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

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/

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Effect of anandamide in Plasmodium Berghei-infected mice.

“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

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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.

 

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

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

“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

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Selective activation of CB2 receptor improves efferocytosis in cultured macrophages.

“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

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The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer’s disease.

“Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by progressive loss of cognition. Over 35 million individuals currently have AD worldwide. Unfortunately, current therapies are limited to very modest symptomatic relief.

The brains of AD patients are characterized by the deposition of amyloid-β and hyperphosphorylated forms of tau protein. AD brains also show neurodegeneration and high levels of oxidative stress and inflammation.

The phytocannabinoid cannabidiol (CBD) possesses neuroprotective, antioxidant and anti-inflammatory properties and reduces amyloid-β production and tau hyperphosphorylation in vitro.

CBD has also been shown to be effective in vivo making the phytocannabinoid an interesting candidate for novel therapeutic interventions in AD, especially as it lacks psychoactive or cognition-impairing properties.

CBD treatment would be in line with preventative, multimodal drug strategies targeting a combination of pathological symptoms, which might be ideal for AD therapy.

Thus, this review will present a brief introduction to AD biology and current treatment options before outlining comprehensively CBD biology and pharmacology, followed by in-vitro and in-vivo evidence for the therapeutic potential of CBD. We will also discuss the role of the endocannabinioid system in AD before commenting on the potential future of CBD for AD therapy (including safety aspects).”

http://www.ncbi.nlm.nih.gov/pubmed/27471947

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Cannabinoids in pain and inflammation.

“Cannabinoids exhibit medicinal properties including analgesic, anti-inflammatory and immunosuppressive properties. This paper reviews some of the recent findings in the study of cannabinoids in pain and inflammation. Some of the effects of cannabinoids are receptor mediated and others are receptor independent. Endocannabinoids naturally reduce pain and are cerebroprotective. Natural and synthetic cannabinoids have the potential to reduce nociception, reverse the development of allodynia and hyperalgesia, reduce inflammation and inflammatory pain and protect from secondary tissue damage in traumatic head injury.”

http://www.ncbi.nlm.nih.gov/pubmed/15265314

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Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism.

“We examined the neuroprotective mechanism of cannabidiol, non-psychoactive component of marijuana, on the infarction in a 4 h mouse middle cerebral artery (MCA) occlusion model in comparison with Delta(9)-tetrahydrocannabinol (Delta(9)-THC).

Both pre- and post-ischemic treatment with cannabidiol resulted in potent and long-lasting neuroprotection, whereas only pre-ischemic treatment with Delta(9)-THC reduced the infarction.

Unlike Delta(9)-THC, cannabidiol did not affect the excess release of glutamate in the cortex after occlusion.

Cannabidiol suppressed the decrease in cerebral blood flow by the failure of cerebral microcirculation after reperfusion and inhibited MPO activity in neutrophils.

Furthermore, the number of MPO-immunopositive cells was reduced in the ipsilateral hemisphere in cannabidiol-treated group.

Cannabidiol provides potent and long-lasting neuroprotection through an anti-inflammatory CB(1) receptor-independent mechanism, suggesting that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/17437545

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Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inhibiting mechanism.

“We examined the cerebroprotective mechanism of cannabidiol, the non-psychoactive component of marijuana, against infarction in a 4-h mouse middle cerebral artery (MCA) occlusion model.

Cannabidiol was intraperitoneally administrated immediately before and 3h after cerebral ischemia.

Cannabidiol significantly prevented infarction and MPO activity at 20h after reperfusion.

Cannabidiol inhibited the MPO-positive cells expressing HMGB1 and also decreased the expression level of HMGB1 in plasma.

In addition, cannabidiol decreased the number of Iba1- and GFAP-positive cells at 3 days after cerebral ischemia.

Moreover, cannabidiol improved neurological score and motor coordination on the rota-rod test.

Our results suggest that cannabidiol inhibits monocyte/macropharge expressing HMGB1 followed by preventing glial activation and neurological impairment induced by cerebral ischemia.

Cannabidiol will open new therapeutic possibilities for post-ischemic injury via HMGB1-inhibiting mechanism.”

http://www.ncbi.nlm.nih.gov/pubmed/18634812

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The future of cannabinoids as analgesic agents: a pharmacologic, pharmacokinetic, and pharmacodynamic overview.

 

“For thousands of years, physicians and their patients employed cannabis as a therapeutic agent.

Despite this extensive historical usage, in the Western world, cannabis fell into disfavor among medical professionals because the technology available in the 1800s and early 1900s did not permit reliable, standardized preparations to be developed.

However, since the discovery and cloning of cannabinoid receptors (CB1 and CB2) in the 1990s, scientific interest in the area has burgeoned, and the complexities of this fascinating receptor system, and its endogenous ligands, have been actively explored.

Recent studies reveal that cannabinoids have a rich pharmacology and may interact with a number of other receptor systems-as well as with other cannabinoids-to produce potential synergies.

Cannabinoids-endocannabinoids, phytocannabinoids, and synthetic cannabinoids-affect numerous bodily functions and have indicated efficacy of varying degrees in a number of serious medical conditions.

Cannabinoid receptor agonists and/or molecules that affect the modulation of endocannabinoid synthesis, metabolism, and transport may, in the future, offer extremely valuable tools for the treatment of a number of currently intractable disorders.”

 http://www.ncbi.nlm.nih.gov/pubmed/17890938

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