Category Archives: Endocannabinoid System

Acute effects of cannabis on core and co-occurring features associated with autism spectrum disorder in adults

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“Pharmacological interventions that treat core and co-occurring features of autism spectrum disorder (ASD) are a persistent unmet need.

As such, use of cannabis to manage ASD features is common in the autistic community. Yet, few studies have examined the acute effects of cannabis on symptoms associated with ASD. Therefore, we measured changes in symptom ratings from before to after cannabis use in a sample of 111 self-identified autistic adults.

Anonymized archival data sourced from the Strainprint® app were analyzed. A subset of tracked information that reflected changes in core and co-occurring symptoms associated with ASD (i.e., Sensory Sensitivity, Repetitive Behaviors, Mental Control, and Negative Affect) were used to assess the impacts of cannabis on symptom severity.

Overall, symptom severity ratings were reduced by 73.09% from before to after cannabis use. More severe symptoms were associated with greater reductions in severity ratings after use.

Higher doses predicted greater reductions in severity of Repetitive Behaviors, Mental Control, and Negative Affect but dose of cannabis used to manage all symptoms remained static across time.

Results from this first empirical examination of the perceived acute effects of cannabis in autistic adults suggest that cannabis provides temporary relief from symptoms associated with ASD.”

https://pubmed.ncbi.nlm.nih.gov/41233406/

“The present study represents the first to demonstrate acute perceived beneficial effects of inhaled cannabis on core and co-occurring symptoms associated with ASD in a large adult sample.”

“These findings indicate that well-powered placebo-controlled trials are warranted to examine the acute effects of various cannabinoids and manipulations of the endocannabinoid system on ASD symptoms.”

“In sum, data from clinical trials of children and adolescents presents an evidence base that supports a continued focus on the impact of CBD on ASD features, while the present data from cannabis-using autistic adults indicates that a sole focus on CBD may not fully capture the potential impact of cannabinoids as a pharmacological intervention for adults with ASD. Thus, additional placebo-controlled clinical trials are needed where THC, CBD, and other non-intoxicating cannabinoids (e.g., cannabigerol), terpenes, and/or medications that modulate the functioning of the endocannabinoid system are administered to autistic adults to determine their relative effects on symptoms associated with ASD.”

https://www.nature.com/articles/s41598-025-23472-3

Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms

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“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.”

https://pubmed.ncbi.nlm.nih.gov/41226728/

“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.”

https://www.mdpi.com/1422-0067/26/21/10692

Cannabinoids Shape Synaptic Activity and Adult Neurogenesis in the Zebrafish Pallium

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“The endocannabinoid system regulates neuronal activity and plasticity, but its role in non-mammalian vertebrates remains poorly understood.

In zebrafish (Danio rerio), the pallium processes cognitive functions such as memory, learning, and emotional behavior. This region expresses cannabinoid receptors and undergoes continuous neuronal remodeling through adult neurogenesis.

Here, we investigate whether cannabinoid receptor type 1 (CB1R) modulates synaptic activity and adult neurogenesis in zebrafish pallial circuits.

Using immunofluorescence and single-cell mRNA analysis, we mapped CB1R expression in the pallium and found it to be distributed in a scattered pattern within the dorsomedial (Dm) and dorsolateral (Dl) regions, predominantly in glutamatergic neurons.

Electrophysiological recordings showed that acute application of rimonabant, a CB1R antagonist, reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) without altering intrinsic or other synaptic properties, suggesting a tonic role for CB1R in modulating synaptic transmission. Additionally, prolonged rimonabant treatment (13 days) significantly reduced ERK phosphorylation, a marker of neuronal activity, further supporting the involvement of CB1R in maintaining basal synaptic activity in the pallium.

To assess whether cannabinoid signaling shapes adult neurogenesis, we analyzed the proliferation of neural stem cells (NSCs) and maturation of adult-born neurons.

Acute phytocannabinoid exposure resulted in a reduction in NSC proliferation, specifically in the anterior Dm. To assess the neurogenic outcome, the cannabinoid treatment was administered during neuronal maturation (12-24 days after BrdU labeling).

We observed an increase in the number of 25-day-old neurons (BrdU+, HuC/D+) in both Dm and Dl regions. This effect was reverted by the CB1R antagonist rimonabant.

