Preclinical evidence on the anticancer properties of phytocannabinoids

Image result for CROSBI“Phytocannabinoids are unique terpenophenolic compounds predominantly produced in the glandular trichomes of the cannabis plant (Cannabis sativa L.). The delta-9- tetrahydrocannabinol (THC) is the main active constituent responsible for the plant’s psychoactive effect and, together with the non- psychoactive cannabidiol (CBD), the most investigated naturally occurring cannabinoid.

The first report on the antitumor properties of cannabis compounds appeared more than forty years ago, but the potential of targeting the endocannabinoid system in cancer has recently attracted increasing interest. Our study aimed to review the last decade’s findings on the anticancer potential of plant- derived cannabinoids and the possible mechanisms of their activity.

A large body of in vitro data has been accumulated demonstrating that phytocannabinoids affect a wide spectrum of tumor cells, including gliomas, neuroblastomas, hepatocarcinoma as well as skin, prostate, breast, cervical, colon, pancreatic, lung and hematological cancer.

It has been found that they can stop the uncontrolled growth of cancer cells through the cell-cycle arrest, inhibition of cell proliferation and induction of autophagy and apoptosis. They can also block all the steps of tumor progression, including tumor cell migration, adhesion and invasion as well as angiogenesis. The observed effects are mainly mediated by the cannabinoid CB1 and/or CB2 receptors, although some other receptors and mechanisms unrelated to receptor stimulation may also be involved.

The majority of available animal studies confirmed that phytocannabinoids are capable of effectively decreasing cancer growth and metastasis in vivo. THC was found to be effective against experimental glioma, liver, pancreatic, breast and lung cancer while CBD showed activity against glioma and neuroblastoma, melanoma, colon, breast, prostate and lung cancer. Further in vitro and in vivo studies also greatly support their use in combination with traditional chemotherapy or radiotherapy, which results in improved efficiency, attenuated toxicity or reduced drug resistance.

Taken together most of available preclinical results emphasize the extensive therapeutic potential of THC and CBD in various types of cancers. The potential clinical interest of cannabinoids is additionally suggested by their selectivity for tumor cells as well as their good tolerance and the absence of normal tissue toxicity, which are still the major limitations of most conventional drugs. The accumulated preclinical evidence strongly suggests the need for clinical testing of cannabinoids in cancer patients.”

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Tetrahydrocannabinol Modulates in Vitro Maturation of Oocytes and Improves the Blastocyst Rates after in Vitro Fertilization.

 

Image result for Cellular Physiology & Biochemistry“Among the assisted reproductive techniques, the in vitro maturation of oocytes (IVM) is less developed than other techniques, but its implementation would entail a qualitative advance.

This technique consists in the extraction of immature oocytes from antral ovarian follicles with the patient under low hormone stimulation or without hormone to mature exogenously in culture media supplemented with different molecules to promote maturation.

In this sense, we are interested in the role that cannabinoids could have as IVM promoters because cannabinoid’s molecular pathway is similar to the one by which oocyte’s meiosis resumption is activated.

With the intention of advancing in the possible use of cannabinoids as supplements for the media for in vitro maturation of oocytes, we intend to deepen the study of the function of the phytocannabinoid Δ-9-tetrahydrocannabinol (THC) in the IVM process.

RESULTS:

This study confirms that the incubation of oocytes with THC during IVM accelerated some events of that process like the phosphorylation pattern of ERK and AKT and was able to increase the blastocyst rate in response to IVF. Moreover, it seems that both CB1 and CB2 are necessary to maintain a healthy oocyte maturation.

CONCLUSION:

Our data suggest that THC may be useful IVM supplements in clinic as is more feasible and reliable than any synthetic cannabinoid.”

https://www.ncbi.nlm.nih.gov/pubmed/31436397

https://www.cellphysiolbiochem.com/Articles/000149/

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The effectiveness of self-directed medical cannabis treatment for pain

Complementary Therapies in Medicine“The prior medical literature offers little guidance as to how pain relief and side effect manifestation may vary across commonly used and commercially available cannabis product types. We used the largest dataset in the United States of real-time responses to and side effect reporting from patient-directed cannabis consumption sessions for the treatment of pain under naturalistic conditions in order to identify how cannabis affects momentary pain intensity levels and which product characteristics are the best predictors of therapeutic pain relief.

Between 06/06/2016 and 10/24/2018, 2987 people used the ReleafApp to record 20,513 cannabis administration measuring cannabis’ effects on momentary pain intensity levels across five pain categories: musculoskeletal, gastrointestinal, nerve, headache-related, or non-specified pain. The average pain reduction was –3.10 points on a 0–10 visual analogue scale (SD = 2.16, d = 1.55, p < .001).

