Monthly Archives: February 2025

The role of cannabinoid-mediated signaling pathways and mechanisms in brain disorders

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“Cannabinoids play significant roles in the central nervous system (CNS), but cannabinoid-mediated physiopathological functions are not elaborated. Cannabinoid receptors (CBRs) mediate functions that include the regulation of neuroinflammation, oxidative stress, apoptosis, autophagy, and neurogenesis.

Microglia are the primary immune cells responsible for mediating neuroinflammation in the CNS. Therefore, this article primarily focuses on microglia to summarize the inflammatory pathways mediated by cannabinoids in the CNS, including nuclear factor-κB (NF-κB), NOD-like receptor protein 3 (NLRP3) inflammasome, mitogen-activated protein kinase (MAPK), protein kinase B (Akt), and cAMP-dependent protein kinase (PKA) signaling pathways. Additionally, we provide a table summarizing the role of cannabinoids in various brain diseases.

Medical use of cannabinoids has protective effects in preventing and treating brain diseases; however, excessive and repeated use can be detrimental to the CNS. We propose that cannabinoids hold significant potential for preventing and treating brain diseases, including ferroptosis, lactate metabolism, and mitophagy, providing new insights for further research on cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/39952540/

“Cannabis plants were historically used by pharmacologists as drugs to treat diseases in ancient India and China. Cannabinoids are natural compounds extracted from the cannabis plant. The most well-known component of cannabis is delta-9-tetrahydrocannabinol (delta9-THC)”

“This article reviews the role of cannabinoids in signaling pathways, including NF-κB, the NLRP3 inflammasome, MAPK, and AKT. Cannabinoids primarily combat neuroinflammation through CB2R-mediated signaling. Additionally, we discuss the effects of cannabinoids on oxidative stress, apoptosis, autophagy, and neurogenesis. Numerous studies demonstrate the neuroprotective effects of cannabinoids”

https://www.sciencedirect.com/science/article/abs/pii/S089865682500066X?via%3Dihub

The Endocannabinoid System as a Target for Ischemic Stroke Therapy

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“Introduction: Cannabinoids are increasingly being explored as a potential treatment for neurodegenerative diseases. This article aims to provide a narrative review of available data on the treatment of neurological disorders with cannabis constituents, focusing on ischemic stroke. 

Methods: Selected articles are summarized to describe design, results, limitations, conclusions, and implications about this theme. 

Results: The growing understanding of the endocannabinoid system and the cannabinoid receptors distribution in all human body systems and organs and particularly in brain structures importantly involved in myelination processes, suggests potential benefits for stroke symptoms and overall patient improvement. However, the variety of studied compounds, the different administration routes, dosages, and timing complicates data comparison, especially due to limited studies about these compounds, peculiarly in stroke patients. Thereat, this review to showcase disparities in findings and to summarize current advancements in cannabinoid use for potential future treatments. 

Conclusion: This article offers a review of the current literature in the field and discuss a pragmatic approach to the clinical use of cannabinoids in patients with ischemic stroke.”

https://pubmed.ncbi.nlm.nih.gov/39951358/

THC shows activity against cultured Plasmodium falciparum

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“The FDA approved drug Dronabinol was identified in a previous study applying virtual screening using the haemozoin crystal as a target against malaria parasites.

The active ingredient of dronabinol is synthetic tetrahydrocannabinol (THC), which is one of the major cannabinoids from Cannabis sativa.

Traditional use of cannabis for malaria fever was reported in the world’s oldest pharmacopoeia, dating to around 5000 years ago.

In this research we report that THC inhibits β-haematin (synthetic haemozoin) and malaria parasite growth.

Due the psychoactivity of THC, CBD, the other major naturally occurring cannabinoid that lacks the off-target psychoactive effects of THC, was also tested and inhibited β-haematin but showed only a mild antimalarial activity. To evaluate whether THC inhibit haemozoin formation, we performed a cellular haem fractionation assay that indicated that is not the likely mechanism of action.

