Established and potential therapeutic applications of cannabinoids in oncology

Cannabis occurs naturally in the dried flowering or fruiting tops of the Cannabis sativa plant. Cannabis is most often consumed by smoking marihuana. Cannabinoids are the active compounds extracted from cannabis. Recently, there has been renewed interest in cannabinoids for medicinal purposes. The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia. Two types of cannabinoid receptors, CB1 and CB2, have been detected. CB1 receptors are expressed mainly in the central and peripheral nervous system. CB2 receptors are found in certain nonneuronal tissues, particularly in the immune cells. Recent discovery of both the cannabinoid receptors and endocannabinoids has opened a new era in research on the pharmaceutical applications of cannabinoids. The use of cannabinoids should be continued in the areas indicated, and further studies are needed to evaluate other potential uses in clinical oncology.     

Therapeutic Use of Synthetic Cannabinoids: Still an OpenIssue?

Cannabis sativa has a long history of use for medical purposes despite marijuana's addictive potential. The discovery of the endogenous cannabinoid system as a neuromodulatory system composed of receptors, endogenous ligands (endocannabinoids), and enzymes responsible for their synthesis and degradation, together with recent advancements in the elucidation of cannabinoid pharmacology, has renewed interest in medicines acting on the endocannabinoid system. Synthetic cannabinoid agonists have been developed and used for treatment of different human pathologic conditions, and promising potent cannabinoid antagonists are currently under clinical evaluation. During the last decade, new generations of synthetic cannabinoids appeared on the global drug market, proposed as marijuana-like compounds and sold as herbal mixture also known as spice drugs or legal highs. Because activation of cannabinoid receptors may induce central and peripheral beneficial effects, the newest synthetic cannabinoids having full agonistic activity and high potency at cannabinoid type 1 and type 2 receptors might have therapeutic potential too. However, case reports of acute and fatal intoxications are accumulating and revealing that this is not the case because adverse effects of the latest generation of synthetic cannabinoids far exceed the desired ones.     

Using Cannabis to Treat Cancer-Related Pain

ObjectiveTo describe which cannabinoids and terpenes are effective for treating pain.Data SourcesPeer-reviewed articles, book chapters.ConclusionCannabis and cannabinoid medicines, as modulators of the endocannabinoid system, offer novel therapeutic options for the treatment of cancer-related pain, not only for patients who do not respond to conventional therapies, but also for patients who prefer to try cannabis as a first treatment option.Implications for Nursing PracticeUnderstanding the endocannabinoid system, cannabinoids, terpenes, routes of administration, potential drug interactions, clinical implications, and potential side effects ensures nurses can better assist patients who use cannabis for the treatment of cancer pain.     

Embattled cannabis: pharmacological,medical, recreational,and adverse effects aspects

Cannabis sativa L. (Cannabaease), currently, is the most widely used illicit drug around the world. The psychoactive chemical of the plant is the (9)-tetrahydrocannabinol (THC). The federal government of the United States as well as other countries classified THC as Schedule I controlled substance. Concerning the use of cannabinoids as therapeutic agents exhibits beneficial therapeutic effects against nausea and vomiting in cancer and AIDS patients. Cannabis decreased the intensity of spasm and tremors in multiple sclerotic patients. On the other hand, the chronic use of Cannabis sativa may cause severe, unwanted, acute, and chronic side effects: cognition, coordination, learning defects, and impairment of memory among users, addiction, and possible suicidal attempts. Still, cannabis may trigger acute cardiovascular diseases including mortality, although there is some progress by introducing new agents that work like THC such as Sativex, Nabilone, and Conador. These agents await further extensive development to enhance efficacy and to decrease toxicity. In conclusion, the outcome of the medical use of cannabis is blurred with the presence of the recreational use. The question of whether it should be legalized still needs extensive discussion.     

