“Chronic pain presents as a complex condition encompassing sensory (Zhang Z et al. Cell Rep 12;752-759, 2015) and emotional components, often accompanied by anxiety, depression, insomnia, and cognitive impairment. These factors significantly hinder daily activities and rehabilitation efforts.
The widespread prevalence of chronic pain imposes substantial clinical, societal, and economic burdens. While current analgesics have limitations and associated side effects such as tolerance, dependency, cognitive deficits, and a narrow therapeutic window, the search for new analgesic options remains imperative.
The endocannabinoid system (ECS), a key modulator in pain processing pathways, plays a crucial role in executive functions. This review specifically focuses on the cognitive impairments associated with chronic pain and highlights the pivotal role of the ECS in the cognitive aspects of pain. Additionally, the effectiveness of cannabinoid-based medications in improving executive functions in patients with chronic pain is evaluated.”
“Mechanical allodynia, the pain caused by innocuous tactile stimuli, is a hallmark symptom of neuropathic pain that is often resistant to currently available treatments.
Cannabinoids are widely used for pain management; however, their therapeutic mechanisms for neuropathic mechanical allodynia remain unclear.
Using transgenic rats that enable to optogenetically stimulate touch-sensing Aβ fibers in the skin, we found that the intrathecal administration of the synthetic cannabinoid, WIN 55,212-2, alleviated the Aβ fiber-derived neuropathic allodynia. Furthermore, we injected adeno-associated virus vectors incorporating the rat cannabinoid receptor 1 (CB1 receptor) (encoded by Cnr1) promoter and tdTomato or short hairpin RNA targeting the CB1 receptor into the spinal dorsal horn (SDH) and demonstrated that the conditional knockdown of CB1 receptors in Cnr1+ SDH neurons attenuates the anti-allodynic effects of intrathecally administered WIN 55,212-2. Electrophysiological analysis revealed that Cnr1+ SDH neurons received excitatory synaptic inputs from the primary afferent Aβ fibers.
Collectively, our results suggest that the CB1 receptors in Cnr1+ SDH neurons are molecular and cellular targets of intrathecal WIN 55,212-2 to alleviate neuropathic allodynia.”
“WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) “
“This chapter will review the basic pharmacology of the canonical cannabinoid receptors. The endocannabinoid system is a complex signalling network involved in a wide range of physiological processes, including pain modulation, appetite regulation, and synaptic plasticity. The canonical cannabinoid receptors, CB1 and CB2, are central in orchestrating this system. CB1 is highly enriched in the central nervous system (CNS), where it plays a crucial role in modulating neurotransmitter release and synaptic plasticity. In contrast, CB2 is predominantly expressed in peripheral tissues and immune cells, participating in anti-inflammatory processes. Here, we focus on cannabinoid receptor distribution, intracellular signalling, and receptor regulation. We describe the intracellular signalling pathways activated by CB1, including the modulation of ion channels, second messengers, and protein kinases. Overall, this chapter provides an overview of the canonical cannabinoid receptors and their role in the regulation of neuronal signalling and plasticity, highlighting the molecular and cellular mechanisms underlying their effects in the CNS.”
“Background/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic effects limit clinical use. ZCZ011, a CB1R allosteric modulator, and cannabidiol (CBD), a non-psychoactive cannabinoid, offer alternatives. This study investigated combining sub-therapeutic THC doses with ZCZ011 or CBD in a murine model of dextran sodium sulphate (DSS)-induced colitis.
Methods: Acute colitis was induced with 4% DSS for 7 days, followed by 3 days of water. Chronic colitis was modelled over 24 days with alternating DSS concentrations. The combination of 2.5 mg/kg THC with 20 mg/kg ZCZ011 or 10 mg/kg CBD was evaluated. Key markers were assessed to determine efficacy and safety, including disease activity index (DAI), inflammation, cytokine levels, GLP-1, and organ health.
Results: DSS-induced colitis resulted in increased DAI scores, cytokines, organ inflammation and dysregulation of GLP-1 and ammonia. THC at 10 mg/kg significantly improved colitis markers but was ineffective at 2.5 and 5 mg/kg. ZCZ011 alone showed transient effects. However, combining 2.5 mg/kg THC with either 20 mg/kg ZCZ011 or 10 mg/kg CBD significantly alleviated colitis markers, restored colon integrity and reestablished GLP-1 homeostasis. This combination also maintained favourable haematological and biochemical profiles, including a notable reduction in colitis-induced elevated ammonia levels.
Conclusions: This study demonstrates the synergistic potential of low-dose THC combined with CBD or ZCZ011 as a novel, effective and safer therapeutic strategy for ulcerative colitis.”
“This study provides compelling evidence that sub-therapeutic doses of THC combined with ZCZ011 or CBD offer a safe and effective strategy for managing both the inflammatory and metabolic components of IBD. Notably, the normalisation of GLP-1 and ammonia levels underscores the dual benefits of these treatments in alleviating colitis while addressing associated metabolic dysregulation and extraintestinal complications. This dual-action approach addresses key limitations of current therapies and emphasizes ECS modulation as a promising avenue for IBD treatment.”
“Introduction: Individuals living with Sickle Cell Disease (SCD) are subject to numerous chronic complications, including disabling chronic pain, often dependent on opioids and with important repercussions on quality of life. The use of Medicinal Cannabis in this scenario may be a promising strategy for mitigating this impact.
