Therapeutic potential of acidic cannabinoids: an update

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“Cannabis sativa yields a wide range of bioactive compounds, including terpenes, flavonoids, and cannabinoids.

Tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and cannabichromenic acid (CBCA) are the acidic biosynthetic precursors of the neutral cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which have been the subject of much research.

This review examines the biosynthesis, decarboxylation, molecular pharmacology, and therapeutic significance of acidic cannabinoids, intending to address a significant knowledge gap. Peer-reviewed literature from major scientific databases was used in a systematic narrative review with an emphasis on investigations of acidic cannabinoid chemistry, pharmacology, pharmacokinetics, and disease-specific applications.

According to the reviewed data, acidic cannabinoids exhibit unique biological activities that distinguish them from their neutral counterparts. These include neuroprotective, anti-inflammatory, anticonvulsant, and anti-proliferative actions, which are mediated by molecular targets such as serotonin 5-HT1A receptors, cyclooxygenase-2 (COX-2), transient receptor potential (TRP) channels, and peroxisome proliferator-activated receptor-γ (PPARγ).

Acidic cannabinoids are more appealing for therapeutic usage in children and the elderly, considering that they are not intoxicating like THC; however, this distinction applies primarily to non‑heated consumption. Chemical instability, low bioavailability, and a dearth of controlled human trials impede clinical translation despite their potential.

According to the findings, acidic cannabinoids are an underutilized yet potentially valuable class of precision medicines.

In this study, we outline existing understanding on acidic cannabinoids, discuss their production and transformation, and identify research needs that could influence cannabis science research.”

https://pubmed.ncbi.nlm.nih.gov/41545891

https://link.springer.com/article/10.1186/s42238-026-00387-y

“Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis”

https://pmc.ncbi.nlm.nih.gov/articles/PMC7409346


The differential effects of CBD and CBDA on viability and mRNA expression in colorectal cancer cells

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“Background: Cannabinoids have attracted significant attention for their potential therapeutic application in cancer research. However, recent studies have reported antitumor activity of cannabidiolic acid (CBDA)-the acidic precursor of CBD-in breast cancer cells, involving modulation of cyclooxygenase signaling. To our knowledge, no investigations have examined the effects of CBDA on RNA expression and signaling pathways in colorectal cancer (CRC) cells. Therefore, we aimed to investigate the effects of CBD, CBDA, and a CBDA-rich Cannabis sativa (C.s). extract on the growth and gene expression in CRC cell lines.

Methods: We assessed cell viability and clonogenic growth of the CRC cell lines HCT116 and DLD1 following treatment with pure CBD, pure CBDA, a CBDA-rich C.s. extract (CBDA/CBD ratio 20:1), and a corresponding mixture of pure CBDA/CBD. RNA sequencing was performed to analyze differentially expressed genes (DEGs) and the cell signaling pathways affected by these treatments.

Results: Of all tested compounds, CBD exhibited the strongest cytotoxic effect in both cell lines, whereas CBDA demonstrated minimal toxicity, particularly in HCT116 cells. Furthermore, we observed a greater inhibitory effect of the CBDA-rich C.s. extract on HCT116 cell growth compared to the CBDA/CBD mixture. RNA sequencing analysis revealed that CBD had the most pronounced impact on gene expression, while CBDA had the least. Notably, treatment with the C.s. extract resulted in a higher number of DEGs than the CBDA/CBD mixture in HCT116. Gene expression analysis indicated an upregulation of the Wnt and Hippo signaling pathways following CBD treatment. Additionally, CBDA, CBD/CBDA (1:20), and the C.s. extract primarily induced metabolic processes in DLD1 cells, suggesting a distinct metabolic response.

Conclusion: Our findings showed that CBD exerts stronger effects on cell survival and gene expression in CRC cells than CBDA, which showed only limited activity. Moreover, the CBDA-rich C.s. extract exhibited greater efficacy than the CBDA/CBD mixture. More research is needed to further elucidate the impact of cannabinoids on CRC cell biology and signaling pathways.”

https://pubmed.ncbi.nlm.nih.gov/41546069

https://link.springer.com/article/10.1186/s42238-026-00391-2

The Exploration of Cannabis Beverage Substitution for Alcohol: A Novel Harm Reduction Strategy

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“Alcohol consumption is associated with nearly 200 health conditions. As cannabis-infused beverages emerge in the legal market, their potential as a substitute for alcohol is of growing interest.

This study investigates whether cannabis beverages may reduce alcohol use.

