Category Archives: Depression

Changes in Pain and Mental Health Symptoms Associated with Prescribed Medicinal Cannabis Use: A One-Year Longitudinal Study

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“Chronic pain and mental health issues like depression and anxiety significantly contribute to disease burden in Western countries.

While cannabinoids are suggested to have analgesic, anxiolytic and antidepressant properties, evidence, especially for long-term use, is inconclusive. This 12-month observational study evaluated the effects of prescribed medicinal cannabis for 96 patients suffering from pain, as well as sleep disturbances, depression and anxiety. Treatment outcomes for pain, depression, anxiety and sleep problems were assessed at 3, 6, and 12 months using validated instruments.

Significant reductions were observed in pain scores and the interference of pain on daily functions, alongside improvements in mental health and sleep. Many patients reported notable improvements in pain severity and reduced use of pain medications in the first 6 months, with a decline at 12 months. Additionally, sustained improvements in depression, anxiety, stress and sleep were observed, with about half reporting substantial improvement. Adverse effects were common but mostly mild or moderate, most commonly dry mouth and sleepiness.

These results show that prescribed medicinal cannabis treatment is associated with improvements in chronic pain and mental health symptoms, such as depression, anxiety and stress. However, findings also suggest reduced effectiveness with longer-term use, emphasizing the need for additional research.”

https://pubmed.ncbi.nlm.nih.gov/39432717/

“Cannabis is a plant that has been used for thousands of years as a traditional medicine to treat various medical ailments, including pain.

Overall, we found that the use of medicinal cannabis was associated with reduced pain during the first 6 months and improved mental well-being over 12 months. Patients reported not only less pain but also experienced reduced interference from pain in their daily functions. Furthermore, they reported decreased use of pain medications and a large proportion felt that their pain symptoms had significantly improved, as reflected in their reported changes in the severity of pain.”

https://www.tandfonline.com/doi/full/10.1080/15360288.2024.2414898

An overview of major depression disorder: The endocannabinoid system as a potential target for therapy

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“Major depressive disorder is the psychiatric disease with the highest global prevalence, impacting social functioning and decreasing the quality of life. The partial pathophysiological knowledge of the disease, the economic burden and the low remission rates are sufficient justification to carry out an update on the subject in the search for new therapeutic approaches and targets.

The endocannabinoid system has been linked to the development of depression, and its stimulation or antagonism is a promising approach in the treatment of major depressive disorder.

Cannabidiol (CBD) and its properties have been widely studied recently; its analgesic, anti-inflammatory, antineoplastic and neuroprotective roles have even been reported in animal models and clinical trials, achieving its approved use for certain neurodegenerative pathologies. The use of CBD in depression biomodels and clinical trials has not been the exception, and here we contrast the current evidence of its administration and pharmacology against the pathological mechanisms of major depressive disorder.”

https://pubmed.ncbi.nlm.nih.gov/39370369/

“This focused review discusses the prevalence of major depressive disorder (MDD) globally, its impact on social functioning and quality of life, and the need for new therapeutic approaches. It highlights the role of the endocannabinoid system in MDD and the potential of cannabidiol (CBD) in treating depression due to its various beneficial properties. CBD’s effectiveness is supported by research in animal models and clinical trials, offering promise as a treatment for MDD by targeting its pathological mechanisms.”

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.14089

“Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866040/

Nanocarriers for Cannabinoid Delivery: Enhancing Therapeutic Potential

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“Medical cannabis has potential therapeutic benefits in managing pain, anxiety, depression, and neurological and movement disorders. Phytocannabinoids derived from the cannabis plant are responsible for their pharmacological and therapeutic properties. However, the complexity of cannabis components, especially cannabinoids, poses a challenge to effective medicinal administration. Even with the increasing acceptance of cannabis-based medicines, achieving consistent bioavailability and targeted distribution remains difficult. Conventional administration methods are plagued by solubility and absorption problems requiring innovative solutions. After conducting a thorough review of research papers and patents, it has become evident that nanotechnology holds great promise as a solution. The comprehensive review of 36 research papers has yielded valuable insights, with 7 papers reporting enhanced bioavailability, while others have focused on improvements in release, solubility, and stability. Additionally, 19 patents have been analyzed, of which 7 specifically claim enhanced bioavailability, while the remaining patents describe various formulation methods. These patents outline effective techniques for encapsulating cannabis using nanocarriers, effectively addressing solubility and controlled release. Studies on the delivery of cannabis using nanocarriers focus on improving bioavailability, prolonging release, and targeting specific areas. This synthesis highlights the potential of nanotechnology to enhance cannabis therapies and pave the way for innovative interventions and precision medicine.”

