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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Neural Effects of Cannabinoid CB1 Neutral Antagonist Tetrahydrocannabivarin (THCv) on Food Reward and Aversion in Healthy Volunteers.

“Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as obesity and eating disorders.

We previously showed that the cannabis receptor (CB1) inverse agonist rimonabant, an anti-obesity drug withdrawn due to depressogenic side effects, diminished neural reward responses yet increased aversive responses. Unlike rimonabant, tetrahydrocannabivarin (THCv) is a neutral CB1 receptor antagonist and may therefore produce different modulations of the neural reward system…

Conclusions: Our findings are the first to show that treatment with the CB1 neutral antagonist THCv increases neural responding to rewarding and aversive stimuli.

This effect profile suggests therapeutic activity in obesity, perhaps with a lowered risk of depressive side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/25542687

http://www.thctotalhealthcare.com/category/obesity-2/

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Evaluation of the potential of the phytocannabinoids, cannabidivarin (CBDV) and Δ9 -tetrahydrocannabivarin (THCV), to produce CB1 receptor inverse agonism symptoms of nausea in rats.

“The cannabinoid 1(CB1 ) receptor inverse agonists/antagonists, rimonabant (SR141716, SR) and AM251, produce nausea and potentiate toxin-induced nausea by inverse agonism (rather than antagonism) of the CB1 receptor. Here, we evaluated two phytocannabinoids, cannabidivarin (CBDV) and Δ9 -tetrahydrocannabivarin (THCV) for their ability to produce these behavioural effects characteristic of CB1 receptor inverse agonism in rats.

…we investigated the potential of THCV and CBDV to produce conditioned gaping (measure of nausea-induced behaviour),..

THC, THCV  and CBDV suppressed LiCl-induced conditioned gaping, suggesting anti-nausea potential…

The pattern of findings indicates that neither THCV nor CBDV produced a behavioural profile characteristic of CB1 receptor inverse agonists.

As well, these compounds may have therapeutic potential in reducing nausea.”

http://www.ncbi.nlm.nih.gov/pubmed/23902479

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Even More Science Suggesting That Cannabinoids May Halt Diabetes

“Preclinical study data published online in the scientific journal Nutrition & Diabetes reports that tetrahydrocannabivarin (THCV) — a naturally occurring analogue of THC — possesses positive metabolic effects in animal models of obesity.

British researchers assessed the effects of THCV administration on dietary-induced and genetically modified obese mice. Authors reported that although THCV administration did not significantly affect food intake or body weight gain in any of the models, it did produce several metabolically beneficial effects, including reduced glucose intolerance, improved glucose tolerance, improved liver triglyceride levels, and increased insulin sensitivity.

Researchers concluded: “Based on these data, it can be suggested that THCV may be useful for the treatment of the metabolic syndrome and/or type 2 diabetes (adult onset diabetes), either alone or in combination with existing treatments. Given the reported benefits of another non-THC cannabinoid, CBD in type 1 diabetes, a CBD/THCV combination may be beneficial for different types of diabetes mellitus.””

More: http://beforeitsnews.com/marijuana-debate/2013/06/even-more-science-suggesting-that-cannabinoids-may-halt-diabetes-2444932.html

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Looking at Cannabis Based Type 2 Treatment

“One of the classic effects of cannabis on people is raging hunger-the “marijuana munchies.” The drug has been used to good effect on people with diseases that diminish appetite, helping them to regain a healthy interest in food. So it is a bit ironic that British drug maker GW Pharmaceuticals has created a cross-bred cannabis plant whose appetite-suppressing qualities could be used to treat type 2 diabetes.”

 
“The new strain contains an appetite-suppressing compound called THCV (tetrahydrocannabivarin), a cannabinoid* found in cannabis sativa-marijuana. The company sees a drug that uses THCV as potentially useful in helping type 2s and obese people control their appetites-a key to good blood sugar control.

In 2010, GW introduced a cannabis-based drug to treat the symptoms of multiple sclerosis. Already, the company has found 60 cannabinoids in the cannabis sativa plant. A company spokesman says that only 12 to 15 of them have been explored in any depth.

*Cannabinoids are the active ingredients in cannabis sativa that create the plant’s physical and mental effects when it is ingested or smoked.”

http://diabeteshealth.com/read/2011/06/30/7200/looking-at-cannabis-based-type-2-treatment/

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The cannabinoid Δ9-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity

“Δ9-Tetra-hydrocannabivarin (THCV) is a naturally occurring analogue of the psychoactive principle of cannabis, Δ9-tetra-hydrocannabinol (THC).