A total of 438 anonymous adults who used cannabis in the past year completed a survey including cannabis use and alcohol consumption items from the Behavioral Risk Factor Surveillance System (BRFSS). Chi-square and t-tests compared alcohol use between cannabis beverage users and non-users, and before vs. after cannabis beverage initiation.About one-third (33.6%) of respondents used cannabis beverages, typically consuming one per session.

Users were more likely to report substituting cannabis for alcohol (58.6%) than non-users (47.2%). They also reported fewer weekly alcoholic drinks after starting cannabis beverages (M = 3.35) compared to before (M = 7.02), and binge drank less frequently (80.7% reported less than monthly or never, vs. 47.2% before). Those who cited reducing other substance use were more likely to use cannabis beverages (45.8%).

Findings suggest cannabis beverages may support alcohol substitution and reduce alcohol-related harms, offering a promising alternative for individuals seeking to lower alcohol intake.”

https://pubmed.ncbi.nlm.nih.gov/41533430

https://www.tandfonline.com/doi/full/10.1080/02791072.2026.2614506

Cannabidiol Inhibits Melanoma Progression by Regulating PPARγ-TET1 Complex-dependent LRASM1 Demethylation

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“Melanoma represents one of the most aggressive forms of skin cancers, with advanced metastatic stages largely managed through chemotherapy. However, current therapeutic strategies remain limited by drug resistance and systemic toxicity. Cannabidiol (CBD), the primary nonpsychoactive constituent of Cannabis sativa, has recently attracted attention for its anticancer properties across multiple tumor types.

OBJECTIVES

This study aimed to explore the antitumor efficacy of CBD in melanoma and elucidate its underlying molecular mechanisms, with the goal of identifying novel therapeutic strategies to overcome resistance and reduce adverse effects associated with conventional treatments.

METHODS

The antiproliferative and pro-apoptotic effects of CBD were assessed in vitro using MTS, EdU, Transwell invasion, and flow cytometry. In vivo efficacy was evaluated using a murine lung metastasis model. Potential CBD targets in melanoma were identified through network pharmacology and molecular docking, with a focus on peroxisome proliferator-activated receptor γ (PPARγ) and validation by western blotting and immunofluorescence. Integrated transcriptomic and genome-wide methylation analyses were performed to investigate epigenetic modifications induced by CBD. Co-immunoprecipitation and chromatin immunoprecipitation assays were employed to detect the interaction between PPARγ and ten-eleven translocation 1 (TET1), including their binding to promoter regions of downstream factors. Methylation-regulated target genes were further validated using qPCR and MeDIP PCR.

RESULTS

CBD significantly induced apoptosis and inhibited cell proliferation and invasion of melanoma cells in vitro, while reducing pulmonary metastasis in vivo. Pharmacological and molecular docking analyses, supported by protein-level validation, identified PPARγ as a critical mediator of CBD activity. Transcriptomic and methylation analyses revealed that CBD modulated global DNA methylation patterns, partly through the formation of a PPARγ-TET1 complex. This complex regulated the demethylation of leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1), a newly identified anticancer gene whose upregulation markedly enhanced melanoma cell apoptosis and suppressed proliferation.

CONCLUSIONS

CBD exhibited strong antitumor activity in melanoma by modulating the PPARγ–TET1 complex to induce demethylation of LRSAM1, thereby suppressing tumor progression. These findings identify CBD as a promising candidate for melanoma therapy.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711326000127

“In summary, this study investigated molecular targets and mechanisms by which CBD suppresses melanoma progression, emphasizing its role in PPARγ activation and epigenetic regulation. These findings establish a mechanistic basis and provide candidate targets for future clinical application of CBD in melanoma treatment.”

“This study provides the first evidence that CBD inhibits melanoma progression by modulating gene methylation. The identification of LRSAM1 as a PPARγ-TET1-regulated tumor suppressor expands current understanding of epigenetic regulation in melanoma and highlights LRSAM1 as a viable therapeutic target.”

https://www.scilit.com/publications/50c9c0a6d08f7880cebb9c69a2c3fca7

Phytocannabinoids influence phospholipid metabolism of melanoma cells: Modulation of in vitro effects of the UVA irradiation

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“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.”

https://pubmed.ncbi.nlm.nih.gov/41529510

“Phytocannabinoids modulate endocannabinoid levels, supporting antitumor activity.”

“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.”

https://www.sciencedirect.com/science/article/pii/S0753332226000351?via%3Dihub

Evaluation of the antibacterial and antioxidant potential of the endophytic fungus EFY14 from Cannabis sativa L. leaves through metabolomics and molecular docking

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“Endophytic fungi are prolific sources of natural antioxidants and antibacterial agents.