https://pubmed.ncbi.nlm.nih.gov/39356097/

https://www.eurekaselect.com/article/141807

Repeated Administration of a Full-Spectrum Cannabidiol Product, Not a Cannabidiol Isolate, Reverses the Lipopolysaccharide-Induced Depressive-Like Behavior and Hypolocomotion in a Rat Model of Low-Grade Subchronic Inflammation

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“Background: Mounting evidence suggests that the phytocannabinoid cannabidiol (CBD) holds promise as an antidepressant agent in conditions underlined by inflammation. Full-spectrum CBD extracts might provide greater behavioral efficacy than CBD-only isolates and might require lower doses to achieve the same outcomes due to the presence of other cannabinoids, terpenes, and flavonoids. However, investigations in this area remain limited. 

Methods: We evaluated the behavioral response to the administration for 7 days of 15 and 30 mg/kg of a CBD isolate and a full-spectrum CBD product in a rat model of subchronic lipopolysaccharide (LPS, 0.5 mg/kg/day/7 days, intraperitoneal)-induced depressive-like and sickness behavior. The forced swim test was used to assess depressive-like behavior, the open field test (OFT) to assess locomotion, and the elevated plus maze to assess anxiety-like behavior. 

Results: The full-spectrum CBD extract at both doses, but not the CBD isolate, reversed the LPS-induced depressive-like behavior in the forced swim test. Moreover, the full-spectrum CBD extract at the higher dose but not the CBD isolate restored the subchronic LPS-induced hypolocomotion in the OFT. Repeated administration of both formulations elicited an anxiogenic-like trend in the elevated plus maze. 

Conclusion: Full-spectrum CBD products might have greater therapeutic efficacy in resolving inflammation-induced depressive and sickness behavior compared to a CBD-only isolate.”

https://pubmed.ncbi.nlm.nih.gov/39347620/

https://www.liebertpub.com/doi/10.1089/can.2024.0086

P2X7 receptors from the perspective of NLRP3 inflammasome pathway in depression: Potential role of cannabidiol

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“Many patients with depressive disorder do not respond to conventional antidepressant treatment. There is an ongoing interest in investigating potential mechanisms of treatment resistance in depression to provide alternative treatment options involving inflammatory mechanisms.

Increasing evidence implicates the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome as a critical factor in neuroinflammation. ATP-induced P2X7 receptor (P2X7R) activation is a major trigger for inflammation, activating the canonical NLRP3 inflammatory cascade.

Psychosocial stress, the primary environmental risk factor for depression, is associated with changes in ATP-mediated P2X7R signaling.

Depression and stress response can be alleviated by Cannabidiol (CBD).

CBD has an anti-inflammatory activity related to the regulation of NLRP3 inflammasome activation. However, CBD’s effects on the inflammasome pathway are poorly understood in central nervous system (CNS) cells, including microglia, astrocytes, and neurons.

This review will emphasize some findings for neuroinflammation and NLRP3 inflammasome pathway involvement in depression, particularly addressing the ATP-induced P2X7R activation. Moreover, we will underline evidence for the effect of CBD on depression and address its potential impacts on neuroinflammation through the NLRP3 inflammasome cascade.”

https://pubmed.ncbi.nlm.nih.gov/39296605/

“Highlights

  • •Neuroinflammation plays an important role in the development of depressive disorder.
  • •The NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome contributes to the pathogenesis of depression.
  • •ATP-induced P2X7 receptor (P2X7R) activation triggers the canonical NLRP3 inflammatory cascade.
  • •P2X7R antagonists have potential antidepressant effects.
  • •CBD has anti-inflammatory properties related to the regulation of NLRP3 inflammasome activation.”

https://www.sciencedirect.com/science/article/pii/S2666354624001315?via%3Dihub


Microglial morphological/inflammatory phenotypes and endocannabinoid signaling in a preclinical model of periodontitis and depression

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“Background: Depression is a chronic psychiatric disease of multifactorial etiology, and its pathophysiology is not fully understood. Stress and other chronic inflammatory pathologies are shared risk factors for psychiatric diseases, and comorbidities are features of major depression. Epidemiological evidence suggests that periodontitis, as a source of low-grade chronic systemic inflammation, may be associated with depression, but the underlying mechanisms are not well understood.

