Tag Archives: therapeutic

Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells

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“Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that Δ9-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy…We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo.”

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“These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.

Δ9-Tetrahydrocannabinol (THC), the main active component of marijuana, exerts a wide variety of biological effects by mimicking endogenous substances — the endocannabinoids — that bind to and activate specific cannabinoid receptors. One of the most exciting areas of research in the cannabinoid field is the study of the potential application of cannabinoids as antitumoral agents.

Cannabinoid administration has been found to curb the growth of several types of tumor xenografts in rats and mice…

 Considering that no signs of toxicity were observed in the clinical trial patients or in tumor-bearing animals treated intracranially, peritumorally, or intraperitoneally with THC, and that no overt toxic effects have been reported in other clinical trials of cannabinoid use in cancer patients for various applications (e.g., inhibition of nausea, vomiting, and pain) and using different routes of administration (e.g., oral, oro-mucosal) our findings support that safe, therapeutically efficacious doses of THC may be reached in cancer patients.”

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673842/

A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol.

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“This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations. Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of cyclo-oxygenase (COX) inhibition.

CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right.

In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are further examined.

The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.”

http://www.ncbi.nlm.nih.gov/pubmed/16209908

Cannabinoid Inhibition of Macrophage Migration to the Trans-Activating (Tat) Protein of HIV-1 Is Linked to the CB2 Cannabinoid Receptor

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“Macrophage-like cells are primary targets for infection by HIV-1…  In the present study, the exogenous cannabinoids δ-9-tetrahydrocannabinol (THC) and (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55940) were shown to significantly inhibit migration of human U937 macrophage-like cells to the Tat protein in a concentration-related manner….

Collectively, the pharmacological and biochemical knockdown data indicate that cannabinoid-mediated modulation of macrophage migration to the HIV-1 Tat protein is linked to the CB2 cannabinoid receptor. Furthermore, these results suggest that the CB2 cannabinoid receptor has potential to serve as a therapeutic target for ablation of HIV-1-associated untoward inflammatory response…

,,, the CB2 receptor has the potential to serve as a molecular target for ablating hyperinflammatory responses of macrophage-like cells while avoiding untoward psychotropic effects caused by activation of the CB1 receptor.

 In conclusion, the immunosuppressive and anti-inflammatory properties of select cannabinoids may have profound therapeutic potential in moderating HIV-associated immunopathology, including microglial activation, chemokine/cytokine dysregulation, and monocyte infiltration in the CNS.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846023/

Cannabinoids may be therapeutic in breast cancer.

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“Cannabinoids are a group of compounds synthesized exclusively by the Cannabis sativa plant, commonly known as marijuana. In 1990, the first cannabinoid-specific membrane (CB1) was characterized and cloned (Matsuda, Lolait, Brownstein, Young, & Bonner, 1990), which catapulted biomedical research on these unique compounds.

 Cannabinoids refer to both marijuana-derived compounds with the active ingredient of 9-tetrahydrocannabinol (THC) and also the synthetic molecules that activate the same primary targets as THC.

Therapeutic properties of marijuana have been well established; however, the clinical use of either plant-sourced or pure cannabinoids remains limited.

The anticachexia properties of cannabinoids are found in tetrahydrocannabinol (oral capsules of synthetically generated THC) and are used to manage weight loss, wasting syndrome, and nausea and vomiting associated with cancer treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/23448745

Cannabis for better sleep

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“The use of both natural cannabinoids and cannabis extracts are associated with improved sleep in patients with various debilitating illnesses, according to a review of clinical trial data published in the journal Chemistry & Biodiversity.

“Cannabis … has been utilized for [the] treatment of pain and sleep disorders since ancient times,” authors wrote. “Modern clinical trials indicate that patients administered cannabis extracts report experiencing “more restful sleep, [an] increase [in] their daytime level of function, and [a] markedly improve[d] … quality of life.”

According to available data, of the 2,000 subjects that have been administered cannabis extracts in clinical trials, most “demonstrate marked improvement in subjective sleep parameters.”

Trial volunteers have not reported developing tolerance to the drug, even after using it for several years.

Full text of the study, “Cannabis, pain, and sleep: Lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine,” appears in the journal Chemistry & Biodiversity.”

http://azarius.net/news/193/Cannabis_for_better_sleep/

Cannabidiol, a constituent of Cannabis sativa, modulates sleep in rats.