This study aims to isolate and identify the endophytic fungus EFY14 from Cannabis sativa L. leaves and to evaluate the antibacterial and antioxidant activities of its culture filtrates.

Non-targeted metabolomics was employed to chemically profile the EFY14 crude extract, a potential biological targets were predicted through molecular docking and molecular dynamics simulations. EFY14 was taxonomically identified as belonging to the Chaetomium genus.

Its extract contained 20.823 ± 1.449 mg gallic acid equivalent (GAE)/L total phenolic and 0.230 ± 0.007 mg rutin equivalent (RE)/mL total flavonoids, displaying antioxidant and antibacterial activities. Metabolomic profiling identified flavonoids and phenolic compounds, including 4′,7-dihydroxy-8-methylisoflavone, scopoletin, xanthohumol, tricin, sophoraflavanone G, prenyl glucoside, melilotoside and maltol. Molecular docking indicated potential molecular targets for these metabolites.

These findings suggest that EFY14 derived endophytic fungi from C. sativa L. may represent a novel source of antioxidant and antibacterial compounds.”

https://pubmed.ncbi.nlm.nih.gov/41527465

“In this study, a strain named Chaetomium globusum EFY14 was identified from the leaves of the Cannabis genus plants. It was determined to be a new source of antioxidants and antibacterial agents. Additionally, the Cannabidiolic acid component was detected through metabolomics. The extract is rich in phenolic and flavonoid substances and has DPPH scavenging activity as well as inhibitory activity against E.coli, B.subtilis, and S.aureus. The metabolites verified through metabolomics and molecular docking provide promising candidate substances for drug development and agricultural biological control, as well as new methods for cannabinoid synthesis.”

“This research is highly relevant for professionals in the fields of pharmaceuticals, agriculture and natural products. The identification of Chaetomium globusum. EFY14 from the Cannabis genus as a source of phenolic substances, flavonoids (such as xanthohumol, tricin) and antioxidant/antibacterial metabolites provides feasible development leads for new drugs, biological pesticides and natural antioxidants. This strain offers new strains for industrial production of antioxidant and antibacterial substances.”

https://www.tandfonline.com/doi/full/10.1080/14786419.2025.2609961

Cannabidiol reduces oxycodone self-administration while preserving its analgesic efficacy in a rat model of neuropathic pain

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“Prescription opioid misuse is a significant public health concern among individuals with chronic pain. Treating severe pain often requires high doses of opioids, increasing the risk of developing an opioid use disorder.

Cannabidiol (CBD) is a non-intoxicating component of cannabis that has shown therapeutic potential without abuse liability.

This study investigated the effects of CBD on oxycodone self-administration and hyperalgesia in an animal model of chronic neuropathic pain.

Adult male rats were trained to self-administer intravenous oxycodone (0.06 mg/kg/infusion). Subsequently, they underwent chronic constriction injury (CCI) of the sciatic nerve or received sham surgery. Paw withdrawal latency was measured using the Hargreaves test as an indicator of thermal pain sensitivity. CBD (0, 1, 3, and 10 mg/kg, IP) was administered before the self-administration sessions, and pain testing was conducted afterward. The rats acquired oxycodone self-administration, as indicated by more active than inactive lever presses. CCI surgery decreased the paw withdrawal latency, confirming the induction of neuropathic pain. CCI alone did not affect oxycodone self-administration, suggesting that neuropathic pain does not substantially influence opioid intake at the dose tested.

Treatment with CBD reduced oxycodone self-administration in both the sham and CCI rats. Oxycodone self-administration in the CCI rats reversed the CCI-induced decrease in paw withdrawal latency. However, CBD did not affect the antinociceptive effect of oxycodone in CCI rats.

Taken together, these findings demonstrate that CBD reduces oxycodone self-administration without affecting the antinociceptive effects of oxycodone in neuropathic pain.

This study supports the potential of CBD to reduce opioid use and misuse, regardless of pain status.”

https://pubmed.ncbi.nlm.nih.gov/41521216

https://www.nature.com/articles/s41598-025-31828-y

Stability and Degradation-based Proteome Profiling Reveals Cannabidiol as a Promising CDC123-eIF2γ Inhibitor for Colorectal Cancer Therapy

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“Natural products (NPs) have long been foundational in drug discovery, offering unparalleled molecular diversity and complex mechanisms of action. However, identifying molecular targets for NPs remains a significant challenge.

