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Background: Clinical experience suggested that a unique porcine serum polypeptide extract, used in hospitals for people with severe malnutrition, serendipitously resulted in a dramatic improvement in many fibromyalgia cases. Aims: The study aims to determine the effectiveness of a unique polypeptide serum extract in improving the symptoms of CFS and fibromyalgia (CFS/FMS). Methods: An open-label prospective study of 43 people with CFS or Fibromyalgia recruited worldwide. Interventions: Four 500 mg tablets twice daily for five weeks. Outcome Measures: Assessed baseline at five weeks of treatment using a VAS(1-10 points) rating energy, sleep, cognitive function, pain, overall well-being, anxiety, and digestive health, as well as the FIQR. The primary outcome measure was the pre- and post-treatment VAS composite score for the first five symptoms. Results: 43 subjects completed the three-week treatment trial. 60.5% of subjects rated themselves as improved, with 18.6% rating themselves as much better. In the 60.5% of subjects that rated themselves as improved, the significant average improvement was seen in all categories: 1. 69.4% increase in energy(p Conclusion: Recovery Factors® resulted in markedly improved energy, sleep, cognition, pain relief, calming, digestion and overall well-being in those with CFS/FMS. Clinical Trial Registration Number: NCT04381793.

Background and purpose Δ9 -Tetrahydrocannabinolic acid (Δ9 -THCA-A), the precursor of Δ9 -THC, is a non-psychotropic phytocannabinoid that shows PPARγ agonist activity. Here, we investigated the ability of Δ9 -THCA-A to modulate the classic cannabinoid CB1 and CB2 receptors and evaluated its anti-arthritis activity in vitro and in vivo. Experimental approach Cannabinoid receptors binding and intrinsic activity, as well as their downstream signalling, were analysed in vitro and in silico. The anti-arthritis properties of Δ9 -THCA-A were studied in human chondrocytes and in the murine model of collagen-induced arthritis (CIA). Plasma disease biomarkers were identified by LC-MS/MS based on proteomic and elisa assays. Key results Functional and docking analyses showed that Δ9 -THCA-A can act as an orthosteric CB1 receptor agonist and also as a positive allosteric modulator in the presence of CP-55,940. Also, Δ9 -THCA-A seemed to be an inverse agonist for CB2 receptors. In vivo, Δ9 -THCA-A reduced arthritis in CIA mice, preventing the infiltration of inflammatory cells, synovium hyperplasia, and cartilage damage. Furthermore, Δ9 -THCA-A inhibited expression of inflammatory and catabolic genes on knee joints. The anti-arthritic effect of Δ9 -THCA-A was blocked by either SR141716 or T0070907. Analysis of plasma biomarkers, and determination of cytokines and anti-collagen antibodies confirmed that Δ9 -THCA-A mediated its activity mainly through PPARγ and CB1 receptor pathways. Conclusion and implications Δ9 -THCA-A modulates CB1 receptors through the orthosteric and allosteric binding sites. In addition, Δ9 -THCA-A exerts anti-arthritis activity through CB1 receptors and PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.

The endocannabinoid system (ECS) is an important physiologic system that interacts with nearly all bodily ones, including the central nervous system (CNS). Overall, the ECS is involved in health and disease. From a therapeutic perspective, modulating and targeting the ECS could be a major disease-modifying medical strategy for the future, with implications for the prevention and treatment of a wide variety of disorders ranging from anxiety and depression to Parkinson's disease, multiple sclerosis, and Alzheimer's disease.

Background and Purpose Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing and storage. While the biological effects of decarboxylated cannabinoids such as Δ9-tetrahydrocannabinol have been extensively investigated, the bioactivity of Δ9-tetahydrocannabinol acid (Δ9-THCA) is largely unknown, despite its occurrence in different Cannabis preparations. Here we have assessed possible neuroprotective actions of Δ9-THCA through modulation of PPARγ pathways. Experimental Approach The effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated. The effect of Δ9-THCA on mitochondrial biogenesis and PPARγ coactivator 1-α expression was investigated in Neuro-2a (N2a) cells. The neuroprotective effect was analysed in STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein and in N2a cells infected with an adenovirus carrying human huntingtin containing 94 polyQ repeats (mHtt-q94). The in vivo neuroprotective activity of Δ9-THCA was investigated in mice intoxicated with the mitochondrial toxin 3-nitropropionic acid (3-NPA). Key Results Cannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. Δ9-THCA increased mitochondrial mass in neuroblastoma N2a cells and prevented cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells and by mutHtt-q94 in N2a cells. Δ9-THCA, through a PPARγ-dependent pathway, was neuroprotective in mice treated with 3-NPA, improving motor deficits and preventing striatal degeneration. In addition, Δ9-THCA attenuated microgliosis, astrogliosis and up-regulation of proinflammatory markers induced by 3-NPA. Conclusions and Implications Δ9-THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases.

