“The advent of antiretroviral therapy has significantly reduced HIV-related morbidity and mortality. However, persistent HIV infection in the central nervous system continues to drive HIV-associated neurocognitive disorders (HAND).
Cannabidiol (CBD), a nonpsychoactive cannabinoid with antioxidant and anti-inflammatory properties, has shown promise in clinical trials as a candidate to address cognitive impairments.
Despite this potential, further research is required to elucidate CBD’s molecular mechanisms in HIV infection and to improve its brain bioavailability. To overcome these challenges, we investigated CBD’s effects on oxidative stress pathways and developed a liposomal nanoformulation (NF) to enhance its delivery and efficacy in brain cells.
CBD treatment significantly upregulated APOE3 gene and protein expression while reducing HIV long terminal repeat (LTR) gene expression in infected microglia. The NF was characterized by hydrodynamic size, polydispersity index, zeta potential, encapsulation efficiency, cellular uptake, HIV infection levels, and APOE3 secretion. Successful CBD encapsulation was confirmed by liquid chromatography-mass/mass spectrometry.
Importantly, the CBD-loaded NF reduced p24 antigen levels and LTR expression, increased APOE secretion, and attenuated mitochondrial reactive oxygen species production more rapidly than free CBD.
This liposomal CBD NF enhances the pharmacological profile of CBD, offering a promising nanotherapeutic strategy to suppress HIV replication, reduce oxidative stress, and mitigate neurocognitive dysfunction associated with HAND.”
“Objecives: Approximately 80 % of people living with HIV (PLWH) develop chronic pain and preclinical studies support the involvement of the HIV-1 regulatory protein, trans-activator of transcription (Tat). Phytocannabinoids may attenuate pain in PLWH; however, these data are controversial, and the biological mechanisms are difficult to untangle from psychosocial factors in people.
Methods: We have examined the therapeutic capacity of minor phytocannabinoids to attenuate Tat-promoted visceral hyperalgesia (acetic acid writhing assay) and reflexive nociception (warm water tail flick assay) in transgenic mice. We hypothesized that conditional expression of Tat1-86 in male and female mice [Tat(+) mice] would amplify pain responses compared to controls [Tat(-) mice], and that phytocannabinoids could ameliorate these effects.
Results: Irrespective of sex, Tat(+) mice demonstrated greater visceral pain responses than did Tat(-) controls. The phytocannabinoids, cannabigerolic acid (CBGA), cannabidiol (CBD), and cannabinol (CBN), attenuated Tat-induced visceral pain in both males and females. However, the effectiveness of these cannabinoids varied by sex with CBN being more efficacious in males, while cannabigerol (CBG) alleviated visceral pain only in Tat(+) females. Cannabidiolic acid (CBDA) and cannabidivarin (CBDV) were not effective in either sex. CBGA and CBG were also efficacious in the tail flick test among Tat(-) males and females, but demonstrated only small, sex-dependent effects to reverse Tat-induced nociception. CBD and CBN exerted little-to-no efficacy in this test.
Conclusions: These data suggest that phytocannabinoids exert analgesia for HIV-related pain, potentially aiding in the development of personalized pain management strategies.”
“Overall, PLWH are more vulnerable to the development of chronic pain, resulting in physical disability and a reduced quality of life. The current pharmacological treatments for managing HIV-related pain lack efficacy and are associated with the risk of substance abuse. The medicinal use of non-psychoactive cannabis constituents for pain management might greatly benefit this population which is at a greater risk for opioid addiction and substance abuse.”
“Neuropathic pain is a clinically challenging syndrome that is largely refractory to conventional therapies. It arises from lesions or diseases affecting somatosensory pathways, which trigger extensive neuroplastic and neuroimmune remodeling. Unlike nociceptive pain, which establishes a protective response to tissue injury, neuropathic pain arises from maladaptive signaling within the nervous system.
In this context, the spinal endocannabinoid system (ECS) has emerged as a pivotal modulator of nociceptive processing. However, its precise role in neuropathic pain remains debated due to its dual effects.
Numerous studies report antinociceptive and neuroprotective effects; however, emerging data indicate that under specific pathological conditions, ECS activation may paradoxically facilitate pain transmission.
