The potential role of cannabidiol (CBD) in lung cancer therapy: a systematic review of preclinical and clinical evidence

Abstract

Background

Lung cancer is one of the most prevalent and lethal cancers worldwide, with limited therapeutic options in advanced stages. Cannabinoids have recently attracted attention as potential anticancer agents; however, cannabidiol (CBD), a non-psychoactive compound derived from Cannabis sativa, has emerged as the most promising candidate. Unlike Δ9-tetrahydrocannabinol (THC), CBD lacks psychoactive properties, is generally well tolerated, and demonstrates a favorable safety profile. Moreover, CBD influences multiple cancer-relevant pathways—including apoptosis, epithelial-to-mesenchymal transition (EMT), and immune modulation—that are particularly relevant to non-small cell lung cancer (NSCLC). These features provide a strong rationale for focusing on CBD in lung cancer therapy.

Methods

A systematic search was conducted in PubMed, Scopus, Web of Science, and Google Scholar, using defined keywords such as “CBD,” “lung cancer,” and “non-small cell lung cancer.” Studies from 2007 to 2025 were screened following PRISMA guidelines, and 19 studies met the inclusion criteria.

Results

Nineteen studies met the inclusion criteria, comprising 13 in vitro studies, 4 in vivo animal studies, and 2 clinical reports. Across these studies, CBD was administered at concentrations ranging from low micromolar levels (1–10 µM) in cell-based experiments to oral doses of 200–600 mg/day in human cases. Mechanistically, CBD induced apoptosis through pathways such as PPAR-γ activation, mitochondrial dysfunction, and oxidative stress. It inhibited epithelial-to-mesenchymal transition (EMT), downregulated invasive markers, and modulated the tumor microenvironment by enhancing CD8 + T cell and NK cell activity. Furthermore, CBD showed synergistic effects with conventional therapies (e.g., cisplatin, radiotherapy) by increasing drug uptake and overcoming resistance.

Conclusions

CBD holds promise as an adjunct in lung cancer therapy, addressing key cancer hallmarks such as tumor growth, metastasis, and treatment resistance. While preclinical evidence is robust, clinical trials remain limited. Future research should focus on optimizing dosing regimens, evaluating long-term safety, and validating these findings in large-scale human studies.

Background

Lung cancer remains one of the most prevalent and lethal malignancies worldwide, with a significant global burden. Despite advances in early detection and the development of targeted therapies and immunotherapies, survival rates for patients with advanced disease remain poor [1]. According to the GLOBOCAN 2020 database, lung cancer is the second most commonly diagnosed malignancy worldwide, with an estimated 2.2 million new cases (11.4% of all cancers) and 1.8 million deaths (18.0% of all cancer-related deaths) annually. More recent U.S. data from Cancer Statistics 2024 similarly rank lung cancer as the leading cause of cancer-related mortality, despite gradual improvements in survival due to advances in early detection and therapy [2, 3]. Conventional treatments such as chemotherapy, radiotherapy, and surgery are associated with severe adverse effects, limited long-term efficacy, and frequent resistance in non-small cell lung cancer (NSCLC) [4]. These limitations highlight the urgent need for innovative adjunctive strategies.

Cannabinoids, a diverse group of bioactive compounds derived from Cannabis sativa, have gained increasing attention in oncology research due to their ability to interact with the endocannabinoid system and influence cancer-related pathways. Among more than one hundred identified cannabinoids, cannabidiol (CBD) stands out as the most promising candidate for therapeutic application in cancer. Unlike Δ9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid, CBD is non-intoxicating, has a favorable safety profile, and has been recognized by the World Health Organization as generally well tolerated and non-addictive [5, 6]. These characteristics make CBD more acceptable for potential clinical use compared with other cannabinoids.

Beyond lung cancer, CBD has demonstrated antitumor effects across several malignancies, including breast, glioblastoma, pancreatic, colorectal, and prostate cancers, as well as hematological malignancies. In these models, CBD suppresses proliferation, induces apoptosis and autophagy, inhibits angiogenesis, and interferes with metastatic signaling cascades [7, 8]. These pleiotropic effects suggest that CBD may represent a multi-target therapeutic agent capable of addressing diverse oncogenic pathways.

Mechanistically, CBD exerts its anticancer effects through mitochondrial dysfunction, activation of PPAR-γ, inhibition of epithelial-to-mesenchymal transition (EMT), and modulation of the tumor immune microenvironment [9–11]. Furthermore, synergistic interactions with standard therapies—such as sensitization to chemotherapy or radiotherapy—underscore its translational potential [5, 12, 13].

Despite this compelling preclinical evidence, clinical translation remains limited. Reports of tumor regression following self-administration of CBD oil and small trials on symptom management (e.g., chemotherapy-induced nausea and vomiting) provide intriguing signals, but robust randomized controlled trials in oncology are still lacking [14, 15].

Importantly, regulatory and legal considerations also complicate the clinical development of CBD. The U.S. Food and Drug Administration (FDA) has only approved a purified CBD formulation [16]. Similarly, in the European Union, CBD is classified as a “novel food,” and multiple regulatory bodies continue to evaluate its safety profile, particularly concerning hepatic effects and drug–drug interactions [17]. These uncertainties underscore the necessity of rigorous safety evaluations alongside efficacy trials.

Taken together, the preclinical breadth of CBD’s anticancer activity, its potential synergy with conventional modalities, and the pressing need for new therapies in NSCLC provide a strong rationale for systematically reviewing its role in lung cancer. This systematic review therefore synthesizes available preclinical and clinical evidence, identifies mechanistic insights, and highlights regulatory and translational challenges that must be addressed before CBD can be responsibly integrated into clinical practice.

