A Bioinformatic Analysis Predicts That Cannabidiol Could Function as a Potential Inhibitor of the MAPK Pathway in Colorectal Cancer

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“Colorectal cancer (CRC), found in the intestinal tract, is initiated and progresses through various mechanisms, including the dysregulation of signaling pathways. Several signaling pathways, such as EGFR and MAPK, involved in cell proliferation, migration, and apoptosis, are often dysregulated in CRC.

Although cannabidiol (CBD) has previously induced apoptosis and cell cycle arrest in vitro in CRC cell lines, its effects on signaling pathways have not yet been determined. An in silico analysis was used here to assess partner proteins that can bind to CBD, and docking simulations were used to predict precisely where CBD would bind to these selected proteins. A survey of the current literature was used to hypothesize the effect of CBD binding on such proteins.

The results predict that CBD could interact with EGFR, RAS/RAF isoforms, MEK1/2, and ERK1/2. The predicted CBD-induced inhibition might be due to CBD binding to the ATP binding site of the target proteins. This prevents the required phosphoryl transfer to activate substrate proteins and/or CBD binding to the DFG motif from taking place, thus reducing catalytic activity.”

https://pubmed.ncbi.nlm.nih.gov/39194723/

“This in silico study predicts that CBD could play a pivotal role in inhibiting the EGFR and MAPK pathways since almost all the proteins involved in this pathway interact with CBD. The most notable interactions occur between CBD and EGFR, KRAS, BRAF, and MEK1, as reflected by docking scores and being the most critically mutated or dysregulated proteins in colorectal cancer. CBD is proposed to act as an inhibitor of these proteins mainly by binding to the ATP catalytic binding site, which prevents phosphotransfer and the subsequent downstream activation of the substrate proteins. Secondly, CBD can act by binding to the DFG, which is adjacent to the hydrophobic pocket. The catalytic activity of this target protein is inhibited by this mechanism. Since the effect of CBD on these proteins has not yet been investigated, future studies should aim to determine if CBD indeed binds to these predicted target sites in these proteins and if the expected inhibitory effect occurs. Furthermore, in vitro phosphorylation studies on the selected proteins may determine if the phosphorylation of these proteins is affected by CBD treatment. In conclusion, CBD is predicted to interact with multiple role-players in the EGFR and MAPK pathways, potentially inhibiting these pathways and proteins.”

https://www.mdpi.com/1467-3045/46/8/506

Use of phytocanabinoids in animal models of parkinson’s disease: systematic review

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“This systematic review was carried out with the aim of evaluating the use of medicinal Cannabis for the treatment of Parkinson’s disease in experimental models. Furthermore, we sought to understand the main intracellular mechanisms capable of promoting the effects of phytocannabinoids on motor disorders, neurodegeneration, neuroinflammation and oxidative stress.

The experimental models were developed in mice, rats and marmosets. There was a predominance of using only males in relation to females; in three studies, the authors evaluated treatments in males and females. Drugs were used as inducers of Parkinson’s disease: 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), lipopolysaccharide (LPS), and rotenone. Substances capable of promoting catalepsy in animals were also used: haloperidol, L-nitro-N-arginine (L-NOARG), WIN55,212-2, and reserpine. The inducing agent was injected stereotaxically or intraperitoneally. The most commonly used treatments were cannabidiol (CBD), Delta-9-tetrahydrocannabinol (Δ-9 THC) and Delta-9-tetrahydrocannabivarin (Δ-9 THCV), administered intraperitoneally, orally, subcutaneously and intramuscularly.

