Category Archives: Endocannabinoid System

Don’t Sweat It: Cannabinoid CB1 Receptors Reduce Sweating in a Mouse Model

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“Numerous exocrine glands play key physiological roles in the body that include tearing, salivation, and lactation, as well as the control of body temperature via sweating. Malfunction of sweat glands can be deeply problematic or-in the case of anhidrosis-life-threatening. The prevalence of sweating disorders is high, affecting millions. The few available therapies are generally of limited effectiveness.

Several lines of evidence point to regulation of sweating by the cannabinoid signaling system, an arrangement that would mirror cannabinoid regulation of tearing and salivation.

Mice sweat in their paws via glands that closely resemble human eccrine sweat glands, including regulation by muscarinic signaling and by temperature. We applied a galvanic skin response-based assay to investigate cannabinoid regulation of sweating in awake, unanesthetized mice. The muscarinic agonist pilocarpine increased conductance while the antagonist glycopyrrolate reduced conductance, validating the model as a measure of sweating. The cannabinoid receptor agonist CP55940 substantially reduced conductance in wild-type and CB2 but not CB1 receptor knockout mice.

The phytocannabinoid tetrahydrocannabinol (THC) also reduced conductance, while the non-psychoactive cannabidiol (CBD) did not. Using immunohistochemistry, we detected CB1 receptors in periglandular cholinergic axons, the anandamide-synthesizing enzyme NAPE-PLD in myoepithelial cells, and the anandamide metabolizing enzyme FAAH in acinar cells. This indicates that a local CB1/anandamide-based circuit is present in mouse walking pads.

In summary, we employed a novel galvanic skin response-based assay to determine that cannabinoid CB1 receptors reduce sweating in a mouse model. This may point to a previously unappreciated effect on sweating in cannabis users.”

https://pubmed.ncbi.nlm.nih.gov/42287607

“In summary, we have made use of a galvanic skin response-based assay to measure the conductivity in the hind paws of awake, unanesthetized mice as a measure of sweating. We find the galvanic skin responses to be stable and consistent over time and, importantly, to be responsive to stimuli that increase or decrease basal sweating. Using this model, we determined that cannabinoid CB1 receptor activation reduces the galvanic skin response.

We propose that cannabinoid CB1 receptor activation reduces basal sweating in mice.

This effect may point the way to a new class of therapeutics for hyperhidrosis.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202601143R

Therapeutic potential of endocannabinoid system activation in opioid use disorder and pain

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“Introduction: Opioid use disorder (OUD) and chronic pain remain major global health challenges. Although opioid-based therapies provide effective analgesia, their long-term use is limited by safety concerns, dependence, and variable efficacy. Modulation of the endocannabinoid system (ECS) has emerged as a promising therapeutic strategy for pain management and opioid-related disorders.

Areas covered: This narrative review summarizes current evidence on ECS-targeted interventions for OUD, chronic non-cancer pain, and cancer-related pain. Relevant literature was identified through PubMed using search terms related to the ECS, cannabinoid receptors (CB1 and CB2), phytocannabinoids (Δ9 -tetrahydrocannabinol [THC] and cannabidiol [CBD]), synthetic cannabinoids, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors, and opioid – cannabinoid interactions. Particular emphasis is placed on mechanistic interactions between ECS and opioid signaling pathways, as well as evidence from preclinical and clinical studies evaluating therapeutic efficacy and safety.

Expert opinion: ECS modulation may alleviate pain, reduce opioid withdrawal symptoms, and improve affective outcomes. Interactions between cannabinoid and opioid receptors may produce synergistic analgesic effects while potentially mitigating opioid tolerance and dependence. However, clinical translation remains limited by small sample sizes, heterogeneous study populations, and variability in trial design. Well-controlled clinical trials are needed to establish optimal dosing strategies, evaluate long-term safety, and clarify the therapeutic role of ECS-targeted interventions in OUD and pain management.”

https://pubmed.ncbi.nlm.nih.gov/42295097

“The endocannabinoid system (ECS) represents a promising therapeutic target for opioid use disorder (OUD), chronic non-cancer pain, and cancer-related pain.”