The endocannabinoid system and the treatment of obesity

The endocannabinoids are endogenous lipids capable of binding to both cannabinoid receptors (CB) CB1 and CB2. These receptors belong to the G protein-coupled family receptors and they were discovered while investigating the mode of action of ?(9)-tetrahydrocannabinol, a component of Cannabis sativa, to which they bind with high affinity. Among many other brain sites, CB1 is present in the hypothalamic nuclei involved in the control of energy balance and body weight, as well as in neurons of the mesolimbic system which is believed to mediate the incentive value of food. At central nervous system level, CB1 activation is necessary to induce food intake after a short period of food deprivation, and when CB1 is activated by endocannabinoids produced in situ, a stimulation of the ingestion of palatable food has been described. CB1 stimulation leads to modulation of the release of some hypothalamic anorexigenic and orexigenic mediators, as well as of dopamine in the nucleus accumbens shell. Recent evidence has proved that CB1 is also present in the peripheral organs, such as the adipose tissue and gastrointestinal system, key organs in the regulation of energy metabolism. Animal models have provided solid evidence that genetically induced obesity leads to long-lasting overstimulation of endocannabinoid system synthesis resulting in permanent overactivation of CB1, which may then contribute to the maintenance of this disease. Importantly, at peripheral level, CB1 activation has been shown to stimulate lipogenesis in adipocytes. CB1 blockers increase adiponectin production in adipocytes, which leads to increased fatty acid oxidation and free fatty acid clearance. Moreover, CB1 has been shown to be up-regulated in adipocytes derived from obese rodents. These results support the role of endocannabinoids in the development and maintenance of obesity, paving the way for the development of a new class of drugs such as the CB1 blockers as a therapy for tackling obesity and the associated major cardiovascular risk factors.     

Cannabinoids in Pain Treatment: An Overview

The current landscape contains conflicting reports regarding the use of medical marijuana, creating fields of misinformation and lack of understanding by health care providers about cannabinoids. In this article we provide a dispassionate look at medical marijuana, while providing a clinical overview focusing on pain management. We examine the mechanisms of the endocannabinoid system, along with the pharmacology of cannabinoids. Current research on the use of marijuana for the treatment of pain is reviewed. Finally, recommendations for pain management nurses on integrating research, clinical practice, and U.S. drug policy are made.     

Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain

OBJECTIVE: To review the literature concerning the physiology of the endocannabinoid system, current drug development of cannabinoid agonists, and current clinical research on the use of cannabinoid agonists for analgesia. DATA SOURCES: Articles were identified through a search of MEDLINE (1966-August 2005) using the key words cannabis, cannabinoid, cannabi*, cannabidiol, nabilone, THC, pain, and analgesia. No search limits were included. Additional references were located through review of the bibliographies of the articles identified. STUDY SELECTION AND DATA EXTRACTION: Studies of cannabinoid agonists for treatment of pain were selected and were not limited by pain type or etiology. Studies or reviews using animal models of pain were also included. Articles that related to the physiology and pharmacology of the endocannabinoid system were evaluated. DATA SYNTHESIS: The discovery of cannabinoid receptors and endogenous ligands for these receptors has led to increased drug development of cannabinoid agonists. New cannabimimetic agents have been associated with fewer systemic adverse effects than delta-9-tetrahydrocannabinol, including recent development of cannabis medicinal extracts for sublingual use (approved in Canada), and have had promising results for analgesia in initial human trials. Several synthetic cannabinoids have also been studied in humans, including 2 cannabinoid agonists available on the international market. CONCLUSIONS: Cannabinoids provide a potential approach to pain management with a novel therapeutic target and mechanism. Chronic pain often requires a polypharmaceutical approach to management, and cannabinoids are a potential addition to the arsenal of treatment options.     

