Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex®): A Review in Multiple Sclerosis-Related Spasticity.

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“Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (THC/CBD, Sativex®, nabiximols) is available in numerous countries worldwide for the treatment of multiple sclerosis (MS)-related moderate to severe spasticity in patients who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

Twelve weeks’ therapy with THC/CBD improved MS-related spasticity in patients with an inadequate response to other anti-spasticity agents who had undergone a successful initial trial of THC/CBD therapy, according to the results of a pivotal phase 3 trial.

Improvements in spasticity were maintained in the longer term with THC/CBD with no evidence of dose tolerance, and results of real-world studies confirm the effectiveness of THC/CBD in everyday clinical practice.

Improvements in health-related quality of life and activities of daily living were also seen with THC/CBD.

THC/CBD is generally well tolerated; adverse effects such as dizziness may occur whilst the THC/CBD dosage is being optimized.

THC/CBD has low abuse potential and a low risk of psychoactive effects.

In conclusion, THC/CBD oromucosal spray is a useful option for the treatment of MS-related spasticity not completely relieved with current anti-spasticity medication.”

https://www.ncbi.nlm.nih.gov/pubmed/28293911

Cannabis in Chinese Medicine: Are Some Traditional Indications Referenced in Ancient Literature Related to Cannabinoids?

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“Cannabis sativa L. has been cultivated in China for millennia for use as a fiber, food, and medicine. Cannabis sativa L. (Cannabaceae) has a long history of utilization as a fiber and seed crop in China, and its achenes (“seeds”) as well as other plant parts have been recorded in Chinese medical texts for nearly 2000 years.

While the primary applications of cannabis in Chinese medicine center around the use of the achenes, ancient indications for the female inflorescence, and other plant parts include conditions such as pain and mental illness that are the subject of current research into cannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC).

In this article, prominent historical applications of cannabis in Chinese medicine are chronologically reviewed, and indications found in ancient Chinese literature that may relate to cannabinoids such as CBD and Δ9-THC are investigated.

In recent years, cannabinoids such as CBD and Δ9-THC have attracted increased attention in the context of modern pharmacology and popular Western culture, yet little research has been done to explore the historical applications of cannabis in Chinese medicine. Given China’s long history of hemp cultivation and its rich body of un-translated medical literature, it is surprising that little academic attention has focused on exploring the ways in which cannabis was used in Chinese medicine. The importance of cannabis as a fiber and food crop in ancient China, combined with the extensive use of the achenes in medicine, makes the Chinese historical record particularly valuable.

Bencao literature opens a window into the history and culture of ancient Chinese medicine. As all parts of the cannabis plant were recorded in bencao texts, the Chinese medical literature can help to clarify many details about the historical applications of cannabis in Chinese medicine, as well as providing clues into the historical prevalence of different biotypes as ancient Chinese farmers gradually selected superior varieties for fiber and seed crops.

The significant differences in how cannabis has been employed in Chinese vs. Western medicine likely relate to differences between drug and fiber biotypes as well as cultural factors, but thus far minimal research has focused on exploring this issue. Similarly, minimal attention has been given to the topic of CBD in Chinese medical history, as even fiber-rich biotypes of cannabis that were not associated with drug use may have had potential therapeutic applications related to CBD. While this modest review can only scratch the surface of the Chinese medical literature of cannabis and the questions it raises, it is hoped that further research will help to further elucidate these questions using a multidisciplinary approach.”

http://journal.frontiersin.org/article/10.3389/fphar.2017.00108/full

Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others?

 

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“The complexity of the endocannabinoid (eCB) system is becoming better understood and new drivers of eCB signaling are emerging. Modulation of the activities of the eCB system can be therapeutic in a number of diseases.

Research into the eCB system has been paralleled by the development of agents that interact with cannabinoid receptors. In this regard it should be remembered that herbal cannabis contains a myriad of active ingredients, and the individual cannabinoids have quite distinct biological activities requiring independent studies.