“Cannabinoids (e.g., CBD and Δ9 -THC) exert analgesic and anti-inflammatory effects through CB1-mediated central mechanisms and CB2-mediated peripheral mechanisms.”

https://www.tandfonline.com/doi/full/10.1080/14728222.2026.2690138

Endocannabinoid system and skeletal muscle health: insights from cannabidiol

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“The endocannabinoid (EC) system is a complex network comprising endogenous ligands, enzymes responsible for their synthesis and degradation, and various receptors (including CB1 and CB2).

Present in many peripheral tissues, including skeletal muscle, EC system is now recognized to influence key physiological processes such as insulin sensitivity, mitochondrial metabolism, protein homeostasis and muscle development. Alterations in this system are associated with a variety of pathologies, including obesity, type 2 diabetes, sarcopenia, cachexia and muscle dystrophies.

In this context, cannabidiol (CBD), a phytocannabinoid devoid of psychoactive properties, is attracting growing interest as a potential therapeutic agent.

This article provides an analysis of the mechanisms by which the EC system, and more specifically the CB1 receptor, influences skeletal muscle development and function, while exploring emerging data on the potential benefits of CBD in various pathological conditions affecting skeletal muscle.”

https://pubmed.ncbi.nlm.nih.gov/42264146

“The endocannabinoid system (ECS) is composed of endogenous ligands (AEA, 2-AG), enzymes for their synthesis or degradation, and receptors (e.g., CB1, CB2). It also includes exogenous molecules like cannabidiol (CBD) produced from Cannabis sativa. Widely expressed in peripheral tissues such, the ECS plays a central role in the regulation of key skeletal muscle physiological processes, including insulin sensitivity, mitochondrial metabolism, protein homeostasis and skeletal muscle development.

Dysregulation of this system is associated with the development of metabolic and muscular disorders, such as obesity, type 2 diabetes, sarcopenia, cachexia and muscular dystrophies.

In this context, CBD, a non-psychoactive phytocannabinoid, has emerged as a potential therapeutic agent capable of modulating ECS activity, thereby contributing to the restoration of skeletal muscle function and homeostasis.”

https://www.sciencedirect.com/science/article/pii/S2212877826000803?via%3Dihub

Potential antitumor effect of cannabidiol (CBD) in canine oncology: a systematic review

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“Introduction: Preparations of Cannabis sativa have been used for medicinal purposes for many centuries Currently, it is known that the phytocannabinoids present in the Cannabis sativa plant can modulate the endocannabinoid system, producing a variety of effects. Among the most abundant phytocannabinoids are delta-9-tetrahydrocannabinol (19-THC) and cannabidiol (CBD). CBD lacks psychotropic properties and has been shown to inhibit cell proliferation and migration, while inducing apoptosis in various human tumor cells. Studies evaluating CBD in dogs are more recent than those in humans, and to date, fewer publications are available. However, CBD has been shown to be safe and well-tolerated in dogs, supporting its potential clinical use. Since approximately 2015, some studies have been conducted evaluating CBD in different types of canine cancer; however, no comprehensive review of these findings has been performed.

Methods: we conducted a systematic review Following the PRISMA 2020 guidelines.to compile the existing evidence on the anticancer effects of CBD in dogs.

Results: We found that the studies conducted so far are pre-clinical, mostly based on cellular models, and that available data are primarily in lymphoma, mammary cancer, glioma, prostate cancer, osteosarcoma, and urothelial carcinoma. These studies consistently show that CBD exerts antiproliferative and proapoptotic effects, in some cases by modulating intracellular signaling pathways, including ERK, JNK, and caspases. Additionally, some studies have evaluated the combination of CBD with other drugs, reporting both synergistic and antagonistic effects.

Overall, these findings highlight the potential of CBD as an anticancer agent across different cancer types.