Methods: Periodontitis (P) was induced in Wistar: Han rats through oral gavage with the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum for 12 weeks, followed by 3 weeks of chronic mild stress (CMS) to induce depressive-like behavior. The following four groups were established (n = 12 rats/group): periodontitis and CMS (P + CMS+), periodontitis without CMS, CMS without periodontitis, and control. The morphology and inflammatory phenotype of microglia in the frontal cortex (FC) were studied using immunofluorescence and bioinformatics tools. The endocannabinoid (EC) signaling and proteins related to synaptic plasticity were analyzed in FC samples using biochemical and immunohistochemical techniques.

Results: Ultrastructural and fractal analyses of FC revealed a significant increase in the complexity and heterogeneity of Iba1 + parenchymal microglia in the combined experimental model (P + CMS+) and increased expression of the proinflammatory marker inducible nitric oxide synthase (iNOS), while there were no changes in the expression of cannabinoid receptor 2 (CB2). In the FC protein extracts of the P + CMS + animals, there was a decrease in the levels of the EC metabolic enzymes N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), and monoacylglycerol lipase (MAGL) compared to those in the controls, which extended to protein expression in neurons and in FC extracts of cannabinoid receptor 1 (CB1) and to the intracellular signaling molecules phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). The protein levels of brain-derived neurotrophic factor (BDNF) and synaptophysin were also lower in P + CMS + animals than in controls.

Conclusions: The combined effects on microglial morphology and inflammatory phenotype, the EC signaling, and proteins related to synaptic plasticity in P + CMS + animals may represent relevant mechanisms explaining the association between periodontitis and depression. These findings highlight potential therapeutic targets that warrant further investigation.”

https://pubmed.ncbi.nlm.nih.gov/39245706/

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-024-03213-5

Neuromolecular and behavioral effects of Cannabidiol on depressive-associated behaviors and neuropathic pain conditions in mice

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“Background and aims: Neuropathic pain (NP) has a high incidence in the general population, is closely related to anxiety disorders, and has a negative impact on the quality of life. Cannabidiol (CBD), as a natural product, has been extensively studied for its potential therapeutic effects on symptoms such as pain and depression (DP). However, the mechanism of CBD in improving NP with depression is not fully understood.

Methods: First, we used bioinformatics tools to deeply mine the intersection genes associated with NP, DP, and CBD. Secondly, the core targets were screened by Protein-protein interaction network, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, molecular docking and molecular dynamics simulation. Next, the effects of CBD intervention on pain and depressive behaviors in the spinal nerve ligation (SNL) mouse model were evaluated using behavioral tests, and dose-response curves were plotted. After the optimal intervention dose was determined, the core targets were verified by Western blot (WB) and Quantitative Polymerase Chain Reaction (qPCR). Finally, we investigated the potential mechanism of CBD by Nissl staining, Immunofluorescence (IF) and Transmission Electron Microscopy (TEM).

Results: A total of five core genes of CBD most associated with NP and DP were screened by bioinformatics analysis, including PTGS2, GPR55, SOD1, CYP1A2 and NQO1. Behavioral test results showed that CBD by intraperitoneal administration 5mg/kg can significantly improve the pain behavior and depressive state of SNL mice. WB, qPCR, IF, and TEM experiments further confirmed the regulatory effects of CBD on key molecules.

Conclusion: In this study, we found five targets of CBD in the treatment of NP with DP. These findings provide further theoretical and experimental basis for CBD as a potential therapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/39245142/

“We identified five core genes associated with comorbid NP and DP targeted by CBD. CBD intervention can improve NP and depressive-associated behavior in mice.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390824003228?via%3Dihub


Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex

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“Preclinical and clinical studies show that cannabis modulates mood and possesses antidepressant-like properties, mediated by the agonistic activity of cannabinoids on central CB1 receptors (CB1Rs). The action of CB1R agonists on the serotonin (5-HT) system, the major transmitter system involved in mood control and implicated in the mechanism of action of antidepressants, remains however poorly understood.