These results indicate that cannabinoid signaling modulates synaptic activity and neuronal integration, highlighting a conserved control of neurogenesis by the endocannabinoid system across vertebrates.”

https://pubmed.ncbi.nlm.nih.gov/41200796/

https://onlinelibrary.wiley.com/doi/10.1111/jnc.70289

“Delta-9-Tetrahydrocannabinol (∆9-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats”

https://link.springer.com/article/10.1007/s12640-017-9806-x


The Development and Therapeutic Potential of Classical and Next-Generation Cannabinoid Ligands

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“The endogenous cannabinoid system (ECS) is a complex network that plays a crucial role in various physiological processes, and its modulation through cannabinoid ligands has garnered significant interest in pharmacological research.

Cannabinoid receptors, primarily CB1 and CB2, are G-protein-coupled receptors that can interact with many different types of ligands, including orthosteric agonists and antagonists and allosteric and biased modulators.

This review provides an updated perspective on cannabinoid receptor ligand development, beginning with natural ligands such as phytocannabinoids and endocannabinoids. These compounds provided the initial inspiration for the design of the first synthetic classical cannabinoids which were later refined into structurally distinct non-classical cannabinoids.

Beyond these traditional orthosteric ligands, we explore the expanding field of allosteric and biased modulators, which offer refined control over receptor signaling and present opportunities to reduce side effects associated with direct receptor activation. We also highlight the significance of covalent ligands and labeled chemical probes in elucidating cannabinoid receptor structure, localization, and function.

Advances in imaging and chemoproteomic techniques have further enhanced our ability to visualize receptor dynamics and identify novel interaction partners. Finally, we examine the clinical landscape of cannabinoid-based therapeutics, from approved drugs to ongoing clinical trials, and discuss the remaining challenges and future directions in ECS-targeted drug development.

This review aims to provide a comprehensive overview of current trends and emerging strategies in cannabinoid ligand research.”

https://pubmed.ncbi.nlm.nih.gov/41192631/

“The endogenous cannabinoid system has broad therapeutic relevance. “

“Natural and synthetic cannabinoids finely regulate the endogenous cannabinoid system.”

https://www.sciencedirect.com/science/article/pii/S1043661825004475?via%3Dihub

The Endocannabinoid System: Pharmacological Targets and Therapeutic Potential in CNS Disorders

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“The endocannabinoid system (ECS) influences a wide range of brain functions, including synaptic transmission, neuroplasticity, emotion, and immune regulation within the central nervous system, with CB1 and CB2 receptors mediating various neurophysiological and pathophysiological outcomes. Thus, growing interest in its therapeutic potential has prompted extensive research into how cannabinoid receptors contribute to the pathophysiology of neurological and psychiatric disorders, particularly CB1 and CB2.

This review has integrated findings from studies published between 2015 and 2025, covering conditions, like depression, anxiety, pain, multiple sclerosis, and Parkinson’s disease. We have also examined recent advances in receptor pharmacology and experimental technologies, including cryo-EM, optogenetics, and chemogenetics.

Although ECS-targeted therapeutics hold considerable promise, some key challenges remain in establishing safe and effective dosing protocols and integrating these approaches into clinical frameworks.

This review has provided an updated perspective on the system’s role in brain health and its potential to inform future therapeutic directions. Thus, ECS-targeted strategies may become increasingly important in managing and treating central nervous system disorders.”

https://pubmed.ncbi.nlm.nih.gov/41178765/

https://www.eurekaselect.com/article/151549

Dysregulation of the endocannabinoid system – a key factor in the progression of multiple sclerosis?

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“The endocannabinoid system has been implicated in the pathophysiology of multiple sclerosis (MS), yet its role across different disease stages and under disease-modifying treatment remains incompletely understood.

This study aimed to evaluate plasma levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in patients with MS at different clinical stages, and to explore their associations with disability, cognition, and quality of life, as well as the potential influence of teriflunomide therapy.

Thirty participants were enrolled: ten healthy controls, ten newly diagnosed relapsing-remitting MS (RRMS) patients in acute relapse, and ten teriflunomide-treated RRMS patients in remission. Plasma AEA and 2-AG were measured by ELISA; clinical assessments included the Mini-Mental State Examination (MMSE) and the SF-36 quality-of-life questionnaire.

