Monthly Archives: May 2018

Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.

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“Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy.

We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.

Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo.”

https://www.ncbi.nlm.nih.gov/pubmed/29768152

https://www.nejm.org/doi/10.1056/NEJMoa1714631

Medication overuse headache following repeated morphine, but not [INCREMENT]9-tetrahydrocannabinol administration in the female rat.

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“The potential of [INCREMENT]-tetrahydrocannabinol (THC) as a treatment for migraine depends on antinociceptive efficacy with repeated administration.

Although morphine has good antinociceptive efficacy, repeated administration causes medication overuse headache (MOH) – a condition in which the intensity/frequency of migraine increases.

The present study compared the effect of repeated morphine or THC administration on the magnitude and duration of migraine-like pain induced by a microinjection of allyl isothiocyanate (AITC) onto the dura mater of female rats.

Acute administration of THC or morphine prevented AITC-induced depression of wheel running. This antinociception was maintained in rats treated repeatedly with THC, but not following repeated administration of morphine. Moreover, repeated morphine, but not THC administration, extended the duration of AITC-induced depression of wheel running.

These data indicate that tolerance and MOH develop rapidly to morphine administration. The lack of tolerance and MOH to THC indicates that THC may be an especially effective long-term treatment against migraine.”

 https://www.ncbi.nlm.nih.gov/pubmed/29462111
https://insights.ovid.com/crossref?an=00008877-900000000-99334

Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol

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“Cannabidiol (CBD), a major constituent of Cannabis, has been shown to be a powerful anti-inflammatory and anti-anxiety drug, without exerting a psychotropic effect. However, when given either intraperitoneally or orally as a purified product, a bell-shaped dose-response was observed, which limits its clinical use.
In the present study, we have studied in mice the anti-inflammatory and anti-nociceptive activities of standardized plant extracts derived from the Cannabis sativa L., clone 202, which is highly enriched in CBD and hardly contains any psychoactive ingredients.
In stark contrast to purified CBD, the clone 202 extract, when given either intraperitoneally or orally, provided a clear correlation between the anti-inflammatory and anti-nociceptive responses and the dose, with increasing responses upon increasing doses, which makes this plant medicine ideal for clinical uses.
The clone 202 extract reduced zymosan-induced paw swelling and pain in mice, and prevented TNFα production in vivo. It is likely that other components in the extract synergize with CBD to achieve the desired anti-inflammatory action that may contribute to overcoming the bell-shaped dose-response of purified CBD.
We therefore propose that Cannabis clone 202 (Avidekel) extract is superior over CBD for the treatment of inflammatory conditions.”  https://www.scirp.org/journal/PaperInformation.aspx?paperID=53912
“In conclusion, we recommend standardized plant extract of the Cannabis clone 202 for treatment of various inflammatory conditions.” https://file.scirp.org/Html/5-2500582_53912.htm

A stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for ocular drug delivery

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Drug Delivery and Translational Research

“Most medications targeting optic neuropathies are administered as eye drops. However, their corneal penetration efficiencies are typically < 5%.

There is a clear, unmet need for novel transcorneal drug delivery vehicles. To this end, we have developed a stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for controlled release of poorly bioavailable drugs into the aqueous humor of the eye.

We subsequently tested the efficacy of our formulation in whole-eye experiments by loading the nanoparticles with cannabigerolic acid (CBGA). Our formulation exhibits over a 300% increase in transcorneal penetration over control formulations.

We have successfully developed a stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for controlled release of poorly bioavailable drugs such as cannabinoids into the aqueous humor of the eye.

Our therapeutic strategy leverages the proven potential of cannabinoids to confer neuroprotection to ganglion cells.

This work paves the way for the introduction of novel products targeting ocular diseases to the market.”

https://link.springer.com/article/10.1007/s13346-018-0504-x

The influence of THC:CBD oromucosal spray on driving ability in patients with multiple sclerosis-related spasticity.

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“Driving ability is a key function for the majority of patients with multiple sclerosis (MS) to help maintain daily interactions. Both physical and cognitive disability, as well as treatments, may affect the ability to drive. Spasticity is a common symptom associated with MS, and it may affect driving performance either directly or via the medications used to treat it.

