Medical Cannabinoids as Treatment for Hypophosphatasia-Related Symptoms

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Karger Publishers – ScienceOpen

“Background: Hypophosphatasia (HPP) is a rare congenital disease caused by a mutation affecting tissue non-specific alkaline phosphatase, an enzyme involved in phosphate metabolism. The clinical manifestation usually includes bone-mineralization disorders, neurological symptoms, and persistent muscle pain.

Case report: This case involves a woman in her sixties of Central European descent who suffers from life-long chronic pain and muscle weakness due to hypophosphatasia and concomitant degenerative changes of the lumbar spine. The patient is physically impaired and limited in her ability to walk as a result. HPP-specific and guideline-based multimodal pain management including enzyme replacement therapy with asfotase alfa, opioids, invasive orthopedic and neurosurgical procedures, long-term physiotherapy, and psychotherapy did not yield sufficient treatment results. The average pain was given as 8.5 on a numerical rating scale (NRS, 0-10) for the last 3 years. Treatment with a cannabidiol-predominant, full-spectrum, prescription cannabis extract led to a clinically meaningful pain reduction to 2.5/10 NRS, a discontinuation of opioids, and a recent resumption of employment as a physician.

Conclusion: A more widespread consideration of medical cannabinoids in the treatment of complex chronic pain is proposed. Cannabinoids may pose a particularly potent treatment option for HPP-related symptoms and inflammation due to their known anti-inflammatory properties.”

https://pubmed.ncbi.nlm.nih.gov/36380652/

https://www.karger.com/Article/Abstract/528069

Virtual Screening and In Vitro Experiments Highlight Cannabidiol as a Drug-like Phosphodiesterase 9 Inhibitor

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“The growing interest on the therapeutic potential against neurodegeneration of Cannabis sativa extracts, and of phytocannabinoids in particular, is paralleled by a limited understanding of the undergoing biochemical pathways in which these natural compounds may be involved. Computational tools are nowadays commonly enrolled in the drug discovery workflow and can guide the investigation of macromolecular targets for such molecules. In this contribution, in silico techniques have been applied to the study of C. sativa constituents at various extents, and a total of 7 phytocannabinoids and 4 terpenes were considered. On the side of ligand-based virtual screening, physico-chemical descriptors were computed and evaluated, highlighting the phytocannabinoids possessing suitable drug-like properties to potentially target the central nervous system. Our previous findings and literature data prompted us to investigate the interaction of these molecules with phosphodiesterases (PDEs), a family of enzymes being studied for the development of therapeutic agents against neurodegeneration. Among the compounds, structure-based techniques such as docking and molecular dynamics (MD), highlighted cannabidiol (CBD) as a potential and selective PDE9 ligand, since a promising calculated binding energy value (-9.1 kcal/mol) and a stable interaction in the MD simulation timeframe were predicted. Additionally, PDE9 inhibition assay confirmed the computational results, and showed that CBD inhibits the enzyme in the nanomolar range in vitro, paving the way for further development of this phytocannabinoid as a therapeutic option against neurodegeneration.”

https://pubmed.ncbi.nlm.nih.gov/36382587/

https://onlinelibrary.wiley.com/doi/10.1111/ejn.15869

Disorders of cancer metabolism: The therapeutic potential of cannabinoids

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Biomedicine & Pharmacotherapy

“Abnormal energy metabolism, as one of the important hallmarks of cancer, was induced by multiple carcinogenic factors and tumor-specific microenvironments. It comprises aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis. Considering that metabolic reprogramming provides various nutrients for tumor survival and development, it has been considered a potential target for cancer therapy.

Cannabinoids have been shown to exhibit a variety of anticancer activities by unclear mechanisms.