THCV is a new potential treatment against obesity-associated glucose intolerance with pharmacology different from that of CB1 inverse agonists/antagonists.

In conclusion, THCV produces therapeutic metabolic effects in two different mouse models of obesity. In particular, its strongest effects are exerted on plasma glucose and insulin levels, especially following an OGTT in DIO mice and on liver triglycerides in ob/obmice.

Based on these data, it can be suggested that THCV may be useful for the treatment of the metabolic syndrome and/or type 2 diabetes, either alone or in combination with existing treatments. Given the reported benefits of another non-THC cannabinoid, CBD in type 1 diabetes, a CBD/THCV combination may be beneficial for different types of diabetes mellitus.”

Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671751/

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Phytocannabinoids

“Phytocannabinoids, also called ”natural cannabinoids”, ”herbal cannabinoids”, and ”classical cannabinoids”, are only known to occur naturally in significant quantity in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes.

In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odour of the cannabis plant.

Phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar organic solvents. However, as phenols, they form more water-soluble phenolate salts under strongly alkaline conditions.

All-natural cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).

Types

At least 66 cannabinoids have been isolated from the cannabis plant. To the right the main classes of natural cannabinoids are shown. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.

Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common cannabinoids are listed below:

  • CBG Cannabigerol
  • CBC Cannabichromene
  • CBL Cannabicyclol
  • CBV Cannabivarin
  • THCV Tetrahydrocannabivarin
  • CBDV Cannabidivarin
  • CBCV Cannabichromevarin
  • CBGV Cannabigerovarin
  • CBGM Cannabigerol Monoethyl Ether

Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is the primary psychoactive component of the plant. It appears to ease moderate pain (analgetic) and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors. Its effects are perceived to be more cerebral.

”Delta”-9-Tetrahydrocannabinol (Δ9-THC, THC) and ”delta”-8-tetrahydrocannabinol (Δ8-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. The THCs produce the ”high” associated with cannabis by binding to the CB1 cannabinoid receptors in the brain.

Cannabidiol

Cannabidiol (CBD) is not psychoactive, and was thought not to affect the psychoactivity of THC. However, recent evidence shows that smokers of cannabis with a higher CBD/THC ratio were less likely to experience schizophrenia-like symptoms.

This is supported by psychological tests, in which participants experience less intense psychotic effects when intravenous THC was co-administered with CBD (as measured with a PANSS test).

It has been hypothesized that CBD acts as an allosteric antagonist at the CB1 receptor and thus alters the psychoactive effects of THC.

It appears to relieve convulsion, inflammation, anxiety, and nausea. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor.

Cannabigerol

Cannabigerol (CBG) is non-psychotomimetic but still affects the overall effects of Cannabis. It acts as an α2-adrenergic receptor agonist, 5-HT1A receptor antagonist, and CB1 receptor antagonist. It also binds to the CB2 receptor.

Tetrahydrocannabivarin

Tetrahydrocannabivarin (THCV) is prevalent in certain South African and Southeast Asian strains of Cannabis. It is an antagonist of THC at CB1 receptors and attenuates the psychoactive effects of THC.

Cannabichromene

Cannabichromene (CBC) is non-psychoactive and does not affect the psychoactivity of THC It is found in nearly all tissues in a wide range of animals.

Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and ”homo”-γ-linolenoylethanolamine, have similar pharmacology.

All of these are members of a family of signalling lipids called ”N”-acylethanolamides, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamine, which possess anti-inflammatory and orexigenic effects, respectively. Many ”N”-acylethanolamines have also been identified in plant seeds and in molluscs.

  • 2-arachidonoyl glycerol (2-AG)

Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1 and CB2 receptors with similar affinity, acting as a full agonist at both, and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling ”in vivo”.

In particular, one ”in vitro” study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this finding are not yet known.

  • 2-arachidonyl glyceryl ether (noladin ether)

In 2001, a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain.

Prior to this discovery, it had been synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at “any appreciable amount” in the brains of several different mammalian species.

It binds to the CB1 cannabinoid receptor (”K”i = 21.2 nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB1 receptor, and only weakly to the CB2 receptor.

Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.

  • Virodhamine (OAE)

A fifth endocannabinoid, virodhamine, or ”O”-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB2 and a partial agonist at CB1, it behaves as a CB1 antagonist ”in vivo”.

In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.

Function

Endocannabinoids serve as intercellular ‘lipid messengers’, signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells.

Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine and dopamine, endocannabinoids differ in numerous ways from them. For instance, they use retrograde signaling.

Furthermore, endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized ‘on-demand’ rather than made and stored for later use.

