“The endocannabinoid system comprises cannabinoid receptors (CBRs) 1 & 2, endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes that regulate their production and degradation.
ECS plays a significant role in both health and disease.
It influences neuronal and glial communications, neurotransmitter regulations, neuroinflammation, and behavioral alterations. Neuropsychiatric symptoms (NPS) are commonly seen in neurodegenerative conditions like Alzheimer’s disease (AD), apart from the core clinical diagnosis of dementia.
NPS consists of various disturbing symptoms, including anxiety, agitation, apathy, hallucinations, delusions, sleeping problems, appetite problems, and depression. In AD, up to 97% exhibit one or more NPS.
Emerging evidence from preclinical and clinical studies suggests that ECS is both a contributor to and a potential therapeutic target for managing NPS. This review explores ECS’s role in NPS and its therapeutic implications.”
“ECS is essential for regulating a range of behaviors and undergoes notable changes during the progression of AD, particularly through modulation of the CB1R and CB2Rs and their endocannabinoids. Further placebo-controlled, randomized clinical trials are needed to confirm the efficacy of cannabinoid receptor-targeting therapies in managing NPS in AD.”
“Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of toxic protein aggregates in the brain, leading to brain cell death and cognitive impairment. Central to AD pathogenesis is the autophagy pathway, a crucial cellular self-digestion process.
Cannabinoids, the fundamental phytochemical compounds derived from the Cannabis sativa plant, have been demonstrated to exhibit neuroprotective qualities when used as a treatment at microdoses.
However, the impact of multi-cannabinoid treatments on autophagy induction and subsequent cell survival in AD in vitro models remains uncertain. This review seeks to explore the potential of a multi-cannabinoid treatment strategy in enhancing neuronal cell survival through autophagy activation within an AD in vitro model.
The proposed approach involves a combination of cannabinoids in their potential to upregulate autophagy mechanisms, potentially supporting neuronal cell resilience. By unravelling the mechanistic link between autophagy, cannabinoid treatment, and neuronal viability, this review aims to elucidate how cannabinoids influence neuronal function and survival at a cellular and molecular level. By offering insights into the exploitation of the endocannabinoid system, this review contributes to the development of novel cannabinoid-based treatment avenues for AD. This pursuit aligns with the broader objective of addressing the debilitating effects of AD on the quality of life for those affected.”
“Emerging evidence, including a recent case report, suggests that cannabinoid microdosing may offer a potential strategy for reducing AD-related symptoms while minimizing adverse effects.”
“Pharmacokinetic data further indicate that multi-cannabinoid formulations, particularly those combining THC and CBD, add additional minor cannabinoids, may provide enhanced therapeutic efficacy and improved safety profiles compared to monotherapy.”
“Background/Objectives: Wound-related pain is a common, yet inadequately managed condition, and new therapeutic strategies are warranted. Limited data suggests that phytocannabinoids and cannabis may alleviate wound-related pain; however, further studies are required. This study investigated the effects of systemic administration of cannabidiol (CBD) on nociceptive behaviour following dorsum incision and on the endocannabinoid system.
Methods: Male Sprague-Dawley rats (150-200 g on arrival, n = 9/group) underwent a 1.2 cm incision on the hairy skin of the dorsum or sham procedure. Back and hind paw mechanical withdrawal thresholds were assessed at baseline and post-surgery/sham days (PSDs) 1, 4, 7, and 8 using manual and electronic von Frey tests, respectively. On PSD 8, the effect of a single acute administration of CBD (3, 10, or 30 mg/kg, i.p.) on mechanical hypersensitivity in the dorsum and hind paws was assessed. The levels of endocannabinoids and N-acylethanolamines in the plasma and discrete brain regions following CBD administration were analysed.
