Interplay between the HPA axis and inflammation as mechanisms therapeutic targets of Cannabis sativa in depression

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“Major Depressive Disorder (MDD) is a highly prevalent and disabling psychiatric disorder, representing a major global health burden across all age groups.

Increasing evidence indicates that its pathophysiology involves a complex interplay between chronic stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, immune activation, and neuroinflammation. Persistent HPA axis hyperactivity, glucocorticoid resistance, and altered expression of key regulators such as FKBP51 contribute to sustained inflammatory signaling and impaired neural plasticity in brain regions involved in mood regulation. Epigenetic mechanisms, including DNA methylation and microRNA-mediated regulation, further modulate stress responsivity, inflammatory pathways, and vulnerability to major depressive disorder.

In this context, growing attention has been directed toward Cannabis sativa and its bioactive constituents as potential therapeutic agents.

Preclinical and clinical evidence suggest that cannabinoids may modulate the endocannabinoid system, attenuate HPA axis hyperactivity, reduce neuroinflammation, and influence monoaminergic and neuroplasticity-related pathways.

This review synthesizes the current literature on the mechanistic links among the HPA axis, inflammation, and MDD, highlighting the emerging role of Cannabis sativa-derived compounds in targeting these interconnected pathways.”

https://pubmed.ncbi.nlm.nih.gov/42239513

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1801474/full

Cannabis for tic control: a systematic review and meta-analysis of its efficacy in Tourette syndrome management

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“Background: Tourette syndrome (TS) involves motor and vocal tics, often with obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD). Cannabis-based medicines (CBMs) are a potential therapy due to their interaction with the endocannabinoid system, potentially reducing tics and associated symptoms. Compared to antipsychotics, CBMs may offer improved tolerability and fewer side effects. Although evidence is limited, emerging studies suggest their potential to improve quality of life in TS. This review was registered with PROSPERO (CRD420251088633).

Aim: To evaluate the effectiveness of CBMs in treating TS.

Methods: We systematically searched PubMed, Google Scholar, ScienceDirect, and the Cochrane Collaboration Database for cohort studies and randomized controlled trials (RCTs) up to July 2, 2025. Data extraction included study characteristics and efficacy outcomes measured by the Yale Global Tic Severity Scale (YGTSS) and Premonitory Urge for Tics Scale (PUTS). Meta-analysis using Review Manager 5.4 compared pre- and post-treatment scores using mean difference (MD) and 95% confidence intervals (CI).

Results: From 1,105 screened articles, eight studies met inclusion criteria for the review, and seven were included in the meta-analysis, involving 306 adult TS patients. CBMs significantly reduced YGTSS scores (MD = – 13.29, 95% CI [-21.67 to – 4.91], P = 0.002) and PUTS scores (MD = – 4.09, 95% CI [-7.24 to – 0.93], P = 0.01).

Conclusion: CBMs show promising potential in reducing tics and premonitory urges in TS. Larger, placebo-controlled trials are needed to confirm efficacy, ensure safety, and optimize dosing.”

https://pubmed.ncbi.nlm.nih.gov/42229830

“Cannabis-based medicines significantly reduced tic severity in Tourette syndrome.”

https://www.ibroneuroscience.org/article/S0306-4522(26)00367-2/abstract

Structural characterization and in vitro evaluation of the hypolipidemic activity of the HSP-Ia, a bioactive polysaccharide derived from hemp (Cannabis sativa L.) seeds

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“A novel polysaccharide, HSP-Ia, with a molecular weight of 973.6 kDa, was isolated from hemp (Cannabis sativa L.) seed residues using sequential aqueous extraction, ethanol-induced precipitation, and chromatographic fractionation.

Its structural attributes were determined through methylation profiling and nuclear magnetic resonance spectroscopy. The physicochemical characteristics were examined using X-ray diffraction, atomic force microscopy, scanning electron microscopy, and circular dichroism spectroscopy. The hypolipidemic potential of HSP-Ia was assessed using oxidized low-density lipoprotein-induced RAW264.7 macrophages.