This paper first reviews the recent progress of related signaling pathways (reactive oxygen species (ROS), AMP-activated protein kinase (AMPK), mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), hypoxia-inducible factor-1alpha (HIF-1α), and p53) mediating the reprogramming of cancer metabolism (including glucose metabolism, lipid metabolism, and amino acid metabolism). Then we comprehensively explore the latest discoveries and possible mechanisms of the anticancer effects of cannabinoids through the regulation of the above-mentioned related signaling pathways, to provide new targets and insights for cancer prevention and treatment.”

https://pubmed.ncbi.nlm.nih.gov/36379120/

“Antitumor effect of cannabinoids may due to the improvement of metabolic disorders.”

https://www.sciencedirect.com/science/article/pii/S0753332222013828?via%3Dihub

Implications of the endocannabinoid system and the therapeutic action of cannabinoids in autism spectrum disorder: A literature review

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Pharmacology Biochemistry and Behavior

“Autism spectrum disorder (ASD) is a neurodevelopmental disorder, onset in early childhood and associated with cognitive, social, behavioral, and sensory impairments. The pathophysiology is still unclear, and it is believed that genetic and environmental factors are fully capable of influencing ASD, especially cell signaling and microglial functions. Furthermore, the endocannabinoid system (ECS) participates in the modulation of various brain processes and is also involved in the pathophysiological mechanisms of this condition. Due to the health and quality of life impacts of autism for the patient and his/her family and the lack of effective medications, the literature has elucidated the possibility that Cannabis phytocannabinoids act favorably on ASD symptoms, probably through the modulation of neurotransmitters, in addition to endogenous ligands derived from arachidonic acid, metabolizing enzymes and even transporters of the membrane. These findings support the notion that there are links between key features of ASD and ECS due to the favorable actions of cannabidiol (CBD) and other cannabinoids on symptoms related to behavioral and cognitive disorders, as well as deficits in communication and social interaction, hyperactivity, anxiety and sleep disorders. Thus, phytocannabinoids emerge as therapeutic alternatives for ASD.”

https://pubmed.ncbi.nlm.nih.gov/36379443/

“Pure or enriched CBD is favorable for the treatment of symptoms and comorbidities related to ASD.”

https://www.sciencedirect.com/science/article/abs/pii/S009130572200171X?via%3Dihub

Promising Action of Cannabinoids on ER Stress-Mediated Neurodegeneration: An In Silico Investigation

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“Neurodegeneration has been recognized as a clinical episode characterized by neuronal death, including dementia, cognitive impairment and movement disorder. Most of the neurodegenerative deficits, via clinical symptoms, includes common pathogenic features as protein misfolding and aggregation. Therefore, the focus highlights the cellular organelle endoplasmic reticulum (ER) critically linked with the quality control and protein homeostasis. Unfolded protein response (UPR) or ER stress have also been considered as hallmarks for neurodegenerative disorders. It has been implicated that the levels of endocannabinoids (ECB) could rise at the platform of neurodegeneration. In addition, phytocannabinoids (PCB) including cannabidiol (CBD) could also initiate the IRE1, PERK, XBP-1, and ATF6, pathways that could lead to the degradation of the misfolded proteins and termination of protein translation. Thus, our aim was to determine if cannabinoids bind to these ER arm proteins involved in UPR by molecular docking and therefore determine its drug resemblance through ADME analysis. In our study, three cannabinoid receptors (CB1, CB2, and CB3) were considered to demonstrate their neuroprotective actions. The chosen ligands were screened as PCB (Δ9-tetrahydrocannabinol or THC), CBD, and two ECB, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The current findings have advocated that the cannabinoids and their molecular targets have shown considerable binding and their ADME properties also reveals that they possess moderate drug-like properties making it as a valuable option for the treatment and management of neurodegenerative diseases.”

https://pubmed.ncbi.nlm.nih.gov/36374961/

https://dl.begellhouse.com/journals/0ff459a57a4c08d0,6b57eefe5f7fdc1a,560f019e6ae36432.html

Effects of Cannabis Legalization on Adolescent Cannabis Use Across 3 Studies

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American Journal of Preventive Medicine

“Introduction: Canada, Uruguay, and 18 states in the U.S. have legalized the use of nonmedical (recreational) cannabis for adults, yet the impact of legalization on adolescent cannabis use remains unclear. This study examined whether cannabis legalization for adults predicted changes in the probability of cannabis use among adolescents aged 13-18 years.

Methods: Data were drawn from 3 longitudinal studies of youth (spanning 1999-2020) centered in 3 U.S. states: Oregon, New York, and Washington. During this time, Oregon (2015) and Washington (2012) passed cannabis legalization; New York did not. In each study, youth average age was 15 years (total N=940; 49%-56% female, 11%-81% Black/African American and/or Latinx). Multilevel modeling (in 2021) of repeated measures tested whether legalization predicted within- or between-person change in past-year cannabis use or use frequency over time.

