Cannabidiol as a novel therapeutic agent in breast cancer: evidence from literature

Abstract

Background

Breast cancer is one of the most prevalent cancers worldwide, posing significant challenges due to its heterogeneity and the emergence of drug resistance. Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis sativa, has recently gained attention for its potential therapeutic effects in breast cancer.

Objective

This review aims to evaluate the antitumor effects of CBD in breast cancer treatment by synthesizing preclinical and clinical evidence, elucidating its mechanisms of action, and exploring its translational potential.

Methods

A systematic review was conducted following PRISMA guidelines. A comprehensive search was performed across PubMed, Google Scholar, Web of Science, and Scopus databases, using keywords such as “Cannabidiol,” “CBD,” “Breast Cancer,” “Therapeutic Agent,” and “Antitumor Effects.” A total of 1,191 articles were initially identified. After duplicate removal and eligibility screening, 34 studies published between 1998 and 2025 were selected, including in vitro, in vivo, and clinical investigations. Studies were assessed based on PRISMA recommendations, considering inclusion criteria such as CBD’s impact on apoptosis, cell proliferation, tumor progression, and molecular mechanisms.

Results

CBD demonstrated significant anticancer effects, including induction of apoptosis, inhibition of cell proliferation, suppression of metastasis, and modulation of the tumor microenvironment. Mechanistically, CBD modulates key pathways such as PI3K/Akt, mTOR, and PPARγ and interacts with CB1, CB2, and non-cannabinoid receptors. Preclinical studies showed CBD’s efficacy, particularly in triple-negative breast cancer (TNBC), while limited clinical trials highlighted its potential as an adjunct to conventional therapies.

Conclusion

CBD offers a promising therapeutic approach for breast cancer, especially for aggressive subtypes like TNBC. However, challenges such as variability in study design, lack of standardized protocols, and limited clinical validation hinder its clinical application. Future research should focus on conducting robust clinical trials, identifying predictive biomarkers, and optimizing combinatorial therapies to integrate CBD into personalized cancer treatment strategies.

Introduction

Breast cancer is one of the most prevalent malignancies among women worldwide, characterized by its heterogeneity and diverse subtypes, each requiring distinct therapeutic strategies [1]. Despite significant advancements in treatment modalities, challenges persist, including resistance to existing therapies and the adverse effects associated with conventional treatments like chemotherapy and radiotherapy [2]. The search for novel therapeutic agents that can complement or enhance existing therapies while minimizing side effects has led to increased interest in plant-derived compounds, particularly cannabinoids [3].

Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has garnered attention due to its potential anticancer properties [4, 5]. Recent studies have highlighted CBD’s ability to inhibit tumor growth, induce apoptosis, and suppress metastasis in preclinical models of breast cancer [6]. CBD exerts its effects through multiple mechanisms, including modulation of the endocannabinoid system, induction of apoptosis, inhibition of cell proliferation, and suppression of metastasis [6, 7]. It interacts with cannabinoid receptors (CB1 and CB2) and non-cannabinoid receptors such as TRPV1 and PPARγ, contributing to its anticancer properties [8].

Preclinical studies have demonstrated the efficacy of CBD in reducing tumor growth and metastasis in various breast cancer models, particularly in triple-negative breast cancer (TNBC), which lacks targeted therapies [9]. Clinical studies have begun to explore CBD’s potential as a complementary therapy in breast cancer patients, with promising results in symptom management and quality of life improvement [10].

This literature review aims to synthesize recent findings on the antitumor effects of CBD in breast cancer, elucidating its mechanisms of action and potential clinical applications. By examining the current evidence, we seek to contribute to the development of novel therapeutic strategies that could enhance the effectiveness of existing treatments and improve patient outcomes.

Materials and methods

Literature search

A comprehensive literature search was conducted using electronic databases including PubMed, Google Scholar, Web of Science, and Scopus. The search terms used were “Cannabidiol,” “CBD,” “Breast Cancer,” “Therapeutic Agent,” and “Antitumor Effects.” The search was limited to articles published in English from 1998 to 2025. Boolean operators (AND, OR) were used to combine terms. Additional articles were identified through manual searches of reference lists from relevant studies.

Eligibility criteria

Inclusion criteria

Studies were included if they met the following criteria:

Studies that investigated the effects of CBD on breast cancer cells or animal models.

Clinical studies that included breast cancer patients receiving CBD as part of their treatment regimen.

Studies published in peer-reviewed journals in the last 27 years.

