Author Archives: David

Deciphering the Phytochemical Potential of Hemp Hairy Roots: A Promising Source of Cannabisins and Triterpenes as Bioactive Compounds

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“Cannabis sativa L., specifically hemp, is a traditional herbaceous plant with industrial and medicinal uses.

While much research has focused on cannabinoids and terpenes, the potential of hemp roots is less explored due to bioproduction challenges. Still, this material is rich in bioactive compounds and demonstrates promising anti-inflammatory, antimicrobial, and antioxidant properties. Biotechnological methods, such as hairy root cultures, enable the efficient production of specialized metabolites while avoiding the issues of outdoors cultures. Despite these benefits, the chemical diversity understanding of hemp hairy roots remains limited.

In this study, we conducted an extensive NMR and LC/MS chemical profiling of hemp hairy roots to determine their chemical composition, revealing the presence of cannabisins for the first time. We then investigated the accumulation of cannabisins and triterpenes in both hemp hairy roots and hemp aeroponic roots.

Our findings reveal that hairy roots produce 12 times more cannabisins and 6 times more triterpenes than aeroponic roots, respectively, in addition to yielding 3 times more biomass in bioreactors. Preliminary bioassays also suggest antioxidant and antifungal properties. This research underscores the potential of hemp hairy roots as a valuable source of specialized metabolites and calls for further exploration into their bioactive compounds and applications.”

https://pubmed.ncbi.nlm.nih.gov/39683949/

“This study highlights the unique phytochemical profile of hemp hairy roots and underscores their potential for various applications. The advantages offered by hairy root cultures, such as improved productivity of biomass and metabolites, better reliability due to in vitro controlled culture and genetic consistency, and water- and energy-saving potential, make them a promising avenue for further exploration and utilization in industrial and medicinal contexts.”

https://www.mdpi.com/1420-3049/29/23/5792

Exploring the Biological Activity of Phytocannabinoid Formulations for Skin Health Care: A Special Focus on Molecular Pathways

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“Recent advancements have highlighted the potential of cannabis and its phytocannabinoids (pCBs) in skin health applications.

These compounds, through their interaction with the endocannabinoid system (ECS), show promise for skin health products. Their ability to regulate inflammation, oxidative stress and cell proliferation makes them useful in addressing skin problems such as inflammation, scarring, healing, acne and aging, positioning them as valuable tools for innovative skincare solutions.

In the present work, the cellular and molecular effects of proprietary pCB-based formulations on ECS modulation, inflammation and skin regeneration were investigated.

Using human dermal fibroblasts (HDF) and keratinocytes (HaCaT), the effect of formulations in both pre-treatment and treatment scenarios following exposure to stress-inducing agents was assessed. Key molecular markers were analyzed to tackle their efficacy in mitigating inflammation and promoting structural integrity and regeneration.

In vitro results showed that these formulations significantly reduced inflammation, promoted skin regeneration and improved structural functions. In vivo studies confirmed that the formulations were well-tolerated and led to noticeable improvements in skin health, including enhanced barrier function.

This study demonstrates the safety and efficacy of pCB-based formulations for cosmeceutical applications. By combining molecular analysis with in vivo testing, this research provides new insights into the therapeutic potential of pCBs for managing various skin conditions.”

https://pubmed.ncbi.nlm.nih.gov/39684852/

“This study confirms the safety and efficacy of pCB-based formulations for skin applications, highlighting their potential to enhance regeneration and structural processes. The findings underscore the promise of cannabis-based products in cosmetics and dermatology, meeting the rising demand for natural, effective skincare solutions and shaping the future of modern skincare and therapeutic approaches.”

https://www.mdpi.com/1422-0067/25/23/13142

Cannabinoid-Induced Immunogenic Cell Death of Colorectal Cancer Cells Through De Novo Synthesis of Ceramide Is Partially Mediated by CB2 Receptor

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“Background: Our recent studies have identified a link between sphingolipid metabolites and the induction of a specialized form of regulated cell death termed immunogenic cell death (ICD). We have recently demonstrated that the synthetic cannabinoid (±) 5-epi CP 55,940 (5-epi) stimulates the accumulation of ceramide (Cer), and that inhibition of sphingosine kinase 1 (SphK1) enhances Cer accumulation and ICD-induction in human colorectal cancer (CRC) cell lines. 

