From cannabis to the endocannabinoid system: refocussing attention on potential clinical benefits.

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“Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the ‘holy grail’ of endocannabinoid research.”

http://www.ncbi.nlm.nih.gov/pubmed/23155985

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

Abstract

  “The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control.”

Summary

“The discovery of an endocannabinoid signaling system has opened new possibilities for research into understanding the mechanisms of marijuana actions, the role of the endocannabinoid system in homeostasis, and the development of treatment approaches based either on the phytocannabinoids or novel molecules. CB1 agonists may have roles in the treatment of neuropathic pain, spasticity, nausea and emesis, cachexia, and potentially neuroprotection after stroke or head injury. Agonists and antagonists of peripheral CB receptors may be useful in the treatment of inflammatory and autoimmune disorders, as well as hypertension and other cardiovascular diseases. CB1 antagonists may find utility in management of obesity and drug craving. Other novel agents that may not be active at CB receptor sites, but might otherwise modify cannabinoid transport or metabolism, may also have a role in therapeutic modification of the endocannabinoid system. While the short and long term toxicities of the newer compounds are not known, one must expect that at least some of the acute effects (psychotropic effects; hypotension) may be shared by CB agonists. While there are few, long-term serious toxicities attributable to marijuana, extrapolation to newer and more potent agonists, antagonists, and cannabinoid system modulators cannot be assumed. CB1 agonists have the potential in animal models to produce drug preference and drug seeking behaviors as well as tolerance and abstinence phenomena similar to, though not generally as severe as those of other drugs of addiction. There is increasing evidence from human observations that withdrawal from the phytocannabinoids can produce an abstinence syndrome characterized primarily by irritability, sleep disturbance, mood disturbance, and appetite disturbance in chronic heavy users, therefore, such possible effects will need to be considered in the evaluation of newer shorter acting and more potent agonists.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2544377/

Cannabinoids for the treatment of inflammation.

“Cannabinoids are effective at suppressing immune and inflammation functions in leukocytes in vitro, and in animal models of acute inflammation, such as the mouse hind paw, ear and air pouch models, as well as gastrointestinal, pulmonary, myocardial, vascular, periodontal, neural, hepatic, pancreatic and arthritic inflammation models.

The non-psychoactive cannabinoid receptor CB2 is emerging as a critical target for cannabinoid regulation of inflammation, and thus CB2-selective agonists are undergoing intense investigation and research. This review discusses the evidence for cannabinoid regulation of inflammation across a range of models and highlights the most promising drug candidates.”

http://www.ncbi.nlm.nih.gov/pubmed/17520866

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

Philosophical Transactions of the Royal Society B: Biological Sciences: 367 (1607)

“Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive ‘multi-targeting’.”  https://www.ncbi.nlm.nih.gov/pubmed/23108552

“Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities”  http://rstb.royalsocietypublishing.org/content/367/1607/3353.long

Therapeutic aspects of cannabis and cannabinoids

The British Journal of Psychiatry

“HISTORY OF THERAPEUTIC USE

The first formal report of cannabis as a medicine appeared in China nearly 5000 years ago when it was recommended for malaria, constipation, rheumatic pains and childbirth and, mixed with wine, as a surgical analgesic. There are subsequent records of its use throughout Asia, the Middle East, Southern Africa and South America. Accounts by Pliny, Dioscorides and Galen remained influential in European medicine for 16 centuries.”

“It was not until the 19th century that cannabis became a mainstream medicine in Britain. W. B. O’Shaughnessy, an Irish scientist and physician, observed its use in India as an analgesic, anticonvulsant, anti-spasmodic, anti-emetic and hypnotic. After toxicity experiments on goats and dogs, he gave it to patients and was impressed with its muscle-relaxant, anticonvulsant and analgesic properties, and recorded its use-fulness as an anti-emetic.”

“After these observations were published in 1842, medicinal use of cannabis expanded rapidly. It soon became available ‘over the counter’ in pharmacies and by 1854 it had found its way into the United States Dispensatory. The American market became flooded with dozens of cannabis-containing home remedies.”

“Cannabis was outlawed in 1928 by ratification of the 1925 Geneva Convention on the manufacture, sale and movement of dangerous drugs. Prescription remained possible until final prohibition under the 1971 Misuse of Drugs Act, against the advice of the Advisory Committee on Drug Dependence.”

“In the USA, medical use was effectively ruled out by the Marijuana Tax Act 1937. This ruling has been under almost constant legal challenge and many special dispensations were made between 1976 and 1992 for individuals to receive ‘compassionate reefers’. Although this loophole has been closed, a 1996 California state law permits cultivation or consumption of cannabis for medical purposes, if a doctor provides a written endorsement. Similar arrangements apply in Italy and Canberra, Australia.”

“Results and Conclusions Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.”

http://bjp.rcpsych.org/content/178/2/107.long

Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.

“Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions).

The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol.

Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol,

the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/19729208

The therapeutic potential of novel cannabinoid receptors.

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“Cannabinoids produce a plethora of biological effects, including the modulation of neuronal activity through the activation of CB(1) receptors and of immune responses through the activation of CB(2) receptors. The selective targeting of either of these two receptor subtypes has clear therapeutic value. Recent evidence indicates that some of the cannabinomimetic effects previously thought to be produced through CB(1) and/or CB(2) receptors, be they on neuronal activity, on the vasculature tone or immune responses, still persist despite the pharmacological blockade or genetic ablation of CB(1) and/or CB(2) receptors. This suggests that additional cannabinoid and cannabinoid-like receptors exist. Here we will review this evidence in the context of their therapeutic value and discuss their true belonging to the endocannabinoid signaling system.”  http://www.ncbi.nlm.nih.gov/pubmed/19248809

“The therapeutic potential of novel cannabinoid receptors”  http://www.sciencedirect.com/science/article/pii/S0163725809000266

Cannabinoid receptors in brain: pharmacogenetics, neuropharmacology, neurotoxicology, and potential therapeutic applications.

