Monthly Archives: October 2019

Cannabidiol directly targets mitochondria and disturbs calcium homeostasis in acute lymphoblastic leukemia.

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 Image result for cell death & disease“Anticancer properties of non-psychoactive cannabinoid cannabidiol (CBD) have been demonstrated on tumors of different histogenesis. Different molecular targets for CBD were proposed, including cannabinoid receptors and some plasma membrane ion channels. Here we have shown that cell lines derived from acute lymphoblastic leukemia of T lineage (T-ALL), but not resting healthy T cells, are highly sensitive to CBD treatment. CBD effect does not depend on cannabinoid receptors or plasma membrane Ca2+-permeable channels. Instead, CBD directly targets mitochondria and alters their capacity to handle Ca2+. At lethal concentrations, CBD causes mitochondrial Ca2+ overload, stable mitochondrial transition pore formation and cell death. Our results suggest that CBD is an attractive candidate to be included into chemotherapeutic protocols for T-ALL treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31611561

“Considering the pivotal role of mitochondria in oncogenic re-programming, CBD may be plausible candidate to be included into chemotherapeutic protocols.”

https://www.nature.com/articles/s41419-019-2024-0

Cannabidiol Administration Prevents Hypoxia-Ischemia-Induced Hypomyelination in Newborn Rats.

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Image result for frontiers in pharmacology“Neonatal hypoxia-ischemia (HI) is a risk factor for myelination disturbances, a key factor for cerebral palsy.

Cannabidiol (CBD) protects neurons and glial cells after HI insult in newborn animals.

We hereby aimed to study CBD’s effects on long-lasting HI-induced myelination deficits in newborn rats.

In conclusion, HI injury in newborn rats resulted in long-lasting myelination disturbance, associated with functional impairment. CBD treatment preserved function and myelination, likely as a part of a general neuroprotective effect.”

https://www.ncbi.nlm.nih.gov/pubmed/31611802

“In conclusion, our study confirms that a HI insult in rats at a brain developmental stage equivalent to term infants leads to long-lasting myelination disturbance which is directly related to long-term functional disturbances. The administration of CBD single dose after the neonatal HI insult protects the maturational process of OL cells, as well as the mOL function and relationship with axons, thus, preserving normal myelination and restoring neurobehavioral function. Those results open exciting perspectives regarding a possible role for CBD in NHIE and other demyelinating pediatric conditions.”

https://www.frontiersin.org/articles/10.3389/fphar.2019.01131/full

‘Standard THC Units’: a proposal to standardise dose across all cannabis products and methods of administration.

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Publication cover image“Cannabis products are becoming increasingly diverse, and they vary considerably in concentrations of ∆9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). Higher doses of THC can increase the risk of harm from cannabis, while CBD may partially offset some of these effects. Lower Risk Cannabis Use Guidelines currently lack recommendations based on quantity of use, and could be improved by implementing standard units. However, there is currently no consensus on how units should be measured or standardised across different cannabis products or methods of administration.

ARGUMENT:

Existing proposals for standard cannabis units have been based on specific methods of administration (e.g. joints) and these may not capture other methods including pipes, bongs, blunts, dabbing, vaporizers, vape pens, edibles and liquids. Other proposals (e.g. grams of cannabis) cannot account for heterogeneity in THC concentrations across different cannabis products. Similar to alcohol units, we argue that standard cannabis units should reflect the quantity of active pharmacological constituents (dose of THC). On the basis of experimental and ecological data, public health considerations, and existing policy we propose that a ‘Standard THC Unit’ should be fixed at 5 milligrams of THC for all cannabis products and methods of administration. If supported by sufficient evidence in future, consumption of Standard CBD Units might offer an additional strategy for harm reduction.

CONCLUSIONS:

Standard THC Units can potentially be applied across all cannabis products and methods of administration to guide consumers and promote safer patterns of use.”

https://www.ncbi.nlm.nih.gov/pubmed/31606008

https://onlinelibrary.wiley.com/doi/abs/10.1111/add.14842

Cellular Distribution of Canonical and Putative Cannabinoid Receptors in Canine Cervical Dorsal Root Ganglia.

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Image result for frontiers in veterinary science“Growing evidence indicates cannabinoid receptors as potential therapeutic targets for chronic pain.