Whole Cannabis flower was associated with greater pain relief than were other types of products, and higher tetrahydrocannabinol (THC) levels were the strongest predictors of analgesia and side effects prevalence across the five pain categories. In contrast, cannabidiol (CBD) levels generally were not associated with pain relief except for a negative association between CBD and relief from gastrointestinal and non-specified pain.

These findings suggest benefits from patient-directed, cannabis therapy as a mid-level analgesic treatment; however, effectiveness and side effect manifestation vary with the characteristics of the product used.

The results suggest that Cannabis flower with moderate to high levels of tetrahydrocannabinol is an effective mid-level analgesic.”

https://www.sciencedirect.com/science/article/abs/pii/S0965229919308040

“UNM study confirms cannabis flower is an effective mid-level analgesic medication for pain treatment. Cannabis likely has numerous constituents that possess analgesic properties beyond THC, including terpenes and flavonoids, which likely act synergistically for people that use whole dried cannabis flower, Cannabis offers the average patient an effective alternative to using opioids for general use in the treatment of pain with very minimal negative side effects for most people.”  https://news.unm.edu/news/unm-study-confirms-cannabis-flower-is-an-effective-mid-level-analgesic-medication-for-pain-treatment

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Cannabidiol and the Remainder of the Plant Extract Modulate the Effects of Δ9-Tetrahydrocannabinol on Fear Memory Reconsolidation.

Image result for frontiers in behavioral neuroscience “Δ9-Tetrahydrocannabinol (THC, a CB1 receptor agonist) and Cannabidiol (CBD, a non-competitive antagonist of endogenous CB1 and CB2 ligands) are two primary components of Cannabis species, and may modulate fear learning in mammals.

The CB1 receptor is widely distributed throughout the cortex and some limbic regions typically associated with fear learning. Humans with posttraumatic disorder (PTSD) have widespread upregulation of CB1 receptor density and reduced availability of endogenous cannabinoid anandamide, suggesting a role for the endocannabinoid system in PTSD.

Pharmacological blockade of memory reconsolidation following recall of a conditioned response modulates the expression of learned fear and may represent a viable target for the development of new treatments for PTSD.

In this study, we focused on assessing the impact of the key compounds of the marijuana plant both singly and, more importantly, in concert on attenuation of learned fear. Specifically, we assessed the impact of THC, CBD, and/or the remaining plant materials (post-extraction; background material), on reconsolidation of learned fear.

Results: CBD alone, but not THC alone, significantly attenuated fear memory reconsolidation when administered immediately after recall. The effect persisted for at least 7 days. A combination of CBD and THC also attenuated the fear response. Plant BM also significantly attenuated reconsolidation of learned fear both on its own and in combination with THC and CBD. Finally, THC attenuated reconsolidation of learned fear only when co-administered with CBD or plant BM.

Conclusion: CBD may provide a novel treatment strategy for targeting fear-memories. Furthermore, plant BM also significantly attenuated the fear response. However, whereas THC alone had no significant effects, its effects were modulated by the addition of other compounds. Future research should investigate some of the other components present in the plant BM (such as terpenes) for their effects alone, or in combination with isolated pure cannabinoids, on fear learning.”

https://www.ncbi.nlm.nih.gov/pubmed/31417379

https://www.frontiersin.org/articles/10.3389/fnbeh.2019.00174/full

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Emerging role of cannabinoids and synthetic cannabinoid receptor 1/cannabinoid receptor 2 receptor agonists in cancer treatment and chemotherapy-associated cancer management

Journal of Cancer Research and Therapeutics“Cannabis was extensively utilized for its medicinal properties till the 19th century. A steep decline in its medicinal usage was observed later due to its emergence as an illegal recreational drug.

Advances in technology and scientific findings led to the discovery of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, that further led to the discovery of endogenous cannabinoids system consisting of G-protein-coupled receptors – cannabinoid receptor 1 and cannabinoid receptor 2 along with their ligands, mainly anandamide and 2-arachidonoylglycerol.  Endocannabinoid (EC) is shown to be a modulator not only for physiological functions but also for the immune system, endocrine network, and central nervous system.

Medicinal research and meta-data analysis over the last few decades have shown a significant potential for both THC and cannabidiol (CBD) to exert palliative effects. People suffering from many forms of advanced stages of cancers undergo chemotherapy-induced nausea and vomiting followed by severe and chronic neuropathic pain and weight loss.

THC and CBD exhibit effective analgesic, anxiolytic, and appetite-stimulating effect on patients suffering from cancer. Drugs currently available in the market to treat such chemotherapy-induced cancer-related ailments are Sativex (GW Pharmaceutical), Dronabinol (Unimed Pharmaceuticals), and Nabilone (Valeant Pharmaceuticals).