Methods: We employed flow-cytometric, western blot analyses, pharmacological inhibitors of the sphingolipid metabolic pathway and small molecule agonists and antagonists of the CB receptors to further analyze the mechanism by which 5-epi induces Cer accumulation. 

Results: Herein, and report that 5-epi induces de novo synthesis of Cer primarily through engagement of the cannabinoid receptor 2 (CB2) and depletion of intracellular calcium levels. Moreover, we report that 5-epi stimulates Cer synthesis through dysregulation of the endogenous inhibitor of the de novo Cer pathway, ORMDL3. We also observed a remarkable and specific accumulation of one Cer species, C20:4 Cer, generated predominantly by ceramide synthase 4, as a key factor required for 5-epi-induced ICD. 

Conclusions: Together, these data indicate that engagement of CB2, by 5-epi, alters regulation of the de novo ceramide synthesis pathway to generate Cer species that mediate ICD.”

https://pubmed.ncbi.nlm.nih.gov/39682160/

“Mounting evidence demonstrates that cannabinoids have anti-cancer properties.

The mechanism by which the cannabinoids induce cell death is still unclear. However, increased intracellular production of the sphingolipid, ceramide, seems to be a commonality. We recently demonstrated that a synthetic cannabinoid induced a specialized form of cell death that is known to activate the patient’s immune system, termed immunogenic cell death (ICD). Herein, we provide evidence of the mechanism by which synthetic cannabinoids increase ceramide production and demonstrate that ceramide is required for ICD.

These findings strengthen the evidence that cannabinoids are effective anti-cancer agents and, importantly, suggest that they may help to recruit the immune system to fight the patient’s tumor.”

https://www.mdpi.com/2072-6694/16/23/3973

Cannabidiol for Scan-Related Anxiety in Women With Advanced Breast Cancer: A Randomized Clinical Trial

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“Importance: Early evidence from studies outside of oncology has suggested that cannabidiol (CBD) may have anxiolytic effects without neuropsychiatric risks. An understanding of oral CBD in patients with cancer-related anxiety is urgently needed.

Objective: To determine whether a single 400-mg oral dose of a US Food and Drug Administration-approved CBD improves clinical anxiety in an oncologic population.

Design, setting, and participants: This phase II, double-masked, placebo-controlled, randomized clinical trial was performed at the Dana-Farber Cancer Institute’s Breast Oncology Center from November 2, 2021, through March 1, 2023. Women aged 18 years or older with advanced breast cancer and baseline clinical anxiety were included.

Interventions: Patients were randomized 1:1 to receive oral CBD, 400 mg, vs placebo within 48 hours before a scan assessing tumor burden.

Main outcomes and measures: The primary end point was a between-arm comparison of change scores on the afraid subscale of the Visual Analog Mood Scale (VAMS) before and 2 to 4 hours after study drug ingestion. The VAMS scores were converted to T-scores to facilitate interpretation of mood change (>20 indicates a reliable change, >30 indicates both a reliable and clinically significant change). Exploratory outcomes included between-arm comparisons of anxiety levels 2 to 4 hours after study drug ingestion, between-arm comparisons of change scores on other VAMS subscales, and safety.