HSP-Ia was predominantly comprised of glucose, with minor proportions of arabinose and galactose. It had a backbone of →6)-α-D-Glcp-(1 → residues with side chains attached at the O-2 and O-3 positions. HSP-Ia possessed an amorphous, nonuniform, and discontinuous morphology, with height distributions ranging from 0.7 to 10.5 nm. It exhibited a zeta potential of -7.4 mV and retained a triple-helix conformation in aqueous media. Notably, HSP-Ia facilitated lipid efflux in foam cells in a dose-dependent manner, associated with the upregulation of Liver X receptor α/ATP-binding cassette transporter signaling pathway.

Overall, these findings enhance the current knowledge of the structural features of hemp seed-derived polysaccharides and underscore the potential application of HSP-Ia as a lipid-modulating agent in the development of functional food products and pharmaceutical formulations.”

https://pubmed.ncbi.nlm.nih.gov/42230038

“Hemp seed, the mature dried seed of Cannabis sativa L., is a prominent traditional medicinal and dietary crop in China, recognized as one of the “Dragon Nine Flavours” and often termed “longevity hemp”. According to traditional Chinese medicine theory, hemp seed is associated with the meridians of the spleen, stomach, and large intestine and is used to lubricate the intestines, alleviate constipation, tonify deficiency, and enhance circulation. Hemp seed is rich in proteins, lipids, vitamins, and carbohydrates and has extensive applications in the food and livestock feed sectors. Contemporary studies support these traditional uses, demonstrating that regular consumption of hemp seed can improve gastrointestinal function and reduce the risk of chronic diseases.”

“This study successfully isolated and characterized a novel polysaccharide, designated HSP-Ia, from hemp (C. sativa L.) seed residues.”

https://www.sciencedirect.com/science/article/abs/pii/S0144861726005564?via%3Dihub

UK Medical Cannabis Registry: an updated analysis of clinical outcomes of medicinal cannabis therapy for hypermobility-associated chronic pain

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“Introduction/objective: The primary aim of this study was to evaluate changes in pain-specific and general health-related quality of life in individuals prescribed cannabis-based medicinal products (CBMPs) for hypermobility-associated chronic pain.

Methods: The case series utilised data from the UK Medical Cannabis Registry. Primary outcomes were changes in Brief Pain Inventory (BPI), Pain Visual Analogue Scale (VAS), Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2), EQ-5D-5L index value, Generalised Anxiety Disorder-7 (GAD-7), and Single-item Sleep Quality Scale (SQS) over 24 months. Repeated measures analysis of variance was used to assess changes over time, with post hoc pairwise comparisons performed for significant findings.

Results: A total of 240 patients were analysed. Changes were observed across all patient-reported outcome measures (PROMs) on repeated measures analysis of variance (p < 0.001). Post hoc pairwise comparisons for the BPI subscales, SF-MPQ-2 and Pain VAS demonstrated improvement from baseline to all subsequent timepoints (p < 0.001). By 24 months, 56.67% (n = 136) and 61.25% (n = 147) of participants reported clinically significant improvements in BPI severity and interference respectively. Clinically significant improvements were also reported for SF-MPQ-2 (47.08%, n = 113) and Pain VAS scores (60.00%, n = 144).

Conclusion: In this real-world cohort, CBMP treatment was associated with sustained improvements in outcomes for individuals with hypermobility-associated chronic pain. These findings support the need for further controlled studies to determine causality.

Key Points • This 24-month real-world study demonstrates sustained improvements in pain, anxiety, and sleep outcomes for patients with hypermobility-associated chronic pain treated with cannabis-based medicinal products, with approximately 60% achieving clinically meaningful pain reductions.

• Cannabis-based medicinal products were associated with reductions in concomitant opioid prescriptions at 12, 18, and 24 months.

• This represents the largest and longest-duration observational study of medical cannabis therapy specifically in hypermobility spectrum disorders and Ehlers-Danlos syndrome, addressing a critical evidence gap in chronic pain management.

