Category Archives: Uncategorized

2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain.

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“2-Arachidonoylglycerol (2-AG) is a signaling lipid in the central nervous system that is a key regulator of neurotransmitter release. 2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor. It is involved in a wide array of (patho)physiological functions, such as emotion, cognition, energy balance, pain sensation and neuroinflammation. In this review, we describe the biosynthetic and metabolic pathways of 2-AG and how chemical and genetic perturbation of these pathways has led to insight in the biological role of this signaling lipid. Finally, we discuss the potential therapeutic benefits of modulating 2-AG levels in the brain.”

 https://www.ncbi.nlm.nih.gov/pubmed/29751000
https://www.sciencedirect.com/science/article/pii/S0163782717300619

Enhanced endocannabinoid tone as a potential target of pharmacotherapy.

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“The endocannabinoid system is up-regulated in numerous pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic and cardiovascular diseases, pain, and cancer. It has been suggested that this phenomenon primarily serves an autoprotective role in inhibiting disease progression and/or diminishing signs and symptoms.

Accordingly, enhancement of endogenous endocannabinoid tone by inhibition of endocannabinoid degradation represents a promising therapeutic approach for the treatment of many diseases. Importantly, this allows for the avoidance of unwanted psychotropic side effects that accompany exogenously administered cannabinoids.

The effects of endocannabinoid metabolic pathway modulation are complex, as endocannabinoids can exert their actions directly or via numerous metabolites. The two main strategies for blocking endocannabinoid degradation are inhibition of endocannabinoid-degrading enzymes and inhibition of endocannabinoid cellular uptake.

To date, the most investigated compounds are inhibitors of fatty acid amide hydrolase (FAAH), an enzyme that degrades the endocannabinoid anandamide. However, application of FAAH inhibitors (and consequently other endocannabinoid degradation inhibitors) in medicine became questionable due to a lack of therapeutic efficacy in clinical trials and serious adverse effects evoked by one specific compound.

In this paper, we discuss multiple pathways of endocannabinoid metabolism, changes in endocannabinoid levels across numerous human diseases and corresponding experimental models, pharmacological strategies for enhancing endocannabinoid tone and potential therapeutic applications including multi-target drugs with additional targets outside of the endocannabinoid system (cyclooxygenase-2, cholinesterase, TRPV1, and PGF2α-EA receptors), and currently used medicines or medicinal herbs that additionally enhance endocannabinoid levels.

Ultimately, further clinical and preclinical studies are warranted to develop medicines for enhancing endocannabinoid tone.”

https://www.ncbi.nlm.nih.gov/pubmed/29729263

https://www.sciencedirect.com/science/article/pii/S0024320518302352

Cannabis in End-of-Life Care: Examining Attitudes and Practices of Palliative Care Providers.

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“Medical cannabis research has become quite extensive, with indications ranging from glaucoma to chemotherapy-induced nausea.

Despite increased interest in cannabis‘ potential medical uses, research barriers, cannabis legislation, stigma, and lack of dissemination of data contribute to low adoption for some medical populations.

Of interest, cannabis use appears low in palliative care settings, with few guidelines available to palliative care providers. The present study sought to examine the attitudes, beliefs, and practices of palliative care providers regarding the use of cannabis for terminally ill patients.

Results demonstrated that palliative care providers endorse cannabis for a wide range of palliative care symptoms, end-of-life care generally, and as an adjuvant medication.

Nevertheless, the gap between these beliefs and actual recommendation or prescription appears vast. Many who support the use of cannabis in palliative care do not recommend it as a treatment. These data suggest recommendations for healthcare providers and palliative care organizations.”

https://www.ncbi.nlm.nih.gov/pubmed/29714640

https://www.tandfonline.com/doi/abs/10.1080/02791072.2018.1462543?journalCode=ujpd20

Cannabis, from Plant to Pill.

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“The therapeutic application of Cannabis is attracting substantial public and clinical interest. The Cannabis plant has been described as a veritable ‘treasure trove’, producing more than a hundred different cannabinoids, although the focus to date has been on the psychoactive molecule delta-9-tetraydrocannabinol (THC) and cannabidiol (CBD).

Other numerous secondary metabolites of Cannabis the terpenes, some of which share the common intermediary geranyl diphosphate (GPP) with the cannabinoids, are hypothesised to contribute synergistically to their therapeutic benefits, an attribute that has been described as the ‘entourage effect’.