The role of endocannabinoids in pain modulation

The endocannabinoid system (ES) is comprised of cannabinoid (CB) receptors, their endogenous ligands (endocannabinoids), and proteins responsible for their metabolism. Endocannabinoids serve as retrograde signaling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission, that interact with other neurotransmitters. Physiological stimuli and pathological conditions lead to differential increases in brain endocannabinoids that regulate distinct biological functions. Furthermore, endocannabinoids modulate neuronal, glial, and endothelial cell function and exert neuromodulatory, anti‐excitotoxic, anti‐inflammatory, and vasodilatory effects. Analgesia is one of the principal therapeutic targets of cannabinoids. Cannabinoid analgesia is based on the suppression of spinal and thalamic nociceptive neurons, but peripheral sites of action have also been identified. The chronic pain that occasionally follows peripheral nerve injury differs fundamentally from inflammatory pain and is an area of considerable unmet therapeutic need. Over the last years, considerable progress has been made in understanding the role of the ES in the modulation of pain. Endocannabinoids have been shown to behave as analgesics in models of both acute nociception and clinical pain such as inflammation and painful neuropathy. The framework for such analgesic effects exists in the CB receptors, which are found in areas of the nervous system important for pain processing and in immune cells that regulate the neuro‐immune interactions that mediate the inflammatory hyperalgesia. The purpose of this review is to present the available research and clinical data, up to date, regarding the ES and its role in pain modulation, as well as its possible therapeutic perspectives.     

A possible role for the endocannabinoid system in the neurobiology of depression

The present review synthetically describes the currently advanced hypotheses for a neurobiological basis of depression, ranging from the classical monoaminergic to the more recent neurotrophic hypothesis. Moreover, the Authors review the available preclinical and clinical evidence suggesting a possible role for the endocannabinoid system in the physiopathology of depression. Indeed, in spite of the reporting of conflicting results, the pharmacological enhancement of endocannabinoid activity at the CB1 cannabinoid receptor level appears to exert an antidepressant-like effect in some animal models of depression. On the contrary, a reduced activity of the endogenous cannabinoid system seems to be associated with the animal model of depression, namely the chronic mild stress model. Moreover, a few studies have reported an interaction of antidepressants with the endocannabinoid system. With regard to clinical studies, several authors have reported an alteration of endocannabinoid serum levels in depression, while post mortem studies have demonstrated increased levels of endocannabinoids associated to a concomitant hyperactivity of CB1 receptor in the prefrontal cortex of suicide victims. No clinical trials carried out using cannabinoids in the treatment of affective disorders have been published to date, although anecdotal reports have described both antidepressant and antimanic properties of cannabis as well as the ability of cannabis to induce mania that has also been documented. These findings are discussed, leading us to conclude that, although data available are sufficient to suggest a possible involvement of the endogenous cannabinoid system in the neurobiology of depression, additional studies should be performed in order to better elucidate the role of this system in the physiopathology of depression.     

Cannabinoid analgesia

During the last decade, rigorous scientific methods have been applied to determine the effects of cannabinoids on nociceptive neurotransmission. Cannabinoids have been observed to markedly decrease signalling in specific neural pathways that transmit messages about pain. These effects were found to be due to the suppression of spinal and thalamic nociceptive neurons, and independent of any actions on either the motor system or sensory neurons that transmit messages related to non-nociceptive stimulation. Spinal, supraspinal, and peripheral sites of cannabinoid analgesia have been identified. The discovery of endocannabinoids raised the question of their natural role in pain. Multiple lines of evidence indicate that endocannabinoids serve naturally to suppress pain. While it is now clear that cannabinoids suppress nociceptive neurotransmission, more work is needed to establish the clinical utility of these compounds. The few human studies conducted to date produced mixed results, with more promising findings coming from studies of clinical pain as compared with experimental pain. The therapeutic potential of cannabinoids remains an important topic for future investigations.     