• Adverse events were predominantly mild-to-moderate in severity, with poor baseline sleep quality and current cannabis use identified as positive predictors of pain improvement, informing patient selection and treatment optimisation.”

https://pubmed.ncbi.nlm.nih.gov/42217098

“This study provides a 24-month real-world evaluation of CBMPs in patients with hypermobility-associated chronic pain. It demonstrates long-term sustained improvement in pain, anxiety and sleep-related outcomes, underpinning health-related quality of life. Despite its observational design, the study provides important insight into potentially addressing an area of significantly unmet therapeutic need.”

https://link.springer.com/article/10.1007/s10067-026-08166-z

Selective opioid-sparing effects of cannabidiol on opioid analgesia in rats

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“Cannabidiol, a major non-psychoactive constituent of cannabis, has generated interest as a novel therapeutic for managing several pathological conditions including chronic pain and opioid use disorder.

Here, we evaluated the effects of cannabidiol (3.2 or 10.0 mg/kg) on the antinociceptive and the reward-related effects of the opioid analgesic oxycodone (0.56 mg/kg) in rats (male and female Sprague-Dawley) using an operant facial pain assay, locomotor activity monitoring, and the conditioned place preference paradigm.

Cannabidiol enhanced the antinociceptive effect of oxycodone without affecting oxycodone-induced rearing behavior, or the acquisition and expression of oxycodone conditioned place preference under the conditions tested.

Together, these findings suggest that cannabidiol potentiates the analgesic effects of oxycodone without affecting its reward-related properties. These results support the potential of cannabidiol as an adjunctive, opioid-sparing agent in pain management.

PERSPECTIVE: Opioids remain important for treating moderate to severe pain, but adverse effects and misuse liability limit their use. These preclinical findings suggest cannabidiol may enhance oxycodone antinociception under acute painful conditions, without increasing abuse-relevant effects under the conditions tested, supporting further study as an opioid-sparing adjunct.”

https://pubmed.ncbi.nlm.nih.gov/42219047

https://www.jpain.org/article/S1526-5900(26)00156-2/abstract

Cannabinoids in Alzheimer’s disease: animal-human evidence and clinical pharmacology challenges

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“Cannabinoids have emerged as potential modulators of pathological processes in Alzheimer’s disease (AD), including neuroinflammation, synaptic dysfunction, and protein aggregation. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the main phytocannabinoids from Cannabis sativa, interact with the endocannabinoid system and may influence neuronal and glial signaling pathways relevant to AD pathology.

This mini review summarizes evidence from transgenic animal models and clinical studies evaluating CBD, THC, and their combination in AD.

Preclinical studies show that CBD and THC reduce β-amyloid accumulation, attenuate tau phosphorylation, and regulate neuroinflammatory responses, often associated with improvements in learning and memory. Cognitive outcomes appear to depend on cannabinoid composition, with CBD or THC administered individually showing more consistent effects, while combined CBD + THC effects appear dose- and ratio-dependent.

Clinical evidence in AD patients remains limited and primarily reports improvements in neuropsychiatric symptoms, such as reductions in agitation, nighttime activity, and behavioral disturbances, whereas cognitive improvements are modest. Cannabinoid-based treatments are generally well tolerated, with mild sedation, somnolence, or disorientation as the most reported adverse effects.

Overall, current data support the biological plausibility of cannabinoids as modulators of neuroinflammatory and synaptic processes in AD. However, heterogeneity in formulations, dosing, and study design limits firm conclusions. Future research should focus on dose optimization, biomarker-guided clinical trials, and long-term safety assessments to better define their therapeutic potential in AD.”

https://pubmed.ncbi.nlm.nih.gov/42211879

“The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway.”

 “cannabinoids should be viewed as pleiotropic modulators of AD-relevant processes rather than as agents acting through a single unified mechanism.”

“cannabinoid-derived compounds with combined receptor-mediated and intrinsic antioxidant properties may represent promising therapeutic candidates.”

https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2026.1833021/full

Emerging preclinical evidence supports a potential role for cannabidiol in the management of sickle cell disease

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“Sickle cell disease (SCD) imposes a substantial global health burden, with acute and chronic pain representing a major component of morbidity. Standard pain management, largely opioid-based, carries significant risks and often provides inadequate long-term relief, highlighting an unmet need for alternative analgesics as well as disease modifiers.