No significant group differences were observed overall in 2-AG (P > 0.05). AEA showed a non-significant overall group effect (ANOVA, P = 0.0919) with a trend toward lower AEA in newly diagnosed patients compared to healthy controls (mean difference = -5.95 ng/ml, SE = 2.66; P = 0.098). In the teriflunomide group, AEA and 2-AG were strongly positively correlated (r = 0.882, P < 0.001). Additionally, SF-36 scores were positively associated with MMSE (r = 0.706, P = 0.023). Furthermore, SF-36 total scores were significantly lower in newly diagnosed patients compared to controls (post-hoc P = 0.044).

These findings suggest possible early dysregulation of the endocannabinoid system in MS and indicate that teriflunomide treatment is associated with a strengthened AEA-2-AG relationship. Larger, longitudinal studies are warranted to confirm these observations and to assess clinical implications for disease progression and patient quality of life.”

https://pubmed.ncbi.nlm.nih.gov/41178906/

Selective activation of cannabinoid receptors by cannabis terpenes

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“Terpenes are aromatic compounds abundantly present in plants, including cannabis. Emerging preclinical and clinical evidence indicates that certain terpenes exhibit pharmacological effects in various physiological and psychological conditions. Yet, their molecular mechanisms of action, particularly in cannabis preparations, remain poorly understood.

We have previously reported results of activating cannabinoid receptor type 1 (CB1R) by several terpenes that are most common in cannabis. Here we employed the same Xenopus oocytes functional heterologous expression system to complement the CB1R data and to study the activation of the cannabinoid receptor type 2 (CB2R) by sixteen individual cannabis terpenes and by terpene mixtures.

Employing receptor- induced GIRK currents as a measure for receptor activation, dose-dependent responses were found for many of these terpenes, reaching a maximal response of about 10-60 % the activation elicited by THC. Terpenes’ apparent EC50 at CB1R and CB2R were similar to, or lower than those obtained for THC at the same apparatus, suggesting lower efficacy but equivalent or even improved potency. At CB2R, multiple terpenes reach ‘clinical effect level’ at concentration equivalent or lower than those of THC (≥ 0.1 µM). Per a given receptor, terpenes differ in their activation level. Additionally, terpenes act differently at the two receptors, giving room for receptor selectivity.

Our results support the role of cannabis terpenes as partial agonists at CB1R and CB2R and provide the basis for selecting terpenes or terpene mixture for affecting physiological functions involving these receptors. These results may further contribute to our understanding of terpenes’ medicinal effects.”

https://pubmed.ncbi.nlm.nih.gov/41173057/

“Terpenes, a vast and chemically diverse class of organic compounds, are widely recognized for imparting characteristic aromas and flavors to plants, including Cannabis sativa. More than 200 terpenes have been identified in the cannabis plant, with approximately 20 being the most prevalent, including myrcene, limonene, pinene, linalool, terpinolene, β-caryophyllene, and humulene.”

“Collectively, these findings suggest a pharmacological basis for incorporating specific terpenes into ECS-focused product design and warrant further research into their tissue-specific activity, and synergistic potential when used in combination with cannabinoids or other therapeutic agents. The broad availability and favorable safety profiles of many terpenes further support their potential as accessible, scalable, and customizable tools in the modulation of endocannabinoid signaling.”

https://www.sciencedirect.com/science/article/pii/S0006295225007634?via%3Dihub

Cannabidiol and Parkinson’s disease: Investigating receptor interactions and their therapeutic implications

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“Cannabidiol (CBD) is one of the major active constituents among the several hundreds of compounds found in the cannabis plant. It is a non-psychoactive compound known for its anti-inflammatory, neuroprotective, antidepressant and anxiolytic effects.

In preclinical studies it has shown to be effective, safe, and well-tolerated in mitigating the symptoms associated with Parkinson’s disease (PD) and other neurodegenerative diseases. However, the mechanism of action is not fully characterised.

CBD is postulated to exert its therapeutic effects through its interaction with the endocannabinoid system (ECS), and via interaction with a large array of non-cannabinoid receptors, neurotransmitters, and enzymes. These interactions are complex and are influenced by cell type, concentration and exposure time.