For the first time, the cannabinoid chemical structure is raised as a new chemical class to be further studied for malaria treatment, aiming to overcome the undesirable psychoactive effects of THC and optimize the antimalarial effects.”

https://pubmed.ncbi.nlm.nih.gov/34763083/

https://www.sciencedirect.com/science/article/abs/pii/S0960894X21006697?via%3Dihub

Cannabidiol restores hematopoietic stem cell stemness in mouse through Atf2-Lrp6 axis after acute irradiation

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“Bone marrow serves as the residence of hematopoietic stem cells and is recognized as one of the most radiosensitive tissues. Exposure to acute radiation leads to severe damage to bone marrow hematopoiesis which can be fatal, while few clinically applicable medication or specific therapeutic targets have been discovered.

In this study, we found that the administration of cannabidiol significantly enhanced individual survival and restored the reconstitution capacity of bone marrow hematopoietic stem cells within 14 days after irradiation.

Single-cell RNA sequencing analysis demonstrated that the expression levels of genes associated with stemness along with Wnt and BMP signaling pathways were restored by the cannabidiol treatment through the upregulation of Atf2, a transcription factor possessing multifunctional properties. Atf2 upregulation induced by cannabidiol treatment potentially upregulated the expression of Lrp6 to improve the stemness of hematopoietic stem cells. Further functional experiments validated the crucial role of Atf2 in regulating multilineage differentiation potential of bone marrow hematopoietic stem and progenitor cells.

Overall, our findings provide evidence for a promising radioprotective function of cannabidiol and Atf2 as a candidate therapeutic target for acute radiation-induced hematopoietic injury, thereby paving the way for future research in the field.”

https://pubmed.ncbi.nlm.nih.gov/39949985/

“Cannabidiol (CBD) is the primary non-psychoactive chemical from Cannabis Sativa and an important component of hemp seed, a traditional Chinese medicine with a long history of application. Based on its multiple function, CBD has been investigated in fields of nervous system diseases, analgesic therapy, aging, anti-tumor therapy, and so on.2 In this study, we first assessed the potential role of CBD in preventing and treating acute irradiation-induced hematopoietic injury in bone marrow. Using single-cell RNA sequencing and functional assay, we dissected molecular alterations and potential mediator under CBD-treatment which led to the facilitated recovery of the HSC function. Collectively, this work strongly supports the therapeutic application of CBD in irradiation-induced bone marrow hematopoietic injury and highlights Atf2 as a promising therapeutic target herein.”

https://onlinelibrary.wiley.com/doi/10.1002/mco2.70092

Moroccan Cannabis sativa essential oil attenuates peripheral neuropathic pain induced by chronic sciatic nerve constriction injury in mice

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“Ethnopharmacological relevance: Cannabis sativa has been widely used in traditional medicine for its therapeutic properties. However, in Morocco, the ethnobotanical applications of Cannabis sativa, especially its essential oils, are underexplored. This study investigates, for the first time, the effects of Moroccan Cannabis sativa essential oil on peripheral neuropathic pain.

Materials and methods: Peripheral neuropathic pain was induced in mice through sciatic nerve injury. The mice were treated daily with cannabis essential oil for 21 days. Behavioral tests were conducted on days 1, 7, 14, and 21 to evaluate thermal, mechanical, and cold sensitivity. The essential oil’s chemical composition was analyzed using gas chromatography-mass spectrometry (GC/MS).

Results: The main constituents of the essential oil were (E)-caryophyllene (41.59%) and α-humulene (14%). Daily treatment with the essential oil significantly reduced pain sensitivity and improved functional and histological recovery over time. These effects are linked to the activity of the dominant terpenoids in the oil.

Conclusion: Moroccan Cannabis sativa essential oil shows significant therapeutic potential for managing peripheral neuropathic pain. By enhancing recovery and alleviating pain symptoms, it offers a promising alternative for treating chronic pain caused by nerve injuries.”

https://pubmed.ncbi.nlm.nih.gov/39947371/

“A multitude of recent studies have explored the broad biological properties of cannabis. Extracts from Cannabis sativa have demonstrated antimicrobial, anti-inflammatory, antinociceptive, and potent antioxidant activities.”

