“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.
“β-caryophyllene, a bicyclic sesquiterpene widely abundant in various plant essential oils, has garnered growing attention for its potential biological effects and therapeutic benefits in liver diseases. This review systematically evaluates preclinical evidence on the pharmacological properties of BCP with emphasis on its hepatoprotective effects primarily through its anti-inflammatory, antioxidant, antifibrotic, and immunomodulatory actions.
BCP is classified as a dietary cannabinoid due to its ability to activate cannabinoid type 2 receptors in the endocannabinoid system and thereby influence key cellular signaling pathways involved in lipid metabolism and tissue remodeling. Emerging studies also highlight BCP interaction with PPAR nuclear receptor and AMPK signaling, further corroborating its role in regulating lipid homeostasis.
In the present review, we compile, summarize, and critically analyze findings from in vitro and in vivo studies on nonalcoholic fatty liver disease, recently termed as metabolic dysfunction-associated fatty liver disease (MAFLD), alcoholic liver disease, and liver fibrosis, highlighting the pharmacological and molecular mechanisms underlying therapeutic effects. These studies consistently demonstrate a reduction in hepatic steatosis, collagen deposition, and hepatocellular markers reflecting a broad spectrum of hepatoprotective effects.
Taken together, the pharmacological properties and mechanistic insights place BCP as a promising natural compound with nutraceutical, phytopharmaceutical, or dietary supplement applications for liver diseases. Despite the robust preclinical evidence, clinical validation remains scarce. Therefore, regulatory toxicology and efficacy studies are needed to establish the therapeutic potential of BCP in liver diseases and its integration as a nutraceutical or phytopharmaceutical in the clinical usage.”
“BCP is one of the important constituents in Cannabis with an abundance of 35%. In addition to its presence in Cannabis, BCP is largely present in numerous edible plants.”
“In conclusion, BCP represents a promising therapeutic avenue for managing liver diseases due to its ability to modulate multiple interrelated molecular and cellular pathways.”
“With continued research, BCP has the potential to evolve from a natural product with hepatoprotective properties to an effective adjunct or alternative in liver disease therapy, offering new hope for patients and advancing the field of liver health management.”
“Neurological disorders such as epilepsy, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis present significant global health care challenges, with complex pathophysiology and limited therapeutic options that often carry substantial side effects.
Hemp-derived compounds, particularly from Cannabis sativa seeds, leaves, and flowers, have gained attention for their potential neuroprotective properties.
This review aims to synthesize the current evidence surrounding the therapeutic benefits of hemp-derived compounds, focusing on their bioactive phytochemical profiles, mechanisms of action, and therapeutic efficacy in treating neurological disorders.
A comprehensive review of pre-clinical and clinical studies was conducted, analyzing the phytochemical composition of hemp extracts, including cannabinoids (such as cannabidiol, CBD), terpenes, flavonoids, and polyunsaturated fatty acids. We explored their mechanisms of action through interactions with the endocannabinoid system, neurotransmitter receptors, inflammatory pathways, and oxidative stress mechanisms.
The review highlights the therapeutic potential of hemp-derived extracts in mitigating various neurological conditions. Pre-clinical and clinical studies have demonstrated their efficacy in reducing seizure frequency in epilepsy, protecting dopaminergic neurons in Parkinson’s disease, alleviating neuroinflammation and oxidative stress in Alzheimer’s disease, and promoting remyelination in multiple sclerosis.
The entourage effect, where cannabinoids, terpenes, and flavonoids work synergistically, enhances these therapeutic effects. Innovations in extraction technologies have optimized yield and preserved bioactivity, further enhancing clinical relevance.
Hemp-derived compounds exhibit significant neuroprotective and therapeutic potential for managing neurological disorders. However, challenges such as product standardization, safety profiles, and regulatory frameworks must be addressed for clinical translation. Further research is essential to optimize dosing, establish safety parameters, and develop standardized formulations, which will be crucial for fully harnessing the therapeutic potential of hemp-derived products in treating neurological conditions.”
“Despite expanding acceptance of cannabis for medicinal use, empirical literature remains sparse regarding the long-term mental and neurobiological outcomes of continuous cannabis exposure over several decades. This self-case study examines the psychobiological trajectory of a biomolecular psychologist who has used cannabis intermittently since the 1970s and therapeutically since 2010 to manage polypharmacy withdrawal, opioid dependence, and psychiatric symptoms. The analysis integrates self-observational data, neurocognitive assessments, pharmacological history, and psychosocial context to evaluate outcomes on affect regulation, cognitive performance, neuroplasticity, and motivation. The case challenges persistent assumptions of irreversible cannabis-induced cognitive decline and supports the hypothesis that sustained cannabinoid modulation may promote neural resilience when employed within a biomolecularly informed framework. Findings are illustrative and intended to generate testable hypotheses rather than establish causality.”
“For more than half a century, the United States has maintained one of the most comprehensive prohibitions on biological cannabinoid research in modern science. The enactment of the Controlled Substances Act in 1970 effectively silenced the empirical study of the plant Cannabis sativa and its naturally occurring cannabinoids, leaving a void in scientific understanding that has persisted for decades. The policy was founded less on biomedical evidence than on sociopolitical ideology—a moral model of addiction that conflated psychoactivity with deviance. By classifying naturally occurring cannabinoids as Schedule I substances, federal policy positioned them alongside heroin and LSD, asserting “no accepted medical use and a high potential for abuse”. Consequently, generations of scientists were restricted from exploring naturally occurring cannabinoids’ molecular, neurobiological, and psychopharmacological functions.”
“While modern prohibition sought to erase the plant’s legitimacy, cannabis itself represents a biological constant—molecules with 12,500 years of medicinal use, abruptly vilified in the modern era. Archaeological and historical records confirm its continuous application in treating pain, inflammation, convulsions, and psychological distress throughout diverse civilizations. Across that immense timeline, humans relied on the plant’s phytochemical complexity—its cannabinoids, terpenes, and flavonoids—to modulate physiological systems long before those systems were scientifically named.”
“The endocannabinoid system (ECS), now recognized as one of the body’s principal homeostatic regulators, mediates neural, immune, and endocrine balance. Yet its formal discovery in the 1990s came paradoxically after half a century of federally enforced ignorance.”
“From a biomolecular perspective, cannabinoids act not as foreign intruders but as complementary ligands within a preexisting molecular conversation between the human body and its endogenous signaling systems. Their therapeutic potential lies not in chemical novelty but in biological familiarity—a fact consistently reaffirmed by modern neurobiological research despite legal obstruction.”
“This five-decade longitudinal case study provides a rare and informative window into the long-term psychobiological effects of sustained botanic cannabinoid use within a cognitively demanding professional context. Contrary to prohibition-era narratives that associate chronic cannabis exposure with cognitive decline, emotional dysregulation and motivational impairment, the findings of this investigation demonstrate a trajectory of preserved neurocognitive integrity, stabilized affective functioning, and enhanced adaptive resilience. These outcomes are consistent with contemporary psychoneuroimmunological models in which the endocannabinoid system operates as a central regulator of homeostatic equilibrium across neural, immune, and endocrine domains.”
