Tandem mass spectrometric quantification of 93 terpenoids in Cannabis using static headspace (SHS) injections.

 Go to Volume 0, Issue ja“The therapeutic effect of Cannabis largely depends on the content of its pharmacologically active secondary metabolites, mainly phytocannabinoids, flavonoids and terpenoids. Recent studies suggest of therapeutic effects of specific terpenoids, as well as synergistic effects with other active compounds in the plant.

Although Cannabis contains an overwhelming milieu of terpenoids, only a limited number are currently reported and used for metabolic analysis of Cannabis chemovars. In this study, we report the development and validation of a method for simultaneous quantification of 93 terpenoids in Cannabis air-dried-inflorescences and extracts.

This method employs the full evaporation technique via a static headspace sampler, followed by gas chromatography-mass spectrometry (SHS-GC-MS/MS). In the validation process, spiked terpenoids were quantified with acceptable repeatability, reproducibility, sensitivity and accuracy. Three medical Cannabis chemovars were used to study the effect of sample preparation and extraction methods on terpenoid profiles. This method was further ap-plied for studying the terpenoid profiles of sixteen different chemovars acquired at different dates.

Our results demonstrate that sample preparation methods may significantly impact the chemical fingerprint compared to the non-treated Cannabis. This emphasizes the importance of performing SHS extraction in order to study the natural terpenoid contents of che-movars. We also concluded that most inflorescences expressed relatively unique terpenoid profiles for the most pronounced terpenoids, even when sampled at different dates, although absolute concentrations may vary due to aging.

The suggested method offer an ideal tool for terpenoid profiling of Cannabis and set the scene for more comprehensive works in the fu-ture.”

https://www.ncbi.nlm.nih.gov/pubmed/31369251

https://pubs.acs.org/doi/10.1021/acs.analchem.9b02844

“Anticancer Terpenoids”

https://link.springer.com/chapter/10.1007/978-3-319-14027-8_5

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Cannabichromene is a cannabinoid CB2 receptor agonist.

British Journal of Pharmacology banner“Cannabichromene (CBC) is one of the most abundant phytocannabinoids in Cannabis spp. It has modest anti-nociceptive and anti-inflammatory effects and potentiates some effects of Δ9 – tetrahydrocannabinol (THC) in vivo. How CBC exerts these effects is poorly defined and there is little information about its efficacy at cannabinoid receptors. We sought to determine the functional activity of CBC at CB1 and CB2 receptors.

KEY RESULTS:

CBC activated CB2 but not CB1 receptors to produce a hyperpolarization of AtT20 cells. This activation was inhibited by a CB2 antagonist AM630, and sensitive to pertussis toxin. Application of CBC reduced activation of CB2 receptors (but not CB1 receptors) by subsequent co-application of CP55,940, an efficacious CB1 and CB2 agonist. Continuous CBC application induced loss of cell surface CB2 receptors and desensitisation of the CB2-induced hyperpolarization.

CONCLUSIONS AND IMPLICATIONS:

CBC is a selective CB2 receptor agonist displaying higher efficacy than THC in hyperpolarising AtT20 cells. CBC can also recruit CB2 receptor regulatory mechanisms. CBC may contribute to the potential therapeutic effectiveness of some cannabis preparations, potentially through CB2-mediated modulation of inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31368508

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14815

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The Endocannabinoid System May Modulate Sleep Disorders In Aging.

“Aging is an inevitable process that involves changes along life in multiple neurochemical, neuroanatomical, hormonal systems, and many others. In addition, these biological modifications lead to an increase in age-related sickness such as cardiovascular diseases, osteoporosis, neurodegenerative disorders, and sleep disturbances, among others that affect activities of daily life. Demographic projections have demonstrated that aging will increase its worldwide rate in the coming years. The research on chronic diseases of the elderly is important to gain insights into this growing global burden.

Novel therapeutic approaches aimed for treatment of age-related pathologies have included the endocannabinoid system as an effective tools since this biological system shows beneficial effects in preclinical models. However, and despite these advances, little has been addressed in the arena of the endocannabinoid system as option for treating sleep disorders in aging since experimental evidence suggests that some elements of the endocannabinoid system modulate the sleep-wake cycle.