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“Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol (CBD) are two major constituents of Cannabis sativa. Delta(9)-THC modulates sleep, but no clear evidence on the role of CBD is available.

In order to determine the effects of CBD on sleep, it was administered intracerebroventricular (icv) in a dose of 10 microg/5 microl at the beginning of either the lights-on or the lights-off period. We found that CBD administered during the lights-on period increased wakefulness (W) and decreased rapid eye movement sleep (REMS). No changes on sleep were observed during the dark phase. Icv injections of CBD (10 microg/5microl) induced an enhancement of c-Fos expression in waking-related brain areas such as hypothalamus and dorsal raphe nucleus (DRD). Microdialysis in unanesthetized rats was carried out to characterize the effects of icv administration of CBD (10 microg/5 microl) on extracellular levels of dopamine (DA) within the nucleus accumbens. CBD induced an increase in DA release. Finally, in order to test if the waking properties of CBD could be blocked by the sleep-inducing endocannabinoid anandamide (ANA), animals received ANA (10 microg/2.5 microl, icv) followed 15 min later by CBD (10 microg/2.5 microl). Results showed that the waking properties of CBD were not blocked by ANA.

 In conclusion, we found that CBD modulates waking via activation of neurons in the hypothalamus and DRD. Both regions are apparently involved in the generation of alertness. Also, CBD increases DA levels as measured by microdialysis and HPLC procedures.

Since CBD induces alertness, it might be of therapeutic value in sleep disorders such as excessive somnolence.”

http://www.ncbi.nlm.nih.gov/pubmed/16844117

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

The effects of cannabidiol on the antigen-induced contraction of airways smooth muscle in the guinea-pig.

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“(-)-Δ(9)-Tetrahydrocannabinol has been demonstrated to have beneficial effects in the airways, but its psychoactive effects preclude its therapeutic use for the treatment of airways diseases. In the present study we have investigated the effects of (-)-cannabidiol, a non-psychoactive component of cannabis for its actions on bronchial smooth muscle in vitro and in vivo.

 Guinea-pig bronchial smooth muscle contractions induced by exogenously applied spasmogens were measured isometrically. In addition, contractile responses of bronchial smooth muscle from ovalbumin-sensitized guinea-pigs were investigated in the absence or presence of (-)-cannabidiol. Furthermore, the effect of (-)-cannabidiol against ovalbumin-induced airway obstruction was investigated in vivo in ovalbumin-sensitized guinea pigs. (-)-Cannabidiol did not influence the bronchial smooth muscle contraction induced by carbachol, histamine or neurokinin A. In contrast, (-)-cannabidiol inhibited anandamide- and virodhamine-induced responses of isolated bronchi. A fatty acid amide hydrolase inhibitor, phenylmethanesulfonyl fluoride reversed the inhibitory effect of (-)-cannabidiol on anandamide-induced contractions. In addition, (-)-cannabidiol inhibited the contractile response of bronchi obtained from allergic guinea-pigs induced by ovalbumin. In vivo, (-)-cannabidiol reduced ovalbumin-induced airway obstruction.

 In conclusion, our results suggest that cannabidiol can influence antigen-induced airway smooth muscle tone suggesting that this molecule may have beneficial effects in the treatment of obstructive airway disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/23428645

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/

[Cannabinoids in multiple sclerosis — therapeutically reasonable?].

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“For centuries extracts from the Cannabis sativa plant have been used for recreational use and as remedies. Anecdotal reports from patients with multiple sclerosis (MS) experiencing relief of their spasticity and pain after smoking marihuana have prompted discussions about a potential therapeutic application of cannabis preparations in MS.

Only recently the first large, multicenter, double-blind, placebo controlled study was conducted evaluating the use of cannabinoids for treatment of spasticity and other symptoms related to MS.

 Based on this trial and previous uncontrolled observations together with insights from basic research and animal experiments there is reasonable evidence for the therapeutical employment of cannabinoids in the treatment of MS related symptoms.

 Furthermore, data are arising that cannabinoids have immunomodulatory and neuroprotective properties. However, results from clinical trials do not allow the recommendation for the general use of cannabinoids in MS.

This article summarizes the present knowledge of clinical and experimental research regarding the therapeutic potential of cannabinoids for the treatment of MS”

http://www.ncbi.nlm.nih.gov/pubmed/16052440