Endocannabinoids increase human adipose stem cell differentiation and growth factor secretion in vitro

Adipose stem cells (ASCs) possess the capacity to proliferate, to differentiate into various cells types, and they are able to secrete growth factors. These characteristics are supposed to contribute to their potential for regenerative medicine approaches. In order to advance the therapeutic effects of ASCs, different modulatory procedures have been examined. In this context, the endocannabinoid system (ECS) represents an interesting possibility, since the increased availability of cannabinoids and the underlying molecular pathways of the ECS are of relevance for the development of new regenerative strategies. The effects of the endocannabinoids anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) were investigated on ASC metabolic activity, quantified by PrestoBlue conversion, and cell numbers, evaluated by crystal violet staining. enzyme‐linked immunosorbent assay (ELISA) measures were performed to determine cytokine release, and differentiation was assessed by specific labeling techniques. AEA increased the metabolic activity, while 2‐AG decreased it in a concentration dependent manner. AEA significantly enhanced OilRed O staining after adipogenic differentiation by over 100%, and both compounds significantly increased cresolphthalein staining after osteogenic differentiation. By contrast, they did not affect sphere diameter or safranin O staining after chondrogenic differentiation. Both substances significantly increased the release of insulin‐like growth factor‐1 and hepatocyte growth factor, while only AEA enhanced transforming growth factor‐β secretion. The results demonstrated that stimulating the ECS exerted significant effects on the biology of ASCs. Exposure to endocannabinoids modulated viability, induced release of regenerative growth factors, and promoted adipogenic and osteogenic differentiation. Our findings could be of specific relevance in ASC based therapies for regenerative medicine.     

The endocannabinoid system and the treatment of obesity

The endocannabinoids are endogenous lipids capable of binding to both cannabinoid receptors (CB) CB1 and CB2. These receptors belong to the G protein–coupled family receptors and they were discovered while investigating the mode of action of Δ⁹‐tetrahydrocannabinol, a component of Cannabis sativa, to which they bind with high affinity. Among many other brain sites, CB1 is present in the hypothalamic nuclei involved in the control of energy balance and body weight, as well as in neurons of the mesolimbic system which is believed to mediate the incentive value of food. At central nervous system level, CB1 activation is necessary to induce food intake after a short period of food deprivation, and when CB1 is activated by endocannabinoids produced in situ, a stimulation of the ingestion of palatable food has been described. CB1 stimulation leads to modulation of the release of some hypothalamic anorexigenic and orexigenic mediators, as well as of dopamine in the nucleus accumbens shell. Recent evidence has proved that CB1 is also present in the peripheral organs, such as the adipose tissue and gastrointestinal system, key organs in the regulation of energy metabolism. Animal models have provided solid evidence that genetically induced obesity leads to long‐lasting overstimulation of endocannabinoid system synthesis resulting in permanent overactivation of CB1, which may then contribute to the maintenance of this disease. Importantly, at peripheral level, CB1 activation has been shown to stimulate lipogenesis in adipocytes. CB1 blockers increase adiponectin production in adipocytes, which leads to increased fatty acid oxidation and free fatty acid clearance. Moreover, CB1 has been shown to be up‐regulated in adipocytes derived from obese rodents. These results support the role of endocannabinoids in the development and maintenance of obesity, paving the way for the development of a new class of drugs such as the CB1 blockers as a therapy for tackling obesity and the associated major cardiovascular risk factors.     

The pharmacology and therapeutic relevance of endocannabinoid derived cyclo-oxygenase (COX)-2 products