Articles must have been published in English.

Provided data on the mechanisms of action, efficacy, and safety of CBD in breast cancer treatment.

Exclusion criteria

Studies were excluded if they:

Studies that did not focus on breast cancer.

Studies with insufficient data or incomplete results.

Studies were not available in full text.

Review process

The review process involved several key steps to ensure the thoroughness and reliability of the findings:

• 1. Initial Screening: Titles and abstracts of all identified studies were screened to determine their eligibility based on the inclusion and exclusion criteria.

• 2. Full-Text Review: Full texts of potentially eligible studies were retrieved and reviewed in detail to confirm their inclusion in the analysis.

• 3. Quality Assessment: The methodological quality of the included studies was assessed using appropriate quality assessment tools (e.g., Cochrane Risk of Bias Tool, Newcastle-Ottawa Scale). Studies were rated as high, moderate, or low quality based on criteria such as randomization, blinding, and completeness of outcome data.

• 4. Data Synthesis: Extracted data were synthesized to provide a comprehensive overview of the effects of CBD on breast cancer. This synthesis included qualitative descriptions of the study findings without performing a meta-analysis.

Figure 1 presents a PRISMA 2020 flow diagram illustrating the search process, including the number of studies identified, screened, assessed for eligibility, and included in the final review.

Fig. 1

The flow diagram of the selection of sources searched in this systematic review

Risk of bias and quality assessment

To ensure the reliability of the included studies, a systematic quality assessment was performed using the Cochrane Risk of Bias Tool for randomized trials and the Newcastle-Ottawa Scale for observational studies. The following parameters were considered:

• Selection Bias: Assessment of randomization and allocation concealment.

• Performance Bias: Evaluation of blinding methodologies used.

• Detection Bias: Analysis of outcome assessment blinding.

• Attrition Bias: Consideration of incomplete outcome data and follow-up rates.

• Reporting Bias: Examination of selective outcome reporting. Each study was rated as having a high, moderate, or low risk of bias based on these criteria.

Data extraction and review process

Data extraction

Data were meticulously extracted from the selected studies using a standardized data extraction form. The following key information was obtained from each study:

• Study Design: The type of study conducted (e.g., in vitro, in vivo, clinical trials).

• Sample Size: The number of participants or samples included in the study.

• Type of Breast Cancer: Specific subtypes of breast cancer being investigated.

• CBD Dosage and Administration: The dosage, frequency, and method of cannabidiol (CBD) administration.

• Outcomes Measured: The primary and secondary outcomes assessed in the study, such as tumor size reduction, apoptosis induction, cell proliferation inhibition, and metastasis prevention.

• Key Findings: Main results and conclusions drawn from the study.

Two independent reviewers conducted the data extraction process to ensure accuracy and consistency. Any discrepancies between the reviewers were resolved through discussion and consensus, or by consulting a third reviewer if necessary. The selected studies are summarized in Tables 1, 2 and 3.

Table 1 CBD as monotherapy in breast Cancer treatment

Table 2 CBD in combination therapy for breast cancer

Table 3 In vivo studies investigating the therapeutic potential of CBD in breast Cancer models

Table 4 Comparison of monotherapy and combination therapy

Table 5 CBD presents unique advantages compared to traditional breast cancer treatments

Results

Study selection

The study selection process adhered to the PRISMA 2020 guidelines, as illustrated in Fig. 1. An initial total of 1,191 records were identified through comprehensive searches across multiple databases, including Web of Science (n = 112), PubMed (n = 59), EMBASE (n = 142), Scopus (n = 254), and Google Scholar (n = 624). After duplicates (n = 347), irrelevant automation-marked records (n = 187), and records removed for other reasons (n = 258) were excluded, 399 records were screened.

Screening phase

During the screening phase, 206 records were excluded. Of these, 78 were review articles, 14 were conference papers, and 114 were excluded due to lack of relevance to the study’s objectives or focus on cannabidiol (CBD) and breast cancer.

Eligibility assessment

At the eligibility assessment stage, 193 reports were sought for retrieval, of which 91 were successfully assessed in detail. Among the 102 reports not retrieved, 61 lacked full-text availability, and 41 were removed for other reasons. Ultimately, 91 full-text articles were rigorously evaluated for inclusion criteria.

Final selection

The final assessment excluded 59 articles for the following reasons:

• 33 studies lacked specific focus on the effects of CBD on breast cancer.

• 24 studies either analyzed other cannabinoids or did not include desired indices relevant to the research aims.

