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A large Australian longitudinal cohort registry demonstrates sustained safety and efficacy of oral medicinal cannabis for at least two years

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Lopiccolo & Chang in PLoS ONE – BU Linguistics

“Introduction: Oral medicinal cannabis (MC) has been increasingly prescribed for a wide range of clinical conditions since 2016. Despite an exponential rise in prescriptions and publications, high quality clinical efficacy and safety studies are lacking. The outcomes of a large Australian clinical electronic registry cohort are presented.

Methods: A prospective cannabis-naïve patient cohort prescribed oral MC participated in an ongoing longitudinal registry at a network of specialised clinics. Patient MC dose, safety and validated outcome data were collected regularly over two years and analysed.

Results: 3,961 patients (mean age 56.07 years [SD 19.08], 51.0% female) with multimorbidity (mean diagnoses 5.14 [SD 4.08]) and polypharmacy (mean 6.26 medications [SD 4.61]) were included in this analysis. Clinical indications were for: chronic pain (71.9%), psychiatric (15.4%), neurological (2.1%), and other diagnoses (10.7%). Median total oral daily dose was 10mg for Δ9-tetrahydrocannabinol (THC) and 22.5mg for cannabidiol (CBD). A stable dose was observed for over two years. 37.3% experienced treatment related adverse events. These were graded mild (67%), moderate (31%), severe (<2%, n = 23) and two (0.1%) serious adverse events. Statistically significant improvements at a p value of <0.001 across all outcomes were sustained for over two years, including: clinical global impression (CGI-E, +39%: CGI-I, +52%; p<0.001), pain interference and severity (BPI, 26.1% and 22.2%; p<0.001), mental health (DASS-21, depression 24.5%, anxiety 25.5%, stress 27.7%; p<0.001), insomnia (ISI, 35.0%; p<0.001), and health status (RAND SF36: physical function, 34.4%: emotional well-being, 37.3%; p<0.001). Mean number of concomitant medications did not significantly change over 2 years (p = 0.481).

Conclusions: Oral MC was demonstrated to be safe and well-tolerated for a sustained period in a large complex cohort of cannabis-naïve, multimorbid patients with polypharmacy. There was significant improvement (p<0.001) across all measured clinical outcomes over two years. Results are subject to limitations of Real World Data (RWD) for causation and generalisability. Future high quality randomised controlled trials are awaited”

https://pubmed.ncbi.nlm.nih.gov/36399463/

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0272241.

Pharmacological Aspects and Biological Effects of Cannabigerol and Its Synthetic Derivatives

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“Cannabigerol (CBG) is a cannabinoid from the plant Cannabis sativa that lacks psychotomimetic effects. Its precursor is the acidic form, cannabigerolic acid (CBGA), which is, in turn, a biosynthetic precursor of the compounds cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBGA decarboxylation leads to the formation of neutral cannabinoid CBG, through a chemical reaction catalyzed by heat. On the basis of the growing interest in CBG and with the aim of highlighting scientific information on this phytocannabinoid, we focused the content of this article on its pharmacokinetic and pharmacodynamic characteristics and on its principal pharmacological effects. CBG is metabolized in the liver by the enzyme CYP2J2 to produce hydroxyl and di-oxygenated products. CBG is considered a partial agonist at the CB1 receptor (R) and CB2R, as well as a regulator of endocannabinoid signaling. Potential pharmacological targets for CBG include transient receptor potential (TRP) channels, cyclooxygenase (COX-1 and COX-2) enzymes, cannabinoid, 5-HT1A, and alpha-2 receptors. Pre-clinical findings show that CBG reduces intraocular pressure, possesses antioxidant, anti-inflammatory, and anti-tumoral activities, and has anti-anxiety, neuroprotective, dermatological, and appetite-stimulating effects. Several findings suggest that research on CBG deserves to be deepened, as it could be used, alone or in association, for novel therapeutic approaches for several disorders.”

https://pubmed.ncbi.nlm.nih.gov/36397993/

https://www.hindawi.com/journals/ecam/2022/3336516/

Nabiximols effect on blood pressure and heart rate in post-stroke patients of a randomized controlled study

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Frontiers - Crunchbase Company Profile & Funding

“Background: Cannabinoids may be useful to treat pain, epilepsy and spasticity, although they may bear an increased risk of cardiovascular events. This study aims to evaluate the cardiovascular safety of nabiximols, a cannabis-based drug, in patients with spasticity following stroke, thus presenting an increased cardiovascular risk.