Discussion: Further studies are required to better elucidate the mechanisms underlying the effects of CBD and to standardize concentrations and formulations, enabling reliable, comparable results and the development of clinical studies evaluating the role of CBD in canine oncology.”

https://pubmed.ncbi.nlm.nih.gov/42254894

“The findings from pre-clinical studies in dogs are consistent with those observed in humans, where CBD triggers antiproliferative and pro-apoptotic effects on several cancer cell types, which support clinical trials to elucidate the pharmacodynamics, pharmacokinetics, and potential antitumor efficacy of CBD in dogs with cancer.”

https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2026.1800410/full

Combined peripheral cannabinoid CB1 and CB2 receptor activation abolishes cystitis-induced bladder hyperalgesia

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“Cannabinoid agonists may ameliorate bladder pain associated with interstitial cystitis/bladder pain syndrome.

Visceromotor responses (VMRs) to bladder distension were recorded in urethane-anesthetised control and protamine/zymosan-treated guinea pigs. The peripherally restricted preferential CB1 receptor agonist PrNMI and the selective CB2 receptor agonist 4Q3C each reduced cystitis-induced enhancement of VMRs at high intravesical pressures.

Co-activation of CB1 and CB2 receptors abolished cystitis-induced bladder hyperalgesia.

These findings indicate that simultaneous targeting of peripheral CB1 and CB2 receptors may provide clinically meaningful benefits for the treatment of bladder pain associated with cystitis.”

https://pubmed.ncbi.nlm.nih.gov/42247877

“Combined activation of peripheral CB1 and CB2 receptors using peripherally restricted agonists effectively reverses bladder hyperalgesia in a preclinical model of IC/BPS.

These findings provide strong support for the development of peripherally acting combination therapies targeting both cannabinoid receptors as a strategy to treat bladder pain and associated symptoms in IC/BPS, while minimising central cannabinoid-related side effects.”

https://www.autonomicneuroscience.com/article/S1566-0702(26)00066-4/fulltext

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

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

Endocannabinoid system modulation in acute, chronic, and neuropathic pain: reviewing experimental models, clinical evidence, and nanotechnology delivery

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“Chronic pain is highly prevalent and inadequately managed by current therapeutic strategies, which present significant limitations such as the development of tolerance, dependence, and cognitive impairment. Therefore, searching for new pain management strategies is an ultimate goal.

The endocannabinoid system (ECS), is a broad crucial regulatory network in central nervous system’s development and in modulating various physiological and cognitive functions. It comprises endogenous cannabinoids, cannabinoid receptors, and the enzymes governing cannabinoid production and breakdown.

Recently, cannabinoids, particularly medical cannabis, have garnered renewed interest for their possibilities in treating different medical conditions, including chronic pain.

Although the risk of lethal overdose is negligible, the prevalence of non-serious adverse effects is significant and requires careful clinical consideration. Currently, there is a paucity of sufficient efficacy and long-term safety data to fully support the systematic use of medical cannabis for chronic non-malignant pain conditions.

Further research is crucial to unlock the future potential of these approaches and to delineate essential directions for exploring the ECS and its role in pain management. Advances in nanotechnology have enabled novel delivery platforms that address key limitations of cannabinoid-based therapies.

Nanocarriers, including lipid and polymeric nanoparticles, nanoemulsions, and self-emulsifying systems, can improve cannabinoid solubility, stability, bioavailability, and targeted delivery. Through controlled release and site-specific targeting, these systems hold promise for enhancing the analgesic efficacy and safety of cannabinoid therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/42154330

https://link.springer.com/article/10.1007/s11011-026-01862-4

Disrupted endocannabinoid signaling contributes to systemic inflammation in acute pancreatitis

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“Acute pancreatitis (AP) is an inflammatory disease that can lead to systemic complications in severe cases. The endocannabinoid system has emerged as a potential modulator of inflammation in AP.

We investigated the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) and the cannabinoid receptors CB1 and CB2 during AP.