Results: Change in legalization status across adolescence was not significantly related to within-person change in the probability or frequency of self-reported past-year cannabis use. At the between-person level, youth who spent more of their adolescence under legalization were no more or less likely to have used cannabis at age 15 years than adolescents who spent little or no time under legalization.

Conclusions: This study addresses several limitations of repeated cross-sectional studies of the impact of cannabis legalization on adolescent cannabis use. Findings are not consistent with changes in the prevalence or frequency of adolescent cannabis use after legalization. Ongoing surveillance and analyses of subpopulations are recommended.”

https://pubmed.ncbi.nlm.nih.gov/36372654/

https://www.ajpmonline.org/article/S0749-3797(22)00491-3/fulltext

Cannabinoid Treatments for Anxiety: A Systematic Review and Consideration of the Impact of Sleep Disturbance

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Neuroscience & Biobehavioral Reviews

“Cannabidiol’s (CBD) safety profile and broad action has made it a popular treatment option for anxiety and co-occurring sleep disturbance. However, its efficacy in healthy and clinical populations, treatment duration, formulation and doses for optimal therapeutic benefits remains unclear. Selected databases were examined from inception to October 2022. Study selection, data extraction and Cochrane Risk of Bias assessments were conducted according to PRISMA guidelines and registered on the PROSPERO database (CRD42021247476) with 58 full-text studies meeting the eligibility criteria and administered CBD only or with Δ-9-tetrahydrocannabinol (THC) across healthy and clinical populations. In healthy populations and certain non-cannabis using clinical populations, CBD had greater anxiolytic effects without prominent effects on sleep. An inverted U-shaped dose relationship, and CBD ratio to THC in combined treatments likely moderated these effects. Mechanistically, observed CBD effects occurred via primary modulation of the endocannabinoid system and secondary regulation of neuroendocrine function. Additional research is needed to understand CBD mechanisms of action across diverse groups.”

https://pubmed.ncbi.nlm.nih.gov/36370842/

https://www.sciencedirect.com/science/article/abs/pii/S0149763422004304?via%3Dihub

Hippocampal CB1 Receptor mediates antidepressant-like effect of Synthetic Cannabinoid-HU210 in Acute Despair Reaction model in mice

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Neuroscience Letters

“Growing evidence suggests that stress may contribute to the pathophysiology of depression. The alleviation of depressive symptoms is one of the most attractive medical applications of cannabis. Here, we investigated the antidepressant-like actions of synthetic cannabinoid-HU210 in acute despair response and explored the possible underlying mechanisms. Acute stress, induced by forced-swimming, induced depression-like behavior in the sucrose preference test (SPT). HU-210 (50 μg/kg) displayed anti-depressant like effect in the forced swim test in naïve mice and decreased depression-like behavior in the SPT, induced by forced swim stress. Pretreatment with AM251, an inhibitor of CB1R or inhibition of long-term depression (LTD) at hippocampal CA3-CA1 synapses by Tat-GluR2 attenuated the antidepressant like action of HU-210. These results indicate that HU210 produces antidepressant-like effects in acute stress and its underlying mechanism may be related to CB1R activation and hence hippocampal LTD production invivo. Synthetic cannabis or cannabis-related drugs may be used as an early intervention after acute stress exposure to prevent or at least reduce depression-like behaviors.”

https://pubmed.ncbi.nlm.nih.gov/36372093/

https://www.sciencedirect.com/science/article/abs/pii/S0304394022005146?via%3Dihub

Nutritional Quality, Chemical, and Functional Characteristics of Hemp (Cannabis sativa ssp. sativa) Protein Isolate

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plants-logo

“(1) Background: Hemp seeds are a source of plant-based protein, making them an appropriate supplement to a plant-based diet. The current work was focused on the preparation of the protein isolate from the hemp seeds with eco-friendly and cheap technology. Moreover, it evaluated the physicochemical and functional properties of hemp protein isolate for its potential application in food manufacturing.

(2) Methods: The protein content of hemp seeds has been isolated through two main steps: (1) extraction of the protein content of an alkaline pH (10-12); (2) precipitation of the extracted protein on an acidic pH as an isoelectric point (pH = 4.5).

