Tag Archives: cannabidiol

Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties.

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Abstract

“We have recently demonstrated that two plant-derived cannabinoids, Delta9-tetrahydrocannabinol and cannabidiol (CBD), are neuroprotective in an animal model of Parkinson’s disease (PD), presumably because of their antioxidant properties. To further explore this issue, we examined the neuroprotective effects of a series of cannabinoid-based compounds, with more selectivity for different elements of the cannabinoid signalling system, in rats with unilateral lesions of nigrostriatal dopaminergic neurons caused by local application of 6-hydroxydopamine. We used the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA), the CB2 receptor agonist HU-308, the non-selective agonist WIN55,212-2, and the inhibitors of the endocannabinoid inactivation AM404 and UCM707, all of them administered i.p. Daily administration of ACEA or WIN55,212-2 did not reverse 6-hydroxydopamine-induced dopamine (DA) depletion in the lesioned side, whereas HU-308 produced a small recovery that supports a possible involvement of CB2 but not CB1 receptors. AM404 produced a marked recovery of 6-hydroxydopamine-induced DA depletion and tyrosine hydroxylase deficit in the lesioned side. Possibly, this is caused by the antioxidant properties of AM404, which are derived from the presence of a phenolic group in its structure, rather than by the capability of AM404 to block the endocannabinoid transporter, because UCM707, another transporter inhibitor devoid of antioxidant properties, did not produce the same effect. None of these effects were observed in non-lesioned contralateral structures. We also examined the timing for the effect of CBD to provide neuroprotection in this rat model of PD. We found that CBD, as expected, was able to recover 6-hydroxydopamine-induced DA depletion when it was administered immediately after the lesion, but it failed to do that when the treatment started 1 week later. In addition, the effect of CBD implied an upregulation of mRNA levels for Cu,Zn-superoxide dismutase, a key enzyme in endogenous defenses against oxidative stress. In summary, our results indicate that those cannabinoids having antioxidant cannabinoid receptor-independent properties provide neuroprotection against the progressive degeneration of nigrostriatal dopaminergic neurons occurring in PD. In addition, the activation of CB2 (but not CB1) receptors, or other additional mechanisms, might also contribute to some extent to the potential of cannabinoids in this disease.”

http://www.ncbi.nlm.nih.gov/pubmed/17196181

Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures.

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Abstract

“Cannabinoids derived from Cannabis sativa demonstrate neuroprotective properties in various cellular and animal models. Mitochondrial impairment and consecutive oxidative stress appear to be major molecular mechanisms of neurodegeneration. Therefore we studied some major cannabinoids, i.e. delta-9-tetrahydrocannabinolic acid (THCA), delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in mice mesencephalic cultures for their protective capacities against 1-methyl-4-phenyl pyridinium (MPP(+)) toxicity. MPP(+) is an established model compound in the research of parkinsonism that acts as a complex I inhibitor of the mitochondrial respiratory chain, resulting in excessive radical formation and cell degeneration. MPP(+) (10 μM) was administered for 48 h at the 9th DIV with or without concomitant cannabinoid treatment at concentrations ranging from 0.01 to 10 μM. All cannabinoids exhibited in vitro antioxidative action ranging from 669 ± 11.1 (THC), 16 ± 3.2 (THCA) to 356 ± 29.5 (CBD) μg Trolox (a vitamin E derivative)/mg substance in the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay. Cannabinoids were without effect on the morphology of dopaminergic cells stained by tyrosine hydroxylase (TH) immunoreaction. THC caused a dose-dependent increase of cell count up to 17.3% at 10 μM, whereas CBD only had an effect at highest concentrations (decrease of cell count by 10.1-20% at concentrations of 0.01-10 μM). It influenced the viability of the TH immunoreactive neurons significantly, whereas THCA exerts no influence on dopaminergic cell count. Exposure of cultures to 10 μM of MPP(+) for 48 h significantly decreased the number of TH immunoreactive neurons by 44.7%, and shrunken cell bodies and reduced neurite lengths could be observed. Concomitant treatment of cultures with cannabinoids rescued dopaminergic cells. Compared to MPP(+) treated cultures, THC counteracted toxic effects in a dose-dependent manner. THCA and CBD treatment at a concentration of 10 μM lead to significantly increased cell counts to 123% and 117%, respectively. Even though no significant preservation or recovery of neurite outgrowth to control values could be observed, our data show that cannabinoids THC and THCA protect dopaminergic neurons against MPP(+) induced cell death.”

http://www.ncbi.nlm.nih.gov/pubmed/22571976

Cannabidiol for the treatment of psychosis in Parkinson’s disease.

