“The pharmacologic and biochemical features of cannabinoids make them candidates for antiseizure medications. At this time, anecdotes have outstripped controlled clinical trials as sources of support for their clinical value.”
Tag Archives: Cannabinoids
Cannabidiol and sodium nitroprusside: two novel neuromodulatory pharmacological interventions to treat and prevent psychosis.
“Since most patients with schizophrenia do not respond properly to treatment, scientific effort has been driven to the development of new compounds acting on pharmacological targets beyond the dopaminergic system.
Therefore, the aim is to review basic and clinical research findings from studies evaluating the effects of cannabidiol (CBD), an inhibitor of the reuptake and metabolism of anandamide and several other effects on nervous system, and sodium nitroprusside, a nitric oxide donor, on the prevention and treatment of psychosis.
Animal and human research supports that CBD and sodium nitroprusside might be effective in the prevention and treatment of psychosis in general and especially in schizophrenia.
The evidence available to date shows that CBD and sodium nitroprusside act in pathways associated with psychotic symptoms and that they may be important agents in the management of prodromal psychotic states and psychosis.
This underscores the relevance of further research on the effects of these agents and others that mediate the activity of the cannabinoid system and of nitric oxide, as well as comparative studies of their antipsychotic effects and those of other antipsychotic drugs currently used to treat schizophrenia.”
Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis.
“Chronic inflammation in rheumatoid arthritis (RA) is accompanied by activation of the sympathetic nervous system, which can support the immune system to perpetuate inflammation. Several animal models of arthritis already demonstrated a profound influence of adrenergic signaling on the course of RA.
Peripheral norepinephrine release from sympathetic terminals is controlled by cannabinoid receptor type 1 (CB1), which is activated by two major endocannabinoids (ECs), arachidonylethanolamine (anandamide) and 2-arachidonylglycerol.
These ECs also modulate function of transient receptor potential channels (TRPs) located on sensory nerve fibers, which are abundant in arthritic synovial tissue. TRPs not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides.
In addition, many cell types in synovial tissue express CB1 and TRPs.
In this review, we focus on CB1 and transient receptor potential vanilloid 1 (TRPV1)-mediated effects on RA since most anti-inflammatory mechanisms induced by cannabinoids are attributed to cannabinoid receptor type 2 (CB2) activation.
We demonstrate how CB1 agonism or antagonism can modulate arthritic disease.
The concept of functional antagonism with continuous CB1 activation is discussed.
Since fatty acid amide hydrolase (FAAH) is a major EC-degrading enzyme, the therapeutic possibility of FAAH inhibition is studied.
Finally, the therapeutic potential of ECs is examined since they interact with cannabinoid receptors and TRPs but do not produce central side effects.”
High Times for Painful Blues: The Endocannabinoid System in Pain-Depression Comorbidity.
“Depression and pain are two of the most debilitating disorders worldwide and have an estimated cooccurrence of up to 80%. Comorbidity of these disorders is more difficult to treat, associated with significant disability and impaired health-related quality of life than either condition alone, resulting in enormous social and economic cost.
Several neural substrates have been identified as potential mediators in the association between depression and pain, including neuroanatomical reorganization, monoamine and neurotrophin depletion, dysregulation of the hypothalamo-pituitary-adrenal axis, and neuroinflammation.
However, the past decade has seen mounting evidence supporting a role for the endogenous cannabinoid (endocannabinoid) system in affective and nociceptive processing, and thus, alterations in this system may play a key role in reciprocal interactions between depression and pain.
This review will provide an overview of the preclinical evidence supporting an interaction between depression and pain and the evidence supporting a role for the endocannabinoid system in this interaction.”
http://www.ncbi.nlm.nih.gov/pubmed/26342110
“The plant Cannabis sativa has been used as a medicine throughout the world for several thousand years, with reports of its use in treating painful symptoms appearing as early as 2600 BC. The principal psychoactive ingredient of Cannabis sativa, delta-9-tetrahydrocannabinol (Δ9-THC), was first identified in 1964, and subsequent studies to understand its mechanism of action led to the discovery of the endogenous cannabinoid (endocannabinoid) system… Because of the distribution of the endocannabinoid system throughout spinal and supraspinal regions, it is in a prime position to regulate neurophysiological activities such as affective and nociceptive processing… evidence suggests a prominent role for the endocannabinoid system in the interaction between depression and pain,” http://ijnp.oxfordjournals.org/content/early/2015/09/04/ijnp.pyv095.long
Issues and promise in clinical studies of botanicals with anticonvulsant potential.
“Botanicals are increasingly used by people with epilepsy worldwide. However, despite abundant preclinical data on the anticonvulsant properties of many herbal remedies, there are very few human studies assessing safety and efficacy of these products in epilepsy.Additionally, the methodology of most of these studies only marginally meets the requirements of evidence-based medicine.
Although the currently available evidence for the use of cannabinoids in epilepsy is similarly lacking, several carefully designed and well controlled industry-sponsored clinical trials of cannabis derivatives are planned to be completed in the next couple of years, providing the needed reliable data for the use of these products.
The choice of the best botanical candidates with anticonvulsant properties and their assessment in well-designed clinical trials may significantly improve our ability to effectively and safely treat patients with epilepsy. ”
Cannabinoids in the Treatment of Neurological Disorders
“The force of the recent explosion of largely unproven and unregulated cannabis-based preparations on medical therapeutics may have its greatest impact in the field of neurology.
Paradoxically, for 10 millennia this plant has been an integral part of human cultivation, where it was used for its fibers long before its pharmacological properties.