Results: Among the 50 participants, 25 were randomized to the placebo arm (mean [range] age, 57 [37-81] years) and 25 were randomized to the CBD arm (mean [range] age, 60 [30-79] years). The primary end point of VAMS afraid subscale change score, although numerically greater in the CBD arm, was not significantly different between arms (mean [SD]: CBD, -19.1 [15.4]; placebo, -15.0 [10.9]; P = .37). The secondary outcome directly comparing anxiety levels between arms 2 to 4 hours after study drug ingestion demonstrated significantly lower VAMS afraid T-scores for participants who received CBD compared with those receiving placebo (mean [SD]: CBD, 51.5 [12.8]; placebo, 58.0 [11.6]; P = .02). No grade 3 or 4 toxic effects were reported.

Conclusions and relevance: The findings of this randomized clinical trial show that CBD can be used safely in women with advanced breast cancer and clinical anxiety. Although the study did not meet its primary end point comparing preingestion vs postingestion anxiety change scores between study arms, anxiety levels in the CBD arm were significantly lower 2 to 4 hours after ingestion, suggesting a possible anxiolytic effect and warranting further investigation.”

https://pubmed.ncbi.nlm.nih.gov/39680411/

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2828077

Anti-staphylococcal activity of soilless cultivated cannabis across the whole vegetation cycle under various nutritional treatments in relation to cannabinoid content

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Scientific Reports

“Antibiotic resistance in staphylococcal strains and its impact on public health and agriculture are global problems. The development of new anti-staphylococcal agents is an effective strategy for addressing the increasing incidence of bacterial resistance.

In this study, ethanolic extracts of Cannabis sativa L. made from plant parts harvested during the whole vegetation cycle under various nutritional treatments were assessed for in vitro anti-staphylococcal effects.

The results showed that all the cannabis extracts tested exhibited a certain degree of growth inhibition against bacterial strains of Staphylococcus aureus, including antibiotic-resistant and antibiotic-sensitive forms. The highest antibacterial activity of the extracts was observed from the 5th to the 13th week of plant growth across all the nutritional treatments tested, with minimum inhibitory concentrations ranging from 32 to 64 µg/mL. Using HPLC, Δ9-tetrahydrocannabinolic acid (THCA) was identified as the most abundant cannabinoid in the ethanolic extracts. A homolog of THCA, tetrahydrocannabivarinic acid (THCVA), reduced bacterial growth by 74%.

These findings suggest that the cannabis extracts tested in this study can be used for the development of new anti-staphylococcal compounds with improved efficacy.”

“In summary, the present study demonstrated the antistaphylococcal activity of ethanolic extracts of C. sativa L. against both of the bacterial strains tested, MSSA and MRSA, across all the vegetation stages, especially from the 5th to the 13th week. The various nutritional treatments had no impact on the resulting antibacterial effect.”

https://www.nature.com/articles/s41598-024-54805-3

Successful management of refractory epilepsy in creatine transporter deficiency with cannabidiol and clobazam: A case report

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“Creatine transporter deficiency (CRTR-D) is a rare X-linked inherited disease belonging to the group of cerebral creatine deficiency disorders. Major clinical features include developmental delay and epilepsy. To date, fewer than 200 individuals with CRTR-D have been reported. As a result, there is little evidence for effective treatment. Available therapies are creatine precursors, with a mild effect on disease progression. Concerning epilepsy, standard management is recommended and no specific anti-seizure medication (ASM) has been shown to be effective in refractory cases.

We report the case of a 28-year-old male patient with CRTR-D and childhood-onset refractory epilepsy. He had an average of 10-20 focal motor seizures with impaired consciousness per month. He had tried several ASMs without significant improvement.

Treatment with cannabidiol (CBD) and clobazam (CLB) in combination was added. The patient became seizure-free from the first week, and up to 1 year of follow-up. Behavioral improvement was also noted by his caregivers. No adverse effects were reported. Very few cases of CRTR-D with refractory epilepsy have been reported.

This calls for more extensive research and suggests a possible role for CBD in cerebral creatine metabolism and transport and valuable option for future studies.