BACKGROUND AND PURPOSE: Δ(9)‐Tetrahydrocannabinolic acid (Δ(9)‐THCA‐A), the precursor of Δ(9)‐THC, is a non‐psychotropic phytocannabinoid that shows PPARγ agonist activity. Here, we investigated the ability of Δ(9)‐THCA‐A to modulate the classic cannabinoid CB(1) and CB(2) receptors and evaluated its anti‐arthritis activity in vitro and in vivo. EXPERIMENTAL APPROACH: Cannabinoid receptors binding and intrinsic activity, as well as their downstream signalling, were analysed in vitro and in silico. The anti‐arthritis properties of Δ(9)‐THCA‐A were studied in human chondrocytes and in the murine model of collagen‐induced arthritis (CIA). Plasma disease biomarkers were identified by LC‐MS/MS based on proteomic and elisa assays. KEY RESULTS: Functional and docking analyses showed that Δ(9)‐THCA‐A can act as an orthosteric CB(1) receptor agonist and also as a positive allosteric modulator in the presence of CP‐55,940. Also, Δ(9)‐THCA‐A seemed to be an inverse agonist for CB(2) receptors. In vivo, Δ(9)‐THCA‐A reduced arthritis in CIA mice, preventing the infiltration of inflammatory cells, synovium hyperplasia, and cartilage damage. Furthermore, Δ(9)‐THCA‐A inhibited expression of inflammatory and catabolic genes on knee joints. The anti‐arthritic effect of Δ(9)‐THCA‐A was blocked by either SR141716 or T0070907. Analysis of plasma biomarkers, and determination of cytokines and anti‐collagen antibodies confirmed that Δ(9)‐THCA‐A mediated its activity mainly through PPARγ and CB(1) receptor pathways. CONCLUSION AND IMPLICATIONS: Δ(9)‐THCA‐A modulates CB(1) receptors through the orthosteric and allosteric binding sites. In addition, Δ(9)‐THCA‐A exerts anti‐arthritis activity through CB(1) receptors and PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.

Cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). Surprisingly, the biological profile of the non-narcotic native precursor of Δ9-THC (Δ9-THC acid A, Δ9-THCA-A) is still largely unexplored. We present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and with an enhanced osteoblastogenic activity in human mesenchymal stem cells. Docking andin vitrofunctional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures at inguinal white adipose tissue (iWAT) from mice treated with Δ9-THCA-A confirmed its mode of action on PPARγ. Administration of Δ9-THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Altogether, our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation. These findings suggest that Δ9-THCA-A, and perhaps non-decarboxylatedCannabis sativaextracts, are worth considering for addition to our inventory of cannabis medicines.SIGNIFICANCE STATEMENTThe medicinal use of Cannabis is gaining momentum, despite the adverse psychotropic effects of Δ9-THC, the decarboxylation product of its naturally occurring and non-psychotropic precursor Δ9-THCA-A. We present evidence that Δ9-THCA-A is a partial ligand agonist of PPARγ with lower adipogenic activity compared to the full PPARγ agonist rosiglitazone (RGZ). Moreover, chronic administration of Δ9-THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced body weight gain and fat mass, improved glucose intolerance and insulin resistance, and prevented liver steatosis and macrophage infiltration in fat tissues, additionally inducing white adipose tissue browning. Collectively, these observations qualify Δ9-THCA-A, a compound devoid of psychotropic effects, as an efficacious pharmacological agent to manage metabolic syndrome and obesity-associated inflammation.Highlights- Δ9-THCA-A is a partial PPARγ ligand agonist with low adipogenic activity- Δ9-THCA-A enhances osteoblastogenesis in bone marrow derived mesenchymal stem cells.- Δ9-THCA-A reduces body weight gain, fat mass, and liver steatosis in HFD-fed mice- Δ9-THCA-A improves glucose tolerance, insulin sensitivity, and insulin profilesin vivo- Δ9-THCA-A induces browning of iWAT and has a potent anti-inflammatory activity

Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing and storage. While the biological effects of decarboxylated cannabinoids such as ΔThe effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated. The effect of ΔCannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. ΔΔ