Methods: This is an ancillary study stemming from the SativexStroke trial: a randomized double-blind, placebo-controlled, crossover study aimed at assessing the effect of nabiximols on post-stroke spasticity. Patients were treated with nabiximols oromucosal spray or placebo and assessed before and after two phases of 1-month duration each. Only the phase with the active treatment was considered for each patient who completed the study. The average values of blood pressure (diastolic, systolic, differential) and heart rate from the first 5 days of the phase (lowest nabiximols dosage) were compared to the average values recorded during the last 5 days at the end of the phase (highest nabiximols dosage). Baseline comparisons between gender, stroke type and affected side and correlation between age and blood pressure and heart rate were performed. The study was registered with the EudraCT number 2016-001034-10.

Results: Thirty-four patients completed the study and were included in the analysis. Thirty-one were taking antihypertensive drugs and, among these, 12 were taking beta-blockers. During the study, no arrhythmic events were recorded, blood pressure and heart rate did not show pathological fluctuations, and no cardiovascular or cerebrovascular events occurred. At baseline blood pressure and heart rate were comparable concerning gender, stroke type and affected side. A significant direct correlation emerged between differential blood pressure and age and an inverse correlation between diastolic blood pressure and age. No correlation emerged between systolic blood pressure or heart rate and age. Blood pressure and heart rate did not change during nabiximols treatment compared to the baseline condition.

Conclusion: This ancillary study adds evidence that, in patients who already underwent a cerebrovascular accident, nabiximols does not determine significant blood pressure and heart rate variation or cardiovascular complications. These data support the cardiovascular safety of nabiximols, encouraging more extensive studies involving cannabinoids characterized by slow absorption rates.”

https://pubmed.ncbi.nlm.nih.gov/36386386/

“In conclusion, an interesting result of this pilot study is the good cardiovascular safety profile of nabiximols in patients with stroke. In these patients, the possible beneficial effect of cannabinoids, such as delaying atherosclerotic progression and inflammation, may deserve further investigation. Furthermore, because of the rapidly changing landscape of cannabis laws and marijuana use in western countries, there is a pressing need for refined policy, education of both clinicians and the public, and new research. Carefully designed, prospective, short- and long-term studies are needed to obtain conclusive data on the safety and efficacy of cannabinoid drugs.”

https://www.frontiersin.org/articles/10.3389/fcvm.2022.990188/full

Foodomics reveals anti-obesity properties of cannabinoids from hemp oil

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“Scope: Molecular networking (MN) analysis intends to provide chemical insight of untargeted mass spectrometry (MS) data to the user’s underlying biological questions. Foodomics is the study of chemical compounds in food using advanced omics methods. In this study, we developed an MS-MN-based foodomics approach to investigate the composition and anti-obesity activity of cannabinoids in hemp oil.

Methods and results: A total of 16 cannabinoids were determined in optimized microwave pretreatment of hemp oil using the developed approach. Untargeted metabolomics analysis revealed that cannabinoid extract (CE) and its major constituent (cannabidiol, CBD), could alleviate high glucose-induced increases in lipids and carbohydrates, and decreases in amino acid and nucleic acid. Moreover, CE and CBD were also found to suppress the expression levels of mdt-15, sbp-1, fat-5, fat-6, fat-7, daf-2, and elevate the expression level of daf-1,daf-7, daf-16, sod-3, gst-4, lipl-4, resulting in the decrease of lipid synthesis and the enhance of kinetism. Canonical correspondence analysis (CCA) uncovered strong associations between specific metabolic alterations and gene expression levels.

Conclusion: These findings from this exploratory study offered a new insight into the roles of cannabinoids in the treatment of obesity and related complications.”

https://pubmed.ncbi.nlm.nih.gov/36382382/

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202200508

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

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

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

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“(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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“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