Terpene blends from Cannabis sativa are cannabimimetic and antinociceptive in a mouse chronic neuropathic pain model via activation of adenosine A2a receptors

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“An increase in the use of medicinal Cannabis for pain management has spurred research into the understudied bioactive compounds in Cannabis, such as terpenes.

In our previous work, we showed that isolated and purified terpenes were cannabimimetic and also relieved chemotherapy-induced peripheral neuropathy (CIPN) pain via activation of Adenosine A2a Receptors (A2aR) in the spinal cord. However, terpenes are most often consumed by the public as complex extracts and mixtures, not purified individual terpenes, and whether this cannabimimetic and antinociceptive activity holds true in terpene extracts and blends is not clear.

In this study, we thus extracted terpene blends from three distinct Cannabis chemovars and assessed these blends in male and female CD-1 mice for their cannabimimetic activity in the tetrad assay and pain-relieving properties in a CIPN model.

Each terpene blend was unique in the relative amounts of different terpenes extracted. Though each blend was unique, each similarly elicited cannabimimetic behaviors of catalepsy, hyperlocomotion, and hypothermia, without tail flick analgesia.

All three terpene blends effectively relieved CIPN, though the antinociception was more robust in male than in female mice. This antinociception was recapitulated by purified Myrcene but not D-Limonene. The A2aR antagonist istradefylline blocked the pain-relieving effects of all three terpene blends, suggesting that the terpene blends act on A2aR to relieve CIPN pain.

Together, these findings suggest that terpene blends have similar pharmacological effects as purified single terpenes, and that observations made with single terpenes may be applicable to the complex terpene mixtures commonly consumed by the public.”

https://pubmed.ncbi.nlm.nih.gov/40122228/

https://www.sciencedirect.com/science/article/abs/pii/S030439402500093X?via%3Dihub

Cannabidiol reduces neuropathic pain and cognitive impairments through activation of spinal PPARγ

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“The purpose of this study was to evaluate the participation of spinal peroxisome proliferator-activated receptor gamma (PPARγ) in the antiallodynic effect of cannabidiol, the expression of PPARγ in sites relevant to the spinal nociceptive processing, and the effect of this cannabinoid on cognitive deficits induced by neuropathic pain in female mice.

Either acute or repeated treatment with cannabidiol reduced tactile allodynia and spontaneous pain (flinching) in female neuropathic mice. Pioglitazone partially reduced tactile allodynia, and this effect was fully blocked by the PPARγ antagonist GW9662. Likewise, intrathecal injection of cannabidiol reduced tactile allodynia, while PPARγ antagonist GW9662 or 5-HT1A receptor antagonist WAY-100635, but not the PPARα antagonist GW6479, partially prevented this effect. GW9662 and WAY-100635 administrated per se did not modify tactile allodynia in neuropathic female mice. Co-administration of GW9662 and WAY-100635 fully prevented the antiallodynic effect of cannabidiol in mice. Nerve injury up-regulated PPARγ expression at the spinal cord and dorsal root ganglia, while cannabidiol further enhanced nerve injury-induced up-regulation of PPARγ expression in both tissues.

Repeated intrathecal injection of cannabidiol reduced tactile allodynia and several pain makers (ERK, p-ERK, p38MAPK and p-p38MAPK). In addition, this treatment restored nerve injury-induced interleukin-10 down-regulation and increased PPARγ expression at the spinal cord. Repeated treatment with cannabidiol also improved nerve injury-induced cognitive impairment in mice.

These results provide compelling evidence for the involvement of PPARγ in the antiallodynic effect of cannabidiol in mice and highlight its multifaceted therapeutic potential in neuropathic pain management and its comorbidities.

PERSPECTIVE: The present study reveals cannabidiol’s dual effects in female mice by reducing neuropathic pain through spinal PPARγ and 5-HT1A receptor activation and ameliorating nerve injury-induced cognitive impairment. These findings may assist clinicians seeking new therapeutic approaches for managing neuropathic pain and its associated cognitive deficits.”

https://pubmed.ncbi.nlm.nih.gov/40112940/

https://www.jpain.org/article/S1526-5900(25)00605-4/abstract

Cannabidiol oil delays pancreatic islet dysfunction in Wistar rats under hypercaloric diet

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“Hypercaloric diet (HCD) intake can lead to metabolic alterations, such as metabolic syndrome and type-2 diabetes mellitus.