This review examines spinal ECS context dependence, uncovering its bidirectional antinociceptive and pronociceptive effects in neuropathic pain. By integrating current evidence on cellular, molecular, and pathophysiological mechanisms, we delineate the factors that determine whether ECS modulation inhibits or promotes pain. A comprehensive understanding of these mechanisms is essential for optimizing cannabinoid-based strategies to maximize therapeutic benefits while minimizing adverse outcomes.
Finally, we highlight the spinal cord’s centrality as the principal site for the initiation and maintenance of neuropathic pain and advocate for rigorous translational research to clarify the therapeutic potential of spinal ECS-targeted interventions.”
“From a therapeutic perspective, ECS duality represents both a challenge and an opportunity. Pharmacological manipulation of the ECS, through selective CB1R and CB2R agonists, FAAH and MAGL enzyme inhibitors, allosteric modulators, or combined strategies including glial modulators, constitutes a promising avenue for developing innovative treatments targeting neuropathic pain. However, the success of these interventions critically depends on a precise understanding of the pathophysiological context of eCB pathways and the evolutionary stage of the pathology.”
“This study investigates the immunomodulatory effects of a well-characterized cannabidiol (CBD)-rich cannabis extract, CAN296, on T lymphocytes (T cells), particularly Cluster of Differentiation 4 (CD4+) helper and Cluster of Differentiation 8 (CD8+) cytotoxic subsets, by examining T-cell activation, cytokine secretion, and cytotoxic molecule expression in comparison with the conventional treatments dexamethasone (DEX) and tacrolimus (TAC).
It addresses key processes involved in the formation of premalignant immune-mediated lesions, such as those seen in oral lichen planus (OLP) and oral manifestations of graft-versus-host disease (oGVHD). CD4+ and CD8+ T cells were isolated from healthy donors and assessed in vitro for T cell activation via CD69 expression, secreted tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels according to enzyme-linked immunosorbent assay (ELISA), and cytotoxic molecule expression Granzyme B, Perforin, Fas Ligand (Fas-L) quantified by flow cytometry. Cells were treated with different doses of CAN296 (2, 4, 8 µg/mL), DEX (0.4, 4, 40 µg/mL), or TAC (0.1, 1, 10 ng/mL), and all parameters were compared to untreated controls.
CAN296 significantly inhibited T cell activation, reducing CD69 expression in CD4+ T cells to 2-11% and in CD8+ T cells to 5-17%. It also markedly suppressed TNF-α secretion in CD4+ T cells at all concentrations (p < 0.0001). In CD8+ T cells, CAN296 led to a near-complete reduction in TNF-α and IFN-γ, leaving both cytokines barely detectable at all tested doses (p < 0.0001).
The effect of cell inhibition was significantly more pronounced than that observed with DEX or TAC, displaying dose-dependent reductions. TAC inconsistently lowered TNF-α while paradoxically increasing IFN-γ at lower concentrations. Additionally, CAN296 consistently suppressed cytotoxic molecule expression, reducing Granzyme B by 81-82%, Perforin by 40-53%, and Fas-L by 40-44%. DEX showed variable effects on cytotoxic molecule expression. At the same time, TAC demonstrated inconsistent modulation of Perforin and Granzyme B.
Overall, CAN296 outperformed DEX and TAC, demonstrating more potent and consistent immunomodulatory effects. CBD-rich cannabis extract, CAN296, exhibits potent immunomodulatory properties by effectively inhibiting T cell activation, lowering pro-inflammatory cytokines, and suppressing cytotoxic molecule expression.
Its efficacy surpasses conventional therapies like DEX and TAC, offering a promising novel treatment modality for T cell-mediated disorders, including OLP and oGVHD.
These findings support further development of CAN296 formulations to optimize dosing and delivery, followed by clinical trials to validate its therapeutic potential.”
“This study demonstrates that the CBD-rich cannabis extract CAN296 effectively suppresses CD4+ helper and CD8+ cytotoxic T cells by reducing activation, pro-inflammatory cytokine secretion, and cytotoxic molecule expression.
By modulating both arms of the immune response, key drivers of immune-mediated lesions such as OLP and oGVHD, CAN296 outperformed conventional therapies like DEX and TAC, even at low concentrations.