Materials and methods

Literature search strategy

A comprehensive literature search was conducted using electronic databases, including PubMed, Google Scholar, Scopus, and Web of Science. The search was limited to studies published between January 2007 and January 2025 to capture the most recent evidence. The search strategy combined Medical Subject Headings (MeSH) and free-text terms. The exact search terms included: (“cannabidiol” OR “CBD”) AND (“lung cancer” OR “non-small cell lung cancer” OR “NSCLC”) AND (“apoptosis” OR “epithelial-to-mesenchymal transition” OR “tumor microenvironment” OR “combination therapy”). Additional keywords such as “mechanisms of CBD,” “CBD chemotherapy,” “CBD radiotherapy,” and “CBD anticancer properties” were also applied. Boolean operators (AND/OR) were tailored to each database to optimize sensitivity and specificity.

Inclusion and exclusion criteria

Studies included in this review were limited to preclinical and clinical research exploring the antitumor effects of CBD in lung cancer. Only peer-reviewed articles published in English were considered. Exclusion criteria included non-original research, case reports, and studies that lacked specific focus on CBD’s effects in lung cancer.

This review was not prospectively registered in PROSPERO, as registration of systematic reviews that include preclinical data was temporarily restricted during our preparation period. A justification statement has now been added here to ensure transparency.

As shown in Fig. 1 (PRISMA flowchart), a total of 691 records were initially identified across electronic databases. After removal of duplicates and ineligible records (n = 406), 285 records were screened. Of these, 174 were excluded based on title/abstract, and 111 full-text reports were sought for retrieval. Eighty-seven reports could not be retrieved, leaving 24 studies assessed for eligibility. Finally, 19 studies met the inclusion criteria and were included in this systematic review.

Fig. 1.

PRISMA flowchart depicting the systematic identification, screening, and inclusion of studies on CBD in lung cancer therapy

Data extraction and quality assessment

To ensure a systematic approach, data from the selected studies were meticulously extracted and organized into the following key parameters: title, year, study type, CBD dose, duration, key findings, mechanisms investigated, pathways/targets, and references.

Screening process

Two independent reviewers (M.E. and M.D.) conducted title/abstract and full-text screening independently. Any discrepancies were resolved through discussion, and when consensus could not be reached, a third senior reviewer was consulted.

Risk of bias assessment

To strengthen methodological rigor, we applied established tools depending on study design.

• Cochrane Risk of Bias 2.0 for randomized clinical trials,

• ROBINS-I for non-randomized clinical studies,

• SYRCLE risk of bias tool for in vivo animal studies, and.

• A tailored laboratory reproducibility checklist for in vitro studies.

A summary of risk of bias assessments has been provided in Supplementary Table 1.

Table 1.

Quality assessment summary of included studies

No.	Study (First author, year)	Study design (as included)	Recommended tool	Overall risk of bias (judgment)	Key concerns/rationale & recommended action
1	Athanasiou A, 2007	In vitro mitochondrial assays	Tailored in-vitro reproducibility checklist	Moderate	In vitro only; typical limitations: limited replicates reported, lack of independent repeats and blinding, generalisability issues. Action: report as mechanistic/preliminary and avoid causal clinical claims.
2	Preet A, 2008	In vitro & in vivo (mouse xenograft)	SYRCLE (in vivo) + tailored in-vitro checklist	Moderate	In vivo component likely lacks explicit randomization/blinding statements; in vitro methods limited. Action: note moderate risk and describe limitations in Results/Discussion.
3	Ramer R, 2010	In vitro & in vivo	SYRCLE + tailored in-vitro checklist	Moderate	Provides mechanistic data and xenograft outcomes but blinding/allocation concealment unclear. Action: report as preclinical evidence with risk caveats.
4	Preet A, 2011	In vitro & in vivo	SYRCLE + tailored in-vitro checklist	Moderate	Animal methods often underreported (randomization/blinding). Action: similar caveats; downgrading translational certainty.
5	Ramer R, 2013	In vitro & in vivo	SYRCLE + tailored in-vitro checklist	Moderate	Some in vivo efficacy reported; risk from unclear blinding/selective reporting. Action: report moderate risk in supplement.
6	Ramer R, 2014	In vitro (endothelial assays)	Tailored in-vitro checklist	Moderate	In vitro endothelial assays informative but limited external validity; small sample/replicate reporting unclear. Action: label as mechanistic.
7	Ravi J, 2016	In vitro & in vivo	SYRCLE + tailored in-vitro checklist	Moderate	In vivo mechanistic claims plausible but reporting of methods incomplete. Action: recommend cautious interpretation.
8	Yasmin-Karim S, 2018	In vitro & in vivo/methods paper	SYRCLE (if animal data)/tailored checklist	Moderate	Methods/development work; risk from heterogeneous reporting. Action: present as preclinical support only.
9	Sulé-Suso J, 2019	Case report (single patient)	CARE checklist (case report)	Critical/High	Single uncontrolled case; high risk of bias/confounding and self-administration. Action: treat as anecdotal; discuss in limitations; do not use to support efficacy claims.
10	Milian L, 2020	In vitro & retrospective patient sample analysis	Tailored in-vitro checklist; ROBINS-I for patient data	Serious	In vitro robust but translational limits; retrospective tissue analysis subject to selection/confounding. Action: downgrading clinical inference; discuss confounding.
11	Hamad H, 2021	In vitro (including cancer stem cells)	Tailored in-vitro checklist	Moderate	In vitro stemness assays useful but often lack independent replication and dose-response clarity. Action: label as preclinical evidence.
12	Liew KL, 2021	Case report/clinical observation	CARE checklist	Critical/High	Single case, prolonged self-administration, uncontrolled — high confounding. Action: report as anecdotal only.
13	Milián L, 2022	In vitro (cancer-associated fibroblasts)	Tailored in-vitro checklist	Moderate	In vitro CAF experiments informative; limitations: generalisability and limited replicates/controls. Action: mechanistic interpretation only.
14	Misri S, 2022	In vitro & (potential) in vivo (cisplatin-resistant models)	SYRCLE (in vivo) + tailored in-vitro checklist	Moderate	Preclinical work on resistant models promising; incomplete reporting on randomization/blinding in vivo. Action: moderate risk; request method details in supplement.
15	Vidlarova M, 2022	In vitro & patient sample prognostic study	ROBINS-I (observational)	Serious	Prognostic observational design with potential confounding and selection bias. Action: interpret associations cautiously; emphasize need for prospective validation.
16	Park Y-J, 2022	In vitro (A549)	Tailored in-vitro checklist	Moderate	Standard cell-line study; limitations include dose selection and in vitro-only context. Action: present as mechanistic.
17	Sarsembayeva A, 2023	In vivo (mouse model)	SYRCLE	Moderate	In vivo immune-context data valuable; often lacking blinding/randomization statements. Action: moderate risk; include method details.
18	Li Y et al., 2024	In vitro (CIK synergy)	Tailored in-vitro checklist	Moderate	Preclinical immune-effector cell synergy experiments; in vitro limits and reproducibility concerns. Action: highlight preliminary nature.
19	Li F et al., 2024	In vitro & in vivo (RNAi screen + in vivo validation)	SYRCLE + tailored in-vitro checklist	Moderate	Screening plus in vivo validation strengthens evidence, but risk remains from incomplete reporting of allocation/blinding. Action: moderate risk; include details in supplement.