The use of phytocannabinoids improved locomotor activity and involuntary movement and reduced catalepsy. There was an improvement in the evaluation of dopaminergic neurons, while in relation to dopamine content, the treatment had no effect. Inflammation, microglial/astrocyte activation and oxidative stress were reduced after treatment with phytocannabinoids, the same was observed in the results of tests for allodynia and hyperalgesia.”

https://pubmed.ncbi.nlm.nih.gov/39182852/

https://www.sciencedirect.com/science/article/abs/pii/S0161813X24000986?via%3Dihub

The renoprotective effects of cannabidiol on lipopolysaccharide-induced systemic inflammation model of rats

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“Sepsis-induced renal damage poses a significant threat, necessitating effective therapeutic strategies. Cannabidiol (CBD) has beneficial effects on tissues and their functions by exhibiting antioxidant and anti-inflammatory effects. This study investigates the potential protective effects of CBD in mitigating lipopolysaccharide (LPS)-induced renal injury in Wistar Albino rats.

Thirty-two Wistar Albino rats were categorized into control, LPS (5 mg/kg i.p.), LPS + CBD, and CBD (5 mg/kg i.p.) groups. After the experiment, samples were collected for biochemical, genetic, histopathological, and immunohistochemical analyses. Oxidative stress markers as total oxidant status (TOS) and total antioxidant status (TAS), oxidative stress index (OSI), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), immune staining as tumor necrosis factor alpha (TNF-α), interleukin-10 (IL-10), caspase-3, gene expressions as nuclear factor erythroid 2-related factor 2 (NRF2), C/EBP homologous protein (CHOP), caspase-9, glucose-regulating protein 78 (GRP78), B-cell leukemia/lymphoma 2 (Bcl2), and tissue histology have been examined.

The LPS-exposed group exhibited significant renal abnormalities, mitigated by CBD intervention in the LPS + CBD group. CBD reduced immunoexpression scores for TNF-α, caspase-3, and IL-10. Biochemically, CBD induced a positive shift in the oxidative balance, increasing TAS, SOD, and GPx, while decreasing TOS, OSI, and MDA levels. Genetic analyses highlighted CBD’s regulatory impact on NRF2, CHOP, caspase-9, GRP78, and Bcl2, providing molecular insights into its protective role against LPS-induced renal damage.

This study underscores CBD as a promising protective agent against sepsis-induced renal damage. Our findings could provide valuable insights into potential therapeutic avenues for addressing renal complications in sepsis.”

https://pubmed.ncbi.nlm.nih.gov/39180672/

https://link.springer.com/article/10.1007/s00210-024-03391-2

Successful use of cannabidiol in nonconvulsive status epilepticus in Angelman syndrome

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“Angelman syndrome (AS) is a rare neurogenetic disorder characterized by developmental delay, epileptic seizures, cognitive impairment, electroencephalographic epileptiform and slow interictal abnormalities, and motor dysfunction.1

In AS, nonconvulsive status epilepticus (NCSE) is frequent, is characterized by period of decreased responsiveness which may last hours to days, and it occur in about 20% of patients.2 Treatment of NCSE in AS is challenging and no specific drugs are approved with this purpose.

Epidyolex® is approved by EMA up to a dose of 20 mg/kg/d for individuals >2 years with Lennox–Gastaut Syndrome (LGS) or Dravet Syndrome (DS), and with a higher maximum dose of 25 mg/kg/d in those with tuberous sclerosis complex (TSC) (EMA).3

We recently treated an 8-year-old boy with AS expressing deletion of 15q11.2q13 (6.23 Mb). At the age of 2 years, he started to present with asynchronous bilateral upper limbs myoclonia. He was treated with clonazepam and ethosuximide with good effects, being almost seizure-free until the age of 5 years, when myoclonia associated with poor responsiveness reappeared consistently.

At the age of 8 years, he was receiving ethosuximide (20.5 mg/kg/d) and clonazepam (0.08 mg/kg/d), he presented with marked drowsiness and an increase of myoclonia (Figure 1A). He was admitted in our Department of Neurology (Bambino Gesù Children Hospital – Rome, Italy). Long-term EEG monitoring showed a NCSE pattern (Figure 1A,B), clinically characterized by a reduction in motor initiative and an increase in tremor. This pattern resolved only intermittently during intravenous Midazolam administration. Intravenous valproate (bolus at 30 mg/kg/d and then continuous infusion at 2 mg/kg/d) (Figure 1C) and levetiracetam (bolus at 60 mg/kg/d) (Figure 1D), were ineffective and therefore stopped.