The effective delivery of such a complex multicomponent pharmaceutical relies upon the stable genetic background and standardised growth of the plant material, particularly if the raw botanical product in the form of the dried pistillate inflorescence (flos) is the source.

Following supercritical CO2 extraction of the inflorescence (and possibly bracts), the secondary metabolites can be blended to provide a specific ratio of major cannabinoids (THC:CBD) or individual cannabinoids can be isolated, purified and supplied as the pharmaceutical. Intensive breeding strategies will provide novel cultivars of Cannabis possessing elevated levels of specific cannabinoids or other secondary metabolites.”

https://www.ncbi.nlm.nih.gov/pubmed/29701252

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bcp.13618

Relation of Cannabis Use and Atrial Fibrillation Among Patients Hospitalized for Heart Failure.

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 The American Journal of Cardiology

“Left ventricular dysfunction triggers the activation of the sympathetic nervous system, providing inotropic support to the failing heart and concomitantly increasing the risk of atrial fibrillation (AF). The cardiovascular effects of cannabis have been characterized as biphasic on the autonomic nervous system with an increased sympathetic effect at low doses and an inhibitory sympathetic activity at higher doses. It is unknown if the autonomic effect of cannabis impacts the occurrence of AF in patients with heart failure (HF).

We used data from the Healthcare Cost and Utilization Project-National Inpatient Sample for patients admitted with a diagnosis of HF in 2014. The outcome variable was the diagnosis of AF, with the main exposure being cannabis use. We identified a cannabis user group and a 1:1 propensity-matched non-cannabis user group, each having 3,548 patients. We then estimated the odds of AF diagnosis in cannabis users. An estimated 3,950,392 patients were admitted with a diagnosis of HF in the United States in 2014. Among these, there were 17,755 (0.45%) cannabis users. In the matched cohort, cannabis users were less likely to have AF (19.08% vs 21.39%; AOR 0.87 [0.77 to 0.98]).

In conclusion, cannabis users have lower odds of AF when compared with nonusers, which was not explained by co-morbid conditions, age, insurance type, and socioeconomic status.”

https://www.ncbi.nlm.nih.gov/pubmed/29685570

https://www.ajconline.org/article/S0002-9149(18)30383-7/fulltext

“Surprising Find: Marijuana Linked with Benefits for Heart Failure Patients. Heart failure patients who used marijuana were also less likely to die in the hospital than those who didn’t use the drug, the study found.”  https://www.livescience.com/60988-marijuana-heart-failure.html

Testing associations between cannabis use and subcortical volumes in two large population-based samples.

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“Disentangling the putative impact of cannabis on brain morphology from other comorbid substance use is critical. After controlling for the effects of nicotine, alcohol and multi-substance use, this study aimed to determine whether frequent cannabis use is associated with significantly smaller subcortical grey matter volumes.

FINDINGS:

After correcting for multiple testing (p=0.007), cannabis use was unrelated to any subcortical ROI. However, maximum nicotine use was associated with significantly smaller thalamus volumes in middle-age males.

CONCLUSIONS:

In exploratory analyses based on young adult and middle age samples, normal variation in cannabis use is statistically unrelated to individual differences in brain morphology as measured by subcortical volume.”

https://www.ncbi.nlm.nih.gov/pubmed/29691937

https://onlinelibrary.wiley.com/doi/abs/10.1111/add.14252

[The impact of cannabinoids on the endocrine system].

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“Cannabinoids are naturally occurring compounds, derivatives of Indian hemp, in which tetrahydrocannabinol (THC) is the most important. Marijuana, hashish and hash oil are among those most commonly used in the group.

Cannabinoids (marjhuana and hashish) have been used throughout recorded history as effective drugs in treating various diseases and conditions such as: malaria, hypertension, constipation, bronchial asthma, rheumatic pains, and as natural pain relief in labour and joint pains.

Marijuana acts through cannabinoid receptors CB 1 and CB2. Both receptors inhibit cAMP accummulation (through Gi/o proteins) and stimulate mitrogen- activated protein kinase. CB1 rceptors are located in CNS and in adipose tissue, digestive tract, muscles, heart, lungs, liver, kidneys, gonads, prostate gland and other peripheral tissues. CB2 cannabinoid receptors are located in the peripheral nervous system (at the ends of peripheral nerves), and on the surfaces of the cells of the immunological system.