This article addresses this less-studied field, focusing on the likely perspective of the implication of the endocannabinoid system in the regulation of sleep problems reported in aged. We conclude that beneficial effects regarding the putative efficacy of the endocannabinoid system as therapeutic tools in aging is either inconclusive or still missing.”

https://www.ncbi.nlm.nih.gov/pubmed/31368874

http://www.eurekaselect.com/174043/article

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Therapeutic potential of cannabinoids as neuroprotective agents for damaged cells conducing to movement disorders.

International Review of Neurobiology“The basal ganglia (BG), an organized network of nuclei that integrates cortical information, play a crucial role in controlling motor function. In fact, movement disorders such as Parkinson’s disease (PD) and Huntington’s disease (HD) are caused by the degeneration of specific structures within the BG.

There is substantial evidence supporting the idea that cannabinoids may constitute novel promising compounds for the treatment of movement disorders as neuroprotective and anti-inflammatory agents.

This potential therapeutic role of cannabinoids is based, among other qualities, on their capacity to reduce oxidative injury and excitotoxicity, control calcium influx and limit the toxicity of reactive microglia.

The mechanisms involved in these effects are related to CB1 and CB2 receptor activation, although some of the effects are CB receptor independent.

Thus, taking into account the aforementioned properties, compounds that act on the endocannabinoid system could be useful as a basis for developing disease-modifying therapies for PD and HD.”

https://www.ncbi.nlm.nih.gov/pubmed/31349929

https://www.sciencedirect.com/science/article/pii/S0074774219300327?via%3Dihub

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Endocannabinoid System and the Kidneys: From Renal Physiology to Injury and Disease.

View details for Cannabis and Cannabinoid Research cover image“As the prevalence of kidney disease continues to rise worldwide, there is accumulating evidence that kidney injury and dysfunction, whether acute or chronic, is associated with major adverse outcomes, including mortality. Meanwhile, effective therapeutic options in the treatment of acute kidney injury (AKI) and chronic kidney disease (CKD) have been sparse.

Many of the effective treatments that are routinely utilized for different pathologies in patients without kidney disease have failed to demonstrate efficacy in those with renal dysfunction. Hence, there is an urgent need for discovery of novel pathways that can be targeted for innovative and effective clinical therapies in renal disease states.

There is now accumulating evidence that the endocannabinoid (EC) system plays a prominent role in normal renal homeostasis and function. In addition, numerous recent studies have described mechanisms through which alteration in the EC system can contribute to kidney damage and disease. These include a potential role for cannabinoid receptors in tubulo-glomerular damage and fibrosis, which are common features of AKI, interstitial nephritis, glomerulopathy, and other conditions leading to AKI and CKD.

These findings suggest that manipulating the EC system may be an effective therapeutic strategy for the treatment of kidney disease and injury. However, further mechanistic studies are needed to fully delineate the role of this system in various conditions affecting the kidneys. Furthermore, while most of the current literature is focused on the role of the EC system as a whole in renal pathophysiology, future studies will also need to clarify the contribution of each component of this system, including the EC mediators, in the pathogenesis of kidney disease and their potential role as part of a therapeutic strategy.”

FIG. 1. 
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Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges

Image result for frontiers in immunology“It is well known that certain active ingredients of the plants of Cannabis genus, i.e., the “phytocannabinoids” [pCBs; e.g., (−)-trans9-tetrahydrocannabinol (THC), (−)-cannabidiol, etc.] can influence a wide array of biological processes, and the human body is able to produce endogenous analogs of these substances [“endocannabinoids” (eCB), e.g., arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol (2-AG), etc.]. These ligands, together with multiple receptors (e.g., CB1 and CB2 cannabinoid receptors, etc.), and a complex enzyme and transporter apparatus involved in the synthesis and degradation of the ligands constitute the endocannabinoid system (ECS), a recently emerging regulator of several physiological processes. The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, antitumor, as well as antipathogen immune responses, etc. Based on this knowledge, many in vitro and in vivo studies aimed at exploiting the putative therapeutic potential of cannabinoid signaling in inflammation-accompanied diseases (e.g., multiple sclerosis) or in organ transplantation, and to dissect the complex immunological effects of medical and “recreational” marijuana consumption. Thus, the objective of the current article is (i) to summarize the most recent findings of the field; (ii) to highlight the putative therapeutic potential of targeting cannabinoid signaling; (iii) to identify open questions and key challenges; and (iv) to suggest promising future directions for cannabinoid-based drug development.