We added Epidyolex® CBD, with a faster titration than usual, starting with 10 mg/kg/d up to 20 mg/kg/d in 8 days. After 1 week, he became more responsive (Figure 1E,F), and after 1 month, he was seizure-free, and the EEG was significantly improved (Figure 1G,H). Epidyolex® was added to ethosuximide and clobazam which were not effective alone. After 4 months of follow-up, no clinical-EEG modifications were observed. The patients did not present adverse events both in the acute phase of administration and during the follow-up.

This case has shown the potential benefits given by Epidyolex® CBD for the treatment of NCSE in a patient with AS. The faster titration was well tolerated.

Given the need for innovative treatments, especially for drug-resistant epilepsies, Epidyolex® CBD may be a promising anti-seizure medication and has been given “off label” to people with epilepsy syndromes outside LGS, DS, and TSC.4 Interestingly, acute CBD (100 mg/kg) treatment attenuated hyperthermia- and acoustically induced seizures in a mouse model of AS supporting the hypothesis that CBD may alleviate seizures and EEG abnormalities in AS, putting the basis for a rational development of CBD as treatment for epilepsy in AS.5 The use of CBD in refractory status epilepticus has been recently reviewed, and in 9 out of 11 treated patients the outcome was favorable.6

We believe this is the first report of the use of CBD in the acute treatment of NCSE in patients with AS. Although anecdotal, this observation ought to encourage further trials and confirmation from future studies.”

https://onlinelibrary.wiley.com/doi/10.1002/epi4.12948

Cannabinoids and triple-negative breast cancer treatment

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“Triple-negative breast cancer (TNBC) accounts for about 10-20% of all breast cancer cases and is associated with an unfavorable prognosis. Until recently, treatment options for TNBC were limited to chemotherapy. A new successful systemic treatment is immunotherapy with immune checkpoint inhibitors, but new tumor-specific biomarkers are needed to improve patient outcomes.

Cannabinoids show antitumor activity in most preclinical studies in TNBC models and do not appear to have adverse effects on chemotherapy.

Clinical data are needed to evaluate efficacy and safety in humans. Importantly, the endocannabinoid system is linked to the immune system and immunosuppression. Therefore, cannabinoid receptors could be a potential biomarker for immune checkpoint inhibitor therapy or a novel mechanism to reverse resistance to immunotherapy. In this article, we provide an overview of the currently available information on how cannabinoids may influence standard therapy in TNBC.”

https://pubmed.ncbi.nlm.nih.gov/39176080/

“Selective CB2R agonists and antagonists are needed to develop potential anti-cancer drugs that target the endocannabinoid system,”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1386548/full

Bioelectronic sensing platform emulating the human endocannabinoid system for assessing and modulating of cannabinoid activity

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“Cannabinoids are involved in physiological and neuromodulatory processes through their interactions with the human cannabinoid receptor-based endocannabinoid system. Their association with neurodegenerative diseases and brain reward pathways underscores the importance of evaluating and modulating cannabinoid activity for both understanding physiological mechanisms and developing therapeutic drugs. The use of agonists and antagonists could be strategic approaches for modulation.