The discovery of endogenous cannabinoids has contributed to a better understanding of their role in the regulation of the intake of food, energetic homeostasis and their significant influence on the endocrine system.”

https://www.ncbi.nlm.nih.gov/pubmed/29689684

Palatability and oral cavity tolerability of THC:CBD oromucosal spray and possible improvement measures in multiple sclerosis patients with resistant spasticity: a pilot study.

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“Complaints about Δ9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex®; GW Pharma Ltd, Sailsbury, UK) in the management of multiple sclerosis spasticity include unpleasant taste and oral mucosal anomalies.

This pilot study assessed the use of sugar-free chewing gum and/or a refrigerated bottle of THC:CBD oromucosal spray to mitigate these effects.

RESULTS:

Taste perception in patients receiving chewing gum ± cold bottle intervention (Groups A and C combined) was significantly (p = 0.0001) improved from baseline to week 4 while maintaining spasticity control.

CONCLUSION:

Patient comfort, satisfaction and treatment adherence may benefit from these interventions.”

https://www.ncbi.nlm.nih.gov/pubmed/29683408

https://www.futuremedicine.com/doi/10.2217/nmt-2017-0056

Paraneoplastic cerebellar degeneration: Yo antibody alters mitochondrial calcium buffering capacity.

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Neuropathology and Applied Neurobiology banner

“Neurodegeneration is associated with dysfunction of calcium buffering capacity and thereby sustained cellular and mitochondrial calcium overload. Paraneoplastic cerebellar degeneration (PCD), characterized by progressive Purkinje neuron degeneration following paraneoplastic Yo antibody internalisation and binding to cerebellar degeneration-related protein CDR2 and CDR2L, has been linked to intracellular calcium homeostasis imbalance due to calbindin D28k malfunction. Therefore, we hypothesized that Yo antibody internalisation affects not only calbindin calcium binding capacity but also calcium-sensitive mitochondrial-associated signalling, causing mitochondrial calcium overload and thereby Purkinje neuron death.

CONCLUSION:

These findings suggest that minimising intracellular calcium overload toxicity either directly with cyclosporin-A or indirectly with cannabidiol or the ROS scavenger butylated hydroxytoluene promotes mitochondrial calcium homeostasis and may therefore be used as future neuroprotective therapy for PCD patients.”

https://www.ncbi.nlm.nih.gov/pubmed/29679372

https://onlinelibrary.wiley.com/doi/abs/10.1111/nan.12492

Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users.

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“Chronic cannabis use is associated with neuroanatomical alterations in the hippocampus. While adverse impacts of cannabis use are generally attributed to Δ9-tetrahydrocannabinol, emerging naturalistic evidence suggests cannabidiol (CBD) is neuroprotective and may ameliorate brain harms associated with cannabis use, including protection from hippocampal volume loss. This study examined whether prolonged administration of CBD to regular cannabis users within the community could reverse or reduce the characteristic hippocampal harms associated with chronic cannabis use.

Results: No change was observed in left or right hippocampus as a whole. However, left subicular complex (parasubiculum, presubiculum, and subiculum) volume significantly increased from baseline to post-treatment (p=0.017 uncorrected) by 1.58% (Cohen’s d=0.63; 2.83% in parasubiculum). Heavy cannabis users demonstrated marked growth in the left subicular complex, predominantly within the presubiculum, and right cornu ammonis (CA)1 compared to lighter users. Associations between greater right subicular complex and total hippocampal volume and higher plasma CBD concentration were evident, particularly in heavy users.

Conclusions: Our findings suggest a restorative effect of CBD on the subicular and CA1 subfields in current cannabis users, especially those with greater lifetime exposure to cannabis. While replication is required in a larger, placebo-controlled trial, these findings support a protective role of CBD against brain structural harms conferred by chronic cannabis use. Furthermore, these outcomes suggest that CBD may be a useful adjunct in treatments for cannabis dependence and may be therapeutic for a range of clinical disorders characterized by hippocampal pathology (e.g., schizophrenia, Alzheimer’s disease, and major depressive disorder).”

https://www.ncbi.nlm.nih.gov/pubmed/29682609

“In conclusion, our findings are the first to demonstrate an ameliorating effect of CBD treatment upon brain structural harms characteristic of regular cannabis use. Furthermore, these results speak to the potential for CBD treatment to restore hippocampal pathology in a range of clinical populations (e.g., schizophrenia, Alzheimer’s disease, and major depressive disorder).”

https://www.liebertpub.com/doi/10.1089/can.2017.0047