Areas covered: This work compiled current knowledge regarding the endocannabinoid system in humans and the role of this system in various organic functions. Articles were retrieved through a comprehensive search of the PubMed NCBI database, covering relevant studies up to 2024. These data bring important speculations on the potential role of the use of medicinal cannabis in modulating SCD chronic complications, and the preliminary results of clinical trials carried out in this condition are discussed.
Expert opinion: The search for understanding the role of cannabis-derived products in the management of chronic complications of sickle cell disease could add resources to the serious challenge of dealing with the multiple aspects of the disease faced by patients. They range from the management of chronic pain itself, the risks of opioid dependence, in addition to other difficult scenarios, such as leg ulcers and chronic inflammation and its consequences.”
“Cannabidiol (CBD) is a non-neurotoxic, phytocannabinoid from cannabis with reported medicinal properties, including antiepileptic and anti-inflammatory activity.
Several in vitro and in vivo studies have shown that CBD has antitumor potential against colorectal cancer (CRC), the third deadliest cancer in the world. However, as different mutations influence the antitumor effects and CBD can bind a variety of receptors, it is yet to be determined whether specific CRC mutations affect CBD’s efficacy in treatment of CRC.
To investigate this, we selected four CRC cell lines, including HCT116, HT-29, LS174T, and LS153, which harbor distinct mutations. Cells were treated with a range of concentrations of CBD to evaluate its cytotoxic effects and impact on cell proliferation, migration, and invasion by using a live-cell imaging system. IC50 values were then calculated for each parameter. The level of endoplasmic reticulum (ER) stress pathway markers was also measured using qRTPCR. The requirements for CB1 or CB2 receptor-medicated signaling were investigated using the selective inhibitors AM251 and SR144528, respectively.
Our results demonstrate that CBD induces apoptosis and halts proliferation, migration, and invasion of CRC cell lines in a concentration-dependent manner.
CBD showed potent antitumor effects in the tested cell lines with no obvious effect from different mutations such as KRAS, BRAF, APC, PTEN, etc. CBD also induced ER stress in CRC cells but not in healthy intestinal organoids. Cotreatment with SR144528 inhibited the effects of indicating involvement of CB2 receptor activation in the anticancer effects of CBD.
Together, these results demonstrated that CBD could be effective for CRC regardless of the underlying mutation through CB2 receptor activation.”
“Objective: Metabolic syndrome is due to dysregulation that starts with fat accumulation, causing inflammatory response, insulin resistance, dyslipidemia, hypertension, and fatty liver disease. The endocannabinoid system, via cannabinoid receptor type 1 (CB1), has been shown to be involved with energy homeostasis and regulation of appetitive behavior via activity in the hypothalamus, limbic forebrain and amygdala and in the peripheral tissues including adipose, liver and muscle. Therefore, two phytocannabinoids, tetrahydrocannabivarin (THCV), a CB1 neutral antagonist, and cannabidiol (CBD), a negative allosteric modulator of CB1, are expected to have therapeutic metabolic benefits, including weight loss.
Method: A placebo-controlled study was conducted on 44 subjects (31 females and 13 males) with an average age of 51.75. The study evaluated the efficacy of two different doses of THCV and CBD (8 mg THCV/10 mg CBD in the lower dose and 16 mg THCV/20 mg CBD in the higher dose), taken once daily for 90 days via mucoadhesive oral strips, for weight loss and improvement of certain metabolic markers.
Results: Use of the THCV/CBD strip was associated with statistically significant weight loss, decreases in abdominal girth, systolic blood pressure, and total and LDL cholesterol. The study was limited by small sample sizes in both the high dose and placebo groups.
Conclusions: The 16 mg/20 mg daily dose was superior for weight loss compared to the 8 mg/10 mg daily dose; both sets of results differed from placebo in a way that was statistically significant. The results of this study were congruent with the prior unpublished studies of a hemp extract containing significant percentages of THCV, CBDV and CBD.”
“Cannabidiol (CBD), a nonpsychoactive compound from Cannabis, has various bioactive functions in humans and animals.
Evidence suggests that CBD promotes muscle injury recovery in athletes, but whether and how CBD improves endurance performance remains unclear.
Here we investigated the effects of CBD treatment on exercise performance in mice and assessed whether this effect involves the gut microbiome.
CBD administration significantly increased treadmill running performance in mice, accompanied by an increase in oxidative myofiber composition. CBD also increased mitochondrial biogenesis and the expression of associated genes such as PGC-1α, phosphorylated CREB and AMPK in muscle tissue. Interestingly, CBD altered the composition of the gut microbiome, and antibiotic treatment reduced the muscle endurance-enhancing effects of CBD and mitochondrial biogenesis.
We isolated Bifidobacterium animalis, a microbe increased by CBD administration, and named it KBP-1. Treatment with B. animalis KBP-1 in mice resulted in improved running performance. Whole-genome analysis revealed that B. animalis KBP-1 presented high expression of genes involved in branched-chain amino acid biosynthesis, expression of branched-chain amino acid release pumps and metabolism of lactic acid.
In summary, our study identified CBD and B. animalis KBP-1 as potential endurance exercise-promoting agents.”
“In summary, we propose that both CBD and the gut bacteria B. animalis KBP-1, which is increased by CBD treatment, could be used in strategies to promote endurance exercise performance.”
“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.”
“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.”
“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.”