Risk of bias was assessed according to study type: in vitro studies using a tailored laboratory reproducibility checklist (replicates, dose–response, independent validation, reporting transparency); animal studies using the SYRCLE risk of bias tool; observational clinical studies using ROBINS-I; randomized clinical trials (if available) using the Cochrane RoB 2.0 tool; and case reports using the CARE checklist. Judgments are expressed as Low, Moderate, Serious, or Critical risk of bias. Two reviewers (M.E. and M.D.) performed assessments independently; discrepancies were resolved by consensus with senior review. Most preclinical studies were rated as Moderate risk due to incomplete reporting of randomization, blinding, or selective reporting. Observational clinical studies were rated Serious risk, and case reports were rated Critical risk, reflecting their uncontrolled nature

Results

A total of 19 studies met the predefined inclusion criteria (Fig. 1). These included 13 in vitro studies, 4 in vivo animal studies, and only 2 clinical/case reports. The PRISMA flow diagram (Fig. 1) illustrates the stepwise process of identification, screening, and eligibility, showing that despite an initially large pool of 691 records, only 19 relevant studies could be included.

Study type distribution As shown in Fig. 2, the evidence base is overwhelmingly preclinical, with in vitro studies representing nearly 70% of the total. In vivo animal studies accounted for about 20%, and only two case reports (~ 10%) contributed human data. This disproportion emphasizes the scarcity of clinical validation.

Fig. 2.

Distribution of study types included in the systematic review. In vitro studies accounted for nearly 70%, in vivo animal studies for about 20%, and only ~ 10% were clinical/case reports

Mechanistic themes A keyword-based frequency analysis (Fig. 3) demonstrates that apoptosis, EMT inhibition, and immune modulation were the most frequently studied mechanisms. Synergistic effects with chemotherapy and radiotherapy were also common, suggesting CBD’s potential role as an adjuvant. By contrast, angiogenesis, metabolic regulation, and epigenetic pathways were less frequently examined, highlighting important gaps for future research.

Fig. 3.

Keyword-based frequency analysis of mechanistic themes. Apoptosis, EMT inhibition, and immune modulation were the most frequently studied mechanisms, while angiogenesis and metabolic regulation were less investigated

Dosing comparisons Dose ranges are summarized in Fig. 4. In vitro experiments used concentrations between 1 and 10 µM, while animal models applied 5–10 mg/kg. In contrast, clinical observations reported oral administration of 200–600 mg/day. This discrepancy underscores the translational uncertainty regarding dose equivalence and pharmacological relevance between laboratory and clinical settings.

Fig. 4.

Summary of dosing ranges across study types. In vitro experiments used concentrations of 1–10 µM, animal models applied 5–10 mg/kg, and clinical observations reported 200–600 mg/day orally

Risk of bias assessment A structured quality appraisal of all included studies is presented in Table 1. Most preclinical studies were rated as having a moderate risk of bias, primarily due to incomplete reporting of randomization, blinding, or selective reporting. Observational patient studies were judged as having a serious risk of bias, while case reports were classified as critical risk, reflecting their anecdotal and uncontrolled nature. This pattern indicates that while preclinical evidence is relatively consistent, the certainty of findings is limited by methodological weaknesses.

Study characteristics Detailed characteristics of the included studies are summarized in Tables 2a and 2b.

• Table 2a presents in vitro and in vivo studies, highlighting CBD’s ability to induce apoptosis, inhibit EMT, reduce angiogenesis, and enhance the efficacy of chemotherapy or radiotherapy. For example, Ramer et al. reported PPAR-γ–mediated apoptosis, while Misri et al. demonstrated activity in cisplatin-resistant NSCLC models via TRPV2 activation.

• Table 2b provides an overview of the two clinical case reports. Both described substantial tumor regression following prolonged self-administration of CBD oil, though without controls or standardized dosing. These findings, while intriguing, must be interpreted with extreme caution given the high risk of confounding and lack of reproducibility.