With regard to the latter, cannabis was well known to healers from China and India thousands of years ago; Greek and Roman doctors during classic times; Arab doctors during the Middle Ages; Victorian and Continental physicians in the nineteenth century; American doctors during the early twentieth century; and English doctors until 1971 when a variety of nonevidence-based remedies were removed from the British Pharmaceutical Codex.
The clinical data on cannabis therapeutics are meager and the vast majority are formed by surveys or small studies that are underpowered and/or suffer from multiple methodological flaws, often by virtue of limited research funding for nonaddiction-focused studies. Thus, we know relatively little about the clinical efficacy of cannabinoids for the various neurological disorders for which historical nonscientific and medical literature have advocated its use.
The relative scarcity of proven cannabis-based therapies is not due to data that show that cannabinoids are ineffective or unsafe, but rather reflects a poverty of medical interest and a failure by pharmaceutical companies arising from regulatory restrictions compounded by limits for patent rights on plant cannabinoid-containing preparations that have been used medicinally for millennia, as is the case for most natural products.
We are pleased to have gathered many of the world’s experts together on the basic biology of cannabinoids, as well as their potential role in treating neurologic and psychiatric disorders…
We hope that this issue of Neurotherapeutics will serve to mark the bounds of verifiable scientific knowledge of cannabinoids in the treatment of neuropsychiatric and neurological disorders. At the same time, our contributors have also helped identify areas for future research, as well as the strategies needed to move our base of knowledge forward.
We hope that this volume will help to accelerate the pace of the appropriately focused and productive research and double-blind placebo-controlled randomized trials to the point at which the care of patients is informed by valid data and not just anecdote.”
http://link.springer.com/article/10.1007/s13311-015-0388-0/fulltext.html
G protein-coupled receptor 18: A potential role for endocannabinoid signalling in metabolic dysfunction.
“Endocannabinoids are products of dietary fatty acids that are modulated by an alteration in food intake levels.
Overweight and obese individuals have substantially higher circulating levels of the arachidonic acid-derived endocannabinoids, anandamide and 2-arachidonoyl glycerol, and show an altered pattern of cannabinoid receptor expression.
These cannabinoid receptors are part of a large family of G protein-coupled receptors (GPCRs).
GPCRs are major therapeutic targets for various diseases within the cardiovascular, neurological, gastrointestinal and endocrine systems, as well as metabolic disorders such as obesity and type 2 diabetes mellitus.
Obesity is considered a state of chronic low grade inflammation elicited by an immunological response.
Interestingly, the newly deorphanised G protein-coupled receptor GPR18, which is considered to be a putative cannabinoid receptor, is proposed to have an immunological function.
In this review, the current scientific knowledge on GPR18 is explored including its localisation, signalling pathways and pharmacology.
Importantly, the involvement of nutritional factors and potential dietary regulation of GPR18 and its (patho)physiological roles are described.
Further research on this receptor and its regulation will enable a better understanding of the complex mechanisms of GPR18 and its potential as a novel therapeutic target for treating metabolic disorders.”
The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells.
“One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs. Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells. By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential mediator of cannabinoid antitumoral action and show that p8 upregulation is dependent on de novo-synthesized ceramide. We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes ATF-4, CHOP, and TRB3. Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.”
http://www.ncbi.nlm.nih.gov/pubmed/16616335
“Marijuana has been used in medicine for many centuries, and nowadays there is a renaissance in the study of the therapeutic effects of cannabinoids. One of the most active areas of research in the cannabinoid field is the study of the potential antitumoral application of these drugs. Our results unravel the mechanism of cannabinoid antitumoral action by demonstrating the proapoptotic role of the stress protein p8 via its downstream targets ATF-4, CHOP, and TRB3.
The identification of this pathway may contribute to the design of therapeutic strategies for inhibiting tumor growth. In particular, our findings can help to improve the efficiency and selectivity of potential antitumoral therapies with cannabinoids.
Our results also support that cannabinoid treatment does not activate this pathway in nontransformed cells, in line with the belief that cannabinoid proapoptotic action is selective for tumor versus nontumor cells, and that cannabinoids act in a synergic fashion with ER stress inducers as well as with other antitumoral agents.
The identification of the p8-regulated pathway described here may contribute to the design of therapeutic strategies for inhibiting tumor growth. In particular, our findings can help to improve the efficiency and selectivity of a potential cannabinoid-based antitumoral therapy.”
http://www.sciencedirect.com/science/article/pii/S1535610806000857
Clinical perspectives on medical marijuana (cannabis) for neurologic disorders.
“The American Academy of Neurology published an evidence-based systematic review of randomized controlled trials using marijuana (Cannabis sativa) or cannabinoids in neurologic disorders.
Several cannabinoids showed effectiveness or probable effectiveness for spasticity, central pain, and painful spasms in multiple sclerosis.
The review justifies insurance coverage for dronabinol and nabilone for these indications.
Many insurance companies already cover these medications for other indications.
It is unlikely that the review will alter coverage for herbal marijuana.
Currently, no payers cover the costs of herbal medical marijuana because it is illegal under federal law and in most states.
Cannabinoid preparations currently available by prescription may have a role in other neurologic conditions, but quality scientific evidence is lacking at this time.”
Medical Marijuana and Chronic Pain: a Review of Basic Science and Clinical Evidence.
“Cannabinoid compounds include phytocannabinoids, endocannabinoids, and synthetics.
The two primary phytocannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), with CB1 receptors in the brain and peripheral tissue and CB2 receptors in the immune and hematopoietic systems.
The route of delivery of cannabis is important as the bioavailability and metabolism are very different for smoking versus oral/sublingual routes.
Gold standard clinical trials are limited; however, some studies have thus far shown evidence to support the use of cannabinoids for some cancer, neuropathic, spasticity, acute pain, and chronic pain conditions.”