“This study examined the analgesic effects of terpenes found in Cannabis sativa essential oil on neuropathy. The results showed that chronic administration of these bioactive terpenes, specifically β-caryophyllene, α-humulene, and caryophyllene oxide, significantly increased pain sensitivity and response time in mice with neuropathy. Although morphine and THC-based treatments are commonly used to relieve neuropathic pain, these terpenes may offer a promising alternative with limited side effects. Clinical research has demonstrated the efficacy of cannabis-based treatments, leading several pain societies to recommend them for neuropathy management. “

https://www.sciencedirect.com/science/article/pii/S0378874125001692?via%3Dihub

The cannabinoid CB2 receptor mediates the analgesic effects of Cannabis sativa extract in a rat model of neuropathic pain

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“Neuropathic pain (NP) is a complex and debilitating condition that is often refractory to currently available analgesic medications.

Cannabis sativa extract (CSE) has been reported to exhibit analgesic properties across various pain models; however, the underlying mechanisms of action are not fully understood.

This study aimed to investigate the involvement of the cannabinoid CB2 receptor in mediating the analgesic effects of CSE in a rat model of NP, where NP was induced in male Wistar rats through chronic constriction injury (CCI) of the sciatic nerve.

Rats were randomly allocated into four groups: (1) Sham + vehicle, (2) CCI + vehicle, (3) CCI + CSE, and (4) CCI + CSE + AM630 (a CB2 receptor antagonist). CSE was administered intraperitoneally at a dosage of 30mg/kg once daily for 7 days, starting from day 7 to day 13 post-CCI surgery. To assess the involvement of the CB2 receptor, 7µg of AM630 was administered intrathecally to the rats in group 4, 30minutes before the CSE injections. Mechanical allodynia and thermal hyperalgesia were assessed using the von Frey filament and hot plate tests, respectively, at baseline (day 0) and on days 3, 7, 10, and 14 after surgery. Additionally, at the end of the study period (day 14), the expression level of Iba1 and GFAP genes was quantified in the lumbar enlargement tissues using real-time PCR.

The results demonstrated that CCI surgery induced mechanical allodynia and thermal hyperalgesia, along with the upregulation of Iba1 and GFAP genes in the vehicle-treated CCI group. Treatment with CSE significantly mitigated both allodynia and hyperalgesia and downregulated the expression of Iba1 and GFAP genes compared to the CCI + vehicle group. Furthermore, the administration of the CB2 receptor antagonist AM630 not only robustly blocked the antinociceptive effects of CSE but also reversed the significant downregulation of Iba1 and GFAP gene expression in the lumbar enlargement tissues.

These findings highlight the novel role of the CB2 receptor in mediating the analgesic effects of CSE, providing new insights into the potential therapeutic mechanisms of CSE in neuropathic pain management.”

https://pubmed.ncbi.nlm.nih.gov/39947333/

“In summary, this study provides evidence that CSE exerts analgesic and anti-inflammatory effects in NP through CB2 receptor activation. These findings contribute to the growing body of research supporting cannabinoids as potential therapeutic agents for NP management.”

https://www.sciencedirect.com/science/article/abs/pii/S0166432825000683?via%3Dihub

Efficacy of cannabidiol alone or in combination with Δ-9-tetrahydrocannabinol for the management of substance use disorders: An umbrella review of the evidence

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“Background and aims: Substance use disorders (SUD) lead to a high burden of disease, yet treatment options are limited. Cannabidiol (CBD) is being investigated as a potential therapeutic target due to its pharmacological properties and mode of action in the endocannabinoid system. Recent systematic reviews (SR) on CBD and SUDs have shown inconsistent results. The objective of this umbrella review was to determine whether CBD alone or in combination with Δ-9-tetrahydrocannabinol (THC) is effective for managing and treating SUDs.

Methods: Following a registered protocol, we searched PubMed, Web of Science and Epistemonikos databases for SRs, with or without a meta-analysis, of randomized controlled trials focusing on interventions dispensing CBD, alone or in combination with THC, to treat SUDs, published from 1 January 2000 to 15 October 2024. Screening, data extraction and quality assessment with the AMSTAR 2 tool were performed by two researchers in parallel and duplicated.