This article reviews the most important current data involving the eCB system in relation to human diseases, to reflect the present (based mainly on the most used prescription cannabinoid medicine, THC/CBD oromucosal spray) and potential future uses of cannabinoid-based therapy.

Expert commentary: From the different therapeutic possibilities, THC/CBD oromucosal spray has been in clinical use for approximately five years in numerous countries world-wide for the management of multiple sclerosis (MS)-related moderate to severe resistant spasticity.

Clinical trials have confirmed its efficacy and tolerability.

Other diseases in which different cannabinoids are currently being investigated include various pain states, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and epilepsy. The continued characterization of individual cannabinoids in different diseases remains important.”

https://www.ncbi.nlm.nih.gov/pubmed/28276775

Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go?

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“Fifty years after the discovery of Δ9-tetrahydrocannabinol (THC) as the psychoactive component of Cannabis, we are assessing the possibility of translating this herb into clinical treatment of inflammatory bowel diseases (IBDs).

Here, a discussion on the problems associated with a potential treatment is given.

From first surveys and small clinical studies in patients with IBD we have learned that Cannabis is frequently used to alleviate diarrhea, abdominal pain, and loss of appetite.

Single ingredients from Cannabis, such as THC and cannabidiol, commonly described as cannabinoids, are responsible for these effects. Synthetic cannabinoid receptor agonists are also termed cannabinoids, some of which, like dronabinol and nabilone, are already available with a narcotic prescription.

Recent data on the effects of Cannabis/cannabinoids in experimental models of IBD and in clinical trials with IBD patients have been reviewed using a PubMed database search. A short background on the endocannabinoid system is also provided.

Expert commentary: Cannabinoids could be helpful for certain symptoms of IBD, but there is still a lack of clinical studies to prove efficacy, tolerability and safety of cannabinoid-based medication for IBD patients, leaving medical professionals without evidence and guidelines.”

Can we make cannabis safer?

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“Cannabis use and related problems are on the rise globally alongside an increase in the potency of cannabis sold on both black and legal markets. Additionally, there has been a shift towards abandoning prohibition for a less punitive and more permissive legal stance on cannabis, such as decriminalisation and legalisation. It is therefore crucial that we explore new and innovative ways to reduce harm.

Research has found cannabis with high concentrations of its main active ingredient, δ-9-tetrahydrocannabinol (THC), to be more harmful (in terms of causing the main risks associated with cannabis use, such as addiction, psychosis, and cognitive impairment) than cannabis with lower concentrations of THC. By contrast, cannabidiol, which is a non-intoxicating and potentially therapeutic component of cannabis, has been found to reduce the negative effects of cannabis use.

Here, we briefly review findings from studies investigating various types of cannabis and discuss how future research can help to better understand and reduce the risks of cannabis use.”  https://www.ncbi.nlm.nih.gov/pubmed/28259650

“Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797438/

“CBD may also potentiate some of Δ9-THC’s beneficial effects as it reduces Δ9-THC’s psychoactivity to enhance its tolerability and widen its therapeutic window.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707667/

The endocannabinoid system modulating levels of consciousness, emotions and likely dream contents.

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“Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is ∆9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors.

These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named as the CB1 and CB2 cannabinoid receptors.

Later, an endogenous molecule that exerts pharmacological effects similar to those described by ∆9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG).

Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2-AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT).

To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various diseases, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity.

Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams.

Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences.”

https://www.ncbi.nlm.nih.gov/pubmed/28240187

Cannabinoid HU210 Protects Isolated Rat Stomach against Impairment Caused by Serum of Rats with Experimental Acute Pancreatitis

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“Acute pancreatitis (AP), especially severe AP, is a potentially lethal inflammatory disease of pancreas which often leads to extra-pancreatic complications, even multiple systemic organ dysfunctions. It has been reported that 52% of patients with acute pancreatitis develop acute gastrointestinal mucosal lesion (AGML) or stress ulcer.

For centuries, Cannabis plant and its extracts have been used to alleviate symptoms of gastrointestinal inflammatory diseases.

It has been established that D9-tetrahydrocannabinol, the major psychoactive component of Cannabis, exerts its primary cellular actions though two G protein-coupled receptors, cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors.