Results: Robust mechanical hypersensitivity was evident in the dorsum and hind paws following the incision. CBD (3 mg/kg) partially attenuated primary mechanical hypersensitivity in the dorsum, in a site- and dose-specific manner. CBD had no effect on secondary mechanical hypersensitivity. CBD did not alter the levels of endocannabinoids or N-acylethanolamines, but in rats that received CBD (3 mg/kg), levels of 2-AG were lower in the contralateral amygdala and levels of AEA were higher in the contralateral lumbar spinal cord, compared to the ipsilateral sides.
Conclusions: These data provide evidence for antinociceptive effects of CBD in a model of incisional wound-related pain. Further research on CBD’s mechanism(s) of action is warranted. The potential antinociceptive effects of other phytocannabinoids in this model should also be investigated.”
“Cannabidiol (CBD) is a phytocannabinoid found in Cannabis sativa L.”
“These results indicate dose- and site-specific antinociceptive effects of CBD in a rat model of incisional wound-related pain, providing preclinical evidence to support the contention that CBD may have therapeutic potential for alleviating incisional wound-related pain.”
“These results also indicate that investigation of the potential antinociceptive effects of other phytocannabinoids in this model of incisional wound-related pain is warranted.”
“An age-related decline in endocannabinoid system (ECS) activity may contribute to conditions such as chronic pain and Alzheimer’s disease. Although cannabis is increasingly used by older adults to alleviate age-related conditions, it remains unclear how cannabinoids affect ECS activity across the lifespan.
The present study assayed levels of seven endocannabinoids (AEA, 2-AG, DEA, LEA, PEA, SEA, and OEA) in a sample of adults (N = 142; younger 21-24 years, n = 38; midlife 25-54, n = 73; older 55-71, n = 31) assayed before cannabis use (baseline [pre-use]) and ~ 1 h after flower or ~ 2 h after edible cannabis use.
At baseline, older adults exhibited lower AEA and DEA than younger adults, and lower LEA than midlife adults.
Acute cannabis use increased AEA, DEA, LEA, PEA, SEA, and OEA across all age groups (all p < .001). 2-AG showed no increase. For AEA and DEA, increases were larger in older adults (Time×Age).
These findings indicate broad endocannabinoid elevations after cannabis use regardless of age, alongside age-related differences at baseline and in acute responses.”
“Hepatocellular carcinoma (HCC) is the main type of liver cancer and one of the malignancies with the highest mortality rates worldwide. HCC is associated with diverse etiological factors including alcohol use, viral infections, fatty liver disease, and liver cirrhosis (a major risk factor for HCC). Unfortunately, many patients are diagnosed at advanced stages of the disease and receive palliative treatment only. Therefore, early markers of HCC and novel therapeutic approaches are urgently needed.
The endocannabinoid system is involved in various physiological processes such as motor coordination, emotional control, learning and memory, neuronal development, antinociception, and immunological processes. Interestingly, endocannabinoids modulate signaling pathways involved in cell survival, proliferation, apoptosis, autophagy, and immune response.
Consistently, several cannabinoids have demonstrated potential antitumor properties in experimental models.
The participation of metabotropic and ionotropic cannabinoid receptors in the biological effects of cannabinoids has been extensively described. In addition, cannabinoids interact with other targets, including several ion channels. Notably, several ion channels targeted by cannabinoids are involved in inflammation, proliferation, and apoptosis in liver diseases, including HCC.
In this literature review, we describe and discuss both the endocannabinoid system and exogenous phytocannabinoids, such as cannabidiol and Δ9-tetrahydrocannabinol, along with their canonical receptors, as well as the cannabidiol-targeted ion channels and their role in liver cancer and its preceding liver diseases. The cannabidiol-ion channel association is an extraordinary opportunity in liver cancer prevention and therapy, with potential implications for several environments that are for the benefit of cancer patients, including sociocultural, public health, and economic systems.”
