Tag Archives: treatment

Latest advances in cannabinoid receptor agonists.

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“Since the discovery of cannabinoid receptors and their endogenous ligands in early 1990s, the endocannabinoid system has been shown to play a vital role in several pathophysiological processes. It has been targeted for the treatment of several diseases including neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and MS), cancer, obesity, inflammatory bowel disease, neuropathic and inflammatory pain. The last decade has witnessed remarkable advances in the development of cannabinergic ligands displaying high selectivity and potency towards two subtypes of cannabinoid receptors, namely CB1 and CB2.”

 “…we highlight the latest advances made in the development of cannabinoid agonists and summarize recently disclosed, novel chemical scaffolds as CB-selective agonists…”

 

“CONCLUSIONS:

Our analysis reveals prolific patenting activity mainly in the CB2 selective agonist area. Limiting the BBB penetrability, thereby, leading to peripherally restricted CB1/CB2 agonists and enhancing CB2-selectivity emerge as likely prerequisites for avoidance of adverse central CB1 mediated side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/19939187

Loss of cannabinoid CB1 receptor expression in the 6-hydroxydopamine-induced nigrostriatal terminal lesion model of Parkinson’s disease in the rat.

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Abstract

“The endocannabinoid system is emerging as a potential alternative to the dopaminergic system for the treatment of Parkinson’s disease. Like all emerging targets, validation of this system’s potential for treating human Parkinsonism necessitates testing in animal models of the condition. However, if components of the endocannabinoid system are altered by the induction of a Parkinsonian state in animal models, this could have an impact on the interpretation of such preclinical experiments. This study sought to determine if expression of the CB(1) subtype of cannabinoid receptor is altered in the two most commonly used rat models of Parkinson’s disease. Parkinsonian lesions were induced by stereotaxic injection of 6-hydroxydopamine into the axons (medial forebrain bundle) or terminals (striatum) of the nigrostriatal pathway. On days 1, 3, 7, 14 and 28 post-lesion, rats were sacrificed and brains were processed for tyrosine hydroxylase and CB(1) receptor immunohistochemistry. The CB(1) receptor was expressed strongly in the substantia nigra pars reticulata, minimally overlapping with tyrosine hydroxylase immunoreactivity in the pars compacta. Interestingly, while there was little change in CB(1) receptor expression following axonal lesion, expression of the receptor was significantly reduced following terminal lesion. Loss of CB(1) receptor expression in the pars reticulata correlated significantly with the loss of striatal and nigral volume after terminal lesion indicating this may have been due to 6-hydroxydopamine-induced non-specific damage of striatonigral neurons which are known to express CB(1) receptors. Thus, this result has implications for the choice of model and interpretation of studies used to investigate potential cannabinoid-based therapies for Parkinson’s disease as well as striatonigral diseases such as Huntington’s disease and Multiple Systems Atrophy.”

http://www.ncbi.nlm.nih.gov/pubmed/20097273

CB1 cannabinoid receptor signalling in Parkinson’s disease.

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Abstract

“Signalling at CB(1) cannabinoid receptors plays a key role in the control of movement in health and disease. In recent years, an increased understanding of the physiological role of transmission at CB(1) receptors throughout the basal ganglia circuitry has led to the identification of novel therapeutic approaches to both the symptoms of Parkinson’s disease and the side effects of current anti-parkinsonian therapies, especially L(3,4) dihydroxyphenylalamine (levodopa)-induced dyskinesia. Thus, because activation of basal ganglia CB(1) receptors can modulate neurotransmission and contribute to synaptic plasticity in a manner similar to that described in other brain regions, it also appears that endocannabinoids might modulate cell-cell signalling via effects on neurotransmitter re-uptake and postsynaptic actions mediating cross talk between multiple receptor types. Recent studies in animal models and in the clinic suggest that CB(1) receptor antagonists could prove useful in the treatment of parkinsonian symptoms and levodopa-induced dyskinesia, whereas CB(1) receptor agonists could have value in reducing levodopa-induced dyskinesia.”

http://www.ncbi.nlm.nih.gov/pubmed/12550742

Depression in Parkinson’s disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1).