In this study, we introduce a bioelectronic sensor designed to monitor cannabinoid binding to receptors and assess their agonistic and antagonistic properties. We produced human cannabinoid receptor 1 (hCB1R) via an Escherichia coli expression system and incorporated it into nanodiscs (NDs). These hCB1R-NDs were then immobilized on a single-walled carbon nanotube field-effect transistor (swCNT-FET) to construct a bioelectronic sensing platform. This novel system can sensitively detect the cannabinoid ligand anandamide (AEA) at concentrations as low as 1 fM, demonstrating high selectivity and real-time response. It also successfully identified the hCB1R agonist Δ9-tetrahydrocannabinol and observed that the hCB1R antagonist rimonabant diminished the sensor signal upon AEA binding, indicating the antagonism-based modulation of ligand interaction. Consequently, our bioelectronic sensing platform holds potential for ligand detection and analysis of agonism and antagonism.”

https://pubmed.ncbi.nlm.nih.gov/39173339/

https://www.sciencedirect.com/science/article/abs/pii/S0956566324006924?via%3Dihub

Unveiling Colombia’s medicinal Cannabis sativa treasure trove: Phenotypic and Chemotypic diversity in legal cultivation

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“Introduction: Cannabis sativa is a highly versatile plant with a long history of cultivation and domestication. It produces multiple compounds that exert distinct and valuable therapeutic effects by modulating diverse biological systems, including the endocannabinoid system (ECS). Access to standardized, metabolically diverse, and reproducible C. sativa chemotypes and chemovars is essential for physicians to optimize individualized patient treatment and for industries to conduct drug-discovery campaigns.

Objective: This study aimed to characterize and assess the phytochemical diversity of C. sativa chemotypes in diverse ecological regions of Colombia, South America.

Methodology: Ten cannabinoids and 23 terpenes were measured using liquid and gas chromatography, in addition to other phenotypic traits, in 156 C. sativa plants that were grown in diverse ecological regions in Colombia, a hotspot for global biodiversity.

Results: Our results reveal significant phytochemical diversity in Colombian-grown C. sativa plants, with four distinct chemotypes based on cannabinoid profile. The significant amount of usually uncommon terpenes suggests that Colombia’s environments may have unique capabilities that allow the plant to express these compounds. Colombia’s diverse climates offer enormous cultivation potential, making it a key player in both domestic and international medicinal and recreational C. sativa trade.

Conclusion: These findings underscore Colombia’s capacity to pioneer global C. sativa production diversification, particularly in South America with new emerging markets.”

https://pubmed.ncbi.nlm.nih.gov/39169651/

https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/pca.3436

Prenatal broad-spectrum cannabidiol administration prevents an autism-like phenotype in male offspring from a maternal stress/terbutaline rat model

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“Recently, the diagnosis of autism spectrum disorder (ASD) has increased from 1 in 150 to every 1 in 36 children in the United States, warranting a need for novel prevention and therapeutic strategies.

Broad-spectrum cannabidiol oil, free from delta-9-tetrahydrocannabinol, the psychoactive component of cannabis, may be one such therapeutic. It has a high safety profile and is frequently used as a complementary and integrative intervention by persons experiencing symptoms of anxiety, stress, and inflammation.

Using a neurodevelopmental rat model of ASD (based on neuroinflammation induced by stress and terbutaline exposure during pre- and postnatal development), we sought to prevent the development of ASD-like behaviors in male offspring by administering broad-spectrum cannabidiol oil to dams throughout pregnancy (10 mg/kg, i.p., daily, embryonic days 3-16). To assess an ASD-like phenotype in the offspring, we used three behavioral measures relevant to three core ASD symptoms: 1) social communication (time spent vocalizing when alone); 2) repetitive behavior (marbles buried during a marble burying test); and 3) social interaction (time spent interacting with a novel conspecific during the three-chamber social interaction test).

Broad-spectrum cannabidiol oil given during pregnancy decreased scores for all three ASD-related behavioral responses, resulting in an overall significant prevention of the ASD-like phenotype. These findings highlight the potential of broad-spectrum cannabidiol oil as a complementary and integrative approach for prevention of stressor-induced sequelae relevant to development of an ASD-like phenotype.”

https://pubmed.ncbi.nlm.nih.gov/39170798/

  • “•CBD prevented an overall autistic-like phenotype from developing in male rats.
  • •CBD may be an appropriate complementary prenatal neuroinflammatory preventative.”

https://www.sciencedirect.com/science/article/pii/S2666354624001066?via%3Dihub


Effects of a cannabidiol/terpene formulation on sleep in individuals with insomnia: a double-blind, placebo-controlled, randomized, crossover study

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“Study objectives: Cannabidiol (CBD) is increasingly used as a health supplement, though few clinical studies have demonstrated benefits. The primary objective of this study was to evaluate the effects of an oral CBD-terpene formulation on sleep physiology in individuals with insomnia.