“The endocannabinoid system (ECS) plays a crucial role in the development and functioning of several biological systems. Classically, the endocannabinoid system comprises receptors, endogenous ligands, and enzymes that synthesize, transport, and degrade such ligands. ECS regulates many biological processes, both in normal conditions like brain function, neurotransmitter release, sleep regulation, appetite, movement, and coordination, as well as pathological states such as neurodegenerative disorders, headaches, chronic pain, anxiety, depression, and cancer, among others.
Accordingly, pharmacological modulation of the endocannabinoid system may be a potential target for preventing disease progression or enhancing symptom relief in multiple conditions, including cancer “
“Dysregulation of voltage-gated sodium channels causes the development of several diseases. CBD is a non-selective Nav1.1–1.7 sodium channel inhibitor and is effective in the treatment of epilepsy.”
“Exploiting the cannabidiol-ion channel-transporters association represents an extraordinary opportunity for liver cancer prevention and therapy, which may help to reduce the high mortality from this malignancy and to involve sociocultural, public health, regulatory, and economic systems.”
“Taken together, preclinical, epidemiological, and clinical data converge to support CBD as a promising candidate for the prevention and management of liver diseases and HCC, with potential implications for sociocultural, public health, and economic systems.”
“Chronic musculoskeletal pain (CMP) is a pervasive condition that can impair daily functioning and quality of life. Traditional pharmaceutical therapies, including non-steroidal anti-inflammatory drugs, gabapentinoids, and opioids, often yield suboptimal results and carry notable risks, such as adverse side effects and dependence.
Increasing interest has turned toward medical cannabis, particularly combined formulations of cannabidiol (CBD) and tetrahydrocannabinol (THC), as a potential alternative or complement to current pain management strategies.
Evidence suggests that cannabinoids interact with the endocannabinoid system to modulate nociception and inflammation, offering meaningful pain relief and possibly reducing opioid requirements.
However, heterogeneity in study designs, product formulations, and regulatory frameworks presents challenges in drawing definitive conclusions. Additionally, while most adverse effects, such as fatigue, dizziness, and mild cognitive changes, are generally reported as tolerable, concerns remain about long-term safety and standardization of dosing.
Taken together, the existing literature points to a promising role for medical cannabis in CMP management, underscoring the need for further high-quality research to establish best practices, clarify patient selection, and guide clinicians in safe and effective cannabinoid therapy.”
“This scoping review highlights the potential role of medical cannabis in managing musculoskeletal pain. Evidence suggests it may reduce pain, enhance well-being, and improve quality of life, particularly as an alternative or adjunct to opioids. Adverse effects are typically mild, supporting its use as a safer long-term option. However, data on long-term efficacy, especially for CBD, remain limited.
Given the risks of opioid dependence, cannabis offers a promising therapeutic alternative.”
“Migraine is a disabling neurovascular disorder with limited therapeutic options, especially for patients unresponsive to current treatments targeting calcitonin gene-related peptide (CGRP) signaling.
The endocannabinoid system (ECS) has emerged as a promising alternative for migraine modulation, offering analgesic, anti-inflammatory, and neuroimmune-regulatory effects through its main ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their degrading enzymes.
This review provides an updated map of endocannabinoid components in central and peripheral migraine-relevant regions, highlighting their spatial distribution and functional regulation in animal models.
We summarize the available preclinical evidence supporting the anti-nociceptive effects of endocannabinoid-degrading enzyme inhibitors and cannabinoid receptor agonists/antagonists, with particular emphasis on the therapeutic potential of multi-target compounds. Moreover, we explore non-canonical ECS pathways, including TRPV1, D2 dopamine receptors, serotonergic and ion channel interactions, and their roles in modulating CGRP release and trigeminovascular signaling to treat migraine pathophysiology.
Finally, we propose two sleep-related directions for treatments involving ECS modulation of circadian rhythms and glymphatic clearance. Although human translational data are limited, the ECS offers a multifaceted framework for developing next-generation therapeutics targeting migraine pathophysiology.”