Table 2.

a. Preclinical studies (in vitro and animal models) evaluating the effects of Cannabidiol (CBD) on lung cancer

Title	Year	Study type	CBD dose	Duration	Key findings	Mechanism investigated	Pathway/Target	Reference
Cannabinoid receptor agonists are mitochondrial inhibitors: A unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death	2007	In vitro	AEA: 10–100 µM; THC: 10–100 µM; HU 210: 10–100 µM	2 h (cell assays); 5 min (mitochondria assays)	Cannabinoid receptor agonists induced apoptosis in H460 lung cancer cells, decreased mitochondrial membrane potential and oxygen consumption, and altered complex I and II-III activities.	Biphasic mitochondrial responses, apoptosis induction, and oxidative stress	Complex I, Complex II–III, ROS production	[18]
Δ9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo	2008	In vitro and in vivo	5 and 10 µM (in vitro); 5 mg/kg (in vivo)	24 h (in vitro); 28 days (in vivo)	THC inhibited EGF-induced migration, invasion, proliferation of NSCLC cells; reduced tumor growth and metastasis in SCID mice. It also showed antiangiogenic and antiproliferative effects.	Inhibition of EGF-induced phosphorylation of AKT, ERK1/2, and JNK1/2 pathways; phosphorylation of FAK (tyrosine 397).	Cannabinoid receptors CB1 and CB2, EGF, EGFR, AKT, ERK1/2, JNK1/2, FAK, VEGF	[27]
Decrease of plasminogen activator inhibitor-1 may contribute to the anti-invasive action of cannabidiol on human lung cancer cells	2010	In vitro & in vivo	0.1–1 µM in vitro, 5 mg/kg in vivo	72 h (in vitro), 42 days (in vivo)	- CBD inhibits A549 cell invasion. - CBD decreases PAI-1 expression and secretion. - CB1, CB2, and TRPV1 antagonists suppress CBD’s effects on PAI-1 secretion and invasion. - Recombinant PAI-1 increases invasiveness, while PAI-1 siRNA decreases invasiveness. - Recombinant PAI-1 reverses CBD’s anti-invasive action. - CBD downregulates PAI-1 protein in A549 xenografts.	- Effects of CBD on PAI-1 expression and secretion. - Involvement of CB1, CB2, and TRPV1 receptors. - Role of PAI-1 in cancer cell invasion.	- PAI-1 (Plasminogen Activator Inhibitor-1). - CB1 and CB2 cannabinoid receptors. - TRPV1 (Transient Receptor Potential Vanilloid 1).	[32]
Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non–small cell lung cancer growth and metastasis	2011	In vitro and in vivo	JWH-015 (1–20 µM); Win55,212-2 (1–20 µM)	24–72 h in vitro; 28 days in vivo	CB1/CB2 agonists inhibited NSCLC proliferation, migration, invasion, tumor growth, and metastasis. Reduction in angiogenesis and increased apoptosis observed in vivo.	Suppressed phosphorylation of AKT and MMP-9 secretion. Reduced focal adhesion and stress fiber formation.	CB1 and CB2 receptors, AKT, MMP-9, Focal Adhesions.	[28]
COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells	2013	In vitro and in vivo	3 µmol/L (A549/H460 cells); 5 mg/kg (in vivo, xenografted mice)	8–48 h (in vitro), 29 days (in vivo)	CBD reduced cell viability and induced apoptosis in NSCLC cells via the upregulation of COX-2 and PPAR-y, leading to tumor regression in xenografted mice	Upregulation of COX-2 and PPAR-y followed by nuclear translocation of PPAR-y activated by COX-2-derived PGs (PGD2 and 15d-PGJ2)	COX-2, PPAR-y, Prostaglandins PGD2 and 15d-PGJ2	[20]
Cannabinoids inhibit angiogenic capacities of endothelial cells via release of tissue inhibitor of matrix metalloproteinases-1 from lung cancer cells	2014	In vitro	3 µM for CBD, THC, and JWH-133	48 h	Conditioned media from cannabinoid-treated lung cancer cells (A549, H460, H358) decreased migration, tube formation, and sprout formation of HUVECs. TIMP-1 induction in cancer cells mediates anti-angiogenic effects on endothelial cells.	Cannabinoid-induced TIMP-1 release from lung cancer cells inhibits angiogenic behavior of HUVECs	ICAM-1, TIMP-1	[33]
Cannabinoid receptor-2 agonist inhibits macrophage induced EMT in non‐small cell lung cancer by downregulation of EGFR pathway	2016	In vitro and In vivo studies	5 µM in vitro, 7.5 mg/kg in vivo	48 h in vitro, 3 weeks in vivo	JWH-015 inhibits EMT, reduces tumor growth and metastasis, and decreases macrophage recruitment.	Downregulation of EGFR signaling in NSCLC cells	EGFR, ERK, STAT3, MMP2, VCAM-1, FAK	[29]
Enhancing the therapeutic efficacy of cancer treatment with cannabinoids	2018	In vitro and in vivo	0, 1, 2, 5 µg/well (in vitro); 0.1 mg, 5 mg/kg (in vivo)	In vitro: 24 h; In vivo: several days (sustained release)	CBDs combined with radiotherapy showed increased tumor cell killing. Sustained delivery via smart biomaterials enhanced survival outcomes and minimized toxicities in preclinical models.	CBDs as radiosensitizers inducing apoptosis, reducing RT toxicity	Tumor cell apoptosis, sustained CBD release pathways	[34]
Cannabinoid receptor expression in non-small cell lung cancer. Effectiveness of tetrahydrocannabinol and cannabidiol inhibiting cell proliferation and epithelial-mesenchymal transition in vitro	2020	In vitro (A549, H460 and H1792 human lung cancer cells) & Retrospective analysis of patient samples	10–100 µM	48 h	- High CB1/CB2 expression correlates with increased survival in NSCLC patients. - THC and CBD inhibit proliferation and EGFR expression in lung cancer cells; CBD potentiates THC effect. - THC and CBD restore epithelial phenotype (increase CDH1, reduce CDH2 and VIM). - THC and CBD reduce in vitro migration of lung cancer cells.	- Effects of THC and CBD on cell proliferation and EGFR expression. - Impact on epithelial-to-mesenchymal transition (EMT). - Effects on cell migration.	- Cannabinoid receptors (CB1 and CB2). - EGFR signaling. - EMT-related markers (CDH1, CDH2, VIM).	[24]