PLAIN LANGUAGE SUMMARY: Creatine transporter deficiency (CRTR-D) is a rare genetic disorder causing mental, behavioral, and movement problems. More than half of patients also have seizures, but because there are fewer than 200 known cases, it is difficult to know the best treatment options. We present a 28-year-old man with CRTR-D who had severe developmental delays and frequent seizures since childhood, despite trying many medications. After starting cannabidiol and clobazam, he has been seizure-free for a year. Sharing this success might help other people with CRTR-D benefit from similar treatments.”

https://pubmed.ncbi.nlm.nih.gov/39679854/

https://onlinelibrary.wiley.com/doi/10.1002/epi4.13116

A novel insight into the antidepressant effect of cannabidiol: possible involvement of the 5-HT1A, CB1, GPR55, and PPARγ receptors

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“Background: Depression is a prevalent and disabling disorder that poses serious problems in mental health care, and rapid antidepressants are novel treatments for this disorder. Cannabidiol (CBD), a non-intoxicating phytocannabinoid, is thought to have therapeutic potential due to its important neurological and anti-inflammatory properties. Despite major advances in pharmacotherapy in experimental animals, the exact mechanism of antidepressant-like effects remains to be elucidated.

Methods: In this paper, we review the current state of knowledge on the antidepressant properties of CBD in numerous experimental and clinical studies.

Results: Accumulating evidence suggests that CBD has antidepressant properties in humans and animals with few side effects, suggesting that CBD may be a potential antidepressant. Furthermore, we discuss CBD may therefore provide a potential treatment to exert antidepressant-like effects through various molecular targets, reducing inflammation, and enhancing neurogenesis.

Conclusions: Taken together with the growing popularity of CBD as a medicine, these findings extend the limited knowledge on the antidepressant effects of CBD. This potentially opens up new therapeutic means for the patients with depression.”

https://pubmed.ncbi.nlm.nih.gov/39657242/

https://academic.oup.com/ijnp/advance-article/doi/10.1093/ijnp/pyae064/7918373?login=false

The synthetic cannabinoid WIN 55,212-2 attenuates cognitive and motor deficits and reduces amyloid load in 5XFAD Alzheimer mice

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“Background: Alzheimer’s disease (AD) is characterized by cognitive decline, with pathological features including amyloid β (Aβ) plaques and inflammation. Despite recent approvals of anti-amyloid antibodies, there remains a need for disease-modifying and easily accessible therapies. The endocannabinoid system presents a promising target for AD treatment, as it regulates various processes implicated in AD pathogenesis.

Aims: This study assesses the effects of the synthetic cannabinoid WIN 55,212-2 on AD pathology and behavior deficits in aged 5XFAD mice, a well-established AD model.

Methods: Male 9-month-old 5XFAD mice received either 0.2 mg/kg WIN 55,212-2 or a vehicle solution for 42 days. Memory, anxiety, and motor tests were conducted at 10 months to identify potential changes in behavior and cognition following WIN 55,212-2 treatment. Additionally, the effects of prolonged WIN 55,212-2 treatment on Aβ pathology and neuroinflammation in the brain were quantified immunohistochemically.

Results: Therapeutic WIN 55,212-2 treatment improved the motor performance of 5XFAD mice on the rotarod and rescued memory deficits in the water maze. However, WIN 55,212-2 treatment did not significantly affect anxiety-like behavior in 5XFAD mice. Additionally, prolonged treatment with WIN 55,212-2 reduced Aβ plaque pathology and astrogliosis in the cortex and hippocampus.