“As alternative treatments, instead of using highly addictive painkillers, such as opioids, there is a great need for alternative, effective and safe medications. Despite potential negative psychoactive side effects and potential medication-overuse headache risk, medical marijuana has been shown to decrease the frequency of migraine headaches, suggesting a perspective for cannabinoids in treating migraine. The use of cannabis to relieve pain dates to ancient civilizations.
Cannabis has been used for millennia in ayurvedic medicine for the management of pain, nausea, and anxiety, as well as to promote appetite and sleep.
The cannabis plant has complex natural compounds, including, in addition to the generally safe cannabidiol (CBD), the psychotropic delta9-tetrahydrocannabinol (THC), and dozens of poorly characterized components. Recent studies have pointed to the therapeutic potential of a combination of CBD and THC in preclinical migraine models and in a clinical trial. These CBD and THC findings point to the importance of targeting the body’s endocannabinoid system (ECS). Thus, the stage is set for testing the enhancement of ECS signaling pathways that might provide analgesia with minimal adverse effects.”
“Current evidence shows that the ECS is embedded in multiple migraine-relevant pathways areas across the CNS and PNS. Preclinical studies demonstrate that enhancing endocannabinoid tone via inhibition of endocannabinoid-degrading hydrolases reduces migraine-like pain and neuroinflammation. Beyond these analgesic strategies, targeting cannabinoid receptors, modulating their activity, and influencing their modulation of circadian regulation and glymphatic clearance further highlight the therapeutic potential of engaging the ECS.”
“The high metastatic potential of melanoma and its poor prognosis in advanced stages motivate the search for innovative therapeutic approaches. Therefore, this study aimed to assess the effects of phytocannabinoids (cannabidiol-CBD, and cannabigerol-CBG) on the structure and function of the melanoma cell membrane, phospholipid metabolism, and the respective metabolites generated in ROS- and enzyme-dependent reactions.
Biochemical and physicochemical parameters were analyzed in melanoma cells (SK-MEL-5) cultured for 24 h with CBD (5 µM), CBG (1 µM), and their combination applied either alone or after UVA irradiation (365 nm) at a dose of 18 J/cm².
Phytocannabinoids have been shown to partially counteract changes in the levels of cell membrane components, including phospholipid polyunsaturated fatty acids (PUFAs) and sialic acid, consequently affecting surface charge density and lipid rafts, which may be a potential target for anticancer therapy. Furthermore, by changing the activity of lipolytic enzymes (PLA2/COX1/2/LOX-5), phytocannabinoids partially enhanced the UVA-induced decrease in free PUFAs. Consequently, the levels of lipid mediators, including endocannabinoids and eicosanoids, were altered.
The use of phytocannabinoids led to a significant increase in 2-AG levels, while the combined action of CBD/CBG reduced the levels of pro-inflammatory eicosanoids. UVA radiation increased the expression of G-protein-coupled receptors in melanoma cells (CB1/2/TRPV1/PPARγ), while the combined use of CBD/CBG reduced their expression.
Therefore, the results have shown that CBD and CBG modulate the metabolism of phospholipids and PUFAs by altering the functions of melanoma cell membranes, potentially offering options for the use of these phytocannabinoids in the integrative biomedicine treatment of melanoma.”
“In summary, the results of this study indicate that phytocannabinoids (CBD and/or CBG) alter the functionality of melanoma cell membranes by modeling the structure and metabolism of phospholipids and free PUFAs, which may offer potential benefits in integrated melanoma therapy.”
“Autophagy is a well-preserved biological mechanism that is essential for sustaining homeostasis by degradation and recycling damaged organelles, misfolded proteins, and other cytoplasmic detritus.
Cannabinoid signaling has emerged as a prospective regulator of diverse cellular functions, including immunological modulation, oxidative stress response, apoptosis, and autophagy. Dysregulation of autophagy contributes to pathogenesis and treatment resistance of several oral diseases, including oral squamous cell carcinoma (OSCC), periodontitis, and gingival inflammation.
