Tag Archives: Cannabinoids

Cannabinoids in Glioblastoma Therapy: New Applications for Old Drugs

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“Glioblastoma (GBM) is the most malignant brain tumor and one of the deadliest types of solid cancer overall. Despite aggressive therapeutic approaches consisting of maximum safe surgical resection and radio-chemotherapy, more than 95% of GBM patients die within 5 years after diagnosis. Thus, there is still an urgent need to develop novel therapeutic strategies against this disease.

Accumulating evidence indicates that cannabinoids have potent anti-tumor functions and might be used successfully in the treatment of GBM.

This review article summarizes the latest findings on the molecular effects of cannabinoids on GBM, both in vitro and in (pre-) clinical studies in animal models and patients.

The therapeutic effect of cannabinoids is based on reduction of tumor growth via inhibition of tumor proliferation and angiogenesis but also via induction of tumor cell death. Additionally, cannabinoids were shown to inhibit the invasiveness and the stem cell-like properties of GBM tumors. Recent phase II clinical trials indicated positive results regarding the survival of GBM patients upon cannabinoid treatment.

Apart from a direct killing effect on tumor cells, cannabinoids can also induce cell cycle arrest thereby inhibiting tumor cell proliferation.

In conclusion, cannabinoids show promising anti-neoplastic functions in GBM by targeting multiple cancer hallmarks such as resistance to programmed cell death, neoangiogenesis, tissue invasion or stem cell-induced replicative immortality.

The effects of cannabinoids can be potentially enhanced by combination of different cannabinoids with each other or with chemotherapeutic agents. This requires, however, a detailed understanding of cannabinoid-induced molecular mechanisms and pharmacological effects.

Ultimately, these findings might foster the development of improved therapeutic strategies against GBM and, perhaps, other diseases of the nervous system as well.”

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00159/full

“Accumulating evidence indicates that cannabinoids have potent anti-tumor functions and might be used successfully in the treatment of GBM.”  https://www.ncbi.nlm.nih.gov/pubmed/29867351

Endocannabinoid system and anticancer properties of cannabinoids

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“Cannabinoids impact human body by binding to cannabinoids receptors (CB1 and CB2).

The two main phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

THC interacts with CB1 receptors occurring in central nervous system and is responsible for psychoactive properties of marijuana. CBD has low affinity to CB1 receptor, has no psychoactive characteristics and its medical applications can be wider.

CB receptors are part of a complex machinery involved in regulation of many physiological processes – endocannabinoid system.

Cannabinoids have found some applications in palliative medicine, but there are many reports concerning their anticancer affects.

Agonists of CB1 receptors stimulate accumulation of ceramides in cancer cells, stress of endoplasmic reticulum (ER stress) and, in turn, apoptosis. Effects of cannabinoids showing low affinity to CB receptors is mediated probably by induction of reactive oxygen species production.

Knowledge of antitumor activity of cannabinoids is still based only on preclinical studies and there is a necessity to conduct more experiments to assess the real potential of these compounds.”

https://content.sciendo.com/view/journals/fobio/12/1/article-p11.xml

Quality Traits of “Cannabidiol Oils”: Cannabinoids Content, Terpene Fingerprint and Oxidation Stability of European Commercially Available Preparations.

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“Cannabidiol (CBD)-based oil preparations are becoming extremely popular, as CBD has been shown to have beneficial effects on human health.

CBD-based oil preparations are not unambiguously regulated under the European legislation, as CBD is not considered as a controlled substance. This means that companies can produce and distribute CBD products derived from non-psychoactive hemp varieties, providing an easy access to this extremely advantageous cannabinoid.

This leaves consumers with no legal quality guarantees. The objective of this project was to assess the quality of 14 CBD oils commercially available in European countries. An in-depth chemical profiling of cannabinoids, terpenes and oxidation products was conducted by means of GC-MS and HPLC-Q-Exactive-Orbitrap-MS in order to improve knowledge regarding the characteristics of CBD oils. Nine out of the 14 samples studied had concentrations that differed notably from the declared amount, while the remaining five preserved CBD within optimal limits.

