Category Archives: Endocannabinoid System

Proof of Concept Trial of Dronabinol in Obstructive Sleep Apnea

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“… Δ9-TetraHydroCannabinol (Δ9THC) stabilizes autonomic output during sleep, reduces spontaneous sleep-disordered breathing, and blocks serotonin-induced exacerbation of sleep apnea. On this basis, we examined the safety, tolerability, and efficacy of dronabinol (Δ9THC), an exogenous Cannabinoid type 1 and type 2 (CB1 and CB2) receptor agonist in patients with Obstructive Sleep Apnea (OSA)…

Conclusion: Dronabinol treatment is safe and well-tolerated in OSA patients at doses of 2.5–10mg daily and significantly reduces AHI in the short-term. These findings should be confirmed in a larger study in order to identify sub-populations with OSA that may benefit from cannabimimetic pharmacologic therapy…

This proof of concept study demonstrates that dronabinol is safe, well-tolerated, and reduces AHI by approximately a third over 3 weeks of oral administration. Dronabinol treatment may be a viable alternative or adjunctive therapy in selected patients with OSA.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550518/

Functional role for cannabinoids in respiratory stability during sleep.

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“Serotonin, acting in the peripheral nervous system, can exacerbate sleep-related apnea, and systemically administered serotonin antagonists reduce sleep-disordered respiration in rats and bulldogs. Because cannabinoid receptor agonists are known to inhibit the excitatory effects of serotonin on nodose ganglion cells, we examined the effects of endogenous (oleamide) and exogenous (delta9-tetrahydrocannabinol; delta9THC) cannabimimetic agents on sleep-related apnea…

Our data show that delta9THC and oleamide each stabilized respiration during all sleep stages… This observation suggests an important role for endocannabinoids in maintaining autonomic stability during sleep…

CONCLUSIONS:

This study demonstrates potent suppression of sleep-related apnea by both exogenous and endogenous cannabinoids. These findings are of relevance to the pathogenesis and pharmacological treatment of sleep-related breathing disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/12071539

Circulating anandamide and blood pressure in patients with obstructive sleep apnea.

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” OBJECTIVE: Obstructive sleep apnea chronically increases blood pressure through sympathetic nervous system activation. In animals, hypertension and sympathetic activity are restrained by cannabinoid receptor activation. Therefore, we hypothesized that increased blood pressure in patients with obstructive sleep apnea is associated with increased circulating endocannabinoid concentrations.

 

CONCLUSION: Obstructive sleep apnea patients show positive correlations between blood pressure and venous anandamide concentrations independent of confounding factors. Our data suggest a previously not recognized role of the endocannabinoid system for blood pressure regulation in patients with high risk for hypertension and cardiovascular disease.”

http://www.ncbi.nlm.nih.gov/pubmed/23032139

Circulating endocannabinoids and N-acyl-ethanolamides in patients with sleep apnea–specific role of oleoylethanolamide.

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“OBJECTIVE:  The endocannabinoid system promotes diverse effects on fat and glucose metabolism as well as on energy balance and sleep regulation. The role of N-acylethanolamides like oleoylethanolamide (OEA) and other endocannabinoids such as anandamide (AEA) and 2-arachidonyl-glycerol (2-AG) has not yet been investigated in patients with sleep apnea.

 

CONCLUSIONS: These results indicate that among the three analyzed fatty acid derivatives, OEA plays a specific role in patients with sleep apnea. Together with animal data, the 2-fold elevation of OEA serum concentrations could be interpreted as a neuroprotective mechanism against chronic oxidative stressors and a mechanism to promote wakefulness in patients with nocturnal sleep deprivation and daytime hypersomnolence.”

http://www.ncbi.nlm.nih.gov/pubmed/20429051

 

[A study on the endogenous cannabinoid system synthetic and catabolic enzyme levels in patients with obstructive sleep apnea].

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“OBJECTIVE: To observe the differences of endogenous cannabinoid system (ECS) synthetic and catabolic enzyme levels between the obstructive sleep apnea syndrome (OSA) patients and the control subjects.

 

CONCLUSION: OSA altered the expression of the ECS synthetic and catabolic enzymes, leading to an increase in endogenous cannabinoid substances.”

 

http://www.ncbi.nlm.nih.gov/pubmed/21729625

Expression of the cannabinoid type I receptor and prognosis following surgery in colorectal cancer.

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“The cannabinoid system has been considered to be a potential target of colorectal carcinoma therapy. The aim of this study was to address the correlation between cannabinoid type 1 (CB1) receptor expression and disease severity/outcomes in patients with colorectal cancer (CRC).”

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 “…The high immunoreactivity of the cannabinoid type 1 receptor is a significant prognostic factor following surgery in stage IV CRC…

The effect of cannabinoids in colorectal cancer (CRC) has been demonstrated in in vitro experiments and animal models, which indicate the antiproliferative, apoptotic and antimetastatic actions of cannabinoid agonists…

Antineoplastic effects are mediated by the activation of cannabinoid type I (CB1), type 2 (CB2) or a non-cannabinoid receptor-mediated mechanism…”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576207/

AM404 attenuates reinstatement of nicotine seeking induced by nicotine-associated cues and nicotine priming but does not affect nicotine- and food-taking.

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“Multiple studies suggest a pivotal role of the endocannabinoid system in the regulation of the reinforcing effects of various substances of abuse. Different approaches have been used to modulate endocannabinoid neurotransmission including the use of endogenous cannabinoid anandamide reuptake inhibitors.