The discovery of anandamide and 2-arachidonyl glycerol (2-AG) as naturally occurring mammalian endocannabinoids has had important and wide-reaching therapeutic implications. This, to a large extent, ensues from the complexity of endocannabinoid biology. One facet of endocannabinoid biology now receiving increased attention is the cyclo-oxygenase-2 (COX-2) derived oxidation products. Anandamide and 2-AG are oxidized to a range of PG-ethanolamides and PG-glyceryl esters that closely approaches that of the prostaglandins (PGs) formed from arachidonic acid. The pharmacology of these electrochemically neutral PG-ethanolamides (prostamides) and PG-glyceryl esters appears to be unique. No meaningful interaction with natural or recombinant prostanoid receptors is apparent. Nevertheless, in certain cells and tissues, prostamides and PG-glyceryl esters exert potent effects. The recent discovery of selective antagonists for the putative prostamide receptor has been a major advance in further establishing prostamide pharmacology as an entity distinct from prostanoid receptors. Since discovery of the prototype prostamide antagonist (AGN 204396), rapid progress has been made. The latest prostamide antagonists (AGN 211334-6) are 100 times more potent than the prototype and are, therefore, sufficiently active to be used in living animal studies. These compounds will allow a full evaluation of the role of prostamides in health and disease. To date, the only therapeutic application for prostamides is in glaucoma. The prostamide analog, bimatoprost, being the most effective ocular hypotensive drug currently available. Interestingly, PGE(2)-glyceryl ester and its chemically stable analog PGE(2)-serinolamide also lower intraocular pressure in dogs. Nevertheless, the therapeutic future of PGE(2)-glyceryl ester is more likely to reside in inflammation.     

Receptor-independent actions of cannabinoids on cell membranes: focus on endocannabinoids

Cannabinoids are a structurally diverse group of mostly lipophilic molecules that bind to cannabinoid receptors. In fact, endogenous cannabinoids (endocannabinoids) are a class of signaling lipids consisting of amides and esters of long-chain polyunsaturated fatty acids. They are synthesized from lipid precursors in plasma membranes via Ca(2+) or G-protein-dependent processes and exhibit cannabinoid-like actions by binding to cannabinoid receptors. However, endocannabinoids can produce effects that are not mediated by these receptors. In pharmacologically relevant concentrations, endocannabinoids modulate the functional properties of voltage-gated ion channels including Ca(2+) channels, Na(+) channels, various types of K(+) channels, and ligand-gated ion channels such as serotonin type 3, nicotinic acetylcholine, and glycine receptors. In addition, modulatory effects of endocannabinoids on other ion-transporting membrane proteins such as transient potential receptor-class channels, gap junctions and transporters for neurotransmitters have also been demonstrated. Furthermore, functional properties of G-protein-coupled receptors for different types of neurotransmitters and neuropeptides are altered by direct actions of endocannabinoids. Although the mechanisms of these effects are currently not clear, it is likely that these direct actions of endocannabinoids are due to their lipophilic structures. These findings indicate that additional molecular targets for endocannabinoids exist and that these targets may represent novel sites for cannabinoids to alter either the excitability of the neurons or the response of the neuronal systems. This review focuses on the results of recent studies indicating that beyond their receptor-mediated effects, endocannabinoids alter the functions of ion channels and other integral membrane proteins directly.     

Comprehensive profiling of the human circulating endocannabinoid metabolome: clinical sampling and sample storage parameters

Abstract Background: Endogenous cannabinoid-receptor ligands (endocannabinoids) and over a dozen related metabolites now comprise the "endocannabinoid metabolome". The diverse (patho)physiological roles of endocannabinoids, the predictive/diagnostic utility of systemic endocannabinoid levels, and the growing interest in endocannabinoid-related pharmacotherapeutics mandate a valid clinical protocol for processing human blood that does not jeopardize profiling of the circulating endocannabinoid metabolome. Methods: We systematically evaluated the potential effect of pre-analytical variables associated with phlebotomy and sample handling/work-up on the human-blood endocannabinoid metabolome as quantified by state-of-the-art liquid chromatography-mass spectrometry. Results: Neither subject posture during phlebotomy nor moderate activity beforehand influenced the blood levels of the 15 endocannabinoid-system lipids quantified. Storage of fresh blood at 4 degrees C selectively enhanced ethanolamide concentrations artifactually without affecting monoglycerides and nonesterified fatty acids, such as arachidonic acid. In marked contrast, ethanolamides and monoglycerides remained stable through three plasma freeze/thaw cycles, whereas plasma arachidonic acid content increased, probably a reflection of ongoing metabolism. Conclusions: Class- and compound-selective pre-analytical influences on circulating human endocannabinoid levels necessitate immediate plasma preparation from fresh blood and prompt plasma apportioning and snap-freezing. Repeated plasma thawing and refreezing should be avoided. This protocol ensures sample integrity for evaluating the circulating endocannabinoid metabolome in the clinical setting. Clin Chem Lab Med 2008;46:1289-95.     