Cannabidiol induces cell death in human lung cancer cells and cancer stem cells	2021	In vitro	0–48 µM (dose-dependent effects)	24 h	- CBD reduced viability in lung cancer cells and cancer stem cells. - Induced cell death via apoptosis and increased ROS levels. - Decreased sphere formation/self-renewal capacity. - Reduced expression of stemness-related genes (e.g., SOX2, PROM1). - Effects were stronger in serum-free conditions.	- Activation of caspases 3/7. - Increased ROS. - Loss of mitochondrial membrane potential. - Downregulation of stemness markers.	Apoptosis pathway, ROS production, mitochondrial dysfunction, stemness-related genes (SOX2, PROM1, etc.)	[21]
In vitro effect of Δ9-tetrahydrocannabinol and cannabidiol on cancer-associated fibroblasts isolated from lung cancer	2022	In Vitro	30 µM CBD (alone) or 10 µM CBD + 10 µM THC (combination)	72 h	CBD decreased cell density and expression of differentiation markers (COL1A1, FSP1). Both cannabinoids inhibited EMT induction in A549 cells and reversed EMT-related gene expression profiles. Combined THC + CBD was more effective in CAFs.	Inhibition of EMT via NF pathways and lower secretion of TGFß from CAFs	CB1/CB2 receptors, EMT markers (e.g., CDH1, CDH2, VIM), TGFβ signaling.	[35]
Cannabidiol inhibits tumorigenesis in cisplatin-resistant non-small cell lung cancer via TRPV2	2022	In vitro and in vivo	10–20 µM (cell lines), 5 mg/kg (mouse model)	48–72 h (in vitro), multiple weeks (in vivo)	CBD significantly induced apoptosis in cisplatin-resistant NSCLC cells, reduced tumor progression and metastasis, and suppressed cancer stem cell properties	TRPV2 activation, ROS production, oxidative stress modulation	TRPV2, ROS, Apoptotic pathways	[22]
Cannabinoid receptor 2 expression in early-stage NSCLC identifies patients with good prognosis and longer survival	2022	In vitro & patient sample study	Not specified (focus on gene/protein expression)	Not specified	- High CB2 gene expression in tumor tissue significantly correlated with longer OS (P < 0.001), CSS (P = 0.002), and DFS (P < 0.001). - High CB2 gene expression associated with fewer lymph node metastases at surgery (P = 0.011). - CB2 gene expression was an independent prognostic factor for longer CSS (HR = 0.274; P = 0.013) and DFS (HR = 0.322; P = 0.009) in multivariate analysis. - Reduced CB1 (P = 0.008) and CB2 (P = 0.056) gene expression in tumor tissues compared to paired tumor-free lung tissue. - CB1 and CB2 protein expression did not significantly affect survival.	- Correlation of CB1 and CB2 gene and protein expression with survival outcomes in NSCLC patients.	- Cannabinoid receptor 2 (CB2) gene expression.	[36]
Cannabidiol Regulates PPARy-Dependent Vesicle Formation as well as Cell Death in A549 Human Lung Cancer Cells	2022	In vitro (A549 Cell Line)	>20 µM	24–48 h	- CBD inhibits growth at concentrations above 20µM. - CBD induces multiple vesicles in the cytoplasmic region. - CBD upregulates apoptosis-related proteins (p53, PARP, RIP1, RIP3, Atg12, Beclin). - CBD upregulates E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101. - CBD decreases intracellular ATP and glucose levels.	PPARy-dependent vesicle formation; Regulation of apoptotic pathways; ATP and glucose metabolism disruption	PPARy, clathrin, β-adaptin, RIP1/RIP3	[26]
Cannabinoid receptor 2 plays a pro-tumorigenic role in non-small cell lung cancer by limiting anti-tumor activity of CD8 + T and NK cells	2023	In vivo (mouse model)	CB2 antagonist (10 mg/kg/d)	15 days	CB2 deficiency reduced tumor burden, increased CD8 + T and NK cell activity, and enhanced response to anti-PD-1 therapy	CB2-mediated immune suppression in the tumor microenvironment	CB2 receptor, PD-1/PD-L1 pathway	[30]
Discovering single cannabidiol or synergistic antitumor effects of cannabidiol and cytokine-induced killer cells on non-small cell lung cancer cells	2024	Preclinical (In vitro)	Variable, different concentrations used in various experiments	24 h (for cytotoxicity assay)	- Synergistic effect of CIK cells and CBD increases tumor lysis and IFN-γ production. - CBD elevates CD25 + CD69 + and CD62L-CD45RA + populations in NKT-CIK cells. - CBD enhances calcium influx (mediated by TRPV2) and elevates p-ERK expression in CIK cells. - CBD induces DNA double-strand breaks via upregulation of histone H2AX phosphorylation in NSCLC cells. - CBD suppresses migration and invasion of NSCLC cells; this suppression is rescued by the TRPV2 antagonist (Tranilast). - CBD decreases LINE-1 mRNA expression and global DNA methylation level in NSCLC cells with KRAS mutation.	- Effect of CBD on CIK cells and NSCLC cells. - Role of TRPV2 channel in CBD effects. - Epigenetic effects of CBD on LINE-1.	- TRPV2 - ERK pathway - Histone H2AX - LINE-1	[25]
RNAi Screen Identifies AXL Inhibition Combined with Cannabinoid WIN55212-2 as a Potential Strategy for Cancer Treatment	2024	In vitro and in vivo	WIN55212-2: 5 µM (in vitro), 2.5 mg/kg (in vivo); TP-0903: Dose-dependent	48 h (in vitro), every 2 days (in vivo)	- AXL inhibition synergistically enhanced anti-proliferative effects of WIN55212-2 in cancer cells - Combined treatment reduced tumor volume and microvessel density in vivo - Combination therapy induced infiltration of cytotoxic CD8 + T cells - Reduced mTOR and STAT3 activation in tumor tissues	Synergistic inhibition of cell viability, induction of apoptosis	AXL, mTOR, STAT3 pathways	[37]

Overall synthesis Taken together, the results demonstrate that CBD exerts antitumor effects through multiple pathways, including apoptosis induction, EMT suppression, immune activation, and enhancement of conventional therapies. However, the dominance of preclinical studies (17/19, ~ 90%), the variability of dosing across models, and the high risk of bias in human evidence highlight the preliminary nature of current knowledge.