The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.

The endocannabinoid 2-AG has been found in bovine and human maternal milk.

Retrograde signal

Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively.

Endocannabinoids, on the other hand, are described as retrograde transmitters because they most commonly travel ‘backwards’ against the usual synaptic transmitter flow.

They are, in effect, released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released.

Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released.

This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic.

The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled.

For instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell.

On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.

Range

Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.

Other thoughts

Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.

”Scientific American” published an article in December 2004, entitled “The Brain’s Own Marijuana” discussing the endogenous cannabinoid system.

The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body.

U.S. Patent # 6630507

In 2003 The U.S.A.’s Government as represented by the Department of Health and Human Services was awarded a patent on cannabinoids as antioxidants and neuroprotectants. U.S. Patent 6630507.”

http://www.news-medical.net/health/Phytocannabinoids.aspx

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Cannabis – the new weight loss secret?

“Now we might know why dopers look so thin and gaunt. Cannabis facilitates weight loss!”

Cannabis

“Two cannabis compounds can raise the quantum of energy the body burns and keep obesity at bay. Called THCV and cannabidiol, they were found to have an appetite suppressing effect too for a short while. Animal tests have shown these compounds can help treat type two diabetes while also lowering levels of cholesterol in the blood stream and fat in key organs like the liver.

Scientists also found the compounds also had an impact on the level of fat and its response to insulin, a hormone that controls blood sugar levels, the Telegraph reports. THCV was also found to increase the animals’ sensitivity to insulin while also protecting the cells that produce insulin, allowing them to work better and for longer.

Steph Wright, director of research and development at GW Pharmaceuticals developing the drugs, said: “The results in animal models have been very encouraging. We are interested in how these drugs effect the fat distribution and utilisation in the body as a treatment for metabolic diseases”. We are conducting four Phase 2 clinical trials and we expect some results later this year,” Wright said. 

Tests in mice showed the compounds boosted their metabolism, leading to lower levels of fat in their livers and reduced cholesterol in their blood stream. They are now conducting clinical trials in 200 patients in the hope of producing a drug that can be used to treat patients suffering from “metabolic syndrome”, where diabetes, high blood pressure and obesity combine to increase the risk of heart disease and stroke.

Mike Cawthorne, director of metabolic research at the University of Buckingham who has been conducting the animal studies, said: “Over all, it seems these molecules increase energy expenditure in the cells of the body by increasing the metabolism”.”

http://health.india.com/news/cannabis-the-new-weight-loss-secret/

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Cannabis Compounds can Help Treat Obesity

“Two cannabis compounds could be a new weapon in the fight against obesity, say researchers. Animal tests have shown these compounds can help treat type two diabetes while also lowering levels of cholesterol in the blood stream and fat in key organs like the liver.”

 Cannabis Compounds can Help Treat Obesity

“Scientists also found the compounds also had an impact on the level of fat and its response to insulin, a hormone that controls blood sugar levels, the Telegraph reports.

THCV was also found to increase the animals’ sensitivity to insulin while also protecting the cells that produce insulin, allowing them to work better and for longer.

Steph Wright, director of research and development at GW Pharmaceuticals developing the drugs, said: “The results in animal models have been very encouraging. We are interested in how these drugs effect the fat distribution and utilisation in the body as a treatment for metabolic diseases…”

Mike Cawthorne, director of metabolic research at the University of Buckingham who has been conducting the animal studies, said: “Over all, it seems these molecules increase energy expenditure in the cells of the body by increasing the metabolism”.”
 
 
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Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ9-THCV in animal models of Parkinson’s disease

“Previous findings have indicated that a cannabinoid, such as Δ(9)-THCV, which has antioxidant properties and the ability to activate CB(2) receptors but to block CB(1) , might be a promising therapy for alleviating symptoms and delaying neurodegeneration in Parkinson’s disease (PD).

…Given its antioxidant properties and its ability to activate CB(2) but to block CB(1) receptors, Δ(9)-THCV has a promising pharmacological profile for delaying disease progression in PD and also for ameliorating parkinsonian symptoms…

Conclusion

In summary, given its antioxidant properties and its ability to activate CB2 but block CB1 receptors at a dose of 2 mg·kg−1, Δ9-THCV seems to have an interesting and therapeutically promising pharmacological profile. Thus, in contrast to other phytocannabinoids that have been investigated to date, it shows promise both for the treatment of disease progression in PD and for the relief of PD symptoms. This represents an important advance in the search for potential novel anti-parkinsonian agents, since Δ9-THCV administered alone or in combination with CBD may provide a much needed improved treatment for PD.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165958/

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