Phytocannabinoid cannabidiol (CBD) is a GPR55 receptor antagonist involved in insulin secretion and other functions in pancreatic islet. The therapeutic use of CBD has been suggested for diabetes, but little is known regarding its effects on pancreatic islet physiology.

Our aim was to evaluate the effects of CBD oil on pancreatic islets, from Wistar rats under HCD.

Male rats were divided in 4 groups: Normal diet vehicle-treated (control) and CBD-treated group. Rats under HCD were subdivided in treated with vehicle (HCD) and with CBD oil administered 21 mg/Kg orally, 0.5 ml in 3 days per week; controls received coconut oil as vehicle. Body weight, food intake, and water consumption were recorded. After 20 weeks, glucose tolerance curve was performed; serum insulin was determined by ELISA, and pancreas was removed for histological and gene expression analysis for insulin, glucagon, PDX-1, MafA and GPR55 receptor.

CBD treatment reduced body weight and food intake but increased fluid consumption, independently of diets. In control group, CBD did not alter blood glucose and serum insulin, but modified expression for GPR55 receptor, glucagon, insulin and MafA. Rats under HCD and treated with CBD decreased glycaemia, insulinaemia, islets relative area, GPR55-positive cells, PDX-1 and MafA gene expression, meanwhile insulin and glucagon expression was increased.

In conclusion, CBD ameliorated HCD effects through changes in insulin, glucagon and GPR55 receptor expressions. We assume CBD interacts with other receptors beside GPR55.”

https://pubmed.ncbi.nlm.nih.gov/40106970/

“The effects of hypercaloric diet in pancreatic islets are ameliorated by CBD.”

https://www.sciencedirect.com/science/article/pii/S0753332225001878?via%3Dihub

Sex- and age-specific sensitivities of the endocannabinoid system in Alzheimer’s disease revealed by PET imaging with [18F]FMPEP- d 2 and [18F]MAGL-2102

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“The endocannabinoid system is a critical brain signaling pathway that is dysregulated in various brain disorders, including Alzheimer’s disease (AD). Cannabinoid-targeted therapies and imaging approaches have gained increasing interest; however, the biological impact of the endocannabinoid system in disease needs further validation. We aimed to study changes in cannabinoid receptor 1 (CB1) and monoacylglycerol lipase (MAGL), components of endocannabinoid signaling and degradation, in a mouse model of AD by PET imaging.

Methods: [18F]FMPEP-d 2 and [18F]MAGL-2102 were produced on a commercial radiosynthesis module. PET-CT images with both tracers were acquired in a knock-in mouse model of AD bearing mutated human amyloid precursor protein (AppNL-G-F ) at 3 ages, and compared to wild-type mice. Excised brains were used for in vitro autoradiography with [18F]FMPEP-d 2 and [18F]MAGL-2102, immunofluorescence, and western blotting. Male wild-type and 5xFAD mice were chronically treated with MAGL inhibitor JZL184 and imaged with [18F]MAGL-2102 two days after ending treatment. 

Results: PET imaging showed sex-, age- and genotype-dependent changes in CB1 and MAGL availability. At 4-months (early-stage β-amyloid pathology), female AppNL-G-F mice had lower CB1 availability, and MAGL availability was increased in male AppNL-G-F , compared to wild-types. At 8-months, no genotype differences in CB1 were observed, yet MAGL availability was reduced in AppNL-G-F frontal cortex, and male AppNL-G-F mice exhibited higher MAGL than transgenic females brain-wide. At 12-months (late-stage β-amyloid pathology), significantly lower uptake of [18F]FMPEP-d 2 was observed in AppNL-G-F compared to wild-type, with no changes in [18F]MAGL-2102 binding. AppNL-G-F plaque staging was confirmed by Thioflavin-S staining. Imaging findings were supplemented by autoradiography, immunofluorescence, and western blots. [18F]MAGL-2102 availability was responsive to target engagement of the MAGL inhibitor JZL184 in wild-type and 5xFAD mice. 

Conclusions: The present study showed dynamic age-, sex- and pathology-related changes in CB1 and MAGL availability from early-stage β-amyloid pathology, suggesting that the endocannabinoid system is a useful target for diagnostics and treatment of AD. Finally, these results highlight that endocannabinoid sex differences should be considered in diagnostics and drug development.”

https://pubmed.ncbi.nlm.nih.gov/40093888/

https://www.thno.org/v15p3368.htm

Cannabidiol Protects Against Neurotoxic Reactive Astrocytes-Induced Neuronal Death in Mouse Model of Epilepsy

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“Reactive astrocytes play a critical role in the initiation and progression of epilepsy, but their molecular subtypes and functional characterization are not fully understood.