Study characteristics

Narrative synthesis of study outcomes

Among the in vitro studies, Athanasiou et al. demonstrated that cannabinoid receptor agonists induced mitochondrial dysfunction and apoptosis in H460 cells [18]. Ramer et al. reported that CBD reduced invasiveness of A549 cells through downregulation of plasminogen activator inhibitor-1 (PAI-1) and induced apoptosis via COX-2/PPAR-γ signaling, respectively [19, 20]. Hamad et al. further showed that CBD targeted both lung cancer cells and cancer stem-like populations by inducing ROS production and caspase activation [21]. Misri et al. highlighted CBD’s ability to overcome cisplatin resistance in NSCLC through TRPV2-mediated apoptosis [22]. Additional studies revealed effects on EMT inhibition [23, 24], immune modulation [25], and regulation of vesicle formation [26].

Clinical evidence remains anecdotal. Sule-Suso et al. [31] described tumor regression following self-administration of CBD in a lung cancer patient, while Liew et al. [15] reported a 76% reduction in tumor size after 2.5 years of CBD oil intake. While intriguing, both cases lack controls and should be interpreted with caution.

Discussion

Cannabidiol (CBD) has emerged as a biologically active phytocannabinoid with multifaceted antitumor properties in lung cancer. By integrating the available preclinical and limited clinical data, several mechanistic domains can be delineated that highlight both the therapeutic promise and the translational limitations of CBD in this malignancy.

1. Apoptosis induction and cancer stemness regulation

   One of the most consistent findings across in vitro and in vivo studies is CBD’s ability to induce apoptosis in NSCLC cells through mitochondrial dysfunction, ROS generation, and activation of PPAR-γ [18, 20, 21, 26]. These pathways converge on caspase activation and programmed cell death, underscoring CBD’s capacity to directly impair tumor cell viability. Importantly, CBD also targets cancer stem-like populations, reducing sphere-forming ability and downregulating stemness-associated genes such as SOX2 and PROM1 [21]. This is of translational relevance given the role of stemness in therapeutic resistance and relapse. Nevertheless, most supporting evidence derives from immortalized cell lines or xenograft models, which lack the complexity of human tumor–host interactions.

2. Inhibition of EMT and metastatic dissemination

   CBD has been shown to counteract epithelial-to-mesenchymal transition (EMT), a central process in metastasis. Upregulation of epithelial markers (E-cadherin) and downregulation of mesenchymal markers (N-cadherin, vimentin) have been repeatedly demonstrated following CBD treatment [23, 24]. Suppression of signaling cascades such as EGFR, MMP-9, and FAK further supports its anti-invasive effects [28, 29]. These findings are promising in the context of NSCLC, where EMT contributes to poor prognosis and resistance to targeted therapies. However, the long-term impact of CBD on metastatic behavior in clinically relevant models remains insufficiently studied.

3. Immune modulation and tumor microenvironment regulation

   The tumor microenvironment plays a decisive role in lung cancer progression and therapeutic response. Preclinical models suggest that CBD enhances the activity of CD8 + T cells and NK cells, while attenuating tumor-induced immunosuppression mediated by CB2 and PD-1/PD-L1 signaling [30]. Furthermore, synergistic effects of CBD with cytokine-induced killer (CIK) cells point toward its potential as an immunomodulatory adjuvant [25]. However, contradictory findings also exist: while some studies support immune activation, others highlight a pro-tumorigenic role of CB2 signaling in dampening antitumor immunity [30]. This duality indicates that the immunological consequences of CBD may be context-dependent and influenced by receptor specificity, tumor subtype, and treatment regimen.

4. Advantages of combination therapy with standard modalities

   Perhaps the most clinically relevant aspect of CBD research lies in its ability to enhance conventional therapies. Multiple studies demonstrate that CBD sensitizes tumor cells to cisplatin and radiotherapy, increasing drug uptake, facilitating DNA damage, and overcoming resistance [22, 34]. CBD has also been implicated in radiosensitization via apoptosis induction and modulation of oxidative stress [34]. These findings position CBD as a potential adjunctive agent rather than a standalone treatment. However, the absence of pharmacokinetic and pharmacodynamic integration with standard regimens represents a significant knowledge gap. Optimal dosing, scheduling, and patient stratification strategies remain undefined.

5. Strengths and gaps in preclinical evidence

   The preclinical body of evidence is characterized by reproducibility of apoptosis, EMT inhibition, and immune modulation across multiple experimental platforms. The use of both in vitro and in vivo approaches, including resistant tumor models [22], enhances mechanistic credibility. Yet, critical methodological weaknesses persist: incomplete reporting of blinding, randomization, and selective outcome reporting are widespread (Table 1). Moreover, heterogeneity in cell lines, animal models, and CBD formulations complicates cross-study comparisons. Notably, nearly 90% of the evidence base is restricted to laboratory settings, with only two uncontrolled case reports contributing human data [15, 31].

   As illustrated in Fig. 5, CBD exerts its effects through multiple mechanisms including apoptosis induction, EMT inhibition, immune modulation, and synergistic interactions with conventional therapies [18, 20, 26, 28].