A severity-dependent decrease in circulating 2-AG was found both in patients and a murine AP model. Restoring 2-AG – by avoiding its degradation via monoacylglycerol lipase inhibitor or direct 2-AG administration – reduced local and systemic inflammation, modulated peritoneal macrophage polarization, and mitigated lung injury. Notably, endocannabinoid system effects were consistent across sexes.

Both cannabinoid receptors were involved in disease pathophysiology.

Genetic Cnr1 knockout and pharmacological CB2 blockade showed distinct and complementary roles of both receptors in regulating inflammation, immune infiltration, and pulmonary damage.

These findings highlight a protective role for 2-AG and highlight the endocannabinoid system – and cannabinoid receptors in particular – as a promising therapeutic target to modulate inflammation and reduce systemic complications in acute pancreatitis.”

https://pubmed.ncbi.nlm.nih.gov/42153289

“These findings raise the possibility that counteracting the inflammation-driven decline in endogenous 2-AG through pharmacological intervention may represent a promising therapeutic strategy for AP.”

“Our data clearly support a role for both CB1 and CB2 receptors in the pathophysiology of AP.”

“Overall, our study supports the ECS as promising therapeutic target to reduce inflammation and systemic complications in AP.”

https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.70076

“The Diminished Availability of 2-AG in Aged Synaptic Terminals is Ameliorated by a Full-Spectrum Cannabis Extract with a High THC Content. This highlights the potential of high THC content extracts as therapeutic agents for restoring the decreased 2-AG levels observed in the aging brain.”

https://pubmed.ncbi.nlm.nih.gov/41880097

Δ9 Tetrahydrocannabinol and cannabis extracts differentially improve adipoinsular dysfunction in diet-induced obesity

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“Diet-induced obesity (DIO) is associated with dysregulated adipoinsular axis and endocannabinoid system (eCBS) function. Acute cannabis consumption stimulates appetite; however, chronic consumption is paradoxically associated with lower prevalence of human obesity and type 2 diabetes.

We investigated the impact of chronic exposure to Δ9 tetrahydrocannabinol (THC) and cannabis extracts on DIO and glucose homeostasis in mice.

Male mice were fed a high-fat/sucrose diet or a low-fat/no-sucrose diet for 60 days. At day 30, mice were administered THC (5 mg/kg) or cannabis extracts matched for THC content daily for 30 days. We assessed adipocyte biology, glucose tolerance, insulin sensitivity, eCBS expression, body weight, food intake and motor activity. Roles for the eCBS in cannabis-induced changes in metabolic processes, including cellular bioenergetics, were analysed in 3T3-L1 adipocytes.

THC and extracts reduced body weight and fat mass in DIO mice, and reversed DIO-associated changes in expression of adipokines that regulate the adipoinsular axis. Extracts normalized expression of adipokines more effectively than THC. Notably, extracts – but not THC – normalized glucose clearance in DIO mice to levels found in lean mice. In addition, THC and extracts promoted anti-adipogenic effects and changes in energy metabolism in 3T3-L1 cells in a concentration-dependent manner.

These studies suggest that chronic cannabinoid exposure improves metabolic function and dysregulated glucose homeostasis in DIO by a mechanism that includes restoring impaired adipoinsular axis function.

KEY POINTS: Δ9 Tetrahydrocannabinol (Δ9THC) and cannabis extracts reduce body weight and fat mass in obese mice. Cannabis extracts, but not Δ9THC alone, improve glucose homeostasis in obese mice. Extracts more effectively normalize expression of components of the adipoinsular axis in obese mice. Δ9THC and extracts promote anti-adipogenic effects in 3T3-L1 cells. Δ9THC and extracts alter cellular bioenergetics in 3T3-L1 cells.”

https://pubmed.ncbi.nlm.nih.gov/42113966

“In conclusion, this study demonstrates that chronic cannabinoid exposure, particularly with cannabis extract, reduces body weight, improves glucose homeostasis and normalizes adipose tissue function in a mouse model of DIO. Our findings highlight the potential therapeutic value of cannabinoids in managing obesity and related metabolic disorders, though further research is needed to fully understand the underlying mechanisms and translate these findings into clinical applications.”

https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP290431