Results: 22 SRs were included, 5 of which performed a meta-analysis. We found mixed evidence regarding the efficacy of CBD to manage and treat SUDs. Findings were interpreted in light of the quality of the SRs. Nabiximols, which contains CBD and THC, demonstrated positive effects on cannabis withdrawal and craving symptoms. Evidence supporting the efficacy of CBD is limited and inconclusive for abstinence, reduction or cessation of use of cannabis, tobacco, alcohol, opiates and other psychoactive substances.

Conclusion: Cannabidiol (CBD) monotherapy does not appear to be efficacious for treatment of substance use disorders. CBD primarily exhibits effects on cannabis withdrawal and craving when combined with Δ-9-tetrahydrocannabinol (THC). Existing data on the efficacy of CBD alone with regard to other outcomes related to substance use disorders are limited.”

https://pubmed.ncbi.nlm.nih.gov/39947878/

“This umbrella review does not suggest any efficacy of CBD monotherapy as a therapeutic agent in SUDs. CBD primarily exhibits effects on cannabis withdrawal and craving symptoms when combined with THC in nabiximols. The CBD:THC 1:1 effects suggest that the potential benefits observed in cannabis withdrawal and craving may be because of THC, with CBD providing no additional benefit. We found no evidence for CBD alone, in the absence of THC, in managing cannabis and other SUDs. “

https://onlinelibrary.wiley.com/doi/10.1111/add.16745

The Presence of the Endocannabinoid System in an In Vitro Model of Gorham-Stout Disease and Its Possible Role in the Pathogenesis

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“Gorham-Stout syndrome (GSD), also known as disappearing bone disease, is an extremely rare bone disorder, characterized by a huge bone loss, which is followed by a lack of new matrix deposition and an excessive proliferation of both blood vessels and lymphatics. Unfortunately, the biological causes of GSD are still unknown. Recent studies that have tried to understand the etiopathogenesis of GSD have been principally focused on the vascular and osteoclastogenic aspects, not considering the possibility of a lack of osteoblast function. Nowadays, a diagnosis is still difficult, and is often made by exclusion of the presence of other pathologies, as well as on radiological evidence, and finally confirmed by histological examination. Treatment also remains a critical issue for clinicians today, who mostly try to control the progression of the disease.

Over the last two decades, clear evidence has emerged that the endocannabinoid system plays an important role in bone metabolism, leading scientists to hypothesize that it could be involved in physiological and pathological bone processes. In this work, we analyzed the presence of the ES in a primary cell line of human mesenchymal stem cells derived from a GSD patient for the first time, to understand if and how this complex network may play a role in the pathogenesis of the syndrome.

Our preliminary results demonstrated that the ES is also present in the pathological tissue. Moreover, the qRT-PCR analysis showed an altered expression of the different ES components (i.e., CNR1, CNR2, TRPV1, and GPR55). We observed an upregulation of CNR1 and TRPV1 expression, while the opposite trend was noticed for CNR2 and GPR55 expression. Thus, these results could lead us to speculate that possible deregulation of the ES may play an important role in the lack of bone regeneration in GSD patients. However, further studies will be necessary to confirm the role of the ES in the progression of GSD and understand whether the natural components of Cannabis Sativa could play a therapeutic role in the treatment of the disease.”

https://pubmed.ncbi.nlm.nih.gov/39940911/

“In conclusion, this is only a preliminary study, and further future analyses are needed to understand the role of the ES during osteogenic differentiation better and to try to comprehend what the molecular mechanisms involved in GSD pathogenesis are. In addition to this, the demonstration that the ES is present in our GSD in vitro model could pave the way to a study of the effects of the natural components of Cannabis Sativa as possible future new molecules that could be useful in the treatment of GSD and other bone diseases.”

https://www.mdpi.com/1422-0067/26/3/1143

The Endocannabinoid System: Implications in Gastrointestinal Physiology and Pathology

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“The endocannabinoid system (ECS), composed of receptors, endocannabinoids, and enzymes that regulate biosynthesis and degradation, plays a fundamental role in the physiology and pathology of the gastrointestinal tract, particularly in the small and large intestine and liver.