In this article, we review the evidence relating the antispasticity medicine, Δ9-tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®), and its potential impact on driving performance.

The results from THC:CBD oromucosal spray driving studies and real-world registries did not show any evidence of an increase in motor vehicle accidents associated with THC:CBD oromucosal spray. The majority of patients reported an improvement in driving ability after starting THC:CBD oromucosal spray, and it was speculated that this may be related to reduced spasticity and/or better cognitive function.

THC:CBD oromucosal spray was shown not to impair driving performance.”

https://www.ncbi.nlm.nih.gov/pubmed/29761015

https://onlinelibrary.wiley.com/doi/abs/10.1002/brb3.962

Cannabinoid 1 receptors are expressed in nociceptive primary sensory neurons.

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 Neuroscience

“Expression of cannabinoid 1 (CB1) and vanilloid 1 (VR1) receptor proteins was studied in adult, cultured rat dorsal root ganglion neurons. Immunostaining of CB1 receptors alone produced labelling in 57+/-2% of the cultured dorsal root ganglion neurons (n=3 cultures). The area of the labelled cells was between 200 and 800 microm(2) with an average of 527+/-68 microm(2). VR1 immunolabelling revealed immunopositivity in 42+/-6% of the total population of dorsal root ganglion neurons. Cells showing VR1-like immunopositivity had an area between 200 and 600 microm(2). The mean area of the VR1-like immunopositive neurons was 376+/-61 microm(2). Double immunostaining with antisera raised against the CB1 and VR1 receptor proteins, showed a high degree of co-expression between CB1 and VR1 receptors. An average of 82+/-3% of the CB1-like immunopositive cells also showed VR1-like immunoreactivity (n=3 cultures) while 98+/-2% of the VR1-like immunolabelled neurons showed CB1 receptor-like immunostaining (n=3 cultures). Our data suggests that nociceptive primary sensory neurons co-express CB1 and VR1 receptors to a very high degree. We propose that this may provide an anatomical basis for a powerful combination of VR1 mediated excitation and CB1-mediated inhibition of nociceptive responses at central and peripheral terminals of nociceptive primary afferents.”

https://www.ncbi.nlm.nih.gov/pubmed/11036202

https://www.sciencedirect.com/science/article/abs/pii/S0306452200003894

Possible mechanisms of cannabinoid-induced antinociception in the spinal cord.

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European Journal of Pharmacology

“Anandamide is an endogenous ligand at both the inhibitory cannabinoid CB(1) receptor and the excitatory vanilloid receptor 1 (VR1). The CB(1) receptor and vanilloid VR1 receptor are expressed in about 50% and 40% of dorsal root ganglion neurons, respectively. While all vanilloid VR1 receptor-expressing cells belong to the calcitonin gene-related peptide-containing and isolectin B4-binding sub-populations of nociceptive primary sensory neurons, about 80% of the cannabinoid CB(1) receptor-expressing cells belong to those sub-populations. Furthermore, all vanilloid VR1 receptor-expressing cells co-express the cannabinoid CB(1) receptor.

In agreement with these findings, neonatal capsaicin treatment that induces degeneration of capsaicin-sensitive, vanilloid VR1 receptor-expressing, thin, unmyelinated, nociceptive primary afferent fibres significantly reduced the cannabinoid CB(1) receptor immunostaining in the superficial spinal dorsal horn.

Synthetic cannabinoid CB(1) receptor agonists, which do not have affinity at the vanilloid VR1 receptor, and low concentrations of anandamide both reduce the frequency of miniature excitatory postsynaptic currents and electrical stimulation-evoked or capsaicin-induced excitatory postsynaptic currents in substantia gelatinosa cells in the spinal cord without any effect on their amplitude. These effects are blocked by selective cannabinoid CB(1) receptor antagonists. Furthermore, the paired-pulse ratio is increased while the postsynaptic response of substantia gelatinosa neurons induced by alpha-amino-3-hydroxy-5-methylisoxasole-propionic acid (AMPA) in the presence of tetrodotoxin is unchanged following cannabinoid CB(1) receptor activation.

