Tag Archives: CBD

Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain.

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Abstract

“Sativex is one of the first cannabis-based medicines to undergo conventional clinical development and to be approved as a prescription medicine. It is an oromucosal spray that allows flexible, individualised dosing. Patients self titrate their overall dose and pattern of dosing according to their response to and tolerance of the medicine. This usually results in the administration of approximately 8-12 sprays/day. Each spray delivers tetrahydrocannabinol 2.7 mg and cannabidiol 2.5 mg, giving an approximate average dose of tetrahydrocannabinol 22-32 mg/day and cannabidiol 20-30 mg/day. Development has concentrated on the treatment of symptoms of multiple sclerosis, notably spasticity and neuropathic pain, as well as the treatment of neuropathic pain of other aetiologies. Positive results in placebo-controlled trials of the use of Sativex as an add-on therapy in these indications demonstrate that Sativex is efficacious and well tolerated in the treatment of these symptoms. Sativex has been approved for use in neuropathic pain due to multiple sclerosis in Canada. If ongoing studies replicate the results already observed, further approvals for the treatment of spasticity in multiple sclerosis and for neuropathic pain are likely.”

http://www.ncbi.nlm.nih.gov/pubmed/16553576

THC and CBD oromucosal spray (Sativex®) in the management of spasticity associated with multiple sclerosis.

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“People with multiple sclerosis may present with a wide range of disease symptoms during the evolution of the disease; among these, spasticity can have a marked impact on their well-being and quality of life. Symptom control, including spasticity, remains a key management strategy to improve the patient’s well-being and functional status. However, available drug therapies for spasticity sometimes have limited benefit and they are often associated with poor tolerability.

 Sativex is a 1:1 mix of 9-delta-tetrahydrocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, which is available as an oromucosal spray. Clinical experience with Sativex in patients with multiple sclerosis is accumulating steadily. Results from randomized, controlled trials have reported a reduction in the severity of symptoms associated with spasticity, leading to a better ability to perform daily activities and an improved perception of patients and their carers regarding functional status when Sativex was added to the current treatment regimen. Adverse events such as dizziness, diarrhea, fatigue, nausea, headache and somnolence occur quite frequently with Sativex, but they are generally of mild-to-moderate intensity and their incidence can be markedly reduced by gradual ‘uptitration’.

 In summary, initial well-controlled studies with Sativex oromucosal spray administered as an add-on to usual therapy have produced promising results and highlight encouraging avenues for future research.”

http://www.ncbi.nlm.nih.gov/pubmed/21456949

Clinical efficacy and effectiveness of Sativex, a combined cannabinoid medicine, in multiple sclerosis-related spasticity.

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Abstract

“Multiple sclerosis (MS) is associated with a wide range of disease symptoms and amongst these, spasticity is one of the most disabling and has the greatest impact on patient well-being and quality of life. Until now, available drug therapies for spasticity appear to have limited benefit and are often associated with poor tolerability. In a recent Spanish survey it was noted that multidrug therapy and a low control rate were common features for a large proportion of patients with MS-related spasticity, suggesting that currently available monotherapies lack significant activity. Sativex is a 1:1 mixture of δ-9-tetrahydrocannabinol and cannabidiol derived from Cannabis sativa chemovars, which is available as an oromucosal spray. Clinical experience with Sativex in patients with MS-related spasticity is steadily accumulating. Results from randomized, controlled trials have reported a reduction in the severity of symptoms associated with spasticity, leading to a better ability to perform daily activities and an improved perception of patients and their carers regarding functional status. These are highly encouraging findings that provide some much needed optimism for the treatment of this disabling and often painful symptom of MS.”

http://www.ncbi.nlm.nih.gov/pubmed/22509985

The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications.

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“Prostate cancer is a global public health problem, and it is the most common cancer in American men and the second cause for cancer-related death. Experimental evidence shows that prostate tissue possesses cannabinoid receptors and their stimulation results in anti-androgenic effects.”

“Cannabis is a bushy plant with palmate leaves and clusters of small green flowers, and it grows wild in regions of tropical weather and can attain up to 3 m height. The genus Cannabis is complemented by sativa which translates to useful. Cannabis has indeed been used throughout history for a variety of purposes, including the production of fiber for paper and textile manufacture. However, its current popularity lies in its use as a recreational drug with psychoactive properties. The plant contains many chemical compounds that have different pharmacological properties, varying in quantity and quality depending on the strain, culture, and storage conditions.”