Consequently, there is an increasing interest in developing cannabinoid receptor agonists for treating human and veterinary pain.

The present study may represent a morphological substrate to consider in order to develop therapeutic strategies against chronic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31608295

“The anti-nociceptive potential of the endocannabinoid system has prompted the development of therapeutic cannabinoid receptors agonists or medical marjiuana to be used in pets in order to treat chronic pain.”

https://www.frontiersin.org/articles/10.3389/fvets.2019.00313/full

Disease associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue specific activity of the cannabinoid-1 receptor gene promoter; implications for cannabinoid pharmacogenetics.

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Publication cover image“Cannabinoid receptor-1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1 (encoded by the CNR1 gene) have been compromised by differences in patient response.

Towards addressing the hypothesis that genetic changes within the regulatory regions controlling CNR1 expression contribute to these differences, we characterised the effects of disease associated allelic variation within a conserved regulatory sequence (ECR1) in CNR1 intron 2 that had previously been shown to modulate cannabinoid response, alcohol intake and anxiety-like behaviour.

We used primary cell analysis of reporters carrying different allelic variants of the human ECR1 and found that human specific C-allele variants of ECR1 (ECR1(C)) drove higher levels of CNR1prom activity in primary hippocampal cells than did the ancestral T-allele and demonstrated a differential response to CB1 agonism.

We further demonstrate a role for the AP-1 transcription factor in driving higher ECR1(C) activity and evidence that the ancestral t-allele variant of ECR1 interacted with higher affinity with the insulator binding factor CTCF. The cell-specific approaches used in our study represent an important step in gaining a mechanistic understanding the roles of non-coding polymorphic variation in disease and in the increasingly important field of cannabinoid pharmacogenetics.”

https://www.ncbi.nlm.nih.gov/pubmed/31608546

https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23931

Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings.

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Progress in Molecular Biology and Translational Science“Cannabis sativa (cannabis) is one of the oldest plants cultivated by men. Cannabidiol (CBD) is the major non-psychomimetic compound derived from cannabis. It has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders.

In this narrative review, we have summarized a selected number of pre-clinical and clinical studies, examining the effects of CBD in neuropsychiatric disorders. In some pre-clinical studies, CBD was demonstrated to potentially exhibit anti-epileptic, anti-oxidant, anti-inflammatory anti-psychotic, anxiolytic and anti-depressant properties. Moreover, CBD was shown to reduce addictive effects of some drugs of abuse.

In clinical studies, CBD was shown to be safe, well-tolerated and efficacious in mitigating the symptoms associated with several types of seizure disorders and childhood epilepsies.

Given that treatment with CBD alone was insufficient at managing choreic movements in patients with Huntington’s disease, other cannabis-derived treatments are currently being investigated. Patients with Parkinson’s disease (PD) have reported improvements in sleep and better quality of life with CBD; however, to fully elucidate the therapeutic potential of CBD on the symptoms of PD-associated movement disorders, larger scale, randomized, placebo-controlled studies still need to be conducted in the future.

Currently, there are no human studies that investigated the effects of CBD in either Alzheimer’s disease or unipolar depression, warranting further investigation in this area, considering that CBD was shown to have effects in pre-clinical studies.

Although, anxiolytic properties of CBD were reported in the Social Anxiety Disorder, antipsychotic effects in schizophrenia and anti-addictive qualities in alcohol and drug addictions, here too, larger, randomized, placebo-controlled trials are needed to evaluate the therapeutic potential of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31601406

https://www.sciencedirect.com/science/article/pii/S187711731930095X?via%3Dihub

The potential role of cannabinoids in dermatology.

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 Publication Cover“Cannabis is increasingly being used world-wide to treat a variety of dermatological conditions. Medicinal cannabis is currently legalized in Canada, 31 states in America and 19 countries in Europe. The authors reviewed the literature on the pharmacology and use of cannabinoids in treating a variety of skin conditions including acne, atopic dermatitis, psoriasis, skin cancer, pruritus, and pain. Cannabinoids have demonstrated anti-inflammatory, antipruritic, anti-ageing, and antimalignancy properties by various mechanisms including interacting with the newly found endocannabinoid system of the skin thereby providing a promising alternative to traditional treatments.”

https://www.ncbi.nlm.nih.gov/pubmed/31599175

https://www.tandfonline.com/doi/abs/10.1080/09546634.2019.1675854?journalCode=ijdt20

CB1 enhanced the osteo/dentinogenic differentiation ability of periodontal ligament stem cells via p38 MAPK and JNK in an inflammatory environment.

