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Targeted proteomics of cannabinoid receptor CB1 and the CB1b isoform.

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“Cannabinoid receptors (CBR), including CB1 and CB2 have been therapeutic targets for a number of conditions.

Recently, splice variants of the CB1R have been identified in humans.

The isoforms differ in their N-terminus sequence and pharmacological activity relative to the CB1R, as a result, the differentiation between the CB1 receptor and its isoform is required.

As a result, a selected reaction monitoring mass spectrometry (SRM-MS) method was developed for the quantitation of CB1 and the CB1b isoform in CHO cells transduced with CB1 and CB1b.

The SRM-MS protocol was assessed with isotopically labeled peptide standards and had high reproducibility of intra-day assay (CVs from 1.9 to 4.3% for CB1 and 0.5 to 5.9% for CB1b) and inter-day assay (CVs from 1.2 to 5.2% for CB1 and 1.2 to 6.1% for CB1b).”

https://www.ncbi.nlm.nih.gov/pubmed/27914737

What is THC?

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“THC, or tetrahydrocannabinol, is the chemical responsible for most of marijuana’s psychological effects. It acts much like the cannabinoid chemicals made naturally by the body, according to the National Institute on Drug Abuse (NIDA).

Cannabinoid receptors are concentrated in certain areas of the brain associated with thinking, memory, pleasure, coordination and time perception. THC attaches to these receptors and activates them and affects a person’s memory, pleasure, movements, thinking, concentration, coordination, and sensory and time perception, according to NIDA.

THC is one of many compounds found in the resin secreted by glands of the marijuana plant. More of these glands are found around the reproductive organs of the plant than on any other area of the plant. Other compounds unique to marijuana, called cannabinoids, are present in this resin.

One cannabinoid, CBD is nonpsychoactive, according to the National Center for Biotechnology Information, and actually blocks the high associated with THC.”

http://www.livescience.com/24553-what-is-thc.html

http://www.thctotalhealthcare.com/category/thc-delta-9-tetrahydrocannabinol/

Δ9-THC-Caused Synaptic and Memory Impairments Are Mediated through COX-2 Signaling

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“Marijuana has been used for thousands of years as a treatment for medical conditions.

However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G protein βγ subunits.

Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories.

Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ9-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition.

These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.”

http://www.cell.com/cell/abstract/S0092-8674(13)01360-3

“Cannabidiolic acid as a selective cyclooxygenase-2 inhibitory component in cannabis.” https://www.ncbi.nlm.nih.gov/pubmed/18556441

Cannabis-induced Moto-Cognitive Dysfunction in Wistar Rats: Ameliorative Efficacy of Nigella Sativa.

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“Cannabis is a widely used illicit drug with various threats of personality syndrome, and Nigella sativa has been widely implicated as having therapeutic efficacy in many neurological diseases.

The present study investigates the ameliorative efficacy of Nigella sativa oil (NSO) on cannabis-induced moto-cognitive defects.

CONCLUSIONS:

The observed ameliorative effects of NSO make it a promising agent against moto-cognitive dysfunction and cerebelo-hippocampal alterations induced by cannabis.”

 https://www.ncbi.nlm.nih.gov/pubmed/27904421

Are adolescents more vulnerable to the harmful effects of cannabis than adults? A placebo-controlled study in human males.

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“Preclinical research demonstrates that cannabinoids have differing effects in adolescent and adult animals. Whether these findings translate to humans has not yet been investigated. Here we believe we conducted the first study to compare the acute effects of cannabis in human adolescent (n=20; 16-17 years old) and adult (n=20; 24-28 years old) male cannabis users, in a placebo-controlled, double-blind cross-over design.

After inhaling vaporized active or placebo cannabis, participants completed tasks assessing spatial working memory, episodic memory and response inhibition, alongside measures of blood pressure and heart rate, psychotomimetic symptoms and subjective drug effects (for example, ‘stoned’, ‘want to have cannabis’).

Results showed that on active cannabis, adolescents felt less stoned and reported fewer psychotomimetic symptoms than adults. Further, adults but not adolescents were more anxious and less alert during the active cannabis session (both pre- and post-drug administration). Following cannabis, cognitive impairment (reaction time on spatial working memory and prose recall following a delay) was greater in adults than adolescents. By contrast, cannabis impaired response inhibition accuracy in adolescents but not in adults.

Moreover, following drug administration, the adolescents did not show satiety; instead they wanted more cannabis regardless of whether they had taken active or placebo cannabis, while the opposite was seen for adults. These contrasting profiles of adolescent resilience (blunted subjective, memory, physiological and psychotomimetic effects) and vulnerability (lack of satiety, impaired inhibitory processes) show some degree of translation from preclinical findings, and may contribute to escalated cannabis use by human adolescents.” https://www.ncbi.nlm.nih.gov/pubmed/27898071

“Developmental observations suggest further that CB1 receptors develop only gradually during the postnatal period, which correlates with an insensitivity to the psychoactive effects of cannabinoid treatment in the young organism. Therefore, it is suggested that children may respond positively to medicinal applications of cannabinoids without undesirable central effects.” https://www.ncbi.nlm.nih.gov/pubmed/15159678

Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation?

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“The endocannabinoid system (ECS) is a major lipid signaling network that plays important pro-homeostatic (allostatic) roles not only in the nervous system but in peripheral organs.

Increasing evidence points towards a dietary component in the modulation of the ECS.

Cannabinoid receptors in hominids co-evolved with diet and the ECS constitutes a feedback loop for food selection and energy metabolism.

Here it is postulated that the mismatch of ancient lipid genes of hunter-gatheres and pastoralists with the high carbohydrate diet introduced by agriculture could be compensated via dietary modulation of the ECS.