“The frequently held view of cannabis and its related products as drugs of abuse have slowed progress in the development of studies designed to take advantage of the properties of cannabinoid derivatives for therapeutic purposes…”

“Delta-9-THC is the substance with the greatest psychoactive potency of the natural cannabinoids and exhibits the greatest analgesic activity. Cannabidiol (CBD), another major constituent of the Cannabis sativa plant, has the same therapeutic effects of THC (analgesic, anti-inflammatory, and others), but with a different pharmacologic profile…”

“It is our conclusion that it would be of interest to conduct clinical trials involving medicinal cannabis or other cannabinoid agonists, comparing clinical markers such as PSA with controls, especially in men with bone metastatic prostate cancer, whom would not only benefit from the possible anti-androgenic effects of cannabinoids but also from analgesia of bone pain, improving quality of life, while reducing narcotic consumption and preventing opioid dependence.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339795/

CYCLOOXYGENASE-2 AND PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR γ CONFER CANNABIDIOL-INDUCED APOPTOSIS OF HUMAN LUNG CANCER CELLS.

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Abstract

“The antitumorigenic mechanism of cannabidiol (CBD) is still controversial. This study investigates the role of cyclooxygenase-2 (COX-2) and peroxisome proliferator activated receptor γ (PPARγ) in CBDs proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a lung cancer patient CBD elicited decreased viability associated with apoptosis. Apoptotic cell death by CBD was suppressed by NS-398 (COX-2 inhibitor), GW-9662 (PPARγ antagonist) and siRNA targeting COX-2 and PPARγ. CBD-induced apoptosis was paralleled by upregulation of COX-2 and PPARγ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 h and continuous increases of PPARγ mRNA when compared to vehicle. In response to CBD tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PGs) among which PGD2 and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) caused a translocation of PPARγ to the nucleus and induced a PPARγ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice CBD caused upregulation of COX-2 and PPARγ in tumor tissue, and tumor regression that was fully reversible by GW-9662. Together, our data demonstrate a novel proapoptotic mechanism of CBD involving initial upregulation of COX-2 and PPARγ and a subsequent nuclear translocation of PPARγ by COX-2-dependent PGs.”

http://www.ncbi.nlm.nih.gov/pubmed/23220503

The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors.

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Abstract

“To investigate the mechanisms involved in cannabidiol (CBD)-induced neuroprotection in hypoxic-ischemic (HI) immature brain, forebrain slices from newborn mice underwent oxygen and glucose deprivation in the presence of vehicle, or CBD alone or with selective antagonists of cannabinoid CB(1) and CB(2), and adenosine A(1) and A(2) receptors. CBD reduced acute (LDH efflux to the incubation medium) and apoptotic (caspase-9 concentration in tissue) HI brain damage by reducing glutamate and IL-6 concentration, and TNFalpha, COX-2, and iNOS expression. CBD effects were reversed by the CB(2) antagonist AM630 and by the A(2A) antagonist SCH58261. The A(1A) antagonist DPCPX only counteracted the CBD reduction of glutamate release, while the CB(1) antagonist SR141716 did not modify any effect of CBD. In conclusion, CBD induces robust neuroprotection in immature brain, by acting on some of the major mechanisms underlying HI cell death; these effects are mediated by CB(2) and adenosine, mainly A(2A), receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/19900555

Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease.