Conclusions: This study highlights the therapeutic potential of WIN 55,212-2 in AD by ameliorating cognitive and motor deficits and reducing neuropathology. These findings support a cannabinoid-based therapy as a promising strategy for AD treatment, with WIN 55,212-2 emerging as a potential candidate.”

https://pubmed.ncbi.nlm.nih.gov/39675388/

“Natural and synthetic cannabinoids exhibit anti-inflammatory, anti-oxidative, anti-proliferative and analgesic properties. The synthetic cannabinoid WIN 55,212-2, an agonist of both CB1 and CB2 receptors, has been shown to possess neuroprotective, anti-inflammatory, and antinociceptive properties. Furthermore, it has been shown to promote neurogenesis, reduce beta-amyloid and tau in vitro and in vivo“

https://www.sciencedirect.com/science/article/abs/pii/S0091305724002387?via%3Dihub

Cost-efficient analysis of cannabinoids in therapeutic oils using HPLC with UV and mass spectrometry detection

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“Cannabis oil, derived from Cannabis sativa plants, is increasingly used for therapeutic purposes across a wide range of diseases.

Accurate quantification of cannabinoids is essential, especially for cannabis products sourced from informal markets where supply origins are uncertain.

This study aimed to develop a cost-effective, robust analytical methodology using liquid chromatography in combination with UV- and mass detectors for the quantification of key cannabinoids (THC, CBD and CBN) and the identification of THCA and CBDA.

Utilising an isocratic flow, the method achieved effective separation within 17 min, ensuring simplicity and reproducibility. The methodology validation was aligned with ICH guidelines’ requirements for selectivity, linearity, precision, accuracy, and matrix effects.

Successful application of this method to both homemade and commercial cannabis oil samples underscores its relevance for adjusting therapeutic doses and optimising CBD:THC ratios for specific disease treatments.”

https://pubmed.ncbi.nlm.nih.gov/39671430/

https://www.tandfonline.com/doi/full/10.1080/14786419.2024.2439024

Lebanese cannabis oil extract protected against folic acid-induced kidney fibrosis in rats

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“Background: Renal fibrosis is a major manifestation of chronic kidney disease. To date, there are no treatments to reverse kidney fibrosis. Cannabis is an aromatic herb that is widely known for its anti-diabetic and anti-inflammatory properties. The aim of this study is to evaluate the protective effect of Lebanese cannabis oil extract (COE) against folic acid (FA) induced renal injury both in vitro and in vivo.

Materials and methods: A single dose of 250 mg/kg of Folic acid was administered to induce renal fibrosis in rats. COE was injected at varying doses of 5, 10, and 20 mg/kg. Body weight of rats were monitored and clinical parameters including serum creatinine, urea, and electrolytes were measured. Moreover, pathological examination of the kidney and heart was performed. Conditionally immortalized cultured rat podocytes were exposed to high concentrations of folic acid in the presence or absence of COE. MTS and in vitro scratch assay were used to assess podocyte cells viability and migration respectively. Western blot analysis was used to evaluate the phosphorylation levels of AKT and p38 MAPK.

Results: Rats that received FA showed a marked increase in serum creatinine when compared to the non-treated control group. COE at doses of 5 and 10 mg/kg significantly decreased serum creatinine induced by FA. Serum sodium was significantly reduced in all the groups receiving COE. Furthermore, COE ameliorated renal and cardiac pathology abnormalities caused by FA in a dose-dependent manner. Cell viability assay revealed that COE reversed cytotoxicity induced by FA in rat podocytes. In vitro scratch assay showed that COE partially restored the migratory capacity of podocytes incubated with FA. Dose-dependent experiments showed that COE (1 and 2μg/ml) induced a significant increase of phospho-(S473)-AKT along with a decrease in phospho (T180 + Y182) P38 levels.

Conclusion: The current results revealed important protective effect of Lebanese cannabis oil extract against folic acid-induced renal fibrosis in rats.”

https://pubmed.ncbi.nlm.nih.gov/39666622/

“The current findings demonstrated that COE was able to significantly reduced serum creatinine in rat model of FA—induced nephrotoxicity. The beneficial effect COE was also evident in kidney and cardiac pathology examination. Furthermore, COE showed promise as a preventive and therapeutic treatment against FA-induced nephrotoxicity. “

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0311790