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Publication cover image

“Periodontitis is an inflammatory immune disease that causes periodontal tissue loss. Inflammatory immunity and bone metabolism are closely related to periodontitis.

The cannabinoid receptor I (CB1) is an important constituent of the endocannabinoid system and participates in bone metabolism and inflammation tissue healing.

It is unclear whether CB1 affects the mesenchymal stem cell (MSC) function involved in periodontal tissue regeneration.

In this study, we revealed the role and mechanism of CB1 in the osteo/dentinogenic differentiation of periodontal ligament stem cells (PDLSCs) in an inflammatory environment.

CONCLUSIONS:

CB1 was able to enhance the osteo/dentinogenic differentiation ability of PDLSCs via p38 MAPK and JNK signalling in an inflammatory environment, which might be a potential target for periodontitis treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31599069

“In conclusion, our findings revealed that CB1 could activate the osteo/dentinogenic differentiation potential of PDLSCs under inflammatory conditions. Our results clarified the potential role and mechanism of CB1 in PDLSCs under inflammatory conditions and provide candidate targets for enhancing MSC function and the treatment of periodontitis.”

https://onlinelibrary.wiley.com/doi/full/10.1111/cpr.12691

The Effects of Dosage-Controlled Cannabis Capsules on Cancer-Related Cachexia and Anorexia Syndrome in Advanced Cancer Patients: Pilot Study.

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Image result for integrative cancer therapies“Cancer-related cachexia and anorexia syndrome (CACS) is a common phenomenon in cancer patients. Cannabis has been suggested to stimulate appetite but research on this issue has yielded mixed results. The current study aimed to evaluate the effect of dosage-controlled cannabis capsules on CACS in advanced cancer patients.

Methods: The cannabis capsules used in this study contained two fractions of oil-based compounds. The planned treatment was 2 × 10 mg per 24 hours for six months of tetrahydrocannabinol (THC) 9.5 mg and cannabidiol (CBD) 0.5 mg. If patients suffered from side effects, dosage was reduced to 5 mg × 2 per day (THC 4.75 mg, CBD 0.25 mg). Participants were weighed on every physician visit. The primary objective of the study was a weight gain of ≥10% from baseline.

Results: Of 24 patients who signed the consent form, 17 started the cannabis capsules treatment, but only 11 received the capsules for more than two weeks. Three of six patients who completed the study period met the primary end-point. The remaining three patients had stable weights. In quality of life quaternaries, patients reported less appetite loss after the cannabis treatment (p=0.05). Tumor necrosis factor-α (TNF-α) levels decreased after the cannabis treatment but without statistical significance. According to patients’ self-reports, improvement in appetite and mood as well as a reduction in pain and fatigue was demonstrated.

Conclusions: Despite various limitations, this preliminary study demonstrated a weight increase of ≥10% in 3/17 (17.6%) patients with doses of 5mgx1 or 5mgx2 capsules daily, without significant side effects. The results justify a larger study with dosage-controlled cannabis capsules in CACS.”

https://www.ncbi.nlm.nih.gov/pubmed/31595793

“The primary objective of the study was a weight gain of ≥10% from baseline. Despite various limitations, the current preliminary study demonstrated a weight increase of ≥10% in 3/17 (17.6%) of the patients with doses of 5 mg × 1 or 5 mg × 2 capsules daily, without significant side effects.”

https://journals.sagepub.com/doi/10.1177/1534735419881498

Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?

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 Publication Cover“Understanding how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the increased financial burden to the medical care system.

Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Modulation of the endocannabinoid system offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic).

Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation.

One major issue is the presence of psychotropic side effects associated with D9-tetrahydrocannabinol (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect prevents the appropriate degree of analgesia .

Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells.

The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release.

This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R’s role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception.

We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoid mediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons.

This work stands to reveal long-standing controversies in the cannabinoid analgesia area that have had an impact on failed clinical trials and implementation of therapeutics targeting this system.”

https://www.ncbi.nlm.nih.gov/pubmed/31596190

https://www.tandfonline.com/doi/abs/10.1080/15504263.2019.1668100?journalCode=wjdd20