Active Components of Cannabis sativa (Hemp)—Phytocannabinoids (pCBs) and Beyond

It is known since ancient times that consumption of different parts of the plant Cannabis sativa can lead to psychotropic effects. Moreover, mostly, but not exclusively because of its potent analgesic actions, it was considered to be beneficial in the management of several diseases. Nowadays it is a common knowledge that these effects were mediated by the complex mixture of biologically active substances produced by the plant. So far, at least 545 active compounds have been identified in it, among which, the best-studied ones are the so-called pCBs. It is also noteworthy that besides these compounds, ca. 140 different terpenes [including the potent and selective CB2 agonist sesquiterpene β-caryophyllene (BCP)], multiple flavonoids, alkanes, sugars, non-cannabinoid phenols, phenylpropanoids, steroids, fatty acids, and various nitrogenous compounds can be found in the plant, individual biological actions of which are mostly still nebulous. Among the so far identified > 100 pCBs, the psychotropic (−)-trans9-tetrahydrocannabinol (THC) and the non-psychotropic (−)-cannabidiol (CBD) are the best-studied ones, exerting a wide-variety of biological actions [including but not exclusively: anticonvulsive, analgesic, antiemetic, and anti inflammatory effects]. Of great importance, pCBs have been shown to modulate the activity of a plethora of cellular targets, extending their impact far beyond the “classical” (see above) cannabinoid signaling. Indeed, besides being agonists [or in some cases even antagonists of CB1 and CB2 cannabinoid receptors, some pCBs were shown to differentially modulate the activity of certain TRP channels, PPARs, serotonin, α adrenergic, adenosine or opioid receptors, and to inhibit COX and lipoxygenase enzymes, FAAH, EMT, etc.. Moreover, from a clinical point-of-view, it should also be noted that pCBs can indirectly modify pharmacokinetics of multiple drugs (e.g., cyclosporine A) by interacting with several cytochrome P 450 (CYP) enzymes. Taken together, pCBs can be considered as multitarget polypharmacons, each of them having unique “molecular fingerprints” created by the characteristic activation/inhibition pattern of its locally available cellular targets.

Concluding Remarks—Lessons to Learn from Cannabis

Research efforts of the past few decades have unambiguously evidenced that ECS is one of the central orchestrators of both innate and adaptive immune systems, and that pure pCBs as well as complex cannabis-derivatives can also deeply influence immune responses. Although, many open questions await to be answered, pharmacological modulation of the (endo)cannabinoid signaling, and restoration of the homeostatic eCB tone of the tissues augur to be very promising future directions in the management of several pathological inflammation-accompanied diseases. Moreover, in depth analysis of the (quite complex) mechanism-of-action of the most promising pCBs is likely to shed light to previously unknown immune regulatory mechanisms and can therefore pave new “high”-ways toward developing completely novel classes of therapeutic agents to manage a wide-variety of diseases.”

https://www.frontiersin.org/articles/10.3389/fimmu.2017.01487/full

www.frontiersin.org

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Spontaneous, anecdotal, retrospective, open‐label study on the efficacy, safety and tolerability of cannabis galenical preparation (Bedrocan)

Image result for Int J Pharm Pract.“Our main aim was to investigate the short‐term therapeutic effects, safety/tolerability and potential side effects of the cannabis galenical preparation (Bedrocan) in patients with a range of chronic conditions unresponsive to other treatments.

These data suggest that a cannabis galenical preparation may be therapeutically effective and safe for the symptomatic treatment of some chronic diseases.

The findings suggested that patients affected by chronic long‐standing (months or years) advanced disease, who had not responded to standard treatment, had improved symptoms when they were treated with Bedrocan. The galenical treatment contributed not only to decreased pain but also to restored physical function in this cohort after 3 months and improvement in overall QOL.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593769/

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From Cannabinoids and Neurosteroids to Statins and the Ketogenic Diet: New Therapeutic Avenues in Rett Syndrome?