In addition to the fatty acid precursors of endocannabinoids the potential role of dietary cannabimimetic phytochemicals in agriculturist nutrition is discussed.

Dietary secondary metabolites from vegetables and spices able to enhance the activity of cannabinoid-type 2 (CB2) receptors may provide adaptive metabolic advantages and counteract inflammation.

Food able to modulate the CB1/CB2 receptor activation ratio may thus play a role in the nutrition transition of Western high calorie diets. In this review the interplay between diet and the ECS is highlighted from an evolutionary perspective.

The emerging potential of cannabimimetic food as nutraceutical strategy is critically discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/27891602

Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia.

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“This study investigated the effects of cannabidiol (CBD), a non-psychotomimetic phytochemical present in Cannabis sativa, on the cognitive and emotional impairments induced by bilateral common carotid artery occlusion (BCCAO) in mice.

Using a multi-tiered behavioral testing battery during 21days, we found that BCCAO mice exhibited long-lasting functional deficits reflected by increase in anxiety-like behavior (day 9), memory impairments (days 12-18) and despair-like behavior (day 21).

Short-term CBD 10mg/kg treatment prevented the cognitive and emotional impairments, attenuated hippocampal neurodegeneration and white matter (WM) injury, and reduced glial response that were induced by BCCAO.

In addition, ischemic mice treated with CBD exhibited an increase in the hippocampal brain derived neurotrophic factor (BDNF) protein levels.

CBD also stimulated neurogenesis and promoted dendritic restructuring in the hippocampus of BCCAO animals.

Collectively, the present results demonstrate that short-term CBD treatment results in global functional recovery in ischemic mice and impacts multiple and distinct targets involved in the pathophysiology of brain ischemic injury.”

https://www.ncbi.nlm.nih.gov/pubmed/27889412

Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex

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“Cannabinoid receptors are able to couple to different families of G proteins when activated by an agonist drug. It has been suggested that different intracellular responses may be activated depending on the ligand.

The goal of the present study was to characterize the pattern of G protein subunit stimulation triggered by three different cannabinoid ligands, Δ9-THC, WIN55212-2, and ACEA in mouse brain cortex.

Results show that, in mouse brain cortex, cannabinoid agonists are able to significantly stimulate not only the classical inhibitory Gαi/osubunits but also other G subunits like Gαz, Gαq/11, and Gα12/13. Moreover, the specific pattern of G protein subunit activation is different depending on the ligand.

In conclusion, our results demonstrate that, in mice brain native tissue, different exogenous cannabinoid ligands are able to selectively activate different inhibitory and non-inhibitory Gα protein subtypes, through the activation of CB1 and/or CB2 receptors.

Results of the present study may help to understand the specific molecular pathways involved in the pharmacological effects of cannabinoid-derived drugs.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095132/

The cannabinoid beta-caryophyllene (BCP) induces neuritogenesis in PC12 cells by a cannabinoid-receptor-independent mechanism.

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“Beta-caryophyllene (BCP) is a phytocannabinoid whose neuroprotective activity has been mainly associated with selective activation of cannabinoid-type-2 (CB2) receptors, inhibition of microglial activation and decrease of inflammation.

Here, we addressed the potential of BCP to induce neuritogenesis in PC12 cells, a model system for primary neuronal cells that express trkA receptors, respond to NGF and do not express CB2 receptors.

We demonstrated that BCP increases the survival and activates the NGF-specific receptor trkA in NGF-deprived PC12 cells, without increasing the expression of NGF itself. The neuritogenic effect of BCP in PC12 cells was abolished by k252a, an inhibitor of the NGF-specific receptor trkA. Accordingly, BCP did not induce neuritogenesis in SH-SY5Y neuroblastoma cells, a neuronal model that does not express trkA receptors and do not respond to NGF.

Additionally, we demonstrated that BCP increases the expression of axonal-plasticity-associated proteins (GAP-43, synapsin and synaptophysin) in PC12 cells. It is known that these proteins are up-regulated by NGF in neurons and neuron-like cells, such as PC12 cells.

Altogether, these findings suggest that BCP activates trka receptors and induces neuritogenesis by a mechanism independent of NGF or cannabinoid receptors. This is the first study to show such effects of BCP and their beneficial role in neurodegenerative processes should be further investigated.”

https://www.ncbi.nlm.nih.gov/pubmed/27871898

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

“The oral intake of this dietary cannabinoid with vegetable food could be advantageous in the daily routine clinical practice over synthetic cannabinoid agonists.” http://www.europeanneuropsychopharmacology.com/article/S0924-977X(13)00302-7/fulltext

Endocannabinoid system in sexual motivational processes: is it a novel therapeutic horizon?

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“The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana’s psychoactive ingredient Δ9-tetrahydrocannabinol (Δ9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors.

For centuries, in addition to its recreational actions, several contradictory claims regarding the effects of Cannabis use in sexual functioning and behavior (e.g. aphrodisiac vs anti-aphrodisiac) of both sexes have been accumulated. The identification of Δ9-THC and later on, the discovery of the ECS have opened a potential therapeutic target for sexual dysfunctions, given the partial efficacy of current pharmacological treatment.

In agreement with the bidirectional modulation induced by cannabinoids on several behavioral responses, the endogenous cannabinoid AEA elicited biphasic effects on sexual behavior as well. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of several aspects of sexuality in preclinical and human studies, highlighting their therapeutic potential.”

https://www.ncbi.nlm.nih.gov/pubmed/27884725

“Cannabis As An Aphrodisiac? The Evidence Is Mounting”  https://www.civilized.life/articles/aphrodisiac-evidence-is-mounting/