Methods: In this double-blind, placebo-controlled, randomized clinical trial, 125 individuals with insomnia received an oral administration of CBD (300 mg) and terpenes (1 mg each of linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene) for ≥ 4 days/week over 4 weeks using a crossover design. The study medication was devoid of Δ9-tetrahydrocannabinol (Δ9-THC). The primary outcome measure was the percentage of time participants spent in the combination of slow wave sleep (SWS) and rapid eye movement (REM) sleep stages, as measured by a wrist-worn sleep-tracking device.

Results: This CBD-terpene regimen marginally increased the mean nightly percentage of time participants spent in SWS + REM sleep compared to the placebo [mean (SEM), 1.3% (0.60%), 95% C.I. 0.1 to 2.5%, P = 0.03]. More robust increases were observed in participants with low baseline SWS + REM sleep, as well as in day sleepers. For select participants, the increase in SWS + REM sleep averaged as much as 48 minutes/night over a four-week treatment period. This treatment had no effect on total sleep time (TST), resting heart rate or heart rate variability, and no adverse events were reported.

Conclusions: Select CBD-terpene ratios may increase SWS + REM sleep in some individuals with insomnia, and may have the potential to provide a safe and efficacious alternative to over-the-counter (OTC) sleep aids and commonly prescribed sleep medications.”

https://pubmed.ncbi.nlm.nih.gov/39167421/

https://jcsm.aasm.org/doi/10.5664/jcsm.11324

Bidirectional Effect of Long-Term Δ9-Tetrahydrocannabinol Treatment on mTOR Activity and Metabolome

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“Brain aging is associated with cognitive decline, reduced synaptic plasticity, and altered metabolism. The activity of mechanistic target of rapamycin (mTOR) has a major impact on aging by regulating cellular metabolism. Although reduced mTOR signaling has a general antiaging effect, it can negatively affect the aging brain by reducing synaptogenesis and thus cognitive functions.

Increased mTOR activity facilitates aging and is responsible for the amnestic effect of the cannabinoid receptor 1 agonist Δ9-tetrahydrocannabinol (THC) in higher doses. Long-term low-dose Δ9-THC had an antiaging effect on the brain by restoring cognitive abilities and synapse densities in old mice. Whether changes in mTOR signaling and metabolome are associated with its positive effects on the aging brain is an open question.

Here, we show that Δ9-THC treatment has a tissue-dependent and dual effect on mTOR signaling and the metabolome. In the brain, Δ9-THC treatment induced a transient increase in mTOR activity and in the levels of amino acids and metabolites involved in energy production, followed by an increased synthesis of synaptic proteins. Unexpectedly, we found a similar reduction in the mTOR activity in adipose tissue and in the level of amino acids and carbohydrate metabolites in blood plasma as in animals on a low-calorie diet.

Thus, long-term Δ9-THC treatment first increases the level of energy and synaptic protein production in the brain, followed by a reduction in mTOR activity and metabolic processes in the periphery. Our study suggests that a dual effect on mTOR activity and the metabolome could be the basis for an effective antiaging and pro-cognitive medication.”

https://pubs.acs.org/doi/10.1021/acsptsci.4c00002

“Low-dose long-term administration of cannabis compound reverses brain aging”

Low-dose long-term administration of cannabis compound reverses brain aging

“Anti-ageing and increased mental capacity through cannabis”

https://www.uni-bonn.de/en/news/164-2024#:~:text=%22We%20concluded%20that%20long%2Dterm,%2C%22%20says%20Bilkei%2DGorzo.