This review delineates the molecular crosstalk between cannabinoid receptor type I (CB1) and type II (CB2) activation and autophagic pathways across oral tissues. Cannabinoids, including cannabidiol (CBD) and tetrahydrocannabinol (THC), modulate key regulators like mTOR, AMPK, and Beclin-1, thereby influencing autophagic flux, inflammation, and apoptosis.
Experimental studies indicate that cannabinoids inhibit the PI3K/AKT/mTOR pathway, promote reactive oxygen species (ROS)-induced autophagy, and modulate cytokine secretion, mechanisms that underline their dual anti-inflammatory and anti-cancer capabilities. In addition, cannabinoid-induced autophagy has been shown to enhance stem cell survival and differentiation, offering promise for dental pulp regeneration. Despite these promising prospects, several challenges remain, including receptor selectivity, dose-dependent variability, limited oral bioavailability, and ongoing regulatory constraints.
A deeper understanding of the context-dependent regulation of autophagy by cannabinoid signaling could pave the way for innovative therapeutic interventions in dentistry. Tailored cannabinoid-based formulations, engineered for receptor specificity, tissue selectivity, and optimized delivery, hold significant potential to revolutionize oral healthcare by modulating autophagy-related molecular pathways involved in disease resolution and tissue regeneration.”
“Cannabinoids are a diverse class of bioactive lipophilic compounds derived from Cannabis sativa and other plant species, as well as synthesized endogenously and pharmacologically, and have attracted significant attention for their immunomodulatory, anti-inflammatory, antioxidant, and anticancer effects.”
“Cannabinoid-based treatments show promise for managing oral diseases by controlling inflammation and promoting tissue regeneration through specific pathways.”
“Introduction: Cannabis has been decriminalized by many states and shows promise in treating both neuropathic and non-neuropathic pain through its interaction with the endocannabinoid system and anti-inflammatory effects. This study examines differences in cannabis use for adults whose most bothersome chronic pain condition is neuropathic vs. non-neuropathic.
Materials and methods: Survey data were collected from adults receiving care at a pain clinic. Participants completed demographic questions and standardized self-report measures (PROMIS Pain Intensity/Interference and the ID-Pain tool). Participants’ most bothersome pain condition(s) were categorized as neuropathic or non-neuropathic pain based on ID-Pain scores. Linear regression models assessed differences in frequency and duration of cannabis product use between groups, adjusting for age and sex.
Results: A total of 113 individuals were recruited; following exclusions and missing data, 104 participants (61.5% female) were included in the final analysis. Of these, 36.5% reported neuropathic pain as their most bothersome, and 63.5% reported non-neuropathic pain. Those with neuropathic pain reported significantly more days per month of Tetrahydrocannabinol/Cannabidiol (THC/CBD) combination (b = 5.96, p = 0.02), Cannabidiol-only (CBD-only) (b = 8.82, p = 0.03), and Tetrahydrocannabinol-only (THC-only) products (b = 7.04, p = 0.02). They also used THC-only (b = 0.97, p < 0.05) and THC/CBD (b = 1.09, p < 0.01) products more frequently per day. Neuropathic pain was positively associated with pain intensity (b = 4.10, p < 0.001) and interference (b = 4.95, p < 0.001).
Discussion: Adults whose most bothersome pain condition(s) were neuropathic used cannabis, especially THC and THC/CBD combination products, more frequently than those whose most bothersome pain was non-neuropathic. Participants with neuropathic pain also reported higher levels of pain intensity and interference. Further longitudinal research is needed to confirm whether increased use of THC-rich cannabis provides symptom relief for adults with neuropathic pain.”
“Cannabis interacts with the endocannabinoid system, making it a potential treatment for neuropathic pain.”
“Because previous studies found THC products to be more effective in managing neuropathic pain by interacting with the endocannabinoid system, it is possible that our participants also experienced benefit; this could explain their higher use of THC containing products.