Medicinal cannabinoids have analgesic and antiinflammatory properties; most clinical studies so far have used Δ9-tetrahydrocannabinol (THC)-containing products with conflicting outcomes. In contrast, purified cannabidiol (CBD) has a broader spectrum of action beyond the endocannabinoid system, lacks psychoactive effects and associated long-term risks, allows safe dose optimization and can be prescribed legally in many settings.

Here, we review evidence for CBD’s potential analgesic and disease-modifying properties for management of SCD.

Pain in SCD arises from local tissue inflammation and neuroinflammation, compounded by abnormal pain modulation and pro-nociceptive CNS alterations. CBD may attenuate the pathophysiological processes of SCD by modulating pro-inflammatory immune pathways, reducing oxidative stress and suppression of neurogenic inflammation. CBD also has a direct inhibitory effect on afferent nociceptive pathways. Furthermore, CBD has an important pain-modulating role by suppressing excitatory mechanisms in the dorsal root ganglia and CNS. Additionally, CBD may modulate pain-processing brain networks and attenuate opioidinduced reward-seeking behavior.

Although human data are very limited, emerging preclinical findings and early patient reports offer cautious optimism for CBD as a therapeutic option with potential disease-modifying properties in SCD. Clinically meaningful benefits may be expected in specific patient subgroups, identifiable through well-designed clinical and mechanistic studies focused on pain processing and neuroinflammation.”

https://pubmed.ncbi.nlm.nih.gov/42206420

https://haematologica.org/article/view/14205

Cannabidiol alleviates chemotherapy-induced cognitive decline and neuropathology

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“Chemotherapy is frequently associated with long-term cognitive impairments in cancer survivors that negatively impact their quality of life. Effective mitigation strategies for cancer therapy-related cognitive impairments (CRCI) are still underdeveloped. Our clinical studies on breast cancer patients treated with doxorubicin (Adriamycin®, ADR) and cyclophosphamide (CYP) found significant CRCI associated with neurodegenerative and neuroinflammatory signatures.

Current preclinical and clinical studies highlight the potential of cannabidiol (CBD) for alleviating cognitive deficits in neurodegenerative conditions.

For example, Epidiolex® is an FDA-approved 99% pure formulation of CBD for treating pediatric epilepsy. CBD, a non-psychoactive component of cannabis, is recognized for its neuroprotective and anti-inflammatory effects.

This study, using a mouse model of adjuvant chemotherapy (ADR and CYP)-induced cognitive decline, tested the efficacy of oral administration of 99% pure CBD (20 mg/kg) in sesame oil. ADR + CYP-treated mice receiving CBD for one month showed significant neurocognitive improvements in learning and memory, executive function, and memory consolidation tasks often impaired in cancer survivors. CBD treatment also restored brain endocannabinoid (ECB) levels and reduced ECB-metabolizing enzymes in vivo. Notably, CBD mitigated chemotherapy-induced loss of neurogenesis, neuronal plasticity, synaptic density, and elevated gliosis.

In summary, this data provides preclinical evidence for a translationally feasible approach to alleviate CRCI, an unmet medical need.”

https://pubmed.ncbi.nlm.nih.gov/42202974

“Oral administration of cannabidiol (CBD, 99% purity) formulation significantly ameliorated chemotherapy-induced cognitive impairments in learning, memory, executive function, and memory consolidation in mice.”

“CBD restored endocannabinoid signaling, reduced neuroinflammation, and preserved neurogenesis, synaptic plasticity, and neuronal integrity.”

“These results identify a translationally feasible CBD-based strategy to mitigate cancer therapy-related cognitive impairment in survivors.”

“Taken together, these findings provide convergent behavioral, molecular, and cellular evidence that oral administration of 99% pure CBD post-chemotherapy can ameliorate CRCI by normalizing ECB tone, reducing microglial and astrocytic activation, preserving synaptic integrity, restoring activity-dependent plasticity, and rescuing neurogenesis.