Since then, these two receptors have been recognized as the major regulators of physiological and pathological processes. Cannabinoids can reduce gastrointestinal secretion, and the activation of CB1 receptor exhibits protective role against stress-induced AGML, but the mechanisms of their action remain elusive.

The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis.

Therefore, our experimental results suggest a novel mechanism in the onset of AGML and new therapeutic values of cannabinoids as supplement of anti-inflammatory therapy in acute pancreatitis.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532296/

Cannabinoids and Cystic Fibrosis

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“Cannabis stimulates appetite and food intake. This property has been exploited to benefit AIDS and cancer patients suffering from wasting disease, by administering the whole plant or its major active ingredient ?-tetrahydrocannabinol (THC). Endogenous cannabinoids (“endocannabinoids”) are found in maternal milk. We have recently shown that endocannabinoids are critical for milk ingestion and survival of newborns because blocking CB1 receptors resulted in death from malnutrition. Lack of appetite resulting in malnutrition is a contributing factor to mortality in many Cystic Fibrosis (CF) patients. It is proposed here for the first time, to administer THC to CF patients. It is hoped that the cannabinoid will alleviate malnutrition and thus help prevent wasting in CF patients. Recent findings suggest that a lipid imbalance (high arachidonic acid/low DHA) is a primary factor in the etiology of CF and that defective CFTR (CF transmembrane conductor regulator) that characterizes the CF condition is responsible for the dysregulation. Endocannabinoids are all fatty acid derivatives. Therefore, it is further proposed here that the CFTR gene product also modulates endocannabinoid synthesis, through regulation of fatty acid biosynthesis. According to this hypothesis, CF patients display decreased levels of endocannabinoids and by elevating these levels, symptoms may improve. Indeed, a number of physiological mechanisms of cannabinoids and endocannabinoids coincide with the pathology of CF. Thus it is suggested that potential benefits from THC treatment, in addition to appetite stimulation, will include antiemetic, bronchodilating, anti-inflammatory, anti-diarrheal and hypo-algesic effects.” https://www.researchgate.net/publication/233294071_Cannabinoids_and_Cystic_Fibrosis

“Cannabinoids and Cystic Fibrosis. A Novel Approach to Etiology and Therapy”  http://www.tandfonline.com/doi/abs/10.1300/J175v02n01_03

Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice.

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“Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood.

The use of antipsychotics and benzodiazepines against CIAPS is limited by side effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed.

Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy.

The neurosteroid pregnenolone has been recently shown to act as a potent endogenous allosteric signal-specific inhibitor of CB1 receptors. Thus, we tested in mice the potential therapeutic use of pregnenolone against acute psychotic-like effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis.

We found that pregnenolone blocks a wide spectrum of THC-induced endophenotypes typically associated with psychotic-like states, including impairments in cognitive functions, somatosensory gating and social interaction. Overall, this work reveals that signal-specific inhibitors mimicking pregnenolone effects can be considered as promising new therapeutic tools to treat CIAPS.”  https://www.ncbi.nlm.nih.gov/pubmed/28220044

“Pregnenolone can protect the brain from cannabis intoxication. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057431/

Effects of tetrahydrocannabinol on glucose uptake in the rat brain.

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“Δ9-Tetrahydrocannabinol (THC) is the psychoactive component of the plant Cannabis sativa and acts as a partial agonist at cannabinoid type 1 and type 2 receptors in the brain.

The goal of this study was to assess the effect of THC on the cerebral glucose uptake in the rat brain.

Low blood THC levels of <1 ng/ml corresponded to an increased glucose uptake while blood THC levels > 10 ng/ml coincided with a decreased glucose uptake. The effective concentration in this region was estimated 2.4 ng/ml.

This glucose PET study showed that stimulation of CB1 receptors by THC affects the glucose uptake in the rat brain, whereby the effect of THC is regionally different and dependent on dose – an effect that may be of relevance in behavioural studies.”

https://www.ncbi.nlm.nih.gov/pubmed/28219717