Apart from exerting palliative effects, THC also shows promising role in the treatment of cancer growth, neurodegenerative diseases (multiple sclerosis and Alzheimer’s disease), and alcohol addiction and hence should be exploited for potential benefits.

The current review discusses the nature and role of CB receptors, specific applications of cannabinoids, and major studies that have assessed the role of cannabinoids in cancer management.

Specific targeting of cannabinoid receptors can be used to manage severe side effects during chemotherapy, palliative care, and overall cancer management. Furthermore, research evidences on cannabinoids have suggested tumor inhibiting and suppressing properties which warrant reconsidering legality of the substance.

Studies on CB1 and CB2 receptors, in case of cancers, have demonstrated the psychoactive constituents of cannabinoids to be potent against tumor growth.

Interestingly, studies have also shown that activation of CB1 and CB2 cannabinoid receptors by their respective synthetic agonists tends to limit human cancer cell growth, suggesting the role of the endocannabinoid system as a novel target for treatment of cancers.

Further explorations are required to exploit cannabinoids for an effective cancer management.”

http://www.cancerjournal.net/preprintarticle.asp?id=263538

“Could Cannabis Kill Cancer Cells? A New Study Looks Promising”  https://www.portlandmercury.com/blogtown/2019/08/15/26977361/could-cannabis-kill-cancer-cells-a-new-study-looks-promising

“Study Reviews How Marijuana Compounds Inhibit Tumor Growth And Kill Cancer Cells” https://www.marijuanamoment.net/study-reviews-how-marijuana-compounds-inhibit-tumor-growth-and-kill-cancer-cells/

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Cannabinoids and inflammation: Implications for People Living with HIV.

Image result for wolters kluwer “Thanks to the success of modern antiretroviral therapy (ART), people living with HIV (PLWH) have life expectancies which approach that of persons in the general population. However, despite the ability of ART to suppress viral replication, PLWH have high levels of chronic systemic inflammation which drives the development of comorbidities such as cardiovascular disease, diabetes and non-AIDS associated malignancies.

Historically, cannabis has played an important role in alleviating many symptoms experienced by persons with advanced HIV infection in the pre-ART era and continues to be used by many PLWH in the ART era, though for different reasons.

Δ-tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD) are the phytocannabinoids which have received most attention for their medicinal properties. Due to their ability to suppress lymphocyte proliferation and inflammatory cytokine production, there is interest in examining their therapeutic potential as immunomodulators.

CB2 receptor activation has been shown in vitro to reduce CD4 T-cell infection by CXCR4-tropic HIV and to reduce HIV replication.

Studies involving SIV-infected macaques have shown that Δ-THC can reduce morbidity and mortality and has favourable effects on the gut mucosal immunity. Furthermore, ΔTHC administration was associated with reduced lymph node fibrosis and diminished levels of SIV proviral DNA in spleens of rhesus macaques compared with placebo-treated macaques.

In humans, cannabis use does not induce a reduction in peripheral CD4 T-cell count or loss of HIV virological control in cross-sectional studies. Rather, cannabis use in ART-treated PLWH was associated with decreased levels of T-cell activation, inflammatory monocytes and pro-inflammatory cytokines secretion, all of which are related to HIV disease progression and co-morbidities.

Randomized clinical trials should provide further insights into the ability of cannabis and cannabinoid-based medicines to attenuate HIV-associated inflammation. In turn, these findings may provide a novel means to reduce morbidity and mortality in PLWH as adjunctive agents to ART.”

https://www.ncbi.nlm.nih.gov/pubmed/31408029

https://insights.ovid.com/crossref?an=00002030-900000000-96855

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Application device for THC:CBD oromucosal spray in the management of resistant spasticity: pre-production testing.

 Publication Cover“Patients with multiple sclerosis spasticity (MSS) and upper limb/hand impairment who are taking 9-delta-tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®) may have difficulty self-administering their medication, possibly limiting adherence and treatment effectiveness.

A Class I EU device is available to support administration of THC:CBD spray. Pre-production testing was undertaken in a patient sample.

Results: Fifteen patients participated. Mean treatment time with THC:CBD spray was 4 (range: 0.1-6.1) years. 87% of participants ‘always’, ‘often’ or ‘sometimes’ had hand impairment, and 53% reported difficulty administering THC:CBD spray. Participants reported better application using the device (73%), with less strength required (54%). Most participants (93%) considered the instruction leaflet to be clear and many (66%) expressed interest in using the device. Most HCPs (93%) did not foresee any difficulties in use of the device.

Conclusion: The proposed adherence device was useful to address self-application difficulties with THC:CBD spray in our sample. Providing the device to MSS patients with upper limb/hand spasticity impairment may restore autonomy and support adherence to THC:CBD spray.”

https://www.ncbi.nlm.nih.gov/pubmed/31393179

https://www.tandfonline.com/doi/abs/10.1080/17434440.2019.1653182?journalCode=ierd20

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Δ9-Tetrahydrocannabinol suppresses monocyte-mediated astrocyte production of MCP-1 and IL-6 in a TLR7-stimulated human co-culture.