Administration of nabilone for postoperative pain control in the marijuana-addicted: Case study

Cannabis has been used for the treatment of pain for centuries. Case reports, small uncontrolled studies among health care providers suggest that cannabis and cannabinoids can be helpful for the relief of pain. However, controlled studies and systematic reviews have been less conclusive. Attempts to administer synthetic cannabinoids for postoperative pain control are disappointing. Moreover, marijuana addiction is an exclusion criterion in all published articles.We report the first, at least to our knowledge, administration of nabilone, a synthetic cannabinoid, for postoperative pain control in a marijuana-addicted patient as an adjuvant drug. The results suggest that nabilone can be considered as part of a multimodal analgesic regimen for habitual marijuana abusers. Nabilone optimizes pain control, improves sleep, decreases irritability and promotes early return of bowel function.     

The endocannabinoid system: body weight and metabolic regulation

The endocannabinoid system elicits multiple physiologic functions that are not fully understood. Antagonism of cannabinoid type 1 (CB(1)) receptors has been the only successful new pharmacologic treatment approach in Phase III studies in obesity in the last 8 years. Whereas antagonism of (CB(1)) receptors acutely reduces food intake, the long-term effects on weight reduction and metabolic regulation appear to be mediated by stimulation of energy expenditure and by peripheral effects related to liver, skeletal muscle, adipose tissue, and pancreas physiology. For example, in the liver, lipogenic enzymes and fatty acid synthesis are upregulated by endocannabinoids, and in adipose tissue, antagonism of (CB(1)) receptors increases secretion of adiponectin. Some studies suggest that endocannabinoid formation is increased in obesity, perhaps because endocannabinoid degradation is decreased. Although many questions remain unanswered at present, the emerging concept of endocannabinoids as metabolic regulators helps to explain the success of rimonabant (SR141716), an antagonist of (CB(1)) receptors, currently in Phase III studies.     

Inhibition of rat C6 glioma cell proliferation by endogenous and synthetic cannabinoids. Relative involvement of cannabinoid and vanilloid receptors.

The effects of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) upon rat C6 glioma cell proliferation were examined and compared with a series of synthetic cannabinoids and related compounds. Cells were treated with the compounds each day and cell proliferation was monitored for up to 5 days of exposure. AEA time- and concentration-dependently inhibited C6 cell proliferation. After 4 days of treatment, AEA and 2-AG inhibited C6 cell proliferation with similar potencies (IC(50) values of 1.6 and 1.8 microM, respectively), whereas palmitoylethanolamide showed no significant antiproliferative effects at concentrations up to 10 microM. The antiproliferative effects of both AEA and 2-AG were blocked completely by a combination of antagonists at cannabinoid receptors (SR141716A and SR144528 or AM251 and AM630) and vanilloid receptors (capsazepine) as well as by alpha-tocopherol (0.1 and 10 microM), and reduced by calpeptin (10 microM) and fumonisin B(1) (10 microM), but not by L-cycloserine (1 and 100 microM). CP 55,940, JW015, olvanil, and arachidonoyl-serotonin were all found to affect C6 glioma cell proliferation (IC(50) values of 5.6, 3.2, 5.5, and 1.6 microM, respectively), but the inhibition could not be blocked by cannabinoid + vanilloid receptor antagonists. It is concluded that the antiproliferative effects of the endocannabinoids upon C6 cells are brought about by a mechanism involving combined activation of both vanilloid receptors and to a lesser extent cannabinoid receptors, and leading to oxidative stress and calpain activation. However, there is at present no obvious universal mechanism whereby plant-derived, synthetic, and endogenous cannabinoids affect cell viability and proliferation.