6. Clinical evidence (Clinical studies of CBD in oncology)

   Clinical evidence on CBD in oncology is still limited and heterogeneous, comprising a small number of case reports suggesting possible antitumor effects, early-phase randomized trials addressing symptom control (e.g., anxiety, pain, nausea), and several ongoing or recently registered clinical studies exploring safety and feasibility. Importantly, randomized data directly testing CBD as an antineoplastic agent are lacking

Fig. 5.

Proposed mechanisms of cannabidiol (CBD) in lung cancer. CBD exerts multiple anticancer effects through distinct but interconnected pathways. (1) Induction of apoptosis via reactive oxygen species (ROS) generation and PPAR-γ activation. (2) Inhibition of epithelial-tomesenchymal transition (EMT) by suppressing EGFR and matrix metalloproteinases (MMPs), thereby reducing invasion and enhancing synergism with chemotherapy and radiotherapy. (3) Modulation of the tumor immune microenvironment through regulation of CB2 and PD-1/PD-L1 signaling, leading to enhanced CD8+ T and NK cell activity. Collectively, these mechanisms highlight CBD’s potential as a multi-target adjunctive therapy in non-small cell lung cancer (NSCLC)

1. Case reports of tumor response. Two well-publicized case reports describe substantial tumour regression temporally associated with self-administration of CBD oil in patients with lung cancer [31]. These reports are hypothesis-generating but uncontrolled, susceptible to confounding (e.g., concurrent behavior changes, undocumented co-interventions), and therefore cannot support efficacy claims.

2. Randomized clinical studies in cancer populations (symptom-focused). Recent randomized trials have evaluated oral CBD for symptom control in cancer patients (for example, scan-related anxiety in women with advanced breast cancer), demonstrating that CBD can be administered safely in these populations and may exert short-term anxiolytic effects; however, these trials were not designed to assess antitumor efficacy [38].

3. Cannabis extracts (THC: CBD) for supportive oncology indications. Several randomized trials testing combined THC: CBD extracts have shown benefit for chemotherapy-induced nausea/vomiting and cancer-related pain in selected settings, but these trials evaluate mixed cannabinoid preparations rather than pure CBD monotherapy; therefore, their results cannot be directly extrapolated to CBD as an antineoplastic agent [39].

4. Ongoing trials and feasibility studies. Multiple registered trials (including NCI-listed and institutional studies) are exploring hemp-derived, full-spectrum CBD formulations for symptom endpoints or safety/tolerability in cancer patients; these will help define pharmacokinetics, dosing ranges, and adverse-event profiles but are unlikely to answer questions about direct tumour response without dedicated efficacy end points [40].

Synthesis and implications for lung cancer

Overall, clinical data specific to CBD’s antitumor activity are restricted to anecdotal case reports in lung cancer, whereas randomized data in oncology focus on symptom control and tolerability rather than tumor outcomes. Therefore, while preclinical evidence supports biological plausibility for antitumor effects (see preclinical synthesis above), there is currently insufficient clinical evidence to recommend CBD as an antineoplastic therapy. Future clinical development should prioritize: (a) early-phase trials that incorporate pharmacokinetic/pharmacodynamic (PK/PD) assessments and biomarker end points; (b) well-controlled combination studies (CBD + chemotherapy/immunotherapy) with safety lead-in cohorts to evaluate drug–drug interactions; and (c) prospective registries to systematically capture patient-reported CBD use and outcomes (Cannabidiol as a chemotherapy adjunct in cancer treatment).

A summary of published case reports, randomized trials, and ongoing studies investigating CBD use in oncology is provided in Table 3.

Table 2.

b. Clinical studies and case reports evaluating the effects of Cannabidiol (CBD) on lung cancer

Title	Year	Study type	CBD dose	Duration	Key findings	Mechanism/Pathway	Reference
Striking lung cancer response to self-administration of cannabidiol	2019	Case report	1.32–6 mg bid	~ 1 month	Partial tumor regression	Apoptosis, ROS, mTOR	[31]
Lung cancer patient who had declined conventional treatment.	2021	Case report	0.5 mL oil, 2–3x/day	2.5 years	76% reduction in tumor size	Endocannabinoid system, apoptosis	[15]

Table 3.

Clinical studies and trials investigating CBD use (alone or in combination) in cancer patients

Title	Study type	Cancer type/Population	Intervention (CBD ± other agents)	Duration	Key findings
Striking lung cancer response to self-administration of cannabidiol	Case report	Advanced lung cancer	Self-administered CBD oil (1.32–6 mg twice daily)	~ 1 month	Partial tumor regression observed; uncontrolled, anecdotal evidence
Lung cancer patient declined conventional treatment	Case report	NSCLC (declined standard therapy)	CBD oil 0.5 mL, 2–3 times/day	2.5 years	~ 76% tumor reduction; uncontrolled and anecdotal
Cannabidiol for scan-related anxiety in women with advanced breast cancer: a randomized clinical trial	Randomized controlled trial	Women with advanced breast cancer undergoing imaging	Oral CBD (300 mg single dose) vs. placebo	Short-term (pre-scan)	Reduced scan-related anxiety; no tumor endpoints assessed
Oral THC: CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial	Randomized trial	Patients with chemotherapy-induced nausea/vomiting (CINV)	THC: CBD extract vs. placebo (add-on)	5 days during chemotherapy cycles	Significant reduction in nausea/vomiting; improved tolerability; no tumor endpoints
Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC: CBD extract and THC extract in …	Randomized trial	Advanced cancer patients with pain unresponsive to opioids	THC: CBD oromucosal spray vs. placebo	2 weeks	Improved analgesia vs. placebo; supportive care outcome only
A Study of the Efficacy of Cannabidiol in Patients With Multiple Myeloma, Glioblastoma Multiforme, and GI Malignancies	Phase I/II trials (registered)	Mixed cancer cohorts	Hemp-derived or purified CBD formulations (various doses)	Ongoing	Aims: safety, PK/PD, symptom control, feasibility; tumor endpoints not primary

Research limitations

To place current findings in perspective, several limitations must be acknowledged:

• Scarcity of clinical data: Human evidence remains anecdotal, limited to two case reports without controls. No randomized controlled trials (RCTs) have been published to date, preventing any firm conclusions about efficacy.