These findings position CAN296 as a promising targeted immunomodulatory agent with the potential to reduce tissue damage and prevent lesion formation and premalignant progression.”
“Colon adenocarcinoma (COAD) is characterized by the metabolic reprogramming, such as the Warburg effect, which drives tumor progression and immunosuppression. Hypoxia-inducible factor 1 (HIF-1) and lactate dehydrogenase A (LDHA) are critical regulators of this metabolic shift, but existing therapies are insufficiently specific to it.
This study investigates the antitumor mechanisms of cannabidiol, a non-psychoactive phytocannabinoid, by using integrative multi-omics and functional validation.
Single-cell transcriptomics revealed that cannabidiol reduced tumor cell proportions and suppressed glycolytic activity in COAD.
Network pharmacology identified PTGS2 as a central target, with proteomic data confirming its overexpression in COAD tissues and association with poor prognosis. In vitro, cannabidiol inhibited COAD cell proliferation, migration, and colony formation while downregulating HIF-1[Formula: see text], LDHA, and GLUT1 expression.
Metabolic assays demonstrated associated dose-dependent reductions in ATP production, glucose uptake, and lactate levels. Rescue experiments using the HIF-1agonist DMOG partially reversed cannabidiol’s antiglycolytic and antitumor effects, and thus confirmed pathway dependency. Synergy with the glycolysis inhibitor 2-DG enhanced therapeutic efficacy, which highlighted cannabidiol’s potential to overcome metabolic resistance.
These findings establish cannabidiol as a novel inhibitor of HIF-1/LDHA-driven glycolysis, and thus provide a translational strategy for metabolic vulnerability in COAD.”
“The phrase “Cannabidiol Reprograms Glucose Metabolism in Colorectal Adenocarcinoma by Targeting HIF-1α/LDHA Pathway” means that cannabidiol (CBD) helps fight colon cancer cells by altering how they use glucose (sugar) for energy, specifically by interfering with a key biological pathway involving the proteins HIF-1α and LDHA.”
“In summary, the study found that CBD acts as a novel inhibitor of the HIF-1α/LDHA pathway, suppressing the abnormal glucose metabolism essential for colorectal cancer growth and providing a potential therapeutic strategy for treatment.”
“Consumer interest in nutrient-rich and sustainable bakery products is stimulating the use of novel flours. Hemp (Cannabis sativa L.) flour represents a promising ingredient, even though its application in breadmaking remains limited.
This study explored the partial substitution of wheat flour with a mixture of two hemp cultivars, Felina 32 and Futura 75, at 10 %, 15 %, and 25 % inclusion levels. Comprehensive characterization addressed chemical composition, antioxidant properties, volatile profile, and sensory quality.
Hemp fortification increased the nutritional value of bread, particularly enhancing polyunsaturated fatty acids (notably linoleic acid), essential amino acids (lysine, leucine, phenylalanine), and total polyphenols, leading to enhance the antioxidant capacity. Volatile compound analysis showed an enrichment in compounds such as hexanoic acid, humulene, and citral. Sensory evaluation confirmed consumer acceptance, despite minor bitterness note.
These results demonstrate hemp flour’s potential as a functional and sustainable ingredient.”
“Hemp (Cannabis sativa L.) is an herbaceous and multipurpose plant that can be used in different fields such as agriculture, food and feed, cosmetics, pharmaceuticals, and building.”
“Hemp flour (HF), naturally gluten-free, has been used to enrich various types of bread to increase the protein content, essential fatty acids, phenolic and antioxidant compounds.”
“Based on these data, HF can be consider an excellent ingredient to improve the nutritional profile of bread.”
“We can conclude that HF is a valuable ingredient, to improve the nutritional properties of bread.”
“Ethnopharmacological relevance: Pain and inflammation are among the many conditions for which Cannabis sativa L. has historically been used. However, little research has been done on the potential therapeutic benefits of employing green extraction techniques to generate an extract from C. sativa that is high in cannabidiol for the treatment of severe pain and inflammation.
Aim of the study: This study investigates the potential chemico-pharmacological profile of a supercritical CO2 extract of Cannabis sativa genotype CIM-CS-64 (CSFE) for managing inflammation and pain responses using an experimental pharmacology approach.
