemic stroke by promoting polarization of microglia toward M2 phenotype via the TLR4 pathway - PubMed (nih.gov)
Taken from above-
The objective of the study was to determine whether β-caryophyllene (BCP) exerts a neuroprotective effect in cerebral ischemia-reperfusion (I/R) injury by inhibiting microglial activation and modulating their polarization via the TLR4 pathway.
The decrease in TLR4 activity mediated, at least in part, the anti-inflammatory effects of BCP and its ability to shift microglia polarization from the M1 to M2 phenotype.
The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation | Request PDF (researchgate.net)
Taken from above-
In conclusion, the low concentration of BCP has higher selective anti-inflammatory effects rather than high levels. On this occasion, BCP by modulating the microglia is able to have potential therapeutic effects in neuro-inflammation conditions and microglia cells such as MS and AD.
Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization - PMC (nih.gov)
Taken from above-
fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA) (an endogenous cannabinoid)
these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype.
Anandamide enhances IL-10 production in activated microglia by targeting CB(2) receptors: roles of ERK1/2, JNK, and NF-kappaB - PubMed (nih.gov)
Taken from above-
This suggests that by altering the cytokine network, AEA could indirectly modify the type of immune responses within the central nervous system (CNS). Accordingly, pharmacological modulation of AEA uptake and degradation might be a useful tool for treating neuroinflammatory diseases.
Leptin Activates the Anandamide Hydrolase Promoter in Human T Lymphocytes through STAT3 - ScienceDirect
Taken from above-
these results suggest that leptin, by up-regulating the FAAH promoter through STAT3, enhances FAAH expression, thus tuning the immunomodulatory effects of anandamide.
Leptin modulates cell morphology and cytokine release in microglia - PubMed (nih.gov)
Taken from above-
These results suggest that leptin has an important role in microglial function in inflammation and given that its circulating levels fluctuate across a number of conditions, these findings can have important implications for an individual's ability to mount an efficient and complete response to invading pathogens.
Effects of CB2 Receptor Modulation on Macrophage Polarization in Pediatric Celiac Disease - PMC (nih.gov)
Taken from above-
CB2 stimulation switches macrophage polarization towards the anti-inflammatory M2 phenotype thus reducing inflammation but also limiting the epithelial dysfunction. Therefore, we suggest CB2 receptor as a possible novel therapeutic target for CD by regulating macrophages polarization and by preventing mucosal barrier damage.
Beta-caryophyllene inhibits cocaine addiction-related behavior by activation of PPARα and PPARγ: repurposing a FDA-approved food additive for cocaine use disorder - PubMed (nih.gov)
Taken from above-
It also failed to maintain self-administration in a drug substitution test, suggesting that BCP has no abuse potential.
We found that BCP is more effective in attenuation of cocaine-enhanced oICSS than eICSS, the former driven by optical activation of midbrain dopamine neurons in DAT-cre mice. These findings indicate that BCP may be useful for the treatment of CUD, likely by stimulation of PPARα and PPARγ in the mesolimbic system.
Naltrexone a potential therapeutic candidate for COVID-19 - PMC (nih.gov)
Taken from above-
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of Coronavirus Disease (COVID-19) that has resulted in a global pandemic. At the time of writing, approximately 16.06 million cases have been reported worldwide. Like other coronaviruses, SARS-CoV-2 relies on the surface Spike glycoprotein to access the host cells, mainly through the interaction of its Receptor Binding Domain (RBD) with the host receptor Angiotensin-Converting Enzyme2 (ACE2). SARS-CoV-2 infection induces a profound downstream pro-inflammatory cytokine storm. This release of the pro-inflammatory cytokines is underpinning lung tissue damage, respiratory failure, and eventually multiple organ failure in COVID-19 patients. The phosphorylation status of ERK1/2 is positively correlated with virus load and ERK1/2 inhibition suppressed viral replication and viral infectivity. Therefore, molecular entities able to interfere with binding of the SARS-CoV-2 Spike protein to ACE2, or damping hyperinflammatory cytokines storm, blocking ERK1/2 phosphorylation have a great potential to inhibit viral entry along with viral infectivity. Herein, we report that the FDA-approved non-peptide opioid antagonist drug, naltrexone suppresses high fat/LPS induced pro-inflammatory cytokine release both from macrophage cells and Adipose Tissue Macrophage. Moreover, Low Dose Naltrexone (LDN) also showed its activity as an ERK1/2 inhibitor. Notably, virtual docking and simulation data also suggest LDN may disrupt the interaction of ACE2 with RBD. LDN may be considered as a target as the treatment and (or) adjuvant therapy for coronavirus infection. Clinical toxicity measurements may not be required for LDN since naltrexone was previously tested and is an approved drug by the FDA.
β-Caryophyllene, A Natural Dietary CB2 Receptor Selective Cannabinoid can be a Candidate to Target the Trinity of Infection, Immunity, and Inflammation in COVID-19 - PubMed (nih.gov)
Taken from above-
Based on its pharmacological properties, molecular mechanisms, and the therapeutic potential of BCP as an immunomodulator, anti-inflammatory, organ-protective, and antiviral, we hypothesize that BCP could be a promising therapeutic and/or preventive candidate to target the triad of infection, immunity, and inflammation in COVID-19. In line with numerous studies that proposed the potential of cannabinoids in COVID-19, BCP may be a novel candidate compound for pharmaceutical and nutraceutical development due to its unique functional receptor selectivity, wide availability and accessibility, dietary bioavailability, nonpsychoactivity, and negligible toxicity along with druggable properties, including favorable pharmacokinetic and physicochemical properties. Based on reasonable pharmacological mechanisms and therapeutic properties, we speculate that BCP has potential to be investigated against COVID-19 and will inspire further preclinical and clinical studies.
So with LDN you have an issue with having to stop pain medication before you start and this is an issue obviously because ME/CFS causes pain. Caryophyllene treats pain also.
Caryophyllene is safe and Copaiba which contains high amounts of Caryophyllene is deemed safe-
From Wiki
The Food and Chemicals Codex lists copaiba oil as safe as a flavoring agent for foods.[9] Copaiba oil has both an acute oral and dermal LD50 exceeding 5 g/kg,[10] which classifies it as non-toxic.[
Copaiba oil-resins extracted have been used in folk medicine dating back to the 16th century by the natives of north and northeastern Brazil. The folk remedies were administered orally or used as an ointment in the treatment of various diseases.[5] In Panama, the Yaviza people mix the resin with honey and give it to newborns to impart knowledge and ward off hexes.[6] Within the Peruvian Amazon near Iquitos, it is also used as an insect repellent.
As you can see it has a long human use with proven safety and has no legal barriers to use at all, not even a prescription required, no need to prove safety and is relatively low cost.