• Small sample sizes in animal studies: Many in vivo experiments were performed with limited cohorts, lacking rigorous randomization and blinding. This diminishes confidence in translational relevance.

• Heterogeneity in dosing and formulations: In vitro studies typically use 1–10 µM, animal models apply 5–10 mg/kg, while clinical cases describe 200–600 mg/day orally. These discrepancies complicate dose extrapolation and pharmacological relevance.

• Safety profile uncertainties: While CBD is generally considered well tolerated, hepatotoxicity and cytochrome P450–mediated drug interactions remain underexplored in oncology. This is particularly concerning for lung cancer patients often receiving polypharmacy.

• Regulatory constraints: Divergent classifications of CBD across jurisdictions (e.g., FDA-approved for epilepsy vs. “novel food” in the EU) hinder clinical development and patient access.

• Biological complexity: The dual role of CB2 signaling—sometimes immunostimulatory, sometimes immunosuppressive—underscores the need for nuanced investigation into receptor-specific and context-dependent effects.

While our review focused on the PI3K/Akt, MAPK, and TGF-β pathways, it should be noted that multiple other signaling cascades—including p53, NF-κB, JAK/STAT, mTOR, and Wnt/β-catenin—are also frequently deregulated in lung cancer. However, the current body of evidence specifically linking CBD to these pathways remains limited. Future studies should therefore expand mechanistic evaluations beyond the three pathways highlighted here to capture the broader landscape of CBD’s anticancer effects.

Future prospects of CBD in lung cancer

Although preclinical studies strongly support the anticancer potential of cannabidiol (CBD), its clinical application in lung cancer remains unproven. Future research should prioritize early-phase clinical trials to define pharmacokinetics, optimal dosing, and drug–drug interactions. Given its ability to sensitize tumors to cisplatin and radiotherapy, combination strategies are especially promising and warrant careful evaluation in controlled settings. The use of biomarkers such as CB2 or TRPV2 expression may help identify patients most likely to benefit. Moreover, advances in formulations and delivery methods (e.g., nanoformulations or inhalation routes) could improve bioavailability in lung tissue. Finally, rigorous long-term safety monitoring and international standardization of CBD preparations are essential to ensure reproducibility and patient safety.

In summary, CBD should be considered an investigational adjunct rather than an established therapy. Its future integration into clinical practice will depend on well-designed trials that confirm efficacy, clarify safety, and optimize its use alongside existing treatments.

Conclusion

Cannabidiol (CBD) demonstrates strong preclinical activity against lung cancer, targeting multiple hallmarks of cancer including apoptosis induction, suppression of EMT and metastasis, modulation of immune responses, and sensitization to chemotherapy and radiotherapy. This multi-target profile highlights its potential as an adjunctive therapeutic candidate capable of complementing existing treatment modalities.

Nevertheless, it is critical to emphasize that the current evidence base remains overwhelmingly preclinical, with human data restricted to two uncontrolled case reports. The absence of randomized controlled trials, the variability in dosing strategies, and unresolved safety concerns—including drug–drug interactions and long-term tolerability—underscore the preliminary nature of CBD’s clinical promise.

Looking forward, several research priorities must be addressed:

1. Large-scale clinical trials to validate efficacy, establish optimal dosing regimens, and evaluate long-term safety.

2. Pharmacokinetic and pharmacodynamic studies to clarify bioavailability, tissue penetration, and interactions with chemotherapeutics.

3. Patient stratification approaches to determine which molecular or immunological subgroups may derive the greatest benefit.

4. Regulatory harmonization to facilitate international trials and clinical adoption.

In conclusion, CBD represents a scientifically intriguing candidate for lung cancer therapy, but its integration into standard clinical practice requires rigorous validation. Until robust evidence from controlled human studies is available, CBD should be regarded as an investigational adjunct rather than an established therapeutic option.

Abbreviations

Akt

Protein kinase B

AXL

Anexelekto (a receptor tyrosine kinase involved in tumor progression)

CB1

Cannabinoid receptor type 1

CB2

Cannabinoid receptor type 2

CINV

Chemotherapy-induced nausea and vomiting

EGFR

Epidermal growth factor receptor

EMT

Epithelial-to-mesenchymal transition

FAK

Focal adhesion kinase

HCC

Hepatocellular carcinoma

ICAM-1

Intercellular adhesion molecule 1

JNK

c-Jun N-terminal kinase

MAPK

Mitogen-activated protein kinase

MMP

Matrix metalloproteinase

mTOR

Mechanistic target of rapamycin

NSCLC

Non-small cell lung cancer

PI3K

Phosphoinositide 3-kinase

PPAR-γ

Peroxisome proliferator-activated receptor gamma

ROS

Reactive oxygen species

STAT3

Signal transducer and activator of transcription 3

TGF-β

Transforming growth factor beta

TIMPs

Tissue inhibitors of metalloproteinases

TRAIL

TNF-related apoptosis-inducing ligand

TRPV

Transient receptor potential vanilloid

VEGF

Vascular endothelial growth factor

Author contributions

“M.E and M.D wrote the protocol. M.E and M.D collated the data for the study. The first draft of the manuscript was written by M.E and M.D and thoroughly revised by all authors. All authors progressed the concept of this study.”

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Ethical considerations

Not applicable.The authors have carefully addressed ethical considerations, including monitoring for text plagiarism, duplicate publications, research misconduct, data fabrication, and falsification.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.