Image result for frontiers in neuroscience “Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene, being one of the leading causes of mental disability in females.

Epilepsy is one of the most common symptoms in RTT, occurring in 60 to 80% of RTT cases, being associated with worsening of other symptoms. At this point, no cure for RTT is available and there is a pressing need for the discovery of new drug candidates to treat its severe symptoms.

New and exciting evidence has been gathered and the etiopathogenesis of this complex, severe and untreatable disease is slowly being unfolded. Advances in gene editing techniques have prompted cure-oriented research in RTT. Nonetheless, at this point, finding a cure is a distant reality, highlighting the importance of further investigating the basic pathological mechanisms of this disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31333401

“Very recently, a new study using CBDV has confirmed the potential of this particular phytocannabinoid in RTT.  The promising antiseizure effects of CBD, even in cases of refractory-epilepsy, observed in both clinical trials with humans and in laboratory animals, the effects of combinations of CBD and Δ9-THC in controlling muscle spasticity and motor symptoms, and the positive results of CBDV administration in two different mouse models of RTT, place cannabinoids as a viable therapeutic strategy in RTT. Moreover, CBD positively modifies impairments in motor, cognitive and social processes in animal models, further highlighting the potential of cannabinoid molecules to tackle RTT-symptomology.”

https://www.frontiersin.org/articles/10.3389/fnins.2019.00680/full

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Pharmacology of Medical Cannabis.

 “The Cannabis plant has been used for many of years as a medicinal agent in the relief of pain and seizures. It contains approximately 540 natural compounds including more than 100 that have been identified as phytocannabinoids due to their shared chemical structure. The predominant psychotropic component is Δ9-tetrahydrocannabinol (Δ9-THC), while the major non-psychoactive ingredient is cannabidiol (CBD). These compounds have been shown to be partial agonists or antagonists at the prototypical cannabinoid receptors, CB1 and CB2. The therapeutic actions of Δ9-THC and CBD include an ability to act as analgesics, anti-emetics, anti-inflammatory agents, anti-seizure compounds and as protective agents in neurodegeneration. However, there is a lack of well-controlled, double blind, randomized clinical trials to provide clarity on the efficacy of either Δ9-THC or CBD as therapeutics. Moreover, the safety concerns regarding the unwanted side effects of Δ9-THC as a psychoactive agent preclude its widespread use in the clinic. The legalization of cannabis for medicinal purposes and for recreational use in some regions will allow for much needed research on the pharmacokinetics and pharmocology of medical cannabis. This brief review focuses on the use of cannabis as a medicinal agent in the treatment of pain, epilepsy and neurodegenerative diseases. Despite the paucity of information, attention is paid to the mechanisms by which medical cannabis may act to relieve pain and seizures.”

https://www.ncbi.nlm.nih.gov/pubmed/31332738

https://link.springer.com/chapter/10.1007%2F978-3-030-21737-2_8

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Cannabinoid Signaling in Cancer.

“The family of chemical structures that interact with a cannabinoid receptor are broadly termed cannabinoids. Traditionally known for their psychotropic effects and their use as palliative medicine in cancer, cannabinoids are very versatile and are known to interact with several orphan receptors besides cannabinoid receptors (CBR) in the body. Recent studies have shown that several key pathways involved in cell growth, differentiation and, even metabolism and apoptosis crosstalk with cannabinoid signaling. Several of these pathways including AKT, EGFR, and mTOR are known to contribute to tumor development and metastasis, and cannabinoids may reverse their effects, thereby by inducing apoptosis, autophagy and modulating the immune system. In this book chapter, we explore how cannabinoids regulate diverse signaling mechanisms in cancer and immune cells within the tumor microenvironment and whether they impart a therapeutic effect. We also provide some important insight into the role of cannabinoids in cellular and whole body metabolism in the context of tumor inhibition. Finally, we highlight recent and ongoing clinical trials that include cannabinoids as a therapeutic strategy and several combinational approaches towards novel therapeutic opportunities in several invasive cancer conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/31332734

https://link.springer.com/chapter/10.1007%2F978-3-030-21737-2_4

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