The lack of specificity for a single receptor system makes CBD an intriguing therapeutic compound and enables it to influence multiple pathways. This broad interaction goes beyond its beneficial therapeutic effects and could lead to potential adverse effects. Detailed understanding of the versatility and complexity of how CBD exerts its effect is required so that the true potential as a therapeutic option can be realised.”

https://pubmed.ncbi.nlm.nih.gov/41161354/

“Most of the available preclinical studies investigating the effects of CBD in PD have demonstrated predominantly positive outcomes, with only a few reporting mild adverse effects such as diarrhea. The positive therapeutic effects include significant reductions in tremor and rigidity, along with improvements in sleep and overall quality of life.”

https://www.sciencedirect.com/science/article/abs/pii/S016372582500155X?via%3Dihub

Cannabinoids in immune system-related diseases: From bench to clinic

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“As a psychoactive drug, marijuana is used for recreational purposes. Given its addictive nature and the serious damage it causes to both individual health and social stability, marijuana has been banned in most countries worldwide. In recent years, with the continuous improvement of basic research, researchers have discovered the vital role of cannabinoids, the primary active ingredient in marijuana, in multiple human systems.

Research found that cannabinoids play roles in regulating immune system function and have therapeutic potential in immune system-related diseases.

However, the use of cannabinoids still poses certain hazards. For instance, the abuse of cannabinoids by pregnant women can exert certain impacts on fetal nervous system development; cannabinoids use can lead to adverse reactions such as dizziness, nausea, and dry mouth. Moreover, there are still numerous contradictions in current research on the effects of cannabinoids, and the mechanisms by which cannabinoids exert protective effects in certain diseases remain unelucidated.

In this review, we systematically discuss the endocannabinoid system and summarize the molecular and cellular bases of cannabinoid function in the immune system, and elucidate the effects of cannabinoids on immune system-related diseases.”

https://pubmed.ncbi.nlm.nih.gov/41146433/

“These findings collectively demonstrate the protective roles of CB1 agonists in immune system-related diseases.”

“These findings underscore the broad therapeutic efficacy of CB2 agonists in immune system-related diseases.”

“Cannabinoids exert immunoregulatory effects by inducing the apoptosis of immune cells, inhibiting immune cell proliferation, suppressing the production of proinflammatory cytokines, and regulating the functions of immune cells such as B cells, NK cells, and Treg cells.”

https://journals.lww.com/cmj/fulltext/9900/cannabinoids_in_immune_system_related_diseases_.1774.aspx

Cannabigerol Modulates Cannabinoid Receptor Type 2 Expression in the Spinal Dorsal Horn and Attenuates Neuropathic Pain Models

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“Background/Objectives: The expanding focus on novel therapeutic pathways for long-term pain relief has directed interest toward compounds obtained from Cannabis sativa. This study evaluated the antinociceptive potential of cannabigerol-enriched extract (CBG) in models of acute and chronic hypernociception, along with morphological outcomes. 

Methods: Formalin and hot plate tests were used on male Swiss mice to assess acute oral antinociception. To the chronic pain model, 8-week-old male Wistar rats underwent spinal nerve ligation (SNL), and CBG was administered orally by gavage once daily for 14 days. 

Results: CBG reduced nociceptive responses in the formalin test and hot plate tests, mainly at a dose of 30 mg/kg, showing antinociceptive activity. CBG attenuated SNL-induced thermal and mechanical hypersensitivity, accompanied by reduced microglial density and spinal morphological changes. Importantly, cannabinoid receptor type 2 (CB2R) signaling contributed to the antinociceptive effects of orally administered CBG, whereas cannabinoid receptor type 1 (CB1R), Brain-Derived Neurotrophic Factor (BDNF), and Tumor Necrosis Factor (TNF) did not appear to play major roles under our experimental conditions. 

Conclusions: Collectively, these findings support CBG as a promising alternative for chronic pain management.”

https://pubmed.ncbi.nlm.nih.gov/41155621/

“In summary, our study provides robust evidence that CBG exerts potent antinociceptive effects across acute, inflammatory, and neuropathic pain models.

Collectively, these results highlight CBG as a promising candidate for pain management and support further translational studies.”

https://www.mdpi.com/1424-8247/18/10/1508