Ultimately, 34 studies met the rigorous inclusion criteria and were incorporated into this systematic review. The final selection process ensured that only high-quality, relevant studies contributed to the analysis, providing a robust overview of the therapeutic potential of cannabidiol (CBD) in breast cancer.

Discussion

Therapeutic potential of Cannabidiol (CBD) in breast Cancer

Cannabidiol (CBD) has emerged as a promising therapeutic agent for breast cancer, exhibiting diverse anticancer properties, including apoptosis induction, inhibition of proliferation, suppression of metastasis, and modulation of the tumor microenvironment [1, 43]. Preclinical studies highlight the effectiveness of CBD in reducing tumor burden and limiting metastatic potential, particularly in triple-negative breast cancer (TNBC)—a highly aggressive subtype with limited targeted therapies [2, 10].

Below, we synthesize key findings to evaluate CBD’s therapeutic potential, molecular mechanisms, and clinical implications, supported by evidence from preclinical and clinical studies.

CBD as monotherapy in breast Cancer

CBD has demonstrated antitumor properties across multiple breast cancer subtypes, including ER + and TNBC. Key mechanisms and findings include:

Mechanisms of action

• ROS Generation and ER Stress: CBD induces apoptosis via reactive oxygen species (ROS) generation and endoplasmic reticulum stress, disrupting mitochondrial dynamics and redox balance in cancer cells [32].

• Pathway Modulation: CBD inhibits PI3K/AKT and MAPK signaling pathways, suppressing cell proliferation and metastasis. For instance, CBD downregulates Id-1, a key regulator of tumor aggressiveness, in MDA-MB-231 cells [10].

• Selective Toxicity: CBD exhibits selective cytotoxicity toward cancer cells while sparing normal cells. For example, CBD-loaded microparticles showed extended antiproliferative activity in MCF-7 and MDA-MB-231 cells without harming non-cancerous counterparts [32].

Mitochondrial dysfunction

CBD modulates mitochondrial dynamics, inducing metabolic stress and apoptosis. In MCF-7 cells, CBD disrupted mitochondrial redox balance, leading to caspase-3 activation and DNA fragmentation [32, 42].

CBD in combination therapy

CBD synergizes with conventional therapies to enhance efficacy and overcome drug resistance:

• Doxorubicin Resistance: Co-administration of CBD with doxorubicin (DOX) reduced TGF-β and PD-L1 expression, reversing chemoresistance in TNBC models [9].

• Taxol Resistance: Abnormal cannabidiol (Abn-CBD) enhanced Taxol’s efficacy in Taxol-resistant MDA-MB-231 cells by inducing apoptosis via non-CB1/CB2 pathways [29].

Table 4 outlines the key distinctions between CBD monotherapy and its combination with other anticancer agents. As presented in the table, combination therapy has demonstrated enhanced chemosensitization and immune response modulation, whereas monotherapy primarily exerts its effects through apoptosis induction.

Immunomodulation

• PD-L1 Upregulation: CBD enhances PD-L1 expression via the cGAS-STING pathway, improving the efficacy of immune checkpoint inhibitors like Atezolizumab in TNBC [3, 32].

Photodynamic therapy (PDT)

Combining CBD with PDT significantly increased apoptosis in MCF-7 cells through oxidative stress pathways, suggesting a dual mechanism of action [42].

Drug delivery systems for CBD in breast Cancer therapy

In preclinical studies evaluating CBD as a monotherapy, various drug delivery systems have been employed to enhance its bioavailability and efficacy:

Oral administration

• Bioavailability Challenge: CBD has low oral bioavailability due to extensive first-pass metabolism.

• Potential Solutions: Nanoencapsulation and lipid-based formulations enhance absorption.

Intravenous (IV) delivery

• Advantages: Allows precise dosing, bypasses metabolism, and achieves rapid systemic circulation.

• Limitations: Requires specialized formulations such as liposomal CBD or CBD nanoparticles.

Nanoencapsulation & nanoparticle systems

• Improved Therapeutic Efficacy: Studies have demonstrated that nanoencapsulated CBD significantly increases tumor inhibition rates (e.g., 82.2% in murine models).

• Combination Potential: Used alongside PPD, nanoparticles improve CBD’s anticancer effects and tolerance.

Transdermal & topical applications

• Localized Targeting: Could be useful in reducing inflammation and tumor-associated pain.

• Limitations: Poor penetration into deeper breast tissues.