Materials and methods: A combination of complementary analytical techniques (GC-FID, GC-MS, HPLC, HRMS, NMR) was used to examine the chemical composition of the CSFE to ensure comprehensive chemical coverage. The experiments were conducted on small laboratory animals to investigate the therapeutic efficacy of CSFE in mitigating inflammation and pain responses.
Results: Altogether, sixty-two compounds with cannabidiol, β-caryophyllene, cannabidivarin, cannabichromene, (E)-phytol, and α-bisabolol as major constituents were annotated in CSFE by GC-FID and GC-MS techniques. The HPLC analysis revealed the presence of CBD (9.75 ± 0.85%), CBDA (2.76 ± 0.69%) and Δ9-THC (4.40±0.16%) as major cannabinoids in the CSFE. In LPS-stimulated macrophages, the CSFE markedly reduced the production of pro-inflammatory cytokines (TNF-α and IL-6) at concentrations of 3, 10, and 30 μg/ml without causing any cytotoxicity. The results demonstrated a significant decrease in inflammation and considerable improvement in pain-relieving potential in a dose-dependent manner.
Conclusions: The present research revealed that CSFE possesses promising analgesic and anti-inflammatory properties in small laboratory animals.”
“Altogether, sixty-two compounds with cannabidiol, β-caryophyllene, cannabidivarin, cannabichromene, (E)-phytol, and α-bisabolol as major constituents were annotated in CSFE by GC-FID and GC-MS techniques.
The HPLC analysis revealed the presence of CBD (9.75 ± 0.85 %), CBDA (2.76 ± 0.69 %) and Δ9-THC (4.40 ± 0.16 %) as major cannabinoids in the CSFE. In LPS-stimulated macrophages, the CSFE markedly reduced the production of pro-inflammatory cytokines (TNF-α and IL-6) at concentrations of 3, 10, and 30 μg/ml without causing any cytotoxicity.
The results demonstrated a significant decrease in inflammation and considerable improvement in pain-relieving potential in a dose-dependent manner.”
“The present research revealed that CSFE possesses promising analgesic and anti-inflammatory properties in small laboratory animals.”
“The findings validate the use of the plant for managing pain and inflammation in traditional medicine.”
“Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) can greatly impair function, leading to disability or truncated treatment in cancer patients. Previous animal studies show that cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC) can ameliorate CIPN. This study assessed the effect of combined CBD and THC on CIPN symptoms amongst cancer patients treated with taxane- or platinum-based agents.
Materials and methods: This 12-week randomized, double-blind, placebo-controlled trial included participants with nonmetastatic breast, colorectal, endometrial, or ovarian cancer experiencing grade 2-3 CIPN. The active group received CBD (125.3-135.9 mg) combined with THC (6.0-10.8 mg) in gelcaps. The Quality-of-Life Questionnaire-CIPN twenty-item scale (QLQ-CIPN20) sensory subscale was used as the primary outcome. Additional outcomes assessed pain, sleep, and function. Neurologic exams evaluated touch, pressure, and vibration sense. Following the randomized controlled trial, participants were invited to enroll in a 12-week open-label observational study.
Results: Of 230 participants identified, 124 met eligibility, 54 were enrolled, 46 were randomized, and 43 completed 12 weeks of treatment. This was lower than our goal of 100 randomized participants. The mean age was 60 +/- 9 years, 88% were female, 63% had breast cancer. All participants had completed chemotherapy. The primary analysis showed no differences in outcome measures between active and placebo groups, likely due to sample size. Although an increase in bilirubin (one participant in active group, and one in placebo) and alkaline phosphatase (one participant in active group) was seen, this did not exceed the exit criteria. A secondary analysis showed that the active group experienced greater improvement in the QLQ-CIPN20 measures of sensory impairment relative to placebo (-10.4 (95% -20.5, -0.3), p = 0.044). There was also improvement in light touch and vibration sensation of the feet on neurological exam that approached significance. There was no effect on other measures, including pain, and no between-group differences in side effects. The uncontrolled observational study showed similar results.
Discussion: The primary analysis showed no between-group difference in CIPN symptoms. The secondary analysis indicated that CBD with THC could improve sensory impairment and might increase touch and vibration sense, although these findings require confirmation in a future, more fully powered study. Nonetheless, our results show that combination CBD/THC can be safely delivered to participants with CIPN and suggest that these cannabinoids should be further investigated for this indication.”