“Much progress has been achieved in cannabinoid research. A major breakthrough in marijuana-cannabinoid research has been the discovery of a previously unknown but elaborate endogenous endocannabinoid system (ECS), complete with endocannabinoids and enzymes for their biosynthesis and degradation with genes encoding two distinct cannabinoid (CB1 and CB2) receptors (CBRs) that are activated by endocannabinoids, cannabinoids, and marijuana use.

Physical and genetic localization of the CBR genes CNR1 and CNR2 have been mapped to chromosome 6 and 1, respectively. A number of variations in CBR genes have been associated with human disorders including osteoporosis, attention deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), drug dependency, obesity, and depression. Other family of lipid receptors including vanilloid (VR1) and lysophosphatidic acid (LPA) receptors appear to be related to the CBRs at the phylogenetic level. The ubiquitous abundance and differential distribution of the ECS in the human body and brain along with the coupling to many signal transduction pathways may explain the effects in most biological system and the myriad behavioral effects associated with smoking marijuana. The neuropharmacological and neuroprotective features of phytocannabinoids and endocannabinoid associated neurogenesis have revealed roles for the use of cannabinoids in neurodegenerative pathologies with less neurotoxicity. The remarkable progress in understanding the biological actions of marijuana and cannabinoids have provided much richer results than previously appreciated cannabinoid genomics and raised a number of critical issues on the molecular mechanisms of cannabinoid induced behavioral and biochemical alterations. These advances will allow specific therapeutic targeting of the different components of the ECS in health and disease.

 This review focuses on these recent advances in cannabinoid genomics and the surprising new fundamental roles that the ECS plays in the retrograde signaling associated with cannabinoid inhibition of neurotransmitter release to the genetic basis of the effects of marijuana use and pharmacotherpeutic applications and limitations. Much evidence is provided for the complex CNR1 and CNR2 gene structures and their associated regulatory elements. Thus, understanding the ECS in the human body and brain will contribute to elucidating this natural regulatory mechanism in health and disease.”

http://www.ncbi.nlm.nih.gov/pubmed/19897083

Endocannabinoids Measurement in Human Saliva as Potential Biomarker of Obesity

Background

“The discovery of the endocannabinoid system and of its role in the regulation of energy balance has significantly advanced our understanding of the physiopathological mechanisms leading to obesity and type 2 diabetes. New knowledge on the role of this system in humans has been acquired by measuring blood endocannabinoids. Here we explored endocannabinoids and related N-acylethanolamines in saliva and verified their changes in relation to body weight status and in response to a meal or to body weight loss.”

“The discovery of the endocannabinoid system (ECS) and of its impact on the regulation of energy homeostasis represents a significant advance in the study of obesity and type 2 diabetes [1][4].”

“The saliva is the first digestive secretion produced in response to the ingestion of food [11]. Therefore, it is reasonable to investigate whether signals and systems involved in the regulation of food intake, such as the ECS, might be present in saliva and exert a functional role. Besides, saliva offers distinctive advantages over serum or plasma as a diagnostic tool, thanks to the non-invasiveness of the collection procedure.”

“The ECS is present in human salivary glands.”

“Changes in salivary endocannabinoids and N-acylethanolamines levels in response to body weight loss.”

“Here we demonstrate that endocannabinoids and related N-acylethanolamines can be reliably detected and quantified in human saliva. Similarly to what already reported for circulating levels in the blood [7], [9], [10], the salivary concentration of AEA and OEA were significantly increased in obese, insulin-resistant subjects as compared to normal weight controls.”

“the present findings overall indicate that salivary AEA might be a useful biomarker in human obesity, in particular considering that salivary samples are easy to collect, require a non-invasive procedure advantageous when performing studies in obese subjects in whom venipuncture may be difficult, and can be repeatedly collected at home by the patient during a therapeutic intervention. This type of tool could therefore be used to better phenotype the obese population, assess responses to treatment, or to further study the physiology of the ECS in humans, by investigating salivary endocannabinoid responses under various conditions.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409167/

Cannabinoid signalling regulates inflammation and energy balance: the importance of the brain-gut axis.

Abstract

“Energy balance is controlled by centres of the brain which receive important inputs from the gastrointestinal tract, liver, pancreas, adipose tissue and skeletal muscle, mediated by many different signalling molecules. Obesity occurs when control of energy intake is not matched by the degree of energy expenditure. Obesity is not only a state of disordered energy balance it is also characterized by systemic inflammation. Systemic inflammation is triggered by the leakage of bacterial lipopolysaccharide through changes in intestinal permeability. The endocannabinoid system, consisting of the cannabinoid receptors, endogenous cannabinoid ligands and their biosynthetic and degradative enzymes, plays vital roles in the control of energy balance, the control of intestinal permeability and immunity. In this review we will discuss how the endocannabinoid system, intestinal microbiota and the brain-gut axis are involved in the regulation of energy balance and the development of obesity-associated systemic inflammation. Through direct and indirect actions throughout the body, the endocannabinoid system controls the development of obesity and its inflammatory complications.”

http://www.ncbi.nlm.nih.gov/pubmed/22269477