Specifically, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), located principally in the nervous system and immune cells, orchestrate processes such as intestinal motility, intestinal and hepatic inflammation, and energy metabolism, respectively.

The main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), influence appetite, body weight regulation, and inflammatory states and thus have implications in obesity, non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS).

Recent studies have highlighted the therapeutic potential of targeting the ECS to modulate gastrointestinal and metabolic diseases. In particular, peripheral CB1R antagonists and CB2R agonists have shown efficacy in treating intestinal inflammation, reducing hepatic steatosis, and controlling IBS symptoms. Moreover, the ECS is emerging as a potential target for the treatment of colorectal cancer, acting on cell proliferation and apoptosis.

This review highlights the opportunity to exploit the endocannabinoid system in the search for innovative therapeutic strategies, emphasizing the importance of a targeted approach to optimize treatment efficacy and minimize side effects.”

https://pubmed.ncbi.nlm.nih.gov/39941074/

“In conclusion, these findings suggest that the ECS offers a versatile approach for modulating gastrointestinal physiological aspects and treating conditions such as obesity and its complications, IBS, and CRC. Future research should refine ECS-targeted therapies to maximize their efficacy and minimize adverse effects, unlocking new opportunities for innovative treatments of disordered metabolism, inflammation, and cancer.

Clinical studies show that medical cannabis could be a valuable adjunct to cancer and treatments for inflammation, providing symptom relief and improving patients’ overall quality of life. However, further research is needed to refine treatment protocols and explore their full therapeutic potential.”

https://www.mdpi.com/1422-0067/26/3/1306

Therapeutic potential of cannabinoids in neurological conditions: a systematic review of clinical trials

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“Overview: Cannabinoids have gained increasing attention for their therapeutic potential in treating several neurological conditions, including neurodegenerative diseases, chronic pain, and epilepsy. This review aims to assess the current clinical trials investigating cannabinoids, primarily Tetrahydrocannabinol and Cannabidiol, for neurological disorders. This review will aim to highlight the efficacy, safety, and outcome measures used in these trials.

Methods: Clinical trials were identified using ClinicalTrials.gov, focusing on studies that examined the effects of cannabinoids in treating neurological conditions. All trials that fulfilled the following criteria were included: Phase 1–4, focused on cannabinoids as primary intervention, and measured relevant outcomes such as pain relief, cognitive function, or spasticity reduction. Data on conditions, interventions, primary and secondary outcomes, and trial phases were extracted and analysed.

Results: A total of 47 clinical trials were identified, including different neurological conditions. The most frequently studied conditions were Multiple Sclerosis, Fibromyalgia, and Parkinson’s Disease. Most trials were in Phase 2, with the primary outcome measures focused on pain management, spasticity, and cognitive function. Secondary outcomes included safety and tolerability measures.

Conclusion: The review highlights the broad therapeutic potential of cannabinoids in neurology, with promising results in symptom management for conditions like Multiple Sclerosis and Fibromyalgia. However, the lack of standardized study protocols, dosing, and outcome measures presents challenges for broader clinical implementation.”

“The results of this analysis showed that both CBD and THC have significant potential as therapeutic agents for neurological disorders, particularly in managing pain, motor dysfunction, and behavioural disturbances. However, their different pharmacological profiles and side effect risks mean that each cannabinoid may be better suited to different patient populations and conditions. While THC’s broader range of applications in cognitive and motor symptoms positions it as a more multipurpose treatment option, the psychoactive risks associated with its use should not be ignored. On the other hand, CBD’s safety and non-psychoactive nature make it more preferred option for managing chronic pain, but its therapeutic benefits may be more limited. Future research should focus on addressing the gaps in long-term safety and efficacy data, as well as exploring the full potential of lesser-known cannabinoids and combination therapies to further enhance the treatment of neurological disorders.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1521792/full