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Abstract

“The management of psychosis in Parkinson’s disease (PD) has been considered a great challenge for clinicians and there is a need for new pharmacological intervention. Previously an antipsychotic and neuroprotective effect of Cannabidiol (CBD) has been suggested. Therefore, the aim of the present study was to directly evaluate for the first time, the efficacy, tolerability and safety of CBD on PD patients with psychotic symptoms. This was an open-label pilot study. Six consecutive outpatients (four men and two women) with the diagnosis of PD and who had psychosis for at least 3 months were selected for the study. All patients received CBD in flexible dose (started with an oral dose of 150 mg/day) for 4 weeks, in addition to their usual therapy. The psychotic symptoms evaluated by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire showed a significant decrease under CBD treatment. CBD did not worsen the motor function and decreased the total scores of the Unified Parkinson’s Disease Rating Scale. No adverse effect was observed during the treatment. These preliminary data suggest that CBD may be effective, safe and well tolerated for the treatment of the psychosis in PD.”

http://www.ncbi.nlm.nih.gov/pubmed/18801821

Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved.

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Abstract

“This study aimed to give a rationale for the employment of phytocannabinoid formulations to treat neuropathic pain. It was found that a controlled cannabis extract, containing multiple cannabinoids, in a defined ratio, and other non-cannabinoid fractions (terpenes and flavonoids) provided better antinociceptive efficacy than the single cannabinoid given alone, when tested in a rat model of neuropathic pain. The results also demonstrated that such an antihyperalgesic effect did not involve the cannabinoid CB1 and CB2 receptors, whereas it was mediated by vanilloid receptors TRPV1. The non-psychoactive compound, cannabidiol, is the only component present at a high level in the extract able to bind to this receptor: thus cannabidiol was the drug responsible for the antinociceptive behaviour observed. In addition, the results showed that after chronic oral treatment with cannabis extract the hepatic total content of cytochrome P450 was strongly inhibited as well as the intestinal P-glycoprotein activity. It is suggested that the inhibition of hepatic metabolism determined an increased bioavailability of cannabidiol resulting in a greater effect. However, in the light of the well known antioxidant and antiinflammatory properties of terpenes and flavonoids which could significantly contribute to the therapeutic effects, it cannot be excluded that the synergism observed might be achieved also in the absence of the cytochrome P450 inhibition.”

http://www.ncbi.nlm.nih.gov/pubmed/18618522

Smoked cannabis for chronic neuropathic pain: a randomized controlled trial.

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“Cannabis sativa has been used to treat pain since the third millennium BC. An endogenous pain-processing system has been identified, mediated by endogenous cannabinoid ligands acting on specific cannabinoid receptors.These findings, coupled with anecdotal evidence of the analgesic effects of smoked cannabis, support a reconsideration of cannabinoid agents as analgesics.”

“Oral cannabinoids such as tetrahydrocannabinol, cannabidiol and nabilone have, alone and in combination, shown efficacy in central and peripheral neuropathic pain, rheumatoid arthritis and fibromyalgia.”

“We conducted a clinical trial using a standardized single-dose delivery system to explore further the safety and efficacy of smoked cannabis in outpatients with chronic neuropathic pain.”

“Conclusion

A single inhalation of 25 mg of 9.4% tetrahydrocannabinol herbal cannabis three times daily for five days reduced the intensity of pain, improved sleep and was well tolerated.”

“Our results support the claim that smoked cannabis reduces pain, improves mood and helps sleep. We believe that our trial provides a methodological approach that may be considered for further research. Clinical studies using inhaled delivery systems, such as vaporizers, are needed.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950205/

Medicinal cannabis extracts for the treatment of multiple sclerosis.

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Abstract

“Prior to 2002, few clinical data were available to indicate whether cannabis extracts may be beneficial. However, in the last two years, results of several placebo-controlled clinical trials of orally administered compounds have been published, and these cast doubt on the efficacy of delta9-tetrahydrocannabinol (delta9-THC) in objectively reducing spasticity in MS. By contrast, it has been claimed that sublingually administered cannabis extracts that contain approximately equal concentrations of delta9-THC and cannabidiol, a natural cannabinoid that does not act on the CB1 receptor, can produce a statistically and clinically significant reduction in spasticity, although this claim has yet to be thoroughly validated. Nonetheless, results of preclinical trials also lend support to the hypothesis that the endogenous cannabinoid system may be involved in the regulation of spasticity and pain. A better indication of the clinical potential of the different cannabis extracts will have to await the publication of the most recent clinical trial data. This review critically evaluates the most recent evidence available on the potential use of medicinal extracts of cannabis to relieve pain and spasticity in multiple sclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/15298068

A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms.

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“OBJECTIVES:

To determine whether plant-derived cannabis medicinal extracts (CME) can alleviate neurogenic symptoms unresponsive to standard treatment, and to quantify adverse effects.

SUBJECTS:

Twenty-four patients with multiple sclerosis (18), spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis (1).

INTERVENTION:

Whole-plant extracts of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), 1:1 CBD:THC, or matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5-120 mg/24 hours. Measures used: Patients recorded symptom, well-being and intoxication scores on a daily basis using visual analogue scales. At the end of each two-week period an observer rated severity and frequency of symptoms on numerical rating scales, administered standard measures of disability (Barthel Index), mood and cognition, and recorded adverse events.