In this study, we report the existence of neurotoxic reactive astrocytes, a recently identified subtype, that contribute to neuronal death in the epileptic brain.

In a kainic acid (KA)-induced mouse model of epilepsy, we show that neurotoxic reactive astrocytes are induced by microglia-secreted cytokines, including IL-1α, TNFα, and C1q, and are detectable as early as 7 days post-KA stimulation. These cells exhibit a distinct molecular signature marked by elevated expression of complement 3 and adenosine 2A receptor. Transcriptomics and metabolomics analyses of human brain tissues from temporal lobe epilepsy (TLE) patients and an epileptic mouse model reveal that neurotoxic reactive astrocytes induce neuronal damage through lipid-related mechanisms.

Moreover, our results demonstrate that the anti-seizure medication cannabidiol (CBD) and an adenosine 2A receptor antagonist can both suppress the formation of neurotoxic reactive astrocytes, mitigate gliosis, and reduce neuronal loss in a mouse model of epilepsy. Electrophysiological and behavioral studies indicate that cannabidiol attenuates seizure symptoms and enhances memory capabilities in epileptic mice.

Our findings suggest that neurotoxic reactive astrocytes are formed at an early stage in both the KA-induced mouse model of epilepsy and TLE patients and can contribute to neuronal loss through releasing toxic lipids.

Importantly, cannabidiol emerges as a promising therapeutic drug for targeted intervention against neurotoxic reactive astrocytes in adult epilepsy.”

https://pubmed.ncbi.nlm.nih.gov/40099400/

https://onlinelibrary.wiley.com/doi/10.1111/jnc.70038

Hemp Seed-Based Foods and Processing By-Products Are Sustainable Rich Sources of Nutrients and Plant Metabolites Supporting Dietary Biodiversity, Health, and Nutritional Needs

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“Processing hemp seeds into foods generates several by-products that are rich in nutrients and bioactive phytochemicals. This paper presents a thorough plant metabolite analysis and a comprehensive assessment of the nutrient content of 14 hemp seed-based foods and by-products and evaluates their feasibility to deliver dietary needs and daily recommendations.

The protein-85-product was the hemp food and hemp fudge the hemp by-product with the highest content of protein, 93.01 ± 0.18% and 37.66 ± 0.37%, respectively. Hemp seed-hull flour had the richest insoluble non-starch polysaccharide content (39.80 ± 0.07%). Linoleic acid was the most abundant fatty acid across all the hemp seed-based samples (ranging from 53.80 ± 2.02% in the protein-85-product to 69.53 ± 0.45% in the hemp cream). The omega-6 to omega-3 fatty acid ratio varied from 3:1 to 4:1 across all hemp seed-based samples.

The majority of hemp seed-based samples were rich sources of potassium, magnesium, and phosphorus. Gentisic acid, p-coumaric acid, and syringaresinol were the most abundant plant metabolites measured and found mainly in bound form.

Hemp seed by-products are valuable sources of nutrients capable of meeting dietary needs and, therefore, should be re-valorized into developing healthy food formulations to deliver a truly zero-waste hemp food production.”

https://pubmed.ncbi.nlm.nih.gov/40077578/

“In conclusion, this study shows that hemp seed-based foods and by-products are rich sources of protein and fiber and are particularly rich in micronutrients, including potassium, magnesium, and phosphorus, and bioactive phytochemicals, particularly p-coumaric acid, gentisic acid, syringaresinol, p-hydroxybenzaldehyde, benzoic acid, and ferulic acid. Almost all the hemp seed-based samples have the potential to deliver the recommended daily reference nutrient intake for several micronutrients, including magnesium, phosphorus, manganese, and iron. One hundred grams of all the hemp seed-based samples delivered the recommended daily intake for fatty acids, including linoleic acid and alpha-linolenic acid. Furthermore, the omega-6:omega-3 ratio found in all the hemp seed-based foods and in all the by-products was between 3:1 and 4:1 across all the samples analyzed and was not altered during the food processing of hemp seed. Therefore, the findings of this study support the consumption of hemp seed foods as part of the diet to diversify and help meet dietary recommendations.”

https://www.mdpi.com/2304-8158/14/5/875

Identification and Molecular Mechanism of Novel α-Glucosidase Inhibitory Peptides from the Hydrolysate of Hemp Seed Proteins: Peptidomic Analysis, Molecular Docking, and Dynamics Simulation

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“There is a growing demand for natural and potent α-glucosidase inhibitors due to the rising prevalence of diabetes.