Our results highlighted a wide variability in cannabinoids profile that justifies the need for strict and standardized regulations. In addition, the terpenes fingerprint may serve as an indicator of the quality of hemp varieties, while the lipid oxidation products profile could contribute in evaluation of the stability of the oil used as milieu for CBD rich extracts.”

https://www.ncbi.nlm.nih.gov/pubmed/29783790
http://www.mdpi.com/1420-3049/23/5/1230

Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2.

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“Psychosocial stress contributes to the development of psychiatric disorders. Repeated social defeat (RSD) is a murine stressor that causes a release of inflammatory monocytes into circulation. Moreover, RSD-induced anxiety-like behavior is dependent on the recruitment of these monocytes to the brain.

Activation of the endocannabinoid (ECB) system may modulate both neuroendocrine and inflammatory responses mediated by stress. Therefore, we hypothesized that a cannabinoid receptor agonist would attenuate RSD-induced inflammation, anxiety, and stress sensitization.

In conclusion, activation of cannabinoid receptors limited the immune and neuroinflammatory responses to RSD and reversed the short-term and long-term behavioral deficits associated with RSD.”

https://www.ncbi.nlm.nih.gov/pubmed/29786066

https://www.nature.com/articles/s41386-018-0064-2

Cannabinoid WIN-55,212-2 mesylate inhibits tumor necrosis factor-α-induced expression of nitric oxide synthase in dorsal root ganglion neurons.

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“Tumor necrosis factor-α (TNF-α) is an established pain modulator in the peripheral nervous system. Elevated levels of TNF-α in dorsal root ganglion (DRG) neurons reportedly is critical for neuropathic pain processing. It has been shown that the production of nitric oxide, a key player in the development and maintenance of nociception, depends on the expression of nitric oxide synthases (NOSs) and their activities.

Accumulating evidence also supports an important role of cannabinoids in modulating neuropathic pain.

In this study, we explored the effects and the underlying mechanisms of crosstalk between TNF-α and cannabinoid on the expression/activity of NOS in DRG neurons.

Our findings suggest that TNF-α induces the expression/activity of nNOS in DRG neurons by increasing its mRNA stability by a p38 MAPK-dependent mechanism; WIN-55 inhibits this effect of TNF-α by inhibiting p38 MAPK via CB2.

By linking the functions of TNF-α, NOS and cannabinoid in DRG neurons, this study adds new insights into the molecular mechanisms underlying the pharmacologic effects of cannabinoids on neuropathic pain as well as into the pathophysiology of neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/29786105

https://www.spandidos-publications.com/10.3892/ijmm.2018.3687

Cannabinoids in the Management of Musculoskeletal Pain: A Critical Review of the Evidence

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  • “The purposes of the present scoping review were to identify (1) the available studies regarding the efficacy of cannabinoids for the management of musculoskeletal pain and related conditions and (2) the knowledge gaps and opportunities in this area of research.
  • There is little high-quality evidence for medical cannabis in the core orthopaedic areas of arthritis, postoperative pain, back pain, and trauma-related pain.
  • The “best available” evidence suggests cannabis can be effective for managing arthritis pain, back pain, and trauma-related pain, although the quality of the evidence is poor.
  • Evidence regarding the use of cannabinoids for the management of postoperative pain is mixed.
  • Research on pain control in patients with arthritis, conditions related to the spine, and traumatic injuries represents major under-represented areas of study for the role of cannabinoids, and high-quality Level-I studies are needed.”

https://journals.lww.com/jbjsreviews/Abstract/latest/Cannabinoids_in_the_Management_of_Musculoskeletal.99892.aspx

Controlled-Deactivation CB1 Receptor Ligands as a Novel Strategy to Lower Intraocular Pressure.

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“Nearly half a century has passed since the demonstration that cannabis and its chief psychoactive component Δ⁸-THC lowers intraocular pressure (IOP).

Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness. It is likely that Δ⁸-THC exerts much of its IOP-lowering effects via the activation of CB1 cannabinoid receptors.