Journal of Pharmacology and Experimental Therapeutics“Cannabis is widely used in the United States with an estimated prevalence of 9.5%. Certain cannabinoids in Cannabis sativa, in particular, Δ9-tetrahydrocannabinol (THC), possess immune modulating and anti-inflammatory activity. Depending on the context, the anti-inflammatory activity of cannabinoids may be beneficial, such as in treating inflammatory diseases, or detrimental to normal immune defense against pathogens. The potential beneficial impact of cannabinoids on chronic neuroinflammation has gained recent attention. Monocyte migration to the brain has been implicated as a key event in chronic neuroinflammation and in the etiology of central nervous system diseases including viral infection (e.g., HIV-associated neurocognitive disorder). In the brain, monocytes can contribute to neuroinflammation through interactions with astrocytes, including inducing astrocyte secretion of cytokines and chemokines. In a human co-culture system, monocyte-derived IL-1β due to toll-like receptor 7 (TLR7)-activation, has been identified to promote astrocyte production of MCP-1 and IL-6. THC treatment of TLR7-stimulated co-culture suppressed monocyte secretion of IL-1β resulting in decreased astrocyte production of MCP-1 and IL-6. Furthermore, THC displayed direct inhibition of monocytes, as TLR7-stimulated monocyte monocultures treated with THC also showed suppressed IL-1β production. The cannabinoid receptor 2 (CB2) agonist, JWH-015, impaired monocyte IL-1β production similar to that of THC, suggesting THC is, in part, acting through CB2. THC also suppressed key elements of the IL-1β production pathway, including IL1B mRNA levels and caspase-1 activity. Collectively, this study demonstrates that the anti-inflammatory properties of THC suppress TLR7-induced monocyte secretion of IL-1β, through CB2, which results in decreased astrocyte secretion of MCP-1 and IL-6.

SIGNIFICANCE STATEMENT: As cannabis use is highly prevalent in the United States and has putative anti-inflammatory properties, it is important to investigate the effect of cannabinoids on immune cell function. Furthermore, cannabinoids have garnered particular interest due to their potential beneficial effects on attenuating viral-induced chronic neuroinflammation. This study utilized a primary human co-culture system to demonstrate that the major psychotropic cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC) and a cannabinoid receptor-2 (CB2) selective agonist, suppress specific monocyte-mediated astrocyte inflammatory responses. In the context of viral-induced chronic neuroinflammation, the findings presented here suggest that cannabinoids via CB2 ligation may have beneficial anti-inflammatory effects.”

https://www.ncbi.nlm.nih.gov/pubmed/31383729

http://jpet.aspetjournals.org/content/early/2019/08/05/jpet.119.260661

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Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome.

Brain, Behavior, and Immunity“Currently, a combination of marijuana cannabinoids including delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is used as a drug to treat muscle spasticity in patients with Multiple Sclerosis (MS).

Because these cannabinoids can also suppress inflammation, it is unclear whether such patients benefit from suppression of neuroinflammation and if so, what is the mechanism through which cannabinoids act.

In the currently study, we used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to study the role of gut microbiota in the attenuation of clinical signs of paralysis and inflammation caused by cannabinoids.

THC+CBD treatment attenuated EAE and caused significant decrease in inflammatory cytokines such as IL-17 and IFN-γ while promoting the induction of anti-inflammatory cytokines such as IL-10 and TGF-β. Use of 16S rRNA sequencing on bacterial DNA extracted from the gut revealed that EAE mice showed high abundance of mucin degrading bacterial species, such as Akkermansia muciniphila (A.muc), which was significantly reduced after THC+CBD treatment.

Fecal Material Transfer (FMT) experiments confirmed that THC+CBD-mediated changes in the microbiome play a critical role in attenuating EAE. In silico computational metabolomics revealed that LPS biosynthesis, a key component in gram-negative bacteria such as A.muc, was found to be elevated in EAE mice which was confirmed by demonstrating higher levels of LPS in the brain, while treatment with THC+CBD reversed this trend. EAE mice treated with THC+CBD also had significantly higher levels of short chain fatty acids such as butyric, isovaleric, and valeric acids compared to naïve or disease controls.

Collectively, our data suggest that cannabinoids may attenuate EAE and suppress neuroinflammation by preventing microbial dysbiosis seen during EAE and promoting healthy gut microbiota.”

https://www.ncbi.nlm.nih.gov/pubmed/31356922

https://www.sciencedirect.com/science/article/pii/S0889159119306476?via%3Dihub

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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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