Immunoactive cannabinoids: Therapeutic prospects for marijuana constituents

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“Marijuana, the common name for Cannabis sativa, is a widely distributed hemp plant whose dried flowering tops and leaves have been used for medicinal purposes for 12,000 years by some estimates.

The article by Malfaitet al. in this issue of PNAS is relevant to the question of whether such traditional uses of marijuana could be clinically justifiable today.

It is conceivable that marijuana contains a series of cannabinoids that, in the aggregate, could alleviate arthritis as implied in the present report, yet remain well tolerated.

Remarkably, the claim that marijuana does so also was made 4,000 years ago by the Chinese emperor Shen-nung whose pharmacobotanical compendium, the Pen-ts’ao Ching, concluded that cannabis “undoes rheumatism””

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC34030/

Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats.

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“The hypothesis was tested that THC and anandamide elicit antinociception in the paw pressure test, and that arthritic rats would exhibit a different response.

THC and anandamide appear to release an as yet unknown endogenous opioid, because naloxone significantly blocked their effects.

This study indicates that anandamide and THC may act at different receptor sites to modulate endogenous opioid levels in mechanical nociception.”

http://www.ncbi.nlm.nih.gov/pubmed/9610941

Effects of cannabinoids on nitric oxide production by chondrocytes and proteoglycan degradation in cartilage.

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“Cannabinoids have been reported to have anti-inflammatory effects and reduce joint damage in animal models of arthritis.

This suggests a potential therapeutic role in arthritis of this group of compounds.

Cannabinoids were studied to determine whether they have direct effects on chondrocyte metabolism resulting in cartilage protection.

Synthetic cannabinoids, R-(+)-Win-55,212 (Win-2) and S-(-)-Win-55,212 (Win-3) and the endocannabinoid, anandamide, were investigated on unstimulated or IL-1-stimulated nitric oxide (NO) production in bovine articular chondrocytes as well as on cartilage proteoglycan breakdown in bovine nasal cartilage explants.

Win-2 significantly inhibited (P < 0.05) NO production in chondrocytes at 1-10 microM concentrations. The combined CB(1) and CB(2) cannabinoid receptor antagonists, AM281 and AM630, respectively, at 100 microM did not block this effect, but instead they potentiated it. Anandamide and Win-2 (5-50 microM) also inhibited the release of sulphated glycosaminoglycans in bovine cartilage explants.

The results suggest that some cannabinoids may prevent cartilage resorption, in part, by inhibiting cytokine-induced NO production by chondrocytes and also by inhibiting proteoglycan degradation.”

http://www.ncbi.nlm.nih.gov/pubmed/15670582

Arthritis and cannabinoids: HU-210 and Win-55,212-2 prevent IL-1alpha-induced matrix degradation in bovine articular chondrocytes in-vitro.

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“Cannabinoids have analgesic, immunomodulatory and anti-inflammatory properties and attenuate joint damage in animal models of arthritis.

Chondrocytes appeared to constitutively express cannabinoid receptors CB1 and CB2.

It is concluded that biologically stable synthetic cannabinoids protect cartilage matrix from degradation induced by cytokines and this effect is possibly CB-receptor mediated and involves effects on prostaglandin and nitric oxide metabolism.”

http://www.ncbi.nlm.nih.gov/pubmed/16536902

Cannabinoids: novel therapies for arthritis?

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“A key feature of osteoarthritis and rheumatoid arthritis is the loss of articular cartilage.

Cartilage breakdown is mediated by complex interactions of proinflammatory cytokines, such as IL-1, inflammatory mediators, including nitric oxide and prostaglandin E(2), and proteases, including matrix metalloproteinases and aggrecanases, such as ADAMTS-4 and -5.

Cannabinoids have been shown to reduce joint damage in animal models of arthritis.

They have also been shown to prevent IL-1-induced matrix breakdown of collagen and proteoglycan, indicating that cannabinoids may mediate chondroprotective effects.

Cannabinoids produce their effects via several cannabinoid receptors and it is important to identify the key cannabinoids and their receptors that are involved in chondroprotection.

This review aims to outline the current and future prospects of cannabinoids as anti-arthritic therapeutics, in terms of their ability to prevent cartilage breakdown.”

http://www.ncbi.nlm.nih.gov/pubmed/22530636

Cannabis in Eurasia: origin of human use and Bronze Age trans-continental connections

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Vegetation History and Archaeobotany

“A systematic review of archaeological and palaeoenvironmental records of cannabis (fibres, pollen, achenes and imprints of achenes) reveals its complex history in Eurasia. A multiregional origin of human use of the plant is proposed, considering the more or less contemporaneous appearance of cannabis records in two distal parts (Europe and East Asia) of the continent. A marked increase in cannabis achene records from East Asia between ca. 5,000 and 4,000 cal bpmight be associated with the establishment of a trans-Eurasian exchange/migration network through the steppe zone, influenced by the more intensive exploitation of cannabis achenes popular in Eastern Europe pastoralist communities. The role of the Hexi Corridor region as a hub for an East Asian spread of domesticated plants, animals and cultural elements originally from Southwest Asia and Europe is highlighted. More systematic, interdisciplinary and well-dated data, especially from South Russia and Central Asia, are necessary to address the unresolved issues in understanding the complex history of human cannabis utilisation.”