However, the initial promise of CB1 as a target for treating glaucoma has not thus far translated into a credible therapeutic strategy. We have recently shown that blocking monoacylglycerol lipase (MAGL), an enzyme that breaks the endocannabinoid 2-arachidonoyl glycerol (2-AG), substantially lowers IOP.

Another strategy is to develop cannabinoid CB1 receptor agonists that are optimized for topical application to the eye. Recently we have reported on a controlled-deactivation approach where the “soft” drug concept of enzymatic deactivation was combined with a “depot effect” that is commonly observed with Δ⁸-THC and other lipophilic cannabinoids.

This approach allowed us to develop novel cannabinoids with a predictable duration of action and is particularly attractive for the design of CB1 activators for ophthalmic use with limited or no psychoactive effects.

We have tested a novel class of compounds using a combination of electrophysiology in autaptic hippocampal neurons, a well-characterized model of endogenous cannabinoid signaling, and measurements of IOP in a mouse model.

We now report that AM7410 is a reasonably potent and efficacious agonist at CB1 in neurons and that it substantially (30%) lowers IOP for as long as 5 h after a single topical treatment. This effect is absent in CB1 knockout mice.

Our results indicate that the direct targeting of CB1 receptors with controlled-deactivation ligands is a viable approach to lower IOP in a murine model and merits further study in other model systems.”

https://www.ncbi.nlm.nih.gov/pubmed/29786643

http://www.mdpi.com/1424-8247/11/2/50

Endogenous systems involved in exercise-induced analgesia.

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“Exercise-induced analgesia is a phenomenon discussed worldwide. This effect began to be investigated in the early 1970s in healthy individuals and rodents during and after an acute or chronic session of running or swimming. Thereafter, studies found this effect was also induced by resistance exercises. Over the years, many studies have demonstrated the importance of exercise-induced analgesia in relieving pain caused by different conditions, such as fibromyalgia, low back pain, neuropathy, and osteoarthritis. This review aims to provide the reader with an in-depth description of the main endogenous systems, substances, neurotransmitters, receptors and enzymes that are thought to be involved in the analgesic effect induced by exercise. Many hypotheses have been proposed to elucidate the mechanisms responsible for exercise-induced analgesia. One of the most accepted hypotheses has been the activation of several endogenous systems described as analgesics. Studies have demonstrated that during and after exercise different endogenous systems are activated, which release substances or neurotransmitters, such as opioids, nitric oxide, serotonin, catecholamines and endocannabinoids, that may modulate the pain perception.”  https://www.ncbi.nlm.nih.gov/pubmed/29769416

http://www.jpp.krakow.pl/journal/archive/02_18/pdf/jpp.2018.1.01.pdf

“Exercise activates the endocannabinoid system.”  https://www.ncbi.nlm.nih.gov/pubmed/14625449

The endocannabinoid-alcohol crosstalk: recent advances on a bi-faceted target.

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“Increasing evidence focuses on the endocannabinoid system as a relevant player in the induction of aberrant synaptic plasticity and related addictive phenotype following chronic excessive alcohol drinking.

Besides, the endocannabinoid system is implicated in the pathogenesis of alcoholic liver disease.

Interestingly, whereas the involvement of CB1 cannabinoid receptors in alcohol rewarding properties is established, the central and peripheral action of CB2 cannabinoid signalling is still to be elucidated.

This review aims at giving the input to deepen knowledge on the role of the endocannabinoid system, highlighting the advancing evidence that suggests that CB1 and CB2 receptors may play opposite roles in the regulation of both the reinforcing properties of alcohol in the brain and the mechanisms responsible for cell injury and inflammation in the hepatic tissue.

The manipulation of the endocannabinoid system could represent a bi-faceted strategy to counteract alcohol-related dysfunction in central transmission and liver structural and functional disarrangement.”

https://www.ncbi.nlm.nih.gov/pubmed/29770478

https://onlinelibrary.wiley.com/doi/abs/10.1111/1440-1681.12967

Review of the neurological benefits of phytocannabinoids.

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“Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.

METHODS:

In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.

RESULTS:

Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.

CONCLUSIONS:

In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/29770251

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/