 Previously, the effects of one of them, N-(4-hydroxyphenyl)-arachidonamide (AM404), have been explored in rodents trained to self-administer ethanol and heroin, producing some promising results. Moreover, AM404 attenuated the development and reinstatement of nicotine-induced conditioned place preference (CPP). In this study, we used the nicotine intravenous self-administration procedure to assess the effects of intraperitoneal administration of 0, 1, 3 and 10 mg/kg AM404 on nicotine-taking and food-taking behaviors under fixed-ratio and progressive-ratio schedules of reinforcement, as well as on reinstatement of nicotine-seeking induced by nicotine priming and by presentation of nicotine-associated cues. The ability of AM404 to produce place preference was also evaluated. AM404 did not produce CPP and did not modify nicotine-taking and food-taking behaviors. In contrast, AM404 dose-dependently attenuated reinstatement of nicotine-seeking behavior induced by both nicotine-associated cues and nicotine priming.

Our results indicate that AM404 could be a potential promising therapeutic option for the prevention of relapse to nicotine-seeking in abstinent smokers.”

http://www.ncbi.nlm.nih.gov/pubmed/23427192

Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity

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“Anecdotal evidence suggests a beneficial effect of cannabis on spasticity as well as pain. Recently, randomized, double-blind, placebo-controlled studies have confirmed the clinical efficacy of cannabinoids for the treatment of spasticity in patients with MS. Based on these data, nabiximols (Sativex), a 1:1 mix of Δ-9-tetrahydrocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, received approval for treating MS-related spasticity in various countries around the globe. In this article we review the current understanding of cannabinoid biology and the value of cannabinoids as a symptomatic treatment option addressing spasticity in patients with MS.

Based on individual case reports, the consumption of plant parts, specifically, the resin of the Cannabis sativa hemp plant, has, for years, been attributed to the capacity to reduce the symptoms of multiple sclerosis (MS), such as spasticity, neuropathic pain, tremor, and disturbed bladder function. As characterization of the endocannabinoid system and its role in the motor system and pain processing continue to advance, there is increasing evidence of a scientific basis for the postulated therapeutic effect of cannabis derivatives.

The oromucosal administration of THC and CBD in a 1:1 ratio has proven to be a well tolerated therapeutic option for treating spasticity in patients with MS who respond poorly to conventional antispastic drugs. Assessment of the efficacy is limited by the fact that spasticity as a symptom is very difficult to measure reliably, objectively, and validly. Current study data support the position that the beneficial effects of nabiximols on subjective and objective endpoints in a selected patient sample outweigh the adverse pharmaceutical effects. The effects of long-term nabiximols treatment on neuropsychological processes and the structure of the endocannabinoid system need to be further characterized.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437528/

Endocannabinoid system modulator use in everyday clinical practice in the UK and Spain.

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“Spasticity is a disabling complication of multiple sclerosis. Some commonly used oral medications include baclofen, tizanidine, anticonvulsants and benzodiazepines, but their benefits are modest.

Sativex(®) (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain) is a unique cannabinoid-based medicine with two main active ingredients; 9-δ-tetrahydrocannabinol, which acts mainly on cannabinoid 1 receptors in the CNS and plays a key role in the modulation of spasticity and spasms, and cannabidiol, which has different properties, including minimization of the psychoactivity associated with 9-δ-tetrahydrocannabinol. Sativex is indicated for symptomatic improvement in adult patients with moderate-to-severe multiple sclerosis-related spasticity who have not responded adequately to other first- or second-line antispasticity medications, and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

Over the past couple of years, Sativex has been approved for use in a number of European countries and ongoing postmarketing studies are evaluating the possible risks associated with Sativex treatment by systematically collecting all suspected adverse reactions that occur in patients from the start of treatment. Interim data from the UK as well as Spanish Sativex safety registries confirm that clinical benefit is maintained over the longer term despite the expected trend for deterioration owing to disease progression.

 Even after more than 2 years of use, no new safety/tolerability signals have emerged with Sativex, including no evidence of driving impairment and no relevant incidence of falls or other adverse events of concern, such as psychiatric or nervous system events.

Sativex appears to be a well-tolerated and useful add-on therapy in patients who have not achieved an adequate response with traditional antispastic agents.”

http://www.ncbi.nlm.nih.gov/pubmed/23369054

The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis

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“The ability of cannabinoids to modulate both inflammatory and degenerative neuronal damage prompted investigations on the potential benefits of such compounds in multiple sclerosis (MS) and in animal models of this disorder. Here we measured endocannabinoid levels, metabolism and binding, and physiological activities in 26 patients with MS (17 females, aged 19–43 years), 25 healthy controls and in mice with experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS.

 Our results show that MS and EAE are associated with significant alterations of the endocannabinoid system. We found that anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), was increased in the CSF of relapsing MS patients. AEA concentrations were also higher in peripheral lymphocytes of these patients, an effect associated with increased synthesis and reduced degradation of this endocannabinoid. Increased synthesis, reduced degradation, and increased levels of AEA were also detected in the brains of EAE mice in the acute phase of the disease, possibly accounting for its anti-excitotoxic action in this disorder. Accordingly, neurophysiological recordings from single neurons confirmed that excitatory transmission in EAE slices is inhibited by CB1 receptor activation, while inhibitory transmission is not.

Our study suggests that targeting the endocannabinoid system might be useful for the treatment of MS.”

http://brain.oxfordjournals.org/content/130/10/2543.abstract