In this study, we demonstrated that, at low doses, the CB1R agonist WIN55,212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate] exerts potent antidepressant-like properties in the rat forced-swim test (FST).

This effect is CB1R dependent because it was blocked by the CB1R antagonist rimonabant and is 5-HT mediated because it was abolished by pretreatment with the 5-HT-depleting agent parachlorophenylalanine. Then, using in vivo electrophysiology, we showed that low doses of WIN55,212-2 dose dependently enhanced dorsal raphe nucleus 5-HT neuronal activity through a CB1R-dependent mechanism.

Conversely, high doses of WIN55,212-2 were ineffective in the FST and decreased 5-HT neuronal activity through a CB1R-independent mechanism. The CB1R agonist-induced enhancement of 5-HT neuronal activity was abolished by total or medial prefrontocortical, but not by lateral prefrontocortical, transection. Furthermore, 5-HT neuronal activity was enhanced by the local microinjection of WIN55,212-2 into the ventromedial prefrontal cortex (mPFCv) but not by the local microinjection of WIN55,212-2 into the lateral prefrontal cortex. Similarly, the microinjection of WIN55,212-2 into the mPFCv produced a CB1R-dependent antidepressant-like effect in the FST.

These results demonstrate that CB1R agonists possess antidepressant-like properties and modulate 5-HT neuronal activity via the mPFCv.”

“These results establish that low doses of a CB1R agonist elicit potent antidepressant-like behavior and enhance 5-HT neurotransmission, mediated by CB1R activation in the mPFCv. Conversely, high doses nullify antidepressant-like behavior and markedly attenuate 5-HT neurotransmission, an effect that appears to be instigated by a non-CB1R mechanism.”

https://pubmed.ncbi.nlm.nih.gov/17959812/

In the weeds: A comprehensive review of cannabis; its chemical complexity, biosynthesis, and healing abilities

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“For millennia, various cultures have utilized cannabis for food, textile fiber, ethno-medicines, and pharmacotherapy, owing to its medicinal potential and psychotropic effects. An in-depth exploration of its historical, chemical, and therapeutic dimensions provides context for its contemporary understanding. The criminalization of cannabis in many countries was influenced by the presence of psychoactive cannabinoids; however, scientific advances and growing public awareness have renewed interest in cannabis-related products, especially for medical use.

Described as a ‘treasure trove,’ cannabis produces a diverse array of cannabinoids and non-cannabinoid compounds. Recent research focuses on cannabinoids for treating conditions such as anxiety, depression, chronic pain, Alzheimer’s, Parkinson’s, and epilepsy. Additionally, secondary metabolites like phenolic compounds, terpenes, and terpenoids are increasingly recognized for their therapeutic effects and their synergistic role with cannabinoids. These compounds show potential in treating neuro and non-neuro disorders, and studies suggest their promise as antitumoral agents. This comprehensive review integrates historical, chemical, and therapeutic perspectives on cannabis, highlighting contemporary research and its vast potential in medicine.”

https://pubmed.ncbi.nlm.nih.gov/39056093/

https://www.sciencedirect.com/science/article/pii/S2214750024000684?via%3Dihub

Therapeutic potential of cannabidiol in depression

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“Major depressive disorder (MDD) is a widespread and debilitating condition affecting a significant portion of the global population.

Traditional treatment for MDD has primarily involved drugs that increase brain monoamines by inhibiting their uptake or metabolism, which is the basis for the monoaminergic hypothesis of depression. However, these treatments are only partially effective, with many patients experiencing delayed responses, residual symptoms, or complete non-response, rendering the current view of the hypothesis as reductionist.

Cannabidiol (CBD) has shown promising results in preclinical models and human studies. Its mechanism is not well-understood, but may involve monoamine and endocannabinoid signaling, control of neuroinflammation and enhanced neuroplasticity. This chapter will explore CBD’s effects in preclinical and clinical studies, its molecular mechanisms, and its potential as a treatment for MDD.”

https://pubmed.ncbi.nlm.nih.gov/39029987/

“CBD exhibits a multi-pharmacological profile with a complex and not fully understood mechanism of action. It engages some pathways similar to those targeted by other antidepressant drugs, such as the facilitation of serotonergic and BDNF-TrkB signaling. However, it also activates distinct pathways that differ from traditional antidepressants.”

https://www.sciencedirect.com/science/article/abs/pii/S0074774224000850?via%3Dihub