RESULTS:

Pain relief associated with both THC and CBD was significantly superior to placebo. Impaired bladder control, muscle spasms and spasticity were improved by CME in some patients with these symptoms. Three patients had transient hypotension and intoxication with rapid initial dosing of THC-containing CME.

CONCLUSIONS:

Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to standard treatments. Unwanted effects are predictable and generally well tolerated. Larger scale studies are warranted to confirm these findings.”

http://www.ncbi.nlm.nih.gov/pubmed/12617376

Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review.

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“Spasticity, an involuntary increase in muscle tone or rapid muscle contractions, is one of the more common and distressing symptoms of multiple sclerosis (MS). Medicinal treatment may reduce spasticity, but may also be ineffective, difficult to obtain, or associated with intolerable side effects. Cannabis, a psychotropic drug known for its analgesic properties, also has a long history as an effective and tolerable treatment for spasticity]. Demographic evidence has shown that many people with MS use cannabis for symptom management.

Clinical studies, animal models, and anecdotal reports have suggested that cannabis may be an effective treatment of MS spasticity. The antispastic effect of cannabis has been supported through a demonstration of the inhibitory properties in exogenous agonists for cannabis receptors found in the CNS. Early clinical trials reporting the efficacy and safety of cannabis use in MS have focused on the effects of Δ9-tetrahydrocannabinol (THC). Although these clinical studies reported a therapeutic benefit for MS symptoms, there were concerns of potential intoxication and other side effects of cannabis-based treatment. Another clinical study using a cannabidiol (CBD) extract documented a reduction in spasticity-related pain but not in spasticity..

More recent combination therapies using whole plant extracts of both THC and CBD have been introduced and there is evidence that CBD, which is not psychotropic, may reduce THC levels in the brain and attenuate its psychotropic side effects. Such therapies may potentially provide a tolerable yet effective treatment for MS symptoms. A number of recent studies have investigated the potential efficacy and safety of whole plant extracts of THC and CBD. One of the first large-scale studies of cannabis treatment for MS-related spasticity compared whole plant cannabis extracts with THC and a placebo, and found mixed evidence for the therapeutic benefit of spasticity in MS. A recent review that included a number of these recent studies provided additional support for the benefit of cannabinoids in MS-related spasticity but called for further study into long-term treatment and side effects. A systematic evaluation of recent research had not previously been conducted, and was needed in order to provide organized evidence of cannabinoid treatments and direction for future clinical studies. We therefore systematically reviewed studies that used a combination extract of THC and CBD for the treatment of spasticity.

We found evidence that combined THC and CBD extracts may provide therapeutic benefit for MS spasticity symptoms…

Finally, there is evidence that cannabinoids may provide neuroprotective and anti-inflammatory benefits in MS. Neuroinflammation, found in autoimmune diseases such as MS, has been shown to be reduced by cannabinoids through the regulation of cytokine levels in microglial cells. The therapeutic potential of cannabinoids in MS is therefore comprehensive and should be given considerable attention.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793241/

Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis.

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“Central pain in multiple sclerosis (MS) is common and often refractory to treatment…

We conducted a single-center, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial in 66 patients with MS and central pain states (59 dysesthetic, seven painful spasms) of a whole-plant cannabis-based medicine (CBM), containing delta-9-tetrahydrocannabinol:cannabidiol (THC:CBD) delivered via an oromucosal spray, as adjunctive analgesic treatment…

CONCLUSIONS:

Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated.”

http://www.ncbi.nlm.nih.gov/pubmed/16186518

Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis.

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Abstract

“Symptoms relating to spasticity are common in multiple sclerosis (MS) and can be difficult to treat. We have investigated the efficacy, safety and tolerability of a standardized oromucosal whole plant cannabis-based medicine (CBM) containing delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), upon spasticity in MS. A total of 189 subjects with definite MS and spasticity were randomized to receive daily doses of active preparation (n = 124) or placebo (n = 65) in a double blind study over 6 weeks. The primary endpoint was the change in a daily subject-recorded Numerical Rating Scale of spasticity. Secondary endpoints included a measure of spasticity (Ashworth Score) and a subjective measure of spasm. The primary efficacy analysis on the intention to treat (ITT) population (n = 184) showed the active preparation to be significantly superior (P = 0.048). Secondary efficacy measures were all in favour of active preparation but did not achieve statistical significance. The responder analysis favoured active preparation, 40% of subjects achieved >30% benefit (P = 0.014). Eight withdrawals were attributed to adverse events (AEs); six were on active preparation and two on placebo. We conclude that this CBM may represent a useful new agent for treatment of the symptomatic relief of spasticity in MS.”

http://www.ncbi.nlm.nih.gov/pubmed/17355549