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Abstract

“Depression is a common symptom in Parkinson’s disease (PD) and it is present in up to 40% of the patients. The cause of depression in PD is thought to be related to disturbance of monoamine neurotransmission. The endogenous cannabinoid system mediates different brain processes that play a role in the control of behaviour and emotions. Cannabinoid function may be altered in neuropsychiatry diseases, directly or through interactions with monoamine, GABA and glutamate systems. For this reason, we have investigated whether there is a genetic risk factor for depression in PD linked to the polymorphisms of CB1 receptor gene. Depression was more frequent in patients with PD than in controls with osteoarthritis. The presence of depression did not correlate with the stage of the disease but it was more frequent in patients with pure akinetic syndrome than in those with tremoric or mixed type PD. The CB1 receptor gene polymorphism (AAT)n is considered to modify the transcription of the gene and, therefore, it may have functional relevance. We analysed the length of the polymorphic triplet (AAT)n of the gene that encodes CB1 (CNR1) receptor in 89 subjects (48 PD patients and 41 controls). In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher’s exact test: P=0.003). This association did not reach significant differences in the control group, but the number of control individuals with depression was too small to allow for statistical analysis. Since the alleles with long expansions may have functional impact in cannabinoid neurotransmission, our data suggest that the pharmacological manipulation of cannabinoid neurotransmission could open a new therapeutic approach for the treatment of depression in PD and possibly in other conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/15668727

Smoked Medical Cannabis May Be Beneficial as Treatment for Chronic Neuropathic Pain, Study Suggests.

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“Medicinal marijuana. A new study provides evidence that cannabis may offer relief to patients suffering from chronic neuropathic pain. (Credit: iStockphoto)”
 

“The medicinal use of cannabis has been debated by clinicians, researchers, legislators and the public at large for many years as an alternative to standard pharmaceutical treatments for pain, which may not always be effective and may have unwanted side effects. A new study by McGill University Health Centre (MUHC) and McGill University researchers provides evidence that cannabis may offer relief to patients suffering from chronic neuropathic pain.”

“This is the first trial to be conducted where patients have been allowed to smoke cannabis at home and to monitor their responses, daily,” says Dr. Mark Ware, lead author of the study, who is also Director of Clinical Research at the Alan Edwards Pain Management Unit at the MUHC and an assistant professor of anesthesia in McGill University’s Faculty of Medicine, and neuroscience researcher at the Research Institute of the MUHC.

In this study, low doses (25mg) of inhaled cannabis containing approximately 10% THC (the active ingredient in cannabis), smoked as a single inhalation using a pipe three times daily over a period of five days, offered modest pain reduction in patients suffering from chronic neuropathic pain (pain associated with nerve injury) within the first few days. The results also suggest that cannabis improved moods and helped patients sleep better. The effects were less pronounced in cannabis strains containing less than 10% THC.

“The patients we followed suffered from pain caused by injuries to the nervous system from post-traumatic (e.g. traffic accidents) or post-surgical (e.g. cut nerves) events, and which was not controlled using standard therapies” explains Dr. Ware. “This kind of pain occurs more frequently than many people recognize, and there are few effective treatments available. For these patients, medical cannabis is sometimes seen as their last hope.”

“This study marks an important step forward because it demonstrates the analgesic effects of cannabis at a low dose over a shot period of time for patients suffering from chronic neuropathic pain,” adds Dr. Ware. The study used herbal cannabis from Prairie Plant Systems (under contract to Health Canada to provide cannabis for research and medical purposes), and a 0% THC ‘placebo’ cannabis from the USA.”

Read more:http://www.sciencedaily.com/releases/2010/08/100830094926.htm

Marijuana May Be Effective For Neuropathic Pain.

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“The growing body of evidence that marijuana (cannabis) may be effective as a pain reliever has been expanded with publication of a new study in The Journal of Pain reporting that patients with nerve pain showed reduced pain intensity from smoking marijuana.