In this study, newly identified α-glucosidase inhibitory peptides were identified from the tryptic hydrolysate of hemp seed proteins based on peptidomics and in silico analysis.

A total of 424 peptides, primarily derived from four cupin-type-1 domain-containing proteins, were identified, and 13 ultimately were selected for validation based on their higher PeptideRanker scores, solubility, non-toxicity, and favorable ADMET properties.

Molecular docking revealed that these 13 peptides primarily interacted with α-glucosidase via hydrogen bonding and hydrophobic interactions. Among them, three novel peptides-NPVSLPGR (-8.7 kcal/mol), LSAERGFLY (-8.5 kcal/mol), and PDDVLANAF (-8.4 kcal/mol)-demonstrated potent α-glucosidase inhibitory activity due to their lower binding energies than acarbose (-8.1 kcal/mol), the first approved α-glucosidase inhibitor for type 2 diabetes treatment.

The molecular mechanism analysis revealed that the peptides NPVSLPGR and LSAERGFLY inhibited α-glucosidase by simultaneously blocking substrate entry through occupying the entrance of the active site gorge and preventing catalysis by binding to active sites. In contrast, the peptide PDDVLANAF primarily exerted inhibitory effects by occupying the entrance of the active site gorge. Molecular dynamics simulation validated the stability of the complexes and provided additional insights into the molecular mechanism determined through docking.

These findings contribute essential knowledge for the advancement of natural α-glucosidase inhibitors and offer a promising approach to effectively manage diabetes.”

https://pubmed.ncbi.nlm.nih.gov/40076843/

“Based on the findings from computational studies, these peptides demonstrate promising α-glucosidase inhibitory potential and may serve as viable natural alternatives to synthetic inhibitors.”

https://www.mdpi.com/1422-0067/26/5/2222

UK Medical Cannabis Registry: An Analysis of Outcomes of Medical Cannabis Therapy for Hypermobility-Associated Chronic Pain

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“Objective: The study aims to evaluate the clinical outcomes in patients with hypermobility spectrum disorder (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) with chronic pain following treatment with cannabis-based medicinal products (CBMPs).

Methods: This was a case series conducted with the UK Medical Cannabis Registry. The primary outcomes were changes in the following validated patient-reported outcome measures at 1, 3, 6, 12, and 18 months compared with baseline: Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2), pain visual analog scale score (Pain-VAS), Brief Pain Inventory (BPI), five-level EQ-5D (EQ-5D-5L), Single-Item Sleep Quality Scale (SQS), General Anxiety Disorder Seven-Item Scale (GAD-7), and Patient Global Impression of Change. The incidence of adverse events was analyzed as secondary outcomes. Statistical significance was defined as P <0.050.

Results: A total of 161 patients met inclusion criteria. Improvements were observed in BPI severity and interference subscales, SF-MPQ-2, and Pain-VAS (P < 0.001). Changes were also seen in the EQ-5D-5L index value, SQS, and GAD-7 (P < 0.001). A total of 50 patients (31.06%) reported one or more adverse event with a total incidence of 601 (373.29%). The most frequent rating for adverse events was moderate (n = 258; 160.25%), with headache being the most common (n = 44; 27.33%).

Conclusion: An association was identified between patients with HSD/hEDS with chronic pain and improvements in pain-specific and general health-related quality of life following the commencement of CBMPs. CBMPs were also well tolerated at 18 months. These findings must be interpreted within the context of the limitations of study design but add further weight to calls for randomized controlled trials.”

https://pubmed.ncbi.nlm.nih.gov/40079426/

“Cannabis-based medicinal products (CBMPs) have emerged as a potential alternative for chronic pain management, acting on the endocannabinoid system (ECS), which plays a pivotal role in pain regulation.”

“This study reports an association between CBMP treatment and reported improvements in pain and HRQoL among patients with HSD/hEDS.”

https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr2.70024

A Multicenter Feasibility Study of a Novel Curriculum for Oncology Trainees Regarding Medical Cannabis

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“Background: Oncology providers often lack the confidence to make clinical recommendations about medical cannabis (MC). This study aimed to develop and evaluate the feasibility of implementing an educational curriculum on the use of MC in patient care for oncology trainees.