These results strongly suggest that the cannabinoid CB(1) receptor is expressed presynaptically and that the activation of these receptors by synthetic cannabinoid CB(1) receptor agonists or low concentration of anandamide results in inhibition of transmitter release from nociceptive primary sensory neurons. High concentrations of anandamide, on the other hand, increase the frequency of miniature excitatory postsynaptic currents recorded from substantia gelatinosa neurons. This increase is blocked by ruthenium red, suggesting that this effect is mediated through the vanilloid VR1 receptor.

Thus, anandamide at high concentrations can activate the VR1 and produce an opposite, excitatory effect to its inhibitory action produced at low concentrations through cannabinoid CB(1) receptor activation. This “dual”, concentration-dependent effect of anandamide could be an important presynaptic modulatory mechanism in the spinal nociceptive system.”

https://www.ncbi.nlm.nih.gov/pubmed/11698030

https://www.sciencedirect.com/science/article/pii/S0014299901013097?via%3Dihub

The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function.

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“Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine.

Cannabidiol is a nonpsychotropic plant constituent of Cannabis sativa.

As we hypothesized that non-CB receptor mechanisms of cannabidiol might contribute to its anti-inflammatory and neuroprotective effects, we investigated the interaction of cannabidiol with strychnine-sensitive alpha(1 )and alpha(1)beta glycine receptors by using the whole-cell patch clamp technique.

Cannabidiol showed a positive allosteric modulating effect in a low micromolar concentration range (EC(50) values: alpha(1) = 12.3 +/- 3.8 micromol/l and alpha(1)beta = 18.1 +/- 6.2 micromol/l). Direct activation of glycine receptors was observed at higher concentrations above 100 micromol/l (EC(50) values: alpha(1) = 132.4 +/- 12.3 micromol/l and alpha(1)beta = 144.3 +/- 22.7 micromol/l).

These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for cannabidiol mediating some of its anti-inflammatory and neuroprotective properties.”

https://www.ncbi.nlm.nih.gov/pubmed/19204413

https://www.karger.com/Article/Abstract/201556

Nutraceutical potential of hemp (Cannabis sativa L.) seeds and sprouts.

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 Food Chemistry

“In this study the antioxidant effect of Cannabis sativa L. seeds and sprouts (3 and 5 days of germination) was evaluated.

Total polyphenols, flavonoids and flavonols content, when expressed on dry weight basis, were highest in sprouts; ORAC and DPPH (in vitro assays), CAA-RBC (cellular antioxidant activity in red blood cells) and hemolysis test (ex vivo assays) evidenced a good antioxidant activity higher in sprouts than in seeds. Untargeted analysis by high resolution mass spectrometry in negative ion mode allowed the identification of main polyphenols (caffeoyltyramine, cannabisin A, B, C) in seeds and of ω-6 (linoleic acid) in sprouts. Antimutagenic effect of seeds and sprouts extracts evidenced a significant decrease of mutagenesis induced by hydrogen peroxide in Saccharomyces cerevisiae D7 strain.

In conclusion our results show that C. sativa seeds and sprouts exert beneficial effects on yeast and human cells and should be further investigated as a potential functional food.”

https://www.ncbi.nlm.nih.gov/pubmed/29751921

https://www.sciencedirect.com/science/article/pii/S0308814618307180?via%3Dihub

2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain.

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“2-Arachidonoylglycerol (2-AG) is a signaling lipid in the central nervous system that is a key regulator of neurotransmitter release. 2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor. It is involved in a wide array of (patho)physiological functions, such as emotion, cognition, energy balance, pain sensation and neuroinflammation. In this review, we describe the biosynthetic and metabolic pathways of 2-AG and how chemical and genetic perturbation of these pathways has led to insight in the biological role of this signaling lipid. Finally, we discuss the potential therapeutic benefits of modulating 2-AG levels in the brain.”

 https://www.ncbi.nlm.nih.gov/pubmed/29751000
https://www.sciencedirect.com/science/article/pii/S0163782717300619