“Overall, this study suggests that combination CBD/THC could help with the sensory impairment seen in CIPN. Since the disorder is prevalent and incurs significant hardship, even a modest sensory improvement could enhance patients’ quality of life, given the lack of alternatives.”
“Tetrahydrocannabinol (THC) has shown efficacy in alleviating chronic pain, particularly in disorders characterized by central sensitization. Offset analgesia (OA) and conditioned pain modulation (CPM) are key biomarkers used to evaluate central pain modulation.
This study aimed to compare the effects of THC on OA and CPM in fibromyalgia syndrome (FMS), a prototypical condition of central sensitization.
Methods
In a randomized, double-blind, placebo-controlled crossover design, 23 FMS patients participated in two experimental sessions. Each session included the McGill Pain Questionnaire, visual analogue scale (VAS) assessments, and evaluations of OA and CPM, conducted both before and after sublingual administration of either THC (0.2 mg/kg) or placebo.
Results
THC significantly reduced spontaneous pain ratings on the McGill scale compared to both baseline and placebo (P = 0.01 and P = 0.02, respectively). THC also significantly enhanced OA relative to baseline and placebo (P = 0.04 and P = 0.008), while no effect was observed on CPM (P = 0.27). Notably, baseline OA magnitude significantly predicted THC-induced pain relief (R² = 0.404, P = 0.003), whereas CPM did not show a significant association (P = 0.121).
Conclusions
This is the first study to evaluate THC’s distinct effects on central pain modulation using both OA and CPM. THC selectively enhanced OA without influencing CPM, highlighting differential neural mechanisms underlying these paradigms. Furthermore, OA predicted treatment response, suggesting its potential as a biomarker for personalized cannabinoid-based therapies in FMS and other central sensitization disorders.”
“Cannabis, particularly its psychoactive component delta-9-tetrahydrocannabinol (THC), has attracted increasing attention as a therapeutic option for chronic pain management. Clinically, THC has been shown to reduce pain intensity, improve quality of life and attenuate hyperalgesia in various chronic pain conditions, including neuropathic pain and fibromyalgia “
“THC is thought to exert its analgesic effects in part by modulating disrupted pain networks. Specifically, THC interacts with the endocannabinoid system.”
“To conclude, this study corroborates the possible effectiveness of THC in alleviating experimental and spontaneous pain in FMS, a study case of central sensitization, and shows an enhancement of OA responses after THC treatment in FMS patients compared to baseline and placebo.”
“This, in turn, reinforces the potential of OA as a reliable marker of pain modulation in FMS and may pave the way for personalized cannabinoid-based therapies for chronic pain in the future.”
“Background: To assess the efficacy and safety of adjunctive cannabidiol (CBD) in children with drug-resistant epileptic spasms (ES) beyond age 2 years.
Methods: We conducted a retrospective longitudinal study of patients with childhood epileptic spasms (CESs) treated with purified CBD (Epidyolex) at Niño Jesus Hospital in Madrid, Spain, from 2020 to 2024. All patients were older than 2 years and had drug-resistant epilepsy and ES as the primary seizure type. Efficacy was assessed by comparing ES frequency before and after CBD treatment, with a good response defined as a ≥50% reduction in ES. Adverse effects (AEs) were recorded to assess safety and tolerability.
Results: Of the 53 patients included, 58.5% achieved a ≥50% reduction in ES frequency, 15% of whom attained complete freedom from ES. Patients with malformations of cortical development and Down syndrome showed the highest response rates. Clobazam was the most frequently associated medication (77.3%), indicating a potential synergistic effect. AEs were reported in 62.2% of patients, with drowsiness, hyperammonemia, and behavioral disturbances being the most common. CBD was discontinued in 17% due to lack of efficacy and in 11.3% due to AEs.
Conclusions: CBD appears to be an effective and well-tolerated adjunctive treatment for drug-resistant ES in children older than 2 years. Significant response rates were found, particularly in patients with Down syndrome and malformations of cortical development. Future studies with larger cohorts and longer follow-up are needed to validate these findings and explore the potential for earlier use of CBD in treatment-resistant epilepsy.”