Inhalation routes

• Rapid Absorption: Inhaled CBD quickly enters systemic circulation, potentially bypassing metabolic barriers.

• Concerns: Variability in dosing and absorption rates.

Combination with other drug delivery technologies

• Photodynamic Therapy (PDT): Studies show CBD enhances PDT-induced apoptosis in breast cancer cells via oxidative stress pathways.

• Chemotherapy Adjuncts: CBD combined with Doxorubicin, Atezolizumab, and Taxol enhances drug efficacy while mitigating resistance.

Direct administration

• Some in vitro studies involve the direct addition of CBD to cell cultures, providing precise control over drug concentration.

Clinical implications and future directions

While preclinical data are compelling, clinical translation requires addressing critical gaps:

• 1. Dosing Optimization: Standardized protocols for CBD administration (e.g., micellar formulations for targeted delivery).

• 2. Subtype-Specific Effects: Further research on CBD’s role in hormone receptor-positive breast cancer, particularly its interaction with ERα and AR signaling.

• 3. Metastasis Prevention: Investigate CBD’s impact on cancer stem cells and metastatic pathways (e.g., ZPR1/SHC1/MAPK and AXL/VAV2/RAC1).

• 4. Safety Profiling: Large-scale trials to assess long-term safety, drug interactions, and effects on non-cancerous tissues.

Challenges and controversies

Despite promising evidence, several challenges hinder CBD’s clinical application in breast cancer treatment:

• • Variability in Study Design: One of the primary concerns surrounding CBD research is the inconsistency in dosing regimens, administration routes, and experimental models used across studies. For instance, McAllister et al. (2007) demonstrated that CBD inhibits tumor progression through Id-1 gene suppression, but variations in drug concentration and cell line-specific responses complicate direct comparisons [8].

• • Regulatory and Legal Barriers: The classification of cannabinoids under regulatory frameworks affects the pace of clinical investigations. While THC-containing formulations face tighter restrictions, CBD’s legal status varies globally, impeding its widespread clinical adoption [7].

• • Pharmacokinetics and Drug Interactions: CBD’s metabolic pathways involve cytochrome P450 enzymes, which can lead to potential drug interactions when combined with conventional chemotherapeutics [5]. Understanding its pharmacokinetics is crucial for optimizing therapeutic applications.

Research gaps and future directions

There are notable gaps in the current literature that need to be addressed to facilitate the clinical transition of CBD in breast cancer treatment:

• • Limited Clinical Trials: While preclinical models provide strong evidence for CBD’s anticancer activity, clinical trials evaluating its efficacy and safety in breast cancer patients remain scarce [6]. Large-scale randomized controlled trials are necessary to validate preclinical findings.

• • Biomarker Identification: Predictive biomarkers for CBD responsiveness need to be identified to facilitate personalized cancer therapy. This includes assessing potential correlations with cannabinoid receptor expression (CB1, CB2) and genetic alterations in tumor cells [32].

• • Long-Term Safety and Toxicity: Comprehensive studies investigating CBD’s long-term effects on tumor recurrence, immune responses, and systemic toxicity are essential for its clinical integration [28].

Comparative analysis of CBD-Based therapies and conventional treatments

Table 5 provides a comparative analysis of CBD-based therapy against conventional breast cancer treatments, including chemotherapy, targeted therapy, and immunotherapy. As the table illustrates, CBD’s potential advantages—such as its minimal toxicity and modulation of the tumor microenvironment—make it a promising therapeutic candidate, despite the current challenges related to standardization and regulatory frameworks.

CBD’s potential to enhance sensitivity to chemotherapy and immunotherapy represents an area of growing interest. For example, Kalvala et al. (2023) demonstrated that CBD can overcome doxorubicin resistance in TNBC models by downregulating immune checkpoint pathways such as PD-L1 [36]. Additionally, CBD’s ability to modulate inflammatory cytokines suggests its use as an adjunct to standard therapies in preventing therapy-induced toxicity [16].

Conclusion

CBD holds significant promise as a complementary or standalone therapeutic agent in breast cancer treatment, particularly in TNBC, where conventional options are limited. However, clinical validation through well-designed trials, biomarker identification, and safety profiling remains imperative before widespread clinical adoption. Future studies should focus on optimizing combinatorial therapies, investigating long-term effects, and refining pharmacological formulations to bridge the gap between preclinical findings and clinical application.

By addressing these challenges, CBD could potentially redefine breast cancer management strategies, offering a safer, more effective, and targeted approach to treatment.