(3) Results: The edastin protein is the most predominant protein in the protein profile with a molecular weight of 58.1 KDa beside albumin with a molecular weight of 31.5 KDa. The FTIR spectrum detected the absorption peaks of the amide I at 1750 and 1600 cm-1, which pointed to C=O stretching while N-H stretching at 1650-1580 cm-1. The peak at 3250 is found to be related to N-H stretching of the aliphatic primary amine (3400-3300 cm-1) and the N-H stretching for the secondary (II) amine appeared at 3350-3310 cm-1. The Hemp protein isolate (HPI) showed a high content of arginine (15.52 g/100 g), phenylalanine + tyrosine (9.63 g/100 g), methionine + cysteine (5.49 g/100 g), leucine + isoleucine (5.21 g/100 g), and valine (4.53 g/100 g). It contains a moderate level of threonine (3.29 g/100 g) and lysine (2.50 g/100 g) with tryptophan as the limiting amino acid (0.22 g/100 g). The HPI showed an appropriate water-and-oil holding capacity (4.5 ± 2.95 and 2.33 ± 1.88 mL/g, respectively). The foaming capacity of the HPI was increased with increasing the pH values to reach the maximum value at pH 11 (67.23 ± 3.20%). The highest emulsion ability index of the HPI was noted at pH 9 (91.3 ± 2.57 m2/g) with low stability (19.15 ± 2.03).

(4) Conclusions: A strong positive correlation (r = 0.623) was shown between protein concentration and solubility. The current easy-to-use, cheap, and eco-friendly technology provides the industrial sector with a cheap protein isolate for manufacturing protein-rich diet and beverages. The HPI showed a good nutritional quality and functional properties that might be helpful in utilizing it in different food products such as beverages and bakery products.”

https://pubmed.ncbi.nlm.nih.gov/36365277/

“It could be concluded that the hemp protein isolate (HPI) of the variety “Cannabis sativa ssp. Sativs” showed adequate nutritional and functional properties that encourage food technologists to use it as a promising alternative protein source for developing/ formulation of rich protein foods and fortification of some food products with a good protein isolate for improving their nutritional quality and technological properties.”

https://www.mdpi.com/2223-7747/11/21/2825/htm

Cannabis-Based Medicinal Products in the Management of Emotionally Unstable Personality Disorder (EUPD): A Narrative Review and Case Series

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brainsci-logo

“Emotionally unstable personality disorder (EUPD) is a common mental health disorder, manifesting with a range of chronic and debilitating symptoms, including impaired social functioning, unstable mood, and risky impulsive or self-injurious behaviour. Whilst the exact aetiology has not been fully elucidated, implicated factors seem to include genetic factors, environmental causes such as trauma, and neurotransmitter deficits.

The literature suggests that impaired functioning of the endocannabinoid system in key brain regions responsible for emotional processing and stress response may underlie the manifestation of EUPD symptoms. The National Institute for Health and Care Excellence (NICE) 2009 guidelines state that “no drugs have established efficacy in treating or managing EUPD”, and yet, patients are commonly prescribed medication which includes antipsychotics, antidepressants, and mood stabilisers.

Here we present a case series of seven participants diagnosed with EUPD and treated with cannabis-based medicinal products (CBMPs). Participants were given an initial assessment and followed up one month after CBMPs prescription. Improvement in symptoms was assessed by the completion of ratified rating scales by the participant and psychiatrist.

Our results indicate that CBMPs were effective and well tolerated, as six participants reported a noticeable improvement in their symptoms and functioning. Although promising, further research is needed to ascertain the long-term tolerability, efficacy, and dosing strategy for CBMPs in EUPD.”

https://pubmed.ncbi.nlm.nih.gov/36358392/

“To our knowledge, this case series represents the first medical evidence of the use of CBMPs for the clinical management of patients with a diagnosis of EUPD, who are met with limited pharmacological options typically based on the off-label use of psychiatric medications.

Cannabinoids may represent a novel, efficacious, and safe treatment alternative for EUPD patients.

The neuro- and immune-modulatory effects of THC and CBD seem theoretically well-aligned with cellular and molecular deficits that are currently being investigated as key features underlying the pathogenesis of EUPD. Although preliminary, our results suggest that, when deployed in a rigorously controlled clinical environment, CBMPs can provide substantial improvement in symptoms associated with EUPD thus warranting the need for further research on this therapeutical strategy.”

https://www.mdpi.com/2076-3425/12/11/1467/htm