Researchers at University of California Davis examined whether marijuana produces analgesia for patients with neuropathic pain. Thirty-eight patients were examined. They were given either high-dose (7%), low-dose (3.5%) or placebo cannabis.

The authors reported that identical levels of analgesia were produced at each cumulative dose level by both concentrations of the agent. As with opioids, cannabis does not rely on a relaxing or tranquilizing effect, but reduces the core component of nociception and the emotional aspect of the pain experience to an equal degree. There were undesirable consequences observed from cannabis smoking, such as feeing high or impaired, but they did not inhibit tolerability or cause anyone to withdraw from the study. In general, side effects and mood changes were inconsequential.

It was noted by the authors that since high and low dose cannabis produced equal analgesic efficacy, a case could be made for testing lower concentrations to determine if the analgesic profile can be maintained while reducing potential cognitive decline.

In addition, the authors said further research could probe whether adding the lowest effective dose of cannabis to another analgesic drug might lead to more effective neuropathic pain treatment for patients who otherwise are treatment-resistant.”

http://www.sciencedaily.com/releases/2008/06/080626150628.htm

Role of cannabinoids in the management of neuropathic pain.

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Abstract

“The treatment of pain, particularly neuropathic pain, is one of the therapeutic applications of cannabis and cannabinoids that is currently under investigation and that stimulates interest among clinicians and basic researchers. Animal pain models, including models of acute, antinociceptive, inflammatory and neuropathic pain, have demonstrated the antinociceptive efficacy of cannabinoids without causing serious alterations in animal behaviour. These data, together with the historic and current empiric use of cannabinoids, support the interest in the analysis of their effectiveness in treating neuropathic pain. The evaluation of controlled trials that focus on the effect of cannabinoids on neuropathic pain reveals that this class of drugs is able to significantly reduce pain perception. Nevertheless, this effect is generally weak and clinical relevance remains under evaluation. Moreover, there is a lack of controlled trials and, in particular, comparisons with other drugs generally used in the treatment of neuropathic pain. Despite the fact that further research is required to achieve a definitive assessment, current data obtained from basic research and from analysis of the available controlled trials indicate that cannabinoids can be accepted as a useful option in the treatment of neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/18601303

More evidence cannabis can help in neuropathic pain.

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“It’s good to see the trial of smoked cannabis in neuropathic pain reported by Ware and colleagues because smoking is the most common way in which patients try this drug. The authors should be congratulated for tackling the question of whether cannabis helps in neuropathic pain, particularly given that the regulatory hurdles for their trial must have been a nightmare. The question is worth investigating because of the ongoing publicity — which patients see, hear and read — that suggests an analgesic activity of cannabis in neuropathic pain, and because of the paucity of robust evidence for such an analgesic effect. If patients are not achieving a good response with conventional treatment of their pain, then they may, reasonably, wish to try cannabis. If medical cannabis is not available where a patient lives, then obtaining it will take the patient outside of the law, often for the first time in his or her life. Good evidence would at least buttress that decision.”

“This trial adds to the three previous studies of smoked cannabis in neuropathic pain that I could find using PubMed and reference lists…”

“Putting together the four trials of smoked cannabis, the provisional conclusions are that an analgesic effect is evident, that this effect, though not great, may be of use to some patients, and that it often carries with it some adverse effects on the central nervous system (though not obviously so in this trial). These conclusions make biological sense, given that cannabinoids taken orally have shown the same sorts of effects. Interestingly, the “moderate” analgesic effect shown here for neuropathic pain seems to hold true for nociceptive pain.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950178/

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

Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial.

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“The objective was to investigate the effectiveness of cannabis-based medicines for treatment of chronic pain associated with brachial plexus root avulsion…”

 “The primary outcome measure was the mean pain severity score during the last 7 days of treatment. Secondary outcome measures included pain related quality of life assessments. The primary outcome measure failed to fall by the two points defined in our hypothesis. However, both this measure and measures of sleep showed statistically significant improvements. The study medications were generally well tolerated with the majority of adverse events, including intoxication type reactions, being mild to moderate in severity and resolving spontaneously…”

http://www.ncbi.nlm.nih.gov/pubmed/15561385