http://link.springer.com/article/10.1007%2Fs00334-016-0579-6

“The Tantalizing Clues That Suggest Cannabis Played a Key Role in the Birth of Civilization Itself” http://theinfluence.org/the-tantalizing-clues-that-suggest-cannabis-played-a-key-role-in-the-birth-of-civilization-itself/

“Stoned age: Humans were getting high on cannabis 10,000 years ago and experts say they also used the drug for food and clothes

“Man’s Stoned Age: cannabis use began 10,000 years ago. After the Ice Age came the Stoned Age. Early humans began using cannabis as long as 10,000 years ago, just as Europe’s glaciers had started their final retreat, scientists have found. An archaeological study suggests early humans in Europe and Asia stumbled on the plant at roughly the same time. The discovery was valued, suggest the scientists, not just for its psychoactive properties but also because its nutritious seeds could quench hunger pangs and hemp fibres could be woven into clothing.”                         http://www.thetimes.co.uk/article/mans-stoned-age-cwvtj2js2

“Founders of Western civilisation were prehistoric dope dealers”  https://www.newscientist.com/article/2096440-founders-of-western-civilisation-were-prehistoric-dope-dealers/

Effect of anandamide in Plasmodium Berghei-infected mice.

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“Eryptosis, the suicidal death of erythrocytes, is characterized by exposure of phosphatidylserine at the erythrocyte surface and cell shrinkage.

Triggers of eryptosis include anandamide.

Enhanced eryptosis of infected human erythrocytes is expected to delay the development of parasitaemia during infection with Plasmodium, the parasite causing malaria.

The present experiments aimed to test, whether anandamide influences eryptosis, parasite growth and/or host survival during in vitro or in vivo infection with Plasmodia.

In vivo administration of anandamide blunted the parasitaemia and significantly enhanced the survival of P. berghei-infected mice.

In conclusion, anandamide stimulated eryptosis of infected erythrocytes thus counteracting parasitaemia and a lethal course of the disease.”

http://www.ncbi.nlm.nih.gov/pubmed/20798520

Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ⁹-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour.

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Psychopharmacology

“Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders.

Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing.

Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ(9)-tetrahydrocannabivarin (Δ(9)-THCV) and cannabigerol (CBG).

RESULTS:

All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ(9)-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile.

CONCLUSIONS:

These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/21796370

Cannabinoid receptor 2 modulates susceptibility to experimental cerebral malaria through a CCL17-dependent mechanism.

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“Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection. It is characterized by parasite sequestration, a breakdown of the blood-brain-barrier and a strong inflammation in the brain.

We investigated the role of the cannabinoid receptor 2 (CB2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ECM).

Strikingly, mice with a deletion of the CB2-encoding gene (Cnr2-/-) mice inoculated with Plasmodium berghei ANKA-erythrocytes exhibited enhanced survival and a diminished blood-brain-barrier disruption.

Therapeutic application of a specific CB2 antagonist also conferred increased ECM resistance in wild type mice.

Hematopoietic-derived immune cells were responsible for the enhanced protection in bone-marrow-chimeric (BM)-Cnr2-/- mice. Mixed BM-chimeras further revealed that CB2-expressing cells contributed to ECM development. A heterogeneous CD11b+ cell population, containing macrophages and neutrophils, expanded in the Cnr2-/- spleen after infection and expressed macrophage mannose receptors, arginase-1 activity and IL-10.

Also in the Cnr2-/-brain CD11b+ cells that expressed selected anti-inflammatory markers accumulated and expression of inflammatory mediators IFN-γ and TNF-α was reduced.

Finally, the M2-macrophage chemokine CCL17 was identified as essential factor for enhanced survival in the absence of CB2, since CCL17 x Cnr2 double-deficient mice were fully susceptible to ECM.

Thus, targeting CB2 may be promising for the development of alternative treatment regimes of ECM.”

http://www.ncbi.nlm.nih.gov/pubmed/27474745

Selective activation of CB2 receptor improves efferocytosis in cultured macrophages.

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“Recent evidence indicates that the defective ability to clear apoptotic cells by macrophages (efferocytosis) and the resultant apoptotic cells accumulation in atherosclerotic plaques play an important role during the progression of unstable plaques.

The cannabinoid type 2 receptor (CB2), has recently been emerging as a new target to reduce vulnerability and promote stability of plaques, however, the underlying mechanisms have not been studied in detail. In the present study, we investigated whether selective activation of CB2 improves efferocytosis of macrophages.

SIGNIFICANCE:

The selective activation of CB2 improves efferosytosis of normal-cultured and OxLDL-loaded macrophages, which might provide a novel mechanism on how CB2 activation reduces vulnerability and promotes stability of atherosclerotic plaques.”

http://www.ncbi.nlm.nih.gov/pubmed/27474129