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Abstract

“Cannabinoids have been reported to provide neuroprotection in acute and chronic neurodegeneration. In this study, we examined whether they are also effective against the toxicity caused by 6-hydroxydopamine, both in vivo and in vitro, which may be relevant to Parkinson’s disease (PD). First, we evaluated whether the administration of cannabinoids in vivo reduces the neurodegeneration produced by a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. As expected, 2 weeks after the application of this toxin, a significant depletion of dopamine contents and a reduction of tyrosine hydroxylase activity in the lesioned striatum were noted, and were accompanied by a reduction in tyrosine hydroxylase-mRNA levels in the substantia nigra. None of these events occurred in the contralateral structures. Daily administration of delta9-tetrahydrocannabinol (delta9-THC) during these 2 weeks produced a significant waning in the magnitude of these reductions, whereas it failed to affect dopaminergic parameters in the contralateral structures. This effect of delta9-THC appeared to be irreversible since interruption of the daily administration of this cannabinoid after the 2-week period did not lead to the re-initiation of the 6-hydroxydopamine-induced neurodegeneration. In addition, the fact that the same neuroprotective effect was also produced by cannabidiol (CBD), another plant-derived cannabinoid with negligible affinity for cannabinoid CB1 receptors, suggests that the antioxidant properties of both compounds, which are cannabinoid receptor-independent, might be involved in these in vivo effects, although an alternative might be that the neuroprotection exerted by both compounds might be due to their anti-inflammatory potential. As a second objective, we examined whether cannabinoids also provide neuroprotection against the in vitro toxicity of 6-hydroxydopamine. We found that the non-selective cannabinoid agonist HU-210 increased cell survival in cultures of mouse cerebellar granule cells exposed to this toxin. However, this effect was significantly lesser when the cannabinoid was directly added to neuronal cultures than when these cultures were exposed to conditioned medium obtained from mixed glial cell cultures treated with HU-210, suggesting that the cannabinoid exerted its major protective effect by regulating glial influence to neurons. In summary, our results support the view of a potential neuroprotective action of cannabinoids against the in vivo and in vitro toxicity of 6-hydroxydopamine, which might be relevant for PD. Our data indicated that these neuroprotective effects might be due, among others, to the antioxidant properties of certain plant-derived cannabinoids, or exerted through the capability of cannabinoid agonists to modulate glial function, or produced by a combination of both mechanisms.”

http://www.ncbi.nlm.nih.gov/pubmed/15837565

Sativex-like Combination of Phytocannabinoids is Neuroprotective in Malonate-Lesioned Rats, an Inflammatory Model of Huntington’s Disease: Role of CB(1) and CB(2) Receptors.

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Abstract

“We have investigated whether a 1:1 combination of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, is neuroprotective in Huntington’s disease (HD), using an experimental model of this disease generated by unilateral lesions of the striatum with the mitochondrial complex II inhibitor malonate. This toxin damages striatal neurons by mechanisms that primarily involve apoptosis and microglial activation. We monitored the extent of this damage and the possible preservation of the striatal parenchyma by treatment with a Sativex-like combination of phytocannabinoids using different histological and biochemical markers. Results were as follows: (i) malonate increased the volume of edema measured by in vivo NMR imaging and the Sativex-like combination of phytocannabinoids partially reduced this increase; (ii) malonate reduced the number of Nissl-stained cells, while enhancing the number of degenerating cells stained with FluoroJade-B, and the Sativex-like combination of phytocannabinoids reversed both effects; (iii) malonate caused a strong glial activation (i.e., reactive microglia labeled with Iba-1, and astrogliosis labeled with GFAP) and the Sativex-like combination of phytocannabinoids attenuated both responses; and (iv) malonate increased the expression of inducible nitric oxide synthase and the neurotrophin IGF-1, and both responses were attenuated after the treatment with the Sativex-like combination of phytocannabinoids. We also wanted to establish whether targets within the endocannabinoid system (i.e., CB(1) and CB(2) receptors) are involved in the beneficial effects induced in this model by the Sativex-like combination of phytocannabinoids. This we did using selective antagonists for both receptor types (i.e., SR141716 and AM630) combined with the Sativex-like phytocannabinoid combination. Our results indicated that the effects of this combination are blocked by these antagonists and hence that they do result from an activation of both CB(1) and CB(2) receptors. In summary, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying signs of disease progression in a proinflammatory model of HD, which adds to previous data obtained in models priming oxidative mechanisms of striatal injury. However, the interest here is that, in contrast with these previous data, we have now obtained evidence that both CB(1) and CB(2) receptors appear to be involved in the effects produced by a Sativex-like phytocannabinoid combination, thus stressing the broad-spectrum properties of Sativex that may combine activity at the CB(1) and/or CB(2) receptors with cannabinoid receptor-independent actions.”

http://www.ncbi.nlm.nih.gov/pubmed/22860209

Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease.

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Abstract

“We studied whether combinations of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington’s disease (HD). We used rats intoxicated with 3-nitropropionate (3NP) that were given combinations of Δ(9)-THC- and CBD-enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Δ(9)-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB(1) receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Δ(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB(1) and CB(2) receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Δ(9)-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies.”

http://www.ncbi.nlm.nih.gov/pubmed/21674569

Neuroprotective antioxidants from marijuana.

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“Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate.

The psychotropic cannabinoid receptor agonist delta 9-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities.

Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system,

it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants in neuronal cultures,

 cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons.

In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both alpha-tocopherol and ascorbate in protective capacity.

Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies.”

http://www.ncbi.nlm.nih.gov/pubmed/10863546