This study introduces stability- and degradation-based proteome profiling (SDPP), which integrates orthogonal principles of thermal stability and degradation activity to enhance target identification precision and expand the NP target landscape, mediating dual regulation of protein stability: extracellularly through small-molecule-binding-induced thermodynamic stabilization and intracellularly via ligand-triggered proteolytic degradation.

Using SDPP, cannabidiol (CBD) is identified as a novel protein-protein interaction (PPI) inhibitor targeting the CDC123-eIF2γ complex, leading to sustained activation of the integrated stress response and apoptosis in colorectal cancer (CRC) cells.

Disruption of the CDC123-eIF2γ complex by CBD offers a selective therapeutic strategy for CRC. Importantly, CDC123 is recognized as an oncogenic driver in CRC, with elevated expression correlating with poor patient prognosis.

These findings establish SDPP as a robust framework for NP target identification and position CBD as a first-in-class natural PPI inhibitor with a promising therapeutic potential.”

https://pubmed.ncbi.nlm.nih.gov/41518300

https://pubs.acs.org/doi/10.1021/jacs.5c20040

Potential Anticancer Effect of Cannabis sativa L. Dichloromethane Extract Through Oxidative Stress-Related Pathways and the Inhibition of the Migration and Invasiveness of Human Breast Cancer Cells (MDA-MB-231 and MCF-7)

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“Breast cancer remains a leading cause of cancer-related morbidity and mortality globally, highlighting the urgent need for novel therapeutic strategies.

This study investigates the molecular mechanisms underlying the anti-proliferative potential of Cannabis sativa dichloromethane extract (C. sativa DCM) on oxidative stress, apoptosis, and invasion in human breast cancer cells.

Key biomarkers, such as antioxidant enzymes (Superoxide Dismutase (SOD) and Glutathione (GSH)), the transcription factor Nrf2, apoptotic proteins (p53, caspase-8 and 9), metalloproteinase (MMP-1 and MMP-9), and Transforming Growth Factor Beta (TGF-β) were examined. Cytotoxicity was assessed using an MTT assay in the MDA-MB-231 and MCF-7 breast cancer cell lines, with comparisons to normal skin fibroblasts (HS27). Oxidative stress biomarkers were quantified using enzymatic assays and ELISA kits, while apoptotic and anti-metastatic factors were determined by Western blotting.

Results demonstrated that C. sativa DCM extract induced significant cell death in a concentration-dependent manner, with IC50 values of 75.46 ± 0.132 μg/mL for MDA-MB-231 and 78.68 ± 0.50 μg/mL for MCF-7 cells. The extract decreased SOD and GSH levels while increasing p53 and caspase activity, confirming apoptosis activation. Additionally, C. sativa DCM inhibited migration and invasion by downregulating MMP-1, MMP-9, and TGF-β. The anti-proliferative potential of C. sativa DCM in breast cancer cells is mediated through a continuous biological pathway involving oxidative stress modulation, apoptotic signaling, and anti-invasive effects. Phytochemical analysis revealed terpenoids and steroids, including compounds like cannabidiol and tetrahydrocannabinol acid.

These findings suggest that C. sativa DCM extract holds potential as an anti-breast cancer therapeutic and warrants further preclinical and clinical investigations.”

https://pubmed.ncbi.nlm.nih.gov/41516029

“Cannabis sativa L., known in many slang languages as marijuana, bhang, ganja, for instance, is an herbaceous species originating from Central Asia and widely distributed around the world. It has been used as a source of fiber, food, oil, and for its multiple curative properties, including anti-parasitic, antipyretic, antibacterial, antitumor, vermifuge, dermatic, and pain-killing properties for centuries. Phytocannabinoids, derived from cannabis, have shown anti-cancer activity in cell lines”

“Based on these research findings, we concluded that C. sativa DCM extract possesses the potential to inhibit the proliferation of breast cancer cells (MCF-7 and MDA-MB-231), while exhibiting minimal cytotoxic effect on normal skin cells Hs27.”

“Given these conclusive findings, the presence of bioactive phytochemicals in C. sativa DCM can be considered as a potential source of anti-cancer agents.”

https://www.mdpi.com/1422-0067/27/1/152


Cannabinoid Signaling and Autophagy in Oral Disease: Molecular Mechanisms and Therapeutic Implications

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“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.”

https://pubmed.ncbi.nlm.nih.gov/41516397

“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.”

https://www.mdpi.com/1422-0067/27/1/525