Methods: A multidisciplinary team designed an educational curriculum for MC use in oncology. The curriculum was piloted as a 1-hour interactive webinar across 8 United States-based hematology/oncology fellowship programs between 2022 and 2023. Incentivized surveys measuring feasibility outcomes, including cultural attitudes/norms, acceptability, compatibility, and self-efficacy (a composite index of self-confidence in discussing MC efficacy, risks, modes of use, and role in symptom management), were distributed before, immediately after, and 12 weeks post-webinar.

Results: Of 103 trainees, 75 (72.8%) completed the pretraining survey and 66 (64.1%) completed the posttraining survey. Most respondents believed discussions about the role of MC in symptom management were valuable (n=56; 74.7%), though few (14.7%) believed trainees were expected to engage in such discussions. Most participants rated the curriculum as helpful (92.4%), beneficial for oncology trainees (84.8%), and likely to be recommended to colleagues (87.9%). Post-webinar, 78.8% of participants reported an increased likelihood of initiating discussions with patients regarding MC. There were significant improvements in the composite self-confidence index from pre- to post-webinar (2.7% vs 65.2%; P<.001), which persisted in the follow-up surveys (n=36; response rate, 34.9%).

Conclusions: This multisite study demonstrates the feasibility of implementing a novel curriculum focused on MC for oncology trainees. These findings can guide the design of a prospective, multi-institutional study to evaluate knowledge expansion, retention, and behavioral changes resulting from the intervention.”

https://pubmed.ncbi.nlm.nih.gov/40073833/

“Our prior work demonstrated that training in MC use for patients with cancer is an area of unmet need among hematology/oncology trainees. The current study demonstrated the feasibility and acceptability of developing and delivering a virtual webinar curriculum on MC for hematology/oncology fellows. Most trainees enjoyed the format and found the content useful and applicable to their practice and education. We observed sustained improvements in self-reported confidence in conducting clinical discussions across all domains included in the curriculum. Furthermore, participants reported increased discussions about MC with patients following the training, aligning with recent expert consensus guidelines. Future efforts should focus on refining this curriculum based on emerging data in the field, developing similar interventions for other oncology health care professionals, and exploring strategies to sustain these educational initiatives. Such efforts are essential to ensure broad implementation, maximize knowledge retention, and facilitate meaningful behavioral changes in real-world clinical practice.”

https://jnccn.org/view/journals/jnccn/23/3/article-p82.xml

A Pilot Randomized Placebo-Controlled Crossover Trial of Medicinal Cannabis in Adolescents with Tourette Syndrome

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“Introduction: Medicinal cannabis (MC) has potential therapeutic effects in Tourette Syndrome (TS), however there has been limited research in adolescent patients. This pilot study aimed to investigate the feasibility of conducting a randomized placebo-controlled crossover trial of MC in adolescents with TS. 

Method: This was a phase I/II double-blind, cross-over pilot study comparing MC with matched placebo in adolescents aged 12-18 years with TS. The active medication was Δ9-tetrahydrocannabinol (THC) 10 mg/mL and CBD 15 mg/mL in peppermint-flavored medium-chain triglyceride oil. The dose titration schedule was stratified into two participant weight bands: below 50 kg (max THC 10 mg/day) or ≥50 kg (max THC 20 mg/day). Each treatment phase lasted 10 weeks, with a 4-week washout period. 

Results: Ten adolescents were randomized (mean age 14.8 years, 50% male) and seven completed the full study protocol. Two adolescents discontinued due to adverse events (one on MC, one placebo) and one was lost to follow-up. The most common adverse event was dizziness (67%). There were no serious adverse events. Among actively enrolled participants, protocol adherence was excellent: study visits 100%, blood test completions 100%, and online questionnaire completion 97.6%. Medication adherence was acceptable in 63.6%. Parents reported a high degree of study design acceptability. On the Clinical Global Impression-Improvement scale, three participants were rated as much improved on MC compared with one on placebo at 10 weeks. 

Discussion: The findings suggest that the study protocol is feasible and acceptable to patients with TS and their families. A fully powered study is needed to evaluate the efficacy of MC in adolescent TS.”

https://pubmed.ncbi.nlm.nih.gov/40082070/

https://www.liebertpub.com/doi/10.1089/can.2024.0188