Considered alongside prior reports that stem cell therapies, BDNF augmentation, and cannabinoid or paracannabinoid agents can reverse neurotoxic treatment-related cognitive deficits, the present study positions CBD as a mechanistically informed, clinically accessible candidate for future trials targeting CRCI in cancer survivors.”

https://www.sciencedirect.com/science/article/pii/S0304383526003757?via%3Dihub

Solubility-improved and antitumor activity of (-)-cannabidiol conjugates

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“Background: (-)-Cannabidiol (CBD) is a naturally occurring terpenoid belonging to the cannabinoid family, which is isolated from the Cannabis sativa L. plant. It possesses significant therapeutic potential, providing minimal side effects and no psychoactive activity. However, CBD applications are limited by a poor aqueous solubility and low bioavailability.

Objective: To address these limitations and investigate the impact of structural modification on solubility, we plan in this work the synthesis of a series of CBD conjugates along with the evaluation of their antitumor activity.

Methods: Conjugates are characterized by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) techniques, along with the solubility in water, glycerine, n-hexane and isooctane evaluated by High-Performance Liquid Chromatography (HPLC). The antitumoral activity of the CBD conjugates has been tested using cytotoxicity (IC50), cell migration and cell colony formation assays against lung adenocarcinoma cells A549.

Results: Specifically, oligo(ethylene glycol)-, alkyl- and L-valine-functionalized CBD derivatives are synthesized via selective esterification of its phenolic groups in good yields. Solubility profiles revealed a marked improvement compared to CBD. Notably, oligo(ethylene glycol) derivatives significantly enhanced solubility in water and glycerine, with 1b exhibiting a 14-fold increase in water solubility. The L-valine bis-conjugated derivative 4 also exhibited substantially improved solubility across all tested solvents, reaching up to a 13-fold increase in glycerine. In contrast, alkyl conjugates 2a,b showed only modest improvements. In addition, the in vitro evaluation against A549 revealed improved cytotoxic activity for 1a, 1b and 4 compared to native CBD, and with 1a additionally displaying antimigratory and colony formation inhibitory effects.

Conclusions: Collectively, our results highlight the critical role of conjugate structure in modulating physicochemical and biological properties of CBD and underscore the potential of these CBD conjugates as promising candidates for further pharmacological investigation and development.”

https://pubmed.ncbi.nlm.nih.gov/42210316

https://link.springer.com/article/10.1186/s42238-026-00453-5

Structural Characterization and Antioxidant Activity of a Crude Polysaccharide from Cannabis sativa Leaves

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“As a traditional Chinese herbal medicine, Cannabis sativa holds broad prospects for application in the development of functional foods, pharmaceutical formulations, dietary supplements, and cosmetic products. However, the bioactivity of polysaccharides in C. sativa has been largely overlooked.

In this study, crude C. sativa leaf polysaccharide (CSLP) was extracted using the hot-water extraction and ethanol-precipitation method.

CSLP contains 64.15 ± 1.96% carbohydrates and 2.13 ± 0.47% protein, with a yield of 6.71 ± 0.84% (w/w). Preliminary structural characterization showed that CSLP was mainly composed of arabinose, galactose, and glucose, with a molecular weight of 28.867 kDa.

CSLP not only demonstrated potential in vitro antioxidant activity against ABTS, DPPH, superoxide anion, and hydroxyl radicals, but also repaired H2O2-induced oxidative damage in RAW 264.7 macrophages by increasing the cellular levels of SOD, CAT, and GSH-Px, and reducing MDA levels. Mechanistically, CSLP possibly modulated the Nrf2/Keap1 signaling pathway in H2O2-stimulated RAW 264.7 cells via upregulating the gene expressions of Nrf2, NQO1, and HO-1, while downregulating Keap1 expression.

These results suggest that CSLP could potentially be used as an antioxidant ingredient in the food, pharmaceutical, and cosmetic industries.”

https://pubmed.ncbi.nlm.nih.gov/42195853

“Hemp (Cannabis sativa L.), a member of the Cannabaceae family, is a plant with both medicinal and edible properties.”

“C. sativa and its extracts exhibit various bioactivities, showing broad application prospects in functional foods, pharmaceutical formulations, dietary supplements, and cosmetics.”

“These findings provide a theoretical foundation for the development of C. sativa leaf polysaccharides as natural antioxidants in the functional food and pharmaceutical sectors.”

https://www.mdpi.com/2304-8158/15/10/1649